Event-Related Potentials in ADHD Associated With Tuberous Sclerosis Complex: A Possible Biomarker of Symptoms Severity?

Background and Aim: Tuberous sclerosis complex (TSC) is associated with a high rate of attention deficit-hyperactivity disorder (ADHD), usually with more severe symptoms than in idiopathic cases. Event-related potentials have been used in idiopathic ADHD, and they have been proposed as a possible biomarker of symptoms severity. Aim of this study was to investigate event-related potential (ERP) characteristics in patients with ADHD secondary to TSC, compared to patients with drug-naive idiopathic ADHD and healthy controls (HCs), to investigate whether (1) distinct clinical features can be due to different pathophysiological mechanisms, and (2) ERPs may reliably predict ADHD symptoms severity in TSC. Materials and Methods: We enrolled 13 patients with idiopathic ADHD (iADHD), 6 patients with ADHD associated with TSC (tscADHD), and 14 age-matched HCs (7-17 years). All of them underwent ERP recording, with mismatch negativity (MMN) preceding the P300 recording. All patients underwent neurocognitive evaluations. Results: Mismatch negativity latency was shorter in iADHD (P = 0.04) and tscADHD (P = 0.06) than in HC, with no difference between patients' groups. Mismatch negativity amplitude was significantly higher in patients (both iADHD and tscADHD) than in HC. The P300 amplitude was significantly lower in iADHD patients than in both tscADHD patients (P = 0.03) and HCs (P < 0.001). No difference was found between tscADHD patients and HCs (P = 0.2). Conclusion: While patients with iADHD present lower P300 amplitude than HC, in tscADHD patients P300 amplitude was not different from that in HC, suggesting that in TSC P300 amplitude does not really reflect symptom severity.

Everolimus Alleviates Obstructive Hydrocephalus due to Subependymal Giant Cell Astrocytomas.

BACKGROUND: Subependymal giant cell astrocytomas (SEGAs) are low-grade tumors affecting up to 20% of patients with tuberous sclerosis complex (TSC). Early neurosurgical resection has been the only standard treatment until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors. Surgical resection of SEGAs is still considered as the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage. We describe four patients with symptomatic or asymptomatic hydrocephalus who were successfully treated with the mTOR inhibitor everolimus. METHODS: We collected the clinical data of four consecutive patients presenting with symptomatic or asymptomatic hydrocephalus due to a growth of subependymal giant cell atrocytomas and who could not undergo surgery for different reasons. RESULTS: All patients experienced a clinically significant response to everolimus and an early shrinkage of the SEGA with improvement in ventricular dilatation. Everolimus was well tolerated by all individuals. CONCLUSIONS: Our clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered in patients with asymptomatic hydrocephalus or even when the symptoms already appeared. It offers a significant therapeutic alternative to individuals that once would have undergone immediate surgery. Everolimus might also allow postponement of a neurosurgical resection, making it elective with an overall lower risk.

OPTICAL COHERENCE TOMOGRAPHY AND INFRARED IMAGES OF ASTROCYTIC HAMARTOMAS NOT REVEALED BY FUNDUSCOPY IN TUBEROUS SCLEROSIS COMPLEX.

PURPOSE: To detect, describe, and classify the morphologic characteristics of astrocytic hamartomas in tuberous sclerosis complex, using both spectral-domain optical coherence tomography (OCT) and infrared images. METHODS: Ten subjects (20 eyes) with tuberous sclerosis complex underwent a complete ophthalmologic examination and multimodality imaging with spectral-domain OCT and infrared images. The imaging protocol included a 30°scan angle of the posterior pole and of the four quadrants. Line scans, detail, raster, and posterior pole patterns were used. The identified astrocytic hamartomas were described and characterized qualitatively and quantitatively. RESULTS: Forty-four hamartomas were detected in 8 patients. In five cases, lesions were bilateral. Thirty of these hamartomas had not been revealed by previous ophthalmoscopy. Through multimodality imaging, it was possible to define multiple lesions with characteristic optical reflective qualities. All the 44 hamartomas were measured and morphologically characterized in terms of the type of tumor, retinal and/or vitreous involvement, calcifications, and posterior optical shadowing. CONCLUSION: The combined imaging with spectral-domain OCT and infrared images improves the detection of hamartomas if compared with the spectral-domain OCT technique alone. Moreover, a new subtype of hamartoma is proposed to complete a previous classification based on OCT.

Asynchronicity of Organic and Psychiatric Symptoms in a Case of Sertraline Intoxication.

Sertraline is a selective serotonin reuptake inhibitor used as an antidepressant and antipanic agent in children and adolescents. Sertraline is well tolerated and its safety profile in overdose is favorable. However, sertraline overdose may cause a toxic hyperserotonergic state known as serotonin syndrome (SS). Serotonin syndrome may be misdiagnosed in children because it has been reported mostly in adults. In the present case report, we describe a 16-year-old female patient who ingested 2000 mg of sertraline to attempt suicide. The patient showed symptoms and signs suggestive of SS, characterized by an asynchronicity between organic and psychiatric symptoms. In addition, the patient showed a variability of psychiatric symptoms through time. Thirteen hours after sertraline overdose, she was poorly cooperative with poverty of speech and marked emotional tension, but she was oriented in space and time and was able to remember what happened to her and to reconstruct the dynamics of the fact. Twenty-four hours after sertraline overdose, the patient developed a delusion of reference associated with intense anxiety and depressed mood. In the present case report, we discuss the pathophysiologic mechanisms of the observed clinical manifestations and propose an observation period for sertraline overdose in children and adolescents that is sufficiently long (at least 72 hours) even in the absence of unstable vital signs.

Combined targeted treatment in early onset epilepsy associated with tuberous sclerosis.

Tuberous sclerosis is associated with epilepsy in up to 85% of cases, and in 2/3, the onset is within the first year of life. An early antiepileptic treatment is crucial to minimize the consequences of epilepsy on cognition and behavior. We present a case report of a child with tuberous sclerosis who presented with infantile spasms at the age of 6 months, immediately treated with vigabatrin. Because of the presence of a subependymal giant cell astrocytoma, he also received everolimus since 18 months of age. We might wonder if an earlier treatment could have produced a better outcome; in fact, despite a targeted combined treatment, he continues to suffer from sporadic focal motor seizures, and at the age of 40 months, he presents severe developmental delay with autism-like behavior.

Reduction in retinal nerve fiber layer thickness in tuberous sclerosis complex.

PURPOSE: The aim of our study was to non-invasively investigate central nervous system axonal integrity in patients with tuberous sclerosis complex (TSC). Diffuse microstructural white matter abnormalities reflecting axonal disorganization, reduced/altered myelination, or gliosis have been described in individuals with TSC. Optical coherence tomography (OCT) is a fast, easy-to-perform, non-invasive, and cost-efficient method to assess retinal morphology in vivo and to measure the thickness of the retinal nerve fiber layer (RNFL). METHODS: In order to assess central nervous system axonal integrity, eight subjects with TSC have been investigated by OCT to evaluate RNFL and they have been compared with matched healthy controls. RESULTS: When comparing mean overall RNFL thicknesses of the TSC group with those of the control group, the TSC group presented with significantly lower RNFL values, compared to the control group, in the temporal quadrant (62.5 ± 6.9 vs. 76.9 ± 5.4; t = 14.438; p < 0.0001). CONCLUSIONS: Since a reduced RNFL thickness might be seen as an indicator of chronic axonal degeneration or lack of appropriate neuronal development, our results support the presence of axonal alterations in TSC and also that white matter disorganization could be much more diffuse than originally thought. Since axonal alterations directly derive from mammalian target of rapamycin (mTOR) overactivation, which occurs early during fetus development, the RNFL thinning we observed could represent one of the facets of such early neurodevelopmental abnormalities.

Reduction in retinal nerve fiber layer thickness in young adults with autism spectrum disorders.

Recent years have seen an increase in the use of retinal nerve fiber layer (RNFL) evaluation as an easy-to-use, reproducible, proxy-measure of brain structural abnormalities. Here, we evaluated RNFL thickness in a group of subjects with high functioning autism (HFA) or with Asperger Syndrome (AS) to its potential as a tool to study autism pathophysiology. All subjects underwent high-resolution spectral domain optical coherence tomography to evaluate RNFL thickness. HFA subjects presented with reduced global RNFL thickness compared both to AS subjects and controls. AS subjects showed a reduced nasal quadrant RNFL thickness compared to controls. Verbal-IQ/performance-IQ discrepancy correlated with RNFL thickness. Our data suggest that RNFL evaluation could help in the development of biological markers of autism pathophysiology.