Discussion:
Long-term epilepsy-associated tumor (LEAT) is a challenge for pediatric epilepsy teams. This condition and the co-morbidities secondary to the lesion and associated with its treatment, result in long-term disabilities, psychosocial difficulties, and poor quality of life for these patients (2, 3).
Ganglioglioma and dysembryoplastic neuroepithelial tumor (DNET) are the most common tumors identified in LEAT patients that undergo surgery for seizures control, followed by other low-grade gliomas (1, 2, 4, 5). The co-existence of these LGG with focal cortical dysplasia (FCD) has been commonly described in LEATs. It has been suggested that the coincidence of both entities, in addition to the temporal lobe and neocortical location in younger patients at the onset of symptoms contribute to chronic and intractable epilepsy (3, 6, 7). Tumor directed therapies, such as chemotherapy or irradiation have been reported in a few case series without major impact on this condition (3, 8, 9). Therefore, in order to improve seizures control, complex neurosurgical interventions may be needed.
Dramatic technological advances in recent years have expanded our knowledge of the molecular landscape of pediatric brain tumors, moving the field towards precision diagnostics and targeted therapies.BRAF V600E mutation is identified in approximately 40% of LGG (4, 5, 10). Particularly, pleomorphic xanthoastrocytomas followed by gangliogliomas and DNETs harbor this mutation in almost 75%, 50%, and 25% respectively (6, 11-13). Of note, it has been also identified in FCD(14).
Remarkable clinical and radiological responses have been reported usingBRAF inhibitors in the treatment of unresectable BRAF V600E mutated pediatric gliomas. In addition, several phase I and II clinical trials in children have demonstrated its effectiveness and safety with an acceptable toxicity profile. Consequently, its use is increasing with promising results (5, 15). However, the use ofBRAF inhibitors in the context of intractable epilepsy has been suggested but not previously reported(6). Interestingly, Ko et aldeveloped a mouse model demonstrating that the presence of BRAF V600E somatic mutation during early brain development contributes intrinsically to epileptogenesis(16). Therein, intraventricular vemurafenib was used, resulting in seizures control. Subsequently, other authors have supported the hypothesis that BRAF inhibition may be considered in patients with persistent post-surgical seizures whenBRAF mutated lesions are identified after surgery (2, 8, 16).
In our patient, and because of the high risk of sequelae secondary to the tumor resection, we opted for starting treatment with dabrafenib. She presented a spectacular radiologic and most importantly clinical response, being able to recover her normal daily activities, without major toxicities. Of note, her seizures vanished, allowing the withdrawal of the AED.
This case is a good proof of principle that BRAF inhibition should be taken into consideration in the treatment of refractory epilepsy secondary to an unresectable BRAF V600E mutated LGG.
Additionally, because of the accumulated experience in the indication and management of these drugs, we suggest that pediatric oncologists should be involved in epilepsy units when discussing tumor-associated seizures.
Conflict of interest: Authors declare no conflict of interest.