cover image European Journal of Neurology

European Journal of Neurology

2023 - Volume 30
Issue 12 | December 2023
Previous Issue

ISSUE INFORMATION

Issue Information

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Article first published online:
08 Nov 2023 | DOI: 10.1111/ene.15403

ORIGINAL ARTICLE

Background and purpose

Therapy for myasthenia gravis (MG) is undergoing a profound change, with new treatments being tested. These include complement inhibitors and neonatal Fc receptor (FcRn) blockers. The aim of this study was to perform a meta‐analysis and network meta‐analysis of randomized and placebo‐controlled trials of innovative therapies in MG with available efficacy data.

Methods

We assessed statistical heterogeneity across trials based on the Cochrane Q test and values, and mean differences were pooled using the random‐effects model. Treatment efficacy was assessed after 26 weeks of eculizumab and ravulizumab, 28 days of efgartigimod, 43 days of rozanolixizumab, 12 weeks of zilucoplan, and 16, 24 or 52 weeks of rituximab treatment.

Results

We observed an overall mean Myasthenia Gravis‐Activities of Daily Living scale (MG‐ADL) score change of −2.17 points (95% confidence interval [CI] −2.67, −1.67;  < 0.001) as compared to placebo. No significant difference emerged between complement inhibitors and anti‐FcRn treatment ( = 0.16). The change in Quantitative Myasthenia Gravis scale (QMG) score was −3.46 (95% CI −4.53, −2.39;  < 0.001), with a higher reduction with FcRns (−4.78 vs. −2.60;  < 0.001). Rituximab did not significantly improve the MG‐ADL (−0.92 [95% CI −2.24, 0.39];  = 0.17) or QMG scores (−1.9 [95% CI −3.97, 0.18];  = 0.07). In the network meta‐analysis, efgartigimod had the highest probability of being the best treatment, followed by rozanolixizumab.

Conclusion

Anti‐complement and FcRn treatments both proved to be effective in MG patients, whereas rituximab did not show a significant benefit for patients. Within the limitations of this meta‐analysis, including efficacy time points, FcRn treatments showed a greater effect on QMG score in the short term. Real‐life studies with long‐term measurements are needed to confirm our results.

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Authors:
Francesco Saccà, Chiara Pane, Pablo Ezequiel Espinosa, Maria Pia Sormani and Alessio Signori
Article first published online:
30 May 2023 | DOI: 10.1111/ene.15872

REVIEW ARTICLE

Background and purpose

The prognosis of prolonged (28 days to 3 months post‐onset) disorders of consciousness (pDoC) due to anoxic brain injury is uncertain. The present study aimed to evaluate the long‐term outcome of post‐anoxic pDoC and identify the possible predictive value of demographic and clinical information.

Method

This is a systematic review and meta‐analysis. The rates of mortality, any improvement in clinical diagnosis, and recovery of full consciousness at least 6 months after severe anoxic brain injury were evaluated. A cross‐sectional approach searched for differences in baseline demographic and clinical characteristics between survivors and non‐survivors, patients improved versus not improved, and patients who recovered full consciousness versus not recovered.

Results

Twenty‐seven studies were identified. The pooled rates of mortality, any clinical improvement and recovery of full consciousness were 26%, 26% and 17%, respectively. Younger age, baseline diagnosis of minimally conscious state versus vegetative state/unresponsive wakefulness syndrome, higher Coma Recovery Scale Revised total score, and earlier admission to intensive rehabilitation units were associated with a significantly higher likelihood of survival and clinical improvement. These same variables, except time of admission to rehabilitation, were also associated with recovery of full consciousness.

Conclusions

Patients with anoxic pDoC might improve over time up to full recovery of consciousness and some clinical characteristics can help predict clinical improvement. These new insights could support clinicians and caregivers in the decision‐making on patient management.

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Authors:
Alfonso Magliacano, Francesco De Bellis, Francesco Panico, Laura Sagliano, Luigi Trojano, Claudio Sandroni and Anna Estraneo
Article first published online:
08 Jun 2023 | DOI: 10.1111/ene.15899

ORIGINAL ARTICLE

Background and purpose

Cerebral amyloid angiopathy (CAA) is a common cause of intracranial hemorrhage (ICH), which is a risk factor for seizures. The incidence and risk factors of seizures associated with a heterogeneous cohort of CAA patients have not been studied.

Methods

We conducted a retrospective study of patients with CAA treated at Mayo Clinic Florida between 1 January 2015 and 1 January 2021. CAA was defined using the modified Boston criteria version 2.0. We analyzed electrophysiological and clinical features, and comorbidities including lobar ICH, nontraumatic cortical/convexity subarachnoid hemorrhage (cSAH), superficial siderosis, and inflammation (CAA with inflammation [CAA‐ri]). Cognition and mortality were secondary outcomes. Univariate and multivariate analyses were performed to determine risk of seizures relative to clinical presentation.

Results

Two hundred eighty‐four patients with CAA were identified, with median follow‐up of 35.7 months (interquartile range = 13.5–61.3 months). Fifty‐six patients (19.7%) had seizures; in 21 (37.5%) patients, seizures were the index feature leading to CAA diagnosis. Seizures were more frequent in females ( = 0.032) and patients with lobar ICH ( = 0.002), cSAH ( = 0.030), superficial siderosis ( < 0.001), and CAA‐ri ( = 0.005), and less common in patients with microhemorrhage ( = 0.006). After controlling for age and sex, lobar ICH (odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.1–4.2), CAA‐ri (OR = 3.8, 95% CI = 1.4–10.3), and superficial siderosis (OR = 3.7, 95% CI = 1.9–7.0) were independently associated with higher odds of incident seizures.

Conclusions

Seizures are common in patients with CAA and are independently associated with lobar ICH, CAA‐ri, and superficial siderosis. Our results may be applied to optimize clinical monitoring and management for patients with CAA.

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Authors:
Brin E. Freund, Sofia S. Sanchez‐Boluarte, Karen Blackmon, Gregory S. Day, Michelle Lin, Aafreen Khan, Anteneh M. Feyissa, Erik H. Middlebrooks and William O. Tatum
Article first published online:
13 Jun 2023 | DOI: 10.1111/ene.15903

ORIGINAL ARTICLE

Background and purpose

After successful mechanical thrombectomy for middle cerebral artery occlusion, basal ganglia infarction is commonly detectable. Whilst the functional outcome of these patients is often good, less knowledge is available about the cognitive outcome. The aim of our study was to assess the presence of cognitive impairment within 1 week after thrombectomy.

Methods

In all, 43 subjects underwent a general cognitive assessment using the Montreal Cognitive Assessment and an extensive battery of tests. Patients were classified as cognitively impaired (CImp) or not (noCImp) according to a Montreal Cognitive Assessment score below 18.

Results

Cognitively impaired and noCImp subjects did not differ either in their National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) at admittance, or in their Fazekas score and Alberta Stroke Program Early Computed Tomography Score. At discharge, CImp subjects showed higher scores than noCImp subjects on NIHSS ( = 0.002) and mRS ( < 0.001). The percentage of pathological performances on each neuropsychological test in the whole sample and in CImp and noCImp patients shows a similar cognitive profile between the groups.

Conclusions

Some patients who underwent thrombectomy experienced a detectable cognitive impairment that probably led to worse NIHSS and mRS. The neuropsychological profile of such cognitive impairment at the acute stage consists of wide deficits in numerous cognitive domains, suggesting that basal ganglia damage may lead to complex functional impairments.

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Authors:
Valeria Guglielmi, Davide Quaranta, Giovanna Masone Iacobucci, Salvatore Citro, Irene Scala, Danilo Genovese, Valerio Brunetti, Camillo Marra, Paolo Calabresi and Giacomo Della Marca
Article first published online:
10 Jul 2023 | DOI: 10.1111/ene.15933

REVIEW ARTICLE

Background and purpose

Despite the growing awareness of academic fraud, its prevalence in the field of neurology has not been fully assessed. This review aims to analyze the characteristics of the retracted papers in the field of neurology and the reasons for the retraction to better understand the trends in this area and to assist to avoid retraction incidents.

Methods

A total of 79 papers were included, which pertained to 22 countries and 64 journals. The marking methods for retracting original papers included watermarks (89.04%), retracted signs in the text (5.48%) and no prompt (5.48%). The median (interquartile range [IQR]) of citations in retractions in neurology was 7 (41). Studies continued to be cited after retraction with an (IQR) of 3 (16). The journal impact factor was between 0 and 157.335, with an (IQR) of 5.127 (3.668). 45.21% and 31.51% papers were mainly published in the first and second quartile journals, respectively. The (IQR) time elapsed between publication and retraction was 32 (44) months. The reasons for retraction included two major categories, academic misconduct (79.75%) and academic unintentional mistakes (20.25%).

Results and conclusions

The number of retractions in neurology has been on the rise over the past decade, with fabricated academic misconduct being the main cause of the retractions. Due to the long time lag between publication and retraction, a number of unreliable findings continue to be cited following retraction. In addition to the requisite standards of academic ethics, augmenting research training and fostering interdisciplinary collaboration are crucial in enhancing research integrity.

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Authors:
Xingbo Wang, Ning Gao, Huan Chen and Weiming Wang
Article first published online:
09 Jul 2023 | DOI: 10.1111/ene.15960

COMMENTARY

Differentiating Charcot–Marie–Tooth disease from chronic inflammatory demyelinating polyradiculoneuropathy: neurophysiology is not the only clue

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Authors:
Claudia Sommer
Article first published online:
19 Jul 2023 | DOI: 10.1111/ene.15966

ORIGINAL ARTICLE

Introduction

Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is considered the prodromal stage of alpha‐synucleinopathies. Thus, iRBD patients are the ideal target for disease‐modifying therapy. The risk FActoRs PREdictive of phenoconversion in iRBD Italian STudy (FARPRESTO) is an ongoing Italian database aimed at identifying risk factors of phenoconversion, and eventually to ease clinical trial enrollment of well‐characterized subjects.

Methods

Polysomnography‐confirmed iRBD patients were retrospectively and prospectively enrolled. Baseline harmonized clinical and nigrostriatal functioning data were collected at baseline. Nigrostriatal functioning was evaluated by dopamine transporter‐single‐photon emission computed tomography (DaT‐SPECT) and categorized with visual semi‐quantification. Longitudinal data were evaluated to assess phenoconversion. Cox regressions were applied to calculate hazard ratios.

Results

365 patients were enrolled, and 289 patients with follow‐up (age 67.7 ± 7.3 years, 237 males, mean follow‐up 40 ± 37 months) were included in this study. At follow‐up, 97 iRBD patients (33.6%) phenoconverted to an overt synucleinopathy. Older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression, and visual semi‐quantification of nigrostriatal functioning predicted phenoconversion. The remaining 268 patients are in follow‐up within the FARPRESTO project.

Conclusions

Clinical data (older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression) predicted phenoconversion in this multicenter, longitudinal, observational study. A standardized visual approach for semi‐quantification of DaT‐SPECT is proposed as a practical risk factor for phenoconversion in iRBD patients. Of note, non‐converted and newly diagnosed iRBD patients, who represent a trial‐ready cohort for upcoming disease‐modification trials, are currently being enrolled and followed in the FARPRESTO study. New data are expected to allow better risk characterization.

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Authors:
Dario Arnaldi, Pietro Mattioli, Matteo Pardini, Silvia Morbelli, Elena Capriglia, Annalisa Rubino, Valter Rustioni, Michele Terzaghi, Elisa Casaglia, Alessandra Serra, Michela Figorilli, Claudio Liguori, Mariana Fernandes, Fabio Placidi, Luca Baldelli, Federica Provini, Luigi Ferini‐Strambi, Sara Marelli, Giuseppe Plazzi, Elena Antelmi, Valerio Brunetti, Enrica Bonanni and Monica Puligheddu
Article first published online:
02 Aug 2023 | DOI: 10.1111/ene.16001

ORIGINAL ARTICLE

Background and purpose

White matter hyperintensities (WMHs) are associated with cognitive deficits and worse clinical outcomes in dementia, but rare studies have been carried out of cognitive impairment in Lewy body disease (CI‐LB) patients. The objective was to investigate the associations between WMHs and clinical manifestations in patients with CI‐LB.

Methods

In this retrospective multicentre cohort study, 929 patients (486 with dementia with Lewy bodies [DLB], 262 with Parkinson's disease dementia [PDD], 74 with mild cognitive impairment [MCI] with Lewy bodies [MCI‐LB] and 107 with Parkinson's disease with MCI [PD‐MCI]) were analysed from 22 memory clinics between January 2018 and June 2022. Demographic and clinical data were collected by reviewing medical records. WMHs were semi‐quantified according to the Fazekas method. Associations between WMHs and clinical manifestations were investigated by multivariate linear or logistic regression models.

Results

Dementia with Lewy bodies patients had the highest Fazekas scores compared with PDD, MCI‐LB and PD‐MCI. Multivariable regressions showed the Fazekas score was positively associated with the scores of Unified Parkinson's Disease Rating Scale Part III ( = 0.001), Hoehn−Yahn stage ( = 0.004) and total Neuropsychiatric Inventory ( = 0.001) in MCI‐LB and PD‐MCI patients. In patients with DLB and PDD, Fazekas scores were associated with the absence of rapid eye movement sleep behaviour disorder ( = 0.041) and scores of Unified Parkinson's Disease Rating Scale Part III ( < 0.001), Hoehn−Yahn stage ( < 0.001) and the Montreal Cognitive Assessment ( = 0.014).

Conclusion

White matter hyperintensity burden of DLB was higher than for PDD, MCI‐LB and PD‐MCI. The greater WMH burden was significantly associated with poorer cognitive performance, worse motor function and more severe neuropsychiatric symptoms in CI‐LB.

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Authors:
Jinghuan Gan, Zhihong Shi, Shuai Liu, Xudong Li, Yiming Liu, Hongcan Zhu, Lu Shen, Guili Zhang, Hao Lu, Baozhi Gang, Zhichao Chen and Yong Ji
Article first published online:
07 Aug 2023 | DOI: 10.1111/ene.16002

SHORT COMMUNICATION

Background and purpose

In 2021, the European Academy of Neurology's training requirements were updated to include functional neurological disorder (FND) as a core topic for the first time. To reinforce these changes, we aimed to understand the proportion of inpatients (in non‐neurology settings) who are diagnosed with FND.

Methods

We prospectively collected data on diagnoses made after inpatient ward reviews from neurology trainees at three tertiary neurology centres in Scotland from April to September 2021. We assessed healthcare utilization data for patients with a diagnosis of FND, epilepsy and epileptic seizures, or a neuroinflammatory disorder over the preceding 12 months.

Results

There were 437 inpatient reviews for 424 patients by 13 trainees. The largest single diagnosis was FND ( = 80, 18%), followed by epilepsy ( = 64, 14%), primary headache disorder ( = 40, 9%) and neuroinflammatory disorders ( = 28, 6%). There was an uncertain diagnosis for 48 reviews (11%). Compared to patients with epilepsy or neuroinflammatory disorders, patients with FND had a similar number of admissions (2 vs. 2 vs. 1) and brain/spine imaging studies (2 vs. 1 vs. 2).

Conclusions

In Scotland, FND was the most common diagnosis made after a request for an inpatient review by a neurologist from another department in the hospital. Patients with FND have similar health resource needs to those with other common neurological disorders when they present to hospitals with tertiary neurology centres. This data supports the inclusion of FND as a core curriculum topic in neurology training.

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Authors:
Neil Ramsay, Jon Stone, Kubra Fadiloglu, Mariella Baxter, Caroline Hutchison, Karina Bennett, Tom Moullaali, Jai Mathur, James Bridson and Ingrid Hoeritzauer
Article first published online:
11 Aug 2023 | DOI: 10.1111/ene.16003

LETTER TO THE EDITOR

‘Mindfulness or meditation therapy for Parkinson's disease: A systematic review and meta‐analysis of randomized controlled trials’

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Authors:
XiaoJing Liu and Huahui Lu
Article first published online:
11 Aug 2023 | DOI: 10.1111/ene.16004

ORIGINAL ARTICLE

Background

To investigate whether the cingulate island sign (CIS) ratio (i.e., the ratio of regional uptake in the posterior cingulate cortex relative to the precuneus and cuneus on cerebral perfusion scans) is associated with early dementia conversion in Parkinson's disease (PD).

Methods

We enrolled 226 patients with newly diagnosed PD and 48 healthy controls who underwent dual‐phase F‐FP‐CIT PET scans. Patients with PD were classified into three groups according to the CIS ratio on early‐phase F‐FP‐CIT PET images: a PD group with CIS or high CIS ratios (PD‐CIS;  = 96), a PD group with inverse CIS or low CIS ratios (PD‐iCIS;  = 40), and a PD group consisting of the remaining patients with normal CIS ratios (PD‐nCIS;  = 90). We compared the risk of dementia conversion within a 5‐year time point between the groups.

Results

There were no significant differences in age, sex, education, or baseline cognitive function between the PD groups. The PD‐CIS group had higher Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and more severely decreased dopamine transporter availability in the putamen. The PD‐iCIS group had a smaller hippocampal volume compared with the other groups. The risk of dementia conversion in the PD‐CIS group did not differ from that in the PD‐iCIS and PD‐nCIS groups. Meanwhile, the PD‐iCIS group had a higher risk of dementia conversion than the PD‐nCIS group.

Conclusion

The results of this study suggest that inverse CIS, rather than CIS, is relevant to early dementia conversion in patients with PD.

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Authors:
Seok Jong Chung, Su Hong Kim, Chan Wook Park, Hye Sun Lee, Yun Joong Kim, Phil Hyu Lee, Yong Jeong and Young H. Sohn
Article first published online:
15 Aug 2023 | DOI: 10.1111/ene.16007

ORIGINAL ARTICLE

Background and purpose

The best management of acute ischemic stroke patients with a minor stroke and large vessel occlusion is still uncertain. Specific clinical and radiological data may help to select patients who would benefit from endovascular therapy (EVT). We aimed to evaluate the relevance of National Institutes of Health Stroke Scale (NIHSS) subitems for predicting the potential benefit of providing EVT after intravenous thrombolysis (IVT; “bridging treatment”) versus IVT alone.

Methods

We extracted demographic, clinical, risk factor, radiological, revascularization and outcome data of consecutive patients with M1 or proximal M2 middle cerebral artery occlusion and admission NIHSS scores of 0–5 points, treated with IVT ± EVT between May 2005 and March 2021, from nine prospectively constructed stroke registries at seven French and two Swiss comprehensive stroke centers. Adjusted interaction analyses were performed between admission NIHSS subitems and revascularization modality for two primary outcomes at 3 months: non‐excellent functional outcome (modified Rankin Scale score 2–6) and difference in NIHSS score between 3 months and admission.

Results

Of the 533 patients included (median age 68.2 years, 46% women, median admission NIHSS score 3), 136 (25.5%) initially received bridging therapy and 397 (74.5%) received IVT alone. Adjusted interaction analysis revealed that only facial palsy on admission was more frequently associated with excellent outcome in patients treated by IVT alone versus bridging therapy (odds ratio 0.47, 95% confidence interval 0.24–0.91;  = 0.013). Regarding NIHSS difference at 3 months, no single NIHSS subitem interacted with type of revascularization.

Conclusions

This retrospective multicenter analysis found that NIHSS subitems at admission had little value in predicting patients who might benefit from bridging therapy as opposed to IVT alone. Further research is needed to identify better markers for selecting EVT responders with minor strokes.

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Authors:
Paola Palazzo, Giovanna Padlina, Tomas Dobrocky, Davide Strambo, Pierre Seners, Laura Mechtouff, Guillaume Turc, Charlotte Rosso, William Almiri, Kateryna Antonenko, Nadia Laksiri, Igor Sibon, Olivier Detante, Pasquale Mordasini, Patrik Michel and Mirjam R. Heldner
Article first published online:
11 Aug 2023 | DOI: 10.1111/ene.16009

POSITION PAPER

Background and purpose

Transparent reporting and appropriate interpretation of statistical methods and results are important to facilitate scientific evaluation and enable future replication. The goal of this study was to describe statistical reporting guidance provided to authors by clinical neurology and neuroscience journals.

Methods

For first‐quartile journals in each discipline (per Clarivate InCites), information collected from Instructions to Authors website sections included whether journals required presentation of sample size justification, estimates of precision, and method of checking assumptions; and guidance for interpretation of ‐values and appropriate presentation of descriptive statistics and graphs. Journal endorsement of common but statistically nonspecific published transparent reporting guidelines for human and animal research was also collected, to capture the select statistical reporting items included in each guideline.

Results

Journals ( = 85) frequently did not require/recommend sample size justifications (15% not required; 62% only required per external transparent reporting guideline), estimates of precision (15% not required; 41% only required per external guidelines), or disclosure of method of checking assumptions (46%); nor provide guidance for reporting/interpretation of ‐values (71%), reporting of descriptive statistics (75%), or use of appropriate graphs (92%). Endorsement of statistically nonspecific standalone reporting guidelines ranged between 52% and 68%, depending on the guideline.

Conclusions

There is opportunity for journals to facilitate improvement in transparency of statistical methods and results for clinical neurology and neuroscience studies by providing guidelines and advice to authors at manuscript submission.

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Authors:
Sanjana Tumma, Claire Sonneborn, Aishwarya Padate and Olivia Hogue
Article first published online:
09 Aug 2023 | DOI: 10.1111/ene.16013

ORIGINAL ARTICLE

Background and purpose

Prodromal infections are associated with neuromyelitis optica spectrum disorder (NMOSD), but it remains unclear which type of infection has a causal association with NMOSD. We aimed to explore the causal associations between four herpesvirus infections (chickenpox, cold sores, mononucleosis and shingles) and NMOSD, as well as between other types of infections and NMOSD.

Methods

For data on infections, we used the genome‐wide association study (GWAS) summary statistics from the 23andMe cohort. For outcomes, we used the GWAS data of participants of European ancestry, including 215 NMOSD patients (132 anti‐aquaporin‐4 antibody [AQP4‐ab]‐positive patients and 83 AQP4‐ab‐negative patients) and 1244 normal controls. Single‐nucleotide polymorphism (SNP) identification and two‐sample Mendelian randomization (MR) analyses were then performed.

Results

In the 23andMe cohort, we identified one SNP for chickenpox (rs9266089 in gene), one SNP for cold scores (rs885950 in the gene), one SNP for mononucleosis (rs2596465 in the gene), and three SNPs for shingles (rs2523591 in the gene; rs7047299 in the gene; rs9260809 in the gene). The association between cold sores and AQP4‐ab‐positive NMOSD reached statistical significance (odds ratio [OR] 745.318; 95% confidence interval [CI] 22.176, 25,049.53 [ < 0.001,  < 0.001]). The association between shingles and AQP4‐ab‐positive NMOSD was also statistically significant (OR 21.073; 95% CI 4.271, 103.974 [ < 0.001,  < 0.001]). No significant association was observed between other infections and AQP4‐ab‐positive or AQP4‐ab‐negative NMOSD.

Conclusion

These findings suggest there are positive associations between cold sores and shingles and AQP4‐ab‐positive NMOSD, indicating there may be causal links between herpes simplex virus and varicella‐zoster virus infection and AQP4‐ab‐positive NMOSD.

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Authors:
Liang Wang, Lei Zhou, Jingzi ZhangBao, Wenjuan Huang, Hongmei Tan, Yuxin Fan, Chuanzhen Lu, Jian Yu, Min Wang, Jiahong Lu, Chongbo Zhao, Tiansong Zhang and Chao Quan
Article first published online:
16 Aug 2023 | DOI: 10.1111/ene.16014

ORIGINAL ARTICLE

Background and purpose

Hybrid immunity to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) develops from a combination of natural infection and vaccine‐generated immunity. Multiple sclerosis (MS) disease‐modifying therapies (DMTs) have the potential to impact humoral and cellular immunity induced by SARS‐CoV‐2 vaccination and infection. The aims were to compare antibody and T‐cell responses after SARS‐CoV‐2 mRNA vaccination in persons with MS (pwMS) treated with different DMTs and to assess differences between naïvely vaccinated pwMS and pwMS with hybrid immunity vaccinated following a previous SARS‐CoV‐2 infection.

Methods

Antibody and T‐cell responses were determined in pwMS at baseline and 4 and 12 weeks after the second dose of SARS‐CoV‐2 vaccination in 143 pwMS with or without previous SARS‐CoV‐2 infection and 40 healthy controls (HCs). The MS cohort comprised natalizumab ( = 22), dimethylfumarate ( = 23), fingolimod ( = 38), cladribine ( = 30), alemtuzumab ( = 17) and teriflunomide ( = 13) treated pwMS. Immunoglobulin G antibody responses to SARS‐CoV‐2 antigens were measured using a multiplex bead assay and FluoroSpot was used to assess T‐cell responses (interferon γ and interleukin 13).

Results

Humoral and T‐cell responses to vaccination were comparable between naïvely vaccinated HCs and pwMS treated with natalizumab, dimethylfumarate, cladribine, alemtuzumab and teriflunomide, but were suppressed in fingolimod‐treated pwMS. Both fingolimod‐treated pwMS and HCs vaccinated following a previous SARS‐CoV‐2 infection had higher antibody levels 4 weeks after vaccination compared to naïvely vaccinated individuals. Antibody and interferon γ levels 12 weeks after vaccination were positively correlated with time from last treatment course of cladribine.

Conclusion

These findings are of relevance for infection risk mitigation and for vaccination strategies amongst pwMS undergoing DMT.

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Authors:
Monika Rabenstein, Olivia G. Thomas, Giorgia Carlin, Mohsen Khademi, Klara Asplund Högelin, Clas Malmeström, Markus Axelsson, Anne Frandsen Brandt, Guro Gafvelin, Hans Grönlund, Ingrid Kockum, Fredrik Piehl, Jan Lycke, Tomas Olsson and Tara Hessa
Article first published online:
24 Aug 2023 | DOI: 10.1111/ene.16015

REVIEW ARTICLE

Background and purpose

The COVID‐19 pandemic, caused by severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2), rapidly spread across the globe. Tremendous efforts have been mobilized to create effective antiviral treatment options to reduce the burden of the disease. This article summarizes the available knowledge about the antiviral drugs against SARS‐CoV‐2 from a neurologist's perspective.

Methods

We summarize neurological aspects of antiviral compounds against SARS‐CoV‐2 with full, conditional, or previous marketing authorization by the European Medicines Agency (EMA).

Results

Nirmatrelvir/ritonavir targets the SARS‐CoV‐2 3c‐like protease using combinatorial chemistry. Nirmatrelvir/ritonavir levels are affected by medications metabolized by or inducing CYP3A4, including those used in neurological diseases. Dysgeusia with a bitter or metallic taste is a common side effect of nirmatrelvir/ritonavir. Molnupiravir is a nucleotide analog developed to inhibit the replication of viruses. No clinically significant interactions with other drugs have been identified, and no specific considerations for people with neurological comorbidity are required. In the meantime, inconsistent results from clinical trials regarding efficacy have led to the withdrawal of marketing authorization by the EMA. Remdesivir is a viral RNA polymerase inhibitor and interferes with the production of viral RNA. The most common side effect in patients with COVID‐19 is nausea. Remdesivir is a substrate for CYP3A4.

Conclusions

Neurological side effects and drug interactions must be considered for antiviral compounds against SARS‐CoV‐2. Further studies are required to better evaluate their efficacy and adverse events in patients with concomitant neurological diseases. Moreover, evidence from real‐world studies will complement the current knowledge.

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Authors:
Tamar Akhvlediani, Raphael Bernard‐Valnet, Sara P. Dias, Randi Eikeland, Bettina Pfausler and Johann Sellner
Article first published online:
13 Aug 2023 | DOI: 10.1111/ene.16017

ORIGINAL ARTICLE

Background and purpose

Biallelic mutation/expansion of the gene has been described in association with a spectrum of manifestations ranging from isolated sensory neuro(no)pathy to a complex presentation as cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Our aim was to define the frequency and characteristics of small fiber neuropathy (SFN) in RFC1 disease at different stages.

Methods

RFC1 cases were screened for SFN using the Neuropathic Pain Symptom Inventory and Composite Autonomic Symptom Score 31 questionnaires. Clinical data were retrospectively collected. If available, lower limb skin biopsy samples were evaluated for somatic epidermal and autonomic subepidermal structure innervation and compared to healthy controls (HCs).

Results

Forty patients, median age at onset 54 years (interquartile range [IQR] 49–61) and disease duration 10 years (IQR 6–16), were enrolled. Mild‐to‐moderate positive symptoms (median Neuropathic Pain Symptom Inventory score 12.1/50, IQR 5.5–22.3) and relevant autonomic disturbances (median Composite Autonomic Symptom Score 31 37.0/100, IQR 17.7–44.3) were frequently reported and showed scarce correlation with disease duration. A non‐length‐dependent impairment in nociception was evident in both clinical and paraclinical investigations. An extreme somatic denervation was observed in all patients at both proximal (fibers/mm, RFC1 cases 0.0 vs. HCs 20.5,  < 0.0001) and distal sites (fibers/mm, RFC1 cases 0.0 vs. HCs 13.1,  < 0.0001); instead only a slight decrease was observed in cholinergic and adrenergic innervation of autonomic structures.

Conclusions

RFC1 disease is characterized by a severe and widespread somatic SFN. Skin denervation may potentially represent the earliest feature and drive towards the suspicion of this disorder.

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Authors:
Matteo Tagliapietra, Alex Incensi, Moreno Ferrarini, Nazarena Mesiano, Alessandro Furia, Giovanni Rizzo, Rocco Liguori, Tiziana Cavallaro, Salvatore Monaco, Gian Maria Fabrizi and Vincenzo Donadio
Article first published online:
13 Aug 2023 | DOI: 10.1111/ene.16018

LETTER TO THE EDITOR

A clinical concern: as a reemerging pathogen with increased antimicrobial resistance

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Authors:
Hideharu Hagiya and Koji Iio
Article first published online:
09 Aug 2023 | DOI: 10.1111/ene.16019

ORIGINAL ARTICLE

Background and purpose

RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS).

Methods

We conducted a randomized, multicenter, placebo‐controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double‐blind period, all patients received RT001 during an open‐label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS‐R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration.

Results

In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%,  0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo,  0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least‐squares mean difference in ALSFRS‐R total score at week 24 of treatment was 1.90 (95% confidence interval = −1.39 to 5.19) in favor of RT001 ( = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed.

Conclusions

Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.

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Authors:
Daphne N. Weemering, Mark Midei, Peter Milner, Vidhya Gopalakrishnan, Anil Kumar, Andrew J. Dannenberg, Tommy M. Bunte, Juliette Foucher, Caroline Ingre, Viktorija Ķēniņa, Karin Rallmann, Leonard H. van den Berg and Ruben P. A. van Eijk
Article first published online:
21 Aug 2023 | DOI: 10.1111/ene.16020

ORIGINAL ARTICLE

Background

Existing data regarding the link between COVID‐19 vaccine and myasthenia gravis (MG) are scarce. We aimed to assess the association between Pfizer‐BioNTech vaccine with both new‐onset MG and MG exacerbation.

Methods

For the first aim, we conducted a nested case–control study in a cohort of 3,052,467 adults, without a diagnosis of MG, from the largest healthcare provider in Israel. Subjects were followed from January 1, 2021 until June 30, 2022 for the occurrence of MG. Ten randomly selected controls were matched to each case of new‐onset MG on age and sex. For the second aim, a nested case–control study was conducted in a cohort of 1446 MG patients. Four randomly selected MG patients (controls) were matched to each case of MG exacerbation. Exposure to COVID‐19 vaccine in the prior 4 weeks was assessed in cases and controls.

Results

Overall, 332 patients had new‐onset MG and were matched with 3320 controls. Multivariable conditional logistic regression models showed that the odds ratio (OR) for new‐onset MG, associated with COVID‐19 vaccine, was 1.14 (95% CI 0.73–1.78). The results were consistent in sensitivity analysis that used more stringent criteria to define MG. Overall, 62 patients with MG exacerbation were matched to 248 MG controls. The multivariable OR for MG exacerbation, associated with COVID‐19 vaccine, was 1.35 (95% CI 0.37–4.89). All results were similar when the prior exposure to COVID‐19 vaccine was extended to 8 weeks.

Conclusion

This study suggests that Pfizer‐BioNTech vaccine is not associated with increased risk of new‐onset nor exacerbation of MG.

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Authors:
Anat Arbel, Haya Bishara, Ofra Barnett‐Griness, Shai Cohen, Ronza Najjar‐Debbiny, Naomi Gronich, Eitan Auriel and Walid Saliba
Article first published online:
13 Aug 2023 | DOI: 10.1111/ene.16025

REVIEW ARTICLE

Background and purpose

Many COVID‐19 patients report persistent symptoms, including cognitive disturbances. We performed a scoping review on this topic, focusing primarily on cognitive manifestations.

Methods

Abstracts and full texts of studies published on PubMed (until May 2023) addressing cognitive involvement persisting after SARS‐CoV‐2 infection were reviewed, focusing on terms used to name the cognitive syndrome, reported symptoms, their onset time and duration, and testing batteries employed. Reported psychiatric symptoms, their assessment tools, and more general manifestations were also extracted.

Results

Among the 947 records identified, 180 studies were included. Only one third of them used a label to define the syndrome. A minority of studies included patients according to stringent temporal criteria of syndrome onset (34%), whereas more studies reported a minimum required symptom duration (77%). The most frequently reported cognitive symptoms were memory and attentional–executive disturbances, and among psychiatric complaints, the most frequent were anxiety symptoms, depression, and sleep disturbances. Most studies reported fatigue among general symptoms. Thirty‐six studies employed cognitive measures: screening tests alone ( = 19), full neuropsychological batteries ( = 25), or both ( = 29); 30 studies performed psychiatric testing. Cognitive deficits were demonstrated in 39% of subjects, the most frequently affected domains being attention/executive functions (90%) and memory (67%).

Conclusions

Currently, no agreement exists on a label for post‐COVID‐19 cognitive syndrome. The time of symptom onset after acute infection and symptom duration are still discussed. Memory and attention–executive complaints and deficits, together with fatigue, anxiety, and depression symptoms, are consistently reported, but the objective evaluation of these symptoms is not standardized.

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Authors:
Alessia Nicotra, Federico Masserini, Francesca Calcaterra, Clara Di Vito, Pietro Emiliano Doneddu, Simone Pomati, Eduardo Nobile‐Orazio, Agostino Riva, Domenico Mavilio and Leonardo Pantoni
Article first published online:
26 Aug 2023 | DOI: 10.1111/ene.16027

ORIGINAL ARTICLE

Background and purpose

Ataxia–telangiectasia (A‐T) is a rare, autosomal recessive, multisystem disorder that leads to progressive neurodegeneration with cerebellar ataxia and peripheral polyneuropathy. Cerebellar neurodegeneration is well described in A‐T. However, peripheral nervous system involvement is an underdiagnosed but important additional target for supportive and systemic therapies. The aim of this study was to conduct neurophysiological measurements to assess peripheral neurodegeneration and the development of age‐dependent neuropathy in A‐T.

Methods

In this prospective study, 42 classical A‐T patients were assessed. The motor and sensory nerve conduction of the median and tibial nerves was evaluated. Data were compared to published standard values and a healthy age‐ and gender‐matched control group of 23 participants. Ataxia scores (Klockgether, Scale for the Assessment and Rating of Ataxia) were also assessed.

Results

In A‐T, neurophysiological assessment revealed neuropathic changes as early as the first year of life. Subjective symptomatology of neuropathy is rarely described. In the upper extremities, motor neuropathy was predominantly that of a demyelinating type and sensory neuropathy was predominantly that of a mixed type. In the lower extremities, motor and sensory neuropathy was predominantly that of a mixed type. We found significant correlations between age and the development of motor and sensory polyneuropathy in A‐T compared with healthy controls ( < 0.001).

Conclusions

In A‐T, polyneuropathy occurs mostly subclinically as early as the first year of life. The current study of a large national A‐T cohort demonstrates that development of neuropathy in A‐T differs in the upper and lower extremities.

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Authors:
Marius Theis, Helena Donath, Sandra Woelke, Shahrzad Bakhtiar, Emilia Salzmann‐Manrique, Stefan Zielen and Matthias Kieslich
Article first published online:
16 Aug 2023 | DOI: 10.1111/ene.16028

COMMENTARY

Basal ganglia matter

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Authors:
Fausto Viader
Article first published online:
23 Aug 2023 | DOI: 10.1111/ene.16029

COMMENTARY

Peripheral neuropathy in ataxia‐telangiectasia: Newly characterized, has potential as a biomarker

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Authors:
William Whitehouse
Article first published online:
17 Aug 2023 | DOI: 10.1111/ene.16032

LETTER TO THE EDITOR

Stroke‐like episodes and stroke‐like lesions: Two aspects of the same phenomenon

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Authors:
Josef Finsterer and Sounira Mehri
Article first published online:
17 Aug 2023 | DOI: 10.1111/ene.16033

ORIGINAL ARTICLE

Background

Evidence‐based recommendations for treatment of Lyme neuroborreliosis (LNB) should rely on the available literature. As new data emerges, close review and evaluation of the recent literature is needed to build evidence‐based recommendations to inform clinical practice and management of LNB. We performed an update of a previous systematic review on treatment of LNB.

Methods

A systematic literature search of Medline and CENTRAL was performed for published studies from 2015 to 2023 to update a previous systematic review. Randomized controlled trials (RCTs) and non‐randomized studies (NRS) were evaluated. Risk of bias was assessed using the Cochrane risk of bias tools for RCTs; NRS were assessed using the ROBINS‐I‐tool. Quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Data were integrated into an existing meta‐analysis of the available literature.

Results

After screening 1530 records, two RCTs and five NRS with new and relevant data were additionally identified. Meta‐analysis showed no statistically significant difference between doxycycline and beta‐lactam antibiotics regarding residual neurological symptoms after 12 months. Meta‐analysis showed no benefit of extended antibiotic treatment of LNB. Three NRS show no benefit for additional steroid use in LNB with facial palsy.

Discussion

Additional incorporated recent research corroborates existing guideline recommendations for treatment of LNB. New RCTs add to the certainty of previous analysis showing similar efficacy for doxycycline and beta‐lactam antibiotics in LNB. Available evidence shows no benefit for extended antibiotic treatment in LNB. NRS do not suggest a role for steroids in facial palsy due to LNB.

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Authors:
Rick Dersch and Sebastian Rauer
Article first published online:
10 Sep 2023 | DOI: 10.1111/ene.16034

ORIGINAL ARTICLE

Background and purpose

The weight of outcome predictors in acute ischemic stroke (AIS) patients older than 60 years is not necessarily mirrored in the younger population, posing the question of whether outcome determinants specific for the latter might vary. Very few data are available on predictors of outcome in young AIS patients receiving endovascular treatment (EVT).

Methods

We analyzed data for patients aged between 16 and 55 years from the Italian Registry of Endovascular Treatment in Acute Stroke. We divided our population into patients <45 years old and patients aged between 45 and 55 years. After testing the differences between groups in terms of 90‐day modified Rankin Scale (mRS) 0–2, mortality, and symptomatic intracranial hemorrhage, we looked for predictors of poor outcome (mRS 3–6), death, and symptomatic intracerebral hemorrhage in the two groups.

Results

A total of 438 patients younger than 45 years and 817 aged 45–55 years were included; 284 (34.8%) patients aged 45–55 years and 112 (25.6%) patients younger than 45 years old showed poor 90‐day functional outcome ( = 0.001). Predictors of poor outcome in the older group were baseline National Institutes of Health Stroke Scale (NIHSS;  < 0.001), diabetes ( = 0.027), poor collateral status ( = 0.036), and groin puncture‐to‐recanalization time ( = 0.010), whereas Thrombolysis in Cerebral Infarction (TICI) 2b–3 had an inverse association ( < 0.001). Predictors of poor outcome in patients younger than 45 years were baseline NIHSS ( < 0.001) and groin puncture‐to‐recanalization time ( = 0.015), whereas an inverse association was found for baseline Alberta Stroke Program Early CT Score ( = 0.010) and TICI 2b–3 ( < 0.001).

Conclusions

Approximately one third of young adults treated with EVT do not reach a good functional outcome. Fast and successful recanalization, rather than common risk factors, has a major role in determining clinical outcome.

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Authors:
Ettore Nicolini, Valentina Saia, Svetlana Lorenzano, Giovanni Pracucci, Marta Iacobucci, Manuela De Michele, Stefano Vallone, Mauro Bergui, Marina Diomedi, Patrizia Nencini, Rossana Tassi, Andrea Saletti, Edoardo Puglielli, Andrea Naldi, Sergio Lucio Vinci, Nicola Giannini, Laura Malfatto, Menozzi Roberto, Daniele G. Romano, Manuel Cappellari, Andrea Zini, Fabrizio Sallustio, Ilaria Casetta, Enrico Fainardi, Salvatore Mangiafico, Danilo Toni, Guido Bigliardi, Paolo Cerrato, Valerio Da Ros, Nicola Limbucci, Sandra Bracco, Alessandro De Vito, Alfonsina Casalena, Davide Castellano, Ludovica Ferrau, Guido Andrea Lanzarotti, Lucio Castellan, Umberto Scoditti, Andrea Giorgianni, Lucia Princiotta, Maria Ruggiero, Marco Longoni, Nicola Cavasin, Adriana Critelli, Simone Comelli, Maurizio Melis, Elvis Lafe, Anna Cavallini, William Auteri, Furio Stancati, Rosa Napoletano, Mauro Plebani, Alessio Comai, Enrica Franchini, Luca Allegretti, Tiziana Tassinari, Luigi Chiumarulo, Marco Petruzzellis, Alessandro Pedicelli, Giovanni Frisullo, Luigi Simonetti, Marco Pavia, Paolo Invernizzi, Ivan Gallesio, Federica Sepe, Michele Besana, Alessia Giossi, Pietro Filuari, Simona Sacco, Nicola Burdi, Giovanni Boero, Paola Feraco, Silvio Piffer, Giuseppe Romano, Maria Federica Grasso, Paolo Versace, Luciano Arcudi, Pietro Amistá, Monia Russo, Emilio Lozupone, Antonio Fasano, Francesco Florio and Vincenzo Inchignolo
Article first published online:
24 Aug 2023 | DOI: 10.1111/ene.16035

SHORT COMMUNICATION

Background and purpose

Data on disease‐modifying therapy (DMT) exposure throughout pregnancy in patients with multiple sclerosis are scarce. In this analysis, we assessed pregnancy and fetal outcomes following maternal glatiramer acetate (GA) exposure in all three trimesters among cases reported between 1997 and 2020.

Methods

Pregnancy reports of maternal in utero exposure to 20 and 40 mg/mL GA in all three trimesters from 1997 to 2020 were eligible. Both prospective pregnancy data, reported prior to knowledge of pregnancy outcome, and retrospective data were included. The primary endpoint was major congenital malformations (MCMs) based on the European Surveillance of Congenital Anomalies and Twins (EUROCAT) classification. Additional endpoints included fetal death, preterm birth, and low birth weight. The MCM rate was compared to the EUROCAT background rate.

Results

A total of 618 GA‐exposed pregnancies in all three trimesters resulted in 634 fetuses, including 14 twin pregnancies. One fetal death was reported. All 414 fetuses with data reported prior to knowledge of pregnancy outcome (prospective data) were live births and no fetal death was reported. Preterm birth was reported in 23/213 (10.8%) pregnancies with known gestational age. Low birth weight was reported in 13/203 (6.4%) infants with known birth weight. The prevalence of MCM in prospective live births ranged from 2.2% to 2.4%, which was similar to background rates (2.1%–3.0%). The frequency of these pregnancy and infant outcomes was comparable across GA doses.

Conclusions

In utero exposure to 20 and 40 mg/mL GA in three trimesters of pregnancy does not appear to be related to adverse pregnancy or infant outcomes.

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Authors:
Sigal Kaplan, Mikhail Zeygarnik, Tal Stern and Kerstin Hellwig
Article first published online:
24 Aug 2023 | DOI: 10.1111/ene.16036

COMMENTARY

Advancements in targeted therapies for generalized acetylcholine receptor antibody positive myasthenia gravis: Beginnings of a paradigm shift

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Authors:
Ali A. Habib and Christiane Schneider‐Gold
Article first published online:
14 Sep 2023 | DOI: 10.1111/ene.16037

REVIEW ARTICLE

Background

The ‐related disorders (‐RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in ‐RD, aiming to provide clinical recommendations for its management.

Methods

A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and ‐RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO.

Results

Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low.

Conclusions

The management of chorea in individuals with ‐RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

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Authors:
Laia Nou‐Fontanet, Carmen Martín‐Gómez, Rebeca Isabel‐Gómez, Anne‐Catherine Bachoud‐Lévi, Giovanna Zorzi, Alessandro Capuano, Juan Antonio Blasco‐Amaro and Juan Darío Ortigoza‐Escobar
Article first published online:
11 Sep 2023 | DOI: 10.1111/ene.16038

ORIGINAL ARTICLE

Background and purpose

Dominantly inherited GAA repeat expansions in the fibroblast growth factor 14 () gene have recently been shown to cause spinocerebellar ataxia 27B (SCA27B). We aimed to study the frequency and phenotype of SCA27B in a cohort of patients with unsolved late‐onset cerebellar ataxia (LOCA). We also assessed the frequency of SCA27B relative to other genetically defined LOCAs.

Methods

We recruited a consecutive series of 107 patients with LOCA, of whom 64 remained genetically undiagnosed. We screened these 64 patients for the GAA repeat expansion. We next analysed the frequency of SCA27B relative to other genetically defined forms of LOCA in the cohort of 107 patients.

Results

Eighteen of 64 patients (28%) carried an (GAA) expansion. The median (range) age at onset was 62.5 (39–72) years. The most common clinical features included gait ataxia (100%) and mild cerebellar dysarthria (67%). In addition, episodic symptoms and downbeat nystagmus were present in 39% (7/18) and 37% (6/16) of patients, respectively. SCA27B was the most common cause of LOCA in our cohort (17%, 18/107). Among patients with genetically defined LOCA, SCA27B was the main cause of pure ataxia, ‐related disease of ataxia with neuropathy, and of ataxia with spasticity.

Conclusion

We showed that SCA27B is the most common cause of LOCA in our cohort. Our results support the use of GAA repeat expansion screening as a first‐tier genetic test in patients with LOCA.

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Authors:
Pablo Iruzubieta, David Pellerin, Alberto Bergareche, Inés Albajar, Elisabet Mondragón, Ana Vinagre, Roberto Fernández‐Torrón, Fermín Moreno, Jon Equiza, David Campo‐Caballero, Juan José Poza, Marta Ruibal, Alessandro Formica, Marie‐Josée Dicaire, Matt C. Danzi, Stephan Zuchner, Ioana Croitoru, Montserrat Ruiz, Agatha Schlüter, Carlos Casasnovas, Aurora Pujol, Bernard Brais, Henry Houlden, Adolfo López de Munain and Javier Ruiz‐Martínez
Article first published online:
27 Aug 2023 | DOI: 10.1111/ene.16039

CASE REPORT

Abstract

Although—considering the risk–benefit ratio—botulinum neurotoxin A (BoNT/A) is unequivocally recommended to treat severe neurological diseases such as dystonia, this has not yet been determined for its endoscopic intragastric injection aimed at weight reduction in obesity. However, severe adverse effects of intragastric BoNT/A had not yet been reported, prompting some European countries to endorse its (off‐label) use and treat patients transnationally. We here present three cases of botulism after intragastric BoNT/A injections for obesity treatment in a Turkish hospital. Patients presented with cranial nerve affection, bulbar symptoms, and descending paresis, and benefited from treatment with BoNT antitoxin and pyridostigmine. We assume that iatrogenic botulism was induced by overdosing in combination with toxin spread via the highly vascularized gastric tissue. Of note, within a few weeks, more than 80 cases of iatrogenic botulism were reported across Europe after identical intragastric BoNT/A injections. These cases demonstrate the risks of BoNT/A injections if they are not applied within the limits of evidence‐based medicine. There is a need for international guidelines to define the indication and a safe dosing scheme, especially in the context of medical tourism.

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Authors:
Christina Hennen, Seda Demir, Haidar Salimi Dafsari, Gilbert Wunderlich, Boris Böll, Christoph Hüser, Michael Thomas Barbe, Gereon Rudolf Fink and Maria Adele Rueger
Article first published online:
29 Aug 2023 | DOI: 10.1111/ene.16040

REVIEW ARTICLE

Background and purpose

Alpha‐synuclein seed amplification assays (α‐syn SAAs) are promising diagnostic methods for Parkinson's disease (PD) and other synucleinopathies. However, there is limited consensus regarding the diagnostic and differential diagnostic performance of α‐syn SAAs on biofluids and peripheral tissues.

Methods

A comprehensive research was performed in PubMed, Web of Science, Embase and Cochrane Library. Meta‐analysis was performed using a random‐effects model. A network meta‐analysis based on an ANOVA model was conducted to compare the relative accuracy of α‐syn SAAs with different specimens.

Results

The pooled sensitivity and specificity of α‐syn SAAs in distinguishing PD from healthy controls or non‐neurodegenerative neurological controls were 0.91 (95% confidence interval [CI] 0.89‐0.92) and 0.95 (95% CI 0.94‐0.96) for cerebrospinal fluid (CSF); 0.91 (95% CI 0.86–0.94) and 0.92 (95% CI 0.87‐0.95) for skin; 0.80 (95% CI 0.66‐0.89) and 0.87 (95% CI 0.69‐0.96) for submandibular gland; 0.44 (95% CI 0.30–0.59) and 0.92 (95% CI 0.79–0.98) for gastrointestinal tract; 0.79 (95% CI 0.70–0.86) and 0.88 (95% CI 0.77–0.95) for saliva; and 0.51 (95% CI 0.39‐0.62) and 0.91 (95% CI 0.84‐0.96) for olfactory mucosa (OM). The pooled sensitivity and specificity were 0.91 (95% CI 0.89–0.93) and 0.50 (95% CI 0.44–0.55) for CSF, 0.92 (95% CI 0.83–0.97) and 0.22 (95% CI 0.06–0.48) for skin, and 0.55 (95% CI 0.42–0.68) and 0.50 (95% CI 0.35–0.65) for OM in distinguishing PD from multiple system atrophy. The pooled sensitivity and specificity were 0.92 (95% CI 0.89–0.94) and 0.84 (95% CI 0.73–0.91) for CSF, 0.92 (95% CI 0.83–0.97) and 0.88 (95% CI 0.64–0.99) for skin and 0.63 (95% CI 0.52‐0.73) and 0.86 (95% CI 0.64‐0.97) for OM in distinguishing PD from progressive supranuclear palsy. The pooled sensitivity and specificity were 0.94 (95% CI 0.90–0.97) and 0.95 (95% CI 0.77–1.00) for CSF and 0.94 (95% CI 0.84–0.99) and 0.86 (95% CI 0.42–1.00) for skin in distinguishing PD from corticobasal degeneration.

Conclusions

α‐Synuclein SAAs of CSF, skin, saliva, submandibular gland, gastrointestinal tract and OM are promising diagnostic assays for PD, with CSF and skin α‐syn SAAs demonstrating higher diagnostic performance.

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Authors:
Yuanchu Zheng, Siming Li, Chen Yang, Zhenwei Yu, Ying Jiang and Tao Feng
Article first published online:
28 Aug 2023 | DOI: 10.1111/ene.16041

ORIGINAL ARTICLE

Background and purpose

Despite the 2017 revisions to the McDonald criteria, diagnosing primary progressive multiple sclerosis (PPMS) remains challenging. To improve clinical practice, the aim was to identify frequent diagnostic challenges in a real‐world setting and associate these with the performance of the 2010 and 2017 PPMS diagnostic McDonald criteria.

Methods

Clinical, radiological and laboratory characteristics at the time of diagnosis were retrospectively recorded from designated PPMS patient files. Possible complicating factors were recorded such as confounding comorbidity, signs indicative of alternative diagnoses, possible earlier relapses and/or incomplete diagnostic work‐up (no cerebrospinal fluid examination and/or magnetic resonance imaging brain and spinal cord). The percentages of patients fulfilling the 2010 and 2017 McDonald criteria were calculated after censoring patients with these complicating factors.

Results

A total of 322 designated PPMS patients were included. Of all participants, it was found that  = 28/322 had confounding comorbidity and/or signs indicative of alternative diagnoses,  = 103/294 had possible initial relapsing and/or uncertainly progressive phenotypes and  = 73/191 received an incomplete diagnostic work‐up. When applying the 2010 and 2017 diagnostic PPMS McDonald criteria on  = 118 cases with a full diagnostic work‐up and a primary progressive disease course without a better alternative explanation, these were met by 104/118 (88.1%) and 98/118 remaining patients (83.1%), respectively ( = 0.15).

Conclusion

Accurate interpretation of the initial clinical course, consideration of alternative diagnoses and a full diagnostic work‐up are the cornerstones of a PPMS diagnosis. When these conditions are met, the 2010 and 2017 McDonald criteria for PPMS perform similarly, emphasizing the importance of their appropriate application in clinical practice.

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Authors:
Katelijn M. Blok, Joost Smolders, Joost van Rosmalen, Carine O. Martins Jarnalo, Beatrijs Wokke and Janet de Beukelaar
Article first published online:
15 Sep 2023 | DOI: 10.1111/ene.16042

ORIGINAL ARTICLE

Background and purpose

In relapsing–remitting multiple sclerosis (RRMS), analyses from observational studies comparing dimethyl fumarate (DMF) and teriflunomide showed conflicting results. We aimed to compare the effectiveness of DMF and teriflunomide in a real‐world setting, where both drugs are licensed as first‐line therapies for RRMS.

Methods

We included all patients who initiated DMF or teriflunomide between 2013 and 2022, listed in the Swiss National Treatment Registry. Coarsened exact matching was applied using age, gender, disease duration, baseline Expanded Disability Status Scale (EDSS) score, time since last relapse, and relapse rate in the previous year as matching variables. Time to relapse and time to 12‐month confirmed EDSS worsening were compared using Cox proportional hazard models.

Results

In total, 2028 patients were included in this study, of whom 1498 were matched (:  = 1090, 69.6% female, mean age 45.1 years, median EDSS score 2.0; :  = 408, 68.9% female, mean age 45.1 years, median EDSS score 2.0). Time to relapse and time to EDSS worsening was longer in the DMF than the teriflunomide group (hazard ratio 0.734,  = 0.026 and hazard ratio 0.576,  = 0.003, respectively).

Conclusion

Analysis of real‐world data showed that DMF treatment was associated with more favorable outcomes than teriflunomide treatment.

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Authors:
Jannis Müller, Sabine Schädelin, Johannes Lorscheider, Pascal Benkert, Peter Hänni, Jürg Schmid, Jens Kuhle, Tobias Derfuss, Cristina Granziera and Özgür Yaldizli
Article first published online:
29 Aug 2023 | DOI: 10.1111/ene.16044

ORIGINAL ARTICLE

Background and purpose

The specific effects of antiseizure medications (ASMs) on cognition are a rich field of study, with many ongoing questions. The aim of this study was to evaluate these effects in a homogeneous group of patients with epilepsy to guide clinicians to choose the most appropriate medications.

Methods

We retrospectively identified 287 refractory patients with medial temporal lobe epilepsy associated with hippocampal sclerosis. Scores measuring general cognition (global, verbal and performance IQ), working memory, episodic memory, executive functions, and language abilities were correlated with ASM type, number, dosage and generation (old vs. new). We also assessed non‐modifiable factors affecting cognition, such as demographics and epilepsy‐related factors.

Results

Key parameters were total number of ASMs and specific medications, especially topiramate (TPM) and sodium valproate (VPA). Four cognitive profiles of the ASMs were identified: (i) drugs with an overall detrimental effect on cognition (TPM, VPA); (ii) drugs with negative effects on specific areas: verbal memory and language skills (carbamazepine), and language functions (zonisamide); (iii) drugs affecting a single function in a specific and limited area: visual denomination (oxcarbazepine, lacosamide); and (iv) drugs without documented cognitive side effects. Non‐modifiable factors such as age at testing, age at seizure onset, and history of febrile seizures also influenced cognition and were notably influenced by total number of ASMs.

Conclusion

We conclude that ASMs significantly impact cognition. Key parameters were total number of ASMs and specific medications, especially TPM and VPA. These results should lead to a reduction in the number of drugs received and the avoidance of medications with unfavorable cognitive profiles.

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Authors:
Cedric Dusanter, Marion Houot, Marie Mere, Marisa Denos, Séverine Samson, Bastien Herlin, Vincent Navarro and Sophie Dupont
Article first published online:
31 Aug 2023 | DOI: 10.1111/ene.16050

ORIGINAL ARTICLE

Background and purpose

Intracranial atherosclerotic disease (ICAD) is a major cause of ischemic stroke in China, but the prevalence and prognosis of asymptomatic ICAD detected using high‐resolution magnetic resonance imaging (HR‐MRI) is largely unknown. The aim of this study was to investigate the prevalence and prognosis in order to guide neurologists in interpreting ICAD detected on HR‐MRI.

Methods

We included stroke‐free participants from a community‐based prospective cohort (Shunyi study participants) who underwent HR‐MRI between July 2014 and April 2016. The participants were divided into two groups: those with or without ICAD (ICAD and ICAD, respectively). ICAD included intracranial artery stenosis and non‐stenotic plaque. The primary outcome was ischemic stroke. Cox proportional hazard models were used to evaluate the association between ICAD and event outcomes.

Results

A total of 1060 stroke‐free participants evaluated by HR‐MRI were included from the Shunyi study. The median age at HR‐MRI was 56 years and 64.7% were female. The ICAD prevalence was 36.3% ( = 385). The ICAD group was older and had more cerebrovascular risk factors. The rates of ischemic stroke in the ICAD and ICAD groups were 1.3% ( = 9) and 5.2% ( = 20), respectively, with a median follow‐up time of 54 months. ICAD was associated with an increased risk of ischemic stroke in the unadjusted and adjusted Cox models, with hazard ratios of 4.12 (95% confidence interval [CI] 1.87–9.05) and 2.50 (95% CI 1.05–5.94), respectively. The greatest risk of an event outcome was observed in participants with ≥70% stenosis or occlusion. The features of high‐risk plaques were also identified.

Conclusions

We found that ICAD detected using HR‐MRI increases the long‐term risk of a first‐ever ischemic stroke in a stroke‐free population, suggesting that the current primary prevention protocol of stroke awaits further optimization.

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Authors:
Shengde Li, Mingyu Tang, Dingding Zhang, Fei Han, Lixin Zhou, Ming Yao, Mingli Li, Liying Cui, Shuyang Zhang, Bin Peng, Zhengyu Jin, Yicheng Zhu and Jun Ni
Article first published online:
22 Sep 2023 | DOI: 10.1111/ene.16057

ORIGINAL ARTICLE

Background and purpose

In clinical practice patients may report migraine worsening as a consequence of COVID‐19 (either infection or vaccines), however, data in this area are lacking. We aimed to investigate the link between COVID‐19 and COVID‐19 vaccination with migraine worsening and its associated factors.

Methods

An online survey was sent to migraine patients followed up in a Spanish Headache Clinic, collecting demographic data, and information regarding SARS‐CoV‐2 infection and vaccination. We asked patients if they had noticed worsening of their migraine after these events and assessed concerns about infection, vaccination and migraine worsening. We also extracted data from participants' own electronic diaries (e‐diaries), including 1‐month data before and after their reported infection and/or vaccination. We compared participants who self‐reported migraine worsening since infection or vaccination with those who did not.

Results

Of 550 participants, 44.9% (247/550) reported having had COVID‐19 at least once and 83.3% (458/550) had been vaccinated. Sixty‐one patients reported migraine worsening since COVID‐19 and 52 since the vaccination. Among the risk factors for perceived migraine worsening in the two settings (infection and vaccination) was concern about migraine worsening itself (infection: odds ratio [OR] 2.498 [95% CI: 1.02–6.273],  = 0.046; vaccination: OR 17.3 [95% CI: confidence interval 5.3–68],  < 0.001). e‐diary information was available for 136 of the 550 patients, 38.2% (52/136) for COVID‐19 and 39.7% (54/136) for vaccination. We observed no significant difference in headache frequency 1 month before and after infection or vaccination, even when comparing patients with and without self‐reported migraine worsening.

Conclusions

Our preliminary data point to a negligible role of the infection and vaccination on migraine worsening and to the possible presence of a nocebo effect in these settings, as a remarkable proportion of patients had a clear perception of migraine worsening.

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Authors:
Laura Melgarejo, Edoardo Caronna, Joana Rosell‐Mirmi, Iker Elosua‐Bayés, Alicia Alpuente, Marta Torres‐Ferrus, Víctor J. Gallardo and Patricia Pozo‐Rosich
Article first published online:
04 Oct 2023 | DOI: 10.1111/ene.16058

EDITORIAL

Reverse Lasagna's law: the ethics and undesirable consequences of overbooking patients for trials

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Authors:
Thomas C. van den Hoek and Michel D. Ferrari
Article first published online:
19 Sep 2023 | DOI: 10.1111/ene.16067

GUIDELINES

Abstract

Guillain–Barré syndrome (GBS) is an acute polyradiculoneuropathy. Symptoms may vary greatly in presentation and severity. Besides weakness and sensory disturbances, patients may have cranial nerve involvement, respiratory insufficiency, autonomic dysfunction and pain. To develop an evidence‐based guideline for the diagnosis and treatment of GBS, using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology a Task Force (TF) of the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) constructed 14 Population/Intervention/Comparison/Outcome questions (PICOs) covering diagnosis, treatment and prognosis of GBS, which guided the literature search. Data were extracted and summarised in GRADE Summaries of Findings (for treatment PICOs) or Evidence Tables (for diagnostic and prognostic PICOs). Statements were prepared according to GRADE Evidence‐to‐Decision (EtD) frameworks. For the six intervention PICOs, evidence‐based recommendations are made. For other PICOs, good practice points (GPPs) are formulated. For diagnosis, the principal GPPs are: GBS is more likely if there is a history of recent diarrhoea or respiratory infection; CSF examination is valuable, particularly when the diagnosis is less certain; electrodiagnostic testing is advised to support the diagnosis; testing for anti‐ganglioside antibodies is of limited clinical value in most patients with typical motor‐sensory GBS, but anti‐GQ1b antibody testing should be considered when Miller Fisher syndrome (MFS) is suspected; nodal–paranodal antibodies should be tested when autoimmune nodopathy is suspected; MRI or ultrasound imaging should be considered in atypical cases; and changing the diagnosis to acute‐onset chronic inflammatory demyelinating polyradiculoneuropathy (A‐CIDP) should be considered if progression continues after 8 weeks from onset, which occurs in around 5% of patients initially diagnosed with GBS. For treatment, the TF recommends intravenous immunoglobulin (IVIg) 0.4 g/kg for 5 days, in patients within 2 weeks (GPP also within 2–4 weeks) after onset of weakness if unable to walk unaided, or a course of plasma exchange (PE) 12–15 L in four to five exchanges over 1–2 weeks, in patients within 4 weeks after onset of weakness if unable to walk unaided. The TF recommends against a second IVIg course in GBS patients with a poor prognosis; recommends against using oral corticosteroids, and weakly recommends against using IV corticosteroids; does not recommend PE followed immediately by IVIg; weakly recommends gabapentinoids, tricyclic antidepressants or carbamazepine for treatment of pain; does not recommend a specific treatment for fatigue. To estimate the prognosis of individual patients, the TF advises using the modified Erasmus GBS outcome score (mEGOS) to assess outcome, and the modified Erasmus GBS Respiratory Insufficiency Score (mEGRIS) to assess the risk of requiring artificial ventilation. Based on the PICOs, available literature and additional discussions, we provide flow charts to assist making clinical decisions on diagnosis, treatment and the need for intensive care unit admission.

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Authors:
Pieter A. van Doorn, Peter Y. K. Van den Bergh, Robert D. M. Hadden, Bert Avau, Patrik Vankrunkelsven, Shahram Attarian, Patricia H. Blomkwist‐Markens, David R. Cornblath, H. Stephan Goedee, Thomas Harbo, Bart C. Jacobs, Susumu Kusunoki, Helmar C. Lehmann, Richard A. Lewis, Michael P. Lunn, Eduardo Nobile‐Orazio, Luis Querol, Yusuf A. Rajabally, Thirugnanam Umapathi, Haluk A. Topaloglu and Hugh J. Willison
Article first published online:
10 Oct 2023 | DOI: 10.1111/ene.16073

COMMENTARY

Long COVID and cognition

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Authors:
François Chollet and Jean‐Marc Leger
Article first published online:
03 Oct 2023 | DOI: 10.1111/ene.16082

LETTER TO THE EDITOR

COVID‐19 vaccination and myasthenia gravis

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Authors:
Amnuay Kleebayoon and Viroj Wiwanitkit
Article first published online:
05 Oct 2023 | DOI: 10.1111/ene.16086

LETTER TO THE EDITOR

COVID‐19 vaccination and myasthenia gravis

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Authors:
Anat Arbel, Haya Bishara, Ofra Barnett‐Griness, Shai Cohen, Ronza Najjar‐Debbiny, Naomi Gronich, Eitan Auriel and Walid Saliba
Article first published online:
05 Oct 2023 | DOI: 10.1111/ene.16087

EDITORIAL

Intracranial atherosclerotic plaques identified on vessel wall imaging are associated with increased risk of first‐ever stroke in a large Chinese cohort

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Authors:
Chengcheng Zhu and Bing Tian
Article first published online:
12 Oct 2023 | DOI: 10.1111/ene.16104

OBITUARY

Professor Hany Mohammed Aref (1961–2023)

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Authors:
Didier Leys and Riadh Gouider
Article first published online:
24 Oct 2023 | DOI: 10.1111/ene.16114