Current management for epilepsy in tuberous sclerosis complex Paolo Curatolo, Roberta Bombardieri and Caterina Cerminara

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1 Current management for epilepsy in tuberous sclerosis complex Paolo Curatolo, Roberta Bombardieri and Caterina Cerminara Purpose of review This article reviews the most significant advances in the field of epilepsy associated with tuberous sclerosis complex, with emphasis on new advances in the knowledge of the pathophysiological mechanisms of epileptogenicity, progress in identifying the epileptogenic zone, and the rationale for surgical management in individuals with intractable seizures. Recent findings Advances in our understanding of the mechanisms and genetics underlying infantile spasms and catastrophic epilepsy associated with tuberous sclerosis complex may facilitate more effective interventions. Early effective seizure control could significantly reduce the adverse developmental effects of chronic epilepsy in tuberous sclerosis. Vigabatrin is the first choice in the short-term treatment of infantile spasms. Some individuals, however, develop seizures that remain highly intractable. The factors that influence the intractability of epilepsy associated with tuberous sclerosis complex remain poorly understood. Multimodality neuroimaging has improved detection of epileptogenic foci, allowing an increased number of individuals to be evaluated for resective surgery. Epilepsy surgery is often associated with significant improvement of the neurologic outcome. Summary Epilepsy in tuberous sclerosis seems to arise from the interaction between multiple areas, all of which have increased excitability and reduced inhibition. Understanding the mechanisms of epileptogenesis might increase the availability of development of a more specific and efficacious treatment. New evidence suggests that it is possible to noninvasively identify children with tuberous sclerosis who are highly likely to become seizure free following surgical treatment. Keywords intractable seizures, outcome, surgery, tuberous sclerosis Curr Opin Neurol 19: ß 2006 Lippincott Williams & Wilkins. Pediatric Neurology Unit, Department of Neurosciences, Tor Vergata University, Rome, Italy Correspondence to Paolo Curatolo, Pediatric Neurology Unit, Department of Neurosciences, Tor Vergata University, Via Montpellier no. 1, Rome, Italy Tel: ; fax: ; curatolo@uniroma2.it Current Opinion in Neurology 2006, 19: Abbreviations AED antiepileptic drug CNS central nervous system GABA g-aminobutyric acid MEG magnetoelectroencephalography TSC tuberous sclerosis complex ß 2006 Lippincott Williams & Wilkins Introduction Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with variable phenotypic expression, resulting from mutations in one of two genes, TSC1 on chromosome 9q34, and TSC2 on chromosome 16p13, respectively encoding for hamartin and tuberin. The disorder is inherited in an autosomal dominant fashion, although up to two-thirds of cases result from spontaneous genetic mutations. More than 1000 mutations are known to exist. Due to the large number of mutations, phenotype genotype correlations are of complex study. TSC2 mutations, however, are overrepresented in sporadic patients, and are associated with a more severe phenotype and neurologic deficits [1]. New schemes of central nervous system (CNS) malformations, which integrate molecular genetic and morphologic criteria, have resulted in a reclassification of TSC as a disorder of cellular lineage [2 ]. Present evidence suggests that CNS lesions of TSC are due to a developmental disorder of neurogenesis and neuronal migration; abnormalities of neuronal migration, cellular differentiation and excessive cellular proliferation all contribute to the formation of the various brain lesions of TSC, and to the production of very different neurological phenotypes, including seizures, mental retardation, learning disabilities and autism [3]. Epilepsy is the most common presenting symptom and the most common medical problem in TSC. The majority of children with TSC have onset of seizures during the first year of life, and up to one-third of them will develop infantile spasms. Seizures have a focal or multifocal origin with a topographic correspondence between electroencephalogram (EEG) foci and magnetic resonance imaging (MRI) high signal lesions, demonstrating the preponderant role of cortical tubers as epileptogenic foci [3]. Seizures are often resistant to antiepileptic drugs (AEDs) and may have a negative impact on the child s neurocognitive development [4 ]. 119

2 120 Developmental disorders In this article we review the pathophysiological mechanisms of epileptogenicity associated with TSC, new advances in the identification of the epileptogenic foci, and the rational for surgical management in individuals with drug-resistant seizures. Brain lesions The TSC1/TSC2 complex plays an important role during cortical development and growth control. At distinct stages of CNS development, including morphogenesis, cell adhesion/migration, and cell fate determination, a precise interaction of tuberin and hamartin appears critical. Gene mutations in either of the two TSC genes influence neural precursors between weeks 7 and 20 of gestation to result in disrupted cell division, abnormal cell differentiation, dysregulated cell size control and abnormal cellular migration [5 ]. As a consequence of impaired hamartin and tuberin functions, the mammalian target of the rapamicin pathway is disrupted, resulting in abnormal proliferation of a subpopulation of precursor cells [6 ]. Pathologically, tubers are characterized by disorganized cortical laminations, aberrant dendritic arbours and axonal projections, astrocitic proliferations and abnormal cell morphology, including dysplastic/heterotopic neurons and giant cells. Giant cells are the hallmark histologic cell type within tubers that are unique to TSC. Despite progress in understanding molecular pathogenesis of tuber formation, the link between loss of function of hamartin and tuberin, and the change from a normal progenitor cell to a giant cell is still unknown [5,6 ]. Ninety percent of individuals with TSC exhibit at least one supratentorial brain lesion, including cortical tubers, subependimal nodules, subependimal giant cell astrocytomas, white matter linear migration lines, and transmantle cortical dysplasia. Brain imaging structural abnormalities observed in TSC can occur due to disturbed neural migration, leading to changes in the number, size and thickness of cortical gyri, heterotopic neuronal aggregates and variable degrees of cortical cytoarchitectural disorganization [7 ]. Association with hemimegalencephaly, representing a more regional tissue dysplasia, has also been rarely reported [7,8]. This is not surprising since TSC and hemimegalencephaly share histopathologic similarities, possible common pathogenetic mechanisms, and are now both considered disorders of cellular lineage [2 ]. Recent computational morphometry MRI studies suggest that bilateral symmetric deficits in subcortical gray matter and intrahemispheric white matter could be considered markers of TSC [9 ]. Tubers are most often located in the frontal lobe. The density of tubers, however, is greatest in the parietal lobes. Cognitive and behavioural phenotypes TSC has a high prevalence of cognitive and behavioural difficulties with a great variability in the occurrence of these problems between individuals, even in monozygotic twins [10,11 ]. Early onset of seizures (less than 3 years of age; infantile spasms) and intractable seizures appear to be associated with an increased risk of neurodevelopmental and cognitive problems [12 ]. Neither seizures nor cortical tubers, however, are necessary or sufficient to explain the cognitive and behavioral risk associated with TSC [12,13]. Features of autistic spectrum disorders are present in about 25% of patients. The co-occurrence of TSC and autism is well recognized, although no definite reason has been determined for the association [14]. The majority of reported TSC children with autistic-like behaviour have experienced infantile spasms and are mentally retarded [15 ]. Autism spectrum disorders appear to be more common in infants with frontal and temporal tubers, and it has been suggested that an early dysfunction in the associative areas owing to the location of cortical tubers may be responsible for the autistic features. Recent evidence suggests that generalized epilepsy during early development and functional deficits in the temporal lobes of the brain may be associated with autism. An alternative explanation is that the behavioural phenotype seen in TSC reflects more direct effects of an abnormal genetic program. According to the experience of the present authors, autistic spectrum disorders are more common in individuals with TSC2 mutation. The TSC2 gene product tuberin is highly expressed in brain regions involved in the behavioural phenotypes of the autistic disorder. Although a close proximity of the TSC2 gene and an autistic spectrum disorder susceptibility gene has been reported, at present there are no data to support a linkage between these two genes [14,15 ]. Epileptogenesis and pathophysiological mechanisms Immunohistochemical and molecular analysis have indicated that the neuronal populations within cortical tubers might have intrinsic epileptogenicity, and actively participate in the generation of partial seizures, through the release of neurotransmitters or neuromodulators into the adjacent brain tissue [16]. Epileptogenesis in TSC may be caused by an imbalance of decreased inhibition secondary to molecular changes of g-aminobutyric acid (GABA) receptors in giant cells and dysplastic neurons, and increased excitation secondary to molecular changes of glutamate receptors in dysplastic neurons. The deficiency of GABAergic interneurons may explain the early onset and severity of seizures in TSC. The importance of GABAergic inhibitory system in TSC has been confirmed by the special efficacy of vigabatrin

3 Tuberous sclerosis complex Curatolo et al. 121 in the treatment of infantile spasms in tuberous sclerosis [17]. Vigabatrin is able to completely stop infantile spasms in 95% of infants with tuberous sclerosis, supporting the current recommendation for the use of this drug as firstline therapy in infantile spasms due to TSC. Unfortunately, although the efficacy is well established, its use has been partly limited due to a possible ophthalmologic toxicity and the occurrence of a GABAergic retinopathy [18]. There are probably other different mechanisms of epileptogenesis in TSC. Astrocytes can have a pivotal role in the generation of hyperexcitability and seizures in many localization-related epilepsy cases and astrocyte dysfunction can be specifically implicated in the pathogenesis of epilepsy associated with TSC. Recent findings by magnetic resonance spectroscopy have demonstrated that the presence of subtle disorganized white matter can be more diffuse than expected and may be undetectable on conventional MRI [19 ]. Treatment of seizures in TSC is similar to that of epilepsy from other causes. Topiramate, lamotrigine, oxacarbazetine, and levetiracetam have all been found to be effective and well tolerated in small populations of individuals with TSC and epilepsy [20 ]. Some individuals become seizure free and are eventually tapered off medications. Others develop seizures that remain highly intractable despite the use of new AEDs. According to our experience, seizures are medically intractable in up to 40% of patients with early onset of epilepsy. Most children have multiple seizure types and multiple independent spikes on the surface EEG. Furthermore, during the course of disease, epileptogenic foci may shift from one epileptogenic tuber to another [1]. In these cases polytherapy only has a minimal impact on seizure control, and should be reserved for selected patients for whom surgical treatment is not a viable option. The exact mechanism involved in drug resistance and the factors that influence the intractability of epilepsy in TSC are poorly understood. Refractory epilepsy phenotype in TSC can be associated with the expression of both multidrug resistance MDR-1 and multidrug resistance protein MRP-1 transporters in epileptogenic cortical tubers [21]. Identification of the epileptogenic tuber Successful surgical treatment rests on an accurate localization of the epileptogenic region and the definition of its spatial and functional relationship with eloquent cortex. Long-term ictal video-eeg monitoring is essential and can be complemented by other functional imaging studies. Ninety percent of patients with TSC show at least one region of consistent interictal epileptiform activity [22 ]. These patients, therefore, could be considered as candidates for epilepsy surgery. Most children with TSC, however, have multiple potentially epileptogenic tubers, rendering localization challenging, and they are rejected as possible surgical candidates. Advances in functional neuroimaging techniques are changing this view, allowing an increased number of TSC patients to be evaluated for resective surgery. Converging clinical, EEG and MRI data, complemented by magnetoencephalography (MEG) imaging and interictal positron emission tomography (PET) are crucial in planning surgical resection of the epileptogenic focus. Concordant preoperative surface and MRI findings are good predictors of seizure outcome [23 ]. MEG contributes to information from EEG and MRI for localizing epileptogenic zones in children with TSC. A single MEG cluster predicts a primary epileptogenic zone, but it is a rare finding in TSC patients. A more frequent finding is represented by multiple MEG clusters of six or more spike sources, partially overlapping multiple prominent tubers and indicating potentially epileptogenic zones. Interictal MEG studies alone, however, could not differentiate a primary epileptogenic zone or a potential epileptogenic zone among multiple clusters [24 ]. Other techniques have recently been applied in an effort to identify epileptogenic zones. A preliminary work has suggested that single-voxel proton spectroscopy performed from the tubers could be a useful noninvasive method to evaluate lesions responsible for generating seizures [25]. Furthermore, recent evidence shows that PET with a-methyl-l-tryptophan might identify the seizure-causing cortical tubers in some individuals with TSC, enhancing the confidence of patient selection for successful epilepsy surgery [26 ]. Epilepsy surgery Surgical management of epilepsy is challenging in individuals with TSC because the epileptogenic tubers are often extratemporal, multifocal and bilateral, and can overlap with eloquent cortex. For these reasons, surgical treatment of refractory epilepsy in children with TSC is usually restricted to patients having an ictal onset associated with a tuber located in noneloquent cortex. In TSC patients with concordant clinical electrophysiological and imaging data, single stage surgery is safe and effective. Resecting concordant MRI and EEG abnormalities offer high (about 90%) seizure freedom, comparable to other focal etiologies [23 ]. The presence of only unifocal seizures and normal neurologic development at the time of tuberectomy/lobectomy is associated with excellent long-term seizure control [27].

4 122 Developmental disorders Focal resection of epileptogenic tuber(s) can result in seizure freedom in 78% (median) of the published patients (range %) and definite improvement in reduction of seizure frequency in 20% (range 10 45%) of patients. Improvement in quality of life of these patients, related to either a reduction in seizure frequency and or reduction in medications, is experienced by 95% of patients [28 ]. This is a remarkable result, given the severity of the epileptic syndromes associated with TSC and the high epileptogenicity of the abnormal cortex. Multiple or bilateral seizure foci are not necessarily a contraindication to surgery in selected TSC patients [29 ]. In selected patients with bilateral tuber seizure foci, aggressive bilateral surgery can be safe and effective. Although multiple tubers are frequently detected, epileptogenic activity can often be localized to one or two tuberal regions and ictal EEG patterns can remain remarkably stable over time. In these patients, particularly when severely disabling seizures and progressive developmental delay are present, a staged surgical approach can produce a worthwhile improvement in seizure control, cognitive function, behaviour, and overall quality of life. The recently proposed technique of multistaged surgery may offer an option to complicated patients with multiple epileptogenic tubers in distant brain regions [29,30]. This multistage surgical approach has been useful in identifying both primary and secondary epileptogenic zones in TSC patients with multiple tubers. In our experience, patients with multiple cortical or subcortical tubers/subepedymal nodules should not be denied a resective surgical option as long as these patients show concordance in localization from seizure semiology, ictal/interictal EEG, intraoperative electrocorticography and a prominent MRI lesion on presurgical investigations. For patients with intractable seizures arising from well mapped epileptogenic zones that may be located in or adjacent to the eloquent cortex, stereotactic radiosurgery could have the potential to represent a suitable alternative to resective surgery [28 ]. In the remaining patients, if medications have failed and surgery is not an available option, the ketogenic diet may be considered. The diet may have a role in children with mixed seizures and a previous history of infantile spasms determining more than 50% reduction in their seizures in 92% of children with limited side effects [31 ]. Conclusion Epilepsy in TSC seems to arise from the interaction between multiple areas all of which have increased excitability or reduced inhibition. Defining the cellular and molecular characteristic of the cortical tubers can improve our understanding of the initiation and the propagation of epileptic discharge. There is sufficient evidence to suggest that we can now identify noninvasively TSC children who are highly likely to become seizure free following surgical treatment. From this point of view, optimizing the time of surgery could offer new hope for a better quality of life for patients, allowing prevention of generalized and catastrophic epilepsy. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Curatolo P. Neurological manifestations. In: Curatolo P, editor. Tuberous sclerosis complex: from basic science to clinical phenotypes. London: Mac Keith Press; pp Sarnat HB. Integrative classification of morphology and molecular genetics in central nervous system malformations. Am J Med Genet 2004; 126: This is a new classification of CNS malformations that integrate molecular genetics and morphologic criteria. 3 Curatolo P, Verdecchia M, Bombardieri R. Tuberous sclerosis complex: a review of neurological aspects. Eur J Pediatr Neurol 2002; 6: Curatolo P, Bombardieri R, Verdecchia M, Seri S. Intractable seizures in tuberous sclerosis complex: from molecular pathogenesis to the rationale for treatment. J Child Neurol 2005; 20: The epileptogenesis in TSC, the pathophysiological mechanisms of seizures and possible factors that may influence intractability are revised. 5 Crino PB. Molecular pathogenesis of tuber formation in tuberous sclerosis complex. J Child Neurol 2004; 19: This experienced author reviews the mechanisms for tuber formation during brain development. 6 Scheidenhelm DK, Gutmann DH. Mouse models of tuberous sclerosis complex. J Child Neurol 2004; 19: The generation of mouse models advances our understanding of the function of the tuberin hamartin complex. 7 DiMario FJ Jr. Brain abnormalities in tuberous sclerosis complex. J Child Neurol 2004; 19: The CNS lesions and the morphometric abnormalities observed in brain imaging studies, the relationship between TSC and neuronal migration disorders. 8 Sakuma H, Iwata O, Ssaki M. Longitudinal MRI findings in a patient with hemimegalencephaly associated with tuberous sclerosis. Brain Dev 2005; 27: Ridler K, Suckling J, Higgins N, et al. Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex. J Child Neurol 2004; 19: Computational morphometry MRI studies found quantitative evidence of predominantly frontal distribution, and predominantly parietal density of tubers. 10 Asato M, Ardan A. Neuropsychiatric problems in tuberous sclerosis complex. J Child Neurol 2004; 19: Humphrey A, Higgins NP, Yates JRW, Bolton PF. Monozygotic twins with tuberous sclerosis discordant for the severity of developmental deficits. Neurology 2004; 62: This paper emphasizes the great variability of cognitive and behavioral abnormalities among TSC individuals. 12 O Callaghan F, Harris T, Johnson C, et al. The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child 2004; 89: The role of infantile spasms and cortical tubers in determining the cognitive outcome is reviewed.

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