Neurology and Systemic Cancer:

 
Dr. A. Vincent Thamburaj,  
Neurosurgeon, Apollo Hospitals,  Chennai , India.

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, paraneoplastic syndromes. 

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:

 

The 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?0%), breast (15?0%), skin (5?0%), and gastrointestinal tract (4?%). 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.  

 

Clinical features: 

 

In 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 cancer.

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..

 

Diagnosis:

 

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.

Single metastasis-corpuscallosum Cerebellar metastases Multiple metastases

It 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):

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.

 

Others:

If a 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:

A 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.

 

Management:  

 

The 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 improves survival.

 

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. 

 

Symptomatic 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. 

It 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 brain tumors.

 

Whole-brain radiation therapy (WBRT):

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 shown to

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.

The 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.

 

Role 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.

 

Surgery:

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 histological diagnosis.

 

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.

No overall survival benefit is seen with WBRT after surgery, although patients in the WBRT group are less likely to die from neurologic causes.

 

Stereotactic radiosurgery,(SRS):

SRS 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 administrative factors.

 

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.

 

SRS 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.

 

The 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.

 

Chemotherapy:

The 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:

 

The 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 metastasis,

  • younger age,

  • 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%?% 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.

 

Both 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.   

 

Clinical features: 

 

The 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. 

As 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. 

 

Diagnosis:

 

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.

 

The 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 levels.

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.

 

Management:

 

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. 

 

In 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):

 

The 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.

 

PND may be focal such as paraneoplastic cerebellar degeneration (PCD) or multifocal such as

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 two disorders

 

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.

 

In 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.

 

Neuropathies:

 

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 tumor-related ones.

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.

 

Metabolic encephalopathy:

 

Of 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 coma.

 

Cerebrovascular complications:

 

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. 

 

Opportunistic infections:

 

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.

 

Treatment Complications: 

 

All 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 diametrically opposed. 

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 abnormalities.

 
 

 

 

 

 

 

 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 

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