Apolipoprotein E Gene in α-Synucleinopathies: A Narrative Review.

In this narrative review, we delved into the intricate interplay between Apolipoprotein E (APOE) alleles (typically associated with Alzheimer's disease-AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). First, in-vitro, animal, and human-based data on the exacerbating effect of APOE4 on LB pathology were summarized. We found robust evidence that APOE4 carriage constitutes a risk factor for PDD-APOE2, and APOE3 may not alter the risk of developing PDD. We confirmed that APOE4 copies confer an increased hazard towards DLB, as well. Again APOE2 and APOE3 appear unrelated to the risk of conversion. Of note, in individuals with DLB APOE4, carriage appears to be intermediately prevalent between AD and PDD-PD (AD > DLB > PDD > PD). Less consistency existed when it came to PD; APOE-PD associations tended to be markedly modified by ethnicity. Finally, we failed to establish an association between the APOE gene and MSA. Phenotypic associations (age of disease onset, survival, cognitive-neuropsychiatric- motor-, and sleep-related manifestations) between APOE alleles, and each of the aforementioned conditions were also outlined. Finally, a synopsis of literature gaps was provided followed by suggestions for future research.

Rituximab as a sole steroid-sparing agent in generalized myasthenia gravis: Long-term outcomes.

BACKGROUND: Rituximab, a B-cell depleting monoclonal antibody, represents an option for the treatment of refractory myasthenia gravis (MG). Its use is more established in muscle-specific tyrosine kinase positive (MuSK +) patients, while its role in managing acetylcholine receptor positive (AChR +), or double seronegative (DSN) patients, remains less clear. This study evaluates the long-term effectiveness and safety of rituximab in MG of various serotypes. METHODS: We conducted an open-label study of MG patients receiving rituximab. Adults with generalized refractory MG, either anti-AChR + or DSN, and anti-MuSK + , refractory or not, who had follow-up > 12 months were selected. Change in quantitative myasthenia gravis (QMG) score at last follow-up, compared with baseline was a primary outcome, as well as factors affecting response to treatment. Secondary outcomes included, long-term safety, the steroid-sparing effect and relapse rates post-rituximab. RESULTS: Thirty patients (16 anti-AChR + , 6 anti-MuSK + , 8 DSN) followed for a mean of 33.3 months were included. Mean scores pre-rituximab compared to last follow-up significantly decreased (p < 0.001), from 11 ± 4.1 to 4.3 ± 3.8, and from 1.9 to 0.3 regarding QMG and relapse rate per patient/year, respectively, while in 93.1% a daily steroid dose ≤ 10 mg was achieved. Antibody status was the only factor independently influencing several endpoints. Throughout the study period no crises or deaths occurred. CONCLUSION: The present study supports that rituximab is an effective and well tolerated treatment for refractory anti-AChR + and DSN MG patients, while anti-MuSK + remains the group experiencing the greater benefits.

Cognitive function in amyotrophic lateral sclerosis: a cross-sectional and prospective pragmatic clinical study with review of the literature.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) can present with either bulbar or spinal symptoms, and in some cases, both types of symptoms may be present. In addition, cognitive impairment has been observed in ALS. The study aimed to evaluate the frontal and general cognitive performance in ALS not only cross-sectionally but also longitudinally. METHODS AND MATERIALS: The Frontal Assessment Battery (FAB) and the Montreal Cognitive Assessment (MoCA) were employed to assess cognitive function in 52 adults with ALS and 52 cognitively healthy individuals. The statistical analyses encompassed the Pearson Chi square test, the Skillings-Mack test, the Spearman's rank correlation coefficient, and the Proportional Odds Logistic Regression Model (POLR). RESULTS: Cross-sectionally, lower cognitive performance was associated with ALS diagnosis, older age, and motor functional decline. The cognitive impairment of individuals with bulbar and spinal-bulbar symptoms showed faster deterioration compared to those with spinal symptoms. The spinal subgroup consistently performed worst in delayed recall and attention, while the spinal-bulbar and bulbar subgroups exhibited inferior scores in delayed recall, attention, visuospatial skills, orientation, and verbal fluency. CONCLUSION: The incorporation of cognitive screening in the diagnostic workup of ALS may be beneficial, as early detection can enhance symptom management and improve the quality of life for both individuals with ALS and their care partners.

The utility of diaphragm ultrasound thickening indices for assessing respiratory decompensation in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) leads to diaphragmatic weakness at some point during its course, which is a major cause of respiratory insufficiency. The aim of this study was to evaluate ultrasound-based measures for assessing the diaphragmatic competency and the need for ventilatory support. METHODS: Twenty-six subjects with ALS and 12 healthy controls were enrolled. All participants underwent B-mode diaphragm ultrasound (DUS). Diaphragm thickness and thickening indices were recorded. In the subjects with ALS, further assessments included functional scales and spirometry. We investigated the diagnostic accuracy of DUS thickening indices in predicting diaphragmatic dysfunction and the correlation between clinical, spirometric, and DUS data. RESULTS: Significant relationships were found between forced vital capacity and all diaphragmatic thickening indices. Similarly, all diaphragmatic thickening indices correlated with both Milano Torino staging and disease progression rate. Only thickening fraction (TFdi) correlated with score on the revised ALS Functional Rating Scale (r = 0.459, P = .024). TFdi had better accuracy in predicting diaphragmatic dysfunction (area under the curve [AUC] = 0.839, 95% confidence interval [CI] 0.643 to 0.953) and the need for initiation of noninvasive ventilation (NIV) (AUC = 0.989, 95% CI 0.847 to 1.000) compared with the other indices. A TFdi cut-off point of 0.50 was a sensitive threshold to consider NIV. DISCUSSION: DUS successfully identifies diaphragmatic dysfunction in ALS, being a valuable accessory modality for investigating respiratory symptoms. TFdi was found to be the most useful DUS index, which encourages further investigation.

Mutational screening of Greek patients with axonal Charcot-Marie-Tooth disease using targeted next-generation sequencing: Clinical and molecular spectrum delineation.

BACKGROUND AND AIMS: Axonal forms of Charcot-Marie-Tooth disease (CMT) are classified as CMT2, distal hereditary motor neuropathy (dHMN) or hereditary sensory neuropathy (HSN) and can be caused by mutations in over 100 genes. We presently aimed to investigate for the first time the genetic landscape of axonal CMT in the Greek population. METHODS: Sixty index patients with CMT2, dHMN or HSN were screened by a combination of Sanger sequencing (GJB1) and next-generation sequencing custom-made gene panel covering 24 commonly mutated genes in axonal CMT. RESULTS: Overall, 20 variants classified as pathogenic or likely pathogenic were identified in heterozygous state in 20 index cases, representing 33.3% of the cohort. Of these, 14 were known pathogenic/likely pathogenic and six were designated as such according to ACMG classification, after in silico evaluation, testing for familial segregation and further literature review. The most frequently involved genes were GJB1 (11.7%), MPZ (5%) and MFN2 (5%), followed by DNM2 (3.3%) and LRSAM1 (3.3%). Single cases were identified with mutations in BSCL2, HSPB1 and GDAP1. INTERPRETATION: A wide phenotypic variability in terms of severity and age of onset was noted. Given the limited number of genes tested, the diagnostic yield of the present panel compares favourably with studies in other European populations. Our study delineates the genetic and phenotypic variability of inherited axonal neuropathies in the Greek population and contributes to the pathogenicity characterization of further variants linked to axonal neuropathies.

Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease.

Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity via interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Myasthenia Gravis and Abdominal Aortic Aneurysm: A Rare Combination.

Abdominal aortic aneurysm in a patient with myasthenia gravis (MG) is extremely rare. We present a 64-year-old male with MG and an asymptomatic abdominal aortic aneurysm treated endovascularly. After extubation, he suffered a cardiac arrest due to an acute myocardial infarction. Cardiopulmonary resuscitation and a primary coronary angioplasty led to a satisfactory outcome. Special care is needed due to higher rates of postoperative complications in these patients.

The evolution of comprehensive genetic analysis in neurology: Implications for precision medicine.

Technological advancements have facilitated the availability of reliable and thorough genetic analysis in many medical fields, including neurology. In this review, we focus on the importance of selecting the appropriate genetic test to aid in the accurate identification of disease utilizing currently employed technologies for analyzing monogenic neurological disorders. Moreover, the applicability of comprehensive analysis via NGS for various genetically heterogeneous neurological disorders is reviewed, revealing its efficiency in clarifying a frequently cloudy diagnostic picture and delivering a conclusive and solid diagnosis that is essential for the proper management of the patient. The feasibility and effectiveness of medical genetics in neurology require interdisciplinary cooperation among several medical specialties and geneticists, to select and perform the most relevant test according to each patient's medical history, using the most appropriate technological tools. The prerequisites for a comprehensive genetic analysis are discussed, highlighting the utility of appropriate gene selection, variant annotation, and classification. Moreover, genetic counseling and interdisciplinary collaboration could improve diagnostic yield further. Additionally, a sub-analysis is conducted on the 1,502,769 variation records with submitted interpretations in the Clinical Variation (ClinVar) database, with a focus on neurology-related genes, to clarify the value of suitable variant categorization. Finally, we review the current applications of genetic analysis in the diagnosis and personalized management of neurological patients and the advances in the research and scientific knowledge of hereditary neurological disorders that are evolving the utility of genetic analysis towards the individualization of the treatment strategy.

Image analysis can reliably quantify median nerve echogenicity and texture changes in patients with carpal tunnel syndrome.

OBJECTIVE: To study the ability of image analysis measures to quantify echotexture changes of median nerve in order to provide a complementary diagnostic tool in CTS. METHODS: Image analysis measures (gray level co-occurrence matrix (GLCM), brightness, hypoechoic area percentage using max entropy and mean threshold) were calculated in normalized images of 39 (19 younger and 20 older than 65y) healthy controls and 95 CTS patients (37 younger and 58 older than 65y). RESULTS: Image analysis measures were equivalent or superior (older patients) to subjective visual analysis. In younger patients, GLCM measures showed equivalent diagnostic accuracy with cross sectional area (CSA) (Area Under Curve (AUC for inverse different moment = 0.97). In older patients all image analysis measures showed similar diagnostic accuracy to CSA (AUC for brightness = 0.88). Moreover, they had abnormal values in many older patients with normal CSA values. CONCLUSIONS: Image analysis reliably quantifies median nerve echotexture alterations in CTS and offers similar diagnostic accuracy to CSA measurement. SIGNIFICANCE: Image analysis may offer added value to existing measures in the evaluation of CTS, especially in older patients. Its clinical implementation would require incorporation of mathematically simple software code for online nerve image analysis in ultrasound machines.

Non-pharmacological Interventions on Pain and Quality of Life in Chemotherapy Induced Polyneuropathy: Systematic Review and Meta-Analysis.

BACKGROUND/AIM: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment, resulting in pain, numbness, instability, and thus affecting quality of life (QoL), occasionally leading to discontinuation of chemotherapy. Pharmacological treatments are not sufficient. Non-pharmacological interventions (NPIs) have also been tried. This study aimed to systematically review the efficacy of NPIs on pain and QoL in patients suffering from CIPN. MATERIALS AND METHODS: The databases searched were Pubmed, Cohrane, and Scopus for randomized controlled trials (RCTs) published in the last 5 years (2017-2022). Studies were considered eligible, if they assessed adult patients suffering from CIPN because of any chemotherapeutic drug for any type and any stage of cancer and if study protocols included non-pharmacological intervention with a structured protocol. RESULTS: A total of 1,496 records were identified. Finally, 10 RCTs including 495 patients (253 in the intervention group and 242 in the control group) were included for meta-analysis. Intervention protocols included acupuncture (n=6), exercise (n=3), and yoga (n=1). NPIs significantly reduced neuropathic pain. However, the effect on QoL was not significant. CONCLUSION: NPIs are beneficial in the treatment of pain in patients with CIPN but their impact on QoL is not statistically supported. Larger sample sizes, more homogenous in outcome measures and interventions are needed to further explore NPIs' efficacy on CIPN symptoms.

Identical late motor responses in early Guillain-Barré syndrome: A-waves and repeater F-waves.

Electrodiagnostic (EDx) studies play a key role in the investigation of suspected Guillain-Barré syndrome (GBS), providing diagnostic and prognostic information. However, initial EDx findings may not fulfill the neurophysiological criteria for the disease. The aim of this study was to estimate the occurrence and characteristics of A-waves and repeaters F-waves (Freps), both late motor responses identical in latency and configuration, in early stages of GBS. We retrospectively analyzed the initial nerve conduction study (NCS) of 26 GBS patients performed within 10 days from symptom onset. The final subtype diagnosis was acute inflammatory demyelinating polyneuropathy (AIDP) in 16 patients (six met the criteria at the initial EDx study and 10 at follow-up) and acute motor axonal neuropathy (AMAN) in 10 patients (six initially). Identical late responses were commonly found in the majority of nerves (84%). A-waves were present in 59% and an increased frequency of Freps was calculated in 61% of the 105 studied nerves. A-waves morphology (single or complex) could not distinguish between AIDP and AMAN. Nerves with normal NCS had a significantly higher frequency of A-waves, either isolated or in combination with increased index total Freps, as compared to nerves with low compound muscle action potential (CMAP) amplitudes or conduction block. Our findings suggest that both late responses can be useful as early markers of conduction changes of various pathophysiology, being frequently present even prior to abnormalities of CMAP parameters.

Can Gait Features Help in Differentiating Parkinson's Disease Medication States and Severity Levels? A Machine Learning Approach.

Parkinson's disease (PD) is one of the most prevalent neurological diseases, described by complex clinical phenotypes. The manifestations of PD include both motor and non-motor symptoms. We constituted an experimental protocol for the assessment of PD motor signs of lower extremities. Using a pair of sensor insoles, data were recorded from PD patients, Elderly and Adult groups. Assessment of PD patients has been performed by neurologists specialized in movement disorders using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-Part III: Motor Examination, on both ON and OFF medication states. Using as a reference point the quantified metrics of MDS-UPDRS-Part III, severity levels were explored by classifying normal, mild, moderate, and severe levels of PD. Elaborating the recorded gait data, 18 temporal and spatial characteristics have been extracted. Subsequently, feature selection techniques were applied to reveal the dominant features to be used for four classification tasks. Specifically, for identifying relations between the spatial and temporal gait features on: PD and non-PD groups; PD, Elderly and Adults groups; PD and ON/OFF medication states; MDS-UPDRS: Part III and PD severity levels. AdaBoost, Extra Trees, and Random Forest classifiers, were trained and tested. Results showed a recognition accuracy of 88%, 73% and 81% for, the PD and non-PD groups, PD-related medication states, and PD severity levels relevant to MDS-UPDRS: Part III ratings, respectively.

A Greek National Cross-Sectional Study on Myotonic Dystrophies.

Myotonic Dystrophies (DM, Dystrophia Myotonia) are autosomal dominant inherited myopathies with a high prevalence across different ethnic regions. Despite some differences, mainly due to the pattern of muscle involvement and the age of onset, both forms, DM1 and DM2, share many clinical and genetic similarities. In this study, we retrospectively analyzed the medical record files of 561 Greek patients, 434 with DM1 and 127 with DM2 diagnosed in two large academic centers between 1994-2020. The mean age at onset of symptoms was 26.2 ± 15.3 years in DM1 versus 44.4 ± 17.0 years in DM2 patients, while the delay of diagnosis was 10 and 7 years for DM1 and DM2 patients, respectively. Muscle weakness was the first symptom in both types, while myotonia was more frequent in DM1 patients. Multisystemic involvement was detected in the great majority of patients, with cataracts being one of the most common extramuscular manifestations, even in the early stages of disease expression. In conclusion, the present work, despite some limitations arising from the retrospective collection of data, is the first record of a large number of Greek patients with myotonic dystrophy and emphasizes the need for specialized neuromuscular centers that can provide genetic counseling and a multidisciplinary approach.

Testing of Motor Coordination in Degenerative Neurological Diseases.

Parkinson's disease (PD) is a progressive movement disorder caused by the death of dopamine-producing cells in the midbrain. PD is the most prevalent movement disorder of the central nervous system and affects more than 6.3 million people in the world. The changes in the motor functions of patients are not easy to be clearly and on-time observed by the clinicians and to make the most well-informed decisions for the treatment. The aim of this paper is the monitoring PD by designing, developing, and evaluating a prototype mobile App using a pressure pen, which collects quantitative and objective information about PD patients, thus allowing clinicians to understand better and make assumptions about the severity and the stage of Parkinson's disease. This study presents a dynamic spiral test that can only be performed with tablet and pen pressure. Furthermore, the handwriting samples by PD patients and healthy controls individuals are collected by a computerized system, and the measurements of Spiral Deviation, Total Time, and Pen Pressure are processed. The results showed an accurate evaluation of the stage of Parkinson's disease. Thus, the clinician may use the proposed PD telemonitoring system as a screening test, storing the history of all the patient's measurements.

Quantitative muscle ultrasound assessment using automatic thresholding methods in amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the usefulness of automatic thresholding methods for quantitative assessments of muscle echogenicity in amyotrophic lateral sclerosis (ALS) patients. METHODS: Thirty-one ALS patients and 31 matched healthy controls underwent ultrasound examination of the biceps brachii, rectus femoris and tibialis anterior muscles. Muscle echogenicity was evaluated using grayscale analysis and the 16 automatic thresholding methods of ImageJ program. The diagnostic value and correlations between ultrasound parameters and muscle strength were investigated. RESULTS: Mean grayscale values (GSV) and mean hyperechoic fractions of 8 out of the 16 automatic thresholding methods were significantly different between patients and controls in all 3 muscles (p < 0.05 for all). Four thresholding methods (Default, Li, Moments, Otsu) showed a significant correlation between hyperechoic fractions and muscle strength, and diagnostic accuracy comparable or superior to GSVs. Otsu method was the only technique that detected ultrasound changes in normal strength muscles of ALS patients. CONCLUSIONS: Our findings support the utility of automatic thresholding methods in muscle echogenicity studies as a supplementary ultrasound image analysis in ALS. SIGNIFICANCE: In an era of advances in developing neurophysiological diagnostic tools and biomarkers in ALS, muscle ultrasonography and echogenicity analysis using automatic thresholding methods could be effectively implemented in clinical research.

Effect of beam attenuation on muscle ultrasound echogenicity measurement in muscular dystrophies.

PURPOSE: In advanced muscular dystrophies (AMD), quantification of muscle echo-intensity (EI) may be influenced by ultrasound beam attenuation, due to fibrosis and fatty infiltration of muscle tissue. Objective of the study was to compare EI measurements using grayscale analysis between a superficial and whole-muscle region of interest (ROI) in subjects with advanced and mild-to-moderate muscular dystrophy (MMD). METHODS: Thirty-two adult subjects diagnosed with a muscular dystrophy and twenty-five matched healthy controls underwent ultrasound assessment of the biceps brachii (BB), rectus femoris (RF) and tibialis anterior (TA) muscles. Based on Heckmatt grading scale of muscles, two disease groups, an AMD (Heckmatt grades 3 or 4) and a MMD (Heckmatt grade 2), were analyzed. Superficial ROI was set as one-fourth of the whole-muscle area, located immediately below the superficial fascia and always inside muscle boundaries. RESULTS: Muscle EI was significantly higher in the superficial compared to whole-muscle ROI, in all evaluated muscle groups of AMD subjects (BB, p = 0.004/RF, p = 0.027/TA, p = 0.002). EI values in superficial ROIs, for individual muscle analysis using z-scores, were more representative in assessments of muscle abnormality in advanced stages of the disease course (Heckmatt grades 3 and 4). In MMD and healthy muscles, no statistical difference was found in EI measurements between the two ROI types. CONCLUSIONS: In AMD, selection of superficial ROI is better representative of changes in muscle texture, although caution should be exercised when comparing ROIs of different sizes.