A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: a double-blind randomized placebo-controlled trial.

BACKGROUND: Facial angiofibromas (FAs) are a major feature of tuberous sclerosis complex (TSC). Topical rapamycin can successfully treat FAs. A new stabilized cream formulation that protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations. OBJECTIVES: To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation. METHODS: This multicentre double-blind randomized placebo-controlled dose-response phase II/III study with a parallel design included participants aged 6-65 years with FAs of mild or moderate severity according to the Investigator's Global Assessment (IGA) scale. Participants were randomized to one of three treatment arms: topical rapamycin 0.5%, topical rapamycin 1% or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182. The primary endpoint was the percentage of participants achieving IGA scores of 'clear' or 'almost clear' after 26 weeks of treatment. Secondary measures included Facial Angiofibroma Severity Index (FASI) and participant- and clinician-reported percentage-based improvement. Safety measures included the incidence of treatment-emergent adverse events and blood rapamycin concentration changes over time. RESULTS: Participants (n = 107) were randomized to receive either rapamycin 1% (n = 33), rapamycin 0.5% (n = 36) or placebo (n = 38). All treated participants were included in the final analysis. The percentage of participants with a two-grade IGA improvement was greater in the rapamycin 0.5% treatment group (11%) and rapamycin 1% group (9%) than in the placebo group (5%). However, this was not statistically significant [rapamycin 0.5%: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.36-8.18 (P = 0.50); rapamycin 1%: OR 1.68, 95% CI 0.33-8.40 (P = 0.53)]. There was a statistically significant difference in the proportion of participants treated with rapamycin cream that achieved at least a one-grade improvement in IGA [rapamycin 0.5%: 56% (OR 4.73, 95% CI 1.59-14.10; P = 0.005); rapamycin 1%: 61% (OR 5.14, 95% CI 1.70-15.57; P = 0.004); placebo: 24%]. Skin adverse reactions were more common in patients following rapamycin application (64%) vs. placebo (29%). CONCLUSIONS: Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA.

Quantification of Zonisamide in Dried Blood Spots and Dried Plasma Spots by UPLC-MS/MS: Application to Clinical Practice.

In this research, a UHPLC-MS/MS method was developed and validated for the determination of zonisamide in dried plasma spots (DPS) and dried blood spots (DBS). Detection of zonisamide and internal standard, 1-(2,3-dichlorphenyl)piperazine, was carried out in ESI+ mode by monitoring two MRM transitions per analyte. Total run time, less than 2.5 min, was achieved using Acquity UPLC BEH Amide (2.1 × 100 mm, 1.7 µm particle size) column with mobile phase comprising acetonitrile-water (85:15%, v/v) with 0.075% formic acid. The flow rate was 0.225 mL/min, the column temperature was 30 °C and the injection volume was 3 µL. Desolvation temperature, desolvation gas flow rate, ion source temperature and cone gas flow rate were set by the IntelliStart software tool in combination with tuning. All of the Guthrie cards were scanned, and DPS/DBS areas were determined by the image processing tool. The influence of hematocrit values (20-60%) on accuracy and precision was evaluated to determine the range within which method for DBSs is free from Hct or dependency is within acceptable limits. The validated method was applied to the determination of zonisamide levels in DPS and DBS samples obtained from patients confirming its suitability for clinical application. Finally, the distribution of zonisamide into the red blood cells was estimated by correlating its DPS and DBS levels.

In silico model of mtDNA mutations effect on secondary and 3D structure of mitochondrial rRNA and tRNA in Leber's hereditary optic neuropathy.

The Leber's hereditary optic neuropathy (LHON) is a rare disease caused by mitochondrial DNA (mtDNA) mutations. Beside primary mutations, the effect of secondary mtDNA mutations in still unclear. We examined the effect of secondary mtDNA mutations on secondary structure of different mitochondrial RNAs. Whole mitochondrial genome sequence of LHON patients has been obtained from in six non related pedigrees by Sanger sequencing method. The effect of mutations located in mitochondrial RNA genes was examined by creating in silico models of RNA secondary and regional 3D structure, accompanied by sequence conservation analysis. All three primary LHON mutations (m.3460G>A, m.11778G>A and m.14484 T>C) were revealed in study families. Four mutations in MT-RNR1 gene (m.750A>G, m.956delC, m.1438A>G and m.1555A>G) were identified and only an m.1555A>G causes significant changes of secondary structure of mitochondrial 12S ribosomal RNA (rRNA), while it is the only mutation which does not alter its 3D structure. Five mutations (m.1811A>G, m.2706A>G, m.2831G>A, m.3010G>A and m.3197T>C) were discovered in MT-RNR2 gene and all of them induced substantial alterations of mitochondrial 16S rRNA secondary structure. Significant changes of mitochondrial 16S rRNA 3D structure are caused by m.1811A>G, m.2706A>G, m.3010G>A and m.3197T>C. A single insertion variant (m.15986insG) has been found in the MT-TP gene which encodes mitochondrial transfer RNA for Proline (tRNA Pro). This mutation does not cause substantial changes of tRNA for Proline secondary structure, while the 3D geometry remains without major changes. Most of the mutation loci exhibited high level of sequence conservation. Presence of multiple mutations in a single family appears to cause more extensive changes in mitochondrial 12S and 16S rRNA, then their individual influence. The effect of discovered mutations on in silico modelled RNA structure is in a significant correlation with the present knowledge about the potential of these mutation to participate in the pathophysiology of LHON and other human diseases. The presence of certain multiple mitochondrial RNA mutations could be a possible explanation of LHON clinical presentation in some families. All revealed mutations have been evaluated for the first time in terms of in silico structural modelling. The application of bioinformatics tools such as secondary and 3D RNA structure prediction can have a great advantage in better understanding of the molecular standpoint of the LHON pathophysiology and clinical phenotype.

Health-related quality of life questionnaire for polycystic ovary syndrome (PCOSQ-50): a psychometric study with the Serbian version.

This study aimed to analyze the measurement properties of the Health-related quality of life questionnaire for polycystic ovary syndrome (PCOSQ-50) in a sample of Serbian women with polycystic ovary syndrome (PCOS). Seventy-six women with PCOS from an endocrinology clinic and 28 healthy women participated between October 2016 and March 2017. The measure was rigorously translated and culturally adapted into Serbian. Psychometric evaluation included descriptive analysis, internal consistency (Cronbach's alpha coefficient), test-retest reliability (intraclass-correlation coefficient - ICC) and construct validity testing. Cronbach's alpha coefficient ranged from 0.67 to 0.96 for domain scales of PCOSQ-50 scores, while the ICCs for test-retest reliability for these domains ranged from 0.66 to 0.89. Women with PCOS had significantly lower scores than healthy women for hirsutism, obesity and menstrual disorders and the total PCOSQ-50 scale score (p ≤ 0.03), but not for the psychosocial and emotional, fertility, sexual function, and coping scales. These results show that the Serbian PCOSQ-50 measure is acceptable and could produce reliable and valid assessments of PCOS-related quality of life for at least four out of seven domains. Considering that validity testing is an iterative process, additional work is needed before the whole measure is used in routine clinical practice.

White Matter Changes in Two Leber's Hereditary Optic Neuropathy Pedigrees: 12-Year Follow-Up.

We are presenting two Leber's hereditary optic neuropathy (LHON) pedigrees with abnormal magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS) findings but without neurological manifestation associated with LHON. The study included 14 LHON patients and 41 asymptomatic family members from 12 genealogically unrelated families. MRI showed white matter involvement and H-MRS exhibited metabolic anomalies within 12 LHON families. Main outcome measures were abnormal MRI and H-MRS findings in two pedigrees. MRI of the proband of the first pedigree showed a single demyelinating lesion in the right cerebellar hemisphere, while the proband of the second family displayed multiple supratentorial and infratentorial lesions, compatible with the demyelinating process, and both the absolute choline (Cho) concentration and Cho/creatinine ratio were increased. MRI and H-MRS profiles of both affected and unaffected mitochondrial DNA mutation carriers suggest more widespread central nervous involvement in LHON. Although even after 12 years our patients did not develop neurological symptoms, MRI could still be used to detect possible changes during the disease progression.

Features of migraine aura in teenagers.

BACKGROUND: Complex migraine aura in teenagers can be complicated to diagnose. The aim of this study was to present detailed features of migraine aura in teenage migraineurs. METHODS: This cross-sectional study was conducted in the period from 2008 till 2013. A total number of 40 teenage migraineurs (20 females and 20 males) met criteria for this study. The patients were interviewed using a specially designed questionnaire for collecting data about migraine aura features. Main outcome measures were frequency of visual, somatosensory and higher cortical dysfunction (HCD) symptoms in teenage migraineurs population during the aura, and also within each individual. RESULTS: Visual aura was reported in every attack, followed by somatosensory (60%) and dysphasic (36.4%) aura. Scintillating scotoma and blurry vision were mostly reported and predominant visual symptoms. The most common somatosensory symptom was numbness in hand. HCD were reported by 22 (55%) patients. Slowed speech was mostly reported symptom of HCD, followed by dyslexia, déjà vu phenomenon, color dysgnosia, and dyspraxia. In patients with HCD, aura frequency per year (6.18 ± 3.17 vs. 3.33 ± 2.03, p = 0.003) and prevalence of somatosensory symptoms (77.3% vs. 38.9%, p = 0.014) were significantly higher than in patients without HCD. CONCLUSIONS: Aura symptoms vary to a great extent in complexity in teenage migraineurs. Consequently, results obtained in this study provide useful information for clinicians when faced with unusual migraine aura.

Anti-seizure Medications: Challenges and Opportunities.

Epilepsy is a chronic neurological condition characterized by unprovoked, recurrent seizures. There are several types of epilepsy, and the cause of the condition can vary. Some cases of epilepsy have a genetic component, while others may be caused by brain injuries, infections, or other underlying conditions. Treatment for epilepsy typically involves anti-seizure medications (ASMs), although different approaches, such as surgery or a special diet, may be considered in specific cases. The treatment aims to effectively manage and potentially eliminate seizures while minimizing any accompanying side effects. Many different ASMs are available, and the choice of medication depends on several factors, including the type of seizures, the patient's age, general health, and potential drug interactions. For the treatment of epilepsy, there have been significant advancements in recent decades, which have led to the approval of many different ASMs. Newer ASMs offer a broader range of mechanisms of action, improved tolerability profiles, and reduced drug interactions compared to older drugs. This review aims to discuss the pharmacological characteristics, clinical applications, effectiveness, and safety of ASMs, with a particular emphasis on various age groups, especially children. Moreover, this review seeks to provide a comprehensive understanding of ASM therapy for epilepsy management, assisting physicians in selecting suitable ASMs for their patients.

Analysis of visual evoked potentials in patients with neurofibromatosis type 1: new concepts.

Introduction: Neurofibromatosis type 1 (NF type 1) is an autosomal dominant disease with typical clinical manifestations, such as skin lesions, Lisch nodules, optic pathway gliomas, and neurofibromas, caused by the mutation of the NF1 gene. Visual evoked potentials (VEP) present a measure of the electrophysiological response of visual cortex to a visual stimulus. The role of VEP in the pathophysiology of NF type 1 is very complex and requires additional research. The Aim: We examined the differences between NF type 1 patients with normal and altered VEP and analyzed the correlation between the prolongation of P100 latency and disease severity. Materials and methods: Two groups were formed: a control group and a study group with NF type 1 patients. Based on the control group analysis, a threshold value for a normal VEP finding of 116 ms was obtained, and it was used to divide the study group into subgroups with normal and altered VEP. We proceeded with examining the differences in clinical manifestations of the disease between the subgroups, after which we checked if there is a correlation between the prolongation of the P100 latency and the severity of the clinical picture according to the Riccardi scale. Statistical analysis was performed using the Pearson chi-square test and the Spearman correlation test in the program SPSS 28.0, with levels of statistical significance p = 0.05 and p = 0.001. Results: In the group with the abnormal VEP we found a statistically significant more frequent occurrence of optic tract glioma (p = 0.008), tumors (p = 0.032), epilepsy (p = 0.043), and cognitive disorders (p = 0.028), while the other clinical signs had an equal prevalence in both groups. A moderately strong correlation (r s = 0.665) was observed between the prolongation of P100 latency and the severity of the clinical picture. Conclusion: Our results showed the important role of VEP in the description of clinical phenotypes of NF type 1. The authors of the study propose VEP to be included in the diagnostic algorithms designed for patients with NF type 1.

The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy.

Pharmacotherapy for neuropsychiatric disorders, such as anxiety and depression, has been characterized by significant inter-individual variability in drug response and the development of side effects. Pharmacogenetics, as a key part of personalized medicine, aims to optimize therapy according to a patient's individual genetic signature by targeting genetic variations involved in pharmacokinetic or pharmacodynamic processes. Pharmacokinetic variability refers to variations in a drug's absorption, distribution, metabolism, and elimination, whereas pharmacodynamic variability results from variable interactions of an active drug with its target molecules. Pharmacogenetic research on depression and anxiety has focused on genetic polymorphisms affecting metabolizing cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, P-glycoprotein ATP-binding cassette (ABC) transporters, and monoamine and γ-aminobutyric acid (GABA) metabolic enzymes, transporters, and receptors. Recent pharmacogenetic studies have revealed that more efficient and safer treatments with antidepressants and anxiolytics could be achieved through genotype-guided decisions. However, because pharmacogenetics cannot explain all observed heritable variations in drug response, an emerging field of pharmacoepigenetics investigates how epigenetic mechanisms, which modify gene expression without altering the genetic code, might influence individual responses to drugs. By understanding the epi(genetic) variability of a patient's response to pharmacotherapy, clinicians could select more effective drugs while minimizing the likelihood of adverse reactions and therefore improve the quality of treatment.

Dehydroepiandrosterone (DHEA): Pharmacological Effects and Potential Therapeutic Application.

Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in primates, which is predominantly synthesized in the adrenal cortex. A characteristic curve of growth and decline of its synthesis during life was observed, together with the corresponding formation of its sulphate ester (DHEAS). High levels of plasma circulating DHEA are suggested as a marker of human longevity, and various pathophysiological conditions lead to a decreased DHEA level, including adrenal insufficiency, severe systemic diseases, acute stress, and anorexia. More recent studies have established the importance of DHEA in the central nervous system (CNS). A specific intranuclear receptor for DHEA has not yet been identified; however, highly specific membrane receptors have been detected in endothelial cells, the heart, kidney, liver, and the brain. Research shows that DHEA and DHEAS, as well as their metabolites, have a wide range of effects on numerous organs and organ systems, which places them in the group of potential pharmacological agents useful in various clinical entities. Their action as neurosteroids is especially interesting due to potential neuroprotective, pro-cognitive, anxiolytic, and antidepressant effects. Evidence from clinical studies supports the use of DHEA in hypoadrenal individuals and in treating depression and associated cognitive disorders. However, there is also an increasing trend of recreational DHEA misuse in healthy people, as it is classified as a dietary supplement in some countries. This article aims to provide a critical review regarding the biological and pharmacological effects of DHEA, its mechanism of action, and potential therapeutic use, especially in CNS disorders.

Agreement between children and parents when reporting anxiety and depressive symptoms in pediatric epilepsy.

The levels of agreement between self- and parent/proxy-reports of anxiety and depressive symptoms in pediatric epilepsy were evaluated. Data were drawn from 56 pairs of children with epilepsy and at least one parent. Anxiety symptoms were assessed using the Screen for Child Anxiety Related Emotional Disorders (SCARED), while depressive symptoms were assessed using the Mood and Feeling Questionnaire (MFQ). Moderate to substantial levels of agreement between raters when reporting various anxiety symptoms, such as panic/somatic disorder, generalized anxiety disorder, separation anxiety disorder, social phobia, and school phobia symptoms, were observed. Levels of agreement between raters were substantial when reporting depressive symptoms. However, levels of agreement differed if raw or criterion-referenced questionnaires' scores were used. In case of using raw questionnaire scores, substantial agreements appeared when reporting overall anxiety and depressive symptoms. On the other hand, moderate agreements appeared when reporting particular anxiety symptoms with raw questionnaire scores or when using criterion-referenced scores that indicate the presence of certain symptoms in a clinical range. Therefore, it is advisable to include both raters when assessing anxiety and depressive symptoms in pediatric epilepsy.

Child Neurology: Bartonella henselae Neuroretinitis in 2 Patients.

Neuroretinitis due to Bartonella henselae infection is a rare cause of vision loss in children. Two pediatric cases of acute unilateral vision loss accompanied by edema of the optic nerve on fundoscopic examination are presented. Severe causes of vision loss were excluded. During the course of the disease, macular stellate exudates emerged on control fundoscopic examinations, and diagnosis of neuroretinitis was made. A causative agent was confirmed by serologic examination, as high titers of IgM and IgG antibodies to Bartonella henselae were detected. Both patients significantly recovered after oral antibiotic treatment.

The usefulness of visual evoked potentials in the assessment of the pediatric multiple sclerosis.

BACKGROUND: To evaluate the significance of visual evoked potentials (VEP) in the early diagnosis of optic neuritis (ON) and detecting clinically silent lesions in pediatric multiple sclerosis (PedMS). This study represents one of the largest series of PedMS which evaluated characteristics of VEP in PedMS patients. METHODS: This was a retrospective study on 52 PedMS patients, aged 7-17 years. VEP analysis were done for all patients, after the first attack of disease and were compared to control subjects according to the pattern-reversal VEP findings. RESULTS: The mean age of patients was 15.65 ± 1.89 years with male to female ratio of 16 (30.8%): 36 (69.2%). All of the patients had a relapsing-remitting course of the disease. ON was discovered on the initial attack in 18 (34.6%) patients, while 30 (57.7%) patients had ON in the second attack. Pathological VEP findings were present in 40 (76.9%) patients, of which 22 (42.3%) PedMS patients had clinically silent lesions. Prolonged latency of P100 waves in the PedMS group was statistically significant when compared to control subjects. The amplitude N1P1 showed a correlation with residual visual deficit. CONCLUSION: Our results show that ON is a common initial manifestation of PedMS in the Serbian PedMS population. The prolonged P100 latency is the main indicator of ON. VEP is an objective, fast and accessible diagnostic method for detecting clinical and subclinical lesions. Thus, VEP deserves evaluation to be considered as an additional criterion for PedMS diagnosis.

Acute Peripheral Facial Nerve Palsy in Children and Adolescents: Clinical Aspects and Treatment Modalities.

BACKGROUND: Peripheral facial nerve palsy is a relatively frequent, rather idiopathic, and isolated nonprogressive disorder with a tendency toward spontaneous recovery in children. It is primarily characterized by unilateral paresis or paralysis of the mimic musculature affecting verbal communication, social interactions, and quality of life. OBJECTIVE: This study aimed to evaluate the clinical aspects and efficacy of different therapeutic modalities in the population of children and adolescents with acute peripheral facial nerve palsy, the quality and recovery rate in comparison to different therapy modalities and etiological factors as well as to determine parameters of recovery according to the age of patients. METHODS: The retrospective study included children and adolescents (n=129) with an acute onset of peripheral facial nerve palsy, diagnosed and treated in the Clinic of Neurology and Psychiatry for Children and Youth in Belgrade (2000-2018). The mean age of the patients was 11.53 years (SD±4.41). Gender distribution: 56.6% female and 43.4% male patients. RESULTS: There were 118 (91.5%) patients with partial and 11 (8.5%) patients with complete paralysis. Left-sided palsy occurred in 67 (51.9%) patients, right-sided in 58 (45.0%), while there were 4 (3.1%) bilateral paralyses. The most common etiological factor was idiopathic (Bell's palsy) - 74 (57.4%) patients followed by middle ear infections - 16 (12.4%). Regardless of etiology, age, and therapy protocols, there was a significant recovery in most of the patients (p<0.001), without significant differences in recovery rate. Comparison of inpatient and outpatient populations showed significant differences regarding the number of relapses, severity of clinical presentation, and recovery rate in relation to etiology. CONCLUSION: Bell's palsy is shown to be the most common cause of peripheral facial nerve palsy in children and adolescents, regardless of gender. It is followed by mid-ear infections, respiratory infections, and exposure to cold. Most children and adolescents recovered in three weeks after initial presentation, regardless of etiology, age, and therapy.

Developing COVID-19 vaccine recommendations during the pandemic: The experience of Serbia's Expert Committee on Immunization.

A National Immunization Technical Advisory Group (NITAG) is a multi-disciplinary body of national experts that provide evidence-based recommendations to policy-makers to assist them in making informed immunization policy and programme decisions. During the COVID-19 pandemic, NITAGs faced many challenges in making evidence-based recommendations for COVID-19 vaccines due to the rapidly evolving situation with new vaccine products available in a short time period and limited data on vaccine effectiveness. The authors reviewed the process used by Serbia's NITAG, which is called the Serbian Expert Committee on Immunization, to develop COVID-19 vaccine recommendations during the pandemic. The article examines the challenges and successes faced by the committee. Serbia's expert committee used the best available evidence to develop over forty recommendations on all aspects of COVID-19 vaccination. These expert committee recommendations facilitated the early procurement and successful roll-out of COVID-19 vaccines, guidance for vaccination of individuals at the highest risk, and high COVID-19 vaccination coverage in the country. The availability of five COVID-19 vaccines in Serbia was an advantage for the successful roll-out but posed challenges for the expert committee. Serbia's expert committee plans to use the experience and best practices developed during the pandemic to improve and expand its work moving forward.

Diagnosis and classification of optic neuritis.

There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.

The impact of depression and anxiety disorder symptoms on the health-related quality of life of children and adolescents with epilepsy.

This study evaluated the effects of depression and anxiety disorder symptoms on the health-related quality of life (HRQOL) of children and adolescents with epilepsy. Sixty children and adolescents and their parents participated in the study. Symptoms of anxiety disorders were identified by the Screen for Child Anxiety Related Emotional Disorders questionnaire (SCARED) and symptoms of depression by the Mood and Feeling Questionnaire (MFQ). The Pediatric Quality of Life Inventory (PedsQL) was used for HRQOL assessments. A series of simple and partial correlations revealed that the levels of HRQOL significantly decrease as symptoms of depression or anxiety disorders increase and vice versa. Stepwise regression method of children's ratings resulted in a final model of school achievement and symptoms of generalized anxiety and separation anxiety disorder as predictors that explain 50.9% of the variation in HRQOL (F = 11.21, p < 0.000). For parents' ratings, the final model included symptoms of depression and separation anxiety disorder as predictors that explain 38.4% of the variation in HRQOL (F = 10.82, p < 0.000). In summary, symptoms of depression and generalized and separation anxiety disorders have the most significant impact on HRQOL.

Involvement of mental health professionals in the treatment of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND): results of a multinational European electronic survey.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare, genetic, multisystem disorder characterized by the growth of hamartomas in several organs, including the brain, kidneys, heart, eyes, and lungs. Even though over 90% of patients will have some form of TSC-associated neuropsychiatric disorder (TAND), there is an apparent lack of involvement of mental health professionals (MHPs) in the care of patients with TSC. The aim of this study was to determine the current level of TAND awareness in the TSC community and to identify possible barriers to effective multidisciplinary collaboration between MHPs and other healthcare providers (HCPs) in TAND management. METHODS: An electronic survey on current TSC and TAND management was conducted, targeting TSC caregivers/families, psychiatrists, neurologists, TSC specialists, and primary care physicians. RESULTS: The invitation to participate in the survey was emailed to 659 HCPs and was disseminated through social media channels of patient advocacy groups. The survey was open for 4 months, with 359 responses collected. The majority of participants were TSC caregivers/families (73.3% of all responses). Of the 96 HCPs who participated, most were neurologists (61.5%) or TSC specialists (28.1%). Only 6 psychiatrists and 4 primary care physicians participated. Approximately half of patients have never had a neuropsychiatric assessment, and it was their caregivers/families who initiated the discussion of TAND with their providers. Almost 70% of TSC caregivers/families believed that psychiatric treatment could improve their quality of life. However, 54% of patients had difficulty obtaining psychiatric assessment. In turn, only 21% of HCPs believed that psychiatric therapy would help and 74% were concerned that their patients would be stigmatized by psychiatric referral. CONCLUSIONS: This study focused on European healthcare systems suggests that current care for mental health issues in patients with TSC is inadequate, despite guideline recommendations for regular neuropsychiatric assessments. This appears to be due to a combination of gaps in diagnosis and surveillance, low frequency of psychiatric referrals, insufficient resources, and stigmatization of mental healthcare. There is a pressing need for further initiatives to study and address the mechanisms underlying the mental health treatment gap. The importance of MHP support must be recognized to optimize TSC management.

Oxidative Stress Profile in Genetically Confirmed Cases of Leber's Hereditary Optic Neuropathy.

The mechanisms of the complex pathophysiology of Leber's hereditary optic neuropathy (LHON) are still insufficiently clarified. The role of oxidative stress as an etiological factor has been proposed and demonstrated in vitro, but without conclusive data that rely on clinical samples. The aim of the study was to evaluate and characterize the existence of oxidative stress in the plasma of LHON patients and healthy individuals. Whole mitochondrial genome sequencing has been performed in order to identify primary LHON mutations. For the assessment of oxidative stress, the following biomarkers were determined in plasma: total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI), while oxidative damage of cellular proteins was estimated by quantifying advanced oxidation protein products (AOPP). All three primary LHON mutations (m.3460G > A, m.11778G > A and m.14484 T > C) were identified as a genetic cause of the disease, where the most prevalent one was m.11778G > A. LHON patients have a highly significant increase of TOS and a marked decrease of TAS levels, which suggests the existence of substantial oxidative stress. OSI is high in LHON patients, which definitely implies the presence of redox imbalance. Elevated level of AOPP in LHON patients refers to the significant deleterious effects of oxidative stress on cellular proteins. Oxidative stress parameters do not significantly differ between LHON individuals with different primary mutations. Both symptomatic and asymptomatic LHON patients have an augmented level of oxidative stress which suggests that primary mutations exhibit a pro-oxidative phenotype. Gender and smoking habit significantly influence examined biochemical parameters when LHON patients are compared with the control group. Different mitochondrial haplogroups are characterized by altered levels of OSI in LHON group. The absence of physiological correlations between redox parameters reflects the deregulation of homeostatic oxidative/antioxidative balance in LHON patients. This is the greatest series of LHON patients that were evaluated for oxidative stress and the first case-controlled study that evaluated TOS, TAS, OSI, and AOPP and their influence on disease phenotype. It is evident that the presence of oxidative stress represents an important pathophysiological event in LHON and that it could potentially serve as a circulatory biomarker for a therapy efficacy understanding.

Mutational Analysis and mtDNA Haplogroup Characterization in Three Serbian Cases of Mitochondrial Encephalomyopathies and Literature Review.

Mitochondrial encephalomyopathies (MEMP) are heterogeneous multisystem disorders frequently associated with mitochondrial DNA (mtDNA) mutations. Clinical presentation varies considerably in age of onset, course, and severity up to death in early childhood. In this study, we performed molecular genetic analysis for mtDNA pathogenic mutation detection in Serbian children, preliminary diagnosed clinically, biochemically and by brain imaging for mitochondrial encephalomyopathies disorders. Sanger sequencing analysis in three Serbian probands revealed two known pathogenic mutations. Two probands had a heteroplasmic point mutation m.3243A>G in the MT-TL1 gene, which confirmed mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome (MELAS), while a single case clinically manifested for Leigh syndrome had an almost homoplasmic (close to 100%) m.8993T>G mutation in the MT-ATP6 gene. After full mtDNA MITOMASTER analysis and PhyloTree build 17, we report MELAS' association with haplogroups U and H (U2e and H15 subclades); likewise, the mtDNA-associated Leigh syndrome proband shows a preference for haplogroup H (H34 subclade). Based on clinical-genetic correlation, we suggest that haplogroup H may contribute to the mitochondrial encephalomyopathies' phenotypic variability of the patients in our study. We conclude that genetic studies for the distinctive mitochondrial encephalomyopathies should be well-considered for realizing clinical severity and possible outcomes.