Journal of Neurology, Neurosurgery, and Psychiatry最新文献

Background: Intranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson's disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial.

Methods: This was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy.

Results: 7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels.

Conclusions: Treatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

Background: Cognitive symptoms are often reported by those with a history of COVID-19 infection. No comprehensive meta-analysis of neurocognitive outcomes related to COVID-19 exists despite the influx of studies after the COVID-19 pandemic. This study meta-analysed observational research comparing cross-sectional neurocognitive outcomes in adults with COVID-19 (without severe medical/psychiatric comorbidity) to healthy controls (HCs) or norm-referenced data.

Methods: Data were extracted from 54 studies published between January 2020 and June 2023. Hedges' g was used to index effect sizes, which were pooled using random-effects modelling. Moderating variables were investigated using meta-regression and subgroup analyses.

Results: Omnibus meta-analysis of 696 effect sizes extracted across 54 studies (COVID-19 n=6676, HC/norm-reference n=12 986; average time since infection=~6 months) yielded a small but significant effect indicating patients with COVID-19 performed slightly worse than HCs on cognitive measures (g=-0.36; 95% CI=-0.45 to -0.28), with high heterogeneity (Q=242.30, p<0.001, τ=0.26). Significant within-domain effects was yielded by cognitive screener (g=-0.55; 95% CI=-0.75 to -0.36), processing speed (g=-0.44; 95% CI=-0.57 to -0.32), global cognition (g=-0.40; 95% CI=-0.71 to -0.09), simple/complex attention (g=-0.38; 95% CI=-0.46 to -0.29), learning/memory (g=-0.34; 95% CI=-0.46 to -0.22), language (g=-0.34; 95% CI=-0.45 to -0.24) and executive function (g=-0.32; 95% CI=-0.43 to -0.21); but not motor (g=-0.40; 95% CI=-0.89 to 0.10), visuospatial/construction (g=-0.09; 95% CI=-0.23 to 0.05) and orientation (g=-0.02; 95% CI=-0.17 to 0.14). COVID-19 samples with elevated depression, anxiety, fatigue and disease severity yielded larger effects.

Conclusion: Mild cognitive deficits are associated with COVID-19 infection, especially as detected by cognitive screeners and processing speed tasks. We failed to observe clinically meaningful cognitive impairments (as measured by standard neuropsychological instruments) in people with COVID-19 without severe medical or psychiatric comorbidities.

Background: The risk-benefit relationship of immunosuppressive therapies (ISTs) for elderly patients with neuromyelitis optica spectrum disorder (NMOSD) is not well established. This study aimed to investigate the safety and efficacy of IST in elderly patients with NMOSD.

Methods: This retrospective study analysed IST efficacy and safety in 101 patients with aquaporin-4 antibody-positive NMOSD aged over 65 years, treated for at least 6 months at five Korean referral centres, focusing on relapse rates, infection events and discontinuation due to adverse outcomes.

Results: The mean age at disease onset was 59.8 years, and female-to-male ratio was 4:1. Concomitant comorbidities at NMOSD diagnosis were found in 87 patients (86%). The median Expanded Disability Status Scale score at the initiation of IST was 3.5. The administered ISTs included azathioprine (n=61, 60%), mycophenolate mofetil (MMF) (n=48, 48%) and rituximab (n=41, 41%). Over a median of 5.8 years of IST, 58% of patients were relapse-free. The median annualised relapse rate decreased from 0.76 to 0 (p<0.001), and 81% experienced improved or stabilised disability. Patients treated with rituximab had a higher relapse-free rate than those treated with azathioprine or MMF (p=0.022). During IST, 21 patients experienced 25 severe infection events (SIEs) over the age of 65 years, and 3 died from pneumonia. 14 patients (14%) experienced 17 adverse events that led to switching or discontinuation of IST. When comparing the incidence rates of SIEs and adverse events, no differences were observed among patients receiving azathioprine, MMF and rituximab.

Conclusion: In elderly patients with NMOSD, IST offers potential benefits in reducing relapse rates alongside a tolerable risk of adverse events.

Background: B-cell depletion displays striking effectiveness in relapsing-remitting multiple sclerosis (RRMS), but is also associated with increased infection risk. To what degree previous treatment history, disease-modifying therapy (DMT) switching pattern and time on treatment modulate this risk is unknown. The objective here was to evaluate previous DMT use and treatment duration as predictors of infection risk with B-cell depletion.

Methods: We conducted a nationwide RRMS cohort study leveraging data from the Swedish MS registry and national demographic and health registries recording all outpatient-treated and inpatient-treated infections and antibiotics prescriptions from 1 January 2012 to 30 June 2021. The risk of infection during treatment was compared by DMT, treatment duration, number and type of prior treatment and adjusted for a number of covariates.

Results: Among 4694 patients with RRMS on B-cell depletion (rituximab), 6049 on other DMTs and 20 308 age-sex matched population controls, we found higher incidence rates of inpatient-treated infections with DMTs other than rituximab used in first line (10.4; 95% CI 8.1 to 12.9, per 1000 person-years), being further increased with rituximab (22.7; 95% CI 18.5 to 27.5), compared with population controls (6.6; 95% CI 6.0 to 7.2). Similar patterns were seen for outpatient infections and antibiotics prescriptions. Infection rates on rituximab did not vary between first versus later line treatment, type of DMT before switch or exposure time.

Conclusion: These findings underscore an important safety concern with B-cell depletion in RRMS, being evident also in individuals with shorter disease duration and no previous DMT exposure, in turn motivating the application of risk mitigation strategies.

This review of vestibular neurology for the general neurologist delves into the multifaceted realm of vestibular neurology where we address the diagnostic and therapeutic challenges associated with dizziness, vertigo and balance disorders. We outline the standard vestibular assessments that can be understood and incorporated by the generalist, discussing their use in common vestibular disorders. Key disorders covered include acute and chronic syndromes, benign paroxysmal positional vertigo, Meniere disease, vestibular migraine and persistent postural-perceptual dizziness. We also touch on emerging advances in vestibular genotyping and novel treatment approaches for balance problems.

Background: Patients with refractory or high-risk myasthenia gravis (MG) respond poorly to conventional immunosuppressive therapy, requiring rescue therapies and often experiencing treatment toxicity. Rescue and injectable therapies do not induce remission and require repetitive administration leading to significant constraints on patients and the healthcare system. This long-term follow-up study demonstrates cyclophosphamide as a rapidly effective and safe treatment in patients with refractory or high-risk MG.

Methods: Retrospective cohort study of MG patients treated with cyclophosphamide between January 2000 and June 2022 conducted at a quaternary neuroimmunology clinic in New South Wales, Australia.

Results: 31 patients were treated: mean age of 64 years; median follow-up 3.6 years (5 months to 11 years); 94% seropositive to acetylcholine receptor (AChR) antibodies and 45% had thymoma. A reduced intensity cyclophosphamide induction protocol followed by oral antiproliferative maintenance is described.Median myasthenia gravis composite scores reduced by >50% after the third cycle of cyclophosphamide. Complete cessation of prednisolone was possible in 11 patients while 20 remained on prednisolone with a median daily dose of 5 mg. Plasma exchange was ceased in 62% of patients and intravenous immunoglobulin ceased in 55%. Cyclophosphamide was generally well tolerated with mild cytopenias. There were no malignancies or cases of haemorrhagic cystitis.

Conclusion: We describe a large cohort of high-risk MG patients treated with cyclophosphamide in a retrospective single-clinic cohort. We suggest cyclophosphamide should be considered for rapid remission induction, corticosteroid reduction and long-term freedom from recurrent injectable therapies in selected patients, typically those with AChR antibodies.

Background: A growing body of evidence suggests inequitable access to disease-modifying therapies (DMTs) for multiple sclerosis (MS) in publicly funded healthcare systems. This retrospective study examined the impact of ethnicity and deprivation on the access to DMTs.

Methods: All adults diagnosed with relapsing-remitting MS between 2010 and 2020 were included. The impact of ethnicity and deprivation on being offered and starting any DMTs and high-efficacy DMTs were measured using binary, multinomial logistic and Cox regression models. These analyses were adjusted for sex, age at diagnosis and year of diagnosis.

Results: 164/1648 people with MS (PwMS) were from non-white ethnicities. 461/1648 who were living in the most deprived areas, were less likely to be offered DMTs, with an OR of 0.66 (95% CI 0.47 to 0.93), less likely to start high-efficacy DMTs with an OR of 0.67 (95% CI 0.48 to 0.93) and more likely to experience a delay in starting high-efficacy DMTs with an HR of 0.76 (95% CI 0.63 to 0.92), when also adjusted for ethnicity. Although the offer of DMTs did not depend on ethnicity, PwMS from non-white ethnicities were more likely to decline DMTs, less likely to start any DMTs and high-efficacy DMTs with ORs of 0.60 (95% CI 0.39 to 0.93) and 0.61 (95% CI 0.38 to 0.98), respectively, and more likely to experience a delay in starting DMTs with an HR of 0.79 (95% CI 0.66 to 0.95), when also adjusted for deprivation.

Conclusions: In a publicly funded healthcare system, the access to DMTs varied depending on ethnicities and levels of deprivation.

Background: Biomarkers of neuronal, glial cells and inflammation in traumatic brain injury (TBI) are available but they do not specifically reflect the damage to synapses, which represent the bulk volume of the brain. Experimental models have demonstrated extensive involvement of synapses in acute TBI, but biomarkers of synaptic damage in human patients have not been explored.

Methods: Single-molecule array assays were used to measure synaptosomal-associated protein-25 (SNAP-25) and visinin-like protein 1 (VILIP-1) (along with neurofilament light chain (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillar acidic protein (GFAP), interleukin-6 (IL-6) and interleukin-8 (IL-8)) in ventricular cerebrospinal fluid (CSF) samples longitudinally acquired during the intensive care unit (ICU) stay of 42 patients with severe TBI or 22 uninjured controls.

Results: CSF levels of SNAP-25 and VILIP-1 are strongly elevated early after severe TBI and decline in the first few days. SNAP-25 and VILIP-1 correlate with inflammatory markers at two distinct timepoints (around D1 and then again at D5) in follow-up. SNAP-25 and VILIP-1 on the day-of-injury have better sensitivity and specificity for unfavourable outcome at 6 months than NFL, UCH-L1 or GFAP. Later elevation of SNAP-25 was associated with poorer outcome.

Conclusion: Synaptic damage markers are acutely elevated in severe TBI and predict long-term outcomes, as well as, or better than, markers of neuroaxonal injury. Synaptic damage correlates with initial injury and with a later phase of secondary inflammatory injury.

Background: Cerebrospinal fluid myelin oligodendrocyte glycoprotein IgG (CSF MOG-IgG) are found in a proportion of patients with MOG antibody-associated disorder (MOGAD) and have been associated with severe disease presentations. However, most studies did not systematically investigate the role of MOG-IgG intrathecal synthesis (ITS).

Methods: We retrospectively studied 960 consecutive patients with paired serum and CSF samples screened for MOG-IgG using a live cell-based assays. MOG-IgG-specific antibody index (AI_MOG) was systematically calculated using serum and CSF titres to assess MOG-IgG ITS, and clinical features were compared between MOG-IgG CSF+/CSF- and ITS+/ITS- patients.

Results: MOG-IgG were found in 55/960 patients (5.7%; serum+/CSF-: 58.2%, serum+/CSF+: 34.5%; serum-/CSF+: 7.3%). Serum/CSF MOG-IgG titres showed a moderate correlation in patients without ITS (ρ=0.47 (CI 0.18 to 0.68), p<0.001), but not in those with ITS (ρ=0.14 (CI -0.46 to -0.65), p=0.65). There were no clinical-paraclinical differences between MOG-IgG CSF+ vs CSF- patients. Conversely, patients with MOG-IgG ITS showed pyramidal symptoms (73% vs 32%, p=0.03), spinal cord involvement (82% vs 39%, p=0.02) and severe outcome at follow-up (36% vs 5%, p=0.02) more frequently than those without MOG-IgG ITS. A multivariate logistic regression model indicated that MOG-IgG ITS was an independent predictor of a poor outcome (OR: 14.93 (CI 1.40 to 19.1); p=0.03). AI_MOG correlated with Expanded Disability Status Scale (EDSS) scores at disease nadir and at last follow-up (p=0.02 and p=0.01).

Conclusions: Consistently with physiopathology, MOG-IgG ITS is a promising prognostic factor in MOGAD, and its calculation could enhance the clinical relevance of CSF MOG-IgG testing, making a case for its introduction in clinical practice.