Most brain metastases (80%) occur in patients in whom the diagnosis of systemic malignancy is already established. The clinical presentation varies considerably among individuals and largely depends on the location of the brain metastasis or metastases. In younger patients, the most common symptoms are headache and seizure. Among elderly patients, focal deficits (e.g., hemiparesis and aphasia) and cognitive changes are distinctly more common, perhaps because older brains have more atrophy and room to accommodate an expanding mass lesion. It is not clear why elderly patients are less likely to present with seizures. Perhaps the seizure threshold of the elderly brain is higher.

Not infrequently, elderly patients with brain metastases are misdiagnosed as having a “stroke.” This is especially common in patients who do not have a previous diagnosis of a primary tumor or in those who present with very acute symptomatology. Focal seizure and tumor hemorrhage can both masquerade clinically as a stroke. The diagnosis usually is not difficult if a careful history is taken and neuroimaging is interpreted appropriately.

A CT of the head with contrast is sufficient in most cases to make the diagnosis of brain metastases, although magnetic resonance imaging (MRI) of the head has become standard for diagnosis in most centers. CT is less expensive than MRI and easier to perform on a patient who is confused or uncooperative. In patients whose condition is deteriorating rapidly, CT is adequate to diagnose secondary conditions such as obstructive hydrocephalus and tumor hemorrhage. Extra care must be taken in elderly patients to ensure that their renal function is adequate to handle the iodinated contrast. Approximately 5% of patients will have an allergic reaction to the iodinated contrast dye, and the dye can precipitate focal seizures in as many as 10% of patients with brain metastases (2). MRI with contrast is more sensitive, particularly for small brain metastases. It is also more expensive and requires better patient cooperation.

Both CT and MRI demonstrate enhancing lesions, typically with central necrosis. Metastases are usually multiple, which can be better appreciated on MRI when the lesions are tiny. Typically in brain metastases, the lesions are well circumscribed and have a disproportionate amount of edema than expected for the size of the enhancing lesion (Fig. 28-1). These features may help distinguish them radiographically from primary brain tumors, which tend to be more diffuse and have a pattern of edema that more closely approximates the area of enhancement. A brain abscess may mimic the appearance of metastasis, although brain abscesses are rare unless the patient is immunocompromised.

In patients who have known metastatic systemic cancer, the diagnosis is generally made radiographically, and pathologic confirmation may not be required before treatment. The situation is more problematic in patients without a known systemic malignancy. If the radiographic picture is suggestive of metastatic tumor, a careful search for systemic malignancy should be undertaken. This begins with a thorough physical examination, followed by appropriate blood tests and imaging procedures [body CT, mammography, positron emission tomography (PET) scan]. Lung, breast, skin, renal, and gastrointestinal system are the most common sources of a primary malignancy in these cases. If no primary tumor can be found, then surgical biopsy or resection of one of the brain lesions is appropriate to make a diagnosis.

Although the approach to treatment can vary, depending on the individual patient and type of malignancy, some interventions apply to all patients. Corticosteroids reduce peritumoral edema and can significantly reduce headache from raised intracranial pressure and may improve neurologic deficits produced by tumor mass effect. Approximately 30% to 40% of patients with brain metastases will have seizures at some point in their illness. This figure is higher among patients with hemorrhagic metastases and those with metastatic melanoma, in whom it is >50% (10). Any patient who has had a seizure should receive anticonvulsants, as should patients with metastatic melanoma. Otherwise, prophylactic anticonvulsants are best avoided because they interact with corticosteroids and various chemotherapy agents. Both phenytoin and carbamazepine can cause Stevens-Johnson syndrome,
particularly in patients receiving whole-brain radiation therapy (WBRT) (16). Moreover, no significant reduction in the incidence of seizures has been seen in patients who received prophylactic anticonvulsants (20).

Surgery In patients with multiple lesions, surgery is limited to those who lack a known primary tumor. In this situation, biopsy without resection is appropriate to make a pathologic diagnosis. More extensive surgery is indicated in selected situations. For instance, in a patient with a large cerebellar metastasis obstructing the fourth ventricle, a resection of the offending metastasis may be life saving and allow the patient to tolerate WBRT without brain herniation. Data suggest that patients who have a surgically accessible solitary metastasis (as proved on enhanced MRI) and limited systemic cancer survive longer with less neurologic disability if they have resection of their metastasis (46,61). Surgery is a further consideration in patients with a recurrent metastasis after WBRT has been administered or in those with tumors that are known to be radiation resistant.

Radiation Therapy WBRT is the mainstay of treatment for most patients with brain metastases. It prolongs survival but is not considered curative. WBRT after resection of a solitary metastasis has been demonstrated to reduce the risk of CNS recurrence and neurologic death but did not improve survival overall when compared to patients receiving surgical resection alone (45). Most patients with brain metastases will die of progressive systemic cancer, not brain disease. The treatment is given to ports encompassing the whole brain, to a total dose of 2,000 to 3,000 cGy in 10 to 15 fractions. More accelerated radiation schedules may be appropriate in very frail patients with a short life expectancy. WBRT is usually well tolerated. Radiation-induced tumor swelling is best managed with corticosteroids. If they survive more than 6 to 12 months, elderly patients can be particularly susceptible to develop radiation encephalopathy. This is characterized by subcortical dementia with gait apraxia and urinary incontinence. CT and MRI demonstrate cortical atrophy, hydrocephalus ex vacuo, and diffuse white matter changes. More localized radiation, including gamma knife and stereotactic linear accelerator therapy, is probably best reserved for small recurrent brain metastases. The value of these latter therapies in the primary treatment of brain metastases remains to be clearly established.

Chemotherapy Most chemotherapy agents do not penetrate the blood-brain barrier well. Historically, chemotherapy agents have little efficacy in the treatment of most types of brain metastases. The recent development of chemotherapy agents that penetrate the blood-brain barrier, including temozolomide, topotecan, and signal transduction inhibitors, holds some promise in the treatment of brain metastases (11).

Once brain metastases have developed, the patient’s cancer, with rare exception, has reached an incurable stage. Without treatment, life expectancy is usually less than 4 to 6 weeks, and most patients die from their neurologic disease in that setting. With radiation therapy, survival extends to a median of 3 to 6 months. Most treated patients will die of progressive systemic cancer, not of brain metastases. Long-term survival (>1 year) is exceedingly rare among elderly patients.

Pain, the most common initial symptom, is present in 95% of patients at presentation to the physician (24). The pain can derive from the bony vertebral involvement or from compression of spinal roots. Vertebral pain is usually sharp or dull, localized over the involved vertebra, and worse with activities that stress the spine, such as standing and twisting. Bone pain is typically worse at night. Radicular pain is sharp and lancinating and is distributed along the root’s cutaneous dermatome. Radicular pain can also be worse with movement and with Valsalva maneuvers. Bone and radicular pain often precede neurologic deficits by weeks or months.

Neurologic deficits can develop acutely or subacutely and depend on the spinal level of involvement. Epidural tumor in the cervical and thoracic region will produce a myelopathy with spastic limb weakness, sensory level to pain and temperature, and loss
of bowel, bladder, and sexual function. Lhermitte phenomenon may occur in patients with epidural tumors in the cervical or thoracic region. Compression of the thecal sac below L1 will produce a cauda equina syndrome with flaccid paraparesis, saddle distribution sensory loss, and loss of bowel, bladder, and sexual function. Epidural cord and cauda equina compression constitutes a neurologic emergency. Once neurologic function is lost, it may not be regained, despite appropriate treatment. Diagnosis and treatment, therefore, should proceed as quickly as possible.

Although a plain X-ray study of the spine can identify the vertebral lesion in approximately 80% to 90% of patients with epidural tumor (48), it does not visualize the epidural space. MRI of the spine is superior in this regard and has largely replaced myelography, except for cases in which MRI cannot be performed (i.e., patients with cardiac pacemakers). MRI will demonstrate the level of vertebral and epidural involvement and confirm the presence of cord or cauda equina compression (Fig. 28-2). In addition to the spinal level of clinical interest, it is generally recommended that the entire spine be visualized with sagittal MRI views to rule out other levels of subclinical epidural involvement. As many as 30% of patients may have other levels of epidural involvement on MRI that are not suspected clinically (54).

If epidural cord or cauda equina compression is clinically suspected, the patient should immediately be given high-dose intravenous corticosteroids. Dexamethasone (100 mg) is the treatment of choice. This reduces tumor swelling and spinal cord edema. It may prevent neurologic deterioration while the patient is awaiting diagnostic procedures and more definitive treatment. Corticosteroids provide analgesia for bone-related pain. Opioid analgesia should be given concomitantly for patients with moderate to severe pain. Side effects of high-dose steroids include manic psychosis, insomnia, and hyperglycemia. Hiccoughs are extremely common. If dexamethasone is given as an intravenous bolus, 50% of patients will experience intense but short-lasting perineal burning (5). This effect is self-limited, but patients should be warned before the steroids are given as a bolus.

In patients with a histologically proved primary malignancy, emergent radiation therapy to the spine is the most appropriate treatment, in most instances. Generally, the treatment is given in 10 to 15 fractions to a maximum dose of 2,000 to 3,000 cGy. The radiation ports usually encompass two levels above and below the area of epidural tumor. Most patients should continue to receive corticosteroids during the radiation therapy on a tapering schedule. Surgical intervention may be appropriate in patients without a tumor diagnosis, those who have received previous radiation to the spine, and those with radiationresistant tumors. Surgical procedures to remove epidural tumor are often extensive, requiring vertebral resection and spinal fusion. Not surprisingly, these aggressive procedures are often not appropriate for frail, elderly patients. Patients with recurrent or progressive epidural tumor in a previously radiated area may be candidates for a second course of radiation, if surgery is not feasible. In this instance, repeat radiation appears to carry a minimal risk of radiation myelopathy (55).

The presence of bony metastases implies advanced cancer, and most patients will die within 6 to 12 months of their systemic malignancy. The presence of epidural tumor will not usually hasten death unless the patient develops a complication of paralysis, such as deep venous thrombosis and pulmonary embolus, urosepsis from neurogenic bladder, or sepsis from decubitus ulcers. Timely diagnosis and treatment of epidural cord compression will reduce the likelihood that the patient will spend his or her remaining days wheelchair bound and dependent on others. If treatment is given before the development of severe neurologic dysfunction, the prognosis for neurologic recovery or maintenance of function is good. If treatment is not begun until after the patient is paraplegic and incontinent, then it is highly unlikely that steroids and radiation will bring recovery of function.