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Article ; Online: Tumor growth in patients with tuberous sclerosis complex on the ketogenic diet.

Chu-Shore, Catherine J / Thiele, Elizabeth A

2010 Volume 32, Issue 4, Page(s) 318–322

Abstract: Purpose: New evidence is emerging that the availability of nutrients plays a key role in regulating the mammalian target of rapamycin complex-1 (mTORC1) signaling pathway in human cancers. Tuberous sclerosis complex (TSC) is a genetic disorder which ... ...

Abstract	Purpose: New evidence is emerging that the availability of nutrients plays a key role in regulating the mammalian target of rapamycin complex-1 (mTORC1) signaling pathway in human cancers. Tuberous sclerosis complex (TSC) is a genetic disorder which results in the growth of hamartomatous lesions in multiple organs due to insufficient suppression of the mTORC1 pathway. A minority of patients with TSC who develop epilepsy which is intractable to standard anticonvulsant medical and/or surgical treatments are treated with the ketogenic diet. To provide insight into the effects of nutrient manipulation on tumor growth in this condition, we describe our experience in a unique group of patients with known tuberous sclerosis complex who are on the ketogenic diet for seizure control. Methods: A retrospective chart review was performed of patients with TSC treated with the ketogenic diet between January 2002 and May 2007 at Massachusetts General Hospital. Results: Five patients with definite TSC underwent serial imaging for tumor growth while on the ketogenic diet or had unchanged imaging prior to the onset of the diet and after termination. Three out of five patients, all children, had progression of a known tumor or tumors or the development of a new tumor while on the ketogenic diet. Conclusion: In this limited case series of five TSC patients, the ketogenic diet did not induce tumor regression or suppress the growth of TSC-related tumors.
MeSH term(s)	Adolescent ; Child ; Child, Preschool ; Diet, Ketogenic/adverse effects ; Disease Progression ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Neoplasms/metabolism ; Neoplasms/pathology ; Retrospective Studies ; Tuberous Sclerosis/diet therapy ; Tuberous Sclerosis/genetics ; Tuberous Sclerosis/pathology ; Young Adult
Language	English
Publishing date	2010-04
Publishing country	Netherlands
Document type	Case Reports ; Journal Article
ZDB-ID	604822-5
ISSN	1872-7131 ; 0387-7604
ISSN (online)	1872-7131
ISSN	0387-7604
DOI	10.1016/j.braindev.2009.04.009
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Article ; Online: New drugs for pediatric epilepsy.

Chu-Shore, Catherine J / Thiele, Elizabeth A

Seminars in pediatric neurology

2010 Volume 17, Issue 4, Page(s) 214–223

Abstract: The last 2 decades have witnessed an unprecedented period of new antiepileptic drug (AED) development. Newer-generation AEDs have been developed with the intention of improving the ease of use, decreasing drug interactions, decreasing adverse side ... ...

Abstract	The last 2 decades have witnessed an unprecedented period of new antiepileptic drug (AED) development. Newer-generation AEDs have been developed with the intention of improving the ease of use, decreasing drug interactions, decreasing adverse side effects, and identifying drugs with unique mechanisms of action, some of which may bear relevance to potential neuroprotective activity. Drug trials have also been refined in some cases to evaluate AED efficacy in children and against distinct epilepsy syndromes. This progress provides many new treatment options for the child neurologist facing children with epilepsy but also introduces the burden of determining appropriate AED choices. Here we highlight 6 new antiepileptic medications recently approved or pending approval for use in the United States: lacosamide, rufinamide, vigabatrin, retigabine, brivaracetam, and clobazam. For each of these medications, we present information regarding the history of drug development, proposed mechanism(s) of action, pharmacokinetics and recommended dosing, evidence for clinical efficacy, tolerability, and when, available, any unique features that are relevant for the pediatric population.
MeSH term(s)	Age Factors ; Anticonvulsants/adverse effects ; Anticonvulsants/pharmacology ; Anticonvulsants/therapeutic use ; Child ; Child, Preschool ; Drugs, Investigational/adverse effects ; Drugs, Investigational/pharmacology ; Drugs, Investigational/therapeutic use ; Epilepsy/drug therapy ; Humans
Chemical Substances	Anticonvulsants ; Drugs, Investigational
Language	English
Publishing date	2010-12
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1290000-x
ISSN	1558-0776 ; 1071-9091
ISSN (online)	1558-0776
ISSN	1071-9091
DOI	10.1016/j.spen.2010.10.003
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Article ; Online: Clobazam as an adjunctive therapy in treating seizures associated with Lennox-Gastaut syndrome.

Leahy, Jennifer T / Chu-Shore, Catherine J / Fisher, Janet L

Neuropsychiatric disease and treatment

2011 Volume 7, Page(s) 673–681

Abstract: Lennox-Gastaut syndrome (LGS) is a devastating childhood epilepsy syndrome characterized by the occurrence of multiple types of seizures and cognitive decline. Most children suffer from frequent seizures that are refractory to current medical management. ...

Abstract	Lennox-Gastaut syndrome (LGS) is a devastating childhood epilepsy syndrome characterized by the occurrence of multiple types of seizures and cognitive decline. Most children suffer from frequent seizures that are refractory to current medical management. Recent clinical trials have suggested that addition of clobazam may improve the clinical outcome for some LGS patients. Although clobazam has been available for over five decades, it has only recently been approved by the US Food and Drug Administration for this indication. As a 1,5-benzodiazepine, clobazam is structurally related to the widely used 1,4-benzodiazepines, which include diazepam. Clobazam has been shown to modulate GABAergic neurotransmission by positive allosteric modulation of GABA(A) receptors, and to increase expression of transporters for both GABA and glutamate. The active metabolite n-desmethylclobazam (norclobazam) also modulates GABA(A) receptors, and the relative importance of these two compounds in the clinical effectiveness of clobazam remains an open question. Clinical trials involving clobazam as an addon therapy in a variety of pediatric epilepsy populations have found a significant improvement in seizure control. In patients with LGS, clobazam may have greatest efficacy for drop seizures. Longstanding clinical experience suggests that clobazam is a safe and well tolerated antiepileptic drug with infrequent and mild adverse effects. These results suggest that adjunctive treatment with clobazam may be a reasonable option for LGS patients, particularly those who are treatment-resistant.
Language	English
Publishing date	2011-11-11
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2186503-6
ISSN	1178-2021 ; 1176-6328
ISSN (online)	1178-2021
ISSN	1176-6328
DOI	10.2147/NDT.S20173
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Article ; Online: Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex.

Chu-Shore, Catherine J / Major, Philippe / Montenegro, Maria / Thiele, Elizabeth

Neurology

2009 Volume 72, Issue 13, Page(s) 1165–1169

Abstract: Background: Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of hamartomatous lesions in multiple organs, including tubers in the brain. The majority of patients with TSC have epilepsy. Some cortical tubers are ... ...

Abstract	Background: Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of hamartomatous lesions in multiple organs, including tubers in the brain. The majority of patients with TSC have epilepsy. Some cortical tubers are epileptic foci, while others appear to be physiologically quiescent. It is unknown whether variations in tuber morphology may account for this difference. The objectives of this study were to determine the frequency of cyst-like tubers in patients with TSC, whether cyst-like tubers correlate with TSC genotype, and whether cyst-like cortical tubers are associated with a history of infantile spasms, epilepsy, or refractory epilepsy. Methods: A retrospective chart review was performed of 173 patients with TSC. MRI images were evaluated for the presence of at least one cyst-like cortical tuber. Patient charts were then reviewed for genetic mutation, a history of infantile spasms, epilepsy, and epilepsy refractory to more than three medications. Results: A total of 46% of patients had at least one cyst-like cortical tuber present on neuroimaging. Patients with a TSC2 mutation were more likely to have a cyst-like tuber than patients with TSC1 mutation (p = 0.002) or patients with no mutation identified (p = 0.039). Patients with at least one cyst-like cortical tuber were more likely to have a history of infantile spasms (p = 0.00005), epilepsy (p = 0.0038), and refractory epilepsy (p = 0.0007) than patients without a cyst-like cortical tuber. Conclusion: Cyst-like cortical tubers are strongly associated with TSC2 gene mutation and a more aggressive seizure phenotype in patients with tuberous sclerosis complex.
MeSH term(s)	Adolescent ; Adult ; Aged ; Cerebral Cortex/metabolism ; Cerebral Cortex/pathology ; Child ; Child, Preschool ; Cysts/complications ; Cysts/genetics ; Cysts/pathology ; Epilepsy/complications ; Epilepsy/genetics ; Epilepsy/pathology ; Female ; Humans ; Infant ; Male ; Middle Aged ; Mutation ; Retrospective Studies ; Tuberous Sclerosis/complications ; Tuberous Sclerosis/genetics ; Tuberous Sclerosis/pathology ; Tumor Suppressor Proteins/genetics ; Young Adult
Chemical Substances	Tumor Suppressor Proteins ; tuberous sclerosis complex 1 protein ; tuberous sclerosis complex 2 protein (4JG2LF96VF)
Language	English
Publishing date	2009-03-31
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/01.wnl.0000345365.92821.86
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Article ; Online: The relationship of ketosis and growth to the efficacy of the ketogenic diet in infantile spasms.

Numis, Adam L / Yellen, Margaret B / Chu-Shore, Catherine J / Pfeifer, Heidi H / Thiele, Elizabeth A

Epilepsy research

2011 Volume 96, Issue 1-2, Page(s) 172–175

Abstract: The ketogenic diet (KD) is a treatment of infantile spasms (IS). Here, we examine the efficacy of KD in medically refractory IS, examine its impact on growth in infants, and explore its mechanism of action. At 1-3 months after the initiation of the KD, ... ...

Abstract	The ketogenic diet (KD) is a treatment of infantile spasms (IS). Here, we examine the efficacy of KD in medically refractory IS, examine its impact on growth in infants, and explore its mechanism of action. At 1-3 months after the initiation of the KD, 46% of twenty-six patients had a greater than 90% reduction in IS. No significant relationships between reduction in IS and serum β-hydroxybutyrate, or glucose levels were identified. Also, the KD had not significantly altered patient's growth parameters. Thus, in corroborating with prior studies, we demonstrate the KD is a well-tolerated and efficacious treatment of IS.
MeSH term(s)	3-Hydroxybutyric Acid/metabolism ; Anthropometry ; Blood Glucose ; Body Height/physiology ; Body Weight/physiology ; Cohort Studies ; Diet, Ketogenic/methods ; Female ; Humans ; Infant ; Male ; Retrospective Studies ; Seizures/diet therapy ; Seizures/etiology ; Spasms, Infantile/complications ; Spasms, Infantile/diet therapy ; Spasms, Infantile/etiology
Chemical Substances	Blood Glucose ; 3-Hydroxybutyric Acid (TZP1275679)
Language	English
Publishing date	2011-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632939-1
ISSN	1872-6844 ; 0920-1211
ISSN (online)	1872-6844
ISSN	0920-1211
DOI	10.1016/j.eplepsyres.2011.05.012
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Zs.A 2193: Show issues

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Article ; Online: Network analysis: applications for the developing brain.

Chu-Shore, Catherine J / Kramer, Mark A / Bianchi, Matt T / Caviness, Verne S / Cash, Sydney S

Journal of child neurology

2011 Volume 26, Issue 4, Page(s) 488–500

Abstract: Development of the human brain follows a complex trajectory of age-specific anatomical and physiological changes. The application of network analysis provides an illuminating perspective on the dynamic interregional and global properties of this ... ...

Abstract	Development of the human brain follows a complex trajectory of age-specific anatomical and physiological changes. The application of network analysis provides an illuminating perspective on the dynamic interregional and global properties of this intricate and complex system. Here, we provide a critical synopsis of methods of network analysis with a focus on developing brain networks. After discussing basic concepts and approaches to network analysis, we explore the primary events of anatomical cortical development from gestation through adolescence. Upon this framework, we describe early work revealing the evolution of age-specific functional brain networks in normal neurodevelopment. Finally, we review how these relationships can be altered in disease and perhaps even rectified with treatment. While this method of description and inquiry remains in early form, there is already substantial evidence that the application of network models and analysis to understanding normal and abnormal human neural development holds tremendous promise for future discovery.
MeSH term(s)	Age Factors ; Brain/anatomy & histology ; Brain/growth & development ; Brain Mapping ; Humans ; Models, Neurological ; Nerve Net/physiology ; Neural Pathways/physiology
Language	English
Publishing date	2011-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639288-x
ISSN	1708-8283 ; 0883-0738
ISSN (online)	1708-8283
ISSN	0883-0738
DOI	10.1177/0883073810385345
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Zs.A 2301: Show issues

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Article ; Online: Progressive multifocal cystlike cortical tubers in tuberous sclerosis complex: Clinical and neuropathologic findings.

Chu-Shore, Catherine J / Frosch, Matthew P / Grant, Patricia E / Thiele, Elizabeth A

Epilepsia

2009 Volume 50, Issue 12, Page(s) 2648–2651

Abstract: Tuberous sclerosis complex (TSC) is a genetic disease characterized by the presence of hamartomatous lesions in multiple organs and cortical tubers in the brain. The majority of patients with TSC have epilepsy, although the mechanisms underlying ... ...

Abstract	Tuberous sclerosis complex (TSC) is a genetic disease characterized by the presence of hamartomatous lesions in multiple organs and cortical tubers in the brain. The majority of patients with TSC have epilepsy, although the mechanisms underlying epileptogenesis remain unknown. Tubers are traditionally thought to be stable lesions that result from abnormal corticogenesis in early fetal development. Recently, cystlike tubers have been identified in nearly half of patients with TSC, although the spectrum and natural history of these lesions remains unknown. Herein we report eight children with a high burden of cystlike tubers and present detailed clinical information on two children with documented progression. We also report neuropathologic findings of one of the cystlike cortical tubers resected in epilepsy surgery. These cases support the notion that cystlike tubers in TSC are not static lesions and can exhibit evolving characteristics over time. Further work evaluating how these lesions relate to epileptogenesis needs to be done.
MeSH term(s)	Brain/pathology ; Brain Diseases/genetics ; Brain Diseases/pathology ; Child ; Epilepsy/genetics ; Epilepsy/pathology ; Hamartoma/genetics ; Hamartoma/pathology ; Humans ; Tuberous Sclerosis/genetics ; Tuberous Sclerosis/pathology
Language	English
Publishing date	2009-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/j.1528-1167.2009.02193.x
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Article ; Online: The natural history of epilepsy in tuberous sclerosis complex.

Chu-Shore, Catherine J / Major, Philippe / Camposano, Susana / Muzykewicz, David / Thiele, Elizabeth A

Epilepsia

2009 Volume 51, Issue 7, Page(s) 1236–1241

Abstract: Background: Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease.: Methods: A retrospective chart review of all patients with TSC seen between ... ...

Abstract	Background: Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease. Methods: A retrospective chart review of all patients with TSC seen between January 2002 and October 2008. Charts were reviewed for a history of infantile spasms (IS), seizure other than IS, refractory epilepsy, Lennox-Gastaut syndrome (LGS), anticonvulsant medication use, ages of seizure onset, last seizure, last clinic visit, clinical seizure phenotype(s), cognitive impairment, and genetic mutation. Results: Two hundred ninety-one patients were included. Among these patients, 37.8% had a history of IS; 85.2% had a history of seizure; 54.1% developed multiple seizure types, not including IS; 63.2% had seizure onset in the first year of life; and 12.1% of adults without a seizure history developed epilepsy. Of epilepsy patients, 62.5% developed refractory epilepsy and 33.5% achieved epilepsy remission; 37.5% of these patients achieved medication freedom. IS was a risk factor for refractory epilepsy (p<0.0001) and LGS (p<0.0001). History of seizure, IS, age at seizure onset, and refractory epilepsy each correlated with poor cognitive outcome (p<0.0001). Epilepsy remission correlated with better cognitive outcome (p<0.0001). TSC2 was a risk factor for IS and epilepsy; patients without an identified mutation were more likely to achieve remission. Conclusion: Most patients with TSC develop epilepsy and most develop multiple seizure types. Onset typically occurs in the first year of life; however, adults remain at risk. Although refractory epilepsy is common, many patients achieve seizure control. Many features of seizure history are predictive of cognitive and epilepsy outcome.
MeSH term(s)	Adolescent ; Adult ; Child ; Child, Preschool ; Epilepsy/etiology ; Epilepsy/physiopathology ; Follow-Up Studies ; Humans ; Infant ; Infant, Newborn ; Middle Aged ; Retrospective Studies ; Tuberous Sclerosis/complications ; Tuberous Sclerosis/physiopathology ; Young Adult
Language	English
Publishing date	2009-12-22
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/j.1528-1167.2009.02474.x
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Article ; Online: Cognitive and adaptive development of patients with tuberous sclerosis complex: a retrospective, longitudinal investigation.

van Eeghen, Agnies M / Chu-Shore, Catherine J / Pulsifer, Margaret B / Camposano, Susana E / Thiele, Elizabeth A

Epilepsy & behavior : E&B

2012 Volume 23, Issue 1, Page(s) 10–15

Abstract: Objective: The aim of the work described here was to systematically analyze the developmental trajectory of patients with tuberous sclerosis complex (TSC).: Methods: A retrospective longitudinal chart review was performed, selecting patients who ... ...

Abstract	Objective: The aim of the work described here was to systematically analyze the developmental trajectory of patients with tuberous sclerosis complex (TSC). Methods: A retrospective longitudinal chart review was performed, selecting patients who received multiple neuropsychological assessments. Intellectual/Developmental Quotients, Adaptive Behavior Composite scores, and clinical data were collected. On available EEGs, interictal epileptiform discharges were counted. Results: Sixty-six (18%) patients with TSC received multiple cognitive and adaptive development assessments. The mean intelligence of this study group remained relatively stable, albeit variable. Significant decline in adaptive functioning was observed, associated with lower age at seizure onset. Patients who underwent neurosurgery prior to baseline testing showed cognitive improvement. Developmental declines were significantly associated with increased numbers of antiepileptic drugs, with a trend toward association with mutation type and interictal epileptiform discharges. Conclusion: This study suggests that the developmental course of patients with TSC may be altered by epilepsy comorbidity and neurosurgery, underlining the need for early and effective interventions in this population.
MeSH term(s)	Adaptation, Psychological/physiology ; Adolescent ; Age of Onset ; Child ; Child, Preschool ; Cognition Disorders/diagnosis ; Cognition Disorders/etiology ; Electroencephalography ; Female ; Humans ; Infant ; Intelligence/physiology ; Intelligence Tests ; Longitudinal Studies ; Male ; Neuropsychological Tests ; Retrospective Studies ; Tuberous Sclerosis/complications ; Tuberous Sclerosis/psychology ; Tuberous Sclerosis/surgery ; Young Adult
Language	English
Publishing date	2012-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2010587-3
ISSN	1525-5069 ; 1525-5050
ISSN (online)	1525-5069
ISSN	1525-5050
DOI	10.1016/j.yebeh.2011.10.005
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Article ; Online: Clobazam as an adjunctive therapy in treating seizures associated with Lennox–Gastaut syndrome

Leahy JT / Chu-Shore CJ / Fisher JL

Neuropsychiatric Disease and Treatment, Vol 2011, Iss Issue 1, Pp 673-

2011 Volume 681

Abstract: Jennifer T Leahy1, Catherine J Chu-Shore1,2, Janet L Fisher3 1Massachusetts General Hospital ...

Abstract	Jennifer T Leahy1, Catherine J Chu-Shore1,2, Janet L Fisher3 1Massachusetts General Hospital, Department of Neurology, Programs in Neurophysiology and Epilepsy, Boston, MA, 2Harvard Medical School, Boston, MA, 3University of South Carolina School of Medicine, Department of Pharmacology, Physiology and Neuroscience, Columbia, SC, USA Abstract: Lennox–Gastaut syndrome (LGS) is a devastating childhood epilepsy syndrome characterized by the occurrence of multiple types of seizures and cognitive decline. Most children suffer from frequent seizures that are refractory to current medical management. Recent clinical trials have suggested that addition of clobazam may improve the clinical outcome for some LGS patients. Although clobazam has been available for over five decades, it has only recently been approved by the US Food and Drug Administration for this indication. As a 1,5-benzodiazepine, clobazam is structurally related to the widely used 1,4-benzodiazepines, which include diazepam. Clobazam has been shown to modulate GABAergic neurotransmission by positive allosteric modulation of GABAA receptors, and to increase expression of transporters for both GABA and glutamate. The active metabolite n-desmethylclobazam (norclobazam) also modulates GABAA receptors, and the relative importance of these two compounds in the clinical effectiveness of clobazam remains an open question. Clinical trials involving clobazam as an addon therapy in a variety of pediatric epilepsy populations have found a significant improvement in seizure control. In patients with LGS, clobazam may have greatest efficacy for drop seizures. Longstanding clinical experience suggests that clobazam is a safe and well tolerated antiepileptic drug with infrequent and mild adverse effects. These results suggest that adjunctive treatment with clobazam may be a reasonable option for LGS patients, particularly those who are treatment-resistant. Keywords: benzodiazepine, epilepsy, gamma aminobutyric acid, pediatric, pharmacoresistance
Keywords	Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	610 ; 616
Language	English
Publishing date	2011-11-01T00:00:00Z
Publisher	Dove Medical Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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