Clinical Features: Neurology of Brain Tumor and Paraneoplastic Disorders

Headaches

Headaches are a common symptom of primary and metastatic brain tumors. They occur in approximately half the patients over the course of the disease and are the presenting symptom in approximately 25% of these patients. The headaches are often not lateralized and present more as tension-type headaches with a bifrontal predilection. However, unlike tension-type headaches, they are worsened with changes in position, particularly on bending. They are more frequently associated with infratentorial or intraventricular tumors but are less commonly seen with pituitary adenomas or glioblastoma. In approximately 10% of patients with brain tumors and headache, the symptom could not be attributed to the tumor. In a meta-analysis of incidental findings on brain MRI scans in approximately 19,500 patients presenting with routine headaches, Morris et al. reported that 0.7% of patients had a brain neoplasm, suggesting that routine headaches are unlikely to be associated with neoplasms. However, specific clinical features of the headache may more accurately correlate with the presence of a brain tumor. The diagnostic criteria for “headache attributed to intracranial neoplasm” based on the third edition of the International Classification of Headache Disorders from the International Headache Society is shown in Box 143.1 . The characteristic headache is described as progressive, worse in the morning, and aggravated by Valsalva maneuvers and is caused by one or more space-occupying intracranial tumors.

Headaches related to intracranial neoplasm are often noted to be associated with postural changes, presenting with nausea and vomiting. This is true especially for posterior fossa tumors and tumors causing increased intracranial pressure. Nocturnal or early morning headaches have been attributed to brain tumors, particularly in relation to increased intracranial pressure, but this feature is inconsistent. Headaches due to brain tumors can occur at any time during the day; conversely, early morning headaches can have other causes ; hence this is generally a nonspecific and unreliable symptom for diagnosis of brain tumors.

Headaches associated with brain tumors can result from mechanical or physiologic causes. Mechanical causes for headaches include hydrocephalus associated with infratentorial or intraventricular tumors, which can obstruct flow of cerebrospinal fluid (CSF), or communicating hydrocephalus, which can result from disturbed function of the arachnoid granulations due to leptomeningeal disease or tumor-related subarachnoid or intraventricular bleeding. The basis for generation of such headaches is that meningeal and vascular components of the brain have sensory innervation through branches of the trigeminal nerve ; distortion of these structures can trigger generation of nociceptive signals, which in turn manifests as pain and headaches. Meninges and their associated portions of the cerebral vasculature are the only intracranial sites from which pain can be evoked ; their distortion by increased intracranial pressure due to tumor mass, surrounding edema, or hydrocephalus can generate headaches. An anecdotal report of a transient response of headaches related to a glioblastoma to sumatriptan, a serotonin receptor agonist, suggests the possible existence of neurotransmitter-mediated mechanisms for some of these headaches.

Seizures

Seizures occur in 30% of all cancer patients. The incidence of seizures in brain tumors has been variably reported to be between 20% and 70%. This is likely a reflection of the numbers of patients included in the study and the nature of tumors that were associated with the seizures. In a retrospective study, seizures were reported to occur as a presenting symptom in approximately 40% of patients with primary brain tumors and 20% of those with brain metastases. A prospective registry study that included patients with brain tumors who also had a seizure found that seizures were the presenting symptoms in approximately 70% of patients. Patients with low-grade gliomas were in general more likely to have seizures; World Health Organization (WHO) grade I tumors such as dysembryoplastic neuroepithelial tumors or gangliogliomas were the most frequently associated with this symptom ( Table 143.1 ). ^, Interesting to note, it was shown that the IDH1 mutation was associated with an increased risk of seizures in patients with gliomas (odds ratio of 2.5). This is thought to be related to increased production of d -2-hydroxyglutarate (D2HG), which mimics the activity of glutamate on the N -methyl- d -aspartate (NMDA) receptor. The most common seizure type is a secondary generalized tonic clonic seizure (approximately 50%), followed in frequency by focal motor seizures (approximately 25%). Seizures are often single (42%) or low frequency (18%) in most cases; only 18% of patients had higher seizure frequency (more than 4 per month) or status epilepticus (12%); such frequent seizures are more frequently associated with low-grade gliomas. ^{, ,} Tumor resection resulted in resolution or improvement in frequency of seizures, particularly in neuroglial tumors. The majority of patients who have seizures associated with their diagnosis are treated with a single antiepileptic drug (AED) (>60%); levetiracetam is the most commonly used anticonvulsant (60%). ^, Newer non–enzyme-inducing antiepileptic drugs (NIAEDs), such as levetiracetam, lacosamide, and lamotrigine, are favored over the older AEDs, given fewer interactions with chemotherapy. The issue of use of prophylactic anticonvulsants was addressed in a meta-analysis from five randomized trials using phenobarbital, phenytoin, or valproic acid as a prophylactic AED and showed that there were no significant differences in seizure incidence in patients in the nonprophylaxis group compared with patients who received prophylactic anticonvulsants. Therefore the American Academy of Neurology guidelines published in 2010 suggest that routine use of prophylactic anticonvulsants in patients with brain tumors is not warranted. However, assessment of the role of anticonvulsants in these studies did not fully take into account tumor grade and type, location and size, and extent of resection, which limits the validity of the results. Moreover, the same question has not been addressed using newer AEDs that have fewer side effects and interactions. On the other hand, a recent meta-analysis from four randomized controlled trials suggested that perioperative AED prophylaxis for brain tumor surgery provides a statistically significant reduction in early postoperative seizure risk.

Glioneuronal tumors, which are most commonly associated with seizures, have dysplastic neurons amid neoplastic glial cells, which appear to generate hyperexcitability in the neuronal elements; this in turn can trigger seizures. ^, Electrophysiologic studies of these tumors have demonstrated continuous electrical spiking and bursts in dysplastic regions with a high neuronal density, suggesting the propensity of these regions to generate seizures. Low-grade gliomas are highly infiltrative and slow-growing tumors that can cause gliosis and chronic inflammatory changes in the surrounding normal brain, causing excitotoxicity in adjacent neurons and triggering seizures. Alteration in glutamate-mediated excitatory neurotransmission due to release of high levels of glutamate from tumor cells mediated by the cystine-glutamate transporter (SXC) in the peritumoral region has been implicated in epileptogenicity of gliomas. An independent disinhibition of the GABAergic interneurons mediated by the combined activity of the K ⁺ -Cl ⁻ cotransporter KCC2 and SXC appears to make peritumoral neuronal networks hyperexcitable and epileptogenic. Other factors that are postulated to drive seizures associated with brain tumors include changes in ion channels (especially extracellular potassium levels), peritumoral alterations in pH that increase membrane excitability, elevated levels of connexin 32 and connexin 43 (leading to synchronization of potentials in peritumoral neuronal networks), and alterations in the blood-brain barrier that can disrupt local homeostasis of electrochemical factors leading to greater propensity to epileptogenesis. ^, These new insights into tumor-related epileptogenesis promise to provide new avenues for treatment of seizures associated with this disease.

Cognitive Dysfunction

Brain tumors are well recognized for their direct ability to disrupt key neuronal circuits and induce alterations in neurocognitive processing of information that affect higher mental functions and induce cognitive deficits. This symptom can also occur more prominently owing to the secondary effects of the tumor, such as increased intracranial pressure, seizures, hydrocephalus, depression, or language disturbances, which may mask the underlying, more subtle direct cognitive dysfunction from these tumors; this is also made more challenging by the fact that cognitive function is not routinely assessed at the time of initial diagnosis. However, formal studies that have assessed baseline cognitive function in patients with brain tumors have indicated that over 90% of these patients manifest some degree of cognitive dysfunction prior to surgery or other treatments, suggesting that this is a fundamental symptom associated with brain tumors. ^, Such dysfunction can occur both in low-grade gliomas and in higher grade malignancies such as glioblastoma but with different degrees of acuity of presentation corresponding to the trajectory of tumor growth. ^, Even intracranial extra-axial tumors such as meningiomas can be associated with significant cognitive dysfunction across multiple domains (such as memory, psychomotor speed, reaction time, complex attention, cognitive flexibility, processing speed, and executive functioning) both before and after tumor resection; 69 % of patients scored low or very low in one or more cognitive domains prior to surgery, as did 44% after surgery.

Cognitive dysfunction in the spheres of language, personality, behavior, and cortical sensory recognition may occur with brain tumors in frontal, temporal, and parietal locations ( Table 143.2 ). Cognitive dysfunction has also served as a predictive and prognostic factor associated with outcome. In a study examining the survival prognostic value of baseline health-related quality of life (HRQOL) for different cancers using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), cognitive functioning emerged as a prognostic factor for outcome in brain tumor patients. Of note, cognitive decline was reported to precede MRI-based tumor progression in patients with primary brain tumor in one study, suggesting potential usefulness of cognitive deterioration as a clinical end point. Brain metastases are also associated with cognitive impairment in 65% to 90% of patients. In a study of medical decision-making capacity, patients with brain metastases had a significantly lower capacity for decision making compared with control patients, with approximately 60% of these patients showing impairment in decision-making capacity on at least one measure. Similar deficiencies in medical decision-making capacity and neurocognitive function were seen in patients with malignant gliomas. The level of understanding in such decision making appeared to be related to neurocognitive functions. These findings have important implications in the ability of patients to participate in decision making related to medical issues, as well as for clinical trials. In addition to the direct effects of tumor on cognition, therapeutic interventions against cancer can also affect cognitive function; systemic therapy can cause cognitive impairment in the absence of brain involvement (the so-called “chemo-fog”). Although such effects can occur in patients of all ages, they are especially seen in long-term survivors of cancer and elderly patients with malignancies. ^,

At initial presentation or at progression, the physical effects of tumors such as hydrocephalus, ventricular entrapment, peritumoral edema, and herniation can cause direct distortion of brain structures and interfere with normal cognitive functions, often in association with other neurological deficits. However, tumors can also induce more subtle effects on the brain that can affect cognitive function. Studies using functional MRI scans and neurocognitive assessments have suggested that a decreased efficiency of the neural network function may underlie the cognitive dysfunction related to low-grade gliomas. Another study using magnetoencephalographic recordings showed that the differences in cognitive effects of low-grade and high-grade gliomas were associated with differences in neuronal plasticity and the effects of specific lesional growth pattern. Of note, patients with low-grade gliomas showed decreased network synchronizability and decreased global integration in magnetoencephalographic recordings compared with healthy controls in the so-called theta frequency range (4–8 Hz) that were similar to those in nonglial lesional patients and tended to make them more susceptible to seizures and cognitive decline. Some studies have looked at the role of long-distance effects of localized brain tumors on cognitive function by using resting state networks derived from functional MRI scans; the results of these studies have shown that changes in connectivity are seen in the side contralateral to the tumor and correlate with aspects of cognitive function indicating onset of cognitive changes prior to emergence of major symptoms. In addition to the primary effects of the tumor, cognitive dysfunction also commonly occurs as a side effect of treatments such as chemotherapy or radiation therapy. An important example is the use of radiation therapy and high-dose methotrexate in close approximation, leading to leukoencephalopathy and cognitive dysfunction; this practice is now largely avoided by oncologists. Emerging evidence points to effects on specific brain pathways such as the parietal and prefrontal cortical connections that may underlie the development of such effects, as well as the role of cytokine release after chemotherapy. ^,

Management of cognitive dysfunction has included preventive strategies, medical therapies, compensatory and coping strategies, and neuroprotective strategies. Stimulants such as methylphenidate have shown benefit in addressing cognitive dysfunction in patients with primary brain tumors in some studies. Treatment with memantine, an NMDA receptor antagonist used in treatment of Alzheimer disease, delayed cognitive decline in patients with brain metastases who underwent whole-brain radiation therapy. ^, Strategies to avoid cognitive effects of radiation therapy have been evolved by tailoring the dose and extent of radiation fields. For instance, stereotactic radiosurgery has largely replaced whole-brain radiation when feasible. Moreover, hippocampal avoidance using carefully planned fields has been used to prevent radiation-induced effects on short-term memory and did not appear to compromise tumor control. ^,