Approach to tumor-induced vasogenic edema

Tumor-induced vasogenic edema occurs due to disruption of the blood-brain barrier, preferentially affecting white matter. The type and severity of neurologic symptoms are affected by the degree of edema and location of edema. Evaluation of cerebral edema is best accomplished with MRI of the brain using T2 fluid-attenuated inversion recovery (FLAIR sequences). Edema appears as T2 hyperintensity. The decision to treat cerebral edema should be based on clinical findings and neurologic symptoms. Asymptomatic patients with cerebral edema seen on imaging do not require treatment. Corticosteroids, particularly dexamethasone, are the primary treatment for clinically symptomatic cerebral edema. Dexamethasone is preferred due to its minimal mineralocorticoid activity. By decreasing blood-brain barrier permeability, corticosteroids can effectively reduce intracranial pressure, improving cerebral edema and neurologic symptoms within days.

Dexamethasone . Dosing of dexamethasone is largely dependent on symptoms. Severe symptomatic cerebral edema can be treated with intravenous dexamethasone 10–24 mg followed by oral dexamethasone. Doses of 2–4 mg of oral dexamethasone administered two to four times per day are commonly used. In the outpatient setting, twice-daily dosing is often sufficient, with the second dose administered in the afternoon to prevent insomnia. Although corticosteroids can quickly improve neurologic symptoms and function, their acute and long-term use is associated with many side effects. Acutely, patients may experience hyperglycemia, insomnia, and mood disturbances such as anxiety or mania. Chronic corticosteroid use is associated with a host of complications including weight gain, Cushing syndrome, and steroid myopathy. Endocrine and neuropsychiatric effects of corticosteroids are discussed later in this chapter.

Given the side effect profile, patients should be maintained on the lowest effective dose of dexamethasone. Tapering or discontinuing corticosteroids should be considered at every patient encounter, although some patients may be unable to safely taper off steroids due to re-emergence of focal neurologic symptoms or seizures. Additionally, patients with chronic corticosteroid use may have difficulty tapering off steroids secondary to adrenal insufficiency. The risks of corticosteroid treatment must be weighed against their symptomatic benefit, as their effects can have profound medical and functional implications. Anti-angiogenic agents such as beva cizumab, a monoclonal antibody against vascular endothelial growth factor, can be used in recurrent malignant gliomas to reduce cerebral edema and corticosteroid dependence.

Approach to tumor-associated epilepsy

Seizures are among the most common complications of brain tumors. The likelihood of developing seizures from a brain tumor is variable and influenced by tumor location, histology, and rate of growth. Tumors involving the cortex, temporal lobe, and insula are associated with higher rates of epilepsy, whereas tumors involving the posterior fossa or deep structures rarely cause seziures. Tumor histology is also associated with increased rates of epilepsy. Dysembryoplastic neuroepithelial tumors and oligodendrogliomas are associated with epilepsy in up to 90% of cases. ^, In such epileptogenic tumors, gross-total surgical resection is strongly associated with seizure freedom. ^, High-grade glioma patients experience rates of tumor-associated epilepsy of 30–50% and may experience seizures at any point during their disease course. ^, Therefore, if a brain tumor patient presents with paroxysmal or fluctuating symptoms, seizure activity should be high on the differential. Electroencephalography may be helpful to characterize episodes that are not clinically consistent with seizure activity.

There is some evidence to suggest that brain tumor–directed treatment, including radiation and chemotherapy, may improve seizure control, although cancer-specific treatments are not considered first line for managing tumor-associated epilepsy. ^, Current standard of care practices involve treating brain tumor patients who present with seizures with antiepileptic drugs (AEDs). No data exists to support the efficacy of one AED compared with another. Given the increasing number of available AEDs, the drug chosen should take into account a patient’s epilepsy syndrome, medical comorbidities, desired speed of titration, and side effect profile of the drug. It is recommended to avoid enzyme-inducing drugs, as these may interact with the metabolism of corticosteroids and cancer-directed treatments such as chemotherapy. Common enzyme-inducing AEDs include phenytoin, phenobarbital, carbamazepine, and oxcarbazepine. Table 19.1 shows non–enzyme- inducing AEDs that are commonly used in brain tumor patients. For example, levetiracetam is an AED frequently used to treat tumor-associated epilepsy. It has no known drug interactions, minimal hepatic metabolism, requires no specific monitoring, and can be administered orally or intravenously. It is generally well tolerated by patients, with the most common adverse effects being agitation and aggression. Enzyme inhibiting AEDs such as valproic acid should be used with caution, especially in patients treated with hepatically cleared chemotherapeutic agents, as it may increase toxicity of these drugs.

AEDs are associated with many adverse effects and nearly 25% of patients will experience side effects of AED therapy requiring drug discontinuation. Common side effects of AEDs include symptoms of central nervous system depression such as fatigue, cognitive slowing, ataxia, and dizziness. Other specific adverse effects that can be seen are drug dependent and are listed in Table 19.1 . When patients present with these symptoms, a thorough history, metabolic workup, and AED serum levels may be used to distinguish whether symptoms are due to adverse effects from the drug rather than direct effects of the tumor itself. Although appropriate treatment of tumor-associated epilepsy may lead to a decrease or cessation of seizures, all patients and their caregivers should be educated on seizure safety and home management of acute, symptomatic seizures. Driving restrictions should be discussed with all patients who have experienced seizures with loss of awareness or consciousness. Driving restrictions are variable by region, therefore patients and physicians should familiarize themselves with local regulations and procedures.

The American Academy of Neurology Quality Standards Subcommittee performed a meta-analysis of randomized studies assessing the benefit of prophylactic AED treatment in brain tumor patients. Prophylactic treatment was found to have an increased burden of side effects without an improvement in rates of tumor-associated epilepsy when compared with placebo or no treatment. This led to a recommendation against administration of prophylactic AEDs in patients with brain tumors. Although this recommendation was based on results from studies utilizing first- or second-generation AEDs, more recent reviews have shown similar findings with newer non–enzyme-inducing AEDs. As such, it is currently recommended to only treat brain tumor patients who have experienced a seizure with AEDs.

Approach to stroke in brain tumor patients

Mechanisms of ischemic and hemorrhagic stroke . Patients with brain tumors are at risk of ischemic or hemorrhagic stroke from a variety of mechanisms including direct tumor effects and side effects of treatment. Ischemia can occur as a result of direct compression of cerebral vasculature either by tumor or associated edema. Brain tumor patients are also at risk of ischemic stroke from other mechanisms including hypercoagulability from malignancy, paroxysmal embolism from a deep venous thrombosis through a patent foramen ovale, and late effects of treatment including radiation induced vasculopathy. Cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes, and smoking may also increase risk of both ischemic and hemorrhagic stroke. Certain drugs used in the management of malignant gliomas, such as bevacizumab, a monoclonal antibody against vascular endothelial growth factor, also increase the risk of arterial stroke. Patients with brain tumors are also at risk for hemorrhagic stroke, with intra-tumoral hemorrhage being the most common presentation in this population. Brain tumor patients may also be at risk for cerebral hemorrhage due to thrombocytopenia or coagulopathy from chemotherapeutic treatments.

Evaluation and management of ischemic stroke in brain tumor patients . Evaluation of stroke in brain tumor patients should occur no differently than in other stroke patients. Emergent evaluation is recommended in a hospital setting. CT head should be obtained without delay to assess for hemorrhage or large vessel occlusion. Very little data exists for the use of acute interventions such as tissue-plasminogen activator (tPA) and thrombectomy in patients with brain tumors presenting with ischemic stroke, which are relatively contraindicated in brain tumor patients. The risk of acute interventions should be weighed with the potential benefit and life expectancy of the patient. All patients should have an MRI Brain with and without contrast to better evaluate the extent of the infarct and assess for tumor growth. In cases where tumor growth or edema have caused direct vascular compression, treatment with corticosteroids and neurosurgical tumor debulking should be considered. Vascular imaging of the head and neck vessels and echocardiogram may be indicated based on the stroke mechanism. If acute management is not appropriate, aggressive risk factor modification should be considered in all brain tumor patients, as they are at particular risk of recurrent thromboembolic strokes. Risk factor modification should include correction of coagulopathy, anticoagulation when appropriate, in addition to blood pressure, cholesterol, and glucose control.

Management of hemorrhagic stroke in brain tumor patients . Patients with hemorrhagic stroke should have all antiplatelet and anticoagulant medications withheld. Aggressive blood pressure management to keep systolic blood pressure <140 mmHg is recommended. In hemorrhages due to thrombocytopenia, patients should be treated with emergent platelet transfusions. In cases of a large volume or expanding hemorrhage, neurosurgical hematoma evacuation should be considered. All brain tumor patients with stroke should be considered for rehabilitation with physical and occupational therapy.

Approach to tumor-induced hydrocephalus

Etiology, presentation, and evaluation of hydrocephalus . Some brain tumors based on their location can cause intraventricular obstruction of cerebral spinal fluid flow, leading to a non-communicating or obstructive hydrocephalus. This occurs from direct obstruction from intraventricular tumors such as subependymoma, meningioma, and central neurocytoma or from extrinsic compression of the ventricle from ependymoma, astrocytoma, and metastases. Hydrocephalus is most commonly seen with tumors of the posterior fossa or deep structures of the brain such as the thalamus. Patients typically present with symptoms of progressive headache, lethargy, ataxia, impaired vision, and cognitive decline, although symptoms can be acute in onset. Neurologic examination should include fundoscopy to assess for papilledema. The patient described in Case 19.1 is a classic clinical and radiographic example of obstructive hydrocephalus.

Management and treatment of obstructive hydrocephalus . All patients with concern for hydrocephalus should have urgent imaging with CT Head without contrast. Classically, imaging will show enlarged lateral ventricles with transependymal flow of CSF and obstruction of the third and fourth ventricle. MRI can be used to better elucidate tumor volume, extent of edema, and aid in surgical planning. Patients with acute non-communicating hydrocephalus should be emergently evaluated, as early detection and treatment can be lifesaving. Corticosteroids are generally administered for acute symptom management. Emergent neurosurgical consultation should be obtained. Treatment of obstructive hydrocephalus depends on the level of obstruction and in the acute setting is focused on reducing elevated intracerebral pressure and diverting CSF flow, often with an extraventricular drain. Definitive treatment may involve endoscopic ventriculostomy or placement or ventriculoperitoneal shunting. Urgent radiotherapy may also be appropriate in certain situations.

Approach to SIADH

Syndrome of inappropriate antidiuretic hormone in brain tumor patients . Patients with any central nervous system disorder, particularly patients with brain tumors, can develop inappropriate release of antidiuretic hormone (ADH). ADH secretion results in water retention and loss of sodium in the urine. The syndrome of inappropriate antidiuretic hormone (SIADH) is characterized by plasma hyponatremia, plasma hypoosmolality, and concentrated urine in the setting of normovolemia, normal blood pressure, and adequate renal, hepatic, adrenal, and thyroid function. Patients with SIADH can present with a myriad of symptoms including weakness, lethargy, fatigue, encephalopathy, seizures, and, in severe cases, coma. SIADH can occur at any point during the disease course and can occur irrespective of brain tumor progression.

Providers should have a high index of suspicion for SIADH in the setting of poorly localizing, progressive neurologic symptoms and polyuria. Initial workup should include serum chemistries to evaluate electrolytes and renal function and urinalysis with urine electrolytes and urine osmolality. Diagnosis is made in the setting of serum hyponatremia and urine hyperosmolality (>100 mosmol/kg). Hyponatremia can induce brain swelling, which can be fatal for patients with brain tumors. Consultation with a nephrologist is recommended, and patients frequently require hospital admission for treatment and close monitoring of sodium levels.

Treatment of hyponatremia. Treatment of hyponatremia depends on the severity of symptoms and degree of hyponatremia. All symptomatic patients should be urgently treated. Mild symptomatic hyponatremia with serum sodium >125 mEq/L is treated with fluid restriction of less than 800 mL of fluid per day. Other treatment options for mild to moderate hyponatremia include oral salt tablets, starting at a dose of 9 g daily, or administration of loop diuretics. These treatments will correct serum sodium levels in 3–10 days. Patients with severe symptomatic hyponatremia should be considered for admission to an intensive care unit and may require administration of hypertonic saline to rapidly raise serum sodium.

Approach to endocrinopathy

Endocrinopathies from tumor involvement . Endocrinopathies occur in patients with brain tumors via involvement or invasion of the hypothalamic-pituitary axis or secondarily as a consequence of radiation to the hypothalamus or pituitary gland. Tumors of the region of the sella turcica, the saddle-shaped midline bony depression in the skull, include pituitary tumors and, less commonly, craniopharyngiomas, or rarely granular cell tumors, pituicytomas, and spindle cell oncocytomas. Pituitary tumors are the most common of these tumors and one of the most common benign brain tumors (e.g., behind meningioma). Neurologists should be generally aware of the clinical presentation, imaging findings, laboratory assessment, and treatment options. Presenting symptoms result from local compression against surrounding structures such as the optic chiasm (e.g., bitemporal hemianopsia) or disruption of pituitary hormone secretion. Pituitary tumors are neoplasms that arise from the neuroendocrine cells in the pituitary gland. They can be classified histologically, radiographically, and biochemically. Histologically, they can be classified as adenomas (most common), carcinomas, and atypical adenomas with benign adenomas. On imaging, pituitary tumors are classified as microadenomas for tumors less than 10 mm in largest cross-sectional diameter, or macroadenomas for tumors larger than 10 mm. Biochemically, about two-thirds of pituitary adenomas are hormonally functional, with prolactinomas being the most common. Treatment involves replacement of hormone function and definitive tumor-directed therapy. Indications for surgery include symptomatic mass effect, vision loss, or inability to achieve hormone stability.

Post-treatment endocrinopathies in brain tumor patients . Children and young adults are most prone to radiation-induced endocrinopathies, which tend to develop several years after treatment. Symptoms vary depending on the deficient hormone. Growth hormone is the most sensitive to treatment-related effects, and its deficiency results in small stature and decreased bone density. Patients with prolactinoma may present with galactorrhea, amenorrhea, hypogonadism, and erectile dysfunction. Other endocrinopathies such as gonadotropic deficiency or adrenocorticotropic hormone deficiency are less common. Cushing syndrome and hyperglycemia often occur in brain tumor patients after prolonged exposure to corticosteroids. Evaluation of endocrinopathy begins with obtaining serum hormone levels. Referral to an endocrinologist is recommended. Some patients will require treatment with hormone replacement therapy or cortico steroids. In patients with hormone-producing macroadenomas, medical treatment with agents such a bromocriptine (for prolactin secreting adenomas) may be considered. Neurosurgical resection of a pituitary mass is recommended for large tumors causing compressive neurologic symptoms and tumors refractory to medical treatment.