Status epilepticus in BRAF-related cardio-facio-cutaneous syndrome: Focus on neuroimaging clues to physiopathology

Abstract

Objective: Cardio-facio-cutaneous syndrome (CFC) is a genetic disorder due to variants affecting genes coding key proteins of the Ras/MAPK signaling pathway. Among the different features of CFC, neurological involvement, including cerebral malformations and epilepsy, represents a common and clinically relevant aspect. Status epilepticus (SE) is a recurrent feature, especially in a specific subgroup of CFC patients with developmental and epileptic encephalopathy (DEE) and history of severe pharmacoresistant epilepsy. Here we dissect the features of SE in CFC patients with a particular focus on longitudinal magnetic resonance imaging (MRI) findings to identify clinical-radiological patterns and discuss the underlying physiopathology.

Methods: We retrospectively analyzed clinical, electroencephalogram (EEG), and MRI data collected in a single center from a cohort of 23 patients with CFC carrying pathogenic BRAF variants who experienced SE during a 5-year period.

Results: Seven episodes of SE were documented in 5 CFC patients who underwent EEG and MRI at baseline. MRI was performed during SE/within 72 hours from SE termination in 5/7 events. Acute/early post-ictal MRI findings showed heterogenous abnormalities: restricted diffusion in 2/7, focal area of pcASL perfusion change in 2/7, focal cortical T2/FLAIR hyperintensity in 2/7. Follow-up images were available for 4/7 SE. No acute changes were detected in 2/7 (MRI performed 4 days after SE termination).

Significance: Acute focal neuroimaging changes concomitant with ictal EEG focus were present in 5/7 episodes, though with different findings. The heterogeneous patterns suggest different contributing factors, possibly including the presence of focal cortical malformations and autoinflammation. When cytotoxic edema is revealed by MRI, it can be followed by permanent structural damage, as already observed in other genetic conditions. A better understanding of the physiopathology will provide access to targeted treatments allowing to prevent long-term adverse neurological outcome.

Plain language summary: Cardio-facio-cutaneous syndrome is a genetic disorder that often causes prolonged seizures known as status epilepticus. This study has a focus on electroclinical and neuroimaging patterns in patients with cardio-facio-cutaneous syndrome. During these status epilepticus episodes, we found different abnormal brain imaging patterns in patients, indicating various causes like brain malformations and inflammation. Understanding these patterns could help doctors find specific treatments, protecting cardio-facio-cutaneous syndrome patients from long-term brain damage.

Keywords: BRAF; CFC; cardio-facio-cutaneous syndrome; focal brain edema; status epilepticus.

FIGURE 1

Pt1 Axial T2w image acquired before SE onset showed frontal CSF spaces and lateral ventricular enlargement, representing atrophic changes. Coronal FLAIR image acquired during post‐ictal phase (3 days after SE termination) showed cortical hyperintensity of right parietal and occipital lobes, with diffusion restriction. Pt2 Coronal T2w image acquired during perictal phase showed right temporal lobe swelling, with cortical and subcortical hyperintensity and diffusion restriction. Coronal T2w image acquired after perictal phase showed resolution of T2w hyperintensity and diffusion restriction; right temporal horn enlargement and reduced hippocampal volume were noted, as for mesial temporal sclerosis. Enlargement of frontal horns and third ventricule was evident, representing atrophic changes. Pt3 Coronal FLAIR image acquired before SE onset showed right hippocampal volume reduction and hyperintensity, representing mesial temporal sclerosis. Coronal FLAIR image acquired during SE showed right hippocampal hyperintensity (with no restricted diffusion).Coronal FLAIR image after the perictal phase showed mild frontal horns enlargement, representing atrophic changes. Pt4 Coronal FLAIR image acquired before SE onset showed punctate white matter hyperintensity. Coronal FLAIR image acquired during post ictalphase (1 day after SE termination) showed cortical swelling and hyperintensity of cingulate gyrus, without restricted diffusion. Complete resolution of cortical signal abnormalities was noted during follow‐up. Pt5 Coronal FLAIR image acquired before SE onset showed left temporal horn enlargement and reduced hippocampal volume, as for mesial temporal sclerosis. Frontal horns enlargement, more evident on the left side, was noted, representing atrophic changes. Axial pc‐ASL acquired during perictal phase showed an area of hypoperfused cortex in the left temporal lobe.

FIGURE 2

(A) Pt1: continuous right occipital spike and wave. (B) Pt2: continuous right temporal spike and waves. (C) Pt3: bifrontal theta activity sequences with spikes.

FIGURE 3

Possible etiologies in status epilepticus with different acute neuroimaging features and relationship between treatment and outcome.