Non-Pharmacological Interventions on Pain in Amyotrophic Lateral Sclerosis Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Some ALS patients exhibit concomitant nonmotor signs; thus, ALS is considered a multisystemic disorder. Pain is an important nonmotor symptom. Observational and case-control studies report high frequency of pain in ALS patients and it has been correlated with depression and quality of life. There are no specific scales for the assessment of pain and no randomized controlled trials (RCTs) regarding the drug management of pain in ALS. AIM: To systematically review the evidence for the nonpharmacological interventions (NPIs) in relieving pain in ALS, on March 2024, we searched the following databases: Pubmed, Scopus, Web of Science, and Cochrane. We also checked the bibliographies of trials identified to include further published or unpublished trials. MAIN RESULTS: A total of 1003 records were identified. Finally, five RCTs including 131 patients (64 in the intervention group and 67 in the control group) were included for meta-analysis. The interventions of the included RCTs consisted of muscle exercise, combined aerobics-strength intervention, and osteopathic manual treatment. The meta-analysis did not find a statistically significant difference in favor of NPIs for alleviating pain in ALS patients. CONCLUSIONS: ALS has a fulminant course and irreversibly leads to death. Pain in ALS patients, although a common nonmotor symptom, is often unrecognized and undertreated, and this is underlined by the lack of any RCTs on drug therapy for pain. Albeit NPIs are considered safe, as adverse effects are rarely reported, this systematic review did not provide sufficient evidence for a beneficial effect on pain. The scarceness of relevant literature highlights the need for future studies, with larger samples, more homogeneous in terms of interventions and population characteristics (stage of disease), and better choice of measurement scales to further investigate the efficacy, if any, of various pain interventions in ALS patients.

Interactions between fatigue and urinary quality of life in patients with Multiple Sclerosis.

INTRODUCTION: Neurogenic bladder as well as fatigue related symptoms are common in patients with Multiple Sclerosis (MS) and have a significant impact on the patients' Quality of Life (QoL). The aim of this study is to investigate the relationship between fatigue related symptomatology (FRS) and Urinary Quality of Life (UQoL). METHODS: A total of 120 consecutive MS patients were recruited from the Outpatient Clinic of Demyelinating Diseases (Second Dept. of Neurology, Attikon University Hospital Greece). Participants were then asked to complete the Modified Fatigue Impact Scale (MFIS) and the Short Form Qualiveen questionnaire. Demographic and bladder function related characteristics (incontinence, urinary frequency, use of intermittent catheterization) were collected. RESULTS: The physical and cognitive dimensions of MFIS had a moderate to high correlation with SF Qualiveen (r = 0.403, p <.000), (r = 0.329, p <.000).Multiple linear regression produced a fitted model (R2 = 0.150, F(3,111) = 5.554, p =.001) in IC use (ß = 1.086, p =.036) and the physical dimension of MFIS (ß = 0.66, p =.046) significantly predicted the SF Qualiveen score. CONCLUSION: UQoL had a moderate correlation with both physical and cognitive dimensions of fatigue. Patients with MS who experience lower levels of physical fatigue and/or manage their neurogenic bladder symptomatology (mainly with the use of intermittent catheterization) appear to have higher levels of UQoL. Due to the versatile and subjective nature of both fatigue related and neurogenic bladder symptoms, more focused studies utilizing objective evaluation tools (e.g urodynamic urine bladder study) are necessary.

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.

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.

Autonomic dysfunction in amyotrophic lateral sclerosis: A neurophysiological and neurosonology study.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Some ALS patients exhibit concomitant nonmotor signs, and thus ALS is considered a multisystem disorder. The aim of this study is to investigate autonomous nervous system involvement in ALS. METHODS: We investigated 21 ALS patients and 28 age-matched controls. ALS patients were assessed for disease severity with the Revised-ALS Functional Rating Scale (ALSFSR) and for the presence of autonomic symptoms with the Composite Autonomic Symptom Score scale. Sympathetic nervous system was evaluated by sympathetic skin response (SSR) and parasympathetic nervous system by ultrasonography of vagus nerve (VN) at the level of the thyroid gland. RESULTS: SSR latencies were shorter and SSR amplitudes were higher in controls compared to ALS patients. The cross-sectional area (CSA) of the VN was significantly smaller in ALS patients (mean CSA right/left: 1.73±0.62 mm2 /1.47±0.53 mm2 ) compared to controls (mean CSA right/left: 2.91±0.79 mm2 /2.30±0.80 mm2 ), right: p <. 001, left: p <. 001. There was a significant negative correlation between disease duration and CSA of left-VN (r = -0.493, p = .023). This correlation was attenuated between disease duration and CSA of right-VN (r = -0.419, p = .059). ALSFSR-R was positively correlated to CSA of right-VN (p = .006, r = 0.590). CSA of VN did not correlate with bulbar involvement. CONCLUSIONS: This study confirms the presence of autonomic dysfunction in ALS patients and provides evidence of VN atrophy that correlates with disease severity and duration and is independent of bulbar involvement. Degeneration of dorsal nucleus neurons of the VN is hypothesized.

Optic disc drusen mimicking Idiopathic Intracranial Hypertension (IIH): rely on ultrasound.

Optic nerve ultrasound is an established routine supplementary diagnostic tool for idiopathic intracranial pressure but it can also be helpful in avoiding misdiagnoses. We describe a case of an obese 15- year-old girl with persistent headaches, fundoscopic findings suggesting papilledema, normal brain imaging who underwent two lumbar punctures with unremarkable cerebrospinal fluid findings before ultrasound revealed optic disc drusen as the cause of the optic disc elevation.

Covalent Bonding of Chlorogenic Acid Induces Structural Modifications on Sunflower Proteins.

Proteins and phenols coexist in the confined space of plant cells leading to reactions between them, which result in new covalently bonded complex molecules. This kind of reactions has been widely observed during storage and processing of plant materials. However, the nature of the new complex molecules and their physicochemical properties are largely unknown. Therefore, we investigated the structural characteristics of covalently bonded complexes between sunflower protein isolate (SFPI, protein content 85 wt %) and the dominant phenol in the confined space of a sunflower seed cell (chlorogenic acid, CGA). It was shown that the efficiency of bond formation goes through a maximum as a function of the SFPI:CGA ratio. Moreover, the bonding of CGA with proteins resulted in changes in the secondary and tertiary structure of the protein. It was also shown that the phenol bound strongly to the protein, which resulted in new crosslinks between the polypeptide chains. As a result, secondary structures like α-helices and ß-sheets diminished, which in turn resulted in more disordered domains and a subsequent modification of the tertiary structure of the proteins. These findings are relevant for establishing future protocols for extraction of high-quality proteins and phenols when utilizing plant material and offer insight into the impact of processing that these ingredients endure.

Trigeminal herpes zoster complicated by Ramsay Hunt syndrome.

We report the case of a 55-year-old woman with herpes zoster of the mandibular branch of the left trigeminal nerve, which was complicated within 4 days by ipsilateral Ramsay Hunt syndrome. Recently, a case of trigeminal herpes zoster and Ramsay Hunt syndrome was described, in which the MRI and CSF findings along with the clinical course urged the authors to suggest the possibility of transaxonal spread of the virus. In our case, the findings and particularly the temporal relation between the 2 conditions render more plausible other pathophysiological mechanisms, such as the spread of the virus through the CSF.

Modified maximal thymectomy for myasthenia gravis: effect of maximal resection on late neurologic outcome and predictors of disease remission.

BACKGROUND: Although thymectomy is a standard practice of care in patients with myasthenia gravis, the best approach to thymic resection remains controversial. This study was conducted to assess the effect of maximal resection on neurologic outcome and identify predictors of disease remission. METHODS: Data of 78 myasthenic patients who underwent modified maximal thymectomy during a 17-year period were retrospectively analyzed. The primary study end point was the achievement of complete remission. Separate analysis was performed for thymoma and nonthymoma patients regarding the factors predicting the neurologic outcome. RESULTS: No patients died perioperatively. Surgical morbidity was 7.7%. The rate of postoperative myasthenic crisis was 3.8%. Thymoma and nonthymoma patients experienced comparable complete stable remission prediction (74.5% vs 85.7% at 15 years; p = 0.632). The absence of steroids in the preoperative medical treatment was statistically related to the prediction for complete stable remission in both thymoma (95% confidence interval [CI], 2.687 to 339.182, p = 0.006) and nonthymoma patients (95% CI, 1.607 to 19.183; p = 0.007) in multivariate analysis. In thymomatous myasthenia gravis, there was a statistically significant association between disease remission and the World Health Organization (WHO) histologic classification (95% CI, 0.262 to 0.827; p = 0.009). CONCLUSIONS: Maximal resections are recommended in myasthenic patients. Disease severity represents the prime determinant of the neurologic outcome after thymectomy. The neurologic outcome in patients after thymectomy may be statistically associated with the WHO classification subtypes but not necessarily with the aggressiveness of these tumors.

The role of postoperative radiotherapy in the management of patients with thymic tumors -- a retrospective study.

BACKGROUND: Thymomas are the most common tumor arising in the anterior mediastinum. Surgery is the cornerstone for the management of these tumors. The role of postoperative radiotherapy in Masaoka stage II thymomas remains controversial, but it is well established in the advanced stages. The aim of this study was to investigate the role of postoperative radiotherapy in the overall management of thymomas, and the evaluation of potential prognostic factors. PATIENTS AND METHODS: Between 1989 and 2007, 41 thymoma patients underwent surgery and 27 of them received radiotherapy with a curative intent. The Masaoka staging system was used. The histopathological records and specimens of patients were thoroughly reviewed. Clinical and radiological evaluations took place every 6 months. The mean patient follow-up was 69 months (range: 2-212). RESULTS: DFS (disease free survival), TS (total survival) and DSS (disease specific survival) differed significantly between stages and histological types (p<0.04). Stage I patients were managed only surgically, with none recurring or dying. Concerning stage II patients, TS was significantly longer in non-irradiated cases (10/21) (p=0.025). Stage III (n=8) and IV (n=8) patients underwent postoperative radiotherapy, with 4/8 of stage IV disease also receiving induction chemotherapy. Six out of 8 stage III-IV patients recurred (1 distant and 5 intrathoracic failure), out of whom 4 died due to disease progression despite further treatment (all type C histology). The mean DFS and TS for stage III patients were 49.2 and 50.3 months respectively, with the corresponding values for stage IV being 14.5 and 29.1 months. Patients with myasthenia had a favorable outcome and the ones with complete resection a significantly longer DFS (p=0.0003) and DSS (p=0.039). The Cox regression analysis showed that myasthenia and tumor size are important prognostic factors for DFS (p<0.05). CONCLUSION: Myasthenic patients have a more favorable prognosis. Radiotherapy can be omitted in totally resected stage I-II patients, whereas it is beneficial in more advanced stages.

Increased Bax/Bcl-2 ratio up-regulates caspase-3 and increases apoptosis in the thymus of patients with myasthenia gravis.

BACKGROUND: In this study the possible relation of Bax (an apoptosis promoter) to Bcl-2 (an apoptosis inhibitor) ratio with the apoptosis co-ordination enzyme, caspase-3, in the thymus of patients with myasthenia gravis (MG) was investigated in correlation with long-term clinical prognosis. PATIENTS AND METHODS: The study included 46 patients (17M/29F, mean age 36.60 +/- 16.09 yr) with MG, who underwent thymectomy for treatment. The clinical staging (Osserman classification) included: stage 1-5, IIA-21, IIB-17, III-3. The pathology of the thymus showed: hyperplasia-26, atrophy-8, thymoma B1 and B2 type-9, thymoma B3 type (well differentiated thymic carcinoma)-3. The patients were evaluated 39-166 (mean 91.87 +/- 38.38) months after thymectomy. At the end of the follow-up period, the patients were classified as follows: group A: complete stable remission, group B: pharmacological remission + minimal manifestations + improvement + deterioration. Paraffin sections of thymic tissue were subjected to: a) immunohistochemistry (bax, bcl-2, caspase-3 protein); b) in situ hybridization (bax, bcl-2 mRNA); and c) TUNEL-stain (apoptotic cells). Bax to bcl-2 mRNA and protein ratio was determined for each sample by dividing the % bax (+) cells by the % bcl-2 (+) cells. RESULTS: Follow-up data were available for 39/46 patients: 13/39 patients belonged to group A and 26/39 to group B. The Bax/Bcl-2 mRNA and protein ratios were increased towards advanced disease stages (+370% for mRNA and +391% for protein, from MG stage I to stage III). These ratios were correlated with caspase-3 expression (r = 0.782 and 0.583, p < 0.01) and apoptosis (r = 0.591 and 0.358 p < 0.01 and p < 0.05). All the 13 cases in group A had a Bax/Bcl-2 ratio < 1 (mean +/- SD: 0.58 +/- 0.04 for mRNA and 0.62 +/- 0.03 for protein), whereas all the 26 cases of group B had a ratio > 1 (1.47 +/- 0.07 for mRNA and 1.52 +/- 0.18 for protein). The Kaplan-Meier survival curve showed higher, free of disease, survival in group A (p = 0.0082). Cox regression analysis revealed that the Bax/Bcl-2 ratio was an independent prognostic factor, however the p-value was marginally significant (95% CI: 1.078-44.073, p = 0.041). CONCLUSION: This study has demonstrated that in patients with MG who underwent thymectomy: a) the Bax/Bcl-2 ratio may up-regulate caspase-3 expression and modulate apoptosis associated with progress of the disease; b) the Bax/Bcl-2 ratio < 1 was associated with complete stable remission after thymectomy; and c) Bax/Bcl-2 ratio was an independent predictive marker for therapeutic response after thymectomy.

The potential role of TGFbeta1, TGFbeta2 and TGFbeta3 protein expression in colorectal carcinomas. Correlation with classic histopathologic factors and patient survival.

PURPOSE: This study investigates the expression of tumor growth factors TGFbeta1, TGFbeta2 and TGFbeta3 in tissue material from patients with colorectal carcinoma and evaluates their correlation with known prognostic markers and patient survival. PATIENTS AND METHODS: The study included 124 patients with colorectal carcinoma. According to the TNM classification of malignant tumors, 26 tumors were identified as being stage I, 30 stage II, 48 stage III, and 20 stage IV, whereas 106 tumors were low-grade and 18 high-grade malignancies. On paraffin sections, the streptavidin-biotin technique using antibodies against TGFbeta1, TGFbeta2 and TGFbeta3 was applied. Morphological and immunohistochemical results were correlated with clinicopathologic parameters. RESULTS: TGFbeta1 protein was expressed in 88 out of 124 (71%) carcinomas, whereas TGFbeta2 and TGFbeta3 proteins were detected in all tumors examined. Normal colonic mucosal epithelial cells expressed TGFbeta2 (significantly less as compared to neoplastic cells; p < 0.01) and TGFbeta3 (p > 0.05 compared to neoplastic cells), but not TGFbeta1. Statistical analysis revealed a higher expression of TGFbeta1 in low-grade carcinomas (p = 0.009) and a higher presence of TGFbeta2 in advanced tumors (p = 0.008). TGFbeta1 expression was related with increased disease-free and overall survival (p < 0.05 each). The presence of TGFbeta2 was correlated with worse prognosis (p < 0.05). Cox analysis revealed that besides tumor grade and stage, TGFbeta1 expression constituted an independent prognostic factor. CONCLUSION: This study shows that in adenocarcinomas of the colon, there is a differential expression of TGFbeta1, TGFbeta2 and TGF3. TGFbeta1 may be implicated in the pathogenesis of these tumors, since it is expressed only in neoplastic but not in normal cells. TGFbeta1 is related with an increased disease-free and overall survival and constitutes an independent prognostic factor. In advanced stages, TGFbeta2 seems to be involved in tumor progression and is related with worse prognosis.