|
1
|
Giliberti A, Frisina AM, Giustiniano S, Carbonaro Y, Roccella M, Nardello R. Autism Spectrum Disorder and Epilepsy: Pathogenetic Mechanisms and Therapeutic Implications. J Clin Med 2025; 14:2431. [PMID: 40217881 PMCID: PMC11989834 DOI: 10.3390/jcm14072431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/24/2025] [Accepted: 03/27/2025] [Indexed: 04/14/2025] Open
Abstract
The co-occurrence of autism spectrum disorder (ASD) and epilepsy is a complex neurological condition that presents significant challenges for both patients and clinicians. ASD is a group of complex developmental disorders characterized by the following: (1) Social communication difficulties: challenges in understanding and responding to social cues, initiating and maintaining conversations, and developing and maintaining relationships. (2) Repetitive behaviors: engaging in repetitive actions, such as hand-flapping, rocking, or lining up objects. (3) Restricted interests: focusing intensely on specific topics or activities, often to the exclusion of other interests. (4) Sensory sensitivities: over- or under-sensitivity to sensory input, such as sounds, touch, tastes, smells, or sights. These challenges can significantly impact individuals' daily lives and require specialized support and interventions. Early diagnosis and intervention can significantly improve the quality of life for individuals with ASD and their families. Epilepsy is a chronic brain disorder characterized by recurrent unprovoked (≥2) seizures that occur >24 h apart. Single seizures are not considered epileptic seizures. Epilepsy is often idiopathic, but various brain disorders, such as malformations, strokes, and tumors, can cause symptomatic epilepsy. While these two conditions were once considered distinct, growing evidence suggests a substantial overlap in their underlying neurobiology. The prevalence of epilepsy in individuals with ASD is significantly higher than in the general population. This review will explore the epidemiology of this comorbidity, delve into the potential mechanisms linking ASD and epilepsy, and discuss the implications for diagnosis, treatment, and management.
Collapse
Affiliation(s)
- Alessandra Giliberti
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialities “G. D’Alessandro”, University of Palermo, 90128 Palermo, Italy (R.N.)
| | - Adele Maria Frisina
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialities “G. D’Alessandro”, University of Palermo, 90128 Palermo, Italy (R.N.)
| | - Stefania Giustiniano
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialities “G. D’Alessandro”, University of Palermo, 90128 Palermo, Italy (R.N.)
| | - Ylenia Carbonaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialities “G. D’Alessandro”, University of Palermo, 90128 Palermo, Italy (R.N.)
| | - Michele Roccella
- Department of Psychology, Educational Science and Human Movement, University of Palermo, 90128 Palermo, Italy
| | - Rosaria Nardello
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialities “G. D’Alessandro”, University of Palermo, 90128 Palermo, Italy (R.N.)
| |
Collapse
|
|
2
|
Eltokhi A, Gamal El-Din TM. Two pores instead of one: Gating pore current and the electrical leak in autism and epilepsy. Prog Neuropsychopharmacol Biol Psychiatry 2025; 137:111291. [PMID: 39947579 DOI: 10.1016/j.pnpbp.2025.111291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 02/05/2025] [Accepted: 02/10/2025] [Indexed: 02/22/2025]
Abstract
Imagine the brain as a dynamic city, where countless vehicles traverse major arterial roads and branching side streets. The smooth traffic flow depends on a balance between excitatory neurons, which act as main roads encouraging vehicles to move forward, and inhibitory neurons, represented by branching side streets that regulate and control the traffic flow back onto the main route. Both systems work in tandem to maintain efficient operations, preventing gridlock or chaos. Zooming in further, the voltage-gated ion channels within neurons resemble traffic lights on arterial roads or side streets. Green means go, red means stop, and yellow signals caution. These channels regulate the flow of bioelectric signals, coordinating transitions between green, yellow, and red-analogous to an action potential. In excitatory neurons (major roads), voltage-gated sodium channels act as green lights, allowing sodium ions to flow in during depolarization. In contrast, voltage-gated potassium channels serve as yellow lights, eventually signaling red to terminate the action potential. In inhibitory neurons (side streets), sodium influx produces action potentials that ultimately control and limit traffic on the major roads. This analogy can be extended to describe neuropsychiatric and neurological disorders, such as autism spectrum disorder (ASD) and epilepsy, which arise from mutations in voltage-gated ion channels. These mutations alter the channels' ability to open and close properly, disrupting the timing and duration of red, yellow and green signals and impairing traffic flow. Now, picture yourself on a major arterial road with green and red flickering simultaneously. Such a disastrous scenario could lead to even more dangerous outcomes, with cars moving when they should stop or stopping when they should move. This specific analogy illustrates a key feature of certain mutations in voltage-gated ion channels that result in the gating pore current (Igp), a secondary pore that leaks electrical current. This mini-review focuses on Igp caused by mutations in the gating charge residues of voltage-gated ion channels. We will discuss how Igp contributes to the pathophysiology of ASD and epilepsy and explore therapeutic strategies targeting this mechanism.
Collapse
Affiliation(s)
- Ahmed Eltokhi
- Department of Biomedical Sciences, Mercer University School of Medicine, Columbus, GA 31901, United States of America.
| | - Tamer M Gamal El-Din
- Department of Pharmacology, University of Washington, Seattle, WA 98195, United States of America.
| |
Collapse
|
|
3
|
Matsuura R, Hamano SI, Hirata Y, Oba A, Horita H, Takeuchi H, Koichihara R, Kikuchi K, Oka A. Elementary school enrollment after ACTH therapy for patients with infantile epileptic spasms syndrome. Seizure 2025; 124:80-84. [PMID: 39705749 DOI: 10.1016/j.seizure.2024.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 11/29/2024] [Accepted: 12/04/2024] [Indexed: 12/22/2024] Open
Abstract
PURPOSE Infantile epileptic spasms syndrome (IESS) often has a severe neurodevelopmental prognosis. However, few studies have examined the aspect of elementary school enrollment. This study evaluated elementary school enrollment after adrenocorticotropic hormone (ACTH) therapy in patients with IESS. METHODS We retrospectively evaluated the elementary school enrollment of patients with IESS who were administered ACTH at the Saitama Children's Medical Center between January 1993 and August 2024. We evaluated elementary school enrollment, seizure outcomes, motor development, and intellectual development at the time of school enrollment in the ACTH responder and nonresponder groups. Response was defined as complete remission of epileptic spasms and no other seizure occurrence from ACTH administration initiation until the age of 6 years. RESULTS In total, 116 patients (62 male) were included in this study. The median age at IESS onset was 5 (range, 0-24) months. Twenty-seven patients (23.3 %) maintained complete remission of epileptic spasms from ACTH initiation to elementary school enrollment. The responder group had a significantly higher rate of regular class attendance (48.1 %) and exhibited normal intelligence or developmental quotient (33.3 %) compared with the nonresponder group (p < 0.01 and p < 0.01, respectively). Patients with an unknown etiology were more likely to attend regular classes (37.5 %). The median age of the last hospital visit was 13 (6.0-24.4) years. Lennox-Gastaut syndrome was diagnosed in 5.2 % (6/116) of patients at the last visit. CONCLUSION Our findings can help pediatricians predict elementary school enrollment and neurodevelopmental outcomes in patients with IESS receiving ACTH therapy.
Collapse
Affiliation(s)
- Ryuki Matsuura
- Division of Neurology, Saitama Children's Medical Center, 1-2, Shintoshin, Chuo-ku, Saitama, Japan; Department of Pediatrics, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, Japan.
| | - Shin-Ichiro Hamano
- Division of Neurology, Saitama Children's Medical Center, 1-2, Shintoshin, Chuo-ku, Saitama, Japan.
| | - Yuko Hirata
- Division of Neurology, Saitama Children's Medical Center, 1-2, Shintoshin, Chuo-ku, Saitama, Japan; Department of Pediatrics, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, Japan.
| | - Azusa Oba
- Division of Neurology, Saitama Children's Medical Center, 1-2, Shintoshin, Chuo-ku, Saitama, Japan.
| | - Haruhito Horita
- Division of Neurology, Saitama Children's Medical Center, 1-2, Shintoshin, Chuo-ku, Saitama, Japan.
| | - Hirokazu Takeuchi
- Division of Neurology, Saitama Children's Medical Center, 1-2, Shintoshin, Chuo-ku, Saitama, Japan; Department of Pediatrics, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, Japan.
| | - Reiko Koichihara
- Division of Child Health and Human Development, Saitama Children's Medical Center, Saitama, Japan.
| | - Kenjiro Kikuchi
- Division of Neurology, Saitama Children's Medical Center, 1-2, Shintoshin, Chuo-ku, Saitama, Japan; Department of Pediatrics, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, Japan.
| | - Akira Oka
- Division of Neurology, Saitama Children's Medical Center, 1-2, Shintoshin, Chuo-ku, Saitama, Japan.
| |
Collapse
|
|
4
|
Hu HT, Hsueh YP. KLHL17 differentially controls the expression of AMPA- and KA-type glutamate receptors to regulate dendritic spine enlargement. J Neurochem 2024; 168:2155-2169. [PMID: 38898681 DOI: 10.1111/jnc.16148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/24/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024]
Abstract
Kelch-like family member 17 (KLHL17), an actin-associated adaptor protein, is linked to neurological disorders, including infantile spasms and autism spectrum disorders. The key morphological feature of Klhl17-deficient neurons is impaired dendritic spine enlargement, resulting in the amplitude of calcium events being increased. Our previous studies have indicated an involvement of F-actin and the spine apparatus in KLHL17-mediated dendritic spine enlargement. Here, we show that KLHL17 further employs different mechanisms to control the expression of two types of glutamate receptors, that is, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and kainate receptors (KARs), to regulate dendritic spine enlargement and calcium influx. We deployed proteomics to reveal that KLHL17 interacts with N-ethylmaleimide-sensitive fusion protein (NSF) in neurons, with this interaction of KLHL17 and NSF enhancing NSF protein levels. Consistent with the function of NSF in regulating the surface expression of AMPAR, Klhl17 deficiency limits the surface expression of AMPAR, but not its total protein levels. The NSF pathway also contributes to synaptic F-actin distribution and the dendritic spine enlargement mediated by KLHL17. KLHL17 is known to act as an adaptor mediating degradation of the KAR subunit GluK2 by the CUL3 ubiquitin ligase complex, and Klhl17 deficiency impairs activity-dependent degradation of GluK2. Herein, we further demonstrate that GluK2 is critical to the increased amplitude of calcium influx in Klhl17-deficient neurons. Moreover, GluK2 is also involved in KLHL17-regulated dendritic spine enlargement. Thus, our study reveals that KLHL17 controls AMPAR and KAR expression via at least two mechanisms, consequently regulating dendritic spine enlargement. The regulatory effects of KLHL17 on these two glutamate receptors likely contribute to neuronal features in patients suffering from certain neurological disorders.
Collapse
Affiliation(s)
- Hsiao-Tang Hu
- Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC
| | - Yi-Ping Hsueh
- Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC
| |
Collapse
|
|
5
|
Matos MBD, Liberalesso PBN, Bara TDS, Gomes PCMA, Zeigelboim BS, Marques JM, Cordeiro ML. Risk of autism spectrum disorder in children with infantile epileptic spasms syndrome: a retrospective study in a single center in Brazil. J Pediatr (Rio J) 2024; 100:552-556. [PMID: 38823785 PMCID: PMC11361869 DOI: 10.1016/j.jped.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 04/16/2024] [Accepted: 04/21/2024] [Indexed: 06/03/2024] Open
Abstract
OBJECTIVE This study aimed to investigate the prevalence of autism spectrum disorder and its possible correlations with clinical characteristics in patients with infantile epileptic spasms syndrome in a single center in Brazil. METHODS This retrospective cross-sectional study examined 53 children with the diagnosis of infantile epileptic spasms syndrome prior to an autism spectrum disorder assessment. Participants were divided into two groups based on the presence or absence of autism spectrum disorder. Available variables (sex, medications, median age at onset of infantile epileptic spasms syndrome, and presence of comorbidities) were compared using Mann-Whitney U or chi-square tests. RESULTS Among the included patients, 12 (23 %) were diagnosed with autism spectrum disorder, corresponding to a relative risk of 0.29 (95 % confidence interval 0.174-0.492). The age at the first seizure ranged from 3 to 15 months, with a mean of 6.65 months. This age significantly differed between participants with autism spectrum disorder (10.58 months) and those without (5.43 months), p<0.001. CONCLUSION Children with infantile epileptic spasms syndrome have a higher risk of being diagnosed with autism spectrum disorder. Later age of onset and period of spasm occurrence might be predisposing risk factors.
Collapse
Affiliation(s)
- Marília Barbosa de Matos
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, PR, Brazil; Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Paulo Breno Noronha Liberalesso
- Hospital Pequeno Príncipe, Departamento de Neurologia Pediátrica, Curitiba, PR, Brazil; Universidade Tuiuti do Paraná, Laboratório de Otoneurologia, Curitiba, PR, Brazil
| | - Tiago Dos Santos Bara
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, PR, Brazil; Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | | | - Bianca Simone Zeigelboim
- Hospital Pequeno Príncipe, Departamento de Neurologia Pediátrica, Curitiba, PR, Brazil; Universidade Tuiuti do Paraná, Laboratório de Otoneurologia, Curitiba, PR, Brazil
| | - Jair Mendes Marques
- Universidade Tuiuti do Paraná, Laboratório de Otoneurologia, Curitiba, PR, Brazil
| | - Mara L Cordeiro
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, PR, Brazil; Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Centro de Reabilitação Neuropediátrica do Hospital Menino Deus (CERENA), Curitiba, PR, Brazil.
| |
Collapse
|
|
6
|
Kaur P, Kaur A. Review of Progress in Diagnostic Studies of Autism Spectrum Disorder Using Neuroimaging. Interdiscip Sci 2023; 15:111-130. [PMID: 36633792 DOI: 10.1007/s12539-022-00548-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 12/27/2022] [Accepted: 12/27/2022] [Indexed: 01/13/2023]
Abstract
This review article summarizes the recent advances in the diagnostic studies of autism spectrum disorders (ASDs) considering some of the most influential research articles from the last two decades. ASD is a heterogeneous neurodevelopmental disorder characterized by abnormalities in social interaction, communication, and behavioral patterns as well as some unique strengths and differences. The current diagnosis systems are based on autism diagnostic observation schedule (ADOS) or autism diagnostic interview-revised (ADI-R), but biological markers are also important for an effective diagnosis of ASDs. The amalgamation of neuroimaging techniques, such as structural and functional magnetic resonance imaging (sMRI and fMRI), with machine-learning and deep-learning approaches helps throw new light on typical biological markers of ASDs at the early stage of life. To assess the performance of a deep neural network, we develop a light-weighted CNN model for ASD classification. The overall accuracy, precision, and F1-score of the proposed model are 99.92%, 99.93% and 99.92%, respectively. All the neuroimaging studies we have reviewed can be divided into 3 categories, viz. thickness, volume and functional connectivity-based studies. We conclude with a discussion of the major findings of considered studies and promising directions for future research in this field.
Collapse
Affiliation(s)
- Palwinder Kaur
- Department of Computer Science and Technology, Central University of Punjab, Bathinda, Punjab, 151001, India
| | - Amandeep Kaur
- Department of Computer Science and Technology, Central University of Punjab, Bathinda, Punjab, 151001, India.
| |
Collapse
|
|
7
|
Gettings JV, Shafi S, Boyd J, Snead OC, Rutka J, Drake J, McCoy B, Jain P, Whitney R, Go C. The Epilepsy Surgery Experience in Children With Infantile Epileptic Spasms Syndrome at a Tertiary Care Center in Canada. J Child Neurol 2023; 38:113-120. [PMID: 36788207 DOI: 10.1177/08830738231151993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
BACKGROUND Infantile epileptic spasms syndrome is an epileptic encephalopathy, characterized by spasms, hypsarrhythmia, and developmental regression. Appropriately selected patients with infantile epileptic spasms syndrome may be candidates for epilepsy surgery. METHODS This is a single-center retrospective case series of children 0-18 years with a current or previous diagnosis of infantile epileptic spasms syndrome with a lesion on magnetic resonance imaging (MRI) and/or positron emission tomography scan who underwent epilepsy surgery at The Hospital for Sick Children (HSC) in Toronto, Canada. The records of 223 patients seen in the infantile epileptic spasms syndrome clinic were reviewed. RESULTS Nineteen patients met inclusion criteria. The etiology of infantile epileptic spasms syndrome was encephalomalacia in 6 patients (32%), malformations of cortical development in 12 patients (63%), and atypical hypoglycemic injury in 1 patient (5%). Nine patients (47%) underwent hemispherectomy, and 10 patients (53%) underwent lobectomy/lesionectomy. Three patients (16%) underwent a second epilepsy surgery. Fifteen patients (79%) were considered ILAE seizure outcome class 1 (completely seizure free; no auras) at their most recent follow-up visit. The percentage of patients who were ILAE class 1 at most recent follow-up decreased with increasing duration of epilepsy prior to surgery. Developmental outcome after surgery was improved in 14 of 19 (74%) and stable in 5 of 19 (26%) patients. CONCLUSIONS Our study found excellent seizure freedom rates and improved developmental outcomes following epilepsy surgery in patients with a history of infantile epileptic spasms syndrome with a structural lesion detected on MRI brain. Patients who undergo surgery earlier have improved seizure freedom rates and improved developmental outcomes.
Collapse
Affiliation(s)
- Jennifer V Gettings
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children (University of Toronto), Toronto, Ontario, Canada
| | - Shatha Shafi
- Division of Neurology, Department of Pediatrics, 37853Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Jennifer Boyd
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children (University of Toronto), Toronto, Ontario, Canada
| | - O Carter Snead
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children (University of Toronto), Toronto, Ontario, Canada
| | - James Rutka
- Division of Neurosurgery, Department of Pediatrics, The Hospital for Sick Children (University of Toronto), Toronto, Ontario, Canada
| | - James Drake
- Division of Neurosurgery, Department of Pediatrics, The Hospital for Sick Children (University of Toronto), Toronto, Ontario, Canada
| | - Bláthnaid McCoy
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children (University of Toronto), Toronto, Ontario, Canada
| | - Puneet Jain
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children (University of Toronto), Toronto, Ontario, Canada
| | - Robyn Whitney
- Division of Neurology, Department of Paediatrics, McMaster Children's Hospital (McMaster University), Hamilton, ON, Canada
| | - Cristina Go
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children (University of Toronto), Toronto, Ontario, Canada.,Division of Neurology, Department of Pediatrics, British Columbia Children's Hospital (University of British Columbia), Toronto, Ontario, Canada
| |
Collapse
|
|
8
|
Fine A, Wirrell E, Nickels K. Optimizing Therapy of Seizures in Children and Adolescents with Developmental Disabilities. NEURODEVELOPMENTAL PEDIATRICS 2023:631-653. [DOI: 10.1007/978-3-031-20792-1_39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
9
|
Pepper J, Lo WB, Agrawal S, Mohamed R, Horton J, Balloo S, Philip S, Basnet A, Wimalachandra WSB, Lawley A, Seri S, Walsh AR. Functional hemispherotomy for epilepsy in the very young. J Neurosurg Pediatr 2022; 30:400-409. [PMID: 35932273 DOI: 10.3171/2022.6.peds21521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 06/02/2022] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Epilepsy is one of the most common neurological disorders in children. Among very young children, one-third are resistant to medical treatment, and lack of effective treatment may result in adverse outcomes. Although functional hemispherotomy is an established treatment for epilepsy, its outcome in the very young child has not been widely reported. In this study the authors investigated seizure and developmental results after hemispherotomy in children younger than 3 years. METHODS The authors reviewed a prospective database of all children younger than 3 years with medically intractable epilepsy who underwent functional hemispherotomy at the authors' institution during the period between 2012 and 2020. Demographic data, epilepsy history, underlying etiology, operative and transfusion details, and seizure and developmental outcomes were analyzed. RESULTS Twelve patients were included in this study. The mean age (± SD) at seizure onset was 3 ± 2.6 months and at surgery was 1.3 ± 0.77 years, with a mean follow-up of 4 years. Diagnoses included hemimegalencephaly (n = 5), hemidysplasia (n = 2), hypoxic/hemorrhagic (n = 2), traumatic (n = 1), Sturge-Weber syndrome (n = 1), and mild hemispheric structural abnormality with EEG/PET correlates (n = 1). Eleven patients achieved an Engel class I outcome, and 1 patient achieved Engel class IV at last follow-up. No deaths, infections, cerebrovascular events, or unexpected long-term neurological deficits were recorded. All children progressed neurodevelopmentally following surgery, but their developmental levels remained behind their chronological age, with an overall mean composite Vineland Adaptive Behavior Scale score of 58 (normal: 86-114, low: < 70). One patient required insertion of a subdural peritoneal shunt, 1 patient required dural repair for a CSF fluid leak, and 1 patient required aspiration of a pseudomeningocele. In 2 patients, both of whom weighed less than 5.7 kg, the first operation was incomplete due to blood loss. CONCLUSIONS Hemispherotomy in children younger than 3 years offers excellent seizure control and an acceptable risk-to-benefit ratio in well-selected patients. Families of children weighing less than 6 kg should be counseled regarding the possibility of staged surgery. Postoperatively, children continue to make appropriate, despite delayed, developmental progress.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Stefano Seri
- 4Department of Neurophysiology, Birmingham Children's Hospital, Birmingham, United Kingdom
| | | |
Collapse
|
|
10
|
Liu X, Chen J, Wan L, Li Z, Liang Y, Yan H, Zhu G, Zhang B, Yang G. Interrater and Intrarater Agreement of Epileptic Encephalopathy Among Electroencephalographers for Children with Infantile Spasms Using the Burden of Amplitudes and Epileptiform Discharges (BASED) EEG Grading Scale: Study Design and Statistical Considerations. Neurol Ther 2022; 11:1427-1437. [PMID: 35809161 PMCID: PMC9338191 DOI: 10.1007/s40120-022-00382-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/17/2022] [Indexed: 11/26/2022] Open
Abstract
Background Infantile spasms are a serious epilepsy syndrome with a poor prognosis. Electroencephalography (EEG) has been a key component in the prognosis and treatment of infantile spasms. This multi-center study protocol is developed to investigate interrater and intrarater agreement of an electroencephalographic grading scale—the Burden of Amplitudes and Epileptiform Discharges (BASED) score among electroencephalographers. Methods Thirty children, aged 0–2 years, with infantile spasms who were hospitalized in the Chinese PLA General Hospital will be recruited into this study by stratified sampling. Seven electroencephalographers from different Class A tertiary hospitals will select a 5-min epoch with the most severe epileptiform discharge, score the EEG reports, and provide the basis for the scoring. The 420 (30 × 7 × 2) scoring results provided by electroencephalographers in two rounds can be analyzed statistically using weighted kappa (weighted \documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$\kappa$$\end{document}κ) statstic, Fless’ kappa (Fless’ \documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$\kappa$$\end{document}κ) statistic, and intraclass correlation coefficient (ICC) to calculate the interrater and intrarater agreement. Discussion We will recruit more electroencephalographers than were included in previous studies to assess the interrater and intrarater agreement in the selection of 5-min EEG epochs, the BASED scores, and the basis for scoring. If the BASED score has an adequate interrater and intrarater agreement, the score will have more significance for guiding the clinical management and for predicting the prognosis of patients with infantile spasms. Supplementary Information The online version contains supplementary material available at 10.1007/s40120-022-00382-4.
Collapse
Affiliation(s)
- Xinting Liu
- Department of Pediatrics, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
- Senior Department of Pediatrics, Seventh Medical Center, PLA General Hospital, Beijing, 100000, China
| | - Jian Chen
- Department of Pediatrics, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Senior Department of Pediatrics, Seventh Medical Center, PLA General Hospital, Beijing, 100000, China
| | - Lin Wan
- Department of Pediatrics, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
- Senior Department of Pediatrics, Seventh Medical Center, PLA General Hospital, Beijing, 100000, China
| | - Zhichao Li
- Department of Pediatrics, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
- Senior Department of Pediatrics, Seventh Medical Center, PLA General Hospital, Beijing, 100000, China
| | - Yan Liang
- Department of Pediatrics, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
- Senior Department of Pediatrics, Seventh Medical Center, PLA General Hospital, Beijing, 100000, China
| | - Huimin Yan
- Department of Pediatrics, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
- Senior Department of Pediatrics, Seventh Medical Center, PLA General Hospital, Beijing, 100000, China
| | - Guangyu Zhu
- Department of Computer Science and Statistics, University of Rhode Island, Kingston, RI, USA
| | - Bo Zhang
- Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
- Biostatistics and Research Design Center, Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Guang Yang
- Department of Pediatrics, First Medical Center, Chinese PLA General Hospital, Beijing, China.
- Senior Department of Pediatrics, Seventh Medical Center, PLA General Hospital, Beijing, 100000, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
| |
Collapse
|
|
11
|
Vasquez A, Buraniqi E, Wirrell EC. New and emerging pharmacologic treatments for developmental and epileptic encephalopathies. Curr Opin Neurol 2022; 35:145-154. [PMID: 35102126 DOI: 10.1097/wco.0000000000001029] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Summarize evidence on Developmental and Epileptic Encephalopathies (DEEs) treatments focusing on new and emerging pharmacologic therapies (see Video, http://links.lww.com/CONR/A61, Supplementary Digital Content 1, which provides an overview of the review). RECENT FINDINGS Advances in the fields of molecular genetics and neurobiology have led to the recognition of underlying pathophysiologic mechanisms involved in an increasing number of DEEs that could be targeted with precision therapies or repurposed drugs, some of which are currently being evaluated in clinical trials. Prompt, optimal therapy is critical, and promising therapies approved or in clinical trials for tuberous sclerosis complex, Dravet and Lennox-Gastaut Syndromes including mammalian target of rapamycin inhibitors, selective membrane channel and antisense oligonucleotide modulation, and repurposed drugs such as fenfluramine, stiripentol and cannabidiol, among others, may improve seizure burden and neurological outcomes. There is an urgent need for collaborative efforts to evaluate the efficacy and safety of emerging DEEs therapies. SUMMARY Development of new therapies promise to address unmet needs for patients with DEEs, including improvement of neurocognitive function and quality of life.
Collapse
Affiliation(s)
- Alejandra Vasquez
- Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
| | | | | |
Collapse
|
|
12
|
Specchio N, Di Micco V, Trivisano M, Ferretti A, Curatolo P. The epilepsy-autism spectrum disorder phenotype in the era of molecular genetics and precision therapy. Epilepsia 2021; 63:6-21. [PMID: 34741464 DOI: 10.1111/epi.17115] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 10/20/2021] [Accepted: 10/20/2021] [Indexed: 11/30/2022]
Abstract
Autism spectrum disorder (ASD) is frequently associated with infants with epileptic encephalopathy, and early interventions targeting social and cognitive deficits can have positive effects on developmental outcome. However, early diagnosis of ASD among infants with epilepsy is complicated by variability in clinical phenotypes. Commonality in both biological and molecular mechanisms have been suggested between ASD and epilepsy, such as occurs with tuberous sclerosis complex. This review summarizes the current understanding of causal mechanisms between epilepsy and ASD, with a particularly genetic focus. Hypothetical explanations to support the conjugation of the two conditions include abnormalities in synaptic growth, imbalance in neuronal excitation/inhibition, and abnormal synaptic plasticity. Investigation of the probable genetic basis has implemented many genes, although the main risk supports existing hypotheses in that these cluster to abnormalities in ion channels, synaptic function and structure, and transcription regulators, with the mammalian target of rapamycin (mTOR) pathway and "mTORpathies" having been a notable research focus. Experimental models not only have a crucial role in determining gene functions but are also useful instruments for tracing disease trajectory. Precision medicine from gene therapy remains a theoretical possibility, but more contemporary developments continue in molecular tests to aid earlier diagnoses and better therapeutic targeting.
Collapse
Affiliation(s)
- Nicola Specchio
- Rare and Complex Epilepsy Unit, Division of Neurology, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy
| | - Valentina Di Micco
- Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy
| | - Marina Trivisano
- Rare and Complex Epilepsy Unit, Division of Neurology, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy
| | - Alessandro Ferretti
- Rare and Complex Epilepsy Unit, Division of Neurology, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy
| | - Paolo Curatolo
- Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy
| |
Collapse
|
|
13
|
Al-Beltagi M. Autism medical comorbidities. World J Clin Pediatr 2021; 10:15-28. [PMID: 33972922 PMCID: PMC8085719 DOI: 10.5409/wjcp.v10.i3.15] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/12/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Medical comorbidities are more common in children with autism spectrum disorders (ASD) than in the general population. Some genetic disorders are more common in children with ASD such as Fragile X syndrome, Down syndrome, Duchenne muscular dystrophy, neurofibromatosis type I, and tuberous sclerosis complex. Children with autism are also more prone to a variety of neurological disorders, including epilepsy, macrocephaly, hydrocephalus, cerebral palsy, migraine/headaches, and congenital abnormalities of the nervous system. Besides, sleep disorders are a significant problem in individuals with autism, occurring in about 80% of them. Gastrointestinal (GI) disorders are significantly more common in children with ASD; they occur in 46% to 84% of them. The most common GI problems observed in children with ASD are chronic constipation, chronic diarrhoea, gastroesophageal reflux and/or disease, nausea and/or vomiting, flatulence, chronic bloating, abdominal discomfort, ulcers, colitis, inflammatory bowel disease, food intolerance, and/or failure to thrive. Several categories of inborn-errors of metabolism have been observed in some patients with autism including mitochondrial disorders, disorders of creatine metabolism, selected amino acid disorders, disorders of folate or B12 metabolism, and selected lysosomal storage disorders. A significant proportion of children with ASD have evidence of persistent neuroinflammation, altered inflammatory responses, and immune abnormalities. Anti-brain antibodies may play an important pathoplastic mechanism in autism. Allergic disorders are significantly more common in individuals with ASD from all age groups. They influence the development and severity of symptoms. They could cause problematic behaviours in at least a significant subset of affected children. Therefore, it is important to consider the child with autism as a whole and not overlook possible symptoms as part of autism. The physician should rule out the presence of a medical condition before moving on to other interventions or therapies. Children who enjoy good health have a better chance of learning. This can apply to all children including those with autism.
Collapse
Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatrics, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama P.O. Box 26671, Bahrain, Bahrain
- Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta 0000000, Al Gharbia, Egypt
| |
Collapse
|
|
14
|
Al-Beltagi M. Autism medical comorbidities. World J Clin Pediatr 2021. [PMID: 33972922 DOI: 10.5409/wjcp.v10.i3.15.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Medical comorbidities are more common in children with autism spectrum disorders (ASD) than in the general population. Some genetic disorders are more common in children with ASD such as Fragile X syndrome, Down syndrome, Duchenne muscular dystrophy, neurofibromatosis type I, and tuberous sclerosis complex. Children with autism are also more prone to a variety of neurological disorders, including epilepsy, macrocephaly, hydrocephalus, cerebral palsy, migraine/headaches, and congenital abnormalities of the nervous system. Besides, sleep disorders are a significant problem in individuals with autism, occurring in about 80% of them. Gastrointestinal (GI) disorders are significantly more common in children with ASD; they occur in 46% to 84% of them. The most common GI problems observed in children with ASD are chronic constipation, chronic diarrhoea, gastroesophageal reflux and/or disease, nausea and/or vomiting, flatulence, chronic bloating, abdominal discomfort, ulcers, colitis, inflammatory bowel disease, food intolerance, and/or failure to thrive. Several categories of inborn-errors of metabolism have been observed in some patients with autism including mitochondrial disorders, disorders of creatine metabolism, selected amino acid disorders, disorders of folate or B12 metabolism, and selected lysosomal storage disorders. A significant proportion of children with ASD have evidence of persistent neuroinflammation, altered inflammatory responses, and immune abnormalities. Anti-brain antibodies may play an important pathoplastic mechanism in autism. Allergic disorders are significantly more common in individuals with ASD from all age groups. They influence the development and severity of symptoms. They could cause problematic behaviours in at least a significant subset of affected children. Therefore, it is important to consider the child with autism as a whole and not overlook possible symptoms as part of autism. The physician should rule out the presence of a medical condition before moving on to other interventions or therapies. Children who enjoy good health have a better chance of learning. This can apply to all children including those with autism.
Collapse
Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatrics, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama P.O. Box 26671, Bahrain, Bahrain
| |
Collapse
|
|
15
|
Holmes H, Sawer F, Clark M. Autism spectrum disorders and epilepsy in children: A commentary on the occurrence of autism in epilepsy; how it can present differently and the challenges associated with diagnosis. Epilepsy Behav 2021; 117:107813. [PMID: 33642176 DOI: 10.1016/j.yebeh.2021.107813] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 01/17/2021] [Accepted: 01/20/2021] [Indexed: 01/02/2023]
Abstract
Autism occurs more frequently in epilepsy, but is often not diagnosed. This could be due to a focus on medical issues, or because it presents differently from classic autism in its timing, phenotype, fluctuating profiles, and high level of comorbidity. Without a diagnosis, these children miss out on interventions that could modify outcome and their families and local teams will struggle to understand and support them. They also become a hidden group that does not participate in or benefit from research. This paper examined the issues and challenges of diagnosing autism in a population with a high-risk of epilepsy, drawing on more than 20 years' experience of a specialist multi-disciplinary Developmental Epilepsy Clinic (DEC).
Collapse
Affiliation(s)
- Harriet Holmes
- Developmental Epilepsy Clinic, Great Ormond Street Hospital, London WC1N3JH, UK
| | - Francesca Sawer
- Developmental Epilepsy Clinic, Great Ormond Street Hospital, London WC1N3JH, UK
| | - Maria Clark
- Developmental Epilepsy Clinic, Great Ormond Street Hospital, London WC1N3JH, UK.
| |
Collapse
|
|
16
|
Abstract
Epilepsy and autism frequently co-occur. Epilepsy confers an increased risk of autism and autism confers an increased risk of epilepsy. Specific epilepsy syndromes, intellectual disability, and female gender present a particular risk of autism in individuals with epilepsy. Epilepsy and autism are likely to share common etiologies, which predispose individuals to either or both conditions. Genetic factors, metabolic disorders, mitochondrial disorders, and immune dysfunction all can be implicated.
Collapse
Affiliation(s)
- Frank M C Besag
- East London NHS Foundation Trust, 5-7 Rush Court, Bedford MK40 3JT, UK; University College London, London, UK; King's College London, London, UK.
| | - Michael J Vasey
- East London NHS Foundation Trust, 5-7 Rush Court, Bedford MK40 3JT, UK
| |
Collapse
|
|
17
|
Chu YJ, Chang CF, Weng WC, Fan PC, Shieh JS, Lee WT. Electroencephalography complexity in infantile spasms and its association with treatment response. Clin Neurophysiol 2021; 132:480-486. [PMID: 33450568 DOI: 10.1016/j.clinph.2020.12.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/03/2020] [Accepted: 12/14/2020] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To investigate the potential of EEG multiscale entropy and complexity as biomarkers in infantile spasms. METHODS We collected EEG data retrospectively from 16 newly diagnosed patients, 16 age- and gender-matched healthy controls, and 15 drug-resistant patients. The multiscale entropy (MSE) and total EEG complexity before anti-epileptic drug (AED) treatment, before adrenocorticotropic hormone (ACTH) treatment, 14 days after ACTH therapy, and after 6 months of follow-up were calculated. RESULTS The total EEG complexity of 16 newly diagnosed infantile spasms patients was lower than the 16 healthy controls (median [IQR]: 351.5 [323.1-388.1] vs 461.6 [407.7-583.4]). The total EEG complexity before treatment was higher in the six patients with good response to AED than the 10 patients without response (median [IQR]: 410.0 [388.1-475.0] vs 344.5 [319.6-352.0]). The total EEG complexity before and after 14-days of ACTH therapy was not different between 13 ACTH therapy responders and nine non-responders. After 6-months follow-up, the total EEG complexity of ACTH therapy responders were higher than non-responders (median [IQR]: 598.5 [517.4-623.3] vs 448.6 [347.1-536.3]). CONCLUSIONS The total EEG complexity before AED and 6 months after ACTH are associated with spasm-freedom. SIGNIFICANCE The total EEG complexity is a potential biomarker to predict and monitor the treatment effect in infantile spasms.
Collapse
Affiliation(s)
- Yen-Ju Chu
- Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatric Neurology, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Chi-Feng Chang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Wen-Chin Weng
- Department of Pediatric Neurology, National Taiwan University Children's Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pi-Chuan Fan
- Department of Pediatric Neurology, National Taiwan University Children's Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jiann-Shing Shieh
- Department of Mechanical Engineering, Yuan Ze University, Taoyuan, Taiwan; Innovation Center for Biomedical and Healthcare Technology, Yuan Ze University, Taoyuan, Taiwan; Innovation Center for Big Data and Digital Convergence, Yuan Ze University, Taoyuan, Taiwan
| | - Wang-Tso Lee
- Department of Pediatric Neurology, National Taiwan University Children's Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan.
| |
Collapse
|
|
18
|
Hu HT, Huang TN, Hsueh YP. KLHL17/Actinfilin, a brain-specific gene associated with infantile spasms and autism, regulates dendritic spine enlargement. J Biomed Sci 2020; 27:103. [PMID: 33256713 PMCID: PMC7708131 DOI: 10.1186/s12929-020-00696-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 11/23/2020] [Indexed: 11/10/2022] Open
Abstract
Background Dendritic spines, the actin-rich protrusions emerging from dendrites, are the subcellular locations of excitatory synapses in the mammalian brain. Many actin-regulating molecules modulate dendritic spine morphology. Since dendritic spines are neuron-specific structures, it is reasonable to speculate that neuron-specific or -predominant factors are involved in dendritic spine formation. KLHL17 (Kelch-like 17, also known as Actinfilin), an actin-binding protein, is predominantly expressed in brain. Human genetic study has indicated an association of KLHL17/Actinfilin with infantile spasms, a rare form of childhood epilepsy also resulting in autism and mental retardation, indicating that KLHL17/Actinfilin plays a role in neuronal function. However, it remains elusive if and how KLHL17/Actinfilin regulates neuronal development and brain function. Methods Fluorescent immunostaining and electrophysiological recording were performed to evaluate dendritic spine formation and activity in cultured hippocampal neurons. Knockdown and knockout of KLHL17/Actinfilin and expression of truncated fragments of KLHL17/Actinfilin were conducted to investigate the function of KLHL17/Actinfilin in neurons. Mouse behavioral assays were used to evaluate the role of KLHL17/Actinfilin in brain function. Results We found that KLHL17/Actinfilin tends to form circular puncta in dendritic spines and are surrounded by or adjacent to F-actin. Klhl17 deficiency impairs F-actin enrichment at dendritic spines. Knockdown and knockout of KLHL17/Actinfilin specifically impair dendritic spine enlargement, but not the density or length of dendritic spines. Both N-terminal Broad-Complex, Tramtrack and Bric-a-brac (BTB) domain and C-terminal Kelch domains of KLHL17/Actinfilin are required for F-actin remodeling and enrichment at dendritic spines, as well as dendritic spine enlargement. A reduction of postsynaptic and presynsptic markers at dendritic spines and altered mEPSC profiles due to Klhl17 deficiency evidence impaired synaptic activity in Klhl17-deficient neurons. Our behavioral assays further indicate that Klhl17 deficiency results in hyperactivity and reduced social interaction, strengthening evidence for the physiological role of KLHL17/Actinfilin. Conclusion Our findings provide evidence that KLHL17/Actinfilin modulates F-actin remodeling and contributes to regulation of neuronal morphogenesis, maturation and activity, which is likely relevant to behavioral impairment in Klhl17-deficient mice. Trial registration Non-applicable.
Collapse
Affiliation(s)
- Hsiao-Tang Hu
- Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Taipei, 11529, Taiwan, Republic of China
| | - Tzyy-Nan Huang
- Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Taipei, 11529, Taiwan, Republic of China
| | - Yi-Ping Hsueh
- Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Taipei, 11529, Taiwan, Republic of China.
| |
Collapse
|
|
19
|
Abstract
Epilepsy and autism frequently co-occur. Epilepsy confers an increased risk of autism and autism confers an increased risk of epilepsy. Specific epilepsy syndromes, intellectual disability, and female gender present a particular risk of autism in individuals with epilepsy. Epilepsy and autism are likely to share common etiologies, which predispose individuals to either or both conditions. Genetic factors, metabolic disorders, mitochondrial disorders, and immune dysfunction all can be implicated.
Collapse
Affiliation(s)
- Frank M C Besag
- East London NHS Foundation Trust, 5-7 Rush Court, Bedford MK40 3JT, UK; University College London, London, UK; King's College London, London, UK.
| | - Michael J Vasey
- East London NHS Foundation Trust, 5-7 Rush Court, Bedford MK40 3JT, UK
| |
Collapse
|
|
20
|
Gupta A, de Bruyn G, Tousseyn S, Krishnan B, Lagae L, Agarwal N, Frost M, Sparagana S, LaJoie J, Riviello J, Devinsky O, LaJoie J, Thiele E, McClintock W, Kohrman M, Brown C, Kuperman R, Wu J, Northrup H, Bebin EM, Korf B, Gupta A, Levisohn P, Koh S, O'Neil Miller I, Duchowny M, Ashwal S, Jansen A, Crino P, Pollard J, Nathanson K, Sahin M, Krueger DA, Wong M, Jeong A. Epilepsy and Neurodevelopmental Comorbidities in Tuberous Sclerosis Complex: A Natural History Study. Pediatr Neurol 2020; 106:10-16. [PMID: 32139167 DOI: 10.1016/j.pediatrneurol.2019.12.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 12/23/2019] [Accepted: 12/27/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND We studied the natural history, genotype influence, and inter-relationship of epilepsy and neuropsychiatric disorders in tuberous sclerosis complex. METHODS Patients were identified using the TSC Natural History Database, the largest repository of longitudinally studied patients enrolled by the TSC Clinics Consortium. RESULTS A cohort of 1657 TSC Natural History Database patients was analyzed. Eighty-eight percent patients (91% TSC2 vs 82% TSC1; P = 0.002) had epilepsy; TSC2 was more frequent with epilepsy onset at age less than two years (TSC2 82% vs TSC1 54%; P < 0.001) and infantile spasms (TSC2 56% vs TSC1 27%; P < 0.001). Frequency of intellectual disability (intelligence quotient less than 70) was higher when epilepsy coexisted (P < 0.001), but was not impacted by genotype (P = 0.08). Severe intellectual disability (intelligence quotient less than 50) was associated with epilepsy onset at age less than two years (P = 0.007), but not with the epilepsy duration (P = 0.45). Autism was diagnosed in 23% and was associated with epilepsy (P < 0.001), particularly with epilepsy onset at age less than two years (P = 0.02) but not with genotype (P = 0.06). Attention-deficit/hyperactivity disorder (age greater than four years) was diagnosed in 18% and was associated with epilepsy (P < 0.001), but genotype made no difference. Nine percent had anxiety (age greater than seven years) and 6% had depression (age greater than nine years), but neither showed association with epilepsy or genotype. CONCLUSIONS Epilepsy is associated with intellectual disability, and when epilepsy begins before age two years the frequency and severity of intellectual disability is much higher. Epilepsy is also associated with autism and attention-deficit/hyperactivity disorder but not with anxiety and depression. Additional trials, blinded, prospective, and adequately powered, will help clarify if early and effective treatment of epilepsy may also mitigate intellectual disability, autism, and attention-deficit/hyperactivity disorder.
Collapse
Affiliation(s)
- Ajay Gupta
- Department of Neurology, Pediatric Epilepsy, Epilepsy Center/Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
| | - Gwendolyn de Bruyn
- Department of Neurology, Pediatric Epilepsy, Epilepsy Center/Neurological Institute, Cleveland Clinic, Cleveland, Ohio; Department of Development and Regeneration, Section Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium; Department of Pediatrics, ZOL Genk, Genk, Belgium; Department of Neurology, Academic Center for Epileptology, Kempenhaeghe and Maastricht UMC+, The Netherlands
| | - Simon Tousseyn
- Department of Neurology, Pediatric Epilepsy, Epilepsy Center/Neurological Institute, Cleveland Clinic, Cleveland, Ohio; Department of Neurology, Academic Center for Epileptology, Kempenhaeghe and Maastricht UMC+, The Netherlands
| | - Balu Krishnan
- Department of Neurology, Pediatric Epilepsy, Epilepsy Center/Neurological Institute, Cleveland Clinic, Cleveland, Ohio
| | - Lieven Lagae
- Department of Development and Regeneration, Section Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium
| | - Nitin Agarwal
- Division of Pediatric Epilepsy, Department of Neurology, Minnesota Epilepsy Group, P.A. and Children's Hospitals and Clinics of Minnesota, St. Paul, Minnesota
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Specchio N, Pietrafusa N, Ferretti A, De Palma L, Santarone ME, Pepi C, Trivisano M, Vigevano F, Curatolo P. Treatment of infantile spasms: why do we know so little? Expert Rev Neurother 2020; 20:551-566. [PMID: 32316776 DOI: 10.1080/14737175.2020.1759423] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Infantile spasm (IS) is an epileptic syndrome with typical onset within the first 2 years of life. This condition might be caused by several etiologies. IS is associated with pathological neuronal networks; however, definite hypotheses on neurobiological processes are awaited. AREAS COVERED Changes in NMDA and GABAB receptors and increase of Ca2+ conductance are some of the possible pathophysiological mechanisms. Animal models can help, but most have only some features of IS. Outcome is strongly affected by etiology and the timing of treatment, which relies still on ACTH, oral steroids, and vigabatrin. No significant differences in terms of efficacy have been documented, though a combination of ACTH and vigabatrin seems to be associated with better long-term outcomes. Despite the increasing knowledge about the etiology and pathophysiology of IS, in the last years, no new treatment approaches have been recognized to be able to modify the neurobiological process underlying IS. Precision medicine has far to come in IS. EXPERT OPINION Recently, no new therapeutic options for IS have emerged, probably due to the lack of reliable animal models and to the extreme variability in etiologies. Consequently, the outlook for patients and families is poor and early recognition and intervention remain research priorities.
Collapse
Affiliation(s)
- Nicola Specchio
- Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS , Rome, 00165, Italy.,Member of European Reference Network EpiCARE
| | - Nicola Pietrafusa
- Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS , Rome, 00165, Italy
| | - Alessandro Ferretti
- Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS , Rome, 00165, Italy
| | - Luca De Palma
- Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS , Rome, 00165, Italy
| | - Marta Elena Santarone
- Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS , 00165, Rome, Italy
| | - Chiara Pepi
- Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS , Rome, 00165, Italy.,Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University , 00133, Rome, Italy
| | - Marina Trivisano
- Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS , Rome, 00165, Italy
| | - Federico Vigevano
- Member of European Reference Network EpiCARE.,Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS , 00165, Rome, Italy
| | - Paolo Curatolo
- Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University , 00133, Rome, Italy
| |
Collapse
|
|
22
|
Besag FMC, Vasey MJ. Social cognition and psychopathology in childhood and adolescence. Epilepsy Behav 2019; 100:106210. [PMID: 31196824 DOI: 10.1016/j.yebeh.2019.03.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 02/04/2019] [Accepted: 03/10/2019] [Indexed: 11/16/2022]
Abstract
There is a substantial body of research on social cognition in adults with epilepsy, and in broad categories such as focal and generalized epilepsies, but much less has been written about social cognition in children with epilepsy (CWE), and in childhood-onset epilepsy syndromes specifically. In several of these syndromes, autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), two disorders with social cognitive impairments, are reported. There is strong evidence for social cognitive deficits in juvenile myoclonic epilepsy (JME). There is also a considerable amount of evidence for such deficits in a number of syndromes that may be associated with ASD or ADHD, including West syndrome (WS), Dravet syndrome (DS), and the Landau-Kleffner syndrome (LKS). However, the evidence is of variable quality and incomplete across the range of childhood epilepsy syndromes. In some syndromes, childhood epilepsy substantially increases the risk of severe social cognitive impairment, which may persist after the seizures remit. This paper presents an overview of current research on social cognition in childhood epilepsy, with a particular focus on syndromes with a high prevalence of autistic and behavioral comorbidities. Social cognitive impairments represent a considerable additional challenge for patients and caregivers. Early diagnosis and intervention might significantly improve long-term social cognitive outcomes, highlighting the need for greater awareness among clinicians of this important topic. This article is part of the Special Issue "Epilepsy and social cognition across the lifespan".
Collapse
Affiliation(s)
- Frank M C Besag
- East London Foundation NHS Trust, 5-7 Rush Court, Bedford MK40 3JT, UK; University College, London, UK; King's College, London, UK.
| | | |
Collapse
|
|
23
|
Frudit P, Vitturi BK, Navarro FC, Rondelli I, Pozzan G. Multiple cardiac rhabdomyomas in tuberous sclerosis complex: case report and review of the literature. AUTOPSY AND CASE REPORTS 2019; 9:e2019125. [PMID: 31641665 PMCID: PMC6771448 DOI: 10.4322/acr.2019.125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 09/04/2019] [Indexed: 11/23/2022] Open
Abstract
Cardiac rhabdomyoma is a benign tumor which constitutes the most common cardiovascular feature of the tuberous sclerosis complex, a multisystem genetically determined neurocutaneous disorder. Cardiac rhabdomyomas can be detected in the prenatal ultrasound, are usually asymptomatic and spontaneously regress within the first three years of life. Less often, the tumors' size, number, and location can produce a mass effect that may lead to blood flow abnormalities or organ dysfunction (heart failure and arrhythmia). In this setting, severe morbidity, and eventually, a lethal outcome despite clinical and surgical treatment may ensue. We describe a fatal case of multiple cardiac rhabdomyomas in a newborn girl. One of the rhabdomyomas was large and unfavorably located, causing significant obstruction of the left ventricular outflow tract. The autopsy identified, in addition to cardiac rhabdomyomas, brain glioneuronal hamartomas (cortical tubers), subependymal nodules and subependymal giant cell tumors, characteristic of the tuberous sclerosis complex. The newborn's family was investigated for the presence of typical clinical symptoms of the complex and image findings showed significant phenotypical variations and a broad symptom spectrum among the family members. This interesting case underscores the variability of tuberous sclerosis complex and the importance of performing a comprehensive postmortem examination in the identification of the cause of death, especially in the setting of familial disease.
Collapse
Affiliation(s)
- Paula Frudit
- Santa Casa de São Paulo School of Medical Sciences. São Paulo, SP, Brazil
| | | | - Flavia Cristina Navarro
- Irmandade da Santa Casa de Misericórdia de São Paulo, Department of Pediatrics. São Paulo, SP, Brazil
| | - Ivan Rondelli
- Irmandade da Santa Casa de Misericórdia de São Paulo, Department of Pathology. São Paulo, SP, Brazil
| | - Geanete Pozzan
- Irmandade da Santa Casa de Misericórdia de São Paulo, Department of Pathology. São Paulo, SP, Brazil
| |
Collapse
|
|
24
|
EEG Abnormalities as a Neurophysiological Biomarker of Severity in Autism Spectrum Disorder: A Pilot Cohort Study. J Autism Dev Disord 2019; 49:2337-2347. [PMID: 30726535 DOI: 10.1007/s10803-019-03908-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
To date, the phenotypic significance of EEG abnormalities in patients with ASD is unclear. In a population affected by ASD we aimed to evaluate: the phenotypic characteristics; the prevalence of EEG abnormalities; the potential correlations between EEG abnormalities and behavioral and cognitive variables. Sixty-nine patients with ASD underwent cognitive or developmental testing, language assessment, and adaptive behavior skills evaluation as well as sleep/wake EEG recording. EEG abnormalities were found in 39.13% of patients. EEG abnormalities correlated with autism severity, hyperactivity, anger outbursts, aggression, negative or destructive behavior, motor stereotypies, intellectual disability, language impairment and self-harm. Our findings confirmed that EEG abnormalities are present in the ASD population and correlate with several associated phenotypic features.
Collapse
|
|
25
|
Pacheva I, Ivanov I, Yordanova R, Gaberova K, Galabova F, Panova M, Petkova A, Timova E, Sotkova I. Epilepsy in Children with Autistic Spectrum Disorder. CHILDREN (BASEL, SWITZERLAND) 2019; 6:15. [PMID: 30691036 PMCID: PMC6406948 DOI: 10.3390/children6020015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/22/2019] [Accepted: 01/22/2019] [Indexed: 12/21/2022]
Abstract
The comorbidity of autistic spectrum disorder (ASD) and epilepsy has been widely discussed but many questions still remain unanswered. The aim of this study was to establish the occurrence of epilepsy among children with ASD to define the type of epileptic seizures and syndromes, the age of onset of epilepsy, EEG abnormalities, the used antiepileptic drugs and the therapeutic responses for seizures and autistic behavior, as well as to find some correlations between epilepsy and gender, etiology and intellectual disability (ID). A retrospective study of medical files of 59 patients (aged 1⁻18 years) with ASD during a 5-year period was performed. ASD diagnosis was based on the DSM-5 diagnostic criteria. The patients were examined with a detailed medical history, physical and neurological examination, as well as some additional functional, imaging, laboratory and genetic investigations ASD etiology was syndromic in 9, probable syndromic in 9, and idiopathic in 41 children. ID was established in 90% of ASD children, and epilepsy in 44.4%. The onset of epilepsy prevailed before 7 years of age. The most common seizure types were focal with or without secondary generalization (53.4%). Focal epileptiform EEG abnormalities prevailed. Therapeutic response to seizures was good: 58% were seizure-free, while 27% had >50% seizure reduction but no improvement in autistic behavior. There was no correlation between epilepsy and either occurrence or degree of ID. There was a correlation between the frequency of epileptic seizures and the degree of ID. There was no significant difference among epilepsy rates in different etiologic, gender, and ID groups, probably because of the high percentage of ID and because this was a hospital-based study. Our study showed a significant percentage of epilepsy in ASD population and more than 1/4 were of symptomatic etiology. Those could be managed with specific treatments based on the pathophysiology of the gene defect.
Collapse
Affiliation(s)
- Iliyana Pacheva
- Department of Pediatrics and Medical Genetics, Medical University-Plovdiv,4000, Bulgaria.
- Department of Pediatrics, University Hospital "St. George"-Plovdiv,4000, Bulgaria.
| | - Ivan Ivanov
- Department of Pediatrics and Medical Genetics, Medical University-Plovdiv,4000, Bulgaria.
- Department of Pediatrics, University Hospital "St. George"-Plovdiv,4000, Bulgaria.
| | - Ralitsa Yordanova
- Department of Pediatrics and Medical Genetics, Medical University-Plovdiv,4000, Bulgaria.
- Department of Pediatrics, University Hospital "St. George"-Plovdiv,4000, Bulgaria.
| | - Katerina Gaberova
- Department of Pediatrics, University Hospital "St. George"-Plovdiv,4000, Bulgaria.
| | - Fani Galabova
- Department of Pediatrics, University Hospital "St. George"-Plovdiv,4000, Bulgaria.
| | - Margarita Panova
- Department of Pediatrics and Medical Genetics, Medical University-Plovdiv,4000, Bulgaria.
- Department of Pediatrics, University Hospital "St. George"-Plovdiv,4000, Bulgaria.
| | - Aneliya Petkova
- Department of Pediatrics, University Hospital "St. George"-Plovdiv,4000, Bulgaria.
| | - Elena Timova
- Department of Pediatrics, University Hospital "St. George"-Plovdiv,4000, Bulgaria.
| | - Iglika Sotkova
- Department of Pediatrics and Medical Genetics, Medical University-Plovdiv,4000, Bulgaria.
- Department of Pediatrics, University Hospital "St. George"-Plovdiv,4000, Bulgaria.
| |
Collapse
|
|
26
|
Jia JL, Chen S, Sivarajah V, Stephens D, Cortez MA. Latitudinal differences on the global epidemiology of infantile spasms: systematic review and meta-analysis. Orphanet J Rare Dis 2018; 13:216. [PMID: 30486850 PMCID: PMC6262963 DOI: 10.1186/s13023-018-0952-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 11/14/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Infantile spasms represent the catastrophic, age-specific seizure type associated with acute and long-term neurological morbidity. However, due to rarity and heterogenous determination, there is persistent uncertainty of its pathophysiological and epidemiological characteristics. The purpose of the current study was to address a historically suspected latitudinal basis of infantile spasms incidence, and to interrogate a geographical basis of epidemiology, including the roles of latitude and other environmental factors, using meta-analytic and -regression methods. METHODS A systematic search was performed in Ovid MEDLINE and Embase for primary reports on infantile spasms incidence and prevalence epidemiology. RESULTS One thousand fifteen studies were screened to yield 54 eligible publications, from which 39 incidence figures and 18 prevalence figures were extracted. The pooled incidence was 0.249 cases/1000 live births. The pooled prevalence was 0.015 cases/1000 population. Univariate meta-regression determined a continental effect, with Europe demonstrating the highest onset compared from Asia (OR = 0.51, p = 0.004) and from North America (OR = 0.50, p = 0.004). Latitude was also positively correlated with incidence globally (OR = 1.02, p < 0.001). Sub-analyses determined a particularly elevated Scandinavian incidence compared to the rest of world (OR = 1.88, p < 0.001), and lack of latitudinal effect with Scandinavian exclusion (p = 0.10). Metrics of healthcare quality did not predict incidence. Multiple meta-regression determined that latitude was the key predictor of incidence (OR = 1.02, p = 0.001). CONCLUSIONS This is the first systematic epidemiological study of infantile spasms. Limitations included lack of Southern hemispheric representation, insufficient study selection and size to support some sub-continental analyses, and lack of accessible ethnic and healthcare quality data. Meta-analyses determined a novel, true geographical difference in incidence which is consistent with a latitudinal and/or ethnic contribution to epileptogenesis. These findings justify the establishment of a global registry of infantile spasms epidemiology to promote future systematic studies, clarify risk factors, and expand understanding of the pathophysiology.
Collapse
Affiliation(s)
- Jason L. Jia
- Department of Medicine, University of Toronto, 190 Elizabeth Street R. Fraser Elliott Wing, Toronto, M5G 2C4 Canada
| | - Shiyi Chen
- Child Health Evaluative Sciences Research Program, SickKids Research Institute, The Hospital for Sick Children, Toronto, Canada
| | - Vishalini Sivarajah
- Department of Medicine, University of Toronto, 190 Elizabeth Street R. Fraser Elliott Wing, Toronto, M5G 2C4 Canada
| | - Derek Stephens
- Child Health Evaluative Sciences Research Program, SickKids Research Institute, The Hospital for Sick Children, Toronto, Canada
| | - Miguel A. Cortez
- Department of Pediatrics, Division of Neurology, University of Toronto, Toronto, Canada
- Neurosciences & Mental Health Program, Peter Gilgan Centre for Research and Learning, SickKids Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8 Canada
| |
Collapse
|
|
27
|
|
|
28
|
Strasser L, Downes M, Kung J, Cross JH, De Haan M. Prevalence and risk factors for autism spectrum disorder in epilepsy: a systematic review and meta-analysis. Dev Med Child Neurol 2018; 60:19-29. [PMID: 29119560 DOI: 10.1111/dmcn.13598] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/12/2017] [Indexed: 12/17/2022]
Abstract
AIM To assess the prevalence and risk factors for autism spectrum disorder (ASD) in epilepsy, and to better understand the relationship and comorbidity between these disorders. METHOD PsychINFO and PubMed were searched for articles published in the past 15 years that examined the prevalence of ASD in individuals with epilepsy. RESULTS A total of 19 studies were found with a pooled ASD prevalence of 6.3% in epilepsy. When divided by type, the risks of ASD for general epilepsy, infantile spasms, focal seizures, and Dravet syndrome were 4.7%, 19.9%, 41.9%, and 47.4% respectively. Studies with populations under 18 years showed a 13.2 times greater risk of ASD than study populations over 18 years, and samples with most (>50%) individuals with intellectual disability showed a greater risk 4.9 times higher than study populations with a minority of individuals with intellectual disability. The main risk factors for ASD reported in the 19 studies included presence of intellectual disability, sex, age, and symptomatic aetiology of epilepsy. INTERPRETATION Current research supports a high prevalence of ASD in epilepsy. This study helps to define the clinical profile of patients with epilepsy who are at risk for ASD, which may help clinicians in early screening and diagnosis of ASD in this population. WHAT THIS PAPER ADDS Critical evaluation of previous studies examining the prevalence of autism spectrum disorder (ASD) in individuals with epilepsy. A meta-analysis of 19 studies showed a pooled ASD prevalence of 6.3% in individuals with epilepsy. Studies that included a majority of individuals with intellectual disability or younger population age had a higher prevalence of autism. Risk factors reported in studies included presence of intellectual disability, sex, age, and symptomatic epilepsy origin.
Collapse
Affiliation(s)
- Lauren Strasser
- UCL Great Ormond Street Institute of Child Health, London, UK
| | - Michelle Downes
- UCL Great Ormond Street Institute of Child Health, London, UK
| | - Jane Kung
- UCL Great Ormond Street Institute of Child Health, London, UK
| | - J Helen Cross
- UCL Great Ormond Street Institute of Child Health, London, UK
| | | |
Collapse
|
|
29
|
Kanner AM, Scharfman H, Jette N, Anagnostou E, Bernard C, Camfield C, Camfield P, Legg K, Dinstein I, Giacobbe P, Friedman A, Pohlmann-Eden B. Epilepsy as a Network Disorder (1): What can we learn from other network disorders such as autistic spectrum disorder and mood disorders? Epilepsy Behav 2017; 77:106-113. [PMID: 29107450 PMCID: PMC9835466 DOI: 10.1016/j.yebeh.2017.09.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 09/16/2017] [Indexed: 01/16/2023]
Abstract
Epilepsy is a neurologic condition which often occurs with other neurologic and psychiatric disorders. The relation between epilepsy and these conditions is complex. Some population-based studies have identified a bidirectional relation, whereby not only patients with epilepsy are at increased risk of suffering from some of these neurologic and psychiatric disorders (migraine, stroke, dementia, autism, depression, anxiety disorders, Attention deficit hyperactivity disorder (ADHD), and psychosis), but also patients with these conditions are at increased risk of suffering from epilepsy. The existence of common pathogenic mechanisms has been postulated as a potential explanation of this phenomenon. To reassess the relationships between neurological and psychiatric conditions in general, and specifically autism, depression, Alzheimer's disease, schizophrenia, and epilepsy, a recent meeting brought together basic researchers and clinician scientists entitled "Epilepsy as a Network Disorder." This was the fourth in a series of conferences, the "Fourth International Halifax Conference and Retreat". This manuscript summarizes the proceedings on potential relations between Epilepsy on the one hand and autism and depression on the other. A companion manuscript provides a summary of the proceedings about the relation between epilepsy and Alzheimer's disease and schizophrenia, closed by the role of translational research in clarifying these relationships. The review of the topics in these two manuscripts will provide a better understanding of the mechanisms operant in some of the common neurologic and psychiatric comorbidities of epilepsy.
Collapse
Affiliation(s)
- Andres M Kanner
- Department of Neurology, University of Miami, Miller School of Medicine, 1120 NW 14th Street, Room #1324, Miami, FL 33136, USA.
| | - Helen Scharfman
- New York University Langone Medical Center, New York, NY 10016, USA; The Nathan Kline Institute, Orangeburg, NY, USA
| | - Nathalie Jette
- Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, NY, USA; Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Evdokia Anagnostou
- Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, 150 Kilgour Road, Toronto, ON M4G 1R8, Canada
| | - Christophe Bernard
- NS - Institute de Neurosciences des Systemes, UMR INSERM 1106, Aix-Marseille Université, Equipe Physionet, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
| | - Carol Camfield
- Department of Pediatrics, Dalhousie University Halifax, Nova Scotia, Canada
| | - Peter Camfield
- Department of Pediatrics, Dalhousie University Halifax, Nova Scotia, Canada
| | - Karen Legg
- Division of Neurology, Department of Medicine, Halifax Infirmary, Halifax B3H4R2, Nova Scotia, Canada
| | - Ilan Dinstein
- Departments of Psychology and Brain & Cognitive Sciences, Zlotowski Centre for Neuroscience, Ben-Gurion University of the Negev, Be'er Sheva, Israel
| | - Peter Giacobbe
- Centre for Mental Health, University of Toronto, University Health Network, Canada
| | - Alon Friedman
- Departments of Physiology and Cell Biology, Brain & Cognitive Sciences, Zlotowski Centre for Neuroscience, Ben-Gurion University of the Negev, Be'er Sheva, Israel; Departments of Medical Neuroscience and Pediatrics, Faculty of Medicine, Dalhousie University Halifax, NS, Canada
| | - Bernd Pohlmann-Eden
- Brain Repair Center, Life Science Research Institute, Dalhousie University, Room 229, PO Box 15000, Halifax, Nova Scotia B3H4R2, Canada
| |
Collapse
|
|
30
|
Tuchman R. What is the Relationship Between Autism Spectrum Disorders and Epilepsy? Semin Pediatr Neurol 2017; 24:292-300. [PMID: 29249509 DOI: 10.1016/j.spen.2017.10.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The association of epilepsy and autism spectrum disorders (ASD) is best understood by examining the relationship between social cognition, nonsocial cognition, and epilepsy. The relationship between ASD and epilepsy is bidirectional and is strongly linked to intellectual disability (ID). The risk of developing ASD in children with epilepsy is highest in children with early onset seizures, with a high prevalence in children with infantile spasms. The risk of developing epilepsy in children first diagnosed with ASD is highest in those with ID. The prevalence of seizures in ASD increases with age. When epilepsy and ASD coexist, they share common pathophysiological mechanisms. In epilepsy with and without ID, social-cognitive deficits are an important determinant of neurodevelopmental outcomes. Early recognition of social deficits is an important aspect of the comprehensive management of children with epilepsy. Treating the seizures in individuals with epilepsy and ASD is crucial but interventions that address social-cognitive deficits are necessary to maximize neurodevelopmental outcomes.
Collapse
Affiliation(s)
- Roberto Tuchman
- From the Department of Neurology, Nicklaus Children's Hospital Miami Children's Health System, Miami, FL.
| |
Collapse
|
|
31
|
Nickels KC, Wirrell EC. Cognitive and Social Outcomes of Epileptic Encephalopathies. Semin Pediatr Neurol 2017; 24:264-275. [PMID: 29249506 DOI: 10.1016/j.spen.2017.10.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The term "epileptic encephalopathy" denotes a disorder in which seizures or frequent interictal discharges exacerbate neurocognitive dysfunction beyond what would be expected on the basis of underlying etiology. However, many underlying causes of epileptic encephalopathy also result in neurocognitive deficits, and it can be challenging to discern to what extent these deficits can be improved with better seizure control. Additionally, as seizures in these conditions are typically refractory, children are often exposed to high doses of multiple antiepileptic drugs which further exacerbate these comorbidities. This review will summarize the neurocognitive and social outcomes in children with various epileptic encephalopathies. Prompt, accurate diagnosis of epilepsy syndrome and etiology allows selection of optimal therapy to maximize seizure control, limiting the impact of ongoing seizures and frequent epileptiform abnormalities on the developing brain. Furthermore, mandatory screening for comorbidities allows early recognition and focused therapy for these commonly associated conditions to maximize neurocognitive outcome.
Collapse
Affiliation(s)
- Katherine C Nickels
- Divisions of Child and Adolescent Neurology and Epilepsy, Mayo Clinic, Rochester, MN
| | - Elaine C Wirrell
- Divisions of Child and Adolescent Neurology and Epilepsy, Mayo Clinic, Rochester, MN.
| |
Collapse
|
|
32
|
Abstract
Epileptic encephalopathies represent a particularly severe form of epilepsy, associated with cognitive and behavioral deficits, including impaired social-communication and restricted, repetitive behaviors that are the hallmarks of autism spectrum disorder (ASD). With the advent of next-generation sequencing, the genetic landscape of epileptic encephalopathies is growing and demonstrates overlap with genes separately implicated in ASD. However, many questions remain about this connection, including whether epileptiform activity itself contributes to the development of ASD symptomatology. In this review, we compiled a database of genes associated with both epileptic encephalopathy and ASD, limiting our purview to Mendelian disorders not including inborn errors of metabolism, and we focused on the connection between ASD and epileptic encephalopathy rather than epilepsy broadly. Our review has four goals: to (1) discuss the overlapping presentations of ASD and monogenic epileptic encephalopathies; (2) examine the impact of the epilepsy itself on neurocognitive features, including ASD, in monogenic epileptic encephalopathies; (3) outline many of the genetic causes responsible for both ASD and epileptic encephalopathy; (4) provide an illustrative example of a final common pathway that may be implicated in both ASD and epileptic encephalopathy. We demonstrate that autistic features are a common association with monogenic epileptic encephalopathies. Certain epileptic encephalopathy syndromes, like infantile spasms, are especially linked to the development of ASD. The connection between seizures themselves and neurobehavioral deficits in these monogenic encephalopathies remains open to debate. Finally, advances in genetics have revealed many genes that overlap in ties to both ASD and epileptic encephalopathy and that play a role in diverse central nervous system processes. Increased attention to the autistic features of monogenic epileptic encephalopathies is warranted for both researchers and clinicians alike.
Collapse
Affiliation(s)
- Siddharth Srivastava
- Department of Neurology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115 USA
| | - Mustafa Sahin
- Department of Neurology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115 USA
| |
Collapse
|
|
33
|
Outcome of childhood-onset epilepsy from adolescence to adulthood: Transition issues. Epilepsy Behav 2017; 69:161-169. [PMID: 28256379 DOI: 10.1016/j.yebeh.2016.11.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 11/06/2016] [Indexed: 11/21/2022]
Abstract
This is the second of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper addresses the outcome for some particularly challenging childhood-onset epileptic disorders with the goal of recommending the best approach to transition. We have grouped these disorders in five categories with a few examples for each. The first group includes disorders presenting in childhood that may have late- or adult-onset epilepsy (metabolic and mitochondrial disorders). The second group includes disorders with changing problems in adulthood (tuberous sclerosis complex, Rett syndrome, Dravet syndrome, and autism). A third group includes epilepsies that change with age (Childhood Absence Epilepsy, Juvenile Myoclonic Epilepsy, West Syndrome, and Lennox-Gastaut syndrome). A fourth group consists of epilepsies that vary in symptoms and severity depending on the age of onset (autoimmune encephalitis, Rasmussen's syndrome). A fifth group has epilepsy from structural causes that are less likely to evolve in adulthood. Finally we have included a discussion about the risk of later adulthood cerebrovascular disease and dementia following childhood-onset epilepsy. A detailed knowledge of each of these disorders should assist the process of transition to be certain that attention is paid to the most important age-related symptoms and concerns.
Collapse
|
|
34
|
Nickels KC, Zaccariello MJ, Hamiwka LD, Wirrell EC. Cognitive and neurodevelopmental comorbidities in paediatric epilepsy. Nat Rev Neurol 2016; 12:465-76. [PMID: 27448186 DOI: 10.1038/nrneurol.2016.98] [Citation(s) in RCA: 144] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cognitive and behavioural comorbidities are often seen in children with epilepsy, and are more common and severe in refractory epilepsy. These comorbidities are associated with worse quality of life, increased behavioural and language problems and worse social skills, all of which adversely affect long-term psychosocial functioning. To enable early intervention and therapy, children and teens with epilepsy should be periodically screened for cognitive comorbidities. The location of the epileptic focus can, to a certain degree, predict the type(s) of comorbidity; however, the spectrum of disability is often broad, presumably because focal perturbations can cause network dysfunction. Comorbidities often result from underlying structural or functional pathology that has led to seizures. In selected cases, therapy targeting the underlying cause, such as the ketogenic diet for GLUT1 deficiency syndromes, may be remarkably effective in ameliorating both seizures and cognitive concerns. In many cases, however, cognitive impairment persists despite seizure control. In epileptic encephalopathies, frequent seizures and/or interictal epileptiform abnormalities exacerbate neurocognitive dysfunction, owing to synaptic reorganization or impaired neurogenesis, or to other effects on developing neural circuits, and prompt initiation of effective antiepileptic therapy is essential to limit cognitive comorbidities.
Collapse
Affiliation(s)
- Katherine C Nickels
- Child and Adolescent Neurology and Epilepsy, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA
| | - Michael J Zaccariello
- Child and Adolescent Neurology and Epilepsy, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA
| | - Lorie D Hamiwka
- Seattle Children's Hospital, MB.7.420 - Neurology, 4800 Sand Point Way NE, Seattle, Washington 98105, USA
| | - Elaine C Wirrell
- Child and Adolescent Neurology and Epilepsy, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA
| |
Collapse
|
|
35
|
Iype M, Saradakutty G, Kunju PAM, Mohan D, Nair MKC, George B, Ahamed SM. Infantile spasms: A prognostic evaluation. Ann Indian Acad Neurol 2016; 19:228-35. [PMID: 27293335 PMCID: PMC4888687 DOI: 10.4103/0972-2327.173314] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background: Few papers address the comprehensive prognosis in infantile spasms and look into the seizure profile and psychomotor outcome. Objective: We aimed to follow up children with infantile spasms to study: a) the etiology, demographics, semiology, electroencephalogram (EEG), and radiological pattern; b) seizure control, psychomotor development, and EEG resolution with treatment; c) the effects of various factors on the control of spasms, resolution of EEG changes, and psychomotor development at 3-year follow-up. Materials and Methods: Fifty newly diagnosed cases with a 1-12 month age of onset and who had hypsarrhythmia in their EEG were recruited and 43 were followed up for 3 years. Results: Of the children followed up, 51% were seizure-free and 37% had a normal EEG at the 3-year follow-up. Autistic features were seen in 74% of the children. Only 22.7% among the seizure-free (11.6% of the total) children had normal vision and hearing, speech with narration, writing skills, gross and fine motor development, and no autism or hyperactivity. On multivariate analysis, two factors could predict bad seizure outcome — the occurrence of other seizures in addition to infantile spasms and no response to 28 days of adrenocorticotropic hormone (ACTH). No predictor could be identified for abnormal psychomotor development. Discussion and Conclusion: In our study, we could demonstrate two factors that predict seizure freedom. The cognitive outcome and seizure control in this group of children are comparable to the existing literature. However, the cognitive outcome revealed by our study and the survey of the literature are discouraging.
Collapse
Affiliation(s)
- Mary Iype
- Department of Paediatric Neurology, Government Medical College, Trivandrum, Kerala, India
| | - Geetha Saradakutty
- Department of Paediatrics, Government Medical College, Trivandrum, Kerala, India
| | | | - Devi Mohan
- Department of Social and Preventive Medicine, Government Medical College, Trivandrum, Kerala, India
| | | | - Babu George
- Department of Pediatrics, Child Development Centre, Trivandrum, Kerala, India
| | - Shahanaz M Ahamed
- Department of Paediatrics, Government Medical College, Trivandrum, Kerala, India
| |
Collapse
|
|
36
|
Park HR, Lee JM, Moon HE, Lee DS, Kim BN, Kim J, Kim DG, Paek SH. A Short Review on the Current Understanding of Autism Spectrum Disorders. Exp Neurobiol 2016; 25:1-13. [PMID: 26924928 PMCID: PMC4766109 DOI: 10.5607/en.2016.25.1.1] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 12/18/2015] [Accepted: 12/30/2015] [Indexed: 12/21/2022] Open
Abstract
Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by a deficit in social behaviors and nonverbal interactions such as reduced eye contact, facial expression, and body gestures in the first 3 years of life. It is not a single disorder, and it is broadly considered to be a multi-factorial disorder resulting from genetic and non-genetic risk factors and their interaction. Genetic studies of ASD have identified mutations that interfere with typical neurodevelopment in utero through childhood. These complexes of genes have been involved in synaptogenesis and axon motility. Recent developments in neuroimaging studies have provided many important insights into the pathological changes that occur in the brain of patients with ASD in vivo. Especially, the role of amygdala, a major component of the limbic system and the affective loop of the cortico-striatothalamo-cortical circuit, in cognition and ASD has been proved in numerous neuropathological and neuroimaging studies. Besides the amygdala, the nucleus accumbens is also considered as the key structure which is related with the social reward response in ASD. Although educational and behavioral treatments have been the mainstay of the management of ASD, pharmacological and interventional treatments have also shown some benefit in subjects with ASD. Also, there have been reports about few patients who experienced improvement after deep brain stimulation, one of the interventional treatments. The key architecture of ASD development which could be a target for treatment is still an uncharted territory. Further work is needed to broaden the horizons on the understanding of ASD.
Collapse
Affiliation(s)
- Hye Ran Park
- Department of Neurosurgery, Seoul National University Hospital, Seoul 03080, Korea
| | - Jae Meen Lee
- Department of Neurosurgery, Seoul National University Hospital, Seoul 03080, Korea
| | - Hyo Eun Moon
- Department of Neurosurgery, Seoul National University Hospital, Seoul 03080, Korea
| | - Dong Soo Lee
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Bung-Nyun Kim
- Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jinhyun Kim
- Center for Functional Connectomics, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea
| | - Dong Gyu Kim
- Department of Neurosurgery, Seoul National University Hospital, Seoul 03080, Korea
| | - Sun Ha Paek
- Department of Neurosurgery, Seoul National University Hospital, Seoul 03080, Korea
| |
Collapse
|
|
37
|
Abstract
The association of epilepsy, autism spectrum disorders (ASD), and intellectual disability (ID) is well recognized. There is a wide range of social-cognitive deficits that can be identified in epilepsy over the life-span, from ASD in infants with an epileptic encephalopathy, to social-cognitive impairments affecting social interaction and comprehension in those with normal nonsocial cognitive function. Identifying ASD and social-cognitive deficits is an important aspect of comprehensive epilepsy care. There are behavioral and educational interventions that exist to treat ASD and social-cognitive deficits. These behavioral, communication, and educational interventions, in conjunction with medications to treat the seizures, should be considered an integral part of the comprehensive management of epilepsy throughout the life-span. The following are the key points of this review: Autism spectrum disorders and social-cognitive deficits are associated with epilepsy throughout the life-span, and identification of these deficits is an important part of epilepsy care.Children with an epileptic encephalopathy such as infantile spasms are at high risk for developing ASD, and the social-cognitive deficits that precede ASD may be recognized in the first year of life.In epilepsy, the likelihood of developing autism spectrum disorders is highest in those with ID, but there is a wide spectrum of manifestations, from ASD in children with epilepsy and ID, to social-cognitive impairments affecting social interaction and comprehension in those with normal nonsocial cognitive function.Implementation of behavioral, communication, and educational interventions that exist to treat ASD and social-cognitive deficits, along with medications to treat the seizures, should be considered an important part of the comprehensive management of epilepsy throughout the life-span.
Collapse
|
|
38
|
Behavioral correlates of epileptiform abnormalities in autism. Epilepsy Behav 2015; 47:163-6. [PMID: 25453621 DOI: 10.1016/j.yebeh.2014.10.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 10/07/2014] [Accepted: 10/15/2014] [Indexed: 11/24/2022]
Abstract
There is a high incidence of epileptiform abnormalities in children with autism even in the absence of clinical seizures. These findings are most prominent during sleep recordings. The significance of these abnormalities is unclear. Although studies do not all agree, there may be some association between cognitive function, behavior, and the presence or absence of epileptiform discharges. Small studies of anticonvulsant treatment mostly suggest an improvement in certain aspects of cognitive or behavioral functioning in these children, but larger and more comprehensive studies are needed to determine the potential relationship between epileptiform discharges on EEG, cognitive and behavioral functioning, and treatment effects in the population with autism. This article is part of a Special Issue entitled "Autism and Epilepsy".
Collapse
|
|
39
|
Bitton JY, Demos M, Elkouby K, Connolly M, Weiss SK, Donner EJ, Whiting S, Ronen GM, Bello-Espinosa L, Wirrell EC, Mohamed IS, Dooley JM, Carmant L. Does treatment have an impact on incidence and risk factors for autism spectrum disorders in children with infantile spasms? Epilepsia 2015; 56:856-63. [PMID: 25944453 DOI: 10.1111/epi.12997] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2015] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Infantile spasms (IS) are a severe form of childhood epilepsy associated with autism spectrum disorders (ASD) in up to 35% of cases. The objective of this post hoc analysis of our randomized control trial was to determine whether rapid diagnosis and treatment of IS could limit the incidence of ASD while identifying risk factors related to ASD outcome. METHODS Patients with IS were randomized in a standardized diagnostic and treatment protocol. Clinical and electroencephalogram (EEG) evaluations were completed at all eight visits over 5 years, while cognitive evaluations were administered at 0, 6, 24 and 60 months, respectively. Autism was initially screened by means of the Checklist for Autism in Toddlers (CHAT) at 24 months, and formally assessed at the 30-and 60-month follow-ups using the Autism Diagnostic Observation Schedule-Generic (ADOS-G). RESULTS Of the 69 patients included in the study, 25 could not be assessed due to severe delay or death. Eleven of the 42 patients screened with CHAT, were found to be at risk of an ASD outcome. ADOS was performed in 44 and 10 were diagnosed with ASD. The CHAT proved to correlate highly with the ADOS (80% ppv). Only patients with symptomatic IS developed ASD (p = 0.003). Earlier diagnosis or successful treatment did not correlate with a reduced rate of ASD. Other risk factors were identified such as having chronic epileptic discharges in the frontotemporal areas after disappearance of hypsarrhythmia (p = 0.005 and p = 0.007) and being of nonwhite origin (p = 0.009). SIGNIFICANCE ASD was only observed in children with sympyomatic IS. Other clinical risk factors include chronic frontotemporal epileptic activity and being of non-white origin. Early diagnosis and treatment did not prevent ASD as an outcome of IS. However, patients at risk for ASD could be identified early on and should in the future benefit from early intervention to potentially improve their long-term outcome.
Collapse
Affiliation(s)
- Jonathan Y Bitton
- Research Centre and Division of Neurology, Department of Pediatrics, Sainte-Justine Hospital (CHU Sainte-Justine), Montreal, Quebec, Canada
| | - Michelle Demos
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Katia Elkouby
- Research Centre and Division of Neurology, Department of Pediatrics, Sainte-Justine Hospital (CHU Sainte-Justine), Montreal, Quebec, Canada
| | - Mary Connolly
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Shelly K Weiss
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Elizabeth J Donner
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Sharon Whiting
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
| | - Gabriel M Ronen
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, McMaster Health Sciences Centre, McMaster University, Hamilton, Ontario, Canada
| | - Luis Bello-Espinosa
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
| | - Elaine C Wirrell
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.,Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota, U.S.A
| | - Ismail S Mohamed
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.,Division of Neurology, Department of Pediatrics, Faculty of Medicine, Izaak Walton Killam (IWK) Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Joseph M Dooley
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, Izaak Walton Killam (IWK) Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Lionel Carmant
- Research Centre and Division of Neurology, Department of Pediatrics, Sainte-Justine Hospital (CHU Sainte-Justine), Montreal, Quebec, Canada
| |
Collapse
|
|
40
|
Werner K, Fosi T, Boyd SG, Baldeweg T, Scott RC, Neville BG. Temporal lobe impairment in West syndrome: event-related potential evidence. Ann Neurol 2014; 77:47-57. [PMID: 25363285 PMCID: PMC4305199 DOI: 10.1002/ana.24297] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 10/14/2014] [Accepted: 10/26/2014] [Indexed: 11/26/2022]
Abstract
Objective This study investigates auditory processing in infants with West syndrome (WS) using event-related potentials (ERPs). Methods ERPs were measured in 25 infants with mainly symptomatic WS (age range = 3–10 months) and 26 healthy term infants (age range = 3–9 months) using an auditory novelty oddball paradigm. The ERP recordings were made during wakefulness and repeated in stage II sleep. Results The obligatory components (P150, N250, P350) and novelty response components (P300, Nc) were recordable during both sleep and wakefulness in patients and controls. All ERP latencies decreased with age in controls but not in the WS group (age × group interaction, F = 22.3, p < 0.0001). These ERP latency alterations were not affected by pharmacological treatment for WS. Interpretation This study demonstrated a persistently altered ERP signature in patients with a recent history of infantile spasms. The prolongation of auditory obligatory and novelty ERPs in WS patients indicates a severe failure of temporal lobe maturation during infancy. It remains to be investigated whether this predicts long-term cognitive impairments characteristic for this epileptic encephalopathy.
Collapse
Affiliation(s)
- Klaus Werner
- Young Epilepsy, Surrey, Great Ormond Street Hospital for Children National Health Service Trust, London; Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children National Health Service Trust, London; Clinical Neurosciences, University College London Institute of Child Health, London
| | | | | | | | | | | |
Collapse
|
|
41
|
Bernard PB, Benke TA. Early life seizures: evidence for chronic deficits linked to autism and intellectual disability across species and models. Exp Neurol 2014; 263:72-8. [PMID: 25284323 DOI: 10.1016/j.expneurol.2014.09.018] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 09/02/2014] [Accepted: 09/16/2014] [Indexed: 11/08/2022]
Abstract
Recent work in Exp Neurol by Lugo et al. (2014b) demonstrated chronic alterations in sociability, learning and memory following multiple early life seizures (ELS) in a mouse model. This work adds to the growing body of evidence supporting the detrimental nature of ELS on the developing brain to contribute to aspects of an autistic phenotype with intellectual disability. Review of the face validity of behavioral testing and the construct validity of the models used informs the predictive ability and thus the utility of these models to translate underlying molecular and cellular mechanisms into future human studies.
Collapse
Affiliation(s)
- Paul B Bernard
- Department of Pediatrics, University of Colorado, School of Medicine, USA
| | - Tim A Benke
- Department of Pediatrics, University of Colorado, School of Medicine, USA; Neuroscience Graduate Program, University of Colorado, School of Medicine, USA; Department of Neurology, University of Colorado, School of Medicine, USA; Department of Pharmacology, University of Colorado, School of Medicine, USA; Department of Otolaryngology, University of Colorado, School of Medicine, USA.
| |
Collapse
|
|
42
|
Abstract
Epileptic encephalopathies represent a group of devastating epileptic disorders that occur early in life and are often characterized by pharmaco-resistant epilepsy, persistent severe electroencephalographic abnormalities, and cognitive dysfunction or decline. Next generation sequencing technologies have increased the speed of gene discovery tremendously. Whereas ion channel genes were long considered to be the only significant group of genes implicated in the genetic epilepsies, a growing number of non-ion-channel genes are now being identified. As a subgroup of the genetically mediated epilepsies, epileptic encephalopathies are complex and heterogeneous disorders, making diagnosis and treatment decisions difficult. Recent exome sequencing data suggest that mutations causing epileptic encephalopathies are often sporadic, typically resulting from de novo dominant mutations in a single autosomal gene, although inherited autosomal recessive and X-linked forms also exist. In this review we provide a summary of the key features of several early- and mid-childhood onset epileptic encephalopathies including Ohtahara syndrome, Dravet syndrome, Infantile spasms and Lennox Gastaut syndrome. We review the recent next generation sequencing findings that may impact treatment choices. We also describe the use of conventional and newer anti-epileptic and hormonal medications in the various syndromes based on their genetic profile. At a biological level, developments in cellular reprogramming and genome editing represent a new direction in modeling these pediatric epilepsies and could be used in the development of novel and repurposed therapies.
Collapse
Affiliation(s)
- Sahar Esmaeeli Nieh
- Departments of Neurology and Pediatrics, University of California, San Francisco, CA USA
| | - Elliott H. Sherr
- Departments of Neurology and Pediatrics, University of California, San Francisco, CA USA
| |
Collapse
|
|
43
|
Ouss L, Saint-Georges C, Robel L, Bodeau N, Laznik MC, Crespin GC, Chetouani M, Bursztejn C, Golse B, Nabbout R, Desguerre I, Cohen D. Infant's engagement and emotion as predictors of autism or intellectual disability in West syndrome. Eur Child Adolesc Psychiatry 2014; 23:143-9. [PMID: 23728914 DOI: 10.1007/s00787-013-0430-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Accepted: 05/19/2013] [Indexed: 11/29/2022]
Abstract
West syndrome (WS) is a rare epileptic encephalopathy with early onset and a high risk of autistic outcome. The PréAut grid assesses this risk following WS onset by taking into account synchrony and emotion in interactions and by evaluating the baby's active desire to engage in pleasant interactions (especially the infant's early active behaviors that encourage being gazed at or kissed by the mother or to share joy with her). We followed a sample of 25 WS patients prospectively from disease onset and assessed whether the PréAut grid before 9 months, and the checklist for autism in toddlers (CHAT) at 18 and 24 months predicted autism or intellectual disability (ID) outcomes at 4 years. We found that the PréAut grid at 9 months (sensitivity = 0.83; specificity = 1) had similar prediction parameters as the CHAT at 18 months (sensitivity = 0.90; specificity = 0.83) and 24 months (sensitivity = 0.92; specificity = 1). WS patients with a positive PréAut screening at 9 months had a risk of having autism or ID at 4 years, which is 38 times that of children with a negative PréAut grid [OR = 38.6 (95 % CI 2.2-2961); p = 0.006]. We conclude that the PréAut grid could be a useful tool for the early detection of autism or ID risk in the context of WS. Further research is needed to assess the PréAut grid in other contexts (e.g. infants at high-risk for non-syndromic autism).
Collapse
Affiliation(s)
- Lisa Ouss
- Service de Psychiatrie de l'Enfant, AP-HP, Hôpital Necker, 149 rue de Sèvres, 75015, Paris, France,
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Amiet C, Gourfinkel-An I, Laurent C, Bodeau N, Génin B, Leguern E, Tordjman S, Cohen D. Does epilepsy in multiplex autism pedigrees define a different subgroup in terms of clinical characteristics and genetic risk? Mol Autism 2013; 4:47. [PMID: 24289166 PMCID: PMC4176303 DOI: 10.1186/2040-2392-4-47] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 09/13/2013] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Autism spectrum disorders (ASD) and epilepsy frequently occur together. Prevalence rates are variable, and have been attributed to age, gender, comorbidity, subtype of pervasive developmental disorder (PDD) and risk factors. Recent studies have suggested disparate clinical and genetic settings depending on simplex or multiplex autism. The aim of this study was to assess: 1) the prevalence of epilepsy in multiplex autism and its association with genetic and non-genetic risk factors of major effect, intellectual disability and gender; and 2) whether autism and epilepsy cosegregate within multiplex autism families. METHODS We extracted from the Autism Genetic Resource Exchange (AGRE) database (n = 3,818 children from 1,264 families) all families with relevant medical data (n = 664 children from 290 families). The sample included 478 children with ASD and 186 siblings without ASD. We analyzed the following variables: seizures, genetic and non-genetic risk factors, gender, and cognitive functioning as assessed by Raven's Colored Progressive Matrices (RCPM) and Vineland Adaptive Behavior Scales (VABS). RESULTS The prevalence of epilepsy was 12.8% in cases with ASD and 2.2% in siblings without ASD (P <10-5). With each RCPM or VABS measure, the risk of epilepsy in multiplex autism was significantly associated with intellectual disability, but not with gender. Identified risk factors (genetic or non-genetic) of autism tended to be significantly associated with epilepsy (P = 0.052). When children with prematurity, pre- or perinatal insult, or cerebral palsy were excluded, a genetic risk factor was reported for 6/59 (10.2%) of children with epilepsy and 12/395 (3.0%) of children without epilepsy (P = 0.002). Finally, using a permutation test, there was significant evidence that the epilepsy phenotype co-segregated within families (P <10-4). CONCLUSIONS Epilepsy in multiplex autism may define a different subgroup in terms of clinical characteristics and genetic risk.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - David Cohen
- Department of Child and Adolescent Psychiatry, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, 47 bd de l'Hôpital, 75013 Paris, France.
| |
Collapse
|
|
45
|
Iacobas DA, Iacobas S, Chachua T, Goletiani C, Sidyelyeva G, Velíšková J, Velíšek L. Prenatal corticosteroids modify glutamatergic and GABAergic synapse genomic fabric: insights from a novel animal model of infantile spasms. J Neuroendocrinol 2013; 25:964-79. [PMID: 23763471 PMCID: PMC3855178 DOI: 10.1111/jne.12061] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 05/25/2013] [Accepted: 06/09/2013] [Indexed: 12/16/2022]
Abstract
Prenatal exposure to corticosteroids has long-term postnatal somatic and neurodevelopmental consequences. Animal studies indicate that corticosteroid exposure-associated alterations in the nervous system include hypothalamic function. Infants with infantile spasms, a devastating epileptic syndrome of infancy with characteristic spastic seizures, chaotic irregular waves on interictal electroencephalogram (hypsarhythmia) and mental deterioration, have decreased concentrations of adrenocorticotrophic hormone (ACTH) and cortisol in cerebrospinal fluid, strongly suggesting hypothalamic dysfunction. We have exploited this feature to develop a model of human infantile spasms by using repeated prenatal exposure to betamethasone and a postnatal trigger of developmentally relevant spasms with NMDA. The spasms triggered in prenatally primed rats are more severe compared to prenatally saline-injected ones and respond to ACTH, a treatment of choice for infantile spasms in humans. Using autoradiography and immunohistochemistry, we have identified a link between the spasms in our model and the hypothalamus, especially the arcuate nucleus. Transcriptomic analysis of the arcuate nucleus after prenatal priming with betamethasone but before trigger of spasms indicates that prenatal betamethasone exposure down-regulates genes encoding several important proteins participating in glutamatergic and GABAergic transmission. Interestingly, there were significant sex-specific alterations after prenatal betamethasone in synapse-related gene expression but no such sex differences were found in prenatally saline-injected controls. A pairwise relevance analysis revealed that, although the synapse gene expression in controls was independent of sex, these genes form topologically distinct gene fabrics in males and females and these fabrics are altered by betamethasone in a sex-specific manner. These findings may explain the sex differences with respect to both normal behaviour and the occurrence and severity of infantile spasms. Changes in transcript expression and their coordination may contribute to a molecular substrate of permanent neurodevelopmental changes (including infantile spasms) found after prenatal exposure to corticosteroids.
Collapse
Affiliation(s)
- D A Iacobas
- Department of Pathology, New York Medical College, Valhalla, NY, USA
| | | | | | | | | | | | | |
Collapse
|
|
46
|
Abstract
BACKGROUND Population-based studies of psychopathology are important in childhood epilepsy given that there is a spectrum of severity with regard to the impact of epilepsy and associated behavioural/psychiatric difficulties. METHOD Population-based studies in childhood epilepsy which have focused on global measures of psychopathology and rates of specific behavioural and psychiatric disorders were reviewed with respect to prevalence of disorders and possible correlates of difficulties. Clinic-based studies and meta-analyses were reviewed where they added to an understanding of the correlates or treatment of psychopathology in childhood epilepsy. The systematic review methodology was based on a search of PubMed from January 1980 to June 2011. RESULTS Children with epilepsy are at significantly higher risk for a range of behavioural and psychiatric disorders including attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depressive and anxiety disorders. Available evidence suggests that these difficulties are under-recognised and there have been few studies focussing on interventions to treat these behavioural and psychiatric issues in childhood epilepsy. CONCLUSION Population-based studies suggest high rates of psychopathology in childhood epilepsy. As a result children with epilepsy need close monitoring with regard to the presence of behavioural difficulties. There is a need for studies on how such difficulties can be best managed so that affected children and their families can maximise their quality of life.
Collapse
Affiliation(s)
- Colin Reilly
- Research and Psychology Departments, National Centre for Young People with Epilepsy (NCYPE), St Piers Lane, Lingfield, Surrey, RH7 6PW, UK
| | | | | |
Collapse
|
|
47
|
Dilber C, Calışkan M, Sönmezoğlu K, Nişli S, Mukaddes NM, Tatlı B, Aydınlı N, Ekici B, Özmen M. Positron emission tomography findings in children with infantile spasms and autism. J Clin Neurosci 2012; 20:373-6. [PMID: 23219829 DOI: 10.1016/j.jocn.2012.03.034] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Revised: 01/19/2012] [Accepted: 03/04/2012] [Indexed: 11/17/2022]
Abstract
The purpose of this study was to evaluate positron emission tomography (PET) findings in patients diagnosed with infantile spasms and autism. This study includes 90 patients who were diagnosed with infantile spasms at the Department of Pediatric Neurology in the Istanbul University Medical Faculty between 1995 and 2007. Of the 90 patients, 15 patients who were diagnosed with autism using the Autism Behaviour Checklist and Childhood Autism Rating Scale and a control group of nine patients without autism but with infantile spasms underwent PET examination. Mean patient age (± standard error, SE) varied between 3 years and 16 years (7.8 ± 4 years), while the mean follow-up time (±SE) varied between 2 years and 16 years (average: 7.1 ± 4 years). Autism was present in 11 patients with symptomatic spasms and in four patients with cryptogenic spasms (p=0.009). On the PET scans of the 15 patients with autism, 13 (86.7%) had significantly decreased metabolic activity in the temporal lobe (p<0.001), nine (60%) had significantly decreased activity in the frontal lobe (p=0.004), and seven (46.7%) had significantly decreased activity in the parietal lobe (p=0.022). In our opinion, hypometabolism in the frontal and parietal lobes, in addition to that previously reported in the temporal lobe, plays a role in the development of autism in patients with infantile spasms.
Collapse
Affiliation(s)
- Cengiz Dilber
- Department of Pediatric Neurology, Istanbul University, Arpaemini/Fatih, İstanbul 34093, Turkey
| | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Iwatani Y, Kagitani-Shimono K, Tominaga K, Okinaga T, Mohri I, Kishima H, Kato A, Sanefuji W, Yamamoto T, Tatsumi A, Murata E, Taniike M, Nagai T, Ozono K. Long-term developmental outcome in patients with West syndrome after epilepsy surgery. Brain Dev 2012; 34:731-8. [PMID: 22336751 DOI: 10.1016/j.braindev.2012.01.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2011] [Revised: 01/11/2012] [Accepted: 01/11/2012] [Indexed: 10/14/2022]
Abstract
It has been hypothesized that early seizure control may prevent children with intractable epileptic spasms (ES) from developmental regression and may contribute to better developmental outcome. The effectiveness of surgery for ES has been reported. We investigated long-term post-operative outcomes of seizure control and development in patients with symptomatic West syndrome (S-WS) who underwent epilepsy surgery. Six children who underwent surgical intervention for intractable ES were retrospectively investigated. Cortical malformations were observed on pre-operative MRI in all patients, with hemispheric or multilobar involvement in four children and focal lesions in two. Following surgery, we measured motor function, developmental age (DA), language skills, and sociopsychological function for up to 7years (mean, 4.9years). Post-operative seizure outcome was Engel Class I (n=4) or III (n=2). Motor function and DA was increased following surgery in six and five patients, respectively. Two patients started to speak in sentences following focal resection. Autistic features were noted in four of the five examined patients post-operatively. None of the patients showed developmental regression following surgery. Epilepsy surgery for S-WS with ES may result in good seizure control and improvement in motor development. Improvement in cognitive function was modest in this small cohort of children and autistic features were noted post-operatively in a substantial proportion of the children. While seizure control can be obtained by epilepsy surgery, early intervention for sociopsychological comorbidities may be warranted in children with S-WS.
Collapse
Affiliation(s)
- Yoshiko Iwatani
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Wheless JW, Gibson PA, Rosbeck KL, Hardin M, O’Dell C, Whittemore V, Pellock JM. Infantile spasms (West syndrome): update and resources for pediatricians and providers to share with parents. BMC Pediatr 2012; 12:108. [PMID: 22830456 PMCID: PMC3411499 DOI: 10.1186/1471-2431-12-108] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Accepted: 07/25/2012] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Infantile spasms (IS; West syndrome) is a severe form of encephalopathy that typically affects infants younger than 2 years old. Pediatricians, pediatric neurologists, and other pediatric health care providers are all potentially key early contacts for families who have an infant with IS. The objective of this article is to assist pediatric health care providers in the detection of the disease and in the counseling and guidance of families who have an infant with IS. METHODS Treatment guidelines, consensus reports, and original research studies are reviewed to provide an update regarding the diagnosis and treatment of infants with IS. Web sites were searched for educational and supportive resource content relevant to providers and families of patients with IS. RESULTS Early detection of IS and pediatrician referral to a pediatric neurologist for further evaluation and initiation of treatment may improve prognosis. Family education and the establishment of a multidisciplinary continuum of care are important components of care for the majority of patients with IS. The focus of the continuum of care varies across diagnosis, initiation of treatment, and short- and long-term needs. Several on-line educational and supportive resources for families and caregivers of patients with IS were identified. CONCLUSIONS Given the possibility of poor developmental outcomes in IS, including the emergence of other seizure disorders and cognitive and developmental problems, early recognition, referral, and treatment of IS are important for optimal patient outcomes. Dissemination of and access to educational and supportive resources for families and caregivers across the lifespan of the child with IS is an urgent need. Pediatric health care providers are well positioned to address these needs.
Collapse
Affiliation(s)
- James W Wheless
- Professor and Chief of Pediatric Neurology, LeBonheur Chair in Pediatric Neurology, University of Tennessee Health Science Center, Memphis, TN, USA
- Director, LeBonheur Comprehensive Epilepsy Program & Neuroscience Institute, LeBonheur Children’s Medical Center, Memphis, TN, USA
- Clinical Chief and Director of Pediatric Neurology, St. Jude Children’s Research Hospital, 777 Washington Avenue, P335, Memphis, TN, 38105, USA
| | - Patricia A Gibson
- Epilepsy Information Service, Comprehensive Epilepsy Program, Wake Forest University, Medical Center Boulevard, Winston-Salem, NC, 27157, USA
| | - Kari Luther Rosbeck
- Tuberous Sclerosis Alliance, 801 Roeder Road, Suite 750, Silver Spring, MD, 20910, USA
| | | | - Christine O’Dell
- The Comprehensive Epilepsy Management Center, Montefiore Medical Center, 111 East 210th Street, Bronx, NY, 10467, USA
| | - Vicky Whittemore
- Tuberous Sclerosis Alliance, 801 Roeder Road, Suite 750, Silver Spring, MD, 20910, USA
| | - John M Pellock
- Division of Child Neurology, Department of Neurology, Virginia Commonwealth University School of Medicine, 1001 East Marshall Street, 1st Floor, Richmond, VA, 23298, USA
| |
Collapse
|
|
50
|
Abstract
Autism (autism spectrum disorders) is a complex, strongly genetically influenced, behaviorally defined disorder of the immature brain associated with very uneven intellectual abilities. Among its most salient and potentially treatable neurologic features that this article focuses on are epilepsy, disorganized sleep patterns, and sensory and motor deficits. Its many causes and wide range of severity means that there is no symptom, no pathology, imaging, electroencephalography, or other biologic feature, and no biologic treatment that is universal or diagnostic of this developmental syndrome.
Collapse
Affiliation(s)
- Wendy G Silver
- Saul R Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
| | | |
Collapse
|