Pearls & Oy-sters: Harnessing New Diagnostic and Therapeutic Approaches to Treat a Patient With Genetic Drug-Resistant Focal Epilepsy

Discussion

We present the case of a young man with DRFE on whom a genetic test was performed, given his age at onset and a strong family history of epilepsy. Identifying a DEPDC5 heterozygous pathologic variant prompted the pursuit of ultra-high field 7T-MRI that revealed a left superior frontal sulcus BOSD. The concordant electroclinical-radiological findings obviated the need for invasive intracranial EEG monitoring. MRLiTT of the presumed BOSD led to seizure freedom, albeit he is yet to attain the ideal 2-year seizure freedom cutoff.

Focal cortical dysplasias (FCDs) are localized regions of the malformed cerebral cortex and are frequently associated with epilepsy. Seizures associated with FCD are often resistant to ASMs.¹ In 2011, the ILAE Commissioned Task Force proposed a 3-tiered classification system for FCDs. In brief, FCD type I refers to isolated lesions with dyslamination of the neocortex, type II consists of isolated lesions characterized by cortical dyslamination and dysmorphic neurons, either without balloon cells (type IIa) or with balloon cells (type IIb), and type III lesions are defined by their association with another principal lesion (e.g., mesial temporal lobe sclerosis).² BOSD is a highly localized form of FCD type II in which the electrophysiologic, MRI, and pathologic abnormalities are confined to a single sulcus, maximal at the bottom-of-the sulcus.³

Cortical thickening, subcortical hyperintensity, blurring in the gray-white matter interface, and transmantle sign are considered major findings in the MRI diagnosis of FCD. However, many of these features are more common in the more conspicuous type IIb FCD.⁴ Other signs include elongation and straightening of the dysplastic sulcus and depression or unusual sulcation of the overlying cerebral surface.⁴ Recently, Tang et al. reported a “black line” sign on the 7T-weighted gradient echo sequence in 20 patients with DRFE with pathologically confirmed FCD, but exclusively seen in type IIb FCD.⁵ FCD type I and IIa are often far more subtle and frequently undetectable with conventional MRI. Besides, BOSDs, which can be type IIa or IIb, typically found in the frontal and parietal lobes, are most likely to be overlooked.⁶

Advanced 7T MRI sequences have been shown to offer a superior contrast-to-noise ratio in detecting previously unseen subtle lesions of FCDs. In a recent study, 67 patients with DRFE and nonlesional 3T MRI reported that an unaided visual review of 7T detected previously unappreciated subtle lesions in 22%; when aided by MRI postprocessing, the yield increased to 43%.⁷ However, morphometric analysis techniques have shown peak performance in detecting type IIb FCD with poor detection of the more subtle type I FCD. We show the value of 3D-EDGE at 7T in detecting subtle FCD. In most, the lesion location identified by 7T was identical or contained within the invasive EEG ictal onset zone. A complete resection of the 7T identified lesion resulted in a seizure-free outcome, with histopathology consisted mainly of FCD. In another study, 7T MRI detected new lesions in more than a third of 3T MRI nonlesional patients, confirmed and better characterized a 3T suspected lesion in one-third of patients, and helped exclude a 3T suspected lesion in the remainder.⁸ Our case illustrates that the inherently low signal-to-noise ratio 3D-EDGE sequence greatly benefits from the added signal obtained at ultra-high field MRI, such as 7T, and may be one of the more valuable sequences in detecting both type I and type II FCD.⁹ In centers where ultra-high field 7T MRI is unavailable, 3D-EDGE and other techniques, including a 3-dimensional fluid-attenuated inversion recovery and proton density MRI can be used to improve the detection of subtle FCDs.¹⁰

Increasing evidence suggests a strong genetic contribution to the pathogenesis of focal structural epilepsies, including FCDs.¹¹ For example, mutations in the Dishevelled, Egl-10, and domain-containing protein 5, a GTPase-activating protein, have recently emerged as a significant gene mutated in familial focal epilepsies associated with FCD IIa. Although genetic testing among children with epilepsy has become a part of routine testing, few studies have focused on genetic testing in adults.¹² A European study found a diagnostic yield of 23% with genetic testing in a cohort of adult patients with DRE.⁴ By contrast, a more recent study from the United States found only 10.9% of diagnostics with genetic testing.¹³ Nevertheless, genetic testing of adults with focal epilepsies can help guide clinical management decisions. The diagnostic finding could have clinical implications beyond epilepsy care, including counseling for family planning. That said, the cost of testing, delays in receiving results, and problems interpreting results are barriers to its routine use in adults with focal epilepsy. Therefore, selecting the appropriate patient population that requires diagnostic genetic testing is crucial. The yield is higher among patients with epileptic encephalopathies, childhood onset and a strong family history of epilepsy, and nonlesional cases.

Identifying structural lesions on high-resolution MRI can obviate the need for an invasive intracranial EEG monitoring, as in our patient. Ideal “skip candidates” for a 1-stage surgery typically have concordant clinical data, including semiology, EEG, and a characteristic epileptogenic lesion on MRI. Traditionally, open resection surgery has been the principal therapeutic option for treating FCD-associated DRFE. Newer minimally invasive therapies such as MRLiTT have also been reported in patients with FCDs.¹⁴ Similar to our case, previous studies had undergone 1-stage MRLiTT when the BOSD was distant from the eloquent cortex.¹⁵ This case sums up the cumulative impact of advancements in epilepsy-genetics, ultra-high field 7T MRI, and minimally invasive surgeries in allowing us to provide a safe and effective treatment for a patient with a genetic DRFE.