Therapeutic Advances in Neurological Disorders最新文献

Background: People with atypical parkinsonism, such as multiple system atrophy and progressive supranuclear palsy, experience a wide range of motor and non-motor symptoms associated with the increasing complexity of care delivery and the increased risk of complications and hospital admissions.

Objectives: To investigate the efficacy and cost-effectiveness of a 12-month remote home-based integrated program aiming to improve healthcare delivery coordinated by a nurse specialized in the management of individuals with atypical parkinsonism (parkinsonism nurse specialist, PKNS) compared to the standard-of-care model.

Design: Multicenter, randomized, single-blind, controlled clinical trial involving 164 individuals with atypical parkinsonism.

Methods and analysis: Participants will be randomized 1:1 in intervention (PKNS) and control (standard-of-care) arms. Assessments will be undertaken at baseline and after 6 and 12 months. Primary outcome measure is the Parkinson's Disease Questionnaire 39-items scale total score. Secondary measures include the clinical scales testing motor and non-motor symptoms, caregiver burden, adherence to therapy, cumulative disease burden and the number of unplanned hospital visits/admissions during the study period. The cost-effectiveness of this method will be evaluated by using the EuroQoL-5, which estimates the incremental cost per quality-adjusted life-years gain. Real-life motor autonomy will be objectively measured by collecting waist-worn wearable data on gait parameters (automatically detecting motor patterns indicative of freezing of gait and falls) in all subjects for five consecutive days each month during the 12-month duration of the study.

Ethic: Study protocol has been approved by the ethics committee of all participating centers. The study is conducted according to good clinical practice and the Declaration of Helsinki.

Discussion: An integrated remote care model at home coordinated by a specialized nurse in the management of parkinsonism (Telenursing) could offer significant benefits to patients and healthcare professionals through better health education, continuity of care, and careful monitoring of complications.

Trial registration: ClinicalTrials.gov identifier NCT05792332.

A 35-year-old gentleman with a traumatic brain injury was diagnosed with refractory epilepsy with electroencephalogram and imaging findings supporting a broad seizure onset pattern in bilateral frontotemporal regions. He therefore received a Medtronic Percept PC Deep Brain Stimulator (DBS) placed bilaterally in the anterior nucleus of the thalamus (ANT). While most refractory epilepsy patients' stimulation parameters use the SANTE trial standard clinical settings of 145 Hz, 90 μs, with cycling 1-min stimulation on and 5 min stimulation off, this participant underwent 7 different stimulation parameter tests at home following testing in the clinic of 24 different stimulation parameters across 12 neurologist visits. This device allows for simultaneous stimulation of the ANT while recording the ANT local field potential (LFP) response under different stimulation parameters. Slepian multitaper analysis, modified Fitting Oscillations, and One Over F method for detrending the aperiodic component were performed to analyze neural oscillations in the frequency domain captured in the clinic. This participant was participating in a clinical study examining the effectiveness of nonstandard DBS settings to minimize broadband neural activity in the ANT. Statistically significant neuromodulatory suppression of gamma oscillations was observed in the clinic under multiple stimulation settings. We compared the ability of these research stimulation parameters to suppress at-home ANT neural activity against the standard clinical settings and examined the effects of both sets of parameters on LFP power nonstationarity. At home, theta/alpha LFP power suppression was statistically significantly reduced under the 125 Hz, 50 μs setting as opposed to the clinical setting of 145 Hz, 90 μs. The participant has achieved greater than 50% seizure reduction for over 1 year since the last neurology visit. Suppression of gamma in the clinic in the right hemisphere and suppression of theta at home in the left hemisphere show promise as quantitative feedback biomarkers for ANT-DBS. Understanding the local and network relationships of theta and slow gamma oscillations in the thalamus would further explain how these modulated oscillations may relate to the onset and propagation of seizures.

Background: The efficacy of efgartigimod in treating myasthenia gravis (MG) patients with muscle-specific kinase (MuSK) antibodies has not been demonstrated in the clinical trial, existing case reports, or observational studies.

Objectives: To evaluate the efficacy and safety of efgartigimod combined with immunotherapies such as tacrolimus or B-cell depleting agents, as maintenance treatment for MuSK-MG patients.

Design: This retrospective study included 14 MuSK-MG patients treated with efgartigimod at three tertiary hospitals from 2023 to 2024.

Methods: Data on the activities of daily living (ADL) scores, Quantitative Myasthenia Gravis scores, and the time reaching minimal symptom expression (MSE) were collected. The combined use of steroids, immunosuppressants, and rescue therapies, as well as the adverse event incidence, were also recorded.

Results: The mean age at first efgartigimod treatment was 55 ± 18 years old with a median follow-up time of 28 weeks. From baseline to week 4, MG-ADL scores decreased significantly from 10.1 ± 4.0 to 2.2 ± 3.1 (n = 14, p = 0.001). The majority of patients (92.9%) maintains a reduction of at least 2 points for more than 8 weeks. The median time to achieve MSE was 4 weeks, with 71.4% (10/14) of patients reaching MSE by week 12. In patients receiving CD20 B cell depleting therapy or tacrolimus as maintenance, the time-weighted average dosage of prednisone was 16 mg while that in those with prednisone alone was 37 mg. Of all the 14 patients, one developed an upper respiratory tract infection 4 weeks after rituximab (RTX), and one was infected with herpes zoster virus 13 weeks after RTX.

Conclusion: A single-cycle efgartigimod as an induction therapy, combined with immunotherapies such as tacrolimus or B cell depleting agents, as maintenance treatment, could benefit MuSK-MG patients.

Background: Limited information exists on the healthcare resource utilization (HCRU) associated with real-world natalizumab used as a first-line (1L) versus later-line (2L+) treatment in multiple sclerosis (MS).

Objectives: To describe natalizumab use in newly diagnosed MS patients treated as 1L or 2L+ and evaluate unadjusted annualized relapse rates (ARR) and MS-related HCRU before and after treatment initiation.

Design: This retrospective observational study utilized Komodo Health Sentinel claims data from October 2015 to August 2022. The study included adults diagnosed with incident MS who initiated natalizumab treatment, with insurance coverage for at least 12 months before diagnosis and 24 months after. The index date was the first natalizumab claim on or after the diagnosis. Baseline was defined as the 365 days prior to the index date, truncated at the time of diagnosis. Follow-up ended at the earliest occurrence of death, insurance disenrollment, treatment discontinuation (gap ⩾45 days), switch to another disease-modifying therapy before natalizumab discontinuation, or study end.

Methods: Relapses and HCRU were assessed using person-time methods to account for varying follow-up times. Relapses were identified using a validated claims-based algorithm, and time to first relapse was analyzed using Kaplan-Meier methods. Hazard ratios for relapse were estimated using univariate Cox models. Mean differences (MD) in HCRU between baseline and follow-up and between 1L and 2L+ treatment groups were calculated.

Results: A total of 1174 patients in the 1L group (mean age 39.0, 72.0% female) and 394 in the 2L+ group (mean age 39.7, 79.4% female) were included. Patients in the 1L group had a significantly higher baseline ARR (1.48 vs 0.92, p < 0.001) and lower on-treatment ARR (0.28 vs 0.41 for 2L+, p < 0.001). HCRU decreased significantly in the 1L group from baseline to follow-up: hospitalizations (MD 17.01 visits/year), length of stay (LOS; MD 20.96 days/year), emergency room visits (MD 9.83 visits/year), non-natalizumab outpatient visits (MD 12.11 visits/year) and long-term care facility stays (MD 22.18 days/year, p = 0.002). The 1L group showed greater reductions in inpatient visits (MD 10.01 visits//year), LOS (MD 16.73 days/year) and non-natalizumab outpatient visits (MD 11.64 visits/year) compared to the 2L+ group.

Conclusion: Natalizumab as a first-line treatment was associated with greater reductions in ARR and MS-related HCRU compared to later-line use.

Background: Fatigue is a prevalent non-motor symptom that often appears in the early stages of Parkinson's disease (PD). Plasma neurofilament light chain (NfL) was elevated in PD patients and may be considered a potential biomarker for both motor and cognitive progression.

Objectives: In this study, we explored the association between plasma NfL levels and various fatigue subtypes and the prediction of baseline plasma NfL levels for fatigue subtype conversion.

Methods: Patients with PD were classified into four categories: persistent fatigue, never fatigue, non-persistent fatigue, and new-onset fatigue. They underwent detailed neurological evaluations at baseline and a 2-year follow-up. Plasma NfL, glial fibrillary acidic protein, phosphorylated tau181, amyloid beta 42, and Aβ40 levels in both PD patients and control subjects were measured using an ultrasensitive single molecule array.

Results: The study enrolled 174 PD patients and 95 control subjects. Plasma NfL levels were significantly higher in the persistent fatigue group compared to the never fatigue group at the 2-year follow-up (p < 0.05). Longitudinally, 45.16% of baseline fatigue patients converted to non-fatigue at the 2-year follow-up. Additionally, 22.12% of patients initially without-figure patients converted to fatigue patients at the 2-year follow-up. Baseline plasma NfL levels were significantly higher in both the persistent fatigue and new-onset fatigue groups compared to the never fatigue group (p < 0.05). Higher baseline NfL levels were significantly associated with new-onset fatigue (odds ratio = 1.127, p = 0.034) after adjusting for confounders.

Conclusion: Baseline plasma NfL levels may serve as a biomarker for predicting fatigue subtype conversion and the progression of fatigue in PD.

Background: Accumulating evidence supports a role of the microbiota in health and disease, including in multiple sclerosis (MS). How MS drugs affect the microbiota and whether this is part of their mode of action is yet unknown.

Objectives: To assess how dimethyl fumarate (DMF) affects the gut microbiota and whether the microbiota is associated with clinical response or adverse events (AEs) to DMF or diet.

Design: An observational cohort study, in which the microbiota from 45 patients with relapsing-remitting MS pre-DMF initiation and following 6 months of DMF therapy, and from 47 matched healthy controls, were compared, and associations with clinical and dietary data assessed.

Data sources and methods: Microbial DNA was sequenced and analyzed using MicrobiomeAnalyst. The clinical response was assessed after 1-year DMF therapy based upon evidence of disease activity (relapse, ΔEDSS increase >1, or MRI activity compared to pre-treatment). Dietary data were obtained by food questionnaires.

Results: Alterations in relative abundance of several microbes were identified post 6-month DMF therapy compared to pre-treatment, including an increase in Firmicutes, Lachnospiraceae, and Ruminococcaceae, while reduction in Bacteroidetes and Proteobacteria. Patients who showed disease activity within 1 year from DMF initiation had pre-treatment higher abundance of Proteobacteria, Flavonifractor, and Acidaminococcaceae, while lower abundance of Firmicutes, Ruminococcaceae, Butyricicoccus, and Massiliprevotella massiliensis, compared to patients without disease activity. Patients who discontinued DMF therapy due to AEs had pre-treatment higher abundance of Proteobacteria, Bacteroidetes, Eggerthella, and Lachnoclostridium and lower abundance of Ruminococcaceae, Megamonas, and Holdemanella, among others. Differentially abundant microbes correlated with intake of several nutrients.

Conclusion: DMF immunotherapy is associated with modifications of the microbiota. The microbiota may affect the severity of AEs and the clinical response to DMF, and is potentially modulated by diet. Microbiota-based, personalized treatment approach, integrating pharmacotherapy with dietary components, carries potential to improved clinical outcome.

Background: Complaints of fatigue and poor sleep quality are common in patients with epilepsy. Fatigue may precipitate seizures, and patients with poor sleep quality have higher frequency of seizures and are more likely to have symptoms of depression.

Objectives: This study aims to determine the association of baseline fatigue and sleep quality with antiseizure medication (ASM) resistance in patients with newly diagnosed epilepsy (PWNDE). We also evaluate whether the association is mediated by depression symptoms.

Methods: We performed a prospective cohort study of PWNDE at comprehensive epilepsy center in Northeast China between June 2020 and May 2024. Fatigue, sleep quality, and depression symptoms were assessed at baseline. All patients were followed for 24 months for ASM-resistant epilepsy. Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) of ASM resistance. Models fitted with restricted cubic spline were performed to test for linear and nonlinear shapes of each association. Mediation analysis was used to estimate the mediating effects of depression severity on association between fatigue, sleep quality, and ASM resistance.

Results: A total of 189 patients (59 ASM-resistant cases and 130 ASM-responsive controls) were included in the final analysis. Baseline fatigue (HR, 1.98; 95% confidence interval (CI), 1.094-3.583, p = 0.024) and poor sleep quality (HR, 2.193; 95% CI, 1.29-3.729, p = 0.004) were associated with an increased hazard of ASM resistance in PWNDE after full adjustments. There exists a nonlinear association between Fatigue Severity Scale score and the hazard of ASM resistance (P for nonlinear = 0.012). Depression severity partly mediated the effect of fatigue and sleep quality on ASM resistance, with mediated proportions of 18.5% for the fatigue and 23.7% for the sleep quality.

Conclusion: Baseline fatigue and poor sleep quality were associated with an increased risk of ASM resistance. The association between fatigue, sleep quality, and ASM resistance were partly mediated by depression severity. These findings emphasize that patients with ASM-resistant epilepsy are more likely to have fatigue, depression, and poor sleep quality at baseline and this may be unrelated to ASM intake.

CACNA1S variants can alter the structure and function of the calcium channel, resulting in abnormal calcium influx and homeostasis. It is well established that pathogenic variants in CACNA1S can lead to hypokalemic periodic paralysis, malignant hyperthermia, and congenital myopathy. Nevertheless, the clinical presentations and disease progression of exertional myalgia and weakness associated with CACNA1S variants remain elusive. In this study, four affected individuals from an autosomal-dominant family were described, exhibiting symptoms of severe exertional myalgia, followed by flaccid weakness or rhabdomyolysis, along with asymptomatic hyperCKemia during the interictal period. Long exercise test showed a late decrease in compound muscle action potential amplitude. Muscle MRI revealed edema-like changes in the early stage, and fatty degeneration and substitution in prolonged disease courses, while closely aligned with the features of chronic myopathy. Ultrastructural examination revealed dilation of the sarcoplasmic reticulum and myofibrillar structural disarrangement. Genetic screening identified a c.3724A>G (p.Arg1242Gly) mutation in the CACNA1S gene. A literature review revealed that 15 patients exhibited the exertional myalgia and weakness phenotype associated with CACNA1S mutations, presenting similar clinical, electrophysiological, radiological, and pathological features. As the disease progressed, these patients developed severe muscle weakness, ultimately leading to wheelchair dependency. This exertional myalgia-weakness phenotype represented a unique CACNA1S-related phenotype that broadened the spectrum of CACNA1S-associated myopathy, bridging between periodic paralysis and congenital myopathies. The similarities between CACNA1S-associated myalgia-weakness and RyR1-associated myalgia-weakness underscored a shared pathogenesis of excitatory-contractile coupling at the triad of skeletal muscle.

Background: Differentiating idiopathic Parkinson's disease (IPD) from multiple system atrophy-parkinsonian type (MSA-P) is essential for optimizing patient care and prognosis, given the differences in disease progression and treatment response.

Objectives: This study aimed to develop and evaluate a radiomics-based model using magnetic resonance imaging (MRI)-derived features to distinguish IPD from MSA-P.

Design: A multicenter retrospective study.

Methods: A multicenter retrospective study was conducted with 287 patients (186 IPD and 101 MSA-P) who underwent brain MRI. Radiomic features were extracted from T1-weighted imaging and T2-weighted imaging sequences, and various machine learning classifiers were applied, including logistic regression, support vector machine (SVM), ExtraTrees, extreme gradient boosting, and Light Gradient Boosting Machine. Model performance was assessed using area under the curve (AUC), accuracy, sensitivity, and specificity. A nomogram combining clinical and radiomic features was also evaluated.

Results: The SVM model, selected as the base for the Rad-signature, achieved the best diagnostic performance, with AUCs of 0.885 and 0.900 in the training and testing cohorts, respectively. The Rad-signature significantly outperformed clinical-only models in distinguishing IPD from MSA-P. The nomogram incorporating radiomic and clinical features yielded the highest diagnostic accuracy (AUC = 0.973 and 0.963 for training and testing cohorts, respectively) and balanced sensitivity and specificity. Decision curve analysis confirmed the nomogram's clinical utility.

Conclusion: Radiomics-based MRI analysis offers a powerful tool for distinguishing IPD from MSA-P, enhancing diagnostic accuracy, and aiding personalized treatment planning. Integrating radiomic and clinical data may improve diagnostic workflows in clinical practice.

Guillain-Barré syndrome (GBS) is a serious neurological condition with limited treatment options. A recent report demonstrated successful treatment with efgartigimod alone in two patients with GBS, although it did not significantly shorten the disease duration. This case series investigates the effects of sequential efgartigimod administration in patients with different GBS phenotypes and varying levels of disease severity. All three patients tested positive for immunoglobulin G (IgG) antibodies against serum gangliosides. In Case 1, the patient was treated with 0.4 g/kg of intravenous immunoglobulin (IVIg) for 5 days, showing minimal recovery. After receiving 3 weekly doses of efgartigimod (10 mg/kg), the patient achieved independent ambulation 19 days post-onset, with a reduction in serum ganglioside antibody titers and total IgG levels. Case 2 involved a middle-aged man with Miller Fisher syndrome (MFS)-GBS overlap, who experienced worsened autonomic dysfunction following IVIg treatment. After three doses of efgartigimod, the patient showed symptom improvement within 1 month, alongside a reduction in IgG antibody levels. In Case 3, a 27-year-old male with MFS-GBS overlap, initially unresponsive to IVIg, showed significant improvement in ophthalmoplegia following two doses of efgartigimod, with his serum ganglioside antibodies eventually becoming undetectable. Our findings suggest that sequential efgartigimod treatment may effectively reduce serum anti-ganglioside antibody titers and potentially shorten the disease course in severe GBS and MFS-GBS overlap syndrome. Additionally, it may offer clinical benefits for patients with GBS who have a poor or no response to IVIg, particularly in treating ophthalmoplegia.