Journal of Neurology, Neurosurgery, and Psychiatry最新文献

Neuroleptic-induced dystonia is a source of great concern in clinical practice because of its iatrogenic nature which can potentially lead to life-threatening conditions. Since all neuroleptics (antipsychotics) share the ability to block the dopamine D₂-type receptors (D₂Rs) that are highly enriched in the striatum, this drug-induced dystonia is thought to be caused by decreased striatal D₂R activity. However, how associations of striatal D₂R inactivation with dystonia are formed remains elusive.A growing body of evidence suggests that imbalanced activities between D₁R-expressing medium spiny neurons and D₂R-expressing medium spiny neurons (D₁-MSNs and D₂-MSNs) in the striatal striosome-matrix system underlie the pathophysiology of various basal ganglia disorders including dystonia. Given the specificity of the striatal dopamine D₁ system in 'humans', this article highlights the striatal striosome hypothesis in causing 'repetitive' and 'stereotyped' motor symptoms which are key clinical features of dystonia. It is suggested that exposure to neuroleptics may reduce striosomal D₁-MSN activity and thereby cause dystonia symptoms. This may occur through an increase in the striatal cholinergic activity and the collateral inhibitory action of D₂-MSNs onto neighbouring D₁-MSNs within the striosome subfields. The article proposes a functional pathology of the striosome-matrix dopamine system for neuroleptic-induced acute dystonia or neuroleptic-withdrawal dystonia. A rationale for the effectiveness of dopaminergic or cholinergic pharmacotherapy is also provided for treating dystonias. This narrative review covers various aspects of the relevant field and provides a detailed discussion of the mechanisms of neuroleptic-induced dystonia.

Objectives: To evaluate the validity, reliability, responsiveness and meaningful change threshold of the Inclusion Body Myositis (IBM) Functional Rating Scale (FRS).

Methods: Data from a large 20-month multicentre, randomised, double-blind, placebo-controlled trial in IBM were used. Convergent validity was tested using Spearman correlation with other health outcomes. Discriminant (known groups) validity was assessed using standardised effect sizes (SES). Internal consistency was tested using Cronbach's alpha. Intrarater reliability in stable patients and equivalence of face-to-face and telephone administration were tested using intraclass correlation coefficients (ICCs) and Bland-Altman plots. Responsiveness was assessed using standardised response mean (SRM). A receiver operator characteristic (ROC) curve anchor-based approach was used to determine clinically meaningful IBMFRS change.

Results: Among the 150 patients, mean (SD) IBMFRS total score was 27.4 (4.6). Convergent validity was supported by medium to large correlations (r_s modulus: 0.42-0.79) and discriminant validity by moderate to large group differences (SES=0.51-1.59). Internal consistency was adequate (overall Cronbach's alpha: 0.79). Test-retest reliability (ICCs=0.84-0.87) and reliability of telephone versus face-to-face administration (ICCs=0.93-0.95) were excellent, with Bland-Altman plots showing good agreement. Responsiveness in the worsened group defined by various external constructs was large at both 12 (SRM=-0.76 to -1.49) and 20 months (SRM=-1.12 to -1.57). In ROC curve analysis, a drop in at least two IBMFRS total score points was shown to represent a meaningful decline.

Conclusions: When administered by trained raters, the IBMFRS is a reliable, valid and responsive tool that can be used to evaluate the impact of IBM and its treatment on physical function, with a 2-point reduction representing meaningful decline.

Trial registration number: NCT02753530.

Background: AQP4-antibody seropositive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) may cause reduced work capability due to disability. Here, we evaluated the socioeconomic status of patients with AQP4-Ab+NMOSD in off-label therapy era compared with the general population.

Methods: A longitudinal nationwide population-based study including all Danish patients with AQP4-Ab+NMOSD and matched controls from the general population. The cohort was linked to other Danish nationwide population-based databases. The study period was from 1992 to 2021. The main outcomes were loss of income from salary, limited work capability, disability pension and civil status. The longitudinal risks of outcomes were presented in cumulative incidence curves. Fisher's exact test, χ² test or Wilcoxon test were applied for comparison.

Results: We included 65 patients with a median follow-up of 8.6 years. Annual income declined significantly after disease onset (index year) compared with the general population. One year after the index year, the median annual income in 2015-indexed Euro for patients averaged 13 285 (IQR: 139 to 36 336) versus controls 33 035 (IQR: 6870 to 45 978); p=0.04. Five years postindex year, the average income for patients further dropped to 276 (IQR: 0 to 23 691) versus controls 22 141 (IQR: 0 to 42 986); p=0.03. At the end of follow-up, significantly higher proportion of patients were either in 'flexjob' (36.9% patients vs 14% controls, p<0.00) or receiving disability pension (16.9% patients vs 4.3% controls, p<0.00).

Conclusions: The socioeconomic status of patients with AQP4-Ab+NMOSD deteriorates rapidly following disease onset. A substantial proportion of these patients lose their work capacity leading to increased financial burden on both their families and society.

Background: Calorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) via multiple mechanisms. These include decreased leptin, a proinflammatory adipokine, but mechanistic studies in humans are lacking. Tests of daily and intermittent CR (iCR) in people with MS (pwMS) showed improvements in fatigue and well-being measures. This trial studied the effects of 12-week iCR on metabolic, immunological, and clinical outcomes in pwMS.

Method: Relapsing-remitting MS participants were randomised to iCR or a control group. Study visits were conducted at baseline, 6 and 12 weeks. The primary outcome was reduction in serum leptin levels at 12 weeks. Feasibility and safety were assessed by diet adherence and adverse events (AEs). Secondary outcomes included changes in anthropometric and body composition measures, metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate outcome differences between and within groups over time.

Results: Forty-two pwMS were randomised, 34 completed the study (17/group). Leptin serum levels at 12 weeks were significantly lower in the iCR versus the control group (mean decrease -6.98 µg/dL, 95% CI: -28.02 to 14.06; p=0.03). Adherence to iCR was 99.5% and 97.2% at 6 and 12 weeks, respectively, and no serious AEs were reported. An increase in blood CD45RO⁺ regulatory T-cell numbers was seen after 6 weeks of iCR. Exploratory cognitive testing demonstrated a significant improvement in the Symbol Digit Modality Test Score in the iCR group at 12 weeks.

Conclusions: iCR has the potential to benefit metabolic and immunologic profiles and is safe and feasible in pwMS.

Trial registration number: NCT03539094 .

Background: Traumatic brain injury (TBI) is common in military campaigns and is a risk factor for dementia. ArmeD SerVices TrAuma and RehabilitatioN OutComE-TBI (ADVANCE-TBI) aims to ascertain neurological outcomes in UK military personnel with major battlefield trauma, leveraging advances in quantification of axonal breakdown markers like neurofilament light (NfL), and astroglial marker glial fibrillar acidic protein (GFAP) in blood. We aimed to describe the causes, prevalence and consequences of TBI, and its fluid biomarker associations.

Methods: TBI history was ascertained in 1145 servicemen and veterans, of whom 579 had been exposed to major trauma. Functional and mental health assessments were administered, and blood samples were collected approximately 8 years postinjury, with plasma biomarkers quantified (n=1125) for NfL, GFAP, total tau, phospho-tau₁₈₁, amyloid-β 42 and 40. Outcomes were related to neurotrauma exposure.

Results: TBI was present in 16.9% (n=98) of exposed participants, with 46.9% classified as mild-probable and 53.1% classified as moderate to severe. Depression (β=1.65, 95% CI (1.33 to 2.03)), anxiety (β=1.65 (1.34 to 2.03)) and post-traumatic stress disorder (β=1.30 (1.19 to 1.41)) symptoms were more common after TBI, alongside poorer 6 minute walk distance (β=0.79 (0.74 to 0.84)) and quality of life (β=1.27 (1.19 to 1.36), all p<0.001). Plasma GFAP was 11% (95% CI 2 to 21) higher post-TBI (p=0.013), with greater concentrations in moderate-to-severe injuries (47% higher than mild-probable (95% CI 20% to 82%, p<0.001). Unemployment was more common among those with elevated GFAP levels post-TBI, showing a 1.14-fold increase (95% CI 1.03 to 1.27, p<0.001) for every doubling in GFAP concentration.

Conclusions: TBI affected nearly a fifth of trauma-exposed personnel, related to worse mental health, motor and functional outcomes, as well as elevated plasma GFAP levels 8 years post-injury. This was absent after extracranial trauma, and showed a dose-response relationship with the severity of the injury.

Background: We report our experience of patients with generalised myasthenia gravis (gMG) treated with efgartigimod, an neonatal Fc receptor antagonist, under the Early Access to Medicine Scheme (EAMS) in the UK.

Methods: Data from all UK patients treated with efgartigimod under the EAMS July 2022 to July 2023 were collected retrospectively. Efgartigimod was administered as per the ADAPT protocol (consisting of a treatment cycle of four infusions at weekly intervals with further cycles given according to clinical need).

Results: 48 patients with acetylcholine receptor antibody-positive gMG were treated in 12 centres. Most (75%) were female and most had a disease duration of over 10 years. The average MG-Activities of Daily Living (ADL) score at baseline was 11.2. Most (72.9%) patients had undergone thymectomy. 77.0% were taking prednisolone at baseline. All patients had used non-steroidal immunosuppressant treatments, the average number tried was 2.6 (range 1-6). 51% had received rituximab. 54.2% of patients required regular intravenous immunoglobulin/plasma exchange.75% of patients had a mean reduction in the MG-ADL of≥2 points in the first cycle and this remained stable throughout the study. The mean intracycle reduction in the MG-ADL score in the first, second, third and fourth cycles were -4.6 to -3.9, -3.4 and -4.2, respectively. Side effects were generally mild. No rescue treatments were required. At the end of the study, 96% of patients remained on efgartigimod.

Conclusion: Efgartigimod is a safe and effective treatment for patients with refractory, treatment-resistant gMG.

Background: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular junctions, leading to fluctuating muscle weakness. While many patients respond well to standard immunosuppression, a substantial subgroup faces ongoing disease activity. Emerging treatments such as complement factor C5 inhibition (C5IT) and neonatal Fc receptor (FcRn) antagonism hold promise for these patients. However, the current landscape is hindered by a paucity of comparative data that is crucial for treatment decisions.

Objective: This study aims to compare the effectiveness and safety of C5IT and FcRn antagonists in a real-world setting.

Methods: A retrospective analysis of 153 MG patients from 8 German specialised MG centres receiving either C5IT (26 eculizumab, 80 ravulizumab) or efgartigimod (47 patients) was conducted. Propensity score matching (PSM) was employed to compare changes in MG-specific outcome parameters within the first 6 months after treatment initiation, along with safety profiles and concomitant MG therapy.

Results: Both treatment strategies led to rapid clinical improvements and substantial reductions in prednisolone doses. However, insufficient response was noted in 20%-49.1% of patients based on Quantitative MG and MG Activities of Daily Living (MG-ADL) scores. We did not identify any new safety concerns. After PSM, 40 patients remained in each group. In both cohorts, reductions in MG-ADL as prespecified primary study endpoint were comparable. Moreover, analyses of secondary outcome parameters demonstrated similar results for C5IT versus FcRn.

Conclusion: In contrast to current meta-analyses and indirect comparisons of clinical trial data, our real-world study demonstrates comparable efficacy and safety of C5IT and FcRn antagonism in MG.