Metastasis to the brain is a frequent complication of many systemic cancers,
arising in 10 to 40% of patients with cancer. The incidence of is increasing due
to better control of the primary disease and thus extending patient survival and
allowing malignant cells time to infiltrate the central nervous system.
Neurological manifestations of systemic malignancy may be due to metastases, or
infiltration neuropathies or indirect effects, such as metabolic encephalopathy,
Metastatic complications which can be further categorized according to location
of the lesion; the cerebral parenchyma, the spine, the skull or skull base, the
leptomeningeal space, and the peripheral nerves. Spinal
and skull metastases are discussed
in different sections.
1) Intraparenchymal metastasis:
brain is a privileged site of systemic cancer metastasis. Virtually any
malignancy can give rise to intraparenchymal metastases which are the most
common intracranial manifestation of systemic cancer. In adults, the most common
sources of metastatic lesions to the brain include the lung (50–60%), breast
(15–20%), skin (5–10%), and gastrointestinal tract (4–6%). Neoplasms of the
reticuloendothelial system, such as, Hodgkin's, and Leukemia, are also frequent
sources. Various types of sarcomas also may be the source. Rare cases of
metastases from Glioblastoma of the spinal cord seeding upwards into the cranial
cavity along the CSF pathways have been reported. The age incidence depends on
the primary tumor, but the highest incidence is in the sixth decade of life. The
incidence of brain metastases is lower in children; about 6% in children
affected by cancer and the most common primary tumors are neurblastoma,
rhabdomyosarcoma and Wilms’ tumor. .
Hematogenous spread of malignancy is the usual mechanism of metastasis.
However, direct extension may occur in the carcinomas of the nasopharynx or
breast and other tumors when they first metastasize to the skull. Epidural
metastases result from direct spread from bones, while subdural plaques are
commonly due to hematogenous spread. On rare occasions, the tumor cells could
make their way to the brain via freely communicating vertebral veins. It is the
least frequent route of spread to the brain.
Metastatic tumors are more often multiple than single. The designation “single”
implies that only one brain metastasis is present and makes no reference to
cancer that neither may or may nor exist elsewhere in the body. The term
“solitary” implies the presence of a single brain metastasis in the patient who
has no known systemic malignancy. “Multiple” describes the condition in which
the patient harbors more than one intraparenchymal lesion. The histology is
similar to that of systemic metastases.
Metastases from the periphery to the brain are driven by molecular events that
tie the original site of disease to the distant host tissue. This preference
includes such critical steps as angiogenesis and the preparation of the
premetastatic niche. It appears that the connection between brain and cancer
cells is made in advance of any metastatic breach of the blood–brain barrier.
These chemotactic factors derived from the target or tumor cells may play a part
in lung and breast cancers and malignant melanoma, as opposed to genitourinary
cancers (prostate and ovary) to have a predilection to metastasize to the brain.
Systemic malignancy can metastasize to any location in the brain but most
commonly affects the cerebral hemispheres; they are characteristically located
in “watershed areas”, suggesting that microemboli lodge in the capillaries of
the most distal parts of the superficial arteries; this accounts for the
tendency of metastases to be located at the gray-white junction. 80% of brain
metastases occur in the cerebral hemispheres, 15% in the cerebellum, and 5% in
the brainstem The distribution of metastases among cerebrum, cerebellum and
brain stem corresponds roughly to the blood supply and weight of these
subdivisions. However, when the respective proportion of the brain in each of
these is considered, metastases are evenly distributed between the supra- and
infratentorial compartments. Metastatic lesions may also occur to the pineal
gland, pituitary gland, and choroid plexus.
the majority, the interval between diagnosis of a primary tumor and that of a
brain metastasis is less than 1 year. This interval depends on the primary
tumor. It is generally short in lung cancer or renal tumors but can be several
years in the cases of breast cancer, sarcoma, gastrointestinal or prostate
Symptoms usually begin sub-acutely. Like any other mass lesion, intraparenchymal
metastases cause symptoms by the local effects of cerebral tissue compression or
invasion. In addition, an increase in intracranial pressure secondary to the
mass effect of the tumor can give rise to symptoms such as headache, nausea, and
vomiting as a result of edema or compression of the surrounding brain and may be
reversed by therapy. Melanoma, choriocarcinoma, and lung and renal cell
carcinoma are the most likely metastases to have a tendency to hemorrhage. These
lesions may present clinically with sudden onset of neurologic deficit due to
acute hemorrhage and mimic a cerebrovascular accident..
Magnetic resonance imaging (MRI):
Since the introduction of gadolinium-labelled diethylenetriamine penta-acetic
acid (Gd-DTPA), MRI with its superior anatomic detail, multiplanar capability,
and sensitivity to detection of both intraparenchymal and extra-axial lesions is
the imaging of choice for detection and evaluation of parenchymal metastases.
The typical MRI appearance of a metastasis is of rounded nodule exhibiting T1
and T2 lengthening. They are associated with a surrounding area of edema
represented by usually differing T1 and T2 lengthening. The cystic or necrotic
centre of metastatic tumor, as it contains highly proteinaceous fluid, is
represented by high signal intensity on T2-weighted images. Sometimes this
cystic zone may be difficult to discriminate from surrounding edema on
T2-weighted images. In such cases differing T1 relaxation rates usually provide
contrast discrimination between central areas of necrosis and surrounding edema
on T1-weighted images.
is not always possible to distinguish metastatic deposits from regions of
ischemic change, edema, demyelination, or other benign lesions. SPECT and
Magnetic resonance spectroscopy (MRS) can help.
Computerized tomography (CT):
allows detection of contrast-enhanced lesions as small as 3 to 5 mm. Metastatic
tumors are seen usually at CT scans as discrete, roughly spherical masses
surrounded by an area of extensive edema. Most of them are hypo- or isodense
and about 90% of them show contrast enhancement. In small lesions below 1 cm
enhancement is usually uniform, while the centre of larger lesions often show
irregular or lack of enhancement due to central necrosis. A ring like peripheral
enhancement may mimic an abscess or a malignant gliom. Acute hemorrhage within
and surrounding metastatic tumor may obscure the presence of the tumor.
brain metastasis is suspected, systemic diagnostic studies should be performed
to identify the primary cancer. A chest X-ray is indicated to search for a
primary or metastatic lung tumor. A chest CT scan should be performed if the
X-ray is negative and the patient is at risk for primary lung cancer. Female
patients should undergo a mammogram. All patients should have a stool
examination for occult blood. Occasionally, CT scan of the abdomen and pelvis
may detect a primary cancer. Endoscopic study of the GIT may be needed. Routine
peripheral blood picture and a search for tumor markers such as PSA (prostatic
specific antigen) will help. This facilitates the choice of the optimum
management for each individual patient.
biopsy of the intracranial lesion should be performed in patients with a single
enhancing lesion, to exclude a primary brain tumor, abscess, or other
pathology. The importance of a biopsy in the patient with multiple lesions is
less clear if the patient has a known primary tumor. If there is no known
primary tumor, sterotactic or excisional biopsy is required for a definitive
diagnosis especially in those cases without a detectable primary.
effects of systemic cancer are not limited to the brain. The majority of
patients who have local CNS tumor control die of extracranial disease
progression, whereas those with uncontrolled brain metastases more often die of
neurological causes. Therefore, achieving local control is of primary
importance when considering treatment options in patients with brain
metastases. Treatment of brain metastases largely relieves symptoms and modestly
Therapeutic approaches to brain metastases include surgery, whole brain
radiotherapy (WBRT), stereotactic radio-surgery (SRS), and chemotherapy. Many
patients are treated with a combination of these, and treatment decisions must
take into account factors such as patient age, functional status, primary tumor
type, extent of extracranial disease, prior therapies, and number of
intracranial lesions. All of these factors have a role in determining the
overall prognosis and response to treatment.
Corticosteroids are recommended in virtually all patients when brain metastasis
is diagnosed because they rapidly ameliorate symptoms. Steroid administration
will decrease cerebral edema. Which commonly accompanies metastases, but the
absolute need for steroids is dictated by the clinical and radiographic
presentation. Steroids should be administered in the lowest dose that provides
relief and usually are continued throughout the treatment period, at which time
they are tapered.
is controversial whether prophylactic anticonvulsants should be administered to
patients with brain metastases who have not experienced seizures. There is no
evidence that this prevents seizures.
There is increasing data to suggest that medications such as methylphenidate
and donepezil can improve cognition, mood, and quality of life in patients with
Whole-brain radiation therapy (WBRT):
is recognized as the mainstay of treatment for most patients with
intraparenchymal metastases and widely available. Radiotherapy is recommended
for both radiosensitive and moderately radiosensitive metastases following
surgery. In clinical practice, WBRT is commonly delivered to patients with
multiple brain metastases not amenable to surgery or SRS, poor functional
status, or active or disseminated systemic disease with effective palliation of
neurological symptoms, and also following surgery. Fractionated therapy has been
permit more aggressive irradiation without an unacceptable increase in toxicity.
Nonrandomized studies suggest that WBRT increases the median survival time by
3-4 months over approximately 1 month without treatment and 2 months with
corticosteroids alone. Although several fractionation schedules have been
studied, meta-analyses suggest that differences in dose, timing, and
fractionation do not significantly alter the median survival times of patients
receiving WBRT for brain metastases. The most common regimen employed is 35 Gy
delivered in 2.5-Gy fractions over 14 treatment days.
response to radiotherapy depends upon the radiosensitivity of the metastasis.
Lymphoma and testicular and breast cancers are more radioresponsive than
melanoma and renal cell and colon cancers. Because of the high prevalence of
multiple lesions and the possibility of micrometastases treatment is given to
the entire brain.
Multiple attempts have been made to improve upon the results of WBRT with
radiosensitizers have been studied in randomized controlled trials, all failing
to show benefit in either local brain tumor control or overall survival: lonidamine,
metronidazole, misonidazole, motexafin gadolinium, bromodeoxyuridine and RSR13 (efiproxiral).
Over the years, several chemotherapeutic agents have been studied in combination
with WBRT for patients with brain metastases, including chloroethylnitrosoureas,
tegafur, fotemustine, and teniposide. More recently, the combination of WBRT and
low-dose (75 mg/m2) daily temozolomide has shown promising response rates with
acceptable toxicity in patients with newly diagnosed brain metastases from a
variety of solid tumors. Current data do not yet support the widespread use of
the combination in patients with new brain metastases.
Addition of SRS to WBRT improves local control in patients with up to four
metastases, it does not affect overall survival in patients with multiple
metastases, and it remains speculative whether select patients with multiple
metastases and indolent extracranial disease may benefit from SRS boost.
of prophylactic cranial irradiation is controversial. Small cell lung cancer
have a >50% estimated 2-year risk for central nervous system (CNS) relapse.
Prophylactic Cranial Irradiation has been recommended in such patients. There is
currently insufficient evidence to support in other lung cancers.
Indication for Surgical excision must be individualized. Since the 1980s,
resection of most single brain metastases has become a standard treatment
option in patients with good functional status and controlled or indolent
extracranial disease It is strongly indicated and most beneficial in a single
lesion which is surgically accessible, with low risk of increasing the
neurological deficit. The systemic disease should be under remission or presumed
eradicated. Expected life expectancy after excision must be relatively long and
good quality of life can be expected.
Resection of metastasis offers important advantages in comparison with other
kinds of therapy. It eliminates the immediate cause of cerebral edema,
accomplishes rapid decompression of the brain and provides samples for
Patients with multiple cerebral metastases do not usually qualify for
surgery. It is occasionally indicated if the patient has one or more small
additional lesions in silent areas of the brain, the systemic disease is under
control and expected quality of life is satisfactory. In such cases excision of
the life threatening or disabling tumor should be undertaken particularly if the
associating lesions are supposed to be radiosensitive or two metastatic lesions
can be removed through the same cranial opening. Surgical removal of all
lesions in selected patients with multiple cerebral metastases results in
significantly increased survival time and offers prognosis similar to that of
patients undergoing surgery for a single metastasis. Patients with good
prognostic features and two to three metastases may gain similar survival
benefit from surgery when the dominant lesion is resected. The role of surgery
is very limited when the extracranial systemic disease is advanced and in
progress. The extent of systemic disease is the most important variable in
qualification to surgery since the major cause of death is progress of cancer
outside the nervous system.
Stereotactic or ultrasound guidance is of help to locate small lesions precisely
before making cortical incision. The use of microsurgical techniques allows
gentler handling of tissue, better visualization and control of bleeding. As
complete a resection as possible should be achieved since this is associated
with increased length and quality of survival.
Surgery for recurrence following prior resection and radiotherapy is advocated
when the lesion remains single, the systemic disease is under control and the
general condition of the patient is satisfactory.
overall survival benefit is seen with WBRT after surgery, although patients in
the WBRT group are less likely to die from neurologic causes.
has emerged as a common treatment modality for newly diagnosed patients, alone
or in combination with WBRT, and as salvage therapy for progressive intracranial
disease after WBRT. The Cyberknife is used to treat cases in which the brain
metastases are complex in shape or are present in locations that are difficult
to treat using frame-based systems. Gamma Knife, linear accelerator, and proton
beam achieve their effects by treating a discrete tumor with a high volume of
radiation.There is no reported preference in the above various systems. Choosing
a particular SRS system is often based on institutional, financial, and
Evidence supports the efficacy of radio surgery in the palliation of symptoms
associated with metastases, providing excellent local control with minimal side
effects. Benefits of radio surgery include its noninvasiveness and ability to
be administered on an outpatient basis, important considerations for those whose
life span is shortened. SRS limited to tissue volumes no greater than 3 cm in
diameter, and the dose administered depends on the tissue volume. The major
drawback of radio surgery is its biological effect of “radio-necrosis” reported
in 4%-6% of patients within 1-2 weeks of treatment. The fractionated
external-beam technique (SRT) allows for corrections to be made in the treatment
regimen as the tumor shrinks, and for most patients it is easily performed
during a short hospital stay. The use of a small number of fractions supports
one of the potential advantages of radiosurgery (that large fractions are more
effective at killing radioresistant tumors) while adding to the advantages of
fractionation. Stereotactic radiosurgery appears to be a reasonable treatment
option in patients with up to three metastatic lesions in selected patients
regardless of extracranial disease status. In patients with four or more
metastases, SRS should be reserved for those with no extracranial disease.
or surgery for single metastasis is debatable. It is generally accepted that
conventional surgery is superior to radio surgery in the treatment of brain
metastases. response rates are mixed for tumors that have traditionally been
considered "radioresistant," for example, renal cell carcinoma, melanoma, and
sarcoma, with some studies showing comparable response rates. One-year
actuarial local control rates in the range of 71 %-79% have been reported with
the use of SRS alone for single and multiple brain metastases.
Controversy exists over whether SRS alone is sufficient. The rationale for
withholding WBRT is to spare patients the risk for late neurotoxicity from WBRT.
Omission of WBRT in patients with new brain metastases results in significantly
worse local control and distant intracranial disease control, though it does not
appear to affect overall survival.
use of SRS for recurrent brain metastases after WBRT has been investigated in
several small series and appears to be an effective treatment in patients with
good functional status and controlled or indolent extracranial disease.
role of chemotherapy in patients with cerebral metastases is limited at present
and reserved for patients who have failed other treatment modalities or for
diseases known to be "chemosensitive," such as lymphoma, small sell lung
cancer, germ-cell tumors, and, to a lesser degree, breast cancer. Methods are
available to reduce systemic dose, and therefore toxicity whilst increasing
tumor dose. These include intra-arterial infusions, intrathecal administration
or even direct placement of drug into tumor. Drugs may be modified to allow them
to pass the BBB, or agents used to open the BBB. However, because brain
metastases are known to have local BBB breakdown, studies showing roughly
equivalent intracranial and extracranial response rates to chemotherapeutic
agents assumed to have little BBB penetration, particularly when first-line
agents for the systemic cancer are chosen
prognosis for most patients with intraparenchymal metastasis is poor despite the
best current treatment with corticosteroids, radiation therapy, and surgery;
however. The prognosis for patients with cerebral metastases is poor generally
in spite of the fact that there are reports of long survivals. Systemic disease
status is the single most reliable predictor of survival.
Favorable factors influencing survival in patients undergoing surgery and
radiation therapy for cerebral metastases are
lack of identifiable disease outside the central nervous system,
minimal neurological deficit prior to surgery,
long interval between diagnosis of primary neoplasm and that of the brain
controlled or successfully treated primary disease.
Postsurgical survival time differs greatly according to the type of primary
cancer. In the most frequent cerebral metastases to the brain from the lung and
breast the median survival time is 11-12months. Prognosis in patients with
multiple metastases and/or progressive systemic cancer is much worse.
Despite surgery and WBRT, 31% to 48% of patients will develop recurrent
metastases in the brain. Therapies available at recurrence include resection,
external beam radiation, radio surgery, and chemotherapy. The fact that the
primary tumor was responsive to a specific agent or combination of agents does
not predict that the metastasis will respond similarly. Drug delivery is also an
important factor in tumor response as some chemotherapeutic agents do not
penetrate the blood-brain barrier opening.
2) Dural metastases:
Metastases to the epidural or subdural surfaces of the cranial vault,
collectively considered “dural metastases, are found in 8%–9% of patients with
advanced systemic cancer and arise by either direct extension from skull
metastases or hematogeneous spread. Diffuse studding of dura was seen primarily
with breast and prostate canSmall surgical series. particularly in patients
with bone metastases to the skull. Surgery is the most commonly described
treatment for dural metastases, followed bt radiation.
3) Lepto-meningeal Metastases:
Diffuse or disseminated infiltration via the subarachnoid space is relatively
uncommon with a poor prognosis, more so than other types of metastasis.
Leptomeningeal disease has been estimated to account for 8 to 10% of
intracranial metastatic diseases
Several terms have been used interchangeably to describe this condition,
including carcinomatous meningitis, neoplastic meningitis, meningeal
carcinomatosis, endothelioma of the meninges, and meningitis carcinomatosa.
Medulloblastoma, ependymoma, and pineoblastoma are the primary intracranial
tumors most frequently associated with subarachnoid seeding. However,
glioblastomas may also disseminate within the subarachnoid space. Of systemic
tumors, melanoma and lymphoma and leukemia are the most common followed by
breast and lung. Solid tumors that spread to the leptomeninges include breast,
small cell lung cancer, melanoma, genitourinary, head and neck (usually by
direct extension), and adenocarcinoma of unknown primary.
hematologic malignancies and solid tumors spread to the leptomeninges. The
involvement of the meninges with metastatic solid tumors is often associated
with parenchymal brain metastases. Acute lymphocytic leukemia and high-grade
non-Hodgkin's lymphomas often spread to the leptomeninges without detectable
brain involvement. Small cell lung cancer often involves the leptomeninges and
brain while non-small cell lung cancer usually manifests only brain metastases.
Breast cancer and melanoma spread to both sites.
Several hypotheses have been set forth regarding the mechanism by which systemic
cancer invades the leptomengines, and there is pathological evidence to support
each of these. There may be hematogenous spread to the vessels of the choroids
plexus or meninges, direct extension from an adjacent parenchymal, or
centripetal extension of tumor along perivascular and perineural lymphatics
through vertebral and cranial foraminae. Tumor most often spreads to the
leptomeninges through thin-walled meningeal vessels with subsequent
dissemination of tumor into the subarachnoid space
Cortical deposits rarely give rise to lepto-meningeal spread; they form fibrous
plaques, perhaps, fibrous scarring prevent free dissemination. Subependymal
metastases may reach the ventricular surface where their spread is not impeded
by fibrous scarring. An important source of dissemination of neoplastic cells
are metastatic deposits in choroid plexuses. Hydrocephalus may manifest due to
occlusion of CSF pathway. Rarely, spinal epidural deposits can extend along the
course of a nerve root into the spinal leptomeninges. Spread along the
perineural lymphatics from a distant foci is controversial.
After invading the meninges, the tumor spreads along the route of CSF
circulation, seeding the subarachnoid space. Infiltration is heaviest in the
basal cisterns, the sylvian fissures, and the cauda equina. The cranial and
spinal roots are almost invariably involved in the neoplastic process. The
invasion may be nodular or diffuse. The cauda equina tends to be involved
abundantly in a nodular pattern. Diffuse infiltration involves the entire root,
from its entry into the brainstem or spinal cord, to its exit through the dura
and beyond to the full extent of the archnoid sheath, which stops short of the
dorsal root ganglia. Some roots the nerve fibres remain apparently unaffected,
others show loss of myelin, in others the destruction is complete and is
accompanied by Wallerian degeneration.
hallmark of the process is the presence of symptoms and signs involving multiple
loci along the neuraxis. As with intra-parenchymal metastasis, signs of
neurological compromise are more common than symptoms. Symptoms and signs
localized to several different anatomic sites.
Leptomeningeal involvement at the base of the brain can use a communicating
hydrocephalus that produces signs and symptoms consistent with intracranial
hypertension, such as nausea, vomiting, and papilledema. Spinal cord and/ or
root involvement is characterized by leg weakness, radiculopathy, reflex
changes, and bowel and bladder dysfunction. Cranial nerve involvement usually
follows spinal involvement is suggested by the signs and symptoms of
ophthalmoplegia, facial weakness, altered facial sensation, or diminished
hearing. Cranial and spinal nerve root symptoms can be attributed to tumor
compression or infiltration of the nerves within the subarachnoid space.
leptomeningeal carcinomatosis progresses, old findings worsen while new signs
and symptoms appear. Treatment usually stabilizes, instead of improving,
neurological disability. Therefore, the clinician must make the diagnosis as
early as possible. This is achieved by suspecting leptomeningeal metastases in
the appropriate clinical setting.
Diagnosing leptomeningeal carcinomatosis can be difficult without a high index
of suspicion. Neuroimaging studies of the affected areas should be performed to
exclude other structural causes of the symptoms and signes and to search for
signs of leptomeningeal tumor. Enhanced CT or, preferably, MRI scans can reveal
linear or nodular leptomenigeal enhancement. Superficial cortical enhancing
nodules are virtually pathognomonic of this disease but are rarely seen.
Enhanced spine MRI is preferable to CT myelography for identifying “sugar
coating” of the leptomeninges or small nodules. Both methods, however, have a
high incidence of false-negative results, and normal findings on neuroimaging do
not exclude the diagnosis of leptomeningeal metastasis. The sensitivity of
contrast-enhanced MR for the detection of leptomeningeal tumor has been reported
from 33% to 78%. Unquestionably, examination of the cerebrospinal fluid remains
the most sensitive modality.
diagnosis of leptomeningeal metastases is usually based on the finding of
malignant cells in the cerebrospinal fluid (CSF). Multiple CSF samples may be
required to isolate malignant cells. CSF often shows increased pressure,
pleocytosis, elevated protein, or low glucose. Other chemistry determinations
are sometimes abnormal in patients with leptomeningeal metastases. These include
CSF beta-glucuronidase, beta 2-microglobulin, human chorionic gonadotropin, CA
125, carcinoembryonic antigen, and lactate dehydrogenase. The combination of CSF
flow cytometry and selective tumor marker analysis has been used to aid in the
diagnosis of leptomeningeal metastases.
Quantification of biochemical markers in the CSF can be helpful; some of these
include B2-glucurondiase, carcinoembryonic antigen (CEA), lactate dehydrogenase
(LDH), and B2-microglobulin. B-Glucuronidase is commonly elevated in patients
with leptomeinigeal metastases from malignant melanoma or breast or lung
carcinoma can be increase in any fungal or tuberculosis infection of the
meninges. Marker levels usually return to baseline with successful treatment of
leptomeningeal metastases, and thus, recurrence can be predicted by rising
Serum CEA levels can indicate the presence of a systemic cancer. Elevated levels
in the CSF suggest leptomeningeal metastases. Newer diagnostic tests use
monoclonal antibodies directed against tumor cell antigens; it is hoped that
these will offer improved sensitivity and specificity.
Because of the multifocal involvement of the CNS, treatment must be directed at
the entire neuraxis to be effective. In practice two modalities are employed;
radiation and chemotherapy. Usually, radiation is given focally to the site of
maximal symptomatology or bulk disease because of the myelosuppression caused by
more extensive radiation therapy. Chemotherapy is used to target the entire CNS
and is usually given intrathecally via lumbar puncture of intraventricularly by
use of a ventricular cannula attached to an Ommaya reservoir. Approximately 50%
of those so treated will have stabilization or improvement of symptoms.
Intraventricular chemotherapy via Ommaya reservoir is preferred over intrathecal
chemotherapy because of its reliable drug delivery to the subarachnoid space
with minimal discomfort to the patient. The three standard chemotherapeutic
agents used. Methotrexate and thiotepa have similar response rates in the
treatment of solid tumors. Cytosine arabinoside is preferred in those with a
primary hematological malignancy. High-dose systemic chemotherapy is an
alternative to intra-CSF chemotherapy is an alternative to intra-CSF
chemotherapy, especially in patients with hematological malignancies who have a
concurrent systemic relapse.
Radionuclide CSF flow studies should be performed prior to the administration of
intra-CSF chemotherapy, to identify blocks that impede the flow of drug and
predispose to toxicity. If flow blocks are detected, radiation should be
administered to correct them.
Lumbar punctures should be performed periodically to analyze the CSF for
response to treatment. Despite palliation of symptoms, the prognosis of
patients with leptomeningeal metastases remains poor; median survival is 4 to 6
months with treatment. A number of innovative chemotherapy and immunotherapy
trials that may improve treatment results are currently under way.
addition to treatment directed at the CNS, optimal treatment for the systemic
malignancy should be undertaken. While fixed neurological deficits may not
improve, local control of tumor can be achieved; many of these patients
eventually die from the primary illness. Accordingly, patients with controlled
or slowly progressive systemic cancer benefit the most from treatment.
3) Other CNS manifestations:
Paraneoplastic neurological disorders (PND):
paraneoplastic neurologic syndromes are a diverse group of diseases
characterized by the presence of neurologic dysfunction in the setting of a
remote cancer. Almost any malignant tumour except brain tumors can be the cause.
PND can affect almost any part of the nervous system, and are most commonly
associated with lung cancer (small cell) and gynecologic tumors. They are
believed to be caused by an autoimmune reaction to an "onconeural" antigen
shared by the cancer and the nervous system. The immune reaction may retard
growth of the cancer, but it also damages the nervous system.
may be focal such as paraneoplastic cerebellar degeneration (PCD) or multifocal
limbic and brainstem encephalitis with sensory neuronopathy. The peripheral
nervous system is more commonly involved than the CNS. Mild distal sensorimotor
neuropathies are quite common in patients with cancer and are not necessarily
paraneoplastic; metabolic, nutritional, and treatment related toxicity must be
ruled out. Other differential diagnosis include vasculitides, inflammatory and
granulomatous CNS disorders, and meningeal infiltrations. They are
degenerative. PCD typically presents as a subacute progressive cerebellar
ataxia, both truncal and appendicular, dizziness, nystagmus (rapid uncontrolled
eye movements), difficulty swallowing, loss of muscle tone, loss of fine motor
coordination, slurred speech, memory loss, vision problems, sleep disturbances,
dementia, seizures, sensory loss in the limbs. It is believed to be due to an
autoimmune reaction targeted against components of the central nervous system
(specifically Purkinje cells and large brain stem nuclei). It is thought to be
caused by an anti-neuronal Antibody known as anti-Yo.
Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder which
affects calcium channels of the nerve-muscle (neuromuscular) junction. The
etiology of LEMS may resemble myasthenia gravis, but there are substantial
differences between the clinical presentation and pathogenetic features of the
Neurological disorders, clinically and pathologically identical to
paraneoplastic syndromes, may occur in some patients without cancer, but
paraneoplastic antibodies are not found in these patients. The diagnosis of a
paraneoplastic syndrome is based on its increased incidence in patients with
cancer, the occasional response of the neurological syndrome to treatment of the
underlying cancer, or the presence of specific autoantibodies.
general, PNDs of the CNS are resistant to treatments except in a few isolated
cases. Some paraneoplastic syndromes respond to treatment of the underlying
cancer or to immunosuppression but, for most syndromes, no effective treatment
exists. A few case reports suggest benefit from intravenous immune globulin when
treatment is started within a few weeks of onset. Low titers of antibody are
associated with a better prognosis of the cancer. PNDs affecting the peripheral
nervous system carry better prognosis.
Tumor invasion of large nerves is rare. In most, the infiltration is confined to
the epineurium and the fascicles may be encased in dense growth without being
invaded. The nerve fibres may escape damage altogether or undergo degenerative
changes, both in the form of demyelination and of axonal degeneration. In the
minority of cases the tumor invades the fascicles and spreads along the
subperineural space and its extensions, along the major endoneurial septa, and
along the blood vessels.
Cervical, brachial, and lumbosacral plexi can be sources of intractable pain in
cancer patients. Pain is produced when these structures are infiltrated by tumor
or compressed by fibrosis after radiation therapy to adjacent structures. Pain
tends to be less prominent in radiation-induced plexopathies than in
Current treatment is symptomatic. Intractable pain relief poses the major
difficulty. The course of illness is short, medication providing most support
and surgical methods are rarely employed. Radiotherapy offers no benefit.
all of the non metastatic neurological complications of systemic cancer,
metabolic encephalopathy is the most common. Metabolic encephalopathy is most
commonly caused by administration of opioids for pain control, vital organ
failure, fluid and electrolyte imbalance, or sepsis. Cognitive difficulties,
exemplified by impairment of memory and orientation, also occur early in the
course of encephalopathy. Characteristically, these changes are reversible if
the underlying systemic metabolic abnormality is identified and treated
appropriately. If uncorrected, metabolic disturbances can lead to stupor and
Cerebrovascular complications (infarction and intracranial hemorrhage) secondary
to the effects of systemic malignancy are the second most common
neuropathological finding in cancer patients. Cerebral hemorrhage and infarction
are equally frequent in those with systemic malignancy. Coagulation disorders,
CNS metastasis, and treatment-related complications are the most common causes
of stroke. Cerebral intravascular coagulation is a second common cause of
symptomatic cerebral infarction. Occlusion of venous sinuses, typically the
superior sagittal sinus, while sometimes caused by an overlying metastasis, can
also occur as a nonmetastatic complication of cancer. The nonmetastatic variety
is presumably due to a coagulopathy caused by the tumor or chemotherapy.
Patients with systemic cancer are susceptible to infections of the CNS either
because of their primary disease process or as a result of treatment that
renders them immunosuppressed. They are prone to infections caused by fungi
(Candida, Cryptococcus or Aspergillus spp.) viruses, parasites, and certain
bacteria, such as Listeria monocytogenes. Survival is dependent on the correct
diagnosis being made as early as possible so that treatment can be initiated.
modalities employed in the treatment of metastases to the brain have their
risks. Most complications occur from radiation or chemotherapy. Often, such
complications present as a neurological deterioration, which need to be
distinguished from that which is an effect of the primary process. This
distinction is important as the treatments for the two situations are
Radiation necrosis well known.
The effects of radiation on the brain can be seen acutely within hours,
subacutely within days, or chronically months to years after treatment.
Chemotherapy can be neurotoxic, either as a direct consequence of the
chemotherapeutic agent on the brain or its vessels or as secondary results from
toxicity to other organs (i.e., hepatic encephalopathy) or from coagulation