Neurol. Int., Volume 16, Issue 6 (December 2024) – 42 articles

Background: Several significant associations between certain Human Leukocyte Antigen (HLA) alleles and myasthenia gravis (MG) subtypes were established in populations from Western Europe and North America and, to a lesser extent, from China and Japan. However, such data are scarcely available for Eastern Europe. This study aimed to analyze the associations of HLA Class I and II alleles with MG and its serological subtypes (with anti-acetylcholine receptor autoantibodies, RAch+MG, and double-seronegative, dSNMG) in myasthenic patients of Romanian descent. Methods: We consecutively enrolled adult Romanian unrelated myasthenic patients, which were genotyped by next-generation sequencing for HLA-A, -B, -C, -DRB1 and -DQB1. The descent-matched controls were represented by two separate groups of random normal subjects genotyped for the main five HLA loci at the two-digit and four-digit levels, respectively, collected from the Allele Frequency Net Database. Results: A total of 40 patients (females: 80.00%; median age at onset: 42.5 years, range: 1–78; RAch+MG: 75.00%; dSNMG: 22.50%) were included. We were able to confirm previously acknowledged allelic associations: positive for HLA-B*08, DRB1*14:54 and DRB1*16:01 and negative for DRB1*13. However, we found some potential novel significant positive associations between MG and the HLA-A*02:36, B*47, B*73, B*44:27 and B*57:02 alleles. All alleles positively associated with MG remained significantly associated with RAch+MG, regardless of the patients’ clinical and thymic heterogeneity. We found significant positive associations between dSNMG and the HLA-B*47, B*44:27 and DRB1*14:54 alleles that are shared with RAch+MG. Conclusions: These results suggest both distinct and common etiopathogenic mechanisms between dSNMG and RAch+MG. Our study pioneers allele associations in Romanian MG patients. Full article

Animal models are valuable tools for studying the underlying mechanisms of and potential treatments for intervertebral disc diseases. In this review, we discuss the advantages and limitations of animal models of disc diseases, focusing on lumbar spinal stenosis, disc herniation, and degeneration, as well as future research directions. The advantages of animal models are that they enable controlled experiments, long-term monitoring to study the natural history of the disease, and the testing of potential treatments. However, they also have limitations, including species differences, ethical concerns, a lack of standardized protocols, and short lifespans. Therefore, ongoing research focuses on improving animal model standardization and incorporating advanced imaging and noninvasive techniques, genetic models, and biomechanical analyses to overcome these limitations. These future directions hold potential for improving our understanding of the underlying mechanisms of disc diseases and for developing new treatments. Overall, although animal models can provide valuable insights into pathophysiology and potential treatments for disc diseases, their limitations should be carefully considered when interpreting findings from animal studies. Full article

Background: Ophthalmoplegic migraine (OM) is an uncommon variant of migraine characterised by headache and cranial nerve palsy, posing significant diagnostic and therapeutic challenges. Objective: This study aimed to describe an extremely rare OM variant with a partial therapeutic response. Clinical Case: A 34-year-old pregnant woman in gestational week 19.1 (G6P2A3) with a history of three consecutive spontaneous abortions presented at the emergency services with insidious onset and mild-to-moderate-intensity pulsatile bifrontal headache for 15 days, and the positional changes exacerbated this. At peak intensity, she experienced nausea, vomiting, tinnitus, and photophobia without phonophobia or osmophobia, prompting multiple visits to the emergency department. Despite a broad range of treatments, including intravenous fluids, analgesia, pericranial blocks, and preventive management, there was a non-significative improvement in the symptomatology described above. However, spontaneous resolution of this clinical picture was observed during the postpartum period. Results: This case highlights the complexity of ophthalmoplegic migraine, especially in the context of pregnancy, and raises questions about the underlying pathophysiological mechanisms. The absence of structural lesions on neuroimaging and postpartum resolution suggests a potential association with the hormonal and physiological changes associated with pregnancy. Conclusions: Despite limited scientific evidence, this report contributes to expanding the knowledge of this rare entity and emphasises the importance of a multidisciplinary approach to its management. Full article

Background: The innate immune response aims to prevent pathogens from entering the organism and/or to facilitate pathogen clearance. Innate immune cells, such as macrophages, mast cells (MCs), natural killer cells and neutrophils, bear pattern recognition receptors and are thus able to recognize common molecular patterns, such as pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), the later occurring in the context of neuroinflammation. An inflammatory component in the pathology of otherwise “primary cerebrovascular and neurodegenerative” disease has recently been recognized and targeted as a means of therapeutic intervention. Activated MCs are multifunctional effector cells generated from hematopoietic stem cells that, together with dendritic cells, represent first-line immune defense mechanisms against pathogens and/or tissue destruction. Methods: This review aims to summarize evidence of MC implication in the pathogenesis of neurodegenerative diseases, namely, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis. Results: In view of recent evidence that the gut–brain axis may be implicated in the pathogenesis of neurodegenerative diseases and the characterization of the neuroinflammatory component in the pathology of these diseases, this review also focuses on MCs as potential mediators in the gut–brain axis bi-directional communication and the possible role of Helicobacter pylori, a gastric pathogen known to alter the gut–brain axis homeostasis towards local and systemic pro-inflammatory responses. Conclusion: As MCs and Helicobacter pylori infection may offer targets of intervention with potential therapeutic implications for neurodegenerative disease, more clinical and translational evidence is needed to elucidate this field. Full article

Background: Post-traumatic pseudomeningoceles are common findings after a brachial or lumbar plexus trauma, in particular after nerve root avulsion. Unlike meningoceles, pseudomeningoceles are CSF full-filled cysts confined by the paraspinous soft tissue, along the normal nerve course, in communication with the spinal subarachnoid spaces. Normally no more than a radiological finding at MRI, in rare instances they might be symptomatic due to their size or might constitute an obstacle during a reconstructive surgery. Methods: A review of the literature was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in a time span ranging from November 1972 to May 2024. A total of five articles were found meeting the inclusion criteria. A case report at our institution was added to the case history. Results: A 30-year-old man with complete right brachial plexus nerve roots avulsion and a voluminous pseudomeningocele at the C6-C7 level after a motorcycle incident in January 2023. The pseudomeningocele covered the entirety of the injured brachial plexus. Pre-operative external lumbar drainage was utilized to prevent relapse or worsening of the already existing cerebral spinal fluid collection, with good results at 6 months. The full case report is reported in detail. Conclusions: To date, no clear guidelines about the management of post-traumatic pseudomeningoceles are reported in the literature. The lack of symptoms or signs related to them does not usually require any surgical intervention. If not, a possible management strategy with the use of an external lumbar drainage is proposed, a solution already in use in other surgical contexts with successful results in preventing CSF fistula or its relapse. Full article

Background/Objectives: Antipsychotic medicines are used to treat several psychological disorders and some symptoms caused by dementia and schizophrenia. Haloperidol (Hal) is a typical antipsychotic usually used to treat psychosis; however, its use causes motor or extrapyramidal symptoms (EPS) such as catalepsy. Hal blocks the function of presynaptic D2 receptors on cholinergic interneurons, leading to the release of acetylcholine (ACh), which is hydrolyzed by the enzyme acetylcholinesterase (AChE). Methods: This study was designed to investigate the Hal-inhibitory effects on AChE activity in regions representative of the cholinergic system of mice and potential associations between cataleptic effects generated by Hal using therapeutic doses and their inhibitory effects on AChE. Results: The distribution of the AChE activity in the different regions of the brain followed the order striatum > hippocampus > (prefrontal cortex/hypothalamus/ cerebellum) > brainstem > septo-hippocampal system. In ex vivo assays, Hal inhibited AChE activity obtained from homogenate tissue of the striatum, hippocampus, and septo-hippocampal system in a concentration-dependent manner. The inhibitory concentration of 50% of enzyme activity (IC₅₀) indicated that the septo-hippocampal system required a higher concentration of Hal (IC₅₀ = 202.5 µmol·L⁻¹) to inhibit AChE activity compared to the striatum (IC₅₀ = 162.5 µmol·L⁻¹) and hippocampus (IC₅₀ = 145 µmol·L⁻¹). In in vivo assays, male Swiss mice treated with concentrations of Hal higher than 0.1 mg·kg⁻¹ induced cataleptic effects. Positive correlations with Spearman’s correlation were observed only between the lack of cataleptic effect and the decreased AChE activity of the hippocampus in the mice treated with 0.01 mg·kg⁻¹ of Hal but not in the striatum and septo-hippocampal system. Conclusions: Our results suggest that Hal could increase cholinergic effects via AChE inhibition, in addition to its dopamine antagonist effect, as an alternative approach to the treatment of behavioral disturbances associated with dementia. Full article

Diabetes mellitus (DM) is a chronic disease associated with numerous complications, including cardiovascular diseases, nephropathy, and neuropathy. Sodium–glucose cotransporter 2 (SGLT-2) inhibitors, a class of novel antidiabetic agents, have demonstrated promising therapeutic effects beyond glycemic control, with potential benefits extending to the cardiovascular and renal systems. Recently, research has increasingly focused on exploring the potential role of SGLT-2 inhibitors in preventing dementia. The aim of this review is to summarize the current research suggesting that SGLT-2 inhibitors, such as empagliflozin and dapagliflozin, may have neuroprotective effects that reduce dementia risk and improve cognitive function in type 2 diabetes patients. These benefits are likely due to better glycemic control, reduced oxidative stress, and less advanced glycation end-product (AGE) formation, all linked to neurodegeneration. Despite these promising findings, existing studies are limited by small sample sizes and short follow-up durations, which may not adequately capture long-term outcomes. To establish more robust evidence, larger-scale, long-term randomized controlled trials (RCTs) involving diverse populations are needed. These studies should involve diverse populations and focus on understanding the mechanisms behind the neuroprotective effects. Addressing these limitations will provide clearer guidelines for using SGLT-2 inhibitors in dementia prevention and management. This will help improve therapeutic strategies for cognitive health in diabetic patients. Full article

Cluster headache is a severe, poorly understood disorder for which there are as yet virtually no rationally derived treatments. Here, Lee Kudrow’s 1983 theory, that cluster headache is an overly zealous response to hypoxia, is updated according to current understandings of hypoxia detection, signaling, and sensitization. It is shown that the distinctive clinical characteristics of cluster headache (circadian timing of attacks and circannual patterning of bouts, autonomic symptoms, and agitation), risk factors (cigarette smoking; male gender), triggers (alcohol; nitroglycerin), genetic findings (GWAS studies), anatomical substrate (paraventricular nucleus of the hypothalamus, solitary tract nucleus/NTS, and trigeminal nucleus caudalis), neurochemical features (elevated levels of galectin-3, nitric oxide, tyramine, and tryptamine), and responsiveness to treatments (verapamil, lithium, melatonin, prednisone, oxygen, and histamine desensitization) can all be understood in terms of hypoxic signaling. Novel treatment directions are hypothesized, including repurposing pharmacological antagonists of hypoxic signaling molecules (HIF-2; P2X3) for cluster headache, breath training, physical exercise, high-dose thiamine, carnosine, and the flavonoid kaempferol. The limits of current knowledge are described, and a program of basic and translational research is proposed. Full article

Background/Objectives: Transverse myelitis (TM) is a rare, acute inflammatory disorder affecting the spinal cord, with severe potential consequences, particularly in pediatric patients. Therapeutic plasma exchange (TPE) has emerged as a possible intervention for children unresponsive to high-dose corticosteroids. This study explores the efficacy of early TPE in pediatric TM through a case report and scoping review aiming to clarify the therapeutic benefits of TPE when used in conjunction with corticosteroids in children. Methods: We present a scoping review of existing literature on the early administration of TPE in pediatric patients with TM, supplemented by a case report of a 5-year-old boy with Longitudinally Extensive Transverse Myelitis (LETM), who received early TPE and corticosteroid therapy. Clinical progression, response to TPE, and functional outcomes were documented over a 9-month follow-up period. Results: Among the reviewed cases, early TPE demonstrated potential to expedite neurological recovery and improve functional outcomes. In our case report, the patient showed rapid recovery, achieving unassisted ambulation by day four of TPE. No adverse effects were observed. MRI findings revealed substantial resolution of spinal cord lesions by three months, with near-complete symptom resolution at nine months. Conclusions: Early initiation of TPE, in conjunction with corticosteroids, may offer significant therapeutic benefit in pediatric TM, potentially accelerating recovery and improving outcomes. This case highlights the need for further controlled studies to establish evidence-based guidelines for TPE use in pediatric TM. Full article

Background: Hereditary Sensory Motor Neuropathy (HSMN) 1A and Multiple Sclerosis (MS) are distinct demyelinating disorders affecting the peripheral and central nervous systems, respectively. We present a case of simultaneous occurrence of both conditions, exploring the clinical presentation, diagnostic workup, and potential interplay between these diseases. Case presentation and clinical approach: A 49-year-old male with a history of optic neuritis presented with progressive numbness, weakness, and sensory loss in all extremities over four years. Neurological examination revealed distal weakness, sensory deficits in a stocking-glove distribution, pes cavus, and hammer toes. Nerve conduction studies and electromyography confirmed sensory motor demyelinating polyneuropathy. The patient’s lack of response to intravenous immunoglobulin therapy suggested hereditary neuropathy as an etiology. Genetic testing identified a PMP22 gene duplication, confirming HSMN 1A. Elevated cerebrospinal fluid protein level and oligoclonal bands, combined with magnetic resonance of the brain showing multiple T2 hyperintense lesions in the brain and spinal cord, fulfilled the diagnostic criteria for MS. Discussion: This case of co-existing HSMN 1A and MS highlights a rare overlap of peripheral and central demyelination. While HSMN 1A results from PMP22 gene duplication, primarily affecting peripheral myelin, MS is driven by immune-mediated central myelin attacks. The co-existence of these disorders suggests potential shared mechanisms, such as immune dysregulation. Some evidence suggests that overexpression of PMP22 in HSMN 1A may disturb immune tolerance, possibly triggering autoimmune responses linked to MS. Further research is needed to explore the genetic and autoimmune interplay between these two diseases, expanding our understanding of demyelinating disorders. Full article

Neurosyphilis-induced dementia represents a severe manifestation of tertiary syphilis, characterized by cognitive and neuropsychiatric impairments. This condition arises from the progression of syphilis to the central nervous system, where the spirochete causes damage through invasion, chronic inflammation, and neurodegeneration. The pathophysiology involves chronic inflammatory responses, direct bacterial damage, and proteinopathies. Treponema pallidum triggers an inflammatory cascade, resulting in neuronal injury and synaptic dysfunction. Abnormal protein accumulations, including TAR DNA-binding protein 43 (TDP-43) and tau, contribute to neuronal loss and cognitive decline. Seizures, psychiatric symptoms, and motor deficits further complicate the progression of dementia. Diagnosis includes clinical assessment, cerebrospinal fluid analysis, and neuroimaging. Diagnostic tests include CSF-VDRL, FTA-ABS, and neuroimaging techniques such as MRI and PET scans, which help detect structural changes and confirm neurosyphilis. Management of neurosyphilis-induced dementia involves antibiotic therapy and psychotropic medications to address both infectious and symptomatic components. While penicillin remains the cornerstone of treatment, psychotropic agents, including haloperidol, risperidone, quetiapine, and divalproex sodium, can manage psychiatric symptoms. However, careful monitoring is required due to potential side effects and interactions with ongoing treatment. Overall, early diagnosis and comprehensive management are crucial for mitigating the cognitive and neuropsychiatric impairments associated with neurosyphilis-induced dementia. Full article

Objectives: Blood pressure (BP) management is challenging in patients with acute ischemic supratentorial stroke undergoing recanalization therapy due to the lack of established guidelines. Assessing dynamic cerebral autoregulation (dCA) may address this need, as it is a bedside technique that evaluates the transfer function phase in the very low-frequency (VLF) range (0.02–0.07 Hz) between BP and cerebral blood flow velocity (CBFV) in the middle cerebral artery. This phase is a prognostically relevant parameter, with lower values associated with poorer outcomes. This study aimed to evaluate whether early cranial computed tomography perfusion (CTP) can predict this parameter. Methods: In this retrospective study, 165 consecutive patients with hemispheric strokes who underwent recanalizing therapy were included (median age: 73 years; interquartile range (IQR) 60–80; women: 43 (26%)). The cohort comprised 91 patients treated with intravenous thrombolysis (IV-lysis) alone (median National Institute of Health Stroke Scale (NIHSS) score: 5; IQR 3–7) and 74 patients treated with mechanical thrombectomy (median NIHSS: 15; IQR 9–18). Regression analysis was performed to assess the relationship between pretreatment CTP-derived ischemic penumbra and core stroke volumes and the dCA VLF phase, as well as CBFV assessed within the first 72 h post-stroke event. Results: Pretreatment penumbra volume was a significant predictor of the VLF phase (adjusted r² = 0.040; β = −0.001, 95% confidence interval (CI): −0.0018 to −0.0002, p = 0.02). Core infarct volume was a stronger predictor of CBFV (adjusted r² = 0.082; β = 0.205, 95% CI: 0.0968–0.3198; p = 0.0003) compared to penumbra volume (p = 0.01). Additionally, in the low-frequency range (0.07–0.20 Hz), CBFV and BP were inversely related to the gain, an index of vascular tone. Conclusion: CTP metrics appear to correlate with the outcome-relevant VLF phase and reactive hyperemic CBFV, which interact with BP to influence vascular tone and gain. These aspects of dCA could potentially guide BP management in patients with acute stroke undergoing recanalization therapy. However, further validation is required. Full article

Background: The Improved Health Care in Neurology and Psychiatry—Longer Life (IHCNP) study was an 18-month prospective, observational, non-interventional research study focused on patients with mild cognitive impairment (MCI) following ischemic stroke. Objectives: Our secondary analysis of the IHCNP data aimed to document the progression of MCI in this patient group. Methods: A total of 100 patients from Romania were recruited, all of whom underwent cognitive assessments using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Rey Auditory Verbal Learning Test (RAVLT). Clinical evaluations were also conducted as part of the study. Baseline cognitive scores were recorded, and subsequent follow-ups documented cognitive changes over time. Results: At baseline, cognitive scores indicated mild impairment, with averages of MMSE 25.41, MoCA 23.27, and RAVLT 33.63. By the end of the study, patients exhibited a significant cognitive decline, with MMSE scores dropping by 8.7%, MoCA by 10.0%, and RAVLT by 29.5% (p < 0.0001 for all measures), reflecting the progressive nature of MCI post-stroke. Conclusions: These findings highlight the importance of early diagnosis and intervention to mitigate cognitive decline in post-stroke patients. The study underscores the need for ongoing cognitive monitoring to improve patient outcomes and manage MCI progression effectively. Full article

Therapeutic treatment of nervous system disorders has represented one of the significant challenges in medicine for the past several decades. Technological and medical advances have made it possible to recognize different neurological disorders, which has led to more precise identification of potential therapeutic targets, in turn leading to research into developing drugs aimed at these disorders. In this sense, recent years have seen an increase in exploration of the therapeutic effects of various metabolites extracted from Maca (Lepidium meyenii), a plant native to the central alpine region of Peru. Among the most important secondary metabolites contained in this plant are macamides, molecules derived from N-benzylamides of long-chain fatty acids. Macamides have been proposed as active drugs to treat some neurological disorders. Their excellent human tolerance and low toxicity along with neuroprotective, immune-enhancing, and and antioxidant properties make them ideal for exploration as therapeutic agents. In this review, we have compiled information from various studies on macamides, along with theories about the metabolic pathways on which they act. Full article

Background/Objectives: Pattern glare, associated with cortical hyperexcitability, induces visual distortions and discomfort, particularly in individuals susceptible to migraines or epilepsy. While previous research has primarily focused on transient EEG responses to patterned stimuli, this study aims to investigate how continuous presentation of pattern-glare stimuli affects neural adaptation over both fine (seconds) and coarse (entire experiment) temporal scales. Methods: EEG recordings were obtained from 40 healthy participants exposed to horizontal square-wave gratings at three spatial frequencies presented continuously for three seconds each across multiple trials. Participants’ susceptibility to visual stress, headaches, and discomfort was assessed using questionnaires before and during the experiment. The experiment employed a two-by-two design to evaluate habituation (exponentially decreasing response) and sensitisation (exponentially increasing response) effects at two different time granularities. Mass univariate analysis with cluster-based permutation tests was conducted to identify significant brain response changes during the period of constant stimulation, which we call the DC-shift period. Results: Significant effects were observed during the DC-shift period, indicating sustained hyper-excitation to the medium-pattern glare stimulus. In particular, the mean/intercept analysis revealed a consistent positive-going response to the medium stimulus throughout the DC-shift period, suggesting continued neural engagement. Participants reporting higher discomfort exhibited sensitisation at fine temporal granularity and habituation at coarser temporal granularity. These effects were predominantly localised to the right posterior scalp regions. Conclusions: The study demonstrates that individuals sensitive to pattern-glare stimuli exhibit dynamic neural adaptation characterised by short-term sensitisation and long-term habituation. These findings enhance the understanding of cortical hyperexcitability mechanisms and may inform future interventions for visual-stress-related conditions, such as migraines and epilepsy. Further research is needed to explore the underlying neural processes and validate these effects in clinical populations. Full article

Background: Numerous studies have evaluated the effect that mindfulness-based interventions (MBIs) have on multiple health outcomes. For its part, stress is a natural response to environmental disturbances and within the associated metabolic responses, alterations in cortisol levels and their measurement in different tissues are a way to determine the stress state of an individual. Therefore, it has been proposed that MBIs can modify cortisol levels. Methods and results: The objective of this systematic review was to analyze and summarize the different studies that have evaluated the effect of MBIs on cortisol levels. The following databases were consulted: MEDLINE, AMED, CINAHL, Web of Science, Science Direct, PsycINFO, SocINDEX, PubMed, the Cochrane Library and Scopus. The search terms “mindfulness”, “mindfulness-based interventions” and “cortisol” were used (and the search was limited to studies from January 1990 to May 2024). In order to reduce selection bias, each article was scrutinized using the JBI Critical Appraisal Checklist independently by two authors. We included those studies with specified intervention groups with at least one control group and excluded duplicate studies or those in which the intervention or control group was not adequately specified. Significant changes in cortisol following MBIs were found in 25 studies, while 10 found no changes. The small sample size, lack of randomization, blinding, and probable confounding and interaction variables stand out in these studies. Conclusion: MBIs have biological plausibility as a means of explaining a positive effect on cortisol levels; however, the weakness of the studies and the absence of robust designs makes it difficult to establish a causal association between both variables. Registration number: INPLASY2024110017. Full article

Background/Objectives: One of the first-line disease-modifying treatments of multiple sclerosis (MS) is Glatiramer Acetate (GA), which requires daily or three-times-weekly subcutaneous injections. Disease progression, while slowed, still occurs with time. Increasing the impact of the treatment while decreasing the frequency of injections would be ideal. The mechanism of action of GA remains undefined. We developed an alternate approach, KGYY₆, whose mechanism of action targets the CD40 receptor with promising results in an Experimental Autoimmune Encephalomyelitis (EAE) model. Methods: GA and a CD40-targeting peptide, KGYY₆, were formulated as slow-release particles used to treat EAE in C57BL/6 mice. Results: Compared to liquid formulations, the particle formulations vastly improved drug efficacy in both cases, which would be advantageous in treating MS. GA is a combination of randomly generated peptides, in the size range of 5000–9000 Da, using the amino acids E, A, Y, and K. This approach introduces batch differences that impacts efficacy, a persistent problem with GA. KGYY₆ is generated in a controlled process and has a motif, K-YY, which could be generated when manufacturing GA. When testing two different lots of GA or KGYY₆, the latter performed equally well across lots, while GA did not. Conclusions: Slow-release formulations of both GA and KGYY₆ vastly improve the efficacy of both, and KGYY₆ is more consistent in efficacy across different lots. Full article

Background: The study aimed to identify Mild Cognitive Impairment (MCI) as an alert clinical manifestation of increased probability of major acute vascular events (MVEs), such as Ischemic Stroke and heart attack. Methods: In a longitudinal study, 181 (M = 81, F = 100; mean age of 75.8 ± 8.69 years) patients were enrolled and divided into three groups based on diagnosis: Subjective Cognitive Impairment (SCI), amnestic MCI Single Domain (aMCI-SD), and amnestic MCI More Domain (aMCI-MD). Clinical assessment and the presence of vascular risk factors were collected. Results: The distribution of MVEs showed a higher incidence in the first two years of follow-up of 7.4% in SCI, 12.17% in aMCI-SD, and 8.57% in aMCI-MD. Acute Myocardial Infarction showed a major incidence in one year of follow-up (41%) and in two years of follow-up (29%). Also, Ischemic Stroke showed a major incidence in one year of follow-up (30%) and in two years of follow-up (40%). A statistically significant difference in the progression to dementia was shown (SCI 3.75%; aMCI-SD 10.43%; aMCI-MD 37%; p-value < 0.001). Conclusions: MCI is considered an expression of the systemic activation of mechanisms of endothelial damage, representing a diagnosis predictive of increased risk of MVEs. Full article

Depression is a mental disorder that depicts a wide variety of symptoms, including mood and cognitive alterations, as well as recurrent thoughts of death or suicide. It could become the second leading cause of premature death or disability worldwide. Treatments with conventional antidepressants have several limitations in terms of effectiveness, side effects, and high costs. Therefore, medicinal plants such as Mucuna pruriens are potent candidates for treating depressive disorders. This review shows a compendium of evidence supporting the antidepressant effect of the Mucuna pruriens plant in diverse animal models. This includes the mechanisms of action underlying the antidepressant activity of the treatment concerning dopamine, serotonin, norepinephrine, reactive oxygen species, nitric oxide, cortisol, and inflammation. Clinical trials are needed to study the efficacy and safety of Mucuna pruriens for depression. Full article

Background and Objectives: Leprosy primarily affects peripheral nerves, leading to significant neurological complications such as polyneuritis, mononeurosis, and autonomic dysfunction, which contribute to severe disabilities and impaired quality of life for patients. This scoping review aims to investigate the neurological manifestations and main treatments of leprosy patients. Materials and Methods: Studies were identified from an online search of PubMed, Web of Science, Cochrane Library, Embase, and Scopus databases. This review has been registered on OSF (n) PQBYH. Results: Neurological complications of leprosy, such as neuropathy and paralysis, necessitate accurate diagnosis and treatment, as immunological reactions can exacerbate nerve damage. Various studies highlight the effectiveness of personalized therapies, such as corticosteroids, multi-drug therapy (MDT), and surgical interventions, in improving symptoms and neurological function in leprosy patients. Conclusions: Managing neurological complications of leprosy necessitates careful diagnosis and treatment, as many patients experience unresolved peripheral neuropathy despite multidrug therapy. Future research should focus on improving diagnostic tools, exploring the link between neuropathic pain and psychological issues, and developing effective vaccines and treatments to enhance patient outcomes. Full article

Background/Objectives—Parkinson’s disease (PD) is the second most common neurodegenerative disorder caused by the destruction of neurons in the substantia nigra of the brain. Clinical diagnosis of this disease, based on monitoring motor symptoms, often leads to a delayed start of PD therapy and control, where over 60% of dopaminergic nerve cells are damaged in the brain substantia nigra. The search for simple and stable characteristics of EEG recordings is a promising direction in the development of methods for diagnosing PD and methods for diagnosing the preclinical stage of PD development. Methods—42 subjects participated in work, of which 4 female/10 male patients were included in the group of patients with non-motor disorders, belonging to the risk group for developing PD (median age: 62 years, height: 164 cm, weight: 70 kg, pulse: 70, BPsys and BPdia: 143 and 80)/(median age: 68 years, height: 170 cm, weight: 73.9 kg, pulse: 75, BPsys and BPdia: 143 and 82). The first control group of healthy participants included 6 women (median age: 33 years, height: 161 cm, weight: 66 kg, pulse: 80, BPsys and BPdia: 110 and 80)/8 men (median age: 36.3 years, height: 175 cm, weight: 69 kg, pulse: 78, BPsys and BPdia: 120 and 85). The second control group of healthy participants included 8 women (median age: 74 years, height: 164 cm, weight: 70 kg, pulse: 70, BPsys and BPdia: 145 and 82)/6 men (median age: 51 years, height: 172 cm, weight: 72.5 kg, pulse: 74, BPsys and BPdia: 142 and 80). Wavelet oscillatory pattern estimation is performed on patients’ nocturnal sleep recordings without separating them into sleep stages. Results—Amplitude characteristics of oscillatory activity in patients without motor disorders and the prodromal PD stage are significantly reduced both in terms of changes in the number of patterns and in terms of their duration. This pattern is especially pronounced for high-frequency activity, in frequency ranges close to 40 Hz. Conclusions—The success of the analysis of the electrical activity of the brain, performed over the entire duration of the night recording, makes it promising to further use during daytime monitoring the concept of oscillatory wavelet patterns in patients with non-motor disorders, belonging to the risk group for developing PD. The daytime monitoring system can become the basis for developing screening tests to detect neurodegenerative diseases as part of routine medical examinations. Full article

Background: Headaches are a common symptom in healthcare workers (HCWs), mainly associated with high levels of stress. Different research has studied their incidence during the COVID-19 pandemic, most of them with correlational designs, and at the beginning of the pandemic and focused on the associated occupational variables. Aims: (1) To analyze the incidence of headaches in HCWs at the beginning of the COVID-19 pandemic and their maintenance six months later. (2) To explore the risk factors associated with their onset and maintenance, including sociodemographic, occupational, emotional symptomatology, and personality variables. (3) To propose a model to explain the chronification of stress in burnout, including the moderating role of chronic headaches. Methods: A prospective study (n = 259 HCWs) at three points in time during the COVID-19 pandemic, from the alarm state phase (T1: May–June 2020) to the post-pandemic stage (T3: April–July 2022), including an intermediate measure six months after T1 (T2). Descriptive analyses, Pearson’s chi-square, Student’s t, logistic regressions, and moderated mediation models were conducted using the Process package for SPSS. In addition to headaches, socio-demographic, occupational, emotional symptomatology, and personality variables were included. Results: At T1 the prevalence of headaches was 69.9%. At T2 the prevalence was 73.7%. Of these, 59.5% are T1–T2 sustained headaches. Headaches at T1 were associated with age (p = 0.010) (younger HCWs), professional category (p = 0.049) (nurses), service (p = 0.023) (ICU, COVID hospitalization), non-availability of PPE (p = 0.010), additional COVID-19 symptomatology (p < 0.001), and concern for contagion of family members (p < 0.001) (higher scores). In addition, HCWs with headaches had higher levels of stress (p = 0.001), anxiety (p = 0.001), depression (p = 0.041), and sleep disorders (p < 0.001). A subsequent logistic regression analysis showed that of the above variables, the presence of additional COVID-19 symptoms (p < 0.001) and depression (p = 0.010) were the predictor variables. With regard to the maintenance of headaches (T1–T2), anxiety (p = 0.035), stress (p = 0.001), and cognitive fusion (p = 0.013) were found to be the significant variables. The tested model proposes anxiety (T1) as antecedent, cognitive fusion (T2) as mediator, burnout (T3) as consequent, and chronic headaches (yes/no) as the moderating variable between anxiety and burnout (model 5). The model is significant (F = 19.84, p < 0.001) and contributes to the explanation of 36% of the variance of burnout. The relationships in the model are all statistically significant, and specifically chronic headaches contribute to a 6-fold increase in the likelihood of burnout. Conclusions: The present research differentiates between precipitating and maintenance factors of headaches in HCWs. The former, more studied in previous research, are usually related to sociodemographic and occupational variables and levels of anxiety and stress. Maintenance factors, scarcely explored, are related to the maintenance of emotional symptomatology and the inability to manage intrusive thoughts (i.e., cognitive fusion). Of particular interest is that the presence of chronic headaches itself is capable of producing burnout as a post-COVID syndrome. Full article

Background/Objective: Muscle synergy analysis based on machine learning has significantly advanced our understanding of the mechanisms underlying the central nervous system motor control of gait and has identified abnormal gait synergies in stroke patients through various analytical approaches. However, discrepancies in experimental conditions and computational methods have limited the clinical application of these findings. This review seeks to integrate the results of existing studies on the features of muscle synergies in stroke-related gait abnormalities and provide clinical and research insights into gait rehabilitation. Methods: A systematic search of Web of Science, PubMed, and Scopus was conducted, yielding 10 full-text articles for inclusion. Results: By comprehensively reviewing the consistencies and differences in the study outcomes, we emphasize the need to segment the gait cycle into specific phases (e.g., weight acceptance, push-off, foot clearance, and leg deceleration) during the treatment process of gait rehabilitation and to develop rehabilitation protocols aimed at restoring normal synergy patterns in each gait phase and fractionating reduced synergies. Conclusions: Future research should focus on validating these protocols to improve clinical outcomes and introducing indicators to assess abnormalities in the temporal features of muscle synergies. Full article

Background: Ventriculoperitoneal (VP) shunt therapy is a crucial intervention for normal-pressure hydrocephalus (NPH). This meta-analysis delves into survival time and the impact of baseline symptom burden on survival after VP shunt therapy for NPH, employing reconstructed pooled survival curves and a one-stage meta-analysis. Methods: IPD regarding overall survival (OS) were acquired from published Kaplan–Meier charts, utilizing the R package IPDfromKM in R (Version 4.3.1, the R Foundation for Statistical Computing). Reconstructed Kaplan–Meier charts were then generated from the pooled IPD data. Both one-stage and two-stage meta-analyses were executed, with hazard ratios (HRs) employed as metrics to evaluate effectiveness. Results: From the initial screening of 216 records, five articles encompassing 1614 patients met the eligibility criteria for inclusion. In two of the five included studies, overall survival was stratified by gait score (1–4 vs. ≥4) in 1043 patients, continence score (1–3 vs. ≥4) in 1022 patients, and mRS (0–2 vs. ≥3) in 956 patients. Patients with good gait demonstrated a mean survival of 8.24 years, while those with poor gait had a mean survival of 6.19 years (log-rank test: p < 0.001). The HR for gait was 2.25 (95% CI: 1.81–2.81, p < 0.001). Continence score stratification revealed a significant difference in survival time (log-rank test: p < 0.001), with an HR of 1.66 (95% CI: 1.33–2.06, p < 0.001). Similarly, mRS stratification demonstrated a significant survival difference (log-rank test: p < 0.001), with an HR of 2.21 (95% CI: 1. 74–2.80, p < 0.001). The reconstructed survival curves for all NPH patients treated with VP shunt therapy, pooling data from five studies, revealed a median survival time of 8.82 years (95% CI: 8.23–9.40). Survival rates at 1, 3, 5, 7, 9, 11, and 13 years were 95.7%, 83.8%, 70.5%, 59.5%, 48.7%, 35.8%, and 25.4%, respectively. Comparison with a general control population showed an HR of 1.79 (95% CI: 1.62–1.98, p < 0.001). Conclusions: This comprehensive meta-analysis underscores the influence of baseline symptom burden on survival after VP shunt therapy in NPH. Therapy in the early stages for those without significant comorbidities may enhance survival. Full article

Background: The utility of single-pulse TMS (transcranial magnetic stimulation)-evoked EEG (electroencephalograph) potentials (TEPs) has been extensively studied in the past three decades. TEPs have been shown to provide insights into features of cortical excitability and connectivity, reflecting mechanisms of excitatory/inhibitory balance, in various neurological and psychiatric conditions. In the present study, we sought to review and summarize the most studied neurological and psychiatric clinical indications utilizing single-pulse TEP and describe its promise as an informative novel tool for the evaluation of brain physiology. Methods: A thorough search of PubMed, Embase, and Google Scholar for original research utilizing single-pulse TMS-EEG and the measurement of TEP was conducted. Our review focused on the indications and outcomes most clinically relevant, commonly studied, and well-supported scientifically. Results: We included a total of 55 publications and summarized them by clinical application. We categorized these publications into seven sub-sections: healthy aging, Alzheimer’s disease (AD), disorders of consciousness (DOCs), stroke rehabilitation and recovery, major depressive disorder (MDD), Parkinson’s disease (PD), as well as prediction and monitoring of treatment response. Conclusions: TEP is a useful measurement of mechanisms underlying neuronal networks. It may be utilized in several clinical applications. Its most prominent uses include monitoring of consciousness levels in DOCs, monitoring and prediction of treatment response in MDD, and diagnosis of AD. Additional applications including the monitoring of stroke rehabilitation and recovery, as well as a diagnostic aid for PD, have also shown encouraging results but require further evidence from randomized controlled trials (RCTs). Full article

Background/Objectives: In acute stroke, often-prolonged hospital transport times present an opportunity for early interventions to salvage brain tissue. Remote ischemic conditioning (RIC), where brief cycles of ischemia–reperfusion in a limb are induced to protect the brain, is a promising treatment for this setting. We assessed the usability of a novel RIC system in a simulated emergency response scenario. Methods: Paramedics were asked to use the RIC device in an emergency stroke care and ambulance transport simulation, overseen by a confederate. Feedback on device use was collected through questionnaires, including the System Usability Scale (SUS) and the NASA Task Load Index (NASA-TLX), and a semi-structured interview. Questionnaire responses were summarized using descriptive statistics; interview transcripts were analyzed thematically. Results: Nine paramedics (including the confederate) participated, with a mean of 10.0 ± 10.3 years of professional experience. Questionnaire responses indicated high device usability (mean SUS score: 85.3 ± 12.9 out of 100) and low task-related demands, effort, and frustration (mean NASA-TLX domain scores: ≤3.9 out of 20). Seven paramedics stated they would use the device in daily practice. They expressed concerns related to display screen clarity, interference with standard procedures, cable management, device fragility, and patient discomfort. Suggested improvements included adding indicators of device performance and refining the cuff design. Conclusions: While the device was considered easy to use, paramedics also identified important areas of improvement. With a small, localized study sample, our findings are primarily applicable to the refinement of the RICovery system for use in future clinical trials in the same healthcare setting. However, feedback on the importance of mitigating potential interference of newly introduced procedures with those already established, robustness of equipment, and effective paramedic–patient communication may also help inform the design of other pre-hospital interventions. Full article

Background: Multiple sclerosis (MS) is an immune-mediated inflammatory disease that primarily targets the myelin of axons. Extremities are frequently affected, resulting in a negative impact on both activities of daily living (ADL) and quality of life. In recent years, there has been increasing interest in the potential benefits of exercise and blood flow restriction training (BFRT) programs as a therapeutic tool in people with neurological disorders. The aim of the present systematic review was to know the clinical effects of BFRT programs in people with MS. Methods: A systematically comprehensive literature search was conducted and registered in PROSPERO prior to its execution under the reference number CRD42024588963. The following data sources were used: Pubmed, Scopus, Web of Science (WOS) and the Cochrane Library. The following data were extracted from the papers: study design, sample, interventions, dosage, outcome measures and results. To assess the methodological quality of the papers included, the Quality Index of Downs and Black was used. Additionally, the articles were classified according to the levels of evidence and grades of recommendation for diagnosis studies established by the Oxford Center for Evidence-Based Medicine. Also, the Cochrane Handbook for Systematic Reviews of Interventions was used by two independent reviewers to assess risk of bias, assessing the six different domains. Results: Seven articles with a total of 71 participants were included in the review. Of the seven articles, five papers studied the effectiveness of BFRT combined with strengthening exercises and two papers studied the effect of BFRT combined with aerobic exercise. Of the five articles that analyzed BFRT combined with strengthening exercises, only two presented a control group. Both performed a low-load resistance training in combination with BFRT with four series, 30/15/15/15 repetitions and a rest of 1 min between the series and 3 min between the exercises. The control groups to which they were compared performed a high intensity strengthening exercise protocol which had the same exercises, sets, rests and duration of the protocol as the experimental groups. For those two papers which investigated the effects of BFRT combined with aerobic training, exercise was performed in two sessions per week for a period of 8 and 6 weeks, respectively. In both studies, the experimental protocol began with a warm-up phase and ended with a cool-down phase, and there were differences in cuff management. All these investigations found positive effects in the interventions that combined exercise with BFRT. The characteristics, outcome measures, effects of the interventions and the assessment of the methodological quality of the included studies and risk of bias are shown in the tables. Conclusions: BFRT in people with MS appears to be effective and safe for people with MS. BFRT might show positive clinical effects on strength, hypertrophy and balance outcomes. Nevertheless, future research should be conducted with better methodological quality to ensure the potential benefits of BFRT in people with MS since the studies analyzed present a high risk of bias and methodological limitations. Full article

Background/Objectives: Glioblastomas (GBMs) are dreadful brain tumors with abysmal survival outcomes. GBM extracellular vesicles (EVs) dramatically affect normal brain cells (largely astrocytes) constituting the tumor microenvironment (TME). We asked if EVs from different GBM patient-derived spheroid lines would differentially alter recipient brain cell phenotypes. This turned out to be the case, with the net outcome of treatment with GBM EVs nonetheless converging on increased tumorigenicity. Methods: GBM spheroids and brain slices were derived from neurosurgical patient tissues following informed consent. Astrocytes were commercially obtained. EVs were isolated from conditioned culture media by ultrafiltration, concentration, and ultracentrifugation. EVs were characterized by nanoparticle tracking analysis, electron microscopy, biochemical markers, and proteomics. Astrocytes/brain tissues were treated with GBM EVs before downstream analyses. Results: EVs from different GBMs induced brain cells to alter secretomes with pro-inflammatory or TME-modifying (proteolytic) effects. Astrocyte responses ranged from anti-viral gene/protein expression and cytokine release to altered extracellular signal-regulated protein kinase (ERK1/2) signaling pathways, and conditioned media from EV-treated cells increased GBM cell proliferation. Conclusions: Astrocytes/brain slices treated with different GBM EVs underwent non-identical changes in various omics readouts and other assays, indicating “personalized” tumor-specific GBM EV effects on the TME. This raises concern regarding reliance on “model” systems as a sole basis for translational direction. Nonetheless, net downstream impacts from differential cellular and TME effects still led to increased tumorigenic capacities for the different GBMs. Full article

Introduction: Painful legs and moving toes (PLMT) syndrome is a rare movement disorder characterized by defuse lower limb neuropathic pain and spontaneous abnormal, involuntary toe movements. Objective: The objective was to present a rare case of PLMT syndrome with a triggering area in an adult patient due to multilevel discogenic pathology, to make a thorough review of this disorder and to provide a practical approach to its management. Case presentation: A 59-years-old male was admitted to the neurology ward with symptoms of defuse pain in the lower-back and the right leg accompanied by involuntary movements for the right toes intensified by tactile stimulation in the right upper thigh. Magnetic resonance imaging (MRI) revealed a multilevel discogenic pathology of the lumbar and cervical spine, with myelopathy at C5-C7 level. A medication with Pregabalin 300 mg/daily significantly improved both the abnormal toe movements and the leg pain. The clinical effect was constant during the 90-day follow-up without any adverse effects. Conclusion: Painful legs and moving toes (PLMT) is a condition that greatly affects the quality of life of patients, but which still remains less known by clinicians. Spontaneous resolution is rare, and oral medications are the first-line treatment. Pregabalin is a safe and effective treatment option for PLMT that should be considered early for the management of this condition. Other medication interventions, such as botulinum toxin injections, spinal blockade, or non-pharmacological treatment options like spinal cord stimulation, and surgical decompressions, are also recommended when the conservative treatment is ineffective in well-selected patients. Full article

Background: Respiratory complications in patients with amyotrophic lateral sclerosis (ALS), due to the involvement of respiratory muscles, are the leading cause of death, and respiratory physiotherapy (RP) focuses on addressing these complications. Objectives: The objective was to evaluate the effectiveness of an RP intervention that combines the four specific techniques (inspiratory muscle training, lung volume recruitment, manually assisted coughing, and diaphragmatic breathing training) in patients with ALS. Methods: A quasi-experimental study was carried out, and a specific RP programme was implemented in 15 patients with ALS (12 sessions, 30 min/session, one session/week, duration of three months), based on directed ventilation techniques, lung volume recruitment, manually assisted coughing, and the use of incentive spirometry and a cough assist device, along with a daily home exercise programme. Respiratory functions were assessed (pre- and post-intervention, with follow-up at three months) using Forced Vital Capacity (FVC) and Peak Expiratory Cough Flow (PECF); functionality was assessed using the Revised ALS Functional Rating Scale (ALSFRS-R) and the Modified Barthel Index by Granger. Results: FVC experienced an increase after three months of the intervention initiation (p = 0.30), which was not sustained at the three-month follow-up after the intervention ended. All other variables remained practically constant after treatment, with their values decreasing at follow-up. Conclusion: A specific RP intervention could have beneficial effects on respiratory functions, potentially preventing pulmonary infections and hospitalisations in patients with ALS. It may improve FVC and help stabilize the patient's functional decline. Considering the progressive and degenerative nature of the disease, this finding could support the usefulness of these techniques in maintaining respiratory function. Full article