Headache

Headache is a common initial symptom of a brain tumor but rarely occurs in isolation. In the majority of patients, headache as a presenting sign of a brain tumor occurs in association with focal or generalized neurological symptoms and signs. Brain tumors, similar to other mass lesions in the brain, can result in the classical symptoms of increased ICP, including onset of the headache at night or upon waking in the morning. The headache usually resolves shortly after rising. It may worsen with Valsalva maneuvers. Unless the underlying tumor is treated, the headache becomes constant and usually associated with other features of increased ICP such as nausea and vomiting, reduced level of alertness, visual disturbance, and possibly focal signs. However, less than half of patients with brain tumors present with these typical clinical features, and the headache pattern may be indistinguishable from other common headache types such as migraine, cluster, or tension headaches. In the patient with a known brain tumor, a headache that develops late in the clinical course should alert the clinician to the possibility of tumor recurrence or structural changes within the tumor, such as intratumoral hemorrhage or cyst expansion.

When headache in adults or children is accompanied by other neurological symptoms as the presenting symptom of a brain tumor, the likelihood of a primary brain tumor is higher than for metastatic brain or leptomeningeal tumors, which more commonly present with isolated headaches. The brain parenchyma does not contain nociceptive receptors, so headache associated with a brain tumor results from direct impingement or traction on pain-sensitive structures including portions of the meninges (e.g., basal dura and the venous sinuses and their tributaries), neural structures (e.g., glossopharyngeal, vagus, and trigeminal cranial nerves, as well as the upper cervical spinal nerves), and vascular structures (e.g., dural arteries; carotid, vertebral, and basilar arteries; circle of Willis; and proximal portions of cerebral, vertebral, and basilar branches).

Because it is not possible to predict with certainty which patients with systemic cancer and a new or changing headache pattern have brain metastasis, a careful neurological examination that includes tests of cognitive function is prudent, as it will often disclose findings additional to the complaints reported by the patient. Even in the presence of a normal examination, brain imaging is recommended.

Contrast-enhanced T1-weighted and fluid-attenuated inversion recovery (FLAIR) brain magnetic resonance imaging (MRI) sequences are the most useful methods to identify tumor, vasogenic edema, mass effect, and patency of the ventricular system. Unenhanced T1-weighted images are useful in identifying intratumoral bleeding if such bleeding is a consideration. Lumbar puncture for cytological examination or flow cytometry may be indicated if leptomeningeal tumor is suspected, but MRI findings are nondiagnostic.

Simple analgesics are usually adequate to treat headache related to impingement on pain-sensitive structures in the brain, but in rare circumstances, opioid analgesics may be required. In general, attempts should be made to treat the underlying tumor and associated vasogenic edema in order to relieve the headache. In patients without hydrocephalus, this treatment typically includes surgical resection and may include radiation and/or chemotherapy as well as the use of corticosteroids to treat vasogenic edema (see Cerebral Edema, later). When hydrocephalus is the cause of increased ICP, ventricular shunting or removal of the mass lesion obstructing the ventricular system is the most effective way to eradicate headache.

Other Cerebral Symptoms

The frontal lobe is a common location of tumors, both primary and metastatic. Therefore, limb weakness, typically unilateral, contralateral to the tumor but sometimes bilateral if both frontal lobes are involved, is a common presenting sign of brain tumors. Alteration of cognition and/or behavior can result from focal or generalized brain dysfunction secondary to brain tumors. Cognitive impairment can occur from lesions in any portion of the cerebral hemispheres and even the cerebellum, and the type of impairment reflects the location. Specifically, patients may have a language disturbance, apraxia, or amnesia that is related to focal brain disruption, or a global encephalopathy that is related to multiple brain lesions (usually metastases) or to increased ICP. Depression occurs as an initial sign of a brain tumor, particularly those affecting bilateral frontal lobes, and is often not initially recognized as a potential organic sign by patients or family members. Limb ataxia and cranial nerve signs are uncommon, except in pediatric tumors such as cerebellar astrocytomas or medulloblastomas.

Cognitive abnormalities that develop after systemic cancer or brain tumor treatment can be the result of neurotoxicity of those treatments, especially whole-brain radiation and systemic or intrathecal chemotherapy. Brain radiation can result in acute symptoms of fatigue and, rarely, temporary cognitive impairment. Early delayed reactions include cognitive impairment and/or somnolence, typically beginning within a few weeks to months of the completion of radiation, and are reversible. Late delayed effects of cognitive impairment, sometimes with gait abnormalities and sphincter incontinence, typically begin several months or longer after the completion of radiation and are irreversible (Dropcho, 2010). The incidence and cause of cognitive impairment and fatigue, termed chemobrain, is debated. This syndrome is reported to occur during and for several months following administration of standard systemic chemotherapy, typically administered for breast cancer. The most common persistent brain tumor–related cognitive impairment associated with chemotherapy is leukoencephalopathy following high-dose systemic or standard-dose intrathecal methotrexate. The risk is significantly greater when the chemotherapy is combined with brain irradiation (Correa et al., 2007).

Routine neurological examination, including testing of cognitive function, Mini-Mental State Examination, and neuropsychological testing, are all useful to confirm subcortical dementia in treatment-related neurotoxicity. In patients who have received whole-brain radiation, testing of hypothalamic and pituitary function by serum hormone tests is indicated to exclude hormonal deficiency as a contributing factor. Contrast-enhanced T1-weighted and FLAIR MRI sequences are also indicated to search for periventricular white-matter changes consistent with delayed leukoencephalopathy and for recurrence of brain tumors; delayed cognitive impairment may also be an early predictor of tumor progression (Brown et al., 2006).

Physical therapy and occupational therapy for rehabilitation are often overlooked in brain tumor patients who experience motor, sensory, or visual deficits, but these rehabilitation treatments play an important role in improving clinical performance and quality of life.

The possible role of depression or the adverse cognitive effects of antiepileptic drugs should be considered in patients with brain tumors who experience cognitive impairment.

Fatigue and cognitive impairment occurring during brain irradiation is self-limited and does not require treatment. Subacute cognitive impairment or somnolence responds well to corticosteroids. Delayed leukoencephalopathy is irreversible, but some improvement is possible with medical therapy. Methylphenidate can be beneficial in treating cognitive impairment as well as motor dysfunction and is well tolerated in these patients. A recent trial of donepezil administered to patients several months after the completion of brain radiation demonstrated improved attention/concentration and verbal and figural memory as well as improved emotional and social functioning (Shaw et al., 2006). In the author’s experience, memantine is also effective in some patients. Memantine is now being tested in a national multicenter clinical protocol as a preventive medication when given with whole-brain radiation for brain metastasis. Modafinil is used to treat cancer-related fatigue, including that associated with brain tumors, and when it is effective, mental clarity is also improved. Ventricular shunting can be effective in the management of treatment-related leukoencephalopathy, even when the ventricles are not significantly enlarged. Cognitive rehabilitation has not been studied systematically in brain tumor patients, but it may have a beneficial role, especially for patients with an expected long-term survival.

Seizures

Seizures are a common symptom in brain tumor patients, occurring in approximately 50% of cases, more often early than late in the clinical course. Seizures that worsen or develop later in the course suggest tumor regrowth. The seizures are typically focal in onset, and the semiology may provide a clue to tumor location. Even when patients or family members describe generalized seizures, the seizure onset is focal, but the patient cannot remember the focal onset, or the focal signs are silent. Most commonly, the partial seizure is motor, manifested by jerking of one limb or of the face. The jerking may progress to the other ipsilateral limb (jacksonian march). The seizure may remain focal or become secondarily generalized. Because the temporal lobe is a common location for tumors, particularly gliomas, other common partial seizures include déjà vu sensations, uncal or gustatory hallucinations, depersonalization, or speech arrest. Tumors in the occipital lobe may result in visual hallucinations. A particularly severe sequela of a partial seizure is Todd paralysis, characterized by prolonged motor weakness. In patients with brain tumors, this postictal weakness may never completely resolve. In those brain tumor patients with generalized seizures, prolonged and irreversible cognitive decline may also ensue. Status epilepticus occurring in brain tumor patients is often difficult to treat and portends a poor prognosis.

The most common brain tumors underlying seizures are slow-growing primary brain tumors, in particular, low-grade gliomas. High-grade gliomas, meningiomas, and brain or leptomeningeal metastases are also associated with seizures but with a lower frequency. The risk of seizure with brain metastasis is higher when there are multiple tumors and when they are accompanied by leptomeningeal metastasis. Seizures are more common with a superficial or cortical tumor location. Although the precise mechanism for brain tumor–associated epilepsy is not known, experimental evidence suggests that tumor cells have biochemical abnormalities capable of generating epileptiform activity, as do cells of the peritumoral cortex.

The new onset of seizures in an adult mandates brain imaging. Contrast-enhanced T1-weighted and FLAIR MRI sequences with special attention to the temporal lobes are standard evaluation. Electroencephalography may prove useful to document a seizure focus but is rarely required to establish the diagnosis of seizures. It can be useful in patients with prolonged confusion, when partial status epilepticus is a consideration.

The management of seizures in the brain tumor patient presents unique considerations compared with patients who do not have a brain tumor. Brain tumor resection can be effective in patients with low-grade primary brain tumors, especially when the resection includes the epileptic focus. Intraoperative electrocortigraphy may be required to establish the seizure focus. Treatment of the tumor with brain irradiation has proven efficacy in reducing seizure frequency, as has administration of systemic chemotherapy. The mechanism for seizure reduction from these treatments is not known. The majority of patients with brain tumor–associated epilepsy require antiepileptic drug therapy. Antiepileptic drug absorption, protein binding, and metabolism and interaction with chemotherapy administered to treat the brain tumor, and corticosteroids to treat vasogenic edema, are critical considerations. The most common metabolic pathway for biotransformation of many antiepileptic drugs and chemotherapy is the cytochrome P450 system. Antiepileptic drugs that induce P450 hepatic metabolism (e.g., phenytoin, carbamazepine, phenobarbital) induce the metabolism of many chemotherapeutic agents and decrease the effectiveness of chemotherapy (Vecht et al., 2003). In contrast, antiepileptic drugs that decrease hepatic metabolism (e.g., valproic acid) will lead to higher levels of chemotherapy, resulting in a greater risk of toxicity (Oberndorfer et al., 2005). Attention should also be paid to the dose of dexamethasone when patients are receiving P450-inducing antiepileptic drugs that increase the metabolic clearance of dexamethasone; higher doses may be required.

When possible, the use of a non-P450-inducing antiepileptic drug is recommended. Several published studies indicate that levetiracetam is effective and well tolerated in brain tumor patients with epilepsy (Usery et al., 2010). Despite diligent attention to the selection of appropriate antiepileptic drugs and patient compliance, complete seizure control is difficult to obtain in patients with brain tumors.

Despite the high frequency of seizures during the lifetime of the brain tumor patient, prophylactic treatment with antiepileptic drugs is not recommended except in unusual circumstances. For example, some clinicians treat patients with melanoma brain metastases prophylactically because of the very high risk of seizures associated with this histology. However, no evidence exists that prophylactic treatment prevents seizure onset (Glantz et al., 2000). In addition, patients with a brain tumor are at risk for more severe and more frequent adverse effects of antiepileptic drugs such as cognitive impairment, sedation, myelosuppression, hepatic dysfunction, and dermatological reactions. The dermatological reactions can be particularly severe when brain radiation is administered.

Cerebral Edema

Because most primary or metastatic brain tumors are associated with vasogenic edema, corticosteroids are one of the most important therapies to reduce neurological symptoms and signs. The standard steroid medication is dexamethasone, owing to its long half-life and low mineralocorticoid activity. If there are signs of increased ICP, a loading dose of 10 to 20 mg intravenously is often given. The typical daily dose is 8 to 16 mg orally in divided doses; twice-daily dosing is appropriate because of the long half-life. The lower dose can be used in the absence of posterior fossa lesions or significant mass effect. The benefit of dexamethasone is usually seen within 48 hours. If there is no improvement at this time, a practical guideline is to double the dose and determine whether a higher dose is beneficial. If not, the dose should be rapidly decreased and the drug discontinued. Lack of response to corticosteroids suggests that the neurological dysfunction is due to neural tissue infiltration by tumor, not compression by edema. If a patient is suspected to have a primary brain lymphoma, steroids should be withheld before surgery because of the potential to effectively treat the lymphoma, resulting in a negative brain biopsy. Corticosteroids are rarely prescribed for symptoms and signs of leptomeningeal metastasis because they are not effective except when a large meningeal deposit produces vasogenic edema by compression of the brain or spinal cord.

The potential for medication-induced side effects must be considered carefully when prescribing dexamethasone, and it is prudent to use the lowest dose and shortest duration clinically feasible. Side effects include myopathy, infection (especially pneumonia due to Pneumocystis carinii when dexamethasone is used in combination with chemotherapy or during the phase of steroid tapering), osteoporosis, mood/behavioral changes, elevated blood glucose, and gastric ulceration. Paroxysmal neurological symptoms upon standing (plateau waves) occurring from increased ICP in brain tumor patients respond well to acetazolamide.