Background and purpose

To explore the relationship between baseline levels of matrix metalloproteinase 9 (MMP9) in peripheral blood and the outcomes in patients with acute minor stroke and transient ischemic attack (TIA).

Methods

We assessed data from patients with acute minor ischemic stroke or TIA who were included in the CHANCE (Clopidogrel in High‐Risk Patients with Acute Nondisabling Cerebrovascular Events) trial. Baseline level of MMP9 in peripheral blood is classified into five quintiles. We assessed the relationship between the baseline MMP9 and outcomes of stroke recurrence, composite vascular events, and poor functional outcomes within 90 days after stroke onset.

Results

Of the 3014 patients included, 295 (9.79%) had recurrent stroke, 289 (9.59%) had recurrent ischemic stroke, 297 (9.85%) had combined vascular events, and 199 (6.64%) had poor functional outcomes within 90 days. We used MMP9 concentrations near hazard ratio (HR) = 1 (Q3) in restricted cubic splines as the reference. The result showed that, compared to patients in the Q3 group, patients in the highest quintile (Q5 group) had an increased risk of poor functional outcomes at 90 days after adjusting the risk factors and confounders ( = 0.030), which may be associated with an increased risk of combined vascular events ( = 0.052). Using Cox regression models or logistic regression models with restricted cubic spline, we also observed that higher MMP9 ratios were associated with an increased risk of stroke recurrence, combined events, and poor functional outcomes at a range of concentrations.

Conclusions

For patients with acute minor stroke or TIA, higher baseline MMP9 level was associated with an increased risk of poor functional outcomes, which might be related to stroke recurrence and combined vascular events.

Abstract

Tolosa–Hunt syndrome (THS) is an idiopathic condition included in the differential diagnosis of painful ophthalmoplegia. Although this was once a common diagnosis, the increasing availability of tests reveals an alternative etiology in many cases. Exclusion of treatable disorders is important, because the prognosis may otherwise be poor. We here describe a patient who presented with painful ophthalmoplegia with an infiltrating lesion in the cavernous sinus. Initially suspected of THS, he had a fatal evolution, and postmortem evaluation revealed cervicocephalic actinomycosis. Actinomycosis diagnosis is often missed, and still represents a challenge to the clinician. We highlight pearls and pitfalls to establish a proper diagnosis to avoid missing a treatable condition in patients with suspected THS.

Background and purpose

Fatigue and low sleep quality in multiple sclerosis (MS) are closely related symptoms. Here, the associations between the brain's functional connectivity (FC) and fatigue and low sleep quality were investigated to determine the degree of neural distinctiveness of these symptoms.

Method

A hundred and four patients with relapsing–remitting MS (age 38.9 ± 10.2 years, 66 females) completed the Modified Fatigue Impact Scale and the Pittsburgh Sleep Quality Index and underwent resting‐state functional magnetic resonance imaging. FC was analyzed using independent‐component analysis in sensorimotor, default‐mode, fronto‐parietal and basal‐ganglia networks. Multiple linear regression models allowed us to test the association between FC and fatigue and sleep quality whilst controlling for one another as well as for demographic, disease‐related and imaging variables.

Results

Higher fatigue correlated with lower sleep quality ( = 0.54,  < 0.0001). Higher fatigue was associated with lower FC of the precentral gyrus in the sensorimotor network, the precuneus in the posterior default‐mode network and the superior frontal gyrus in the left fronto‐parietal network, independently of sleep quality. Lower sleep quality was associated with lower FC of the left intraparietal sulcus in the left fronto‐parietal network, independently of fatigue. Specific associations were found between fatigue and the sensorimotor network's global FC and between low sleep quality and the left fronto‐parietal network's global FC.

Conclusion

Despite the high correlation between fatigue and low sleep quality in the clinical picture, our findings clearly indicate that, on the neural level, fatigue and low sleep quality in MS are associated with decreased FC in distinct functional brain networks.

Background and purpose

Diabetic sensorimotor peripheral neuropathy is usually considered to affect predominantly the lower limbs (LL‐N), whereas the impact of upper limb neuropathy (UL‐N) on hand functional performance and quality of life (QoL) has not been evaluated systematically. This study aims to investigate the prevalence and characteristics of UL‐N and its functional and psychosocial consequences in type 2 diabetes.

Methods

Individuals with type 2 diabetes ( = 141) and an age‐ and sex‐matched control group ( = 73) underwent comprehensive assessment of neuropathy, hand functional performance, and psychosocial status.

Results

The prevalence of UL‐N was 30.5% in patients with diabetes and that of LL‐N was 49.6%, with 25.5% exhibiting both. Patients with diabetes showed similar sensory phenotype regarding both large and small fiber functions in hands and feet. Patients with UL‐N showed reduced manual dexterity, but normal hand grip force. Additionally, there was a correlation between reduced dexterity and sensory deficits. Patients with UL‐N had reduced estimates of psychosocial health including health‐related QoL compared to control subjects and patients without UL‐N. UL‐N correlated with the severity of LL‐N, but not with duration of diabetes, glycemia, age, or sex.

Conclusions

This study points to a substantial prevalence of UL‐N in type 2 diabetes. The sensory phenotype of patients with UL‐N was similar to LL‐N and was characterized by loss of sensory function. Our study demonstrated an association of UL‐N with impaired manual dexterity and reduced health‐related QoL. Thus, upper limb sensorimotor functions should be assessed early in patients with diabetes.

Background and purpose

In the quest for in vivo diagnostic biomarkers to discriminate Parkinson's disease (PD) from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA, mainly p phenotype), many advanced magnetic resonance imaging (MRI) techniques have been studied. Morphometric indices, such as the Magnetic Resonance Parkinsonism Index (MRPI), demonstrated high diagnostic value in the comparison between PD and PSP. The potential of quantitative susceptibility mapping (QSM) was hypothesized, as increased magnetic susceptibility (Δ) was reported in the red nucleus (RN) and medial part of the substantia nigra (SNImed) of PSP patients and in the putamen of MSA patients. However, disease‐specific susceptibility values for relevant regions of interest are yet to be identified. The aims of the study were to evaluate the diagnostic potential of a multimodal MRI protocol combining morphometric and QSM imaging in patients with determined parkinsonisms and to explore its value in a population of undetermined cases.

Method

Patients with suspected degenerative parkinsonism underwent clinical evaluation, 3 T brain MRI and clinical follow‐up. The MRPI was manually calculated on T1‐weighted images. QSM maps were generated from 3D multi‐echo T2*‐weighted sequences.

Results

In determined cases the morphometric evaluation confirmed optimal diagnostic accuracy in the comparison between PD and PSP but failed to discriminate PD from MSA‐p. Significant nigral and extranigral differences were found with QSM. RN Δ showed excellent diagnostic accuracy in the comparison between PD and PSP and good accuracy in the comparison of PD and MSA‐p. Optimal susceptibility cut‐off values of RN and SNImed were tested in undetermined cases in addition to MRPI.

Conclusions

A combined use of morphometric imaging and QSM could improve the diagnostic phase of degenerative parkinsonisms.

Background and purpose

Vertigo and dizziness are common complaints in emergency departments and primary care, and pose major diagnostic challenges due to their various underlying etiologies. Most supportive diagnostic algorithms concentrate on either identifying cerebrovascular events (CVEs) or diagnosing specific vestibular disorders or are restricted to specific patient subgroups. The aim of the present study was to develop and validate a comprehenisve algorithm for identifying patients with CVE and classifying the most common vestibular disorders.

Methods

The study was conducted within the scope of the “PoiSe” project (revention, nline feedback, and nterdisciplinary Therapy of Acute Vestibular yndromes by ‐health). A three‐level algorithm was developed according to international guidelines and scientific evidence, addressing both the detection of CVEs and the classification of non‐vascular vestibular disorders (unilateral vestibulopathy, benign paroxysmal positional vertigo, vestibular paroxysmia, Menière's disease, vestibular migraine, functional dizziness). The algorithm was validated in a prospectively collected dataset of 407 patients with acute vertigo and dizziness presenting to the Emergency Department at the Ludwig‐Maximilian University of Munich.

Results

The algorithm assigned 287 of 407 patients to the correct diagnosis, corresponding to an overall accuracy of 71%. CVEs were identified with high sensitivity of 94%. The six most common vestibular disorders were classified with high specificity, above 95%. Random forest identified presence of a paresis, sensory loss, central ocular motor and vestibular signs (HINTS [head impulse test, nystagmus assessment, and test of skew deviation]), and older age as the most important variables indicating a cerebrovascular event.

Conclusions

The proposed diagnostic algorithm can correctly classify the most common vestibular disorders based on a comprehensive set of key questions and clinical examinations. It is easily applied, not limited to subgroups, and might therefore be transferred to broad clinical settings such as primary healthcare.

Background and purpose

Little is known about the character and underlying lesions of ischaemic amnesia. Episodic memory functions and brain lesions were therefore studied in 84 patients with acute ischaemic infarcts in the supply territory of the posterior cerebral artery. The aim was also to learn how the neural memory systems are organized.

Methods

Standard neuropsychological tests were used to assess verbal and figural memory. Patients were split into memory‐impaired and memory‐intact groups. Lesions were demarcated, normalized and anatomically labelled, using standard mapping procedures.

Results

Of the 84 patients more than 80% had an amnestic syndrome, mostly with combined memory impairment, less often with figural or verbal memory impairment. Amnesia in subjects with left hemispheric lesions was more frequent and more severe, with significantly lower scores on the verbal memory test. Normal performance or figural amnesia were prevalent after right hemispheric lesions. However, no amnesia subtype was strictly tied to left‐ or right‐sided brain damage. Hippocampal and thalamic lesions were common, but 30% of lesions were extrahippocampal located in the ventral occipito‐temporal cortex and long occipital white matter tracts. Most amnestic patients lacked awareness for their memory impairment.

Conclusions

Memory impairment is a key clinical manifestation of acute posterior cerebral artery stroke. Amnesia is more frequent and more severe after left stroke, suggesting a left hemisphere dominance of the two memory systems. Domain specific memory appears not to be strictly lateralized, since deficits in verbal and figural memory were found after lesions of both sides. Extrahippocampal lesions may also cause memory impairment.

Background and purpose

Cerebral amyloid angiopathy (CAA) is characterized by β‐amyloid deposition in cortical and leptomeningeal arterioles, which might result from glymphatic dysfunction. The aim was to explore glymphatic function in CAA using the non‐invasive diffusion tensor image analysis along the perivascular space method.

Methods

Sixty‐three patients with CAA were prospectively recruited together with seventy age‐ and sex‐matched normal controls. The Mini‐Mental State Examination and Montreal Cognitive Assessment were applied to screen global cognitive status. Magnetic resonance imaging scans were conducted to calculate the index for diffusivity along the perivascular space (ALPS index), and linear regression models were used to assess its relationships with cerebral small vessel disease (CSVD) markers, cognitive status and blood biomarkers. Cox proportional hazard models were applied to explore the role of the baseline ALPS index in disease recurrence.

Results

Patients with CAA exhibited a lower ALPS index than controls globally ( < 0.001). In addition, a lower ALPS index was related to more enlarged perivascular space in basal ganglia ( = 0.026), more lacunes ( < 0.001), higher white matter hyperintensity Fazekas score ( = 0.049), elevated total magnetic resonance imaging burden of CSVD ( = 0.034) and lower Mini‐Mental State Examination ( = 0.001) as well as Montreal Cognitive Assessment ( < 0.001) in CAA. During a median follow‐up of 4.1 years, a higher ALPS index was associated with lower disease recurrence ( = 0.022). The ALPS index was also negatively correlated with serum soluble intercellular adhesion molecule‐1, neurofilament light and chitinase‐3‐like protein 1 in CAA.

Conclusions

Patients with CAA showed impaired glymphatic function. The ALPS index was significantly related to CSVD severity, cognitive impairment and disease recurrence in CAA.

Background and purpose

Synaptic loss is well established as the major correlate of characteristic and consistent pathology in amyotrophic lateral sclerosis (ALS). We aimed to assess the possible discriminant diagnostic value of F‐SynVesT‐1 positron emission tomography (PET) as a marker of ALS pathology and investigate whether specific synaptic density signatures are present in ALS with different subtypes.

Methods

Twenty‐one patients with ALS and 25 healthy controls (HCs) were recruited. All participants underwent F‐SynVesT‐1‐PET. Synaptic density between ALS and HCs and between different ALS subgroups were compared. Correlation between synaptic density and clinical features in ALS was also analyzed.

Results

Low uptake distribution was found in the group comprising 21 ALS patients as compared with HCs in the right temporal lobe and the bilateral inferior frontal gyrus, anterior cingulate, and hippocampus–insula region. We also found low uptake in the bilateral superior temporal gyrus, hippocampus–insula, anterior cingulate, and left inferior frontal gyrus in ALS patients with cognitive impairment compared to HCs. Furthermore, compared to spinal onset ALS, bulbar onset ALS showed low uptake in the bilateral cingulate gyrus and high uptake in the bilateral superior temporal gyrus and left occipital lobe. No significant result was found in correlation analysis.

Conclusions

This approach may provide a direct measure of synaptic density, and it therefore might represent a potentially useful biomarker for ALS diagnosis, as well as for estimating the cognitive decline and site of onset in ALS. F‐SynVesT‐1‐PET is presently not justified as a routine investigation to detect evidence of brain dysfunction leading to progression in ALS.

Background and purpose

Sturge–Weber syndrome (SWS) is a neurocutaneous disorder characterized by clinical manifestations involving the brain, eye and skin. SWS is commonly caused by somatic mutations in (). Five cases of s () mutations have been reported. We studied phenotypic features of GNA11‐SWS and compared them with those of classic SWS.

Methods

Within two European multidisciplinary centers we looked for patients with clinical characteristics of SWS and a mutation. Clinical and radiological data were collected retrospectively and prospectively.

Results

We identified three patients with SWS associated with a somatic mutation. All had disseminated capillary malformation (CM) and hyper‐ or hypotrophy of an extremity. At birth, the CMs of the face, trunk and limbs were pink and patchy, and slowly darkened with age, evolving to a purple color. Two of the patients had glaucoma. All had neurological symptoms and moderate brain atrophy with a lower degree of severity than that classically associated with SWS. Susceptibility‐weighted imaging (SWI) and contrast‐enhanced fluid‐attenuated inversion recovery (FLAIR) magnetic resonance imaging demonstrated the best sensitivity to reveal the pial angiomas.

Conclusions

We have differentiated two distinct clinical/radiological phenotypes of SWS; GNAQ‐ and GNA11‐SWS. The classic GNAQ‐SWS is characterized by a homogeneous dark‐red CM, commonly associated with underlying soft tissue hypertrophy. The CM in GNA11‐SWS is more reticulate and darkens with time, and the neurological picture is milder. SWI and post‐contrast FLAIR sequences appear to be necessary to demonstrate leptomeningeal angiomatosis. Anti‐epileptic medication or future targeted therapies may be useful, as in classic SWS.

Background and purpose

Approximately 1% of patients with multiple sclerosis (MS) have uveitis, but data on the effects of immunotherapies for MS on MS‐associated uveitis are scarce. The aim of this study was to investigate the ophthalmological outcomes in patients with MS‐associated uveitis treated with anti‐CD20 therapy.

Methods

A retrospective study of 12 eyes of six patients with MS‐associated uveitis, refractory to previous immunotherapies, was conducted. Uveitis activity was assessed before initiation of anti‐CD20 therapy and at regular follow‐up visits. Primary outcome measures were: vitreous haze score; retinal vasculitis score, determined on fluorescein angiography images; macular edema, as quantified by central retinal thickness (CRT) on optical coherence tomography; and visual acuity (VA). Secondary outcomes included number of annualized uveitis or MS relapses, disease activity on cerebral magnetic resonance imaging (cMRI) and Expanded Disability Status Scale (EDSS) score.

Results

After a median (interquartile range [IQR]) treatment time of 28.5 (8–43) months, anti‐CD20 therapy was associated with an improvement of vitreous haze score ( = 0.002), retinal vasculitis score ( = 0.001), CRT ( = 0.002), and VA ( = 0.007). The median (IQR) annualized uveitis relapse rate declined from 0.59 (0.56–0.94) before to 0 (0–0.49) after the start of anti‐CD20 therapy. The median (IQR) annualized MS relapse rate declined from 0.62 (0.26–2.84) before to 0 (0–0) after the start of anti‐CD20 therapy. After initiation of anti‐CD20 therapy, there was no disease activity on cMRI, and EDSS score improved ( = 2) or remained stable ( = 4). No severe adverse events were observed.

Conclusion

These findings suggest that anti‐CD20 therapy may be a valuable treatment option for MS‐associated uveitis.

We report a patient with right‐predominant semantic variant primary progressive aphsia linked with p.Asp40Gly variant of , which is the first description of frontotemporal dementia without clinical and electrophysiological evidences of amyotrophic lateral sclerosis associated with a known pathogenic variant of .

Background and purpose

We aimed to assess the association of diabetes mellitus (DM) and admission hyperglycaemia (AH), respectively, and outcome in patients with acute ischaemic stroke with large vessel occlusion in the anterior circulation treated with endovascular therapy (EVT) in daily clinical practice.

Methods

Consecutive EVT patients admitted to our stroke centre between February 2015 and April 2020 were included in this observational cohort study. Patients with versus without DM and with versus without AH (glucose ≥ 7.8 mmol/L) were compared.

Results

We included 1020 patients (48.9% women, median age = 73.1 years); 282 (27.6%) had DM, and 226 (22.2%) had AH. Patients with versus without DM less often showed successful reperfusion (odds ratio [OR] = 0.61,  = 0.023) and worse 3‐month functional outcome (modified Rankin Scale [mRS] = 0–2: 31.3% vs. 48%, OR = 0.59,  = 0.004; death: 38.9% vs. 24.1%, OR = 1.75,  = 0.002; mRS shift:  < 0.0001; if moderate/good collaterals and mismatch, mRS = 0–2: OR = 0.52,  = 0.005; death: OR = 1.95,  = 0.005). If analysis was additionally adjusted for AH, only mRS shift was still significantly worse in patients with DM ( = 0.012). Patients with versus without AH showed similar successful reperfusion rates and worse 3‐month functional outcome (mRS = 0–2: 28.3% vs. 50.4%, OR = 0.52,  < 0.0001; death: 40.4% vs. 22.4%, OR = 1.80,  = 0.001; mRS shift:  < 0.0001; if moderate/good collaterals and mismatch, mRS = 0–2: OR = 0.38,  < 0.0001; death: OR = 2.39,  < 0.0001). If analysis was additionally adjusted for DM, 3‐month functional outcome remained significantly worse in patients with AH (mRS = 0–2: OR = 0.58,  = 0.004; death: OR = 1.57,  = 0.014; mRS shift:  = 0.004). DM independently predicted recurrent/progressive in‐hospital ischaemic stroke (OR = 1.71,  = 0.043) together with admission National Institutes of Health Stroke Scale score (OR = 0.95,  = 0.005), and AH independently predicted in‐hospital symptomatic intracranial haemorrhage (OR = 2.21,  = 0.001). The association of admission continuous glucose levels and most outcome variables was (inversely) J‐shaped.

Conclusions

Hyperglycaemia more than DM was associated with worse 3‐month outcome in the patients studied, more likely so in the case of moderate/good collaterals and mismatch in admission imaging.

Background and purpose

In recent decades, the global incidence of aneurysmal subarachnoid hemorrhage (aSAH) has declined. However, significant regional differences exist. We present the first comprehensive analysis of time trends in the incidence of aSAH and case fatality in Germany.

Methods

All patients hospitalized with aSAH in Germany between 2005 and 2018 were identified using International Classification of Disease, 10th Revision codes I60.0–I60.7.

Results

A total of 101,105 cases were included. The incidence of aSAH in Germany decreased at a mean annual rate of 0.5% ( = 0.003) from 8.9 per 100,000 population in 2005 to 8.2 in 2018. Over time, incidences of aSAH declined among patients younger than 55 years and patients aged 70–79 years, increased among ages 60–64 years, and remained stable in age groups 65–69 and 85–89 years. This corresponded to an increase in the mean age of aSAH onset from 55.6 (±14.3) to 59.0 (±14.0) years. Throughout the study period, the mean age of aSAH onset was higher in women compared to men (58.3 ± 14.4 years vs. 56.1 ± 14.1 years). There were no changes in in‐hospital case fatality (16.2 vs. 16.6%,  = 0.18), but the duration of hospital stay increased significantly from 19.7 to 24.8 days ( < 0.001). The most frequent aSAH‐associated aneurysm location was the anterior circulation throughout the entire study period.

Conclusions

In Germany, the incidence of aSAH decreased between 2005 and 2018, especially in younger parts of the population. This may reflect effects of lifestyle adjustments most pronounced in younger age groups.

Background and purpose

Several variables have been reported to be associated with anti‐calcitonin gene‐related peptide (CGRP) receptor or ligand antibody response, but with differing results. Our objective was to determine whether machine‐learning (ML)‐based models can predict 6‐, 9‐ and 12‐month responses to anti‐CGRP receptor or ligand therapies among migraine patients.

Methods

We performed a multicenter analysis of prospectively collected data from patients with migraine receiving anti‐CGRP therapies. Demographic and clinical variables were collected. Response rates in the 30% to 50% range, or at least 30%, in the 50% to 75% range, or at least 50%, and response rate of at least 75% regarding the reduction in the number of headache days per month at 6, 9 and 12 months were calculated. A sequential forward feature selector was used for variable selection and ML‐based predictive models for the response to anti‐CGRP therapies at 6, 9 and 12 months, with model accuracy not less than 70%, were generated.

Results

A total of 712 patients were included, 93% were women, and the mean (SD) age was 48 (11.6) years. Eighty‐four percent of patients had chronic migraine. ML‐based models using headache days/month, migraine days/month and the Headache Impact Test (HIT‐6) yielded predictions with an F1 score range of 0.70–0.97 and an area under the receiver‐operating curve score range of 0.87–0.98. SHAP (SHapley Additive exPlanations) summary plots and dependence plots were generated to evaluate the relevance of the factors associated with the prediction of the above‐mentioned response rates.

Conclusions

Our results show that ML models can predict anti‐CGRP response at 6, 9 and 12 months. This study provides a predictive tool that can be used in a real‐world setting.

Background and purpose

Autoimmune encephalitis (AE) is a potentially treatable cause of rapidly progressive dementia that may mimic Creutzfeldt–Jakob disease (CJD). Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers may discriminate CJD from AD, but utility in discriminating CJD and AE is unclear. This study compared AD CSF biomarkers in CJD and AE.

Methods

Patients with probable or definite CJD and probable or definite AE who underwent Roche Elecsys AD CSF biomarker testing at Mayo Clinic from March 2020 through April 2021 were included. Total‐tau, phosphorylated tau and amyloid‐β levels were compared.

Results

Of 11 CJD cases, four were autopsy proven; the rest had positive real‐time quaking‐induced conversion testing. Disease‐associated autoantibodies were detected in 8/15 cases of AE: leucine‐rich glioma‐inactivated 1 and neuronal intermediate filaments (two cases each), and ‐methyl‐‐aspartate receptor, contactin‐associated protein‐like 2, dipeptidyl‐peptidase‐like protein 6 and immunoglobulin‐like cell adhesion molecule IgLON family member 5. Total‐tau provided excellent discrimination between CJD and AE in a univariate model (odds ratio 1.46 per 100 pg/ml, 95% confidence interval 1.17–2.11,  < 0.05,  = 0.93). Total‐tau was elevated in 91% of CJD cases (median > 1300, range 236–>1300 pg/ml), of which 55% were above the limit of assay measurement (>1300 pg/ml). Total‐tau was elevated in 20% of AE cases (median 158, range 80–>1300 pg/ml).

Conclusion

Total‐tau was greater in CJD than AE. Given that amyloid‐β and phosphorylated tau were comparable, the ratio differences were probably driven by elevated total‐tau in CJD. This study supports the role for AD biomarker testing in patients with rapidly progressive dementia.

Background and purpose

Animal studies suggest that exposure to severe ambient hypoxia for several days may have beneficial long‐term effects on neurodegenerative diseases. Because, the acute risks of exposing human beings to prolonged severe hypoxia on brain structure and function are uncertain, we conducted a pilot study in healthy persons.

Methods

We included two professional mountaineers (participants A and B) in a 35‐day study comprising an acclimatization period and 14 consecutive days with oxygen concentrations between 8% and 8.8%. They underwent cerebral magnetic resonance imaging at seven time points and a cognitive test battery covering a spectrum of cognitive domains at 27 time points. We analysed blood neuron specific enolase and neurofilament light chain levels before, during, and after hypoxia.

Results

In hypoxia, white matter volumes increased (maximum: A, 4.3% ± 0.9%; B, 4.5% ± 1.9%) whilst gray matter volumes (A, −1.5% ± 0.8%; B, −2.5% ± 0.9%) and cerebrospinal fluid volumes (A, −2.7% ± 2.4%; B, −5.9% ± 8.2%) decreased. Furthermore, the number (A, 11–17; B, 26–126) and volumes (A, 140%; B, 285%) of white matter hyperintensities increased in hypoxia but had returned to baseline after a 3.5‐month recovery phase. Diffusion weighted imaging of the white matter indicated cytotoxic edema formation. We did not observe changes in cognitive performance or biochemical brain injury markers.

Discussion

In highly selected healthy individuals, severe sustained normobaric hypoxia over 2 weeks elicited reversible changes in brain morphology without clinically relevant changes in cognitive function or brain injury markers. The finding may pave the way for future translational studies assessing the therapeutic potential of hypoxia in neurodegenerative diseases.

Background and purpose

We used two‐sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid‐modifying drugs on intracranial aneurysm (IA).

Methods

Genetic variants for the effects of high‐density lipoprotein cholesterol (HDL‐C), apolipoprotein A1, low‐density lipoprotein cholesterol (LDL‐C), apolipoprotein B, and triglycerides and targets for lipid‐modifying drugs were selected from the genome‐wide discovery analyses of the UK Biobank. Summary‐level data on IAs were obtained from the International Stroke Genetics Consortium. Univariate and multivariate MR analyses were performed.

Results

Univariate MR analyses showed that the HDL‐C was negatively correlated with IA (odds ratio [OR] = 0.816, 95% confidence interval [CI] = 0.715–0.932,  = 0.003) and ruptured IA (rIA; OR = 0.775, 95% CI = 0.663–0.906,  = 0.001). The multivariate MR–inverse variance weighted analysis showed that the HDL‐C was negatively correlated with IA (OR = 0.655, 95% CI = 0.434–0.988,  = 0.043) and rIA (OR = 0.563, 95% CI = 0.347–0.913,  = 0.02), and the LDL‐C was negatively correlated with IA (OR = 0.402, 95% CI = 0.191–0.848,  = 0.017) and rIA (OR = 0.376, 95% CI = 0.160–0.883,  = 0.025). Using genetic proxies of known lipid‐modifying drugs, we found that the increased HDL‐C with cholesterol ester transfer protein proxies was associated with a decreased risk of rIA (OR = 0.852, 95% CI = 0.747–0.973,  = 0.018), and the decreased LDL‐C with 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase proxies was associated with increased risk of IA (OR = 1.772, 95% CI = 1.080–2.908,  = 0.024) and rIA (OR = 1.856, 95% CI = 1.022–3.371,  = 0.042).

Conclusions

Genetically determined HDL‐C and LDL‐C reduce the risk of IA and rIA. The effects of different lipid‐modifying drugs on IA need to be further investigated.

Background and purpose

Our objectives were to identify differences in clinical characteristics between patients with out‐of‐hospital and in‐hospital status epilepticus (SE) onset, and to evaluate the influence of SE onset setting on 30‐day mortality and SE cessation.

Methods

We included consecutive patients with SE admitted from 2013–2021 at Modena Academic Hospital. A propensity score was obtained with clinical variables unevenly distributed between the two groups.

Results

Seven hundred eleven patients were included; 55.8% (397/711) with out‐of‐hospital and 44.2% (314/711) with in‐hospital onset. Patients with in‐hospital SE onset were older and had a higher frequency of comorbidities, acute and/or potentially fatal etiologies, impaired consciousness before treatment, and nonconvulsive or myoclonic SE. No difference was found in SE cessation between the groups. Patients with in‐hospital SE had higher 30‐day mortality (127/314, 62.9% vs. 75/397, 37.1%;  < 0.001). In‐hospital onset was an independent risk factor for 30‐day mortality (adjusted odds ratio = 1.720; 95% confidence interval = 1.107–2.674;  = 0.016). In the propensity group ( = 244), no difference was found in 30‐day mortality and SE cessation between out‐of‐hospital and in‐hospital SE onset groups (36/122, 29.5% vs. 34/122, 27.9%;  = 0.888; and 47/122, 38.5% vs. 39/122; 32%;  = 0.347, respectively).

Conclusions

In‐hospital SE is associated with higher 30‐day mortality without difference in SE cessation. The two groups differ considerably for age, acute and possibly fatal etiologies, comorbidities, and SE semiology. The patient location at SE onset is an important prognostic predictor. However, the increased mortality is probably unrelated to the setting of SE onset and reflects intrinsic prognostic predictors.

Background and purpose

Data from neuro‐imaging techniques allow us to estimate a brain's age. Brain age is easily interpretable as ‘how old the brain looks’ and could therefore be an attractive communication tool for brain health in clinical practice. This study aimed to investigate its clinical utility by investigating the relationship between brain age and cognitive performance in multiple sclerosis (MS).

Methods

A linear regression model was trained to predict age from brain magnetic resonance imaging volumetric features and sex in a healthy control dataset (HC_train,  = 1673). This model was used to predict brain age in two test sets: HC_test ( = 50) and MS_test ( = 201). Brain‐predicted age difference (BPAD) was calculated as BPAD = brain age minus chronological age. Cognitive performance was assessed by the Symbol Digit Modalities Test (SDMT).

Results

Brain age was significantly related to SDMT scores in the MS_test dataset ( = −0.46,  < 0.001) and contributed uniquely to variance in SDMT beyond chronological age, reflected by a significant correlation between BPAD and SDMT ( = −0.24,  < 0.001) and a significant weight (−0.25,  = 0.002) in a multivariate regression equation with age.

Conclusions

Brain age is a candidate biomarker for cognitive dysfunction in MS and an easy to grasp metric for brain health.

Background

The longitudinal association between serum folate concentrations and the risk of cognitive impairment remains unclear in populations with low folate levels. We examined the association between serum folate concentrations and mild cognitive impairment (MCI) in older adults in China, where mandatory fortification of foods with folic acid has not been implemented. We further explored if homocysteine (Hcy) and leukocyte telomere length (LTL) mediate the association between serum folate and MCI.

Methods

We performed a longitudinal analysis of 3974 participants aged ≥60 years from the Tianjin Elderly Nutrition and Cognition (TENC) cohort study. The associations between serum folate level and the risk of cognitive impairment overall and stratified by apolipoprotein E () ε4 genotypes were evaluated using multivariable Cox proportional hazards models. The mediating effects of Hcy and LTL on the folate–MCI association were explored via a path analysis approach.

Results

Within a 3‐year follow‐up, we documented 560 incident MCI cases. After multivariable adjustment, higher serum folate concentrations were associated with lower incidence of MCI, with hazard ratios (95% confidence interval) across quartiles of folate (from lowest to highest concentrations) of 1.00 (reference), 0.66 (0.52, 0.83), 0.57 (0.45, 0.73), 0.66 (0.52, 0.84), respectively ( for trend <0.001). In mediation analyses, the status of serum folate deficiency and MCI were correlated via two intermediary pathways, Hcy and Hcy‐telomere ( < 0.05).

Conclusions

Lower folate concentrations, independently of genotype, were associated with increased risk of MCI among elderly Chinese people, a population with relatively low folate intake. Our data were compatible with the mediation hypothesis that the association between folate status and MCI was mediated by Hcy and LTL.

Background and purpose

Multiple system atrophy (MSA) has no definitive genetic or environmental (G‐E) risk factors, and the integrated effect of these factors on MSA etiology remains unknown. This study was undertaken to investigate the integrated effect of G‐E factors associated with MSA and its subtypes, MSA‐P and MSA‐C.

Methods

A consecutive case–control study was conducted at two medical centers, and the interactions between genotypes of five previously reported susceptible single nucleotide polymorphisms (SNPs; _rs3857059, _rs11931074, _rs148156462, _rs16872704, _rs9303521) and graded exposure (never, ever, current) of four environmental factors (smoking, alcohol, drinking well water, pesticide exposure) were analyzed by a stepwise logistic regression model.

Results

A total of 207 MSA patients and 136 healthy controls were enrolled. In addition to SNP _rs148156462 (TT), MSA risk was correlated with G‐E interactions, including _rs148156462 (Tc) × pesticide nonexposure, _rs148156462 (TT) × current smokers, _rs11931074 (tt) × alcohol nonusers, and _rs11931074 (GG) × well water nondrinkers (all  < 0.01), with an area under the receiver operating characteristic curve (AUC) of 0.804 (95% confidence interval [CI] = 0.671–0.847). Modulated risk of MSA‐C, with MSA‐P as a control, correlated with _rs148156462 (TT) × alcohol nondrinkers, _rs11931074 (GG) × well water ever drinkers, _rs11931074 (Gt) × well water never drinkers, and _rs3857059 (gg) × pesticide nonexposure (all  < 0.05), with an AUC of 0.749 (95% CI = 0.683–0.815).

Conclusions

Certain and SNPs interact with common environmental factors to modulate MSA etiology and subtype disposition. The mechanisms underlying the observed correlation between G‐E interactions and MSA etiopathogenesis warrant further investigation.

Background and purpose

Motoric cognitive risk syndrome (MCR) is a gait‐based pre‐dementia syndrome associated with risk of dementia. Ascertaining subjective cognitive and motoric complaints may facilitate early and remote identification of individuals with MCR as they are reported to precede and predict objective cognitive and motoric impairments in aging.

Methods

The validity of five subjective motoric complaint (SMC) questions and 10 subjective cognitive complaint (SCC) questions was examined for discriminating MCR in 538 non‐demented community‐dwelling adults. Backward logistic regression was used to identify questions to develop a weighted score to define subjective MCR (MCR‐S). Receiver operating characteristic analysis was applied to determine the discriminative ability of MCR‐S for the objective MCR (MCR‐O) definition based on SCCs and objectively measured gait. Cox proportional hazard models adjusted for potential confounders were used to examine the predictive validity of MCR‐S for incident dementia.

Results

Five subjective complaint questions (three SCC and two SMC) were associated with MCR‐O. They were combined to define an MCR‐S score (range 0–7) which yielded an area under the curve of 0.89 for discriminating MCR‐O from receiver operating characteristic analysis. An optimal cut‐score of 2 on the MCR‐S score was determined to have good sensitivity (84%) and specificity (82%) for MCR‐O. Over a median follow‐up of 2.5 years, 29 participants developed dementia. Both MCR‐S (adjusted hazard ratio 2.39) and MCR‐O at baseline (adjusted hazard ratio 3.16) predicted risk of incident dementia.

Conclusions

Subjective MCR had high concordance with MCR‐O and can provide a remote screening assessment for MCR‐O, which can identify those at high risk for dementia.

Background and purpose

Long‐term outcome after COVID‐19 in patients with multiple sclerosis (pwMS) has scarcely been studied, and controlled data are lacking. The objective of this study was to compare long‐term outcome after COVID‐19 in pwMS to a matched control group of pwMS without COVID‐19.

Methods

We included pwMS with polymerase chain reaction‐confirmed diagnosis of COVID‐19 and ≥6 months of follow‐up and, as a control group, pwMS matched 1:1 for age, sex, disability level, and disease‐modifying treatment type.

Results

Of 211 pwMS with COVID‐19 (mean age = 42.6 years [SD = 12.2], 69% female, median Expanded Disability Status Scale = 1.5 [range = 0–7.5], 16% anti‐CD20), 90.5% initially had a mild COVID‐19 course. At follow‐up, 70% had recovered completely 3 months (M3) after COVID‐19, 83% after 6 months (M6), and 94% after 12 months (M12). Mild initial COVID‐19 course was the only significant predictor of complete recovery (odds ratio [OR] = 10.5,  < 0.001). The most frequent residual symptoms were fatigue (M3: 18.5%, M6: 13.7%, M12: 7.3%), hyposmia (M3: 13.7%, M6: 5.2%, M12: 1.7%), and dyspnea (M3: 7.1%, M6: 6.6%, M12: 2.8%). Compared to matched controls, fatigue, hyposmia, and dyspnea were significantly more frequent at M3 and still slightly more frequent at M6, whereas there was no difference at M12. pwMS with COVID‐19 had neither a significantly increased risk for relapses (OR = 1.1,  = 0.70) nor disability worsening (OR = 0.96,  = 0.60).

Conclusions

Long‐term outcome of COVID‐19 is favorable in a large majority of pwMS, with only a small proportion of patients suffering from persistent symptoms usually resolving after 3–6 months. COVID‐19 is not associated with increased risk of relapse or disability.

Background and purpose

Enterovirus infections pose a serious threat for patients with humoral deficiencies and may be lethal, whilst the efficacy of proposed treatment options such as corticosteroids, intravenous immunoglobulins and fluoxetine remains debated.

Methods

Viral clearance was investigated in a patient with rituximab‐induced B‐cell depletion and chronic echovirus 13 (E13) meningoencephalitis/myofasciitis in response to intravenous immunoglobulins and fluoxetine using sequential semi‐quantitative E13 viral load measurements by real‐time reverse transcription polymerase chain reaction. Fluoxetine concentrations in plasma and cerebrospinal fluid were determined by liquid chromatography mass spectrometry.

Results

Intravenous immunoglobulins appeared ineffective in this case of E13 infection, whereas virus clearance in cerebrospinal fluid was obtained after 167 days of oral fluoxetine. Since treatment with corticosteroids resulted in a flare of symptoms, rechallenge with viral load measurements was not attempted.

Conclusion

In this report of a patient with rituximab‐associated chronic echovirus 13 meningoencephalitis, viral clearance in response to single treatment options is assessed for the first time. Our observations further support the efficacy of fluoxetine against enteroviral infections. More research is needed to establish its efficacy in different enterovirus strains.

Background and purpose

Intravenous immunoglobulin (IVIg) is recommended in Guillain–Barré syndrome (GBS), but its efficacy may vary in different subtypes. We report the outcomes of patients with GBS following IVIg treatment compared to the natural course (NC). We also compare the effect of IVIg treatment in different subtypes of GBS.

Methods

From a cohort of 528 GBS subjects, we have extracted 189 patients who received IVIg and compared their outcomes with 199 age‐ and peak disability‐matched patients who did not receive IVIg, plasmapheresis, or corticosteroid. Disability was assessed using the 0–6 Guillain–Barré Syndrome Disability Scale (GBSDS). Clinical and neurophysiological subtypes were recorded. The primary outcome was functional disability at 6 months, which was categorized as complete (GBSDS ≤ 1), partial (GBSDS 2–3), or poor (GBSDS > 3). The secondary outcomes were in‐hospital death, duration of hospitalization, and mechanical ventilation.

Results

In‐hospital death (2.6% vs. 2%,  = 0.74) and 3‐month poor recovery (20.7% vs. 18%) were similar in the IVIg and NC groups. At 6 months, however, a lesser proportion of patients in the IVIg group had poor recovery (2.2% vs. 8.3%,  = 0.026). The outcomes of IVIg and NC were compared in 72 acute motor axonal neuropathy (AMAN) and 256 acute inflammatory demyelinating polyradiculoneuropathy (AIDP) patients. IVIg therapy did not alter the outcome in AMAN but resulted in a lesser proportion of poor recovery at 6 months in AIDP (0.8% vs. 6.6%,  = 0.03).

Conclusions

IVIg is beneficial in AIDP variants of GBS but not in the AMAN subtype. A customized treatment may be cost‐effective until a randomized controlled trial is conducted in AMAN.