DXTX Brain Tumor

Dx/Rx:
Brain Tumors
Eudocia Quant, MD
Center for Neuro-Oncology
Dana-Farber/Brigham and Women’s Cancer Center
Boston, MA
Series Editor: Kevin N. Sheth, MD
Division of Neuro-Critical Care & Stroke
University of Maryland Medical Center
R. Adams Cowley Shock Trauma Center
Baltimore, MD
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Library of Congress Cataloging-in-Publication Data

Quant, Eudocia.
Dx/Rx. Brain tumors / Eudocia Quant.
p. ; cm. — (Dx/Rx neurology series)
Other title: Brain tumors
Includes bibliographical references and index.
ISBN-13: 978-0-7637-7372-4
ISBN-10: 0-7637-7372-7
1. Brain—Tumors—Handbooks, manuals, etc. I. Title. II. Title: Brain
tumors. III. Series: Jones and Bartlett Publishers Dx/Rx neurology series.
[DNLM: 1. Brain Neoplasms—diagnosis—Handbooks. 2. Brain Neoplasms—
therapy—Handbooks. WL 39 Q15d 2011]
RC280.B7.Q83 2011
616.99'481—dc22
2010000301
6048
Printed in the United States of America

14 13 12 11 10 10 9 8 7 6 5 4 3 2 1
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Contents
Editor’s Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
1 Primary Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . 1

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Histological Classification of Primary Brain Tumors . . . . 1
Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Gliomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Meningioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Primary CNS Lymphoma (PCNSL) . . . . . . . . . . . . . . . 28
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2 Brain Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Clinical Features in Parenchymal Metastases . . . . . . . . 43
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Prognosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Brain Metastases from Breast Cancer . . . . . . . . . . . . . . 53
Brain Metastases from Non-Small Cell
Lung Cancer (NSCLC) . . . . . . . . . . . . . . . . . . 55
Brain Metastases from Melanoma . . . . . . . . . . . . . . . . 57
Brain Metastases from Renal Cell
Carcinoma (RCC) . . . . . . . . . . . . . . . . . . . . . . . 58
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3 Spinal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Extradural Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Intradural Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
iii
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iv Contents
4 Leptomeningeal Metastases . . . . . . . . . . . . . . . . 83
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Prognosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
5 Neurologic Complications
of Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . 93
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Radiation Effects on the Central
Nervous System . . . . . . . . . . . . . . . . . . . . . . . . 94
Radiation Effects on the Peripheral
Nervous System . . . . . . . . . . . . . . . . . . . . . . . 101
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
6 Neurologic Complications
of Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . 107
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Common Chemotherapy Agents . . . . . . . . . . . . . . . . . 107
Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . 110
Peripheral Nervous System . . . . . . . . . . . . . . . . . . . . . 115
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
7 Paraneoplastic Disorders . . . . . . . . . . . . . . . . . . 127

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Common Paraneoplastic Disorders . . . . . . . . . . . . . . . 131
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
8 Cerebrovascular Complications . . . . . . . . . . . . 161

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Ischemic Strokes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
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Contents v
Embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Thrombotic Disease (Including Small, Medium,
and Large Vessel Disease) . . . . . . . . . . . . . . . . 166
Intracranial Hemorrhages . . . . . . . . . . . . . . . . . . . . . . 169
Cerebral Venous Thrombosis (CVT) . . . . . . . . . . . . . . 173
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
9 Medical Complications of Brain

Tumor Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Seizures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Venous Thromboembolism (VTE). . . . . . . . . . . . . . . . 186
Cerebral Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Cognitive Impairment . . . . . . . . . . . . . . . . . . . . . . . . . 194
Fatigue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
Treatment Complications and Their Management . . . 196
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
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Editor’s Preface
Welcome to the Dx/Rx Neurology series. This is a new series

of books focusing on common neurological disorders. This
book, Dx/Rx: Brain Tumors, is a comprehensive overview of
tumors of the central nervous system and complications of
cancer and cancer therapy. Dr. Eudocia Quant provides a
succinct and easy-to-read overview for the neurological
trainee, neurologist, and practicing oncologist as well as the
general internist. The additional focus on complications of
nervous system tumors and their associated therapies is
most useful in addressing the significant morbidity patients
with brain tumors face. I believe you will find this, and the
entire neurology series, an invaluable resource to you and
your colleagues.
Kevin N. Sheth, MD
vii
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Preface
This book focuses on two difficult issues in neuro-oncology:

brain tumors and neurologic complications of cancer. The
former represents a heterogeneous group that includes
benign and malignant histologies as well as primary and
metastatic lesions.
The latter is often a source of significant morbidity for
cancer patients. While some patients may ultimately be
referred to neuro-oncologists, it often falls upon general
internists, neurologists, or oncologists to initially manage
these issues. This book is intended for them.
Eudocia Quant, MD
ix
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C H A P T E R 1
Primary Brain Tumors
Epidemiology
■ Central Brain Tumor Registry of the United Status
(CBTRUS)1
• The overall incidence rate for 2004–2005 in the
United States for primary brain and CNS tumors was
23.62 per 100,000 person-years for adults (ages 201
years).
• The most frequently reported histology is meningioma
(33.4%), followed by glioblastoma (17.6%).
■ Mortality rates from nervous system tumors (including
meningiomas) in North America, Western Europe, and
Australia are approximately 4 to 7 per 100,000 persons
per year in men and 3 to 5 per 100,000 persons per year
in women.2
Histological Classification of Primary

Brain Tumors
■ Primary brain tumors rarely metastasize outside of the
CNS.
■ Grading of primary brain tumors is as follows:
• Conventional TNM grading is not used for primary
brain tumors.
• Several grading systems exist for primary brain tumors,
but the WHO classification is the most widely adopted
(Table 1-1).3
■ Tumors are graded I to IV, which correlates with
the degree of malignancy.

■ Subclassification is based on the morphologic
appearance of tumor cells.
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2 Chapter 1
Table 1-1: WHO Classification of Primary Brain Tumors
Classification WHO Grade (I–IV)
Astrocytic tumors
Pilocytic astrocytoma I
Diffuse astrocytoma II
Anaplastic astrocytoma III
Glioblastoma IV
Gliosarcoma IV
Gliomatosis cerebri
Oligodendroglial tumors
Oligodendroglioma II
Anaplastic oligodendroglioma III
Oligoastrocytic tumors
Oligoastrocytoma II
Anaplastic oligoastrocytoma III
Ependymal tumors
Subependymoma I
Myxopapillary ependymoma I
Ependymoma II
Anaplastic ependymoma III
Choroid plexus tumors
Choroid plexus papilloma I
Atypical choroid plexus papilloma II
Choroid plexus carcinoma III
(Continues)

Primary Brain Tumors 3
Table 1-1: WHO Classification of Primary Brain

Tumors (Continued)
Neuronal and mixed neuronal-glial tumors
Gangliocytoma I
Ganglioglioma I
Anaplastic ganglioglioma III
Central neurocytoma II
Pineal tumors
Pineocytoma I
Pineoblastoma IV
Embryonal tumors
Medulloblastoma IV
Tumors of the cranial and peripheral nerves
Schwannoma I
Neurofibroma I
Malignant peripheral nerve II–IV

sheath tumor
Meningeal tumors
Meningioma I
Atypical meningioma II
Anaplastic/malignant meningioma III
Hemangioblastoma I
Tumors of the hematopoietic system
Primary CNS lymphoma
(Continues)

4 Chapter 1
Table 1-1: WHO Classification of Primary Brain

Tumors (Continued)
Germ cell tumors
Germinoma
Teratoma
Choriocarcinoma
Tumors of the sellar region
Craniopharyngioma I
Data are from Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds.
WHO Classification of Tumors of the Central Nervous System, 4th ed.
Lyon: International Agency for Research on Cancer; 2007.
Risk Factors4
■ Genetic syndromes account for only a few cases.
• Neurofibromatosis 1: an autosomal dominant disorder
that is characterized by multiple neurofibromas, malig-
nant peripheral nerve sheath tumors, optic nerve
gliomas, café-au-lait spots, axillary/inguinal freckling,
and iris hamartomas.2
• Neurofibromatosis 2: an autosomal dominant disorder
that is characterized by schwannomas, meningiomas,
and gliomas.
• Tuberous sclerosis: an autosomal dominant disor-
der that is characterized by cortical tubers, facial
angiofibroma, subependymal nodules, and giant cell
astrocytomas.
• Retinoblastoma
• Li-Faumeni (TP53): an autosomal dominant disorder
that is characterized by multiple primary neoplasms
in children and young adults, with a predominance
of soft-tissue sarcomas, osteosarcomas, and breast
cancer, as well as an increased incidence of brain
tumors (mostly astrocytic gliomas).2

• Turcot syndrome: an autosomal dominant disorder

that is characterized by adenomatous colorectal pol-
yps, colon carcinomas, and malignant neuroepithelial
tumors.2
• Multiple hamartoma syndrome
■ Genetic polymorphisms: several polymorphisms have
been implicated, but too few studies have been con-
ducted to assure consistency.
■ Ionizing radiation exposure is a generally accepted cause
of primary brain tumors.
• This is based on data from bomb studies, nuclear test
fallout data, therapeutic radiation for cancer and benign
conditions, and occupational and environmental studies.
• Cranial irradiation (even low doses) can increase the
incidence of meningiomas by a factor of 10 and the
incidence of glial tumors by a factor of 3 to 7, with a
latency period of 10 years to more than 20 years.5
■ Nonionizing radiation exposure: the association of elec-
tromagnetic fields or radiofrequency cell phones with
brain tumors remains unresolved because of inconsis-
tency between studies.2,4
Diagnosis
■ MRI with gadolinium is generally the test of choice in
primary brain tumors.
• Imaging is useful for tumor diagnosis, preoperative
planning, intraoperative imaging, postoperative care,
and treatment response.6
• The appearance varies depending on histology (dis-
cussed later in this chapter).
• Imaging cannot substitute for tissue diagnosis because
it is difficult to differentiate between glioma histolo-
gies based on imaging alone.
■ Pathology (obtained via surgical biopsy or resection) is
often required for definitive diagnosis.
Gliomas (Table 1-2)

■ These arise from glial cells (astrocytes, oligodendrocytes,
ependymal cells, etc.).

Table 1-2: Astrocytic Versus Oligodendroglial Tumors
Astrocytic Tumors Oligodendroglial Tumors
Diffuse Anaplastic Anaplastic
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6 Chapter 1
Astrocytoma Astrocytoma Glioblastoma Oligodendroglioma Oligodendroglioma
WHO grade Grade II Grade III Grade IV Grade II Grade III
Demographics Peak incidence ages Mean age of diagnosis is Peak incidence ages Peak incidence ages Peak incidence ages
30–40, slight male approximately 45 years, 45–75, slight male 40–45, slight male 45–50, slight male
predominance slight male predominance predominance predominance predominance
Histopathology Well-differentiated Compared with Poorly differentiated, Diffusely infiltrating Compared with
neoplastic astrocytes diffuse astrocytoma, often pleomorphic gliomas of moderate oligodendroglioma
on background of increased cellularity, astrocytic tumor cells cellularity, composed of WHO grade II, mitotic
loosely structured distinct nuclear atypical, with marked nuclear monomorphic cells with activity, prominent
matrix mitotic activity. atypia and high mitotic uniform round nuclei and microvascular
Microvascular activity. Prominent perinuclear halos on proliferation, or
proliferation and necrosis microvascular paraffin sections. Other conspicuous necrosis
are absent. proliferation and/or features include
necrosis are essential. microcalcifications,
mucoid/cystic
degeneration, and a
dense network of
branching capillaries.
(continues)
03/29/09 2:35:00 PM
Table 1-2: Astrocytic Versus Oligodendroglial Tumors (Continued)
Astrocytic Tumors Oligodendroglial Tumors
Typical MRI Nonenhancing mass, Irregularly shaped mass Irregularly shaped, Nonenhancing mass, Heterogenous patterns
appearance T1-hypointense, with peritumoral edema, contrast-enhancing mass T1-hypointense, due to variable
T2-hyperintense typically contrast with necrotic center. T2-hyperintense presence of necrosis,
enhancing with necrotic Typically more extensive cystic degeneration,
center peritumoral edema than intratumoral
anaplastic gliomas hemorrhages, and
calcifications. Contrast
enhancement may be
patchy or
homogenous.
Median 5–10 years 2–3 years 9–12 years Depends on 1p/19q status: median survival in
survival patients with 1p/19q codeletions is more than
7 years compared with 2.8 years in patients with
1p/19q retained
Data are from Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumors of the Central Nervous System, 4th ed. Lyon: International Agency
for Research on Cancer; 2007. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):494–507.
03/29/09 2:35:00 PM
8 Chapter 1
■ Glioblastomas account for 54% of all gliomas.1

■ Most low-grade gliomas undergo malignant transforma-
tion to higher grade tumors.
■ The incidence of gliomas has increased slightly over the
past 2 decades, primarily because of improved diagnostic
imaging.7
■ They rarely spread outside of the CNS.
Astrocytoma
Pilocytic Astrocytoma (WHO Grade I/IV)
■ These are mostly seen in the pediatric population.
Diffuse Astrocytoma (WHO Grade II/IV)

■ Biology
• p53 tumor suppressor mutations are found in more

than 60% of astrocytomas.8
• The combined loss of 1p and 19q is a rare event in
low-grade astrocytomas.9
■ Clinical features
• The mean age of presentation is 34 years.6

• Patients may present with generalized or focal signs/
symptoms.
• There is a high rate of seizures in low-grade tumors
because of frequent involvement of the cortex and
slower growth than higher grade tumors.
■ MRI appearance: typically nonenhancing mass, hypoin-
tense on T1-weighted images, hyperintense on

T2-weighted images
■ Treatment for low-grade gliomas
• There is no standard of care, and treatment recom-

mendations vary widely.
• Studies of low-grade glioma often combine astrocy-
toma, oligoastrocytoma, and oligodendroglioma patient
populations.
• Surgery
■ Surgery is important for establishing a diagnosis.
■ It is controversial whether the extent of resection
improves outcomes.

• Gliomas are often infiltrative, diffuse, and/or

near eloquent brain regions.
• There is an increasing trend among neurosur-
geons toward aggressive resection.
• No randomized studies are available on the
extent of resection in low-grade gliomas, but
several retrospective reviews show improved
survival with aggressive tumor resection.10,11
■ Benefits of more extensive resection include
• Minimizing tumor burden

• Reducing symptoms
• Decreasing sampling error and improving diag-
nostic accuracy12
■ Results from a phase II study of 111 “good-risk”
patients with low-grade glioma (neurosurgeon-

defined gross total resection and age #40) followed
with serial MRI imaging13:
• Overall 5-year survival rate, 93%
• Five-year progression-free survival rate, 48%
• Factors associated with poorer progression-free
survival in multivariate analysis: preoperative
tumor diameter $4 cm, astrocytoma or oligoas-
trocytoma histologic type, and residual tumor
$1 cm on an MRI
• Radiation therapy
■ Radiation therapy is considered standard treatment
for low-grade gliomas.

■ The total dose is typically 50–54 Gy.
• A randomized, multicenter study of 379 patients

with low-grade glioma comparing lower dose
(45 Gy over 5 weeks) versus higher dose (59.4 Gy
over 6.6 weeks) conventional, limited-field,
external-beam radiation demonstrated no differ-
ence in overall survival or 5-year progression-
free survival.14
• A randomized, multicenter study of 211 patients
with low-grade glioma comparing lower dose
(50.5 Gy in 28 fractions) versus higher dose

10 Chapter 1
(64.8 Gy in 36 fractions) conventional, limited-

field, external-beam radiation demonstrated no
difference in overall survival or progression-free
survival but did demonstratemore radiation-
induced toxicity with higher dose.15
■ Timing of radiation therapy
• A randomized, multicenter trial of 311 patients

with low-grade glioma comparing immediate
radiation therapy after resection versus delayed
radiation until tumor progression demonstrated
a significant difference in 5-year progression-
free survival in the early radiation arm over the
delayed radiation arm (55% vs. 34.6%) but no
difference in overall survival and it is unclear if
there is any impact on quality of life16
■ Long-term side effects of radiation
• There is concern for an effect on cognitive

functioning.
• Results from a longitudinal neuropsychological
study of patients with radiographically and clini-
cally stable low-grade glioma:
■ At mean of 6 years after diagnosis, results
suggested that the tumor itself (not radia-

tion) had the most deleterious effect on
cognitive functioning, and only high frac-
tion dose radiation (daily fractions .2 Gy)
was associated with additional cognitive
deterioration.17
■ At mean of 12 years after diagnosis, the
patients who received radiation therapy (even

those with daily fractions #2 Gy) showed a
progressive decline in attentional function-
ing, whereas those who never received radia-
tion therapy had stable radiological and
cognitive status.18
• Chemotherapy
■ There is interest in developing effective chemo-
therapy for low-grade glioma in an attempt to

spare patients the late toxicities associated with
radiation.

■ Randomized studies evaluating chemotherapy in

low-grade glioma
• A randomized, multicenter trial of radiation with
or without lomustine showed no difference in
survival.19
• A randomized, multicenter trial of high-risk
patients with low-grade glioma (defined as resid-
ual tumor or age .40) of radiation with or with-
out six cycles of adjuvant procarbazine, CCNU,
and vincristine (PCV) chemotherapy.20
■ The overall median survival and progression-
free survival were similar for both arms between

the years 0 and 2.
■ Beyond 2 years, the overall survival and
progression-free survival curves separated sig-

nificantly, favoring PCV and radiation therapy.
• Results are pending on a randomized, multi-
center trial of patients with low-grade glioma
comparing radiation versus temozolomide.
■ Phase II studies have demonstrated objective
responses with the following regimens.9

• Procarbazine, CCNU, and vincristine (PCV)
• Temozolomide
■ Prognosis
• Based on a Swiss population-based study, the median
overall survival for patients with low-grade astrocytoma
was 5.6 years.21
• In a study of newly diagnosed low-grade gliomas trea-
ted with temozolomide, methylated methylguanine-
methytransferase (versus unmethylated MGMT) and
loss of 1p/19q were associated with longer progression-
free survival.22
Anaplastic Astrocytoma (WHO Grade III/IV)

■ Biology
• They frequently arise from lower grade astrocytomas.

• They frequently undergo malignant transformation
into glioblastomas.
• p53 mutations and platelet-derived growth factor
receptor (PDGFR) overexpression are common.23

12 Chapter 1
• Patients may present with generalized or focal signs/
symptoms.
• The median age at the time of diagnosis is 40 to 50 years.
■ MRI appearance: irregularly shaped mass with associated
edema, typically contrast enhancing
■ Treatment
• Most trials to date that include anaplastic astrocy-
tomas have lumped grade III and grade IV astrocy-
tomas together, although ongoing trials are beginning
to separate grade III from grade IV astrocytomas.
• Treatment decisions are often extrapolated from glio-
blastoma trials.
• Surgery
■ Surgery is important for establishing diagnosis.
■ Pathology should be taken from the contrast-
enhancing margin of the lesion rather than the

necrotic core.23
improves outcomes.
• Retrospective studies suggest that more aggres-
sive resections increase survival, but such stud-
ies are prone to bias.
• In a randomized study of 30 older patients (age
.65) with grade III or grade IV gliomas compar-
ing stereotactic biopsy with open craniotomy
and resection, median survival was longer after
resection (171 days vs. 85 days).24
■ The role of radiation therapy is clearly established
in anaplastic astrocytoma.
■ For patients with adequate performance status, a
radiation therapy dose of 60 Gy in 30 fractions/day

is the standard of care.25
• Chemotherapy
■ The role of chemotherapy in newly diagnosed ana-
plastic astrocytoma is less well established than the

role of radiation therapy.

■ Preliminary results from a randomized, multicenter

trial of patients with newly diagnosed anaplastic
glioma randomized to sequential radiochemother-
apy (radiation therapy upfront followed by PCV or
temozolomide at first progression versus PCV or
temozolomide upfront followed by radiation therapy
at first progression):26
• There was no difference in time to failure (pro-
gression after radiotherapy and chemotherapy
in either sequence) or median overall survival
between initial radiotherapy and initial chemo-
therapy and between temozolomide and PCV.
• Patients with anaplastic astrocytoma had a worse
time to failure than those with anaplastic astro-
cytoma or anaplastic oligoastrocytoma.
■ Based on data from the glioblastoma population,27
there is an increasing trend toward using radia-
tion therapy with concurrent and adjuvant temo-
zolomide.
■ Results from a randomized, multicenter trial of 193
patients with newly diagnosed anaplastic astrocy-
toma comparing radiation therapy with concurrent
and adjuvant BCNU and dibromodulcitol (DBD)
versus radiation therapy alone:28
• This study demonstrated no statistically signifi-
cant difference in overall survival or progression-
free survival.
• The study terminated early because of decreas-
ing accrual.
• The 2-year survival rate was 56% in the com-
bined therapy arm versus 49% in the radiation
therapy-only arm.
• At central pathology review, 53% of the locally
diagnosed cases of anaplastic astrocytoma could
not be confirmed.
■ In a randomized multicenter trial of 290 patients
with newly diagnosed anaplastic oligodendro-
glioma or anaplastic oligoastrocytoma comparing

14 Chapter 1
PCV chemotherapy followed by radiation therapy

versus radiation therapy alone, there was no
difference in overall survival or progression-free
survival.29
■ Results are pending on an ongoing randomized
phase III trial in anaplastic astrocytoma of radia-

tion therapy with temozolomide versus radiation
therapy with a nitrosourea.
• Recurrent disease
■ Chemotherapy is frequently given for recurrent
disease.
■ Preliminary results from a multicenter, randomized
phase III trial of 447 patients with chemotherapy-

naïve, recurrent grade III or grade IV astrocytomas
or oligoastrocytomas comparing temozolomide ver-
sus PCV chemotherapy:30
• The study demonstrated no difference in over-
all median survival comparing temozolomide
to PCV.
• There was no clear evidence of differential
treatment effect in either GBM or anaplastic
astrocytoma.
• A 5-day regimen of temozolomide was supe-
rior to a 21-day regimen of temozolomide
with respect to progression-free and overall
survival.
■ In a multicenter phase II trial of patients with ana-
plastic astrocytoma or anaplastic oligoastrocytoma

who recurred after radiation therapy, temozolo-
mide demonstrated good activity with 6-month
progression-free survival rate of 46% and an objec-
tive response rate of 35%.31
■ Several investigational agents have also been tested
in phase II clinical trials for malignant glioma

(i.e., grade III and grade IV gliomas), although none
has become a standard therapy yet.7
■ Prognosis
• Based on European population studies for patients
diagnosed during 1990–1994, the 1-year survival was
44%, and the 5-year survival was 16%.23


overall survival for anaplastic astrocytoma was
1.6 years.21
• Based on a phase III clinical trial of radiation with
or without DBD and BCNU, the median overall
survival for anaplastic astrocytoma was 2 to 2.6
years.28
• Good prognostic factors are younger age (,50 years
old), good performance status, and intact neurologic
function.
Glioblastoma (WHO Grade IV/IV)

■ Biology
• Other histologic variants include gliosarcoma, giant-

cell glioblastoma, small-cell glioblastoma, and glio-
blastoma with oligodendroglial features.
• It may present de novo (primary GBM) or arise from a
lower grade tumor (secondary GBM).
• Genetic differences exist between primary and second-
ary GBMs.7
■ Primary GBMs are characterized by epidermal
growth factor receptor (EGFR) amplification and

mutations, loss of heterozygosity of chromosome
10q, deletion of PTEN, and p16 deletion.
■ Secondary GBMs are characterized by p53 muta-
tions, overexpression of PDGFR, abnormalities in

p16 and retinoblastoma pathways, and loss of
heterozygosity of chromosome 10q.
• GBMs may present with focal or generalized signs/

symptoms.
• The median age at the time of diagnosis is 64 years,7
although patients presenting with a primary GBM are
generally older than patients with a secondary GBM.
■ MRI appearance
• Heterogeneous enhancement with nonenhancing

necrotic center, surrounding edema, and mass effect
• Most commonly disseminate along white matter
tracts, especially the corpus callosum, to involve the
contralateral hemisphere

16 Chapter 1
■ Treatment
• Primary and secondary GBMs are currently treated
similarly despite their genetic differences, but this
may change in the future.
• Surgery
■ This is important for establishing a diagnosis.
■ It is somewhat controversial about whether the
extent of resection improves outcomes, although

recent prospective studies suggest a survival benefit
for more extensive resections.
• Because of the infiltrating nature of GBMs, it is
not possible to remove the tumor in its entirety,
and thus, the extent of resection is defined by
the contrast-enhancing portion of the tumor on
postoperative MRI with contrast.
• Retrospective studies suggest that more aggres-
sive resections increase survival, but such stud-
ies are prone to bias.
• In a randomized study of 30 older patients (age
.65) with grade III or grade IV gliomas compar-
ing stereotactic biopsy with open craniotomy
and resection, median survival was longer after
resection (171 days vs. 85 days).24
• Results from a randomized study of 322 patients
with grade III or IV glioma comparing the extent
of resection by fluorescence-guided resection
with 5-aminolevulinic acid versus conventional
microsurgery:
■ Interim analysis suggested that patients with-
out residual contrast-enhancing tumor had a

higher overall median survival than those
with residual-enhancing tumor (17.9 months
vs. 12.9 months).32
■ Subgroup analysis of 243 patients with GBM
demonstrated treatment bias regarding com-

plete versus incomplete resection, but when
patients were stratified based on age and
eloquent location, survival advantages from
complete resection remained significant.33

• Newly diagnosed glioblastoma

■ The current standard of care for newly diagnosed
glioblastoma is radiation plus concomitant temozo-

lomide followed by adjuvant temozolomide.27
■ Based on a randomized phase III clinical trial,
initial treatment with radiation plus concomitant

temozolomide followed by adjuvant temozolo-
mide for six cycles increased the median overall
survival compared with radiation alone (15 vs.
12 months).
■ The regimen is well tolerated, with myelosuppres-
sion occurring in less than 10%.

■ There is no data showing an improvement in over-
all survival with prolonged adjuvant temozolomide.

■ Several studies have demonstrated correlations
between treatment outcome and expression of the

DNA repair enzyme methylguanine methyltrans-
ferase (MGMT).34
■ There are several phase II trials of promising tar-
geted molecular therapies added to the standard

radiation/temozolomide regimen, but none has
been adopted as a new standard of care.7
• Recurrent glioblastoma
■ There is no clear standard of care, but a bevacizumab-
containing regimen is often given to patients with

recurrent GBM.
■ FDA approval of bevacizumab for recurrent glio-
blastoma is based on several phase II clinical trials

with bevacizumab monotherapy35,36 or bevacizumab
plus irinotecan36–38 demonstrating prolongation
of progression-free survival and improvement
in response rates compared with historical
controls.
■ There are several phase II trials of other promising
targeted molecular therapies,7 but none has been

as widely adopted as bevacizumab.
■ Prognosis
survival for glioblastoma was 0.4 years.21

18 Chapter 1
• Based on the phase III clinical trial of radiation with

or without temozolomide, the median survival for glio-
blastoma was 12 to 15 months.27
Oligodendroglioma
Oligodendroglioma (WHO Grade II/IV)
■ Biology
• Loss of heterozygosity of 1p and 19q chromosomes is

associated with response to treatment and good
prognosis but is studied less extensively in low-grade
oligodendrogliomas than in anaplastic oligodendro-
gliomas.9
• Other less common genetic abnormalities in low-grade
oligodendroglioma include overexpression of platelet-
derived growth factor or receptor, epidermal growth
factor receptor, or vascular endothelial growth factor.39
• They arise in white matter, commonly in the frontal
lobes.
• Oligodendrogliomas may present with generalized or

focal signs/symptoms.
• There is a high rate of seizures in low-grade tumors
because of the frequent involvement of the cortex and
slower growth than higher grade tumors.
• The median age of presentation is 35 to 40 years.
■ MRI appearance
• MRI typically shows a nonenhancing mass, hyperin-

tense on T2-weighted imaging.
• Calcifications may be present and may be more con-
spicuous on gradient echo sequences.6
• Features that favor oligodendroglioma over astrocy-
toma include cortical involvement, the presence of
calcifications, and a heterogeneous signal.6
■ Treatment
• No standard of care exists for low-grade oligodendro-

glioma, and treatment recommendations vary widely.
• Treatment options are similar to low-grade astrocy-
toma (discussed previously in this chapter).

■ Prognosis
• Low-grade oligodendrogliomas have a better prognosis
than low-grade astrocytomas.
overall survival for a low-grade oligodendroglioma was
11.6 years.21
Anaplastic Oligodendroglioma (WHO Grade III/IV)

■ Biology
• Loss of heterozygosity of 1p and 19q chromosomes is
associated with an increased response to treatment
and good prognosis.39
■ The incidence of either 1p or 19q deletions in oli-
godendrogliomas is approximately 75%.40

■ The incidence of combined 1p 19q loss in oligo-
dendrogliomas is 60% to 70%.40

■ The combined loss of 1p 19q is mediated by trans-
location of 1 and 19q.41,42

• Other less common genetic changes include amplifi-
cation of CDK4 or MYC, mutations of CDKN2A or
CDKN2C, and deletions on chromosome 10.39
• Progression from low-grade oligodendroglioma to ana-
plastic oligodendroglioma is associated with defects in
PTEN, retinoblastoma, p53, and cell cycle pathways.7
■ Clinical features: generalized or focal signs/symptoms
■ MRI appearance6
• Marked enhancement is associated with anaplastic

grades.
• Calcifications may be present and may be more con-
spicuous on gradient echo sequences.
• Features that favor oligodendroglioma over astrocy-
toma include cortical involvement, the presence of
calcifications, and a heterogeneous signal.
■ Treatment
• No standard of care is set for anaplastic oligodendro-

glioma.
• The best treatment regimen is unknown, and treat-
ment recommendations vary widely.
• Surgery

20 Chapter 1
■This is important for establishing a diagnosis.

■Pathology should be taken from the contrast-
enhancing margin of the lesion rather than the
necrotic core.23
improves outcomes.
■ Randomized trials in malignant gliomas demonstrate
a survival advantage with adjuvant radiation therapy,

but no trials have specifically addressed radiation
therapy in the anaplastic oligodendroglioma.40
• Chemotherapy
■ Two large multicenter randomized phase III trials
of newly diagnosed anaplastic oligodendroglioma

showed that the addition of PCV chemotherapy to
radiation does not prolong overall survival but does
increase progression-free survival.
• One study included 368 patients with anaplas-
tic oligoastrocytoma and oligodendroglioma
randomized to standard radiation therapy alone
or radiation therapy followed by six cycles of
adjuvant PCV (procarbazine, lomustine,
vincristine).43
• The other study included 289 patients with ana-
plastic oligodendroglioma randomized to stan-
dard radiation therapy alone or four cycles of
neoadjuvant dose-intensive PCV followed by
radiation therapy.29
• In both trials, 80% of patients assigned to radia-
tion therapy alone were treated with chemother-
apy at progression.
• There was no effect of treatment on survival
even in the subgroup with 1p 19q codeletion.
• The subgroup with 1p 19q codeletion had a lon-
ger median survival than those with 1p 19q
retained.
• The addition of PCV to radiation was associated
with greater toxicity than radiation therapy
alone.

■ Temozolomide is effective in newly diagnosed

anaplastic oligodendroglioma (based on phase II
trials44–46) and is less toxic than PCV chemotherapy,26
but it is unclear whether temozolomide is equiva-
lent, inferior, or superior to PCV chemotherapy.
■ Results are pending in several ongoing randomized
phase III trials in anaplastic oligodendroglioma.

• CATNON: radiation plus temozolomide versus
radiation alone in anaplastic glioma without 1p
19q loss.
• Codeleted trial: radiation alone versus temozolo-
mide alone versus radiation plus temozolomide
in newly diagnosed anaplastic oligodendro-
glioma or anaplastic oligoastrocytoma with 1p
19q codeletions.
• Recurrent anaplastic oligodendroglioma
■ 1p 19q codeleted tumors that previously responded
to chemotherapy will often respond again, although

for a shorter period.
■ Procarbazine, CCNU, and vincristine chemother-
apy (PCV) produced favorable responses in several

phase II studies of recurrent anaplastic oligo-
dendroglioma.47,48
• Radiographic response rates were 62% to 73%.
• Median time to progression was 12 to 24
months.
• Toxicities, including hematologic and gastroin-
testinal side effects, limit the duration of PCV
administration.
■ Temozolomide produced favorable responses in
several phase II studies of recurrent anaplastic oli-

godendroglioma.
• Response rates were 25% to 44% following pro-
gression on PCV chemotherapy.49,50
• The response rate was 53% after progression on
surgery and radiation.51
■ Prognosis
• Anaplastic oligodendrogliomas have a better prognosis
than anaplastic astrocytomas.

22 Chapter 1
• Based on a Swiss population-based study, median

overall survival for anaplastic oligodendroglioma was
3.5 years.21
• Based on randomized phase III trials of radiation ther-
apy with or without PCV chemotherapy in anaplastic
oligodendroglioma and oligoastrocytoma, median
overall survival was 2.6 to 4.9 years.29,43
■ The difference in overall survival between two trials
may be explained by stricter selection criteria in

one trial resulting in a larger number of patients
with 1p 19q codeletions and with fewer anaplastic
features.
Meningioma
■ Tumors arising from arachnoid (meningothelial) cap cells
■ Most common type of primary brain tumor, accounting
for 33.4% of all primary brain tumors, with an annual
incidence rate of 6.03 per 100,000 person-years1
■ Twice as common in women than men1
Risk Factors
■ Ionizing radiation52
• Cranial radiotherapy for gliomas, leukemias, lympho-
mas, or cerebral metastases is associated with the
development of meningiomas within the previous radi-
ation field after a median latency period of 24 years.
• Most meningiomas associated with radiotherapy are
higher grade with a high proliferation index.
■ Hereditary syndromes, including neurofibromatosis type 2,
Gorlin syndrome, and Cowden syndrome

■ Other suspected factors with insufficient evidence to
determine definitively whether they increase the risk for

meningiomas include cellular phones and head injury.
Clinical Features
■ The most common locations (in descending order) are
the convexities, parasagittal areas, sphenoid and middle

cranial fossa, frontal base, posterior fossa, cerebellar

convexity, cerebellopontine angle, intraventricular, and

clivus.53
■ Spinal meningiomas are most often found in the thoracic
spine.
■ Symptoms depend on location (Table 1-3).
• Parasagittal meningiomas occur most frequently in the
frontal lobe and can grow to a large size before causing
symptoms such as seizures or papilledema.
• Frontal skull base meningiomas may present with
vision changes, headache, anosmia, mental status
changes, and seizures.
Pathology
■ WHO grades
• Benign meningiomas (WHO grade I/IV)

■ Most common grade
■ Subtypes: meningothelial, fibrous (fibroblastic),
transitional (mixed), psammomatous, angiomatous,

microcystic, secretory, lymphoplasmacyte rich, and
metaplastic
• Atypical meningiomas (WHO grade II/IV)
■ Represent 5% to 7% of all meningiomas
■ Subtypes: atypical, clear cell, and choroid
■ Compared with benign meningiomas, increased
mitotic activity, increased cellularity, small cells

with high nucleus:cytoplasm ratio, prominent
nucleoli, pattern-less or sheet-like growth, or foci
of spontaneous or geographic necrosis
• Anaplastic/malignant meningiomas (WHO grade III/IV)
■ Less common
■ Subtypes: rhabdoid, papillary, and anaplastic
(malignant)
■ Other pathologic changes
• Genetic changes
■ Deletion of chromosome 22q, which contains the
NF2 gene
• Sex hormones54
■ Progesterone receptors are found in 76% of menin-
giomas, mostly benign meningiomas.

Table 1-3: Meningioma Location and Associated Typical Clinical Presentations
Meningioma Location Clinical Presentation
24 Chapter 1
Parasagittal and falcine Anterior one third Headache, mental status changes
Middle one third Jacksonian seizures, progressive hemiparesis
Posterior one third Headache, visual symptoms, seizures, mental status changes
Sphenoid wing Lateral/pterional Similar to convexity tumors
Middle one third (alar) Hemiparesis, dysphagia
Medial (clinoidal) Visual acuity/field disturbance due to optic nerve compression, proptosis, cranial
nerve dysfunction (III, IV, V, VI)
Olfactory groove Foster Kennedy syndrome (anosmia, ipsilateral optic atrophy with contralateral
papilledema), frontal lobe syndromes, mental status changes, urinary
incontinence, seizure
(continues)
03/29/09 2:35:00 PM
Table 1-3: Meningioma Location and Associated Typical Clinical Presentations (Continued)
Meningioma Location Clinical Presentation
Tuberculum sella/ Visual acuity/field disturbance, anosmia, hydrocephalus, endocrinologic
suprasellar syndromes
Cavernous sinus Cranial nerve deficits (III, IV, V, VI)
Cerebellopontine angle Hearing loss, facial pain/numbness/weakness/spasms, headaches,

cerebellar signs
Foramen magnum Unilateral cervical pain, extremity motor and sensory loss (clockwise
involvement), cold and clumsy hands with intrinsic hand atrophy
Petroclival Hearing loss, vertigo, tinnitus, facial pain, cranial nerve deficits (V, VI, VIII, VIII)
Adapted from Asthagiri AR, Helm GA, Sheehan JP. Current concepts in management of meningiomas and schwannomas. Neurol Clin. 2007;
25(4):1209–1230.
03/29/09 2:35:00 PM
26 Chapter 1
■ More aggressive meningiomas are associated with

low numbers or absence of progesterone receptors.
■ Estrogen receptors are found in 19% of meningiomas.
Imaging
■ Characteristic findings on MRI with gadolinium include
the following6:
• Sessile or pedunculated mass that homogeneously and
intensely enhances
• CSF cleft sign between the tumor and the brain
• Involvement of the dura with a dural tail sign in 40%
to 60%
• Intratumoral calcification may be present
• Presence of peritumoral edema is variable
■ Staging for metastatic disease
• There are no consensus guidelines regarding systemic

staging but meningioma metastases are uncommon;
thus, further staging is unnecessary in most cases.
• The most common sites of metastases are lung, bone,
liver, and lymph nodes.
• If lung metastases are suspected, then staging should
include chest CT with contrast.
Treatment
■ Surgery
• Approximately 80% of meningiomas (mostly grade I

meningiomas) can be cured by surgery.52
• The goal is for complete resection, including the dural
attachment and infiltrated bone.
• The extent of resection is associated with the recur-
rence rate.53
• Complete resection is not achievable in some patients
because of inaccessibility or proximity to vital struc-
tures, such as the cavernous sinus and clivus.
• Preoperative embolization may facilitate removal and
improve surgical outcomes by reducing vascularity and
operative blood loss, but embolization is associated with
a risk of ischemic and hemorrhagic complications.

■ Radiation therapy
• Focal external beam radiation therapy is considered
standard treatment for recurrent meningiomas and
after surgery for atypical and malignant meningiomas.
• Stereotactic radiosurgery can also be considered for
small lesions (,3 cm) and/or for locations not amena-
ble to surgery (i.e., cavernous sinus).
• The use and timing of radiation after resection of a
benign meningioma are controversial.
■ Some centers withhold radiation, even after subto-
tal resection of benign meningioma, until the time

of progression.
■ In patients with WHO grade I meningiomas, radi-
ation in single daily doses of 1.8–2.0 Gy to total

doses of 45–60 Gy after subtotal resection pro-
duces comparable 5-year progression-free survival
rates to rates after complete surgical resection.52
• Radiation is often provided after resection, even after
total resection, in atypical and anaplastic meningiomas.
■ Medical therapy52,55
• Mostly used as investigational agents or after pro-
gression despite multiple surgeries and/or radiation
treatments
• Agents with possible benefit (mostly based on pilot
studies and phase II studies) include the following:
■ Interferon-a
■ Somatostatin analogues
■ Hydroxyurea
■ Observation
• There are no clear guidelines on observation versus
treatment.
• The decision for treatment depends on clinical history,
severity of symptoms, rate of growth, amenability of
the tumor to surgery, and the estimated benefit of
treatment.
■ Patients with small asymptomatic meningiomas
can be followed with serial imaging.

■ Atypical or anaplastic meningiomas should be
treated.

28 Chapter 1
Prognosis
■ The overall 5-year survival ranges from 69% to 90%
depending on the study.52
■ Atypical and anaplastic meningiomas
• Poorer prognosis than benign meningiomas

• Usually demonstrate recurrence and aggressive growth
rates regardless of treatment modality (extirpation,
radiosurgery, or external beam radiation therapy)53
■ Unfavorable prognostic factors include old age, male
gender, and significant comorbidities56

■ Tumor growth rates based on volumetric analysis57
• In study of patients with WHO grade I meningiomas

who underwent subtotal resection, doubling time was
5.2 years.
• Growth rates were higher in young patients.
• Growth rates were lower in meningiomas with calcifi-
cations and in asymptomatic meningiomas.
■ Recurrences
• High recurrence rates are associated with high histo-

logical grading, papillary and hemangiopericytic mor-
phology, large tumor size, and high mitotic index.52
• In one series of 936 meningiomas, the 5-year recur-
rence rate after complete resection was 3% in benign
meningiomas, 38% in atypical meningiomas, and 78%
in anaplastic meningiomas.
Primary CNS Lymphoma (PCNSL)

■ Rare form of extranodal non-Hodgkin lymphoma con-
fined to the brain, leptomeninges, spinal cord, and eyes
■ Accounted for 2.5% of all primary brain and CNS tumors
diagnosed in the United States between 2004 and 20051
Risk Factors
■ Congenital or acquired immunodeficiency (discussed
later in this chapter) is a risk factor.
■ HIV infection is associated with a 3,600-fold increased
risk of developing PCNSL.58

Pathology
■ Ninety percent of PCNSL are diffuse large B-cell
lymphoma (DLBCL), with the remaining 10% poorly
characterized low-grade lymphomas, Burkitt lymphomas,
and T-cell lymphomas.59
■ The DLBCL type is composed of immunoblasts or cen-
troblasts with a predilection for blood vessels, resulting in

lymphoid clustering around small cerebral vessels.60
■ They are classified as stage I disease according to the Ann
Arbor staging system, but the prognostic significance of

the Ann Arbor staging system does not apply to PCNSL.
Clinical Features
■ The median age of diagnosis in immunocompetent pati-
ents is 53 to 57 years.60
■ Patients present with neurologic signs and symptoms
depending on the location of the tumor, including focal

deficits, neuropsychiatric symptoms, increased intracra-
nial pressure, seizures, and ocular symptoms.
■ Sixteen percent to 42% of patients with PCNSL have
leptomeningeal involvement at diagnosis, but most do

not show clinical signs of leptomeningeal disease.60
■ Twenty percent have ocular involvement, presenting as
floaters, blurred vision, diminished visual acuity, and

painful red eyes.60
■ Systemic B symptoms (fever, weight loss, night sweats)
are less common, unlike systemic DLBCL.

■ Occult systemic disease has been reported in up to 8% of
patients initially thought to have isolated PCNSL.61
Diagnosis61
■ A definitive diagnosis usually requires a stereotactic
biopsy.
■ MRI with gadolinium of the entire neuroaxis
• Lesions appear clearly delineated and are isointense

to hypointense on T2-weighted MRI because of high
cell density and scant cytoplasm.

30 Chapter 1
• Lesions are typically homogeneously enhancing on

postcontrast T1-weighted MRI in immunocompetent
patients.
• Lesions are solitary in 65% of patients and multifocal
in 35%.60
• Locations include cerebral hemispheres (38%),
thalamus/basal ganglia (16%), corpus callosum (14%),
ventricular region (12%), and cerebellum (9%).60
• Lesions may appear to vanish with steroids because
steroids reduce swelling and cause tumor lysis.
■ Lumbar puncture with cytology, flow cytometry, and
immunoglobulin heavy-chain gene rearrangement studies
• CSF typically demonstrates increased WBC count,
high protein concentrations, and low glucose.
■ Complete ophthalmologic examination, including dilated
fundus and slip-lamp examinations
■ Other recommended studies to look for systemic disease
• Chest, abdomen, and pelvic CT scan with contrast
• Bone marrow biopsy
• Clinical and ultrasound testicular examination in men
• Clinical examination of peripheral lymph nodes
• Routine blood work including HIV testing, CBC,
LDH
• Possibly PET scan
Treatment
■ PCNSLs are sensitive to corticosteroids, but responses
are not durable.

■ There is no standard treatment.
■ There are no randomized, controlled phase III trials in
PCNSL.
■ Treatment options are based on the results from phase II
clinical trials.62
• Newly diagnosed PCNSL
■ Surgery
• Stereotactic biopsy is indicated for diagnosis.

• Gross total resection or tumor debulking confers
no survival benefit over surgery alone.60

■ High-dose methotrexate monotherapy

• CNS penetration of methotrexate is poor at con-
ventional doses.
• High doses (3 to 8 g/m2) can achieve cytocidal
concentrations of methotrexate in cerebrospinal
fluid.63
• High-dose methotrexate monotherapy is associ-
ated with response rates of 35% to 74% and with
median progression-free survival of 12.8–13.7
months.
• High doses $3 g/m2 require intensive inpatient
management and good renal function.
■ Methotrexate-based multidrug regimens
• The incremental benefit from additional chemo-
therapy beyond high-dose methotrexate is
unclear.
■ Preliminary results from a randomized phase
II study of high-dose methotrexate (followed

by whole brain radiation) with or without
high-dose cytarabine found that the addition
of cytarabine increased response rates from
40% to 69%.64
• Radiographic response rates and disease-free
survival may be slightly higher in trials with
methotrexate-based multidrug regimens com-
pared with trials with methotrexate monother-
apy, but rates often overlap.62
• Multidrug regimens may be associated with
higher toxicity than methotrexate monotherapy.
• Common regimens include methotrexate, pro-
carbazine, and vincristine (MPV); high-dose
cytarabine and methotrexate; and temozolomide
and methotrexate in older patients (age .60).62
■ Intrathecal chemotherapy
• Intrathecal chemotherapy is standard treatment
for patients with proven leptomeningeal disease.
• However, the use of adjuvant intrathecal che-
motherapy with high-dose methotrexate-based
regimens is controversial because methotrexate

32 Chapter 1
doses $3 g/m2 can achieve adequate concentra-

tions in the CSF.62
■ Adjuvant corticosteroids
• Corticosteroids are useful for edema and symp-
tomatic management.
• Incorporation of corticosteroids into multidrug
regimens has not increased response rates com-
pared with non-steroid-containing regimens and
is associated with side effects.
■ High-dose chemotherapy with autologous stem-cell
transplantation
• Based on results from several phase II clinical
trials, this approach is feasible in a selected pop-
ulation (younger and chemotherapy sensitive).
• It is unclear whether patients in transplantation
trials would have done as well with standard
high-dose methotrexate-based chemotherapy
regimens.
• Studies show that transplantation is associated
with higher mortality and morbidity than chemo-
therapy regimens without transplantation.
■ Whole-brain radiation (WBRT)
• WBRT was historically the standard of care in
PCNSL but has been replaced by high-dose
methotrexate-based regimens.
• WBRT is often deferred, especially in patients
older than 60 years of age and depending on
response to chemotherapy.
■ WBRT alone does not produce durable remis-
sions in most patients.65

■ It is associated with neurotoxicity, including
dementia, gait disturbance, and urinary incon-

tinence (see Chapter 5 for additional infor-
mation regarding radiation-related toxicities).
■ Adjuvant rituximab
• Rituximab is a humanized monoclonal antibody
to CD20, a cell surface protein found on mature
B cells.
• It may be incorporated into treatment regimens
for patients with DLBCL, which express
CD20.

• Response rates with rituximab monotherapy in

PCNSL are modest.
• Rituximab combined with methotrexate, procar-
bazine, vincristine, and cytarabine produced a
high response rate of 93% in a phase II clinical
trial.66
• There are several ongoing trials of rituximab in
PCNSL.
■ Recurrent or refractory PCNSL
• Up to 50% of patients with PCNSL will relapse,
and 10% to 15% of patients have primary refractory
PCNSL.62
• Optimal management is unclear because of limited
data.
• Options include whole-brain radiation (for patients
who had this treatment option initially deferred),
reinduction with high-dose methotrexate, single
agent topotecan, and single agent temozolomide.
■ Ocular lymphoma
• Ocular lymphoma may occur in isolation or in com-
bination with parenchymal PCNSL.
• Symptoms are similar to a nonspecific uveitis but
eventually become refractory to topical steroids.
• Definitive diagnosis is made with vitreal cytology.
• For those with isolated ocular lymphoma, the risk of
developing brain involvement is as high as 80%.62
• Treatment may include the following:
■ Primary intraocular lymphoma: directed ocular
treatment with ocular radiotherapy or intraocu-

lar methotrexate.
■ Parenchymal brain and ocular lymphoma: the
addition of directed ocular treatment may

improve disease control, but a methotrexate dose
of 8 g/m2 can also produce cytocidal concentra-
tions in the vitreous body.
Prognosis
■ Durable complete responses and long-term survival are
possible with treatment.

■ Outcomes are worse compared with patients with a simi-
larly staged systemic non-Hodgkin lymphoma.

34 Chapter 1
Table 1-4: Prognostic Factors in PCNSL and Estimated

2-Year Overall Survival Rates
Poor Prognostic • Age .60 years

Factors • Performance status of 1 on the Eastern
Cooperative Oncology Group (ECOG)
performance status scale
• Elevated serum LDH
• High CSF protein concentration
• Tumor location in the deep brain regions
(periventricular regions, basal ganglia,
brainstem and/or cerebellum)
Number of Poor Prognostic

Factors Two-Year Overall Survival Rates
0–1 80%
2–3 48%
4–5 15%
Data are from Ferreri AJ, Blay JY, Reni M, et al. Prognostic scoring system
for primary CNS lymphomas: the International Extranodal Lymphoma
Study Group experience. J Clin Oncol. 2003;21(2):266–272.
■ Poor prognostic factors in PCNSL and 2-year survival

rates are listed in Table 1-4.67
HIV-Related PCNSL
■ Nearly 6% of the AIDS population will be afflicted with
PCNSL.6
■ The disease incidence has decreased during the highly
active antiretroviral therapy (HAART) era.68

■ MRI with gadolinium in HIV-related PCNSL
• This may demonstrate ring enhancing lesions, which

makes it difficult to differentiate from toxoplasmosis.
• Compared with PCNSL in immunocompetent
patients, there is a higher frequency of multiple lesions,
cortical-based lesions, lesions with irregular margins,
heterogeneity, and hemorrhage.6

■ Pathophysiology involves Epstein-Bar virus (EBV).

■ Optimal management is unclear, but high-dose methotrex-
ate, whole-brain radiation, and/or HAART may be used.62
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CD005419.

C H A P T E R 2
Brain Metastases
Epidemiology
■ Brain metastases are the most common intracranial
neoplasm in adults.1
■ The exact incidence is unknown, but it is estimated to be
as high as 200,000 cases per year in the United States.2
■ The incidence of CNS metastases appears to be rising
because of more effective systemic treatments resulting
in longer survival, earlier detection, and better imaging
modalities.
■ Most brain metastases originate from the following pri-
mary malignancies.1
• Lung cancer (40% to 50%)
• Breast cancer (15% to 25%)
• Melanoma (5% to 20%)
■ Most brain metastases occur through hematogenous and
spread with a predilection for vascular border zones and
gray-white matter junction.
■ The distribution parallels blood flow: 80% in cerebral
hemispheres, 15% in cerebellum, and 5% in brainstem.3
Clinical Features in Parenchymal Metastases

■ Headache
■ Neurologic deficits depending on location of lesion
(i.e., ataxia with cerebellar lesions, motor deficits with
corticospinal tract involvement)
■ Cognitive and mental status changes
■ Seizures
43

44 Chapter 2
Diagnosis
■ Brain MRI with gadolinium is the preferred imaging
modality for evaluation of brain metastases.
• Lesions typically are well circumscribed and enhance
with gadolinium because of an impaired blood–brain
barrier.
• A brain MRI should not be used in emergency situa-
tions if the patient is too unstable.
• Posterior fossa and leptomeninges are better visual-
ized on MRI than CT.
■ In an acute presentation, head CT without contrast is
appropriate to identify life-threatening pathology, includ-
ing intracranial hemorrhage, acute hydrocephalus, or
herniation.
■ Brain biopsy is indicated if the diagnosis is in question.
• Multiple, widespread brain metastases in a patient
with cancer are strongly suggestive of brain metasta-
ses, but brain abscesses can have a similar appear-
ance, especially in immunosuppressed or septic
patients.
• Single or solitary brain lesions may be more difficult to
diagnose.
■ In one study, 11% of patients with cancer undergo-
ing surgery for a single brain lesion had pathology

consistent with a primary brain tumor, an infec-
tious disease, or an inflammatory disease.4
Prognosis
■ Important prognostic factors include age, Karnofsky per-
formance status (KPS) (Table 2-1), number of brain
metastases (single or multiple), primary tumor type, sys-
temic tumor activity (controlled or uncontrolled), and
time since primary tumor diagnosis.5,6

Brain Metastases 45
Table 2-1: Karnofsky Performance Status Scale
Percentage Description
100 Normal, no complaints, no evidence of disease
90 Able to carry on normal activity; minor signs or

symptoms of disease
80 Normal activity with effort; some signs or symptoms

of disease
70 Cares for self, unable to carry on normal activity or

to do active work
60 Requires occasional assistance but is able to care for

most of his or her needs
50 Requires considerable assistance and frequent

medical care
40 Disabled, requires special care and assistance
30 Severely disabled, hospitalization indicated; death

not imminent
20 Very sick, hospitalization indicated; death not

imminent
10 Moribund, fatal processes progressing rapidly
0 Dead
■ Recursive partitioning analysis (RPA) classes (Table 2-2)5

• Patients can be divided into subgroups based on
prognosis.
• Subgroups are based on a review of 1,200 patients in
the Radiation Therapy Oncology Group (RTOG) data-
base who received whole-brain radiation therapy.

46 Chapter 2
Table 2-2: Recursive Partitioning Analysis (RPA) Classes in

Patients with Brain Metastases
Class I Class II Class III
KPS $70 ,70
Age ,65 Any patient Any

not in class I
Extent of disease Controlled or class III Any
primary tumor,
no extracranial
metastases
Median overall 7.1 months 4.2 months 2.3 months

survival
Modified from Gaspar L, Scott C, Rotman M, et al. Recursive

partitioning analysis (RPA) of prognostic factors in three Radiation
Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat
Oncol Biol Phys. 1997;37(4):745–751.
Treatment
■ The treatment approach often depends on tumor histol-
ogy, number of brain metastases, the control of systemic
disease, and the status of neurologic function.
■ Main treatment options include whole-brain radiation,
surgical resection, radiosurgery, and systemic treatments.
■ Fifty percent of patients with CNS metastasis have a
single brain metastasis.
Whole-Brain Radiation Therapy (WBRT)

■ This is the mainstay of treatment for patients with brain
metastases.
■ Indications for WBRT are as follows:
• Curative intent
• Palliation
• Consolidation to reduce neurological morbidity
• Prophylaxis in specific patients with SCLC, NSCLC,
or breast cancer with curative intent

Brain Metastases 47
■ Nonrandomized studies suggest that WBRT increases

median survival by 3 to 4 months over no treatment (the
median survival is approximately 1 month with no
treatment).1
■ Radiographic response rate (complete responses or par-
tial responses) to WBRT is approximately 60% in RTOG
randomized controlled trials.7
■ Symptom stabilization or improvement is achieved in
approximately 60% of patients, although this may be
overestimated because corticosteroids are often adminis-
tered with WBRT.8
■ Neurologic complications from radiation therapy are fur-
ther discussed in Chapter 5.
WBRT Treatment Regimens

■ The most common regimen used is 35 Gy delivered in
2.5 Gy fractions over 14 treatment days.
■ Fractions of .3 Gy increase the risk of neurotoxicity.
■ Differences in dose, timing, and fractionation do not alter
the median survival of patients receiving WBRT for brain

metastases.9
WBRT 1 Radiation Sensitizers

■ Most radiosensitizers (lonidamine, metronidazole, mis-
onidazole, gadolinium, or bromodeoxyuridine) have dem-

onstrated no benefit over WBRT alone in terms of local
brain tumor control or overall survival.
■ In a randomized phase III study of WBRT with or without
motexafin gadolinium for treatment of brain metastases

from solid tumors, there were no significant differences
between the two arms in terms of survival or time to neu-
rologic progression.10
• In the follow-up trial in patients with NSCLC, the
motexafin arm exhibited a nonsignificant trend toward
improved neurologic outcomes (time to neurologic
progression 10.0 months for WBRT vs. 15.4 months
for WBRT 1 motexafin, P 5 0.122).11
■ In a randomized phase III study of WBRT and supplemental
oxygen with or without efaproxiral for treatment of brain

48 Chapter 2
metastases from solid tumors, there was no significant

difference between the two arms for survival.12
• In subgroup analysis of patients with breast cancer,
the efaproxiral arm had significantly reduced death
rates by 46% and improved quality of life.13
• Preliminary results from the follow-up phase III open-
label trial in patients with breast cancer, however, sug-
gest no difference in overall survival, response rate,
performance status, or neurologic signs/symptoms.14
WBRT 1 Chemotherapy
■ Several chemotherapeutic agents yield higher response
rates at the expense of greater toxicity and no benefit in

overall survival, including chloroethylnitrosoureas, tega-
fur, fotemustine, and teniposide.
■ Efficacy and safety of temozolomide and radiation in
brain metastases have been evaluated in several phase II

trials, but the combination does not seem to improve
survival.
• Antonadou et al. reported significant improvement in
the response rate with temozolomide 1 WBRT com-
pared with WBRT alone (96% vs. 67%) but survival
data were not evaluated.15
• In a randomized phase II trial of temozolomide 1 WBRT
versus WBRT alone, overall survival and response rates
were similar in both arms, but the percentage of patients
with progression-free survival of brain metastases at
90 days was significantly higher for the temozolomide 1
WBRT arm (72% vs. 54%).16
Stereotactic Radiosurgery (SRS)

■ SRS uses multiple convergent beams to deliver a single
high dose of focal radiation to a small target volume.

■ This is a common treatment modality for newly diagnosed
brain metastases, alone or in combination with WBRT,

and as salvage therapy after WBRT.
■ The most common delivery systems include linear accel-
erator, gamma knife, and cyclotron.

Brain Metastases 49
■ Maximum tolerated doses are based on the RTOG 90-05

protocol.17
• Tumors 31 to 40 mm: 15 Gy
• Tumors 21 to 30 mm: 18 Gy
• Tumors less than or equal to 20 mm: 24 Gy but subse-
quent retrospective analysis suggested that doses
.20 Gy increase neurotoxicity and do not improve
local control.18
■ One-year actuarial local control rates for single and
multiple brain metastases with SRS alone are 71%
to 79%.18–21
■ Based on a small series, SRS at recurrence is an accept-
able treatment for patients with good functional status
and controlled/indolent extracranial disease with local
control rates of 57% to 100% and overall brain control
rates of 65% to 78%.17,22–25
■ SRS does not prevent distant failure.
■ The complications from SRS are the following:
• Early treatment-induced cerebral edema (4% to 6%
patients within 1 to 2 weeks of treatment)
• Seizures (2% to 6% patients within the first 24 to
48 hours)
• Delayed radiation necrosis (2% to 17%)
■ There is a higher risk for radiation necrosis with
larger tumor volume, higher radiation dose, and prior

radiotherapy.
WBRT with or without SRS

■ Based on three randomized controlled trials and two
retrospective studies, SRS boost after WBRT improves

survival in select patients with single brain metastases.1
■ In patients with two to three brain metastases, the role of
SRS boost is less clear.

• Based on subgroup analysis of a large randomized con-
trolled trial, SRS boost after WBRT did not improve
survival or local control.26
• Based on a smaller randomized study 27 and retrospec-
tive series,28 SRS boost did improve survival.

50 Chapter 2
SRS with or without WBRT

■ It is controversial whether patients can be treated with
SRS alone in order to spare the risk for late neurotoxicity
from WBRT.
■ Based on a randomized controlled trial, SRS alone as
compared with WBRT 1 SRS results in worse local con-

trol and worse distant intracranial disease control with no
difference in overall survival.19
■ Preliminary results from the SRS arm of the European
Organization for Research and Treatment of Cancer

(EORTC) study 22952-26001 (patients with good per-
formance status and 1–3 brain metastases with stable
systemic cancer or asymptomatic synchronous primary
tumor without metastases outside the CNS)29:
• No difference in overall survival between SRS alone
versus SRS 1 WBRT
• Significant reduction of intracranial progression after
WBRT in both arms of the study
■ There is a risk of distant brain failure in patients who
receive SRS alone.30

• The low-risk (median time to distant brain failure
47.9 weeks) group had three or fewer metastases, an
absence of extracranial disease, and nonmelanoma
histologic characteristics.
• The median time to distant brain failure for all other
possible groupings ranged from 12.3 to 28.7 weeks.
Surgery
■ The benefits of surgery include pathology for definitive
diagnosis, rapid relief of neurologic symptoms caused by

mass effect, and local control.
■ Resection of single brain metastasis is a standard option
in patients with good, functional status and controlled or

indolent extracranial disease.31
■ The in-hospital mortality for resection of brain metasta-
ses in high-volume centers is as low as 1.8%.31

Brain Metastases 51
Surgery for a Single Brain Metastasis

■ Three randomized controlled trials have compared surgical
resection 1 WBRT versus WBRT alone in patients with a
single brain metastasis (Table 2-3).4,32,33
• Patchell et al. 1990: resection 1 WBRT versus biopsy
1 WBRT associated with longer median survival time,
better local control rate, longer duration of functional
independence (KPS $ 70) and longer freedom from
death due to neurologic causes.
• Vetch et al. 1993: resection 1 WBRT associated with
longer median survival time as compared with WBRT
alone.
• Mintz et al. 1996: no survival difference between
two groups but patients had a poorer functional status
and more active extracranial disease than other studies.
Table 2-3: Results from Randomized Controlled Trials

of Patients with a Single Brain Metastasis
Comparing Surgical Resection ⴙ WBRT
Versus WBRT Alone
Resection ⴙ
WBRT Median WBRT Median
Study Overall Survival Overall Survival
Patchell et al., 1990 9.2 months 3.4 months
Vecht et al., 1993 10.0 months 6.0 months
Mintz et al., 1996 5.6 months 6.3 months
Data are from Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial
of surgery in the treatment of single metastases to the brain. N Engl
J Med. 1990;322(8):494–500. Vecht CJ, Haaxma-Reiche H, Noordijk EM,
et al. Treatment of single brain metastasis: radiotherapy alone or
combined with neurosurgery? Ann Neurol. 1993;33(6):583–590.
Mintz AH, Kestle J, Rathbone MP, et al. A randomized trial to assess the
efficacy of surgery in addition to radiotherapy in patients with a single
cerebral metastasis. Cancer. 1996;78(7):1470–1476.

52 Chapter 2
Surgery for Multiple Brain Metastases

■ Patients with good prognostic features and two to three
metastases may benefit from resection of the dominant
lesion.34,35
■ A highly selected subset of patients with multiple metas-
tases may benefit from resection of all lesions.36
Surgery with or without WBRT

■ Based on a randomized controlled trial, resection of a
single brain metastasis 1 WBRT versus resection alone

is associated with better local, distant, and overall intrac-
ranial control rates.37
■ No benefit is seen in overall survival from combined ther-
apy, although the patients who received WBRT were less

likely to die from neurologic causes.
■ Preliminary results from the surgery arm of EORTC
22952-26001 (patients with one to three brain metasta-

ses with stable systemic cancer or asymptomatic synchro-
nous primary tumor without metastases outside of the
CNS)29:
• No difference in overall survival between surgery alone
versus surgery 1 WBRT
• Significant reduction of intracranial progression with
WBRT
Surgery Versus SRS

■ There are no prospective studies directly comparing sur-
gery versus SRS.

■ Most retrospective studies demonstrate no difference in
survival between surgery and SRS.38

■ Surgery is probably better for larger tumors with exten-
sive edema and mass effect or tumors requiring rapid

relief of neurologic symptoms.
■ SRS is noninvasive and can treat tumors that are not
amenable to surgery.
Chemotherapy
■ This is traditionally reserved for patients who have
failed other treatment modalities or tumors that are

Brain Metastases 53
chemosensitive (lymphoma, SCLC, germ cell tumors

more chemosensitive than breast cancer).
■ Because brain metastases represent a late event in the
natural history of most cancers, tumors may have acquired
resistance to many drugs.
■ For patients with active systemic disease and brain metas-
tases, chemotherapy provides an opportunity to treat both
compartments.39
■ Delivery to the CNS is limited by the blood–brain barrier,
efflux by P-glycoprotein, nonuniform drug distribution in
the tumor (preferential concentration in necrotic areas),
and poor drug accumulation (due to tumor interstitial
fluid gradients).40
■ This is discussed further later in this chapter.
Brain Metastases from Breast Cancer

Epidemiology
■ Breast cancer is the second most frequent cause of brain
metastasis.41
■ Up to 30% patients with breast cancer will develop CNS
metastases.42–44
■ Breast cancer is the solid tumor most commonly associ-
ated with leptomeningeal metastases.44

■ Leptomeningeal involvement is found at autopsy in 5% to
16% of breast cancer patients.44

■ In the majority of breast cancer patients, metastases to
the CNS develop following extracranial metastases,

although the CNS may be the first site of recurrence in
20% to 39% of patients.45
Incidence in Patients Receiving Trastuzumab

■ Trastuzumab is a monoclonal antibody against the HER2/
neu oncoprotein used to treat HER2/neu-positive breast

cancer.
■ Some studies report a higher incidence of CNS metasta-
ses in patients who received trastuzumab-based regimens

for HER2 overexpressing metastatic breast cancer,46–49
whereas other studies did not find a higher incidence.

54 Chapter 2
■ The proposed causes for possible higher incidence are as

follows:
• Trastuzumab does not cross the blood–brain barrier,
and therefore, the CNS may act as a sanctuary site for
metastatic disease.
• There is prolonged survival in HER2-positive meta-
static breast cancer due to trastuzumab, resulting in
an increased risk for CNS relapse.
• There is an inherent biology of HER2-positive breast
cancer (which may be associated with higher risk for
CNS metastases).
■ Continued use of trastuzumab in patients with brain
metastases may improve overall survival compared with
discontinuation of trastuzumab, possibly because of bet-
ter control of systemic disease.50
Risk Factors for the Development of CNS Metastases

in Breast Cancer44,45,51
■ Young age
■ Negative hormone receptor status
■ Invasive ductal carcinoma
Treatment Options for Brain Metastases

from Breast Cancer
■ Treatment recommendations are similar to brain metas-
tases from other primary tumors.
Surgery
■ This is indicated for urgent decompression and solitary
brain metastasis.
■ Surgery is typically reserved for patients with a single
brain lesion, minimal extracranial disease, and/or better

performance status.
■ Surgical resection for single brain metastases followed by
WBRT is superior to WBRT alone with stable/absent

extracranial disease.4
SRS
■ SRS is typically recommended for #3 brain metastases,
with each lesion measuring #3 cm, but the failure rate

outside the SRS field is 37%.

Brain Metastases 55
■ There are no randomized trials comparing SRS with

surgery for treatment of single brain metastasis.
■ Combining SRS 1 WBRT is better than WBRT alone.44
WBRT
■ Seventy-five percent to 85% of patients who receive
WBRT experience improvement or stabilization of

symptoms (seizures and headaches most effectively
palliated).44
■ Postoperative WBRT does not extend survival but does
reduce brain recurrences.37
Systemic Treatments
■ This is generally recommended after failure with surgery
and radiation.
■ Selected chemotherapy agents such as capecitabine,
5-fluorouracil, platinum analogues, temozolomide, meth-

otrexate, topotecan, bendamustine have known activity
in the CNS.40,51
■ Lapatinib has modest antitumor activity against CNS
metastases in HER2-positive breast cancer patients.52

■ Capecitabine in combination with temozolomide or lapa-
tinib may have activity in new and recurrent brain metas-

tases, but larger studies are needed.50
Brain Metastases from Non-Small Cell Lung

Cancer (NSCLC)
Epidemiology
■ Brain metastases may develop in 20% to 40% of patients
with NSCLC.53
■ NSCLC is usually chemoresistant, and thus, patients
who develop brain metastases usually have been heavily

pretreated.
■ RPA classification scheme (Table 2-2) was based on a
study in which lung cancer accounted for 61% of the

patients studied (almost all had NSCLC).5
■ Although survival times are short for patients with brain
metastases, patients with brain metastases from NSCLC

may have a worse prognosis than patients with brain
metastases from other solid tumors.54

56 Chapter 2
Risk Factors for Development of CNS Metastases

in NSCLC
■ Age5
■ Clinical stage (later stage)55
■ Adenocarcinoma histology56
■ CEA serum levels $40 ng/mL56
Treatment Options for Brain Metastases from NSCLC

■ Treatment decisions in NSCLC are often based on the
extent of disease characterized as follows:

• Single brain metastasis with controlled or controllable
primary disease
• Oligometastatic disease (primary disease and less than
three distant metastases)
• Multiple metastases
■ Carefully selected patients with resectable N0,1 primary
NSCLC and an isolated brain metastasis as the only site

of metastatic disease may benefit from aggressive therapy
of the primary site and brain lesion (surgery or SRS) to
prolong survival.57
■ In patients with a single brain metastasis and previously
resected primary NSCLC, surgical resection or SRS of

the isolated brain metastasis should be considered.57
■ Select patients with oligometastatic disease may be
treated with surgical resection or radiosurgery followed

by WBRT.58
■ Patients with multiple brain metastases from NSCLC
are generally treated with WBRT.
Systemic Treatments
■ For patients with brain metastases, chemotherapy and
targeted therapies have a greater role for patients with
active systemic disease or contraindications to other
treatment modalities.53
■ For patients with brain metastases but controlled or
stable systemic disease, surgery and radiation are more

commonly used.
■ Chemotherapy-naïve patients with brain metastases may
benefit from cisplatin alone (radiographic response rates

Brain Metastases 57
30%)59 or in combination with other agents (radiographic

response rates 28% to 45%).60–64
■ Patients with recurrent brain metastases may benefit
from TMZ alone (RR 0% to 20%)65–68 or in combination
with vinorelbine (higher RR but more toxicity).69
■ Data on the response of brain metastases to small
molecular epidural growth factor receptor (EGFR) inhib-
itors (erlotinib, gefitinib) is limited, but responses to
these agents likely depend on the presence of EGFR
mutations.70
Brain Metastases from Melanoma

Epidemiology
■ CNS metastases detectable on imaging develop in nearly
50% of patients with metastatic melanoma.71

■ Patients with metastatic melanoma to the brain have a
medial survival of 4 to 6 months.72

■ Brain metastases from melanoma tend to be hemorrhagic.
Imaging
■ The typical melanotic pattern on MRI consists of high
signal intensity on T1-weighted images and low signal

intensity on T2-weighted images.
• The MRI appearance is attributed to free radicals in
melanin as well as blood products.
■ An amelanotic pattern is also frequently described
consisting of a hypointense/isointense appearance on

T1-weighted images and hyperintense/isointense appear-
ance on T2-weighted images.
■ Dural involvement by malignant melanoma is rare.
Treatment Options for Brain Metastases from

Melanoma
■ Whole brain radiation therapy is moderately effective for
the control of melanoma metastatic to the brain (a com-

plete response rate of less than 20% and a partial response
rate of approximately 50%).72

58 Chapter 2
■ Select patients with limited disease may benefit from

stereotactic surgery for local control.
■ Chemotherapy does not significantly increase the local
control rate.
• Fotemustine (response rate 5% to 25%) and temozolo-
mide (response rate of 6% to 10%) are the most active
agents.38
■ A select subset of patients achieve disease stabilization
with aggressive local control 1 WBRT.1
Brain Metastases from Renal Cell

Carcinoma (RCC)
Epidemiology
■ Only 4% to 11% of patients with RCC develop brain
metastases.73
■ Over 90% of patients with brain metastases from RCC
are symptomatic (headaches, mental status changes,

confusion, and seizures).74
■ Development of brain metastases suggests late-stage dis-
ease, and patients frequently have extracranial disease.

■ Brain metastases from RCC tend to be hemorrhagic.
Treatment Options for Brain Metastases from RCC

■ A select subset of patients, particularly those with one to
two brain metastases and an absence of extracranial dis-

ease, can achieve long-term survival with surgical resec-
tion 1 radiation.75
■ Brain metastases from RCC are considered “radioresis-
tant,” although in a published case series of patients with

up to five lesions, SRS with or without WBRT has
produced good local control and prolonged survival.76
Prospective studies are needed to confirm these results
and to characterize better which patients would benefit
most from SRS treatment.
■ The role of vascular endothelial growth factor (VEGF)
and VEGF receptor inhibitors in brain metastases from

RCC is unclear because most published phase II and
phase III clinical trials of systemic disease excluded
patients with brain metastases.

Brain Metastases 59
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64 Chapter 2
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from non-small cell lung cancer. Eur J Cancer. 1996;32A(1):
69–71.
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motherapy with cisplatin and etoposide for patients with
brain metastases from breast carcinoma, nonsmall cell lung
carcinoma, or malignant melanoma: a prospective study.
Cancer. 1999;85(7):1599–1605.
64. Minotti V, Crino L, Meacci ML, et al. Chemotherapy with
cisplatin and teniposide for cerebral metastases in non-small
cell lung cancer. Lung Cancer. 1998;20(2):93–98.
65. Abrey LE, Olson JD, Raizer JJ, et al. A phase II trial of temo-
zolomide for patients with recurrent or progressive brain
metastases. J Neurooncol. 2001;53(3):259–265.
66. Christodoulou C, Bafaloukos D, Kosmidis P, et al. Phase II
study of temozolomide in heavily pretreated cancer patients
with brain metastases. Ann Oncol. 2001;12(2):249–254.
67. Dziadziuszko R, Ardizzoni A, Postmus PE, et al. Temo-
zolomide in patients with advanced non-small cell lung can-
cer with and without brain metastases. a phase II study of
the EORTC Lung Cancer Group (08965). Eur J Cancer.
2003;39(9):1271–1276.
68. Giorgio CG, Giuffrida D, Pappalardo A, et al. Oral temozo-
lomide in heavily pre-treated brain metastases from non-
small cell lung cancer: phase II study. Lung Cancer. 2005;
50(2):247–254.
69. Omuro AM, Raizer JJ, Demopoulos A, Malkin MG, Abrey LE.
Vinorelbine combined with a protracted course of temozolo-
mide for recurrent brain metastases: a phase I trial.
J Neurooncol. 2006;78(3):277–280.
70. Shimato S, Mitsudomi T, Kosaka T, et al. EGFR mutations
in patients with brain metastases from lung cancer: associa-
tion with the efficacy of gefitinib. Neuro Oncol. 2006;8(2):
137–144.
71. Amer MH, Al-Sarraf M, Baker LH, Vaitkevicius VK.
Malignant melanoma and central nervous system metasta-
ses: incidence, diagnosis, treatment and survival. Cancer.
1978;42(2):660–668.

Brain Metastases 65
72. McLoughlin JM, Zager JS, Sondak VK, Berk LB. Treatment
options for limited or symptomatic metastatic melanoma.
Cancer Control. 2008;15(3):239–247.
73. Muacevic A, Siebels M, Tonn JC, Wowra B. Treatment of
brain metastases in renal cell carcinoma: radiotherapy, radio-
surgery, or surgery? World J Urol. 2005;23(3):180–184.
74. Klatte T, Lam JS, Shuch B, Belldegrun AS, Pantuck AJ.
Surveillance for renal cell carcinoma: why and how? When
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75. Harada Y, Nonomura N, Kondo M, et al. Clinical study of
brain metastasis of renal cell carcinoma. Eur Urol. 1999;
36(3):230–235.
76. Samlowski WE, Majer M, Boucher KM, et al. Multi-
disciplinary treatment of brain metastases derived from clear
cell renal cancer incorporating stereotactic radiosurgery.
Cancer. 2008;113(9):2539–2548.

C H A P T E R 3
Spinal Tumors
Introduction
■ Spinal tumors are uncommon but can cause significant
neurologic morbidity.
■ Early diagnosis and adequate treatment are critical for
functional outcomes and long-term prognosis.
Spinal Cord Anatomy (Figure 3-1)

■ Bone: the spinal cord is housed within a canal formed by
vertebral bodies and neural arches.

• The vertebral body lies on the ventral (anterior) side of the
spinal cord.
• The neural arch lies on the dorsal (posterior) side of the
spinal cord.
• The spinal ner ves pass through an opening between
the vertebrae called the inter vertebral foramen.
Figure 3-1: Spinal cord anatomy
67

68 Chapter 3
■ Meninges: the spinal cord is covered by three membranes

known together as the meninges.
• Dura mater
• Arachnoid mater
• Pia mater
■ Potential spaces between meningeal layers
• Epidural space: between the bone and the dura mater,
contains fat and vertebral veins
• Subdural space: between the dura mater and the
arachnoid mater
• Subarachnoid space: between the arachnoid mater
and the pia mater, contains cerebrospinal fluid
■ Spinal cord tumors are classified according to their ana-
tomical location.
• Extradural: between bone and the dura mater
• Intradural: inside the dura mater
■ Extramedullary: between the dura mater and the
pia mater
■ Intramedullary: within the spinal cord parenchyma
Extradural Tumors
■ The extradural space is the most common site for spinal
tumors, with 60% of all spinal cord neoplasms located in
the extradural space and another 10% spanning the extra-
dural and intradural spaces.1
• Most tumors in the extradural space are metastatic, such
as epidural metastases (discussed later in this chapter).
• Some extradural tumors may arise in the vertebra,
such as osteosarcomas, hemangiomas, lymphoma, and
plasmacytoma.
■ Some extradural tumors may undermine the structural
stability of the vertebrae, leading to painful vertebral
fractures.
Metastatic Epidural Spinal Cord Compression (MESCC)

Epidemiology
■ MESCC is second only to brain metastasis as the cause
of neurological dysfunction caused by metastasis.2

Spinal Tumors 69
■ In patients with cancer, approximately 2% to 5% will

develop MESCC.2
■ MESCC most frequently occurs in patients with known
cancer but can be the presenting manifestation in 20% of
patients.3
Pathophysiology
■ Compression of the dural sac and its contents (spinal
cord and/or cauda equina) is caused by an extradural

tumor mass.
■ Common causes of MESCC include prostate cancer,
breast cancer, lung cancer, non-Hodgkin lymphoma,

renal cell cancer, and multiple myeloma.2
■ The site(s) of compression in the spinal column is pro-
portional to the relative bone mass and blood flow for

each part of the spine.2
• 15% in the cervical spine
• 60% in the thoracic spine
• 25% in the lumbosacral spine
■ Methods of metastatic spread to the epidural space are as
follows:
• Hematogenous spread to the vertebral body followed
by extension into the epidural space
• Direct extension into the spinal canal through inter-
vertebral foramen, most commonly associated with
lymphoma and neuroblastomas4
■ Spinal cord damage is caused by direct spinal cord com-
pression and secondary vascular damage.

• Acute compression causes stenosis and occlusion of
the epidural venous plexus, resulting in breakdown of
the blood–spinal cord barrier and vasogenic edema.
• Prolonged compression causes arterial flow obstruc-
tion, resulting in spinal cord ischemia.
Clinical Features
■ Worsening back pain: often localized
■ Radicular pain: often worse at night, lying down, with
Valsalva
■ Weakness: may be upper motor neuron or lower motor
neuron, depending on location of compression

70 Chapter 3
■ Sensory deficits: usually follow pain and weakness

■ Bladder or bowel dysfunction
■ Inability to walk
Diagnosis
■ A whole-spine MRI with gadolinium is the imaging
modality of choice to evaluate for MESCC.

• The minimum radiologic evidence for cord compres-
sion is indentation of the thecal sac at the level of
clinical features.5
• If patient is not able to undergo an MRI, the CT or
conventional myelogram is an alternative but subopti-
mal choice.
■ Definitive diagnosis is based on pathology, but a pre-
sumptive diagnosis may be made on imaging in a patient

with cancer.
Treatment
■ MESCC is a medical emergency causing paraplegia if
left untreated.
■ Early diagnosis and appropriate treatment can prevent or
reverse paraplegia in most patients.6

■ Corticosteroids
• Corticosteroids are first-line treatment to reduce

edema for all tumor types and to induce tumor lysis
for leukemias and lymphomas.
• The addition of steroids to radiation may improve
ambulatory outcomes.7
■ In patients with MESCC from solid tumors, treat-
ment with dexamethasone followed by radiation

improved ambulatory rates at 3 and 6 months com-
pared with radiation alone.
■ Dexamethasone was given as 96 mg IV followed by
96 mg/day PO 3 3 days followed by a 10-day taper.

• The optimal dosing regimen of corticosteroids is
unknown.
■ Randomized studies of high boluses of dexame-
thasone 96–100 mg versus moderate doses

10–16 mg show no differences in pain or ambula-
tion outcomes.8,9

Spinal Tumors 71
■ Animal studies suggest that steroids have a

dose–response effect on spinal cord compres-
sion, and thus, some advocate the use of high-
dose dexamethasone for patients who cannot
walk at diagnosis or have rapidly progressive motor
symptoms.2
■ Based on a small phase II study of 20 patients with
MESCC but no neurologic deficits or massive inva-

sion of the spine, radiation therapy without steroids
is a feasible regimen.10
■ Radiation therapy
• There are no randomized studies comparing external
beam radiation to supportive care, but multiple retro-
spective studies demonstrate improvement or stabili-
zation in function with radiation.2
• This is most effective for radiosensitive tumors and for
patients who are ambulatory prior to treatment.
• Nonambulant patients have only an 18% to 29%
chance of regaining ambulation with radiotherapy.5
• In a randomized phase III study of MESCC patients
with short life expectancies, #6 months, or unfavorable
histologies (NSCLC, colorectal, kidney, gastric, head
and neck, liver, bladder, sarcoma, melanoma, uterine
carcinoma), there is no difference in ability to walk,
pain relief, survival, or toxicity between short-course
(16 Gy in two fractions) versus split-course (30 Gy in
eight fractions) radiotherapy.11
• The optimal dose, schedule, or technique for patients
with good prognosis are unknown.5
• Data on newer radiation techniques such as stereotac-
tic radiosurgery in MESCC are sparse.
■ Surgery2
• This may be beneficial in selected groups of patients.
■ Unknown primary tumor
■ Relapse after radiation therapy
■ Progression while on radiation therapy
■ Unstable spine or pathological features
■ Less radiosensitive primary tumors with single area
of cord compression, paraplegia ,48 hours, and a

predicted survival .3 months

72 Chapter 3
• An anterior surgical approach is often preferred over

laminectomy because most epidural metastases extend
from the vertebral body.
■ An anterior approach allows direct decompression
and spine reconstruction.

■ Laminectomy does not remove the tumor and may
result in spine destabilization.

• The benefit from surgery was demonstrated in a ran-
domized study of patients with less radiosensitive
tumors, a single area of MESCC, paraplegia ,48 hours,
and a predicted survival .3 months comparing direct
decompressive surgery plus radiation therapy versus
radiation therapy alone.12
■ The study was terminated after interim analysis
because of positive results.

■ The surgical arm had higher ambulatory rates (84%
versus 57%) and retained ability to ambulate longer

(median 122 days vs. 13 days).
■ For those unable to walk prior to treatment, more
patients regained the ability to ambulate (10 versus

3 patients).
■ The median overall survival was longer in the surgi-
cal arm (126 days vs. 100 days).

• The benefit of direct decompressive surgery in patients
with good neurological function and stable spines is
unclear.5
■ Chemotherapy
• Chemotherapy is rarely used to treat MESCC even in
chemosensitive tumors because the response is too
slow and unpredictable.
• Chemotherapy may be used as salvage therapy for
patients who are no longer candidates for radiation
therapy or surgery.
■ Recurrent MESCC
• The recurrence rate after successful initial treatment
is 7% to 14%.2
• If the recurrence is within the original radiation field,
then reirradiation is not recommended because of
possible adverse events such as radiation-induced
myelopathy.

Spinal Tumors 73
Prognosis
■ The median survival for patients with MESCC (based on
retrospective studies) is 3 to 6 months.2
■ Good prognostic factors associated with prolonged sur-
vival include the ability to ambulate before and after

treatment, radiosensitive tumors (multiple myeloma,
germ cell tumors, lymphomas, small cell carcinomas),
no visceral or brain metastases, and a single site of epi-
dural cord compression (as opposed to multiple
sites).2
■ Poor prognostic factors for treatment with radiation
include bony compression and spinal instability.5
Intradural Tumors
■ Thirty percent of all spinal cord tumors are contained
within the intradural space, with an additional 10% span-
ning the extradural and intradural spaces.1
■ Intradural tumors can be further subdivided into
extramedullary (outside the spinal cord parenchyma) and
intramedullary (within the spinal cord parenchyma).
Extramedullary Tumors
■ These account for more than 70% of intradural tumors in
adults.1
Nerve Sheath Tumors

■ Arise from nerve sheath cells covering the spinal nerve
roots
■ Most commonly arise in the lumbosacral region13
■ Histology
• Schwannomas
■ Typically round or oval, lobulated, encapsulated
tumors that contain Schwann cells without inva-

sion of nerve fibers
■ Generally considered benign
■ Most commonly seen in patients with neurofibro-
matosis type 2
■ Represent 25% to 30% of all intraspinal masses14

74 Chapter 3
■ Intradural in 70% to 75%, extradural in 15%, com-

bined intradural–extradural (dumbbell) in 15%14
■ Commonly arises from the dorsal sensory roots of
the cervical and lumbar spine

• Neurofibromas
■ Contain Schwann cells, fibroblasts, and nerve
fibers
■ Generally considered benign
■ Rare intraspinal tumors except in patients with
neurofibromatosis type 2
• Malignant peripheral nerve-sheath tumors (MPNSTs)
■ Uncommon primary tumor of nerve sheath origin
■ More than 50% of MPNSTs associated with neuro-
fibromatosis type 115

■ Prognosis generally poor despite treatment
■ Diagnosis
• MRI with contrast is the imaging modality of choice.
■ Nerve sheath tumors are isointense on T1-weighted
images and hyperintense on T2-weighted images.

■ Schwannomas and neurofibromas are indistinguish-
able on MRIs.
■ Enhancement may be seen with benign or malig-
nant tumors.
■ They may contain both intradural and extradural com-
ponents, creating a dumbbell-shaped appearance.

■ Imaging features suggestive of MPNST include
larger size (.5 cm), heterogeneity, indistinct mar-

gins, and a lack of a pseudocapsule.14
• Definitive diagnosis is made on the basis of histology.
■ Treatment
• Observation
■ Benign, asymptomatic schwannomas, or neurofibro-
mas could be followed with serial imaging.

■ Definitive diagnosis requires pathology, however.
• Surgery
■ Total resection is the primary treatment for nerve
sheath tumors.
■ Total resection often requires removal of the
involved ventral or dorsal nerve root and is usually

Spinal Tumors 75
not associated with pronounced postoperative

motor or sensory deficit.16
• Radiation and/or chemotherapy
■ These treatment modalities are used primarily for
MPNSTs.
• Radiation therapy may provide local control and
delay recurrence in MPNSTs but has little effect
on long-term survival.17
• The role of chemotherapy is controversial in
MPNSTs because they are traditionally consid-
ered chemotherapy insensitive.17
■ These treatment modalities are not indicated for
completely resected schwannomas or neurofibromas.

■ Partially resected or unresectable schwannomas or
neurofibromas
• The role of radiation is controversial.
• Because tumors are benign and slow growing,
tumors could be monitored with serial imaging
and undergo further resection if necessary.
• Patients with neurofibromatosis may be at
higher risk for secondary malignancies from
radiation.
Spinal Meningioma
■ These arise from meningeal cells along the spinal cord
surface.
■ Ninety percent of spinal meningiomas are intradural,
whereas the remaining 10% are extradural or dumbbell

tumors.18
■ Epidemiology is as follows:
• Most occur between the fifth and seventh decades of

life and are more common in women than men.18
• They account for 25% to 46% of all primary intraspinal
neoplasms.19
• They are most commonly located in the thoracic region,
lateral or posterior to the spinal cord.
• They are usually solitary lesions, although patients
with neurofibromatosis type 2 may have multiple
spinal meningiomas.

76 Chapter 3
• The most common presenting symptom is focal pain.
• Myelopathy may be present.
• Neurologic deficits depend on tumor location.
■ Pathology
• Psammomatous meningiomas is the most common
histology, followed by meningothelial and transitional.18
• Atypical or anaplastic meningiomas are rare.
■ Diagnosis
• Spine MRI with contrast is the imaging modality of
choice.
■ Meningiomas are well-circumscribed lesions, are
hypointense to isointense on T1-weighted images,

are hyperintense on T2-weighted images, and dis-
play homogeneous enhancement.
■ Dural tail and calcification may be seen but less
commonly than with intracranial meningiomas.

• Presumptive diagnosis can often be made with imaging,
although definitive diagnosis is based on pathology.
■ Treatment
• Surgery
■ Gross total resection is the primary treatment and
is feasible as meningiomas are usually well circum-

scribed.
■ Recurrence rates with total or subtotal resection is
3% to 7% in WHO grade I meningomas.1

■ Not indicated for completely resected low-grade
meningiomas
■ Indications
• Adjuvant therapy after subtotal resection

• Treatment after recurrence
My xopapillary Ependymoma
■ Typically benign
■ Account for 40% to 50% of spinal ependymomas1
■ Arise from the conus medullaris and filum terminalis
■ Clinical features: may present with features suggestive of
conus medullaris or cauda equina syndrome, including

radicular pain, lower extremity numbness or weakness,
bowel or bladder dysfunction

Spinal Tumors 77
■ Imaging: circumscribed mass with homogeneous

enhancement, hypointense on T1-weighted images and
hyperintense on T2-weighted images
■ Treatment
• Gross total resection is the primary treatment, but
entrapment of nerve roots may limit resectability.
• Adjuvant radiation may be considered after subtotal
resection or for disseminated tumors.
Extramedullary Leptomeningeal Metastasis (see Chapter 4)
Intramedullary Tumors
■ Account for 20% to 30% of intradural tumors in adults1
• May present with slowly progressive myelopathy

• Midline back pain with or without radicular pain at
the level of the tumor
• Leg weakness and sensory changes
• Bowel/ bladder dysfunction are late symptoms
Ependymoma
■ They account for 40% to 60% of intramedullary spinal
cord tumors in adults.1

■ They can occur anywhere in the central nervous system,
but nearly 50% of all ependymomas arise within the spi-

nal canal.20
■ Most arise in the cervical or cervicothoracic regions.
■ Most are benign, slow growing, and tend to compress
rather than infiltrate normal adjacent tissue.21

■ The diagnosis is as follows:

choice.
■ Homogeneously enhancing mass
■ Hypointense on T1-weighted images and hyperin-
tense on T2-weighted images

• Definitive diagnosis requires pathology.
• All patients with spinal ependymomas should undergo
screening of the entire neuroaxis with brain MRI with
contrast, whole-spine MRI with contrast, and CSF
cytology.

78 Chapter 3
■ Treatment
• Surgery
■ Gross total resection is the primary treatment and
is achieved in 50% to 65% of patients.21

■ The extent of resection is the strongest predictor of
survival.21
■ Not indicated after gross total resection in low-
grade tumors
■ May increase tumor-free survival rates in patients
with high-grade ependymomas or after subtotal

resection1
• The role of chemotherapy is controversial.
• Five-year survival rates for low-grade intramedullary
ependymomas are 83% to 100%.1
Astrocytoma
■ These can occur anywhere in the CNS, with approxi-
mately 3% originating in the spinal cord.20

■ The most common locations are the cervical and cervico-
thoracic regions.
■ Astrocytomas usually extend multiple levels at the time
of diagnosis.
■ The pathology is as follows:
• They are graded according to the same WHO criteria

as intracranial astrocytomas.
• Almost two-thirds of intramedullary astrocytomas are
pilocytic astrocytoma or fibrillary astrocytoma.1
• Approximately 10% of intramedullary astrocytomas
are anaplastic astrocytoma and glioblastoma.1
• Except for pilocytic astrocytomas, most spinal cord
astrocytomas typically grow in a diffuse manner, infil-
trating surrounding normal neural tissue.
• Thirty percent to 60% of the tumors are associated with
rostral, caudal, or intratumoral cysts or syringomelias.1
■ Diagnosis

choice.

Spinal Tumors 79
■ Low-grade tumors
• Focal fusiform expansions of the spinal cord,
hypointense to isointense on T1-weighted
images, hyperintense on T2-weighted images
• Little or no cord edema
• May enhance with contrast
• Calcifications are rare
■ High-grade tumors
• Appear heterogeneous because of intratumor

cysts, necrosis, and surrounding edema22
• Heterogeneous enhancement with contrast
• A definitive diagnosis requires pathology.
■ Treatment
• Treatment depends on tumor histology.
• Surgery
■ Gross total resection is feasible in pilocytic
astrocytomas, but may not be feasible in higher

grade tumors because of their infiltrative nature.
■ Electrophysiological monitoring of the spinal cord
during surgery may help with resection.

• Radiation
■ Recommended as adjuvant therapy for high-grade
astrocytomas
■ Could be considered for progressive disease or for
unresectable tumors
• Chemotherapy
■ The role in spinal cord astrocytomas is unknown.
■ Based on its role in intracranial glioblastomas,
temozolomide and other chemotherapies could

be considered in patients with intramedullary
glioblastomas.
Intramedullary Metastasis
■ These are extremely rare and suggest advanced meta-
static disease.
■ The most common tumors causing intramedullary metas-
tases are lung and breast cancer.20

80 Chapter 3
References
1. Traul DE, Shaffrey ME, Schiff D. Part I: spinal-cord
neoplasms-intradural neoplasms. Lancet Oncol. 2007;8(1):
35–45.
2. Cole JS, Patchell RA. Metastatic epidural spinal cord com-
pression. Lancet Neurol. 2008;7(5):459–466.
3. Schiff D, O’Neill BP, Suman VJ. Spinal epidural metastasis
as the initial manifestation of malignancy: clinical features
and diagnostic approach. Neurology. 1997;49(2):452–456.
4. Sioutos PJ, Arbit E, Meshulam CF, Galicich JH. Spinal
metastases from solid tumors. Analysis of factors affecting
survival. Cancer. 1995;76(8):1453–1459.
5. George R, Jeba J, Ramkumar G, Chacko AG, Leng M,
Tharyan P. Interventions for the treatment of metastatic
extradural spinal cord compression in adults. Cochrane
Database Syst Rev. 2008(4):CD006716.
6. Abrahm JL, Banffy MB, Harris MB. Spinal cord compres-
sion in patients with advanced metastatic cancer: “all I care
about is walking and living my life.” JAMA. 2008;299(8):
937–946.
7. Sorensen S, Helweg-Larsen S, Mouridsen H, Hansen HH.
Effect of high-dose dexamethasone in carcinomatous meta-
static spinal cord compression treated with radiotherapy:
a randomised trial. Eur J Cancer. 1994;30A(1):22–27.
8. Graham PH, Capp A, Delaney G, et al. A pilot randomised
comparison of dexamethasone 96 mg vs 16 mg per day for
malignant spinal-cord compression treated by radiotherapy:
TROG 01.05 Superdex study. Clin Oncol (R Coll Radiol).
2006;18(1):70–76.
9. Vecht CJ, Haaxma-Reiche H, van Putten WL, de Visser M,
Vries EP, Twijnstra A. Initial bolus of conventional versus
high-dose dexamethasone in metastatic spinal cord com-
pression. Neurology. 1989;39(9):1255–1257.
10. Maranzano E, Latini P, Beneventi S, et al. Radiotherapy
without steroids in selected metastatic spinal cord compres-
sion patients. A phase II trial. Am J Clin Oncol. 1996;19(2):
179–183.
11. Maranzano E, Bellavita R, Rossi R, et al. Short-course ver-
sus split-course radiotherapy in metastatic spinal cord
compression: results of a phase III, randomized, multicenter
trial. J Clin Oncol. 2005;23(15):3358–3365.

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12. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive
surgical resection in the treatment of spinal cord compression
caused by metastatic cancer: a randomised trial. Lancet.
2005;366(9486):643–648.
13. Conti P, Pansini G, Mouchaty H, Capuano C, Conti R.
Spinal neurinomas: retrospective analysis and long-term out-
come of 179 consecutively operated cases and review of the
literature. Surg Neurol. 2004;61(1):34–43; discussion 44.
14. Parmar HA, Ibrahim M, Castillo M, Mukherji SK. Pictorial
essay: diverse imaging features of spinal schwannomas.
J Comput Assist Tomogr. 2007;31(3):329–334.
15. Acharya R, Bhalla S, Sehgal AD. Malignant peripheral nerve
sheath tumor of the cauda equina. Neurol Sci. 2001;22(3):
267–270.
16. Jinnai T, Koyama T. Clinical characteristics of spinal nerve
sheath tumors: analysis of 149 cases. Neurosurgery. 2005;
56(3):510–515.
17. Gupta G, Maniker A. Malignant peripheral nerve sheath
tumors. Neurosurg Focus. 2007;22(6):E12.
18. Saraceni C, Harrop JS. Spinal meningioma: chronicles of
contemporary neurosurgical diagnosis and management.
Clin Neurol Neurosurg. 2009;111(3):221–226.
19. Albanese V, Platania N. Spinal intradural extramedullary
tumors. Personal experience. J Neurosurg Sci. 2002;46(1):
18–24.
20. Parsa AT, Lee J, Parney IF, Weinstein P, McCormick PC,
Ames C. Spinal cord and intradural-extraparenchymal spi-
nal tumors: current best care practices and strategies.
J Neurooncol. 2004;69(1–3):291–318.
21. Ruda R, Gilbert M, Soffietti R. Ependymomas of the adult:
molecular biology and treatment. Curr Opin Neurol. 2008;
21(6):754–761.
22. Runge VM, Muroff LR, Jinkins JR. Central nervous system:
review of clinical use of contrast media. Top Magn Reson
Imaging. 2001;12(4):231–263.

C H A P T E R 4
Leptomeningeal
Metastases
Introduction
■ Neoplastic meningitis: spread of malignant cells to the
leptomeninges and subarachnoid space
■ Carcinomatous meningitis or leptomeningeal carcinoma-
tosis: neoplastic meningitis in patients with solid tumors
■ Leukemic meningitis: neoplastic meningitis in patients
with leukemia
■ Lymphomatous meningitis: neoplastic meningitis in
patients with lymphoma
Epidemiology
■ The number of patients diagnosed with neoplastic men-
ingitis varies according to the type of tumor.1,2
• Solid tumors: breast cancer 3%, small cell lung cancer
6%, non-small cell lung cancer 1%, and melanoma 1%
to 5%
• Leukemia 5% to 15%
• Diffuse high-grade non-Hodgkin lymphoma 5% to 15%
■ Risk factors include high serum LDH, low serum
albumin, age ,60, involvement of testis, breast,

bone marrow or more than two extranodal sites
• Non-Hodgkin lymphomas with aggressive clinical
course (e.g., Burkitt lymphoma, lymphoblastic lym-
phoma) have a .25% risk of meningeal relapse without
CNS-directed therapy.3
• Primary brain tumors 1% to 2%
■ Based on autopsy studies, 19% of cancer patients with
neurologic signs/symptoms have evidence of neoplastic
meningitis.4
83

84 Chapter 4
■ Carcinomas of unknown primary account for 1% to 7% of

patients with neoplastic meningitis.5
■ Presentation may occur in the following circumstances6:
• Widely disseminated and progressive systemic cancer
(60% to 70%)5,7
• Following a disease-free interval (20%)
• First manifestation of cancer (5% to 10%)8
• Synchronous with intraparenchymal brain metastases
(11% to 31%)5,9
Pathogenesis
■ Routes of metastasis are as follows6:
• Hematogenous (arterial or venous plexus of Batson)
• Direct extension from a tumor adjacent to the CSF
space
• Migration along perineural or perivascular spaces
■ Dissemination occurs throughout the CSF to the entire
neuroaxis.
■ Tumor infiltration is most prominent at the skull base,
dorsal surface of spinal cord, and cauda equina.1,10
Clinical Features
■ Clinical features depend on the location of tumor depos-
its and may be multifocal.
• Cerebral hemispheres: headache, mental status changes,
seizures
• Skull base: cranial nerve deficits with diplopia (CN IV
more commonly affected than III, VI), sensory loss
(CN V), facial weakness (CN VII), cochlear dysfunc-
tion (CN VIII), and optic neuropathy (CN II)
• Spine: weakness (lower extremities more than upper
extremities), sensory loss in a dermatomal pattern, pain
in neck or back, radiculopathy, cauda equina syndrome
■ Nuchal rigidity is present in only 15% of cases.6
■ Raised intracranial pressure or hydrocephalus may occur
from obstruction of CSF outflow by tumor deposits.
■ Thirty percent to 40% of patients with leptomeningeal
disease may also have parenchymal brain metastases.6

Leptomeningeal Metastases 85
Diagnosis
■ Diagnosis in early stages is important to prevent progressive
neurologic dysfunction, as fixed neurologic deficits rarely
respond to treatment.
■ Three methods are used to diagnose leptomeningeal
metastases and should be used in combination: clinical
presentation, cerebrospinal fluid (CSF) cytology, and
neuroimaging.
■ CSF studies
• Increased opening pressure (.200 mm H2O)
• Elevated WBC (.4 per mm3)
• Elevated protein (.50 mg/dL)
• Decreased glucose (,60 mg/dL)
• Positive cytology is diagnostic
■ A volume .10.5 mL is recommended.11
■ A normal CSF cytology does not exclude the diag-
nosis of leptomeningeal metastases.

■ If the first cytology is negative but suspicion for
neoplastic meningitis remains high, CSF studies

should be repeated.
• Up to 45% of patients eventually found to have
positive cytology had a negative cytology on first
examination.4
• Diagnostic yield increases to 80% with second
CSF cytology.5
• Up to 40% of patients with clinically suspected
leptomeningeal disease and negative CSF
cytology had pathologically proven disease at
autopsy.4
■ Factors associated with false negative cytology
include the following11:

• Not collecting CSF from a site of symptomatic
or radiographic involvement
• Small CSF volumes (,10.5 mL)
• Delayed processing of samples
• Obtaining fewer than two samples
• In leukemia and lymphoma, positive flow cytometry or
cytogenetic studies may be more sensitive than CSF
cytology.6

86 Chapter 4
■ Meningeal biopsy may be considered if no primary cancer

is found and CSF studies are not diagnostic.
■ Radiographic imaging
• A brain and spine MRI with gadolinium is the radio-
graphic test of choice, but findings are nonspecific.
■ Enhancement of leptomeninges (occurring in the
gyri and superficial sulci), ventricles, cranial nerves,

or intradural extramedullary nodules may be seen.
■ Imaging should be performed prior to lumbar
puncture because the procedure can cause a men-

ingeal reaction resulting in dural-arachnoidal
enhancement.12
■ A normal MRI does not exclude diagnosis, as the
false-negative rate is $30%.6

• Radionuclide studies (111indium-diethylenetriamine
pentaacetic acid or 99tecnetium macroaggregated
albumin)
■ These may be used to evaluate CSF flow dynamics
but are not routinely done in many centers.

■ Patients with CSF flow obstruction (as demonstrated
on radionuclide studies) have decreased survival

times compared with patients with normal CSF
flow.13–15
■ Involved field radiation to sites of CSF flow obstruc-
tion restores flow in 30% of patients with spinal

disease and 50% of patients with intracranial
disease.16,17
■ Reestablishment of CSF flow with radiation 1
intrathecal chemotherapy is associated with longer

survival and lower rates of treatment-related mor-
bidity compared with patients with persistent CSF
flow obstruction.13,14
Prognosis
■ The median survival without treatment is 4 to 6 weeks;
death is usually related to neurologic dysfunction.5
■ Treatment may prolong survival to 4 to 6 months,18 but
responses depend on the primary tumor type.

• Breast cancer is the best responder among solid

tumors, with a median survival of 6 months and 1-year
survival rates of 11% to 25%.11,19
• Favorable responses are also seen in patients with
lymphoma.
• Less than 15% survive longer than 12 months and have
a complete treatment response.2
■ Treatment may improve or stabilize neurologic symp-
toms but generally does not improve fixed neurologic
deficits.
■ The following are poor prognostic factors for survival and
response to treatment6:
• Poor performance status
• Multiple fixed neurologic deficits
• Bulky CNS disease
• Coexistent carcinomatous encephalopathy
• CSF flow abnormalities on radionuclide ventricu-
lography
• Widely metastatic and aggressive cancers that do not
respond well to systemic therapies
Treatment
■ Important for palliation and may prolong survival
• There is no standard treatment.
• Most treatment studies are small, nonrandomized,
and retrospective.
• Conversion of a positive CSF cytology/flow into a
negative result suggests response and continuation of
therapy.
• More aggressive treatments are generally reserved for
patients with a life expectancy of more than 3 months
and a Karnofsky performance status score of more
than 60%.
Surgery
■ Placement of an intraventricular catheter with a subgaleal
reservoir (e.g., Ommaya reservoir) for intrathecal chemo-
therapy and CSF sampling

88 Chapter 4
• Often preferred to repeated lumbar punctures, as

drug distribution in CSF is more uniform through a
reservoir20–22
• Complications include malposition, obstruction, and
infection
■ Ventriculoperitoneal (VP) shunt for symptomatic hydro-
cephalus
• Does not appear to result in peritoneal dissemination
of cancer23
• May include an in-line on/off valve to allow chemo-
therapy administration in the off position, although it
is unclear whether this improves outcomes
Radiation Therapy
■ Decreasing bulky disease because intrathecal chemo-
therapy is unable to penetrate further than 2 to 3 mm

into a tumor nodule6
■ Palliation of symptoms regardless of presence of bulky
disease or not, including symptoms related to cauda

equina or cranial nerve involvement
■ Restore CSF flow due to obstruction (see the previous
section on radionuclide imaging)

■ Radiation to the entire CNS axis not feasible because of
systemic toxicity
Chemotherapy
Intrathecal (IT) Chemotherapy
■ Agents include methotrexate, liposomal cytarabine, and
thiotepa.
■ This may be administered via lumbar puncture or ven-
tricular reservoir (Ommaya).

■ Complications include the following:
• CSF infection with Ommaya reservoir

■ This occurs in 2% to 13% of patients on IT chemo-
therapy.6
■ Signs/symptoms include headache, mental status
change, fever, and reservoir malfunction.

■ These are most frequently caused by Staphylococcus
epidermidis.

■ Treatment includes intravenous antibiotics 6 oral/

intraventricular antibiotics and possibly removal of
the ventricular reservoir.
• Myelosuppression
• Chemical aseptic meningitis
■ Occurs in almost 50% of patients on IT chemo-
therapy6
■ Usually caused by an inflammatory reaction
■ Signs/symptoms: fever, headache, nausea, vomiting,
meningismus, and photophobia

■ May be managed as an outpatient with antipyretics,
antiemetics, and corticosteroids

• Chemotherapy-related neurotoxicity, including sub-
acute leukoencephalopathy or myelopathy, is rare.
• The combination of radiation and chemotherapy
(especially methotrexate) may result in late leukoen-
cephalopathy.6
Systemic Chemotherapy
■ Some agents are able to penetrate the blood–brain bar-
rier, resulting in cytotoxic CSF levels, including high-dose

methotrexate, cytarabine, and thiotepa.
■ Some studies suggest that certain systemic chemothera-
pies are associated with better outcomes than IT

chemotherapies while sparing the complications of IT
treatments.24–26
■ In patients with methotrexate sensitive cancers (i.e.,
lymphoma and breast cancer), high-dose methotrexate

may be used to treat parenchymal and leptomeningeal
metastases.26
■ Hormone therapy is occasionally useful in breast
cancer.27,28
Supportive Care
■ Should be offered to all patients with neoplastic meningitis
regardless of treatment plan

■ Anticonvulsants for seizures
■ Analgesia and pain control
■ Corticosteroids for vasogenic edema from intraparen-
chymal or epidural metastases

90 Chapter 4
■ Antiemetics for nausea and vomiting

■ Psychostimulants for decreased attention and somno-
lence
References
1. Chamberlain MC. Carcinomatous meningitis. Arch Neurol.
1997;54(1):16–17.
2. Gleissner B, Chamberlain MC. Neoplastic meningitis.
Lancet Neurol. 2006;5(5):443–452.
3. Gokbuget N, Hoelzer D. Meningeosis leukaemica in adult
acute lymphoblastic leukaemia. J Neurooncol. 1998;38
(2–3):167–180.
4. Glass JP, Melamed M, Chernik NL, Posner JB. Malignant
cells in cerebrospinal fluid (CSF): the meaning of a positive
CSF cytology. Neurology. 1979;29(10):1369–1375.
5. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and
treatment of leptomeningeal metastases from solid tumors:
experience with 90 patients. Cancer. 1982;49(4):759–772.
6. Chamberlain MC. Neoplastic meningitis. Oncologist.
2008;13(9):967–977.
7. Balm M, Hammack J. Leptomeningeal carcinomatosis.
Presenting features and prognostic factors. Arch Neurol.
1996;53(7):626–632.
8. Yap HY, Yap BS, Tashima CK, DiStefano A, Blumenschein GR.
Meningeal carcinomatosis in breast cancer. Cancer.
1978;42(1):283–286.
9. Freilich RJ, Krol G, DeAngelis LM. Neuroimaging and cere-
brospinal fluid cytology in the diagnosis of leptomeningeal
metastasis. Ann Neurol. 1995;38(1):51–57.
10. Little JR, Dale AJ, Okazaki H. Meningeal carcinomatosis.
Clinical manifestations. Arch Neurol. 1974;30(2):138–143.
11. Glantz MJ, Cole BF, Glantz LK, et al. Cerebrospinal fluid
cytology in patients with cancer: minimizing false-negative
results. Cancer. 1998;82(4):733–739.
12. Mittl RL, Jr., Yousem DM. Frequency of unexplained men-
ingeal enhancement in the brain after lumbar puncture.
AJNR Am J Neuroradiol. 1994;15(4):633–638.
13. Chamberlain MC, Kormanik PA. Prognostic significance of
111
indium-DTPA CSF flow studies in leptomeningeal metas-
tases. Neurology. 1996;46(6):1674–1677.
14. Glantz MJ, Hall WA, Cole BF, et al. Diagnosis, management,
and survival of patients with leptomeningeal cancer based

on cerebrospinal fluid-flow status. Cancer. 1995;75(12):

2919–2931.
15. Mason WP, Yeh SD, DeAngelis LM. 111Indium-diethylene-
triamine pentaacetic acid cerebrospinal fluid flow studies
predict distribution of intrathecally administered chemo-
therapy and outcome in patients with leptomeningeal metas-
tases. Neurology. 1998;50(2):438–444.
16. Chamberlain MC, Corey-Bloom J. Leptomeningeal metas-
tases: 111indium-DTPA CSF flow studies. Neurology. 1991;
41(11):1765–1769.
17. Chamberlain MC, Kormanik P, Jaeckle KA, Glantz M.
111
Indium-diethylenetriamine pentaacetic acid CSF flow
studies predict distribution of intrathecally administered
chemotherapy and outcome in patients with leptomeningeal
metastases. Neurology. 1999;52(1):216–217.
18. Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis.
Cancer Treat Rev. 1999;25(2):103–119.
19. Hildebrand J. Prophylaxis and treatment of leptomeningeal
carcinomatosis in solid tumors of adulthood. J Neurooncol.
1998;38(2–3):193–198.
20. Berweiler U, Krone A, Tonn JC. Reservoir systems for intra-
ventricular chemotherapy. J Neurooncol. 1998;38(2–3):
141–143.
21. Sandberg DI, Bilsky MH, Souweidane MM, Bzdil J, Gutin PH.
Ommaya reservoirs for the treatment of leptomeningeal
metastases. Neurosurgery. 2000;47(1):49–54; discussion
54–55.
22. Shapiro WR, Young DF, Mehta BM. Methotrexate: distribu-
tion in cerebrospinal fluid after intravenous, ventricular and
lumbar injections. N Engl J Med. 1975;293(4):161–166.
23. Omuro AM, Lallana EC, Bilsky MH, DeAngelis LM.
Ventriculoperitoneal shunt in patients with leptomeningeal
metastasis. Neurology. 2005;64(9):1625–1627.
24. Bokstein F, Lossos A, Siegal T. Leptomeningeal metastases
from solid tumors: a comparison of two prospective series
treated with and without intra-cerebrospinal fluid chemo-
therapy. Cancer. 1998;82(9):1756–1763.
25. Boogerd W, van den Bent MJ, Koehler PJ, et al. The rele-
vance of intraventricular chemotherapy for leptomeningeal
metastasis in breast cancer: a randomised study. Eur J
Cancer. 2004;40(18):2726–2733.
26. Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous
methotrexate for patients with nonleukemic leptomeningeal

92 Chapter 4
cancer: is intrathecal chemotherapy necessary? J Clin Oncol.

1998;16(4):1561–1567.
27. Boogerd W, Dorresteijn LD, van Der Sande JJ, de Gast GC,
Bruning PF. Response of leptomeningeal metastases from
breast cancer to hormonal therapy. Neurology. 2000;
55(1):117–119.
28. Ozdogan M, Samur M, Bozcuk HS, et al. Durable remission
of leptomeningeal metastasis of breast cancer with letrozole:
a case report and implications of biomarkers on treatment
selection. Jpn J Clin Oncol. 2003;33(5):229–231.

C H A P T E R 5
Neurologic
Complications of
Radiation Therapy
Introduction
■ Ionizing radiation damages DNA to create permanent
cell injury or death but can also damage other intracellu-
lar molecules such as lipids or proteins.
■ Radiation is nonspecifically toxic and therefore can dam-
age surrounding normal neural tissue.
Description of Radiation Terms

■ Fractionation: administration of radiation therapy in
divided doses
• Equally efficacious and better tolerated than a single
dose
• Spares normal tissues by allowing time to repair and
repopulation of normal cells between fractions
■ Gray (Gy): absorption of 1 joule per kilogram
■ External beam therapy (EBRT): uses a focused beam of
high-energy rays generated outside the patient

■ Intensity-modulated radiation therapy (IMRT): assigns
nonuniform intensities to individual rays within each

beam to better control dose distributions
■ Stereotactic radiosurgery (SRS): technique used to pre-
cisely deliver a single, high-dose fraction of external beam

radiation to a small intracranial volume. Methods of
delivery include charged particle beams, modified linear
accelerators, and gamma knife units.
■ Stereotactic radiotherapy (SRT): delivery of multiple
fractions using the stereotactic process

■ Brachytherapy: a form of radiation therapy where a radio-
active source is placed inside or next to the tumor
93

94 Chapter 5
■ Whole-brain radiation therapy (WBRT): a form of

external radiation that treats the entire brain
■ Prophylactic cranial irradiation (PCI): radiation ther-
apy provided to the head to reduce the risk of brain
metastases
Radiation Effects on the Central Nervous

System
■ Cranial irradiation is used as a treatment modality in
many primary brain tumors, metastatic disease to the
brain, CNS involvement of leukemia/lymphomas, and
head/neck cancers.
■ The radiation field may include healthy brain tissue,
resulting in radiation toxicity.
Timing of Radiation Toxicity

Acute Effects
■ Acute radiation toxicity occurs during or shortly after
radiation.
■ Symptoms include the following:
• The most common symptom is progressive fatigue,

which may persist for several weeks after the comple-
tion of radiation, but is generally reversible.
• A less common, more severe acute radiation enceph-
alopathy (dizziness, signs of increased intracranial
pressure, or focal neurologic deficits) may occur.
■ Symptoms may be secondary to edema and disruption of
the blood–brain barrier.

■ Steroid treatment results in clinical improvement of
progressive fatigue and other mild symptoms, but

increased intracranial pressure requires more aggressive
intervention.
Early-Delayed Effects
■ Early-delayed radiation toxicity occurs 6 to 12 weeks after
radiation.
■ Symptoms after cranial radiation include general-
ized weakness, fatigue, somnolence, and cognitive

dysfunction.

Neurologic Complications of Radiation Therapy 95
■ Manifestations are mostly transient and reversible.

■ These are secondary to transient demyelination, edema,
and disruption of the blood–brain barrier.
Late-Delayed Effects
■ Late delayed radiation toxicity occurs months to years
after radiation.
■ Clinical manifestations may include
• Minor to severe neurocognitive dysfunction (discussed

further later in this chapter)
• Focal radiation necrosis of brain parenchyma (discussed
further later in this chapter)
• Diffuse radiation necrosis of brain parenchyma
• Chronic progressive myelopathy due to spinal cord
injury
• Endocrine dysfunction, usually due to hypothalamic
injury
• Radiation-induced brain tumors (discussed further
later in this chapter)
• Accelerated atherosclerosis affecting the carotid arter-
ies, after neck irradiation (see Chapter 8)
■ Manifestations are often irreversible.
■ Hippocampal dysfunction may account for some of the
neurocognitive changes.
■ The pathophysiology is not completely understood, but
the following have been implicated:

• Excessive generation of reactive oxygen species from
injured and/or proinflammatory cells
• Vascular endothelial damage
• Long-term damage to neural cell types
Risk Factors for Radiation Toxicity

■ Total radiation dose (.50 Gy)
■ Fraction size (.2 Gy)
■ Volume of tissue being irradiated
■ Administration of radiation with chemotherapy1
■ Novel radiation delivery technique (e.g., stereotactic
radiosurgery)
■ Young children, especially during developmental stages
of neural tissue

96 Chapter 5
■ Old age (.60 years)

■ Vascular risk factors
■ Genetic instability syndromes (e.g., neurofibromatosis)
■ Close proximity to nervous system structures
■ Tumors compatible with long survival
Pathology
■ Pathological changes are not specific to radiation and
include the following:
• Parenchymal cell loss, including white matter
demyelination, encephalomalacia, gliosis, and neural
cell loss
• Vascular changes, including endothelial damage and
fibrinoid necrosis in vessels, resulting in vascular
occlusion and tissue necrosis
■ Brain damage can be focal or diffuse.
Imaging Abnormalities Following Radiation Therapy

■ White matter changes
• White matter abnormalities may be present in some

patients as early as 2 to 6 months after completion of
radiation therapy, likely representing early-delayed
radiation-induced injury.2
• Periventricular white matter changes occur 12 to
18 months after radiation therapy.2,3
• White matter changes are more severe in older
patients.4,5
• The data are conflicting on whether white matter
changes correlate with neurologic dysfunction.
■ Lacunar lesions
■ Cerebral atrophy
Neurocognitive Dysfunction
■ Radiation may have long-term detrimental effects on
neurocognitive function.
■ Radiation may also have short-term beneficial effects
on neurocognitive function because of improved tumor

control.

■ It is often difficult to determine whether the decline in

cognitive function is attributable to therapy or another
etiology such as
• Disease progression
• Radiation
• Surgery
• Chemotherapy
• Medications (including corticosteroids)
• Paraneoplastic disorder
Clinical Features 6
■ Short-term memory deficits
■ Difficulty with spatial relations
■ Difficulty with visual motor processing
■ Difficulty with quantitative skills
■ Deficits in attention
■ Subcortical dementia with gait disturbance and inconti-
nence
Pathophysiology
■ Early memory impairment after WBRT may be related to
hippocampus damage.7–9
Clinical Studies
■ Radiation is an important cause of neurocognitive dys-
function based on data from retrospective studies10,11 and
nonrandomized prospective studies12 in brain metastases
and primary brain tumors.
■ Progression of cognitive deficits may only become appar-
ent after several years.

• In a longitudinal study of patients with low-grade
glioma at a mean 12 years after diagnosis, patients
who received radiation therapy had more deficits in
attentional functioning, executive functioning, and
information processing speed than patients who did
not have radiation therapy (no differences seen
between groups at a mean 6 years after diagnosis).13
• Data on late cognitive effects in patients with brain metas-
tases are sparse because of death in all studies.12

98 Chapter 5
■ Studies on neurocognitive function, however, may also be

confounded by other factors such as tumor progression
and baseline cognitive dysfunction.
• Several prospective studies report cognitive impairment
in cancer patients even before radiation therapy.14,15
• Results from other prospective studies suggest that
tumor control is strongly associated with neurocogni-
tive stability.15
■ Some data suggest that radiation does not significantly
affect cognition in patients with brain metastases based
on short-term (1–2 years) follow-up.
• A prospective study of 208 patients with brain metas-
tases treated with WBRT showed stable neurocogni-
tive function on formal testing in long-term survivors
at 15 months compared with baseline.16
• Randomized studies of prophylactic cranial irradiation
(PCI) in patients with small cell lung cancer suggest
that patients have substantial levels of impairments at
randomization (even before PCI)17 and show no differ-
ences in neuropsychological testing between the PCI
group and the no PCI group.17,18
■ One should consider the likelihood of radiation-induced
neurocognitive decline versus tumor progression when
considering whether to provide or delay brain radiation.
Treatment
• Donepezil may improve cognition and quality of life in
irradiated brain tumor patients.19
• VP shunting is an option for radiation-induced hydro-
cephalus.
• Other interventions used in the treatment of cognitive
impairment (such as cognitive rehabilitation) may also
be considered but have not been tested specifically in
the irradiated brain tumor population.
Focal Radiation Necrosis

■ This is a severe form of radiation-induced injury, mostly
affecting white matter, although lesions may extend into

cortex or deep gray matter.

Epidemiology
■ The incidence after conventional therapy is unknown
because most studies were performed prior to modern
imaging, but ranges from 3% to 24% have been reported.1
Clinical Features
■ Best characterized following conventional external beam
radiation, although may be relatively more common after
stereotactic radiosurgery or brachytherapy
■ Rarely occurs with cumulative doses of standard fraction-
ated radiation less than 50–60 Gy to the brain or 45 Gy

to the spinal cord20
■ Uncommon in patients who receive WBRT for brain
metastases, although radiation necrosis after WBRT has

been reported
■ Generally occurs as a late complication of radiation, as
early as 2 months and as late as 47 months after radiation

therapy1
• The mean interval from the end of radiation therapy is
approximately 12 months.
• The latency period is approximately five times shorter
in patients with glioma than other types of tumors.
■ Nonspecific presenting signs and symptoms such as focal
neurologic deficits, seizures, confusion, or headaches
Pathophysiology
■ Poorly understood
■ Pathologically characterized by necrosis with hypocellu-
lar edges and dystrophic calcifications, vasculopathy

(telangiectatic, hyalinized, angionecrotic blood vessels),
hemorrhage, edema, and gliosis
■ Potential causes21
• Vascular damage: radiation-induced endothelial dam-

age leading to microvasculopathy, vascular insuffi-
ciency, and infarction followed by gray and/or white
matter necrosis
• Glial damage: radiation-induced glial damage leading to
ablation of glial precursors and demyelinative necrosis

100 Chapter 5
Diagnosis
■ Radiation necrosis is difficult to distinguish from tumor
recurrence.
■ Specific patterns of enhancement on MRI (“soap bub-
bles” or “Swiss cheese”) have been associated with radia-

tion necrosis as opposed to tumor recurrence.22
■ Radiation necrosis is typically hypometabolic on PET,
whereas tumor recurrence may be hypermetabolic.

■ A definitive diagnosis requires pathology.
Treatment
■ Surgery is not always necessary but may be an option
for symptomatic control in the setting of raised intrac-

ranial pressure or progression despite conservative
management.
■ Resolution of radionecrosis is reported in cases or case
series with the following treatments, but efficacy has not

been established.
• Corticosteroids1
• Bevacizumab
■ A retrospective review of six glioma patients with
biopsy-confirmed radiation necrosis demonstrated

radiographic response in six of six patients and clin-
ical improvements in three of six patients.23
■ A retrospective review of eight glioma patients (two
with biopsy-confirmed radiation necrosis) demon-

strated radiographic improvements in postcontrast
and FLAIR images.24
• Anticoagulation
■ In a small study of eight patients with biopsy-
confirmed radiation necrosis treated with heparin

followed by warfarin for 3–6 months, clinical improve-
ment were noted in five of eight patients, but symp-
toms reemerged after stopping anticoagulation.25
• Hyperbaric oxygen therapy
■ Typical regimen: oxygen was delivered at 20–24
atmospheres for 20–30 sessions, with each session

lasting 90–120 minutes.
■ In a study of 10 patients (8 with biopsy-confirmed
radiation necrosis), clinical improvements were

noted in 6 of 10 patients, with three documented

radiographic responses, but many of these patients
also received high-dose steroids.26
Radiation-Induced Brain Tumors

■ The most common secondary tumors in the CNS are
meningiomas, nerve sheath tumors, pituitary adenomas,

gliomas, sarcomas, and embryonal neoplasms.
■ Radiation-induced brain tumors tend to be more aggres-
sive and higher grade.
Epidemiology
■ Based on a retrospective review of 10,080 children treated
with low-dose scalp irradiation (mean 1.4–1.8 Gy) for

tinea capitis, relative risks as compared with matched
nonirradiated controls for meningiomas were 9.5 and for
gliomas were 2.6.27
■ In a study of 9,720 children treated for prophylactic or
therapeutic CNS irradiation for ALL, these patients suf-

fered a 22-fold excess of neoplasms, mostly gliomas and
primitive neuroectodermal tumors (PNET).28
■ The latency period after radiation varies but typically
presents years to decades after therapy.29
Risk Factors
■ Radiation during childhood
■ Higher radiation doses
Treatment
■ Treatment options are similar to analogous non–
radiation-induced tumors but are rarely successful.30
Radiation Effects on the Peripheral Nervous

System
■ Most effects on the peripheral nervous system occur in a
late-delayed fashion.
Postradiation Optic Neuropathy

■ This is caused by injury to the optic nerve and apparatus.

102 Chapter 5
■ It is most often associated with radiation to the optic

pathways but can occur with radiation to tumors in close
proximity to the optic pathways.
■ It occurs 3 months to 8 years after radiation therapy.31
■ It presents with painless, progressive, monocular vision
loss and constriction of visual fields.30
■ It is usually irreversible.
■ Optimal management is unknown.31
Radiation Plexopathy
■ It may occur in the brachial plexus after radiation for lung
or breast cancer or the lumbosacral plexus following radi-

ation for pelvic or lower abdominal tumors.
Clinical Features
■ Most occur 5 to 30 months after radiation therapy.
■ Predominating symptoms are gradually progressive weak-
ness and paresthesias.

■ Ipsilateral lymphedema is common in radiation-induced
brachial plexopathy.
■ Bilateral plexus involvement (although asymmetric) is
common in radiation-induced lumbosacral plexopathy.

■ Pain is uncommon, which distinguishes radiation plex-
opathy from tumor infiltration or compression.

Diagnosis
■ It is based on clinical diagnosis.
■ Electromyography may demonstrate myokymias, which is
seen only in radiation plexopathy.22

■ MRI of the plexus may be used to exclude tumor infiltra-
tion or compression.
Treatment
■ Pain can be managed with NSAIDs or opioids.
■ For severe plexopathy, surgical exploration may be con-
sidered to release neural elements from fibrotic tissues.32
Radiation-Induced Peripheral Nerve Tumors

■ Includes schwannomas, neurofibromas, and malignant
peripheral nerve sheath tumors (MPNSTs)

Epidemiology
■ This is a rare complication from radiation, but the true
incidence is unknown.
■ The association between radiation and peripheral nerve
tumors has been demonstrated in several large retrospec-

tive studies.33
■ Based on a retrospective review of 10,080 children
treated with low-dose scalp irradiation for tinea capitis,

the relative risk of developing cranial nerve schwanno-
mas compared with matched nonirradiated controls
was 18.8.27
Risk Factors
■ Clinical risk factors for development of radiation-induced
neurofibromas include radiation at a young age, heavy
use of radiation, and long-term survival (owing to the long
latency between radiation and diagnosis of a peripheral
nerve sheath tumor).34
■ Patients with neurofibromatosis are at elevated risk
of developing peripheral nerve tumors after radiation

therapy.35
References
1. Ruben JD, Dally M, Bailey M, Smith R, McLean CA,
Fedele P. Cerebral radiation necrosis: incidence, outcomes,
and risk factors with emphasis on radiation parameters and
chemotherapy. Int J Radiat Oncol Biol Phys. 2006;65(2):
499–508.
2. Constine LS, Konski A, Ekholm S, McDonald S, Rubin P.
Adverse effects of brain irradiation correlated with MR
and CT imaging. Int J Radiat Oncol Biol Phys. 1988;15(2):
319–330.
3. Packer RJ, Zimmerman RA, Bilaniuk LT. Magnetic reso-
nance imaging in the evaluation of treatment-related central
nervous system damage. Cancer. 1986;58(3):635–640.
4. Johannesen TB, Lien HH, Hole KH, Lote K. Radiological
and clinical assessment of long-term brain tumour survivors
after radiotherapy. Radiother Oncol. 2003;69(2):169–176.
5. Tsuruda JS, Kortman KE, Bradley WG, Wheeler DC, Van
Dalsem W, Bradley TP. Radiation effects on cerebral white

104 Chapter 5
matter: MR evaluation. AJR Am J Roentgenol. 1987;149(1):

165–171.
6. Akyurek S, Senturk V, Oncu B, Ozyigit G, Yilmaz S, Gokce SC.
The effect of tianeptine in the prevention of radiation-induced
neurocognitive impairment. Med Hypotheses. 2008;71(6):
930–932.
7. Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD,
Fike JR. Extreme sensitivity of adult neurogenesis to low
doses of X-irradiation. Cancer Res. 2003;63(14):4021–4027.
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on cognitive function, mood, and quality of life. J Clin
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20. Schultheiss TE, Kun LE, Ang KK, Stephens LC. Radiation
response of the central nervous system. Int J Radiat Oncol
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imaging spectrum of radiation therapy- and chemotherapy-
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with bevacizumab treatment for biopsy confirmed cerebral
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24. Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bev-
acizumab on radiation necrosis of the brain. Int J Radiat
Oncol Biol Phys. 2007;67(2):323–326.
25. Glantz MJ, Burger PC, Friedman AH, Radtke RA, Massey
EW, Schold SC, Jr. Treatment of radiation-induced nervous
system injury with heparin and warfarin. Neurology.
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therapy for radiation-induced brain injury in children.
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27. Ron E, Modan B, Boice JD, Jr., et al. Tumors of the brain
and nervous system after radiotherapy in childhood. N Engl
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plasms after acute lymphoblastic leukemia in childhood.
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30. Cross NE, Glantz MJ. Neurologic complications of radia-
tion therapy. Neurol Clin. 2003;21(1):249–277.

106 Chapter 5
31. Durkin SR, Roos D, Higgs B, Casson RJ, Selva D.

Ophthalmic and adnexal complications of radiotherapy.
Acta Ophthalmol Scand. 2007;85(3):240–250.
32. Gosk J, Rutowski R, Reichert P, Rabczynski J. Radiation-
induced brachial plexus neuropathy-aetiopathogenesis, risk
factors, differential diagnostics, symptoms and treatment.
Folia Neuropathol. 2007;45(1):26–30.
33. Zadeh G, Buckle C, Shannon P, Massicotte EM, Wong S,
Guha A. Radiation induced peripheral nerve tumors: case
series and review of the literature. J Neurooncol. 2007;83(2):
205–212.
34. Donohue WL, Jaffe FA, Rewcastle NB. Radiation induced
neurofibromata. Cancer. 1967;20(4):589–595.
35. Sznajder L, Abrahams C, Parry DM, Gierlowski TC,
Shore-Freedman E, Schneider AB. Multiple schwannomas
and meningiomas associated with irradiation in childhood.
Arch Intern Med. 1996;156(16):1873–1878.

C H A P T E R 6
Neurologic
Complications of
Chemotherapy
Introduction
■ Chemotherapy: the use of chemical agents in the treatment
or control of disease such as cancer
Common Chemotherapy Agents (Table 6-1)

Table 6-1: Common Chemotherapy Agents
Mechanism of
Class of Agent Action Examples
Alkylating Add alkyl groups to Cisplatin

agents DNA, resulting in Carboplatin
cross-linking,
Oxaliplatin
miscoding, or DNA
strand breakage Busulfan
Carmustine (BCNU)
Lomustine (CCNU)
Temozolomide
Cyclophosphamide
Antimetabolites Inhibits DNA synthesis 5-Fluorouracil (5-FU)

Capecitabine
Cytarabine
Gemcitabine
Fludarabine
(Continues)
107

108 Chapter 6
Table 6-1: Common Chemotherapy Agents (Continued)
Mechanism of
Antifolates Inhibits multiple Methotrexate

enzymatic sites
leading to the
depletion of
intracellular folates
and direct blockage
of purine and
pyrimidine
biosynthesis
Vinca alkaloids Bind to tubulin and Vincristine

inhibit the assembly Vinblastine
of tubulin into
Vinorelbine
microtubules,
thereby preventing
mitosis and cell
division
Taxanes Stabilize Paclitaxel

microtubules, Docetaxel
resulting in inhibition
of mitosis and cell
division
Topoisomerase Inhibit topoisomerase Irinotecan

inhibitors I or II, enzymes which Topotecan
promote DNA strand
Etoposide
unwinding essential
for DNA synthesis and Teniposide
repair Doxorubicin
Epirubicin
Thalidomide and Immunomodulatory, Thalidomide

its analogues anti-inflammatory and Revlimid
antiangiogenic prop-
erties due to down-
regulation of certain
signaling molecules
(Continues)

Neurologic Complications of Chemotherapy 109
Table 6-1: Common Chemotherapy Agents (Continued)
Mechanism of
Molecular Mechanism varies, Trastuzumab

targeted agents target specific (monoclonal antibody
molecules associated of HER2/neu)
with tumorigenesis, Rituximab (monoclonal
tumor growth and/or antibody of CD20)
progression
Bevacizumab
(monoclonal antibody
of VEGF)
Imatinib (tyrosine
kinase inhibitor of
BCR-Abl)
Erlonitib (ATP pocket
binding inhibitor
of EGFR)
Bortezomib
(proteosome inhibitor)
Antiestrogens Bind the estrogen Tamoxifen

receptor and exert
either estrogenic or
antiestrogenic effects
depending on the
specific organ
Data are from Chabner BA, Lynch TJ, Longo DL, eds. Harrison’s Manual of
Oncology. New York: McGraw Hill Companies; 2008.
Treatment Schemes
Treatment Modalities
■ Neoadjuvant: chemotherapy prior to surgery or radiother-
apy designed to shrink the tumor

■ Concomitant: chemotherapy given during radiation
■ Adjuvant: chemotherapy after surgery or radiotherapy
Palliative Chemotherapy
■ Chemotherapy is given without curative intent.
■ The goal is to decrease tumor burden, provide symptom-
atic relief, and increase life expectancy.

110 Chapter 6
Central Nervous System

Chemotherapy-Related Cognitive Impairment
(“Chemobrain”)
■ The nature and extent of chemotherapy-related cognitive
impairment is unknown.
■ Studies of cancer-related cognitive dysfunction (prior to
chemotherapy administration) demonstrate baseline dys-

function in several cancer types.1
Clinical Features
■ Symptoms may be subtle but adversely affect quality
of life.
■ They may arise shortly after starting chemotherapy and
persist after the completion of chemotherapy.

■ The neuropsychological profile suggests disruption of
frontal–subcortical networks, including problems with

• Short-term memory
• Executive function
• Working memory
• Sustained attention
Risk Factors1
■ Higher doses of chemotherapy (either through high-dose
regimens or exposure to higher doses caused by impaired

systemic clearance)
■ Multiagent chemotherapy
■ Intrathecal chemotherapy
Pathophysiology
■ Unknown but postulated hypotheses include2
• Chemotherapeutic agents crossing the blood–brain

barrier
• DNA damage and shortened telomere length
• Cytokine dysregulation resulting in higher levels of
proinflammatory cytokines
• Problems with neural repair
• Decreased neurotransmitter activity

Treatment
■ There are no standard treatments because of a lack of
studies.
■ Empirical treatments include psychostimulants and cog-
nitive therapy.
Reversible Posterior Leukoencephalopathy

Syndrome (RPLE)
■ Also known as posterior reversible encephalopathy syn-
drome (PRES)
■ Etiologies
• Uncontrolled hypertension
• Eclampsia
• Immunosuppressants such as cyclosporine and
FK-506
• Described in association with several antineoplastic
agents, including asparaginase, bevacizumab, capecit-
abine, carboplatin, cisplatin, cyclophosphamide, cytara-
bine, doxorubicin, etanercept, fluorouracil, gemcitabine,
interferon alpha, irinotecan, melphalan, methotrexate,
oxaliplatin, paclitaxel, prednisone, sorafenib, tacrolimus,
thalidomide, and vincristine3
• No single antineoplastic agent consistently associated
with RPLE
• More frequently associated with multidrug chemo-
therapy than single-agent chemotherapy3
■ Characterized by bilateral, reversible, symmetric abnor-
malities predominantly involving white matter in the

cerebral hemisphere
• Typically subacute at onset

• Characterized by headache and altered mental status
with or without seizures
• Occipital involvement may present with visual symp-
toms such as cortical blindness
■ MRI demonstrates bilateral T2-hyperintensities caused
by vasogenic edema typically involving the subcortical

white matter, although additional areas of the brain can
be involved.

112 Chapter 6
■ Management3
• Early diagnosis important
• Discontinuation of offending agent
• Correction of high blood pressure, renal dysfunction,
and low magnesium
CNS Neurotoxicity of Specific Agents

Cytarabine
■ Also known as cytosine arabinoside and ara-C
■ Used in acute leukemias, chronic myelogenous leukemia,
non-Hodgkin lymphoma, and neoplastic meningitis

■ High-dose cytarabine associated with an acute cerebellar
syndrome4
• Clinical features
■ The predominant clinical feature is cerebellar dys-
function, including dysarthria, dysdiadochokinesia,

dysmetria, and ataxia.
■ Many patients also develop a concomitant cerebral
dysfunction characterized by somnolence, altered

mentation, headache, or seizures.
■ Symptoms are usually noted between 3 and 8 days
after initiation of therapy.

• The outcome is variable, but neurologic dysfunction
resolves within 5 days of discontinuing agent in the
majority of cases.4
■ Intrathecal liposomal cytarabine is associated with aseptic
meningitis.
• Signs and symptoms include headache, nuchal rigidity,
nausea, vomiting, and fever.
• The incidence is higher without dexamethasone pro-
phylaxis.5
• It may resolve spontaneously or respond to steroid
therapy.
5-Fluorouracil (5-FU)
■ Used in colorectal cancer, gastric cancer, breast cancer,
basal cell cancer, head and neck cancer, and bladder cancer
■ Associated with acute and delayed neurotoxicities, although
both are uncommon6

• Acute cerebellar toxicity

■ Characterized by incoordination, ataxia, dysarthria,
and nystagmus
■ Often reversible with drug discontinuation
• Acute encephalopathy
■ Characterized by confusion, cognitive disturbances,
and altered mentation

■ Associated with hyperammonemia and lactic acidosis
• Subacute multifocal leukoencephalopathy

■ Reported in cases of fluorouracil and levamisole as
combination therapy in patients with stage C colon

cancer
■ Develops 3 to 5 months after beginning chemo-
therapy
■ Characterized by cognitive abnormalities, altered
consciousness, dysarthria, focal extremity weak-

ness, and ataxia
■ MRI that demonstrates multifocal enhancing
white-matter lesions
■ Clinical improvement with discontinuation of fluo-
rouracil and levamisole as well as administration of

corticosteroids
Fludarabine
■ Used in chronic lymphocytic leukemia and low-grade
lymphoma
■ Associated with a severe neurotoxicity syndrome7
• Described at doses greater than 40 mg/m2/day

• Signs and symptoms that include blindness, encephal-
opathy, coma
• Caused by a diffuse, necrotizing leukoencephalopathy,
most severe in the occipital lobes
Ifosfamide
■ Used in lung cancer, breast cancer, gastric cancer,
Hodgkin lymphoma, non-Hodgkin lymphoma, and soft-
tissue sarcoma
■ Neurotoxicity often the dose-limiting toxicity when
appropriate preventative measures are used to reduce

urotoxicity8

114 Chapter 6
■ Associated with encephalopathy7

• Seen in 10% to 16% of patients treated with ifosfamide
• Signs and symptoms that range from agitation to sei-
zures to coma
• May improve with discontinuation of ifosfamide and
administration of methylene blue
Interferon-a
■ Uses include hairy cell leukemia, Kaposi sarcoma, mela-
noma, chronic myelogenous leukemia, follicular non-
Hodgkin lymphoma, multiple myeloma, kidney cancer,
and bladder cancer
■ Associated with neuropsychiatric symptoms
• Predominantly depression, which is often reversible

• Rarely associated with cognitive dysfunction
Methotrexate
■ Uses include acute lymphoblastic leukemia, acute myel-
ogenous leukemia, neoplastic meningitis, trophoblastic
tumors, breast cancer, lung cancer, head and neck can-
cers, Burkitt lymphoma, osteosarcoma, and primary CNS
lymphoma
■ CNS toxicity may be associated to homocysteine levels,
folate levels, and genetic variants of methionine metabolism

■ Associated with delayed leukoencephalopathy
• Ranging from asymptomatic white matter changes on

imaging to severe CNS demyelination
• Rarely associated with a disseminated necrotizing
leukoencephalopathy9,10
■ May occur with intrathecal or intravenous metho-
trexate alone but more commonly associated with

the combination of methotrexate and radiation
■ Presenting signs and symptoms that include per-
sonality changes, confusion, altered consciousness,

seizures, and coma
■ MRI that demonstrates multifocal T2-weighted
hyperintensities in the deep white matter with

patchy or diffuse contrast enhancement
■ Often fatal

■ Intrathecal methotrexate is associated with aseptic

meningitis.
• Signs and symptoms include headache, nuchal rigid-
ity, nausea, vomiting, and fever occurring 2 to 4 hours
after IT methotrexate and lasting for 12 to 72 hours.
• CSF studies show pleocytosis with negative cultures.
• This may resolve spontaneously or respond to steroid
therapy.
Peripheral Nervous System

Chemotherapy-Induced Peripheral Neuropathy (CIPN)
■ CIPN is a common dose-limiting toxicity for many older
chemotherapeutic agents.
■ CIPN may lead to chemotherapeutic dose reduction,
treatment delay, or treatment discontinuation even if the

patient is responding to the agent.
■ There is no standard of care for the prevention or treat-
ment of CIPN.
Common Chemotherapeutic Agents That Cause Peripheral
Neuropathy (Table 6-2)
■ Vincristine, paclitaxel, cisplatin, and thalidomide are the
most neurotoxic.
Risk Factors11
■ Patient age
■ Dose intensity, cumulative dose, therapy duration
■ Coadministration of other neurotoxic agents
■ Preexisting conditions associated with neuropathy
(i.e., diabetes, alcohol abuse)

Clinical Signs and Symptoms
■ The pattern depends on drug class (Table 6-2).
• Vinca alkaloids, taxanes, and bortezomib are associ-
ated with length-dependent neuropathy predomi-
nantly affecting the small fibers.
• Cisplatin is associated with ataxic neuropathy involv-
ing all four limbs.
• Vincristine and taxanes are also associated with auto-
nomic neuropathy.

Table 6-2: Chemotherapy-Induced Peripheral Neuropathy
Cumulative
Drugs Pathophysiology Toxic Dose Neuropathy Installation Evolution Electrophysiology
116 Chapter 6
Vinca Inhibition of .30–50 mg Sensory more Acute Recovery or Axonal distal

alkaloids microtubule than motor Chronic improvement neuropathy
Vincristine assembly painful length- After effect
Axonal transport dependent
Vinblastine
neuropathy
Vinorelbine
Cranial nerves
(oculomotor, facial,
trigeminal,
recurrent)
Optic neuropathy
Autonomic
neuropathy
(especially paralytic
ileus)
(Continues)
03/29/09 2:38:00 PM
Table 6-2: Chemotherapy-Induced Peripheral Neuropathy (Continued)
Cumulative
Taxanes Promotion of .175–200 mg/m2 Sensory . Acute Recovery or Axonal distal
Paclitaxel microtubule motor, improvement neuropathy
assembly painful, length-
Docetaxel
Axonal dependent
transport neuropathy
Facial nerve palsy
Autonomic
dysfunction
Platinum Inhibition of .300 mg/m2 Sensory Acute Improvement Axonal sensory

analogues protein synthesis for cisplatin and neuronopathy Subacute After effect neuronopathy
Cisplatin Dorsal root oxaliplatin (with all) (Sensory evoked
ganglion apoptosis 400 mg/m2 for Acute transient potentials show a
Carboplatin
carboplatin sensory ganglionopathy)
Oxaliplatin Axonal transport
neuropathy and
Nerve
neuromyotonia
hyperexcitability
(with oxaliplatin)
Antiangiogenesis
(Continues)
03/29/09 2:38:00 PM
Cumulative
Suramin Inhibition of Guillain-Barré Improvement Demyelinating
118 Chapter 6
. 350 µg/mL
growth factors max plasma syndrome-like After effect polyneuropathy with
Glycolipid level neuropathy conduction blocks
Lysosomal Sensorimotor Axonal distal
length- neuropathy
Inclusion in
dependent
dorsal root
neuropathy
Ganglion
Thalidomide Inhibition of nerve 50 mg/day Sensory painful Chronic Recovery or Axonal sensory
growth factor length-dependent improvement neuropathy
transcription factors neuropathy (sensory evoked
Immunomodulation Sensory potentials show a
neuronopathy ganglionopathy)
antiangiogenesis
Rare sensorimotor
neuropathy
(Continues)
03/29/09 2:38:00 PM
Cumulative
Bortezomib Proteasome Unknown Sensory length- Subacute Recovery or Mainly axonal
inhibition dependent improvement sensory/motor
neuropathy neuropathy
Sensorimotor
length-dependent
neuropathy
Mononeuropathy
multiplex
Demyelinating
neuropathy
Epothilones Promotion of Unknown Sensory

microtubule neuropathy
assembly
From Antoine JC, Camdessanche JP. Peripheral nervous system involvement. Lancet Neurol. 2007;6(1):75–86.
03/29/09 2:38:00 PM
120 Chapter 6
■ Paresthesias and dysesthesias are commonly seen in toes

and fingers.
■ Symptoms often begin distally and spread proximally to
affect lower and upper extremities in a stocking-glove
distribution.
Prevention
■ Calcium (Ca21) and magnesium (Mg21) infusions may
reduce the severity of oxaliplatin-induced chronic periph-

eral sensory neurotoxicity without reducing response
rates.
• This is based on preliminary results from three ran-
domized, placebo-controlled, double-blinded studies
of intravenous Ca21–Mg21 in oxaliplatin-based treat-
ment regimens for colon or colorectal cancer: the com-
bined oxaliplatin neurotoxicity prevention trial
(CONcePT),12,13 the North Central Cancer Treatment
Group (NCCTG) N04C7 trial,14 and the Neuroxa
trial.15,16
• Based on patient reported outcome analysis in the
NCCTG trial, Ca 21–Mg 21 significantly reduced
muscle cramps and chronic cumulative sensory neu-
rotoxicity, but no effect was noted on phenomena
associated with acute sensory neurotoxicity.
■ Vitamin E may reduce the incidence and/or severity of
chemotherapy-induced peripheral neurotoxicity, but its

effect on chemotherapy responses is unknown.
• The benefit of vitamin E was shown in several trials.
■ Pilot open-label study of patients randomized to
vitamin E 300 mg per day versus no intervention in

patients receiving cisplatin-based regimens17
■ Pilot open-label study of patients randomized to
vitamin E 300 mg twice per day versus no interven-

tion in patients receiving cisplatin and/or paclitaxel
regimens18,19
■ Preliminary results from prospective, randomized,
placebo-controlled, double-blinded study of vitamin E

400 mg per day in patients receiving cisplatin-based
regimens20

■ Preliminary results from a prospective, randomized,

placebo-controlled, double-blinded study of vita-
min E 300 mg twice per day in patients receiving a
variety of neurotoxic chemotherapies21
• None of these trials determined whether vitamin E
had adverse effects on responses to treatment.
■ Glutathione may prevent cisplatin- or oxaliplatin-induced
peripheral neurotoxicity without reducing response
rates.
• A randomized, double-blinded study of glutathione in
patients receiving a cisplatin-based regimen for ovar-
ian cancer showed that glutathione reduced neurotox-
icity and improved quality of life.22
• Randomized, placebo-controlled, double-blinded
studies of glutathione in patients receiving a cisplatin-
based regimen for advanced gastric cancer23 or an
oxaliplatin-based regimen for advanced colorectal
cancer24 showed that glutathione reduced neurotoxic-
ity without affecting response rates.
■ Xaliproden may reduce the severity of oxaliplatin-induced
peripheral neurotoxicity without reducing response
rates.
• Xaliproden is an orally administered nonpeptide neu-
rotrophic agent.
• Preliminary results from a phase III randomized,
placebo-controlled, double-blinded study suggest that
xaliproden reduces the risk of higher grade oxaliplatin-
induced peripheral sensory neuropathy without
impacting antitumor activity.25
■ Other agents may protect against CIPN but have not
been tested in large trials.
• Glutamate: earlier small studies performed in patients
receiving paclitaxel suggested a benefit with glutamate
prophylaxis, but in a recent small randomized,
placebo-controlled, double-blinded study with gluta-
mate 500 mg three times per day in ovarian cancer
patients receiving a paclitaxel-based regimen, glutamate
failed to protect against peripheral neurotoxicity.26
• Glutamine for high-dose paclitaxel or oxaliplatin-
induced peripheral neurotoxicity.27

122 Chapter 6
• Oxcarbazepine: in a small randomized, open-label

study of oxcarbazepine 600 mg twice daily in patients
receiving an oxaliplatin-based regimen for colon can-
cer, the incidence of peripheral neuropathy was
reduced in patients receiving oxcarbazepine.28
■ Agents that may not be effective as prophylaxis include
• Amifostine for the prevention of platinum- or paclitaxel-
associated neuropathy: several randomized controlled
trials have demonstrated inconsistent results29
• Nimodipine for the prevention of cisplatin-associated
neuropathy30
• Org 2766 (an adrenocorticotrophic hormone ana-
logue) for the prevention of vincristine-31 or cisplatin-
associated32 neuropathy
• rhuLIF (a recombinant human leukemia inhibitory
factor) for the prevention of carboplatin/paclitaxel-
associated neuropathy33
Treatment
■ Treatments for diabetic neuropathies are not necessarily
helpful in CIPN.
■ Topical baclofen, amitriptyline, and ketamine (BAK):
preliminary results from a randomized, placebo-con-

trolled, double-blinded study of BAK in patients receiv-
ing a variety of neurotoxic agents suggest that BAK may
improve tingling and functioning in the hands.34
■ Other agents that have been tested in small randomized,
placebo-controlled trials but demonstrated no benefit in

improving neuropathic symptoms over placebo are11
• Tricyclic antidepressants, including amitriptyline and
nortriptyline
• Gabapentin
• Lamotrigine
Prognosis
■ Variable depending on the agent (may or may not be
reversible)

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19. Argyriou AA, Chroni E, Koutras A, et al. A randomized con-
trolled trial evaluating the efficacy and safety of vitamin E
supplementation for protection against cisplatin-induced
peripheral neuropathy: final results. Support Care Cancer.
2006;14(11):1134–1140.
20. Pace A, Carpano S, Galie E, et al. Vitamin E in the
neuroprotection of cisplatin induced peripheral neurotoxicity
and ototoxicity. J Clin Oncol (Meeting Abstracts). 2007;
25(Suppl):abstr 9114.
21. Kottschade LA, Sloan JA, Mazurczak MA, et al. The use of
vitamin E for prevention of chemotherapy-induced periph-
eral neuropathy: a phase III double-blind, placebo controlled
study—N05C31. J Clin Oncol (Meeting Abstracts). 2009;
27(Suppl):abstr 9532.
22. Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the
toxicity and improves quality of life of women diagnosed with

ovarian cancer treated with cisplatin: results of a double-blind,

randomised trial. Ann Oncol. 1997;8(6):569–573.
23. Cascinu S, Cordella L, Del Ferro E, Fronzoni M, Catalano G.
Neuroprotective effect of reduced glutathione on cisplatin-
based chemotherapy in advanced gastric cancer: a random-
ized double-blind placebo-controlled trial. J Clin Oncol.
1995;13(1):26–32.
24. Cascinu S, Catalano V, Cordella L, et al. Neuroprotective
effect of reduced glutathione on oxaliplatin-based chemo-
therapy in advanced colorectal cancer: a randomized,
double-blind, placebo-controlled trial. J Clin Oncol. 2002;
20(16):3478–3483.
25. Cassidy J, Bjarnason GA, Hickish T, et al. Randomized dou-
ble blind (DB) placebo (Plcb) controlled phase III study
assessing the efficacy of xaliproden (X) in reducing the cumu-
lative peripheral sensory neuropathy (PSN) induced by the
oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in
first-line treatment of patients (pts) with metastatic colorec-
tal cancer (MCRC). J Clin Oncol (Meeting Abstracts).
2006;24(Suppl):abstr 3507.
26. Loven D, Levavi H, Sabach G, et al. Long-term glutamate
supplementation failed to protect against peripheral neuro-
toxicity of paclitaxel. Eur J Cancer Care (Engl). 2009;18(1):
78–83.
27. Amara S. Oral glutamine for the prevention of chemothera-
py-induced peripheral neuropathy. Ann Pharmacother.
2008;42(10):1481–1485.
28. Argyriou AA, Chroni E, Polychronopoulos P, et al. Efficacy
of oxcarbazepine for prophylaxis against cumulative
oxaliplatin-induced neuropathy. Neurology. 2006;67(12):
2253–2255.
29. Hensley ML, Hagerty KL, Kewalramani T, et al. American
Society of Clinical Oncology 2008 clinical practice guide-
line update: use of chemotherapy and radiation therapy
protectants. J Clin Oncol. 2009;27(1):127–145.
30. Cassidy J, Paul J, Soukop M, et al. Clinical trials of nimo-
dipine as a potential neuroprotector in ovarian cancer
patients treated with cisplatin. Cancer Chemother Pharmacol.
1998;41(2):161–166.
31. Koeppen S, Verstappen CC, Korte R, et al. Lack of neuro-
protection by an ACTH (4–9) analogue: a randomized trial
in patients treated with vincristine for Hodgkin’s or non-
Hodgkin’s lymphoma. J Cancer Res Clin Oncol. 2004;
130(3):153–160.

126 Chapter 6
32. Roberts JA, Jenison EL, Kim K, Clarke-Pearson D,

Langleben A. A randomized, multicenter, double-blind,
placebo-controlled, dose-finding study of ORG 2766 in the
prevention or delay of cisplatin-induced neuropathies in
women with ovarian cancer. Gynecol Oncol. 1997;67(2):
172–177.
33. Davis ID, Kiers L, MacGregor L, et al. A randomized,
double-blinded, placebo-controlled phase II trial of recom-
binant human leukemia inhibitory factor (rhuLIF, emfiler-
min, AM424) to prevent chemotherapy-induced peripheral
neuropathy. Clin Cancer Res. 2005;11(5):1890–1898.
34. Barton DL, Wos E, Qin R, et al. A randomized controlled
trial evaluating a topical treatment for chemotherapy-
induced neuropathy: NCCTG trial N06CA. J Clin Oncol
(Meeting Abstracts). 2009;27(Suppl):abstr 9531.

C H A P T E R 7
Paraneoplastic
Disorders
Introduction
■ Paraneoplastic disorders (PND) are an extensive group of
syndromes that can affect any part of the nervous system
by mechanisms that are immune mediated.
■ Symptoms may develop prior to discovery of a tumor.
■ The diagnosis is complex.
• Symptoms can mimic other neurological complica-
tions of cancer or its treatments.
• Not all patients with PND have detectable or recog-
nized paraneoplastic antibodies.
• Not all patients with paraneoplastic antibodies have
PND, although titers are usually much higher in
patients with PND than those without PND.1,2
• There are patients in whom no tumor is ever detected
despite presenting with classic PND and high titers of
well-characterized onconeural antibody.3
■ Tumor treatment and immunotherapy may stabilize or
improve symptoms.
Epidemiology
■ The true prevalence is unknown.
• Based on serological screening of patients with sus-
pected PND (generally unselected population), 553 of
60,000 consecutive cases over 4 years (0.9%) were
positive for antibodies associated with PND.4
• Based on serological screening of preselected popula-
tion using clinical criteria, 163 of 649 consecutive cases
over 23 months (25%) were positive for antibodies
associated with PND.5
■ The incidence varies depending on type of cancer: SCLC
(3% develop a paraneoplastic disorder), thymoma (30%),
127

128 Chapter 7
plasma cell dyscrasias associated with malignant mono-

clonal gammopathy (5% to 15%), and other solid tumors
(including breast cancer or ovarian cancer) (,1%).6
■ Central nervous system disorders are more frequently
found in the following tumors:
• Tumors that express neuroendocrine proteins (e.g.,
SCLC, neuroblastoma)
• Tumors that affect organs with immunoregulatory
properties (e.g., thymoma)
• Tumors that contain mature or immature neuronal tis-
sue (e.g., teratomas)
■ Peripheral nervous system disorders are more frequently
found in tumors that derive from cells that produce
immunoglobulins (e.g., plasma cell dyscrasias, B-cell
lymphomas).7
Pathogenesis
■ The pathogenesis is not entirely clear.
■ Most PNDs are probably caused by immunological
responses against intraneuronal antigens expressed by
the underlying cancer.
• Tumor cells express antigens found in only the ner-
vous system.8,9
• Tumor antigens are identified as foreign, resulting in
an immune response.
• The antitumor immune response cross-reacts with the
normal nervous system.
Antibody-Mediated PND
■ The direct pathogenic role of antibodies has been dem-
onstrated in a few disorders (i.e., development of charac-

teristic syndrome after passive transfer of antibodies in
mice or rats).
• Myasthenia gravis (MG): antibodies to the acetylcho-
line receptor of the neuromuscular junction
• Lambert-Eaton myasthenic syndrome (LEMS):
antibodies to voltage-gated calcium channels
• Stiff-person syndrome (SPS): antibodies to amphy-
physin10

Paraneoplastic Disorders 129
• Single case report of two patients in remission from

Hodgkin lymphoma who developed cerebellar ataxia
found to have antibodies against mGluR111
■ Antibodies usually react with cell surface antigens, but
antibodies to intracellular antigens are also described
(e.g., antibodies against amphiphysin in paraneoplastic
stiff-person syndrome).
■ Associated disorders can occur with or without cancer.12
• The likelihood of an underlying tumor with LEMS is
50%, most commonly SCLC.13
• The likelihood of an underlying tumor with MG is
10%, most commonly thymoma.13
■ The presence of antibodies does not confer disease
because some paraneoplastic antibodies are commonly
present in cancer patients without a PND.12,14
T-Cell–Mediated PND
■ Some PNDs may be mediated by T-cell immune
responses against target antigens of accompanying anti-

bodies, although the evidence is mostly circumstantial.5
• Yo- or Hu-specific T-cells identified in blood or CSF
of patients with anti-Yo or anti-Hu antibodies
• Difficulty in treating these T-cell–mediated disorders
with strategies directed at humoral immune response
• Extensive T-cell infiltrates in CNS
Clinical Features
■ There is a rapid development of symptoms and signs of
inflammation in the CSF,5 including moderate lympho-
cytic pleocytosis (30–40 cells/mL), an elevated protein
concentration (50–100 mg/dL), a high IgG index, and
CSF-specific oligoclonal bands15
■ Neurologic symptoms are the first manifestation of tumor
in 70% of patients with PND; 70% to 80% of these
patients are found to have cancer on initial screening.5
■ Symptoms are progressive over weeks to months followed
by stabilization.
■ In 80% of patients with no known cancer history who
develop a PND, cancer is usually diagnosed within
months to years.16

130 Chapter 7
Diagnosis
Diagnostic Criteria (Figure 7-1)17
Definite PND
■ Classic syndrome with cancer diagnosed within 5 years
of neurologic symptom development

■ Nonclassic syndrome that resolves or significantly
improves after cancer treatment without concomitant

immunotherapy, provided that the syndrome is not sus-
ceptible to spontaneous remission
■ Nonclassic syndrome with cancer diagnosed within
5 years of neurologic symptom development and positive

neuronal antibodies
■ Neurologic syndrome (classic or not) without cancer and
with well-characterized antineuronal antibodies (Hu, Yo,

CV2/CRMP5, Ri, Ma2, or amphiphysin)
Possible PND
■ Classic syndrome with high risk of cancer, without anti-
neuronal antibodies
■ Neurologic syndrome (classic or not) without cancer and
with partly characterized antineuronal antibodies
Figure 7-1: Paraneoplastic diagnosis flowchart. Graus F, et al.

Recommended diagnostic criteria for paraneoplastic neurological
syndromes. J Neurol Neurosurg Psychiatry. 2004;75(8):1135–1140.

■ Nonclassic syndrome with cancer diagnosed within

2 years of neurologic symptom development, without
neuronal antibodies
Diagnostic Workup18
■ If PND is suspected, the initial workup should include
MRI, neurophysiologic studies, CSF studies, including

paraneoplastic antibody testing, and serum paraneoplas-
tic antibody testing.
■ If paraneoplastic antibodies are present or clinical
suspicion is high, the workup should also include cancer

screening.
• In general, a full-body CT scan and an FDG-PET scan
are recommended.
• For breast cancer-associated syndromes, a careful
breast examination and mammography are also
recommended.
• For gynecologic-associated syndromes (i.e., anti-Yo–
associated paraneoplastic cerebellar degeneration), a
careful pelvic examination and pelvic ultrasound are
also recommended.
• For testicular-associated syndromes (i.e., anti-Ma2–
associated limbic encephalitis in young men), a
testicular ultrasound is also recommended.
• If an ovarian or testicular malignancy is strongly sus-
pected but not found on screening, some advocate
elective oophorectomy or orchidectomy.19
• For neuroblastoma-associated opsoclonus-myoclonus,
when conventional imaging is negative, metaiodoben-
zylguanidine whole-body scintigraphy may identify
occult cases.20
■ If a tumor is not initially detected, continued surveillance
at regular intervals is necessary.18
Common Paraneoplastic Disorders (Table 7-1)

Paraneoplastic Cerebellar Degeneration
■ Commonly associated tumors: SCLC, gynecologic
cancers, breast cancers, Hodgkin lymphoma5


Table 7-1: Antibodies, Paraneoplastic Syndromes, and Associated Tumors
Antibody Syndrome Associated Tumors
Well-characterized paraneoplastic antibodies (identified by several investigators)
132 Chapter 7
Anti-Hu (ANNA-1) Paraneoplastic encephalomyelitis, including Small cell lung cancer

cortical, limbic, brainstem encephalitis Others
Paraneoplastic cerebellar degeneration
Myelitis
Paraneoplastic sensory neuronopathy
Autonomic dysfunction
Anti-Yo (PCA-1) Paraneoplastic cerebellar degeneration Gynecologic cancers

Breast cancer
Anti-Ri (ANNA-2) Paraneoplastic cerebellar degeneration Breast cancer

Brainstem encephalitis Gynecologic cancers
Opsoclonus-myoclonus Small cell lung cancer
(Continues)
03/29/09 2:40:00 PM
Table 7-1: Antibodies, Paraneoplastic Syndromes, and Associated Tumors (Continued)
Anti-CV2/CRMP5 Paraneoplastic encephalomyelitis Small cell lung cancer
Paraneoplastic cerebellar degeneration Thymoma
Chorea Others
Uveitis
Optic neuritis
Peripheral neuropathy
Anti-Ma proteins Limbic, hypothalamic, brainstem encephalitis Germ cell tumors of testis
(Ma2, Ma1) Infrequently paraneoplastic cerebellar Nonsmall cell lung cancer
degeneration Other solid tumors
Antiamphiphysin Stiff-person syndrome Small cell lung cancer

Paraneoplastic encephalomyelitis Breast cancer
Limbic encephalitis
Myelopathy
(Continues)
03/29/09 2:40:00 PM
Partly characterized paraneoplastic antibodies
Anti-Tr Paraneoplastic cerebellar degeneration Hodgkin lymphoma
134 Chapter 7
Anti-Zic 4 Paraneoplastic cerebellar degeneration Small cell lung cancer
mGluR1 Paraneoplastic cerebellar degeneration Hodgkin lymphoma
ANNA3 Various paraneoplastic disorders of the CNS Small cell lung cancer
PCA2 Various paraneoplastic disorders of the CNS Small cell lung cancer
Antibodies that occur with and without cancer association
Anti-NR1/NR2 of Characteristic encephalitis with prominent Teratoma (usually in the ovary)

NMDA receptor psychiatric symptoms, memory loss,
decreased consciousness with frequent
hypoventilation, autonomic instability,
dyskinesias
(Continues)
03/29/09 2:40:00 PM
Anti-VGKC Limbic encephalitis Thymoma
Peripheral nerve hyperexcitability Small cell lung cancer
(neuromyotonia) Others
Other
Anti-VGCC Lambert-Eaton myasthenic syndrome Small cell lung cancer

Paraneoplastic cerebellar degeneration
Anti-AChR Myasthenia gravis Thymoma
Anti-nAChR Subacute pandysautonomia Small cell lung cancer

Others
Anti-GAD Stiff-person syndrome Thymoma

Cerebellar ataxia Others
Limbic encephalitis
Others
Modified from Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327–340.
03/29/09 2:40:00 PM
136 Chapter 7
• Gait unsteadiness rapidly progresses into truncal and

appendicular ataxia, nystagmus, diplopia, dysarthria,
dysphagia
• Occasionally prodromal symptoms (viral-like illness,
dizziness, nausea, or vomiting) before the onset of
neurologic signs that might be attributed to a vestibu-
lar process21
• Neurologic symptoms that begin abruptly, progress
over weeks to months, and then stabilize but usually
leave the patient significantly impaired
• Occasionally blurry vision, oscillopsia, and transient
opsoclonus5
• Anti-Yo, anti-Hu, anti-CRMP5 associated with more
severe neurologic deficits5
■ CSF studies: may show signs of inflammation with ele-
vated protein, lymphocytic pleocytosis, and oligoclonal
banding
■ Imaging
• Early stages
■ The MRI is initially normal in most patients,
although some may have transient diffuse cerebel-

lar hemispheric enlargement or cortical-meningeal
enhancement.22
■ A fluorodeoxyglucose PET may show cerebellar
hypermetabolism.23
• Later stages
■ An MRI shows cerebellar atrophy.
■ A PET shows hypometabolism.
■ Differential diagnosis includes

• Alcohol-related cerebellar degeneration
• Infectious or postinfectious cerebellitis
• Cerebellar metastasis
• Vitamin deficiency (thiamine, vitamin E)
• Toxins (antiepileptic agents, chemotherapy-related
agents such as fluorouracil or cytarabine)
• Creutzfeldt-Jakob disease (12% to 15% of patients
with CNS PND have 14-3-3 protein in CSF24)
• Glutamic acid decarboxylase (GAD)-associated cerebel-
lar degeneration: slower progression than paraneoplastic

cerebellar degeneration, milder and asymmetric limb

ataxia (mainly affecting gait), associated with endocrine
dysfunction (insulin-dependent diabetes, thyroiditis,
pernicious anemia),25 may be associated with transient
or self-limited muscle spasms26
■ Pathology: extensive loss of Purkinje cells
■ Serologic testing
• Gynecologic cancer or breast cancer is often associ-
ated with anti-Yo (cdr2).5
■ Anti-Yo has high syndrome specificity.
■ Patients with anti-Yo usually have a significant long-
term disability because of irreversible Purkinje cell

destruction.27,28
• Hodgkin lymphoma is often associated with anti-Tr.29
■ Anti-Tr has high syndrome specificity.
■ It is more commonly present in young men.
• SCLC is associated with one or multiple antibodies:

41% develop antibodies against voltage-gated calcium
channels with or without associated LEMS, 23%
develop anti-Hu, and the minority develop antibodies
against other targets (CRMP or CV2, amphiphysin,
PCA2, ANNA3).5
■ Treatment
• There is no standard of care.
• The treatment of the underlying tumor is necessary
for stabilization or symptom improvement.
• Immunotherapy (corticosteroids, plasma exchange, intra-
venous immunoglobulin, cyclophosphamide, tacrolimus)
does not substantially modify the neurologic outcome in
patients whose tumors are successfully treated.5
• There are case reports where immunotherapy
benefitted.30,31
■ Patients with anti-Yo who improved were treated
within 1 month of symptom onset and usually

received concurrent cancer therapy.31
■ Prognosis
• Antibodies associated with more severe neurological
deficits (Yo, Hu, CRMP5) are the most refractory to
treatment.5

138 Chapter 7
• The median survival from time of PND diagnosis

(defined as first positive antineuronal antibody result)28
is as follows:
■ Anti-Yo 13 months
■ Anti-Hu 7 months
■ Anti-Tr .113 months
■ Anti-Ri .69 months
• Patients who received tumor treatment lived longer

than those who did not, regardless of whether they
also received immunotherapy or not.28
Paraneoplastic Opsoclonus-Myoclonus
■ Commonly associated tumors: SCLC, breast cancer,
ovarian cancer in adults; neuroblastoma in children

• Opsoclonus: involuntary, arrhythmic, chaotic, multidi-

rectional saccades with horizontal, vertical and tor-
sional components—may be constant, even during
sleep
• Myoclonic jerks involving limbs and trunk
• Cerebellar ataxia, most often in children
• Tremor
• Encephalopathy
■ CSF Studies: may show mild pleocytosis
■ Imaging: brain MRI may be normal
■ Differential diagnosis: opsoclonus-myoclonus associated
with infectious, toxic-metabolic disorders

■ Pathology: disinhibition of fastigial nucleus of cerebellum
may be involved32,33
■ Laboratory abnormalities
• Most patients are antibody negative.

• Anti-Ri
■ Found in a small subset of adults (usually with
breast or ovarian cancer) with paraneoplastic brain-

stem and cerebellar dysfunction34
■ Opsoclonus often present but not always35,36
• In neuroblastoma-associated opsoclonus-myoclonus,
no consistent specific autoantibodies have been
isolated, although antibodies to surface proteins in
cerebellar granular neurons have been reported.37,38

■ Treatment
• Pediatric cases
■ Opsoclonus often responds to immunotherapies
(corticosteroids, adrenocorticotropic hormone,

intravenous immunoglobulin, plasma exchange,
cyclophosphamide, rituximab).39
■ There is a high frequency of residual motor, speech,
behavioral, and sleep disorders.40

■ Symptoms can relapse during illnesses.
• Adult cases
■ There is improvement with tumor control.41
■ Improvement with immunotherapy is only mild or
not sustained unless the tumor is controlled.42

■ Prognosis
• In children, neurologic symptoms may resolve sponta-
neously or with treatment, but may relapse.43
• In adults, partial or complete neurologic recovery may
be seen with treatment of the underlying tumor.41
Paraneoplastic Limbic Encephalitis

■ Commonly associated tumors: SCLC, testicular germ-cell
neoplasms, thymoma, Hodgkin lymphoma, and ovarian

teratoma44
• Similar to nonparaneoplastic limbic encephalitis

• Mood disturbances
• Sleep disturbances
• Seizures
• Hallucinations
• Short-term memory loss that can progress to
dementia44
■ CSF studies: may show signs of inflammation with
elevated protein, lymphocytic pleocytosis, oligoclonal

banding
■ Imaging and other studies
• An EEG typically demonstrates foci of epileptic activ-

ity in one or both temporal lobes or focal or general-
ized slow activity.45
• A brain MRI typically demonstrates FLAIR or T2
hyperintensity in one or both mesial temporal lobes,44,45

140 Chapter 7
although these areas rarely demonstrate gadolinium

enhancement.
• A PET may demonstrate hypermetabolism in one or
both temporal lobes that can precede MRI changes or
clinical symptoms.46
■ The differential diagnosis includes
• Viral encephalitis, including herpes simplex virus: the
course is more rapid and severe than paraneoplastic
limbic encephalitis
• Encephalitis associated with rheumatic disease such as
systemic lupus erythematous and Sjogren syndrome.
• Primary autoimmune limbic encephalitis: some may
be associated with antibodies to voltage-gated potas-
sium channels without an underlying tumor.47,48
• Anti-Hu
■ Patients develop extensive or multifocal encephalo-
myelitis, which may begin as limbic encephalitis or

cerebellar degeneration.5
■ SCLC is the most commonly associated tumor, but
only 50% of patients with SCLC and limbic

encephalitis have anti-Hu antibodies.
• Anti-CRMP5 (anti-CV2)
■ The disease is rarely confined to the limbic system
because the antibody is also associated with enceph-

alomyelitis, sensorimotor neuropathy, cerebellar
ataxia, chorea, uveitis, and optic neuritis.5
■ SCLC and thymoma are the most commonly asso-
ciated tumors.
• Anti-Ma2 (Ta)
■ This typically affects the limbic system, hypothala-
mus, and brainstem, resulting in limbic dysfunction

as well as excessive daytime sleepiness, narcolepsy,
cataplexy, REM-sleep abnormalities, hyperphagia,
hypothalamic–pituitary hormone deficits, and
supranuclear gaze palsy.5
■ This may resemble CNS Whipple disease.49
■ The commonly associated tumors are as follows:
• In men less than 50 years old, anti-Ma2 enceph-

alitis is almost always associated with testicular

germ-cell tumors, which can be microscopic and

difficult to diagnose.50
• In older men and women, NCLC and breast
cancer are more common.5
• Anti-VGKC (voltage-gated potassium channels)
■ The two main CNS syndromes are as follows:
• Limbic encephalitis
• More diffuse encephalitis with psychiatric
symptoms, hallucinations, peripheral nerve
hyperexcitability, autonomic dysfunction (e.g.,
hyperhydrosis)5
■ REM sleep disturbances and hyponatremia are
common.51
■ Approximately 30% with anti-VGKC have tumors.
■ CSF shows less pleocytosis, lower protein concen-
tration, less intrathecal synthesis of IgG compared

with other paraneoplastic disorders, or immune-
mediated limbic encephalitis.5
■ Anti-SOX antibodies may help differentiate para-
neoplastic limbic encephalitis from the nonpara-

neoplastic form.
• Anti-NMDA receptors
■ This typically affects young women.
■ Patients first develop prodromal syndromes
(including headache, fever, or viral-like illness) and

then progress to develop severe psychiatric
symptoms or memory loss, seizures, decreased
consciousness associated with dyskinesias, hypoven-
tilation, or autonomic instability.5
■ Approximately 65% have an underlying tumor,
usually a cystic ovarian teratoma (mature or

immature).
■ Treatment
• For anti-Hu associated limbic encephalitis, early
treatment can result in substantial and prolonged
recovery.52
• For anti-CRMP5, treatment response is generally
poor.53
• For anti-Ma2–associated limbic encephalitis in men
with a testicular germ-cell tumor, treatment includes

142 Chapter 7
orchiectomy and immunotherapy (corticosteroids and

intravenous immunoglobulin).
• For anti-VGKC–associated limbic encephalitis, treat-
ment includes corticosteroids, plasma exchange, or
intravenous immunoglobulin. About 80% respond to
treatment.5
• For patients with limbic encephalitis caused by ovar-
ian teratoma and antibodies against NMDA receptors,
an unstable clinical condition may hinder teratoma
removal.
■ Immunotherapy (corticosteroids, plasma exchange,
intravenous immunoglobulin, rituximab or cyclo-

phosphamide) often results in sufficient improve-
ment to enable tumor removal.54
■ Patients who do not respond to one form of immu-
notherapy may respond to another.

■ Improvement may be slow and take several
months.
■ Tumor removal speeds up recovery and decreases
the relapse rate.

■ Prognosis
• In patients with SCLC, the prognosis is worse in
patients without anti-Hu antibodies than patients with
anti-Hu antibodies.55
• For anti-Hu-associated limbic encephalitis, early
treatment can result in substantial and prolonged
recovery.52
• For anti-Ma2-associated limbic encephalitis, 35%
have neurologic responses to treatment.5
• For anti-VGKC-associated limbic encephalitis, the
prognosis is worse in patients with lung cancer than
those without lung cancer.56
• For patients with limbic encephalitis caused by ovar-
ian teratoma and antibodies against NMDA receptors,
65% have near or full recovery.57
Stiff-Person Syndrome
■ This syndrome may be idiopathic or paraneoplastic.
■ The commonly associated tumors are breast cancer,
SCLC, and Hodgkin lymphoma.

■ The nonparaneoplastic variant is also autoimmune, asso-

ciated with glutamic acid decarboxylase antibodies, and
usually affects patients with other autoimmune diseases,
especially diabetes mellitus type I.58
■ Clinical features are as follows:
• Gradual onset of stiffness and rigidity, initially in axial
muscles and progressing to proximal limb muscles,
primarily involving the legs
• EMG that demonstrates continuous motor unit activ-
ity in affected muscles
• Paraspinal muscle rigidity that may lead to lumbar
hyperlordosis, difficulty ambulating, and frequent falls
• Continuously contracting antagonist muscles that
cause a rock-hard or board-like sensation to palpation
• Sudden, painful muscle spasms usually precipitated
by touch or involuntary movement, sudden loud noise,
or emotional stress59
■ CSF studies are usually normal.60
■ MRI studies are usually normal.60
■ The differential diagnosis includes tetanus, hyperekplexia,
and myelopathy.
■ Laboratory abnormalities are as follows:
• Amphiphysin antibodies are most commonly detected
in the paraneoplastic form.
• There are reports of anti-GAD in paraneoplastic stiff-
person syndrome, but this antibody is most commonly
found in the nonparaneoplastic form.
■ Treatment
• Intravenous immunoglobulin proven effective in two
placebo-controlled studies in nonparaneoplastic SPS
and reported effective in paraneoplastic SPS in a few
case reports61
• Dramatic response to diazepam in relieving stiffness62
Paraneoplastic Visual Syndromes

Cancer-Associated Retinopathy (CAR)
■ CAR presents with progressive, painless visual loss, pho-
tosensitivity, peripheral and ring scotomata, and flickering,

light-induced glare.

144 Chapter 7
■ An electroretinogram demonstrates evidence of cone-

and rod-mediated abnormalities.
■ A funduscopic examination may demonstrate arteriolar
narrowing.63
■ Antirecoverin is the most commonly associated antibody,
usually in patients with SCLC.64
Melanoma-Associated Retinopathy (MAR)

■ MAR presents as an abrupt onset night blindness and
flickering light phenomena with normal visual acuity.63

■ Symptoms generally develop long after a diagnosis of
melanoma, usually in the setting of tumor progression.

■ The exact target antigen is unknown.
Paraneoplastic Optic Neuropathy

■ This typically presents with unilateral painless vision loss
progressing to involve both eyes.63

■ It is usually associated with encephalomyelopathy.
■ Anti-CMRP5 is the most commonly associated antibody,
usually in patients with SCLC.65
Paraneoplastic Motor Neuron Disease

■ It is usually idiopathic.
■ There are rare case reports of association with solid
tumors and motor neuron disease.18

■ There is a slightly higher incidence of lymphoproliferative
disorders (including Hodgkin lymphoma, non-Hodgkin

lymphoma, Waldenström macroglobulinemia, multiple
myeloma, chronic lymphocytic leukemia) in patients with
motor neuron disease.18
■ For both solid tumors and lymphoproliferative disorders,
patients rarely recover despite treatment of the underly-

ing tumor/disorder.
Peripheral Neuropathy
■ Causes in cancer patients
• More commonly caused by toxic-metabolic disorders

(i.e., chemotherapy, diabetes, malnutrition)
• Paraneoplastic peripheral neuropathy (i.e., subacute
sensory neuronopathy)

• Leptomeningeal disease
• Direct tumor invasion
Subacute Sensory Neuronopathy 66
■ Classic paraneoplastic peripheral neuropathy
■ Commonly associated tumor: SCLC (70% to 80% of
cases67), Hodgkin lymphoma
■ Clinical features68
• Subacute onset and rapidly progressive, although an
indolent course has been reported69
• Asymmetric, multifocal pain and paresthesias, ini-
tially involving arms but progressing to include all
extremities
• Sensory ataxia and pseudoathetoid movements of the
hands
• Neuropathy isolated in only 24% of patients with
anti-Hu, others have various combinations of central
nervous system (e.g., encephalomyelitis, limbic enceph-
alitis) and peripheral nervous system involvement70
■ CSF studies: elevated protein, pleocytosis, oligoclonal
bands67
■ EMG/NCS: small or absent sensory nerve action
potentials18
■ Pathophysiology: destruction of dorsal root ganglia by
cytotoxic T-lymphocytes71
■ Laboratory testing: anti-Hu 99% specific and 82% sensi-
tive for cancer diagnosis in patients with subacute sensory
neuropathy66
■ Treatment
• Tumor therapy
• No clear benefit to immunosuppressive treatment
■ Prognosis
• Poor despite immunosuppressive treatment18
• Possible stabilization if tumor therapy initiated early
Paraneoplastic Sensory or Sensorimotor Neuropathy
■ Commonly associated tumors: SCLC or thymoma
• Often with CNS dysfunction (i.e., cerebellar ataxia,

limbic encephalitis, or ocular involvement)
• Predominates in lower limbs

146 Chapter 7
■ EMG/NCS: axonal or mixed axonal/demyelinating

pattern
■ Laboratory testing: anti-CV2 (peripheral neuropathy
occurs in 57% of patients with anti-CV2 antibodies67)
Paraproteinemic Neuropathy
■ Not included in diagnostic criteria but often considered
paraneoplastic17
■ Commonly associated with plasma cell dyscrasias,
including
• Monoclonal gammopathy of undetermined signifi-
cance (MGUS): associated with a polyneuropathy that
may improve with treatment of MGUS72
• Multiple myeloma: neuropathy that may be associated
with amyloidosis (painful sensory or sensorimotor
neuropathy mainly affecting small fibers73) or type 1
cryoglobulinemia
• POEMS syndrome: polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein, and skin
changes
■ Associated with osteosclerotic myeloma
■ Primarily demyelinating and sensorimotor neuropa-
thy similar to chronic inflammatory demyelinating

polyneuropathy (CIDP)74
• Waldenström macroglobulinemia (lymphoplasmacytic
lymphoma)
■ Monoclonal IgM antibodies against myelin-associ-
ated glycoprotein (anti-MAG) associated with

chronic, distal, symmetric, large and small fiber,
predominantly demyelinating polyneuropathy
■ Monoclonal IgM antibodies against sulfatide asso-
ciated with more profound symptoms, sensory or

sensorimotor neuropathy67
■ Monoclonal IgM antibodies against disialosyl gan-
gliosides associated with predominantly sensory

neuropathy and ophthalmoplegia75
■ Monoclonal IgM antibodies against GM1 associated
with multifocal motor neuropathy67

Autonomic Neuropathy
■ Rarely occurs in isolation, most commonly with limbic
encephalitis and subacute sensory neuronopathy in
patients with SCLC or with LEMS in patients with
voltage-gated calcium channel antibodies74
• Chronic gastrointestinal pseudo-obstruction caused

by destruction of autonomic neurons in myenteric
plexuses
• Orthostatic hypotension
• Bladder dysfunction
• Impotence
• Sudomotor alterations
• Absence of heart rate variability
Neuromyotonia
■ Idiopathic or paraneoplastic
■ Commonly associated tumors: thymoma, SCLC, rarely
Hodgkin lymphoma18
• Muscle twitching and myokymia (continuous,

undulating, ripple of muscles described as a bag of
worms)
• Stiffness
• Painful cramps worse with muscle contraction
• Hyperhidrosis
• Muscle hypertrophy
• Pseudomyotonia (slow relaxation of muscle after con-
traction without percussion myotonia)
■ EMG/NCS: spontaneous, continuous, high-frequency
(150–300 Hz) doublet, triplet or multiple single motor

unit discharges76
• Antibodies to voltage-gated potassium channels

(VGKC) often present in autoimmune and paraneo-
plastic neuromyotonia
• Anti-Hu antibodies in SCLC reported77

148 Chapter 7
■ Treatment
• Responds well to plasma exchange more than intrave-
nous immunoglobulin78
• Symptomatic treatment with anticonvulsants such as
phenytoin and carbamazepine
■ Prognosis: may remit after tumor treatment
Lambert-Eaton Myasthenic Syndrome

■ Idiopathic or paraneoplastic, underlying malignancy in
60% of cases79
■ Commonly associated tumor: SCLC (LEMS affects 3%
of patients with SCLC)80

• Proximal muscle weakness (usually legs worse than

arms)
• Generalized fatigue
• Depressed tendon reflexes
• Autonomic dysfunction
■ Dry mouth
■ Eye dryness, blurred vision
■ Impotence
■ Constipation
■ Impaired sweating
■ Orthostatic hypotension
• Improved strength and tendon reflexes with exercise

• Very rarely ocular and bulbar muscle involvement
• Respiratory muscle weakness as a late complication
but rare
■ EMG/NCS
• Decreased CMAP amplitudes with repetitive nerve

stimulation between 1 to 5 Hz
• More than 100% increment in CMAP amplitudes
after repetitive nerve stimulation at 20 Hz or greater or
after brief maximal effort
• Normal motor and sensory latencies and conduction
velocities
• Jitter on single-fiber EMG
■ Pathology: antibodies to presynaptic P/Q voltage-gated
calcium channels preventing calcium influx into the cell

and acetylcholine release

• P/Q voltage-gated calcium channel (VGCC) antibodies
present in almost 100% of patients with cancer and
90% without cancer81
• Anti-SOX antibodies found in 65% of patients with
cancer-associated LEMS and may help differentiate
paraneoplastic from nonparaneoplastic LEMS82
■ Treatment
• Treatment of the underlying malignancy is important.
• Immunotherapy without treatment of underlying
tumor usually produces little or no improvement in
strength.83
• 3,4-Diaminopyridine improves strength regardless of
etiology.84
■ Prognosis: LEMS may remit with tumor therapy, good
response to treatment.
Myasthenia Gravis
■ Idiopathic or paraneoplastic (10% to 15%)18
■ Commonly associated tumor: thymoma (up to 40% of
patients with thymoma will develop MG85)

• Weakness: ocular and bulbar symptoms predominate,

may progress to generalized weakness
• Normal deep tendon reflexes
• No associated autonomic features
• Muscle fatigability, noticeable to patients later in the
day or with prolonged use, which may be elicited on
examination through repetitive confrontational
strength testing or sustained upgaze (extraocular
muscles)
■ EMG/NCS
• Greater than 10% CMAP amplitude decrement

after exercise or with repetitive nerve stimulation at
2 to 5 Hz76
• Jitter on single-fiber EMG
■ Pathology: antibodies against postsynaptic acetylcholine
receptor, resulting in activation of complement, acceler-

ated receptor degradation, or blocking of acetylcholine
receptor binding86

150 Chapter 7
■ Laboratory abnormalities18
• Anti-acetylcholine receptor (AChR) antibodies are
found in 80% to 90% of patients with MG and almost
all patients with thymoma-associated MG.
• Anti-titin antibodies and anti-ryanodine antibodies are
also associated with thymoma-associated MG.
■ Treatment
• All patients with MG should have CT or MRI of the
anterior mediastinum to look for thymoma.
• A select population should have a thymectomy.
• Short-term symptomatic treatment should include
acetylcholinesterase inhibitors.
• Long-term symptomatic control may be achieved with
immunosuppression.
• Exacerbations or myasthenic crisis may be managed
with intravenous immunoglobulin and/or plasma
exchange.
■ Prognosis
• The presence of thymoma is a poor prognostic factor
in MG.
• Long-term neurologic outcome is similar to patients
with nonthymomatous MG with early thymectomy.87
Inflammatory Myopathies
Polymyositis
■ Idiopathic or paraneoplastic, increased risk of malignancy
■ Commonly associated tumors: non-Hodgkin lymphoma,
lung cancer, bladder cancer88

■ Clinical features: symmetrical proximal muscle
weakness
■ EMG/NCS: small polyphasic motor unit potentials and
abnormal spontaneous activity

■ Pathophysiology: T-cell mediated
• Elevated creatine kinase

• Autoantibodies found in idiopathic polymyositis (anti-
Jo-1, anti-OJ, anti-Mi-2) less commonly found in
paraneoplastic polymyositis18

■ Treatment: same as idiopathic polymyositis. Immunosup-

pression with corticosteroids, intravenous immunoglobulin,
plasma exchange, immunomodulatory drugs (methotrexate,
azathioprine, cyclosporine, mycophenolate mofetil), TNF-a
inhibitors (infliximab, etanercept)
■ Prognosis: good response to treatment
Dermatomyositis
■ Idiopathic or paraneoplastic, increased risk of malignancy
(higher than polymyositis)

■ Commonly associated tumors: ovarian, lung, gastric, col-
orectal, pancreatic cancers, non-Hodgkin lymphoma88

■ Clinical features: symmetrical proximal muscle weakness
with characteristic skin changes (purplish heliotrope rash

of the eyelids, Grotton’s sign, photosensitive erythema-
tous rash of chest and shoulders)

■ Pathophysiology: complement-mediated intramuscular
microangiopathy leading to ischemia, muscular fiber

necrosis, and perifascicular atrophy89
• Creatine kinase may be elevated.

• Patients with interstitial lung disease may have
anti-Jo 1.68
■ Treatment: same as idiopathic polymyositis. Immunosup-
pression with corticosteroids, intravenous immunoglobu-

lin, plasma exchange, immunomodulatory drugs
(methotrexate, azathioprine, cyclosporine, mycopheno-
late mofetil), TNF-a inhibitors (infliximab, etanercept)
■ Prognosis: good response to treatment
Inclusion Body Myositis

■ Idiopathic or paraneoplastic
■ Clinical features: distal weakness

■ Pathology: rimmed vacuoles, congophilic inclusions

152 Chapter 7
■ Laboratory abnormalities: mildly elevated or normal

creatine kinase
■ Treatment: generally unresponsive to corticosteroids or
immunosuppressive drugs. Intravenous immunoglobulin
may be beneficial in a small number of cases.
■ Prognosis: generally resistant to therapies.
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C H A P T E R 8
Cerebrovascular
Complications
Introduction
■ Conflicting data exist between autopsy and clinical series
on whether cerebrovascular disease is elevated in cancer
patients.
• Based on a large autopsy series, cerebrovascular com-
plications, including hemorrhages and infarctions,
were the second most common CNS lesion in patients
with cancer.1
• Based on large modern clinical series, the frequency
of ischemic stroke was not elevated in cancer patients.2,3
• The risk of cerebral hemorrhages appears to be ele-
vated in hematological malignancies.4
■ Although some of the causes of cerebrovascular disease
in cancer patients may be similar to noncancer patients,
there are several cancer-specific and treatment-related
causes to be considered.
Ischemic Strokes
Risk Factors in Cancer Patients
■ Similar risk factors as the noncancer population, includ-
ing hypertension, diabetes mellitus, hyperlipidemia, atrial

fibrillation, smoking, and carotid artery disease
■ Additional risk factors in cancer patients that are treat-
ment and/or disease related discussed later in this chapter
Management of Ischemic Strokes in Cancer Patients

■ Guidelines for stroke management in cancer patients
should generally follow recommendations for noncancer

patients with special consideration of cancer-specific
causes of stroke.
161

162 Chapter 8
• The American Stroke Association and American Heart

Association have published guidelines for early man-
agement of adults with ischemic stroke.5
• The American Stroke Association and American Heart
Association have published guidelines for secondary
prevention of ischemic stroke.6
■ Patients with acute stroke symptoms should be urgently
referred to the hospital for early management, including
diagnosis, imaging, treatment of acute complications,
and consideration of thrombolysis.
■ After emergency department management, additional
management may include the following:
• Risk factor management includes hypertension, hyper-
lipidemia, and diabetes mellitus.
• Noninvasive vessel imaging should be performed to
look for vascular stenoses, dissections, and so forth.
■ Carotid duplex ultrasound (although does not pro-
vide information about intracranial vasculature)

■ CT angiogram
■ MR angiogram
• A cardiac ultrasound should be performed to look for

valvular abnormalities, left ventricular thrombus, and
so forth.
■ A transthoracic echocardiogram may be sufficient,
but if the suspicion for endocarditis is high, then a

transesophageal echocardiogram may be more sen-
sitive in detecting valvular vegetations.
■ If strokes appear embolic in origin and there is no
left-sided source, then consider performing a bub-

ble study with the cardiac ultrasound to look for a
cardiac shunt.
• If strokes appear embolic in origin and the patient has
a patent foramen ovale, then venous studies should be
considered, including lower-extremity Doppler ultra-
sound and pelvic MR venography (as pelvic veins may
be an important source of paradoxical emboli).

Cerebrovascular Complications 163
Treatment Considerations in Cancer Patients

■ The American Stroke Association and American Heart
Association have published guidelines for secondary pre-
vention of stroke.6
■ Additional considerations regarding thrombolysis in cancer
patients include the following:

• Further investigations are needed to determine the
role of thrombolysis in cancer patients, as large stud-
ies of recombinant tissue plasminogen activator (rTPA)
excluded patients with malignancy.
• Case series have reported the use of thrombolysis in
cancer patients.3
• Neither brain tumor nor cancer is an established
exclusion criteria for thrombolysis.
• Established exclusion criteria that may apply to cancer
patients include thrombocytopenia (platelet count
,100,000), major surgery within 14 days, and a prior
history of intracranial hemorrhage.5
Embolism
■ Signs and symptoms may not be limited to the CNS, as
emboli may spread to multiple organs or extremities.
■ The most common source of emboli in the general popu-
lation is the heart (usually caused by atrial fibrillation).
■ Other cancer-related causes of embolism are discussed
later in this chapter.
Tumor Embolism
■ Rare cause of stroke in cancer patients
■ Common sources of tumor emboli include
• Atrial myxomas and other cardiac tumors

• Lung cancer: most often occurs within 48 hours of sur-
gical manipulation of lung tissue but may also result
form tumor invasion of pulmonary veins or the left
atrium of the heart7

164 Chapter 8
Nonbacterial Thrombotic Endocarditis (NBTE)

■ Formerly known as marantic endocarditis
■ Defined as sterile vegetations on cardiac valves in the
absence of bacteremia
Clinical Features
■ Cases have been reported in several malignancies, includ-
ing lung (especially adenocarcinoma), pancreatic, gastric,

breast, prostate, colorectal, ovarian, and thyroid.8
■ Although more common in cancer patients, NBTE
may also occur in patients with nonneoplastic hyperco-

agulable disorders such as antiphospholipid antibody
syndrome.
■ NBTE may occur in association with disseminated intra-
vascular coagulopathy (DIC).

■ Systemic emboli occur in nearly 50% of patients with
NBTE.8
■ Presenting signs and symptoms may depend on the site(s)
of embolization.
• Central nervous system infarcts may present as focal
or diffuse neurologic symptoms depending on the loca-
tion and number of emboli.
• Renal infarcts may present as hematuria.
• Splenic infarcts may present as left upper quadrant
pain.
• Peripheral artery emboli may present as a cold, cyan-
otic, or pulseless limb.
■ Cardiac murmurs are infrequently noted.
Characteristics of Vegetations8
■ The most commonly affected valves are the aortic and
mitral valves.
■ Vegetations generally do not alter or impede valve
function.
■ Vegetations contain degenerating platelets interwoven
with strands of fibrin.

■ Vegetations observed in NBTE tend to detach and
cause extensive infarction more readily than vegetations

observed in infective endocarditis.

Diagnosis
■ An MRI is more sensitive and specific for diagnosing
embolic strokes acutely than CT.
■ A two-dimensional echocardiogram is useful, but a
transesophageal echocardiogram may be more sensitive

in detecting valvular vegetations than a transthoracic
echocardiogram.
■ Blood cultures are negative in NBTE.
Treatment
■ Optimal treatment is not well established.
■ Anticoagulation has been reported to prevent recurrent
embolism.8
• Several reports show successful management with
unfractionated heparin.
• Low molecular weight heparin may also be effective,
although the experience is limited.
• Recurrent thromboembolic events may occur on war-
farin and therefore warfarin is not recommended.
■ Anticoagulation may need to be continued indefinitely.
■ Cardiac surgery may be indicated for severe valvular dys-
function and recurrent emboli despite anticoagulation.9
Septic Embolism
■ Immunocompromised patients and leukemic patients are
susceptible to septic infection, infectious endocarditis,

and infectious vasculitis.
■ Causes include Aspergillus and Candida.
■ Infarctions may be multiple and/or hemorrhagic and may
evolve into cerebral abscesses.
Paradoxical Embolism
■ Embolism of venous origin through cardiac shunt (e.g.,
patent foramen ovale [PFO], atrial septal defect [ASD],
ventricular septal defect [VSD])
■ Strokes in patients with PFOs cannot be assumed due to
paradoxical embolism, as PFOs are common (detected in

20% to 35% of the general population at autopsy10).

166 Chapter 8
■ Diagnostic criteria for the diagnosis of paradoxical

embolism11
• Cerebral or systemic embolism without a left-sided
source
• Presence of a venous thrombus or pulmonary embolism
• Demonstration of a right-to-left shunt
• Elevated right heart pressure, either constant eleva-
tion (e.g., pulmonary hypertension) or transient eleva-
tion (e.g., cough, Valsalva maneuver)
Thrombotic Disease (Including Small, Medium,

and Large Vessel Disease)
Postradiation Vasculopathy
■ Can affect intracranial and extracranial vessels
■ Typically involves medium and large vessels
Internal Carotid Artery (ICA) Stenosis

■ The frequency of ICA stenosis after external neck radia-
tion ranges from 12% to 60%.12
■ In a meta-analysis based on case series and retrospective
studies, the odds of a cerebrovascular event after neck

irradiation were 9.0 compared with nonirradiated
patients.13
■ Neck irradiation is associated with intimal damage with
mural thrombosis formation in 5 years, fibrotic occlusion

in 10 years, and atheroma formation with periarterial
fibrosis in 20 years or more.14
■ Other vascular pathologies after radiation have been
described, including vascular malformations, aneurysm

formation, and accelerated atherosclerosis.15
Postoperative Complications
■ Neurosurgical patients with brain tumors have an
increased risk of thromboembolic disease.16,17

■ Adjacent ischemic lesions are found on MRI in about
70% of high-grade glioma patients after craniotomy.18

Intravascular Lymphoma
■ Also known as angiotropic large-cell lymphoma or malig-
nant angioendotheliomatosis
■ Rare type of non-Hodgkin lymphoma, typically a large
B-cell lymphoma, characterized by selective growth of

neoplastic cells within the lumina of small- and medium-
sized blood vessels
Clinical Features
■ Typically disseminated, although clinical presentations
often different depending on geographical location of

patient
■ In Western countries, propensity to manifest more fre-
quently in the central nervous system and skin19

• The central nervous system is affected in almost two
thirds of cases in Western patients with IVL.20
• Neurologic manifestations depend on location of
involvement but may include multifocal cerebrovascu-
lar events, dementia, subacute encephalopathy, sei-
zures, and myelopathy.
• Neurologic signs are caused by obliteration of vessels
and may transiently respond to corticosteroid
treatment.
■ In Asian countries, often presents as a hemophagocytic
syndrome (bone marrow involvement, fever, hepatosple-

nomegaly, thrombocytopenia)21
Diagnosis
■ Suggested workup based on international consensus
meeting22
• Physical examination with emphasis on nervous
system and skin (suspicious skin lesions should be
referred for biopsy)
• Routine blood studies, including hepatic, pulmonary,
renal, and thyroid function tests (with any abnormal
results further investigated by imaging or biopsy)
• Peripheral blood smear

168 Chapter 8
• Body CT with contrast

• Brain MRI with contrast
• Lumbar puncture for CSF examination and cytology
• Bone marrow biopsy
• Possibly PET study
■ Laboratory findings are not specific and may include
anemia, increased serum lactate dehydrogenase, and
increased b2-microglobulin levels.
■ CSF may demonstrate elevated protein and pleocytosis,
with lymphona cells ancedotally reported in cases.
■ Neuroimaging and body CT are associated with a rela-
tively high proportion of false negatives.19
■ A brain MRI may demonstrate multiple infarct-like
lesions in the white matter, focal parenchymal enhance-
ment, dural and arachnoid enhancement, and vasculitis-
like lesions.23
Treatment
■ Limited data on best treatment options, although inter-
national consensus guidelines have been published22
■ Anthracycline-based chemotherapy recommended by
consensus panel, although a more intensive regimen with

greater CNS penetration is needed in patients with CNS
involvement
Prognosis
■ Commonly fatal disease characterized by an aggressive
course and short outcome with few long-term survivors
reported19
■ Aggressive chemotherapy early in the disease process
increases survival24 and therefore early diagnosis important
Hyperviscous Obstruction
■ Hyperviscosity may be caused by an increase in serum
proteins or an increase in cells.

■ Symptoms from hyperviscosity usually occur at a serum
viscosity greater than 5 centipoises (normal serum viscosity

is between 1.4 and 1.8 centipoises).25
■ Symptoms of hyperviscosity include

• Spontaneous bleeding from mucous membranes

• Visual disturbances caused by retinopathy
• Neurologic symptoms, including headaches, vertigo,
seizures, altered consciousnesses, and cerebral
infarction
■ Cerebral infarction caused by hyperviscous obstruction is
rarely seen with polycythemia vera, acute myelogenous
leukemia (cell count .100,000 mm3), chronic lymphatic
leukemia (cell count .250,000 mm3), and multiple
myeloma.4
Intracranial Hemorrhages
Types of Intracranial Hemorrhages
Intraparenchymal Hemorrhage
■ This occurs more frequently in hematological malignancies,
especially acute myelogenous leukemia, and in patients

with coagulation disorders.4
■ This may occur as a result of venous infarction (see
cerebral venous thrombosis section later in this chapter).

■ Other causes include hypertension and cerebral amyloid
angiopathy.
Intratumoral Hemorrhage
■ Hemorrhage can be the presenting sign of a brain mass.
• Can obscure the tumor’s appearance on imaging

studies
• Neuroimaging clues to an underlying tumor include
■ More perifocal edema than expected for the
hemorrhage
■ Hemorrhage in unusual locations (e.g., close to the
subarachnoid space)
■ Pattern of contrast enhancement not expected for
the age of the hemorrhage

■ CNS metastases
• The risk of bleeding into CNS metastases varies accor-

ding to histology.
• Brain metastases from lung cancer, especially broncho-
genic carcinoma, are the most common hemorrhagic

170 Chapter 8
lesions because they occur in greater numbers;

however, fewer than 1% of brain metastases are from
lung cancer bleed.26
• The risk of bleeding into CNS metastases is high in
thyroid cancer, melanoma (40% to 50%), renal cell
carcinoma (70%), and choriocarcinoma.26
■ Primary brain tumors
• The reported rates in primary brain tumors range from
0.6% to 14.6% with the majority of cases involving
high-grade astrocytomas and oligodendrogliomas.27
• Intracranial hemorrhage rates in patients with menin-
giomas range from 1.3% to 2.4%28,29 and may present as
subarachnoid, intratumoral, or subdural hemorrhage.
Intraventricular Hemorrhage
■ Rare in cancer patients
■ May be seen in primary brain tumors in or near the ven-
tricular space
Subarachnoid Hemorrhage
■ Neoplastic aneurysms (discussed further later in this
chapter)
■ Infectious aneurysms caused by fungal (e.g., Aspergillus,
Candida) or bacterial infections

■ Other causes include trauma, coagulation disorders
Subdural Hemorrhage
■ Tumors with propensity to invade or metastasize to the
subdural space may include leukemia, lymphoma, pros-
tate cancer, and breast cancer.
■ MRI with contrast may demonstrate thickened dura and
subdural hemorrhage.
■ Other causes include trauma, coagulation disorders, and
thrombocytopenia.
Epidural Hemorrhage
■ May occur in association with a primary brain tumor or
skull metastasis

Clinical Features
■ Presentation depends on the size and location of hemor-
rhage and is similar to hemorrhages from noncancer
causes.
■ Presenting signs and symptoms may include acute onset
neurologic deficits, headache, and altered consciousness.
Diagnosis
■ A noncontrast head CT is the first-line diagnostic
approach.
■ MRI with gradient echo can also detect hyperacute
hemorrhages and may be more accurate for detecting

microhemorrhages.30
■ Angiography (CT or MR) may help identify aneurysms,
arteriovenous malformations, and vasculitis.
Management
■ This is based on management principles of intracranial
hemorrhages in the noncancer population.

■ Urgent referral to the hospital is recommended for diag-
nosis by imaging, correction of any potentially reversible

causes of hemorrhage (e.g., thrombocytopenia, antico-
agulation), and management of any adverse events (e.g.,
neurologic deterioration, cardiovascular instability).
Cancer-Related Causes of Intracranial Hemorrhage

Coagulation Disorders
■ This may result in intraparenchymal or subdural hemor-
rhages.
■ Examples of coagulopathies seen in cancer patients
include chemotherapy-induced thrombocytopenia,

disseminated intravascular coagulopathy, vitamin K defi-
ciency (due to poor diet), clotting factor deficiencies
caused by liver damage, immune-mediated platelet
destruction, and thrombotic thrombocytopenia purpura.
Neoplastic Aneurysms
■ These are aneurysms caused by neoplastic infiltration of
arteries.

172 Chapter 8
■ Rupture may result in subarachnoid or intraparenchymal

hemorrhages.
■ Neoplastic aneurysms are usually small and located in
distal artery branches.
■ They are typically caused by metastasis of cardiac myxoma
or choriocarcinoma, although cases of lung cancer metas-
tasis have been reported.
Pituitary Tumor Apoplexy

■ Refers to hemorrhage or infarction of a preexisting pitu-
itary adenoma
■ Uncommon syndrome
■ Often spontaneous
■ Signs/symptoms caused by a sudden increase in sellar
contents compressing surrounding structures and portal

vessels
• Sudden, severe headache
• Visual disturbances
• Impairment in pituitary function
■ Management
• Supportive therapy with intravenous fluids and

corticosteroids
• Clinically unstable patients may require urgent surgi-
cal decompression
• Long-term follow-up for management of tumor and
pituitary dysfunction
Vascular Endothelial Growth Factor (VEGF) Pathway Inhibitors

■ Includes monoclonal antibodies against VEGF (e.g., bev-
acizumab) and tyrosine kinase inhibitors targeting the

VEGF receptor (e.g., sorafenib, sunitinib)
■ Increased risk of bleeding noted in early clinical studies
of bevacizumab ranging from minor mucocutaneous

bleeding (e.g., epistaxis) to major life-threatening bleed-
ing (e.g., hematemesis, hemoptysis)26
■ CNS metastases
• Until recently, patients with brain metastases were

often excluded from clinical trials of VEGF and
VEGFR inhibitors.26,31

• Based on a review of clinical trials of VEGF and

VEGFR therapies in systemic cancer, rates of intrac-
ranial hemorrhage are negligible.26 In patients with
known brain metastases treated with anti-VEGFR
therapy, there were no episodes of intracranial
hemorrhage.
• Preliminary results from retrospective review of all
patients treated with bevacizumab in clinical trials (undi-
agnosed brain metastases at time of enrollment or
developed brain metastases during trial) are as follows31:
■ Data set A (13 completed randomized controlled
phase II and III trials in which 187 patients with

CNS metastases identified): low incidence of hem-
orrhage, 3/91 (3.29%) in bevacizumab arm, and
1/96 (1.04%) in nonbevacizumab arm
■ Data set B (2 open-label, single-arm safety studies
in which 321 patients with CNS metastases identi-

fied): low incidence of cerebral hemorrhage 3/321
(0.93%)
■ Data set C (2 ongoing trials in which 131 patients
with NSCLC and pretreated CNS metastases were

included): low incidence of cerebral hemorrhage,
1/131 (0.8%)
■ High-grade gliomas
• Based on phase II clinical trials of bevacizumab in
recurrent high-grade gliomas, rates of major intracra-
nial hemorrhage have ranged from 0 to 2.9%.32–37 Of
note, many of these trials excluded patients with
evidence of intracranial hemorrhage on imaging prior
to the initiation of therapy.
• In a small retrospective study of high-grade glioma
patients, the addition of anticoagulation to bevaci-
zumab treatment was not associated with major intrac-
erebral hemorrhage causing neurologic deficits or
death.38
Cerebral Venous Thrombosis (CVT)

■ Nonseptic thrombosis of the intracranial veins and/or
sinuses

174 Chapter 8
Risk Factors
■ Similar risk factors as deep venous thrombosis, including
coagulation disorders, cancer, and pregnancy
■ May also be caused by compression or invasion of cere-
bral sinuses from dural-based lesions such as menin-

giomas, brain metastases, or lymphoma
Clinical Features
■ Clinical presentation is often nonspecific.
■ Most common signs and symptoms are headache, sei-
zures, focal neurologic deficits, altered consciousness,

and papilledema.
■ The onset of symptoms may be acute ( ,48 hours),
subacute (48 hours to 30 days), or chronic (.30 days).

■ Main patterns of presentation include39
• Isolated intracranial hypertension (headache and

papilledema)
• Focal syndrome (focal deficit, seizure)
• Cavernous sinus syndrome including orbital pain,
chemosis, proptosis, oculomotor palsies
• Subacute encephalopathy
Diagnosis
■ Imaging of the venous system demonstrating occlusion is
most helpful. Options include MR venography or CT

venography.
■ MRI and MR venography have been the noninvasive
imaging techniques of choice, although CT venography is

emerging as a competing technique.40
• Thrombus may manifest as absence of flow void, best
seen on FLAIR images and T2-weighted spin-echo
images.
• Imaging may demonstrate indirect signs of CVT,
including
■ Diffuse cerebral edema
■ Venous infarction
• Suspicion for a venous infarction should be raised if

the infarction does not conform to an arterial vascular
territory.

• The lesion may be hemorrhagic.

• Deep venous thrombosis is typically associated with
bilateral or unilateral infarction in the thalami, basal
ganglia, and internal capsules.
■ A head CT may show direct or indirect signs of CVT,
although it may be negative in 10% to 30% of cases
of CVT.40
• Noncontrast head CT may demonstrate a dense clot
sign from thrombosis of the dural sinus or a cord sign
from thrombosis of a cortical vein.
• Contrast-enhanced head CT may demonstrate an
empty delta sign from thrombosis of the dural sinus.
• A head CT may also demonstrate indirect signs of CVT,
as seen in MRI (discussed previously in this chapter).
Treatment
■ Therapeutic anticoagulation
• Acute treatment of CVT with intravenous or subcuta-

neous heparin has been demonstrated on the basis of
randomized trials, a meta-analysis, and case series.39
• The length of treatment is unclear, although anticoag-
ulation with warfarin should be continued for at least
6 to 12 months, possibly longer depending on the risk
of further thromboses.
■ The utility of thrombolysis for CVT in cancer and non-
cancer patients is unclear.

■ The management of elevated intracranial pressure is the
same as the management of elevated intracranial pres-

sure from other causes.
Prognosis39
■ The prognosis in all patients with acute CVT (not just
cancer patients) is a 15% overall death and dependency

rate.
■ Long-term predictors of poor prognosis include any type
of cancer, CNS infection, deep venous system thrombosis,

intracranial hemorrhage, and age greater than 37 years.
■ Predictors of death at 30-days include depressed con-
sciousness, deep venous system thrombosis, right hemi-

spheric hemorrhage, and posterior fossa lesions.

176 Chapter 8
■ The main causes of acute death include transtentorial

herniation caused by large hemorrhage, multiple lesions,
or diffuse brain edema.
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C H A P T E R 9
Medical Complications
of Brain Tumor Patients
Seizures
Epidemiology
■ Up to 60% of patients with brain tumors may present
with seizures or may have a seizure for the first time after
diagnosis of the tumor.1
■ The risk of seizure depends on the type of brain tumor,
grade, location, changes in peritumoral environment, and

genetic factors.1,2
• Slow-growing tumors (i.e., low-grade gliomas) are the
most epileptogenic, although the high frequency of
seizures may be related to longer survival.
• Seizure frequency is based on tumor type: dysem-
bryoplastic neuroepithelial tumors 100%, low-grade
astrocytomas and oligodendrogliomas 60% to 85%,
glioblastomas 30% to 50%, and brain metastases 20%
to 35%.
• Cortical tumors (frontal, temporal, parietal more than
occipital) cause seizures more frequently than infraten-
torial or sellar tumors.
■ In patients with systemic cancer, the incidence of seizures
unrelated to brain metastases is only 5%.3

■ Incidence of seizures in patients with brain metastases is
approximately 25% to 40%.4
Clinical Features
■ May present as simple or complex seizures with or with-
out secondary generalization

■ Causes of seizures in patients with cancer
• Related to parenchymal tumor: epileptogenic activity

likely arises from adjacent cortex since tumors are
usually electrically inert5
181
73724_CH09_Printer.indd 181 04/01/10 12:07:00 AM

182 Chapter 9
• Related to infiltrative lesions such as leptomeningeal

carcinomatosis or intravascular lymphomatosis
• Related to radiation necrosis, including temporal lobe
radionecrosis from head and neck radiation
• Related to central nervous system infection or oppor-
tunistic infection
• Related to epileptogenic medications including some
antidepressants, neuroleptics, antibiotics, and chemo-
therapy (e.g., high-dose busulfan, cisplatin, chloram-
bucil, isophosphamide, paclitaxel, methotrexate)
• Related to paraneoplastic syndromes such as limbic
encephalitis
• Related to metabolic disorders
• Related to cerebrovascular complications such as intrac-
ranial hemorrhages, venous sinus thrombosis, or stroke
Seizure Prophylaxis
Perioperative Period
■ Conflicting data regarding the prophylactic use of anti-
epileptic drugs in patients undergoing surgery for a brain

tumor2
Outside the Perioperative Period

■ American Academy of Neurology Practice Parameters6
• “Because of their lack of efficacy and their potential

side effects, prophylactic anticonvulsants should not
be routinely used in patients with newly diagnosed
brain tumors.”
• “In patients with brain tumors who have not had a
seizure, tapering and discontinuing anticonvulsants
after the first postoperative week is appropriate. . . .”
■ Cochrane Review: “Evidence for seizure prophylaxis
with phenobarbital, phenytoin, and divalproex sodium in

people with brain tumors is inconclusive. . . . Therefore,
there are no data supporting the use of prophylactic
antiepileptics and the risk of adverse events lessens their
overall potential benefit.”1

Medical Complications of Brain Tumor Patients 183
■ Sirven et al. meta-analysis: “In patients with no history of

seizures, evidence does not support the use of seizure
prophylaxis with phenobarbital, phenytoin, or valproic
acid for gliomas, cerebral metastases or meningiomas.”7
Seizure Treatment
■ Limited data are available on the efficacy of specific anti-
epileptic medications in patients with brain tumors.

• Several prospective and retrospective studies showed
that add-on levetiracetam decreased seizure frequency
in 27% to 90% of patients with brain tumors.2
• Small prospective study of add-on gabapentin showed
seizure reduction in all patients with 57% becoming
seizure free.8
■ Some patients may develop medical refractory epilepsy
due to several reasons, including multidrug resistance.

Treatment options include
• Surgical resection of epileptogenic zone: 70% to 90%
of patients become seizure free or enjoy a substantial
reduction in seizure frequency after total resection of
the epileptogenic zone.2
• Radiation: small series demonstrated reductions in
seizure frequency following radiation.9,10
• Chemotherapy: temozolomide reduced seizure fre-
quency in 50–60% of glioma patients.11,12
■ Side effects are more frequent in patients with brain
tumors compared with the overall epilepsy population.2
Antiepileptic Drug–Drug Interactions

■ Enzyme-inducing antiepileptic drugs (EIAED) (Table 9-1)
• Includes phenobarbital, primidone, carbamazepine,
and phenytoin
• Induce cytochrome P450 coenzymes, resulting in
decreased effectiveness of medications metabolized
by the P450 system, including several chemothera-
peutic agents and corticosteroids

Table 9-1: Common Antiepileptic Medications
Generic Name Trade Name Special Considerations in Brain Tumor Patients
Drugs that cause little or no induction of P450 enzymes
184 Chapter 9
Clonazepam Klonopin Used as adjuvant therapy; side effects that include sedation
Gabapentin Neurontin Three to four times daily dosing, perceived as less efficacious than other antiepileptics,
although data are conflicting
Lamotrigine Lamictal Slow titration to minimize rash risk and therefore may take several weeks to get to
therapeutic levels
Levetiracetam Keppra Therapeutic starting dose; side effects that include depression
Lorazepam Ativan Used for status epilepticus; side effects that include sedation
Tiagabine Gabitril Side effects that include depression
Topiramate Topamax Weak enzyme inducer; side effects that include cognitive slowing; slow titration needed to
minimize CNS adverse effects.
(Continues)
04/01/10 12:07:00 AM
Table 9-1: Common Antiepileptic Medications (Continued)
Generic Name Trade Name Special Considerations in Brain Tumor Patients
Valproic Acid Depakote, Side effects that include hepatotoxicity, thrombocytopenia and abnormal coagulation at higher
Depakene doses, enzyme inhibiting effects (which may raise levels of certain chemotherapeutic agents)
Zonisamide Zonegran Side effects that include cognitive impairment; slow titration necessary
Drugs that induce P450 enzymes
Carbamazepine Tegretol Side effects that include hyponatremia, small risk of bone marrow suppression
Oxcarbazepine Trileptal Dose-related effects that are similar to carbamazepine, although oxcarbazepine is a weaker
P450 inducer
Phenobarbital Luminal Behavioral and cognitive side effects
Phenytoin Dilantin Strong P450 inducer
Primidone Mysoline Similar side effects as phenobarbital but possibly more sedating that phenobarbital
Data are from Bromfield EB. Epilepsy. In: Samuels MA, ed. Manual of Neurologic Therapeutics, 7th ed. Philadelphia: Lippincott Williams &
Wilkins; 2004:33–64. Porter RJ, Meldrum BS. Antiseizure drugs. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology,
11th ed. New York: McGraw-Hill Companies; 2009:399–422.
04/01/10 12:07:00 AM
186 Chapter 9
• Chemotherapeutic agents affected by EIAEDs include

nitrosureas (e.g., temozolomide), paclitaxel, cyclo-
phosphamie, etoposide, topotecan, irinotecan,
thiotepa, doxorubicin, and methotrexate
• Phenytoin and phenobarbital shorten the half-life of
dexamethasone and prednisone13
■ Valproic acid is an enzyme-inhibiting antiepileptic drug,
which may result in raised plasma concentrations of other
agents and possibly increased toxic effects.
■ Many chemotherapeutic agents may affect the plasma
concentrations of antiepileptic medications.2
■ Agents with minimal or no induction of P450 enzymes
are found in Table 9-1.
Practice Considerations
■ New-onset seizures in a patient with known systemic
cancer should raise suspicion for brain metastases.
A brain MRI with contrast is the imaging modality of
choice for brain metastases.
■ Seizure prophylaxis is generally not recommended in
patients with no history of seizures.

■ Antiepileptic treatment is recommended in patients with
brain tumors after the first seizure.

■ The length of treatment after the first and only seizure is
unclear, although patients may require lifetime antiepi-

leptic treatment, especially if the tumor is still present.
■ Each state has specific laws regarding driving after a
seizure. In general, physicians should warn their patients

regarding the risks of driving and other behaviors that
could result in injury or death should a seizure occur
(i.e., swimming).
■ Consider drug–drug interactions and side-effect profiles
(e.g., bone marrow suppression, cognitive impairment)

when choosing an antiepileptic for a patient.
Venous Thromboembolism (VTE)

■ VTE includes deep vein thrombosis (DVT) and pulmonary
embolism (PE).

Epidemiology
■ VTE is common in patients with cancer, including
primary brain tumors.
■ The incidence of symptomatic VTE in patients with
high-grade glioma outside the perioperative period is 20%

to 30%.14
■ The risk for VTE in high-grade glioma patients is
higher in the postoperative period and in patients with

hemiplegia.
■ The incidence of symptomatic VTE in primary CNS
lymphoma is 18%.14
■ The incidence of VTE is higher in patients with cancer
than patients without cancer.15

■ It is the second leading cause of death in cancer
patients.16
Risk Factors14
■ Postoperative period
■ Hemiparesis
■ Age ⬎60
■ Large tumor size
■ Chemotherapy
■ Hormonal therapy
■ Steroids and osmotic diuretic agents, which may also
increase the rate of clot formation17
Clinical Features
■ DVT: erythema, warmth, pain, tenderness, and edema in
one leg
■ PE: chest pain, cough, tachypnea, tachycardia, and short-
ness of breath
Diagnosis
■ DVT: duplex ultrasonography
■ PE: chest CT angiogram
Prophylaxis
■ Prophylaxis is recommended in the perioperative setting
and during hospitalization.

188 Chapter 9
■ An optimal prophylactic regimen has not been established.

■ Options for prophylaxis include the following:
• Compression stockings and sequential pneumatic
compression devices
• Unfractionated heparin
• Low molecular weight heparin (LMWH) (e.g., enox-
aparin, dalteparin, tinzaparin, and nadroparin)
■ In patients with brain tumors, LMWH and unfraction-
ated heparin reduce the risk of VTE from 12.5% to 6.2%
and carry a 2% risk for major bleeding.18
■ The need for prophylaxis beyond the perioperative period
is less clear.
• A randomized phase III clinical trial of malignant
glioma patients that tested the safety and efficacy
of long-term dalteparin for prevention of VTE versus
placebo closed early due to expiration of study med-
ication.19
• In this study, there was a trend in favor of dalteparin
in reducing VTE but the results were not statistically
significant (although the study may have been under-
powered).
• There was also a trend for increased intracranial
hemorrhage in the dalteparin group, although the
difference was not statistically significant.
Treatment
■ The main objective of treatment of a DVT is to prevent
PE, as pulmonary emboli are associated with increased

morbidity and mortality.
■ Consider a noncontrast head CT before initiating therapy
to evaluate for intracerebral hemorrhage.

■ Options for treatment include the following:
• Low molecular weight heparin (LMWH)

• Unfractionated heparin IV or LMWH with transition
to warfarin
• In patients with a contraindication to therapeutic anti-
coagulation (i.e., intracerebral hemorrhage, recent
craniotomy, prolonged thrombocytopenia), an inferior
vena cava (IVC) filter should be placed.

■ An IVC filter is not necessary if the patient is able

to receive therapeutic anticoagulation.
■ IVC filters are associated with a higher complica-
tion rate and are less effective in preventing PEs as

compared to anticoagulation.20
■ IVC filter complications include pneumothorax,
infection, bleeding, IVC wall damage, recurrent

VTE, postphlebitic syndrome, and IVC thrombosis.
• In patients with heparin-induced thrombocytopenia,
direct thrombin inhibitors (e.g., lepirudin, argatroban,
bivalirudin) should be used instead.
■ Clinical trials and systematic reviews comparing differ-
ent anticoagulants in cancer patients with VTE suggest
that LMWHs are more effective than unfractionated
heparin and at least as effective or possibly more effec-
tive than warfarin.
• In a multicenter, randomized, open-label trial com-
paring enoxaparin versus warfarin for 3 months, war-
farin was associated with a high bleeding rate,
although the differences were not statistically signifi-
cant.21 When combining recurrent VTE and major
hemorrhage as the primary endpoint, the enoxaparin
group had statistically significant lower rates of this
combined endpoint.
• In a multicenter, randomized, open-label trial compar-
ing dalteparin followed by warfarin versus dalteparin
alone for 6 months, rates of recurrent VTE were lower
in the dalteparin alone group. There was no signifi-
cant difference in the rate of major bleeding or any
bleeding.
• Meta-analyses show that LMWHs are more effective
than unfractionated heparin for the initial treatment
of VTE and are associated with less major
bleeding.22,23
■ Initial treatment with unfractionated heparin (as opposed
to LMWH) should be considered in patients with serious
PEs and in patients at high risk for hemorrhage (as
protamine is able to reverse unfractionated heparin more
completely than LMWH).

190 Chapter 9
■ Properly monitored anticoagulation can be relatively safe

in patients with primary and metastatic brain tumors.20
• The incidence of cerebral hemorrhage is generally not
significantly elevated in studies.
• Hemorrhagic complications most commonly occur in
the setting of supratherapeutic anticoagulation.
■ The optimal length of treatment after an initial VTE is
unknown.
• No clinical trials have been performed to answer this
question.
• Some advocate using therapeutic anticoagulation
indefinitely in patients with cancer or at least as long
as the cancer is active.24
Cerebral Edema
■ There are two main types of cerebral edema.
• Vasogenic edema is most commonly associated with
brain tumors.
• Cytotoxic edema is due to hypoxia and is often caused
by ischemic strokes or traumatic brain injury.
■ Vasogenic edema results from the extravasation of intra-
vascular fluid and proteins into cerebral parenchyma
extracellular space due to breakdown of tight endothelial
junctions in the blood–brain barrier.
Clinical Features
■ Depend on location of cerebral edema
■ May include focal neurologic deficits, headaches, nau-
sea, vomiting, and lethargy
Diagnosis
■ The diagnosis is based on clinical history, symptoms, and
imaging.
■ MRI is the best imaging modality for assessment of
cerebral edema.
• Cerebral edema is hypointense on T1-weighted images
and hyperintense on T2-weighted images.
• It may be difficult to differentiate cerebral edema
from an infiltrating tumor.

Management14
Corticosteroids
■ Indicated for symptomatic peritumoral edema (usually
not necessary in asymptomatic patients with peritumoral

edema on neuroimaging)
■ Usually adequate for managing most peritumoral edema
■ Mechanism of action not well understood
■ Side effects (also discussed later in “Treatment Compli-
cations and Their Management” section)

• The side effects include osteoporosis, compression
fractures, avascular necrosis, steroid myopathy, gastro-
intestinal bleeding, pneumocystis jiroveci pneumoni-
tis (PJP), Cushingnoid features, adrenal insufficiency,
and cataracts.
• The severity of complications corresponds to the dose
and duration of symptoms.
• Most resolve after stopping steroids (except for osteo-
porosis and posterior subcapsular cataracts).
• The severity may be reduced with using the lowest
dose possible.14
■ Dexamethasone
• This is the preferred corticosteroid because of less

mineralocorticoid activity, and possibly lower risk of
infection and cognitive impairment compared with
other corticosteroids.25
• Dosing depends on the severity of symptoms.
■ The typical starting dose is 10 mg.
■ The typical initial maintenance dose is 16 mg per
day (divided into two to four times a day dosing),

but lower doses may be used if less symptomatic.
■ PO and IV dosing are equivalent.
■ In general, use the lowest dose that still provides
symptomatic benefit.
■ If lowering the dose, the dose should be tapered.
The longer the patient has been on steroids, the

slower the taper, although the length of the taper
will vary from patient to patient according to
symptoms.
• This induces improvement of neurologic symptoms
caused by peritumoral edema within 48 hours.

192 Chapter 9
• Improvement on imaging studies often lags behind

clinical improvement.
• Prophylactic treatment for potential side effects from
dexamethasone should be considered for the following
complications:
■ Gastrointestinal complications: histamine H 2
receptor blocker (e.g., famotidine, ranitidine) or

proton pump inhibitor (e.g., omeprazole, lansopra-
zole, pantoprazole)
■ Pneumocystis jiroveci pneumonitis (PJP)
■ Osteoporosis
Vascular Endothelial Growth Factor (VEGF)

Pathway Inhibitors
• VEGF is a major proangiogenic peptide that is partly
responsible for the loss of integrity of the blood–brain
barrier in brain tumors.26
• Anti-VEGF agents could be used to reduce vasogenic
cerebral edema.
■ In a phase II study of cediranib in patients with
glioblastoma patients, this agent significantly

reduced tumor-associated edema.27
■ For significantly elevated intracranial pressure and mass
effect not responsive to corticosteroids or for impending

herniation, hospitalization is warranted.
• Immediate measures to decrease intracranial pressure
such as elevation of the head of the bed, hyperventila-
tion, and fluid restriction should be started before
providing more definitive therapy.
• Hypertonic fluids
• Mannitol
• Surgical debulking
Pain
Headaches
Causes
■ These are typically caused by increased intracranial pres-
sure from the brain tumor and/or peritumoral edema.

■ Other causes should be considered in the correct clinical

context, including intratumoral hemorrhages, meningeal
processes, venous sinus thrombosis, analgesic medica-
tion overuse, depression, and migraines.
Clinical Features
■ Headaches that cause early morning awakening or are
more prominent on waking should raise suspicion for
increased intracranial pressure.
■ Headaches are typically associated with nausea and
vomiting.
■ Headaches are worse with coughing or Valsalva maneuver.
■ Papilledema may be present on funduscopic examination.
Treatment
■ Steroids are an option.
■ All classes of pain medications, including opioids, may be
considered; however, nonsteroidal anti-inflammatory

medications may increase the risk of gastric toxicity from
corticosteroids.
Neuropathic Pain
Potential Causes
■ Leptomeningeal disease
■ Lymphomatous invasion of nerves
■ Skull base involvement
■ Herpes zoster
■ Radiation
■ Chemotherapy (see Chapter 6 for chemotherapy-induced
peripheral neuropathy)
Clinical Features
■ Painful dysesthesias typically localized to specific der-
matomes, nerve root distributions, or peripheral extremi-

ties in a stocking-glove distribution
■ May be spontaneous and/or evoked by a stimulus
Treatment
■ May require a combination of agents
■ Spontaneous resolution

194 Chapter 9
• Pain associated with acute chemotherapy-induced

neuropathy may resolve after discontinuation of the
culprit chemotherapy.
• Neuropathic symptoms may progress for up to 2
months after stopping oxaliplatin or cisplatin.
• Recovery may be incomplete in some patients, result-
ing in chronic neuropathic pain.
■ Antiepileptic medications for neuropathic pain, includ-
ing gabapentin, carbamazepine, and pregabalin
• High doses of gabapentin may be required for pain
control (maximum up to 3,200 mg per day divided in
TID or QID dosing).
■ Antidepressants for neuropathic pain, including tricy-
clics (desipramine, amitriptyline, nortriptyline) and
serotonin/norepinephrine reuptake inhibitors (venlafax-
ine, duloxetine)
■ Topical or transdermal agents, including lidocaine
patches
■ All classes of pain medications, including opioids; how-
ever, nonsteroidal anti-inflammatory medications may
increase the risk of gastric toxicity.
■ Corticosteroids for patients with neuropathic pain from
leptomeningeal disease
Cognitive Impairment
Potential causes
■ Brain tumor
■ Radiation (see Chapter 5)
■ Chemotherapy (see Chapter 6)
■ Epilepsy and antiepileptic drugs
• In a study of low-grade gliomas, the presence of epi-

lepsy and the use of antiepileptic drugs were indepen-
dently associated with changes in memory, attention,
and communication.28
• The use of antiepileptics is associated with a sixfold
increase in cognitive deficits (such as attention, psy-
chomotor speed, executive function) as compared
with radiation.29
■ Other medical factors and complications contributing to
cognitive and neurobehavioral changes include endocrine

dysfunction, metabolic disturbances, infection, pain,

fatigue, anxiety, and depression.
Treatment
■ Only a few treatment trials in patients with brain tumors
have been conducted.
■ Psychostimulants
• Methylphenidate
■ Case study of methylphenidate in three high-grade
glioma patients with cognitive deficits from primary

brain tumors or radiation described improvements
in arousal, attention, initiation speed of tasks, and
mood.30
■ Open-labeled study of methylphenidate in high-
grade glioma patients showed significant improve-

ments in psychomotor speed, memory, visual–motor
function, executive function, motor speed, and dex-
terity, as well as subjective improvements in their
ability to function despite progressive disease and
increasing radiation damage.31
• Modafinil
■ In a pilot study of primary brain tumor patients
with fatigue or cognitive dysfunction, modafinil

improved cognition, mood, and fatigue.32
■ Donepezil
• In a study of brain tumor patients who received radia-

tion, donepezil improved cognitive functioning, includ-
ing memory, mood, and quality of life in patients with
brain tumors who received radiation therapy.33
■ Ventriculoperitoneal shunting
• Could be considered in patients with cognitive dys-

function due to communicating hydrocephalus34
■ Cognitive rehabilitation
Fatigue
■ Negatively affects quality of life
Potential Causes
■ Radiation (fatigue tends to increase with the number of
fractions)

196 Chapter 9
■ Antiepileptics
■ Chemotherapy
■ Anemia
■ Metabolic disturbances
■ Depression
■ Endocrine dysfunction
Treatment
■ Psychostimulants (e.g., methylphenidate, pemoline, dex-
troamphetamine, modafinil) are generally well tolerated
in brain tumor patients but may lower the seizure thresh-
old (except for modafinil)
Treatment Complications and Their

Management
Musculoskeletal
Osteoporosis and Compression Fractures
■ Chronic corticosteroids (prednisone dose greater than
2.5 to 5 mg/day) increase the risk of osteoporosis, which,

in turn, predisposes a patient to fractures such as verte-
bral compression fractures.35,36
■ Clinical features associated with compression fractures
include back pain, nerve impingement (numbness, tin-

gling, weakness), urinary/stool incontinence, or retention
due to spinal cord compression.
■ Diagnosis
• Osteoporosis is diagnosed with a bone mineral density

(BMD) test.
• Vertebral compression fractures can be seen on X-rays
or spine CT scans, but a spine MRI may be necessary
to evaluate for spinal cord compression (if neurologic
symptoms are present).
■ Prophylactic therapy should be provided to patients on
chronic steroids.
• Calcium supplementation 1,500 mg/day
• Vitamin D 800 IU daily or activated vitamin D such as
calcitriol 0.5 µm/day

■ Treatment
• Calcium and vitamin D should be given to all patients
with osteoporosis.
• Bisphosphonates (e.g., etidronate, alendronate,
risedronate, zoledronate) improve BMD and may
reduce the risk of fractures although the data are
not definitive.20
• Compression fractures may require hospitalization if
neurologic symptoms are present or if the pain is too
severe to manage as an outpatient.
• Spine surgeon consultation is warranted if the patient
has spinal cord compression or spine instability.
• Vertebroplasty is often used to relieve pain from com-
pression fractures, but two recent multicenter ran-
domized, placebo-controlled trials demonstrated no
benefit for painful osteoporotic vertebral fractures.
■ In a randomized trial of 131 patients with painful
osteoporotic vertebral compression fractures com-

paring vertebroplasty versus a simulated procedure
without cement, improvements in pain and pain-
related disability at 1 month were similar in both
groups.37
■ In a randomized trial of 78 patients with painful
osteoporotic vertebral fractures comparing verte-

broplasty with a sham procedure, the authors found
no beneficial effect at 1 week or at 1, 3, or 6 months
after treatment.38
Steroid Myopathy
■ Occurs in up to 60% of cancer patients39
■ More common in older persons and after prolonged use
of high-dose corticosteroids
• Subacute onset proximal muscle weakness and

wasting (especially in the lower extremities) result-
ing in difficulty climbing stairs or rising from a
seated position
• Normal muscle enzymes

198 Chapter 9
■ Diagnosis
• Diagnosis is primarily based on clinical history.
• Electromyography is nonspecific and may demonstrate
myopathic changes.
• Muscle biopsy is only necessary if the diagnosis is in
question and may contain type IIb muscle fiber
atrophy.
■ Prophylactic therapy
• Nonfluorinated steroids (e.g., prednisone, hydrocorti-
sone) may carry a lower risk of steroid myopathy than
fluorinated steroids (e.g., dexamethasone).20
• Regular exercise may attenuate symptoms of steroid
myopathy.
■ Treatment
• Stopping steroids or decreasing to the lowest possi-
ble dose
• Physical therapy
■ Prognosis: recovery may take several months
Syndromes Associated With Steroid Withdrawal

Adrenal Insufficiency
■ Caused by impaired adrenal steroid synthesis
■ Seen with mitotane, ketoconazole, aminoglutethimide,
megestrol, prior cranial irradiation for childhood brain

tumors, or rapid reduction in corticosteroid therapy
■ Rarely seen with replacement of both adrenal glands by
metastases
• Patients may develop nausea, vomiting, anorexia, and

lethargy.
• Acute adrenal crisis (hypotension, mental status
changes, hypoglycemia) may occur with abrupt ces-
sation.
■ Diagnosis: rapid ACTH stimulation test
■ Treatment
• Mild symptoms can be managed as an outpatient by

increasing the steroid dose and then tapering more
gradually or using alternate day administration.
• Acute adrenal insufficiency may require hospitaliza-
tion for intravenous hydration, glucose, and steroids.

Steroid-Withdrawal Syndrome
■ Clinical features include nausea, headache, myalgias,
malaise, and weight loss.40
■ Treatment includes slower steroid taper or alternate day
administration.
Steroid Pseudorheumatism41
■ Clinical features include diffuse arthralgias.
■ Treatment includes slower steroid taper and NSAIDs.
Gastrointestinal Complications
Peptic Ulceration
■ Peptic ulceration may theoretically occur with continued
use of corticosteroids.
■ From studies of patients on steroids, the overall inci-
dence of peptic ulceration is low, but the incidence is

increased in patients on both steroids and nonsteroidal
anti-inflammatory medications.14
■ Clinical features include nonspecific epigastric pain with
variable relationship to meals, nausea, and anorexia.

■ Diagnosis
• Upper endoscopy
• Abdominal CT only when complications such as per-
foration, penetration, or obstruction suspected
■ Prophylaxis includes histamine H 2 receptor blocker
(e.g., famotidine, ranitidine) or a proton pump inhibitor

(e.g., omeprazole, lansoprazole, pantoprazole)
■ Treatment regimens differ based on presence or absence
of H. pylori infection
Upper Gastrointestinal Hemorrhage

■ This may occur as a complication from peptic ulcer
disease.
■ Clinical features include melena, hematemesis, melenem-
esis, and hemodynamic instability.

■ Prophylaxis includes histamine H receptor blocker
2
(e.g., famotidine, ranitidine) or a proton pump inhibitor
(e.g., omeprazole, lansoprazole, pantoprazole).
■ Hospitalization is indicated, as this could be a life-
threatening emergency.

200 Chapter 9
Bowel Perforation
■ This is a rare complication of VEGF inhibitors such as
bevacizumab or peptic ulcer disease.
■ Clinical features include typically sudden-onset severe
abdominal pain. Shock, fever, nausea, and vomiting may

be present, although patients may be asymptomatic as
steroids can mask symptoms.
■ Hospitalization is indicated, as this could be a life-
threatening emergency.
Opportunistic Infections
Oropharyngeal Candidiasis (Thrush)
■ Most common opportunistic infection from steroid
immunosuppression
■ Caused by the fungus Candida albicans
• Oral pain, dysphagia, odynophagia, dysgeusia, and

aversion to food
• Thrush: characterized by white patches on the sur-
face of the buccal and labial mucosa, tongue, and soft
palate
■ Treatment
• Nystatin oral suspension 100,000 units four times a

day (swish and swallow) should be continued for sev-
eral days after clinical healing.
• If thrush does not improve with nystatin oral suspen-
sion, an azole antifungal agent should be provided.
■ Fluconazole 100 mg daily for 1 to 2 weeks
■ Clotrimazole troche 5 mL three to four times per
day for a 2-week minimum

■ Itraconazole capsule or oral solution 100 mg daily
for 2 weeks
• “Miracle mouthwash” (containing diphenhydramine,
lidocaine, and a Maalox-type aluminum/magnesium
antacid) may help with symptomatic relief of pain but
does not treat thrush.
Pneumocystis Jiroveci Pneumonitis (PJP)

■ PJP was previously known as pneumocystis carinii pneu-
monitis (PCP).

■ It is caused by the fungus Pneumocystis Jiroveci.

■ The frequency of PJP is low in cancer (187 cases per
100,000 patients with hematological cancer, 16 cases per
100,000 patients with solid tumors)42 but can be life
threatening.
■ Predisposing factors include corticosteroids, intensity
of chemotherapy treatment (e.g., daily temozolomide
treatment in glioma patients), and low CD4 cell count
(⬍200 cells/mm3).43
■ Clinical features are similar to acute pneumonia.
■ Diagnosis is as follows:
• Radiological imaging demonstrates bilateral interstitial
infiltrates.
• Definitive diagnosis requires cytologic examination of
bronchoalveolar lavage.
■ There are no published guidelines for prophylaxis in
patients without HIV, but the following regimens are
commonly used:
• Trimethoprim-sulfamethoxazole (TMP-SMZ) double
strength three times a week or single strength daily
• Aerosolized pentamidine 300 mg monthly
• Dapsone 50 mg twice per day or 100 mg daily
• Atovaquone 1,500 mg daily
■ For treatment, consider consultation with an infectious
disease specialist.
Behavioral and Psychiatric Changes

• Steroids may induce behavioral or psychiatric changes,

including anxiety, insomnia, emotional lability, eupho-
ria, and psychosis.44
• Steroids may also induce cognitive deficits such as
distractibility and memory impairment.45
■ Treatment
• Stopping or tapering steroids to the lowest possible

dose
• Consider neuroleptics (e.g., haldol, olanzapine, ris-
peridone, quetiapine) for more severe behavioral
changes such as psychosis, aggression, or agitation
• Consider antidepressants for depression

202 Chapter 9
• Consider mood stabilizers for mania

• Consider consultation with a psychiatrist
Endocrine Abnormalities
■ Hyperglycemia should be monitored in patients on ste-
roids because diabetes predisposes patients to infections.

■ Hyperglycemia is associated with shorter survival in
patients with glioblastoma, even after controlling for

mean daily dexamethasone dose.46
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Index
A Anti-Ma2 (Ta), 140–141

Anti-NMDA receptors, 141
Acute cerebellar toxicity, 113 Anti-voltage-gated potassium
Acute encephalopathy, 113 channels, 141
American Academy of Neurology Astrocytoma
Practice Parameters on seizure anaplastic astrocytoma, 11–15
prophylaxis, 182 diagnosis, 78–79
Amifostine, 122 diffuse astrocytoma, 8–11
Anaplastic astrocytoma (WHO glioblastoma, 15–18
Grade III/IV) pathology of, 78
biology, 11 pilocytic astrocytoma, 8
clinical features, 12 treatment, 79
MRI appearance, 12 Atypical meningiomas, 23
prognosis, 14–15 Autonomic neuropathy, 147
treatment Autosomal dominant
chemotherapy, 12 disorders, 4–5
radiation therapy, 12
recurrent disease, 14
surgery, 12
B
Anaplastic/malignant
meningiomas, 23 Benign meningiomas, 23
Anaplastic oligodendroglioma Bevacizumab, 100
biology, 19 Bowel perforation, 200
clinical features, 19 Brachytherapy, 93
MRI appearance, 19 Brain biopsy, 44
prognosis, 21–22 Brain metastases
treatment breast cancer, 53–55
chemotherapy, 20–21 diagnosis, 44
radiation therapy, 20 epidemiology, 43
recurrent, 21 melanoma, 55–57
surgery, 19–20 non-small cell lung cancer,
Angiotropic large-cell lymphoma. 57–58
See Intravascular lymphoma parenchymal metastases, 43
Antibody-mediated PND, 128–129 prognostic factors
Anticoagulation, 100 RPA classes, 45–46
Anti-CRMP5 (anti-CV2), 140 renal cell carcinoma, 58
Antiepileptic drug-drug surgery approach
interactions, 183–186 for multi brain metastasis, 52
Anti-Hu, 140 for single brain metastasis, 51
207
73724_IDXx_Printer.indd 207 04/02/10 09:50:00 PM

208 Index
Brain metastases (continued) management

vs. SRS, 52 corticosteroids, 191
with/without WBRT, 52 dexamethasone, 191–192
treatment approach VEGF pathway inhibitors, 192
chemotherapy, 52–53 types of, 190
SRS, 48–50 Cerebral venous thrombosis (CVT)
whole-brain radiation therapy, clinical features, 174
46–48 diagnosis, 174–175
Breast cancer, brain metastases prognosis, 175–176
epidemiology, 53–54 risk factors, 174
risk factors, 54 treatment, 175
treatment recommendations Chemical aseptic meningitis, 89
stereotactic radiosurgery, 54–55 Chemotherapy
surgery, 54 agents, 55
systemic treatments, 55 anaplastic astrocytoma, 12
whole-brain radiation therapy, 55 anaplastic oligodendroglioma,
20–21
astrocytomas, 79
C
brain metastases treatment, 52–53
Cancer-associated retinopathy common chemotherapy agents,
(CAR), 143–144 107–109
Capecitabine, 55 diffuse astrocytoma, 10–11
Carcinomatous meningitis, 83 leptomeningeal metastases
Central nervous system (CNS) intrathecal chemotherapy, 88–89
chemotherapy-related cognitive systemic chemotherapy, 89
impairment (Chemobrain), in melanoma, 58
110–111 metastatic epidural spinal cord
focal radiation necrosis, 99–101 compression, 72
imaging abnormalities following nerve sheath tumors, 75
radiation therapy, 96 seizure treatment, 183
metastases treatment schemes, 109
in breast cancer, 54 and WBRT, 48
in melanoma, 57 Chemotherapy-induced peripheral
in NSCLC, 56 neuropathy (CIPN)
neurocognitive dysfunction clinical signs and symptoms,
clinical features, 97 115, 120
clinical studies, 97–98 common chemotherapeutic
pathophysiology, 97 agents, 116–119
radiation, 96–97 prevention, 120–122
treatment, 98 risk factors, 115
neurotoxicity of specific agents, treatments and prognosis, 122
112–115 Chemotherapy-related cognitive
radiation-induced brain impairment (Chemobrain),
tumors, 101 110–111
radiation toxicity, 94–96 CIPN. See Chemotherapy-induced
RPLE, 111–112 peripheral neuropathy
Cerebral edema CNS. See Central nervous system
clinical features, 190 Coagulation disorders, 171
diagnosis, 190 Corticosteroids, 70–71, 191

Index 209
Cranial irradiation, 5, 94 5-Fluorouracil (5-FU), 112–113

CVT. See Cerebral venous Focal external beam radiation
thrombosis therapy, 27
Cytarabine, 112 Focal radiation necrosis, 98–101
Fractionation, 93
Frontal skull base meningiomas, 23
D
Deep vein thrombosis (DVT). See
Venous thromboembolism
G
Dermatomyositis, 151 Gastrointestinal complications
Dexamethasone, 191–192 bowel perforation, 200
Diffuse astrocytoma (WHO peptic ulceration, 199
Grade II/IV) upper gastrointestinal
biology of, 8 hemorrhage, 199
clinical features, 8 Glioblastoma (WHO Grade IV/IV)
MRI appearance, 8 biology, 15
prognosis, 11 clinical features, 15
treatment MRI appearance, 15
chemotherapy, 10–11 prognosis, 17–18
radiation therapy, 9–10 treatment
resection benefits, 9 newly diagnosed glioblastoma, 17
surgery, 8–9 recurrent glioblastoma, 17
Diffuse large B-cell lymphoma surgery, 16
(DLBCL), 29. See also Primary Gliomas
CNS lymphoma (PCNSL) astrocytic vs. oligodendroglial
Donepezil, 195 tumors, 6–7
astrocytoma
anaplastic, 11–15
E diffuse, 8–11
Embolism glioblastoma, 15–18
NBTE pilocytic, 8
characteristics of vegetations, 164 oligodendroglioma
clinical features, 164 anaplastic, 19–22
diagnosis and treatment, 165 oligodendroglioma, 18–19
paradoxical, 165–166 Glutamate, 121
septic, 165 Glutathione, 121
tumor, 163
Endocrine abnormalities, 202
Enzyme-inducing antiepileptic H
drugs (EIAED), 183–186 Headaches, 192–193
Epidural hemorrhage, 170 High-dose chemotherapy
Epidural spinal cord space, 68 with autologous stem-cell
External beam therapy (EBRT), 93 transplantation, 32
High-dose cytarabine, 112
F High-dose methotrexate
monotherapy, 31
Fatigue, 195–196 High-grade astrocytoma tumors, 79
Fludarabine, 113 High-grade gliomas, 173

210 Index
HIV-related PCNSL, 34–35 Intratumoral hemorrhage

Hodgkin lymphoma, 137 CNS metastases, 169–170
Hyperbaric oxygen therapy, 100–101 imaging studies, 169
Hyperglycemia, 202 primary brain tumors, 170
Hyperviscous obstruction, 168–169 Intravascular lymphoma
clinical features, 167
diagnosis, 167–168
I prognosis and treatment, 168
Intraventricular hemorrhage, 170
Ifosfamide, 113–114
Ionizing radiation exposure, 5
Inclusion body myositis, 151–152
Ischemic strokes, cancer patients
Inflammatory myopathies
management guidelines, 161–162
dermatomyositis, 151
risk factors, 161
inclusion body myositis, 151–152
treatment considerations, 163
polymyositis, 150–151
Intensity-modulated radiation
therapy (IMRT), 93 K
Interferon-␣, 114
Internal carotid artery (ICA) Karnofsky performance status
stenosis, 166 (KPS) scale, 44–45
Intracranial hemorrhages
cancer-related causes L
coagulation disorders, 171
neoplastic aneurysms, Lambert-Eaton myasthenic
171–172 syndrome (LEMS), 128, 148–149
pituitary tumor apoplexy, 172 Lapatinib, 55
VEGF pathway inhibitors, Leptomeningeal carcinomatosis, 83
172–173 Leptomeningeal metastases
clinical features, 171 clinical features, 84
diagnosis, 171 diagnosis, 85–86
management principles, 171 epidemiology, 83–84
types of, 169–170 pathogenesis, 84
Intramedullary astrocytoma. See prognosis, 86–87
Intramedullary spinal cord tumors treatment
Intramedullary metastasis, 79 chemotherapy, 88–89
Intramedullary spinal cord tumors radiation therapy, 88
astrocytoma supportive care, 89–90
diagnosis, 78–79 surgery, 87–88
pathology of, 78 Leukemic meningitis, 83
treatment, 79 Li-Faumeni (TP53), 4
clinical features, 77 Low-grade astrocytoma tumors, 79
ependymoma Low molecular weight heparin
diagnosis, 77 (LMWH), 188–189
treatment, 78 Lymphomatous meningitis, 83
intramedullary metastasis, 79 Lymphoplasmacytic lymphoma, 146
Intraparenchymal hemorrhage, 169
Intrathecal (IT) chemotherapy, M
31–32, 88–89
Intrathecal liposomal Malignant angioendotheliomatosis.
cytarabine, 112 See Intravascular lymphoma

Index 211
Malignant peripheral nerve-sheath histology

tumors (MPNSTs), 74 MPNSTs, 74
Melanoma-associated retinopathy neurofibromas, 74
(MAR), 144 schwannomas, 73–74
Melanoma, brain metastases treatment, 74–75
epidemiology, 55 Neurocognitive dysfunction
imaging, 56 clinical features, 97
treatment recommendations, clinical studies, 97–98
56–57 pathophysiology, 97
Meningeal layers, 68 radiation, 96–97
Meningioma, 76 treatment, 98
clinical features, 22–23 Neurofibromas, 74
imaging characteristics, 26 Neurofibromatosis, 4
pathology, 23, 26 Neuromyotonia, 147–148
prognosis, 28 Neuropathic pain, 193–194
risk factors, 22 Newly diagnosed glioblastoma, 17
treatment, 26–27 Nimodipine, 122
Metastatic epidural spinal cord Nonbacterial thrombotic
compression (MESCC) endocarditis (NBTE)
clinical features, 69–70 characteristics of vegetations, 164
diagnosis, 70 clinical features, 164
epidemiology, 68–69 diagnosis and treatment, 165
pathophysiology, 69 Nonionizing radiation exposure, 5
prognosis, 73 Non-small cell lung cancer
treatment (NSCLC), brain metastases
chemotherapy, 72 epidemiology, 55
corticosteroids, 70–71 risk factors, 56
radiation therapy, 71 treatment recommendations, 56–57
recurrence, 72
surgery, 71–72
Methotrexate, 31, 114–115 O
Methylphenidate, 195 Ocular lymphoma, 33
Modafinil, 195 Oligodendroglial tumors, 18–22
Monoclonal IgM antibodies, 146 Oligodendroglioma (WHO Grade
Musculoskeletal complications, II/IV), 18–19
196–198 Ommaya reservoir, 87–88
Myasthenia gravis (MG), 128, Opportunistic infections, 200–201
149–150 Org 2766, 122
Myxopapillary ependymoma, Oropharyngeal candidiasis
76–77 (Thrush), 200
Osteoporosis and compression
fractures, 196–197
N Oxcarbazepine, 122
NBTE. See Nonbacterial
thrombotic endocarditis P
Neoplastic aneurysms, 171–172
Neoplastic meningitis, 83 Pain
Nerve sheath tumors headaches, 192–193
diagnosis, 74 neuropathic, 193–194

212 Index
Palliative chemotherapy, 109 PCNSL. See Primary CNS

Paradoxical embolism, 165–166 lymphoma
Paraneoplastic cerebellar Peptic ulceration, 199
degeneration Peripheral nervous system
clinical features, 131, 136 CIPN
differential diagnosis, 136–137 clinical signs and symptoms,
imaging stages, 136 115, 120
prognosis, 137–138 common chemotherapeutic
serologic testing, 137 agents, 116–119
treatment, 137 prevention, 120–122
Paraneoplastic disorders (PND) risk factors, 115
antibodies, paraneoplastic treatments and prognosis, 122
syndromes, and associated disorders, 128
tumors, 132–135 postradiation optic neuropathy,
clinical features, 129 101–102
diagnosis, 127 radiation-induced peripheral
criteria, 130 nerve tumors, 102–103
workup, 131 radiation plexopathy, 102
epidemiology, 127–128 Peripheral neuropathy
pathogenesis autonomic, 147
antibody-mediated PND, causes in cancer patients, 144–145
128–129 chemotherapy-induced
T-cell mediated PND, 129 neuropathy, 115–122
Paraneoplastic limbic encephalitis paraneoplastic sensory, 145–146
clinical features, 139 paraproteinemic, 146
differential diagnosis, 140 sensorimotor neuropathy,
imaging studies, 139–140 145–146
laboratory abnormalities, 140–141 subacute sensory, 145
prognosis, 142 Pilocytic astrocytoma (WHO
treatment, 141–142 Grade I/IV), 8
Paraneoplastic motor neuron Pituitary tumor apoplexy, 172
disease, 144 PND. See Paraneoplastic disorders
Paraneoplastic opsoclonus- Pneumocystis jiroveci pneumonitis
myoclonus, 138–139 (PJP), 200–201
Paraneoplastic optic neuropathy, 144 Polymyositis, 150–151
Paraneoplastic sensory neuropathy, Posterior reversible encephalopathy
145–146 syndrome (PRES), 111–112
Paraneoplastic visual syndromes Postradiation optic neuropathy,
cancer-associated retinopathy, 101–102
143–144 Postradiation vasculopathy, 166
melanoma-associated Primary brain tumors
retinopathy, 144 astrocytic tumors
paraneoplastic optic anaplastic astrocytoma, 11–15
neuropathy, 144 diffuse astrocytoma, 8–11
Paraproteinemic neuropathy, 146 glioblastoma, 15–18
Parasagittal meningiomas, 23 pilocytic astrocytoma, 8
Parenchymal metastases, 43 diagnosis, 5
PCI. See Prophylactic cranial epidemiology, 1
irradiation histological classification of, 1–4

Index 213
Primary brain tumors (continued) radiation-induced brain

oligodendroglial tumors tumors, 101
anaplastic oligodendroglioma, radiation toxicity, 94–96
19–22 peripheral nervous system
oligodendroglioma, 18–19 postradiation optic neuropathy,
risk factors, 4–5 101–102
Primary CNS lymphoma (PCNSL) radiation-induced peripheral
clinical features, 29 nerve tumors, 102–103
diagnosis, 29–30 radiation plexopathy, 102
HIV-related PCNSL, 34–35 Radiation-induced brain tumors, 101
pathology, 29 Radiation-induced peripheral nerve
prognosis, 33–34 tumors, 102–103
risk factors, 28 Radiation necrosis, 100
treatment Radiation plexopathy, 102
adjuvant corticosteroids, 32 Radiation sensitizers, 47–48
adjuvant rituximab, 32–33 Radiation therapy
high-dose chemotherapy anaplastic astrocytoma, 12
with autologous stem-cell anaplastic oligodendroglioma, 20
transplantation, 32 Radiation therapy
high-dose methotrexate diffuse astrocytoma, 9–10
monotherapy, 31 leptomeningeal metastases, 88
intrathecal chemotherapy, meningioma, 27
31–32 MESCC, 71
methotrexate-based multidrug Radiation toxicity
regimens, 31 acute effects, 94
ocular lymphoma, 33 early-delayed effects, 94–95
recurrent/refractory PCNSL, 33 late-delayed effects, 95
surgery, 30 risk factors, 95–96
WBRT, 32 Recombinant human leukemia
Prophylactic cranial irradiation inhibitory factor (rhuLIF), 122
(PCI), 94, 98 Recurrent anaplastic
Prophylactic therapy, 196, 198 oligodendroglioma, 23
Psammomatous meningioma, 76 Recurrent glioblastoma, 17
Psychiatric and behavioral Recurrent MESCC, 72
complications, 201–202 Recurrent/refractory PCNSL, 33
Psychostimulants, 195 Recursive partitioning analysis
Pulmonary embolism (PE). See (RPA) classes, 45–46, 55
Venous thromboembolism Renal cell carcinoma (RCC), brain
metastases, 58
Reversible posterior
R
leukoencephalopathy syndrome
Radiation effects (RPLE), 111–112
central nervous system
focal radiation necrosis, 99–101 S
imaging abnormalities following
radiation therapy, 96 Schwannomas, 73–74
neurocognitive dysfunction, Seizures
96–98 antiepileptic drug-drug
pathology, 96 interactions, 183–186

214 Index
Seizures (continued) postoperative complications, 166

clinical features, 181–182 postradiation vasculopathy, 166
epidemiology, 181 Trastuzumab, 53–54
practice considerations, 186 Tuberous sclerosis, 4
prophylaxis, 182–183 Tumor embolism, 163
treatment, 183 Turcot syndrome, 5
Sensorimotor neuropathy, 145–146
Septic embolism, 165
Spinal cord tumors V
anatomy of, 67–68
extradural tumors Valproic acid, 186
extradural space, 68 Vascular endothelial growth factor
MESCC, 68–72 (VEGF) pathway inhibitors,
intradural tumors 172–173, 192
extramedullary tumors, 73–76 Vasogenic edema, 190
intramedullary tumors, 77–79 Venous thromboembolism (VTE)
Spinal ependymoma, 77–78 clinical features, 187
Spinal meningioma, 75–76 diagnosis, 187
Stereotactic radiosurgery (SRS), 27 epidemiology, 187
in breast cancer, 54–55 prophylaxis, 187–188
in brain metastases, 48–49 risk factors, 187
description of, 93 treatment, 188–190
with SRS/without WBRT, 50 Vertebroplasty, 197
surgery approach, 52 VTE. See Venous thromboembolism
with WBRT/without SRS, 49
Stereotactic radiotherapy (SRT), 93
Steroid myopathy, 197–198 W
Steroid pseudorheumatism, 199
Whole-brain radiation therapy
Steroid-withdrawal syndrome, 199
(WBRT), 32, 55
Stiff-person syndrome (SPS), 128,
and chemotherapy, in brain
142–143
metastases, 48
Subacute multifocal
description of, 94
leukoencephalopathy, 113
indications in brain
Subacute sensory neuronopathy, 145
metastases, 46
Subarachnoid hemorrhage, 170
melanoma in brain
Subarachnoid spinal cord space, 68
metastases, 57
Subdural hemorrhage, 170
and radiation sensitizers, 47–48
Subdural spinal cord space, 68
and surgery in brain
Systemic chemotherapy, 89
metastases, 52
treatment regimens, 47
T
T-cell mediated PND, 129 X
Thrombotic disease
Xaliproden, 121
hyperviscous obstruction,
168–169
intravascular lymphoma, 167–168

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Library of Congress Cataloging-in-Publication Data

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Editor’s Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

1 Primary Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . 1

73724_FM00_Printer.indd iii 03/29/09 2:40:00 PM

7 Paraneoplastic Disorders . . . . . . . . . . . . . . . . . . 127

8 Cerebrovascular Complications . . . . . . . . . . . . 161

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9 Medical Complications of Brain

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Welcome to the Dx/Rx Neurology series. This is a new series

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This book focuses on two difficult issues in neuro-oncology:

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Primary Brain Tumors

Histological Classification of Primary

the degree of malignancy.

appearance of tumor cells.

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Table 1-1: WHO Classification of Primary Brain Tumors

Classification WHO Grade (I–IV)

Anaplastic astrocytoma III

Anaplastic oligodendroglioma III

Anaplastic oligoastrocytoma III

Anaplastic ependymoma III

Choroid plexus tumors

Choroid plexus papilloma I

Atypical choroid plexus papilloma II

Choroid plexus carcinoma III

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Table 1-1: WHO Classification of Primary Brain

Classification WHO Grade (I–IV)

Neuronal and mixed neuronal-glial tumors

Anaplastic ganglioglioma III

Tumors of the cranial and peripheral nerves

Malignant peripheral nerve II–IV

Anaplastic/malignant meningioma III

Tumors of the hematopoietic system

Primary CNS lymphoma

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Table 1-1: WHO Classification of Primary Brain

Classification WHO Grade (I–IV)

Germ cell tumors

Tumors of the sellar region

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• Turcot syndrome: an autosomal dominant disorder

Gliomas (Table 1-2)

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Astrocytic Tumors Oligodendroglial Tumors

Diffuse Anaplastic Anaplastic

Astrocytoma Astrocytoma Glioblastoma Oligodendroglioma Oligodendroglioma

WHO grade Grade II Grade III Grade IV Grade II Grade III

Astrocytic Tumors Oligodendroglial Tumors

■ Glioblastomas account for 54% of all gliomas.1

Diffuse Astrocytoma (WHO Grade II/IV)

• p53 tumor suppressor mutations are found in more

• The mean age of presentation is 34 years.6

tense on T1-weighted images, hyperintense on

• There is no standard of care, and treatment recom-