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\begin{document}

\title{BRAF inhibition efficacy in drug-refractory epilepsy}



\author[1]{Marta Perez-Somarriba}%
\author[2]{Vicente  Santa-María López  }%
\author[1]{Ofelia Cruz Martinez}%
\author[1]{Jordi Muchart}%
\author[1]{Nagore Gene}%
\author[2]{Jose Hinojosa}%
\author[1]{Veronica Gonzalez}%
\author[1]{Andres Morales La Madrid}%
\affil[1]{Hospital Sant Joan de Deu}%
\affil[2]{Hospital Sant Joan de Déu}%


\vspace{-1em}



  
  \date{May 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Low-grade gliomas (LGG) are the most frequent pediatric tumors
associated with epilepsy. Molecular sequencing analyses have defined the
genomic landscape of these tumors leading to the use of targeted
therapies, which have proven to be efficacious. Ongoing clinical trials
are testing the incorporation of these drugs, especially in unresectable
LGG that progress after standard treatment. Nevertheless, this strategy
is not extended in the field of tumor-induced epilepsy. We present a
patient with drug-resistant epilepsy secondary to a BRAF V600E-mutated
ganglioglioma treated with dabrafenib who showed a dramatic radiological
and clinical response with marked improvement in her quality of life.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Low-grade gliomas can appear in any region of the neuroaxis. When
located in particular areas of the brain, seizures can be a common
manifestation at diagnosis. Characteristically, temporal-mesial and
insular lobe areas tend to harbor such lesions (1). Not infrequently,
tumor-associated epilepsy may be hard to control and even refractory to
multiple antiepileptic drugs (AED). In the context of long-term epilepsy
associated tumors (LEATS), extensive neurosurgical interventions are
usually necessary to improve seizures control (2). Quality of life of
children and adolescents under multiple AED and/or with post-surgical
neurologic sequelae must be taken into consideration when proposing a
treatment plan for these challenging patients. Frequently, these tumors
tend to present an aberrant activation of MAPK signaling either through
a \emph{BRAF} tandem duplication or \emph{V600E} mutation. The
development and introduction of oral targeted therapies
including\emph{BRAF} inhibitors are changing the treatment paradigm for
these patients. However, its clinical efficacy in tumor-associated
epilepsy has not been reported.

\textbf{Case report:}

A previously healthy 12-year-old girl presented with a 12-month history
of intermittent right facial paresthesias which occasionally extended to
the right superior and inferior limbs, associated with variable
tonic-clonic movements, headaches, and aphasia. Video-EEG monitoring
showed left temporal/parietal ictal activity. A brain and spine magnetic
resonance imaging (MRI) identified a lesion involving the left insular
cortex and frontal operculum with extension into the deep white matter
suspicious of low-grade glioma (Fig1A, 1B). The patient was started on 3
different AED without efficacy in seizures control. Furthermore, and
secondary to her poor controlled epilepsy, she developed panic attacks
and symptoms of anxiety and depression, isolating herself at home from
friends and family. Ten days after the first scan, a functional MRI for
language localization with diffuse tensor imaging (DTI) was performed.
The lesion had significantly increased in size (Fig1C) and depicted a
close relationship with language areas and major white matter tracts
(arcuate fasciculus and corticospinal tract, Fig1D). Because of the high
risk associated with a radical surgery, a stereotactic biopsy was
performed without complications. The pathology review was consistent
with a WHO grade 1 ganglioglioma. The \emph{BRAF p.V600E} mutation, in
addition to monoallelic \emph{CDKN2A} deletion was identified by using
droplet digital PCR (ddPCR).

Treatment was initiated with dabrafenib at 150 mg BID. A few weeks into
therapy, seizures frequency decreased and two months later, they
stopped. After 4 months on dabrafenib, a follow-up MRI showed no
evidence of disease (Fig2). After 14 months, AED were discontinued with
no clinical signs nor epileptic activity in the EEG. Anxiety and
depression symptoms decreased, and the patient was able to go back to
her normal activities including school and sports. Therapy was overall
well tolerated. However, because of fatigue and headaches, the dosage
had to be decreased progressively to 75 mg BID with further good
tolerance and compliance. She is still in complete remission and
seizures free 30 months after diagnosis.

\textbf{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.\emph{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
using\emph{BRAF} inhibitors in the treatment of unresectable \emph{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
of\emph{BRAF} inhibitors in the context of intractable epilepsy has been
suggested but not previously reported(6). Interestingly, Ko \emph{et
al}developed a mouse model demonstrating that the presence of \emph{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 \emph{BRAF} inhibition may be
considered in patients with persistent post-surgical seizures
when\emph{BRAF} 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 \emph{BRAF} inhibition
should be taken into consideration in the treatment of refractory
epilepsy secondary to an unresectable \emph{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.

\textbf{Conflict of interest:} Authors declare no conflict of interest.

\textbf{References:}

1. Ruda R, Soffietti R. What is New in the Management of Epilepsy in
Gliomas? Curr Treat Options Neurol. 2015;17(6):351.

2. Mulcahy Levy JM, McMahon M. Linking brain tumors and epileptic
seizures. Nature Medicine. 2018;24(11):1638-9.

3. Holthausen H, Blumcke I. Epilepsy-associated tumours: what
epileptologists should know about neuropathology, terminology, and
classification systems. Epileptic Disord. 2016;18(3):240-51.

4. Luzzi S, Elia A, Del Maestro M, Elbabaa SK, Carnevale S, Guerrini F,
et al. Dysembryoplastic Neuroepithelial Tumors: What You Need to Know.
World Neurosurg. 2019;127:255-65.

5. Lassaletta A, Zapotocky M, Mistry M, Ramaswamy V, Honnorat M,
Krishnatry R, et al. Therapeutic and Prognostic Implications of BRAF
V600E in Pediatric Low-Grade Gliomas. J Clin Oncol. 2017;35(25):2934-41.

6. Phi JH, Kim SK. Clinical Pearls and Advances in Molecular Researches
of Epilepsy-Associated Tumors. J Korean Neurosurg Soc.
2019;62(3):313-20.

7. Blumcke I, Budday S, Poduri A, Lal D, Kobow K, Baulac S. Neocortical
development and epilepsy: insights from focal cortical dysplasia and
brain tumours. The Lancet Neurology. 2021;20(11):943-55.

8. Luyken C, Blumcke I, Fimmers R, Urbach H, Elger CE, Wiestler OD, et
al. The spectrum of long-term epilepsy-associated tumors: long-term
seizure and tumor outcome and neurosurgical aspects. Epilepsia.
2003;44(6):822-30.

9. Huberfeld G, Vecht CJ. Seizures and gliomas--towards a single
therapeutic approach. Nat Rev Neurol. 2016;12(4):204-16.

10. Battaglia DI, Gambardella ML, Veltri S, Contaldo I, Chillemi G,
Veredice C, et al. Epilepsy and BRAF Mutations: Phenotypes, Natural
History and Genotype-Phenotype Correlations. Genes (Basel). 2021;12(9).

11. Slegers RJ, Blumcke I. Low-grade developmental and epilepsy
associated brain tumors: a critical update 2020. Acta Neuropathol
Commun. 2020;8(1):27.

12. Stone TJ, Rowell R, Jayasekera BAP, Cunningham MO, Jacques TS.
Review: Molecular characteristics of long-term epilepsy-associated
tumours (LEATs) and mechanisms for tumour-related epilepsy (TRE).
Neuropathol Appl Neurobiol. 2018;44(1):56-69.

13. Xing H, Song Y, Zhang Z, Koch PD. Clinical Characteristics of BRAF
V600E Gene Mutation in Patients of Epilepsy-Associated Brain Tumor: a
Meta-analysis. J Mol Neurosci. 2021;71(9):1815-24.

14. Marucci G, de Biase D, Visani M, Giulioni M, Martinoni M, Volpi L,
et al. Mutant BRAF in low-grade epilepsy-associated tumors and focal
cortical dysplasia. Ann Clin Transl Neurol. 2014;1(2):130-4.

15. Perez JPM, Muchart J, Lopez VS, Capella MS, Salvador N, Jaume SP, et
al. Targeted therapy for pediatric low-grade glioma. Childs Nerv Syst.
2021.

16. Koh HY, Kim SH, Jang J, Kim H, Han S, Lim JS, et al. BRAF somatic
mutation contributes to intrinsic epileptogenicity in pediatric brain
tumors. Nat Med. 2018;24(11):1662-8.

\textbf{Figure legends:}

Figure~1.~

Initial MRI. A: axial 3D T1 with gadolinium, B: coronal FLAIR
T2.~Tumefactive~white matter lesion with gadolinium enhancement (A) and
subtle cortical component with

peripheral edema (B). A low-grade~glioma~was suspected.

MRI study 10 days later. C: MPR 3D T1 with~tractography~of
the~pyramidal~tract and language functional MRI (BOLD) study. D: coronal
FLAIR T2. This second study was

performed to depict anatomic landmarks of the lesion with
the~pyramidal~tract (blue in C) and language areas (yellow-orange areas
in C). More tumefaction and edema

was also found in just 10 days (D).



Figure 2.

\begin{enumerate}
\tightlist
\item
  Axial 3D T1 with gadolinium. MRI before stereotactic biopsy.
\item
  Axial 3D T1 with gadolinium 4 months after treatment. The lesion has
  almost disappeared and there isn't any enhancement.
\item
  Axial 3D T1 with gadolinium 8 months after treatment shows the same
  findings as in B.
\end{enumerate}\selectlanguage{english}
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