Expanding the Clinical Phenotype of PLECTIN-Related Plectinopathies.

Background: Plectinopathy-associated disorders are caused by mutations in the PLECTIN (PLEC) gene encoding Plectin protein. PLEC mutations cause a spectrum of diseases defined by varying degrees of signs, mostly with epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and plectinopathy-related disorder is limb-girdle muscular dystrophy type 2Q (LGMD2Q). Here we report three cases with EBS-MD and LGMD2Q disorders analyzed by exome sequencing followed by mutation confirmation. Methods: A complete clinical examination was done by expert specialists and clinical geneticists in Next Generation Genetic polyclinic, Mashhad, Iran (NGC, years 2020_2021),. Genomic DNA was extracted and evaluated through whole-exome sequencing analysis followed by Sanger sequencing for co-segregation analysis of PLEC candidate variants. Results: We found three cases with the plectinopathy-related disease, two patients with limb-girdle muscular dystrophy type 2Q (LGMD2Q), and the other affected proband suffers from epidermolysis bullosa simplex combined with muscular dystrophy (EBS-MD) with variable zygosity mutations for PLEC. Motor development disorder and muscular dystrophy symptoms have different age onset in affected individuals. Patients with EBS demonstrated symptoms such as blistering, skin scars, neonatal-onset, and nail dystrophy. Conclusion: We report plectinopathy-associated disorders to expand clinical phenotypes in different types of PLEC-related diseases. We suppose to design more well-organized research based on comprehensive knowledge about the genetic basis of plectinopathy diseases.

Therapeutic Potential of the Ketogenic Diet: A Metabolic Switch with Implications for Neurological Disorders, the Gut-Brain Axis, and Cardiovascular Diseases.

The Ketogenic Diet (KD) is a dietary regimen that is low in carbohydrates, high in fats, and contains adequate protein. It is designed to mimic the metabolic state of fasting. This diet triggers the production of ketone bodies through a process known as ketosis. The primary objective of KD is to induce and sustain ketosis, which has been associated with numerous health benefits. Recent research has uncovered promising therapeutic potential for KD in the treatment of various diseases. This includes evidence of its effectiveness as a dietary strategy for managing intractable epilepsy, a form of epilepsy that is resistant to medication. We are currently assessing the efficacy and safety of KD through laboratory and clinical studies. This review focuses on the anti-inflammatory properties of the KD and its potential benefits for neurological disorders and the gut-brain axis. We also explore the existing literature on the potential effects of KD on cardiac health. Our aim is to provide a comprehensive overview of the current knowledge in these areas. Given the encouraging preliminary evidence of its therapeutic effects and the growing understanding of its mechanisms of action, randomized controlled trials are warranted to further explore the rationale behind the clinical use of KD. These trials will ultimately enhance our understanding of how KD functions and its potential benefits for various health conditions. We hope that our research will contribute to the body of knowledge in this field and provide valuable insights for future studies.

Diagnostic biomarker discovery from brain EEG data using LSTM, reservoir-SNN, and NeuCube methods in a pilot study comparing epilepsy and migraine.

The study introduces a new online spike encoding algorithm for spiking neural networks (SNN) and suggests new methods for learning and identifying diagnostic biomarkers using three prominent deep learning neural network models: deep BiLSTM, reservoir SNN, and NeuCube. EEG data from datasets related to epilepsy, migraine, and healthy subjects are employed. Results reveal that BiLSTM hidden neurons capture biological significance, while reservoir SNN activities and NeuCube spiking dynamics identify EEG channels as diagnostic biomarkers. BiLSTM and reservoir SNN achieve 90 and 85% classification accuracy, while NeuCube achieves 97%, all methods pinpointing potential biomarkers like T6, F7, C4, and F8. The research bears implications for refining online EEG classification, analysis, and early brain state diagnosis, enhancing AI models with interpretability and discovery. The proposed techniques hold promise for streamlined brain-computer interfaces and clinical applications, representing a significant advancement in pattern discovery across the three most popular neural network methods for addressing a crucial problem. Further research is planned to study how early can these diagnostic biomarkers predict an onset of brain states.

Sleep profiles in epilepsy patients undergoing monotherapy and polytherapy: A comparative cross-sectional study.

OBJECTIVE: Sleep disturbances commonly reported among epilepsy patients have a reciprocal relationship with the condition; While epilepsy and anti-seizure medications (ASMs) can disrupt sleep structure, disturbed sleep can also exacerbate the frequency of seizures. This study explored subjective sleep disturbances and compared sleep profiles in patients who underwent ASM monotherapy and polytherapy. METHODS: We enrolled 176 epilepsy patients who completed a structured questionnaire containing demographic and clinical information and the Persian versions of the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), and Patient Health Questionnaire-9 (PHQ-9) to evaluate sleep quality, insomnia, excessive daytime sleepiness (EDS), and depressive symptoms, respectively. Chi-square and Mann-Whitney U tests were employed to analyze the association between variables, and logistic regression analysis was conducted to identify factors predicting sleep disturbances. RESULTS: Comparative analysis of mono/polytherapy groups revealed a significantly higher prevalence of insomnia and EDS among patients on polytherapy compared to monotherapy. However, no significant difference was found in sleep quality between the two groups. Logistic regression analysis revealed that a depressive mood serves as a robust predictor for sleep issues, whereas treatment type did not emerge as an independent predictor of sleep disturbances. CONCLUSION: Our findings suggest that an increased number of ASMs does not inherently result in a higher incidence of sleep issues. Therefore, multiple ASMs may be prescribed when necessary to achieve improved seizure control. Furthermore, this study underscores the importance of comprehensive management that addresses seizure control and treating affective symptoms in individuals with epilepsy.

Lysine ε-aminolysis and incorporation of sulfhydryl groups into human brain tau 4R/1N and 306VQIVYK311 enhances the formation of beta structures and toxicity.

In the present study, we investigated the effects of N-homocysteine thiolactone (tHcy) modification on expressed and purified tau protein and the synthesized VQIVYK target peptide. The modified constructs were subjected to comprehensive validation using various methodologies, including mass spectrometry. Subsequently, in vivo, in vitro, and in silico characterizations were performed under both reducing and non-reducing conditions, as well as in the presence and absence of heparin as a cofactor. Our results unequivocally confirmed that under reducing conditions and in the presence of heparin, the modified constructs exhibited a greater propensity for aggregation. This enhanced aggregative behavior can be attributed to the disruption of lysine positive charges and the subsequent influence of hydrophobic and p-stacking intermolecular forces. Notably, the modified oligomeric species induced apoptosis in the SH-SY5Y cell line, and this effect was further exacerbated with longer incubation times and higher concentrations of the modifier. These observations suggest a potential mechanism involving reactive oxygen species (ROS). To gain a deeper understanding of the molecular mechanisms underlying the neurotoxic effects, further investigations are warranted. Elucidating these mechanisms will contribute to the development of more effective strategies to counteract aggregation and mitigate neurodegeneration.

The effectiveness of agomelatine on headache severity and frequency in episodic migraine without aura; a parallel randomized controlled trial study.

BACKGROUND: Migraine is a headache disorder that affects public health and reduces the patient's quality of life. Preventive medication is necessary to prevent acute attacks and medication overuse headaches (MOH). Agomelatine is a melatonin antagonist. AIMS: This study aimed to determine the effectiveness of agomelatine on the severity and frequency of migraine attacks. METHODS: The study is a parallel randomized controlled trial with two groups of intervention and control. 400 patients were evaluated. Eligible individuals, including those with episodic migraine headaches without aura between the ages of 18 and 60 years who did not receive preventive treatment beforehand, were enrolled. Also, patients did not receive any specific medications for other diseases. Among these, 100 people met the inclusion criteria and entered the study. These subjects were randomly assigned to one of the two groups. The intervention group received 25 mg of agomelatine daily and the control group received B1. In this study, the effect of agomelatine on the frequency and severity of attacks, mean monthly migraine days (MMD), and migraine disability assessment (MIDAS), were assessed. The study was triple-blind and after three months, a post-test was performed. Data were analyzed using SPSS software. RESULTS: A total of 100 patients were randomly assigned to either intervention or control groups. The prescriber physician and the data collector did not know about the allocation of patients to groups. Before the intervention, there was no significant difference in the headache frequency per month (t=-0.182, df = 98, p = 0.85), mean MMD (p = 0.17), headache severity (p = 0.076), and MIDAS (p = 0.091). After the study, there was a significant difference between the two groups in terms of the headache frequency per month (p = 0.009), and mean of MMD (p = 0.025). There was also a significant difference between pretest and posttest in two groups in the headache severity (p < 0.001) and MIDAS (p < 0.001). CONCLUSION: Agomelatine can be used as a preventive medication for migraine without aura. It is suggested that agomelatine be studied in comparison with other preventive drugs for patients with migraine. TRIAL RETROSPECTIVELY REGISTRATION: Trial Retrospectively registration= IRCT20230303057599N1. Date: 2023-5-24 The present study is a residency thesis approved by the Tehran University of Medical Sciences.

The effects of atomoxetine and trazodone combination on obstructive sleep apnea and sleep microstructure: A double-blind randomized clinical trial study.

STUDY OBJECTIVES: we aimed to compare the effects of atomoxetine and trazodone (A-T) in combination with placebo in patients with obstructive sleep apnea (OSA). METHODS: This randomized, placebo-controlled, double-blind, crossover trial study was conducted in adults with OSA referred to a Sleep Clinic. Participants with eligibility criteria were recruited. Patients were studied on two separate nights with one-week intervals, once treated with trazodone (50 mg) and atomoxetine (80 mg) combination and then with a placebo and the following polysomnography tests. RESULTS: A total of 18 patients with OSA completed the study protocol, 9(50%) were male, the mean age was 47.5 years (SD = 9.8) and the mean Body mass index of participants was 28.4 kg/m2 (SD = 3.4). Compared with the placebo, the A-T combination resulted in significant differences in AHI (28.3(A-T) vs. 42.7 (placebo), p = 0.025), duration of the REM stage (1.3%TST (A-T) vs. 13.1%TST (placebo), p = 0.001), and the number of REM cycles (0.8 (A-T) vs. 4.7 (placebo), p = 0.001), number of apneas (38.3 (A-T) vs. 79.3 (placebo), p = 0.011), number of obstructive apneas (37.2 (A-T) vs. 75.2 (placebo), p = 0.011), oxygen desaturation index (29.5 (A-T) vs. 42.3 (placebo), p = 0.022) and number of respiratory arousals (43.2 (A-T) vs. 68.5 (placebo), p = 0.048). This decrement effect did not change among those with a low-arousal phenotype of OSA. CONCLUSIONS: The A-T combination significantly improved respiratory events' indices compared with placebo in patients with OSA. This combination is recommended to be assessed in a large trial. It could be an alternative for those who do not adhere to the standard available treatments for OSA.

Clinical Functional Seizure Score (CFSS): a simple algorithm for clinicians to suspect functional seizures.

Purpose: Distinguishing functional seizures (FS) from epileptic seizures (ES) poses a challenge due to similar clinical manifestations. The creation of a clinical scoring system that assists in accurately diagnosing patients with FS would be a valuable contribution to medical practice. This score has the potential to enhance clinical decision-making and facilitate prompt diagnosis of patients with FS. Methods: Participants who met the inclusion criteria were randomly divided into three distinct groups: training, validation, and test cohorts. Demographic and semiological variables were analyzed in the training cohort by univariate analyses. Variables that showed a significant difference between FS and ES were then further scrutinized in two multivariate logistic regression models. The CFSS was developed based on the odds ratio of the discriminating variables. Using the validation group, the optimal cutoff value was determined based on the AUC, and then the CFSS was evaluated in the test cohort to assess its performance. Results: The developed score yielded an AUC of 0.78 in the validation cohort, and a cutoff point of 6 was established with a focus on maximizing sensitivity without significantly compromising specificity. The score was then applied in the test cohort, where it achieved a sensitivity of 86.96% and a specificity of 73.81%. Conclusion: We have developed a new tool that shows promising results in identifying patients suspicious of FS. With further analysis through prospective studies, this innovative, simple tool can be integrated into the diagnostic process of FS.

Plasma cytokines profile in patients with Alzheimer's and Parkinson's Disease: a comparative study in terms of inflammation.

BACKGROUND: Neurodegenerative disorders such as Alzheimer's and Parkinson's disease inflict economic and health burdens on societies. Alzheimer's disease (AD), the most prevalent form of dementia, is accompanied by progressive degradation of memory, decision-making, and judgment. Parkinson's disease (PD) is characterized by resting tremor, rigidity, bradykinesia, and loss of balance. Extensive research has pinpointed inflammation as a cause of the onset and progression of both diseases. However, it has not been confirmed which one is more formidable in terms of inflammation. METHODS: To assess the extent of inflammation that is implicated in AD and PD and answer the question of which one is more inflammatory, serum levels of inflammatory biomarkers, including cytokines, chemokines, and prostaglandin E2 (PEG2), were measured in AD and PD patients as well as a healthy group. RESULTS: Our results showed a significant increase in IL-1α, IL-1ß, IL-4, IL-6, IL-10, IL-12p70, IP-10, MCP-1, PEG2, and TNF-α in AD and PD patients compared with the control. Interestingly, IFN-γ did not manifest any significant difference in AD or PD patients compared with the control. CONCLUSION: As a hallmark of our results, it could be inferred that inflammation, as the underlying etiological cause, plays a more crucial role in PD compared with AD. Based on our results, it is proposed that anti-inflammatory remedies would be putatively more effective in PD rather than AD.

A biallelic loss-of-function variant in TMEM147 causes profound intellectual disability and spasticity.

Intellectual disability (ID), occurring in syndromic or non-syndromic forms, is the most common neurodevelopmental disorder. Although many cases are caused by single gene defects, ID is highly genetically heterogeneous. Biallelic variants in the transmembrane protein TMEM147 have recently been linked to intellectual disability with dysmorphic facial features. TMEM147 is believed to localize to the endoplasmic reticulum membrane and nuclear envelope and also involved in biogenesis of multi-pass membrane proteins. Here, we report two patients born to a consanguineous family with a novel loss-of-function variant; (NM_001242597.2:c.193-197del) in TMEM147 causing intellectual disability and spasticity. Whole exome sequencing and validating Sanger sequencing were utilized to confirm the identified causal variant. Our findings were in line with the previously described patients with TMEM147 variants manifesting intellectual disability as a major clinical sign but also featured spasticity as a phenotypic expansion. This study provides additional evidence for the pathogenicity of TMEM147 mutations in intellectual disability and expands the phenotypic and variant spectrum linked to this gene.

The effect of cannabidiol on seizure features and quality of life in drug-resistant frontal lobe epilepsy patients: a triple-blind controlled trial.

Background: Treatment-resistant epileptic seizures are associated with reduced quality of life (QoL). As polypharmacy with routine antiseizure medications has many side effects, novel add-on treatments are necessary. Recent research showed the efficacy of add-on therapy by cannabidiol (CBD) on refractory epilepsy. We attempted to extend data on the efficacy and safety profile of CBD in patients with frontal lobe treatment-resistant epilepsy. Methods: A total of 27 patients were recruited into two CBD (n = 12) and placebo (n = 15) groups. The CBD group received a highly purified liposomal preparation of the drug in addition to routine antiseizure medications. The placebo group only received antiseizure medications. This experiment followed a triple-blinding protocol. Outcome measures were seizure frequency, the Chalfont seizure severity scale (CSSS), and the quality of life questionnaire score (QOLIE-31) assessed at baseline, 4 weeks, and 8 weeks. Results: At 4 weeks, results indicated that a higher fraction of patients in the CBD group (66.67%) showed improvement in seizure, compared to the placebo group (20.00%). Before-after comparison revealed that CBD, unlike routine ADEs, was effective in reducing the occurrence of seizures at the study's final timepoint [mean difference 45.58, 95% CI (8.987 to 82.18), p = 0.009]. Seizure severity was not affected by study groups or time intervals (repeated-measures ANOVA p > 0.05). Post-hoc tests found that the QoLI-31 score was improved at 8 weeks compared to baseline [mean diff. -5.031, 95% CI (-9.729 to -0.3328), p = 0.032]. The difference in cases who experienced enhanced QoL was meaningful between the CBD and placebo groups at 8 weeks [RR: 2.160, 95% CI (1.148 to 4.741), p = 0.018] but not at 4 weeks (p = 0.653). A positive finding for QoL improvement was associated with a positive finding for seizure frequency reduction [r = 0.638, 95% CI (0.296 to 0.835), p = 0.001]. Interestingly, limiting the correlation analysis to cases receiving CBD indicated that QoL improvement was not linked with seizure parameters such as severity and frequency (p > 0.05). Conclusion: The present study suggests the benefit of a purified and highly efficient preparation of CBD for seizure frequency reduction and improvement of QoL in refractory frontal lobe epilepsy. Further study with longer follow-ups and larger sample size is advised. Clinical trial registration: https://www.irct.ir/trial/56790, identifier: IRCT20210608051515N1.

Comparison of myocardial perfusion between the users of two antiepileptic medications: valproate vs. carbamazepine.

Objectives: The prevalence of coronary artery disease (CAD) is high in patients with epilepsy using antiepileptic drugs (AED). Epilepsy, AED, or the type and duration of AED use , may contribute to higher CAD risk.In this study, myocardial perfusion imaging (MPI) was compared between patients using carbamazepine and valproate. Method: Out of 73 patients receiving carbamazepine or valproate monotherapy for more than 2 years, visited at a tertiary referral clinic, 32 patients participated in a 2-day stress and rest phases MPI. For each phase, 15-25 mCi 99mTc-MIBI was injected, at peak exercise or by pharmacologic stimulation for the stress phase. SPECT with cardiac gating was done by a dual-head gamma camera and processed and quantified. Scans with at least one definite reversible hypo-perfusion segment were considered abnormal. Results: Seventeen patients received carbamazepine monotherapy and 15 valproates. Age and duration of AED use were similar between the groups. Two scans were abnormal (6.3%) both in valproate group (13.3%). Duration of AED use was higher in patients with abnormal scans. In patients receiving monotherapy >2 years, the frequency of abnormal MPI was similar between groups (P-value=0.12). In patients receiving monotherapy > 5 years, prevalence of abnormal MPI was higher in the valproate group (28.6% vs. 0.0%; P-value=0.042). Considering valproate subgroup, ischemic patients had higher duration of AED use, comparing with the normal patients (17.0±4.2 vs. 6.4±4.8, P-value=0.014). Conclusion: MPIs were abnormal in patients receiving valproate after 5 years compared to patients receiving carbamazepine. Long-term valproate use may increase the risk of CAD.

Boswellic Acids Improve Clinical Cognitive Scores and Reduce Systemic Inflammation in Patients with Mild to Moderate Alzheimer's Disease.

BACKGROUND: Recent therapeutic approaches for Alzheimer's disease (AD) have had limited success. Considering the association of neuroinflammation with AD symptoms as demonstrated in multiple studies, assessment of the clinical efficacy of molecules that reduce systemic or brain inflammation is warranted. OBJECTIVE: This clinical trial assessed whether boswellic acids can improve cognitive and neuropsychiatric symptoms while reducing inflammation in AD patients. METHODS: A double-blind, placebo-controlled, study was conducted on 85 AD patients randomized to boswellic acids (K-Vie™ as the main ingredient in Memowell™) or placebo for 6 months. Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores were compared to baseline and between groups and constituted the co-primary clinical efficacy endpoints. Secondary outcomes included neuropsychiatric assessment (Neuropsychiatric Inventory-Questionnaire, NPI-Q) and assessment of AD and inflammation biomarkers. RESULTS: Patients on K-Vie™ showed a 3.1- and 1.6-unit improvement in MMSE and CDR-SOB scores, respectively, when compared to patients on placebo. NPI-Q analysis revealed significant improvement in the K-Vie™ but not in the placebo group. Only mild gastrointestinal side effects were reported in a few patients. Patients on K-Vie™ showed improvement in plasma AD biomarkers and reduction of key inflammatory cytokines including IL-6 and TNF. CONCLUSION: Our results support the positive cognitive effects of boswellic acids by reducing the systemic inflammation.

Glia Signaling and Brain Microenvironment in Migraine.

Migraine is a complicated neurological disorder affecting 6% of men and 18% of women worldwide. Various mechanisms, including neuroinflammation, oxidative stress, altered mitochondrial function, neurotransmitter disturbances, cortical hyperexcitability, genetic factors, and endocrine system problems, are responsible for migraine. However, these mechanisms have not completely delineated the pathophysiology behind migraine, and they should be further studied. The brain microenvironment comprises neurons, glial cells, and vascular structures with complex interactions. Disruption of the brain microenvironment is the main culprit behind various neurological disorders. Neuron-glia crosstalk contributes to hyperalgesia in migraine. In the brain, microenvironment and related peripheral regulatory circuits, microglia, astrocytes, and satellite cells are necessary for proper function. These are the most important cells that could induce migraine headaches by disturbing the balance of the neurotransmitters in the nervous system. Neuroinflammation and oxidative stress are the prominent reactions glial cells drive during migraine. Understanding the role of cellular and molecular components of the brain microenvironment on the major neurotransmitters engaged in migraine pathophysiology facilitates the development of new therapeutic approaches with higher effectiveness for migraine headaches. Investigating the role of the brain microenvironment and neuroinflammation in migraine may help decipher its pathophysiology and provide an opportunity to develop novel therapeutic approaches for its management. This review aims to discuss the neuron-glia interactions in the brain microenvironment during migraine and their potential role as a therapeutic target for the treatment of migraine.

An application of dynamical directed connectivity of ictal intracranial EEG recordings in seizure onset zone localization.

BACKGROUND: Identification of the seizure onset zone (SOZ) is a challenging task in epilepsy surgery. Patients with epilepsy have an altered brain network, allowing connectivity-based analyses to have a great potential in SOZ identification. We investigated a dynamical directed connectivity analysis utilizing ictal intracranial electroencephalographic (iEEG) recordings and proposed an algorithm for SOZ identification based on grouping iEEG contacts. NEW METHODS: Granger Causality was used for directed connectivity analysis in this study. The intracranial contacts were grouped into visually detected contacts (VDCs), which were identified as SOZ by epileptologists, and non-resected contacts (NRCs). The intragroup and intergroup directed connectivity for VDCs and NRCs were calculated around seizure onset. We then proposed an algorithm for SOZ identification based on the cross-correlation of intragroup outflow and inflow of SOZ candidate contacts. RESULTS: Our results revealed that the intragroup connectivity of VDCs (VDC→VDC) was significantly larger than the intragroup connectivity of NRCs (NRC→NRC) and the intergroup connectivity between NRCs and VDCs (NRC→VDC) around seizure onset. We found that the proposed algorithm had 90.1 % accuracy for SOZ identification in the seizure-free patients. COMPARISON WITH EXISTING METHODS: The existing connectivity-based methods for SOZ identification often use either outflow or inflow. In this study, SOZ contacts were identified by integrating outflow and inflow based on the cross correlation between these two measures. CONCLUSIONS: The proposed group-based dynamical connectivity analysis in this study can aid our understanding of underlying seizure network and may be used to assist in identifying the SOZ contacts before epilepsy surgery.

A novel mutation in the ALS2 gene in an iranian kurdish family with juvenile amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare disorder that affects both upper and lower motor neurons. Mutations in Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) correlates with three similar but distinctive syndromes, including the juvenile form of ALS. An Iranian Kurdish family was involved in this study and all members were evaluated with relevant clinical guidelines. Whole exome sequencing and sanger sequencing were applied to all family members to undermine the possible genetic factors. A substitution c. 2110 C>T (p. Arg704X) identified in the ALS2 gene. Bioinformatics analysis indicated the mutation is located in the well-conserved and functional domain of the protein. This study recognized a novel mutation in the ALS2 gene in a proband with the juvenile form of ALS. To our knowledge, this is the first identified ALS2 mutation among the Iranian population.

Thyroid hormone levels in Alzheimer disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Thyroid hormone (TH) disturbances are perceived to contribute to cognitive impairment and dementia. However, there is no consensus on the association between TH levels and Alzheimer Disease (AD). In this study, we aimed to compare serum and cerebrospinal fluid (CSF) TH levels in AD patients to controls by performing a meta-analysis. METHODS: We systematically searched online databases for papers comparing CSF or serum TH levels in AD patients to controls, and performed a meta-analysis on the extracted data. RESULTS: Out of 1604 records identified, 32 studies were included. No significant difference in serum TSH (standardized mean difference (SMD): -0.03; 95% confidence interval (CI): -0.22-0.16), total T4 (SMD: 0.10; 95% CI: -0.29-0.49), and free T4 (SMD: 0.25; 95% CI: -0.16-0.69) levels were observed. However, there was significantly lower serum total T3 (SMD: -0.56; 95%CI: -0.97 to -0.15) and free T3 (SMD: -0.47; 95%CI: -0.89 to -0.05) levels in AD group compared to controls. Subgroup analyses on studies including only euthyroid patients did not show any significant difference in either of the thyroid hormone levels. Also, no significant difference in CSF total T4 and total T3/total T4 ratios but significantly lower CSF total T3 (SMD: -2.45; 95% CI: -4.89 to -0.02) in AD group were detected. CONCLUSION: Serum total and free T3 and CSF total T3 levels are significantly lower in AD patients compared to controls. The temporality of changes in thyroid hormone levels and AD development should be illustrated by further longitudinal studies.

Effects of Botulinum Toxin Injection on Reducing Myogenic Artifacts during Video-EEG Monitoring: A Longitudinal Study.

Medically refractory seizures affect one-third of patients with epilepsy (PwE), for whom epilepsy surgery is considered. Video electroencephalography (vEEG) monitoring is a fundamental tool for pre-operative seizure localization. Facial and cranial myogenic artifacts can obscure vEEG findings, thus interfering with seizure localization. Studies have shown the beneficial effects of botulinum toxin type A (BTX-A) injection into cranial muscles for reducing myogenic artifacts. This longitudinal study aimed to assess the effects of BTX-A injection on these artifacts. Twenty-two patients with medically refractory hypermotor seizures with daily seizure frequency and undetermined epilepsy localization were included in this study and underwent Dysport® injection (200 units) into the frontotemporal region. vEEG recordings were performed at baseline (one week before the injection), and at three days and six days post-injection. Before and after the injection, the amplitudes of myogenic artifacts were compared during various states (ictal, blinking, chewing, bruxism, head lateralization, scowling, talking, and yawning). BTX-A injection significantly reduced the amplitudes of EEG myogenic artifacts, except during blinking (day three) and talking (days three and six). On day six, significant reduction in EEG myogenic artifacts were noted during blinking, chewing, and bruxism for the greatest number of patients (95.5%, 90.9%, 81.8%), while significant reductions in EEG myogenic artifacts during talking, head lateralization, and ictal phase were associated with the least number of patients (22.7%, 36.3%, and 40.9%). Therefore, BTX-A injection could be a convenient method for filtering myogenic contamination, improving EEG interpretation, and facilitating seizure localization in patients with medically refractory seizures.

Memantine administration in patients with optic neuritis: a double blind randomized clinical trial.

INTRODUCTION: As an inflammatory phenomenon, optic neuritis (ON) that causes demyelination in the optic nerve damages the retinal cells, and leads to visual impairment. Herein, we aimed to investigate the potential therapeutic effects of memantine on ON. METHODS: In this double-blinded randomized clinical trial, participants with the first episode of acute ON meeting the inclusion criteria were enrolled and were randomly divided into memantine group (MG; N = 20) and placebo group (PG; N = 18). Patients of MG received memantine for 6 weeks. The thickness of the retinal nerve fiber layer (RNFL), visual evoked potential (VEP), and visual acuity (VA) was measured in both groups at baseline and 3-month follow-up. RESULTS: Thirty-eight patients with ON were enrolled. In the follow-up, mean RNFL thickness of both groups significantly decreased in all quadrants (P < 0.001). Also, RNFL thickness of all but temporal quadrants were significantly higher in the MG than placebo. The reduction in RNFL thickness difference was insignificant between two groups in all but the inferior quadrant which was significantly lower in MG (P = 0.024). In follow-up, mean-to-peak of P100 of the affected eye were significantly lowered (P < 0.001). The changes in VEP were insignificant. Originally, the mean VA was 0.15 ± 0.08 and 0.17 ± 0.09 in MG and PG, respectively, but was improved significantly to 0.92 ± 0.06 and 0.91 ± 0.06 in MG and PG, respectively, in follow-up. CONCLUSION: Memantine can reduce the RNFL thinning in three quadrants by blocking NMD receptors. However, visual acuity did not show a significant difference between the two groups.

Safety and efficacy of melatonin, clonazepam, and trazodone in patients with Parkinson's disease and sleep disorders: a randomized, double-blind trial.

BACKGROUND: Sleep disturbances are common non-motor symptoms of Parkinson's disease (PD). We aimed to compare the safety and efficacy of trazodone with melatonin and clonazepam in patients with PD and sleep complaints. METHODS: This single-center, double-blind, randomized clinical trial was conducted on PD patients with subjective sleep complaints. Eligible patients were randomized 1:1:1 to receive melatonin 3 mg/day, clonazepam 1 mg/day, or trazodone 50 mg/day for 4 weeks. The primary outcome measure was the changes in Pittsburgh Sleep Quality Index (PSQI) scores. The mean change in Epworth Sleepiness Scale (ESS) and RBD screening questionnaire (RBDSQ) was considered as the secondary outcome measures. RESULTS: A total of 112 eligible patients were randomized and 93 participants, melatonin (n = 31), trazodone (n = 31), and clonazepam (n = 31), completed the study. There was a significant decrease in PSQI scores after 4 weeks of treatment in all groups. The mean changes of PSQI from baseline were similar among the treatment arms (P = 0.325). Mean changes of RBDSQ and ESS from baseline were significantly different between study arms (P < 0.05). Melatonin intake was associated with a higher decrease in RBDSQ score compared to trazodone (P = 0.011) and clonazepam (P = 0.004). Trazodone intake was associated with a higher decrease in ESS score compared to clonazepam (P = 0.010). Mild adverse events were reported in three patients in the clonazepam, two patients in the trazodone group, and none in the melatonin group. CONCLUSIONS: Trazodone 50 mg/day, clonazepam 1 mg/day, and melatonin 3 mg/day were all tolerable and effective in improving sleep quality in patients with PD. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (registration number; IRCT20170821035819N2).