The development of epilepsy as a consequence of neurological infections and brain tumors represents a clinically important and mechanistically distinct category of symptomatic epilepsy in which the seizure disorder arises from the direct or indirect effects of an identifiable pathological process on brain tissue. These structural and infectious etiologies of epilepsy collectively account for a substantial proportion of all new epilepsy diagnoses, particularly in low-income and middle-income countries where infectious neurological disease is highly prevalent, and in older adults where primary brain tumors and brain metastases are the most common newly identified structural epilepsy causes. The characterization of infection-related and tumor-related epilepsy as distinct from idiopathic and genetic epilepsies has important implications not only for understanding the pathophysiology of seizures in these contexts but for treatment planning, which must address both seizure management and the underlying neurological disease simultaneously, recognizing that optimal control of the underlying infection or tumor may be the most effective anti-epileptic intervention available.
Globally, infectious causes of epilepsy are of paramount clinical importance and yet are systematically underrepresented in the epilepsy literature because the clinical research from high-income countries, where infectious epilepsy is less prevalent, has historically dominated the field. Neurocysticercosis, the cerebral infection caused by the larval stage of the pork tapeworm Taenia solium, is estimated to be responsible for approximately thirty percent of epilepsy cases in endemic regions of Latin America, sub-Saharan Africa, and South and Southeast Asia, making it the single most common preventable cause of epilepsy worldwide. Cerebral malaria, bacterial meningitis and encephalitis, viral encephalitis, tuberculosis meningitis, and human immunodeficiency virus-associated neurological disease each contribute substantially to the global infectious epilepsy burden in different geographic and demographic contexts. The recognition that a large proportion of the global epilepsy burden is attributable to preventable infectious diseases underscores the public health importance of improving sanitation, vaccination coverage, and access to early infectious disease treatment as strategies for reducing epilepsy incidence in affected populations.
Brain tumors as a cause of epilepsy span the full spectrum of neuro-oncological pathology, from the low-grade gliomas including gangliogliomas and dysembryoplastic neuroepithelial tumors that are strongly epileptogenic and often present in young adults with chronic focal epilepsy, to the high-grade glioblastoma multiforme that produces new-onset seizures in older adults alongside its rapid neurological deterioration, to the brain metastases that complicate advanced systemic malignancies and produce seizures through cortical irritation at the tumor periphery. The relationship between brain tumors and epilepsy is not unidirectional: while tumors clearly cause seizures through their direct effects on cortical tissue, emerging evidence suggests that chronic seizure activity may in some cases influence tumor biology and that the glutamate released during seizures may promote tumor cell proliferation and invasion through AMPA receptor-mediated signaling, creating a bidirectional interaction between epileptic activity and tumor progression that has therapeutic implications.
Neurocysticercosis and Infectious Epilepsy
Neurocysticercosis, caused by the establishment of Taenia solium larvae within the central nervous system following the ingestion of tapeworm eggs shed in the feces of a human tapeworm carrier, produces epilepsy through a sequence of pathological events that begins with viable cyst formation and ends with calcified granuloma deposition after cyst death, with different stages of the parasite lifecycle producing different mechanisms of cortical irritation and different clinical responses to antiparasitic and anti-inflammatory treatment. The viable cyst stage, in which intact larvae surrounded by their fluid-filled cyst membrane reside within the brain parenchyma, typically produces no or minimal local inflammatory response because the larvae actively evade the host immune response through immune evasion mechanisms, meaning that viable cysts may be asymptomatic or may cause seizures through mass effect or subtle local cortical disturbance rather than severe inflammation.
The transitional stage of cysticercus degeneration, in which the larva dies spontaneously or following antiparasitic drug treatment and the cyst membrane breaks down, triggers a vigorous host inflammatory response to the released parasite antigens that is the primary driver of symptomatic epilepsy in neurocysticercosis. The perilesional inflammatory edema, enhanced blood-brain barrier permeability, and local cortical irritation produced by the inflammatory reaction around a degenerating cysticercus create an intensely epileptogenic microenvironment that generates acute symptomatic seizures and, through the structural changes left after resolution of inflammation, may establish a chronic epileptogenic focus that continues to generate unprovoked seizures long after the acute inflammatory episode has resolved and the cysticercus has calcified. The calcified stage of neurocysticercosis, representing the end-stage healed lesion after cyst death and inflammation resolution, is not inert from an epileptogenic perspective but continues to generate seizures in a substantial proportion of patients through mechanisms that include persistent local inflammatory activity at the calcification periphery and iron deposition from residual hemosiderin that generates oxidative stress.
The diagnosis of neurocysticercosis in a patient with new-onset epilepsy rests on the combination of neuroimaging findings characteristic of different stages of the parasite lifecycle and serological confirmation using enzyme-linked immunoelectrotransfer blot assay, the most sensitive and specific serological test available for Taenia solium antibody detection. Computed tomography of the brain is often the most practical initial neuroimaging modality in resource-limited settings and provides excellent visualization of calcified lesions and perilesional edema, while magnetic resonance imaging provides superior characterization of cyst morphology, the degree of perilesional inflammation, and the presence of subarachnoid and intraventricular cysts that may not be visible on computed tomography. The management of neurocysticercosis-related epilepsy requires the simultaneous consideration of antiseizure medication, antiparasitic treatment with albendazole or praziquantel, anti-inflammatory corticosteroid therapy to manage the inflammatory response to cyst death, and in selected cases surgical removal of accessible cysts producing refractory symptoms or hydrocephalus.
Viral and Bacterial Encephalitis
Viral encephalitis, encompassing infections of the brain parenchyma by herpes simplex virus, autoimmune encephalitis triggered by viral infection, Japanese encephalitis virus, La Crosse encephalitis virus, eastern and western equine encephalitis viruses, and in recent decades the emerging and re-emerging flaviviruses, is a major cause of both acute symptomatic seizures during the encephalitic illness and long-term post-encephalitic epilepsy that develops as a sequela of the permanent neuronal damage and structural brain changes produced by the acute infectious process. Herpes simplex virus encephalitis, the most common viral encephalitis in immunocompetent individuals in developed countries, has a particular predilection for the temporal lobes and orbitofrontal cortex, producing hemorrhagic necrosis in these regions that generates mesial temporal lobe epilepsy with hippocampal sclerosis in a substantial proportion of survivors, as the combination of herpes simplex virus-induced neuronal death, inflammatory scarring, and mossy fiber reorganization in the damaged temporal cortex creates the classic epileptogenic substrate of mesial temporal lobe epilepsy.
Autoimmune encephalitis, an increasingly recognized cause of new-onset seizures that was historically classified as viral encephalitis of unknown etiology, represents a group of conditions in which autoantibodies against neuronal surface antigens including the NMDA receptor, CASPR2, LGI1, GABA-B receptor, and AMPA receptor produce limbic encephalitis with prominent seizures, psychiatric symptoms, and movement disorder through their direct antagonistic or agonistic effects on the targeted receptor or synaptic protein. Anti-NMDA receptor encephalitis, the most common form of autoimmune encephalitis and particularly prevalent in young women and children, causes an acute onset of psychiatric symptoms, memory disturbance, seizures, movement disorder, and autonomic instability mediated by the antibody-induced internalization and degradation of NMDA receptor subunits from the neuronal surface, reducing NMDA receptor-mediated inhibitory control of dopaminergic pathways and producing the characteristic clinical syndrome. The recognition of autoimmune encephalitis as a cause of new-onset seizures and status epilepticus has important therapeutic implications because these conditions respond to immunotherapy including intravenous immunoglobulin, plasma exchange, and corticosteroids rather than to antiviral treatment.
Bacterial meningitis and encephalitis, caused by organisms including Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, and Mycobacterium tuberculosis, produce epilepsy through multiple mechanisms including direct cortical invasion and neuronal injury, cerebrovascular complications from septic thromboembolism and vasculitis, cortical spreading depression from the toxic and metabolic consequences of severe bacterial infection, and the structural changes of cortical scarring and hippocampal injury that produce chronic epileptogenic foci. Bacterial meningitis complicated by seizures carries a substantially worse prognosis than uncomplicated meningitis, with higher rates of neurological sequelae including epilepsy, hearing loss, cognitive impairment, and motor disability, reflecting the severity of the inflammatory process that generates both the acute seizures and the chronic structural damage. Tuberculous meningitis, prevalent in high-burden tuberculosis settings and affecting immunocompromised individuals including those with HIV infection, produces an exuberant basilar meningeal inflammation with vasculitis, hydrocephalus, and tuberculomas that collectively generate a high rate of seizures during the acute illness and chronic post-meningitic epilepsy that often proves drug-resistant because of the diffuse structural brain damage from which it arises.
Brain Tumor-Related Epilepsy
Brain tumor-related epilepsy encompasses a spectrum of clinical presentations reflecting the diverse pathological and anatomical characteristics of the tumors that cause it, from the chronic, well-controlled focal epilepsy of the young adult with a long-standing low-grade glioma to the new-onset focal or generalized seizures that herald the presentation of a rapidly expanding glioblastoma in an older adult and that may be the first manifestation of a previously unsuspected malignancy. The molecular biology of tumor-related epilepsy has advanced substantially with the identification of tumor-specific molecular alterations that directly influence epileptogenicity, most notably the IDH1 and IDH2 mutations that are characteristic of lower-grade gliomas and that produce an oncometabolite, two-hydroxyglutarate, that inhibits normal enzymatic function and may directly influence neuronal excitability and seizure threshold in the peritumoral cortex.
The epileptogenicity of brain tumors is determined by a complex interaction between tumor biology, including its invasiveness, rate of growth, molecular characteristics, and neurotransmitter release properties, and the characteristics of the cortical tissue in which it is embedded, including the susceptibility of the peritumoral cortex to hyperexcitability from the biochemical changes imposed by the tumor microenvironment. Glutamate release from tumor cells through the system xCT cystine-glutamate transporter, which is overexpressed in gliomas to support cystine uptake for glutathione biosynthesis and releases glutamate as a stoichiometric exchange partner, creates perilesional extracellular glutamate concentrations that are sufficient to excite neighboring neurons, impair AMPA receptor desensitization, and potentially cause excitotoxic neuronal injury at the tumor periphery. The disruption of the extracellular potassium buffering capacity of peritumoral astrocytes, which fail to maintain the normal potassium spatial buffering that prevents post-ictal extracellular potassium accumulation from reaching seizure-triggering concentrations, contributes to the recurrent seizure susceptibility of the peritumoral cortex.
The management of brain tumor-related epilepsy requires an integrated oncological and epileptological approach that addresses both adequate tumor control and optimal seizure management while carefully considering the interactions between antitumor therapies and antiseizure medications. The surgical resection of epileptogenic tumors, which for low-grade glioneuronal tumors including ganglioglioma and dysembryoplastic neuroepithelial tumor aims for complete gross total resection of the tumor including the surrounding epileptogenic cortex identified through intraoperative electrocorticography, achieves seizure freedom in approximately sixty to ninety percent of appropriately selected patients, representing the most effective single intervention for tumor-related epilepsy. The selection of antiseizure medications for tumor-related epilepsy must account for the pharmacokinetic interactions between antiseizure medications and chemotherapy agents, with the enzyme-inducing antiseizure medications including phenytoin, carbamazepine, and phenobarbital reducing the plasma concentrations of multiple chemotherapy agents through cytochrome P450 induction, potentially compromising antitumor efficacy and making the non-enzyme-inducing medications including levetiracetam, lamotrigine, and lacosamide the preferred antiseizure agents in the oncological setting.
The palliative management of epilepsy in patients with progressive brain tumors that are not amenable to curative resection focuses on optimizing seizure control to maintain the best possible quality of life in the context of an advancing neurological illness. As brain tumor progression produces increasing edema, mass effect, and cortical infiltration, seizure frequency and severity often increase and the response to additional antiseizure medications frequently diminishes, producing a challenging clinical situation in which the goals of care must be explicitly discussed with patients and families to ensure that the intensity of antiseizure treatment remains aligned with the patient’s values and preferences. Corticosteroids, used primarily for the management of peritumoral edema in brain tumor patients, may provide temporary seizure improvement by reducing edema-related cortical irritation, providing a rapidly acting and practical adjunct to antiseizure medication optimization in the setting of tumor-related seizure worsening associated with increased edema.