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To determine and quantify the effect of blue lenses (Z1) on photosensitivity (PS) suppression in patients aged 5-18 years with and without epilepsy.The retrospective cohort study was carried out in 100 pediatric patients aged 5-18 years with grade 4 PS assessed with EEG for medical indications. All EEG procedures were carried out and recordings assessed by two independent researchers. The study cohort was divided into groups with and without the diagnosis of epilepsy. The overall effect of the Z1 lenses on photoparoxysmal response (PPR) was determined by directly comparing the maximum discharge values in each patient without and with Z1 lenses in a within-subject design yielding the index of overall improvement (IOI). The differences in PS suppression by brain region and side were assessed by an additional between-subject comparison of age groups (below and above 14 years). Then, overall findings were compared with the PPR change criteria developed in 2006 by Capovilla (PPR disappearance, persistence, or attenuation) which warranted another subset analysis. Finally, in a between-subject design, we assessed whether the presence of epilepsy affects the intensity of PPR in children with PS, compared to non-epilepsy children.The IOI in the entire cohort was 66.1±2.5% (P0.001). There were no significant differences in IOI between the left and right hemispheres, between the age groups, and between the epilepsy and non-epilepsy groups, despite some qualitative variation. With reference to literature findings, whereas median IOI were comparable in PPR disappearance and attenuation subsets, they differed significantly from the median IOI in the PPR persistence subset.Using Z1 lenses results in neither a complete PPR disappearance, nor a complete lack of effect. However, the correlation between the quantified PS suppression and the Z1 filter may be expected to become a valuable piece of information for both clinicians and manufacturers.

Background. Paediatric-onset MS (POMS) has a unique clinical profile compared to the more prevalent adult-onset MS. For this study, we aimed to determine the demographic and clinical characteristics of POMS in Poland as well as addressing some of its epidemiological aspects. Methods. A retrospective study was conducted based on the Polish Multiple Sclerosis Registry, considering a population of children and adolescents with MS (age ≤ 18 years). Data were collected by all 13 centres across Poland specializing in diagnosing and treating POMS. The actual course of the disease and its clinical properties were compared between child (≤12 years) and juvenile (>12 years) patients. MS onset and its prevalence were assessed at the end of 2019, stratified by age range. Results. A total of 329 paediatric or juvenile patients (228 girls, 101 boys) with a clinically definite diagnosis of MS, in conformity with the 2017 McDonald Criteria, were enrolled. For 71 children (21.6%), the first symptoms appeared before the age of 12. The female: male ratio increased with age, amounting to 1:1 in the ≤12 years group and to 2.9:1 in the >12 years group. In most cases, the disease had multi-symptomatic onset (31.3%), and its course was mostly of a relapsing–remitting character (95.7%). The initial Expanded Disability Status Score for both groups was 1.63 ± 1.1, whereas the annual relapse rate was 0.84 during the first 2 years. The time between the onset of symptoms and diagnosis was longer in the younger patients (8.2 ± 4.2 vs. 4.6 ± 3.6 months; p < 0.005). On 31 December 2019, the age-adjusted prevalence standardized to the European standard population was 5.19/100,000 (95% CI, 4.64–5.78). Significantly higher prevalence was noted in the 13–18 years group (7.12; 95% CI, 6.64–7.86) than in the 9–12 years group (3.41; 95% CI, 2.98–3.86) and the

Celem pracy było podsumowanie aktualnej wiedzy na temat zaburzeń neuropsychiatrycznych związanych ze stwardnieniem guzowatym (ang. Tuberous Sclerosis Complex, TSC). TSC jest rzadką chorobą genetyczną, zaliczaną do fakomatoz. Ze względu na szerokie spektrum objawów klinicznych wiele przypadków pozostaje niezdiagnozowanych. U zdecydowanej większości osób z mutacją w genach TSC1 lub TSC2 w ciągu życia dochodzi do rozwoju niektórych z objawów neuropsychiatrycznych. W pracy przedstawiono aktualne kryteria diagnostyczne TSC. Opisana została również patologia neuroanatomiczna i patofizjologia leżąca u podłoża objawów psychiatrycznych, neuropsychologicznych, rozwojowych i psychospołecznych występujących w TSC. Przedstawiono specyfikę padaczki w TSC i jej rolę w rozwoju neuropsychiatrycznym i neuropsychologicznym. Szczegółowo omówione zostały wszystkie poziomy (intelektualny, rozwojowy, behawioralny, psychiatryczny, szkolny, neuropsychologiczny i psychospołeczny) zaburzeń neuropsychiatrycznych związanych ze stwardnieniem guzowatym (ang. Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders, TAND). W pracy opisane zostało narzędzie do oceny wszystkich potencjalnie zaburzonych aspektów funkcjonowania osób z TSC - Lista kontrolna TAND. Podkreślono wagę właściwej diagnozy zaburzeń neuropsychiatrycznych i multidyscyplinarnej opieki nad pacjentem.

Introduction: Tuberous Sclerosis Complex (TSC) is a rare genetic disease. Around 90% of individuals with TSC present some neuropsychiatric manifestations (TSC-associated neuropsychiatric disorders, TAND). To date, none of the studies have focused on the TAND profile of the adult population. Thus, the aim of the study was to describe their potential specific needs and difficulties, including differences in cohorts with or without epilepsy and/or intellectual disability. Method: The Polish version of the TAND Checklist was used for assessment of individuals with TSC. Participants had to meet the criteria for diagnosis of TSC. One hundred adult participants (forty-eight males/ fifty-two females; mean age 32.33 ± 11.29) were enrolled in the study. Epilepsy was present in 71% of patients; intellectual disability occurred in a total of 37%. Results: Only 11% of individuals received complete TAND features examination in the past. Moreover, 91.5 of the subjects had four and more TAND symptoms. Intellectually disabled patients and those with epilepsy had more neuropsychiatric problems than epilepsy-free subjects. Conclusions: Findings reveal that TANDs are common in adults with TSC and are underdiagnosed. Most individuals present several behavioural and cognitive problems. Among psychiatric disorders, the most common are ASD, depression, and anxiety disorder. TAND screening should be widely disseminated and applied in clinical practice for early identification, prevention, and rehabilitation of their difficulties. TAND is one of the most significant issues affecting the quality of life of TSC patients and their carers.

This is a summary report of clinical and regulatory issues discussed at the 2018 NINDS workshop, entitled “Accelerating Therapies for Antiepileptogenesis and Disease Modification.” The intent of the workshop was to optimize and accelerate development of therapies for antiepileptogenesis (AEG) and disease modification in the epilepsies. The working group discussed nomenclature for antiepileptogenic therapies, subdividing them into “antiepileptogenic therapies” and “disease modifying therapies,” both of which are urgently needed. We use the example of traumatic brain injury to explain issues and complexities in designing a trial for disease‐preventing antiepileptogenic therapies, including identifying timing of intervention, selecting the appropriate dose, and the need for biomarkers. We discuss the recent trials of vigabatrin to prevent onset and modify epilepsy outcome in children with tuberous sclerosis (Epistop and PreVeNT). We describe a potential approach to a disease modification trial in adults, using patients with temporal lobe epilepsy. Finally, we discuss regulatory hurdles for antiepileptogenesis and disease‐modifying trials.

This paper aimed to assess language development in infants and toddlers with tuberous sclerosis complex (TSC) and epilepsy, which increase the risk of autism spectrum disorder. We assessed language development in 61 patients with TSC at 8–36 months using a standardized Speech Development and Communication Inventory tool. The results showed differences in outcomes due to the duration of the seizures and the number of drugs (pFDR = 0.007 **—pFDR = 0.037 *). Children with TSC with longer epilepsy duration and receiving more antiepileptic drugs have a greater risk of language development delay.

The aim of this study was to determine the serum profiles of miRNAs in patients with tuberous sclerosis (TSC) upon sirolimus treatment and compare them with those previously treated with everolimus in a similarly designed experiment. Serum microRNA profiling was performed in ten TSC patients before sirolimus therapy and again after 3–6 months using qPCR panels (Exiqon). Of 752 tested miRNAs, 28 showed significant differences in expression between TSC patients before and after sirolimus treatment. Of these, 11 miRNAs were dysregulated in the same directions as in the sirolimus groupcompared with the previously described everolimus group, miR-142-3p, miR-29c-3p, miR-150-5p, miR-425-5p, miR-376a-3p, miR-376a-3p, miR-532-3p, and miR-136-5p were upregulated, while miR-15b-3p, miR-100-5p, and miR-185-5p were downregulated. The most significant changes of expression, with fold changes exceeding 1.25 for both treatments, were noted for miR-136-5p, miR-376a-3p, and miR-150-5p. The results of a pathway analysis of the possible target genes for these miRNAs indicated the involvement of the Ras and MAPK signaling pathway. Upregulation of miR-136, miR-376a-3p, and miR-150-5p was noted in TSC patients treated with mTOR inhibitors, indicating a role in the downregulation of the mTOR pathway. Further studies are needed to determine the relationship between upregulated microRNAs and treatment efficacy.

Gadolinium-based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI) to help with the diagnostic and monitoring processes of many diseases, including neurological disorders. Initially, it was assumed that GBCAs carry minimal risk, are safe and well tolerated. But recent reports of GBCA-associated deposition in many body tissues have raised concerns about the broader health impacts of gadolinium exposure. The aim of this review was to summarise knowledge regarding gadolinium deposition, primarily in the brain structures, and of potential GBCA-associated toxicity. Moreover, we discuss the current recommendations on the use of GBCAs, as well as alternative contrast agents and imaging techniques.

Background: Epilepsy affects 70–90% of patients with tuberous sclerosis complex (TSC). In one-third of them, the seizures become refractory to treatment. Drug-resistant epilepsy (DRE) carries a significant educational, social, cognitive, and economic burden. Therefore, determining risk factors that increase the odds of refractory seizures is needed. We reviewed current data on risk factors associated with DRE in patients with tuberous sclerosis. Methods: The review was performed according to the PRISMA guidelines. Embase, Cochrane Library, MEDLINE, and ClinicalTrial.gov databases were searched. Only full-text journal articles on patients with TSC which defined risk factors related to DRE were included. Results: Twenty articles were identified, with a cohort size between 6 and 1546. Seven studies were prospective. Three factors appear to significantly increase DRE risk: TSC2 mutation, infantile spasms, and a high number of cortical tubers. Conclusions: A proper MRI and EEG monitoring, along with genetic testing, and close observation of individuals with early onset of seizures, allow identification of the patients at risk of DRE.

The aim of this study was to assess the potential implication of microRNA on tuberous sclerosis (TSC) pathogenesis by performing microRNA profiling on cell lines silencing TSC1 or TSC2 genes using qPCR panels, before and after incubation with rapamycin. (Qiagen). Significant differences in expression were observed between samples before and after rapamycin treatment in 19 miRNAs in TSC1, five miRNAs in TSC2 and seven miRNAs in controls. Of six miRNAs dysregulated before rapamycin treatment in the TSC1 group, three normalized after treatment (miR-21-3p, miR-433-3p, let-7g-3p). Of three miRNAs dysregulated before rapamycin incubation in TSC2 group, one normalized after treatment (miR-1224-3p). Of the miRNAs dysregulated before rapamycin treatment in TSC1 and TSC2 group, two did not normalize after treatment (miR-33a-3p, miR-29a-3p). The results of the possible targets indicated that there are four common genes with seed regions susceptible to the regulation by those miRNAs: ZBTB20, PHACTR2, PLXNC1 and ATP1B4. Our data show no changes in mRNA expression of these targets before rapamycin treatment. These data suggest that miRNA may play a pivotal role in TSC pathogenesis. Some may serve as biomarkers of treatment efficacy. The variability of miR-29a-3p and miR-33a-3p after rapamycin treatment and the lack of changes in their downstream regulatory targets suggests that they might be mTOR independent.

Background\ud Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.\ud Methods\ud Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required.\ud Results\ud Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.\ud Conclusions\ud Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.

Objective The aim of this study is the investigation of early-life EEG background abnormalities or “dysmature” traits in infants with tuberous sclerosis complex (TSC) and their capacity to predict autism spectrum disorder or neurodevelopmental outcome. Methods EEG data were prospectively collected from TSC patients during the EPISTOP trial (NCT02098759). Subjects were younger than 4 months, and ASD risk and neurodevelopmental outcome were assessed at the age of 2 years. The EEG at the first visit was analyzed by means of Multiscale Entropy (MSE), multifractality (MFA), amplitude integrated EEG features and topological indices of the EEG network. These features were associated with both ASD and abnormal Bayley outcome of the infants using linear discriminant analysis. Results The classification of the ASD patients shows that MFA and MSE had the best discrimination performances, with an area under the ROC curve AUC (MFA) = 0.74 and AUC(MSE) = 0.79 respectively, and kappa scores of Kappa(MFA) = 0.48 and Kappa(MSE) = 0.26. Concerning both abnormal Bayley outcome and ASD, the developmental abnormalities detection shows that entropy and fractal features outperform the other subsets of attributes and the multiclass analysis shows that those features can also discriminate patients with ASD from patients with only developmental abnormalities (Kappa(MFA) = 0.41 and Kappa(MSE) = 0.36). Conclusion Quantitative EEG analysis shows that a dysmature EEG, i.e. a signal with higher fractal regularity and lower entropy, is associated with autism spectrum disorder or abnormal Bayley outcome at 2 years of age.

Introduction: Tuberous sclerosis complex (TSC) is a genetic disease affecting 1:6000 newborns. It is a multisystem disease caused by overactivation of mechanistic target of rapamycin (mTOR) pathway...

The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 μM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 μM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size.

Introduction: Vigabatrin (VGB), a second-generation antiepileptic drug, is effective for the treatment of infantile spasms and focal seizures, primarily in tuberous sclerosis complex (TSC) patients. However, reports of adverse events of VGB, including VGB-associated visual field loss and brain abnormalities in neuroimaging, have raised concerns about the broader use of VGB and thus significantly limited its application. Aim of the study: The goal of this review was to summarise the recent therapeutic guidelines, the use of VGB in focal seizures and new VGB applications as a disease-modifying treatment in TSC patients. Moreover, we discuss the current opinions on potential VGB-associated toxicity and the safety of VGB.

Background: Cardiac rhabdomyomas (CRs) are the earliest sign of tuberous sclerosis complex (TSC). Most of them spontaneously regress after birth. However, multiple and/or large tumors may result in heart failure or cardiac arrhythmia. Recently, the attempts to treat CRs with mTOR inhibitors (mTORi) have been undertaken. We reviewed the current data regarding the effectiveness and safety of mTORi in the treatment of CRs in children with TSC. Methods: The review was conducted according to the PRISMA guidelines. Medline, Embase, Cochrane library, and ClinicalTrial.gov databases were searched for original, full-text articles reporting the use of mTORi (everolimus or sirolimus) in the treatment of CRs in children with TSC. Results: Thirty articles describing 41 patients were identified (mostly case reports, no randomized or large cohort studies). Thirty-three children (80.5%) had symptomatic CRs and mTORi therapy resulted in clinical improvement in 30 of them (90.9%). CRs size reduction was reported in 95.1%. Some CRs regrew after mTORi withdrawal but usually without clinical symptoms recurrence. The observed side effects were mostly mild. Conclusions: mTORi may be considered as a temporary and safe treatment for symptomatic CRs in children with TSC, especially in high-risk or inoperable tumors. However, high-quality, randomized trials are still lacking.

OBJECTIVE: To study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED-EEG) and epilepsy and neurodevelopment at 24 months in infants with tuberous sclerosis complex (TSC). METHODS: Patients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy - Tuberous sclerosis complex (EPISTOP) trial, had serial EEG monitoring until the age of 24 months. The timing and characteristics of the first ED-EEG were studied in relation to clinical outcome. Epilepsy-related outcomes were analyzed separately in a conventionally followed group (initiation of vigabatrin after seizure onset) and a preventive group (initiation of vigabatrin before seizures, but after appearance of interictal epileptiform discharges [IEDs]). RESULTS: Eighty-three infants with TSC were enrolled at a median age of 28 days (interquartile range [IQR] 14-54). Seventy-nine of 83 patients (95%) developed epileptiform discharges at a median age of 77 days (IQR 23-111). Patients with a pathogenic TSC2 variant were significantly younger (P-value .009) at first ED-EEG and more frequently had multifocal IED (P-value .042) than patients with a pathogenic TSC1 variant. A younger age at first ED-EEG was significantly associated with lower cognitive (P-value .010), language (P-value .001), and motor (P-value .013) developmental quotients at 24 months. In the conventional group, 48 of 60 developed seizures. In this group, the presence of focal slowing on the first ED-EEG was predictive of earlier seizure onset (P-value .030). Earlier recording of epileptiform discharges (P-value .019), especially when multifocal (P-value .026) was associated with higher risk of drug-resistant epilepsy. In the preventive group, timing, distribution of IED, or focal slowing, was not associated with the epilepsy outcomes. However, when multifocal IEDs were present on the first ED-EEG, preventive treatment delayed the onset of seizures significantly (P-value

The aim of this study was to evaluate a cost-effective diagnostic strategy for identification of casual variants for tuberous sclerosis complex (TSC) in the Polish population and to correlate the genetic results with selected phenotypic features. Fifty-five patients, aged 3–44 years, with a clinical diagnosis of TSC were enrolled into the study. All patients received a three-step analysis: next generation sequencing screening (NGS), multiplex ligation-dependent probe amplification (MLPA) and deep sequencing. This multistep approach obtained positive results in 51/55 (93%) patients: of the 51 positives TSC1 variants were observed in 16 (31%) and TSC2 variants in 35 (69%); these included 13 novel variants and two patients with mosaicism. Four patients (7%) had no mutation identified (NMI). Among the TSC1 gene variants, there were five nonsense, four frameshift, three large deletions, two missense and two splicing variants. For the TSC2 gene, 11 were missense, eight splicing, six frameshift, four large deletions, two in-frame deletions and four nonsense variants. The patients with TSC2 changes had their clinical diagnosis of TSC at a younger age than those with TSC1 changes (one year vs three years, p = 0.041). The TSC2 group demonstrated a higher number of major symptoms per patient (p = 0.04). Subependymal giant cell astrocytoma with concomitance of other brain lesions was more common in patients with missense mutations in either gene (23% vs 0%, p = 0.02). Such a multistep molecular diagnostic strategy could increase the possibility of detecting causal variants for TSC and may allow detection of mosaicism at low levels. Missense pathogenic variants in TSC1 or TSC2 gene might be associated with a higher risk of brain lesions.

Objectives: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors. The aim of the study was to assess the prevalence of oral lesions in patients with TSC and healthy individuals. Study design: The study included 120 patients aged 1.1 to 42.7 years: 60 patients with TSC and 60 controls. Clinical assessment of oral hygiene (Plaque Index–PLI), gingiva (Gingival Index–GI, Gingival Overgrowth Index–GOI), oral mucosa and dentition (caries, tooth wear, enamel defects) was performed. Statistical analysis was performed. Results: 40 patients with TSC received anticonvulsants. Neglected hygiene (PLI: 1.50±0.96 vs 0.92±0.72), gingival hyperplasia (50.0% vs.1.7%), gingivitis (80.7% vs. 53.4%), oral mucosal fibromas (10.0% vs. 0.0%), mucous membrane traumatic lesions (11.7% vs. 1.7%), enamel pits and hypoplasia of incisal borders (41.7% vs. 6.7%), tooth wear (35.0% vs. 11.7%) were more common in patients with TSC compared to controls; increased gingival hyperplasia was correlated with vigabatrin and levetiracetam treatment (r = 0.266 and 0.279, respectively), gingivitis was correlated with PLI (r= 0.635). Conclusions: Although gingival fibromas in TSC are independent of patient’s age, young age, anticonvulsant therapy and local factors increase their severity. Enamel defects in TSC include pits, but also enamel loss on the incisal edges and tooth wear.

Tuberous sclerosis complex (TSC) represents a genetic condition, in which the clinical manifestations are caused by the disinhibition of the mammalian target of rapamycin (mTOR) pathway due to mutations in the TSC1 (hamartin) or TSC2 (tuberin) genes. The deregulated mTOR activity leads to multi-site tumors, including subependymal giant cell astrocytoma (SEGA). SEGA is a brain tumor that affects around 15% of TSC patients. The aim of the study was to evaluate miR-21 expression in the serum of two groups of TSC patients: with or without SEGA tumors. We found no differences in the level of miR-21 depending on the presence of SEGA. Next, we studied the influence of prolonged rapamycin administration on miR-21 level in the blood serum of TSC patients (6-12 months of rapamycin) and in primary cultures of SEGA-derived cells treated with rapamycin in vitro . Here we show that rapamycin treatment leads to the upregulation of miR-21 in both patients’ serum and in primary SEGA tumor cells in the culture indicating the regulatory relationship between rapamycin treatment and miR-21 expression.

Arterial type of thoracic outlet syndrome belongs to the most unusual mechanisms of stroke in children in the first decade of life. We present a case diagnosed for bilateral and symmetric changes due to retrograde thromboembolic phenomenon. Regarding the age of the patient, the appropriate diagnostics and management are still a matter of debate in pediatric and neurological literature.

Background Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence of 1:6000 live births and associated with the development of benign tumors in several organs. It is also characterized by high rates of neurological and neuropsychiatric abnormalities, including epilepsy affecting 70–90% of patients and being one of the major risk factors of intellectual disability. The first seizures in TSC patients appear usually between the 4th and the 6th months of life. Recent studies have shown the beneficial role of preventative antiepileptic treatment in TSC patients, with the possibility for improvement of cognitive outcome. Moreover, European recommendations suggest early introduction of Vigabatrin if ictal discharges occur on EEG recordings, with or without clinical manifestation. The aim of this study was to define the most useful approach to make the diagnosis of TSC before seizure onset (before age 4th months), in order to start early EEG monitoring with possible preventative treatment intervention. Methods We performed a retrospective review of children who were suspected of having TSC due to single or multiple cardiac tumors as the first sign of the disease. We analyzed the medical records in terms of conducted clinical tests and TSC signs, which were observed until the end of the 4th month of age. Subsequently, we described the different clinical scenarios and recommendations for early diagnosis. Results 82/100 children were diagnosed with TSC within the first 4 months of life. Apart from cardiac tumors, the most frequently observed early TSC signs were subependymal nodules (71/100, 71%), cortical dysplasia (66/100, 66%), and hypomelanotic macules (35/100, 35%). The most useful clinical studies for early TSC diagnosis were brain magnetic resonance imaging (MRI), skin examination and echocardiography. Genetic testing was performed in 49/100 of the patients, but the results were obtained within the first 4 months of life in only 3 children. Conclusions Early diagnosis of TSC, before seizure onset, is feasible and it is becoming pivotal for epilepsy management and improvement of cognitive outcome. Early TSC diagnosis is mostly based on clinical signs. Brain MRI, echocardiography, skin examination and genetic testing should be performed early in every patient suspected of having TSC.

Neurofibromatosis type 1 (NF1) is a relatively frequent genetic disorder inherited in an autosomal dominant fashion and the most common phakomatosis. The disease can affect many organs and systems, mainly the skin, bones and nervous system, but manifestations are extremely variable, even within a family. Patients have an increased risk of benign and malignant tumor formation. Because of the great clinical heterogeneity, patients may present to different specialists; therefore, the diagnosis may be difficult and delayed. A multidisciplinary specialist care is recommended throughout the lifetime of the patient. The purpose of the article is a review of up-to-date recommendations on NF1 and demonstration of the latest discoveries in this area. In this review, we describe benign and malignant features of NF1, diagnostic strategies, monitoring and treatment of disorders associated with NF1.

Stroke, increasingly recognised in children in recent years, is an important cause of long-term morbidity and disability. It can be classified by the stroke type as either arterial ischaemic stroke (AIS), haemorrhagic stroke (HS), or cerebral sinovenous thrombosis (CSVT). Furthermore, perinatal and childhood stroke can be distinguished. A wide range of conditions associated with paediatric stroke has been identified, which differ significantly from those in adults. A paediatric stroke can also present with a variety of symptoms and signs, both specific and non-specific. Because of the diversity of the underlying risk factors, limited awareness among the medical community, and therefore insufficient recognition of paediatric stroke symptoms, diagnosis can be difficult and is often delayed. This limits access to acute interventions. The goal of this paper was to examine the current guidelines for the diagnosis and treatment of paediatric stroke.

Tuberous sclerosis complex (TSC) is a genetic disease that leads to formation of tumors i.e. in brain kidneys, heart, lungs, and skin.The aim of the study was to summarize center's experience in the first year of program of nephrologic follow-up in patients with TSC.During 12 months 30 children with TSC (14 boys and 16 girls aged from 3 months to 17 years 11 months, mean 7.57±5.02 years) were hospitalized. Following parameters were evaluated: genetic and biochemical tests, blood pressure in ambulatory blood pressure monitoring (ABPM), kidney lesions in ultrasonography (30 patients) and in magnetic resonance (14 patients).Genetic tests were performed in 6 children - in 5 TSC2 mutation was found, in one boy with TSC and numerous renal cysts only PKD1 mutation was revealed. Mean GFR was 130.81±23.23 mL/ min/1.73 m2. Four children (13.3%) had arterial hypertension. Renal lesions were found in 28 (93.3%) children: 18 patients had angiomyolipomas (AML) (mean diameter 15.4±12.5, max 38 mm), 23 patients had renal cysts (mean diameter 7.6±7.0, max 30 mm); 13 patients had AMLs and cysts. A dysplastic lesion (39x26x15 mm) in right kidney was found in one girl. Children with AML were older than remaining patients (10.08±4.55 vs. 4.25±3.50 [years], p0.001). Children with cysts were characterized by higher systolic (p=0.017), diastolic (p=0.027) and mean (p=0.014) arterial pressure, and mean arterial pressure Z-score (p=0.025) in ABPM. Maximal kidney cyst diameter correlated positively with systolic, diastolic, mean arterial pressure, mean arterial pressure Z-score, and diastolic blood pressure load in ABPM (r = 0.61-0.75, p = 0.033-0.005). Two children with numerous AML with diameter30 mm were treated with sirolimus.Because of common focal lesions in kidneys children with TSC should be kept under regular nephrologic follow-up. Presence of large renal cysts may predispose children with TSC to arterial hypertension.

Altres ajuts: The authors would like to especially thank Clare Stuart (Tuberous Sclerosis Australia, New South Wales, Australia) and Eva Schoeters (be-TSC vzw, Antwerp, Belgium) for their feedback on our work from the patient perspective. Editorial assistance was provided by Traci Stuve, MA, and Robert J. Schoen, PharmD, of ApotheCom (Yardley, PA, USA) and was funded by Novartis Pharmaceuticals Corporation. Jóźwiak was partly financed by the European Community's Seventh Framework Programme (FP7/2007-2013; EPISTOP, grant agreement no. 602391), the Polish Ministerial funds for science (years 2013-2019) for the implementation of international co-financed project and the grant EPIMAR-KER of the Polish National Center for Research and Development No STRA-TEGMED3/306306/4/2016. L Kerecuk has served as a speaker for and received travel honoraria from Novartis, and as a consultant for Roche Pharmaceuticals. JC Kingswood has received research grants (to his institution) from Novartis and has served as a consultant for Novartis. R Moavero has participated in advisory boards for Novartis and has research that was partly funded by EPISTOP. R Torra has nothing to disclose. V Villanueva has participated in advisory boards and symposia for Eisai, UCB Pharma, BIAL, Esteve, Novartis, and GW Pharma. Novartis Pharmaceuticals Corporation hosted the meeting of physicians that served as the basis for this manuscript and provided funding support for medical/editorial writing assistance. Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder associated with mutations in TSC1 and TSC2 genes, upregulation of mammalian target of rapamycin signaling, and subsequent tumor formation in various organs. Due to the many manifestations of TSC and their potential complications, management requires the expertise of multiple medical disciplines. A multidisciplinary care approach is recommended by consensus guidelines. Use of multidisciplinary teams (MDTs) has been shown to be beneficial in treating other complex diseases, such as cancer. In a lifelong disease such as TSC, an MDT may facilitate the transition from pediatric to adult care. However, little guidance exists in the literature regarding how to organize an MDT in TSC. Methods: To discuss the best approach to assembling an MDT, this project was initiated in October 2017 with a meeting of 12 physicians from various specialties and various countries. Following this first meeting, the experts generated statements on the most important aspects to implement in establishing an MDT for TSC by 3 rounds of selection using a Delphi process via electronic correspondence. Finally, TSC patient advocates reviewed the findings and provided additional insights from a patient perspective. Results: A 3-step roadmap was recommended, starting with identifying a single individual to begin organizing care (Step 1), then establishing a small core team (Step 2), and finally, establishing a larger multi-disciplinary team (Step 3). Because of the multisystemic nature of TSC, the MDT should include specialists such as a neurologist, a neurosurgeon, a nephrologist, a urologist, a pulmonologist, an ophthalmologist, a cardiologist, a dermatologist, a geneticist, and a psychiatrist/psychologist. The MDT should recommend a care plan for each patient based on the individual's needs and in consultation with him/her or his/her family. Some of the most important aspects of an MDT that were agreed upon included identifying a case manager to help coordinate care, providing access to health care professionals of varying specialties, and including a lead physician who takes medical responsibility for patients' overall care. Conclusions: The results of our consensus provide guidance to support the initiation of an MDT in TSC.

Despite the availability of many antiepileptic medications and some alternative therapies, up to 30% of epilepsies are still treatment-resistant. In recent years the growing interest in the use of Cannabis extracts to treat drug-resistant epilepsy in humans appeared. The genus Cannabis contain more than 100 terpenoid compounds called ‘cannabinoids’ of which tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol, cannabidivarin (CBDV) and tetrahydrocannabidivarin showed anticonvulsant properties in variety of animal models. Furthermore, 3 of 4 randomized and blinded studies revealed antiepileptic efficacy of CBD also in humans, but the number of enrolled patients was very low. While the clinicians mostly understand need to conduct well-designed studies of CBD and THC, patients and their families tend to use cannabinoids without waiting for reliable scientific data. Although CBD appears to be a good candidate for a new antiepileptic drug, up to now there are not available clinical trials assessing its long-term effects. Keeping this in mind, in this paper we try to present current knowledge on ‘medical’ marijuana in epilepsy.