SUMMARYPurpose: Focal cortical dysplasias (FCD) are localized regions of malformed cerebral cortex and are very frequently associated with epilepsy in both children and adults. A broad spectrum of histopathology has been included in the diagnosis of FCD. An ILAE task force proposes an international consensus classification system to better characterize specific clinicopathological FCD entities.

he tuberous sclerosis complex (tsc), a multisystem, autosomal dominant disorder affecting children and adults, results from mutations in one of two genes, TSC1 (encoding hamartin) or TSC2 (encoding tuberin) (see the Glossary). First described in depth by Bourneville in 1880, 1 TSC often causes disabling neurologic disorders, including epilepsy, mental retardation, and autism. Additional major features of the disease include dermatologic manifestations such as facial angiofibromas, renal angiomyolipomas, and pulmonary lymphangiomyomatosis. TSC has a wide clinical spectrum of disease, and many patients have minimal signs and symptoms with no neurologic disability. With the discovery of the two genes responsible for TSC and insights derived from observations in Drosophila melanogaster models, our understanding of the pathogenesis of this disorder has progressed rapidly during the past decade. Clinical trials predicated on the cellular targets of hamartin and tuberin are under way. Clinic a l Fe at ur es a nd Di agnosis The diagnostic criteria for TSC consist of a set of major and minor diagnostic features 2 (Table 1). Cases meeting these criteria fulfill a clinical diagnosis of TSC; the results of molecular genetic testing of the TSC1 or TSC2 loci are currently viewed as corroborative. Many affected persons come to medical attention because of seizures or dermatologic manifestations. However, no single feature of TSC is diagnostic; thus, an evaluation that includes consideration of all clinical features is necessary to make the diagnosis. The clinical manifestations of TSC appear at distinct developmental points (Table 1). For example, cortical tubers and cardiac rhabdomyomas form during embryogenesis and thus are typical findings in infancy. Skin lesions are detected at all ages in more than 90% of patients with TSC. Hypopigmented macules (formerly known as ash-leaf spots) are generally detected in infancy or early childhood, whereas the so-called shagreen patch is identified with increasing frequency after the age of 5 years. Ungual fibromas typically appear after puberty and may develop in adulthood. Facial angiofibromas (Fig. 1A, 1B, and 1C), formerly called adenoma sebaceum, may be detected at any age but are generally more common in late childhood or adolescence. A subependymal giant-cell tumor of the brain may develop in childhood or adolescence. Renal cysts can be detected in infancy or early childhood, whereas angiomyolipomas develop in childhood, adolescence, or adulthood. Pulmonary lymphangiomyomatosis is found in adolescent girls or women with TSC. Clinical manifestations of TSC have variable penetrance. For example, two underrecognized groups of patients are asymptomatic adults with one or two minor features who meet the diagnostic criteria on the basis of a physical examination, radiographic findings, or both and asymptomatic women who give birth to a child with early neurologic manifestations of TSC.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes and is associated with hamartoma formation in multiple organ systems. The neurological manifestations of TSC are particularly challenging and include infantile spasms, intractable epilepsy, cognitive disabilities, and autism. Progress over the past 15 years has demonstrated that the TSC1 or TSC2 encoded proteins modulate cell function via the mTOR signaling cascade and serve as keystones in regulating cell growth and proliferation. The mTOR pathway provides an intersection for an intricate network of protein cascades that respond to cellular nutrition, energy levels, and growth-factor stimulation. In the brain, TSC1 and TSC2 have been implicated in cell body size, dendritic arborization, axonal outgrowth and targeting, neuronal migration, cortical lamination, and spine formation. Antagonism of the mTOR pathway with rapamycin and related compounds may provide new therapeutic options for TSC patients.

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods: Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. Results: Only two changes were made to clinical diagnostic criteria reported in 2013: "multiple cortical tubers and/or radial migration lines" replaced the more general term "cortical dysplasias," and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSCassociated neuropsychiatric disorders, and new medication approvals. Conclusions: Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.

Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.