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.