Molecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years.

We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC.

miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients' serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients.

Antiepileptic Effect and Safety Profile of Rapamycin in Pediatric Patients With Tuberous Sclerosis Complex.

Background: Epilepsy develops in 70-90% of children with Tuberous Sclerosis Complex (TSC) and is often resistant to medication. Treatment with mTOR pathway inhibitors is an important therapeutic option in drug-resistant epilepsy associated with TSC. Our study evaluated the antiepileptic effect of rapamycin in the pediatric population of patients diagnosed with TSC. Methods: This single center, open-label study evaluated safety and anti-epileptic efficacy of 12 months of rapamycin treatment in 32 patients aged from 11 months to 14 years with drug-resistant TSC- associated epilepsy. Results: After the first 6 months of treatment, the improvement in seizure frequency, defined as at least a 50% reduction in the number of seizures per week compared to baseline, was seen in 18 individuals (56.25%). We observed no change in 12 individuals (37.5%) and worsening, defined as increase in the number of seizures-in 2 patients (6.25%). The overall improvement defined as at least a 50% reduction in seizure frequency was found in 65.6% of all patients after 12 months with 28% of patients obtaining complete remission. Another five patients experienced at least an 80% reduction in the frequency of seizures. Concomitant treatment with vigabatrin, and to a much lesser extent topiramate and levetiracetam, was an additional favorable prognostic factor for the success of the therapy. A linear relationship between the cumulative dose of rapamycin and its therapeutic effect was observed. The safety profile of the drug was satisfactory. In none of the observed cases did the adverse events reach the level that required withdrawal of the rapamycin treatment. The reason for dropouts was insufficient drug efficacy in 3 cases. Conclusions: Long-term use of rapamycin, especially in combination with vigabatrin, might be a beneficial therapeutic option in the treatment of drug-resistant epilepsy in children with TSC.

Patterns of dyslipidemia in young patients with seronegative spondyloarthropathies without cardiovascular diseases.

OBJECTIVES: Patients with seronegative spondyloarthritis (SpA) - psoriatic arthritis (PsA) and ankylosing spondylitis (AS) - have a higher risk of cardiovascular morbidity and mortality. The aim of the present study was to evaluate the incidence and type of dyslipidemia, a potent atherosclerosis risk factor, in SpA patients. MATERIAL AND METHODS: It was a two-center, case-control study. Patients diagnosed with PsA and AS aged 23-60 years, with disease duration < 10 years, were enrolled. The inflammatory activity, serum levels of C-reactive protein (CRP) and lipid profile were evaluated in each patient. In patients > 40 years old, the 10-year risk of fatal cardiovascular disease (CVD), using Systematic Coronary Risk Evaluation (SCORE), was estimated. RESULTS: In total 79 patients with SpA were included in the study, with PsA diagnosed, n = 39 (mean age 45.1 ±9.6 years; 21, 53.9%, women), and with AS diagnosed, n = 40 (age 40.3 ±9.5; 12.3%, women), control group (CG): n = 88 (age 42.3 ±8.1; 42, 47.7% women). Based on the interview and laboratory tests, dyslipidemia was diagnosed in 19 (47.5%) patients with AS and in 28 (71.8%) patients with PsA. Most patients had hypercholesterolemia or mixed hyperlipidemia. Types of dyslipidemia were similar. In SpA patients (PsA and AS), the level of triglycerides (TG) and atherogenic index (AI) were significantly higher than in the CG, respectively TG in SpA: 116 (83-156) and in the CG: 91.2 (72.6-134.6) mg/dl, p = 0.0182; AI in SpA: 3.77 ±1.26 and in the CG: 2.58 ±1.27, p < 0.0001.The low-density cholesterol (LDL) level was significantly lower in SpA patients than in the CG, SpA: 109.1 ±29.4 vs. CG: 125.2 ±35.9 mg/dl, p = 0.0023. There was a strong negative correlation between CRP levels and HDL cholesterol levels in patients with PsA, rho = 0.42, p = 0.0132. Mean SCORE values were 2.33% in PsA patients and 2.38% in AS patients, which results in moderate 10-year risk of death from CVD. CONCLUSIONS: In young patients with spondyloarthropathies, inflammatory factors significantly influence dyslipidemia patterns, which result in higher TG and lower LDL cholesterol levels. In patients with PsA, dyslipidemia was diagnosed more often than in patients with AS.

Use of an exercise test to enhance sensing vector assessment and prevent inadequate subcutaneous implantable cardioverter-defibrillator discharges.

Subcutaneous implantable cardioverter-defibrillators are a modern alternative to classic cardioverter-defibrillators. Prior to implantation of the device, qualification based on assessment of the heart's specific rhythm shape during a resting electrocardiogram examination must be performed. In the presented case, a patient with a subcutaneous implantable cardioverter-defibrillator experienced numerous discharges during exercise. An exercise test was performed, which revealed a bundle branch block that appeared during exercise. The wide QRS complex was double- or triple-counted by the device, resulting in an inaccurate heart rate estimation and multiple discharges. Optimising the sensing vectors during exercise solved this problem.

Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial.

OBJECTIVE: Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants. METHODS: In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open-label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure. RESULTS: In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty-seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223-535) vs 124 days (95% CI = 33-149); OLT: 426 days (95% CI = 258-628) vs 106 days (95% CI = 11-149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug-resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted. INTERPRETATION: Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304-314.

Is autism driven by epilepsy in infants with Tuberous Sclerosis Complex?

OBJECTIVE: To evaluate the relationship between age at seizure onset and neurodevelopmental outcome at age 24 months in infants with TSC, as well as the effect on neurodevelopmental outcome of early versus conventional treatment of epileptic seizures with vigabatrin (80-150 mg/kg/day). METHODS: Infants with TSC, aged ≤4 months and without previous seizures were enrolled in a prospective study and closely followed with monthly video EEG and serial standardized neurodevelopmental testing (Bayley Scales of Infant Development and Autism Diagnostic Observation Schedule). RESULTS: Eighty infants were enrolled. At the age of 24 months testing identified risk of Autism Spectrum Disorder (ASD) in 24/80 children (30.0%), and developmental delay (DD) in 26/80 (32.5%). Children with epilepsy (51/80; 63.8%) had a higher risk of ASD (P = 0.02) and DD (P = 0.001). Overall, no child presented with moderate or severe DD at 24 months (developmental quotient < 55). In 20% of children abnormal developmental trajectories were detected before the onset of seizures. Furthermore, 21% of all children with risk of ASD at 24 months had not developed seizures at that timepoint. There was no significant difference between early and conventional treatment with respect to rate of risk of ASD (P = 0.8) or DD (P = 0.9) at 24 months. INTERPRETATION: This study confirms a relationship between epilepsy and risk of ASD/DD. However, in this combined randomized/open label study, early treatment with vigabatrin did not alter the risk of ASD or DD at age 2 years.

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study.

PURPOSE: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. METHODS: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. RESULTS: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. CONCLUSION: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

Preventive Antiepileptic Treatment in Tuberous Sclerosis Complex: A Long-Term, Prospective Trial.

BACKGROUD: Drug-resistant epilepsy is the main risk factor for future intellectual disability in patients with tuberous sclerosis complex. Clinical epileptic seizures are often preceded by electroencephalographic changes, which provide an opportunity for preventive treatment. We evaluated the neuropsychologic and epilepsy outcomes at school age in children with tuberous sclerosis complex who received preventive antiepileptic treatment in infancy. METHODS: We performed a prospective, nonrandomized clinical trial with 14 infants diagnosed with tuberous sclerosis complex in whom serial electroencephalographic recordings were performed and preventive treatment with vigabatrin initiated when active epileptic discharges were detected. An age-matched control group consisted of 31 infants with tuberous sclerosis complex in whom treatment with vigabatrin was given only after onset of clinical seizures. Results of clinical assessment of epilepsy and cognitive outcomes were analyzed. RESULTS: All patients in the preventive group (n = 14) and 25 of 31 patients in the standard treatment group were followed through minimum age five years, median 8.8 and 8.0 years in the preventive and standard groups, respectively. The median intelligence quotient was 94 for the preventive group when compared with 46 for the standard group (P < 0.03). Seven of 14 patients (50%) in the preventive group never had a clinical seizure when compared with one of 25 patients (5%) in the standard treatment group (P = 0.001). CONCLUSIONS: This study provides evidence that preventive antiepileptic treatment in infants with tuberous sclerosis complex improves long-term epilepsy control and cognitive outcome at school age.

GSK3ß activity alleviates epileptogenesis and limits GluA1 phosphorylation.

BACKGROUND: Glycogen synthase kinase-3ß (GSK3ß) is a key regulator of cellular homeostasis. In neurons, GSK3ß contributes to the control of neuronal transmission and plasticity, but its role in epilepsy remains to be defined. METHODS: Biochemical and electrophysiological methods were used to assess the role of GSK3ß in regulating neuronal transmission and epileptogenesis. GSK3ß activity was increased genetically in GSK3ß[S9A] mice. Its effects on neuronal transmission and epileptogenesis induced by kainic acid were assessed by field potential recordings in mice brain slices and video electroencephalography in vivo. The ion channel expression was measured in brain samples from mice and followed by analysis in samples from patients with temporal lobe epilepsy or focal cortical dysplasia in correlation to GSK3ß phosphorylation. FINDINGS: Higher GSK3ß activity decreased the progression of kainic acid induced epileptogenesis. At the biochemical level, higher GSK3ß activity increased the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 4 under basal conditions and in the epileptic mouse brain and decreased phosphorylation of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 at Serine 831 under basal conditions. Moreover, we found a significant correlation between higher inhibitory GSK3ß phosphorylation at Serine 9 and higher activating GluA1 phosphorylation at Serine 845 in brain samples from epileptic patients. INTERPRETATION: Our data imply GSK3ß activity in the protection of neuronal networks from hyper-activation in response to epileptogenic stimuli and indicate that the anti-epileptogenic function of GSK3ß involves modulation of HCN4 level and the synaptic AMPA receptors pool.

The level of microRNA 21 is upregulated by rapamycin in serum of tuberous sclerosis complex patients and subependymal giant cell astrocytoma (SEGA)-derived cell cultures.

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.

Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures?

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.

GAMBIT: A Parameterless Model-Based Evolutionary Algorithm for Mixed-Integer Problems.

Learning and exploiting problem structure is one of the key challenges in optimization. This is especially important for black-box optimization (BBO) where prior structural knowledge of a problem is not available. Existing model-based Evolutionary Algorithms (EAs) are very efficient at learning structure in both the discrete, and in the continuous domain. In this article, discrete and continuous model-building mechanisms are integrated for the Mixed-Integer (MI) domain, comprising discrete and continuous variables. We revisit a recently introduced model-based evolutionary algorithm for the MI domain, the Genetic Algorithm for Model-Based mixed-Integer opTimization (GAMBIT). We extend GAMBIT with a parameterless scheme that allows for practical use of the algorithm without the need to explicitly specify any parameters. We furthermore contrast GAMBIT with other model-based alternatives. The ultimate goal of processing mixed dependences explicitly in GAMBIT is also addressed by introducing a new mechanism for the explicit exploitation of mixed dependences. We find that processing mixed dependences with this novel mechanism allows for more efficient optimization. We further contrast the parameterless GAMBIT with Mixed-Integer Evolution Strategies (MIES) and other state-of-the-art MI optimization algorithms from the General Algebraic Modeling System (GAMS) commercial algorithm suite on problems with and without constraints, and show that GAMBIT is capable of solving problems where variable dependences prevent many algorithms from successfully optimizing them.

Liver Angiomyolipomas in Tuberous Sclerosis Complex-Their Incidence and Course.

BACKGROUND: The purpose of this study was to evaluate the epidemiology and clinical significance of hepatic angiomyolipomas in patients with tuberous sclerosis complex. METHODS: We performed a retrospective analysis of clinical and imaging data from 187 patients with tuberous sclerosis complex. The prevalence, progression, and potential relationship between liver lesions and other clinical findings, including genetic associations, were assessed. RESULTS: Twenty-eight of 187 patients (14.9%) had hepatic lesions. There was a predominance of female over male patients in individuals with liver lesions (17 versus 11), with statistical significance in patients under five years of age (P < 0.05). All individuals having hepatic lesions who also had available genetic testing data (n = 20) were diagnosed with a TSC2 gene mutation. All patients with liver lesions had coexisting renal angiomyolipomas (AMLs) (P < 0.05). The age of onset of renal lesions was lower and their prevalence was significantly higher in patients with liver involvement (P < 0.05). In most instances, hepatic lesions measured several millimeters in diameter and were clinically asymptomatic. Progressive lesion growth was documented in six individuals but with no clinical consequences to date. CONCLUSIONS: This study confirms the association of hepatic lesions with TSC2 mutations, a common origin of liver and renal AMLs, as well as the predominance of female patients in this group. Hepatic AMLs are relatively common but mostly benign lesions.

Topical Use of Mammalian Target of Rapamycin (mTOR) Inhibitors in Tuberous Sclerosis Complex-A Comprehensive Review of the Literature.

BACKGROUND: Tuberous sclerosis complex is a genetically determined multisystem disorder that may affect almost any human organ. The discovery of the mammalian target of rapamycin (mTOR) pathway and its involvement in tuberous sclerosis complex-related pathology has led to the introduction of mTOR inhibitors into clinical practice. Topical administration of mTOR inhibitors for skin lesions related to tuberous sclerosis complex may represent a reasonable alternative for more invasive procedures. A growing number of patients have been described exhibiting positive therapeutic effects from the topical administration of these agents. The aim of this review was to systematically analyze available literature on the use of topical mTOR inhibitors to treat dermatologic lesions related to tuberous sclerosis complex. RESULTS: A comprehensive review of PubMed, Medscape, and Cochrane databases between 1995 and 2015 was performed to identify available studies describing topical use of mTOR inhibitors in individuals with tuberous sclerosis complex. In most studies, topical mTOR inhibitor application proved to be effective in the treatment of skin lesions related to tuberous sclerosis complex. Facial angiofibromas were the target lesions in most instances. Few studies reported clinical improvement of hypomelanotic macules. These drugs directly address the molecular defect related to tuberous sclerosis complex manifestations. CONCLUSIONS: Currently available clinical data suggest that topical application of mTOR inhibitors may be effective in the treatment of facial angiofibromas associated with tuberous sclerosis complex. Ongoing randomized clinical trials of topical mTOR inhibitors for TSC-related cutaneous lesions should add clarity to the role of these agents.

Management of side effects of mTOR inhibitors in tuberous sclerosis patients.

mTOR inhibitors represent a relatively new therapeutic option in the management of patients affected by tuberous sclerosis complex (TSC). Randomized clinical trials support the use of everolimus in the treatment of subependymal giant cell astrocytomas (SEGA) and renal angiomyolipomas (AML) related to TSC. Accumulating data suggest also systemic disease-modifying potential of mTOR inhibitors. Given that increasing number of patients with TSC receive mTOR inhibitors, the issue of adverse events associated with this therapy becomes practically important. In the present study we provide the overview of clinical manifestations and therapeutic options for the most common adverse events related to mTOR inhibitors in TSC patients.

Role of mTOR inhibitors in epilepsy treatment.

In spite of the fact, that subsequent new antiepileptic drugs (AEDs) are being introduced into clinical practice, the percentage of drug-resistant epilepsy cases remains stable. Although a substantial progress has been made in safety profile of antiepileptic drugs, currently available substances have not been unambiguously proven to display disease-modifying effect in epilepsy and their mechanisms of action influence mainly on the end-stage phase of epileptogenesis, namely seizures. Prevention of epileptogenesis requires new generation of drugs modulating molecular pathways engaged in epileptogenesis processes. The mammalian target of rapamycin (mTOR) pathway is involved in highly epileptogenic conditions, such as tuberous sclerosis complex (TSC) and represents a reasonable target for antiepileptogenic interventions. In animal models of TSC mTOR inhibitors turned out to prevent the development of epilepsy and reduce underlying brain abnormalities. Accumulating evidence from animal studies suggest the role of mTOR pathway in acquired forms of epilepsy. Preliminary clinical studies with patients affected by TSC demonstrated seizure reduction and potential disease-modifying effect of mTOR inhibitors. Further studies will determine the place for mTOR inhibitors in the treatment of patients with TSC as well as its potential antiepileptogenic effect in other types of genetic and acquired epilepsies. This review presents current knowledge of mTOR pathway physiology and pathology in the brain, as well as potential clinical use of its inhibitors.

Basal ganglia echogenicity in tauopathies.

Accumulating data confirm the usefulness of transcranial sonography (TCS) in the diagnosis of Parkinson's disease. The relevance of basal ganglia abnormalities depicted by TCS in atypical parkinsonian syndromes still needs further assessment. In the present study, 20 patients with progressive supranuclear palsy (PSP) and 13 patients with corticobasal syndrome (CBS) were studied with the use of transcranial sonography. Echogenicity of the substantia nigra (SN) and lenticular nucleus (LN) were assessed. 0/20 patients with PSP and 8/12 (66.6 %) patients with CBS were characterized with SN hyperechogenicity. LN hyperechogenicity was observed in 9/20 patients diagnosed with PSP and 0/11 of CBS patients. The combination of SN isoechogenicity and LN hyperechogenicity reached 100 % sensitivity and positive predictive value for the diagnosis of PSP. The results of this study point out that CBS has to be taken into consideration when SN hyperechogenicity is depicted in a patient with parkinsonian syndrome. Normal echogenicity of the SN coexisting with LN hyperechogenicity practically excludes CBS.

Brain tissue echogenicity--implications for substantia nigra studies in parkinsonian patients.

The aim of the present study was to assess the origin of the substantia nigra hyperechogenicity in Parkinson disease patients. The cause of hyperechogenicity was tested on an animal model. Fresh porcine brains were injected consecutively with ferritin, apoferritin and water. Then, glioma samples were inserted into animal model. The echogenicity of the region of interest was assessed before and after experimental procedures. We observed the same echogenicity of porcine brain before and after injections of iron-loaded ferritin, apoferritin and water. Increased echogenicity of glioma samples compared to surrounding porcine brain tissue could be clearly seen. We postulate that the relative gliosis might be, at least partially, responsible for the increased echogenicity of the substantia nigra in Parkinson disease patients. Keeping in mind all limitations and inaccuracies of animal model used, it seems that hyperechogenicity of substantia nigra is caused rather by structural changes within the brain tissue than by increased iron concentration.

[Non-compaction of the left ventricle - not only in children]. / Kardiomiopatia gabczasta - nie tylko u dzieci.

A case of a 44-year-old woman with left ventricular non-compaction which manifested in adulthood as dyspnea, fatique and NYHA class III heart failure, is described. She received treatment typical for heart failure and was offered heart transplantation and cardioverter-defibrillator implantation which she refused. Unfortunately, she died suddenly three months after the diagnosis was established.