cover image European Journal of Neurology

European Journal of Neurology

2024 - Volume 31
Issue 10 | October 2024

ISSUE INFORMATION

Issue Information

POSITION PAPER

Background

Functional neurological disorder (FND) is a common cause of neurological disability. Despite recent advances in pathophysiological understanding and treatments, application of this knowledge to clinical practice is variable and limited.

Objective

Our aim was to provide an expert overview of the state of affairs of FND practice across Europe, focusing on education and training, access to specialized care, reimbursement and disability policies, and academic and patient‐led representation of people with FND.

Methods

We conducted a survey across Europe, featuring one expert per country. We asked experts to compare training and services for people with FND to those provided to people with multiple sclerosis (MS).

Results

Responses from 25 countries revealed that only five included FND as a mandatory part of neurological training, while teaching about MS was uniformly included. FND was part of final neurology examinations in 3/17 countries, unlike MS that was included in all 17. Seventeen countries reported neurologists with an interest in FND but the estimated mean ratio of FND‐interested neurologists to MS neurologists was 1:20. FND coding varied, with psychiatric coding for FND impacting treatment access and disability benefits in the majority of countries. Twenty countries reported services refusing to see FND patients. Eight countries reported an FND special interest group or network; 11 reported patient‐led organizations.

Conclusions

FND is largely a marginal topic within European neurology training and there is limited access to specialized care and disability benefits for people with FND across Europe. We discuss how this issue can be addressed at an academic, healthcare and patient organization level.

ORIGINAL ARTICLE

Background and purpose

The co‐occurrence of amyloid‐β pathology in Parkinson's disease (PD) is common; however, the role of amyloid‐β deposition in motor prognosis remains elusive. This study aimed to investigate the association between striatal amyloid deposition, motor complications and motor prognosis in patients with PD.

Methods

Ninety‐six patients with PD who underwent F florbetaben (FBB) positron emission tomography were retrospectively assessed. The ratio of the striatum to global (STG) FBB uptake was obtained for each individual, and patients were allotted into low and high STG groups according to the median value. The effect of STG group on regional amyloid deposition, the occurrence of motor complications and longitudinal change in levodopa equivalent dose (LED) requirement were investigated after controlling for age, sex, LED and disease duration at FBB scan.

Results

The high STG group was associated with lower cortical FBB uptake in the parietal, occipital and posterior cingulate cortices and higher striatal FBB uptake compared to the low STG group. Patients in the high STG group had a higher risk of developing wearing off and levodopa‐induced dyskinesia than those in the low STG group, whereas the risk for freezing of gait was comparable between the two groups. The high STG group showed a more rapid increase in LED requirements over time than the low STG group.

Conclusions

These findings suggest that relatively high striatal amyloid deposition is associated with poor motor outcomes in patients with PD.

ORIGINAL ARTICLE

Background

Multiple sclerosis (MS) is a demyelinating disease affecting millions of people worldwide. Hereditary susceptibility and environmental factors contribute to disease risk. Infection with Epstein–Barr virus (EBV) and human herpesvirus 6A (HHV‐6A) have previously been associated with MS risk. Other neurotropic viruses, such as rubella virus (RV), are possible candidates in MS aetiopathogenesis, but previous results are limited and conflicting.

Methods

In this nested case–control study of biobank samples in a Swedish cohort, we analysed the serological response towards RV before the clinical onset of MS with a bead‐based multiplex assay in subjects vaccinated and unvaccinated towards RV. The association between RV seropositivity and MS risk was analysed with conditional logistic regression.

Results

Seropositivity towards RV was associated with an increased risk of MS for unvaccinated subjects, even when adjusting for plausible confounders including EBV, HHV‐6A, cytomegalovirus and vitamin D (adjusted odds ratio [AOR] = 4.0, 95% confidence interval [CI] 1.8–8.8). Cases also had stronger antibody reactivity towards rubella than controls, which was not seen for other neurotropic viruses such as herpes simplex or varicella zoster. Furthermore, we observed an association between RV seropositivity and MS in vaccinated subjects. However, this association was not significant when adjusting for the aforementioned confounders (AOR = 1.7, 95% CI 1.0–2.9).

Conclusions

To our knowledge, these are the first reported associations between early RV seropositivity and later MS development. This suggests a broadening of the virus hypothesis in MS aetiology, where molecular mimicry between rubella epitopes and human central nervous system molecules could be an attractive possible mechanism.

ORIGINAL ARTICLE

Background and Purpose

Parkinson's disease (PD) is an age‐related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising insulin‐like growth factor 1–α‐Klotho–sirtuin 1–forkhead box O3–peroxisome proliferator‐activated receptor γ, may potentially influence disease progression.

Methods

Cerebrospinal fluid (CSF) levels of α‐Klotho in 471 PD patients were examined. Of the 471 patients, 96 carried a variant (PD ), whilst the 375 non‐carriers were classified as PD wild‐type (PD WT). Each patient was stratified into a CSF α‐Klotho tertile group based on the individual level. Kaplan–Meier survival curves and Cox regression analysis stratified by tertile groups were conducted. These longitudinal data were available for 255 patients. Follow‐up times reached from 8.4 to 12.4 years. The stratification into PD WT and PD was undertaken to evaluate potential continuum patterns, particularly in relation to CSF levels.

Results

Higher CSF levels of α‐Klotho were associated with a significant later onset of cognitive impairment. Elevated levels of α‐Klotho in CSF were linked to higher Montreal Cognitive Assessment scores in male PD patients with mutations.

Conclusions

Our results indicate that higher CSF levels of α‐Klotho are associated with a delayed cognitive decline in PD. Notably, this correlation is more prominently observed in PD patients with mutations, potentially reflecting the accelerated biological aging profile characteristic of individuals harboring variants.

ORIGINAL ARTICLE

Background and Purpose

The aim was to investigate whether neurofilament light chain (NfL) and profilin‐1 (PFN‐1) might qualify as surrogate disease and treatment‐response biomarkers by correlating their concentrations dynamic with clinical status in a cohort of 30 adult spinal muscular atrophy type 3 patients during nusinersen therapy up to 34 months.

Methods

Neurofilament light chain was measured in cerebrospinal fluid at each drug administration with a commercial enzyme‐linked immunosorbent assay (ELISA); PFN‐1 concentrations were tested in serum sampled at the same time points with commercial ELISA assays. Functional motor scores were evaluated at baseline, at the end of the loading phase and at each maintenance dose and correlated to biomarker levels. The concurrent effect of age and clinical phenotype was studied.

Results

Neurofilament light chain levels were included in the reference ranges at baseline; a significant increase was measured during loading phase until 1 month. PFN‐1 was higher at baseline than in controls and then decreased during therapy until reaching control levels. Age had an effect on NfL but not on PFN‐1. NfL was partially correlated to functional scores at baseline and at last time point, whilst no correlation was found for PFN‐1.

Conclusion

Cerebrospinal fluid NfL levels did not qualify as an optimal surrogate treatment biomarker in adult spinal muscular atrophy patients with a long disease duration, whilst PFN‐1 might to a greater extent represent lower motor neuron pathological processes. The observed biomarker level variation during the first 2 months of nusinersen treatment might suggest a limited effect on axonal remodeling or rearrangement.

ORIGINAL ARTICLE

Background

Adherence to post‐stroke secondary prevention medications mitigates recurrence risk. This study aimed to measure adherence to secondary prevention medications during 3 years post‐ischemic stroke/transient ischemic attack, using prescription and dispensing data, and identify factors associated with suboptimal adherence.

Methods

This multicenter, prospective, cohort study involved patients from the STROKE 69 cohort, which included all consecutive patients with suspected acute stroke admitted between November 2015 and December 2016 to any emergency department or stroke center in the Rhône area in France. Prescription data for antihypertensive agents, antidiabetic agents, lipid‐lowering drugs, and antithrombotics were collected. Dispensing data were provided by the French regional reimbursement database. Adherence was calculated using the continuous medication acquisition index. Associations between suboptimal adherence and potential influencing factors across the World Health Organization's five dimensions were explored through univariate and multivariate analyses.

Results

From 1512 eligible patients, 365 were included. Optimal adherence to overall treatment (≥90%) was observed in 61%, 62%, and 65% of patients in the first, second, and third years, respectively. Education level (high school diploma or higher: OR = 3.24, 95% CI [1.49; 7.36]) and depression (Hospital Anxiety and Depression Scale–Depression scores 8–10: OR = 1.90, 95% CI [1.05; 3.44]) were significantly associated with suboptimal adherence.

Conclusions

Overall adherence to secondary prevention medications was fairly good. Having an initial diagnosis of transient ischemic attack, a high level of education, or depression was associated with increased odds of suboptimal adherence, while having a history of heart rhythm disorder was associated with lower odds.

SHORT COMMUNICATION

Background and purpose

Relapse presentation in relapsing multiple sclerosis (RMS) differs between sexes, leading to differential outcomes. An influence of age seems likely but is less well investigated separately for women and men.

Methods

Using the large well‐defined dataset of the pivotal trials of ocrelizumab in RMS, OPERA I and II, and their open‐label extension, we performed a post hoc analysis to investigate relapse phenotypes for sex‐ and age‐related differences in  = 929 relapses in 534 subjects (171 men, 363 women). Frequencies of affected functional systems were analyzed separated by sex and for three age strata (<35, 35–44, ≥45 years). Exact ‐values are given for this exploratory analysis.

Results

Frequencies of mono‐ versus polysymptomatic relapse presentations were different neither between sexes nor in different age groups. Cerebellar symptoms were more frequent in relapses in men (female [f]: 23.1%, male [m]: 33.0%,  = 0.002), and women's relapses included more sensory (f: 53.8%, m: 32.3%,  < 0.001) and fatigue symptoms (f: 22.6%, m: 14.7%,  = 0.006). Whereas the sex difference for sensory involvement was present over all age groups (<35 years: f: 58.3%, m: 30.4%,  < 0.001; 35–44 years: f: 53.7%, m: 36.0%,  = 0.003; ≥45 years: f: 47.8%, m: 28.8%,  = 0.009), the difference for cerebellar involvement diminished with age (<35 years: f: 20.1%, m: 33.3%,  = 0.009; 35–44 years: f: 22.7%, m: 34.2%,  = 0.034; ≥45 years: f: 27.8%, m: 30.3%,  = 0.750). Relapse presentation seemed to shift with age in women only.

Conclusions

We describe sex‐specific relapse presentations and an influence of age only for women. Underlying causal factors warrant further investigations.

SHORT COMMUNICATION

Background and purpose

Cervical artery dissection (CAD) represents a leading cause of unilateral lower cranial nerve IX–XII palsy, known as Collet–Sicard syndrome (CSS). High‐resolution magnetic resonance imaging (HR‐MRI) is widely used in the evaluation of patients with CAD, providing information regarding vessel wall abnormalities and intraluminal thrombus.

Methods

We present a patient with palsy of multiple lower cranial nerves in the context of CSS, attributed to unilateral spontaneous internal carotid artery dissection.

Results

We describe a 68‐year‐old man with unremarkable previous history, who presented with subacute, gradually worsening dysphagia and hoarse voice. Clinical examination revealed right‐sided palsy of cranial nerves IX–XII. Three‐dimensional fat‐saturated black‐blood T1‐weighted high‐resolution vessel wall imaging disclosed spontaneous dissection with intramural hematoma along the distal right internal carotid artery. Neck MRI showed inward displacement of right aryepiglottic fold, right pyriform sinus dilatation, and right true vocal cord in middle position, indicative of right vagus nerve palsy, atrophy of right trapezius and sternocleidomastoid muscles, due to right spinal accessory nerve palsy, and unilateral tongue atrophy with fatty infiltration, characteristic for right hypoglossal nerve palsy.

Conclusions

This case highlights the utility of high‐resolution vessel wall imaging and especially fat‐saturated T1‐weighted black‐blood SPACE (sampling perfection with application‐optimized contrast using different flip‐angle evolutions) sequences in the accurate diagnosis of CAD, revealing the characteristic mural hematoma and intimal flap. HR‐MRI is also valuable in the recognition of indirect signs of lower cranial nerve compression.

ORIGINAL ARTICLE

Background and purpose

The amplitude, timing, and determinants of improvement with available treatments are uncertain in chronic inflammatory demyelinating polyneuropathy (CIDP). Our primary objective was to quantify categorized outcomes with routine care.

Methods

We retrospectively studied treatment response within 36 months from initiation in 112 consecutive subjects with CIDP. Response was classified into a proposed new "CIDP treatment‐response category" (CT‐RC), based on achieved endpoints. Determinants of the CT‐RC, of timing of maximum improvement, and of treatment discontinuation were ascertained.

Results

The CT‐RC demonstrated high concurrent validity with current outcome measures. Thirty‐six subjects (32.1%) achieved a “complete response,” 37 (33%) a “good partial response,” 10 (8.9%) a “moderate partial response,” and 15 (13.4%) a “poor partial response.” Fourteen subjects (12.5%) were “nonresponsive.” The CT‐RC was independently predicted only by age. Mean time to maximum improvement was 12.1 months (range = 1–36) and was not associated with any pretreatment covariate. Treatment discontinuation occurred in 24 of 62 (38.2%) partial responders and was only associated with shorter pretreatment disease duration. Nonresponders were older and received a similar number of treatments compared to responders.

Conclusions

CT‐RC classification indicates persistent disability in >60% of treatment responders in CIDP. Timing of maximum improvement is variable, frequently delayed, and unpredictable. Treatment withdrawal without deterioration is achievable in approximately 40% of subjects and may be more likely with prompt treatment. Treatment withdrawal in partial responders and limited escalation in nonresponders suggest implication of physician‐ and patient‐related factors in suboptimal response. More effective treatments/treatment methods and better understanding of other factors influencing response are needed in CIDP.

ORIGINAL ARTICLE

Background and purpose

Preclinical studies of amyotrophic lateral sclerosis (ALS) have shown altered endocannabinoid (eCB) signalling that may contribute to the disease. Results from human studies are sparse and inconclusive. The aim of this study was to determine the association between serum levels of eCBs or their congeners, the so‐called endocannabinoidome, and disease status and activity in ALS patients.

Methods

Serum concentrations of 2‐arachidonoylglycerol and ‐arachidonoylethanolamine (AEA), and AEA congeners palmitoylethanolamide (PEA), oleoylethanolamide (OEA), eicosapentaenoylethanolamide (EPEA), 2‐docosahexaenoylglycerol (2‐DHG) and docosahexaenoylethanolamide (DHEA) were measured in samples from 65 ALS patients, 32 healthy controls (HCs) and 16 neurological disease controls (NALS). A subset of 46 ALS patients underwent a longitudinal study. Disease activity and progression were correlated with eCB and congener levels.

Results

Most circulating mediators were higher in ALS than HCs (all  < 0.001), but not NALS. Across clinical stages, ALS patients showed increased levels of PEA, OEA and EPEA (all  < 0.02), which were confirmed by the longitudinal study (all  < 0.03). Serum PEA and OEA levels were independent predictors of survival and OEA levels were higher in patients complaining of appetite loss. Cluster analysis revealed two distinct profiles of circulating mediators associated with corresponding patterns of disease activity (severe vs. mild). Patients belonging to the ‘severe’ cluster showed significantly higher levels of OEA and PEA and lower levels of 2‐DHG compared to NALS and HCs.

Conclusion

Circulating endocannabinoidome profiles are indicative of disease activity, thus possibly paving the way to a personalized, rather than a ‘one‐fits‐all’, therapeutic approach targeting the endocannabinoidome.

ORIGINAL ARTICLE

Background and purpose

Management of idiopathic intracranial hypertension (IIH) is complex requiring multiple specialized disciplines. In practice, this creates considerable organizational and communicational challenges for healthcare professionals and patients. Thus, an interdisciplinary integrated outpatient clinic for IIH (comprising neurology, neuroophthalmology, neuroradiology, neurosurgery and endocrinology) was established with central coordination and a one‐stop concept. Here, the aim was to evaluate the effects of this one‐stop concept on objective clinical outcome.

Methods

In a retrospective cohort study, the one‐stop era with integrated care (IC) (1 July 2021 to 31 December 2022) was compared to a reference group receiving standard care (SC) (1 July 2018 to 31 December 2019) regarding visual impairment/worsening and headache improvement/freedom 6 months after diagnosis. Multivariate binary logistic regression models were used to adjust for confounders.

Results

Baseline characteristics of the IC group ( = 85) and SC group ( = 81) were comparable (female 90.6% vs. 90.1%; mean age 33.6 vs. 32.8 years; median body mass index 31.8 vs. 33.0; median cerebrospinal fluid opening pressure 32 vs. 34 cmHO; at diagnosis, visual impairment was present in 71.8% vs. 69.1% and chronic headache in 55.3% vs. 56.8% in IC vs. SC). IC was associated with a higher likelihood of achieving both headache improvement (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.52–4.33,  < 0.001) and headache freedom (OR 1.75, 95% CI 1.11–3.09,  = 0.031). Regarding the risk of visual impairment and visual worsening IC was superior numerically but not statistically significantly (OR 0.87, 95% CI 0.69–1.16,  = 0.231, and OR 0.67, 95% CI 0.41–1.25,  = 0.354).

Conclusions

Interdisciplinary integrated care of IIH is favourably associated with headache outcomes and potentially also visual outcomes.

ORIGINAL ARTICLE

Background and purpose

This study investigated the effects of deep abdominal breathing on cardiovascular parameters and symptoms in patients with postural orthostatic tachycardia syndrome (POTS) during head‐up tilt‐table (HUT) challenge.

Methods

Thirty POTS patients completed two consecutive rounds of 10‐min HUT in a crossover design. One round was HUT without intervention, and one round combined the HUT with deep breathing at a rate of 6 breaths/min. Cardiovascular parameters, including mean blood pressure and maximum and mean heart rate (HR), were measured supine and standing. Symptoms were assessed using the Vanderbilt Orthostatic Symptom Score (VOSS).

Results

During the breathing technique, the mean HR increase was −7.35 bpm (95% confidence interval [CI] = −11.71 to −2.98), and the maximum HR increase was −6.27 bpm (95% CI = −11.85 to −0.68,  = 0.041), significantly lower compared to normal breathing. Additionally, improvements were observed in all absolute cardiovascular parameters during standing, with VOSS symptoms simultaneously and significantly decreasing by −5.38 (95% CI = −10.43 to −0.36).

Conclusions

Slow deep abdominal breathing can act as a simple technique to reduce the standing HR increase upon HUT in patients with POTS. This suggests that modulation of the cardiopulmonary neurocircuits and the respiratory pump may reduce HR increase and symptoms in patients with POTS. The findings of this study highlight the use of a safe, zero‐cost, and simple behavioral tool to suggest to POTS patients for symptom relief apart from standard treatment. The observed improvements in cardiovascular parameters and symptoms offer a promising therapeutic approach for patients in times of inadequate treatment options.

ORIGINAL ARTICLE

Background and purpose

Migraine and sleep disorders share a bidirectional relationship, but little is known about the specific association between migraine and rapid eye movement (REM) sleep behaviour disorder (RBD). The aim was to assess the prevalence of RBD and associated clinical characteristics in adults with migraine.

Methods

This analysis is part of a cross‐sectional survey study conducted at the Headache Centre of the Charité—Universitätsmedizin Berlin between August 2020 and March 2023. At the end of their regular medical consultation, patients with migraine filled out (1) the validated RBD Screening Questionnaire (RBDSQ), (2) a questionnaire on REM sleep intrusions and (3) the Depression, Anxiety and Stress Scale 21. The primary endpoint was the percentage of patients with a positive RBD screening. A multivariate analysis was performed to identify characteristics independently associated with features of RBD.

Results

A total of 751 patients (44.1 ± 13.2 years; 87.4% female) with complete RBDSQ were included in this analysis, of which 443 (58.9%) screened positive for RBD. In multivariate analysis, a positive screening for RBD was associated with younger age (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.8–0.9 per 10‐year increase;  = 0.005) and with features suggestive of REM sleep intrusions (OR 4.3, 95% CI 1.8–10.4;  = 0.001). Migraine aura remained in the model without reaching statistical significance (OR 1.3, 95% CI 0.9–1.8;  = 0.079).

Discussion

Symptoms of RBD are frequent in adults with migraine. Further studies including polysomnography are required to confirm this association, and to explore potential common pathophysiological mechanisms.

ORIGINAL ARTICLE

Background and purpose

Although air pollution (AP) has been associated with stroke and dementia, data regarding its relationship with covert cerebrovascular disease (cCVD) and cognition over time are sparse. The aim of this study was to explore these relationships.

Methods

A prospective population‐based study of 976 stroke‐free and non‐demented individuals living in Barcelona, Spain, was conducted during 2010–2016. A land use regression model was used to estimate the exposure of each participant to AP: NO, NO, PM, PM, PM and PM absorbance. Cognitive function and cCVD were assessed at baseline ( = 976) and 4 years after ( = 317). Multivariate‐adjusted models were developed.

Results

At baseline, 99 participants (10.1%) had covert brain infarcts and 91 (9.3%) had extensive periventricular white matter hyperintensities (WMHs). Marked subcortical WMH progression was seen in 19.7%; the incidence of other covert cerebrovascular lessons ranged between 5% and 6% each. PM was related to higher odds of having a covert brain infarct (odds ratio [OR] 2.21; 95% confidence interval [CI] 1.06–4.60). PM absorbance was related to higher odds of having extensive subcortical WMHs (OR 1.72; 95% CI 1.13–2.60), whereas NO was related to higher odds of having extensive subcortical (OR 1.66; 95% CI 1.17–2.35) or periventricular (OR 1.96; 95% CI 1.10–3.50) WMHs and to higher odds of developing marked subcortical WMH progression (OR 1.40; 95% CI 1.05–1.90). NO was related to incident cerebral microbleeds (OR 1.36; 95% CI 1.04–1.79). There was no association between AP and cognition.

Conclusions

Air pollutant predicts the presence and accumulation of cCVD. Its impact on cognitive impairment remains to be determined.

CASE REPORT

Background and purpose

Late‐onset mitochondrial disorders are diagnostically challenging with significant heterogeneity in disease presentation. A case is reported of a 67‐year‐old gentleman who presented with a 3‐month history of seizures, recurrent encephalopathy, ataxia and weight loss, preceded by recent initiation of haemodialysis for end‐stage chronic kidney disease.

Methods

Extensive work‐up including serological, cerebrospinal fluid, magnetic resonance imaging and electroencephalography was performed. Whole exome sequencing and muscle biopsy confirmed the diagnosis.

Results

Magnetic resonance imaging brain demonstrated a single non‐enhancing T2 fluid attenuated inversion recovery hyperintense cortical/subcortical signal change in the right temporal lobe and cerebellar atrophy. Given the subacute presentation of uncertain aetiology, he was empirically treated for autoimmune/paraneoplastic encephalitis. Despite radiological resolution of the cortical abnormality 2 weeks later, there was no clinical improvement. Further collateral history unveiled a mildly ataxic gait and longstanding hearing loss suggestive of a genetic cause. Whole exome sequencing revealed a likely pathogenic, heteroplasmic mitochondrial DNA variant in the gene, m.1659T>C, present at higher levels of heteroplasmy in muscle (91%) compared to other mitotic tissues. A high fat/protein diet and multivitamins including co‐enzyme Q10 were commenced. Treatment of the nutritional deficiency and avoidance of intermittent fasting due to unreliable oral intake secondary to encephalopathy probably contributed to the clinical improvement seen over the ensuing few months, with resolution of his encephalopathy and return to his baseline gait and weight.

Conclusion

An adult case is reported with an acute neurological presentation mimicking encephalitis, caused by a heteroplasmic m.1659T>C variant, previously reported once in a child who displayed a different clinical phenotype.

ORIGINAL ARTICLE

Background and purpose

Reports of patients who have autoimmune nodopathies concurrent with nephrotic syndrome are increasing. We investigated whether proteinuria could be a biomarker of autoimmune nodopathies.

Methods

Qualitative urinalysis results were retrospectively obtained from 69 patients who were diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) at a hospital in Japan. Proteinuria was graded as mild to severe (i.e., mild, 30–99; moderate, 100–299; severe, 300 mg/dL or more) according to the results of the urine dipstick test. Autoantibodies against the paranodal proteins contactin 1 (CNTN1), neurofascin 155 (NF155), and contactin‐associated protein 1 (Caspr1) and the nodal protein neurofascin 186 (NF186) were measured, and the predominant IgG subclass was determined by enzyme‐linked immunosorbent assay in sera from the 69 patients.

Results

Four patients (6%), five patients (7%), and one (1%) patient were positive for anti‐CNTN1, anti‐NF155, and anti‐Caspr1 IgG4 antibodies, respectively. No patients had IgG4 antibodies against NF186. Proteinuria of mild or greater levels was found in three patients with anti‐CNTN1 IgG4 and two patients with anti‐NF155 IgG4 antibodies. The autoantibody‐positive patients more frequently had proteinuria of mild or greater levels than the seronegative patients ( = 0.01).

Conclusions

Proteinuria is a possible biomarker of autoimmune nodopathies associated with autoantibodies targeting CNTN1 or NF155. Urinalysis results should be carefully checked for quick differentiation of autoimmune nodopathies from CIDP. Patients who present with nephrotic syndrome should be tested for anti‐CNTN1 IgG4 antibodies, and patients who exhibit mild proteinuria should be tested for anti‐NF155 IgG4 antibodies.

GUIDELINES

Background and purpose

In October 2020, the European Academy of Neurology (EAN) consensus statement for management of patients with neurological diseases during the coronavirus disease 2019 (COVID‐19) pandemic was published. Due to important changes and developments that have happened since then, the need has arisen to critically reassess the original recommendations and address new challenges.

Methods

In step 1, the original items were critically reviewed by the EAN COVID‐19 Task Force. In addition, new recommendations were defined. In step 2, an online survey with the recommendations forged in step 1 was sent to the Managing Groups of all Scientific and Coordinating Panels of EAN. In step 3, the final set of recommendations was made.

Results

In step 1, out of the original 36 recommendations, 18 were judged still relevant. They were edited to reflect the advances in knowledge and practice. In addition, 21 new recommendations were formulated to address the new knowledge and challenges. In step 2, out of the 39 recommendations sent for the survey, nine were approved as they were, whilst suggestions for improvement were given for the rest. In step 3, the recommendations were further edited, and some new items were formed to accommodate the participants' suggestions, resulting in a final set of 41 recommendations.

Conclusion

This revision of the 2020 EAN Statement provides updated comprehensive and structured guidance on good clinical practice in people with neurological disease faced with SARS‐CoV‐2 infection. It now covers the issues from the more recent domains of COVID‐19‐related care, vaccine complications and post‐COVID‐19 conditions.

ORIGINAL ARTICLE

Background and purpose

National quality registries for stroke care operate under the assumption that the included patients are correctly diagnosed. We aimed to validate the clinical diagnosis of spontaneous intracerebral hemorrhage (ICH) in Riksstroke (RS) by evaluating radiological data from a large, unselected ICH population.

Methods

We conducted a retrospective, multicenter study including all ICH patients registered in RS between 2016 and 2020 residing in Skåne County in Sweden (1.41 million inhabitants). Radiological data from first imaging were evaluated for the presence of spontaneous ICH. Other types of bleeds were registered if a spontaneous ICH was not identified on imaging. The radiological evaluation was independently performed by one radiology fellow and one senior neuroradiologist.

Results

Between 2016 and 2020, 1784 ICH cases were registered in RS, of which 1655 (92.8%) had a radiological diagnosis consistent with spontaneous ICH. In the 129 (7.2%) remaining cases, the radiological diagnosis was instead traumatic bleed ( = 80), subarachnoid hemorrhage ( = 15), brain tumor bleed ( = 14), ischemic lesion with hemorrhagic transformation ( = 14), ischemic lesion ( = 3), or no bleed at all ( = 3). There was a higher degree of incorrect coding in the older age groups.

Conclusion

At radiological evaluation, 92.8% of ICH diagnoses in RS were consistent with spontaneous ICH, yielding a high rate of agreement that strengthens the validity of the diagnostic accuracy in the register, justifying the use of high coverage quality register data for epidemiological purposes. The most common coding error was traumatic bleeds that were classified as spontaneous ICH.

ORIGINAL ARTICLE

Background and Purpose

Pathogenic variants of the glycyl‐tRNA synthetase 1 () gene have been described as a cause of Charcot–Marie–Tooth disease type 2D, motor axonal neuropathy with upper limb predominance (distal hereditary motor neuropathy [dHMN] type V), and infantile spinal muscular atrophy.

Methods

This cross‐sectional, retrospective, observational study was carried out on 12 patients harboring the c.794C>T (p.Ser265Phe) missense pathogenic variant in . The patients' clinical data, nerve conduction studies, magnetic resonance imaging (MRI), and intraepidermal nerve fiber density in skin biopsies were reviewed.

Results

The mean age at onset was 9.5 years; the intrinsic hand muscles were affected before or at the same time as the distal leg musculature. The clinical examination revealed greater weakness of the distal muscles, with a more pronounced involvement of the thenar complex and the first dorsal interosseous in upper limbs. Electrophysiological studies were concordant with an exclusively motor axonal neuropathy. A pathologic split hand index was found in six patients. Muscle MRI showed predominant fatty infiltration and atrophy of the anterolateral and superficial posterior compartment of the legs. Most patients reported distal pinprick sensory loss. A reduced intraepidermal nerve fiber density was evident in skin biopsies from proximal and distal sites in nine patients.

Conclusions

variants may produce a dHMN phenotype with “split hand” and sensory disturbances, even when sensory nerve conduction studies are normal. This could be explained by a dysfunction of sensory neurons in the dorsal ganglion that is reflected as a reduction of dermal nerve endings in skin biopsies without a distal gradient.

ORIGINAL ARTICLE

Background and purpose

The aim of this study was to examine the discriminative validity of the Brief Assessment of Impaired Cognition (BASIC) case‐finding instrument in a general practice (GP) setting and compare it with other widely used brief cognitive instruments.

Methods

Patients aged ≥70 years were prospectively recruited from 14 Danish GP clinics. Participants were classified as having either normal cognition ( = 154) or cognitive impairment ( = 101) based on neuropsychological test performance, reported instrumental activities of daily living, and concern regarding memory decline. Comparisons involved the Mini‐Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Rowland Universal Dementia Assessment Scale (RUDAS), the Mini‐Cog, the 6‐item Clock Drawing Test (CDT‐6) and the BASIC Questionnaire (BASIC‐Q).

Results

BASIC demonstrated good overall classification accuracy with an area under the receiver operating characteristic curve (AUC) of 0.88 (95% confidence interval [CI] 0.84–0.92), a sensitivity of 0.72 (95% CI 0.62–0.80) and a specificity of 0.86 (95% CI 0.79–0.91). Pairwise comparisons of the AUCs of BASIC, MMSE, MoCA and RUDAS produced non‐significant results, but BASIC had significantly higher classification accuracy than Mini‐Cog, BASIC‐Q and CDT‐6. Depending on the pretest probability of cognitive impairment, the positive predictive validity of BASIC varied from 0.83 to 0.36, and the negative predictive validity from 0.97 to 0.76.

Conclusions

BASIC demonstrated good discriminative validity in a GP setting. The classification accuracy of BASIC is equivalent to more complex, time‐consuming instruments, such as the MMSE, MoCA and RUDAS, and higher than very brief instruments, such as the CDT‐6, Mini‐Cog and BASIC‐Q.

ORIGINAL ARTICLE

Background and purpose

The aim of this study is to investigate the efficacy and safety of preoperative versus intraoperative tirofiban in patients with large vessel occlusion (LVO) due to large artery atherosclerosis (LAA).

Methods

This is a retrospective multicenter cohort study based on the RESCUE‐RE (Registration Study for Critical Care of Acute Ischemic Stroke After Recanalization) trial enrolling patients with anterior circulation LVO classified as LAA within 24 h of onset. Patients were divided into three groups: preoperative tirofiban (PT), intraoperative tirofiban (IT), and no tirofiban (NT). Propensity score matching (PSM) was used to balance baseline characteristics. The efficacy outcomes included 90‐day functional independence (modified Rankin Scale score = 0–2) and early partial recanalization (EPR; defined as a modified Thrombolysis in Cerebral Infarction score = 1–2a). The safety outcomes included symptomatic intracranial hemorrhage (sICH).

Results

A total of 104 matched triplets were obtained through PSM. Compared with NT, PT increased 90‐day functional independence (60.8% vs. 42.3%,  = 0.008) and EPR (42.7% vs. 18.3%,  < 0.001) rate, with a tendency to increase the asymptomatic intracranial hemorrhage (aICH) proportion (28.8% vs. 18.3%,  = 0.072). Compared with IT, PT had a higher 90‐day functional independence (60.8% vs. 45.2%,  = 0.025) and EPR (42.7% vs. 20.2%,  = 0.001) rate, with no significant difference in sICH (14.4% vs. 7.7%,  = 0.122) and aICH (28.8% vs. 21.2%,  = 0.200). Compared with NT, IT had a lower 90‐day mortality rate (9.6% vs. 24.0%,  = 0.005).

Conclusions

Tirofiban shows good adjuvant therapy potential in acute ischemic stroke–LVO due to LAA patients. PT is associated with higher rates of EPR and better therapeutic efficacy. In addition, EPR may be a potential way to improve prognosis.

ORIGINAL ARTICLE

Background and purpose

Parent artery atherosclerosis is an important aetiology of recent subcortical ischaemic stroke (RSIS). However, comparisons of RSIS with different degrees of parent artery atherosclerosis are lacking.

Methods

Prospectively collected data from our multicentre cohort (all were tertiary centres) of the Stroke Imaging Package Study between 2015 and 2017 were retrospectively reviewed. The patients with RSIS defined as a single clinically relevant diffusion‐weighted imaging positive lesion in the territory of lenticulostriate arteries were categorized into three subgroups: (1) normal middle cerebral artery (MCA) on magnetic resonance angiography and high‐resolution magnetic resonance imaging (HR‐MRI); (2) low‐grade MCA atherosclerosis (normal or <50% stenosis on magnetic resonance angiography and with MCA plaques on HR‐MRI); (3) steno‐occlusive MCA atherosclerosis (stenosis ≥50% or occlusion). The primary outcome was 90‐day functional dependence (modified Rankin Scale score >2). The clinical and imaging findings were compared between subgroups.

Results

A total of 239 patients (median age 60.0 [52.0–67.0] years, 72% male) were enrolled, including 140 with normal MCA, 64 with low‐grade MCA atherosclerosis and 35 with steno‐occlusive MCA atherosclerosis. Patients with steno‐occlusive MCA atherosclerosis had the largest infarct volume. Low‐grade MCA atherosclerosis was independently associated with cerebral microbleeding, more severe perivascular spaces in basal ganglia and higher total cerebral small vessel disease burden. Low‐grade MCA atherosclerosis was an independent determinant of 90‐day functional dependence (odds ratio 3.897; 95% confidence interval 1.309–11.604).

Conclusions

Our study suggested RSIS with varying severity of parent artery atherosclerosis exhibits distinctive clinical and neuroimaging characteristics, with low‐grade MCA atherosclerosis associating with higher cerebral small vessel disease burden and worse prognosis.

ORIGINAL ARTICLE

Background and purpose

The aim was to demonstrate the feasibility, reliability and validity of an in‐home remote levodopa challenge test (LCT), as delivered through an online platform, for patients with Parkinson's disease (PwPD).

Methods

Patients with Parkinson's disease eligible for deep brain stimulation surgery screening were enrolled. Participants sequentially received an in‐home remote LCT and an in‐hospital standard LCT (separated by 2.71 weeks). A modified Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III omitting rigidity and postural stability items was used in the remote LCT. The reliability of the remote LCT was evaluated using the intraclass correlation coefficient and the concurrent validity was evaluated using the Pearson's correlation coefficient between the levodopa responsiveness of the remote and standard LCT.

Results

Out of 106 PwPD screened, 80 (75.5%) completed both the remote and standard LCT. There was a good reliability (intraclass correlation coefficient 0.81, 95% confidence interval 0.69–0.88) and a strong correlation ( = 0.84, 95% confidence interval 0.77–0.90) between the levodopa responsiveness of the remote and standard LCT. The mean cost for PwPD was estimated to be reduced by 91% by using the remote LCT.

Conclusion

The remote LCT is feasible, reliable and valid and may reduce healthcare‐related costs for PwPD and their caregivers.

SHORT COMMUNICATION

Background and Purpose

Precise and timely diagnosis is crucial for the optimal use of emerging disease‐modifying treatments for Alzheimer disease (AD). Electroencephalography (EEG), which is noninvasive and cost‐effective, can capture neural abnormalities linked to various dementias. This study explores the use of individual alpha frequency (IAF) derived from EEG as a diagnostic and prognostic tool in cognitively impaired patients.

Methods

This retrospective study included 375 patients from the tertiary Memory Clinic of IRCCS San Raffaele Hospital, Milan, Italy. Participants underwent clinical and neuropsychological assessments, brain imaging, cerebrospinal fluid biomarker analysis, and resting‐state EEG. Patients were categorized by amyloid status, the AT(N) classification system, clinical diagnosis, and mild cognitive impairment (MCI) progression to AD dementia. IAF was calculated and compared among study groups. Receiver operating characteristic (ROC) analysis was used to calculate its discriminative performance.

Results

IAF was higher in amyloid‐negative subjects and varied significantly across AT(N) groups. ROC analysis confirmed IAF's ability to distinguish A–T–N– from the A+T+N+ and A+T–N+ groups. IAF was lower in AD and Lewy body dementia patients compared to MCI and other dementia types, with moderate discriminatory capability. Among A+ MCI patients, IAF was significantly lower in those who converted to AD within 2 years compared to stable MCI patients and predicted time to conversion ( < 0.001,  = 0.38).

Conclusions

IAF is a valuable tool for dementia diagnosis and prognosis, correlating with amyloid status and neurodegeneration. It effectively predicts MCI progression to AD, supporting its use in early, targeted interventions in the context of disease‐modifying treatments.

ORIGINAL ARTICLE

Background and purpose

Although the Boston criteria version 2.0 facilitates the sensitivity of cerebral amyloid angiopathy (CAA) diagnosis, there are only limited data about precursor symptoms. This study aimed to determine the impact of neurological and imaging features in relation to the time of CAA diagnosis.

Methods

Patients diagnosed with probable CAA according to the Boston criteria version 1.5, treated between 2010 and 2020 in our neurocentre, were identified through a keyword search in our medical database. Neuroimaging was assessed using Boston criteria versions 1.5 and 2.0. Medical records with primary focus on the clinical course and the occurrence of transient focal neurological episodes were prospectively evaluated.

Results

Thirty‐eight out of 81 patients (46.9%) exhibited transient focal neurological episodes, most often sensory (13.2%) or aphasic disorders (13.2%), or permanent deficits at a mean time interval of 31.1 months (SD ±26.3; range 1–108 months) before diagnosis of probable CAA (Boston criteria version 1.5). If using Boston criteria version 2.0, all patients receiving magnetic resonance imaging (MRI) met the criteria for probable CAA, and diagnosis could have been made on average 44 months earlier. Four patients were younger than 50 years, three of them with supporting pathology. Cognitive deficits were most common (34.6%) at the time of diagnosis.

Conclusions

Non‐haemorrhagic MRI markers enhance the sensitivity of diagnosing probable CAA; however, further prospective studies are proposed to establish a minimum age for inclusion. As the neurological overture of CAA may occur several years before clinical diagnosis, early clarification by MRI including haemosensitive sequences are suggested.

ORIGINAL ARTICLE

Background and purpose

Late onset Pompe disease (LOPD) is a rare neuromuscular disorder caused by a deficit in acid alpha‐glucosidase. Macroglossia and swallowing disorders have already been reported, but no study has focused yet on its frequency and functional impact on patients' daily life.

Methods

We reviewed 100 adult LOPD patients followed in 17 hospitals in France included in the French national Pompe disease registry. The Swallowing Quality of Life Questionnaire and the Sydney Swallow Questionnaire were completed by patients, and a specialist carried out a medical examination focused on swallowing and assigned a Salassa score to each patient. Respiratory and motor functions were also recorded. Subgroup analysis compared patients with and without swallowing difficulties based on Salassa score.

Results

Thirty‐two percent of patients presented with swallowing difficulties, often mild but sometimes severe enough to require percutaneous endoscopic gastrostomy (1%). Daily dysphagia was reported for 20% of our patients and aspirations for 18%; 9.5% were unable to eat away from home. Macroglossia was described in 18% of our patients, and 11% had lingual atrophy. Only 15% of patients presenting with swallowing disorders were followed by a speech therapist. Swallowing difficulties were significantly associated with macroglossia ( = 0.015), longer duration of illness ( = 0.032), and a lower body mass index ( = 0.047).

Conclusions

Swallowing difficulties in LOPD are common and have significant functional impact. Increased awareness by physicians of these symptoms with systematic examination of the tongue and questions about swallowing can lead to appropriate multidisciplinary care with a speech therapist and dietitian if needed.

ORIGINAL ARTICLE

Background and Purpose

Healthy lifestyle behaviour modification may improve health outcomes in people with multiple sclerosis (pwMS), but empirical evidence is needed to confirm prior study findings. We developed an online multimodal lifestyle intervention (Multiple Sclerosis Online Course) to examine the impact of lifestyle modification on health outcomes in pwMS via a randomized control trial (RCT). However, the present study specifically analyses baseline data to assess engagement with healthy lifestyles by RCT participants and cross‐sectional associations with health outcomes.

Methods

Baseline engagement with six “healthy lifestyle behaviours” of the intervention course (high‐quality, plant‐based diet; ≥5000 IU/day vitamin D; omega‐3 supplementation; ≥30 min physical activity 5 times/week; ≥30 min/week meditation; and nonsmoking) was examined. Associations between individual versus collective behaviours (individual behaviours summated) and health outcomes (quality of life [QoL]/fatigue/disability) were evaluated using multivariate modelling (linear/log‐binomial/multinomial).

Results

At baseline, 33.7% and 30.0% of participants ( = 857) engaged in one or two healthy behaviours, respectively. In total, engagement with healthy lifestyles by participants was as follows: nonsmoking, 90.7%; omega‐3 supplementation, 34.5%; vitamin D supplementation, 29.8%; physical activity, 29.4%; diet, 10.7%; and meditation, 10.5%. Individual behaviours (nonsmoking/physical activity/diet) were independently associated with better health outcomes. Engagement with multiple behaviours, especially diet and physical activity, was associated with better outcomes; engaging with ≥4 behaviours was associated with a 9.0‐point higher mental QoL and a 9.5‐point higher physical QoL, as well as 23% and 56% lower prevalence of fatigue and moderate disability, respectively.

Conclusions

Baseline engagement with ≥4 healthy behaviours, including diet and physical activity, was associated with better health outcomes.

SHORT COMMUNICATION

Background and purpose

Prior studies highlighted the high diagnostic specificity (ranging from 92% to 100%) of clinical signs observed in functional neurological disorders (FNDs). However, these signs are rarely looked for by epileptologists when trying to distinguish between functional dissociative seizure (FDS) and epileptic seizure. The aim of this study was to determine the prevalence of inter‐ictal clinical signs of FND in a cohort of patients with probable FDS. The secondary objective was to compare the prevalence of inter‐ictal FND clinical signs in FDS patients with age‐ and gender‐matched epileptic patients without FDS.

Methods

Patients diagnosed with FDS seen at two tertiary care centres and epileptic outpatients were included in the study. Each patient underwent a physical examination, searching for inter‐ictal clinical signs of FND.

Results

In the FDS group, 79% of patients presented at least one sign of FND, compared to 16.6% of patients with epilepsy ( < 0.001). Moreover, 66.6% of FDS patients presented three or more FND signs, whereas only 4.1% of epileptic patients did ( < 0.001). The median number of FND clinical signs in the FDS group was four (SD 1.7; 5.5). Using the threshold of three signs or more, the specificity of detecting three or more FND signs was 83.3%, with a sensitivity of 79.2%.

Conclusion

Inter‐ictal clinical signs of FND are present in patients with FDS and should be looked for during neurological examination.