Neurologic complications of cancer

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.