cover image European Journal of Neurology

European Journal of Neurology

2022 - Volume 29
Issue 8 | August 2022
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Article first published online:
15 Jul 2022 | DOI: 10.1111/ene.14928

CASE REPORT

Background and purpose

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited disorder that manifests as a mixture of cerebellar ataxia, parkinsonism, and polyneuropathy; in type IV SCA3, pure parkinsonism is the only symptom. Currently, no disease‐modifying treatment is available, but variable responses to antiparkinsonism agents have been reported. However, the benefits of deep brain stimulation (DBS) for treating parkinsonism in this subtype of SCA3 remain unclear.

Methods

A 39‐year‐old male patient with a rare disorder of type IV SCA3 presented with pure parkinsonism including unilateral resting tremor, rigidity, and bradykinesia at the age of 30 years. Young‐onset Parkinson disease was diagnosed at the age of 32 years. His family history revealed a mild ataxia in his father since the age of 55 years. Genetic testing confirmed an expanded CAG repeated number, with 66 in this case and 63 in his father for SCA3 mutation. Excellent response to levodopa and dopamine agonists in the first 3 years was noted, but wearing‐off phenomena, levodopa‐induced dyskinesia, and severe impulse control disorders later developed. To alleviate drug‐induced complications, he received bilateral subthalamic nucleus deep brain stimulation (STN‐DBS) in the absence of cerebellar signs, depression, and cognitive impairment.

Results

As of 2019, no impulsive control disorders, motor fluctuations, or DBS‐related complications were observed during a 4‐year follow‐up, with 66% Unified Parkinson's Disease Rating Scale Part III reduction at medication OFF state noted, whereas levodopa equivalent daily dosage decreased by almost half.

Conclusions

STN‐DBS may be considered as adjunct treatment for severe dopa‐related motor/nonmotor complications in patients with parkinsonian phenotype of SCA 3.

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Authors:
Ming‐Che Kuo, Chun‐Hwei Tai, Sheng‐Hong Tseng and Ruey‐Meei Wu
Article first published online:
15 Jul 2022 | DOI: 10.1111/ene.15339

ORIGINAL ARTICLE

Background and purpose

The aim was to explore the association of residual inflammatory risk (RIR) with stroke recurrence after an index acute ischaemic stroke or transient ischaemic attack.

Methods

This study was based on the Third China National Stroke Registry. A total of 5840 patients with two high sensitivity C‐reactive protein (hsCRP) measurements at baseline and at 3 months were included in the analysis. High RIR was defined as an hsCRP ≥3 mg/l. Patients were divided into four groups: persistent high RIR (first high then high hsCRP), attenuated RIR (first high then low hsCRP), increased RIR (first low then high hsCRP) and persistent low RIR (first low then low hsCRP). The primary outcome was new stroke onset during the 1‐year follow‐up. Secondary outcomes included composite vascular events, all‐cause mortality and poor functional outcome (modified Rankin Scale score 3–6).

Results

During the 1‐year follow‐up, 523 (9.0%) patients had stroke recurrence. Patients with persistent high RIR had an increased risk of stroke recurrence (hazard ratio with 95% confidence interval 1.39, 1.08–1.78), compared with those with persistent low RIR. Similar results were found for the outcome of composite vascular events, mortality and poor functional outcome. An increased risk of stroke recurrence was further found in patients with persistent high RIR and intracranial artery stenosis or large‐artery atherosclerosis stroke subtype.

Conclusions

In patients with acute ischaemic stroke or transient ischaemic attack, persistent high RIR increased the risks of 1‐year stroke recurrence, especially in those with intracranial artery stenosis or large‐artery atherosclerosis subtype, composite vascular events, mortality and poor functional outcome.

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Authors:
Huihui Liu, Mengxing Wang, Xianglong Xiang, Yuesong Pan, Jiejie Li, Xia Meng, Hao Li, Zixiao Li, Jing Jing and Yongjun Wang
Article first published online:
27 Apr 2022 | DOI: 10.1111/ene.15344

SHORT COMMUNICATION

Background and purpose

Oropharyngeal dysphagia is generally recognized to increase the risk of malnutrition; however, its role in patients with neurodegenerative disease has yet to be determined. This cross‐sectional study aimed to investigate the impact of swallowing function on malnutrition risk in patients with neurodegenerative diseases.

Methods

Patients with oral nutrition and diagnosis of Huntington disease (HD), Parkinson disease (PD), or amyotrophic lateral sclerosis (ALS) were recruited. Demographic and clinical data were collected. The swallowing assessment included a fiberoptic endoscopic evaluation of swallowing, an oral phase assessment, and a meal observation scored with the Mealtime Assessment Scale (MAS). Malnutrition risk was assessed with the Mini Nutritional Assessment.

Results

Overall, 148 patients were recruited (54 HD, 33 PD, and 61 ALS). One hundred (67.6%) patients were considered at risk of malnutrition. In the multivariate analysis, age ≥ 65 years (odds ratio [OR] = 3.16,  = 0.014), disease severity (moderate vs mild OR = 3.89, severe vs mild OR = 9.71,  = 0.003), number of masticatory cycles (OR = 1.03,  = 0.044), and MAS safety (OR = 1.44,  = 0.016) were significantly associated with malnutrition risk.

Conclusions

Prolonged oral phase and signs of impaired swallowing safety during meals, together with older age and disease severity, are independent predictors of malnutrition risk in neurodegenerative diseases. This study broadens the focus on dysphagia, stressing the importance of early detection not only of pharyngeal signs, but also of oral phase impairment and meal difficulties through a multidimensional swallowing assessment.

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Authors:
Nicole Pizzorni, Andrea Ciammola, Giovanni Casazza, Daniela Ginocchio, Federica Bianchi, Sarah Feroldi, Barbara Poletti, Lorenzo Nanetti, Caterina Mariotti, Gabriele Mora and Antonio Schindler
Article first published online:
15 Apr 2022 | DOI: 10.1111/ene.15345

ORIGINAL ARTICLE

Background and purpose

Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP‐P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in and genes have been associated with longer disease duration (DD).

Methods

Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology.

Results

We identified four cases with long (>10–15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP‐P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP‐RS) and Stage 4/6 (PSP‐P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309‐C allele of the gene and the H1 haplotype. Two were heterozygous for rs2242367 (G/A) in , whereas the third was homozygous for the G‐allele.

Conclusions

We propose a protracted course subtype of PSP (PC‐PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309‐C allele may influence the protracted disease course. Crystallizing the concept of PC‐PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation.

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Authors:
Blas Couto, Ivan Martinez‐Valbuena, Seojin Lee, Isabel Alfradique‐Dunham, Richard J. Perrin, Joel S. Perlmutter, Carlos Cruchaga, Ain Kim, Naomi Visanji, Christine Sato, Ekaterina Rogaeva, Anthony E. Lang and Gabor G. Kovacs
Article first published online:
21 Apr 2022 | DOI: 10.1111/ene.15346

ORIGINAL ARTICLE

Background and purpose

Stridor treatment in multiple system atrophy (MSA) mainly comprises tracheostomy or continuous positive airway pressure (CPAP), but guidelines for the use of these treatments are lacking. The aim of the study was to evaluate the predictive value of stridor treatment in an MSA cohort.

Methods

This is a retrospective and prospective monocentric cohort study including MSA patients evaluated at least once a year during the disease course. Stridor was video‐polysomnography confirmed. The time of stridor treatment (CPAP or tracheostomy) and latency from stridor onset were collected. Survival and predictors of survival were calculated.

Results

A total of 182 (107 males, mean age at disease onset 57.3 ± 8.4 years) MSA patients were included in the study; 141 were deceased at the time of study. Of the total sample, 75 patients were diagnosed with stridor: 22 patients were treated with tracheostomy and 29 with CPAP, whilst 24 patients did not receive treatment. Treatment with tracheostomy showed longer survival compared with both treatment with CPAP or no treatment (incidence rate of death 12 vs. 21 vs. 23 per 100 person‐years, respectively). Tracheostomy remained an independent factor associated with longer survival (hazard ratio 0.38,  = 0.029), also after adjustment for other confounders and latency for stridor treatment.

Conclusions

This is the largest monocentric and long‐term follow‐up study comparing survival between tracheostomy and CPAP in MSA patients with stridor. Treatment with tracheostomy showed longer survival compared with both treatment with CPAP or no treatment. A careful multidisciplinary approach is required for the management of MSA patients with stridor.

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Authors:
Giulia Giannini, Federica Provini, Ilaria Cani, Annagrazia Cecere, Francesco Mignani, Pietro Guaraldi, Cristian Vincenzo Francesco Di Mirto, Pietro Cortelli and Giovanna Calandra‐Buonaura
Article first published online:
15 Apr 2022 | DOI: 10.1111/ene.15347

SHORT COMMUNICATION

Background and purpose

During the COVID‐19 pandemic, myasthenia gravis (MG) patients have been identified as subjects at high risk of developing severe COVID‐19, and thus were offered vaccination with priority. The lack of direct data on the safety and tolerability of SARS‐CoV‐2 vaccines in MG have contributed to vaccine hesitancy. To address this issue, the safety and tolerability of SARS‐CoV‐2 vaccines were assessed in a large cohort of MG patients from two referral centers.

Methods

Patients with confirmed MG diagnosis, consecutively seen between October and December 2021 at two MG centers, were enrolled. Demographics, clinical characteristics, and information regarding SARS‐CoV‐2 infection/vaccination were extracted from medical reports and/or collected throughout telephonic or in‐person interviews.

Results

Ninety‐eight (94.2%) of 104 patients included were administered at least two vaccine doses 4 weeks before the interview or earlier, and among them, 63 of 98 (64.2%) have already received the “booster” dose. The most frequently used vaccines were BNT162b2‐Pfizer‐BioNTech and mRNA‐1273‐Moderna. Overall, only minor side effects were reported, most commonly local pain and fever. MG worsening after vaccination was observed in eight of 104 (7.7%) cases. The frequency of worsening among muscle‐specific tyrosine kinase MG cases (3/9, 33.3%) was significantly higher compared to other serological subgroups. Spontaneous symptom regression was observed in six of eight cases. Twelve of 104 (11.5%) patients had SARS‐CoV‐2 infection, and none of the SARS‐CoV‐2‐infected MG patients worsened after vaccination.

Conclusions

Our data support the safety and tolerability of mRNA COVID‐19 vaccines, which should be strongly recommended in MG patients, who could be at higher risk of complications if exposed to SARS‐CoV‐2 infection.

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Authors:
Antonio Farina, Silvia Falso, Sara Cornacchini, Gregorio Spagni, Gabriele Monte, Alice Mariottini, Luca Massacesi, Alessandro Barilaro, Amelia Evoli and Valentina Damato
Article first published online:
17 Apr 2022 | DOI: 10.1111/ene.15348

ORIGINAL ARTICLE

Background

The risk of thrombosis increases in infectious diseases, yet observational studies from single centers have shown a decrease in admission of acute ischemic stroke patients during the COVID‐19 pandemic. To investigate unselected stroke admission rates we performed a nationwide study in Denmark.

Methods

We extracted information from Danish national health registries. The following mutually exclusive time periods were compared to the year before the lockdown: (1) first national lockdown, (2) gradual reopening, (3) few restrictions, (4) regional lockdown, and (5) second national lockdown.

Results

Generally, admission rates were unchanged during the pandemic. In the unadjusted data, we observed a small decrease in the admission rate for all strokes under the first lockdown (incidence rate ratio: 0.93, confidence interval [CI]: 0.87–0.99) and a slight increase during the periods with gradual reopening, few restrictions, and the regional lockdown driven by ischemic strokes. We found no change in the rate of severe strokes, mild strokes, or 30‐day mortality. An exception was the higher mortality for all strokes during the first lockdown (risk ratio: crude 1.30 [CI: 1.03–1.59]; adjusted 1.17 [CI: 0.93–1.47]). The quality of care remained unchanged.

Conclusion

Stroke admission rates remained largely unchanged during the pandemic, while an increased short‐term mortality rate in patients admitted with stroke observed during the first lockdown was seen, probably reflecting that the more frail patients constituted a higher proportion of admitted patients at the beginning of the pandemic.

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Authors:
Claus Z. Simonsen, Rolf A. Blauenfeldt, Jakob N. Hedegaard, Christina Kruuse, David Gaist, Troels Wienecke, Boris Modrau, Søren P. Johnsen and Grethe Andersen
Article first published online:
21 Apr 2022 | DOI: 10.1111/ene.15350

ORIGINAL ARTICLE

Background and purpose

The Faroe Islands are a geographically isolated population in the North Atlantic with a similar prevalence of Alzheimer's disease (AD) and all‐cause dementia as other European populations. However, the genetic risk underlying AD and other dementia susceptibility has yet to be elucidated.

Methods

Forty‐nine single‐nucleotide polymorphisms (SNPs) were genotyped in 174 patients with AD and other dementias and 159 healthy controls. Single variant and polygenic risk score (PRS) associations, with/without variability, were assessed by logistic regression. Performance was examined using receiver operating characteristic area under the curve (ROC AUC) analysis.

Results

rs429358 was associated with AD in the Faroese cohort after correction for multiple testing (odds ratio [OR] 6.32, 95% confidence interval [CI] 3.98–10.05,  = 6.31e), with suggestive evidence for three other variants: rs41289512 (OR 2.05, 95% CI 1.20–3.51,  = 0.01), rs6931277 (OR 0.67, 95% CI 0.48–0.94,  = 0.02) and rs7412 [ε2] (OR 0.28, 95% CI 0.11–0.73,  = 0.01). PRSs were associated with AD with or without the inclusion of (PRS OR = 4.5, 95% CI 2.90–5.85,  = 4.56e, and PRS OR = 1.53, 95% CI 1.21–1.98,  = 6.82e). AD ROC AUC analyses demonstrated a PRS AUC = 80.3% and PRS AUC = 63.4%. However, PRS was also significantly associated with all‐cause dementia (OR = 3.39, 95% CI 2.51–4.71,  = 2.50e) with an AUC = 76.9%, that is, all‐cause dementia showed similar results albeit less significant.

Discussion

In the Faroe Islands, SNP analyses highlighted and immunogenomic variability in AD and dementia risk. PRS, based on 25 SNPs/loci, had excellent sensitivity and specificity for AD with an AUC of 80.3%. High PRSs were also associated with an earlier onset of late‐onset AD.

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Authors:
Malan Johansen, Sofus Joensen, Marjun Restorff, Tórmóður Stórá, Darren Christy, Emil K. Gustavsson, Jiang Bian, Yi Guo, Matthew J. Farrer and Maria Skaalum Petersen
Article first published online:
19 Apr 2022 | DOI: 10.1111/ene.15351

CORRIGENDUM

Corrigendum

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Article first published online:
15 Jul 2022 | DOI: 10.1111/ene.15352

ORIGINAL ARTICLE

Background and purpose

No previous study has assessed the frequency and clinical–radiological characteristics of patients with diabetes mellitus (DM) and acute onset nonchoreic and nonballistic movements. We conducted a prospective study to investigate the spectrum of acute onset movement disorders in DM.

Methods

We recruited all the patients with acute onset movement disorders and hyperglycemia who attended the wards of three hospitals in West Bengal, India from August 2014 to July 2021.

Results

Among the 59 patients (mean age = 55.4 ± 14.3 years, 52.5% men) who were included, 41 (69.5%) had choreic or ballistic movements, and 18 (30.5%) had nonchoreic and nonballistic movements. Ballism was the most common movement disorder ( = 18, 30.5%), followed by pure chorea ( = 15, 25.4%), choreoathetosis ( = 8, 13.6%), tremor ( = 5, 8.5%), hemifacial spasm ( = 3, 5.1%), parkinsonism ( = 3, 5.1%), myoclonus ( = 3, 5.1%), dystonia ( = 2, 3.4%), and restless leg syndrome ( = 2, 3.4%). The mean duration of DM was 9.8 ± 11.4 years (89.8% of the patients had type 2 DM). Nonketotic hyperglycemia was frequently (76.3%) detected. The majority (55.9%) had no magnetic resonance imaging (MRI) changes; the remaining showed striatal hyperintensity. Eight patients with MRI changes exhibited discordance with sidedness of movements. Most of the patients (76.3%) recovered completely.

Conclusions

This is the largest clinical series depicting the clinical–radiological spectrum of acute onset movement disorders in DM. Of note was that almost one third of patients had nonchoreic and nonballistic movements. Our findings highlight the importance of a capillary blood glucose measurement in patients with acute or subacute onset movement disorders, irrespective of their past glycemic status.

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Authors:
Souvik Dubey, Subhankar Chatterjee, Ritwik Ghosh, Elan D. Louis, Avijit Hazra, Samya Sengupta, Shambaditya Das, Abhirup Banerjee, Alak Pandit, Biman Kanti Ray and Julián Benito‐León
Article first published online:
28 Apr 2022 | DOI: 10.1111/ene.15353

ORIGINAL ARTICLE

Background and purpose

Advances in medicine have resulted in treatments that can extend the survival of patients with prolonged disorders of consciousness (PDOC) for several years. However, several diagnostic and prognostic uncertainties remain, particularly in the care of pediatric patients. In the absence of international guidelines, we aimed to explore physicians' decision‐making when managing pediatric patients with PDOC.

Methods

We conducted a qualitative study using semistructured, individual interviews and employed an inductive thematic analytical approach to explore physicians' subjective experiences and decision‐making when managing pediatric patients with PDOC. We recruited a purposive sample of 19 Italian‐speaking physicians currently or previously employed in intensive care units or pediatric, internal medicine, or neurology departments in Switzerland.

Results

Participants stated that making clinical decisions involving pediatric patients with PDOC is extremely challenging, because the decisional process requires finding a balance between several contending factors. We found that physicians experienced ambivalence in three domains of care (time, goals of care, and target of care), and that they were aware of the risk of self‐fulfilling prophecies for both prognosis and main clinical outcomes.

Conclusions

Our study confirmed that experienced clinicians acknowledge the complex nature and challenge of clinical decision‐making in the care of pediatric patients with PDOC. More research is warranted to improve and expand existing guidelines aimed at assisting and facilitating clinical and ethical decision‐making, and improving physicians' awareness of the factors affecting their decisions when dealing with patients with PDOC.

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Authors:
Federica Merlo, Roberto Malacrida, Samia Hurst, Claudio L. A. Bassetti, Emiliano Albanese and Marta Fadda
Article first published online:
26 Apr 2022 | DOI: 10.1111/ene.15354

ORIGINAL ARTICLE

Background and purpose

Data regarding the efficacy and safety of currently widely available preventive therapies in neuromyelitis optica spectrum disorder (NMOSD) are needed. We compared the efficacy and safety of azathioprine (AZA), mycophenolate mofetil (MMF), and reduced dose of rituximab (RTX) in NMOSD based on a large multicenter retrospective cohort.

Methods

Patients with aquaporin 4 (AQP4) antibody‐positive NMOSD with AZA ( = 167), MMF ( = 131), or RTX ( = 55) as initial preventive treatment were included. The main outcome was the occurrence of relapse after the initiation of immunotherapy. Secondary outcomes were annual relapse rate, disability accumulation, drug persistence, and adverse events.

Results

The median follow‐up time of the 353 patients was 30.3 months. The regimen of RTX was 100 mg on Day 1 and 500 mg on Day 2, followed by 500 mg every 6 months. The proportions of patients with concomitant steroid therapy at baseline were 96.4%, 95.4%, and 76.4% in the AZA, MMF, and RTX groups. Risk of relapse was significantly reduced in patients treated with RTX compared with those treated with AZA (hazard ratio [HR] = 4.40, 95% confidence interval [CI] = 1.41–13.80,  = 0.011) or MMF (HR = 5.20, 95% CI = 1.60–16.86,  = 0.006) after adjusting for potential confounding variables. Drug discontinuations were less likely on RTX than AZA (HR = 2.22, 95% CI = 1.34–3.66,  = 0.002). RTX exhibited lower incidence of adverse events (32.7%) than AZA (62.3%,  < 0.001).

Conclusions

We provide Class III evidence that reduced dose of RTX is superior to AZA and MMF as initial treatment to reduce the risk of relapse and is better tolerated than AZA in Chinese patients with AQP4 antibody‐positive NMOSD.

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Authors:
Wenjuan Huang, Liang Wang, Junhui Xia, Wenyu Li, Min Wang, Jian Yu, Qinying Li, Bei Wang, Juyuan Pan, Lei Du, Jianhua Ma, Hongmei Tan, Xuechun Chang, Chuanzhen Lu, Chongbo Zhao, Jiahong Lu, Lei Zhou, Jingzi ZhangBao and Chao Quan
Article first published online:
27 Apr 2022 | DOI: 10.1111/ene.15355

ORIGINAL ARTICLE

Background and purpose

It is currently thought that embolic stroke of undetermined source (ESUS) has diverse underlying hidden etiologies, of which cardioembolism is one of the most important. The subgroup of patients with this etiology could theoretically benefit from oral anticoagulation, but it remains unclear if these patients can be correctly identified from other ESUS subgroups and which markers should be used. We aimed to determine whether a machine‐learning (ML) model could discriminate between ESUS patients with cardioembolic and those with non‐cardioembolic profiles using baseline demographic and laboratory variables.

Methods

Based on a prospective registry of consecutive ischemic stroke patients submitted to acute revascularization therapies, an ML model was trained using the age, sex and 11 selected baseline laboratory parameters of patients with known stroke etiology, with the aim of correctly identifying patients with cardioembolic and non‐cardioembolic etiologies. The resulting model was used to classify ESUS patients into those with cardioembolic and those with non‐cardioembolic profiles.

Results

The ML model was able to distinguish patients with known stroke etiology into cardioembolic or non‐cardioembolic profile groups with excellent accuracy (area under the curve = 0.82). When applied to ESUS patients, the model classified 40.3% as having cardioembolic profiles. ESUS patients with cardioembolic profiles were older, more frequently female, more frequently had hypertension, less frequently were active smokers, had higher CHADS‐VASc (Congestive heart failure or left ventricular systolic dysfunction, Hypertension, Age ≥ 75 [doubled], Diabetes, Stroke/transient ischemic attack [doubled], Vascular disease, Age 65–74, and Sex category) scores, and had more premature atrial complexes per hour.

Conclusions

An ML model based on baseline demographic and laboratory variables was able to classify ESUS patients into cardioembolic or non‐cardioembolic profile groups and predicted that 40% of the ESUS patients had a cardioembolic profile.

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Authors:
Max Christian Martin, Thorsten Sichtermann, Kolja Schürmann, Pardes Habib, Martin Wiesmann, Jörg B. Schulz, Omid Nikoubashman, João Pinho and Arno Reich
Article first published online:
25 Apr 2022 | DOI: 10.1111/ene.15356

ORIGINAL ARTICLE

Background and purpose

Progression rate is quite variable in amyotrophic lateral sclerosis (ALS); thus, tools for profiling disease progression are essential for timely interventions. The objective was to apply dynamic Bayesian networks (DBNs) to establish the influence of clinical and demographic variables on disease progression rate.

Methods

In all, 664 ALS patients from our database were included stratified into slow (SP), average (AP) and fast (FP) progressors, according to the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS‐R) rate of decay. The sdtDBN framework was used, a machine learning model which learnt optimal DBNs with both static (gender, age at onset, onset region, body mass index, disease duration at entry, familial history, revised El Escorial criteria and ) and dynamic (ALSFRS‐R scores and sub‐scores, forced vital capacity, maximum inspiratory pressure, maximum expiratory pressure and phrenic amplitude) variables.

Results

Disease duration and body mass index at diagnosis are the foremost influences amongst static variables. Disease duration is the variable that better discriminates the three groups. Maximum expiratory pressure is the respiratory test with prevalent influence on all groups. ALSFRS score has a higher influence on FP, but lower on AP and SP. The bulbar sub‐score has considerable influence on FP but limited on SP. Limb function has a more decisive influence on AP and SP. The respiratory sub‐score has little influence in all groups. ALSFRS‐R questions 1 (speech) and 9 (climbing stairs) are the most influential in FP and SP, respectively.

Conclusions

The sdtDBN analysis identified five variables, easily obtained during clinical evaluation, which are the most influential for each progression group. This insightful information may help to improve prognosis and care.

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Authors:
Marta Gromicho, Tiago Leão, Miguel Oliveira Santos, Susana Pinto, Alexandra M. Carvalho, Sara C. Madeira and Mamede De Carvalho
Article first published online:
29 Apr 2022 | DOI: 10.1111/ene.15357

CASE REPORT

Background and purpose

Coronavirus disease 2019 (COVID‐19) is now known to cause neurological complications in both the central and the peripheral nervous system. Two new cases of typical neuralgic amyotrophy or Parsonage–Turner (PT) syndrome following coronavirus 2 infection (SARS‐CoV‐2) are reported here with explicit electrophysiological and imaging pathological features, underlining the possible association between COVID‐19 and PT syndrome.

Case reports

Case 1 was a 45‐year‐old schoolteacher presenting with acute pain in the right shoulder a few days after SARS‐CoV‐2 infection, with shoulder abduction and elbow flexion weakness. Needle electromyography showed a decrease in motor unit recruitment in the biceps brachii, and plexus magnetic resonance imaging (MRI) revealed a hyperintense signal involving the right C6 root and the superior truncus of the brachial plexus. Case 2 was a 21‐year‐old man hospitalized for dyspnea secondary to SARS‐CoV‐2 infection. Ten days after symptom onset, he presented right shoulder pain with difficulty in raising his right arm, revealing an isolated deficit of the serratus major muscle with a right scapula winging. Electrophysiological evaluation exhibited an isolated involvement of the long thoracic nerve with a neurogenic recruitment pattern in the serratus major muscle. Plexus MRI displayed a thickening and hyperintense signal involving the right long thoracic nerve.

Discussion

Parsonage–Turner syndrome triggered by SARS‐CoV‐2 seems to present clinical, electrophysiological and MRI characteristics similar to classic para‐infectious PT syndrome, including the time frame between viral infection and neurological symptom onset.

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Authors:
Etienne Fortanier, Thomas Le Corroller, Marie Hocquart, Emilien Delmont and Shahram Attarian
Article first published online:
15 Jul 2022 | DOI: 10.1111/ene.15358

ORIGINAL ARTICLE

Background and purpose

This study was undertaken to investigate short‐ and long‐term outcome following thymectomy in patients with acetylcholine receptor antibody (AChR‐Ab)‐positive myasthenia gravis (MG).

Methods

Rates of clinical response (defined as minimal manifestation, pharmacological remission, or complete stable remission) lasting for at least 1 year were retrospectively analyzed using Cox proportional hazard models. The occurrence of relapses was recorded during follow‐up. Clinical factors associated with achieving an initial or a sustained response were analyzed.

Results

Ninety‐four patients with a median age of 33 years (interquartile range [IQR] = 22–51), 68% with nonthymomatous MG and 32% with thymoma‐associated MG, were included. An initial clinical response was reached in 72% (68/94). Neither sex, age at onset, thymus histology, delay to surgery after disease onset, surgical approach, corticosteroid treatment, nor clinical severity before thymectomy was significantly associated with achieving this endpoint. During long‐term follow‐up (median = 89.5 months, IQR = 46–189.5), only half of the patients with an initial response (34/68) had a sustained response without relapses. No clinical factors predicted whether the response would become sustained. In patients without immunosuppressive treatment before thymectomy ( = 24), a high AChR‐Ab reduction rate after thymectomy was associated with a higher likelihood of achieving an initial response ( = 0.03).

Conclusions

Sustained long‐term clinical response of MG patients after thymectomy is significantly lower than the initial response rates would suggest. The observation that none of the evaluated clinical factors was associated with a worse outcome supports the current clinical practice of patient selection for thymectomy. The relative decline of AChR‐Abs after surgery appears to be a promising prognostic marker.

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Authors:
Jakob Rath, Manuela Taborsky, Bernhard Moser, Gudrun Zulehner, Rosa Weng, Martin Krenn, Hakan Cetin, José Ramon Matilla, Leonhard Müllauer and Fritz Zimprich
Article first published online:
30 Apr 2022 | DOI: 10.1111/ene.15362

REVIEW ARTICLE

Background and purpose

The aim was to investigate whether cerebral small vessel disease (CSVD) markers and the total CSVD burden are associated with functional outcome, mortality, stroke recurrence and haematoma expansion in patients with spontaneous intracerebral haemorrhage (ICH).

Methods

Following a previously registered protocol (PROSPERO protocol: CRD42021287743), PubMed, Web of Science and Embase were systematically searched to identify relevant literature up to November 2021. Cohort studies that examined the association between CSVD markers (white matter hyperintensity [WMH], lacune, enlarged perivascular space [EPVS], cerebral microbleed [CMB] and brain atrophy) or CSVD burden and prognosis in patients with ICH were included. The pooled estimates were calculated using random effects models.

Results

Forty‐one studies with 19,752 ICH patients were pooled in the meta‐analysis. WMH (odds ratio [OR] 1.50, 95% confidence interval [CI] 1.32–1.70), lacune (OR = 1.32, 95% CI 1.18–1.49), CMB (OR = 2.60, 95% CI 1.13–5.97) and brain atrophy (OR = 2.22, 95% CI 1.48–3.31) were associated with worse functional outcome. CSVD markers concerning increased risk of mortality were WMH (OR = 1.57, 95% CI 1.38–1.79) and brain atrophy (OR = 1.84, 95% CI 1.11–3.04), and markers concerning increased risk of stroke recurrence were WMH (OR = 1.62, 95% CI 1.28–2.04) and lacune (OR = 3.00, 95% CI 1.68–5.37). Enlarged perivascular space was not related to prognosis. There was a lack of association between CSVD markers and haematoma expansion. CSVD burden increased the risk of worse functional outcome, mortality and stroke recurrence by 57%, 150% and 44%, respectively.

Conclusions

In patients with spontaneous ICH, WMH, lacune, CMB, brain atrophy and the total CSVD burden are associated with substantially increased risk of worse functional outcome, mortality or stroke recurrence.

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Authors:
Zicheng Cheng, Wenyuan Zhang, Zhenxiang Zhan, Lingfan Xia and Zhao Han
Article first published online:
01 May 2022 | DOI: 10.1111/ene.15363

ORIGINAL ARTICLE

Background and purpose

Chronic migraine is a highly disabling primary headache disorder that is the most common diagnosis of patients seen at tertiary headache centres. Typical oral preventive therapies are associated with many limitations that impact their therapeutic utility. Erenumab was the first available calcitonin gene‐related peptide monoclonal antibody in the UK. It had proven efficacy in migraine prevention in clinical trials and limited real‐world data in tertiary settings.

Methods

We audited our first 92 patients ( = 73 females) with severely disabling chronic migraine who were given monthly erenumab 70 mg sc for 6 months between December 2018 and December 2019.

Results

At 3 months, monthly migraine days were significantly reduced by a median of 4 days, and all other variables also showed significant improvement. The improvement was not affected by baseline analgesic use status. More than half of our patients experienced a clinically meaningful improvement in migraine days. No serious adverse events were reported.

Conclusions

Our real‐world data with erenumab demonstrate it is effective and well tolerated in managing patients with chronic migraine in a tertiary care setting.

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Authors:
Modar Khalil, David Moreno‐Ajona, María Dolores Villar‐Martínez, Fiona Greenwood, Jan Hoffmann and Peter J. Goadsby
Article first published online:
09 May 2022 | DOI: 10.1111/ene.15364

SHORT COMMUNICATION

Background and purpose

Central nervous system (CNS) B‐cell lymphoma‐mimicking demyelinating diseases creates a diagnostic dilemma. This study aimed to determine the specific magnetic resonance imaging (MRI) features of CNS B‐cell lymphoma to facilitate the early identification of the disease.

Methods

We retrospectively reviewed the brain MRI of biopsy‐confirmed CNS B‐cell lymphoma patients. They were initially diagnosed with CNS demyelination, and these images were compared with those of actual patients with demyelinating diseases.

Results

A total of 20 patients with CNS B‐cell lymphoma and 12 patients with demyelination were included in this study. Cohesive enhancement with satellite enhancing foci surrounded by prominent non‐enhancing areas of oedema is the major contrast‐enhancing pattern of lymphoma patients, accounting for 81% (13) of patients with primary diffuse large B‐cell lymphoma (DLBCL). This imaging pattern revealed a sensitivity of 81% and a specificity of 75% for lymphoma in the differential diagnosis between primary DLBCL and demyelinating disease in our cohort. Among these lesions, most of the nodules were located deeply, which yielded a specificity of 100% and a sensitivity of 69% for primary DLBCL. Enhancement in a single pattern (mainly ring‐like, patchy or punctate; 57%) and no enhancement (30%) were commonly observed in demyelinating lesions, distinct from primary DLBCL (< 0.05).

Conclusions

Lesions with cohesive enhancement and satellite foci on T1 contrast‐enhanced imaging could be a specific hallmark of CNS B‐cell lymphoma, suggesting the need to withdraw steroidal therapy and biopsy confirmation.

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Authors:
Xiaoyu Ma, Zhuoxin Guo, Zhenchao Huang, Dayang Hui, Yuxin Liu, Yuxuan Jiang, Zhengqi Lu, Wei Qiu, Tingting Lu and Feng Qin
Article first published online:
04 May 2022 | DOI: 10.1111/ene.15365

ORIGINAL ARTICLE

Background and purpose

Despite the rapid increase in research examining outcomes in autoimmune encephalitis (AE) patients, there are few cohort studies examining cognitive outcomes in this population. The current study aimed to characterise psychometric outcomes in this population, and explore variables that may predict psychometric outcomes.

Methods

This retrospective observational study collected psychometric data from 59 patients across six secondary and tertiary referral centres in metropolitan hospitals in Victoria, Australia between January 2008 and July 2019. Frequency and pattern analysis were employed to define and characterize psychometric outcomes. Univariable logistic regression was performed to examine predictors of intact and pathological psychometric outcomes.

Results

Deficits in psychometric markers of executive dysfunction were the most common finding in this cohort, followed by deficits on tasks sensitive to memory. A total of 54.2% of patients were classified as having psychometric impairments across at least two cognitive domains. Twenty‐nine patterns were observed, suggesting outcomes in AE are complex. None of the demographic data, clinical features or auxiliary examination variables were predictors of psychometric outcome.

Conclusions

Cognitive outcomes in AE are complex. Further detailed and standardized cognitive testing, in combination with magnetic resonance imaging volumetrics and serum/cerebrospinal fluid biomarkers, is required to provide rigorous assessments of disease outcomes.

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Authors:
Sarah Griffith, Robb Wesselingh, James Broadley, Marie O'Shea, Chris Kyndt, Catherine Meade, Brian Long, Udaya Seneviratne, Natalie Reidy, Robert Bourke, Katherine Buzzard, Wendyl D'Souza, Richard Macdonell, Amy Brodtmann, Helmut Butzkueven, Terence J. O'Brien, Rubina Alpitsis, Charles B. Malpas and Mastura Monif
Article first published online:
20 May 2022 | DOI: 10.1111/ene.15367

POSITION PAPER

Background and purpose

Health risks associated with SARS‐CoV‐2 infection are undisputed. Moreover, the capability of vaccination to prevent symptomatic, severe, and fatal COVID‐19 is recognized. There is also early evidence that vaccination can reduce the chance for long COVID‐19. Nonetheless, the willingness to get vaccinated and receive booster shots remains subpar among people with neurologic disorders. Vaccine scepticism not only jeopardizes collective efforts to end the COVID‐19 pandemic but puts individual lives at risk, as some chronic neurologic diseases are associated with a higher risk for an unfavorable COVID‐19 course.

Methods

In this position paper, the NeuroCOVID‐19 Task Force of the European Academy of Neurology (EAN) summarizes the current knowledge on the prognosis of COVID‐19 among patients with neurologic disease, elucidates potential barriers to vaccination coverage, and formulates strategies to overcome vaccination hesitancy. A survey among the Task Force members on the phenomenon of vaccination hesitancy among people with neurologic disease supports the lines of argumentation.

Results

The study revealed that people with multiple sclerosis and other nervous system autoimmune disorders are most skeptical of SARS‐CoV‐2 vaccination. The prevailing concerns included the chance of worsening the pre‐existing neurological condition, vaccination‐related adverse events, and drug interaction.

Conclusions

The EAN NeuroCOVID‐19 Task Force reinforces the key role of neurologists as advocates of COVID‐19 vaccination. Neurologists need to argue in the interest of their patients about the overwhelming individual and global benefits of COVID‐19 vaccination. Moreover, they need to keep on eye on this vulnerable patient group, its concerns, and the emergence of potential safety signals.

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Authors:
Martin Rakusa, Serefnur Öztürk, Elena Moro, Raimund Helbok, Claudio L. Bassetti, Ettore Beghi, Daniel Bereczki, Benedetta Bodini, Giovanni Di Liberto, Thomas M. Jenkins, Antonella Macerollo, Luis F. Maia, Filippo Martinelli‐Boneschi, Antonio Pisani, Alberto Priori, Anna Sauerbier, Riccardo Soffietti, Pille Taba, Tim J. von Oertzen, Marialuisa Zedde, Michael Crean, Anja Burlica, Francesco Cavallieri and Johann Sellner
Article first published online:
10 May 2022 | DOI: 10.1111/ene.15368

ORIGINAL ARTICLE

Background and purpose

Andersen–Tawil syndrome (ATS) is a skeletal muscle channelopathy caused by mutations, characterized by a clinical triad of periodic paralysis, cardiac arrhythmias and dysmorphism. The muscle phenotype, particularly the atypical forms with prominent permanent weakness or predominantly painful symptoms, remains incompletely characterized.

Methods

A retrospective clinical, histological, electroneuromyography (ENMG) and genetic analysis of molecularly confirmed ATS patients, diagnosed and followed up at neuromuscular reference centers in France, was conducted.

Results

Thirty‐five patients from 27 unrelated families carrying 17 different missense mutations (four novel mutations) and a heterozygous duplication are reported. The typical triad was observed in 42.9% of patients. Cardiac abnormalities were observed in 65.7%: 56.5% asymptomatic and 39.1% requiring antiarrhythmic drugs. 71.4% of patients exhibited dysmorphic features. Muscle symptoms were reported in 85.7%, amongst whom 13.3% had no cardiopathy and 33.3% no dysmorphic features. Periodic paralysis was present in 80% and was significantly more frequent in men. Common triggers were exercise, immobility and carbohydrate‐rich diet. Ictal serum potassium concentrations were low in 53.6%. Of the 35 patients, 45.7% had permanent weakness affecting proximal muscles, which was mild and stable or slowly progressive over several decades. Four patients presented with exercise‐induced pain and myalgia attacks. Diagnostic delay was 14.4 ± 9.5 years. ENMG long‐exercise test performed in 25 patients (71.4%) showed in all a decremental response up to 40%. Muscle biopsy performed in 12 patients revealed tubular aggregates in six patients (associated in two of them with vacuolar lesions), dystrophic features in one patient and non‐specific myopathic features in one patient; it was normal in four patients.

Discussion

Recognition of atypical features (exercise‐induced pain or myalgia and permanent weakness) along with any of the elements of the triad should arouse suspicion. The ENMG long‐exercise test has a high diagnostic yield and should be performed. Early diagnosis is of utmost importance to improve disease prognosis.

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Authors:
Rocio Nur Villar‐Quiles, Damien Sternberg, Grégoire Tredez, Norma Beatriz Romero, Teresinha Evangelista, Pascal Lafôret, Pascal Cintas, Guilhem Sole, Sabrina Sacconi, Said Bendahhou, Jérôme Franques, Claude Cances, JB Noury, Emilien Delmont, Patricia Blondy, Laurence Perrin, Marianne Hezode, Emmanuel Fournier, Bertrand Fontaine, Tanya Stojkovic and Savine Vicart
Article first published online:
04 May 2022 | DOI: 10.1111/ene.15369

ORIGINAL ARTICLE

Background and purpose

Although several case series have described nitrous‐oxide‐associated neurological disorders, a comprehensive assessment of exposure characteristics (e.g., time to onset, level of exposure) in substance abusers has not been performed. The aim of this study was to describe the onset patterns of recreational use of nitrous‐oxide‐induced neurological disorders.

Methods

All cases of neurological disorders related to nitrous oxide recreational use reported to the Hauts‐de‐France addictovigilance center between January 2019 and August 2020 were selected. Only cases requiring hospitalization with informative data to perform the nitrous oxide causality assessment were included.

Results

A total of 20 cases from five hospitals were included. The male‐to‐female ratio was 6:1 and the median age was 19 years (range 16–34). The neurological presentation (myeloneuropathy 64%, 7/11; sensorimotor neuropathy 36%, 4/11) included for all patients gait disorders due to proprioceptive ataxia and limb hypoesthesia. The median dose used per occasion was 100 cartridges (range 5–960;  = 19). The median time from the start of nitrous oxide use to the onset of neurological symptoms was 6 months (range 0.7–54;  = 16). The cumulative dose was significantly higher in patients with damage to all four limbs than in patients with lower limb symptoms only ( = 0.042).

Conclusions

A low intermittent exposure may be sufficient to cause neurological damage in some subjects, suggesting that, at the population level, there is no safe exposure to nitrous oxide in recreational settings. The severity of neurological impairment could increase once used at high doses and for prolonged durations of nitrous oxide.

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Authors:
Bérenger Largeau, Arnaud Karam, Camille Potey, Anne‐Sylvie Caous, Céline Tard, Louise Carton, Grégory Kuchcinski, Sophie Gautier, Sylvie Deheul and Régis Bordet
Article first published online:
27 May 2022 | DOI: 10.1111/ene.15370

REVIEW ARTICLE

Background and purpose

With the progression of coronavirus infectious disease 2019 (COVID‐19), various neurological manifestations have been noticed in infected patients, and Bell's Palsy (BP) is one of the peripheral neuropathies among those. BP has been associated with various other viral agents. Its evidence in patients with COVID‐19 signifies the possibility of association between BP and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). This research was undertaken to evaluate the number of published cases of BP as the only major neurological manifestation in patients with COVID‐19 from March 2020 to December 2021 and to investigate the association of SARS‐CoV‐2 and BP.

Methods

A systematic review of the published English literature was performed using an electronic search in the PubMed/Medline, Scopus, Research Gate, Research Square, and Google Scholar databases, using keywords such as "COVID‐19" OR/AND "SARS‐CoV‐2" OR/AND "Bell's palsy" OR/AND "facial nerve palsy" OR/AND "neurological" OR/AND "manifestation".

Results

The search strategy revealed 32 relevant publications with a total of 46 patients. BP was the initial manifestation in 37% of cases, and in 63% of cases it developed after COVID‐19 symptoms; 71.7% of cases showed complete recovery, and 21.7% showed only partial relief from BP.

Conclusions

Although the number of documented cases in this research is low, evidence of BP as the only major neurological manifestation in patients with COVID‐19 signifies an important clinical finding and the possibility of another viral etiology of BP. More evidence is needed to establish the exact correlation between these two entities.

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Authors:
Sonia Gupta and Manveen Kaur Jawanda
Article first published online:
19 May 2022 | DOI: 10.1111/ene.15371

ORIGINAL ARTICLE

Background and purpose

Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.

Methods

To evaluate total tau (t‐tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and neurofilament light‐chain (NfL) as fluid biomarkers in SCA3, mutation carriers ( = 143) and controls ( = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD‐1 platform. Eleven mutation carrier cerebrospinal fluid samples were analysed for t‐tau and phosphorylated tau (p‐tau). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t‐tau levels.

Results

Plasma t‐tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non‐Ataxia Signs was associated with t‐tau in ataxic patients (= 0.004). Pre‐ataxic carriers showed higher cerebrospinal fluid t‐tau and p‐tau concentrations compared to ataxic patients (= 0.025 and = 0.014, respectively). Cerebellar t‐tau was elevated in MJDTg mice compared to wild‐type (= 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (< 0.001).

Conclusion

Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.

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Authors:
Hector Garcia‐Moreno, Mercedes Prudencio, Gilbert Thomas‐Black, Nita Solanky, Karen R. Jansen‐West, Rana Hanna AL‐Shaikh, Amanda Heslegrave, Henrik Zetterberg, Magda M. Santana, Luis Pereira de Almeida, Ana Vasconcelos‐Ferreira, Cristina Januário, Jon Infante, Jennifer Faber, Thomas Klockgether, Kathrin Reetz, Mafalda Raposo, Ana F. Ferreira, Manuela Lima, Ludger Schöls, Matthis Synofzik, Jeannette Hübener‐Schmid, Andreas Puschmann, Sorina Gorcenco, Zbigniew K. Wszolek, Leonard Petrucelli and Paola Giunti
Article first published online:
26 May 2022 | DOI: 10.1111/ene.15373

ORIGINAL ARTICLE

Background and purpose

Hypoperfusion, vascular pathology, and cardiovascular risk factors are associated with disease severity in multiple sclerosis (MS). We aimed to assess relationships between cerebral arterial blood flow (CABF) and serum neurofilament light chain (sNfL) as neuronal damage biomarkers.

Methods and Materials

Total CABF was measured in 137 patients (86 with clinically isolated syndrome/relapsing‐remitting (RR) MS and 51 with progressive MS [PMS]) and 48 healthy controls using Doppler ultrasonography. sNfL was quantitated using a single‐molecule assay (Simoa). Examination using 3.0‐T magnetic resonance imaging (MRI) allowed quantification of T2 lesions and whole‐brain volume (WBV). Multiple linear regression models determined the sNfL association with CABF after correction for demographic and MRI‐derived variables.

Results

After adjustment for age, sex and body mass index (BMI), total CABF remained statistically significant and model comparisons showed that CABF explained an additional 2.6% of the sNfL variance (β = −0.167,  = 0.044). CABF also remained significant in a stepwise regression model (β = 0.18,  = 0.034) upon the inclusion of T2 lesion burden and WBV effects. Patients in the lowest CABF quartile (CABF ≤ 761 ml/min) had significantly higher sNfL levels (34.6 vs. 23.9 pg/ml, age and BMI‐adjusted‐ = 0.042) when compared to the highest quartile (CABF ≥ 1130 ml/min).

Conclusion

Lower CABF is associated with increased sNfL in MS patients, highlighting the relationship between cerebral hypoperfusion and axonal pathology.

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Authors:
Dejan Jakimovski, Brianna L. Gibney, Karen Marr, Deepa P. Ramasamy, Michael G. Dwyer, Niels Bergsland, Bianca Weinstock‐Guttman, Murali Ramanathan and Robert Zivadinov
Article first published online:
06 May 2022 | DOI: 10.1111/ene.15374

ORIGINAL ARTICLE

Background and purpose

This study was undertaken to investigate the association between human leukocyte antigen (HLA) genotype and clinical characteristics of anti‐LGI1 encephalitis.

Methods

HLA genotyping was performed in 34 patients with anti‐LGI1 encephalitis admitted to West China Hospital between April 2014 and May 2021, as well as in 305 healthy controls. The online tool NetMHCIIpan 4.0 and AutoDock Vina software were used to predict binding between LGI1 peptide and HLA class II molecules.

Results

Risk of anti‐LGI1 encephalitis was strongly associated with the DRB1*03:01 allele (odds ratio [OR] = 4.31, 95% confidence interval [CI] = 1.96–9.25, corrected  = 2.75 × 10) and the DRB1*03:01‐DQB1*02:01 haplotype (OR = 4.45, 95% CI = 2.02–9.59, corrected  = 2.94 × 10). Compared to carriers of the DRB1*07:01 allele, those with the DRB1*03:01 allele were more likely to be female (93.3% vs. 33.3%,  = 0.004) and to be younger (median age = 38 vs. 65 years,  < 0.001). DRB1*03:01 carriers showed stronger response to immunotherapy than carriers of the DRB1*07:01 allele, based on median score decrease on the modified Rankin scale (2, interquartile range = 1–2 vs. 1, interquartile range = 0–1;  = 0.03) at 4 weeks after immunotherapy. Prediction and docking algorithms suggested that the LGI1 peptide can bind to the DRB1*03:01 molecule strongly.

Conclusions

The strong association between anti‐LGI1 encephalitis and certain HLA class II alleles supports a primary autoimmune origin for the disease. Carriers of the DRB1*03:01 allele in Chinese patients with anti‐LGI1 encephalitis are more likely to be female, to suffer earlier disease onset, and to respond better to immunotherapy.

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Authors:
Xu Liu, Kun Dian Guo, Jingfang Lin, Xue Gong, Ai Qing Li, Dong Zhou and Zhen Hong
Article first published online:
10 May 2022 | DOI: 10.1111/ene.15376

ORIGINAL ARTICLE

Background

Non‐alcoholic fatty liver disease and particularly liver fibrosis are related to cardiovascular disease and may indicate an increased risk for atrial fibrillation (AF), but this association has not yet been systematically investigated in a cohort of ischemic stroke patients.

Methods

We analyzed data from a prospective single‐center study enrolling all consecutive ischemic stroke patients admitted to our stroke unit over a 1‐year period. All patients received a thorough etiological workup. For evaluation of liver fibrosis, we determined the Fibrosis‐4 (FIB‐4) index, a well‐established noninvasive liver fibrosis test. Laboratory results were analyzed from a uniform blood sample taken at stroke unit admission.

Results

Of 414 included patients (mean age 70.2 years, 57.7% male), FIB‐4 indicated advanced liver fibrosis in 92 (22.2%). AF as the underlying stroke mechanism was present in 28.0% (large vessel disease: 25.6%, small vessel disease: 11.4%, cryptogenic: 29.2%). Patients with FIB‐4 ≥ 2.67 had higher rates of AF (53.3% vs. 20.8%,  < 0.001), and this association remained significant after correction for established AF risk factors (odds ratio 2.53, 95% confidence interval 1.44–4.46,  = 0.001). FIB‐4 was further associated with worse functional outcome 3 months ( < 0.001) and higher mortality 4 years post‐stroke ( < 0.02), but these relationships were no longer present after correction for age and initial stroke severity. Moreover, FIB‐4 was not associated with long‐term recurrent vascular events.

Conclusions

Liver fibrosis assessed by the FIB‐4 index is independently associated with AF in acute ischemic stroke patients. Further studies should evaluate whether adding the FIB‐4 index to AF risk scores increases their precision.

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Authors:
Simon Fandler‐Höfler, Markus Kneihsl, Rudolf E. Stauber, Egbert Bisping, Harald Mangge, Gerit Wünsch, Melanie Haidegger, Linda Fabisch, Isra Hatab, Peter Fickert, David Werring, Christian Enzinger and Thomas Gattringer
Article first published online:
24 May 2022 | DOI: 10.1111/ene.15377

ORIGINAL ARTICLE

Background and purpose

Whilst retinal microvasculature represents cerebral small vessels, the retinal nerve fiber layer is the extended white matter of the brain. The aim was to investigate the correlation between changes in retina and white matter hyperintensities (WMHs).

Methods

Sixty‐four candidates with WMHs received an optical coherence tomography angiography examination. WMHs were divided into mild or moderate/severe groups according to the Fazekas score. After imaging the superficial capillary plexus (SCP) and deep capillary plexus (DCP), the microvascular density parameters (vascular perfusion density [VPD], vascular length density [VLD] and fovea avascular zone area) and morphological parameters (vessel diameter index [VDI], fractal dimension [FD] and vessel tortuosity) were identified. A software algorithm measured the thickness of the peripapillary retina nerve fiber layer (PRNFL).

Results

Thirty‐two were classified as having mild WMHs and 32 were moderate/severe. The median (interquartile range) ages of the two groups were 58 (54–64) and 61 (57–67) years, respectively. A decrease of FD, VPD and VLD in either SCP or DCP appeared with an increased risk of moderate/severe WMHs. Although changes of capillary plexus were not associated with paraventricular WMHs, decreased FD, VPD, VLD and fovea avascular zone area in either SCP or DCP were associated with an increased risk of moderate/severe deep WMHs (DWMHs). Participants with moderate/severe WMHs demonstrated reduced PRNFL thickness, particularly in the DWMHs, compared with mild WMHs.

Conclusions

Abnormalities of retinal microvascular density, morphological parameters and PRNFL thickness are correlated with the incidence of moderate/severe WMHs, particularly the DWMHs, suggesting that arteriosclerosis and hypoperfusion are the causes of DWMHs.

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Authors:
Xirui Zhou, Tao Li, Wensheng Qu, Dengji Pan, Qianwen Qiu, Lingshan Wu, Jing Zhao, Zhiyuan Yu, Huang Hao and Xiang Luo
Article first published online:
16 May 2022 | DOI: 10.1111/ene.15378

ORIGINAL ARTICLE

Background

Heidenhain variant of Creutzfeldt–Jakob disease (CJD) remains a diagnostic challenge in clinical practice. We aimed to describe the clinical and prognostic features of Heidenhain cases, through a case series study.

Methods

We retrospectively reviewed the definite or probable CJD cases admitted to two tertiary referral university hospitals over a decade to identify Heidenhain cases and investigated their survival status by telephone follow‐up. Their clinical characteristics, neuroimaging features, electroencephalography (EEG) results, cerebrospinal fluid profiles, and gene mutations were also analyzed.

Results

Of a total of 85 CJD cases, 20 (24%) Heidenhain cases (11 women [55%]; median age, 64 years [range, 44–72 years]) were identified. The median survival time was 22 weeks (range, 5–155 weeks). The median duration of isolated visual symptoms was 3 weeks (range, 1–12 weeks). The most common early visual symptom was blurred vision (16/20, 80%), followed by diplopia (6/20, 30%). The prevalence significantly increased for complex visual hallucination (= 0.005) and cortical blindness (= 0.046) as the disease progressed. The positive rate of serial magnetic resonance images (20/20, 100%) was higher than that of serial EEGs (16/20, 80%). Two patients (2/10, 20%) had pathogenic mutations, E196A and T188K, respectively. Heidenhain cases with mutations had significantly longer survival time than those without mutations (= 0.047).

Conclusions

Besides blurred vision (80%), diplopia (30%) was also a frequent early visual symptom among Heidenhain cases. Heidenhain phenotype can occur in genetic CJD cases. mutation status might be an important prognostic factor for Heidenhain cases.

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Authors:
Shi‐Lin Yang, Lin‐Yuan Zhang, Shu‐Fan Zhang, Miao‐Yi Zhang, Ming Zhu, Qiang Dong, Qiao‐Shu Wang and Xiang Han
Article first published online:
17 May 2022 | DOI: 10.1111/ene.15380

ORIGINAL ARTICLE

Background and purpose

The antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 () messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator‐free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients.

Methods

Thirty‐four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively.

Results

Lower baseline levels of two muscle microRNAs (miR‐206 and miR‐133a‐3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR‐206 levels were inversely correlated with the HFMSE score.

Conclusions

Lower miR‐206 and miR‐133a‐3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long‐term benefit.

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Authors:
Iddo Magen, Sharon Aharoni, Nancy Sarah Yacovzada, Itay Tokatly Latzer, Christiano R. R. Alves, Liora Sagi, Aviva Fattal‐Valevski, Kathryn J. Swoboda, Jacob Katz, Elchanan Bruckheimer, Yoram Nevo and Eran Hornstein
Article first published online:
07 Jun 2022 | DOI: 10.1111/ene.15382

ORIGINAL ARTICLE

Background and purpose

Faciobrachial dystonic seizures (FBDS) and hyponatremia are the distinct clinical features of autoimmune encephalitis (AE) caused by antibodies against leucine‐rich glioma‐inactivated 1 (LGI1). The present study aims to explore the pathophysiological patterns and neural mechanisms underlying these symptoms.

Methods

We included 30 patients with anti‐LGI1 AE and 30 controls from a retrospective observational cohort. Whole‐brain metabolic pattern analysis was performed to assess the pathological network of anti‐LGI1 AE, as well as the symptom networks associated with FBDS. Logistic regression was applied to explore independent predictors of FBDS. Finally, we used a multiple regression model to investigate the hyponatremia‐associated brain network and its effect on serum sodium levels.

Results

The pathological network of anti‐LGI1 AE involved hypermetabolism in the cerebellum, subcortical structures and Rolandic area, as well as hypometabolism in the medial prefrontal cortex. The symptom network of FBDS included hypometabolism in the cerebellum and Rolandic area ( <0.05). Hypometabolism in the cerebellum was an independent predictor of FBDS ( < 0.001). Hyponatremia‐associated network highlighted a negative effect on the caudate nucleus, frontal and temporal white matter. The metabolism of the hypothalamus was negatively associated with (Pearson's = −0.180, = 0.342), while not the independent predictor for serum sodium level (path = −7.238, 95% confidence interval = −30.947 to 16.472).

Conclusions

Our results provide insights into the whole‐brain metabolic patterns of patients with anti‐LGI1 AE, including the symptom network associated with FBDS and the hyponatremia‐associated brain network. The findings help us to understand the neural mechanisms underlying anti‐LGI1 AE and to evaluate the progress of this disease.

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Authors:
Jiajie Mo, Wenyu Dong, Tao Cui, Chao Chen, Weixiong Shi, Wenhan Hu, Chao Zhang, Xiu Wang, Kai Zhang and Xiaoqiu Shao
Article first published online:
29 May 2022 | DOI: 10.1111/ene.15384

ORIGINAL ARTICLE

Background

Huntington's disease (HD) is a rare neurodegenerative disease that presents with progressive psychological, cognitive and motor impairment. These diverse symptoms place a high burden on the patient, families and the healthcare systems they rely on. This study aimed to describe the epidemiology and clinical burden in individuals with HD compared with controls from the general population.

Methods

This cohort study utilised data from general practitioner medical records to estimate the prevalence and incidence of HD between January 2000 and December 2018. A cohort of incident HD cases were matched 1:3 to controls from the general population, in whom common clinical diagnoses, medications and healthcare interventions were compared at the time of first recorded diagnosis and at a time close to death. Incidence rates of common diagnoses and mortality were compared with matched controls in the time following HD diagnosis.

Results

Prevalence of HD increased between 2000 and 2018, whilst incidence remained stable. Prevalence of psychiatric diagnoses and symptomatic treatments were higher in HD cases than controls. A higher relative risk of psychotic disorders, depression, insomnia, dementia, weight loss, pneumonia and falls was observed in HD cases. Risk of death was >4 times higher in HD, with a median survival of ~12 years from first recorded diagnosis.

Conclusions

This study demonstrates the significant and progressive clinical burden in individuals with HD up to 18 years after first recorded diagnosis.

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Authors:
Hannah Furby, Athanasios Siadimas, Loes Rutten‐Jacobs, Filipe B. Rodrigues and Edward J. Wild
Article first published online:
27 May 2022 | DOI: 10.1111/ene.15385

ORIGINAL ARTICLE

Background and purpose

Cerebrospinal fluid (CSF) real‐time quaking‐induced conversion (RT‐QuIC) has a high degree of sensitivity and specificity for the diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) and this has led to its being included in revised European CJD Surveillance Network diagnostic criteria for sCJD. As CSF RT‐QuIC becomes more widely established, it is crucial that the analytical performance of individual laboratories is consistent. The aim of this ring‐trial was to ascertain the degree of concordance between European countries undertaking CSF RT‐QuIC.

Methods

Ten identical CSF samples, seven from probable or neuropathologically confirmed sCJD and three from non‐CJD cases, were sent to 13 laboratories from 11 countries for RT‐QuIC analysis. A range of instrumentation and different recombinant prion protein substrates were used. Each laboratory analysed the CSF samples blinded to the diagnosis and reported the results as positive or negative.

Results

All 13 laboratories correctly identified five of the seven sCJD cases and the remaining two sCJD cases were identified by 92% of laboratories. Of the two sCJD cases that were not identified by all laboratories, one had a disease duration >26 months with a negative 14‐3‐3, whilst the remaining case had a 4‐month disease duration and a positive 14‐3‐3. A single false positive CSF RT‐QuIC result was observed in this study.

Conclusions

This study shows that CSF RT‐QuIC demonstrates an excellent concordance between centres, even when using a variety of instrumentation, recombinant prion protein substrates and CSF volumes. The adoption of CSF RT‐QuIC by all CJD surveillance centres is recommended.

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Authors:
Neil McKenzie, Gabriele Piconi, Audrey Culeux, Anna‐Lena Hammarin, Christos Stergiou, Socrates Tzartos, Alexandra A. M. Versleijen, Jacqueline van de Geer, Patrick Cras, Franco Cardone, Anna Ladogana, Angela Mannana, Marcello Rossi, Matilde Bongianni, Daniela Perra, Guenther Regelsberger, Sigrid Klotz, Simone Hornemann, Adriano Aguzzi, Matthias Schmitz, Mary Andrews, Kimberley Burns, Stéphane Haïk, Raquel Ruiz‐García, Jenny Verner‐Carlsson, John Tzartos, Marcel M. Verbeek, Bart De Vil, Anna Poleggi, Piero Parchi, Gianluigi Zanusso, Ellen Gelpi, Karl Frontzek, Regina Reimann, Peter Hermann, Inga Zerr, Suvankar Pal and Alison Green
Article first published online:
25 May 2022 | DOI: 10.1111/ene.15387

ORIGINAL ARTICLE

Background and purpose

Social cognition (SC) deficits are included in amyotrophic lateral sclerosis (ALS)–frontotemporal spectrum disorder revised diagnostic criteria. However, SC performance among ALS patients is heterogeneous due to the phenotypic variability of the disease and the wide range of neuropsychological tools employed. The aim of the present study was to assess facial emotion recognition and theory of mind in ALS patients compared to controls and to evaluate correlations with the other cognitive domains and degree of motor impairment.

Methods

Eighty‐three patients and 42 controls underwent a cognitive evaluation and SC assessment through the Ekman 60 Faces Test (EK‐60F), the Reading the Mind in the Eyes Test–36 Faces (RMET‐36), and the Story‐Based Empathy Task (SET).

Results

ALS patients showed significantly worse performance compared to controls in EK‐60F global score ( < 0.001), recognition of disgust ( = 0.032), anger ( = 0.038), fear ( < 0.001), and sadness ( < 0.001); RMET‐36 ( < 0.001), and SET global score ( < 0.001). Also, cognitively normal patients (ALS‐CN) showed significantly worse performance compared to controls in EK‐60F global score ( < 0.001), recognition of fear ( = 0.002), sadness ( < 0.001), and SET ( < 0.001). RMET‐36 showed a significant correlation with the Category Fluency Test ( = 0.041). SC tests showed no correlation with motor impairment expressed by Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised.

Conclusions

ALS patients, also when categorized as ALS‐CN, may show impairment in SC performance. The frequent identification of early SC impairment in ALS patients supports the need to routinely assess SC for its impact on end‐of‐life decisions and its potential influence on patients' quality of life.

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Authors:
Francesca Palumbo, Barbara Iazzolino, Laura Peotta, Antonio Canosa, Umberto Manera, Maurizio Grassano, Federico Casale, Giorgio Pellegrino, Mario Giorgio Rizzone, Rosario Vasta, Cristina Moglia, Adriano Chiò and Andrea Calvo
Article first published online:
30 May 2022 | DOI: 10.1111/ene.15388

ORIGINAL ARTICLE

Background and purpose

Although fundoscopy is a crucial part of the neurological examination, it is challenging, under‐utilized and unreliably performed. The aim was to determine the prevalence of fundus pathology amongst neurology inpatients and the diagnostic accuracy of current fundoscopy practice compared with systematic screening with smartphone fundoscopy (SF) and portable non‐mydriatic fundus photography (NMFP).

Methods

This was a prospective cross‐sectional surveillance and diagnostic accuracy study on adult patients admitted under neurology in an Australian hospital. Inpatients were randomized to initial NMFP (RetinaVue 100, Welch Allyn) or SF (D‐EYE) followed by a crossover to the alternative modality. Images were graded by neurology doctors, using telemedicine consensus neuro‐ophthalmology NMFP grading as the reference standard. Feasibility parameters included ease, comfort and speed.

Results

Of 79 enrolled patients, 14.1% had neurologically relevant pathology (seven, disc pallor; one, hypertensive retinopathy; three, disc swelling). The neurology team performed direct ophthalmoscopy in 6.6% of cases and missed all abnormalities. SF had a sensitivity of 30%–40% compared with NMFP (45.5%); however, it had a lower rate of screening failure (1% vs. 13%,  < 0.001), a shorter examination time (1.10 vs. 2.25 min,  < 0.001) and a slightly higher patient comfort rating (9.2 vs. 8/10,  < 0.001).

Conclusion

Our study demonstrates a clinically significant prevalence of fundus pathology amongst neurology inpatients which was missed by current fundoscopy practices. Portable NMFP screening appears more accurate than SF, whilst both are diagnostically superior to routine fundoscopic practice, feasible and well tolerated by patients.

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Authors:
George He, Hamish P. Dunn, Kate E. Ahmad, Eloise Watson, Andrew Henderson, Dominique Tynan, John Leaney, Andrew J. White, Alex W. Hewitt and Clare L. Fraser
Article first published online:
31 May 2022 | DOI: 10.1111/ene.15390

ORIGINAL ARTICLE

Background and purpose

Venous thromboembolic events (VTEs) are a major complication in cancer patients, and therefore, also in brain cancer patients, anticoagulants are considered appropriate in the treatment of VTEs.

Methods

Frequency, risk factors, and treatment of VTEs, as well as associated complications, were assessed in a population‐based cohort of glioblastoma patients in the Canton of Zurich, Switzerland. Correlations between clinical data and survival were retrospectively analyzed using the log‐rank test and Cox regression models.

Results

Four hundred fourteen glioblastoma patients with isocitrate dehydrogenase wild‐type status were identified. VTEs were documented in 65 patients (15.7%). Median time from tumor diagnosis to the occurrence of a VTE was 1.8 months, and 27 patients were diagnosed with VTEs postoperatively (within 35 days; 42.2%). History of a prior VTE was more common in patients who developed VTEs than in those who did not ( = 0.004). Bevacizumab treatment at any time during the disease course was not associated with occurrence of VTEs ( = 0.593). Most patients with VTEs ( = 61, 93.8%) were treated with therapeutic anticoagulation. Complications occurred in 14 patients (23.0%), mainly intracranial hemorrhages ( = 7, 11.5%). Overall survival did not differ between patients diagnosed with VTEs and those who had no VTE ( = 0.139). Tumor progression was the major cause of death ( = 283, 90.7%), and only three patients (1.0%) died in association with acute VTEs.

Conclusions

Venous thromboembolic events occurred early in the disease course, suggesting that the implementation of primary venous thromboembolism prophylaxis during first‐line chemoradiotherapy could be explored in a randomized setting.

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Authors:
Amanda Eisele, Katharina Seystahl, Elisabeth J. Rushing, Patrick Roth, Emilie Le Rhun, Michael Weller and Dorothee Gramatzki
Article first published online:
31 May 2022 | DOI: 10.1111/ene.15404

ORIGINAL ARTICLE

Background and purpose

The aim of this study was to investigate the relevance of compartmentalized grey matter (GM) pathology and network reorganization in multiple sclerosis (MS) patients with concomitant epilepsy.

Methods

From 3‐T magnetic resonance imaging scans of 30 MS patients with epilepsy (MSE group; age 41 ± 15 years, 21 females, disease duration 8 ± 6 years, median Expanded Disability Status Scale [EDSS] score 3), 60 MS patients without epilepsy (MS group; age 41 ± 12 years, 35 females, disease duration 6 ± 4 years, EDSS score 2), and 60 healthy subjects (HS group; age 40 ± 13 years, 27 females) the regional volumes of GM lesions and of cortical, subcortical and hippocampal structures were quantified. Network topology and vulnerability were modelled within the graph theoretical framework. Receiver‐operating characteristic (ROC) curve analysis was applied to assess the accuracy of GM pathology measures to discriminate between MSE and MS patients.

Results

Higher lesion volumes within the hippocampus, mesiotemporal cortex and amygdala were detected in the MSE compared to the MS group (all  < 0.05). The MSE group had lower cortical volumes mainly in temporal and parietal areas compared to the MS and HS groups (all  < 0.05). Lower hippocampal tail and presubiculum volumes were identified in both the MSE and MS groups compared to the HS group (all  < 0.05). Network topology in the MSE group was characterized by higher transitivity and assortativity, and higher vulnerability compared to the MS and HS groups (all  < 0.05). Hippocampal lesion volume yielded the highest accuracy (area under the ROC curve 0.80 [0.67–0.91]) in discriminating between MSE and MS patients.

Conclusions

High lesion load, altered integrity of mesiotemporal GM structures, and network reorganization are associated with a greater propensity for epilepsy occurrence in people with MS.

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Authors:
Dumitru Ciolac, Gabriel Gonzalez‐Escamilla, Yaroslav Winter, Nico Melzer, Felix Luessi, Angela Radetz, Vinzenz Fleischer, Stanislav A. Groppa, Michael Kirsch, Stefan Bittner, Frauke Zipp, Muthuraman Muthuraman, Sven G. Meuth, Matthias Grothe and Sergiu Groppa
Article first published online:
05 Jun 2022 | DOI: 10.1111/ene.15405

ORIGINAL ARTICLE

Background and purpose

The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short‐term treatment effects on disability. This study aimed to define criteria for 6‐month confirmed disability progression events of MS with a high probability of resulting in sustained long‐term disability worsening.

Methods

In total, 14,802 6‐month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6‐month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long‐term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial.

Results

The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29–0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score ˃1.5).

Conclusions

Clinicodemographic characteristics of 6‐month confirmed disability progression events identify those at high risk of sustained long‐term disability. This knowledge will allow future trials to better assess the effect of therapy on long‐term disability accrual.

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Authors:
Sifat Sharmin, Francesca Bovis, Charles Malpas, Dana Horakova, Eva Kubala Havrdova, Guillermo Izquierdo, Sara Eichau, Maria Trojano, Alexandre Prat, Marc Girard, Pierre Duquette, Marco Onofrj, Alessandra Lugaresi, Francois Grand'Maison, Pierre Grammond, Patrizia Sola, Diana Ferraro, Murat Terzi, Oliver Gerlach, Raed Alroughani, Cavit Boz, Vahid Shaygannejad, Vincent van Pesch, Elisabetta Cartechini, Ludwig Kappos, Jeannette Lechner‐Scott, Roberto Bergamaschi, Recai Turkoglu, Claudio Solaro, Gerardo Iuliano, Franco Granella, Bart Van Wijmeersch, Daniele Spitaleri, Mark Slee, Pamela McCombe, Julie Prevost, Radek Ampapa, Serkan Ozakbas, Jose Luis Sanchez‐Menoyo, Aysun Soysal, Steve Vucic, Thor Petersen, Koen de Gans, Ernest Butler, Suzanne Hodgkinson, Youssef Sidhom, Riadh Gouider, Edgardo Cristiano, Tamara Castillo‐Triviño, Maria Laura Saladino, Michael Barnett, Fraser Moore, Csilla Rozsa, Bassem Yamout, Olga Skibina, Anneke van der Walt, Katherine Buzzard, Orla Gray, Stella Hughes, Angel Perez Sempere, Bhim Singhal, Yara Fragoso, Cameron Shaw, Allan Kermode, Bruce Taylor, Magdolna Simo, Neil Shuey, Talal Al‐Harbi, Richard Macdonell, Jose Andres Dominguez, Tunde Csepany, Carmen Adella Sirbu, Maria Pia Sormani, Helmut Butzkueven and Tomas Kalincik
Article first published online:
09 Jun 2022 | DOI: 10.1111/ene.15406

ORIGINAL ARTICLE

Background and purpose

High levels of 25‐hydroxyvitamin D (25[OH]D) are associated with a lower risk for multiple sclerosis (MS). The bioavailability of 25(OH)D is regulated by its main plasma carrier, vitamin D‐binding protein (DBP). Free 25(OH)D can be estimated by also measuring DBP concentration. In addition, DBP has immunomodulatory functions that may independently affect MS pathogenesis. No previous studies have assessed free 25(OH)D or DBP in presymptomatically collected samples. This study was undertaken to assess free 25(OH)D and DBP as risk factors for MS.

Methods

A nested case–control study was performed with presymptomatic serum samples identified through cross‐linkage of MS registries and Swedish biobanks. Concentration of 25(OH)D was measured with liquid chromatography and DBP levels with sandwich immunoassay. Free 25(OH)D was approximated as free vitamin D index: (25[OH]D/DBP) × 10. MS risk was analyzed by conditional logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CIs).

Results

Serum samples from 660 pairs of matched cases and controls were included.

Conclusions

These findings support the hypothesis that high levels of free 25(OH)D at a young age reduce the risk of MS later in life. They also implicate a role for DBP in MS etiology.

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Authors:
Viktor Grut, Martin Biström, Jonatan Salzer, Pernilla Stridh, Anna Lindam, Lucia Alonso‐Magdalena, Oluf Andersen, Daniel Jons, Martin Gunnarsson, Magnus Vrethem, Johan Hultdin and Peter Sundström
Article first published online:
04 Jun 2022 | DOI: 10.1111/ene.15407

SHORT COMMUNICATION

Background and Purpose

The progressive nature of epileptogenesis raises the question of whether the latent period may already carry information about the characteristics of the subsequent epilepsy. This study aimed to explore whether the time from stroke to epilepsy onset was related to the risk of drug resistance in patients with poststroke epilepsy (PSE).

Methods

Patients with epilepsy secondary to cerebral infarct or spontaneous intracerebral hemorrhage were included. Study outcome was the occurrence of drug resistance defined as failure of adequate trials of two tolerated and appropriately chosen and used antiseizure medication schedules to achieve sustained seizure freedom.

Results

One hundred fifty‐nine patients with PSE and a median follow‐up of 5 (interquartile range [IQR] = 3–9) years were included. In the study cohort, 29 (18.2%) participants were drug resistant. The median length of the time interval between stroke and PSE onset was 13 (IQR = 7–15) months in drug‐resistant patients and 19 (IQR = 14–42) months ( < 0.001) in patients with seizure control. According to multivariable regression analysis, the time from stroke to PSE was an independent predictor of drug resistance ( < 0.001). The risk of drug resistance was highest when the onset of PSE occurred within the first months from stroke and decreased progressively with a steeper decline over the first 12 months.

Conclusions

Substantial variability may exist in the pathways leading to PSE and distinguish patients with a variable risk of drug resistance.

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Authors:
Simona Lattanzi, Eugen Trinka, Gianni Turcato, Claudia Rinaldi, Claudia Cagnetti, Nicoletta Foschi, Serena Broggi, Davide Norata, Francesco Brigo and Mauro Silvestrini
Article first published online:
30 May 2022 | DOI: 10.1111/ene.15408

SHORT COMMUNICATION

Background and purpose

Epileptic encephalopathy (EE) refers to a heterogeneous group of epilepsy syndromes characterized by seizures as well as encephalopathies, leading to cognitive and behavioral disturbances. These conditions vary in their age at onset, their severity, and their electroencephalographic patterns. Whereas genetic factors are involved in approximately 40% of all epilepsy cases, they contribute to 80% of early infantile EEs (EIEEs), with approximately 125 genes previously linked to this disease.

Methods

Whole exome sequencing (WES) was performed in a 9‐month‐old Lebanese girl presenting with EIEE.

Results

WES enabled the detection of a homozygous missense mutation in the gene (NM_015509.3: p.Glu8Lys) in the proband.

Conclusions

Here, we report the first homozygous missense mutation in the gene in a 9‐month‐old girl presenting with EIEE. Our findings allow a better characterization of the ‐linked disease and enable broadening its clinical spectrum by including, in addition to EIEE, severe generalized hypotonia, poor feeding, developmental delay, severe microcephaly, delayed myelination, abnormalities of the corpus callosum, and eye abnormalities.

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Authors:
Eliane Chouery, Cybel Mehawej, Sandra Sabbagh, Jamal Bleik and Andre Megarbane
Article first published online:
09 Jun 2022 | DOI: 10.1111/ene.15424