HHE Neurology supplement 2018 - Page 9

neurology Managing refractory seizures in tuberous sclerosis complex TSC-related epilepsy is highly refractory and represents a challenge for clinicians. Recently, some therapies have proved to be effective, acting not only on seizures but also on the underlying mechanisms Romina Moavero MD Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University Hospital of Rome; Child Neurology Unit, Neuroscience and Neurorehabilitation Department, Bambino Gesù Children’s Hospital, Rome, Italy Paolo Curatolo MD PhD Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University Hospital of Rome, Italy Tuberous sclerosis complex (TSC) is a multisystem disease caused by the mutation in one of the two tumour suppressor genes TSC1 and TSC2. 1 It affects about 1 in 6000 newborns, and although it can affect multiple organs and systems (brain, skin, heart, kidneys, lungs, liver, eyes), neurological involvement is the cause of the major mortality and morbidity, above all in the paediatric age. 2 From a neuropathological point of view, patients with TSC might present with cortical/subcortical tubers, subependymal nodules, subependymal giant cell astrocytomas and white matter migration lines. 2 From a clinical point of view, neurological manifestations include epilepsy and its comorbidities, including cognitive disability, autism spectrum disorders, attention deficit hyperactivity disorder and other neuropsychiatric disorders. 2 Epilepsy is a very common manifestation, affecting up to 85% of subjects, and presenting in the first years of life in two thirds of subjects. 3 Early onset epilepsy can be in the form of infantile spasms or focal seizures, which can coexist or evolve into infantile spasms. The latter 9 HHE 2018 | hospitalhealthcare.com represent a significant risk factor for later refractory epilepsy because approximately 75% of patients with a history of infantile spasms will present with refractory seizures up to severe epileptic encephalopathies, including focal refractory seizures and a Lennox-Gastaut phenotype. 3 Epileptogenesis in TSC is a very long process, starting far before birth. Indeed, the mutation of TSC1/2 genes determines an overactivity of the mTOR (mammalian target of rapamycin) pathway, which is already evident during foetal life. 4 This early mTOR overactivation determines alterations of migration and orientation of neural cells, thus leading to abnormal cortical lamination and dendritic arborisation. 5 Abnormalities in this crucial pathway also include the disruption of GABAergic interneuron development as well as the regulation of glutamatergic function, thus meaning an imbalance between excitation and inhibition, which is a clear predisposing factor to epileptic seizures. 6 The early dysregulation of the mTOR pathway, causing altered migration and cell morphology, causes the formation of tubers. These are the hallmark of the pathology and can be already visible during prenatal life with foetal magnetic resonance imaging, and include different abnormal cells, such as dysplastic neurons and giant cells. 5 Tubers are dynamic lesions, and their continuous changes, both in pre- and postnatal life, can contribute to the establishment of extensive epileptogenic networks. 7 Tubers represent focal malformations of cortical development and are characterised by loss of the hexalaminar cortical architecture, presence of an excessive number of astrocytes, and by dysmorphic neurons and giant cells. 7 However, although tubers are the most clear lesions, and for which there is a documented link with epilepsy, many other structural and microstructural lesions are evident in TSC brains. In particular, mTOR alteration leads to focal dyslamination and isolated giant, cells even in the absence of major structural abnormalities, resulting in global and focal network alterations that might play a role in both epileptogenicity and abnormal neurodevelopment. White matter also appears to be extensively involved, with white matter migration lines detectable on conventional brain MRI as a result of abnormal migration. 2 However, normal appearing white matter can also be involved by microstructural changes, which are evident when diffusion