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Official Journal of the European Paediatric Neurology Society
Original article
Epilepsy in newborns with tuberous sclerosis complex _ Katarzyna Kotulska a,b,*, Elzbieta Jurkiewicz c, ska-Pakieła a, Wiesława Grajkowska d, Marek Mandera e, Dorota Doman zwiak a Julita Borkowska a, Sergiusz Jo a
Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland Department of Science, The Children's Memorial Health Institute, Warsaw, Poland c Department of Radiology, The Children's Memorial Health Institute, Warsaw, Poland d Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland e Department of Paediatric Neurosurgery, Silesian Medical University, Katowice, Poland b
article info
abstract
Article history:
Background: Epilepsy affects up to 90% of TSC patients and majority of them have seizure at the
Received 18 March 2014
age of 3e5 months, after a period of latent epileptogenesis, but some develop epilepsy earlier.
Received in revised form
Aims: The aim of this work was to identify incidence, clinical characteristics, and risk
11 June 2014
factors for neonatal onset of epilepsy in a large cohort of TSC patients.
Accepted 28 June 2014
Methods: A retrospective review of medical data of 421 TSC patients was performed. Patients who developed epilepsy within first 4 weeks of life were included in the study.
Keywords:
Clinical and treatment data, EEG, MRI, and genetic analyses were assessed.
TSC
Results: Epilepsy was present in 366 (86.9%) patients. Twenty-one (5.7%) developed epilepsy
Epilepsy
as newborns. Mean follow-up was 44.86 (6e170) months. Six patients were seizure free and
Outcome
15 had drug-resistant seizures at the end of follow-up. Mental retardation was found in 81%
Newborn
of patients. In 11 (52.4%) patients brain MRI revealed large malformations of cerebral cor-
Focal cortical dysplasia
tex, meeting the criteria for focal cortical dysplasia (FCD). FCD was revealed in both TSC1 and TSC2 mutation cases. Other risk factors for neonatal epilepsy included: perinatal complications and congenital SEGAs. Presence of FCD was associated with more severe epilepsy and worse neuropsychological outcome. Epilepsy surgery resulted in improvement in seizure control. Conclusions: Neonatal onset of epilepsy in TSC is frequently associated with large malformations of cerebral cortex. Patients with FCD are at high risk of severe drug-resistant epilepsy and poor neuropsychological outcome. Early epilepsy surgery may be beneficial and should be considered in such cases. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Science, Department of Neurology and Epileptology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland. Tel.: þ48 22 8157404; fax: þ48 22 8157402. E-mail address: [email protected] (K. Kotulska). http://dx.doi.org/10.1016/j.ejpn.2014.06.009 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 7 1 4 e7 2 1
1.
Introduction
Tuberous sclerosis complex (TSC) is a genetic disorder occurring in approximately 1 in 6000 live births.1 TSC is caused by the mutation of either of two genes: TSC1 and TSC2 and has an autosomal dominant inheritance.1,2 The hallmark of the disease is the development of benign hamartomatic growth in various tissues and organs, including the brain, kidneys, heart, liver, lungs, retina, and skin.2 TSC is characterized by multisystem involvement occurring at different times during the affected individual life, as well as wide phenotypic variability.1,3,4 In children with TSC, the neurological features of the disease present the major cause of mortality and morbidity.5 Neuropathological findings in TSC include cortical and subcortical tubers, subependymal nodules, subependymal giant cell astrocytomas (SEGAs), and radial glial lines.6 These lesions form in the fetal and developing brain and most of them can be disclosed early after birth or even prenatally by means of magnetic resonance imaging (MRI). Clinical symptoms of nervous system involvement in TSC patients include epilepsy, cognitive impairment, and autism spectrum disorders.6e8 Epilepsy affects up to 90% of TSC patients and about 70% of them have seizure onset in infancy.1,8 Usually, epilepsy in TSC starts at the age of 3e5 months classically with focal seizures, followed by other types of seizures, including epileptic spasms.8 It is also established that clinical seizures in TSC infants are preceded by a latent phase of epileptogenesis, which can be followed by progressive deterioration of EEG.9,10 Recently, this latent period is increasingly recognized as a potential window for early intervention.10 However, some reports indicate that TSC patients might develop clinical seizures soon after birth.8,11 There are no published studies on the pathogenesis and risk factors, as well as clinical characteristics of neonatal onset epilepsy in TSC. The aim of this work was to analyze the clinical data of cases with epilepsy onset within first 28 days of life in a large cohort of TSC patients.
2.
Material and methods
2.1.
Patients
The study was approved by the Ethics Committee at The Children's Memorial Health Institute. We retrospectively reviewed the clinical, EEG, and neuroimaging data of patients with TSC seen at the Children's Memorial Health Institute in order to identify the patients with epilepsy onset within the first 4 weeks of life. Only patients meeting the clinical criteria for definite TSC according to International Tuberous Sclerosis Complex Consensus Group were included in the study.12 The demographic data, age of the patient at seizure onset, type of seizures, treatment applied, neuroimaging data, EEG recordings, genetic mutations, and outcome was analyzed in order to characterize neonatal epilepsy in TSC patients.
715
Epilepsy was diagnosed if at least two clinical seizures were observed in a child. The types of seizures were classified according to newly proposed Report of the ILAE Commission on Classification and Terminology 2005e2009.13 Drug resistant epilepsy was recognized if when seizures were uncontrolled after at least two appropriate medication trials. Given that the study refers to very young children, the exact period of seizure freedom, if any, was reported for each patient. Neuropsychological examination in infants and young children was performed using PsycheeCattell test performed by certified neuropsychologist. Patients were classified as intellectually normal when their score was 69 or more. Those with an IQ < 69 were considered mentally retarded. Children with scores between 52 and 68 were classified as having mild mental retardation, those with score between 36 and 51 were classified as moderately retarded, and those with score 35 or less received a diagnosis of severe mental retardation. Mutational analysis of TSC1 and TSC2 genes was done in either of two laboratories: Genetics Laboratory, Translational Medicine Division, Brigham and Women Hospital, Boston, MA, or Institute of Medical Genetics, Cardiff University School of Medicine, Cardiff, Great Britain. Patients with large deletions of TSC2 gene, affecting also the adjacent PKD1 gene were classified as TSC2/PKD1. Patients with inconclusive mutational analysis were classified as no mutation identified (NMI). Results were analyzed statistically using chi-square test with significance set at p 0.05.
3.
Results
We identified 421 patients in whom TSC diagnosis was definite according to the International Tuberous Sclerosis Complex Consensus Group criteria.12 In this group, 366 (86.9%) patients had epilepsy. Twenty-one (5% of all TSC patients in the database and 5.7% of TSC patients with epilepsy) had epilepsy onset in first 28 days of life. Mean follow-up of the patients was 44.86 months, ranging from 6 to 170 months. In 14 patients, mutational analysis was done and in 10 patients (71.4%) TSC2 mutation was found, including 2 patients (14.3%) with large TSC2/PKD1 mutation. Two patients (14.3%) had TSC1 mutation, and in 2 patients (14.3%) no mutation was identified. Seven children had significant perinatal complications: prematurity, significant asphyxia, severe pneumonia, cardiac arrest during surgery for cardiac rhabdomyoma, and renal problems associated with polycystic kidney disease. All patients had typical lesions in the brain revealed by MRI. Two patients were born with large SEGAs, causing hydrocephalus and requiring treatment in the first months of life. One of them had SEGA surgery at the age of 5 months, the second one received medical treatment with everolimus at the age of 8 months. Additionally, other 4 patients developed SEGA requiring either surgery or medical treatment during follow-up. Altogether, SEGA incidence in TSC patients with neonatal presentation of epilepsy was 28.6%. Clinical data of the patients are presented in Table 1. In 11 patients, large brain lesions meeting the criteria for focal cortical dysplasia (FCD)14 was identified on MRI (Fig. 1). In 10 cases (90.9%) FCD was found in the frontal lobes. FCD was
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Table 1 e Clinical characteristics of TSC patients with neonatal onset of epilepsy. TSC1/ Patient, Perinatal Age at seizure Type of gender, TSC2 complications onset (day seizures at gestational mutation of life) epilepsy onset age at birth (weeks)
Other seizures
Follow-up (months)
Treatment during follow-up
Seizure Treatment at Neuropsychological the end of status at status at the the end of follow-up end of follow-up follow-up.
MRI
VPA
Normal
CTs, SENs, Large congenital SEGA
Daily seizures
VGB þ VPA þ CBZ
Severe MR
VGB, VPA, ACTH 3-5 seizures per week
VGB þ VPA
Moderate MR
13
VGB
VGB
Mild retardation
TC, T,
25
VGB þ LEV
Moderate MR
TC, ES, T
13
VGB, PB, LEV, VPA, ACTH, at the age of 4 mo epilepsy surgery PB, DZP, NZP, PHT
CTs, SENs, Large FCD affecting left frontal lobe Multiple CTs, some with contrast enhancement, SENs Multiple CTs, SENs, SEGA CTs, SENs, FCD affecting right frontal and parietal lobe
PHT þ NZP
Severe retardation
VGB, everolimus Seizure free for SEGA for 5 mo VGB, Seizure free for 5 mo
VGB þ everolimus VGB
Mild retardation Mild retardation
35
VPA, NZP, PHT
1 seizure per week
VPA þ PHT
Severe MR
e
96
1 seizure per day
15
VGB þ VPA þ VNS þ everolimus VGB
Severe MR
e
VGB, VPA, VNS, everolimus for SEGA PB, VGB
VGB þ VPA
Severe retardation
ND
No
4
Focal
TC, T
18
2.Female, 38
ND
No
27
Focal
TC, C, M, ES
48
3. Female, 39
ND
No
28
Focal
ES
86
4. Male, 36
TSC2
28
Focal
5. Female, 37
ND
Perinatal asphyxia No
15
Focal
6. Female, 35
TSC2
No
4
Focal
7. Male, 34
Perinatal asphyxia e
16
focal
e
9
8. Female, 40
TSC2/ PKD1 ND
27
Focal
e
7
9. Female, 39
TSC2
No
5
Focal
e
10. Male, 38
NMI
No
21
Focal
11. Female, 40
TSC1
No
1
Focal
12. Female, 40
TSC2
No
5
Focal
e
C, EM
20
PB, VPA, DZP, NZP, SEGA surgery at the age of 7mo VGB, VPA, CBZ, PB, ACTH
Seizure free for 6 months 2-5 seizures per week
Daily seizures
1-2 seizures per month
VGB, ACTH, VPA 1 seizure per week
Severe retardation
Multiple CTs, large FCD affecting left frontal, parietal, and temporal lobe Multiple CTs, SEN, congenital SEGA CTs, SEN, 2 FCDs affecting left and right frontal lobe CTs, SENs, large FCD affecting left parietal and frontal lobe Multiple CTs, SENs, SEGA (at the age of 5 yrs) CTs, SENs, FCD affecting right frontal lobe CTs, SENs, 2 FCDs affecting left frontal and right parietal lobe
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 7 1 4 e7 2 1
Seizure efree for 5 months
1. Male, 40
13. Female, 37
TSC1
No
1
e
Focal
15
1 seizure per month after surgery Daily seizures
VGB þ VPA
Normal
CTs, SENs, large FCD affecting left frontal lobe
VPA þ CBZ þ LEV
Severe MR
CTs, SENs, SEGA (surgery at 11 yrs), HHE
TC
T, focal, C, AT
6
Focal
TC, C, ES
13
VGB, VPA, Daily seizures TPM, LEV, ACTH
VGB þ TPM þ LEV
Severe retardation
16. Female, 36
TSC2
No
3
Focal
TC, C, ES
85
1 seizure per week (seizure free for 18 mo after surgery)
TPM þ LEV þ VGB
Severe MR
17. Female, 35
TSC2
No
2
Focal
TC
11
ACTH, VGB, VPA, TPM, LEV, CBZ, epilepsy surgery at 6 mo, everolimus for SEGA LEV, TPM, VGB, VPA, CBZ
Daily seizures
VPA þ TPM þ LEV
Severe retardation
18. Female, 36
TSC2/ PKD1
28
Focal
TC, ES, C, AT
ACTH, LEV, VGB, 3-5 seizures LTG, TPM, VPA per week
LEV þ VPA þ LTG
Moderate MR
19. Female, 30
TSC2
10
T
TC, C, focal
VPA, LEV
Seizure free for 3 yrs
LEV þ VPA
Moderate MR
CTS, SENs
20. Female, 32
ND
Renal insufficiency and hypertension from the age of 3 weeks Prematurity, perinatal asphyxia Prematurity
CTs, SENs, large FCD affecting right parietal lobe CTs, SENs, SEGA (surgery at 4 yrs, second SEGA at 6 yrs), FCD affecting left frontal lobe CTs, SENs, FCD affecting left frontal a d parietal lobe CTs, SENs,
28
Focal
e
6
VGB
Normal
CTs, SENs
21. Male, 40
NMI
2
Focal
e
60
Seizure free VGB for 5 mo Seizure free for nearly 5 yrs
Normal
CTs, SENs
ND
15. Female, 39
Inborn infection (pneumonia)
170
82
PB
e
Abbrevations: ND e no data, NMI e no mutation identified, TSC2/PKD1 e large deletion affecting TSC2 and adjacent PKD1 gene, T e tonic, C e clonic, TC e tonic-clonic, ES e epileptic spasms, AT e atonic, EM e eyelid myoclonia, M e myoclonic, PB e phenobarbitone, LEV e levetiracetam, VGB e vigabatrin, LTG e lamotrigine, TPM e topiramate, VPA e valproic acid, CBZ e carbamazepine, OXC e oxcarbazepine, PHT e phenytoin, NZP e nitrazepam, DZP e diazepam, VNS e vagus nerve stimulation, MR e mental retardation (for children >2 yrs of age), CT e cortical tuber, SEN e subependymal nodule, SEGA e subependymal giant cell astrocytoma, FCD e focal cortical dysplasia.
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3
TSC2
Severe cardiac arrhythmia and cardiac arrest, heart surgery at the age of 2 days due to cardiac rhabdomyoma No
14. Male, 35
130
PB, PHT, ACTH, VPA, VGB, epilepsy surgery at 4 mo PHT, PB, VGB, ACTH, LEV, CBZ, OXC,
717
718
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Fig. 1 e Brain MRI of a newborn with TSC, showing cortical tubers, subependymal nodules, and large malformations of cerebral cortex, affecting right frontal lobe and left parietal lobe.
found both in patients with TSC1, and TSC2 mutation (2 and 6 patients, respectively). Taken together, in 20 out of 21 TSC patients with neonatal onset of epilepsy at least one of the following features was found: perinatal complications (prematurity, asphyxia, or infection), inborn SEGA, and FCD. In 20 (95.2%) TSC patients with neonatal onset of epilepsy, focal seizures were observed as first type of seizures. One patient (4.7%), who had cardiac arrest due to arrhythmia associated with cardiac rhabdomyoma, developed tonic seizures at the onset of epilepsy. However, 12 patients developed in time other types of seizures, including tonic-clonic, clonic, tonic, myoclonic seizures, and epileptic spasms (infantile spasms). EEG recordings were available in all newborns in the study. All patients presented with EEG abnormalities: background abnormalities in 15 patients (71.2%), sharp waves and/or spikes in 19 patients (90.5%), and electroencephalographic seizures in 7 patients (33.3%) (Fig. 2). Follow-up EEG was normal in 3 patients (14.3%). Five patients (23.8%) developed epileptic spasm and in 4 of them hypsarrhythmic pattern on EEG was recorded. Seventeen patients (81%) had drug-resistant seizures. Seven patients (33.3%) were seizure free for at least 5 months at the end of follow-up. Additionally, one patient was seizure free for 18 months after epilepsy surgery and resection of FCD, however, after this period developed seizures again. Among 11 patients with FCD, only one (9%) was seizure free for 5 months at the end of follow-up, however, this patients was 7 month-old at this moment. Among 7 patients with prenatal
complications, 5 (71.4%) were seizure free at the end of followup for at least 5 months. Among all patients without features of FCD, 6 out of 10 (60%) were seizure free for at least 5 months. The difference in the number of seizure free patients with FCD and without this malformation was statistically significant (p ¼ 0.134). Epilepsy surgery was performed in 3 patients at the age of 4e6 months and in all of them resulted in significant reduction of the number of seizures: one patient was seizure free for 18 months after surgery, and in two patients the number of seizures decreased by 90%. Upon histopathological analysis, in all 3 patients morphological features of focal cortical dysplasia of Taylor's balloon cell type were found (Fig. 3). Three patients received everolimus for growing SEGAs. One of them had been seizure free for few weeks prior to this treatment and remained seizure while on everolimus. In the other patient, adding everolimus resulted in >75% reduction of the number of seizures. In the third patient everolimus was just started and no relevant observations were available at the time of analysis. Retardation of psychomotor development was observed in 17 patients (81%). Normal result of neuropsychological examination was noted in 2 children with history of perinatal complications (prematurity, inborn infection) one child with inborn SEGA, and one child with FCD who underwent epilepsy surgery at the age of 4 months. Three of these children were seizure free at the end of follow-up. Severe mental retardation was observed in 12 (57.1%) patients and was more frequently observed in patients with FCD (8 out of 11 children, 72.7%) than in children without FCD (2 out of 10 patients, 20%). This difference was statistically significant (p ¼ 0.015).
4.
Discussion
Epilepsy in TSC is recognized as a major, though not specific and not recognized as diagnostic symptom of the disease.1,8,10 It is also variable, but until now little is known about the factors determining the clinical course of epilepsy and the responsiveness of seizures to antiepileptic medication.4,8 For the majority of TSC patients, epilepsy starts in the first year of life, usually at the age of 3e5 months.7,8 It is believed that before clinical seizures appear, the complex process of cellular and molecular changes called epileptogenesis is taking place in the brain.15,16 It can be disclosed by progressive deterioration of EEG recordings.9 However, there were some anecdotal reports on earlier seizure onset.11 Our study of a largest cohort of TSC patients ever published as well as recent study of Chu-Shore et al.8 show that 5e6% of TSC individuals with epilepsy have onset of seizures in neonatal period, suggesting the distinct mechanisms of epilepsy in this group of patients. Pathogenesis of epilepsy in TSC is not fully understood, however, it is thought that the cortical tubers are associated with the presentation of epilepsy.17e19 However, the relation of tuber count, their location, and imaging to epilepsy development is not clear.17,20,21 It is well established that tubers differ in MRI characteristics and size. Patients with large as well as hypointense on T1weighted, hyperintense on T2 weighted and heterogeneous on FLAIR images tubers were reported to be more likely to have severe epilepsy than
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719
Fig. 2 e Electroencephalogram of TSC newborn with focal seizures, showing rhythmic, continuous right sided spikes and spike and waves complexes.
patients with tubers presenting other MRI features or small ones.20,21 In our study, 11 out of 21 patients who developed seizures in neonatal period showed large malformations of cerebral cortex, meeting the MRI criteria for FCD. Neuropathological examination of all surgically removed lesions revealed features characteristic for FCD type IIb: dysmorphic neurons and balloon cells together with disruption of cortical lamination. Our study indicates that large malformations of cerebral cortex are not uncommon in TSC patients and are associated with early presentation of epilepsy.
Fig. 3 e Microscopic pathology of large malformation of frontal lobe cerebral cortex removed from 6-month-old TSC patient having epilepsy from neonatal age. Balloon cells (arrow) are visible in a disorganized background (hematoxylin and eosin, original magnification £400).
Developmental pathogenesis of cortical tubers and cortical dysplasia in TSC is not clear. It is widely accepted that brain pathology in TSC is associated with mTOR pathway activation resulting form TSC1/TSC2 loss. In animal models, mTOR signaling is activated in fetal tubers and in neural progenitor cells following TSC2 knockdown.22 It has been showed that deletion of TSC1 or TSC2 in mice at different embryonic stages results in various phenotypes, with the most severe brain cortex malformations and early spontaneous epilepsy being associated with mutations in early neural progenitors.23,24 mTOR pathway activation is also implicated in the development of FCD.25 Focal cortical dysplasia type IIB and cortical tubers in TSC share many morphological and molecular features.26,27 Recently, the defect of autophagy associated with mTOR activation were reported in both TSC-related cortical tubers and FCD.28 There are also evidence of similar mechanisms of cell injury in FCD and TSC-related cortical tubers, with induction of apoptosis-signaling pathways and premature activation of mechanisms of neurodegeneration, including expression of phosphorylated tau and beta-amyloid precursor protein.29 The significance of those findings in epileptogenesis is not clear. In our study, most (80%) patients with neonatal onset of epilepsy and no features of FCD presented with other known risk factors for neonatal seizures beyond TSC: prematurity, perinatal asphyxia, congenital SEGA with hydrocephalus present at birth, renal insufficiency. In our group of TSC patients, features of FCD were observed in patients harboring both TSC1 and TSC2 gene mutations. It is widely accepted that TSC2 mutations are associated with more severe clinical presentation of the disease, including earlier onset and more active epilepsy.3 Our study indicates that apart from TSC2 mutation, large tuber load, and cyst-like
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tubers, also the presence of FCD is associated with severe neurological presentation of TSC. The pathogenesis of large malformations of cerebral cortex in not known, but our study suggests that their development is not related to specific TSC1 or TSC2 gene changes. Our study is the first to describe the course of epilepsy with neonatal onset in TSC patients. The severity of epilepsy and related neurological comorbidities seem to be different in the group of patients with and without FCD. Patients with FCD are more likely to have drug resistant and very active epilepsy as well as more severe mental retardation than patients without large malformations of cerebral cortex. Three patients in our cohort underwent epilepsy surgery in infancy. In all of them resection of dysplastic region was performed and resulted in significant improvement in seizure control. Moreover, one of the operated patients was the only one in group with FCD, whose psychomotor development was normal. The number of the patients in this group, and particularly the number of operated patients in our study is too small to give conclusive results, however it is in concordance with other reports suggesting that early epilepsy surgery is beneficial for TSC patients with drug resistant seizures.30e33 In our study, in two patients (9%) neonatal seizures coexisted with congenital SEGA. This finding shows that TSC patients with early onset of seizures should be screened for brain tumors and hydrocephalus. Recently, medical treatment with mTOR inhibitor, everolimus, was introduced for brain and kidney tumors associated with TSC.34 It was also shown to exert some antiepileptic effect in patients with drug resistant seizures, including young children.35 In this study, two patients received everolimus for SEGA. In one of them, everolimus resulted in significant improvement in seizure control. It should be noted, however, that the duration of treatment with everolimus was relatively short.
5.
Conclusions
In summary, neonatal presentation of epilepsy in TSC patients is not uncommon and is frequently associated with malformations of cerebral cortex meeting the criteria for FCD. Thus, brain MRI and EEG monitoring should be recommended for all newborns with TSC. Patients with features of FCD may benefit from early epilepsy surgery.
Acknowledgments This work was supported by EPISTOP Project 7FP grant No 602391. The authors would like to thank Ms. Natalia kowiak for her excellent technical support. Mac
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20. Gallagher A, Grant EP, Madan N, et al. MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex. J Neurol 2010;257(8):1373e81. ndez-Moneo JL, Pascual21. Pascual-Castroviejo I, Herna Pascual SI, et al. Significance of tuber size for complications of tuberous sclerosis complex. Neurologia 2013;28(9):550e7. 22. Tsai V, Parker WE, Orlova KA, et al. Fetal brain mTOR signaling activation in tuberous sclerosis complex. Cereb Cortex 2014;24(2):315e27. 23. Zeng LH, Rensing NR, Zhang B, et al. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum Mol Genet 2011;20:445e54. 24. Magri L, Cominelli M, Cambiaghi M, et al. Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models. Dis Model Mech 2013;6(5):1185e97. 25. Wong M. Mammalian target of rapamycin (mTOR) activation in focal cortical dysplasia and related focal cortical malformations. Exp Neurol 2013;244:22e6. 26. Grajkowska W, Kotulska K, Matyja E, et al. Expression of tuberin and hamartin in tuberous sclerosis complexassociated and sporadic cortical dysplasia of Taylor's balloon cell type. Folia Neuropathol 2008;46:43e8. 27. Yasin SA, Latak K, Becherini F, et al. Balloon cells in human cortical dysplasia and tuberous sclerosis: isolation of a pathological progenitor-like cell. Acta Neuropathol 2010;120(1):85e96. 28. Yasin SA, Ali AM, Tata M, et al. mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal
29.
30.
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34.
35.
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cortical dysplasia and tuberous sclerosis. Acta Neuropathol 2013;126(2):207e18. A1 Iyer, Prabowo A, Anink J, et al. Cell injury and premature neurodegeneration in focal malformations of cortical development. Brain Pathol 2014;24(1):1e17. Krsek P, Jahodova A, Kyncl M, et al. Predictors of seizure-free outcome after epilepsy surgery for pediatric tuberous sclerosis complex. Epilepsia 2013;54(11):1913e21. Wu JY, Salamon N, Kirsch HE, et al. Noninvasive testing, early surgery, and seizure freedom in tuberous sclerosis complex. Neurology 2010;74(5):392e8. z wiak S, Nabbout R. TSC Consensus Meeting Curatolo P, Jo for SEGA and Epilepsy Management. Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol 2012;16(6):582e6. Fallah A, Guyatt GH, Snead 3rd OC, et al. Predictors of seizure outcomes in children with tuberous sclerosis complex and intractable epilepsy undergoing resective epilepsy surgery: an individual participant data meta-analysis. PLoS One 2013;8(2):e53565. zwiak S, Stein K, Kotulska K. Everolimus (RAD001): first Jo systemic treatment for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Future Oncol 2012;8(12):1515e23. Kotulska K, Chmielewski D, Borkowska J, et al. Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Eur J Paediatr Neurol 2013;17(5):479e85.
Official Journal of the European Paediatric Neurology Society
Original article
Epilepsy in newborns with tuberous sclerosis complex _ Katarzyna Kotulska a,b,*, Elzbieta Jurkiewicz c, ska-Pakieła a, Wiesława Grajkowska d, Marek Mandera e, Dorota Doman zwiak a Julita Borkowska a, Sergiusz Jo a
Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland Department of Science, The Children's Memorial Health Institute, Warsaw, Poland c Department of Radiology, The Children's Memorial Health Institute, Warsaw, Poland d Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland e Department of Paediatric Neurosurgery, Silesian Medical University, Katowice, Poland b
article info
abstract
Article history:
Background: Epilepsy affects up to 90% of TSC patients and majority of them have seizure at the
Received 18 March 2014
age of 3e5 months, after a period of latent epileptogenesis, but some develop epilepsy earlier.
Received in revised form
Aims: The aim of this work was to identify incidence, clinical characteristics, and risk
11 June 2014
factors for neonatal onset of epilepsy in a large cohort of TSC patients.
Accepted 28 June 2014
Methods: A retrospective review of medical data of 421 TSC patients was performed. Patients who developed epilepsy within first 4 weeks of life were included in the study.
Keywords:
Clinical and treatment data, EEG, MRI, and genetic analyses were assessed.
TSC
Results: Epilepsy was present in 366 (86.9%) patients. Twenty-one (5.7%) developed epilepsy
Epilepsy
as newborns. Mean follow-up was 44.86 (6e170) months. Six patients were seizure free and
Outcome
15 had drug-resistant seizures at the end of follow-up. Mental retardation was found in 81%
Newborn
of patients. In 11 (52.4%) patients brain MRI revealed large malformations of cerebral cor-
Focal cortical dysplasia
tex, meeting the criteria for focal cortical dysplasia (FCD). FCD was revealed in both TSC1 and TSC2 mutation cases. Other risk factors for neonatal epilepsy included: perinatal complications and congenital SEGAs. Presence of FCD was associated with more severe epilepsy and worse neuropsychological outcome. Epilepsy surgery resulted in improvement in seizure control. Conclusions: Neonatal onset of epilepsy in TSC is frequently associated with large malformations of cerebral cortex. Patients with FCD are at high risk of severe drug-resistant epilepsy and poor neuropsychological outcome. Early epilepsy surgery may be beneficial and should be considered in such cases. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Science, Department of Neurology and Epileptology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland. Tel.: þ48 22 8157404; fax: þ48 22 8157402. E-mail address: [email protected] (K. Kotulska). http://dx.doi.org/10.1016/j.ejpn.2014.06.009 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 7 1 4 e7 2 1
1.
Introduction
Tuberous sclerosis complex (TSC) is a genetic disorder occurring in approximately 1 in 6000 live births.1 TSC is caused by the mutation of either of two genes: TSC1 and TSC2 and has an autosomal dominant inheritance.1,2 The hallmark of the disease is the development of benign hamartomatic growth in various tissues and organs, including the brain, kidneys, heart, liver, lungs, retina, and skin.2 TSC is characterized by multisystem involvement occurring at different times during the affected individual life, as well as wide phenotypic variability.1,3,4 In children with TSC, the neurological features of the disease present the major cause of mortality and morbidity.5 Neuropathological findings in TSC include cortical and subcortical tubers, subependymal nodules, subependymal giant cell astrocytomas (SEGAs), and radial glial lines.6 These lesions form in the fetal and developing brain and most of them can be disclosed early after birth or even prenatally by means of magnetic resonance imaging (MRI). Clinical symptoms of nervous system involvement in TSC patients include epilepsy, cognitive impairment, and autism spectrum disorders.6e8 Epilepsy affects up to 90% of TSC patients and about 70% of them have seizure onset in infancy.1,8 Usually, epilepsy in TSC starts at the age of 3e5 months classically with focal seizures, followed by other types of seizures, including epileptic spasms.8 It is also established that clinical seizures in TSC infants are preceded by a latent phase of epileptogenesis, which can be followed by progressive deterioration of EEG.9,10 Recently, this latent period is increasingly recognized as a potential window for early intervention.10 However, some reports indicate that TSC patients might develop clinical seizures soon after birth.8,11 There are no published studies on the pathogenesis and risk factors, as well as clinical characteristics of neonatal onset epilepsy in TSC. The aim of this work was to analyze the clinical data of cases with epilepsy onset within first 28 days of life in a large cohort of TSC patients.
2.
Material and methods
2.1.
Patients
The study was approved by the Ethics Committee at The Children's Memorial Health Institute. We retrospectively reviewed the clinical, EEG, and neuroimaging data of patients with TSC seen at the Children's Memorial Health Institute in order to identify the patients with epilepsy onset within the first 4 weeks of life. Only patients meeting the clinical criteria for definite TSC according to International Tuberous Sclerosis Complex Consensus Group were included in the study.12 The demographic data, age of the patient at seizure onset, type of seizures, treatment applied, neuroimaging data, EEG recordings, genetic mutations, and outcome was analyzed in order to characterize neonatal epilepsy in TSC patients.
715
Epilepsy was diagnosed if at least two clinical seizures were observed in a child. The types of seizures were classified according to newly proposed Report of the ILAE Commission on Classification and Terminology 2005e2009.13 Drug resistant epilepsy was recognized if when seizures were uncontrolled after at least two appropriate medication trials. Given that the study refers to very young children, the exact period of seizure freedom, if any, was reported for each patient. Neuropsychological examination in infants and young children was performed using PsycheeCattell test performed by certified neuropsychologist. Patients were classified as intellectually normal when their score was 69 or more. Those with an IQ < 69 were considered mentally retarded. Children with scores between 52 and 68 were classified as having mild mental retardation, those with score between 36 and 51 were classified as moderately retarded, and those with score 35 or less received a diagnosis of severe mental retardation. Mutational analysis of TSC1 and TSC2 genes was done in either of two laboratories: Genetics Laboratory, Translational Medicine Division, Brigham and Women Hospital, Boston, MA, or Institute of Medical Genetics, Cardiff University School of Medicine, Cardiff, Great Britain. Patients with large deletions of TSC2 gene, affecting also the adjacent PKD1 gene were classified as TSC2/PKD1. Patients with inconclusive mutational analysis were classified as no mutation identified (NMI). Results were analyzed statistically using chi-square test with significance set at p 0.05.
3.
Results
We identified 421 patients in whom TSC diagnosis was definite according to the International Tuberous Sclerosis Complex Consensus Group criteria.12 In this group, 366 (86.9%) patients had epilepsy. Twenty-one (5% of all TSC patients in the database and 5.7% of TSC patients with epilepsy) had epilepsy onset in first 28 days of life. Mean follow-up of the patients was 44.86 months, ranging from 6 to 170 months. In 14 patients, mutational analysis was done and in 10 patients (71.4%) TSC2 mutation was found, including 2 patients (14.3%) with large TSC2/PKD1 mutation. Two patients (14.3%) had TSC1 mutation, and in 2 patients (14.3%) no mutation was identified. Seven children had significant perinatal complications: prematurity, significant asphyxia, severe pneumonia, cardiac arrest during surgery for cardiac rhabdomyoma, and renal problems associated with polycystic kidney disease. All patients had typical lesions in the brain revealed by MRI. Two patients were born with large SEGAs, causing hydrocephalus and requiring treatment in the first months of life. One of them had SEGA surgery at the age of 5 months, the second one received medical treatment with everolimus at the age of 8 months. Additionally, other 4 patients developed SEGA requiring either surgery or medical treatment during follow-up. Altogether, SEGA incidence in TSC patients with neonatal presentation of epilepsy was 28.6%. Clinical data of the patients are presented in Table 1. In 11 patients, large brain lesions meeting the criteria for focal cortical dysplasia (FCD)14 was identified on MRI (Fig. 1). In 10 cases (90.9%) FCD was found in the frontal lobes. FCD was
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Table 1 e Clinical characteristics of TSC patients with neonatal onset of epilepsy. TSC1/ Patient, Perinatal Age at seizure Type of gender, TSC2 complications onset (day seizures at gestational mutation of life) epilepsy onset age at birth (weeks)
Other seizures
Follow-up (months)
Treatment during follow-up
Seizure Treatment at Neuropsychological the end of status at status at the the end of follow-up end of follow-up follow-up.
MRI
VPA
Normal
CTs, SENs, Large congenital SEGA
Daily seizures
VGB þ VPA þ CBZ
Severe MR
VGB, VPA, ACTH 3-5 seizures per week
VGB þ VPA
Moderate MR
13
VGB
VGB
Mild retardation
TC, T,
25
VGB þ LEV
Moderate MR
TC, ES, T
13
VGB, PB, LEV, VPA, ACTH, at the age of 4 mo epilepsy surgery PB, DZP, NZP, PHT
CTs, SENs, Large FCD affecting left frontal lobe Multiple CTs, some with contrast enhancement, SENs Multiple CTs, SENs, SEGA CTs, SENs, FCD affecting right frontal and parietal lobe
PHT þ NZP
Severe retardation
VGB, everolimus Seizure free for SEGA for 5 mo VGB, Seizure free for 5 mo
VGB þ everolimus VGB
Mild retardation Mild retardation
35
VPA, NZP, PHT
1 seizure per week
VPA þ PHT
Severe MR
e
96
1 seizure per day
15
VGB þ VPA þ VNS þ everolimus VGB
Severe MR
e
VGB, VPA, VNS, everolimus for SEGA PB, VGB
VGB þ VPA
Severe retardation
ND
No
4
Focal
TC, T
18
2.Female, 38
ND
No
27
Focal
TC, C, M, ES
48
3. Female, 39
ND
No
28
Focal
ES
86
4. Male, 36
TSC2
28
Focal
5. Female, 37
ND
Perinatal asphyxia No
15
Focal
6. Female, 35
TSC2
No
4
Focal
7. Male, 34
Perinatal asphyxia e
16
focal
e
9
8. Female, 40
TSC2/ PKD1 ND
27
Focal
e
7
9. Female, 39
TSC2
No
5
Focal
e
10. Male, 38
NMI
No
21
Focal
11. Female, 40
TSC1
No
1
Focal
12. Female, 40
TSC2
No
5
Focal
e
C, EM
20
PB, VPA, DZP, NZP, SEGA surgery at the age of 7mo VGB, VPA, CBZ, PB, ACTH
Seizure free for 6 months 2-5 seizures per week
Daily seizures
1-2 seizures per month
VGB, ACTH, VPA 1 seizure per week
Severe retardation
Multiple CTs, large FCD affecting left frontal, parietal, and temporal lobe Multiple CTs, SEN, congenital SEGA CTs, SEN, 2 FCDs affecting left and right frontal lobe CTs, SENs, large FCD affecting left parietal and frontal lobe Multiple CTs, SENs, SEGA (at the age of 5 yrs) CTs, SENs, FCD affecting right frontal lobe CTs, SENs, 2 FCDs affecting left frontal and right parietal lobe
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 7 1 4 e7 2 1
Seizure efree for 5 months
1. Male, 40
13. Female, 37
TSC1
No
1
e
Focal
15
1 seizure per month after surgery Daily seizures
VGB þ VPA
Normal
CTs, SENs, large FCD affecting left frontal lobe
VPA þ CBZ þ LEV
Severe MR
CTs, SENs, SEGA (surgery at 11 yrs), HHE
TC
T, focal, C, AT
6
Focal
TC, C, ES
13
VGB, VPA, Daily seizures TPM, LEV, ACTH
VGB þ TPM þ LEV
Severe retardation
16. Female, 36
TSC2
No
3
Focal
TC, C, ES
85
1 seizure per week (seizure free for 18 mo after surgery)
TPM þ LEV þ VGB
Severe MR
17. Female, 35
TSC2
No
2
Focal
TC
11
ACTH, VGB, VPA, TPM, LEV, CBZ, epilepsy surgery at 6 mo, everolimus for SEGA LEV, TPM, VGB, VPA, CBZ
Daily seizures
VPA þ TPM þ LEV
Severe retardation
18. Female, 36
TSC2/ PKD1
28
Focal
TC, ES, C, AT
ACTH, LEV, VGB, 3-5 seizures LTG, TPM, VPA per week
LEV þ VPA þ LTG
Moderate MR
19. Female, 30
TSC2
10
T
TC, C, focal
VPA, LEV
Seizure free for 3 yrs
LEV þ VPA
Moderate MR
CTS, SENs
20. Female, 32
ND
Renal insufficiency and hypertension from the age of 3 weeks Prematurity, perinatal asphyxia Prematurity
CTs, SENs, large FCD affecting right parietal lobe CTs, SENs, SEGA (surgery at 4 yrs, second SEGA at 6 yrs), FCD affecting left frontal lobe CTs, SENs, FCD affecting left frontal a d parietal lobe CTs, SENs,
28
Focal
e
6
VGB
Normal
CTs, SENs
21. Male, 40
NMI
2
Focal
e
60
Seizure free VGB for 5 mo Seizure free for nearly 5 yrs
Normal
CTs, SENs
ND
15. Female, 39
Inborn infection (pneumonia)
170
82
PB
e
Abbrevations: ND e no data, NMI e no mutation identified, TSC2/PKD1 e large deletion affecting TSC2 and adjacent PKD1 gene, T e tonic, C e clonic, TC e tonic-clonic, ES e epileptic spasms, AT e atonic, EM e eyelid myoclonia, M e myoclonic, PB e phenobarbitone, LEV e levetiracetam, VGB e vigabatrin, LTG e lamotrigine, TPM e topiramate, VPA e valproic acid, CBZ e carbamazepine, OXC e oxcarbazepine, PHT e phenytoin, NZP e nitrazepam, DZP e diazepam, VNS e vagus nerve stimulation, MR e mental retardation (for children >2 yrs of age), CT e cortical tuber, SEN e subependymal nodule, SEGA e subependymal giant cell astrocytoma, FCD e focal cortical dysplasia.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 7 1 4 e7 2 1
3
TSC2
Severe cardiac arrhythmia and cardiac arrest, heart surgery at the age of 2 days due to cardiac rhabdomyoma No
14. Male, 35
130
PB, PHT, ACTH, VPA, VGB, epilepsy surgery at 4 mo PHT, PB, VGB, ACTH, LEV, CBZ, OXC,
717
718
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 7 1 4 e7 2 1
Fig. 1 e Brain MRI of a newborn with TSC, showing cortical tubers, subependymal nodules, and large malformations of cerebral cortex, affecting right frontal lobe and left parietal lobe.
found both in patients with TSC1, and TSC2 mutation (2 and 6 patients, respectively). Taken together, in 20 out of 21 TSC patients with neonatal onset of epilepsy at least one of the following features was found: perinatal complications (prematurity, asphyxia, or infection), inborn SEGA, and FCD. In 20 (95.2%) TSC patients with neonatal onset of epilepsy, focal seizures were observed as first type of seizures. One patient (4.7%), who had cardiac arrest due to arrhythmia associated with cardiac rhabdomyoma, developed tonic seizures at the onset of epilepsy. However, 12 patients developed in time other types of seizures, including tonic-clonic, clonic, tonic, myoclonic seizures, and epileptic spasms (infantile spasms). EEG recordings were available in all newborns in the study. All patients presented with EEG abnormalities: background abnormalities in 15 patients (71.2%), sharp waves and/or spikes in 19 patients (90.5%), and electroencephalographic seizures in 7 patients (33.3%) (Fig. 2). Follow-up EEG was normal in 3 patients (14.3%). Five patients (23.8%) developed epileptic spasm and in 4 of them hypsarrhythmic pattern on EEG was recorded. Seventeen patients (81%) had drug-resistant seizures. Seven patients (33.3%) were seizure free for at least 5 months at the end of follow-up. Additionally, one patient was seizure free for 18 months after epilepsy surgery and resection of FCD, however, after this period developed seizures again. Among 11 patients with FCD, only one (9%) was seizure free for 5 months at the end of follow-up, however, this patients was 7 month-old at this moment. Among 7 patients with prenatal
complications, 5 (71.4%) were seizure free at the end of followup for at least 5 months. Among all patients without features of FCD, 6 out of 10 (60%) were seizure free for at least 5 months. The difference in the number of seizure free patients with FCD and without this malformation was statistically significant (p ¼ 0.134). Epilepsy surgery was performed in 3 patients at the age of 4e6 months and in all of them resulted in significant reduction of the number of seizures: one patient was seizure free for 18 months after surgery, and in two patients the number of seizures decreased by 90%. Upon histopathological analysis, in all 3 patients morphological features of focal cortical dysplasia of Taylor's balloon cell type were found (Fig. 3). Three patients received everolimus for growing SEGAs. One of them had been seizure free for few weeks prior to this treatment and remained seizure while on everolimus. In the other patient, adding everolimus resulted in >75% reduction of the number of seizures. In the third patient everolimus was just started and no relevant observations were available at the time of analysis. Retardation of psychomotor development was observed in 17 patients (81%). Normal result of neuropsychological examination was noted in 2 children with history of perinatal complications (prematurity, inborn infection) one child with inborn SEGA, and one child with FCD who underwent epilepsy surgery at the age of 4 months. Three of these children were seizure free at the end of follow-up. Severe mental retardation was observed in 12 (57.1%) patients and was more frequently observed in patients with FCD (8 out of 11 children, 72.7%) than in children without FCD (2 out of 10 patients, 20%). This difference was statistically significant (p ¼ 0.015).
4.
Discussion
Epilepsy in TSC is recognized as a major, though not specific and not recognized as diagnostic symptom of the disease.1,8,10 It is also variable, but until now little is known about the factors determining the clinical course of epilepsy and the responsiveness of seizures to antiepileptic medication.4,8 For the majority of TSC patients, epilepsy starts in the first year of life, usually at the age of 3e5 months.7,8 It is believed that before clinical seizures appear, the complex process of cellular and molecular changes called epileptogenesis is taking place in the brain.15,16 It can be disclosed by progressive deterioration of EEG recordings.9 However, there were some anecdotal reports on earlier seizure onset.11 Our study of a largest cohort of TSC patients ever published as well as recent study of Chu-Shore et al.8 show that 5e6% of TSC individuals with epilepsy have onset of seizures in neonatal period, suggesting the distinct mechanisms of epilepsy in this group of patients. Pathogenesis of epilepsy in TSC is not fully understood, however, it is thought that the cortical tubers are associated with the presentation of epilepsy.17e19 However, the relation of tuber count, their location, and imaging to epilepsy development is not clear.17,20,21 It is well established that tubers differ in MRI characteristics and size. Patients with large as well as hypointense on T1weighted, hyperintense on T2 weighted and heterogeneous on FLAIR images tubers were reported to be more likely to have severe epilepsy than
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 7 1 4 e7 2 1
719
Fig. 2 e Electroencephalogram of TSC newborn with focal seizures, showing rhythmic, continuous right sided spikes and spike and waves complexes.
patients with tubers presenting other MRI features or small ones.20,21 In our study, 11 out of 21 patients who developed seizures in neonatal period showed large malformations of cerebral cortex, meeting the MRI criteria for FCD. Neuropathological examination of all surgically removed lesions revealed features characteristic for FCD type IIb: dysmorphic neurons and balloon cells together with disruption of cortical lamination. Our study indicates that large malformations of cerebral cortex are not uncommon in TSC patients and are associated with early presentation of epilepsy.
Fig. 3 e Microscopic pathology of large malformation of frontal lobe cerebral cortex removed from 6-month-old TSC patient having epilepsy from neonatal age. Balloon cells (arrow) are visible in a disorganized background (hematoxylin and eosin, original magnification £400).
Developmental pathogenesis of cortical tubers and cortical dysplasia in TSC is not clear. It is widely accepted that brain pathology in TSC is associated with mTOR pathway activation resulting form TSC1/TSC2 loss. In animal models, mTOR signaling is activated in fetal tubers and in neural progenitor cells following TSC2 knockdown.22 It has been showed that deletion of TSC1 or TSC2 in mice at different embryonic stages results in various phenotypes, with the most severe brain cortex malformations and early spontaneous epilepsy being associated with mutations in early neural progenitors.23,24 mTOR pathway activation is also implicated in the development of FCD.25 Focal cortical dysplasia type IIB and cortical tubers in TSC share many morphological and molecular features.26,27 Recently, the defect of autophagy associated with mTOR activation were reported in both TSC-related cortical tubers and FCD.28 There are also evidence of similar mechanisms of cell injury in FCD and TSC-related cortical tubers, with induction of apoptosis-signaling pathways and premature activation of mechanisms of neurodegeneration, including expression of phosphorylated tau and beta-amyloid precursor protein.29 The significance of those findings in epileptogenesis is not clear. In our study, most (80%) patients with neonatal onset of epilepsy and no features of FCD presented with other known risk factors for neonatal seizures beyond TSC: prematurity, perinatal asphyxia, congenital SEGA with hydrocephalus present at birth, renal insufficiency. In our group of TSC patients, features of FCD were observed in patients harboring both TSC1 and TSC2 gene mutations. It is widely accepted that TSC2 mutations are associated with more severe clinical presentation of the disease, including earlier onset and more active epilepsy.3 Our study indicates that apart from TSC2 mutation, large tuber load, and cyst-like
720
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 7 1 4 e7 2 1
tubers, also the presence of FCD is associated with severe neurological presentation of TSC. The pathogenesis of large malformations of cerebral cortex in not known, but our study suggests that their development is not related to specific TSC1 or TSC2 gene changes. Our study is the first to describe the course of epilepsy with neonatal onset in TSC patients. The severity of epilepsy and related neurological comorbidities seem to be different in the group of patients with and without FCD. Patients with FCD are more likely to have drug resistant and very active epilepsy as well as more severe mental retardation than patients without large malformations of cerebral cortex. Three patients in our cohort underwent epilepsy surgery in infancy. In all of them resection of dysplastic region was performed and resulted in significant improvement in seizure control. Moreover, one of the operated patients was the only one in group with FCD, whose psychomotor development was normal. The number of the patients in this group, and particularly the number of operated patients in our study is too small to give conclusive results, however it is in concordance with other reports suggesting that early epilepsy surgery is beneficial for TSC patients with drug resistant seizures.30e33 In our study, in two patients (9%) neonatal seizures coexisted with congenital SEGA. This finding shows that TSC patients with early onset of seizures should be screened for brain tumors and hydrocephalus. Recently, medical treatment with mTOR inhibitor, everolimus, was introduced for brain and kidney tumors associated with TSC.34 It was also shown to exert some antiepileptic effect in patients with drug resistant seizures, including young children.35 In this study, two patients received everolimus for SEGA. In one of them, everolimus resulted in significant improvement in seizure control. It should be noted, however, that the duration of treatment with everolimus was relatively short.
5.
Conclusions
In summary, neonatal presentation of epilepsy in TSC patients is not uncommon and is frequently associated with malformations of cerebral cortex meeting the criteria for FCD. Thus, brain MRI and EEG monitoring should be recommended for all newborns with TSC. Patients with features of FCD may benefit from early epilepsy surgery.
Acknowledgments This work was supported by EPISTOP Project 7FP grant No 602391. The authors would like to thank Ms. Natalia kowiak for her excellent technical support. Mac
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