scholarly journals Secular changes in severity of intellectual disability in tuberous sclerosis complex: A reflection of improved identification and treatment of epileptic spasms?

2018 ◽  
Vol 3 (2) ◽  
pp. 276-280 ◽  
Author(s):  
Charlotte Tye ◽  
Laura E. Thomas ◽  
Julian R. Sampson ◽  
Julia Lewis ◽  
Finbar O'Callaghan ◽  
...  
Neurology ◽  
2019 ◽  
Vol 93 (2) ◽  
pp. e200-e209 ◽  
Author(s):  
Iris E. Overwater ◽  
André B. Rietman ◽  
Sabine E. Mous ◽  
Karen Bindels-de Heus ◽  
Dimitris Rizopoulos ◽  
...  

ObjectiveTo investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis complex (TSC).MethodsIn this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4–17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5–10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems.ResultsThirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect −5.6 IQ points, 95% confidence interval −12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questionnaires examining behavioral problems, social functioning, communication skills, executive functioning, sleep, quality of life, and sensory processing. All patients had adverse events. Two patients on everolimus and 2 patients on placebo discontinued treatment due to adverse events.ConclusionsEverolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC. The use of everolimus in children with TSC with the aim of improving cognitive function and behavior should not be encouraged in this age group.Clinicaltrials.gov identifierNCT01730209.Classification of evidenceThis study provides Class I evidence that for children with TSC, everolimus does not improve intellectual disability, autism, behavioral problems, or other neuropsychological deficits.


Author(s):  
James C. Harris

Although intellectual disability has been recognized since antiquity, interest in its classification did not develop until the nineteenth century, when it became apparent that intellectual disability is not one homogeneous category, as was previously thought, but has many causes. Moreover, it became apparent that intervention could be beneficial and that interventions might be tailored for specific disorders. Early authors prepared the way for modern efforts to differentiate specific conditions that differ in both etiology and pathology, yet all result in intellectual disability. Some attempts were misguided. J. Langdon Hayden Down, in his ethnic classification (1866; Jordan, 2000), sought to classify based on the physical appearance of the individuals he examined. His goal was to absolve parents of self-blame for the handicap by emphasizing a constitutional basis for their child’s disorder. He proposed an “ethnic classification,” suggesting that the various forms of intellectual disability represented regressions to stereotypical racial forms (e.g., mongoloid, Aztec). Although he later abandoned this unfortunate idea, he continues to be known for it. Still, he is credited with drawing scientific attention to the syndrome bearing his name (Jordan, 2000) and for suggesting that the best classification is one based on etiology. Subsequently, he anticipated current efforts at classification by describing three major groups: (1) congenital, which included microcephalic, macrocephalic, hydrocephalic, epileptic, and paralytic types; (2) developmental, with a vulnerability to mental breakdown with stress during a developmental crisis; and (3) accidental (caused by injury or illness). Later, William Weatherspoon Ireland (1877), in his textbook on intellectual disability, suggested 10 subdivisions. Among these are genetous (congential), microcephalic, epileptic, eclamptic, hydrocephalic, paralytic, traumatic, inflammatory, cretinism, and idiocy by social and physical deprivation. In 1880, tuberous sclerosis complex was identified by Désiré-Maglione Bourneville (1880), who established that intellectual disability might result from brain pathology. Subsequently, many other intellectual disability syndromes were recognized. Thus began a new era, with investigators searching for clearly defined disorders associated with intellectual disability; these were commonly named after their discoverers. It was an era when intellectual disability syndromes were beginning to be recognized, but medicine had little to offer therapeutically.


2013 ◽  
Vol 106 (1-2) ◽  
pp. 200-210 ◽  
Author(s):  
David T. Hsieh ◽  
Melanie M. Jennesson ◽  
Elizabeth A. Thiele

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110128
Author(s):  
Daad Alsowat ◽  
Robyn Whitney ◽  
Stacy Hewson ◽  
Puneet Jain ◽  
Valerie Chan ◽  
...  

Objective: We aimed to further elucidate the phenotypic spectrum of Tuberous Sclerosis Complex (TSC) depending on genotype. Methods: A retrospective review of patients seen in the TSC clinic at the Hospital for Sick Children was conducted and the frequency of TSC manifestations was compared based on genotype. Results: Nineteen-patients had TSC1 mutations, 36 had TSC2 mutations and 11 had no mutation identified (NMI). Patients with TSC2 mutations had a higher frequency of early-onset epilepsy and more frequent systemic manifestations. The NMI group had milder neurologic and systemic manifestations. Our data did not demonstrate that intellectual disability and infantile spasms were more common in TSC2 mutations. Conclusions: This is the first Canadian pediatric cohort exploring the genotype-phenotype relationship in TSC. We report that some manifestations are more frequent and severe in TSC2 mutations and that NMI may have a milder phenotype. Disease surveillance and counseling should continue regardless of genotype until this is better elucidated.


2019 ◽  
Vol 34 (12) ◽  
pp. 770-777 ◽  
Author(s):  
Anne-Elise C. de Groen ◽  
Jeffrey Bolton ◽  
Ann Marie Bergin ◽  
Mustafa Sahin ◽  
Jurriaan M. Peters

Background:Subclinical seizures are electrographic seizures that present without subjective or objective clinical symptoms. In tuberous sclerosis complex, it is not known whether subclinical seizures occur alone, forewarn, or coexist with clinical seizures. To address this knowledge gap, we studied the prevalence and evolution of subclinical seizures in tuberous sclerosis complex.Methods:We retrospectively reviewed electroencephalography (EEG) data from our tuberous sclerosis complex clinic with subclinical seizures and clinical seizures in a blinded fashion. Based on EEG location and ictal pattern, subclinical seizures were classified as having a clinical counterpart from the same epileptogenic region (match) or not (no match).Results:Of 208 children with tuberous sclerosis complex, 138 had epilepsy and available EEG data. Subclinical seizures were detected in 26 of 138 (19%) children. Twenty-four children had both subclinical seizures and clinical seizures captured on EEG. In 13 of 24, subclinical seizures were detected as a novel, not previously recorded seizure type. In these children, subclinical seizures preceded matching clinical seizures in 4 (31%) within a median time of 4.5 months (range 2-14), whereas 9 (69%) never had any matching clinical seizure. In 11 of 24 children, subclinical seizures were not novel and could be matched to a previously recorded clinical seizure. Matching seizure types were focal (n = 10, 67%), tonic (n = 2), epileptic spasms (n = 2), and status epilepticus (n = 1).Conclusions:Subclinical seizures occur in one-fifth of children with tuberous sclerosis complex and epilepsy, and match with clinical seizures in a small majority. In a third of patients presenting with a novel subclinical seizure, matching clinical seizures follow.


2021 ◽  
Author(s):  
Fiona McEwen ◽  
Charlotte Tye ◽  
Holan Liang ◽  
Emma Woodhouse ◽  
Lisa Underwood ◽  
...  

Tuberous Sclerosis Complex (TSC) is a single gene disorder – caused by mutation in the TSC1 or TSC2 gene – that carries a high risk of autism spectrum disorder (ASD). Various neurological complications increase the risk of ASD but the way risk factors operate together is unclear. We aimed to explore risk pathways to ASD by modelling the interplay between genetic mutation (TSC1/TSC2), cortical tuber count, seizure type and severity. The Tuberous Sclerosis 2000 Study is a UK population-based, prospective study of the natural history of TSC. We recruited newly diagnosed children (N=125, 49.6% male, median age=2.7 years [range 4 weeks – 18 years]) and collected data on mutation, cortical tuber count (cranial MRI/CT), seizure history, and IQ. ASD and IQ assessments were carried out at 10-year follow up (N=86, 45.0% male, median age=12.5 years [range 7.8 – 26.9 years]). Assessment for ASD included the Autism Diagnostic Interview–Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS-2). Structural equation modelling using full information maximum likelihood estimation was used to explore pathways that mediate between mutation and ASD. Risk of ASD was high: 39.5% met research criteria for ASD and a further 41.9% showed autistic traits. Structural equation modelling resulted in two indirect pathways, with cortical tuber count and occurrence/severity of epileptic spasms in infancy mediating between mutation and ASD (mutation→tubers→spasms→ASD, B=2.08, 95% CI 0.15–8.02; mutation→spasms→ASD, B=2.98, 95% CI 0.04–8.89). Concurrent seizures (B=3.08, 95% CI 0.42–6.18) and IQ (B=-117.10, 95% CI -183.57–-59.16) were also associated with ASD symptoms. There was significantly elevated risk of ASD and subclinical autistic traits. Tuber count and severity of epileptic spasms predicted ASD severity, suggesting that seizures in infancy may push genetically vulnerable individuals over the threshold for an ASD diagnosis. Prevention/control of seizures in infancy may decrease severity of ASD symptoms. However, ASD was occasionally reported in the absence of overt seizures in infancy, so their causal role requires further investigation.


2018 ◽  
Vol 33 (8) ◽  
pp. 519-524 ◽  
Author(s):  
Emma A. van der Poest Clement ◽  
Mustafa Sahin ◽  
Jurriaan M. Peters

Vigabatrin is recommended as first-line treatment for infantile spasms in tuberous sclerosis complex (TSC), but other indications in children with tuberous sclerosis complex are less known. We retrospectively reviewed 201 children with tuberous sclerosis complex, and identified 21 children older than 1 year started on vigabatrin for any indication and with sufficient follow-up data. The indication for vigabatrin was epileptic spasms (n = 13), tonic seizures (n = 5), both (n = 2), and status epilepticus (n = 1). Mean age of treatment onset was 4.0 years (range 1.1-18.3). All but 1 patient had a reduction in seizures. Ten patients became seizure free and 4 had an improvement of >90%. In 9 patients, vigabatrin was tapered successfully after 8 to 33 months. Side effects reported included rash (n = 1) and behavioral decline (n = 1). No retinal toxicity was detected in 14 of 21 patients with adequate ophthalmologic surveillance data. In conclusion, vigabatrin may be an effective treatment for epileptic spasms and tonic seizures beyond the infantile age.


Intelligence ◽  
2009 ◽  
Vol 37 (2) ◽  
pp. 174-180 ◽  
Author(s):  
Chunshui Yu ◽  
Fuchun Lin ◽  
Li Zhao ◽  
Jing Ye ◽  
Wen Qin

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