cover image European Journal of Neurology

European Journal of Neurology

2022 - Volume 29
Issue 7 | July 2022
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ISSUE INFORMATION

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Article first published online:
11 Jun 2022 | DOI: 10.1111/ene.14927

ORIGINAL ARTICLE

Background

More than 500,000 dementia cases can be estimated among migrants living in Europe. There is the need to collect “real world” data on the preparedness of healthcare services to support the inclusion of migrants in the public health response to dementia. The present study aimed (i) to estimate the number of migrants referred to Italian memory clinics (Centers for Cognitive Disorders and Dementia [CCDDs]) and (ii) to identify possible barriers and resources for the provision of diversity‐sensitive care.

Methods

A survey of all Italian CCDDs was conducted between December 2020 and April 2021. An online questionnaire was developed to obtain information on the number of migrants referred to Italian CCDDs in 2019, the challenges encountered in the diagnostic approach, and possible facilitators in the provision of care.

Results

Overall, 343 of the 570 contacted CCDDs completed the survey questionnaire (response rate: 60.2%). Nearly 4527 migrants were referred to these services in 2019. Migrants accounted for a median 1.1% (IQR: 0.9%–2.8%) of overall CCDD referrals. More than one‐third of respondents reported that the number of migrants referred to their facilities had increased in the last 5 years. The overall quality of the migrants' cognitive assessment was deemed to be very poor or insufficient in most cases. A minority of CCDDs had translated information material on dementia and reported the possibility to contact cultural mediators and interpreters.

Conclusions

A relevant number of migrants are being referred to Italian CCDDs that are still not adequately prepared to deliver diversity‐sensitive care and support.

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Authors:
Marco Canevelli, Ilaria Cova, Giulia Remoli, Ilaria Bacigalupo, Emanuela Salvi, Giorgia Maestri, Alessia Nicotra, Martina Valletta, Antonio Ancidoni, Francesco Sciancalepore, Silvia Cascini, Anna Maria Bargagli, Simone Pomati, Leonardo Pantoni, Nicola Vanacore, Guido Bellomo, Angela Giusti, Eleonora Lacorte, Ilaria Palazzesi, Paola Piscopo, Mariacristina Porrello, Francesca Zambri, Giuseppe Bruno, Valerio Zaccaria, Norina Di Blasio, Luca De Fiore and Caterina Visco
Article first published online:
10 Mar 2022 | DOI: 10.1111/ene.15297

ORIGINAL ARTICLE

Background and purpose

Reperfusion therapy is the mainstay of treatment for acute ischaemic stroke (AIS); however, little is known about the use of reperfusion therapy and time delay amongst immigrants.

Methods

This is a Danish nationwide register‐based cohort study of patients with AIS aged ≥18 years ( = 49,817) recruited from 2009 to 2018. Use of reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy) and time delay between immigrants and Danish‐born residents were compared using multivariable logistics and quantile regression.

Results

Overall, 10,649 (39.8%) Danish‐born residents and 452 (39.0%) immigrants with AIS were treated with reperfusion therapy in patients arriving <4.5 h following stroke onset. Compared with Danish‐born residents, immigrants had lower odds of receiving reperfusion therapy after adjustment for prehospital delay, age, sex, stroke severity, sociodemographic factors and comorbidities (adjusted odds ratio 0.67; 95% confidence interval 0.49‒0.92,  = 0.01). The lowest odds were observed amongst immigrants originating from Poland and non‐Western countries. Similarly, immigrants had a longer prehospital delay than Danish‐born residents in the fully adjusted model in patients arriving <4.5 h after stroke onset (15 min; 95% confidence interval 4‒26 min,  = 0.03). No evidence was found that system delay and clinical outcome differed between immigrants and Danish‐born residents in patients eligible for reperfusion therapy after adjustment for sociodemographic factors and comorbidities.

Conclusion

Immigration status was significantly associated with lower chances of receiving reperfusion therapy and there may be differences in patient delay between immigrants and Danish‐born residents in patients arriving to a stroke unit <4.5 h after stroke onset.

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Authors:
George F. Mkoma, Marie Norredam, Helle K. Iversen, Grethe Andersen and Søren P. Johnsen
Article first published online:
09 Mar 2022 | DOI: 10.1111/ene.15303

SHORT COMMUNICATION

Background and purpose

Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients.

Methods

After unremarkable whole‐exome sequencing (WES) analysis, we performed repeat‐primed PCR to detect intronic expansions in 12 HSAN families, who all presented with chronic cough.

Results

In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared with −/− cases, +/+ cases presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the +/+ cohort and cerebellar ataxia was a common feature (21%).

Conclusions

We demonstrate that is a frequent cause of (WES‐negative) HSAN with chronic cough and ataxia. The diagnostic yield of repeat‐primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy‐ataxia spectrum.

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Authors:
Danique Beijer, Maike F. Dohrn, Jonathan De Winter, Sarah Fazal, Andrea Cortese, Tanya Stojkovic, Gorka Fernández‐Eulate, Gauthier Remiche, Mattia Gentile, Rudy Van Coster, Claudia Dufke, Matthis Synofzik, Peter De Jonghe, Stephan Züchner and Jonathan Baets
Article first published online:
23 Mar 2022 | DOI: 10.1111/ene.15310

ORIGINAL ARTICLE

Background and purpose

Chronic axonal polyneuropathy is a common disease, but the etiology remains only partially understood. Previous etiologic studies have identified clinical risk factors, but genetic evidence supporting causality between these factors and polyneuropathy are largely lacking. In this study, we investigate whether there is a genetic association of clinically established important risk factors (diabetes, body mass index [BMI], vitamin B12 levels, and alcohol intake) with chronic axonal polyneuropathy.

Methods

This study was performed within the population‐based Rotterdam Study and included 1565 participants (median age = 73.6 years, interquartile range = 64.6–78.8, 53.5% female), of whom 215 participants (13.7%) had polyneuropathy. Polygenic scores (PGSs) for diabetes, BMI, vitamin B12 levels, and alcohol intake were calculated at multiple significance thresholds based on published genome‐wide association studies.

Results

Higher PGSs of diabetes, BMI, and alcohol intake were associated with higher prevalence of chronic axonal polyneuropathy, whereas higher PGS of vitamin B12 levels was associated with lower prevalence of polyneuropathy. These effects were most pronounced for PGSs with lenient significance thresholds for diabetes and BMI (odds ratio [OR] = 1.21, 95% confidence interval [CI] = 1.05–1.39 and OR = 1.21, 95% CI = 1.04–1.41) and for the strictest significance thresholds for vitamin B12 level and alcohol intake (OR  = 0.79, 95% CI = 0.68–0.92 and OR = 1.17, 95% CI = 1.02–1.35). We did not find an association between different PGSs and sural sensory nerve action potential amplitude, nor between individual lead variants of PGS and polyneuropathy.

Conclusions

This study provides evidence for polygenic associations of diabetes, BMI, vitamin B12 level, and alcohol intake with chronic axonal polyneuropathy. This supports the hypothesis of causal associations between well‐known clinical risk factors and polyneuropathy.

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Authors:
Noor E. Taams, Maria J. Knol, Rens Hanewinckel, Judith Drenthen, Hieab H. H. Adams, Pieter A. van Doorn and Mohammad Arfan Ikram
Article first published online:
18 Mar 2022 | DOI: 10.1111/ene.15311

ORIGINAL ARTICLE

Background and purpose

The aim was to evaluate whether adaptive NKG2C+ natural killer (NK) cells, characterized by enhanced antibody‐dependent cell cytotoxicity (ADCC), may influence time to B cell repopulation after rituximab treatment in multiple sclerosis (MS) patients.

Methods

This was a prospective observational study of MS patients treated with rituximab monitoring peripheral B cells for repeated doses. B cell repopulation was defined as CD19+ cells above 2% of total lymphocytes, classifying cases according to the median time of B cell repopulation as early or late (≤9 months, >9 months, respectively). Basal NK cell immunophenotype and in vitro ADCC responses induced by rituximab were assessed by flow cytometry.

Results

B cell repopulation in 38 patients (24 relapsing–remitting MS [RRMS]; 14 progressive MS) was classified as early (≤9 months,  = 19) or late (>9 months,  = 19). RRMS patients with late B cell repopulation had higher proportions of NKG2C+ NK cells compared to those with early repopulation (24.7% ± 16.2% vs. 11.3% ± 10.4%,  < 0.05), and a direct correlation between time to B cell repopulation and percentage of NKG2C+ NK cells ( 0.45,  < 0.05) was observed. RRMS cases with late repopulation compared with early repopulation had a higher secretion of tumor necrosis factor α and interferon γ by NK cells after rituximab‐dependent NK cell activation. The NK cell immunophenotype appeared unrelated to B cell repopulation in progressive MS patients.

Conclusions

Adaptive NKG2C+ NK cells in RRMS may be associated with delayed B cell repopulation after rituximab, a finding probably related to enhanced depletion of B cells exerted by NK‐cell‐mediated ADCC, pointing to the use of personalized regimens with anti‐CD20 monoclonal antibody therapy in some patients.

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Authors:
Antía Moreira, Elvira Munteis, Andrea Vera, Adrián Macías Gómez, Bernat Bertrán Recasens, Miguel Ángel Rubio Pérez, Mireia Llop and Jose E. Martínez‐Rodríguez
Article first published online:
15 Mar 2022 | DOI: 10.1111/ene.15312

ORIGINAL ARTICLE

Background and purpose

In the REFLEX trial (ClinicalTrials.gov identifier: NCT00404352), patients with a first clinical demyelinating event (FCDE) displayed significantly delayed onset of multiple sclerosis (MS; McDonald criteria) when treated with subcutaneous interferon beta‐1a (sc IFN β‐1a) versus placebo. This analysis evaluated the effect of sc IFN β‐1a on spatio‐temporal evolution of disease activity, assessed by changes in T2 lesion distribution, in specific brain regions of such patients and its relationship with conversion to MS.

Methods

analysis of baseline and 24‐month magnetic resonance imaging data from FCDE patients who received sc IFN β‐1a 44 μg once or three times weekly, or placebo in the REFLEX trial. Patients were grouped according to McDonald MS status (converter/non‐converter) or treatment (sc IFN β‐1a/placebo). For each patient group, a baseline lesion probability map (LPM) and longitudinal new/enlarging and shrinking/disappearing LPMs were created. Lesion location/frequency of lesion occurrence were assessed in the white matter.

Results

At Month 24, lesion frequency was significantly higher in the anterior thalamic radiation (ATR) and corticospinal tract (CST) of converters versus non‐converters ( < 0.05). Additionally, the overall distribution of new/enlarging lesions across the brain at Month 24 was similar in placebo‐ and sc IFN β‐1a‐treated patients (ratio: 0.95). Patients treated with sc IFN β‐1a versus placebo showed significantly lower new lesion frequency in specific brain regions (cluster corrected): ATR ( = 0.025), superior longitudinal fasciculus ( = 0.042), CST ( = 0.048), and inferior longitudinal fasciculus ( = 0.048).

Conclusions

T2 lesion distribution in specific brain locations predict conversion to McDonald MS and show significantly reduced new lesion occurrence after treatment with sc IFN β‐1a in an FCDE population.

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Authors:
Marco Battaglini, Hugo Vrenken, Riccardo Tappa Brocci, Giordano Gentile, Ludovico Luchetti, Adriaan Versteeg, Mark S. Freedman, Bernard M. J. Uitdehaag, Ludwig Kappos, Giancarlo Comi, Andrea Seitzinger, Dominic Jack, Maria Pia Sormani, Frederik Barkhof and Nicola De Stefano
Article first published online:
04 Apr 2022 | DOI: 10.1111/ene.15314

ORIGINAL ARTICLE

Background and purpose

The association between alcohol intake and cognitive decline has been widely studied. Sex differences and cognitive domains affected by alcohol intake patterns make this topic complex. The objective of this study was to investigate the effect of alcohol intake on cognition in middle‐aged participants in the Brazilian Longitudinal Study of Adult Health by sex during 4 years of follow‐up.

Methods

A total of 7595 participants (55% women) aged between 50 and 75 years at baseline were assessed. Semantic and phonemic fluency, memory, and executive functions were assessed at baseline (2008–2010) and repeated during Visit 2. Linear mixed models were used to investigate the association between cognition and current abstainers, never drinkers, light drinkers, moderate drinkers, and heavy drinkers.

Results

Heavy alcohol intake accentuated the decline in executive functions for men (β = −0.01,  < 0.05), and in semantic fluency (β = −0.02,  < 0.05) and memory (β = −0.02,  < 0.05) for women. Never drinker men also showed an accentuated decline in semantic fluency (β = −0.02,  < 0.01). Moderate alcohol intake slowed cognitive decline in phonemic fluency for men (β = 0.02,  < 0.01) and women (β = 0.01,  < 0.01), and in executive functions (β = 0.01,  < 0.05) for women.

Conclusions

Having more than 14 drinks per week can impact executive functions in men and memory in women. In addition, alcohol consumption of seven to 14 drinks per week may have a protective effect on gender‐specific cognitive functions. These findings should be considered in public health policies and guidelines on alcohol and cognitive aging.

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Authors:
Larissa Salvador, Luana Giatti, Maria Carmen Viana, Claudia Kimie Suemoto, Bruce B. Duncan, Maria del Carmen Bisi Molina, Maria de Jesus Mendes da Fonseca, André R. Brunoni, Sandhi Maria Barreto and Paulo Caramelli
Article first published online:
28 Mar 2022 | DOI: 10.1111/ene.15315

SHORT COMMUNICATION

Background and purpose

The aim was to show the application of the prevalence estimator of Expanded Disability Status Scale (EDSS) improvement over time in patients treated with cladribine tablets in the phase III CLARITY/CLARITY extension trials.

Methods

Relapsing–remitting multiple sclerosis patients who entered the CLARITY extension study were evaluated. Patients originally randomized in CLARITY to cladribine tablets 3.5 mg/kg and placebo in CLARITY extension (early cladribine [EC]) were compared to patients originally randomized to placebo and then assigned to cladribine tablets 3.5 mg/kg (delayed cladribine [DC]). The EC group was compared to the DC group on the prevalence of EDSS improvement over time and on the cumulative incidence of EDSS improvement. Prevalence of improvement was assessed by a new approach based on the difference of Kaplan–Meier estimators, whilst the incidence of improvement was assessed by standard Kaplan–Meier curves.

Results

A total of 98 patients in the EC group and 244 patients in the DC group were compared. Patients in the EC group showed a significantly higher ( = 0.011) prevalence of improvement at year 2 (EC 21.3%, 95% confidence interval [CI] 13.6–29.3; DC 8.9%, 95% CI 5.5–12.8) and at year 5 (EC 15.7%, 95% CI 8.2–23.7; DC 8.3%, 95% CI 4.5–12.4). The cumulative incidence of improvement was also significantly different (hazard ratio 1.82, 95% CI 1.13–2.94,  = 0.013).

Conclusions

Assessment of the prevalence of EDSS improvement is an alternative outcome to assess if a treatment induces and maintains an improvement over the long term. This estimator was found to be more powerful than the cumulative incidence of improvement to detect a treatment effect of cladribine versus placebo over 5 years.

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Authors:
Alessio Signori, Marta Ponzano, Nektaria Alexandri, Gavin Giovannoni and Maria Pia Sormani
Article first published online:
15 Mar 2022 | DOI: 10.1111/ene.15316

ORIGINAL ARTICLE

Background and purpose

Demyelinating events are listed as adverse events with tumor necrosis factor alpha inhibitors (TNFi), but epidemiological studies have provided partly conflicting risk estimates. Furthermore, studies examining long‐term outcomes of demyelinating events associated with TNFi are rare.

Methods

This was a retrospective, observational study comprising validation and tracking of long‐term outcomes in patients referred to a tertiary neurology referral center for suspected neurological complications associated with TNFi.

Results

Of 48 patients evaluated, only 14 showed signs of demyelinating disease on magnetic resonance imaging, where six fulfilled criteria for a clinically isolated syndrome (CIS) and eight were diagnosed with multiple sclerosis (MS). However, 13 patients had received an International Classification of Diseases code for MS at some stage. Mean follow‐up from referral was 13 and 10.5 years among subjects with MS and CIS, respectively. Continued disease activity was recorded among several of those fulfilling MS criteria, and two ultimately underwent autologous hematopoietic stem cell transplantation. In contrast, subjects with CIS showed no progression after cessation of TNFi.

Conclusions

Our findings suggest that only a minority of those with suspected demyelinating disease following TNFi fulfill diagnostic criteria for MS and that MS diagnoses among those not fulfilling MS criteria may contribute to inflated epidemiological risk estimates. Nevertheless, in those fulfilling MS criteria, initiation of disease‐modulating therapy, with escalation as needed, was important to suppress further disease activity.

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Authors:
Erik Kalén, Fredrik Piehl and Magnus Andersson
Article first published online:
21 Mar 2022 | DOI: 10.1111/ene.15318

ORIGINAL ARTICLE

Background and purpose

The aim of this study was to determine the contributions of background disorders responsible for participation restriction as indexed by a structured interview for the modified Rankin Scale (mRS‐SI).

Methods

A subset of 256 patients was assessed at 6 months after stroke using the National Institutes of Health Stroke Scale (NIHSS), gait score, comprehensive cognitive battery (yielding a global cognitive Z‐score), behavioral dysexecutive disorders (DDs), anxiety and depressive symptoms, epilepsy, and headache. Following bivariate analyses, determinants of participation restriction were selected using ordinal regression analysis with partial odds.

Results

Poststroke participation restriction (mRS‐SI score > 1) was observed in 59% of the patients. In bivariate analyses, mRS‐SI score was associated with prestroke mRS‐SI score, 6‐month NIHSS score, gait score, global cognitive Z‐score, behavioral DDs, and presence of anxiety and depression (all:  = 0.0001; epilepsy:  =0.3; headache:  = 0.7). After logistic regression analysis, NIHSS score was associated with increasing mRS‐SI score ( = 0.00001). Prestroke mRS‐SI score ( = 0.00001), behavioral DDs ( = 0.0008) and global cognitive Z‐score ( = 0.01) were associated with both mRS‐SI score > 1 and mRS‐SI score > 2. In addition, gait score was associated with mRS‐SI score > 2 ( = 0.00001). This model classified 85% of mRS‐SI scores correctly ( = 0.001). Structural equation modeling showed the contributions of gait limitation (standardized coefficient [SC]: 0.68;  = 0.01), prestroke mRS‐SI (SC: 0.41;  = 0.01), severity of neurological impairment (SC: 0.16;  = 0.01), global cognitive Z‐score (SC: −0.14;  = 0.05), and behavioral DDs (SC: 0.13;  = 0.01).

Conclusion

These results provide a statistical model of weights of determinants responsible for poststroke participation restriction and highlight a new independent determinant: behavioral DDs.

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Authors:
Sophie Tasseel‐Ponche, Mélanie Barbay, Martine Roussel, Adnane Lamrani, Thibaud Sader, Audrey Arnoux‐Courselle, Sandrine Canaple, Chantal Lamy, Claire Leclercq, Ardalan Aarabi, Alexis Schnitzler, Alain Pierre Yelnik and Olivier Godefroy
Article first published online:
23 Mar 2022 | DOI: 10.1111/ene.15319

POSITION PAPER

Background and purpose

Seven thousand rare diseases have been identified; most of them are of genetic origin. The diagnosis of a neurogenetic disease is difficult, and management and training programs are not well defined through Europe. To capture and assess care needs, the Neurogenetics Panel of the European Academy of Neurology (EAN) has performed an explorative survey.

Methods

The survey covering multiple topics of neurogenetics was sent to all neurologists and neuropediatricians affiliated with the EAN practicing in Europe.

Results

We collected answers from 239 members based in 40 European member states. Even though most of the responders were aware of neurogenetic diseases, when we came to amenability of carrying out a complete genetic diagnosis, almost one‐third of the responders declared they were not happy with the current way of ordering genetic analyses in their countries. Furthermore, although single‐gene analysis is diffusely present in Europe, whole exome and genome sequencing are not easily accessible, with considerable variabilities among countries. Almost 10% of the responders did not know if presymptomatic and prenatal diagnosis was available in their countries, and 47.3% were not aware of which newborn screening programs were available. Finally, 96.3% of responders declared that there is a need for education and training in neurogenetics.

Conclusions

We believe that this survey may be of importance for all European stakeholders in neurogenetics in identifying key priorities, targeting areas to encourage education/travel fellowships, and educational seminars in the future, because this area will only accelerate, and diagnostic requirements will expand.

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Authors:
Michelangelo Mancuso, Henry Houlden, Maria Judit Molnar, Alessandro Filla, Marianthi Breza, Holm Graessner, Claudio L. A. Bassetti and Sylvia Boesch
Article first published online:
22 Mar 2022 | DOI: 10.1111/ene.15320

ORIGINAL ARTICLE

Background and purpose

This study was undertaken to determine the diagnostic and prognostic value of a panel of serum biomarkers and to correlate their concentrations with several clinical parameters in a large cohort of patients with amyotrophic lateral sclerosis (ALS).

Methods

One hundred forty‐three consecutive patients with ALS and a control cohort consisting of 70 patients with other neurodegenerative disorders (DEG), 70 patients with ALS mimic disorders (ALSmd), and 45 healthy controls (HC) were included. Serum neurofilament light chain (NfL), ubiquitin carboxyl‐terminal hydrolase isozyme L1 (UCHL1), glial fibrillary acidic protein (GFAP), and total tau protein levels were measured using ultrasensitive single molecule array.

Results

NfL correlated with disease progression rate ( < 0.001) and with the measures of upper motor neuron burden ( < 0.001). NfL was higher in the ALS patients with classic and pyramidal phenotype. GFAP was raised in ALS with cognitive–behavioral impairment compared with ALS with normal cognition. NfL displayed the best diagnostic performance in discriminating ALS from HC (area under the curve [AUC] = 0.990), DEG (AUC = 0.946), and ALSmd (AUC = 0.850). UCHL1 performed well in distinguishing ALS from HC (AUC = 0.761), whereas it was not helpful in differentiating ALS from DEG and ALSmd. In multivariate analysis, NfL ( < 0.001) and UCHL1 ( = 0.038) were independent prognostic factors. Survival analysis combining NfL and UCHL1 effectively stratified patients with lower NfL levels ( < 0.001).

Conclusions

NfL is a useful biomarker for the diagnosis of ALS and the strongest predictor of survival. UCHL1 is an independent prognostic factor helpful in stratifying survival in patients with low NfL levels, likely to have slowly progressive disease. GFAP reflects extramotor involvement, namely cognitive impairment or frontotemporal dementia.

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Authors:
Yuri Matteo Falzone, Teuta Domi, Alessandra Mandelli, Laura Pozzi, Paride Schito, Tommaso Russo, Alessandra Barbieri, Raffaella Fazio, Maria Antonietta Volontè, Giuseppe Magnani, Ubaldo Del Carro, Paola Carrera, Andrea Malaspina, Federica Agosta, Angelo Quattrini, Roberto Furlan, Massimo Filippi and Nilo Riva
Article first published online:
23 Mar 2022 | DOI: 10.1111/ene.15321

ORIGINAL ARTICLE

Background

Ipsilateral hand (ILH) impairment is documented following motor stroke, but its impact on long‐term outcome remains unknown. We assessed ILH impairment in subacute stroke and tested whether ILH impairment predicted long‐term outcome.

Methods

We performed a longitudinal study in 209 consecutive patients with unilateral stroke and sensorimotor deficit at admission. ILH impairment was evaluated using the Purdue Pegboard Test (PPT) and handgrip strength and defined as mild (‐score < −1) or moderate (‐score < −1.65). We used logistic regression (LR) to predict outcome assessed 9 (range, 7–12) months post‐stroke with the modified Rankin scale (mRS) categorized into good (mRS ≤ 1) and poor outcome (mRS ≥ 2). For internal validation, LR‐bootstrapping and cross‐validation with LASSO and Random Forest were performed.

Results

ILH impairment assessed at 89.04 ± 45.82 days post‐stroke was moderate in 10.53% (95% CI 6.7, 14.83) for PPT and 17.22% (95% CI 11.96, 22.49) for grip, and mild in 21.05% (95% CI 15.78, 26.79) for PPT and 35.89 (95% CI 29.67, 42.58) for grip. Good outcome was predicted by ILH‐PPT ( = 1.03 [95% CI 0.39, 3.31]), ILH‐grip ( = 1.16 [95% CI 0.54, 3.53]), low NIHSS‐discharge ( = −1.57 [95% CI −4.0, −1.19]), and no depression ( = −0.62 [95% CI −1.63, −0.43]), accounting for stroke delay ( = −0.011 [95% CI −0.06, 0.01]). Model efficiency was 91.6% (AUC = 0.977; 95% CI 0.959, 0.996). LASSO and Random Forest methods provided similar results, confirming the LR model robustness.

Conclusions

ILH impairment is frequent after motor stroke and predicts long‐term outcome. We propose to integrate ILH impairment into rehabilitation programs to improve recovery and serve research interventions such as neuromodulation.

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Authors:
Rien Anggraini Razak, Firdaus Fabrice Hannanu, Bernadette Naegele, Marc J. G. Hommel, Olivier Detante and Assia Jaillard
Article first published online:
25 Mar 2022 | DOI: 10.1111/ene.15323

ORIGINAL ARTICLE

Background and purpose

Cognitive dysfunction has been observed following recovery from COVID‐19. To the best of our knowledge, however, no study has assessed the progression of cognitive impairment after 1 year. The aim was to assess cognitive functioning at 1 year from hospital discharge, and eventual associations with specific clinical variables.

Methods

Seventy‐six patients (aged 22–74 years) who had been hospitalized for COVID‐19 were recruited. Patients received neuropsychological assessments at 5 ( = 76) and 12 months ( = 53) from hospital discharge.

Results

Over half (63.2%) of the patients had deficits in at least one test at 5 months. Compared to the assessment at 5 months, verbal memory, attention and processing speed improved significantly after 1 year (all  < 0.05), whereas visuospatial memory did not (all  > 0.500). The most affected domains after 1 year were processing speed (28.3%) and long‐term visuospatial (18.1%) and verbal (15.1%) memory. Lower PaO/FiO ratios in the acute phase were associated with worse verbal long‐term memory ( = 0.029) and visuospatial learning ( = 0.041) at 5 months. Worse visuospatial long‐term memory at 5 months was associated with hyposmia ( = 0.020) and dysgeusia ( = 0.037).

Conclusion

Our study expands the results from previous studies showing that cognitive impairment can still be observed after 1 year. Patients with severe COVID‐19 should receive periodic cognitive follow‐up evaluations, as cognitive deficits in recovered patients could have social and occupational implications.

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Authors:
Roberta Ferrucci, Michelangelo Dini, Chiara Rosci, Antonella Capozza, Elisabetta Groppo, Maria R. Reitano, Elisa Allocco, Barbara Poletti, Agostino Brugnera, Francesca Bai, Alessia Monti, Nicola Ticozzi, Vincenzo Silani, Stefano Centanni, Antonella D’Arminio Monforte, Luca Tagliabue and Alberto Priori
Article first published online:
29 Mar 2022 | DOI: 10.1111/ene.15324

SHORT COMMUNICATION

Background and purpose

Hereditary transthyretin (TTR) amyloidosis (ATTRv) is a dominantly inherited, adult‐onset, progressive, and fatal disease caused by mutations in the gene. Therapeutic agents approved for this disease include the TTR stabilizer tafamidis and the gene‐silencing drugs patisiran and inotersen. Inotersen is an antisense oligonucleotide that suppresses the hepatic production of transthyretin. After European Medical Agency approval in 2018, an early‐access program was opened in Italy, and in this article, we present the long‐term outcome of a cohort of Italian ATTRv patients who received inotersen within this program.

Methods

This is a multicenter, observational, retrospective study of patients affected by ATTRv that started inotersen during the early‐access program. The primary end point was safety. Secondary end points included change from baseline in familial amyloid polyneuropathy (FAP) stage, Polyneuropathy Disability, Neuropathy Impairment Scale, Compound Autonomic Dysfunction Test, Norfolk Quality of Life–Diabetic Neuropathy, troponin, N‐terminal pro–brain natriuretic peptide, interventricular septum thickness, and body mass index.

Results

In total, 23 patients were enrolled. No patient permanently discontinued the treatment because of thrombocytopenia, and no cases of severe thrombocytopenia were observed. Five patients discontinued the treatment permanently because of voluntary withdrawal (two patients), renal failure after infective pyelonephritis, not related to inotersen, drug‐related hypotension, and amyloid‐negative crescentic glomerulonephritis. In seven patients, dosing frequency was reduced to every 2 weeks due to recurrent thrombocytopenia. Considering the FAP stage, only two patients worsened, whereas the other 21 patients remained stable until the last follow‐up available.

Conclusions

The long‐term safety profile of inotersen is favorable. Neurologic disease severity at baseline is the main factor associated with progression.

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Authors:
Marco Luigetti, Giovanni Antonini, Andrea Di Paolantonio, Luca Gentile, Marina Grandis, Luca Leonardi, Alessandro Lozza, Fiore Manganelli, Anna Mazzeo, Roberta Mussinelli, Filomena My, Laura Obici, Elena Maria Pennisi, Marina Romozzi, Massimo Russo, Mario Sabatelli, Alessandro Salvalaggio, Matteo Tagliapietra and Stefano Tozza
Article first published online:
28 Mar 2022 | DOI: 10.1111/ene.15325

ORIGINAL ARTICLE

Background and purpose

Mutations in are associated with autosomal recessive hereditary motor neuropathies/ Charcot‐Marie‐Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous mutation and provide insight into the pathomechanisms.

Methods

Patients with mutations were characterized clinically, electrophysiologically and by means of skin biopsy. mRNA and protein levels were studied in lymphoblastoid cells (LCLs) from patients and controls.

Results

Three affected siblings were found to carry a homozygous null mutation segregating with the disease. The disease manifested in the second to third decade of life. Clinical examination showed severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles. Sensation was reduced in the lower limbs. All patients had severe hearing loss and the proband also had Parkinson’s disease (PD). Nerve conduction studies showed an axonal motor and sensory length‐dependent polyneuropathy. DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy. Interestingly, we detected phospho‐alpha‐synuclein deposits in the proband, as already seen in PD patients, and demonstrated TDP‐43 accumulation in patients’ skin.

Conclusions

Our results broaden the clinical spectrum of ‐related neuropathies and provide evidence that  mutations should be taken into account as another causative gene of CMT2 with hearing loss and parkinsonism. The mutation likely acts through a loss‐of‐function mechanism, leading to toxic protein aggregation such as TDP‐43. The associated parkinsonism resembles the classic PD form with the addition of abnormal accumulation of phospho‐alpha‐synuclein.

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Authors:
Paola Saveri, Stefania Magri, Emanuela Maderna, Francesca Balistreri, Raffaella Lombardi, Claudia Ciano, Fabio Moda, Barbara Garavaglia, Chiara Reale, Giuseppe Lauria Pinter, Franco Taroni, Davide Pareyson and Chiara Pisciotta
Article first published online:
23 Mar 2022 | DOI: 10.1111/ene.15326

SHORT COMMUNICATION

Background

Posterior cortical atrophy (PCA) is one of the atypical Alzheimer's disease variants, characterized by predominant visuospatial and visuoperceptual deficits, with established dorsal and ventral subtypes. A third primary occipital (caudal) variant has been suggested. We aimed to determine its demographics, clinical manifestations, and biomarker findings.

Methods

Fifty‐two PCA patients were investigated. Patients underwent neuropsychological assessment, magnetic resonance imaging, and fluorodeoxyglucose (FDG)‐, amyloid‐, and tau‐positron emission tomography (tau‐PET) scans. Normalized regional FDG‐PET values were represented as z‐scores relative to a control population. Patients were divided into “primary occipital” and “other PCA” subgroups according to FDG‐PET‐defined criteria, with primary occipital defined as patients in which the z‐scores for occipital subregions were at least one standard deviation lower (SD) (i.e., more abnormal) than the z‐scores in all other brain regions. Global amyloid‐PET, temporo‐parietal FDG‐PET, and temporal tau‐PET regions‐of‐interest (ROIs) were calculated.

Results

Nine patients were classified as primary occipital; they were older ( = 0.034) and had more years of education ( = 0.007) than other PCA patients. The primary occipital group performed worse on the Ishihara test for color perception ( < 0.001), while other PCA patients performed worse on the Western Aphasia Battery (WAB) praxis scale ( = 0.005). Overall neuropsychiatric symptom burden was lower in the primary occipital group ( < 0.001). The FDG‐PET meta‐ROI was higher in the primary occipital subtype ( = 0.006), but no differences were observed in amyloid‐ and tau‐PET.

Conclusions

Our findings suggest that primary occipital PCA is characterized by an older age at onset, more color perception dysfunction, less severe ideomotor apraxia, and less hypometabolism in temporo‐parietal meta‐ROI compared to established phenotypes.

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Authors:
Dror Shir, Jonathan Graff‐Radford, Mary M. Machulda, Nha Trang Thu Pham, Clifford R. Jack, Val J. Lowe, Jennifer L. Whitwell and Keith A. Josephs
Article first published online:
30 Mar 2022 | DOI: 10.1111/ene.15327

ORIGINAL ARTICLE

Background and purpose

Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin‐gene‐related peptide, has demonstrated efficacy as a preventive treatment for adults with episodic migraine or chronic migraine and inadequate response to two to four prior preventive treatment classes in the phase 3b FOCUS study. In this post hoc analysis, efficacy and effects on quality‐of‐life outcomes for fremanezumab were evaluated in subgroups of patients with and without aura or similar neurological symptoms, here referred to as migraine with or without associated neurological dysfunction.

Methods

In the FOCUS study, 838 patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab or matched placebo for 12 weeks of double‐blind treatment. For this post hoc analysis, subgroups of patients with migraine with and without associated neurological dysfunction at baseline were identified based on patient response to questions about symptoms.

Results

In patients with migraine with associated neurological dysfunction at baseline, fremanezumab significantly reduced monthly average days with neurological symptoms (quarterly, −1.7 days; monthly, −1.8 days) compared to placebo (−0.5 days; both  ≤ 0.01). In comparison with placebo, both dosing regimens of fremanezumab yielded greater reductions in monthly migraine days over 12 weeks ( < 0.0001) and improvements in Headache Impact Test 6 and Migraine‐Specific Quality of Life scores over the last 4 weeks ( < 0.05), regardless of neurological dysfunction at baseline.

Conclusions

Fremanezumab reduced days with neurological symptoms, effectively prevented migraine, and improved quality of life in patients with migraine with associated neurological dysfunction, including those with previous inadequate response to two to four migraine preventive medication classes.

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Authors:
Christian Lampl, Alan M. Rapoport, Joshua M. Cohen, Steve Barash, Verena Ramirez Campos, Michael J. Seminerio, Xiaoping Ning and Stephen D. Silberstein
Article first published online:
29 Mar 2022 | DOI: 10.1111/ene.15328

ORIGINAL ARTICLE

Background and purpose

To investigate the relationship between the functional connectivity (FC) of the sensorimotor and cognitive cerebellum and measures of structural damage in patients with multiple sclerosis (MS) and no physical disability.

Methods

We selected 144 relapsing–remitting MS patients with an Expanded Disability Status Scale score of ≤1.5 and 98 healthy controls from the Italian Neuroimaging Network Initiative database. From multimodal 3T magnetic resonance imaging (MRI), including functional MRI at rest, we calculated lesion load, cortical thickness, and white matter, cortical gray matter, and caudate, putamen, thalamic, and cerebellar volumes. Voxel‐wise FC of the sensorimotor and cognitive cerebellum was assessed with seed‐based analysis, and multiple regression analysis was used to evaluate the relationship between FC and structural damage.

Results

Whole brain, white matter, caudate, putamen, and thalamic volumes were reduced in patients compared to controls, whereas cortical gray matter was not significantly different in patients versus controls. Both the sensorimotor and cognitive cerebellum showed a widespread pattern of increased and decreased FC that were negatively associated with structural measures, indicating that the lower the FC, the greater the tissue loss. Lastly, among multiple structural measures, cortical gray matter and white matter volumes were the best predictors of cerebellar FC alterations.

Conclusions

Increased and decreased cerebellar FC with several brain areas coexist in MS patients with no disability. Our data suggest that white matter loss hampers FC, whereas, in the absence of atrophy, cortical volume represents the framework for FC to increase.

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Authors:
Silvia Tommasin, Viktoriia Iakovleva, Maria Assunta Rocca, Costanza Giannì, Gioacchino Tedeschi, Nicola De Stefano, Carlo Pozzilli, Massimo Filippi, Patrizia Pantano, Nikolaos Petsas, Serena Ruggieri, Claudia Piervincenzi, Paola Valsasina, Mauro Sibilia, Paolo Preziosa, Loredana Storelli, Antonio Gallo, Alvino Bisecco, Alessandro d’Ambrosio, Maria Laura Stromillo and Riccardo Tappa Brocci
Article first published online:
04 Apr 2022 | DOI: 10.1111/ene.15329

ORIGINAL ARTICLE

Background

Pompe disease is a rare neuromuscular disorder caused by a deficiency of a lysosomal enzyme, acid α‐glucosidase. Macroglossia is a classic clinical sign of several inherited myopathies and has also been reported to occur progressively in late‐onset Pompe disease (LOPD).

Methods

We describe patients with LOPD and macroglossia included in the French national Pompe disease registry. Clinical, functional, and radiological data were collected during periodic follow‐up and analyzed retrospectively. These cases were compared with 15 previously reported cases.

Results

Five patients, three females and two males, aged 71–88 years, were included in this study. All but one of the patients suffered from symptoms related to macroglossia before the diagnosis of Pompe disease. Three had localized tongue atrophy and one had significant localized tongue hypertrophy which led to glossectomy 10 years before diagnosis. Two patients had severe dysphagia, one of whom underwent gastrostomy for enteral nutritional support. One patient experienced the persistence of numerous sleep apneas despite nocturnal bilevel positive airway pressure (BiPAP) ventilation. All our patients had dysarthria, and two required speech therapy. Four patients had a tongue hypersignal on magnetic resonance imaging (MRI) T1 sequences.

Conclusions

Detection of macroglossia should be part of the clinical diagnosis and follow‐up of patients with LOPD, with a careful evaluation of its main consequences. Macroglossia can have severe functional impacts on speech, swallowing, and sleep. Whole‐body MRI with facial sections may facilitate the early diagnosis of Pompe disease with the “bright tongue sign”.

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Authors:
Charlotte Dupé, Claire Lefeuvre, Guilhem Solé, Anthony Behin, Corinne Pottier, Fanny Duval, Robert‐Yves Carlier, Hélène Prigent, Jean Lacau St Guily, Azzeddine Arrassi, Nadjib Taouagh, Dalil Hamroun, Guillaume Nicolas and Pascal Laforêt
Article first published online:
01 Apr 2022 | DOI: 10.1111/ene.15330

ORIGINAL ARTICLE

Background and purpose

The therapeutic landscape of spinal muscular atrophy (SMA) has changed dramatically during the past 4 years, but treatment responses differ remarkably between individuals, and therapeutic decision‐making remains challenging, underlining the persistent need for validated biomarkers.

Methods

We applied untargeted proteomic analyses to determine biomarkers in cerebrospinal fluid (CSF) samples of SMA patients under treatment with nusinersen. Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and enzyme‐linked immunosorbent assay. Furthermore, levels of peripheral neurofilament heavy and light chain were determined.

Results

Untargeted proteomic analysis of CSF samples of three SMA type 1 patients revealed the lysosomal protease cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1,  = 12; type 2,  = 9; type 3,  = 6; presymptomatically treated,  = 4; age = 0–16 years) revealed a significant decline of cathepsin D levels in SMA patients aged ≥2 months at the start of treatment. Although evident in all older age categories, this decline was only significant in the group of patients who showed a positive motor response. Moreover, downregulation of cathepsin D was evident in muscle biopsies of SMA patients.

Conclusions

We identified a decline of cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of "treatment responders" than in "nonresponders." We believe that our results indicate a suitability of cathepsin D levels as a possible biomarker in SMA also in older patients, in combination with analysis of peripheral neurofilament light chain in adolescents or alone in adult patients.

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Authors:
David C. Schorling, Heike Kölbel, Andreas Hentschel, Astrid Pechmann, Nancy Meyer, Brunhilde Wirth, Roman Rombo, Albert Sickmann, Janbernd Kirschner, Ulrike Schara‐Schmidt, Hanns Lochmüller, Andreas Roos, Thea Beatrice Abele, Barbara Andres, Daniela Angelova‐Toshkina, Petra Baum, Tobias Baum, Matthias Baumann, Manuela Baumgartner, Ute Baur, Benedikt Becker, Bettina Behring, Günther Bernert, Theresa Birsak, Julia Bellut, Astrid Bertsche, Markus Blankenburg, Astrid Blaschek, Nathalie Braun, Sarah Braun, Nadine Burgenmeister, Nicole Claus, Isabell Cordts, Heike de Vries, Timo Deba, Adela Della Marina, Jonas Denecke, Marcus Deschauer, Katharina Dörnbrack, Joenna Driemeyer, Matthias Eckenweiler, Astrid Eisenkölbl, Barbara Fiedler, Michal Fischer, Marina Flotats‐Bastardas, Maren Freigang, Johannes Friese, Philippa Gaiser, Axel Gebert, Stephanie Geitmann, Klaus Goldhahn, Michael Grässl, Kristina Gröning, Julian Grosskreutz, Ursula Gruber‐Sedlmayr, Helene Guillemot, René Günther, Maja von der Hagen, Tim Hagenacker, Andreas Hahn, Hans Hartmann, Miriam Hiebeler, Elke Hobbiebrunken, Georg Friedrich Hoffmann, Britta Holtkamp, Dorothea Holzwarth, Veronka Horber, Ralf A. Husain, Sabine Illsinger, Eva Jansen, Jessika Johannsen, Angela Kaindl, Nadja Kaiser, Jennifer Klamroth, Jan Christoph Koch, Cornelia Köhler, Stefan Koelker, Kirsten Kolzter, Brigitte Korschinsky, Hanna Küpper, Thorsten Langer, Ilka Lehnert, Paul Lingor, Wolfgang N. Löscher, Dana LoudoviciüKrug, Kyriakos Martakis, Iris Mayer, Moritz Metelmann, Sascha Meyer, Arpad von Moers, Katharina Mueller‐Kaempffer, Monika Müller, Petra Müller, Wolfgang Müller‐Felber, Christoph Neuwirth, Johanna Niederschweiberer, Anja Nolte, Thorsten Odorfer, Heymut Omran, Josefine Pauschek, Katrin Pickrodt, Barbara Plecko, Manuel Pühringer, Anna Lisa Quinten, Mika Rappold, Christof Reihle, Tabea Reinhardt, Annekathrin Rödiger, Gerda Roetmann, Afshin Saffari, Mareike Schimmel, Kurt Schlachter, Joanna Schneider, Christoph Schoene‐Bake, Gudrun Schreiber, Oliver Schwartz, Anette Schwerin‐Nagel, Inge Schwersenz, Martin Smitka, Sabine Stein, Robert Steinbach, Elisabeth Steiner, Daniela Steuernagel, Eva Stögmann, Benjamin Stolte, Corinna Stoltenburg, Burkhard Stüve, Adrian Tassoni, Manuela Theophil, Simone Thiele, Raffi Topakian, Regina Trollmann, Matthias Türk, Lieske van der Stam, Katharina Vill, Sibylle Vogt, Peter Vollmann, Maggie C. Walter, Birgit Warken, Markus Weber, Markus Weiler, Claudia Weiß, Deike Weiss, Simone Weiss, Franziska Wenzel, Sabine Wider, Nils Wiebe, Gert Wiegand, Ekkehard Wilichowski, Bernd Wilken, Katarzyna Wochner, Fiona Zeiner, Daniela Zeisler, Daniel Zeller, Michael Zemlin and Andreas Ziegler
Article first published online:
04 May 2022 | DOI: 10.1111/ene.15331

ORIGINAL ARTICLE

Background and purpose

Previous studies have reported the association between frailty and stroke or Alzheimer's disease (AD). However, the causality remains unclear. The aim of the present study was to evaluate whether genetically predicted frailty is associated with the risk of stroke or AD by a Mendelian randomization (MR) study.

Methods

Genetic variants associated with the frailty index (FI) were obtained from a large genome‐wide association study (GWAS). Summary‐level data for stroke and AD were adopted from the corresponding large GWAS of individuals of European ancestry. The inverse variance weighted method was used for estimating causal effects. Multivariable analysis was performed for further adjustment.

Results

The present MR study indicated a suggestive association between genetically predicted FI and a higher risk of any stroke (odds ratio 1.360, 95% confidence interval 1.006–1.838,  = 0.046). Regarding the subtypes of stroke, genetically predicted FI was associated with a higher risk of large artery atherosclerosis stroke (LAS) (odds ratio 2.487, 95% confidence interval 1.282–4.826,  = 0.007). No causal links were identified between genetically predicted FI and any ischaemic stroke, intracranial haemorrhage, cardioembolic stroke, small artery stroke, AD or AD‐by‐proxy. Multivariable MR analysis indicated that the association of genetically predicted FI with LAS was attenuated after adjustment for inflammatory bowel disease ( = 0.114).

Conclusions

The MR study suggested that genetically predicted FI may be associated with an increased risk of any stroke. Subgroup analysis indicated a suggestive association between genetically predicted FI and the risk of LAS. The underlying mechanisms need further investigation.

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Authors:
Weishi Liu, Luyang Zhang, Hui Fang, Yuan Gao, Kai Liu, Shen Li, Hongbing Liu, Xin Wang, Chen Liu, Bo Song, Zongping Xia and Yuming Xu
Article first published online:
05 Apr 2022 | DOI: 10.1111/ene.15332

ORIGINAL ARTICLE

Background and purpose

The pathogenesis of diabetic gastroparesis due to visceral neuropathy involves multidimensional mechanisms with limited exploration of gastric mucosal innervation. This study aimed to examine quantitatively this topic and its relationship with gastroparesis symptoms and gastric emptying in diabetes.

Methods

We prospectively enrolled 22 patients with type 2 diabetes and gastroparesis symptoms and 25 age‐ and gender‐matched healthy controls for comparison. The assessments included: (i) neuropathology with quantification of gastric mucosal innervation density (MID) on endoscopic biopsy; (ii) clinical manifestations based on the Gastroparesis Cardinal Symptom Index (GCSI) questionnaire; and (iii) functional tests of gastric emptying scintigraphy (GES).

Results

In patients with diabetes, stomach fullness, bloating and feeling excessively full after meals constituted the most common GCSI symptoms. Seven patients with diabetes (32%) had prolonged gastric emptying patterns. In diabetes, gastric MID was significantly lower in all the regions examined compared with the controls: antrum (294.8 ± 237.0 vs. 644.0 ± 222.0 mm/mm;  < 0.001), body (292.2 ± 239.0 vs. 652.6 ± 260.9 mm/mm;  < 0.001), and fundus (238.0 ± 109.1 vs. 657.2 ± 332.8 mm/mm;  < 0.001). Gastric MID was negatively correlated with gastroparesis symptoms and total scores on the GCSI ( < 0.001). Furthermore, gastric MID in the fundus was negatively correlated with fasting glucose and glycated hemoglobin levels. Gastric emptying variables, including half emptying time and gastric retention, were prolonged in patients with diabetes, and gastric retention at 3 h was correlated with fasting glucose level.

Conclusion

In diabetes, gastric MID was reduced and GES parameters were prolonged. Both were correlated with gastroparesis symptoms and glycemic control. These findings provide pathology and functional biomarkers for diabetic visceral neuropathy of gastroparesis and underlying pathophysiology.

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Authors:
Ping‐Huei Tseng, Chi‐Chao Chao, Ya‐Yin Cheng, Chieh‐Chang Chen, Ping‐Hao Yang, Wei‐Kang Yang, Shao‐Wei Wu, Yen‐Wen Wu, Mei‐Fang Cheng, Wei‐Shiung Yang, Ming‐Shiang Wu and Sung‐Tsang Hsieh
Article first published online:
03 Apr 2022 | DOI: 10.1111/ene.15333

ORIGINAL ARTICLE

Background

The IL‐33/ST2 immune axis plays crucial roles in infection and immunity. A dysregulated IL‐33/ST2 axis can induce autoimmune reaction and inflammatory responses. Guillain‐Barré syndrome (GBS) is an acute peripheral neuropathy, mostly caused by post‐infection autoimmunity. The role of IL‐33/ST2 axis is not known in GBS. This study aimed to explore the role of IL‐33/ST2 axis in GBS.

Methods

Three single nucleotide polymorphisms (SNPs) of gene (rs16924159, rs7044343, rs1342336) and three SNPs of gene (rs10192157, rs1041973, rs10206753) coding for suppressor of tumorigenicity 2 (ST2) were genotyped in 179 GBS patients and 186 healthy controls by TaqMan Allelic Discrimination Assay. Plasma levels of IL‐33 and sST2 were measured in a subset of GBS patients ( = 80) and healthy controls ( = 80) by ELISA.

Results

The frequencies of CC genotype of rs10192157 ( = 0.043) and TT genotype of rs10206753 ( = 0.036) SNPs of gene differed significantly between GBS patients and healthy controls. Gene–gene interaction between and genes also conferred significant risk for GBS. In addition, the plasma sST2 levels were significantly elevated in GBS patients compared to healthy subjects (24,934.31 ± 1.81 pg/ml vs. 12,518.97 ± 1.51 pg/ml,  < 0.001). Plasma sST2 levels showed a significant correlation with the disability scores at the peak of neurological deficit in GBS patients.

Conclusions

The IL‐33/ST2 axis is suggested to influence the immunopathogenesis of GBS. Genetic variants of gene might serve as a risk determinant of GBS and plasma sST2 levels might emerge as a biomarker of severity of GBS, if replicated further by other studies.

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Authors:
Praveen P. Sharma, Doniparthi V. Seshagiri, Madhu Nagappa, Thrinath Mullapudi, Nikhitha Sreenivas, Saikat Dey, Sumanth Shivaram, Rahul Wahatule, Vijay Kumawat, Binu V. Sreekumaran Nair, Sriganesh Kamath, Sanjib Sinha, Arun B. Taly and Monojit Debnath
Article first published online:
12 Apr 2022 | DOI: 10.1111/ene.15334

POSITION PAPER

Background and purpose

This position paper makes recommendations following an audit of care provided to people presenting with a seizure to emergency departments (EDs) in Europe.

Methods

Participating countries were asked to include five hospitals agreeing to identify 50 consecutive seizure patients presenting to their ED between 1 August 2016 and 31 August 2017. Anonymous data were collected to a web database. Where quoted, percentages are mean site values and ranges are the 10th–90th centile.

Results

Data were collected on 2204 ED visits (47 sites, up to six per country, across 15 countries): 1270 (58%) known epilepsy, 299 (14%) previous blackouts but no epilepsy diagnosis, 634 (29%) with a first seizure. Wide variability was identified for most variables. Of those with known epilepsy, 41.2% (range 26.2%–59.6%) attended the ED in the previous 12 months, but only 64.7% (range 37.2%–79.8%) had seen an epilepsy specialist in the previous 12 months. 67.7% (range 34.0%–100%) were admitted, 53.1% to a neurology ward (range 0.0%–88.9%). Only 37.5% first seizure patients (range 0.0%–71.4%) were given advice about driving.

Conclusions and recommendations

It is recommended that in Europe guidance is agreed on the management and onward referral of those presenting to the ED with a seizure; a referral process is created that can be easily implemented; it is ensured that the seizure services receive referrals and see the patients within a short time period; and a simple system is developed and implemented to allow continuous monitoring of key indices of epilepsy care.

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Authors:
Claire Taylor, Catrin Tudur‐Smith, Pete Dixon, Christine Linehan, Aleksei Gunko, Jakob Christensen, Mike Pearson, Torbjorn Tomson, Anthony Marson, Eugen Trinka, Helene Visee, Chantal Depondt, Susana Ferrao Santos, Annelies Van Dycke, Wim Van Paesschen, Cara Conway, Geraldine O’Rourke, Cora Flynn, Allan McCarthy, Denise Cunningham, Abel Wakai, Masha Petricevic, Daniel Costello, Johan Zelano, Firal Al‐Jasami, Sara Melin, Mans Berglund, Lisa Bergstrom, Victor Vall, Rob Rouhl, Nicola Dingli, Sylvain Rheims, Karim Tazarourte, Louise Tyvaert, Phillipe Derambure, Marie Girot, Cecile Marchal, Eivind Kolstad, Silje Holt Jahr, Siri Hylleraas Bo, Christian Samsonsen, Reetta Kalvianen, Maria Mazurkiewicz‐Beldzinska, Igor Kaymovskiy, Phillipe Ryvlin, Ilona Wisiewski, Celia Bader, Felix von Podewils, Susanne Knake, Katja Menzler, Martin Hirsch, Jochen Brich, Rainer Surges, Karmele Olaciregui Dague, Tim Wehner, Adam Strzelczyk, Lara Kay, Lea Miklic, Vasilios Kimiskidis, Martha Spilioti, Theodora Afrantou, Aikaterina Terzoudi, Dimitrios Kazis, Sofia Markoula, Katerina Markou, Savvas Papacostas and Yiolanda Panayiota Christou
Article first published online:
07 May 2022 | DOI: 10.1111/ene.15336

ORIGINAL ARTICLE

Background

The underlying cause of cognitive decline in individuals who are positive for biomarkers of neurodegeneration (N) but negative for biomarkers of amyloid‐beta (A), designated as Suspected non‐Alzheimer's pathophysiology (SNAP), remains unclear. We evaluate whether cerebrovascular disease (CeVD) is more prevalent in those with SNAP compared to A−N− and A+N+ individuals and whether CeVD is associated with cognitive decline over time in SNAP patients.

Methods

A total of 216 individuals from a prospective memory clinic cohort (mean [SD] age, 72.7 [7.3] years, 100 women [56.5%]) were included and were diagnosed as no cognitive impairment (NCI), cognitive impairment no dementia (CIND), Alzheimer's dementia (AD) or vascular dementia (VaD). All individuals underwent clinical evaluation and neuropsychological assessment annually for up to 5 years. Carbon 11‐labeled Pittsburgh Compound B ([C]‐PiB) or [F]‐flutafuranol‐positron emission spectrometry imaging was performed to ascertain amyloid‐beta status. Magnetic resonance imaging was performed to assess neurodegeneration as measured by medial temporal atrophy ≥2, as well as significant CeVD (sCeVD) burden, defined by cortical infarct count ≥1, Fazekas score ≥2, lacune count ≥2 or cerebral microbleed count ≥2.

Results

Of the 216 individuals, 50 (23.1%) A−N+ were (SNAP), 93 (43.1%) A−N−, 36 (16.7%) A+N− and 37 (17.1%) A+N+. A+N+ individuals were significantly older, while A+N+ and SNAP individuals were more likely to have dementia. The SNAP group had a higher prevalence of sCeVD (90.0%) compared to A−N−. Moreover, SNAP individuals with sCeVD had significantly steeper decline in global cognition compared to A−N− over 5 years ( = 0.042).

Conclusions

These findings suggest that CeVD is a contributing factor to cognitive decline in SNAP. Therefore, SNAP individuals should be carefully assessed and treated for CeVD.

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Authors:
Francis Nicole Saridin, Kimberly Ann Chew, Anthonin Reilhac, Bibek Gyanwali, Steven Gayoles Villaraza, Tomotaka Tanaka, Phillip Scheltens, Wiesje M. van der Flier, Christopher Li Hsian Chen and Saima Hilal
Article first published online:
06 Apr 2022 | DOI: 10.1111/ene.15337

ORIGINAL ARTICLE

Background and purpose

Atrial fibrillation (AF) in stroke patients can be classified as either “known AF” (KAF), defined as AF confirmed before stroke onset, or “AF detected after stroke” (AFDAS), defined as AF diagnosed after stroke onset. While KAF is considered primarily cardiogenic, AFDAS includes patients with stroke‐triggered neurogenic arrhythmias. This study aimed to investigate the clinical course of stroke, functional outcomes and the value of oral anticoagulation (OAC) for secondary prevention according to AF subtype.

Methods

Acute ischemic stroke patients were consecutively enrolled and AF was classified as AFDAS or KAF. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and 3‐month functional outcomes were measured on the modified Rankin scale. Inverse probability weighting was applied to adjust for baseline confounders in patients with AFDAS and KAF. Multivariate logistic regression models were calculated to investigate the value of OAC for secondary prevention.

Results

A total of 822 stroke patients with AF were included, of whom 234 patients (28.5%) had AFDAS. AFDAS patients had a lower prevalence of coronary artery disease, heart failure, and sustained AF, but higher rates of large vessel occlusion compared to KAF patients. NIHSS scores were lower in patients on pre‐stroke anticoagulation. OAC for secondary prevention was associated with favorable 3‐month functional outcome (odds ratio 7.60, 95% confidence interval 3.42–16.88) independently of AF subtype. The rate of stroke recurrence did not differ significantly.

Conclusions

Clinical characteristics suggest that AFDAS might comprise a distinct pathophysiological and clinical entity among stroke patients with AF. The benefit of anticoagulation for secondary prevention was not affected by AF subtype.

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Authors:
Ruihao Wang, Kosmas Macha, David Haupenthal, Luise Gaßmann, Gabriela Siedler, Svenja Stoll, Kilian Fröhlich, Julia Koehn, Stefan Schwab and Bernd Kallmünzer
Article first published online:
12 Apr 2022 | DOI: 10.1111/ene.15338

ORIGINAL ARTICLE

Background and purpose

Huntington's disease (HD) is an autosomal dominant condition caused by CAG‐triplet repeat expansions. CAG‐triplet repeat expansion is inversely correlated with age of onset in HD and largely determines the clinical features. The aim of this study was to examine the phenotypic and genotypic correlates of late‐onset HD (LoHD) and to determine whether LoHD is a more benign expression of HD.

Methods

This was a retrospective observational study of 5053 White European HD patients from the ENROLL‐HD database. Sociodemographic, genetic and phenotypic variables at baseline evaluation of subjects with LoHD, common‐onset HD (CoHD) and young‐onset HD (YoHD) were compared. LoHD subjects were compared with healthy subjects (HS) aged ≥60 years. Differences between the CoHD and LoHD groups were also explored in subjects with 41 CAG triplets, a repeat number in the lower pathological expansion range associated with wide variability in age at onset.

Results

Late‐onset HD presented predominantly as motor‐onset disease, with a lower prevalence of both psychiatric history and current symptomatology. Absent/unknown HD family history was significantly more common in the LoHD group (31.2%) than in the other groups. The LoHD group had more severe motor and cognitive deficits than the HS group. Subjects with LoHD and CoHD with 41 triplets in the larger allele were comparable with regard to cognitive impairment, but those with LoHD had more severe motor disorders, less problematic behaviors and more often an unknown HD family history.

Conclusions

It is likely that cognitive disorders and motor symptoms of LoHD are at least partly age‐related and not a direct expression of the disease. In addition to CAG‐triplet repeat expansion, future studies should investigate the role of other genetic and environmental factors in determining age of onset.

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Authors:
Martina Petracca, Sonia Di Tella, Marcella Solito, Paola Zinzi, Maria Rita Lo Monaco, Giulia Di Lazzaro, Paolo Calabresi, Maria Caterina Silveri and Anna Rita Bentivoglio
Article first published online:
17 Apr 2022 | DOI: 10.1111/ene.15340

ORIGINAL ARTICLE

Background and purpose

Pain, fatigue and depression in chronic inflammatory demyelinating polyneuropathy (CIDP) are often underestimated, as the focus lies on sensorimotor dysfunction and gait instability. The aim of this study was to investigate their prevalence, characteristics and contribution to disability in a prospective cohort of 84 patients with CIDP.

Methods

Pain, fatigue, depression and quality of life were measured using the Pain Detect Questionnaire, Krupp's Fatigue Severity Scale, Beck Depression Inventory II and the German Short‐Form 36 Health Survey. Sensorimotor deficits and disability were assessed using the Inflammatory Neuropathy Cause and Treatment overall disability score, the Rasch‐built Overall Disability Scale, the Medical Research Council sum score and the Inflammatory Neuropathy Cause and Treatment sensory sum score. The interrelation between the five factors was assessed using analysis of variance and linear regression analysis.

Results

Pain was reported in 62%, mostly of moderate and severe intensity, whereas pain characteristics indicated neuropathic pain (NP) in 29%. Sensory dysfunction was stronger in NP patients compared to pain‐free patients ( = 0.001). Pain of any type, especially NP, was associated with more pronounced fatigue symptoms ( = 0.010). Depressive symptoms were more frequent in patients with pain compared to the pain‐free patients (61% vs. 33%,  = 0.02) and were more severe and frequent in NP than in non‐NP patients ( = 0.005). Patients with pain had a worse physical quality of life than pain‐free patients ( = 0.001).

Conclusion

Pain, depression and fatigue are relevant disability factors in CIDP affecting quality of life. Sensory dysfunction is associated with NP. Therefore, evaluation of CIDP‐related disability should include pain and sensory function for adequate monitoring of therapeutic interventions.

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Authors:
Hannah Mork, Jeremias Motte, Anna Lena Fisse, Thomas Grüter, Jil Brünger, Zornitsa Stoykova, Yesim Bulut, Diamantis Athanasopoulos, Dietrich Sturm, Martin Tegenthoff, Ralf Gold, Elena Enax‐Krumova and Kalliopi Pitarokoili
Article first published online:
12 Apr 2022 | DOI: 10.1111/ene.15341

ORIGINAL ARTICLE

Background

Short‐term exposure to ambient air pollution has been linked to increased risk of stroke mortality, but its adverse effects on mortality from specific types of stroke including ischemic stroke and hemorrhagic stroke remain poorly understood.

Methods

Using the China National Mortality Surveillance System, we conducted a time‐stratified case‐crossover study among 412,567 stroke deaths in Jiangsu province, China during 2015–2019. Residential daily PM, PM, SO, NO, CO, and O exposure concentrations were extracted from the ChinaHighAirPollutants dataset for each subject. Conditional logistic regression models were performed to conduct exposure–response analyses.

Results

Each 10 μg/m increase of PM, PM, SO, NO, CO, and O was respectively associated with a 1.44%, 0.93%, 5.55%, 2.90%, 0.148%, and 0.54% increase in odds of mortality from ischemic stroke, which was significantly stronger than that from hemorrhagic stroke (percent change in odds: 0.74%, 0.51%, 3.11%, 1.15%, 0.090%, and 0.10%). The excess fraction of ischemic stroke mortality associated with PM, PM, SO, NO, CO, and O exposure was 6.90%, 6.48%, 8.21%, 8.61%, 9.67%, and 4.76%, respectively, which was also significantly higher than that of hemorrhagic stroke mortality (excess fraction: 3.49%, 3.48%, 4.69%, 3.48%, 5.86%, and 0.88%). These differences in adverse effects generally remained across sex, age, and season.

Conclusions

Short‐term exposure to ambient air pollution was significantly associated with increased risk of both ischemic and hemorrhagic stroke mortality and posed considerable excess mortality. Our results suggest that air pollution exposure may lead to substantially greater adverse effects on mortality from ischemic stroke than that from hemorrhagic stroke.

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Authors:
Ruijun Xu, Qingqing Wang, Jing Wei, Wenfeng Lu, Rui Wang, Tingting Liu, Yaqi Wang, Zhaoyu Fan, Yingxin Li, Luxi Xu, Chunxiang Shi, Guo Li, Gongbo Chen, Lan Zhang, Yun Zhou, Yuewei Liu and Hong Sun
Article first published online:
11 Apr 2022 | DOI: 10.1111/ene.15343

COMMENTARY

Registry studies revisited: indispensable in improving care

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Authors:
Paul J. Nederkoorn
Article first published online:
15 Apr 2022 | DOI: 10.1111/ene.15349

COMMENTARY

Dementia among international migrants: An urgent call for better care

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Authors:
Yaohua Chen and Paulo Caramelli
Article first published online:
03 May 2022 | DOI: 10.1111/ene.15361

COMMENTARY

Role of genetics in the bio‐immunological dysregulation of the IL‐33/ST2 axis in Guillain‐Barré syndrome

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Authors:
Rajesh Verma and Rajarshi Chakraborty
Article first published online:
28 Apr 2022 | DOI: 10.1111/ene.15366

COMMENTARY

Biomarker development in amyotrophic lateral sclerosis: Challenges and viable strategies

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Authors:
Peter Bede and Jasmin Lope
Article first published online:
04 May 2022 | DOI: 10.1111/ene.15372

COMMENTARY

Atrial fibrillation detection after stroke: Is all created equal?

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Authors:
Luciano A. Sposato and Thalia S. Field
Article first published online:
08 May 2022 | DOI: 10.1111/ene.15375

LETTERS TO THE EDITOR

Guillain–Barré syndrome, the IL‐33/ST2 axis, and vitamin D

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Authors:
Maria Maddalena Sirufo, Lina Maria Magnanimi, Lia Ginaldi and Massimo De Martinis
Article first published online:
16 May 2022 | DOI: 10.1111/ene.15379

LETTER TO THE EDITOR

Modulatory effects of vitamin D on IL ‐33/ ST2 immune axis in Guillain–Barré syndrome…?

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Authors:
Praveen Pallathadka Sharma, Doniparthi V. Seshagiri, Madhu Nagappa, Thrinath Mullapudi, Nikhitha Sreenivas, Saikat Dey, Sumanth Shivaram, Rahul Wahatule, Vijay Kumawat, Binu V. Sreekumaran Nair, Sriganesh Kamath, Sanjib Sinha, Arun B. Taly and Monojit Debnath
Article first published online:
19 May 2022 | DOI: 10.1111/ene.15389