FULL-LENGTH ORIGINAL RESEARCH
Epilepsy in TSC: Certain etiology does not mean certain prognosis *Aglaia Vignoli, *Francesca La Briola, *Katherine Turner, *Giulia Scornavacca, *Valentina Chiesa, *Elena Zambrelli, *Ada Piazzini, *Miriam Nella Savini, *†Rosa Maria Alfano, and *Maria Paola Canevini Epilepsia, 54(12):2134–2142, 2013 doi: 10.1111/epi.12430
SUMMARY
Aglaia Vignoli, MD is a Researcher in Child and Adolescent Neurology and Psychiatry at Epilepsy Center, San Paolo Hospital, University of Milan, Italy.
Purpose: Prevalence and long-term outcome of epilepsy in tuberous sclerosis complex (TSC) is reported to be variable, and the reasons for this variability are still controversial. Methods: We reviewed the clinical characteristics of patients with TSC who were regularly followed since 2000 at the San Paolo Multidisciplinary Tuberous Sclerosis Centre in Milan, Italy. From patient charts we collected data about age at epilepsy onset, seizure frequency and seizure type, history of infantile spasms (IS), epileptic syndrome, evolution to refractory epilepsy or to seizure freedom and/or medication freedom, electroencephalography (EEG) features, magnetic resonance imaging (MRI) findings, cognitive outcome, and genetic background. Key Findings: Among the 160 subjects (120 adults and 40 children), 116 (72.5%) had epilepsy: 57 (35.6%) were seizure-free, and 59 (36.9%) had drug-resistant epilepsy. Most seizure-free patients had a focal epilepsy (89.5%), with 54.4% of them drug resistant for a period of their lives. Epilepsy onset in the first year of life with IS and/or focal seizures was characteristic of the drug-resistant group of patients, as well as cognitive impairment and TSC2 mutation (p < 0.05). A small group of patients (7 patients, 4.4%) experienced a seizure only once; all of them had normal cognition. Significance: Although epilepsy management can be challenging in TSC, more than one third of patients had their seizures controlled: through monotherapy in 56% and by polytherapy in 32%. Moreover, 12% of the patients became seizure-free and were off medication. Identifying predictive features of epilepsy and cognitive outcome can ensure better management for patients with TSC and delineate genotype–phenotype correlations. KEY WORDS: Epilepsy, Tuberous sclerosis complex, Outcome, Prognostic factors.
Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystemic disease with variable expression. TSC occurs in at least one in 6,000 individuals (Crino et al., 2006) and is caused by a mutation in either the TSC1 Accepted September 20, 2013; Early View publication November 8, 2013. *Neurology Unit, Epilepsy Center – Neurology Unit 2, San Paolo Hospital, DISS University of Milan, Milan, Italy; and †Molecular Biology Department, San Paolo Hospital, Milan, Italy Address correspondence to Aglaia Vignoli, Epilepsy Center – Neurology Unit 2, San Paolo Hospital, DISS University of Milan, Via di Rudinı 8, 20142 Milan, Italy. E-mail: [email protected] Wiley Periodicals, Inc. © 2013 International League Against Epilepsy
or TSC2 gene. Roughly two thirds of TSC cases reported in mutational and epidemiologic studies are sporadic (simplex), whereas the remaining cases are familial (Jones et al., 1999). The TSC1/TSC2 complex plays an important role during cortical development and growth control through the hyperactivation of the downstream mammalian target of rapamycin (mTOR) pathway and the associated kinase signaling cascades and translational factors. Therefore, mutations of TSC genes potentially induce abnormal cell morphology, imbalance in excitation and inhibition, as well as alterations in network properties, providing a likely underlying substrate for epilepsy (Moavero et al., 2010).
2134
2135 Epilepsy in TSC Neurologic phenotype of TSC is highly variable, ranging from normal to severe, and consisting of refractory epilepsy, intellectual impairment, and psychiatric comorbidity. Although a clear phenotypic/genotypic correlation has not been found as of yet, it is globally accepted that patients with TSC1 gene mutations show a milder phenotype than patients carrying TSC2 gene mutations (Jentarra et al., 2011). TSC is one of the leading genetic causes of epilepsy, with a high incidence (about 85%) of patients with TSC affected by seizures, often refractory to antiepileptic treatment (Curatolo et al., 2008). Nevertheless the prevalence and long-term outcome of epilepsy in TSC has not been widely investigated. A wide population of patients with epilepsy in TSC was investigated retrospectively: the authors reported a wide spectrum of severity for epilepsy in TSC, ranging from seizure-free patients to severe drug-resistant epilepsies (ChuShore et al., 2010). The present study aims to review the clinical characteristics of epilepsy in the population of adult and pediatric patients followed regularly since 2000 at the San Paolo Hospital Tuberous Sclerosis Center in Milan, Italy.
Methods We reviewed the clinical records of all patients with TSC, regularly followed at San Paolo Hospital Tuberous Sclerosis Center, San Paolo Hospital, Milan, Italy, from January 2000 to June 2012. Of 160 individuals with an established diagnosis of TSC, according to the International criteria (Roach et al., 1998), 116 had epilepsy. Only patients with at least 1 year of follow-up participated in this study. We collected data from patient charts about age at epilepsy onset, seizure frequency and seizure type, history of IS, epileptic syndrome, evolution to refractory epilepsy or to seizure freedom and/or medication freedom, electroencephalography (EEG) features, magnetic resonance imaging (MRI) findings, cognitive outcome, and genetic background. Results of presurgical evaluation for drugresistant cases were also assessed, when performed. Seizure types were classified according to clinical semiology provided by description from a witness or when possible by video-EEG recording of the episode. Refractory epilepsy was defined as uncontrolled seizures after at least two first-line anticonvulsant medication trials (Kwan et al., 2009). Patients were considered seizure-free if they were without clinical seizures for at least 1 year, using the last clinical visit documenting seizure status as the end point of follow-up. Genetic testing of the TSC1 and TSC2 genes was performed on DNA extracted from peripheral lymphocytes using a standard protocol for all patients and their firstdegree relatives. Polymerase chain reaction (PCR) was used to amplify all exons of TSC1 and TSC2 genes. Negative patients for the first level of investigation were evaluated
with Multiple Ligation-dependent Probe Amplification test. Patients in which genetic analysis was inconclusive were classified as no mutation identified (NMI). Among 160 subjects (120 adults and 40 children), 31 (19.4%) were familial cases (17 TSC1, 13 TSC2, and 1 NMI). We divided patients into five groups according to intelligence quotient (IQ): (1) normal IQ with IQ > 85; (2) borderline intellectual functioning (BIF) with IQ from 84 to 71; (3) mild intellectual disability (ID) with IQ from 70 to 55; (4) moderate ID with IQ from 54 to 40, and (5) severe ID with IQ < 40 (American Psychiatric Association, 2000). Education was measured in years of schooling. As part of their clinical management, patients were evaluated through a psychiatric interview in order to assess possible Axis I and II disorders (American Psychiatric Association, 2000). All data collected were transferred into an electronic database and processed using the Statistical Package for the Social Sciences (SPSS, IBM, Chicago, IL, U.S.A.) for Macintosh version 19.0. Continuous variables were presented as mean and standard deviation (SD). Patients (seizure-free vs. drug resistant vs. no epilepsy) were compared on sociodemographic and clinical characteristics, using chi-square test for categorized variables and not normally distributed variables and one-way analyses of variance (ANOVA) with Bonferroni post hoc for variables with a normal distribution. In particularly, significance was determined among three groups of patients simultaneously: seizure-free versus drugresistant + seizure-free versus no epilepsy + drug-resistant versus no epilepsy. Variables (seizure-free vs. drug resistant) with a normal distribution were analyzed using independent sample twotailed Student t-tests. Results were considered statistically significant for p-values < 0.05 (two-sided). The institutional review board of San Paolo Hospital, Milan, approved the study.
Results Among the 160 patients (64 [40.0%] male, 96 [60.0%] female; mean age 29.6, range 1–74 years) presently followed for TSC at San Paolo Hospital, 116 had epilepsy (72.5%), whereas 7 (4.4%) presented only one isolated seizure. Table 1 shows demographic and clinical characteristics of the entire TSC population, and Table 2 refers to the TSC patients with epilepsy, respectively. The mean follow-up period was 3.5 years (range 1–29 years). In relation to epilepsy, patients were divided into four subgroups: seizure-free (57 patients, 35.6%), drugresistant epilepsy (59 patients, 36.9%), patients with only one seizure in their lives (7 patients, 4.4%), and no epilepsy (37 patients, 23.1%). Seizure-free patients Seizure-free patients were in the great majority adults (45/57), with a mean age of 31.6 years (SD 16.7). Mean age Epilepsia, 54(12):2134–2142, 2013 doi: 10.1111/epi.12430
2136 A. Vignoli et al. at TSC diagnosis was 13.2 years (SD 15.9). Mutation analysis demonstrated a TSC2 gene mutation in most cases (52.7%) and a TSC1 gene mutation in 33.3%, and NMI in 7.0%. In 10 cases (17.5%) there was a family history of TSC (7 TSC1; 3 TSC2). Cognitive profile revealed normal IQ in 43.9% (p < 0.05), BIF in 17.5%, mild ID in 12.3%, moderate ID in 14%, and severe ID in 12.3%. Moreover the mean level of education was 8.9 (SD 3.7) years. Neurologic examination was considered normal in 87.7% of cases, whereas a psychiatric disorder was diagnosed in 26.3% of patients. MRI findings demonstrated cortical tubers in 98.2% (with more than six tubers in 75.4%), subependymal nodules (SENs) in 75.4%, and subependymal giant astrocytoma (SEGA) in 12.3% of patients. Most patients in this group had a focal epilepsy (89.5%), and 35.1% of these patients experienced IS in their early life. A history of drug-resistant epilepsy was
experienced by 52.6% of patients, who successively went on to become seizure-free. Most of them were on monotherapy (56.1%), mainly on carbamazepine (21.0%) and valproic acid (12.3%). No patients were treated with vigabatrin. Patients were seizure-free for a mean period of 12.9 years (range from 1 to 49 years). The mean age at seizure control was 19.4 years (range from 7 months to 71 years). Three patients were seizure-free after epilepsy surgery (Engel class IA) (follow-up 7.5 years; range 1–14.5 years). Ten patients withdrew from therapy after a seizure-free period and seven of these patients are still seizure-free (follow-up 20–49 years). Considering epilepsy diagnosis, six of seven had focal epilepsy and one of seven had IS. Most (six of seven) had seizure onset in the first year of life (range 3 months to 9 years); five of seven subjects experienced IS in their epilepsy history. Six patients carried a TSC2 mutation, and NMI in one patient NMI.
Table 1. Demographic and clinical characteristics
Adult/children Gender Male/female Age (years) Mean SD Level of education (years) Mean SD Genetic analysis (%) TSC1 TSC2 No mutation identified Ongoing Familial cases (%) Cognitive profiles (%) Normal IQ BIF Mild ID Moderate ID Severe ID Neurologic examination (%) Normal Hemiparesis Cranial nerves Tetraparesis Extrapyramidal N.e. Cortical tubers (%) Yes No N.e. No. of tuber from 1 to 6 No. of tuber >6 N.e.
Seizure-free N = 57 (35.6%)
Drug-resistant N = 59 (36.9%)
45/12
38/21
32/5
22/35
26/33
13/24
31.6 16.7
24.1 16.2
36.8 15.5
0.05
25 (43.9) 10 (17.5) 7 (12.3) 8 (14) 7 (12.3)
12 (20.3) 5 (8.5) 12 (20.3) 9 (15.3) 21 (35.6)
35 (94.6)
0.05 0.05 0.05 0.05
1 (1.7)
>0.05
32 (56.1) 18 (31.6) 7 (12.3)
9 (15.3) 50 (84.7) 0
0.05 >0.05 >0.05
12 7 4 2 2 1 1 1 1 1 6 (10.5) 1 (1.7) 0
8 (13.6) 7 (11.9) 4 (6.8)
>0.05 60%) operated on remain seizure-free after surgery, improvement is strongly related to focal stereotypical seizures, single EEG focus, and/or focal lesion. A number of novel noninvasive methods (positron emission tomography [PET], single-photon emission computerized tomography [SPECT], and magnetoencephalography [MEG]), as well as invasive monitoring with intracranial electrodes, can be used in preoperative evaluation in order to better define the area for resection and expand the number of surgical candidates (Evans et al., 2012). In medically refractory patients who are not suitable for surgery, vagus nerve stimulation has proven efficacy in significantly reducing seizure frequency in >50% of cases (Elliott et al., 2009; Zamponi et al., 2010; ). Few patients in our series underwent resective or palliative surgery for their drug-resistant seizures, and we cannot extrapolate certain data from these cases. New evidence suggests that mammalian targets of rapamycin (mTOR) inhibitors may be helpful in the management of intractable seizures for individuals with TSC, Epilepsia, 54(12):2134–2142, 2013 doi: 10.1111/epi.12430
2142 A. Vignoli et al. but this treatment may need to be continuous and long term to maintain seizure control, and the benefit and the safety of this alternative therapeutic option is still unknown (Curatolo et al., 2012).
Conclusions Wider knowledge about epilepsy characteristics and long-term prognosis in patients with TSC is needed to ensure better management for patients and their families. Age-dependent characteristics of epilepsy in TSC should be identified to develop strategic therapeutic options tailored to the single patient. Moreover, delineating different categories of epileptic patients with TSC will further allow identification of specific biomarkers that could be fundamental for delineation of genotype–phenotype correlations, and to address early preventive treatment when indicated.
Acknowledgments We are grateful to all patients and families who participated in the study.
Disclosure None of the Authors have any conflicts of interest to report. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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Curatolo P, Bombardieri R, Jozwiak S. (2008) Tuberous sclerosis. Lancet 372:657–668. Curatolo P, Jozwiak S, Nabbout R, on behalf of the participants of the TSC Consensus Meeting for SEGA and Epilesy Management. (2012) Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol 16:582–586. Cusmai R, Moavero R, Bombardieri R, Vigevano F, Curatolo P. (2011) Long-term neurological outcome in children with early-onset epilepsy associated with tuberous sclerosis. Epilepsy Behav 22:735–739. Elliott RE, Carlson C, Kalhorn SP, Moshel YA, Weiner HL, Devinsky O, Doyle WK. (2009) Refractory epilepsy in tuberous sclerosis: vagus nerve stimulation with or without subsequent respective surgery. Epilepsy Behav 16:454–460. Evans LT, Morse R, Robets DW. (2012) Epilepsy surgery in tuberous sclerosis: a review. Neurosurg Focus 32:1–6. Goh S, Kwiatkowski DJ, Dorer DJ, Thiele EA. (2005) Infantile spasms and intellectual outcomes in children with tuberous sclerosis complex. Neurology 65:235–238. Jentarra GM, Rice SG, Olfers S, Saffen D, Narayanan V. (2011) Evidence for population variation in TSC1 and TSC2 gene expression. BMC Med Genet 12:29. Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP. (1999) Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet 64:1305–1315. Jozwiak S, Shwarz RA, Janniger CK, Bielicka-Cymerman J. (2000) Uselfulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J Child Neurol 15:652–659. Jozwiak S, Kotulska K, Domanska-Pakiela D, Lojszczyk B, Syczewska M, Chmielewski D, Dunin-Wasowicz D, Kmiec T, Szymkiewicz-Dangel J, Kornacka M, Kawalec W, Kuczynski D, Borkowska J, Tomaszek K, Jurkiewicz E, Respondek-Liberska M. (2011) Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatr Neurol 15:424–431. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshe’ SL, Perucca E, Wiebe S, French J. (2009) Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 3:1–9. Moavero R, Cerminara C, Curatolo P. (2010) Epilepsy secondary to tuberous sclerosis: lessons learned and current challenges. Childs Nerv Syst 26:1495–1504. O'Callaghan FJ, Harris T, Joinson C, Bolton P, Noakes M, Presdee D, Renowden S, Shiell A, Martyn CN, Osborne JP. (2004) The relation of infantile spasms, tubers and intelligence in tuberous sclerosis complex. Arch Dis Child 89:530–533. Roach ES, Gomez MR, Northup H. (1998) Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 13:624–628. Soo MP, Yong JL, Yong JS, Yong OK, Yong JW. (2011) Clinical progress of epilepsy in children with tuberous sclerosis: prognostic factors for seizure outcome. Chonnam Med J 47:150–154. Sparagana SP, Delgado MR, Batchelor LL, Roach ES. (2003) Seizure remission and antiepileptic drug discontinuation in children with tuberous sclerosis complex. Arch Neurol 60:1286–1289. Van Eeghen AM, Nellist M, van Eeghen EE, Thiele EA. (2013) Epilepsy Res 103:83–87. Zamponi N, Petrelli C, Passamonti C, Moavero R, Curatolo P. (2010) Vagus nerve stimulation for refractory epilepsy in tuberous. Pediatr Neurol 43:29–34.
Epilepsy in TSC: Certain etiology does not mean certain prognosis *Aglaia Vignoli, *Francesca La Briola, *Katherine Turner, *Giulia Scornavacca, *Valentina Chiesa, *Elena Zambrelli, *Ada Piazzini, *Miriam Nella Savini, *†Rosa Maria Alfano, and *Maria Paola Canevini Epilepsia, 54(12):2134–2142, 2013 doi: 10.1111/epi.12430
SUMMARY
Aglaia Vignoli, MD is a Researcher in Child and Adolescent Neurology and Psychiatry at Epilepsy Center, San Paolo Hospital, University of Milan, Italy.
Purpose: Prevalence and long-term outcome of epilepsy in tuberous sclerosis complex (TSC) is reported to be variable, and the reasons for this variability are still controversial. Methods: We reviewed the clinical characteristics of patients with TSC who were regularly followed since 2000 at the San Paolo Multidisciplinary Tuberous Sclerosis Centre in Milan, Italy. From patient charts we collected data about age at epilepsy onset, seizure frequency and seizure type, history of infantile spasms (IS), epileptic syndrome, evolution to refractory epilepsy or to seizure freedom and/or medication freedom, electroencephalography (EEG) features, magnetic resonance imaging (MRI) findings, cognitive outcome, and genetic background. Key Findings: Among the 160 subjects (120 adults and 40 children), 116 (72.5%) had epilepsy: 57 (35.6%) were seizure-free, and 59 (36.9%) had drug-resistant epilepsy. Most seizure-free patients had a focal epilepsy (89.5%), with 54.4% of them drug resistant for a period of their lives. Epilepsy onset in the first year of life with IS and/or focal seizures was characteristic of the drug-resistant group of patients, as well as cognitive impairment and TSC2 mutation (p < 0.05). A small group of patients (7 patients, 4.4%) experienced a seizure only once; all of them had normal cognition. Significance: Although epilepsy management can be challenging in TSC, more than one third of patients had their seizures controlled: through monotherapy in 56% and by polytherapy in 32%. Moreover, 12% of the patients became seizure-free and were off medication. Identifying predictive features of epilepsy and cognitive outcome can ensure better management for patients with TSC and delineate genotype–phenotype correlations. KEY WORDS: Epilepsy, Tuberous sclerosis complex, Outcome, Prognostic factors.
Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystemic disease with variable expression. TSC occurs in at least one in 6,000 individuals (Crino et al., 2006) and is caused by a mutation in either the TSC1 Accepted September 20, 2013; Early View publication November 8, 2013. *Neurology Unit, Epilepsy Center – Neurology Unit 2, San Paolo Hospital, DISS University of Milan, Milan, Italy; and †Molecular Biology Department, San Paolo Hospital, Milan, Italy Address correspondence to Aglaia Vignoli, Epilepsy Center – Neurology Unit 2, San Paolo Hospital, DISS University of Milan, Via di Rudinı 8, 20142 Milan, Italy. E-mail: [email protected] Wiley Periodicals, Inc. © 2013 International League Against Epilepsy
or TSC2 gene. Roughly two thirds of TSC cases reported in mutational and epidemiologic studies are sporadic (simplex), whereas the remaining cases are familial (Jones et al., 1999). The TSC1/TSC2 complex plays an important role during cortical development and growth control through the hyperactivation of the downstream mammalian target of rapamycin (mTOR) pathway and the associated kinase signaling cascades and translational factors. Therefore, mutations of TSC genes potentially induce abnormal cell morphology, imbalance in excitation and inhibition, as well as alterations in network properties, providing a likely underlying substrate for epilepsy (Moavero et al., 2010).
2134
2135 Epilepsy in TSC Neurologic phenotype of TSC is highly variable, ranging from normal to severe, and consisting of refractory epilepsy, intellectual impairment, and psychiatric comorbidity. Although a clear phenotypic/genotypic correlation has not been found as of yet, it is globally accepted that patients with TSC1 gene mutations show a milder phenotype than patients carrying TSC2 gene mutations (Jentarra et al., 2011). TSC is one of the leading genetic causes of epilepsy, with a high incidence (about 85%) of patients with TSC affected by seizures, often refractory to antiepileptic treatment (Curatolo et al., 2008). Nevertheless the prevalence and long-term outcome of epilepsy in TSC has not been widely investigated. A wide population of patients with epilepsy in TSC was investigated retrospectively: the authors reported a wide spectrum of severity for epilepsy in TSC, ranging from seizure-free patients to severe drug-resistant epilepsies (ChuShore et al., 2010). The present study aims to review the clinical characteristics of epilepsy in the population of adult and pediatric patients followed regularly since 2000 at the San Paolo Hospital Tuberous Sclerosis Center in Milan, Italy.
Methods We reviewed the clinical records of all patients with TSC, regularly followed at San Paolo Hospital Tuberous Sclerosis Center, San Paolo Hospital, Milan, Italy, from January 2000 to June 2012. Of 160 individuals with an established diagnosis of TSC, according to the International criteria (Roach et al., 1998), 116 had epilepsy. Only patients with at least 1 year of follow-up participated in this study. We collected data from patient charts about age at epilepsy onset, seizure frequency and seizure type, history of IS, epileptic syndrome, evolution to refractory epilepsy or to seizure freedom and/or medication freedom, electroencephalography (EEG) features, magnetic resonance imaging (MRI) findings, cognitive outcome, and genetic background. Results of presurgical evaluation for drugresistant cases were also assessed, when performed. Seizure types were classified according to clinical semiology provided by description from a witness or when possible by video-EEG recording of the episode. Refractory epilepsy was defined as uncontrolled seizures after at least two first-line anticonvulsant medication trials (Kwan et al., 2009). Patients were considered seizure-free if they were without clinical seizures for at least 1 year, using the last clinical visit documenting seizure status as the end point of follow-up. Genetic testing of the TSC1 and TSC2 genes was performed on DNA extracted from peripheral lymphocytes using a standard protocol for all patients and their firstdegree relatives. Polymerase chain reaction (PCR) was used to amplify all exons of TSC1 and TSC2 genes. Negative patients for the first level of investigation were evaluated
with Multiple Ligation-dependent Probe Amplification test. Patients in which genetic analysis was inconclusive were classified as no mutation identified (NMI). Among 160 subjects (120 adults and 40 children), 31 (19.4%) were familial cases (17 TSC1, 13 TSC2, and 1 NMI). We divided patients into five groups according to intelligence quotient (IQ): (1) normal IQ with IQ > 85; (2) borderline intellectual functioning (BIF) with IQ from 84 to 71; (3) mild intellectual disability (ID) with IQ from 70 to 55; (4) moderate ID with IQ from 54 to 40, and (5) severe ID with IQ < 40 (American Psychiatric Association, 2000). Education was measured in years of schooling. As part of their clinical management, patients were evaluated through a psychiatric interview in order to assess possible Axis I and II disorders (American Psychiatric Association, 2000). All data collected were transferred into an electronic database and processed using the Statistical Package for the Social Sciences (SPSS, IBM, Chicago, IL, U.S.A.) for Macintosh version 19.0. Continuous variables were presented as mean and standard deviation (SD). Patients (seizure-free vs. drug resistant vs. no epilepsy) were compared on sociodemographic and clinical characteristics, using chi-square test for categorized variables and not normally distributed variables and one-way analyses of variance (ANOVA) with Bonferroni post hoc for variables with a normal distribution. In particularly, significance was determined among three groups of patients simultaneously: seizure-free versus drugresistant + seizure-free versus no epilepsy + drug-resistant versus no epilepsy. Variables (seizure-free vs. drug resistant) with a normal distribution were analyzed using independent sample twotailed Student t-tests. Results were considered statistically significant for p-values < 0.05 (two-sided). The institutional review board of San Paolo Hospital, Milan, approved the study.
Results Among the 160 patients (64 [40.0%] male, 96 [60.0%] female; mean age 29.6, range 1–74 years) presently followed for TSC at San Paolo Hospital, 116 had epilepsy (72.5%), whereas 7 (4.4%) presented only one isolated seizure. Table 1 shows demographic and clinical characteristics of the entire TSC population, and Table 2 refers to the TSC patients with epilepsy, respectively. The mean follow-up period was 3.5 years (range 1–29 years). In relation to epilepsy, patients were divided into four subgroups: seizure-free (57 patients, 35.6%), drugresistant epilepsy (59 patients, 36.9%), patients with only one seizure in their lives (7 patients, 4.4%), and no epilepsy (37 patients, 23.1%). Seizure-free patients Seizure-free patients were in the great majority adults (45/57), with a mean age of 31.6 years (SD 16.7). Mean age Epilepsia, 54(12):2134–2142, 2013 doi: 10.1111/epi.12430
2136 A. Vignoli et al. at TSC diagnosis was 13.2 years (SD 15.9). Mutation analysis demonstrated a TSC2 gene mutation in most cases (52.7%) and a TSC1 gene mutation in 33.3%, and NMI in 7.0%. In 10 cases (17.5%) there was a family history of TSC (7 TSC1; 3 TSC2). Cognitive profile revealed normal IQ in 43.9% (p < 0.05), BIF in 17.5%, mild ID in 12.3%, moderate ID in 14%, and severe ID in 12.3%. Moreover the mean level of education was 8.9 (SD 3.7) years. Neurologic examination was considered normal in 87.7% of cases, whereas a psychiatric disorder was diagnosed in 26.3% of patients. MRI findings demonstrated cortical tubers in 98.2% (with more than six tubers in 75.4%), subependymal nodules (SENs) in 75.4%, and subependymal giant astrocytoma (SEGA) in 12.3% of patients. Most patients in this group had a focal epilepsy (89.5%), and 35.1% of these patients experienced IS in their early life. A history of drug-resistant epilepsy was
experienced by 52.6% of patients, who successively went on to become seizure-free. Most of them were on monotherapy (56.1%), mainly on carbamazepine (21.0%) and valproic acid (12.3%). No patients were treated with vigabatrin. Patients were seizure-free for a mean period of 12.9 years (range from 1 to 49 years). The mean age at seizure control was 19.4 years (range from 7 months to 71 years). Three patients were seizure-free after epilepsy surgery (Engel class IA) (follow-up 7.5 years; range 1–14.5 years). Ten patients withdrew from therapy after a seizure-free period and seven of these patients are still seizure-free (follow-up 20–49 years). Considering epilepsy diagnosis, six of seven had focal epilepsy and one of seven had IS. Most (six of seven) had seizure onset in the first year of life (range 3 months to 9 years); five of seven subjects experienced IS in their epilepsy history. Six patients carried a TSC2 mutation, and NMI in one patient NMI.
Table 1. Demographic and clinical characteristics
Adult/children Gender Male/female Age (years) Mean SD Level of education (years) Mean SD Genetic analysis (%) TSC1 TSC2 No mutation identified Ongoing Familial cases (%) Cognitive profiles (%) Normal IQ BIF Mild ID Moderate ID Severe ID Neurologic examination (%) Normal Hemiparesis Cranial nerves Tetraparesis Extrapyramidal N.e. Cortical tubers (%) Yes No N.e. No. of tuber from 1 to 6 No. of tuber >6 N.e.
Seizure-free N = 57 (35.6%)
Drug-resistant N = 59 (36.9%)
45/12
38/21
32/5
22/35
26/33
13/24
31.6 16.7
24.1 16.2
36.8 15.5
0.05
25 (43.9) 10 (17.5) 7 (12.3) 8 (14) 7 (12.3)
12 (20.3) 5 (8.5) 12 (20.3) 9 (15.3) 21 (35.6)
35 (94.6)
0.05 0.05 0.05 0.05
1 (1.7)
>0.05
32 (56.1) 18 (31.6) 7 (12.3)
9 (15.3) 50 (84.7) 0
0.05 >0.05 >0.05
12 7 4 2 2 1 1 1 1 1 6 (10.5) 1 (1.7) 0
8 (13.6) 7 (11.9) 4 (6.8)
>0.05 60%) operated on remain seizure-free after surgery, improvement is strongly related to focal stereotypical seizures, single EEG focus, and/or focal lesion. A number of novel noninvasive methods (positron emission tomography [PET], single-photon emission computerized tomography [SPECT], and magnetoencephalography [MEG]), as well as invasive monitoring with intracranial electrodes, can be used in preoperative evaluation in order to better define the area for resection and expand the number of surgical candidates (Evans et al., 2012). In medically refractory patients who are not suitable for surgery, vagus nerve stimulation has proven efficacy in significantly reducing seizure frequency in >50% of cases (Elliott et al., 2009; Zamponi et al., 2010; ). Few patients in our series underwent resective or palliative surgery for their drug-resistant seizures, and we cannot extrapolate certain data from these cases. New evidence suggests that mammalian targets of rapamycin (mTOR) inhibitors may be helpful in the management of intractable seizures for individuals with TSC, Epilepsia, 54(12):2134–2142, 2013 doi: 10.1111/epi.12430
2142 A. Vignoli et al. but this treatment may need to be continuous and long term to maintain seizure control, and the benefit and the safety of this alternative therapeutic option is still unknown (Curatolo et al., 2012).
Conclusions Wider knowledge about epilepsy characteristics and long-term prognosis in patients with TSC is needed to ensure better management for patients and their families. Age-dependent characteristics of epilepsy in TSC should be identified to develop strategic therapeutic options tailored to the single patient. Moreover, delineating different categories of epileptic patients with TSC will further allow identification of specific biomarkers that could be fundamental for delineation of genotype–phenotype correlations, and to address early preventive treatment when indicated.
Acknowledgments We are grateful to all patients and families who participated in the study.
Disclosure None of the Authors have any conflicts of interest to report. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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