Quality of Life in Myasthenia Gravis and Correlation of MG-QOL15 with Other Functional Scales

Health-related quality of life (HRQOL) in myasthenia gravis (MG) is frequently decreased. Further, there are many validated clinical scales and questionnaires to evaluate the clinical status in MG. We aimed to determine if there was an improvement in HRQOL following an intensive treatment for MG, identify which demographic and clinical features influenced patients' HRQOL, and investigate if the questionnaire MG-QOL15 correlated with other evaluation scales. We recruited 45 patients with generalised MG who were starting immunomodulatory treatment with intravenous immunoglobulins and prednisone for the first time. At each visit, we administered several validated scales for MG. The mean MG-QOL15 score improved significantly at 4 and 6 weeks of the study. Additionally, the MG-QOL15 score correlated strong with the Myasthenia Gravis-Activities of Daily Living (MG-ADL) and the Neuro-QOL Fatigue and weakest with the Quantitative Myasthenia Gravis Scoring System (QMG). The QMG score prior to study enrolment was associated with HRQOL. We observed that HRQOL in MG improved after receiving an intensive immunomodulatory treatment and achieving better control of the symptoms. The questionnaire MG-QOL15 correlated positively with other clinical measures. As MG is a fluctuating condition, and some symptoms are difficult to examine, we direct physicians toward the use of scales and questionnaires composed of items perceived by the patient

Intravenous immunoglobulins may prevent prednisone-exacerbation in myasthenia gravis

Corticosteroids may produce a paradoxical worsening of myasthenia gravis (MG) symptoms within the first weeks of treatment. We therefore wanted to assess the hypothesis that a prior infusion of intravenous immunoglobulin (IVIG) may have a protective effect. Our primary objectives were to show that the coadministration of immunoglobulins and glucocorticoids is safe and effective for controlling myasthenic symptoms, and to compare the exacerbation rate with this approach and historical practice without IVIG. We recruited 45 patients with generalized MG who required corticosteroids for the first time and we gave all IVIG before starting the full doses of prednisone. Monitoring was performed with validated scales, questionnaires, and blood tests over a 6-week period. Only 4.4% had severe adverse effects related to IVIG and 86.7% improved clinically. Notably, only 2.2% had a paradoxical symptom exacerbation in the first weeks of starting prednisone, which was statistically lower than the 42% reported in a historical series. We conclude that adjuvant therapy with IVIG when starting prednisone for the first time in patients with generalized MG is safe and effective. Given that the rate of paradoxical worsening was lower than that previously reported, the addition of IVIG may have a protective effect against such exacerbations

Eculizumab as a promising treatment in thymoma-associated myasthenia gravis

Myasthenia gravis is a chronic autoimmune disorder caused by antibodies directed against the neuromuscular junction. Some patients may have an associated thymoma, which confers a worse prognosis. Eculizumab, a monoclonal antibody that inhibits the activation of terminal complement, has recently been approved for the treatment of refractory generalized myasthenia gravis. This is an early case report of thymoma-associated refractory myasthenia gravis successfully treated with eculizumab in a real-world setting

Observational study of patients in Spain with amyotrophic lateral sclerosis: correlations between clinical status, quality of life, and dignity

Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that dramatically affects patients' quality of life (QoL) and dignity of life (DoL). We aimed to study the impact of ALS on QoL and DoL and how these evolve throughout the duration of the disease. Methods: First, we performed an observational, descriptive study of 43 patients with ALS recruited from the ALS unit at our center and compared them with 20 healthy age- and sex-matched controls. Second, we performed a prospective cohort study, following up 23 patients with ALS over 3 months. All participants completed questionnaires about their functional status, QoL, and DoL. Results: QoL and DoL were significantly worse in the ALS group than in controls (both p < 0.001). During the three-month follow-up in the ALS cohort, statistically significant declines were observed in clinical status and QoL. For clinical status, median scores on the ALS Functional Rating scale changed from 30.95 points at baseline to 27.24 points after 3 months (p = 0.0003). For QoL, median scores on the ALS Assessment Questionnaire changed from 124.19 points at baseline to 131.81 at 3 months (p = 0.0062). However, no significant differences were found between the DoL scores at baseline (48. 14 points) and 3 months (45 points) (p-value = 0.12). Conclusions: ALS is a neurodegenerative disease that affects QoL and DoL alike. We found that clinical status and QoL both deteriorated in patients with ALS as the disease progressed, but that DoL was preserved. However, our findings are limited by small sample sizes. The preservation of DoL may be due to multiple factors, including the therapies provided by the ALS unit. These findings suggest that alongside QoL, DoL may be an important target in the management and care of ALS patients

A novel mutation in the GFAP gene expands the phenotype of Alexander disease

Background: Alexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in GFAP. Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist. Methods: A family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by WES. A candidate variant was functionally tested in an astrocytoma cell line. Results: The novel variant in GFAP N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterized so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models. Conclusion: We suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander Disease type II, probably associated with alternative pathogenic mechanisms, i.e. astrocyte enlargement. GFAP analysis should be considered in adult-onset neurologic presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases

ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization

BackgroundWhole-exome sequencing (WES) and whole-genome sequencing (WGS) have become indispensable tools to solve rare Mendelian genetic conditions. Nevertheless, there is still an urgent need for sensitive, fast algorithms to maximise WES/WGS diagnostic yield in rare disease patients. Most tools devoted to this aim take advantage of patient phenotype information for prioritization of genomic data, although are often limited by incomplete gene-phenotype knowledge stored in biomedical databases and a lack of proper benchmarking on real-world patient cohorts.MethodsWe developed ClinPrior, a novel method for the analysis of WES/WGS data that ranks candidate causal variants based on the patient's standardized phenotypic features (in Human Phenotype Ontology (HPO) terms). The algorithm propagates the data through an interactome network-based prioritization approach. This algorithm was thoroughly benchmarked using a synthetic patient cohort and was subsequently tested on a heterogeneous prospective, real-world series of 135 families affected by hereditary spastic paraplegia (HSP) and/or cerebellar ataxia (CA).ResultsClinPrior successfully identified causative variants achieving a final positive diagnostic yield of 70% in our real-world cohort. This includes 10 novel candidate genes not previously associated with disease, 7 of which were functionally validated within this project. We used the knowledge generated by ClinPrior to create a specific interactome for HSP/CA disorders thus enabling future diagnoses as well as the discovery of novel disease genes.ConclusionsClinPrior is an algorithm that uses standardized phenotype information and interactome data to improve clinical genomic diagnosis. It helps in identifying atypical cases and efficiently predicts novel disease-causing genes. This leads to increasing diagnostic yield, shortening of the diagnostic Odysseys and advancing our understanding of human illnesses

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Observational study of patients in Spain with amyotrophic lateral sclerosis: correlations between clinical status, quality of life, and dignity

Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that dramatically affects patients' quality of life (QoL) and dignity of life (DoL). We aimed to study the impact of ALS on QoL and DoL and how these evolve throughout the duration of the disease. Methods: First, we performed an observational, descriptive study of 43 patients with ALS recruited from the ALS unit at our center and compared them with 20 healthy age- and sex-matched controls. Second, we performed a prospective cohort study, following up 23 patients with ALS over 3 months. All participants completed questionnaires about their functional status, QoL, and DoL. Results: QoL and DoL were significantly worse in the ALS group than in controls (both p < 0.001). During the three-month follow-up in the ALS cohort, statistically significant declines were observed in clinical status and QoL. For clinical status, median scores on the ALS Functional Rating scale changed from 30.95 points at baseline to 27.24 points after 3 months (p = 0.0003). For QoL, median scores on the ALS Assessment Questionnaire changed from 124.19 points at baseline to 131.81 at 3 months (p = 0.0062). However, no significant differences were found between the DoL scores at baseline (48. 14 points) and 3 months (45 points) (p-value = 0.12). Conclusions: ALS is a neurodegenerative disease that affects QoL and DoL alike. We found that clinical status and QoL both deteriorated in patients with ALS as the disease progressed, but that DoL was preserved. However, our findings are limited by small sample sizes. The preservation of DoL may be due to multiple factors, including the therapies provided by the ALS unit. These findings suggest that alongside QoL, DoL may be an important target in the management and care of ALS patients

Observational study of patients in Spain with amyotrophic lateral sclerosis: correlations between clinical status, quality of life, and dignity

Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that dramatically affects patients' quality of life (QoL) and dignity of life (DoL). We aimed to study the impact of ALS on QoL and DoL and how these evolve throughout the duration of the disease. Methods: First, we performed an observational, descriptive study of 43 patients with ALS recruited from the ALS unit at our center and compared them with 20 healthy age- and sex-matched controls. Second, we performed a prospective cohort study, following up 23 patients with ALS over 3 months. All participants completed questionnaires about their functional status, QoL, and DoL. Results: QoL and DoL were significantly worse in the ALS group than in controls (both p < 0.001). During the three-month follow-up in the ALS cohort, statistically significant declines were observed in clinical status and QoL. For clinical status, median scores on the ALS Functional Rating scale changed from 30.95 points at baseline to 27.24 points after 3 months (p = 0.0003). For QoL, median scores on the ALS Assessment Questionnaire changed from 124.19 points at baseline to 131.81 at 3 months (p = 0.0062). However, no significant differences were found between the DoL scores at baseline (48. 14 points) and 3 months (45 points) (p-value = 0.12). Conclusions: ALS is a neurodegenerative disease that affects QoL and DoL alike. We found that clinical status and QoL both deteriorated in patients with ALS as the disease progressed, but that DoL was preserved. However, our findings are limited by small sample sizes. The preservation of DoL may be due to multiple factors, including the therapies provided by the ALS unit. These findings suggest that alongside QoL, DoL may be an important target in the management and care of ALS patients