Glioblastoma (GBM) is recognized as the most common and aggressive primary brain tumor in adults. The presence of seizures, often referred to as tumor-associated epilepsy, is a significant complication for many individuals living with GBM. This neurological symptom can be the first sign of the disease, occurring in an estimated 30% to 62% of patients during their illness. This frequent co-occurrence highlights a complex relationship between the tumor’s biology and the brain’s electrical stability. Understanding the mechanisms linking glioblastoma to seizures, their identification, and management is an important part of comprehensive patient care.
Why Glioblastoma Causes Seizures
The presence of a glioblastoma disrupts the normal electrical environment of the brain, creating a state of neuronal hyperexcitability that leads to seizures. This process is driven by biological and molecular changes within the tumor and the surrounding brain tissue, known as the peritumoral zone. One significant mechanism involves the neurotransmitter glutamate, a primary excitatory signal in the central nervous system.
Glioblastoma cells release excessive amounts of glutamate into the extracellular space, sometimes up to 100 times higher than in healthy brain tissue. Tumor cells achieve this by overexpressing the cystine/glutamate antiporter (system xCT). This massive surge of glutamate over-activates receptors on nearby neurons, leading to uncontrolled firing and excitotoxicity, which is the underlying cause of seizures.
The tumor’s presence also causes a breakdown of the blood-brain barrier, allowing inflammatory substances and fluid to accumulate, creating brain swelling or edema. This inflammation and pressure irritate the surrounding healthy neurons, lowering their threshold for electrical discharge. Additionally, the physical invasion of tumor cells into the cortex directly interferes with established neuronal circuits. This combination of chemical imbalance, physical irritation, and structural disruption transforms the peritumoral tissue into an epileptogenic zone.
Recognizing and Diagnosing Seizures in GBM Patients
Seizures in glioblastoma patients can manifest in various ways, depending on the tumor’s location. They are most commonly focal seizures, meaning they start in a specific area, often corresponding to the site of the tumor, such as the frontal or temporal lobes. A focal seizure might present as a subtle, involuntary twitching of a limb, a tingling sensation, or a brief period of staring or confusion.
A focal seizure can sometimes evolve into a generalized seizure, involving both sides of the brain, such as a tonic-clonic seizure with loss of consciousness and full-body convulsions. Caregivers should also be vigilant for non-convulsive symptoms, like sudden changes in behavior, unexplained periods of unresponsiveness, or unusual smells or tastes. These subtle signs can represent electrical activity that requires intervention.
The diagnosis of a seizure is typically confirmed using a combination of imaging and functional testing. Magnetic Resonance Imaging (MRI) locates the tumor and assesses the extent of surrounding edema, helping to correlate the seizure’s origin with the tumor’s site. An Electroencephalogram (EEG) is the primary tool for measuring the brain’s electrical activity, identifying abnormal patterns such as epileptiform discharges or focal slowing characteristic of a seizure disorder.
Current Treatment Strategies for Seizure Control
The management of glioblastoma-associated seizures relies primarily on Anti-Epileptic Drugs (AEDs) once a seizure has occurred. A major consideration in selecting an AED is the potential for drug-drug interactions, particularly with the standard chemotherapy agent, temozolomide (TMZ). Some older AEDs are known as enzyme-inducing AEDs (EIAEDs) because they accelerate the metabolism of other drugs in the liver.
EIAEDs, such as phenytoin or carbamazepine, can significantly reduce the concentration and effectiveness of TMZ and corticosteroids. For this reason, non-enzyme-inducing AEDs (non-EIAEDs) are generally preferred as a first-line treatment. Levetiracetam and valproic acid are the most frequently used non-EIAEDs in this patient population, as they have fewer problematic interactions with chemotherapy.
Levetiracetam is often favored due to its favorable side effect profile and minimal impact on the metabolism of other drugs. Valproic acid is also used and has the added benefit of potentially enhancing the anti-tumor activity of TMZ in some patients, though it can carry a broader side effect profile. In cases where the tumor is surgically accessible, tumor resection can contribute significantly to improving seizure control and reducing seizure frequency.
The Effect of Seizures on GBM Treatment and Quality of Life
The occurrence of seizures, especially if poorly controlled, profoundly affects both the patient’s quality of life and the continuity of their cancer treatment. A seizure event can necessitate an emergency room visit or hospitalization, potentially delaying scheduled chemotherapy or radiation sessions. Interruptions in the oncology treatment schedule may compromise the overall efficacy of the therapy.
Seizures and the medications used to control them contribute to cognitive dysfunction, including issues with memory, focus, and mental clarity. This decline in neurocognitive function decreases the patient’s daily independence and increases the burden on caregivers. Furthermore, seizure activity often results in temporary or permanent loss of driving privileges, which restricts independence and mobility.
Prophylactic use of AEDs—administering the drugs to patients who have not yet had a seizure—remains a controversial practice. Clinical evidence does not consistently support the routine, long-term use of AEDs in seizure-free GBM patients to prevent a first seizure. This conservative approach helps avoid unnecessary drug side effects and potential drug-drug interactions that do not offer a proven benefit. Therefore, AEDs are typically reserved for patients who have experienced at least one documented seizure event.