Epilepsy in women with gynecologic malignancies

Abstract

Women with gynecologic malignancies are a population with various risk factors for epilepsy. Gynecologic malignancies can substantially affect daily life, even if the tumor is well controlled. Gynecologic malignancies may cause brain metastasis, paraneoplastic neurological disorders, or leptomeningeal carcinomatosis, which potentially directly cause seizures and epilepsy. Moreover, metabolic disorders, central nervous system infections, cerebrovascular complications, and chemotherapeutic drugs can indirectly induce ictus. Radiotherapy of brain metastases can also lead to seizure and epilepsy. Understanding these pathogenic mechanisms may provide novel viewpoints or methods for diagnosis, prevention and treatment of epilepsy associated with gynecologic malignancies. In this article, we extensively review the related literature regarding potential aetiologies, their mechanisms, clinical features, diagnosis and treatment.

Keywords::

• antiepileptic drugs
• brain metastasis
• CNS infection
• cerebrovascular complications
• chemotherapeutic drug
• epilepsy
• gynecologic malignancy
• leptomeningeal carcinomatosis
• metabolic disorder
• paraneoplastic neurological disorder

Financial & competing interests disclosure

This manuscript was supported by the National Natural Science Foundation Project (81271445 and 81201003) and the Found for PAR-EU Scholars program. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Women with gynecologic malignancies may develop epilepsy. Gynecologic malignancies may cause brain metastasis, paraneoplastic neurological disorders, leptomeningeal carcinomatosis, metabolic disorders, CNS infections and cerebrovascular complications. These causes can provoke seizures or epilepsy, and chemotherapeutic drugs may also cause epileptiform activity.

• The pathogenesis of seizures associated with brain metastases from gynecological cancers include the following: the theory of denervation hypersensitivity, microvascular disorder, neurotransmitter abnormalities, pH and enzymatic abnormalities and radiation necrosis. The most common type of seizures is simple partial seizures with or without secondary generalization. Lamotrigine, valproic acid and topiramate are first-line treatments for seizures.

• Gynecological cancers are the second most frequent cancers associated with PND. Anti-Yo antibody is the most specific onconeural antibody, and anti-NMDAR antibody is the most specific antimembrane antibody. The most common type of seizures are generalized seizures, complex seizures or partial status epilepticus. Nonenzyme-inducing AEDs cause interactions between enzyme-inducing AEDs and immunosuppressive drugs.

• The pathogenesis of seizures caused by LM includes irritation of the adjacent brain areas, increased intracranial pressure and hydrocephalus, formation of neovascularization, secondary ischemia or infarction and the compression of brain structures. The most common type of seizures are generalized or partial seizures. Nonenzyme-inducing AEDs are favored because of their lack of interactions with chemotherapeutic drugs.

• Among all antitumor drugs, chemotherapeutic agents are the most frequent cause of seizures. Cisplatin-induced seizures are associated with drug neurotoxicity and electrolyte disturbance. Paclitaxel may cross the BBB, and its carrier is thought to be neurotoxic. Additionally, 5-FU may inhibit the Krebs cycle and lead to thiamine deficiency. All of these mechanisms can lead to encephalopathy and seizures. Generalized tonic–clonic seizures are the most common type. Immediate drug withdrawal and symptomatic treatment are necessary.

• The pathogenesis of seizures caused by metabolic disorders is mainly associated with electrolyte disturbances caused by antitumor drugs. Seizures caused by metabolic disturbances usually occur after chemotherapeutic drug infusion, and the most common type is generalized tonic–clonic seizures. Immediate drug withdrawal and symptomatic treatment are required.

• Gynecologic malignancies may cause ischemic or hemorrhagic cerebrovascular complications. Both of these complications can lead to seizures; however, different pathogeneses are involved in each. Generalized tonic–clonic seizures is the most common type. For early seizures, there is no need for antiepileptic treatment, whereas for late seizures, antiepileptic treatment is necessary.

• The pathogenesis of CNS infections that lead to seizures include pathogens that affect signal transmission and nutrition cycles. There is no need to treat early seizures. However, for late seizures with chronic or recurrent infections, if seizures occur during the period of active infection, then long-term antiepileptic treatment is not necessary. If seizures appear after the infection is controlled, long-term antiepileptic therapy is required.

• Diagnosis is divided into the following two parts: whether the seizure is epileptic is determined, and the secondary cause is identified. The time period of the seizures, type of seizures, concomitant symptoms and laboratory test, and findings of radiological examination are important for accurate diagnoses.

• Nonenzyme-inducing AEDs are recommended for this disease. Levetiracetam, gabapentin, lamotrigine, topiramate and pregabalin are first-line AEDs. Most patients start using one agent.

Notes