cover image European Journal of Neurology

European Journal of Neurology

2023 - Volume 30
Issue 9 | September 2023

ISSUE INFORMATION

Issue Information

ORIGINAL ARTICLE

Background

Although the incidence of stroke in the young is rising, data on long‐term outcomes in these patients are scarce. We thus aimed to investigate the long‐term risk of recurrent vascular events and mortality in a multicenter study.

Methods

We followed 396 consecutive patients aged 18–55 years with ischemic stroke (IS) or transient ischemic attack (TIA) enrolled in three European centers during the period 2007–2010. A detailed outpatient clinical follow‐up assessment was performed between 2018 and 2020. When an in‐person follow‐up visit was not possible, outcome events were assessed using electronic records and registry data.

Results

During a median follow‐up of 11.8 (IQR 10.4–12.7) years, 89 (22.5%) patients experienced any recurrent vascular event, 62 (15.7%) had any cerebrovascular event, 34 (8.6%) had other vascular events, and 27 (6.8%) patients died. Cumulative 10‐year incidence rate per 1000 person‐years was 21.6 (95% CI 17.1–26.9) for any recurrent vascular event and 14.9 (95% CI 11.3–19.3) for any cerebrovascular event. The prevalence of cardiovascular risk factors increased over time, and 22 (13.5%) patients lacked any secondary preventive medication at the in‐person follow‐up. After adjustment for demographics and comorbidities, atrial fibrillation at baseline was found to be significantly associated with recurrent vascular events.

Conclusions

This multicenter study shows a considerable risk of recurrent vascular events in young IS and TIA patients. Further studies should investigate whether detailed individual risk assessment, modern secondary preventive strategies, and better patient adherence may reduce recurrence risk.

ORIGINAL ARTICLE

Background

5q Spinal muscular atrophy (SMA) is a progressive, inherited, and severely disabling – yet treatable – motor neuron disease. Although treatment options have evolved in recent years, biomarkers for treatment monitoring and prognosis prediction remain elusive. Here, we investigated the utility of corneal confocal microscopy (CCM), a non‐invasive imaging technique to quantify small corneal nerve fibres in vivo, as a diagnostic tool in adult SMA.

Methods

In this cross‐sectional study, 19 patients with SMA type 3 and 19 healthy controls underwent CCM to measure corneal nerve fibre density (CNFD), corneal nerve fibre length (CNFL), and corneal nerve branch density (CNBD), as well as corneal immune cell infiltration. Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores and a 6‐Minute Walk Test (6MWT) were conducted to explore any correlation between CCM findings and motor function.

Results

Corneal nerve fibre parameters were decreased in SMA patients versus healthy controls (CNFD:  = 0.030; CNFL:  = 0.013; CNBD:  = 0.020) in the absence of relevant immune cell infiltration. CNFD and CNFL correlated with HFMSE scores (CNFD:  = 0.492,  = 0.038; CNFL:  = 0.484,  = 0.042) and distance covered in the 6MWT (CNFD:  = 0.502,  = 0.042; CNFL:  = 0.553,  = 0.023).

Conclusions

Corneal confocal microscopy CCM reveals sensory neurodegeneration in SMA, thereby supporting a multisystem view of the disorder. Subclinical small nerve fibre damage correlated with motor function. Thus, CCM may be ideally suited for treatment monitoring and prognosis.

ORIGINAL ARTICLE

Background and purpose

This study was undertaken to investigate the longitudinal impact of type 2 diabetes mellitus (T2DM) on the prodromal and dementia stages of Alzheimer disease (AD), focusing on diabetes duration and other comorbidities.

Methods

A total of 1395 dementia‐free individuals aged 55–90 years with maximum 15‐year follow‐up data were enrolled from the Alzheimer's Disease Neuroimaging Initiative database. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of the incidence of prodromal or dementia stages of AD.

Results

Longer T2DM duration (≥5 years; multiadjusted HR = 2.19, 95% confidence interval [CI] = 1.05–4.58), but not shorter T2DM duration (<5 years), was associated with a significantly increased risk of incident prodromal AD over a mean follow‐up of 4.8 years. ε4 allele (HR = 3.32, 95% CI = 1.41–7.79) and comorbid coronary artery disease (CAD; HR = 3.20, 95% CI = 1.29–7.95) further increased the risk of incident prodromal AD in patients with T2DM. No significant association was observed between T2DM and the risk of progression from prodromal AD to AD dementia.

Conclusions

T2DM, which is characterized by a longer duration, increases the incidence risk of prodromal AD but not AD dementia. ε4 allele and comorbid CAD strengthen the relationship between T2DM and prodromal AD. These findings highlight T2DM characteristics and its comorbidities as predictors for accurate prediction of AD and screening of at‐risk populations.

ORIGINAL ARTICLE

Background and purpose

Recent studies suggest a possible association between Tarlov cysts (TCs), usually considered as incidental radiological findings, and neurological symptoms such as pain, numbness and urogenital complaints. The aim was to explore the relationship between TCs and sacral nerve root functions using pelvic neurophysiology tests, and to correlate changes with clinical symptoms and magnetic resonance imaging (MRI) findings.

Methods

Consecutive patients with sacral TCs, referred for pelvic neurophysiology testing and presenting with at least one symptom related to the pelvic area, participated in a cross‐sectional review of symptoms using validated questionnaires. Findings of pelvic neurophysiology (pudendal sensory evoked potentials, sacral dermatomal sensory evoked potentials, external anal sphincter electromyography) and urodynamics testing were collected retrospectively. The relationship between neurophysiology, MRI findings and patients' symptoms was assessed using Fisher and ANOVA tests.

Results

Sixty‐five females were included (mean age 51.2 ± 12.1 years). The commonest symptom was pain (92%). Urinary (91%), bowel (71%) and sexual (80%) symptoms were also frequently reported. Thirty‐seven patients (57%) had abnormal neurophysiology findings reflecting sacral root dysfunction. No association was seen between MRI findings (size, location of the cysts, severity of compression) and neurophysiology. A negative association was observed between neurophysiology abnormalities and occurrence of urgency urinary incontinence ( = 0.03), detrusor overactivity ( < 0.01) and stress urinary incontinence ( = 0.04); however, there was no association with voiding difficulties.

Conclusions

Contrary to current understanding, TCs are associated with injury to the sacral somatic innervation in the majority of patients with presumed symptomatic cysts. However, urinary incontinence is unlikely to be related to TC‐induced nerve damage.

REVIEW ARTICLE

Background

Since the results of previous studies regarding the safety and efficacy of miglustat in GM2 gangliosidosis (GM2g) were inconsistent, we aimed to assess miglustat therapy in GM2g patients.

Methods

This study followed the latest version of PRISMA. We included the observational or interventional studies reporting GM2g patients under miglustat therapy by searching PubMed, Web of Science, and Scopus. Data extracted included the natural history of individual patient data, as well as the safety and efficacy of miglustat in GM2g patients. The quality assessment was performed using the Joanna Briggs Institute Critical Appraisal checklist.

Results

A total of 1023 records were identified and reduced to 621 after removing duplicates. After screening and applying the eligibility criteria, 10 articles and 2 abstracts met the inclusion criteria. Overall, the studies represented 54 patients with GM2g under treatment with miglustat and 22 patients with GM2g in the control group. Among patients with available data, 14 and 54 have been diagnosed with Sandhoff disease and Tay‐Sachs disease, respectively. Patients included in this review consisted of 23 infantile, 4 late‐infantile, 18 juvenile, and 31 adult‐onset GM2g.

Conclusions

Although miglustat should not be considered a definite treatment for GM2g, it appears that patients, particularly those with infantile or late‐infantile GM2g, could benefit from miglustat therapy to some extent. We also make some suggestions regarding future studies presenting their findings in a standard format to facilitate pooling the available data in such rare diseases for a more comprehensive conclusion.

SHORT COMMUNICATION

Background

Pseudoprogression in gliomas has been extensively described after radiotherapy with or without chemotherapy, but not after chemotherapy alone. Here we describe the occurrence of pseudoprogression in patients with anaplastic oligodendrogliomas treated with postoperative procarbazine, lomustine and vincristine (PCV) chemotherapy alone.

Methods

We retrospectively reviewed the medical and radiological files of patients with 1p/19q codeleted, IDH‐mutant anaplastic oligodendrogliomas treated with PCV chemotherapy alone who presented magnetic resonance imaging (MRI) modifications suggestive of tumour progression and in whom the final diagnosis was a pseudoprogression.

Results

We identified six patients. All patients underwent a surgical resection and were treated with PCV chemotherapy without radiotherapy. After a median of 11 months following the initiation of chemotherapy (range: 3–49 months), the patients developed asymptomatic white matter MRI modifications around the surgical cavity leading to the suspicion of a tumour progression. These modifications appeared as hyperintense on T2‐fluid‐attenuated inversion recovery (FLAIR) sequence, hypointense on T1 sequence, and lacked mass effect (0/6), contrast enhancement (0/6), restriction on diffusion‐weighted imaging (0/4), relative cerebral blood volume (rCBV) increase on perfusion MRI (0/4), and hypermetabolism on F‐fluoro‐L‐dopa positron emission tomography (F‐DOPA PET) scan (0/3). One patient underwent a surgical resection demonstrating no tumour recurrence; the five other patients were considered as having post‐therapeutic modifications based on imaging characteristics. After a median follow‐up of 4 years all patients were progression‐free.

Conclusions

Anaplastic oligodendroglioma patients treated with postoperative PCV chemotherapy alone occasionally develop T2/FLAIR hyperintensities around the surgical cavity that can wrongly suggest tumour progression. Multimodal imaging and close follow‐up should be considered in this situation.

POSITION PAPER

Background

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease, and the time from symptom onset to diagnosis remains long. With the advent of disease‐modifying treatments, the need to identify and diagnose ALS in a timely fashion has never been greater.

Methods

We reviewed the literature to define the severity of ALS diagnostic delay, the various factors that contribute to this delay (including patient and physician factors), and the role that site of symptom onset plays in a patient's diagnostic journey.

Results

Diagnostic delay is influenced by general practitioners’ lack of recognition of ALS due to disease rarity and heterogenous presentations. As a result, patients are referred to non‐neurologists, have unnecessary diagnostic testing, and may ultimately be misdiagnosed. Patient factors include their illness behavior—which impacts diagnostic delay—and their site of symptom onset. Limb‐onset patients have the greatest diagnostic delay because they are frequently misdiagnosed with degenerative spine disease or peripheral neuropathy.

Conclusion

Prompt ALS diagnosis results in more effective clinical management, with earlier access to disease‐modifying therapies, multidisciplinary care, and, if desired, clinical trial involvement. Due to lack of commercially available ALS biomarkers, alternative strategies to identify and triage patients who likely have ALS must be employed. Several diagnostic tools have been developed to encourage general practitioners to consider ALS and make an urgent referral to ALS specialists, bypassing unnecessary referrals to non‐neurologists and unnecessary diagnostic workup.

ORIGINAL ARTICLE

Background and purpose

Valid measurements of cardiorespiratory fitness in persons with multiple sclerosis (pwMS) are essential during inpatient rehabilitation for a precise evaluation of the current health status, for defining appropriate exercise intensities, and for evaluation of exercise intervention studies. We aim (i) to examine the proportion of pwMS who attain the American College of Sports Medicine (ACSM) criteria for maximal effort during graded cardiopulmonary exercise testing (CPET) and (ii) to provide insight into participant characteristics that limit maximal exercise performance.

Methods

This cross‐sectional study comprises a retrospective examination of ACSM criteria for maximal effort during graded CPET of  = 380 inpatient pwMS (mean age = 48 ± 11 years, 66% female). Chi‐squared or Fisher's exact tests were conducted to compare differences in the distribution of criteria achieved. Participants' characteristics were examined as potential predictors using binary logistic regression.

Results

Only 60% of the overall sample attained a respiratory exchange ratio ≥ 1.10. With regard to the definition applied, only 24% or 40% of the participants achieved an oxygen consumption plateau, and 17% or 50% attained the heart rate criterion. Forty‐six percent met at least two of three criteria. Disability status, gender, disease course, and body mass index were associated with the attainment of maximal effort.

Conclusions

Our findings suggest that a relevant proportion of inpatient pwMS do not attain common criteria utilized to verify maximal oxygen consumption. Identified predictors for criteria attainment can be used to create models to predict cardiorespiratory fitness and to optimize CPET protocols in restrictive groups of pwMS.

LETTER TO THE EDITOR

Comment on: Prognostic significance of the clinical and radiological haemorrhagic transformation subtypes in acute ischaemic stroke: a systematic review and meta‐analysis

ORIGINAL ARTICLE

Background

Anxiety affects approximately 40% of Parkinson's disease (PD) patients. However, little is known about its predictors and development over time.

Objective

To identify the clinical factors and biomarkers associated with development of anxiety in patients with newly diagnosed PD, and to test which risk factors predict increases in anxiety over time.

Methods

Data from the Parkinson's Progression Markers Initiative (PPMI) were utilized. The primary outcome was the State–Trait Anxiety Inventory (STAI). Covariates were demographics, motor and non‐motor symptoms, cognitive functions, dopamine transporter imaging data, and cerebrospinal fluid (CSF) biomarkers. We examined the association of risk factors at baseline and over 4 years with changes in anxiety scores over time.

Results

A total of 252 patients met the inclusion criteria (mean age: 61.36 years, SD 9.53). At year 4, 42 patients had developed anxiety. Baseline predictors of increase in anxiety scores were greater autonomic dysfunction, dysexecutive function, CSF t‐tau levels, excessive daytime sleepiness, and lower olfactory function scores but not motor scores. Over 4 years, change in anxiety scores correlated with deterioration in overall cognitive function, excessive daytime sleepiness, as well as depression and disability, and to a lesser degree worsening of Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) motor scores and caudate dopaminergic uptake changes.

Conclusions

These findings suggest that development of anxiety in PD is not primarily based on a dopaminergic deficit in the basal ganglia but related to non‐dopaminergic or extrastriatal pathology. Early dysexecutive function predicts development of anxiety but increase in anxiety levels correlates most strongly with more global cognitive decline.

SHORT COMMUNICATION

Background and purpose

During the COVID‐19 pandemic, ocrelizumab administration was frequently postponed because of a lack of safety information and to favour vaccination. The clinical implications of ocrelizumab administration delay in multiple sclerosis (MS) patients were assessed.

Methods

Relapsing (RMS) and primary progressive (PPMS) MS patients receiving ocrelizumab for at least 6 months at our centre were retrospectively classified, according to the possible occurrence of a delay (≥4 weeks) in treatment administration. Patients were categorized in the extended‐interval dosing (EID) group in the presence of at least one delayed infusion; otherwise they were considered as part of the standard interval dosing (SID) cohort. MS history, magnetic resonance imaging examinations and B‐cell counts were also retrospectively collected and analysed.

Results

A total of 213 RMS and 61 PPMS patients were enrolled; 115 RMS and 29 PPMS patients had been treated according to the SID regimen, whilst 98 RMS and 32 PPMS patients were included in the EID cohort. Average follow‐up after delay was 1.28 ± 0.7 years in the EID cohort. In RMS, comparing SID and EID patients, no differences were found considering the occurrence of clinical relapses (9.6% vs. 16.3%,  = 0.338), magnetic resonance imaging activity (9.8% vs. 14.1%,  = 0.374) or disability progression (11.3% vs. 18.4%,  = 0.103). Similar findings were observed in PPMS patients. In the pooled EID group, treatment delay correlated with CD19‐positive relative ( = 0.530,  < 0.001) and absolute ( = 0.491,  < 0.001) cell counts, without implications on disease activity.

Conclusions

Sporadic ocrelizumab administration delay granted sustained treatment efficacy in our cohort. Prospective data should be obtained to confirm these observations and set up systematic extended‐interval regimens.

ORIGINAL ARTICLE

Background and purpose

Chronic pain is a common comorbidity in those with functional neurological disorder (FND); however, the prevalence and characteristics of FND in those with chronic pain is unknown.

Methods

A retrospective electronic records review was made of consecutive new patients attending a chronic pain clinic of a regional service. Clinical features, medication for and outcome of chronic pain, any lifetime diagnoses of functional disorders, FND, and psychiatric disorders, and undiagnosed neurological symptoms were recorded.

Results

Of 190 patients attending the chronic pain clinic, 32 (17%) had a lifetime diagnosis of FND and an additional 11 (6%) had undiagnosed neurological symptoms. Pain patients with comorbid FND were more likely to have chronic primary pain (88% with FND, 44% without FND,  < 0.0001), widespread chronic primary pain (53%, 15%,  < 0.00001), and depression (84%, 52%,  < 0.005) and less likely to have a pain‐precipitating event (19% vs. 56%,  < 0.001). However, there was no significant difference between these patients in opiate prescription, benzodiazepine prescription, or pain outcome.

Conclusions

This first study of FND in a chronic pain patient population found a remarkably high prevalence of FND (17%) and is possibly an underestimation. The size of the overlap indicates that FND and chronic pain research fields are likely to have a lot to learn from each other.

SHORT COMMUNICATION

Background and purpose

A genome‐wide association study‐linked variant ( rs6679073) modulates the risk of Parkinson's disease (PD). We postulate that there may be differences in clinical characteristics between rs6679073 carriers and noncarriers. In a prospective study, we investigate the clinical characteristics between rs6679073 A allele carriers and noncarriers over 4 years.

Methods

A total of 204 PD patients, comprising 158 rs6679073 A allele carriers and 46 noncarriers, were recruited. All patients underwent motor and nonmotor symptom and cognitive assessments yearly over 4 years.

Results

rs6679073 carriers were less likely to have mild cognitive impairment (MCI) compared to noncarriers at both baseline (48.1% vs. 67.4%,  = 0.027) and 4‐year follow‐up (29.3% vs. 58.6%,  = 0.007).

Conclusions

PD rs6679073 carriers had significantly lower frequency of MCI in a 4‐year follow‐up study, suggesting that the variant may have a neuroprotective effect on cognitive functions.

ORIGINAL ARTICLE

Background

Classical infantile‐onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long‐term outcomes.

Methods

We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020.

Results

Sixty‐four patients were identified. At diagnosis (median age 4 months) all patients had cardiomyopathy and most had severe hypotonia (57 of 62 patients, 92%). ERT was initiated in 50 (78%) patients and stopped later due to being ineffective in 10 (21%). Thirty‐seven (58%) patients died during follow‐up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first 3 years of life and after the age of 12 years. Persistence of cardiomyopathy during follow‐up and/or the presence of heart failure were highly associated with an increased risk of death. In contrast, cross‐reactive immunologic material (CRIM)‐negative status ( = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Besides survival, decreased ERT efficacy appeared after the age of 6 years, with a progressive decline in motor and pulmonary functions for most survivors.

Conclusions

This study reports the long‐term follow‐up of one of the largest cohorts of classical IOPD patients and demonstrates high long‐term mortality and morbidity rates with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance of developing new therapeutic approaches targeting various aspects of pathogenesis.

ORIGINAL ARTICLE

Background and purpose

Bilateral deep brain stimulation (DBS) surgery targeting the globus pallidus internus (GPi) or the subthalamic nucleus (STN) is widely used in medication‐refractory dystonia. However, evidence regarding target selection considering various symptoms remains limited. This study aimed to compare the effectiveness of these two targets in patients with isolated dystonia.

Methods

This retrospective study evaluated 71 consecutive patients (GPi‐DBS group, = 32; STN‐DBS group, = 39) with isolated dystonia. Burke–Fahn–Marsden Dystonia Rating Scale scores and quality of life were evaluated preoperatively and at 1, 6, 12, and 36 months postoperatively. Cognition and mental status were assessed preoperatively and at 36 months postoperatively.

Results

Targeting the STN (STN‐DBS) yielded effects within 1 month (65% vs. 44%;  = 0.0076) and was superior at 1 year (70% vs. 51%;  = 0.0112) and 3 years (74% vs. 59%;  = 0.0138). For individual symptoms, STN‐DBS was preferable for eye involvement (81% vs. 56%;  = 0.0255), whereas targeting the GPi (GPi‐DBS) was better for axis symptoms, especially for the trunk (82% vs. 94%;  = 0.015). STN‐DBS was also favorable for generalized dystonia at 36‐month follow‐up ( = 0.04) and required less electrical energy ( < 0.0001). Disability, quality of life, and depression and anxiety measures were also improved. Neither target influenced cognition.

Conclusions

We demonstrated that the GPi and STN are safe and effective targets for isolated dystonia. The STN has the benefits of fast action and low battery consumption, and is superior for ocular dystonia and generalized dystonia, while the GPi is better for trunk involvement. These findings may offer guidance for future DBS target selection for different types of dystonia.

ORIGINAL ARTICLE

Background and purpose

The association between Parkinson's disease (PD) and age‐related macular degeneration (AMD) has been shown in previous reports. However, the association between the severity of AMD and PD development is unknown. The aim was to evaluate the association of AMD with/without visual disability (VD) with the risk of PD occurrence using the National Health Insurance data in South Korea.

Methods

A total of 4,205,520 individuals, 50 years or older and without a previous diagnosis of PD, participated in the Korean National Health Screening Program in 2009. AMD was verified using diagnostic codes, and participants with VD were defined as those with loss of vision or visual field defect as certified by the Korean Government. The participants were followed up until 31 December 2019, and incident cases of PD were identified using registered diagnostic codes. The hazard ratio was calculated for groups (control and AMD with/without VD) using multivariable adjusted Cox regression analysis.

Results

In total, 37,507 participants (0.89%) were diagnosed with PD. Amongst individuals with AMD, the risk of PD development was higher in individuals with VD (adjusted hazard ratio [aHR] 1.35, 95% confidence interval [CI] 1.09–1.67) than in those without (aHR 1.22, 95% CI 1.15–1.30) compared with controls. Additionally, an increased risk of PD was observed in individuals with AMD compared with controls, regardless of the presence of VD (aHR 1.23, 95% CI 1.16–1.31).

Conclusions

Visual disability in AMD was associated with the development of PD. This suggests that neurodegeneration in PD and AMD may have common pathways.

SHORT COMMUNICATION

Background

The kappa free light chains index (‐index) is increasing in importance as a fast, easy, cost‐effective, and quantitative biomarker in multiple sclerosis (MS), which can replace cerebrospinal fluid (CSF)‐restricted oligoclonal bands (OCB) detection. In previous studies, controls often included mixed patients with several inflammatory central nervous system disorders. The aim of the present study was to assess the κ‐index in patients with serum aquaporin‐4 (AQP4)‐IgG or myelin‐oligodendrocyte‐glycoprotein (MOG)‐IgG.

Methods

We analyzed CSF/serum samples of patients with AQP4‐IgG or MOG‐Ig and evaluated distinct κ‐index cut‐offs. We described clinical and magnetic resonance imaging (MRI) features of patients with the highest ‐index values.

Results

In 11 patients with AQP4‐IgG, median ‐index was 16.8 (range 0.2; 63) and 6/11 (54.5%) had ‐index >12. Among 42 patients with MOG‐IgG, 2 had low positive MOG‐IgG titers, were ultimately diagnosed with MS, and had a markedly increased ‐index (54.1 and 102.5 respectively). For the remaining 40 MOG‐IgG‐positive patients the median ‐index was 0.3 (range 0.1; 15.5). Some 6/40 (15%) and 1/40 (2.5%) patients had a ‐index >6 and >12, respectively. None fulfilled MRI dissemination in space and dissemination in time (DIS/DIT) criteria and the final diagnosis was MOG‐IgG‐associated disease (MOGAD) for these 40 patients. Four of the 40 (10%) MOG‐IgG‐positive patients had OCB.

Conclusion

While a marked increase in κ‐index could discriminate MS from MOGAD, a low ‐index threshold could lead to confusion between MS and MOGAD or AQP4 antibody‐positive neuromyelitis optica spectrum disorder.

ORIGINAL ARTICLE

Background and purpose

Mechanical thrombectomy (MT) has proven to be the standard of care for patients with acute ischemic stroke due to large vessel occlusion (AIS‐LVO). However, high revascularization rates do not necessarily result in favorable functional outcomes. We aimed to investigate imaging biomarkers associated with futile recanalization, defined as unfavorable functional outcome despite successful recanalization in AIS‐LVO patients.

Methods

A retrospective multicenter cohort study was made of AIS‐LVO patients treated by MT. Successful recanalization was defined as modified Thrombolysis in Cerebral Infarction score of 2b–3. A modified Rankin Scale score of 3–6 at 90 days was defined as unfavorable functional outcome. Cortical Vein Opacification Score (COVES) was used to assess venous outflow (VO), and the Tan scale was utilized to determine pial arterial collaterals on admission computed tomography angiography (CTA). Unfavorable VO was defined as COVES ≤ 2. Multivariable regression analysis was performed to investigate vascular imaging factors associated with futile recanalization.

Results

Among 539 patients in whom successful recanalization was achieved, unfavorable functional outcome was observed in 59% of patients. Fifty‐eight percent of patients had unfavorable VO, and 31% exhibited poor pial arterial collaterals. In multivariable regression, unfavorable VO was a strong predictor (adjusted odds ratio = 4.79, 95% confidence interval = 2.48–9.23) of unfavorable functional outcome despite successful recanalization.

Conclusions

We observe that unfavorable VO on admission CTA is a strong predictor of unfavorable functional outcomes despite successful vessel recanalization in AIS‐LVO patients. Assessment of VO profiles could help as a pretreatment imaging biomarker to determine patients at risk for futile recanalization.

ORIGINAL ARTICLE

Background and purpose

The differences in cognitive function between primary progressive and secondary progressive multiple sclerosis (MS) remain unclear. We compared cognitive performance between primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), and explored the structural and functional magnetic resonance imaging (MRI) correlates of their cognitive functions.

Methods

Seventy‐five healthy controls and 183 MS patients (60 PPMS and 123 SPMS) underwent 3.0‐T MRI. MS patients were administered the Brief Repeatable Battery of Neuropsychological Tests; cognitive domain ‐scores were calculated and then averaged to obtain a measure of global cognition. Using hierarchical linear regression analysis, the contribution of lesion volumes, normalized brain volumes, white matter (WM) fractional anisotropy (FA) and mean diffusivity abnormalities, and resting state (RS) functional connectivity (FC) alterations to global cognition in PPMS and SPMS was investigated.

Results

PPMS and SPMS had similar ‐scores in all investigated cognitive domains. Poor global cognitive function was associated with decreased FA of the medial lemniscus (Δ  = 0.11,  = 0.011) and lower normalized gray matter volume (Δ  = 0.29,  < 0.001) in PPMS, and with decreased FA of the fornix (Δ  = 0.35,  < 0.001) and lower normalized WM volume (Δ  = 0.05;  = 0.034) in SPMS.

Conclusions

PPMS and SPMS had similar neuropsychological performance. Cognitive dysfunction in PPMS and SPMS was related to distinct patterns of structural MRI abnormalities and involvement of different WM tracts, whereas RS FC alterations did not contribute to explaining their global cognitive functioning.

ORIGINAL ARTICLE

Background and purpose

Having good collaterals is associated with better clinical outcomes in patients undergoing endovascular thrombectomy. This study aims to evaluate whether the effect of collateral status on functional outcomes is modified by volemia at admission.

Methods

This is a single‐center, retrospective analysis of patients who had acute proximal anterior circulation occlusion and underwent endovascular thrombectomy between January 2019 and June 2022. Volemia at admission, evaluated by blood urea nitrogen‐to‐creatinine ratio, was used to dichotomize patients into dehydrated and hydrated groups. The primary outcome was functional independence (90‐day modified Rankin Scale score = 0–2). Secondary outcomes were the rates of successful reperfusion, 24‐h symptomatic intracranial hemorrhage, and 90‐day all‐cause mortality. Multivariable logistic regression analysis was used to assess the interaction between collateral status and volemia at admission on outcomes.

Results

A total of 290 patients were enrolled, among whom having good collaterals was associated with functional independence (adjusted odds ratio [OR] = 2.71, 95% confidence interval [CI] = 1.41–5.22,  = 0.003). Having good collaterals benefited dehydrated patients (adjusted OR = 3.33, 95% CI = 1.45–7.63,  = 0.004) but not hydrated patients (adjusted OR = 2.21, 95% CI = 0.73–6.68,  = 0.161). However, an interaction between collaterals and volemia at admission on functional independence was not observed ( = 0.319). The rates of successful reperfusion, symptomatic intracerebral hemorrhage, and all‐cause mortality were similar between those with good and poor collaterals in both dehydrated and hydrated patients.

Conclusions

The effect of collateral status on the functional independence of patients undergoing thrombectomy is not modified by volemia at admission.

ORIGINAL ARTICLE

Background and purpose

A heart age biomarker has been developed using deep neural networks applied to electrocardiograms. Whether this biomarker is associated with cognitive function was investigated.

Methods

Using 12‐lead electrocardiograms, heart age was estimated for a population‐based sample ( = 7779, age 40–85 years, 45.3% men). Associations between heart delta age (HDA) and cognitive test scores were studied adjusted for cardiovascular risk factors. In addition, the relationship between HDA, brain delta age (BDA) and cognitive test scores was investigated in mediation analysis.

Results

Significant associations between HDA and the Word test, Digit Symbol Coding Test and tapping test scores were found. HDA was correlated with BDA (Pearson's  = 0.12,  = 0.0001). Moreover, 13% (95% confidence interval 3–36) of the HDA effect on the tapping test score was mediated through BDA.

Discussion

Heart delta age, representing the cumulative effects of life‐long exposures, was associated with brain age. HDA was associated with cognitive function that was minimally explained through BDA.

SHORT COMMUNICATION

Background and purpose

Easy and reliable tools for the differential diagnosis between idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) are needed.

Materials and methods

In this cross‐sectional study iNPH and AD patients referred to the Neurology Unit of the University of Catania from 1 January 2020 to 1 December 2022 were enrolled. The following brain linear measurements (BLMs) were calculated: Evan's index (EI), the parieto‐occipital ratio (POR) and the temporal ratio (TR). For each index, sensitivity, specificity and the area under the curve (AUC) were calculated. Moreover, a cumulative index, the BLM index, was also considered.

Results

Fifty patients (25 iNPH and 25 AD) were enrolled. In differentiating iNPH from AD, EI had the highest AUC (0.956), POR had the highest specificity (100%) whilst TR had the highest sensitivity (92%). The BLM index differentiated iNPH and AD with a sensitivity of 96%, a specificity of 92% and an AUC of 0.963 with an optimal cut‐off value of 0.303.

Conclusion

Evan's index, POR and TR may be useful in the differential diagnosis between iNPH and AD. At an individual level, the BLM index represents a valid and reliable tool to achieve an accurate differentiation between these two conditions.

SHORT COMMUNICATION

Background and purpose

Adult onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with a heterogeneous clinical presentation that can mimic stroke and various forms of dementia. To date, it has been described almost exclusively in Asian individuals.

Methods

This case presentation includes magnetic resonance imaging (MRI) of the neurocranium, histology by skin biopsy, and long‐read genome sequencing.

Results

A 75‐year‐old Caucasian female presented with paroxysmal encephalopathy twice within a 14‐month period. Brain MRI revealed high‐intensity signals at the cerebral corticomedullary junction (diffusion‐weighted imaging) and the paravermal area (fluid‐attenuated inversion recovery), a typical distribution observed in adult onset NIID. The diagnosis was corroborated by skin biopsy, which demonstrated eosinophilic intranuclear inclusion bodies, and confirmed by long‐read genome sequencing, showing an expansion of the GGC repeat in exon 1 of .

Conclusions

Our case proves adult onset ‐GGC‐positive NIID with typical findings on MRI and histology in a Caucasian patient and underscores the need to consider this diagnosis in non‐Asian individuals.

EDITORIAL

Long‐term follow‐up after minor ischaemic strokes or transient ischaemic attacks: not as good as previously thought

ORIGINAL ARTICLE

Background and purpose

The purpose of this study was to explore the relationship between intracranial atherosclerosis and cerebral small vessel disease (CSVD).

Methods

Community‐dwelling residents of Lishui, China in the PRECISE (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) study were involved. Intracranial atherosclerosis was grouped by the severity of intracranial artery plaques with stenosis and burden. Four imaging markers including lacunes, white matter hyperintensity (WMH), cerebral microbleeds (CMBs), and perivascular spaces (PVS) as well as the CSVD burden scores were assessed. Logistic regression or ordinal logistic regression models with odds ratio (OR) or common OR (cOR) were used to estimate the relationship between intracranial atherosclerosis and CSVD markers and burdens.

Results

The mean age was 61.20 ± 6.68 years, and 1424 (46.52%) were men among 3061 participants included at baseline. Intracranial atherosclerotic burden was associated with the severity of the lacunes (OR = 4.18, 95% confidence interval [CI] = 1.83–9.58), modified WMH burden (cOR = 1.94, 95% CI = 1.01–3.71), presence of CMBs (OR = 2.28, 95% CI = 1.05–4.94), and CMB burden (OR = 2.23, 95% CI = 1.03–4.80). However, it was not associated with the WMH burden and PVS. Intracranial atherosclerotic burden was associated with CSVD burden (Wardlaw: cOR = 2.73, 95% CI = 1.48–5.05; Rothwell: cOR = 2.70, 95% CI = 1.47–4.95). The association between intracranial atherosclerosis and CSVD was obvious in participants with both anterior and posterior circulation artery stenosis.

Conclusions

Based on a Chinese community population, there may be an association between intracranial atherosclerosis and CSVD, but its mechanism in relation to vascular risk factors still needs to be clarified.

ORIGINAL ARTICLE

Background and purpose

The overall disability in patients with relapsing–remitting multiple sclerosis is likely to be partly rather than entirely attributed to relapse.

Materials and methods

The aim was to investigate the determinants of recovery from first relapse and relapse‐associated worsening (RAW) in relapsing–remitting multiple sclerosis patients from the Italian MS Registry during a 5‐year epoch from the beginning of first‐line disease‐modifying therapy. To determine recovery, the functional system (FS) score was used to calculate the difference between the score on the date of maximum improvement and the score before the onset of relapse. Incomplete recovery was defined as a combination of partial (1 point in one FS) and poor recovery (2 points in one FS or 1 point in two FSs or any other higher combination). RAW was indicated by a confirmed disability accumulation measured by the Expanded Disability Status Scale score confirmed 6 months after the first relapse.

Results

A total of 767 patients had at least one relapse within 5 years of therapy. Of these patients, 57.8% experienced incomplete recovery. Age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01–1.04;  0.007) and pyramidal phenotype were associated with incomplete recovery (OR = 2.1, 95% CI 1.41–3.14;  0.001). RAW was recorded in 179 (23.3%) patients. Age (OR = 1.02, 95% CI 1.01–1.04;  0.029) and pyramidal phenotype (OR = 1.84, 95% CI 1.18–2.88;  0.007) were the strongest predictors in the multivariable model.

Conclusions

Age and pyramidal phenotype were the strongest determinants of RAW in early disease epochs.

LETTER TO THE EDITOR

Response to ‘Functional neurological disorder in people with long COVID: A systematic review’

SHORT COMMUNICATION

Background and purpose

People with multiple sclerosis (MS) suffer from higher infection‐related mortality compared to the general population; however, sparse data are available on the increased risk of death associated with coronavirus disease 2019 (COVID‐19) and other common types of infections.

Methods

All mortality records and multiple‐cause‐of‐death data in 2010–2021 of residents in the Veneto region (northeastern Italy) were extracted. Mention of specific infections was compared between death certificates reporting MS or not. Odds ratios (OR) with 95% confidence intervals (95% CI) were estimated by conditional logistic regression matching by age, sex and calendar year. The bimonthly averages of MS‐related deaths in 2010–2019 were compared with those registered during the pandemic (2020–2021).

Results

Of 580,015 deaths through 2010–2021, MS was mentioned in 850 cases (0.15%), 59.3% women. Influenza and pneumonia were reported in 18.4% of MS‐related compared to 11.0% non‐MS‐related deaths (OR 2.72, 95% CI 2.28–3.25). The odds of mention of urinary tract infections was significantly greater in MS‐related deaths of men (OR 8.16, 95% CI 5.23–12.7) than women (OR 3.03, 95% CI 1.82–5.02). Aspiration pneumonia, pressure ulcers/skin infections and sepsis were also significantly associated with MS‐related deaths. Reporting of COVID‐19 as a cause of death did not significantly differ between deaths with and without mention of MS (approximately 11% of both). However, compared to 2010–2019, peaks in MS‐related deaths were observed during the pandemic waves.

Conclusions

Infections continue to play a significant role in MS‐related deaths, underlying the need to improve prevention and management strategies.

ORIGINAL ARTICLE

Background

Patients with multiple sclerosis (MS) who discontinue fingolimod might present with rebound activity. The reasons for the development of rebound have been identified, but there are limited data on the long‐term clinical outcomes of these patients. This study aimed to compare the long‐term outcomes of patients with MS with and without rebound activity after fingolimod discontinuation.

Methods

A total of 31 patients who discontinued fingolimod for various reasons with a minimum follow‐up of 5 years were included in the study. Of these, 10 were assigned to the rebound group and 21 to the non‐rebound group. Clinical and demographic data and 5‐year clinical outcomes of both groups were prospectively examined.

Results

At fingolimod initiation, there were no significant differences in age, disease duration, and Expanded Disability Status Scale (EDSS) score. The annualized relapse rate (ARR) was significantly higher in the rebound group than in the non‐rebound group before the fingolimod treatment ( = 0.005). In the rebound group, EDSS scores 2 months after rebound treatment and at the 5‐year follow‐up were not significantly different than before fingolimod initiation ( = 0.14 and  = 0.46, respectively). The last recorded EDSS was significantly higher in the non‐rebound group than in the rebound group (3.6 ± 2.3 vs. 2.15 ± 1.4,  = 0.045). At the last follow‐up, one patient was diagnosed with secondary progressive multiple sclerosis in the rebound group (10%), and 11 patients were in the non‐rebound group (52.4%,  = 0.05).

Conclusion

When rebound activity is well‐monitored and treated after fingolimod discontinuation, no overall EDSS change is expected in the long‐term follow‐up.

ORIGINAL ARTICLE

Background and purpose

It is currently unknown whether vaginal oestradiol is associated with development of meningioma and glioma. The aim of this study was to examine associations between cumulative use and treatment intensity of vaginally administered oestradiol tablets and incidence of meningioma and glioma in a nationwide, population‐based study.

Methods

We conducted a nested case–control study within a nationwide cohort of Danish women followed from 2000 to 2018. The cohort consisted of 590,676 women aged 50–60 years at study start, without prior cancer diagnosis or use of systemic hormone therapy. Information on cumulative dose, duration, and intensity of vaginal oestradiol tablet use was assessed from filled prescriptions. Conditional logistic regression provided adjusted hazard ratios (HRs) for the association between vaginal oestradiol use and diagnosis of meningioma or glioma.

Results

We identified 1108 women with meningioma and 835 with glioma. Of these, 19.8% and 14.0% used vaginal oestradiol tablets, respectively. The HRs in those with ever‐use of vaginal oestradiol tablets was 1.14 (95% confidence interval [CI] 0.97–1.34) for meningioma and 0.90 (95% CI 0.73–1.11) for glioma. The corresponding HRs for new users exclusively were 1.18 (95% CI 0.99–1.40) for meningioma and 0.89 (95% CI 0.71–1.13) for glioma. Intensity of vaginal oestradiol tablet use according to duration and user status yielded slightly elevated HRs for meningioma without an apparent dose–response pattern, while the HRs for glioma were generally below unity. Among new users, the HR with high intensity of current or recent vaginal oestradiol tablet use for 2+ years was 1.66 (95% CI 1.09–2.55) for meningioma and 0.77 (95% CI 0.41–1.44) for glioma.

Conclusion

Use of vaginal oestradiol tablets was associated with a slightly increased incidence of meningioma but not of glioma. Owing to the observational nature of the study, residual bias cannot be ruled out.

EDITORIAL

will flip to open access in January 2024

REVIEW ARTICLE

Background and purpose

Hormonal replacement therapy (HRT) is used for symptomatic treatment of menopause. Some evidence suggests a proconvulsant effect of estrogen and an anticonvulsant role of progesterone. Thus, the use of exogenous sex steroid hormones might influence the course of epilepsy in peri‐ and postmenopausal women with epilepsy (WWE). We conducted a systematic review on the impact of HRT on the frequency of seizures of WWE.

Methods

PubMed and Scopus were searched for articles published from inception until August 2022. Abstracts from the past 5 years from the European Academy of Neurology and European Epilepsy Congresses were also reviewed. Article reference lists were screened, and relevant articles were retrieved for consultation. Interventional and observational studies on WWE and animal models of estrogen deficiency were included. Critical appraisal was performed using the revised Cochrane risk‐of‐bias tool for randomized trials and ROBINS‐E tool.

Results

Of 497 articles screened, 13 studies were included, including three human studies. One cross‐sectional study showed a decrease in seizure frequency in WWE using combined HRT, a case–control study showed an increase in comparison with controls, and a randomized clinical trial found a dose‐dependent increase in seizure frequency in women with focal epilepsy taking combined HRT. Ten studies addressing the impact of HRT in rat models were also included, which showed conflicting results.

Conclusions

There is scarce evidence of the impact of HRT in WWE. Further studies should evaluate the harmful potential, and prospective registries are needed for monitoring this population.

LETTER TO THE EDITOR

SARS‐CoV‐2 cannot unmask Parkinson's disease if there was none before infection

ORIGINAL ARTICLE

Introduction

While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions.

Methods

We processed T1‐weighted MRI from IMAGE‐HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp‐HD), 40 pre‐symptomatic (pre‐HD), and 36 healthy control individuals across three timepoints over 36 months.

Results

Mixed‐model analyses revealed significantly lower subfield volumes in symp‐HD, compared with pre‐HD and control groups, in the subicular regions of the perforant‐pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp‐HD. Volumes between pre‐HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant‐pathway subfield volumes. Hippocampal left tail and perforant‐pathway subfields were associated with motor onset in the pre‐HD group.

Conclusions

Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant‐pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.

ORIGINAL ARTICLE

Background and purpose

Epstein–Barr virus (EBV) is implicated in multiple sclerosis (MS) risk; evidence for other herpesviruses is inconsistent. Here, we test blood markers of infection with human herpesvirus 6 (HHV‐6), varicella zoster virus (VZV), and cytomegalovirus (CMV) as risk factors for a first clinical diagnosis of central nervous system demyelination (FCD) in the context of markers of EBV infection.

Methods

In the Ausimmune case–control study, cases had an FCD, and population controls were matched on age, sex, and study region. We quantified HHV‐6‐ and VZV‐DNA load in whole blood and HHV‐6, VZV, and CMV antibodies in serum. Conditional logistic regression tested associations with FCD risk, adjusting for Epstein–Barr nuclear antigen (EBNA) IgG, EBV‐DNA load, and other covariates.

Results

In 204 FCD cases and 215 matched controls, only HHV‐6‐DNA load (positive vs. negative) was associated with FCD risk (adjusted odds ratio = 2.20, 95% confidence interval = 1.08–4.46,  = 0.03). Only EBNA IgG and HHV‐6‐DNA positivity were retained in a predictive model of FCD risk; the combination had a stronger association than either alone. CMV‐specific IgG concentration modified the association between an MS risk‐related human leucocyte antigen gene and FCD risk. Six cases and one control had very high HHV‐6‐DNA load (>1.0 × 10 copies/mL).

Conclusions

HHV‐6‐DNA positivity and high load (possibly due to inherited HHV‐6 chromosomal integration) were associated with increased FCD risk, particularly in association with markers of EBV infection. With growing interest in prevention/management of MS through EBV‐related pathways, there should be additional consideration of the role of HHV‐6 infection.

ORIGINAL ARTICLE

Background and purpose

The timed 25‐foot walk (T25FW) and nine‐hole peg test (NHPT) exhibit random variability in the short term. A threshold of ≥20% change from baseline has been used to indicate true disability change, but other threshold definitions may be better suited to exclude false and include true change events. The aim of this study was to use patient‐level original trial data to investigate the short‐term variation in T25FW and NHPT, and to compare its extent with disability change at 12‐month follow‐up in people with primary progressive multiple sclerosis (PPMS).

Methods

We used original patient‐level data from PROMISE, a large PPMS trial. In this trial, three separate T25FW and NHPT measurements were performed 1 week apart during screening. We used these repeated measures to describe the extent of short‐term variation. We used binary logistic regression models to investigate the association between screening characteristics and unacceptable short‐term variation.

Results

The traditional 20% threshold excluded a reasonable number of false change events, while also yielding a large number of change events at follow‐up. Increasing index values on the T25FW and NHPT were associated with higher short‐term variation.

Conclusions

The traditional ≥20% change threshold for the T25FW and NHPT represents a reasonable compromise between reducing the number of false change events and achieving the largest number of change events in people with PPMS. Our analyses inform the design of clinical trials in PPMS.

LETTER TO THE EDITOR

Reply to the letter “SARS‐CoV‐2 cannot unmask Parkinson's disease if there was none before infection”

REVIEW ARTICLE

Abstract

The widespread use of magnetic resonance imaging (MRI) has led to an increase in incidental findings in the central nervous system. Radiologically isolated syndrome (RIS) is a condition where imaging reveals lesions suggestive of demyelinating disease without any clinical episodes consistent with multiple sclerosis (MS). The prognosis for RIS patients is uncertain, with some remaining asymptomatic while others progress to MS. Several risk factors for disease progression have been identified, including male sex, younger age at diagnosis, and spinal cord lesions. This article reviews two promising biomarkers, the central vein sign (CVS) and the paramagnetic rim sign (PRS), and their potential role in the diagnosis and prognosis of MS and RIS. Both CVS and PRS have been shown to be accurate diagnostic markers in MS, with high sensitivity and specificity, and have been useful in distinguishing MS from other disorders. Further research is needed to validate these findings and determine the clinical utility of these biomarkers in routine practice.

ORIGINAL ARTICLE

Background and purpose

Following increasing demands of patients with suspected neurological symptoms after infection with severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2), the Department of Neurology at the Medical University of Vienna established a new outpatient clinic to systematically assess, diagnose, and document neurological complaints potentially associated with a prior SARS‐CoV‐2 infection.

Methods

The data presented here include prospectively collected 156 outpatients from May 2021 to April 2022. Patients underwent semistandardized interviewing about symptoms with reported onset after SARS‐CoV‐2 infection, neurological examination, and comprehensive diagnostic workup.

Results

Reported new onset symptoms after infection included fatigue (77.6%), subjective cognitive impairment (72.4%), headache (47.7%), loss of smell and/or taste (43.2%), and sleep disturbances (42.2%). Most patients had a mild coronavirus disease (COVID‐19) disease course (84%) and reported comorbidities (71%), of which the most frequent were psychiatric disorders (34%). Frequency of symptoms was not associated with age, sex, or severity of COVID‐19 course. A comprehensive diagnostic workup revealed no neurological abnormalities in the clinical examination, or electrophysiological or imaging assessments in the majority of patients ( = 143, 91.7%). Neuropsychological assessment of a subgroup of patients ( = 28, 17.9%) showed that cognitive impairments in executive functions and attention, anxiety, depression, and somatization symptoms were highly common.

Conclusions

In this systematic registry, we identified fatigue, cognitive impairment, and headache as the most frequently reported persisting complaints after SARS‐CoV‐2 infection. Structural neurological findings were rare. We also suspect a link between the growing burden of the COVID‐19 pandemic on personal lives and the increase in reported neurological and psychiatric complaints.

ORIGINAL ARTICLE

Background and purpose

There is increasing evidence that cardiovascular risk (CVR) contributes to disability progression in multiple sclerosis (MS). CVR is particularly prevalent in secondary progressive MS (SPMS) and can be quantified through validated composite CVR scores. The aim was to examine the cross‐sectional relationships between excess modifiable CVR, whole and regional brain atrophy on magnetic resonance imaging, and disability in patients with SPMS.

Methods

Participants had SPMS, and data were collected at enrolment into the MS‐STAT2 trial. Composite CVR scores were calculated using the QRISK3 software. Prematurely achieved CVR due to modifiable risk factors was expressed as QRISK3 premature CVR, derived through reference to the normative QRISK3 dataset and expressed in years. Associations were determined with multiple linear regressions.

Results

For the 218 participants, mean age was 54 years and median Expanded Disability Status Scale was 6.0. Each additional year of prematurely achieved CVR was associated with a 2.7 mL (beta coefficient; 95% confidence interval 0.8–4.7;  = 0.006) smaller normalized whole brain volume. The strongest relationship was seen for the cortical grey matter (beta coefficient 1.6 mL per year; 95% confidence interval 0.5–2.7;  = 0.003), and associations were also found with poorer verbal working memory performance. Body mass index demonstrated the strongest relationships with normalized brain volumes, whilst serum lipid ratios demonstrated strong relationships with verbal and visuospatial working memory performance.

Conclusions

Prematurely achieved CVR is associated with lower normalized brain volumes in SPMS. Future longitudinal analyses of this clinical trial dataset will be important to determine whether CVR predicts future disease worsening.

ORIGINAL ARTICLE

Background and purpose

An enhanced severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine regimen could improve humoral vaccine response in patients with multiple sclerosis (MS) treated by anti‐CD20. The aim was to evaluate the serological response and the neutralizing activity after BNT162b2 primary and booster vaccination in MS patients, including patients on anti‐CD20 receiving a primary vaccine regimen enhanced with three injections.

Methods

In this prospective longitudinal cohort study of 90 patients (47 on anti‐CD20, 10 on fingolimod, 33 on natalizumab, dimethylfumarate or teriflunomide), anti‐SARS‐CoV‐2 receptor binding domain (RBD) immunoglobulin G antibodies were quantified and their neutralization capacity was evaluated by enzyme‐linked immunosorbent assay (GenScript) and a virus neutralization test against B.1 historical strain, Delta and Omicron variants, before and after three to four BNT162b2 injections.

Results

After the primary vaccination scheme, the anti‐RBD positivity rate was strongly decreased in patients on anti‐CD20 (28% [15%; 44%] after two shots, 45% [29%; 62%] after three shots) and fingolimod (50% [16%; 84%]) compared to other treatments (100% [90%; 100%]). Neutralization activity was also decreased in patients on anti‐CD20 and fingolimod, and notably low for the Omicron variant in all patients (0%–22%). Delayed booster vaccination was performed in 54 patients, leading to a mild increase of anti‐RBD seropositivity in patients on anti‐CD20 although it was still lower compared to other treatments (65% [43%; 84%] vs. 100% [87%; 100%] respectively). After a booster, Omicron neutralization activity remained low on anti‐CD20 and fingolimod treated patients but was strongly increased in patients on other treatments (91% [72%; 99%]).

Discussion

In MS patients on anti‐CD20, an enhanced primary vaccination scheme moderately increased anti‐RBD seropositivity and anti‐RBD antibody titre, but neutralization activity remained modest even after a fourth booster injection.

Trial registration information

COVIVAC‐ID, , first patient included on 20 April 2021.

ORIGINAL ARTICLE

Background and purpose

Autoantibodies have been found to contribute to pathology and are used in the diagnosis of some neurological diseases. We examined the prevalence of autoantibodies in patients with various neurological diseases and whether patients who had autoantibodies differed in age, sex, or disability from those who did not.

Methods

We examined the prevalence of neural surface and onconeural autoantibodies in cerebrospinal fluid (CSF) and serum from patients with multiple sclerosis ( = 64), Parkinson disease plus atypical parkinsonism ( = 150), amyotrophic lateral sclerosis ( = 43), or autoimmune encephalitis (positive control;  = 7) and a healthy control group ( = 37). A total of 12 onconeural autoantibodies and six neural surface autoantibodies were tested in all participants.

Results

Autoantibodies were present in all cohorts. The prevalence of autoantibodies was high (>80%) in the autoimmune encephalitis cohort but low (<20%) in all other cohorts. When comparing patients within cohorts who were positive for autoantibodies to patients who were not, there was no difference in age, sex, and disability. This was apart from the multiple sclerosis and Parkinson disease plus atypical parkinsonism cohorts, where those with positivity for autoantibodies in the CSF were significantly older.

Conclusions

The presence of the autoantibodies examined does not appear to have a substantial clinical impact within the diseases examined in this study. The presence of autoantibodies in all cohorts presents a risk for misdiagnosis when the method is used incorrectly on patients with atypical clinical presentation.

ORIGINAL ARTICLE

Objective

Cognitive impairment is common in multiple sclerosis (MS), significantly impacts daily functioning, is time‐consuming to assess, and is prone to practice effects. We examined whether the alpha band power measured with magnetoencephalography (MEG) is associated with the different cognitive domains affected by MS.

Methods

Sixty‐eight MS patients and 47 healthy controls underwent MEG, T1‐ and FLAIR‐weighted magnetic resonance imaging (MRI), and neuropsychological testing. Alpha power in the occipital cortex was quantified in the alpha1 (8–10 Hz) and alpha2 (10–12 Hz) bands. Next, we performed best subset regression to assess the added value of neurophysiological measures to commonly available MRI measures.

Results

Alpha2 power significantly correlated with information processing speed ( < 0.001) and was always retained in all multilinear models, whereas thalamic volume was retained in 80% of all models. Alpha1 power was correlated with visual memory ( < 0.001) but only retained in 38% of all models.

Conclusions

Alpha2 (10–12 Hz) power in rest is associated with IPS, independent of standard MRI parameters. This study stresses that a multimodal assessment, including structural and functional biomarkers, is likely required to characterize cognitive impairment in MS. Resting‐state neurophysiology is thus a promising tool to understand and follow up changes in IPS.

REVIEW ARTICLE

Background

Cognitive impairment is common in patients with chronic kidney disease (CKD), and early intervention may prevent the progression of this condition.

Methods

Here, we review interventions for the complications of CKD (anemia, secondary hyperparathyroidism, metabolic acidosis, harmful effects of dialysis, the accumulation of uremic toxins) and for prevention of vascular events, interventions that may potentially be protective against cognitive impairment. Furthermore, we discuss nonpharmacological and pharmacological methods to prevent cognitive impairment and/or minimize the latter's impact on CKD patients' daily lives.

Results

A particular attention on kidney function assessment is suggested during work‐up for cognitive impairment. Different approaches are promising to reduce cognitive burden in patients with CKD but the availabe dedicated data are scarce.

Conclusions

There is a need for studies assessing the effect of interventions on the cognitive function of patients with CKD.

Editorial

Machine‐learning‐derived heart and brain age are independently associated with cognition

COMMENTARY

Spinal muscular atrophy: are small sensory fibres involved?