Beruflich Dokumente
Kultur Dokumente
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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Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
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
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
Embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Thrombotic Disease (Including Small, Medium,
and Large Vessel Disease) . . . . . . . . . . . . . . . . 166
Intracranial Hemorrhages . . . . . . . . . . . . . . . . . . . . . . 169
Cerebral Venous Thrombosis (CVT) . . . . . . . . . . . . . . 173
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Kevin N. Sheth, MD
vii
Eudocia Quant, MD
ix
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
Astrocytic tumors
Pilocytic astrocytoma I
Diffuse astrocytoma II
Glioblastoma IV
Gliosarcoma IV
Gliomatosis cerebri
Oligodendroglial tumors
Oligodendroglioma II
Oligoastrocytic tumors
Oligoastrocytoma II
Ependymal tumors
Subependymoma I
Myxopapillary ependymoma I
Ependymoma II
(Continues)
Gangliocytoma I
Ganglioglioma I
Central neurocytoma II
Pineal tumors
Pineocytoma I
Pineoblastoma IV
Embryonal tumors
Medulloblastoma IV
Schwannoma I
Neurofibroma I
Meningeal tumors
Meningioma I
Atypical meningioma II
Hemangioblastoma I
(Continues)
Germinoma
Teratoma
Choriocarcinoma
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
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.
73724_CH01_Printer.indd 6
6 Chapter 1
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)
Typical MRI Nonenhancing mass, Irregularly shaped mass Irregularly shaped, Nonenhancing mass, Heterogenous patterns
73724_CH01_Printer.indd 7
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.
Primary Brain Tumors 7
03/29/09 2:35:00 PM
8 Chapter 1
Astrocytoma
Pilocytic Astrocytoma (WHO Grade I/IV)
■ These are mostly seen in the pediatric population.
improves outcomes.
■ Clinical features
• 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.
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
• Radiation therapy
■ The role of radiation therapy is clearly established
in anaplastic astrocytoma.
■ For patients with adequate performance status, a
disease.
■ Preliminary results from a multicenter, randomized
■ 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.
Oligodendroglioma
Oligodendroglioma (WHO Grade II/IV)
■ Biology
■ Prognosis
• Low-grade oligodendrogliomas have a better prognosis
than low-grade astrocytomas.
• Based on a Swiss population-based study, the median
overall survival for a low-grade oligodendroglioma was
11.6 years.21
■ MRI appearance6
improves outcomes.
• Radiation therapy
■ Randomized trials in malignant gliomas demonstrate
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,
Clinical Features
■ The most common locations (in descending order) are
Pathology
■ WHO grades
(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-
73724_CH01_Printer.indd 24
24 Chapter 1
Parasagittal and falcine Anterior one third Headache, mental status changes
Posterior one third Headache, visual symptoms, seizures, mental status changes
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)
73724_CH01_Printer.indd 25
suprasellar syndromes
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.
Primary Brain Tumors 25
03/29/09 2:35:00 PM
26 Chapter 1
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
Treatment
■ Surgery
■ 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-
■ 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
treated.
Prognosis
■ The overall 5-year survival ranges from 69% to 90%
depending on the study.52
■ Atypical and anaplastic meningiomas
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
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-
Clinical Features
■ The median age of diagnosis in immunocompetent pati-
ents is 53 to 57 years.60
■ Patients present with neurologic signs and symptoms
Diagnosis61
■ A definitive diagnosis usually requires a stereotactic
biopsy.
■ MRI with gadolinium of the entire neuroaxis
Treatment
■ PCNSLs are sensitive to corticosteroids, but responses
PCNSL.
■ Treatment options are based on the results from phase II
clinical trials.62
• Newly diagnosed PCNSL
■ Surgery
Prognosis
■ Durable complete responses and long-term survival are
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.
HIV-Related PCNSL
■ Nearly 6% of the AIDS population will be afflicted with
PCNSL.6
■ The disease incidence has decreased during the highly
References
1. CBTRUS. Statistical report: primary brain and central
nervous system tumors diagnosed in the United Status in
2004–2005. Hinsdale, IL: Central Brain Tumor Registry of
the United States; 2009. http://www.cbtrus.org/reports//
2007–2008/2007report.pdf. Accessed August 15, 2009.
2. Ohgaki H. Epidemiology of brain tumors. Methods Mol Biol.
2009;472:323–342.
3. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO
Classification of Tumours of the Central Nervous System, 4th ed.
Lyon: International Agency for Research on Cancer; 2007.
4. Bondy ML, Scheurer ME, Malmer B, et al. Brain tumor epi-
demiology: consensus from the Brain Tumor Epidemiology
Consortium. Cancer. 2008;113(7 Suppl):1953–1968.
5. DeAngelis LM. Brain tumors. N Engl J Med. 2001;344(2):
114–123.
6. Mechtler L. Neuroimaging in neuro-oncology. Neurol Clin.
2009;27(1):171–201, ix.
7. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med.
2008;359(5):492–507.
8. Okamoto Y, Di Patre PL, Burkhard C, et al. Population-based
study on incidence, survival rates, and genetic alterations of
low-grade diffuse astrocytomas and oligodendrogliomas. Acta
Neuropathol. 2004;108(1):49–56.
9. Lang FF, Gilbert MR. Diffusely infiltrative low-grade gliomas
in adults. J Clin Oncol. 2006;24(8):1236–1245.
10. Claus EB, Horlacher A, Hsu L, et al. Survival rates in patients
with low-grade glioma after intraoperative magnetic reso-
nance image guidance. Cancer. 2005;103(6):1227–1233.
11. Smith JS, Chang EF, Lamborn KR, et al. Role of extent of
resection in the long-term outcome of low-grade hemi-
spheric gliomas. J Clin Oncol. 2008;26(8):1338–1345.
12. Jackson RJ, Fuller GN, Abi-Said D, et al. Limitations of ste-
reotactic biopsy in the initial management of gliomas. Neuro
Oncol. 2001;3(3):193–200.
13. Shaw EG, Berkey B, Coons SW, et al. Recurrence following
neurosurgeon-determined gross-total resection of adult
supratentorial low-grade glioma: results of a prospective clin-
ical trial. J Neurosurg. 2008;109(5):835–841.
67. 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.
68. Marti-Carvajal AJ, Cardona AF, Lawrence A. Interventions
for previously untreated patients with AIDS-associated non-
Hodgkin’s lymphoma. Cochrane Database Syst Rev. 2009(3):
CD005419.
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
43
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-
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
Percentage Description
0 Dead
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.
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
WBRT 1 Chemotherapy
■ Several chemotherapeutic agents yield higher response
Surgery
■ The benefits of surgery include pathology for definitive
Resection ⴙ
WBRT Median WBRT Median
Study Overall Survival Overall Survival
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.
amenable to surgery.
Chemotherapy
■ This is traditionally reserved for patients who have
failed other treatment modalities or tumors that are
metastases.42–44
■ Breast cancer is the solid tumor most commonly associ-
Surgery
■ This is indicated for urgent decompression and solitary
brain metastasis.
■ Surgery is typically reserved for patients with a single
SRS
■ SRS is typically recommended for #3 brain metastases,
WBRT
■ Seventy-five percent to 85% of patients who receive
Systemic Treatments
■ This is generally recommended after failure with surgery
and radiation.
■ Selected chemotherapy agents such as capecitabine,
with NSCLC.53
■ NSCLC is usually chemoresistant, and thus, patients
■ Adenocarcinoma histology56
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
Imaging
■ The typical melanotic pattern on MRI consists of high
References
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brain metastases. Arch Neurol. 1988;45(7):741–744.
4. 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.
5. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning
analysis (RPA) of prognostic factors in three Radiation
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8. Bezjak A, Adam J, Barton R, et al. Symptom response after
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Eur J Cancer. 2002;38(4):487–496.
9. Tsao MN, Lloyd N, Wong R, Chow E, Rakovitch E,
Laperriere N. Whole brain radiotherapy for the treatment of
multiple brain metastases. Cochrane Database Syst Rev.
2006;3:CD003869.
10. Mehta MP, Rodrigus P, Terhaard CH, et al. Survival and
neurologic outcomes in a randomized trial of motexafin gad-
olinium and whole-brain radiation therapy in brain metasta-
ses. J Clin Oncol. 2003;21(13):2529–2536.
11. Mehta MP, Shapiro WR, Phan SC, et al. Motexafin gado-
linium combined with prompt whole brain radiotherapy pro-
longs time to neurologic progression in non-small-cell lung
cancer patients with brain metastases: results of a phase III
trial. Int J Radiat Oncol Biol Phys. 2009;73(4):1069–1076.
12. Suh JH, Stea B, Nabid A, et al. Phase III study of efaproxiral
as an adjunct to whole-brain radiation therapy for brain
metastases. J Clin Oncol. 2006;24(1):106–114.
13. Scott C, Suh J, Stea B, Nabid A, Hackman J. Improved sur-
vival, quality of life, and quality-adjusted survival in breast
cancer patients treated with efaproxiral (Efaproxyn) plus
24. Loeffler JS, Kooy HM, Wen PY, et al. The treatment of
recurrent brain metastases with stereotactic radiosurgery.
J Clin Oncol. 1990;8(4):576–582.
25. Noel G, Proudhom MA, Valery CA, et al. Radiosurgery for
re-irradiation of brain metastasis: results in 54 patients.
Radiother Oncol. 2001;60(1):61–67.
26. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain
radiation therapy with or without stereotactic radiosurgery
boost for patients with one to three brain metastases: phase III
results of the RTOG 9508 randomised trial. Lancet.
2004;363(9422):1665–1672.
27. Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC.
Stereotactic radiosurgery plus whole brain radiotherapy versus
radiotherapy alone for patients with multiple brain metastases.
Int J Radiat Oncol Biol Phys. 1999;45(2):427–434.
28. Sanghavi SN, Miranpuri SS, Chappell R, et al. Radiosurgery
for patients with brain metastases: a multi-institutional
analysis, stratified by the RTOG recursive partitioning anal-
ysis method. Int J Radiat Oncol Biol Phys. 2001;51(2):
426–434.
29. Mueller RP, Soffietti R, Abacioglu MU, et al. Adjuvant
whole-brain radiotherapy versus observation after radiosur-
gery or surgical resection of 1–3 cerebral metastases: Results
of the EORTC 22952-26001 study. J Clin Oncol (Meeting
Abstracts). 2009;27(Suppl):abstr 2008.
30. Sawrie SM, Guthrie BL, Spencer SA, et al. Predictors
of distant brain recurrence for patients with newly
diagnosed brain metastases treated with stereotactic radio-
surgery alone. Int J Radiat Oncol Biol Phys. 2008;70(1):
181–186.
31. Barker FG, 2nd. Craniotomy for the resection of metastatic brain
tumors in the U.S., 1988–2000: decreasing mortality and the
effect of provider caseload. Cancer. 2004;100(5):999–1007.
32. 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.
33. 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.
34. Paek SH, Audu PB, Sperling MR, Cho J, Andrews DW.
Reevaluation of surgery for the treatment of brain metastases:
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
and how often? Urol Oncol. 2008;26(5):550–554.
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.
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.
67
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.
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-
Valsalva
■ Weakness: may be upper motor neuron or lower motor
Diagnosis
■ A whole-spine MRI with gadolinium is the imaging
Treatment
■ MESCC is a medical emergency causing paraplegia if
left untreated.
■ Early diagnosis and appropriate treatment can prevent or
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-
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
roots
■ Most commonly arise in the lumbosacral region13
■ Histology
• Schwannomas
■ Typically round or oval, lobulated, encapsulated
matosis type 2
■ Represent 25% to 30% of all intraspinal masses14
fibers
■ Generally considered benign
neurofibromatosis type 2
• Malignant peripheral nerve-sheath tumors (MPNSTs)
■ Uncommon primary tumor of nerve sheath origin
■ Diagnosis
• MRI with contrast is the imaging modality of choice.
■ Nerve sheath tumors are isointense on T1-weighted
able on MRIs.
■ Enhancement may be seen with benign or malig-
nant tumors.
■ They may contain both intradural and extradural com-
• Surgery
■ Total resection is the primary treatment for nerve
sheath tumors.
■ Total resection often requires removal of the
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
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,
■ Clinical features
• 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
meningiomas
■ Indications
Intramedullary Tumors
■ Account for 20% to 30% of intradural tumors in adults1
■ Clinical features
Ependymoma
■ They account for 40% to 60% of intramedullary spinal
■ Treatment
• Surgery
■ Gross total resection is the primary treatment and
survival.21
• Radiation therapy
■ Not indicated after gross total resection in low-
grade tumors
■ May increase tumor-free survival rates in patients
thoracic regions.
■ Astrocytomas usually extend multiple levels at the time
of diagnosis.
■ The pathology is as follows:
■ 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
astrocytomas
■ Could be considered for progressive disease or for
unresectable tumors
• Chemotherapy
■ The role in spinal cord astrocytomas is unknown.
Intramedullary Metastasis
■ These are extremely rare and suggest advanced meta-
static disease.
■ The most common tumors causing intramedullary metas-
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.
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.
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
83
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
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
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.
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
Radiation Therapy
■ Decreasing bulky disease because intrathecal chemo-
systemic toxicity
Chemotherapy
Intrathecal (IT) Chemotherapy
■ Agents include methotrexate, liposomal cytarabine, and
thiotepa.
■ This may be administered via lumbar puncture or ven-
therapy.6
■ Signs/symptoms include headache, mental status
epidermidis.
therapy6
■ Usually caused by an inflammatory reaction
Systemic Chemotherapy
■ Some agents are able to penetrate the blood–brain bar-
cancer.27,28
Supportive Care
■ Should be offered to all patients with neoplastic meningitis
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
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.
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
93
radiation.
■ Symptoms include the following:
Early-Delayed Effects
■ Early-delayed radiation toxicity occurs 6 to 12 weeks after
radiation.
■ Symptoms after cranial radiation include general-
neurocognitive changes.
■ The pathophysiology is not completely understood, but
radiosurgery)
■ Young children, especially during developmental stages
of neural tissue
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.
■ Cerebral atrophy
Neurocognitive Dysfunction
■ Radiation may have long-term detrimental effects on
neurocognitive function.
■ Radiation may also have short-term beneficial effects
Clinical Features 6
■ Short-term memory deficits
■ Deficits in attention
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-
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.
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-
Pathophysiology
■ Poorly understood
■ Pathologically characterized by necrosis with hypocellu-
Diagnosis
■ Radiation necrosis is difficult to distinguish from tumor
recurrence.
■ Specific patterns of enhancement on MRI (“soap bub-
Treatment
■ Surgery is not always necessary but may be an option
Epidemiology
■ Based on a retrospective review of 10,080 children treated
Risk Factors
■ Radiation during childhood
■ Higher radiation doses
Treatment
■ Treatment options are similar to analogous non–
Radiation Plexopathy
■ It may occur in the brachial plexus after radiation for lung
brachial plexopathy.
■ Bilateral plexus involvement (although asymmetric) is
tion or compression.
Treatment
■ Pain can be managed with NSAIDs or opioids.
Epidemiology
■ This is a rare complication from radiation, but the true
incidence is unknown.
■ The association between radiation and peripheral nerve
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
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
Neurologic
Complications of
Chemotherapy
Introduction
■ Chemotherapy: the use of chemical agents in the treatment
or control of disease such as cancer
Mechanism of
Class of Agent Action Examples
(Continues)
107
Mechanism of
Class of Agent Action Examples
(Continues)
Mechanism of
Class of Agent Action Examples
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-
Palliative Chemotherapy
■ Chemotherapy is given without curative intent.
■ The goal is to decrease tumor burden, provide symptom-
impairment is unknown.
■ Studies of cancer-related cognitive dysfunction (prior to
Clinical Features
■ Symptoms may be subtle but adversely affect quality
of life.
■ They may arise shortly after starting chemotherapy and
Risk Factors1
■ Higher doses of chemotherapy (either through high-dose
■ Intrathecal chemotherapy
Pathophysiology
■ Unknown but postulated hypotheses include2
Treatment
■ There are no standard treatments because of a lack of
studies.
■ Empirical treatments include psychostimulants and cog-
nitive therapy.
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-
■ Management3
• Early diagnosis important
• Discontinuation of offending agent
• Correction of high blood pressure, renal dysfunction,
and low magnesium
syndrome4
• Clinical features
■ The predominant clinical feature is cerebellar dys-
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
and nystagmus
■ Often reversible with drug discontinuation
• Acute encephalopathy
■ Characterized by confusion, cognitive disturbances,
therapy
■ Characterized by cognitive abnormalities, altered
white-matter lesions
■ Clinical improvement with discontinuation of fluo-
Fludarabine
■ Used in chronic lymphocytic leukemia and low-grade
lymphoma
■ Associated with a severe neurotoxicity syndrome7
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
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
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,
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
73724_CH06_Printer.indd 116
Drugs Pathophysiology Toxic Dose Neuropathy Installation Evolution Electrophysiology
116 Chapter 6
(Continues)
03/29/09 2:38:00 PM
Table 6-2: Chemotherapy-Induced Peripheral Neuropathy (Continued)
Cumulative
Drugs Pathophysiology Toxic Dose Neuropathy Installation Evolution Electrophysiology
73724_CH06_Printer.indd 117
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
(Continues)
03/29/09 2:38:00 PM
Table 6-2: Chemotherapy-Induced Peripheral Neuropathy (Continued)
Cumulative
Drugs Pathophysiology Toxic Dose Neuropathy Installation Evolution Electrophysiology
73724_CH06_Printer.indd 118
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
Table 6-2: Chemotherapy-Induced Peripheral Neuropathy (Continued)
Cumulative
Drugs Pathophysiology Toxic Dose Neuropathy Installation Evolution Electrophysiology
73724_CH06_Printer.indd 119
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
From Antoine JC, Camdessanche JP. Peripheral nervous system involvement. Lancet Neurol. 2007;6(1):75–86.
Neurologic Complications of Chemotherapy 119
03/29/09 2:38:00 PM
120 Chapter 6
Prevention
■ Calcium (Ca21) and magnesium (Mg21) infusions may
Treatment
■ Treatments for diabetic neuropathies are not necessarily
helpful in CIPN.
■ Topical baclofen, amitriptyline, and ketamine (BAK):
Prognosis
■ Variable depending on the agent (may or may not be
reversible)
References
1. Wefel JS, Witgert ME, Meyers CA. Neuropsychological
sequelae of non-central nervous system cancer and cancer
therapy. Neuropsychol Rev. 2008;18(2):121–131.
2. Ahles TA, Saykin AJ. Candidate mechanisms for chemo-
therapy-induced cognitive changes. Nat Rev Cancer. 2007;
7(3):192–201.
3. Bhatt A, Farooq MU, Majid A, Kassab M. Chemotherapy-
related posterior reversible leukoencephalopathy syndrome.
Nat Clin Pract Neurol. 2009;5(3):163–169.
4. Baker WJ, Royer GL, Jr., Weiss RB. Cytarabine and neuro-
logic toxicity. J Clin Oncol. 1991;9(4):679–693.
5. Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A random-
ized controlled trial comparing intrathecal sustained-release
cytarabine (DepoCyt) to intrathecal methotrexate in patients
with neoplastic meningitis from solid tumors. Clin Cancer
Res. 1999;5(11):3394–3402.
6. Pirzada NA, Ali, II, Dafer RM. Fluorouracil-induced neuro-
toxicity. Ann Pharmacother. 2000;34(1):35–38.
7. Sioka C, Kyritsis AP. Central and peripheral nervous sys-
tem toxicity of common chemotherapeutic agents. Cancer
Chemother Pharmacol. 2009;63(5):761–767.
8. Fleming RA. An overview of cyclophosphamide and ifosf-
amide pharmacology. Pharmacotherapy. 1997;17(5 Pt 2):
146S–154S.
9. Pande AR, Ando K, Ishikura R, et al. Disseminated necro-
tizing leukoencephalopathy following chemoradiation ther-
apy for acute lymphoblastic leukemia. Radiat Med. 2006;
24(7):515–519.
10. Matsubayashi J, Tsuchiya K, Matsunaga T, Mukai K.
Methotrexate-related leukoencephalopathy without radia-
tion therapy: distribution of brain lesions and pathological
heterogeneity on two autopsy cases. Neuropathology. 2009;
29(2):105–115.
11. Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi C.
Chemotherapy-induced peripheral neuropathy: prevention and
treatment strategies. Eur J Cancer. 2008;44(11):1507–1515.
12. Hochster H, Grothey A, Shpilsky A, Childs B. Effect of
intravenous (IV) calcium and magnesium (Ca/Mg) versus
placebo on response to FOLFOX 1 bevacizumab (BEV)
in the CONcePT trial (abstract 280). Paper presented
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
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-
T-Cell–Mediated PND
■ Some PNDs may be mediated by T-cell immune
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
Diagnosis
Diagnostic Criteria (Figure 7-1)17
Definite PND
■ Classic syndrome with cancer diagnosed within 5 years
neuronal antibodies
■ Neurologic syndrome (classic or not) without cancer and
Diagnostic Workup18
■ If PND is suspected, the initial workup should include
73724_CH07_Printer.indd 132
Well-characterized paraneoplastic antibodies (identified by several investigators)
132 Chapter 7
(Continues)
03/29/09 2:40:00 PM
Table 7-1: Antibodies, Paraneoplastic Syndromes, and Associated Tumors (Continued)
73724_CH07_Printer.indd 133
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
(Continues)
03/29/09 2:40:00 PM
Table 7-1: Antibodies, Paraneoplastic Syndromes, and Associated Tumors (Continued)
73724_CH07_Printer.indd 134
Anti-Tr Paraneoplastic cerebellar degeneration Hodgkin lymphoma
134 Chapter 7
ANNA3 Various paraneoplastic disorders of the CNS Small cell lung cancer
PCA2 Various paraneoplastic disorders of the CNS Small cell lung cancer
(Continues)
03/29/09 2:40:00 PM
Table 7-1: Antibodies, Paraneoplastic Syndromes, and Associated Tumors (Continued)
73724_CH07_Printer.indd 135
Peripheral nerve hyperexcitability Small cell lung cancer
(neuromyotonia) Others
Other
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
hypermetabolism.23
• Later stages
■ An MRI shows cerebellar atrophy.
■ Anti-Hu 7 months
Paraneoplastic Opsoclonus-Myoclonus
■ Commonly associated tumors: SCLC, breast cancer,
may be involved32,33
■ Laboratory abnormalities
• 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
• Adult cases
■ There is improvement with tumor control.41
ciated tumors.
• Anti-Ma2 (Ta)
■ This typically affects the limbic system, hypothala-
• 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.
months.
■ Tumor removal speeds up recovery and decreases
Stiff-Person Syndrome
■ This syndrome may be idiopathic or paraneoplastic.
Peripheral Neuropathy
■ Causes in cancer patients
• 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
■ Clinical features
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
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
■ Clinical features
Neuromyotonia
■ Idiopathic or paraneoplastic
Hodgkin lymphoma18
■ Clinical features
■ 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
■ Impotence
■ Constipation
■ Impaired sweating
■ Orthostatic hypotension
■ Laboratory abnormalities
• 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
■ 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
weakness
■ EMG/NCS: small polyphasic motor unit potentials and
■ Laboratory abnormalities
Dermatomyositis
■ Idiopathic or paraneoplastic, increased risk of malignancy
References
1. Dalmau J, Furneaux HM, Gralla RJ, Kris MG, Posner JB.
Detection of the anti-Hu antibody in the serum of patients
with small cell lung cancer: a quantitative western blot anal-
ysis. Ann Neurol. 1990;27(5):544–552.
2. Roberts WK, Darnell RB. Neuroimmunology of the parane-
oplastic neurological degenerations. Curr Opin Immunol.
2004;16(5):616–622.
3. Greenlee JE. Recommended diagnostic criteria for paraneo-
plastic neurological syndromes. J Neurol Neurosurg
Psychiatry. 2004;75(8):1090.
4. Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies
coexist and predict cancer, not neurological syndrome. Ann
Neurol. 2004;56(5):715–719.
5. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the
CNS. Lancet Neurol. 2008;7(4):327–340.
6. Bataller L, Dalmau J. Paraneoplastic disorders of the ner-
vous system. Continuum. 2005;11(5):69–92.
7. Viala K, Behin A, Maisonobe T, et al. Neuropathy in lym-
phoma: a relationship between the pattern of neuropathy,
type of lymphoma and prognosis? J Neurol Neurosurg
Psychiatry. 2008;79(7):778–782.
8. Dalmau J, Gultekin HS, Posner JB. Paraneoplastic neuro-
logic syndromes: pathogenesis and physiopathology. Brain
Pathol. 1999;9(2):275–284.
9. Darnell RB, Posner JB. Paraneoplastic syndromes affecting
the nervous system. Semin Oncol. 2006;33(3):270–298.
10. Sommer C, Weishaupt A, Brinkhoff J, et al. Paraneoplastic
stiff-person syndrome: passive transfer to rats by means of
IgG antibodies to amphiphysin. Lancet. 2005;365(9468):
1406–1411.
36. Sutton IJ, Barnett MH, Watson JD, Ell JJ, Dalmau J.
Paraneoplastic brainstem encephalitis and anti-Ri anti-
bodies. J Neurol. 2002;249(11):1597–1598.
37. Blaes F, Fuhlhuber V, Korfei M, et al. Surface-binding
autoantibodies to cerebellar neurons in opsoclonus syn-
drome. Ann Neurol. 2005;58(2):313–317.
38. Korfei M, Fuhlhuber V, Schmidt-Woll T, Kaps M, Preissner
KT, Blaes F. Functional characterisation of autoantibodies
from patients with pediatric opsoclonus-myoclonus-
syndrome. J Neuroimmunol. 2005;170(1–2):150–157.
39. Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab
(anti-CD20) adjunctive therapy for opsoclonus-myoclonus
syndrome. J Pediatr Hematol Oncol. 2006;28(9):585–593.
40. Mitchell WG, Davalos-Gonzalez Y, Brumm VL, et al.
Opsoclonus-ataxia caused by childhood neuroblastoma:
developmental and neurologic sequelae. Pediatrics. 2002;
109(1):86–98.
41. Bataller L, Graus F, Saiz A, Vilchez JJ. Clinical outcome
in adult onset idiopathic or paraneoplastic opsoclonus-
myoclonus. Brain. 2001;124(Pt 2):437–443.
42. Erlich R, Morrison C, Kim B, Gilbert MR, Alrajab S. ANNA-2:
an antibody associated with paraneoplastic opsoclonus in a
patient with large-cell carcinoma of the lung with neuroendo-
crine features—correlation of clinical improvement with
tumor response. Cancer Invest. 2004;22(2):257–261.
43. Wong A. An update on opsoclonus. Curr Opin Neurol.
2007;20(1):25–31.
44. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB,
Dalmau J. Paraneoplastic limbic encephalitis: neurological
symptoms, immunological findings and tumour association
in 50 patients. Brain. 2000;123(Pt 7):1481–1494.
45. Lawn ND, Westmoreland BF, Kiely MJ, Lennon VA,
Vernino S. Clinical, magnetic resonance imaging, and elec-
troencephalographic findings in paraneoplastic limbic
encephalitis. Mayo Clin Proc. 2003;78(11):1363–1368.
46. Scheid R, Lincke T, Voltz R, von Cramon DY, Sabri O.
Serial 18F-fluoro-2-deoxy-D-glucose positron emission
tomography and magnetic resonance imaging of paraneo-
plastic limbic encephalitis. Arch Neurol. 2004;61(11):
1785–1789.
47. Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M,
Vernino S. Potentially reversible autoimmune limbic enceph-
alitis with neuronal potassium channel antibody. Neurology.
2004;62(7):1177–1182.
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-
161
■ MR angiogram
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
absence of bacteremia
Clinical Features
■ Cases have been reported in several malignancies, includ-
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
Diagnosis
■ An MRI is more sensitive and specific for diagnosing
embolic strokes acutely than CT.
■ A two-dimensional echocardiogram is useful, but a
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.
Septic Embolism
■ Immunocompromised patients and leukemic patients are
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
Postoperative Complications
■ Neurosurgical patients with brain tumors have an
Intravascular Lymphoma
■ Also known as angiotropic large-cell lymphoma or malig-
nant angioendotheliomatosis
■ Rare type of non-Hodgkin lymphoma, typically a large
Clinical Features
■ Typically disseminated, although clinical presentations
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
Treatment
■ Limited data on best treatment options, although inter-
national consensus guidelines have been published22
■ Anthracycline-based chemotherapy recommended by
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
Hyperviscous Obstruction
■ Hyperviscosity may be caused by an increase in serum
Intracranial Hemorrhages
Types of Intracranial Hemorrhages
Intraparenchymal Hemorrhage
■ This occurs more frequently in hematological malignancies,
angiopathy.
Intratumoral Hemorrhage
■ Hemorrhage can be the presenting sign of a brain mass.
hemorrhage
■ Hemorrhage in unusual locations (e.g., close to the
subarachnoid space)
■ Pattern of contrast enhancement not expected for
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,
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
Diagnosis
■ A noncontrast head CT is the first-line diagnostic
approach.
■ MRI with gradient echo can also detect hyperacute
Management
■ This is based on management principles of intracranial
rhages.
■ Examples of coagulopathies seen in cancer patients
Neoplastic Aneurysms
■ These are aneurysms caused by neoplastic infiltration of
arteries.
itary adenoma
■ Uncommon syndrome
■ Often spontaneous
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-
Clinical Features
■ Clinical presentation is often nonspecific.
Diagnosis
■ Imaging of the venous system demonstrating occlusion is
■ Venous infarction
Treatment
■ Therapeutic anticoagulation
Prognosis39
■ The prognosis in all patients with acute CVT (not just
References
1. Graus F, Rogers LR, Posner JB. Cerebrovascular complica-
tions in patients with cancer. Medicine (Baltimore). 1985;
64(1):16–35.
2. Cestari DM, Weine DM, Panageas KS, Segal AZ, DeAngelis
LM. Stroke in patients with cancer: incidence and etiology.
Neurology. 2004;62(11):2025–2030.
3. Oberndorfer S, Nussgruber V, Berger O, Lahrmann H,
Grisold W. Stroke in cancer patients: a risk factor analysis.
J Neurooncol. 2009;94(2):227.
4. Grisold W, Oberndorfer S, Struhal W. Stroke and cancer:
a review. Acta Neurol Scand. 2009;119(1):1–16.
5. Adams HP, Jr., del Zoppo G, Alberts MJ, et al. Guidelines
for the early management of adults with ischemic stroke:
a guideline from the American Heart Association/American
Stroke Association Stroke Council, Clinical Cardiology
Council, Cardiovascular Radiology and Intervention
Council, and the Atherosclerotic Peripheral Vascular Disease
and Quality of Care Outcomes in Research Interdisciplinary
Working Groups: the American Academy of Neurology
affirms the value of this guideline as an educational tool for
neurologists. Stroke. 2007;38(5):1655–1711.
6. Sacco RL, Adams R, Albers G, et al. Guidelines for preven-
tion of stroke in patients with ischemic stroke or transient
ischemic attack: a statement for healthcare professionals
from the American Heart Association/American Stroke
Association Council on Stroke: co-sponsored by the Council
on Cardiovascular Radiology and Intervention: the American
Academy of Neurology affirms the value of this guideline.
Stroke. 2006;37(2):577–617.
7. Lefkovitz NW, Roessmann U, Kori SH. Major cerebral
infarction from tumor embolus. Stroke. 1986; 17(3):
555–557.
8. el-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic
endocarditis in cancer patients: pathogenesis, diagnosis, and
treatment. Oncologist. 2007;12(5):518–523.
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,
Clinical Features
■ May present as simple or complex seizures with or with-
181
Seizure Prophylaxis
Perioperative Period
■ Conflicting data regarding the prophylactic use of anti-
Seizure Treatment
■ Limited data are available on the efficacy of specific anti-
73724_CH09_Printer.indd 184
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
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)
Valproic Acid Depakote, Side effects that include hepatotoxicity, thrombocytopenia and abnormal coagulation at higher
73724_CH09_Printer.indd 185
Depakene doses, enzyme inhibiting effects (which may raise levels of certain chemotherapeutic agents)
Zonisamide Zonegran Side effects that include cognitive impairment; slow titration necessary
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
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 &
Medical Complications of Brain Tumor Patients 185
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
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
Epidemiology
■ VTE is common in patients with cancer, including
primary brain tumors.
■ The incidence of symptomatic VTE in patients with
lymphoma is 18%.14
■ The incidence of VTE is higher in patients with cancer
patients.16
Risk Factors14
■ Postoperative period
■ Hemiparesis
■ Age ⬎60
■ Chemotherapy
■ Hormonal therapy
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
Prophylaxis
■ Prophylaxis is recommended in the perioperative setting
and during hospitalization.
Treatment
■ The main objective of treatment of a DVT is to prevent
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
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
symptomatic benefit.
■ If lowering the dose, the dose should be tapered.
■ Osteoporosis
Pain
Headaches
Causes
■ These are typically caused by increased intracranial pres-
vomiting.
■ Headaches are worse with coughing or Valsalva maneuver.
Treatment
■ Steroids are an option.
Neuropathic Pain
Potential Causes
■ Leptomeningeal disease
■ Herpes zoster
■ Radiation
peripheral neuropathy)
Clinical Features
■ Painful dysesthesias typically localized to specific der-
Treatment
■ May require a combination of agents
■ Spontaneous resolution
Cognitive Impairment
Potential causes
■ Brain tumor
■ Radiation (see Chapter 5)
Treatment
■ Only a few treatment trials in patients with brain tumors
have been conducted.
■ Psychostimulants
• Methylphenidate
■ Case study of methylphenidate in three high-grade
Fatigue
■ Negatively affects quality of life
Potential Causes
■ Radiation (fatigue tends to increase with the number of
fractions)
■ 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)
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
Steroid Myopathy
■ Occurs in up to 60% of cancer patients39
■ More common in older persons and after prolonged use
of high-dose corticosteroids
■ Clinical features
■ 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
metastases
■ Clinical features
■ Treatment
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.
Gastrointestinal Complications
Peptic Ulceration
■ Peptic ulceration may theoretically occur with continued
use of corticosteroids.
■ From studies of patients on steroids, the overall inci-
• Upper endoscopy
• Abdominal CT only when complications such as per-
foration, penetration, or obstruction suspected
■ Prophylaxis includes histamine H 2 receptor blocker
of H. pylori infection
disease.
■ Clinical features include melena, hematemesis, melenem-
threatening emergency.
Bowel Perforation
■ This is a rare complication of VEGF inhibitors such as
bevacizumab or peptic ulcer disease.
■ Clinical features include typically sudden-onset severe
threatening emergency.
Opportunistic Infections
Oropharyngeal Candidiasis (Thrush)
■ Most common opportunistic infection from steroid
immunosuppression
■ Caused by the fungus Candida albicans
■ Clinical features
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.
monitis (PCP).
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207
T
T-cell mediated PND, 129 X
Thrombotic disease
Xaliproden, 121
hyperviscous obstruction,
168–169
intravascular lymphoma, 167–168