Lisa M. DeAngelis
I. METASTASES TO THE BRAIN
A. Pathogenesis
1. Incidence. Autopsy series show that 25% of patients who die of cancer have intracranial metastases; 15% have brain and 10% have dural or leptomeningeal metastases.
2. Tumor of origin. The tumor that most commonly metastasizes to the brain is lung cancer, which is responsible for 30% of brain metastases. Brain metastases from pulmonary tumors can occur early in the course of malignancy, and their diagnosis is synchronous (i.e., before or at the same time as the primary tumor) in about one-third of cases. Other types of tumors that commonly metastasize to the brain include breast and renal cancers and melanoma (each comprising 10% of cases), along with metastases from tumors of unknown primary sites (15%). Carcinomas of the gastrointestinal tract, ovary, and uterus rarely produce intracerebral metastases.
3. Mechanism. Tumor dissemination to the central nervous system (CNS) is usually by the hematogenous route, and the distribution of lesions parallels the distribution of arterial blood flow. Of brain metastases, 80% are supratentorial, 15% are cerebellar, and 5% are in the brainstem. However, metastases from certain primaries have a predilection for particular regions in the brain. For example, colon cancer and pelvic primaries have a propensity ro metastasize to the posterior fossa, whereas lung cancer tends to metastasize to the supratentorial compartment. About one-half of the metastases are single, especially those from lung, renal, and colon cancers; metastases from melanoma and breast cancer are more likely to be multiple. Metastases can be solid, cystic, or hemorrhagic (especially lung, choriocarcinoma, melanoma, and thyroid carcinoma).
B. Natural history. Left untreated, metastatic brain tumors cause progressive neurologic deterioration leading to coma and death; the median survival time is only 1 month. About one-half of patients with brain metastases die of their neurologic disease, and the remainder die of systemic causes. Among treated patients, the overall median survival is 3 to 8 months; however, patients with limited systemic disease and one to three brain metastases can have vigorous focal treatment and survive longer, sometimes years.
C. Clinical presentation. Metastases can cause focal or global cerebral dysfunction at presentation. Symptoms usually develop insidiously and progress over a few weeks. Occasionally, the onset is sudden when there is an acute hemorrhage into a metastatic lesion.
1. Global signs and symptoms. Headache and mental status changes are each seen in 50% of patients. Other nonlocalizing findings include symptoms of increased intracranial pressure, such as papilledema, nausea, and vomiting.
2. Focal signs and symptoms, including hemiparesis, visual field defect, and aphasia, depend on the site of metastasis.
3. Seizures are the presenting manifestation in about 20% of patients.
4. Differential diagnosis. Conditions that should be considered in the differential diagnosis of brain metastasis include the following:
a. Metabolic encephalopathy, including hyponatremia, hypercalcemia, hypoxemia, uremia, hepatic encephalopathy, and hypothyroidism
b. Drug-induced encephalopathy from analgesics, sedatives, glucocorticoids, chemotherapeutic agents, and other drugs
c. CNS infections, including bacterial and fungal meningitis, herpes encephalitis, progressive multifocal leukoencephalopathy, and cerebral abscess (see Chapter 35, Section III.B)
d. Nutritional deficiency, such as Wernicke encephalopathy
e. Cerebrovascular disease (CVD), including stroke, hemorrhage, and venous obstruction owing to thrombotic disorders and disseminated intravascular coagulation (DIC)
f. Paraneoplastic disorders, especially subacute paraneoplastic cerebellar degeneration (see Section V.A)
D. Evaluation. An MRI is the optimal test to detect brain metastases. A CT scan should only be used in those patients unable to undergo MRI (e.g., pacemaker). Most metastatic tumors enhance after administration of contrast material, and both a noncontrast and contrast study should be performed in every patient. Lesions detectable by CT or MRI that may resemble brain metastases include cerebral abscesses, parasitic disease, and occasionally stroke. Lumbar puncture is not useful in diagnosing brain metastases and is often contraindicated.
E. Management. The aims of therapy for patients with brain metastases are to relieve neurologic symptoms and prolong survival. Exact treatment recommendations depend on the histology of the tumor, the degree of systemic dissemination of the tumor, and the patient’s clinical condition.
1. Dexamethasone, usually 16 mg IV followed by 4 to 8 mg PO or IV twice a day, results in a dramatic reversal of neurologic deficits and alleviates headaches. The effect is short lived (weeks), however, but further improvement is possible with dose escalation and definitive treatment. Dexamethasone is unnecessary for asymptomatic patients whose brain metastases were identified on a screening MRI. In most patients, steroids can be tapered off once definitive therapy has been administered.
2. Anticonvulsant therapy should be administered only to patients who have had a seizure. Antiepileptics that do not induce the hepatic microsomal system, such as levetiracetam, valproic acid, lamotrigine, or others, are the best options. There is no role for prophylactic anticonvulsants in patients with brain metastases. They do not protect against future seizures, are associated with frequent side effects, and can enhance the metabolism and thus reduce the efficacy of many chemotherapeutic agents.
3. Radiation therapy (RT) is the standard treatment of brain metastases. The field usually encompasses the whole brain, and doses range from 2,000 to 4,000 cGy, administered by larger fractions in the lower-dose regimens.
4. Surgery provides a significant survival advantage for patients with a single brain metastasis. Median survival for surgically treated patients is 10 to 12 months, and 12% of patients live 5 years or longer. Candidates for surgical resection should have a single or possibly two brain metastases and limited or controlled systemic disease. Surgical resection is considered in other cases on an individual basis and may be influenced by the need for a tissue diagnosis. Whole-brain RT after surgical resection improves control of CNS disease but does not prolong survival.
5. Radiosurgery delivers a single large dose of radiation to a well-defined target; the steep dose curve of this technique ensures that little radiation is delivered to surrounding tissues. Radiosurgery can be delivered with equal efficacy by a gamma knife or linear accelerator. It is an effective, minimally invasive outpatient procedure that is a treatment option for patients with one to three intracranial metastases. Radiosurgery may be used in place of surgical resection or whole-brain radiation therapy or as an adjunct to either treatment. Local control rates appear to be equal for surgery and radiosurgery. Radiosurgery offers an advantage for metastases that are not surgically accessible, for multiple metastases, or for tumor types that are resistant to standard radiation therapy (e.g., renal cell carcinoma, melanoma) where control by radiosurgery appears to be superior. Radiosurgery must be limited to lesions ≤3 cm in diameter and can occasionally produce symptomatic radionecrosis or a prolonged dependence on corticosteroids.
6. Chemotherapy. Cytotoxic agents are primarily used to treat brain metastases at relapse or occasionally asymptomatic lesions found on screening MRI. Responses have been documented in patients with metastatic breast cancer, small cell lung cancer, and lymphoma. Effective regimens are selected on the basis of the underlying primary and the patient’s prior therapies.
Temozolomide is effective for some patients with brain metastases from non–small cell lung cancer and melanoma. Targeted therapy has proven effective against tumors and even their CNS metastases that harbor sensitizing mutations such as erlotinib in EGFR mutant non–small cell lung cancer or BRAF inhibitors in BRAF mutant melanomas.
II. METASTASES TO THE MENINGES
A. Pathogenesis
1. Incidence. Leptomeningeal metastases have been demonstrated at autopsy in 8% of patients with systemic malignancy.
2. Associated tumors. Although any systemic tumor can metastasize to the leptomeninges, those that do so most commonly are lymphoma, leukemia (especially acute), lung carcinoma (especially small cell), breast carcinoma, and melanoma.
3. Mechanism. Metastasis to the leptomeninges occurs by hematogenous spread through arachnoid vessels or the choroid plexus, by infiltration along nerve roots, and by extension from brain or dural metastases. The sites of heaviest infiltration are usually at the base of the brain, the major brain fissures, and the cauda equina.
B. Natural history. Leptomeningeal metastasis can involve any area of the CNS in direct contact with the cerebrospinal fluid (CSF). Tumor can grow as a sheet along the surface of the brain, spinal cord, cranial nerves, or nerve roots and can also invade these structures causing focal dysfunction. Tumor cells can obstruct the arachnoid villi and impair CSF reabsorption causing hydrocephalus.
C. Clinical presentation. The hallmarks of leptomeningeal metastasis are evidence of multilevel, noncontiguous neurologic signs and more neurologic findings identified on examination than the patient has symptoms. There are four basic clinical presentations that may be seen alone or in combination; meningismus is rarely present.
1. Spinal. At least 50% of patients with leptomeningeal metastasis have spinal symptoms. Symptoms and signs include back pain, radicular pain, weakness, numbness (leg more often than arm), and loss of bowel and bladder control.
2. Cerebral. About one-half of the patients present with cerebral symptoms and signs including headache, lethargy, change in mental status, ataxia, and seizures (partial and generalized).
3. Cranial nerve. Symptoms and signs include visual loss, diplopia, facial numbness, facial weakness, dysphagia, and hearing loss.
4. Hydrocephalus. Symptoms and signs of increased intracranial pressure include headache, decreased level of consciousness, gait apraxia, and urinary incontinence.
D. Evaluation. The diagnosis of leptomeningeal metastasis is often strongly suspected on clinical grounds, but it can sometimes be difficult to make a definitive diagnosis. The diagnosis may be confirmed by characteristic findings on MRI or by the demonstration of tumor cells in the CSF.
1. Imaging studies. Contrast-enhanced MRI of the brain and complete spine should be obtained in all patients to evaluate the full extent of disease. If the patient cannot have an MRI, CT scan of the head and CT myelography of the spine can be performed. Definitive neuroimaging findings include nodules on the cauda equina, enhancement of the cranial nerves, enhancement within sulci or the cisterns, or enhancement along the surface of the spinal cord. In a patient with known cancer, these findings suffice to establish the diagnosis and do not require CSF confirmation of tumor cells. Radiographic evidence of communicating hydrocephalus or brain metastases adjacent to a ventricular surface or deep within sulci are suggestive of leptomeningeal disease but require definitive spinal imaging or the demonstration of tumor cells in the CSF to confirm the diagnosis.
2. CSF examination. CSF is examined for protein and glucose concentrations, cell count, and cytology. Routine cultures should be performed because the differential diagnosis includes chronic infectious meningitis. CSF may be obtained by lumbar puncture or, in cases of suspected spinal block, by cervical puncture under radiographic guidance.
a. Opening pressure. The opening pressure should always be measured to assess the intracranial pressure (ICP). Patients can have marked elevation of ICP even in the absence of hydrocephalus.
b. Routine studies. Elevated protein and pleocytosis (usually lymphocytic) are nonspecific findings that occur in about 75% of patients with leptomeningeal metastases. A low glucose concentration occurs in <25% but is strongly suggestive when present.
c. Cytologic examination confirms the diagnosis in about one-half of patients on the first lumbar puncture. The diagnostic yield increases to about 90% by the third tap, but 10% of patients remain undiagnosed. The use of molecular diagnostic techniques, particularly for hematopoietic neoplasms, may be useful. Immunohistochemical staining and fluorescence in situ hybridization (FISH) to detect aneusomy of chromosome 1 may enhance the diagnostic yield. Flow cytometry studies, which evaluate DNA abnormalities and estimate the degree of aneuploidy, may also be useful in cases of suspected leptomeningeal metastasis (especially from leukemia or lymphoma) with a nondiagnostic CSF cytology.
d. Tumor markers may serve as additional diagnostic tests and are useful in following response to therapy. Tumor-specific biochemical markers include β2-microglobulin (leukemia and lymphoma), carcinoembryonic antigen (solid tumors such as lung, colon, and breast cancer), cancer antigen 15-3 (breast cancer), human chorionic gonadotropin and α-feto-protein (germ cell tumors), and lymphocyte markers (especially B-cell markers) to differentiate leukemic or lymphomatous cells from normal reactive T-lymphocytes. Nonspecific markers that may be elevated in a variety of tumor types include β-glucuronidase and lactate dehydrogenase isoenzyme 5; newer markers also include telomerase and vascular endothelial growth factor (VEGF). All tumor markers should be measured in the serum, and if the serum to CSF ratio is less than 60:1, the marker is being produced inside the CNS. Brain metastases do not increase CSF tumor marker concentration.
E. Management. The optimal therapy for neoplastic meningitis has not been established. The basic premise is to treat clinically active or bulky disease with RT and to treat the remainder of the neuraxis with intrathecal chemotherapy. Systemic chemotherapy appears, however, to have an important role and may be associated with improved outcome. A response can be achieved in about one-half of patients, but the median survival is <6 months. Patients with breast cancer, leukemia, and lymphoma have the best prognosis.
1. Dexamethasone is of limited benefit in patients with leptomeningeal disease, except in patients with lymphoma where it acts as a chemotherapeutic agent. It should be avoided unless the patient has elevated ICP.
2. RT is limited to areas of clinical involvement even if disease is not evident at that location radiographically. The typical dose is 3,000 cGy delivered in 10 fractions. This frequently relieves pain and may stabilize the patient neurologically. Fixed neurologic deficits do not usually improve. Complete neuraxis RT is avoided because it is associated with a high morbidity, causes myelosuppression, and does not improve outcome.
3. Intrathecal chemotherapy may be used to treat the entire subarachnoid space, although intrathecal drug does not penetrate into nodules of subarachnoid disease. The drug can be administered by lumbar puncture or preferably through an intraventricular reservoir (an Ommaya reservoir). The drug is usually given twice weekly until abnormal cells are no longer found in the CSF, and it is then given at progressively longer intervals. Preservative-free agents should be used. The dose is fixed and not calculated on a meter-squared basis because the volume of CSF is identical in all adults regardless of size. There must be normal CSF flow dynamics for intrathecal chemotherapy to be effective. Patients with large bulky lesions or hydrocephalus always have impaired CSF flow, and intrathecal drug should not be administered to these patients until normal CSF flow is documented by an intrathecal indium radionuclide study. Intrathecal chemotherapy can be complicated by an acute chemical meningitis or arachnoiditis. This can cause headache, nausea, fever, and neck stiffness mimicking an infectious meningitis. Arachnoiditis may be seen with any agent but is pronounced with liposomal cytarabine (DepoCyt), and patients must be treated with corticosteroids for several days before and after each DepoCyt injection to minimize this toxicity.
a. Methotrexate, 12 mg twice weekly followed by leucovorin rescue
b. Cytarabine, 30 to 60 mg twice weekly
c. Thiotepa, 10 mg twice weekly
d. DepoCyt (liposomal cytarabine), 50 mg every other week
4. Systemic chemotherapy has the advantage of reaching all areas of disease, penetrating into bulky lesions that intrathecal drug cannot reach, and being independent of CSF flow to reach the whole subarachnoid space. The choice of drug is based on its ability to penetrate into the CSF and on the chemosensitivity spectrum of the underlying primary. The most widely used agents are high-dose methotrexate (≥3 g/m2), high-dose cytarabine (3 g/m2), and thiotepa. A wide variety of other drugs, however, have been used effectively, such as capecitabine (Xeloda) for breast cancer. There are isolated reports that bevacizumab has been beneficial.
III. EPIDURAL SPINAL CORD COMPRESSION. Epidural spinal cord compression is a neuro-oncologic emergency. Any cancer patient with back pain should receive a prompt and thorough evaluation, and those with neurologic dysfunction localizing to the spinal cord or cauda equina require emergency evaluation and treatment.
A. Pathogenesis
1. Incidence. About 5% of patients with cancer develop clinical evidence of spinal cord compression.
2. Distribution. About 10% of epidural metastases occur in the cervical spine, 70% in the thoracic spine, and 20% in the lumbosacral spine. About 10% to 40% of patients have multifocal epidural tumor.
3. Responsible tumors. Any tumor can cause spinal cord compression, but lung cancer accounts for 15% of cases; breast, prostate, carcinoma of unknown primary site, lymphoma, and myeloma each account for about 10% of cases.
4. Mechanisms. A tumor reaches the epidural space by several mechanisms. The most common is direct extension from a metastasis to the vertebral body growing into the epidural space resulting in cord compression. Other tumors, particularly neuroblastoma and lymphoma, can grow into the spinal canal through the intervertebral foramina without destroying bone. Secondary vascular compromise can also occur resulting in venous infarction that can cause the sudden, irreversible deterioration seen in some patients. Direct metastasis to the spinal cord parenchyma is a rare cause of spinal cord dysfunction in cancer patients.
B. Diagnosis
1. Natural history. The progression of disease from the spinal column to the epidural space with neural encroachment is manifested clinically as local back pain followed by radicular symptoms and eventually myelopathy.
a. The initial stage of localized pain can last for several weeks or, in tumors such as breast or prostate cancer and lymphoma, for several months.
b. Radicular symptoms, such as pain radiating in a root distribution, usually herald further progression of the metastatic tumor but are still a relatively early symptom.
c. Once paraparesis or ascending numbness of the legs occurs, the progression may be extremely rapid and a complete myelopathy may develop within hours. Rapid progression is especially common with lung cancer, renal cancer, and multiple myeloma.
2. Clinical presentation depends on the level of spinal involvement.
a. Back pain is the initial symptom in >95% of patients with spinal cord compression caused by malignancy. The pain is dull, aching, and often localized to the upper back; it typically worsens with recumbency, unlike back pain from spinal degenerative disease. Tenderness over the appropriate spinal level may be readily elicited.
b. Radiculopathy is usually manifested by pain in a dermatomal distribution but can also include sensory or motor loss in the distribution of the involved roots. Cervical and lumbar diseases usually cause unilateral radiculopathy, whereas thoracic disease causes bilateral radiculopathy, resulting in a band-like distribution of pain. The pain from thoracic radiculopathies can sometimes be similar to pain from pleurisy, cholecystitis, or pancreatitis. The pain from cervical or lumbar radiculopathies can simulate disk herniation.
c. Myelopathy can rapidly result from further disease progression. Depending on the level of spinal involvement, the signs of myelopathy include bilateral weakness and numbness in the legs and loss of bowel and bladder function. Associated neurologic findings include hyperactive deep tendon reflexes, Babinski responses, and decreased anal sphincter tone. Disease at the level of the cauda equina usually causes urinary retention and saddle anesthesia. Unusual presentations of spinal cord compression include ataxia without motor, sensory, or autonomic dysfunction. Metastasis to the spinal cord parenchyma can cause a myelopathy without back pain.
3. Evaluation. Because the prognosis worsens when myelopathy develops, the diagnosis of epidural metastasis should be established before the onset of spinal cord injury. The extent of workup depends on the clinician’s suspicion for metastatic disease and the degree and rate of neurologic progression of the patient.
a. MRI is the procedure of choice for evaluating patients with suspected cord compression. MRI defines the degree of neural impingement and the extent of bone involvement; it is noninvasive and accurately detects other entities in the differential diagnosis of myelopathy. In addition, the entire spine can be imaged, which is essential in any patient with an epidural metastasis. Images should be obtained without gadolinium; a negative, nonenhanced spine MRI excludes epidural tumor. If leptomeningeal metastasis is a diagnostic consideration, the scan can be obtained without and with contrast, but this is not required in the emergency setting and postcontrast images can always be obtained at a later date.
b. CT myelography can be used if the patient cannot undergo an MRI. If myelography shows a complete block, contrast material needs to be administered at both the lumbar and the high cervical levels to establish the extent of disease. If myelography is performed, CSF should always be sent for routine studies and cytologic examination. Myelography is contraindicated in patients with coagulopathy and may worsen a neurologic deficit below the level of a complete spinal block.
c. Bone scan can identify metastatic disease to the spinal column and may suggest the level of tumor involvement. It cannot, however, visualize the epidural space and should never be done in a patient suspected of cord compression.
d. Plain radiographs have no role in the assessment of epidural metastasis.
4. Differential diagnosis
a. Structural lesions. Epidural hematoma (may occur spontaneously or after invasive procedures, especially in patients with a coagulopathy), epidural abscess, herniated disk, osteoporotic vertebral collapse.
b. Nonstructural lesions. Paraneoplastic syndromes (see Section V), radiation myelopathy (see Section VI.B.3), Guillain-Barré syndrome.
c. Back pain in the absence of neurologic findings in patients with normal imaging studies of the spine may be caused by leptomeningeal, lumbosacral, or brachial plexus or retroperitoneal metastases, which can be diagnosed by enhanced MRI, CSF studies, or body MRI or CT scans.
C. Prognosis. The outcome is greatly improved if treatment is initiated before spinal cord symptoms appear. In general, if the patient is walking at diagnosis, he or she will remain ambulatory after treatment, but if the patient is not walking at diagnosis, restoration of ambulation is less likely. Other prognostic factors include the level of spinal cord involvement and the rate of neurologic progression. Patients with breast cancer and lymphoma tend to do better because their tumors respond to therapy. Patients with lung or prostate cancer that is refractory to treatment, and who have cord compression that has progressed rapidly, tend to do poorly.
D. Management. Once the diagnosis of epidural tumor has been established, rapid therapeutic intervention is essential.
1. Dexamethasone is useful for alleviating neurologic symptoms and helps to control pain associated with epidural cord compression. Treatment should begin immediately, even before diagnostic studies are performed, unless the patient has lymphoma in which case corticosteroids can cause tumor regression and a false-negative finding on MRI. Dosing depends on the degree of neurologic involvement. For radiculopathy only, doses are usually 16 mg IV followed by 8 to 12 mg IV or PO twice a day. For rapidly evolving disease, or with evidence of myelopathy, treat with 100 mg IV followed by 24 mg IV every 6 hours; a rapid taper is essential for these high-dose regimens and should start within 48 hours.
2. RT has been the primary treatment for spinal cord compression. It not only retards tumor growth but also alleviates pain. RT is especially useful for tumors that are sensitive to radiation (e.g., lymphoma, breast), early and slowly progressive lesions, and metastases below the conus medullaris. The usual dose is 3,000 to 4,000 cGy over 2 to 4 weeks.
3. Surgery is used in the treatment of some patients with tumor metastatic to the spine. A randomized, prospective trial demonstrated that surgery followed by RT is superior to RT alone, giving significantly longer survival and better neurologic outcome, including restoration of ambulation in paraplegic patients. These operations usually involve resection of the vertebral body through an anterior surgical approach; the body is reconstructed and the spine stabilized with hardware. Patients must be in reasonable condition with controlled systemic disease to qualify for this approach. RT is performed after surgery. Laminectomy has limited value in the management of metastatic spinal disease because the tumor usually originates anteriorly and posterior decompression does not relieve pressure on the spinal cord. Other specific indications for surgery include the following:
a. Need for a pathologic diagnosis.
b. Progression of neurologic abnormalities during RT; surgery rarely restores lost neurologic function in this situation.
c. Recurrent spinal cord compression in a previously irradiated area.
d. Spinal instability.
4. Chemotherapy is rarely used for treatment of malignant spinal cord compression. It is occasionally used in highly responsive tumors, such as lymphoma or germ cell tumors, if neurologic involvement is limited.
IV. METASTASES TO THE PERIPHERAL NERVOUS SYSTEM
A. Brachial plexus
1. Anatomy. The brachial plexus is composed of the C5 through T1 nerve roots. The upper portion of the plexus (C5 and C6) innervates the proximal arm musculature and sensation to the forearm and thumb. The lower portion (C8 and T1) innervates the hand musculature and sensation to the fifth digit. In the axillary region, the lower portion of the plexus is in close proximity to the lymphatic system.
2. Mechanism. Tumor is most likely to involve the brachial plexus by contiguous growth from the upper lobe of the lung or the axillary or paraspinal lymph nodes. Lung cancer, breast cancer, and lymphoma are the most common tumors to cause a metastatic brachial plexopathy.
3. Clinical presentation. The most common presenting symptom is pain, which tends to radiate from the shoulder to the digits in a radicular fashion and is exacerbated by shoulder movement. Paresthesias and weakness, with loss of deep tendon reflexes and evidence of muscle atrophy, occur in relation to the extent of involvement of the brachial plexus. Associated findings may include a palpable axillary or supraclavicular mass or Horner syndrome.
4. Differential diagnosis. The primary differential diagnosis is radiation plexopathy in patients who have been irradiated as treatment for their primary disease (e.g., breast cancer). Metastatic tumors tend to involve the lower trunk of the plexus because of its close proximity to lymphatic vessels, whereas RT plexopathy is more likely to involve the upper trunk. Features of both upper and lower plexus involvement are usually found, however, so this distinction is not diagnostic. Other causes of plexopathy include surgical trauma, trauma secondary to poor limb placement during anesthesia, brachial neuritis, and radiation-induced tumors of the plexus.
a. Metastatic plexopathy is suggested by early severe pain, hand weakness, and Horner syndrome.
b. Radiation plexopathy is suggested by absent or mild pain, weakness of the shoulder girdle, and progressive lymphedema. Often cutaneous radiation changes, such as telangiectasias, can be identified within the previous RT port.
5. Evaluation. Imaging with CT or MRI will demonstrate a tumor mass in the plexus in most patients with metastatic plexopathy. Surgical exploration and biopsy are rarely required to confirm the diagnosis but are necessary in patients who have diffusely infiltrative disease that does not form a discrete mass. Epidural disease of the cervical or upper thoracic spine may accompany metastatic plexopathy in some patients, particularly those with Horner syndrome; therefore, additional imaging of the spine may be required.
6. Management. The tumor is usually treated with RT if not previously administered; otherwise, chemotherapy may be helpful. The primary management problem is often pain control; neurologic function may not return even with effective treatment of the metastatic lesion. No treatment exists for radiation plexopathy. Physical therapy can help maintain residual arm and hand function after both types of plexus injury.
B. Lumbosacral plexus
1. Mechanism. Malignant lumbosacral plexopathy is caused primarily from direct extension of intra-abdominal tumors, but 25% of cases are from metastases of extra-abdominal tumors. Nearly one-half of the patients with metastatic plexopathy also have spinal epidural disease. Radiation plexopathy can result from pelvic irradiation and present in a similar fashion.
2. Clinical presentation. The most common presenting symptom is pain; severe, unremitting low back or pelvic pain usually radiates into one leg. Pain is later followed by paresthesias, weakness, and loss of deep tendon reflexes. Bladder function is usually preserved. Lymphedema, painless weakness, and paresthesias are more commonly seen with radiation plexopathy.
3. Evaluation. CT or MRI scans will detect tumor involving the plexus, presacral areas, or sacral erosion. MRI of the spine may also be required.
4. Management. RT and chemotherapy are used to treat the malignancy as indicated. Pain control and physical therapy are often required.
C. Peripheral nerves. Spread of systemic tumors to peripheral nerves is an unusual neurologic complication of malignancy. It occurs primarily in two settings:
1. Infiltrative polyneuropathy can result from invasion of the endoneurium by lymphoma or leukemia. This syndrome is rare, even at autopsy, but produces a recognizable clinical picture. Over weeks to months, it causes a widespread, asymmetric, often painful, multifocal neuropathy, which may be fulminant in some cases and lead to death. Secondary seeding of the CSF may develop with subsequent leptomeningeal metastasis. The diagnosis may be made by biopsy of an involved sensory nerve or more frequently by hypermetabolism seen on body positron emission tomography (PET) as tumor tracks along the roots and peripheral nerves.
2. Perineural spread of tumors is seen with cutaneous and primary cancers of the head and neck (i.e., cancers of the larynx, pharynx, and tongue). Tumors invade the perineural space, spread proximally along the nerve, and may enter the intracranial cavity and extend into the brainstem. The trigeminal and facial nerves are most commonly involved, often together, probably because of their rich coinnervation of the face. Orbital nerves may also be involved. The tumors most likely to disseminate along nerves are spindle cell variant and atypical squamous cell carcinomas. The diagnosis is based on clinical suspicion and is confirmed by biopsy of a cutaneous nerve. MRI rarely shows thickened, enhancing cranial nerves.
V. PARANEOPLASTIC SYNDROMES. Neurologic paraneoplastic syndromes are rare and frequently present before the cancer is diagnosed and can be associated with neoplastic disease that is not yet radiographically detectable but is potentially curable. Patients with paraneoplastic syndromes tend to present with less extensive tumor and have a prolonged survival time compared with the standard population with the same cancer. An autoimmune pathogenesis has been demonstrated for some of these disorders, and specific antibodies are associated with many of the paraneoplastic disorders. These antibodies are generated as an antitumor response and are directed against the patient’s tumor; they are thought to cross-react with specific neuronal subgroups, producing neurologic dysfunction and the clinical syndrome. It is important to realize that clinically identical disorders can occur in patients without cancer, but such patients do not demonstrate these autoantibodies.
A. Paraneoplastic cerebellar degeneration (PCD) is a syndrome of pancerebellar dysfunction of subacute onset. Manifestations include truncal and appendicular ataxia, dysarthria, and nystagmus; patients are usually so severely affected that they are bedridden, have unintelligible speech, and are unable to care for themselves. Associated neurologic symptoms, such as dementia or neuropathy, may be present, but they tend to be much less severe.
1. Pathogenesis. This disorder is associated with circulating antibodies that bind to both tumor and Purkinje cells in the cerebellum. The tumors in patients with PCD express antigens normally present only in the cerebellum, and the paraneoplastic syndrome is believed to result as a consequence of an immune response against the tumor. About one-half of the affected patients have antitumor antibodies, the most common of which is anti-Yo. Anti-Yo is seen primarily in women with breast and gynecologic malignancies. Other antibodies that may be associated with this syndrome include anti-Hu (mostly with small cell lung cancer), anti-Ri (breast cancer), and anti-Tr (mostly in men with Hodgkin lymphoma).
2. Diagnosis. The diagnosis is suggested on the basis of the neurologic presentation. A definitive diagnosis is possible when anti-Yo, anti-Hu, or anti-Ri antibodies are detected in the patient’s serum or CSF. Other diagnostic features include inflammatory cells in the CSF, normal brain scans except for cerebellar atrophy, and the absence of other causes of cerebellar dysfunction. If there is no known malignancy, a thorough search for cancer must be undertaken. Body PET is the most sensitive test to detect these small cancers. Occasionally, exploratory surgery with hysterectomy and oophorectomy are performed in the absence of an obvious mass and microscopic tumors are identified. This has also been seen at autopsy where an occult malignancy is discovered, and examination of the brain shows loss of Purkinje cells of the cerebellum.
3. Therapy is ineffective. Patients with PCD do not respond to plasmapheresis, immunosuppressive treatment with steroids or cytotoxic agents, or treatment of the underlying malignancy. The patient’s condition usually stabilizes at a level of severe disability.
B. Paraneoplastic sensory neuronopathy (PSN), also referred to as dorsal root ganglionitis, is a syndrome of subacute progressive loss of proprioception and vibratory sense. Pain, temperature, and touch modalities of sensation are also affected but to a lesser degree. Painful dysesthesias and paresthesias are usually present. The result is a severe sensory ataxia that leaves patients unable to walk. The neuropathy may affect the autonomic system, causing urinary retention, hypotension, pupillary changes, impotence, and hyperhidrosis. Sparing of the motor system is a hallmark of the syndrome, although patients are usually so impaired that they may have mild weakness from disuse atrophy. In patients with more widespread neurologic disease, such as dementia, myelopathy, or cerebellar dysfunction, the disorder is referred to as paraneoplastic encephalomyelitis (PEM).
1. Pathogenesis. A circulating antibody, called anti-Hu (also called ANNA-1 for antineuronal nuclear antibody type 1), has been demonstrated in patients with PSN or PEM; it is primarily associated with small cell lung cancer. This antibody reacts with all small cell carcinomas as well as with neurons throughout the nervous system. Clinically, the antibody mainly targets the dorsal root ganglia, causing inflammation and loss of neurons. Despite the presence of antigen in all small cell cancers, only about 15% of patients develop the antibody, and few of these patients develop the neurologic syndrome that is associated with very high titers of anti-Hu. The anti-Hunti-Hu antibody is also associated with PCD and PEM, again primarily in patients with small cell carcinoma (see parts A, E, F, and G of Section V); sites of antibody binding in the nervous system roughly correlate with a patient’s neurologic symptoms and signs.
2. Diagnosis. The diagnosis is often suspected clinically because the neurologic syndrome is highly specific. Electromyographic (EMG) studies in patients with PSN usually show a total absence of sensory action potentials and normal or nearly normal compound muscle action potentials. A definitive diagnosis can be made by detecting the anti-Hu antibody in serum and CSF. CSF studies show increased protein, a mild pleocytosis, and oligoclonal bands. A thorough attempt to diagnose an underlying malignancy must be made in patients who present without known cancer.
3. Therapy is ineffective. Plasmapheresis, immunosuppressive therapy, or treatment of the underlying malignancy does not reverse neurologic deficits, although treatment may arrest progression of the disorder.
C. Opsoclonus–myoclonus. Opsoclonus is an ocular motility disorder consisting of irregular, involuntary, multidirectional eye movements that persist with eye closure and sleep. It may be associated with myoclonus (brief, jerking contractions of flexor muscles). Opsoclonus–myoclonus is classically associated with neuroblastoma in children, in whom it heralds a good prognosis. Less commonly, it is associated with ataxia and encephalopathy in adults with breast cancer. In the latter disorder, opsoclonus–myoclonus is associated with the anti-Ri antibody (or ANNA-2). Unlike PCD and PSN, opsoclonus–myoclonus can be relapsing and remitting and may resolve spontaneously.
D. Cancer-associated retinopathy is a syndrome of visual loss that begins with obscurations and night blindness and proceeds to total blindness. It is most commonly associated with small cell lung carcinoma and melanoma. This disorder is associated with an antibody that recognizes the protein recoverin in the photoreceptor cells of the retina. It can be diagnosed by detection of this antibody in serum and by electroretinography.
E. Limbic encephalitis. Early manifestations of this disorder include personality changes (depression and anxiety), which are followed by a profound loss of short-term memory. Seizures, hallucinations, and hypersomnia may also be present. Limbic encephalitis is most commonly associated with small cell lung cancer and, in some cases, is attributable to the anti-Hu antibody.
F. Anti-NMDAR encephalitis. A recently recognized paraneoplastic syndrome, it occurs predominantly in young women and is associated with ovarian teratomas. Patients develop a multistage illness characterized by psychosis, memory deficits, and seizures that progresses to unresponsiveness, abnormal movements, and autonomic instability. The diagnosis is established by the presence of antibodies against the N-methyl-D-aspartate receptor (NMDAR). Unlike most paraneoplastic syndromes, patients improve with tumor resection and immunosuppressive therapy.
G. Brainstem encephalitis causes vertigo, nystagmus, facial numbness, oculomotor disorders, dysphagia, dysarthria, deafness, and long-tract signs. It is most commonly seen in small-cell lung carcinoma and may be associated with the anti-Hu antibody.
H. Motor neuronopathy, or motor neuron disease, is a spectrum of disorders involving the motor system for which the association with malignancy is still poorly characterized. Unlike most other paraneoplastic disorders, this syndrome can arise late in the course of the malignancy, even during remission. It is most commonly seen in lymphoma (both non-Hodgkin and Hodgkin lymphoma), where it is frequently associated with a paraproteinemia. A similar condition can be seen as part of the spectrum of disease associated with the anti-Hu antibody and small cell lung carcinoma.
These disorders are characterized by a progressive loss of motor function that may resolve spontaneously; the sensory system is spared. Loss of anterior horn cells is seen pathologically. EMG studies can help establish the diagnosis.
I. Neuropathies associated with plasma cell dyscrasias. A symmetric, distal sensorimotor polyneuropathy may be associated with plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma with or without systemic amyloidosis, osteosclerotic myeloma, and Waldenström macroglobulinemia. The polyneuropathy can occur as part of the POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome. It is often associated with a monoclonal paraprotein (often immunoglobulin M-κ), which reacts with a myelin-associated glycoprotein, resulting in a demyelinating neuropathy. The neuropathy is progressive, but usually no pain or autonomic involvement occurs. Treatment of the underlying disease or with plasmapheresis is beneficial in some patients.
J. Polymyositis and dermatomyositis. These disorders cause painful symmetric, proximal muscle weakness manifested as difficulty rising from a chair or combing hair. Only a small minority of patients with polymyositis or dermatomyositis have an associated malignancy. These disorders are discussed further in Chapter 28, Section II.D.
K. Myasthenia gravis causes progressive fatigue with exercise. It occurs in 30% of patients with a thymoma, and 10% of patients with myasthenia gravis have a thymoma. The syndrome is caused by antiacetylcholine receptor antibodies that block function at the postsynaptic membrane of the neuromuscular junction or anti–muscle-specific kinase (MuSK) antibodies that have both pre- and postsynaptic effects. The diagnosis is made by detecting an antibody in the serum, by the response to edrophonium chloride (the Tensilon test), and by the characteristic EMG response to repetitive stimulation. Treatments include pyridostigmine bromide (Mestinon), steroids, plasmapheresis, and resection of an associated thymoma or the thymus. Myasthenia gravis may be difficult to treat, especially during the postoperative period after tumor resection. Treatment should be undertaken only by those familiar with the disorder.
L. Lambert-Eaton myasthenic syndrome (LEMS) is characterized by proximal muscle weakness, especially of the pelvic girdle. In contrast to myasthenia gravis, the weakness improves with exercise, and this can be demonstrated on physical examination. Hyporeflexia, muscle tenderness, and autonomic dysfunction (orthostatic hypotension, impotence, dry mouth) may be associated with the condition. LEMS results from an autoantibody that reacts with voltage-gated calcium channels (VGCC) of peripheral cholinergic nerve terminals.
1. Associated tumors. Mostly small cell lung cancers are found; LEMS may also be seen in association with lymphoma and thymoma. One-third of patients have no malignancy.
2. Diagnosis. The diagnosis of LEMS is established by detection of the antibody against P/Q-type VGCC and by EMG, which demonstrates small compound muscle action potentials that increase after brief exercise or repetitive stimulation at high frequencies (20 to 50 Hz).
3. Therapy. Effective therapies include treatment of the underlying malignancy, guanidine hydrochloride (125 to 500 mg PO three or four times daily), 3-4-diamino-pyridine (5 to 25 mg PO three or four times daily), steroids, IV immune globulin, and plasmapheresis.
VI. ADVERSE EFFECTS OF RADIATION TO THE NERVOUS SYSTEM
A. Mechanism. The CNS is highly susceptible to damage from radiation. The degree of neural dysfunction depends on the total radiation dose and fraction size, the volume of irradiated brain or spinal cord, and the time elapsed since RT. Reactions are classified as acute, early delayed, and late delayed. Acute reactions during RT are believed to be caused by a transient breakdown in the blood–brain barrier, leading to increased ICP. The risk for acute reactions increases with fraction sizes >200 cGy. Early delayed reactions, occurring weeks to months after irradiation, are usually self-resolving and are thought to be caused by demyelination. Late delayed reactions, usually occurring months to years after irradiation, result in permanent CNS damage. Tissue destruction with coagulative necrosis of the involved white matter is seen pathologically. Hyalinization of blood vessels leading to vascular thrombosis is a specific feature of radionecrosis.
B. Radiation syndromes. Specific neurologic syndromes occur in response to RT, depending on the site of irradiation. The skin, hair, subcutaneous tissues, and bone are at risk as well. Hair loss occurs when the dose to the brain is >2,000 cGy over 2 weeks; incomplete regrowth is common after higher doses.
1. Radiation encephalopathy. Acute radiation encephalopathy manifests as headache, nausea, and vomiting. Early delayed encephalopathy often mimics tumor recurrence, both clinically and radiographically, and consists of headache, lethargy, and worsening or reappearance of neurologic symptoms. Children undergoing prophylactic whole-brain RT for acute lymphoblastic leukemia may develop the radiation somnolence syndrome that causes profound lethargy and sleep for 18 or more hours per day; this resolves spontaneously over several weeks. Chronic radiation encephalopathy is associated with atrophy of the brain and is more likely to occur after whole-brain RT than after focal RT. Clinical findings include memory loss, cognitive dysfunction (learning disabilities in children), gait abnormalities, and urinary incontinence. This chronic disorder sometimes responds to CSF shunting.
2. Radiation necrosis is a late delayed reaction to RT that mimics tumor recurrence. It causes worsening focal neurologic deficits and progressive enhancing lesions on imaging studies. PET or MRI spectroscopy may be useful in differentiating radiation necrosis from tumor recurrence, but these tests can also give false-negative and false-positive results. Glucocorticoids are beneficial, and because the necrotic lesion has mass effect, surgical extirpation is often useful.
3. Radiation myelopathy. No acute reactions to irradiation of the spine occur. Early delayed reactions occur as electric shock-like sensations in the arms or legs that last for several seconds and are precipitated by flexion of the neck (Lhermitte symptom). The condition is usually self-limited. Late delayed damage to the spinal cord results in a progressive myelopathy that may be asymmetric in onset; typically, numbness and weakness ascend and progress to symmetric paraplegia. This disorder is secondary to necrosis of the white matter and usually occurs with doses ≥5,000 cGy given over 5 weeks by conventional fractionation.
4. Radiation plexopathy. Brachial and lumbosacral plexopathy, a late delayed reaction to RT, are discussed in Section IV.A.4.
5. Loss of special senses. Loss of vision and hearing are relatively common sequelae of cranial irradiation. Visual loss can result from radiation-induced optic neuropathy, retinopathy, glaucoma, cataract formation, and dry-eye syndrome. Hearing loss is caused by otitis media (acute or early delayed effect) or by sensorineural damage (late delayed effect).
6. Hormonal deficiencies occur as a result of hypothalamic and pituitary dysfunction after cranial irradiation. The most common deficiency involves growth hormone, but thyroid, adrenal, and gonadal dysfunctions also occur.
C. Management. Acute and early delayed reactions are self-limited but often respond to treatment with steroids. Acute reactions and some early delayed reactions, such as the somnolence syndrome, may be prevented by premedicating patients with steroids before the start of cranial RT. Patients with large CNS tumor(s) and surrounding edema should always receive steroids for at least 48 hours before RT is started. Late delayed reactions, which are usually caused by neuronal and glial injury, do not recover with treatment; however, steroids can reduce swelling and symptoms in patients with radionecrosis. If small, the radionecrosis will eventually resolve on its own, but if the involved region is large, resection of the dead tissue may be necessary.
D. Radiation-induced tumors tend to occur decades after irradiation and include meningiomas, nerve sheath tumors, astrocytomas, and sarcomas; these tumors are usually malignant.
E. Radiation-induced CVD disease is caused by accelerated atherosclerosis that becomes manifest years after irradiation. It is thought to result from occlusion of the vasa vasorum. Patients are at high risk for transient ischemic attacks and strokes.
VII. NEUROLOGIC COMPLICATIONS OF CHEMOTHERAPY. Neurologic complications of chemotherapy are common and depend on the dose of the chemotherapeutic agent, whether the drug is given as part of a multidrug regimen and whether it is given in conjunction with RT. Chemotherapeutic agents may be toxic to the entire nervous system or cause more limited neurotoxicity, affecting only the central or peripheral nervous system. A variety of clinical syndromes are seen, many of which are drug-specific.
A. Encephalopathy (insomnia, agitation, drowsiness, depression, confusion, headache) usually develops acutely after administration of the offending agent. Responsible agents include methotrexate, cytarabine, procarbazine, mitotane, L-asparaginase, ifosfamide, cisplatin, vincristine, 5-fluorouracil, tamoxifen, nitrosourea, etoposide, interferon-α, pentostatin, tegafur, levamisole, and, rarely, hexamethylmelamine, fludarabine, and 5-azacitidine.
B. Cerebellar syndrome (ataxia, nausea and vomiting, nystagmus) can be seen after the use of cytarabine, procarbazine, fluorouracil, and the nitrosoureas.
C. Seizures may occur after cisplatin, hydroxyurea, L-asparaginase, ifosfamide, procarbazine, and rarely vincristine.
D. Peripheral neuropathy (paresthesias, loss of deep tendon reflexes, distal extremity weakness) is a common neurologic complication of chemotherapy. Vincristine, paclitaxel (Taxol), and cisplatin cause some degree of peripheral neuropathy in almost all patients. The neuropathy is cumulative and is at least partially (if not completely) reversible with discontinuation of the offending agent. Other drugs that can cause neuropathy include bortezomib (Velcade), docetaxel (Taxotere), paclitaxel (Taxol), thalidomide, vindesine, vinblastine, procarbazine, suramin, hexamethylmelamine, etoposide, and teniposide.
E. Cranial neuropathy (loss of hearing, vision, taste) may develop from the use of cisplatin, vincristine, and the nitrosoureas.
F. Myelopathy (quadriparesis, paraparesis, bowel and bladder dysfunction) is a rare complication of intrathecal chemotherapy, including methotrexate and cytarabine. Myelopathy has been reported only after drug administration via lumbar puncture, not through an intraventricular (Ommaya) reservoir.
G. Combined radiation and chemotherapy-induced neurotoxicity. The combination of cranial irradiation and chemotherapy, particularly with methotrexate, nitrosoureas, or cytarabine, can have a synergistic toxic effect on normal brain structures. This can lead to permanent damage, often affecting the white matter and causing a leukoencephalopathy that produces a progressive dementing process. No known treatment exists, but some patients temporarily benefit from a ventriculoperitoneal shunt. Other drugs can have this effect but are less well studied than those mentioned.
VIII. OTHER COMPLICATIONS OF CANCER
A. Cerebrovascular disease (CVD). Strokes and hemorrhages are the second most common cause of CNS lesions in cancer patients after metastases. Autopsy series show that 15% of cancer patients have CVD, of whom one-half have symptoms during their lifetime. In addition to standard risk factors that apply to the general population, patients with cancer have additional conditions that predispose to CVD.
1. Cerebral embolism can result from the following:
a. Nonbacterial thrombotic endocarditis, seen especially with adenocarcinoma of the lung and gastrointestinal tract, is probably the most common cause of cerebral infarction in patients with carcinoma, although it is difficult to diagnose. Diagnosis of the valvular lesions is best established by transesophageal echocardiogram.
b. Septic emboli from systemic fungal infections, most commonly Aspergillus species.
c. Tumor emboli (uncommon).
2. Thrombosis can cause strokes (arterial) as well as occlusion of the superior sagittal sinus (venous). The latter syndrome presents with headache, obtundation, and sometimes bilateral venous infarcts that may be hemorrhagic. Thrombotic disorders in cancer are caused by the following:
a. DIC
b. Hyperviscosity syndromes
c. Chemotherapy, especially with L-asparaginase, which causes venous sinus thrombosis.
d. Vasculitis, usually as a complication of herpes zoster infection or seen in patients with Hodgkin disease.
3. Hemorrhages are more common in patients with leukemia but can occur in those with solid tumors as well. Specific causes include:
a. Thrombocytopenia
b. DIC
c. Hyperleukocytosis (acute myelogenous leukemia).
d. Tumor invasion of blood vessels.
e. Bleeding diatheses/coagulopathy (e.g., in hepatic failure).
f. Brain metastasis
4. Subdural hematomas can result from the following:
a. Metastases
b. Lumbar puncture producing intracranial hypotension.
c. Thrombocytopenia
d. Head trauma (minor or postoperative)
B. CNS infections are discussed in Chapter 35, Section III.B.
C. Ocular complications in cancer
1. Metastases to the eye and orbit
a. Etiology. Ocular and orbital metastases occur most frequently in breast cancer. Hematogenous dissemination to the eye also complicates acute leukemia, melanoma, sarcoma, and carcinomas of the lung, bladder, and prostate. Lymphoma can also invade the globe or orbit. Several head and neck cancers can erode directly into the orbit.
b. Diagnosis.
(1) Signs. Patients develop eye pain, diplopia, loss of vision, and exophthalmos. Fundal hemorrhages, leukemic infiltrates, or masses may be evident on ophthalmoscopy.
(2) MRI or CT scans of the orbits, brain, and surrounding tissues must be obtained in patients with symptoms of ocular or orbital metastases.
(3) Biopsy is performed if the retro-orbital mass is the sole site of disease.
c. Management. Prednisone, 40 mg/m2 PO daily, should be given to decrease pain. RT to the orbit is the treatment of choice for metastatic disease and can improve vision. Emergency treatment of the eye with small doses of RT may prevent blindness in patients with ocular involvement from acute leukemia. Ocular or orbital RT can produce subsequent cataracts but rarely causes permanent visual loss.
2. Central retinal vein thrombosis
a. Etiology. Central retinal vein thrombosis occurs in hyperviscosity syndromes associated with Waldenström macroglobulinemia and occasionally with plasma cell myeloma. Marked erythrocytosis from polycythemia vera may also cause the problem.
b. Diagnosis. Patients develop a sudden, painless loss of vision. “Sausage-link” widening of conjunctival and fundal veins may be present. The fundus may also have hemorrhages, hard and soft exudates, and microaneurysms.
c. Management. Plasmapheresis is used for malignant paraproteinemias (see Chapter 22, Section IX.A.1), and phlebotomy for polycythemia vera (see “Polycythemia Vera” in Chapter 24).
3. Retinal artery occlusion
a. Etiology. Embolic retinal artery occlusion is most commonly caused by atherosclerosis but may rarely be seen with atrial myxoma, nonbacterial thrombotic endocarditis, and cryoglobulinemia.
b. Diagnosis. Patients develop sudden, painless loss of vision and a pale fundus with a bright red spot over the fovea.
c. Management. Ophthalmologic consultation should be obtained immediately in all cases. In appropriate candidates, intra-arterial thrombolytic therapy is considered if symptoms are only of a few hours duration. Conservative measures include vigorous massage of the eye, administration of a vasodilator, and aspiration of aqueous humor.
4. Amaurosis fugax can occur in patients with marked thrombocytosis (platelet count >800,000/µL) caused by myeloproliferative diseases, especially essential thrombocythemia or polycythemia vera. Treatment consists of antiplatelet drugs (e.g., aspirin, 81 to 325 mg/d) and chemotherapy. Plateletpheresis may also be used in severe cases.
Suggested Reading
Clarke JL, Perez HR, Jacks LM, et al. Leptomeningeal metastases in the MRI era. Neurology 2011;76:200.
Dalmau J, Lancaster E, Martinez-Hernandez E, et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10:63.
DeAngelis LM, Posner JB. Neurologic Complications of Cancer. 2nd ed. Oxford University Press; New York, 2009.
Grommes C, Bosl GJ, DeAngelis LM. Treatment of epidural spinal cord involvement from germ cell tumors with chemotherapy. Cancer 2011;117:1911.
Jenkinson MD, Haylock B, Shenoy A, et al. Management of cerebral metastasis: Evidence-based approach for surgery, stereotactic radiosurgery and radiotherapy. Eur J Cancer 2011;47:649.
Kaley TJ, DeAngelis LM. Therapy of chemotherapy-induced peripheral neuropathy. Br J Haematol 2009;145:3.
Navi BB, Reichman JS, Berlin D, et al. Intracerebral and subarachnoid hemorrhage in patients with cancer. Neurology 2010;74:494.