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Article first published online:
04 Jul 2023 | DOI: 10.1111/ene.15399

ORIGINAL ARTICLE

Burden of suspected epileptic seizures on emergency services: A population‐based study

Background and purpose

Patients with acute epileptic seizures form a large patient group in emergency neurology. This study aims to determine the burden caused by suspected epileptic seizures at different steps in emergency care.

Methods

A retrospective, cross‐sectional, population‐based (>1,000,000 inhabitants), 4‐year (2015–2018) study was conducted in an urban setting with a single dispatch centre, a university hospital‐affiliated emergency medical service (EMS), and five emergency departments (EDs). The study covered all adult (≥16 years old) emergency neurology patients receiving medical attention due to suspected epileptic seizures from the EMS and EDs and during hospital admissions in the Helsinki metropolitan area.

Results

Epileptic seizures were suspected in 14,364 EMS calls, corresponding to 3.3% of all EMS calls during the study period. 9,112 (63.4%) cases were transported to hospital due to suspected epileptic seizures, and 3368 (23.4%) were discharged on the scene. 6969 individual patients had 11,493 seizure‐related ED visits, accounting for 3.1% of neurology‐ and internal medicine‐related ED visits and 4607 hospital admissions were needed with 3 days’ median length of stay (IQR=4, Range 1‐138). Male predominance was noticeable at all stages (EMS 64.7%, EDs 60.1%, hospital admissions 56.2%). The overall incidence was 333/100,000 inhabitants/year for seizure‐related EMS calls, 266/100,000 inhabitants/year for ED visits and 107/100,000 inhabitants/year for hospital admissions. Total estimated costs were 6.8 million €/year, corresponding to 0.5% of all specialized healthcare costs in the study area.

Conclusions

Patients with suspected epileptic seizures cause a significant burden on the health care system. Present‐day epidemiological data are paramount when planning resource allocation in emergency services.

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Authors:
Leena Kämppi, Tuukka Puolakka, Jaakko Ritvanen, Kati Tuppurainen, Jari Päkkilä, Markku Kuisma and Jukka Peltola

Article first published online:
07 Apr 2023 | DOI: 10.1111/ene.15800

CONSENSUS STATEMENT

European Committee for Treatment and Research in Multiple Sclerosis and European Academy of Neurology consensus on vaccination in people with multiple sclerosis: Improving immunization strategies in the era of highly active immunotherapeutic drugs

Background and purpose

With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy. We aimed to develop a European evidence‐based consensus for the vaccination strategy of pwMS who are candidates for disease‐modifying therapies (DMTs).

Methods

This work was conducted by a multidisciplinary working group using formal consensus methodology. Clinical questions (defined as population, interventions and outcomes) considered all authorized DMTs and vaccines. A systematic literature search was conducted and quality of evidence was defined according to the Oxford Centre for Evidence‐Based Medicine Levels of Evidence. The recommendations were formulated based on the quality of evidence and the risk–benefit balance.

Results

Seven questions, encompassing vaccine safety, vaccine effectiveness, global vaccination strategy and vaccination in subpopulations (pediatric, pregnant women, elderly and international travelers) were considered. A narrative description of the evidence considering published studies, guidelines and position statements is presented. A total of 53 recommendations were agreed by the working group after three rounds of consensus.

Conclusion

This first European consensus on vaccination in pwMS proposes the best vaccination strategy according to current evidence and expert knowledge, with the goal of homogenizing the immunization practices in pwMS.

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Authors:
Susana Otero‐Romero, Christine Lebrun‐Frénay, Saúl Reyes, Maria Pia Amato, Magda Campins, Mauricio Farez, Massimo Filippi, Yael Hacohen, Bernhard Hemmer, Rosa Juuti, Melinda Magyari, Celia Oreja‐Guevara, Aksel Siva, Sandra Vukusic and Mar Tintoré

Article first published online:
09 Jun 2023 | DOI: 10.1111/ene.15809

ORIGINAL ARTICLE

Improved automatic identification of isolated rapid eye movement sleep behavior disorder with a 3D time‐of‐flight camera

Background and purpose

Automatic 3D video analysis of the lower body during rapid eye movement (REM) sleep has been recently proposed as a novel tool for identifying people with isolated REM sleep behavior disorder (iRBD), but, so far, it has not been validated on unseen subjects. This study aims at validating this technology in a large cohort and at improving its performances by also including an analysis of movements in the head, hands and upper body.

Methods

Fifty‐three people with iRBD and 128 people without RBD (of whom 89 had sleep disorders considered RBD differential diagnoses) were included in the study. An automatic algorithm identified movements from 3D videos during REM sleep in four regions of interest (ROIs): head, hands, upper body and lower body. The movements were divided into categories according to duration: short (0.1–2 s), medium (2–15 s) and long (15–300 s). For each ROI and duration range, features were obtained from the identified movements. Logistic regression models using as predictors the features from one single ROI or a combination of ROIs were trained and tested in a 10‐runs 10‐fold cross‐validation scheme on the task of differentiating people with iRBD from people without RBD.

Results

The best differentiation was achieved using short movements in all four ROIs (test accuracy 0.866 ± 0.007, test F1 score = 0.783 ± 0.010). Single group analyses showed that people with iRBD were distinguished successfully from subjects with RBD differential diagnoses.

Conclusions

Automatic 3D video analysis might be implemented in clinical routine as a supportive screening tool for identifying people with RBD.

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Authors:
Matteo Cesari, Laurenz Ruzicka, Birgit Högl, Abubaker Ibrahim, Evi Holzknecht, Anna Heidbreder, Melanie Bergmann, Elisabeth Brandauer, Heinrich Garn, Bernhard Kohn and Ambra Stefani

Article first published online:
23 May 2023 | DOI: 10.1111/ene.15822

REVIEW ARTICLE

Non‐lesional treatments for tremor in Parkinson's disease: A systematic review and meta‐analysis

Introduction

Tremor is often perceived as severely disabling by patients with idiopathic Parkinson's disease (iPD) and yet ranges among the most difficult symptoms to treat. To date, no comprehensive analysis of non‐lesional therapies to manage tremor in iPD exists to base recommendations upon. We therefore present a systematic literature review and meta‐analysis assessing the efficacy/effectiveness and safety of non‐lesional treatments for tremor in iPD.

Methods

Three electronic databases were searched using a combination of title/abstract keywords complemented by hand‐searching of reference lists. A random‐effects meta‐analysis of standardized mean change scores was conducted where appropriate.

Results

Some 114 studies met inclusion criteria involving 8045 patients. The meta‐analysis revealed an overall reduction of standardized mean change scores by (−0.93 [CI: −1.42; −0.43], < 0.001) by 14 different dopaminergic and non‐dopaminergic classes of agents. No significant differences were identified between direct comparisons. Subgroup analysis comparing dopamine receptor agonists resulted in superior effects of pramipexole and rotigotine compared with ropinirole. There was little cumulative evidence to support the use of individual non‐pharmacological interventions for tremor, except for electrical stimulation.

Conclusions

The results of this meta‐analysis suggest a large but nonspecific effect of established pharmacological therapies on tremor in iPD. Based on high‐quality studies, there is sufficient evidence to support that levodopa, dopamine receptor agonists, and monoamine oxidase inhibitors provide tremor relief in most patients, while evidence supporting other treatments is less well established. Sufficient evidence to draw conclusions on effects of non‐lesional treatments in cases with refractory tremor is lacking.

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Authors:
Anna J. Pedrosa, Josefine Waldthaler, Felicitas Mügge, Lars Timmermann and David J. Pedrosa

Article first published online:
25 May 2023 | DOI: 10.1111/ene.15823

CASE REPORT

Deep brain stimulation in Parkinson disease with valosin‐containing protein gene mutation

Background and purpose

Mutations in the gene encoding valosin‐containing protein () are related to myriad medical conditions, including familial amyotrophic lateral sclerosis, inclusion body myopathy, and frontotemporal dementia. There are several reports of a link between these mutations and early onset Parkinson disease (PD).

Case description

We report a 53‐year‐old PD patient with mutation who later developed motor complications, thus receiving subthalamic nucleus deep brain stimulation (DBS) at the age of 56 years. However, myopathy emerged 1.5 years after surgery.

Conclusions

With the phenotype variability of , DBS should be carefully evaluated, considering the possible unfavorable long‐term outcomes due to other symptoms of this mutation.

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Authors:
Yoon Seob Kim, Don Gueu Park, Min Seung Kim and Jung Han Yoon

Article first published online:
24 May 2023 | DOI: 10.1111/ene.15824

ORIGINAL ARTICLE

Respiratory symptoms are common in stiff person syndrome spectrum disorders and are associated with number of body regions involved

Background and purpose

Stiff person syndrome (SPS) spectrum disorders (SPSSD) cause spasms and rigidity throughout different body regions and can be associated with apnea and acute respiratory failure. There are limited data on the prevalence and predictors of respiratory symptoms with spasms (RSwS) in SPSSD. We sought to characterize the spirometry patterns and the frequency and predictors of RSwS in a large SPSSD cohort.

Methods

Participants were recruited from the Johns Hopkins SPS Center between 1997 and 2021, as part of an ongoing, longitudinal observational study. Medical records were reviewed to assess demographics and clinical characteristics. Data were analyzed using descriptive statistics and multivariable logistic regression models.

Results

One‐hundred ninety‐nine participants (mean age = 53.4 ± 13.6 years, median time to diagnosis = 36 [IQR 66] months, 74.9% women, 69.8% White, 62.8% classic SPS phenotype) were included in final analyses; 35.2% of participants reported RSwS, of whom 24.3% underwent spirometry as part of routine clinical care. Obstructive (23.5%) and restrictive (23.5%) patterns were most commonly observed in those with SPSSD. An increasing number of body regions involved predicted the presence of RSwS (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.50–2.53); those with ≥5 body regions involved (vs. ≤4) had higher odds (OR = 6.19, 95% CI = 2.81–13.62) of experiencing RSwS in adjusted models. Two patients died from SPSSD‐associated respiratory compromise.

Conclusions

RSwS are common in SPSSD and may be predicted by an increasing number of body regions involved by SPSSD. Close clinical monitoring and having a low threshold to obtain spirometry should be considered in people with SPSSD.

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Authors:
Daniela A. Pimentel Maldonado, Alexandra Balshi, Chen Hu, Kathryn C. Fitzgerald, Jacqueline Koshorek, Maria I. Reyes‐Mantilla, Danielle Obando, Yujie Wang and Scott D. Newsome

Article first published online:
21 May 2023 | DOI: 10.1111/ene.15825

ORIGINAL ARTICLE

Antioxidant defense enzymes in multiple sclerosis: A 5‐year follow‐up study

Background and purpose

Oxidative stress biomarkers are increased in multiple sclerosis (MS) lesions. Antioxidant defense enzymes regulate reactive oxygen species that can cause tissue injury in MS.

Methods

The study of 91 subjects included 64 relapsing–remitting MS (RR‐MS; 72% female, baseline age ± SD = 44.6 ± 11 years, disease duration = 13.3 ± 8.8 years, median Expanded Disability Status Scale [EDSS] = 2.0, interquartile range = 1.8) and 27 healthy controls (HC) at baseline and 5‐year follow‐up (5YFU). Serum glutathione peroxidase (GPX), glutathione‐S‐transferase (GST), glutathione reductase (GSHR), superoxide dismutase, and paraoxonase‐1 (PON1) arylesterase and paraoxonase activities were measured using kinetic enzyme assays. Total cholesterol (TC), high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol (LDL‐C), and an apolipoprotein (Apo) panel with ApoA‐I, ApoA‐II, ApoB, ApoC‐II, and ApoE were obtained. Serum neurofilament (sNfL) was used to assess axonal injury. Disability was measured on the EDSS.

Results

GSHR activity was lower in HC compared to RR‐MS at baseline and 5YFU. GPX ( = 0.008) and PON1 arylesterase and paraoxonase activities (both = 0.05) increased between baseline and 5YFU in HC but did not increase in RR‐MS. At baseline and 5YFU, GPX and GST were associated with TC, LDL‐C, and ApoA‐II; GSHR was associated with ApoA‐II and ApoC‐II. Antioxidant enzymes were not associated with sNfL or EDSS in RR‐MS.

Conclusions

RR‐MS patients did not exhibit the changes in antioxidant enzyme activities over 5YFU found in HC; however, the differences were modest. Antioxidant enzyme activities are not associated with disability.

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Authors:
Carson Essenburg, Richard W. Browne, Diala Ghazal, Miriam Tamaño‐Blanco, Dejan Jakimovski, Bianca Weinstock‐Guttman, Robert Zivadinov and Murali Ramanathan

Article first published online:
24 May 2023 | DOI: 10.1111/ene.15826

ORIGINAL ARTICLE

Pathophysiology of multiple sclerosis damage and repair: Linking cerebral hypoperfusion to the development of irreversible tissue loss in multiple sclerosis using magnetic resonance imaging

Background and purpose

Reduced cerebral perfusion has been observed in multiple sclerosis (MS) and may contribute to tissue loss both acutely and chronically. Here, we test the hypothesis that hypoperfusion occurs in MS and relates to the presence of irreversible tissue damage.

Methods

In 91 patients with relapsing MS and 26 healthy controls (HC), gray matter (GM) cerebral blood flow (CBF) was assessed using pulsed arterial spin labeling. GM volume, T1 hypointense and T2 hyperintense lesion volumes (T1LV and T2LV, respectively), and the proportion of T2‐hyperintense lesion volume that appears hypointense on T1‐weighted magnetic resonance imaging (T1LV/T2LV) were quantified. GM CBF and GM volume were evaluated globally, as well as regionally, using an atlas‐based approach.

Results

Global GM CBF was lower in patients (56.9 ± 12.3 mL/100 g/min) than in HC (67.7 ± 10.0 mL/100 g/min; < 0.001), a difference that was widespread across brain regions. Although total GM volume was comparable between groups, significant reductions were observed in a subset of subcortical structures. GM CBF negatively correlated with T1LV ( = −0.43, = 0.0002) and T1LV/T2LV ( = −0.37, = 0.0004), but not with T2LV.

Conclusions

GM hypoperfusion occurs in MS and is associated with irreversible white matter damage, thus suggesting that cerebral hypoperfusion may actively contribute and possibly precede neurodegeneration by hampering tissue repair abilities in MS.

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Authors:
Daniele Mascali, Alessandro Villani, Antonio M. Chiarelli, Emma Biondetti, Ilona Lipp, Anna Digiovanni, Valeria Pozzilli, Alessandra S. Caporale, Marianna G. Rispoli, Paola Ajdinaj, Maria D'Apolito, Eleonora Grasso, Stefano L. Sensi, Kevin Murphy, Valentina Tomassini and Richard G. Wise

Article first published online:
30 May 2023 | DOI: 10.1111/ene.15827

ORIGINAL ARTICLE

Etiologic distribution of isolated abducens nerve palsy: Analysis of 807 patients and literature review

Background and Purpose

The etiologies of abducens nerve palsy have shown a large variability among studies. This study aimed to establish the clinical features and underlying etiologies of isolated abducens nerve palsy by recruiting patients from all departments in a referral‐based university hospital.

Methods

We reviewed the medical records of 807 patients with a confirmed diagnosis of isolated abducens nerve palsy at all departments of Seoul National University Bundang Hospital, Seongnam, Republic of Korea, from 2003 to 2020. We also compared the proportion of etiology with that of the patients pooled from the previous studies.

Results

The most common etiology was microvascular ( = 296, 36.7%), followed by idiopathic ( = 143, 17.7%), neoplastic ( = 115, 14.3%), vascular anomalies ( = 82, 10.2%), inflammatory ( = 76, 9.4%), and traumatic ( = 35, 4.3%). Patients were mostly managed by ophthalmologists ( = 576, 71.4%), followed by neurologists ( = 479, 59.4%), emergency physicians ( = 278, 34.4%), neurosurgeons ( = 191, 23.7%), and others ( = 72, 8.9%). The proportion of etiology significantly differed according to the age and sex of the patients and the specialties involved in the management ( < 0.001). Compared to the pooled data from the previous reports, the current study showed a higher prevalence of microvascular cause but a lower occurrence of traumatic and neoplastic causes.

Conclusions

The results of previous studies on etiologic distribution of isolated abducens nerve palsy should be interpreted with consideration of the demographic features of patients recruited and the specialties involved.

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Authors:
Hyun‐Jae Kim, Hyo‐Jung Kim, Jeong‐Yoon Choi, Hee Kyung Yang, Jeong‐Min Hwang and Ji‐Soo Kim

Article first published online:
25 May 2023 | DOI: 10.1111/ene.15828

ORIGINAL ARTICLE

Neural correlates of photophobia in prodromal and mild dementia with Lewy bodies

Background and objectives

Photophobia is a sensory disturbance provoked by light. Little is known about the association between photophobia and dementia with Lewy bodies (DLB). In this study, we aimed to identify the frequency and the neural basis of photophobia in prodromal and mild DLB.

Methods

One hundred and thirteen DLB patients, 53 Alzheimer's disease (AD) patients, 20 AD and DLB patients, 31 patients with other neurocognitive diseases (including prodromal and mild demented patients), and 31 healthy elderly controls were included in this case–control study. Photophobia was systematically looked for and compared between groups. Among a selection of 77 DLB patients, we used voxel‐based morphometry (VBM) to compare those with and those without photophobia (gray matter volume; SPM12, XjView, and Matlab R2021b software).

Results

The frequency of photophobia was higher in the DLB group (47.3%) than in the other groups ( = 0.002). The photophobia questionnaire score was higher in the DLB group than in the AD group ( = 0.001). Comparison between DLB patients with and those without photophobia showed decreased gray matter in the photophobia subgroup, in the right precentral cortex, in the eyelid motor region of Penfield's homunculus ( = 0.007, family‐wise error [FWE] corrected).

Conclusions

Photophobia is a quite frequent symptom of prodromal and mild DLB. The neural basis of photophobia in DLB involves the right precentral cortex, which could have a role in the decrease of cerebral excitability, but also the motricity of the eyelids.

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Authors:
Alice Tisserand, Benjamin Cretin, Mary Mondino, Anne Botzung, Lea Sanna, Catherine Demuynck, Pierre Anthony, Candice Muller, Olivier Bousiges, Nathalie Philippi and Frédéric Blanc

Article first published online:
22 May 2023 | DOI: 10.1111/ene.15829

ORIGINAL ARTICLE

Antibody response elicited by the SARS‐CoV‐2 vaccine booster in patients with multiple sclerosis: Who gains from it?

Background and purpose

Although two doses of COVID‐19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease‐modifying therapies (DMTs) showed less efficient responses.

Methods

This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS.

Results

Four hundred seventy‐three pwMS were analyzed. Compared to untreated patients, there was a 50‐fold decrease (95% confidence interval [CI] = 14.3–100.0, < 0.001) in serum SARS‐CoV‐2 antibody levels in those on rituximab, a 20‐fold decrease (95% CI = 8.3–50.0, < 0.001) in those on ocrelizumab, and a 2.3‐fold decrease (95% CI = 1.2–4.6, = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti‐CD20 drugs rituximab and ocrelizumab showed a 2.3‐fold lower gain (95% CI = 1.4–3.8, = 0.001), whereas those on fingolimod showed a 1.7‐fold higher gain (95% CI = 1.1–2.7, = 0.012), compared to patients treated with other DMTs.

Conclusions

All pwMS increased their serum SARS‐CoV‐2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff.

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Authors:
Irene Schiavetti, Matilde Inglese, Jessica Frau, Elisabetta Signoriello, Francesca Caleri, Maria Laura Stromillo, Maria Teresa Ferrò, Maria Teresa Rilla, Ilaria Gandoglia, Paola Gazzola, Giampaolo Brichetto, Livia Pasquali, Luigi Grimaldi, Monica Ulivelli, Fabiana Marinelli, Susanna Cordera, Marinella Clerico, Antonella Conte, Marco Salvetti, Mario Alberto Battaglia, Diego Franciotta, Antonio Uccelli, Maria Pia Sormani, Alessandro Maglione, Alessia Di Sapio, Alice Laroni, Aniello Iovino, Antonio Mannironi, Antonio Uccelli, Barbara Nucciarone, Carlo Serrati, Carolina Gabri Nicoletti, Caterina Lapucci, Chiara Rosa Mancinelli, Cinzia Cordioli, Daiana Bezzini, Daniele Carmagnini, Davide Brogi, De Stefano Nicola, Doriana Landi, Eduardo Nobile Orazio, Eleonora Cocco, Elisabetta Signoriello, Enri Nako, Ester Assandri, Fabiana Marinelli, Federica Baldi, Francesca Caleri, Gabriele Siciliano, Gaia Cola, Germana Perego, Giacomo Lus, Giampaolo Brichetto, Gianmarco Bellucci, Giorgio Da Rin, Girolama Alessandra Marfia, Giulia Vazzoler, Giuseppe Liberatore, Giuseppe Trivelli, Graziella Callari, Ilaria Gandoglia, Irene Schiavetti, Jessica Frau, Livia Pasquali, Loredana Petrucci, Lorena Lorefice, Lucia Ruggiero, Marco Salvetti, Margherita Monti Bragadin, Maria Chiara Buscarinu, Maria Gagliardi, Maria Pia Sormani, Maria Teresa Ferrò, Maria Teresa Rilla, Marinella Clerico, Mario Alberto Battaglia, Marzia Fronza, Massimo Del Sette, Matilde Inglese, Matteo Scialabba, Michele Bedognetti, Monica Ulivelli, Nicola De Rossi, Paola Gazzola, Rachele Bigi, Raffaele Dubbioso, Roberta Reniè, Rosa Iodice, Sabrina Fabbri, Sarah Rasia, Sergio Parodi, Simona Rolla, Stefan Platzgummer, Stromillo Maria Laura, Tiziana Tassinari and Valentina Carlini

Article first published online:
28 May 2023 | DOI: 10.1111/ene.15830

GUIDELINES

Joint European Academy of Neurology–European Pain Federation–Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment

Background and Purpose

In these guidelines, we aimed to develop evidence‐based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP).

Methods

We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP.

Results

Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I‐DN4 (self‐administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S‐LANSS (self‐administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases.

Conclusions

These recommendations provide evidence‐based clinical practice guidelines for NeP diagnosis. Due to the poor‐to‐moderate quality of evidence identified by this review, future large‐scale, well‐designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

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Authors:
Andrea Truini, Katina Aleksovska, Christopher C. Anderson, Nadine Attal, Ralf Baron, David L. Bennett, Didier Bouhassira, Giorgio Cruccu, Elon Eisenberg, Elena Enax‐Krumova, Karen Deborah Davis, Giulia Di Stefano, Nanna B. Finnerup, Luis Garcia‐Larrea, Ibrahem Hanafi, Simon Haroutounian, Pall Karlsson, Martin Rakusa, Andrew S. C. Rice, Juliane Sachau, Blair H. Smith, Claudia Sommer, Thomas Tölle, Josep Valls‐Solé and Abirami Veluchamy

Article first published online:
30 May 2023 | DOI: 10.1111/ene.15831

ORIGINAL ARTICLE

Caveolinopathy: Clinical, histological, and muscle imaging features and follow‐up in a multicenter retrospective cohort

Background and purpose

gene mutations, mostly inherited as an autosomal dominant trait, cause various skeletal muscle diseases. Clinical presentations encompass proximal myopathy, distal myopathy, or isolated persistent high creatine kinase (CK) with a major overlapping phenotype.

Methods

Twenty‐three patients with symptomatic mutations, from 16 different families, were included in a retrospective cohort. Mean follow‐up duration was 24.2 ± 15.0 years. Clinical and functional data were collected during the follow‐up. The results of muscle imaging, electroneuromyography, muscle histopathology, immunohistochemistry, and caveolin‐3 Western blot analysis were also compiled.

Results

Exercise intolerance was the most common phenotype (52%). Eighty percent of patients had calf hypertrophy, and only 65% of patients presented rippling. One patient presented initially with camptocormia. A walking aid was required in only two patients. Electroneuromyography was mostly normal. CK level was elevated in all patients. No patient had cardiac or respiratory impairment. Muscle imaging showed fatty involvement of semimembranosus, semitendinosus, rectus femoris, biceps brachialis, and spinal muscles. Almost all (87%) of the biopsies were abnormal but without any specific pattern. Whereas a quarter of patients had normal caveolin‐3 immunohistochemistry results, Western blots disclosed a reduced amount of the protein. We report nine mutations, including four not previously described. No phenotype–genotype correlation was evidenced.

Conclusions

Caveolinopathy has diverse clinical, muscle imaging, and histological presentations but often has limited functional impact. Mild forms of the disease, an atypical phenotype, and normal caveolin‐3 immunostaining are pitfalls leading to misdiagnosis.

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Authors:
Edouard Berling, Camille Verebi, Nadia Venturelli, Stéphane Vassilopoulos, Anthony Béhin, Céline Tard, Maud Michaud, Rocio Nur Villar Quiles, Savine Vicart, Marion Masingue, Robert‐Yves Carlier, Norma Beatriz Romero, Emmanuelle Lacene, France Leturcq, Bruno Eymard, Pascal Laforêt and Tanya Stojkovic

Article first published online:
25 May 2023 | DOI: 10.1111/ene.15832

ORIGINAL ARTICLE

Clinical response following hypertension induction for clinical delayed cerebral ischemia following subarachnoid hemorrhage: A retrospective, multicenter, cohort study

Background

Hypertension induction (HTI) is often used for treating delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH); however, high‐quality studies on its efficacy are lacking. We studied immediate and 3−/6‐month clinical efficacy of HTI in aSAH patients with clinical DCI.

Methods

A retrospective, multicenter, comparative, observational cohort study in aSAH patients with clinical deterioration due to DCI, admitted to three tertiary referral hospitals in the Netherlands from 2015 to 2019. Two hospitals used a strategy of HTI (HTI group) and one hospital had no such strategy (control group). We calculated adjusted relative risks (aRR) using Poisson regression analyses for the two primary (clinical improvement of DCI symptoms at days 1 and 5 after DCI onset) and secondary outcomes (DCI‐related cerebral infarction, in‐hospital mortality, and poor clinical outcome [modified Rankin Scale 4–6] assessed at 3 or 6 months), using the intention‐to‐treat principle. We also performed as‐treated and per‐protocol analyses.

Results

The aRR for clinical improvement on day 1 after DCI in the HTI group was 1.63 (95% CI 1.17–2.27) and at day 5 after DCI 1.04 (95% CI 0.84–1.29). Secondary outcomes were comparable between the groups. The as‐treated and per‐protocol analyses yielded similar results.

Conclusions

No clinical benefit of HTI is observed 5 days after DCI due to spontaneous reversal of DCI symptoms in patients treated without HTI. The 3−/6‐month clinical outcome was similar for both groups. Therefore, these data suggest that one may consider to not apply HTI in aSAH patients with clinical DCI.

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Authors:
Maud A. Tjerkstra, Marcella C. A. Müller, Bert A. Coert, Friso W. A. Hoefnagels, Mervyn D. I. Vergouwen, Peter van Vliet, Lizzy Ooms, Gabriël J. E. Rinkel, Arjen J. C. Slooter, Wouter A. Moojen, Korné Jellema, W. Peter Vandertop and Dagmar Verbaan

Article first published online:
28 May 2023 | DOI: 10.1111/ene.15833

ORIGINAL ARTICLE

Longitudinal stability of progression‐related microglial activity during teriflunomide treatment in patients with multiple sclerosis

Background and purpose

The aim was to study brain innate immune cell activation in teriflunomide‐treated patients with relapsing–remitting multiple sclerosis.

Methods

Imaging with 18‐kDa translocator protein positron emission tomography (TSPO‐PET) using the [C]PK11195 radioligand was employed to assess microglial activity in the white matter, thalamus and areas surrounding chronic white matter lesions in 12 patients with relapsing–remitting multiple sclerosis who had been treated with teriflunomide for at least 6 months before inclusion. Magnetic resonance imaging (MRI) was used to measure lesion load and brain volume, and quantitative susceptibility mapping (QSM) was used to detect iron rim lesions. These evaluations were repeated after 1 year of inclusion. Twelve age‐ and gender‐matched healthy control subjects were imaged for comparison.

Results

Half of the patients had iron rim lesions. In TSPO‐PET, the proportion of active voxels indicating innate immune cell activation was slightly greater amongst patients compared with healthy individuals (7.7% vs. 5.4%, = 0.033). The mean distribution volume ratio of [C]PK11195 was not significantly different in the normal‐appearing white matter or thalamus amongst patients versus controls. Amongst the treated patients, no significant alteration was observed in positron emission tomography distribution volume ratio, the proportion of active voxels, the number of iron‐rim‐positive lesions, lesion load or brain volume during follow‐up.

Conclusions

Compared to controls, treated patients exhibited modest signs of diffuse innate immune cell activity, which was unaltered during follow‐up. Lesion‐associated smoldering inflammation was negligible at both timepoints. To our knowledge, this is the first study applying both TSPO‐PET and QSM‐MRI to longitudinally evaluate smoldering inflammation.

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Authors:
Jussi Lehto, Marjo Nylund, Markus Matilainen, Marcus Sucksdorff, Anna Vuorimaa, Johan Rajander, Saara Wahlroos, Parisa Hariri and Laura Airas

Article first published online:
23 May 2023 | DOI: 10.1111/ene.15834

ORIGINAL ARTICLE

Immune checkpoint inhibitor‐associated central nervous system autoimmunity

Background and purpose

Outcome and rechallenge data on central nervous system (CNS) autoimmunity triggered by immune checkpoint inhibitors (ICIs) are limited. We aim to describe a large series of patients with ICI‐triggered CNS autoimmunity, and to compare these patients with spontaneous paraneoplastic syndromes (PNS).

Methods

We retrospectively reviewed Mayo Clinic patients with ICI‐triggered CNS autoimmunity (February 2015–June 2021). Clinical characteristics were compared to spontaneous PNS patients (with antineuronal nuclear antibody [ANNA]‐1 or anti‐Hu neurological autoimmunity, and/or neuroendocrine tumors [NET]) evaluated within the same period.

Results

Thirty‐one patients were included (55% female, median age = 63 years, range = 39–76). Median time from ICI initiation was 3.65 months (range = 0.8–44.5). The most common associated malignancies were melanoma and small cell lung cancer. CNS manifestations included encephalitis ( = 16), meningoencephalitis ( = 8), cerebellar ataxia ( = 4), demyelinating syndrome ( = 2), and myelopathy ( = 1). Magnetic resonance imaging was abnormal in 62%. Cerebrospinal fluid was inflammatory in 70%. Neural autoantibodies were identified in 47%, more frequently in patients with NET ( = 0.046). ICI was discontinued in 97%; 90% received immunosuppressive treatment. After median 6.8 months follow‐up (range = 0.7–46), 39% had unfavorable outcomes (grade ≥ 3). This was associated with higher severity degree at onset, shorter period from ICI to neurological symptom onset, and encephalitis. Four patients were rechallenged with ICI, and one relapsed. Patients with NET and with ANNA‐1 ICI‐triggered CNS autoimmunity had associated peripheral nervous system manifestations more frequently than their spontaneous counterparts ( = 0.007 and = 0.028, respectively).

Conclusions

One third of ICI‐related CNS autoimmunity patients have unfavorable outcomes. Relapses may occur after ICI rechallenge. Neural autoantibodies are often present, more commonly in patients with NET.

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Authors:
Cristina Valencia‐Sanchez, Elia Sechi, Divyanshu Dubey, Eoin P. Flanagan, Andrew McKeon, Sean J. Pittock and Anastasia Zekeridou

Article first published online:
18 May 2023 | DOI: 10.1111/ene.15835

ORIGINAL ARTICLE

Decreasing incidence of stroke, ischaemic heart disease and dementia in Norway, 1990–2019, a Global Burden of Disease study: an opportunity

Background and purpose

The declining incidence of stroke, ischaemic heart disease (IHD) and dementia (the ‘triple threat’) in Norway encourages further investigation. The risks and trends of the three conditions were analysed using data from the Global Burden of Disease study.

Methods

Global Burden of Disease 2019 estimations were used for age‐, sex‐ and risk‐factor‐specific incidence and prevalence of the ‘triple threat’, their risk‐factor‐attributed deaths and disability combined, their age‐standardized rates per 100,000 population in 2019 and their changes during 1990–2019. Data are presented as means and 95% uncertainty intervals.

Results

In 2019, 71.1 thousand Norwegians were living with dementia, 157.2 thousand with IHD and 95.2 thousand with stroke. In 2019, there were 9.9 thousand (8.5 to 11.3) new cases of dementia (35.0% increase since 1990), 17.0 thousand (14.6 to 19.6) with IHD (3.6% decrease) and 8.0 thousand (7.0 to 9.1) with stroke (12.9% decrease) in Norway. During 1990–2019, their age‐standardized incidence rates decreased significantly—dementia by −5.4% (−8.4% to −3.2%), IHD by −30.0% (−31.4% to −28.6%) and stroke by −35.3% (−38.3% to −32.2%). There were significant declines in the attributable risks to both environmental and behavioural factors in Norway, but contradictory trends for metabolic risk factors during 1990–2019.

Conclusions

The risk of the ‘triple threat’ conditions is declining in Norway, despite the increased prevalence. This offers the opportunity to find out why and how and to accelerate their joint prevention through new approaches and the promotion of the National Brain Health Strategy.

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Authors:
Abolfazl Avan, Anne Hege Aamodt, Geir Selbæk, Gunnar Bovim, Claudio L. A. Bassetti, Paul Boon, Wolfgang Grisold and Vladimir Hachinski

Article first published online:
21 May 2023 | DOI: 10.1111/ene.15836

ORIGINAL ARTICLE

Decreased emotion recognition and reduced focus on facial hallmarks in behavioral variant frontotemporal dementia compared to primary psychiatric disorders and controls

Background and purpose

Early diagnosis of behavioral variant frontotemporal dementia (bvFTD) is challenging due to symptomatic overlap with primary psychiatric disorders (PPD). As emotion recognition deficits are early and key features of bvFTD, the aim was to explore processes driving social cognition deficits that may aid in the differentiation between bvFTD and PPD.

Methods

The total sample ( = 51) included 18 patients with bvFTD, 11 patients with PPD (mood, autism spectrum and psychotic disorders) and 22 controls from the Alzheimer Center Amsterdam of the Amsterdam UMC. Emotion recognition was assessed with the Ekman 60 Faces test, during which eye tracking metrics were collected in the first 5 s a face was presented. Group differences in dwell time on the total image as well as the circumscribed eyes area and mouth area were analysed using ANOVA, with post hoc comparisons.

Results

Patients with bvFTD scored lowest, patients with PPD scored intermediate and controls scored highest on emotion recognition. During facial processing, patients with bvFTD spent less dwell time on the total image than controls (mean difference 11.3%, (2, 48) = 6.095, = 0.004; bvFTD−controls = 0.001, 95% confidence interval [CI] −892.64, −239.70). Dwell time on the eyes area did not differ between diagnostic groups, whilst patients with bvFTD spent less dwell time on the mouth area than PPD patients (mean difference 10.7%; (2, 48) = 3.423, = 0.041; bvFTD−PPD = 0.022, 95% CI −986.38, −79.47) and controls (mean difference 7.8%; bvFTD−controls = 0.043, 95% CI −765.91, −12.76).

Conclusions

In bvFTD, decreased emotion recognition may be related to reduced focus on facial hallmarks. These findings suggest a valuable role for biometrics in social cognition assessment and the differentiation between bvFTD and PPD.

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Authors:
Jay L. P. Fieldhouse, Ellen H. Singleton, Marie‐Paule E. van Engelen, Jochum J. van't Hooft, Sterre C. M. de Boer, Violet E. Froeling, Michelle Braun, Mardien L. Oudega, Daniël van Grootheest, Cora Kerssens, Flora H. Duits, Argonde C. van Harten, Everard G. B. Vijverberg and Yolande A. L. Pijnenburg

Article first published online:
25 May 2023 | DOI: 10.1111/ene.15837

REVIEW ARTICLE

Risk of myocardial infarction in Parkinson's disease: A systematic review and meta‐analysis

Background and purpose

Previous studies investigating cardiovascular disorders in patients with Parkinson's disease (PD) showed heterogeneous results regarding whether there is a higher or lower risk of myocardial infarction (MI) in these patients compared to the general population. Because of the inconsistency in findings, herein the aim was to perform a systematic review and meta‐analysis to investigate the risk of MI in patients with PD.

Methods

A comprehensive literature search was performed using four databases, PubMed, Web of Science, Scopus and Embase, in June 2022. Peer‐reviewed observational studies comprising case–controls, cohort, cross‐sectional and longitudinal studies that reported MI in the PD population were included.

Results

After the screening, 20 studies with a total of 80,441 patients with PD and 802,857 controls were included in our qualitative and quantitative synthesis. The pooled estimated odds ratio for MI in PD patients compared to controls was 0.80 (95% confidence interval [CI] 0.56–1.05) which indicates that there is no association. The pooled prevalence of MI was 5% (95% CI 3%–7%) with a range of 1%–20% amongst patients with PD. The men (6%, 95% CI 1%–13%) and women (6%, 95% CI 1%–14%, = 29.27, = 98.50%, < 0.001) had similar MI prevalence.

Conclusion

This comprehensive systematic review and meta‐analysis provide compelling evidence that PD is associated with a reduced risk of MI. Whilst the exact mechanism underlying this association remains to be fully elucidated, it is clear that certain risk factors for cardiac events appear to be less present in PD patients, which may serve as a protective factor. However, given the reports of increased risk for cerebrovascular events in PD patients, it is possible that the major risk factors for MI and cardiovascular accidents in this population differ. These findings have important implications for clinical management and further research in this area is warranted.

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Authors:
Fardin Nabizadeh, Parya Valizadeh, Parisa Sharifi, Rasa Zafari and Omid Mirmosayyeb

Article first published online:
21 May 2023 | DOI: 10.1111/ene.15838

ORIGINAL ARTICLE

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

Background

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Mindfulness and meditation therapies have been demonstrated as effective alternative treatments for patients with neurological disorders. However, the effects of mindfulness and meditation therapies on PD remain unclear. This meta‐analysis investigated the effects of mindfulness and meditation therapies in PD patients.

Methods

A literature search was conducted using PubMed, Embase, Cochrane Library, and for randomized controlled trials comparing mindfulness and meditation therapies with control treatments in patients with PD.

Results

Nine articles involving eight trials were included, with a total of 337 patients. Our meta‐analysis revealed that mindfulness and meditation therapies significantly improved Unified Parkinson's Disease Rating Scale‐Part III score (mean difference [MD] = −6.31, 95% confidence interval [95% CI] = −8.57 to −4.05) and cognitive function (standard mean difference [SMD] = 0.62, 95% CI = 0.23 to 1.02). However, no significant differences were discovered between mindfulness therapies and control in gait velocity (MD = 0.05, 95% CI = −0.23 to 0.34), Parkinson's Disease Questionnaire‐39 Summary Index (MD = 0.51, 95% CI = −1.12 to 2.14), activities of daily living (SMD = −1.65, 95% CI = −3.74 to 0.45), depression (SMD = −0.43, 95% CI = −0.97 to 0.11), anxiety (SMD = −0.80, 95% CI = −1.78 to 0.19), pain (SMD = 0.79, 95% CI = −1.06 to 2.63), or sleep disturbance (SMD = −0.67, 95% CI = −1.58 to 0.24).

Conclusion

Mindfulness and meditation therapies may serve as complementary and alternative treatments for PD patients.

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Authors:
Ho‐Wei Lin, Ka‐Wai Tam and Yi‐Chun Kuan

Article first published online:
21 May 2023 | DOI: 10.1111/ene.15839

SHORT COMMUNICATION

Spinocerebellar ataxia type 15 caused by missense variants in the gene

Background and purpose

Spinocerebellar ataxia type 15 (SCA15) is a degenerative, adult onset autosomal dominant cerebellar ataxia, caused almost exclusively by deletions in the inositol 1,4,5 triphosphate receptor type 1 (ITPR1) gene (). ITPR1 mediates calcium release from the endoplasmic reticulum, and particularly abounds in Purkinje cells. It plays a pivotal role in excitatory and inhibitory actions on Purkinje cells, and alterations in their balance cause cerebellar dysfunction in knockout mice. To date, only two single missense mutations have been reported to cause SCA15. They were considered pathogenic because cosegregation occurred with disease, and haploinsufficiency was hypothesized as their pathogenic mechanism.

Methods

In this study, three Caucasian kindreds with different heterozygous missense variants in are reported. The main clinical manifestation was a slowly progressive gait ataxia with onset after 40 years of age, with chorea in two patients and hand tremor in another one, concordant with manifestations found in SCA15.

Results

The three missense variants identified in ITPR1 were c.1594G>A; p.(Ala532Thr) in Kindred A, c.56C>T; p.(Ala19Val) in Kindred B, and c.256G>A; p.(Ala86Thr) in Kindred C. Every variant was labelled as of unknown significance; however, each one cosegregated with disease and was predicted to be pathogenic by in silico tests.

Conclusions

The three missense variants found in this study exhibited cosegregation with disease, a result that sustains their pathogenicity. Further studies are needed to confirm the role of missense mutations in SCA15.

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Authors:
José Gazulla, Elena Bellosta‐Diago, Silvia Izquierdo‐Alvarez and José Berciano

Article first published online:
19 May 2023 | DOI: 10.1111/ene.15840

ORIGINAL ARTICLE

Peripheral nerve involvement in hereditary spastic paraplegia characterized by quantitative magnetic resonance neurography

Background and objectives

Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders. While peripheral nerve involvement is frequent in spastic paraplegia 7 (SPG7), the evidence of peripheral nerve involvement in SPG4 is more controversial. We aimed to characterize lower extremity peripheral nerve involvement in SPG4 and SPG7 by quantitative magnetic resonance neurography (MRN).

Methods

Twenty‐six HSP patients carrying either the SPG4 or SPG7 mutation and 26 age‐/sex‐matched healthy controls prospectively underwent high‐resolution MRN with large coverage of the sciatic and tibial nerve. Dual‐echo turbo‐spin‐echo sequences with spectral fat‐saturation were utilized for T2‐relaxometry and morphometric quantification, while two gradient‐echo sequences with and without an off‐resonance saturation rapid frequency pulse were applied for magnetization transfer contrast (MTC) imaging. HSP patients additionally underwent detailed neurologic and electroneurographic assessments.

Results

All microstructural (proton spin density [ρ], T2‐relaxation time, magnetization transfer ratio) and morphometric (cross‐sectional area) quantitative MRN markers were decreased in SPG4 and SPG7 indicating chronic axonopathy. ρ was superior in differentiating subgroups and identifying subclinical nerve damage in SPG4 and SPG7 without neurophysiologic signs of polyneuropathy. MRN markers correlated well with clinical scores and electroneurographic results.

Conclusions

MRN characterizes peripheral nerve involvement in SPG4 and SPG7 as a neuropathy with predominant axonal loss. Evidence of peripheral nerve involvement in SPG4 and SPG7, even without electroneurographically manifest polyneuropathy, and the good correlation of MRN markers with clinical measures of disease progression, challenge the traditional view of the existence of HSPs with isolated pyramidal signs and suggest MRN markers as potential progression biomarkers in HSP.

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Authors:
Heike Jacobi, Markus Weiler, Georges Sam, Sabine Heiland, John M. Hayes, Martin Bendszus, Rebecca Schüle and Jennifer C. Hayes

Article first published online:
26 May 2023 | DOI: 10.1111/ene.15841

ORIGINAL ARTICLE

Predictors for clinical and functional outcomes in stroke patients with first‐pass complete recanalization after thrombectomy

Background and purpose

The aim was to identify baseline clinical and radiological/procedural predictors and 24‐h radiological predictors for clinical and functional outcomes in stroke patients obtaining complete recanalization in one pass of mechanical thrombectomy (MT) in an optimal baseline and procedural setting.

Methods

A retrospective analysis was conducted of prospectively collected data from 924 stroke patients with anterior large vessel occlusion, Alberta Stroke Program Early Computed Tomography (ASPECT) score ≥6 and pre‐stroke modified Rankin Scale score 0, who started MT ≤6 h from symptom onset and obtained first‐pass complete recanalization. A first logistic regression model was performed to identify baseline clinical predictors and a second model to identify baseline radiological/procedural predictors. A third model including baseline clinical and radiological/procedural predictors was performed, and a fourth model including independent baseline predictors from the third model plus 24‐h radiological variables (hemorrhagic transformation [HT] and cerebral edema [CED]).

Results

In the fourth model, higher National Institutes of Health Stroke Scale (NIHSS) score (odds ratio [OR] 1.089) and higher ASPECT score (OR 1.292) were predictors of early neurological improvement (ENI) (NIHSS score ≤4 points from baseline or NIHSS score of 0 at 24 h), whereas older age (OR 0.973), longer procedure time (OR 0.990), HT (OR 0.272) and CED (OR 0.569) were inversely associated with ENI. Older age (OR 0.970), diabetes mellitus (OR 0.456), higher NIHSS score (OR 0.886), general anesthesia (OR 0.454), longer onset‐to‐groin time (OR 0.996), HT (OR 0.340) and CED (OR 0.361) were inversely associated with 3‐month excellent functional outcome (mRS score 0–1), whereas higher ASPECT score (OR 1.294) was a predictor of excellent outcome.

Conclusions

Higher NIHSS score was a predictor of ENI but inversely associated with 3‐month excellent outcome. Older age, HT and CED were inversely associated with both good outcomes.

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Authors:
Manuel Cappellari, Valentina Saia, Giovanni Pracucci, Enrico Fainardi, Ilaria Casetta, Fabrizio Sallustio, Patrizia Nencini, Guido Bigliardi, Andrea Saletti, Maria Ruggiero, Valerio Da Ros, Lucio Castellan, Rossana Tassi, Nicolò Mandruzzato, Danilo Toni and Salvatore Mangiafico

Article first published online:
21 May 2023 | DOI: 10.1111/ene.15842

ORIGINAL ARTICLE

History of cerebrovascular disease but not dementia increases the risk for secondary vascular events during SARS‐CoV‐2 infection with presumed Omicron variant: a retrospective observational study

Background and purpose

This study aimed to investigate if pre‐existing neurological conditions, such as dementia and a history of cerebrovascular disease, increase the risk of severe outcomes including death, intensive care unit (ICU) admission and vascular events in patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in 2022, when Omicron was the predominant variant.

Methods

A retrospective analysis was conducted of all patients with SARS‐CoV‐2 infection, confirmed by polymerase chain reaction test, admitted to the University Medical Center Hamburg‐Eppendorf from 20 December 2021 until 15 August 2022. In all, 1249 patients were included in the study. In‐hospital mortality was 3.8% and the ICU admission rate was 9.9%. Ninety‐three patients with chronic cerebrovascular disease and 36 patients with pre‐existing all‐cause dementia were identified and propensity score matching by age, sex, comorbidities, vaccination status and dexamethasone treatment was performed in a 1:4 ratio with patients without the respective precondition using nearest neighbor matching.

Results

Analysis revealed that neither pre‐existing cerebrovascular disease nor all‐cause dementia increased mortality or the risk for ICU admission. All‐cause dementia in the medical history also had no effect on vascular complications under investigation. In contrast, an increased odds ratio for both pulmonary artery embolism and secondary cerebrovascular events was observed in patients with pre‐existing chronic cerebrovascular disease and myocardial infarction in the medical history.

Conclusion

These findings suggest that patients with pre‐existing cerebrovascular disease and myocardial infarction in their medical history may be particularly susceptible to vascular complications following SARS‐CoV‐2 infection with presumed Omicron variant.

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Authors:
Christina Mayer, Marcel S. Woo, Thomas Theo Brehm, Andreas Heyer, Marlene Fischer, Felix Fischbach, Lukas C. Bal, Marylyn M. Addo, Stefan Kluge, Götz Thomalla, Nils Schweingruber and Julian Schulze zur Wiesch

Article first published online:
25 May 2023 | DOI: 10.1111/ene.15843

ORIGINAL ARTICLE

A scoring tool to predict mortality and dependency after cerebral venous thrombosis

Background and purpose

A prognostic score was developed to predict dependency and death after cerebral venous thrombosis (CVT) to identify patients for targeted therapy in future clinical trials.

Methods

Data from the International CVT Consortium were used. Patients with pre‐existent functional dependency were excluded. Logistic regression was used to predict poor outcome (modified Rankin Scale score 3–6) at 6 months and Cox regression to predict 30‐day and 1‐year all‐cause mortality. Potential predictors derived from previous studies were selected with backward stepwise selection. Coefficients were shrunk using ridge regression to adjust for optimism in internal validation.

Results

Of 1454 patients with CVT, the cumulative number of deaths was 44 (3%) and 70 (5%) for 30 days and 1 year, respectively. Of 1126 patients evaluated regarding functional outcome, 137 (12%) were dependent or dead at 6 months. From the retained predictors for both models, the SINCALC score was derived utilizing the following components: absence of female‐sex‐specific risk factor, intracerebral hemorrhage, infection of the central nervous system, neurological focal deficits, coma, age, lower level of hemoglobin (g/l), higher level of glucose (mmol/l) at admission, and cancer. C‐statistics were 0.80 (95% confidence interval [CI] 0.75–0.84), 0.84 (95% CI 0.80–0.88) and 0.84 (95% CI 0.80–0.88) for the poor outcome, 30‐day and 1‐year mortality model, respectively. Calibration plots indicated a good model fit between predicted and observed values. The SINCALC score calculator is freely available at .

Conclusions

The SINCALC score shows adequate performance for estimating individual risk of mortality and dependency after CVT but external validation of the score is warranted.

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Authors:
Erik Lindgren, Katarzyna Krzywicka, Maria A. de Winter, Mayte Sánchez Van Kammen, Mirjam R. Heldner, Sini Hiltunen, Diana Aguiar de Sousa, Maryam Mansour, Patrícia Canhão, Esme Ekizoğlu, Miguel Rodrigues, Elisa Martins Silva, Carlos Garcia‐Esperon, Valentina Arnao, Paolo Aridon, Naaem Moin Simaan, Suzanne M. Silvis, Susanna M. Zuurbier, Adrian Scutelnic, Mine Sezgin, Andrey Marisovich Alasheev, Andrey Smolkin, Daniel Guisado‐Alonso, Nilufer Yesilot, Miguel Barboza, Masoud Ghiasian, Ronen R. Leker, Antonio Arauz, Marcel Arnold, Jukka Putaala, Turgut Tatlisumak, Jonathan M. Coutinho and Katarina Jood

Article first published online:
28 May 2023 | DOI: 10.1111/ene.15844

ORIGINAL ARTICLE

Lower initial red blood cell count in cerebrospinal fluid predicts good functional outcome in patients with spontaneous subarachnoid haemorrhage

Background and purpose

Red blood cell (RBC) degradation after subarachnoid haemorrhage (SAH) negatively affects functional outcome. Although the detection of RBCs in the cerebrospinal fluid (CSF) is a widely available part of neurological routine diagnostics, the prognostic value as a biomarker remains unclear. This study was undertaken to investigate whether CSF RBC count correlates with established radiological markers of SAH volume and whether the CSF RBC count can predict functional outcome in SAH patients.

Methods

A total of 121 consecutive spontaneous SAH patients were retrospectively analyzed. CSF was collected from external ventricular drain as part of routine diagnostic procedures. We used multivariable binary logistic regression to investigate associations between CSF RBC counts and functional outcome 3 months after SAH or hospital survival. Good functional outcome was defined as modified Rankin Scale ≤ 2.

Results

Patients' age was 60 ± 14 years, and the median admission Hunt & Hess grade (H&H) was 4. CSF samples were collected 2 days after intensive care unit admission. High CSF RBC counts positively correlated with radiological measurements for SAH volume, for example, modified Fisher score ( = 0.002) and Hijdra ventricle score ( = 0.016). Multivariable regression analysis adjusted for age, H&H grade, modified Fisher and Hijdra scores showed that low CSF RBC counts predicted hospital survival (per 100,000 CSF RBCs: adjusted odds ratio [adjOR] = 0.74, 95% confidence interval [CI] = 0.61–0.89, = 0.001) and good functional outcome after 3 months (per 100,000 CSF RBC: adjOR = 0.76, 95% CI = 0.60–0.96, = 0.020).

Conclusions

CSF RBC counts correlate with radiographic scores quantifying SAH volume and may serve as an early independent biomarker for hospital survival and good functional 3‐month outcome in patients requiring ventriculostomy after SAH.

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Authors:
Anna Lindner, Klaus Berek, Verena Rass, Franziska Di Pauli, Mario Kofler, Anne Zinganell, Lauma Putnina, Philipp Kindl, Alois J. Schiefecker, Bettina Pfausler, Ronny Beer, Florian Deisenhammer, Harald Hegen and Raimund Helbok

Article first published online:
27 May 2023 | DOI: 10.1111/ene.15845

ORIGINAL ARTICLE

Early predictors of dysphagia in ischaemic stroke patients

Background and purpose

Post‐stroke dysphagia affects outcome. In acute stroke patients, the aim was to evaluate clinical, cognitive and neuroimaging features associated with dysphagia and develop a predictive score for dysphagia.

Methods

Ischaemic stroke patients underwent clinical, cognitive and pre‐morbid function evaluations. Dysphagia was retrospectively scored on admission and discharge with the Functional Oral Intake Scale.

Results

In all, 228 patients (mean age 75.8 years; 52% males) were included. On admission, 126 (55%) were dysphagic (Functional Oral Intake Scale ≤6). Age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00–1.05), pre‐event modified Rankin scale (mRS) score (OR 1.41, 95% CI 1.09–1.84), National Institutes of Health Stroke Scale (NIHSS) score (OR 1.79, 95% CI 1.49–2.14), frontal operculum lesion (OR 8.53, 95% CI 3.82–19.06) and Oxfordshire total anterior circulation infarct (TACI) (OR 1.47, 95% CI 1.05–2.04) were independently associated with dysphagia at admission. Education (OR 0.91, 95% CI 0.85–0.98) had a protective role. At discharge, 82 patients (36%) were dysphagic. Pre‐event mRS (OR 1.28, 95% CI 1.04–1.56), admission NIHSS (OR 1.88, 95% CI 1.56–2.26), frontal operculum involvement (OR 15.53, 95% CI 7.44–32.43) and Oxfordshire classification TACI (OR 3.82, 95% CI 1.95–7.50) were independently associated with dysphagia at discharge. Education (OR 0.89, 95% CI 0.83–0.96) and thrombolysis (OR 0.77, 95% CI 0.23–0.95) had a protective role. The 6‐point “NOTTEM” (NIHSS, opercular lesion, TACI, thrombolysis, education, mRS) score predicted dysphagia at discharge with good accuracy. Cognitive scores had no role in dysphagia risk.

Conclusions

Dysphagia predictors were defined and a score was developed to evaluate dysphagia risk during stroke unit stay. In this setting, cognitive impairment is not a predictor of dysphagia. Early dysphagia assessment may help in planning future rehabilitative and nutrition strategies.

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Authors:
Daniele Mattavelli, Francesco Mele, Ilaria Cova, Silvia Rosa, Pierluigi Bertora, Simone Pomati, Nicole Pizzorni, Antonio Schindler and Leonardo Pantoni

Article first published online:
23 May 2023 | DOI: 10.1111/ene.15846

ORIGINAL ARTICLE

Age‐dependent retinal neuroaxonal degeneration in children and adolescents with Leber hereditary optic neuropathy under idebenone therapy

Background

The aim of this study was to investigate the neuroretinal structure of young patients with Leber hereditary optic neuropathy (LHON).

Methods

For this retrospective cross‐sectional analysis, the peripapillary retinal nerve fiber layer (pRNFL) thickness and the macular retinal layer volumes were measured by optical coherence tomography. Patients aged 12 years or younger at disease onset were assigned to the childhood‐onset (ChO) group and those aged 13–16 years to the early teenage‐onset (eTO) group. All patients received treatment with idebenone. The same measurements were repeated in age‐matched control groups with healthy subjects.

Results

The ChO group included 11 patients (21 eyes) and the eTO group 14 patients (27 eyes). Mean age at onset was 8.6 ± 2.7 years in the ChO group and 14.8 ± 1.0 years in the eTO group. Mean best‐corrected visual acuity was 0.65 ± 0.52 logMAR in the ChO group and 1.60 ± 0. 51 logMAR in the eTO group ( < 0.001). Reduced pRNFL was evident in the eTO group compared to the ChO group (46.0 ± 12.7 μm vs. 56.0 ± 14.5 μm, = 0.015). Additionally, a significantly lower combined ganglion cell and inner plexiform layer volume was found in the eTO compared to the ChO group (0.266 ± 0.0027 mm vs. 0.294 ± 0.033 mm, = 0.003). No difference in these parameters was evident between the age‐matched control groups.

Conclusion

Less neuroaxonal tissue degeneration was observed in ChO LHON than in eTO LHON, a finding that may explain the better functional outcome of ChO LHON.

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Authors:
Benedikt Schworm, Jakob Siedlecki, Claudia Catarino, Bettina von Livonius, Daniel R. Muth, Guenther Rudolph, Joachim Havla, Thomas Klopstock and Claudia Priglinger

Article first published online:
23 May 2023 | DOI: 10.1111/ene.15847

ORIGINAL ARTICLE

Incidental demyelination in magnetic resonance imaging and 10‐year risk of multiple sclerosis: A data lake cohort study

Background and purpose

There is an absence of data from large population‐based cohort studies on the incidence of radiologically isolated syndrome (RIS). The incidence of RIS and the subsequent risk for multiple sclerosis (MS) were investigated.

Methods

A population‐based, retrospective cohort study was conducted using a data‐lake‐based analysis of digitalized radiology reports. All brain and spinal cord magnetic resonance imaging (MRI) in people aged 16–70 during the years 2005–2010 ( = 102,224) were screened using optimized search terms to detect cases with RIS. The subjects with RIS were followed up until January 2022.

Results

The cumulative incidence of RIS was 0.03% when all MRI modalities were included and 0.06% when only brain MRI was included according to MAGNIMS 2018 recommendation criteria. With the Okuda 2009 criteria, the respective figures were 0.03% and 0.05% (86% concordance). The overall risk for MS after RIS was similar, 32% by using the MAGNIMS and 32% by using the Okuda definition of RIS. Individuals aged <35.5 years exhibited the most significant predisposition to MS (80%), whilst those >35.5 years had less than 10% risk of MS. MS diagnosed after RIS constituted 0.8% of the incident MS cases in the population during 2005–2010.

Conclusions

A population‐wide context was provided for the incidence of RIS and its relationship to MS. MAGNIMS recommendations were only slightly more sensitive to detect RIS compared to the Okuda criteria. RIS has a subtle effect on the overall incidence of MS, yet the risk for MS in individuals under the age of 35.5 years is substantial.

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Authors:
Anna Maunula, Juha Martola, Sari Atula, Sini M. Laakso and Pentti J. Tienari

Article first published online:
21 May 2023 | DOI: 10.1111/ene.15849

EDITORIAL

Seizures—the second most frequent neurological emergency

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Authors:
Camilla Dyremose Cornwall and Christoph Patrick Beier

Article first published online:
22 May 2023 | DOI: 10.1111/ene.15851

ORIGINAL ARTICLE

Rapid recovery of poststroke cardiac autonomic dysfunction: Causes to be considered

Background and purpose

Acute stroke frequently causes cardiovascular–autonomic dysfunction (CAD). Studies of CAD recovery are inconclusive, whereas poststroke arrhythmias may wane within 72 h. We evaluated whether poststroke CAD recovers within 72 h upon stroke onset in association with neurological improvement or increased use of cardiovascular medication.

Methods

In 50 ischemic stroke patients (68 ± 13 years old) who—prior to hospital‐admission—had no known diseases nor took medication affecting autonomic modulation, we assessed National Institutes of Health Stroke Scale (NIHSS) scores, RR intervals (RRIs), systolic and diastolic blood pressure (BP), respiration rate, parameters reflecting total autonomic modulation (RRI SD, RRI total powers), sympathetic modulation (RRI low‐frequency powers, systolic BP low‐frequency powers), and parasympathetic modulation (square root of mean squared differences of successive RRIs [RMSSD], RRI high‐frequency powers), and baroreflex sensitivity within 24 h (Assessment 1) and 72 h after stroke onset (Assessment 2) and compared data to those of 31 healthy controls (64 ± 10 years). We correlated delta NIHSS values (Assessment 1 – Assessment 2) with delta values of autonomic parameters (Spearman rank correlation tests; significance: < 0.05).

Results

At Assessment 1, patients were not yet on vasoactive medication and had higher systolic BP, respiration rate, and heart rate, that is, lower RRIs, but lower RRI SD, RRI coefficient of variance, RRI low‐frequency powers, RRI high‐frequency powers, RRI total powers, RMSSDs, and baroreflex sensitivity. At Assessment 2, patients were on antihypertensives, had higher RRI SD, RRI coefficient of variance, RRI low‐frequency powers, RRI high‐frequency powers, RRI total powers, RMSSDs, and baroreflex sensitivity but lower systolic blood pressure and NIHSS values than at Assessment 1; values no longer differed between patients and controls except for lower RRIs and higher respiration rate in patients. Delta NIHSS scores correlated inversely with delta values of RRI SD, RRI coefficient of variance, RMSSDs, RRI low‐frequency powers, RRI high‐frequency powers, RRI total powers, and baroreflex sensitivity.

Conclusions

In our patients, CAD recovery was almost complete within 72 h after stroke onset and correlated with neurological improvement. Most likely, early initiation of cardiovascular medication and probably attenuating stress supported rapid CAD recovery.

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Authors:
Ruihao Wang, Sebastian Moeller, Aynur Akhundova, Harald Marthol, Rainer Kollmar, Martin Köhrmann and Max J. Hilz

Article first published online:
23 May 2023 | DOI: 10.1111/ene.15853

ORIGINAL ARTICLE

Demographic and clinical determinants of the quality of life in adults with inherited and acquired myopathies

Background and purpose

Measuring health‐related quality of life (QOL) is vital for understanding the disease impact, but the complex relationship between clinical parameters and QOL remains unclear. The objective was to determine the demographic and clinical factors that influence the QOL in adults with inherited and acquired myopathies.

Methods

The study was of cross‐sectional design. Detailed demographic and clinical details were collected. Patients answered Neuro‐QOL and Patient‐Reported Outcomes Measurement Information System short‐form questionnaires.

Results

Data was collected from 100 consecutive in‐person patient visits. Mean age of the cohort was 49.5 ± 20.1 (18–85) years, and the majority were male (53, 53%). Bivariate analysis between the various demographic and clinical features with the QOL scales revealed single simple question (SSQ), handgrip strength, Medical Research Council (MRC) sum score, female gender, and age to be nonuniformly associated with the QOL scales. There was no difference between inherited and acquired myopathies for any of the QOL scores, except for the poorer lower limb function domain in inherited myopathies (36.7 ± 7.3 vs. 40.9 ± 11.2, = 0.049). Linear regression models revealed lower SSQ, lower handgrip strength, and lower MRC sum score to independently predict poor QOL.

Conclusions

Handgrip strength and SSQ serve as novel predictors of QOL in myopathies. Handgrip strength has a significant impact on physical, mental, and social domains and deserves special attention with respect to rehabilitation. SSQ correlates well with QOL and can be employed as a quick and global assessment of a patient's well‐being. Differences in QOL scores between patients with inherited and acquired myopathies were minimal.

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Authors:
Deepak Menon, Sara Alnajjar, Hans Katzberg, Carolina Barnett and Vera Bril

Article first published online:
28 May 2023 | DOI: 10.1111/ene.15854

ORIGINAL ARTICLE

Advantages of routine next‐generation sequencing over standard genetic testing in the amyotrophic lateral sclerosis clinic

Background

Next‐generation sequencing has enhanced our understanding of amyotrophic lateral sclerosis (ALS) and its genetic epidemiology. Outside the research setting, testing is often restricted to those who report a family history. The aim of this study was to explore the added benefit of offering routine genetic testing to all patients in a regional ALS centre.

Methods

expansion testing and exome sequencing was offered to consecutive patients (150 with ALS and 12 with primary lateral sclerosis [PLS]) attending the Oxford Motor Neuron Disease Clinic within a defined time period.

Results

A total of 17 (11.3%) highly penetrant pathogenic variants in , , , and were detected, of which 10 were also found through standard clinical genetic testing pathways. The systematic approach resulted in five additional diagnoses of a expansion (number needed to test [NNT] = 28), and two further missense variants in and (NNT = 69). Additionally, 3 patients were found to carry pathogenic risk variants in , and 13 patients harboured common missense variants in and , also associated with an increased risk of ALS. We report two novel non‐coding loss‐of‐function splice variants in and . No relevant variants were found in the PLS patients. Patients were offered double‐blinded participation, but >80% requested disclosure of the results.

Conclusions

This study provides evidence that expanding genetic testing to all patients with a clinical diagnosis of ALS enhances the potential for recruitment to clinical trials, but will have direct resource implications for genetic counselling.

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Authors:
Jakub Scaber, Alexander G. Thompson, Lucy Farrimond, Emily Feneberg, Malcolm Proudfoot, Lynn Ossher, Martin R. Turner and Kevin Talbot

Article first published online:
28 May 2023 | DOI: 10.1111/ene.15855

COMMENTARY

Improving brain and vascular health at the population level: Lessons from the Norwegian success story

Abstract

Stroke, dementia and ischemic heart disease are a triple threat which combined are the leading causes of death and disability globally. Fortunately, the three diseases share similar risk factors along the vascular cascade which can be targeted for primordial and primary prevention. In Norway, during 1990–2019, the age‐standardised incidence rates decreased significantly for dementia by −5.4%, ischemic heart disease by −30.0%, and stroke by −35.3%. This was possible because Norway ensured equitable income for her citizens, and committed sufficient funds to universal health coverage while implementing a semi‐decentralized and responsive health system with robust primary health care. This included monitoring the burden of the triple threat and their cardinal risk factors; ensuring primordial, primary and secondary preventive interventions; implementing acute care for ischemic heart disease and stroke; and ensuring interdisciplinary rehabilitation and chronic care for the triple threat. Overall, all countries will need to develop national strategies for combating the triple threat within the context of sustainable development goals with adequate allocation and utilization of resources.

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Authors:
Mayowa O. Owolabi

Article first published online:
25 May 2023 | DOI: 10.1111/ene.15856

REVIEW ARTICLE

Efficacy of hematopoietic stem cell transplantation treatment in refractory chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review and meta‐analysis

Background and purpose

Treatment options for chronic inflammatory demyelinating polyneuropathy (CIDP) are intravenous immunoglobulin, plasmapheresis, corticosteroids and immunosuppressive drugs. However, a substantial proportion of patients with CIDP remain refractory to treatment and develop severe functional disability. A systematic review and a meta‐analysis of the efficacy of hematopoietic stem cell transplantation (HSCT) treatment in refractory CIDP patients was performed.

Methods

The study is based on queries in the PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science and databases on 4 December 2022. Articles that met our eligibility criteria were included after screening. Patients' characteristics, treatment regime and outcome measures were extracted.

Results

Eighty‐nine patients in 11 studies were included. The pooled estimate of responsiveness amongst the four included studies was 87.04% (95% confidence interval 66.7%–99.5%) and the pooled estimate of freedom of all immune modulating or suppressive drugs was 80.75% (95% confidence interval 71.2%–90.2%).

Conclusion

This meta‐analysis and systematic review suggested that HSCT can be effective in the treatment of refractory CIDP. Whilst there are risks involved, HSCT may be a beneficial and viable therapy for refractory CIDP when carefully evaluated.

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Authors:
Yongsheng Zheng, Jianian Hu, Chong Sun, Chongbo Zhao and Jie Lin

Article first published online:
29 May 2023 | DOI: 10.1111/ene.15857

ORIGINAL ARTICLE

Plasma neurofilament light chain level is not a biomarker of Charcot–Marie–Tooth disease progression: Results of 3‐year follow‐up study

Background and purpose

Charcot–Marie–Tooth disease (CMT) is a hereditary, slowly progressive neuropathy. Currently, there are no effective pharmacological treatments or sensitive disease activity biomarkers available. The aim of this study was to demonstrate the change in plasma neurofilament light chain (NfL) over time in a CMT cohort and analyse the association between CMT severity and NfL level.

Methods

Initially, 101 CMT patients and 64 controls were enrolled in the study. Repeated evaluation was performed in 73 patients and 28 controls at a 3‐year interval. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Plasma NfL concentration was measured using the Simoa (single molecule array) NfL assay.

Results

Plasma NfL concentration was increased in the CMT group compared with controls ( < 0.001). Overall NfL level increased over the 3‐year interval in both CMT ( = 0.012) and control ( = 0.001) groups. However, in 22 of 73 CMT patients and seven of 28 controls, the NfL level decreased from the baseline. Analysing the association between 3‐year change in plasma NfL and disease severity (CMTNSv2), there was no correlation in the CMT group ( = 0.228, = 0.052) or different CMT subgroups.

Conclusions

Our study verifies increased plasma NfL concentrations in patients with CMT compared with controls. Longitudinal 3‐year data showed a variable change in NfL levels between CMT subtypes. There was no association between change in NfL over time and disease severity. These findings suggests that NfL is not a biomarker for CMT progression.

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Authors:
Signe Setlere, Arta Grosmane, Natalja Kurjane, Linda Gailite, Dmitrijs Rots, Kaj Blennow, Henrik Zetterberg and Viktorija Kenina

Article first published online:
05 Jun 2023 | DOI: 10.1111/ene.15858

ORIGINAL ARTICLE

NT‐proBNP and changes in cognition and global brain structure: The Rotterdam Study

Objective

To investigate the association between N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and changes in cognition and global brain structure.

Methods

In the Rotterdam Study, baseline NT‐proBNP was assessed at baseline from 1997 to 2008. Between 1997 and 2016, participants without dementia or stroke at baseline ( = 9566) had repeated cognitive tests (every 3–6 years) for global cognitive function, executive cognitive function, fine manual dexterity, and memory. Magnetic resonance imaging of the brain was performed repeatedly at re‐examination visits between 2005 and 2015 for 2607 participants to obtain brain volumes, focal brain lesions, and white matter microstructural integrity as measures of brain structure.

Results

Among 9566 participants (mean age 65.1 ± 9.8 years), 5444 (56.9%) were women, and repeated measures of cognition were performed during a median follow‐up time of 5.5 (range 1.1–17.9) years, of whom 2607 participants completed at least one brain imaging scan. Higher levels of NT‐proBNP were associated with a faster decline of scores in the global cognitive function ( value = 0.003) and the Word‐Fluency test ( value = 0.003) but were not related to a steeper deterioration in brain volumes, global fractional anisotropy, and mean diffusivity, as indicators of white matter microstructural integrity, or focal brain lesions.

Conclusions

Higher baseline NT‐proBNP levels were associated with a faster decline in cognition; however, no association with global brain structure was found.

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Authors:
Tian Xiao, Isabelle F. van der Velpen, Wiro J. Niessen, Martijn J. Tilly, Maryam Kavousi, M. Arfan Ikram, M. Kamran Ikram and Meike W. Vernooij

Article first published online:
25 May 2023 | DOI: 10.1111/ene.15859

ORIGINAL ARTICLE

Clinical spectrum and frequency of Charcot–Marie–Tooth disease in Italy: Data from the National CMT Registry

Background and purpose

Data are reported from the Italian CMT Registry.

Methods

The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot–Marie–Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted.

Results

Overall, 1012 patients had registered (535 females) and 711 had received a genetic diagnosis. Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The duplication was the most frequent mutation (45.2%), followed by variants in and (both ~10%) and (3.3%) genes. A relatively high mutation rate in some “rare” genes ( 1.6%, 1.5%, 1.5%) and the presence of multiple mutation clusters across Italy was observed. CMT4A was the most disabling type, followed by CMT4C and CMT1E. Disease progression rate differed depending on the CMT subtype. Foot deformities and walking difficulties were the main features. Shoe inserts and orthotic aids were used by almost one‐half of all patients. Scoliosis was present in 20% of patients, especially in CMT4C. Recessive forms had more frequently walking delay, walking support need and wheelchair use. Hip dysplasia occurred in early‐onset CMT.

Conclusions

The Italian CMT Registry has proven to be a powerful data source to collect information about epidemiology and genetic distribution, clinical features and disease progression of CMT in Italy and is a useful tool for recruiting patients in forthcoming clinical trials.

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Authors:
Chiara Pisciotta, Alessandro Bertini, Irene Tramacere, Fiore Manganelli, Gian Maria Fabrizi, Angelo Schenone, Stefano Tozza, Tiziana Cavallaro, Federica Taioli, Moreno Ferrarini, Marina Grandis, Emilia Bellone, Paola Mandich, Stefano C. Previtali, Yuri Falzone, Isabella Allegri, Luca Padua, Costanza Pazzaglia, Aldo Quattrone, Paola Valentino, Luca Gentile, Massimo Russo, Daniela Calabrese, Isabella Moroni, Emanuela Pagliano, Paola Saveri, Stefania Magri, Silvia Baratta, Franco Taroni, Anna Mazzeo, Lucio Santoro, Giuseppe Vita and Davide Pareyson

Article first published online:
26 May 2023 | DOI: 10.1111/ene.15860

ORIGINAL ARTICLE

Comparison of acute flaccid myelitis and transverse myelitis in children and evaluation of diagnostic criteria

Background and purpose

Acute flaccid myelitis (AFM) and transverse myelitis (TM) are serious conditions that may be difficult to differentiate, especially at onset of disease. In this study, we compared clinical features of pediatric AFM and TM and evaluated current diagnostic criteria, aiming to improve early and accurate diagnosis.

Methods

Two cohorts of children with enterovirus D68‐associated AFM and clinically diagnosed TM were compared regarding presenting clinical features, additional investigations, and outcome. Current diagnostic criteria for AFM and TM were applied to evaluate their specificity.

Results

Children with AFM ( = 21) compared to those with TM ( = 36) were younger (median 3 vs. 10 years), more often had a prodromal illness (100% vs. 39%), predominant proximal weakness (69% vs. 17%), and hyporeflexia (100% vs. 44%), and less often had sensory deficits (0% vs. 81%), bowel and/or bladder dysfunction (12% vs. 69%), and hyperreflexia (0% vs. 44%). On magnetic resonance imaging, brainstem involvement was more common in AFM (74% vs. 21%), whereas supratentorial abnormalities were only seen in TM (0% vs. 40%). When omitting the criterion of a sensory level, 11 of 15 (73%) children with AFM fulfilled the diagnostic criteria for TM. Of children with TM, four of 33 (12%) fulfilled the diagnostic criteria for probable/definite AFM.

Conclusions

Although there is considerable overlap between AFM and TM in children, we found important early differentiating clinical and diagnostic features. Meeting diagnostic criteria for AFM in children with TM and vice versa underlines the importance of thorough clinical examination and early and accurate diagnostic studies.

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Authors:
Jelte Helfferich, Arlette L. Bruijstens, Marjolein Knoester, Oebele F. Brouwer and Rinze F. Neuteboom

Article first published online:
02 Jun 2023 | DOI: 10.1111/ene.15861

ORIGINAL ARTICLE

Association between age and inflammatory disease activity on magnetic resonance imaging in relapse onset multiple sclerosis during long‐term follow‐up

Background and purpose

Inflammatory disease activity in multiple sclerosis (MS) decreases with advancing age. Previous work found a decrease in contrast‐enhancing lesions (CELs) with age. Here, we describe the relation of age and magnetic resonance imaging (MRI) measures of inflammatory disease activity during long‐term follow‐up in a large real‐world cohort of people with relapse onset MS.

Methods

We investigated MRI data from the long‐term observational Amsterdam MS cohort. We used logistic regression models and negative binomial generalized estimating equations to investigate the associations between age and radiological disease activity after a first clinical event.

Results

We included 1063 participants and 10,651 cranial MRIs. Median follow‐up time was 6.1 years (interquartile range = 2.4–10.9 years). Older participants had a significantly lower risk of CELs on baseline MRI (40–50 years vs. <40 years: odds ratio [OR] = 0.640, 95% confidence interval [CI] = 0.45–0.90; >50 years vs. <40 years: OR = 0.601, 95% CI = 0.33–1.08) and a lower risk of new T2 lesions or CELs during follow‐up (40–50 years vs. <40 years: OR = 0.563, 95% CI = 0.47–0.67; >50 years vs. <40 years: OR = 0.486, 95% CI = 0.35–0.68).

Conclusions

Greater age is associated with a lower risk of inflammatory MRI activity at baseline and during long‐term follow‐up. In patients aged >50 years, a less aggressive treatment strategy might be appropriate compared to younger patients.

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Authors:
Eline Coerver, Sophie Janssens, Aroosa Ahmed, Mark Wessels, Zoé van Kempen, Bas Jasperse, Frederik Barkhof, Marcus Koch, Jop Mostert, Bernard Uitdehaag, Joep Killestein and Eva Strijbis

Article first published online:
26 May 2023 | DOI: 10.1111/ene.15862

SHORT COMMUNICATION

A score that predicts aquaporin‐4 IgG positivity in patients with longitudinally extensive transverse myelitis

Background and purpose

Longitudinally extensive transverse myelitis (LETM) associated with aquaporin‐4 autoantibodies (AQP4‐IgG) can cause severe disability. Early diagnosis and prompt treatment are critical to prevent relapses. A novel score is described based on clinical and neuroimaging characteristics that predicts AQP4‐IgG positivity in patients with LETM.

Methods

Patients were enrolled both retrospectively and prospectively from multiple Italian centers. Clinical and neuroimaging characteristics of AQP4‐IgG positive and negative patients were compared through univariate and multivariate analysis.

Results

Sixty‐six patients were included. Twenty‐seven (41%) were AQP4‐IgG positive and median age at onset was 45.5 years (range 19–81, interquartile range 24). Female sex (odds ratio [OR] 17.9, 95% confidence interval [CI] 2.6–381.9; = 0.014), tonic spasms (OR 45.6, 95% CI 3.1–2197; = 0.017) and lesion hypointensity on T1‐weighted images (OR 52.9, 95% CI 6.8–1375; = 0.002) were independently associated with AQP4‐IgG positivity. The AQP4‐IgG positivity in myelitis (AIM) score predicted AQP4‐IgG positivity with 85% sensitivity and 95% specificity. Positive and negative likelihood ratios were 16.6 and 0.2 respectively. The inter‐rater and intra‐rater agreement in the score application were both excellent.

Conclusions

The AIM score predicts AQP4‐IgG positivity with good sensitivity and specificity in patients with a first episode of LETM. The score may assist clinicians in early diagnosis and treatment of AQP4‐IgG positive LETM.

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Authors:
Lucia Campetella, Claudia Papi, Gregorio Spagni, Eleonora Sabatelli, Sara Mariotto, Matteo Gastaldi, Gianvito Masi, Sara Carta, Lara Ahmad, Francesca Rossi, Giorgia Teresa Maniscalco, Giovanna De Luca and Raffaele Iorio

Article first published online:
26 May 2023 | DOI: 10.1111/ene.15863

ORIGINAL ARTICLE

Clinical correlates of fear of falling in progressive supranuclear palsy and multiple system atrophy

Background and purpose

Clinical correlates of fear of falling (FoF) are scarcely studied in patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). This study was undertaken to evaluate the clinical correlates of FoF in PSP and MSA.

Methods

This cross‐sectional study features motor, cognitive, and psychiatric assessment and longitudinal evaluation of falls and FoF at 6‐month follow‐up.

Results

Twenty‐one patients with PSP‐parkinsonism, 22 patients with MSA (13 parkinsonian type and nine cerebellar type), and 22 healthy controls were evaluated; 76.2% of patients with PSP and 86.4% of patients with MSA had FoF regardless of falls. Berg Balance Scale ( < 0.001), Tinetti Mobility Test ( < 0.01), Beck Anxiety Inventory ( = 0.001), and Beck Depression Inventory‐II ( = 0.01) correlated with FoF in patients with PSP and MSA, whereas Timed Up and Go test ( = 0.01) and Starkstein Apathy Scale correlated only in MSA ( = 0.04).

Conclusions

Mobility, balance, and gait performance as well as anxiety and depression in PSP and MSA, and apathy in MSA, were determinants of FoF. These findings underline the importance of a multidisciplinary approach to FoF in neurodegenerative atypical parkinsonism.

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Authors:
Viviana A. Martínez‐Villota, Cinthia Terroba‐Chambi, Sergio A. Castillo‐Torres, Malco Rossi and Marcelo Merello

Article first published online:
29 May 2023 | DOI: 10.1111/ene.15864

ORIGINAL ARTICLE

Relevance of dedicated multiple sclerosis serum biomarkers in predicting contrast enhancement with gadolinium: Results from the REDUCE‐GAD trial

Background

The presence of contrast enhancement (CE) on magnetic resonance imaging (MRI) is one of the principal criteria for diagnosis and disease activity of multiple sclerosis (MS). Therefore, MS patients are frequently exposed to contrast agents, which may cause deposition in the brain, restricting its use in repeat examinations. Thus, serum biomarkers may be valuable as surrogate parameters to evaluate MS activity.

Methods

REDUCE‐GAD was a prospective, multicentric, biobanking study to determine whether established serum markers (neurofilament light chain [NfL], glial fibrillary acidic protein [GFAP], tau protein, ubiquitin‐carboxyl‐terminal‐hydrolase (UCH‐L1), S100B and matrix‐metalloproteinase 9 [MMP9]) are predictive of CE‐positive MRI lesions. Blood samples were obtained from patients undergoing MRI 5 days before or after collection.

Results

Patients ( = 102) from four different centers with confirmed MS or related disorders were included; = 57 (55.9%) showed CE on MRI versus = 45 (44.1%) without CE. Only higher NfL values indicated CE (odds ratio [OR] 1.05; 95% CI 1.0–1.09) and were correlated with number ( = 0.47; < 0.001) and diameter of CE lesions ( = 0.58; < 0.001). Nfl Z‐scores improved diagnostic accuracy (OR 1.52; 95% CI 1.06–2.18). Receiver operator characteristic analysis revealed a reasonable cut‐off value for NfL at 14.1 pg/mL (sensitivity 49.1%; specificity 82.2%; positive predictive value 77.8%; negative predictive value 56.0%). NfL ≥59.2 pg/mL was exclusively observed in patients with CE.

Conclusions

Evaluation of several possible serum biomarkers for CE in MS patients provided the most robust results for NfL, particularly as Z‐scores. Following further evaluation, biomarkers may help stratify the application of contrast agents for brain imaging in MS patients.

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Authors:
Jan Hendrik Schaefer, Martin A. Schaller‐Paule, Katharina Wenger, Christoph Mayer, Ulrike Mann, Alexander Bickert, Falk Steffen, Stefan Bittner, Yavor Yalachkov and Christian Foerch

Article first published online:
29 May 2023 | DOI: 10.1111/ene.15865

ORIGINAL ARTICLE

The gene variant rs2762943 is associated with low serum 1,25‐dihydroxyvitamin D levels in multiple sclerosis patients

Background and purpose

Vitamin D is considered to play a role in multiple sclerosis (MS) etiopathogenesis. A polymorphism in the gene, rs2762943, was recently identified that was associated with an increased MS risk. encodes a protein involved in the catabolism of the active form of vitamin D. The immunological effects of carrying the rs2762943 risk allele were investigated, as well as its role as genetic modifier.

Methods

Serum levels of 25‐hydroxyvitamin D and 1,25‐dihydroxyvitamin D (1,25(OH)D) were measured in a cohort of 167 MS patients. In a subgroup of patients, expression levels of major histocompatibility complex class II and co‐stimulatory molecules were determined by flow cytometry, and serum levels of pro‐inflammatory (interferon gamma, granulocyte macrophage colony‐stimulating factor, C‐X‐C motif chemokine ligand 13) and anti‐inflammatory (interleukin 10) cytokines and neurofilament light chain were measured by single‐molecule array assays. The effect of the rs2762943 polymorphism on disease activity and disability measures was evaluated in 340 MS patients.

Results

Compared to non‐carriers, carriers of the rs2762943 risk allele were characterized by reduced levels of 1,25(OH)D ( = 0.0001) and elevated levels of interferon gamma ( = 0.03) and granulocyte macrophage colony‐stimulating factor ( = 0.008), whereas no significant differences were observed for the other markers. The presence of the rs2762943 risk allele had no significant impact on disease activity and disability outcomes during follow‐up. However, risk allele carriers were younger at disease onset ( = 0.04).

Conclusions

These findings suggest that the rs2762943 polymorphism plays a more important role in MS susceptibility than in disease prognosis and is associated with lower 1,25(OH)D levels and a heightened pro‐inflammatory environment in MS patients.

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Authors:
Sunny Malhotra, Luciana Midaglia, Omar Chuquisana, Nikolaos A. Patsopoulos, Roser Ferrer, Marina Giralt, Nicolas Fissolo, Elia Gil‐Varea, Juan Carlos Triviño, Jan D. Lünemann, Xavier Montalban and Manuel Comabella

Article first published online:
28 May 2023 | DOI: 10.1111/ene.15866

ORIGINAL ARTICLE

New‐onset functional tics during the COVID‐19 pandemic: Clinical characteristics of 105 cases from a single centre

Background and purpose

The COVID‐19 pandemic has been associated amongst other things with a sharp increase in adolescents and young adults presenting acutely with functional tics. Initial reports have suggested clinically relevant differences between functional tics and neurodevelopmental tics seen in primary tic disorders such as Tourette syndrome. We aimed to provide confirmatory findings from the largest single‐centre cohort to date.

Methods

In the present study we present data from 105 consecutive patients who developed functional tics during a 3‐year period overlapping with the COVID‐19 pandemic (April 2020–March 2023). All patients underwent a comprehensive neuropsychiatric assessment at a single specialist centre for tic disorders.

Results

Female adolescents and young adults accounted for 69% of our sample. Functional tics had an acute/subacute onset in most cases (75% with a peak of severity within 1 month). We found a disproportionately high frequency of complex movements (81%) and vocalizations (75%). A subset of patients (23%) had a pre‐existing primary tic disorder (Tourette syndrome with functional overlay). The most common psychiatric co‐morbidities were anxiety (70%) and affective disorders (40%). Moreover, 41% of patients had at least one functional neurological disorder in addition to functional tics. Exposure to tic‐related social media content was reported by half of the patients.

Conclusions

Our findings confirm substantial clinical differences between functional tics developed during the pandemic and neurodevelopmental tics. Both patient‐ and tic‐related red flags support the differential diagnostic process and inform ongoing monitoring in the post‐pandemic era.

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Authors:
Andrea Eugenio Cavanna, Giulia Purpura, Anna Riva, Renata Nacinovich and Stefano Seri

Article first published online:
26 May 2023 | DOI: 10.1111/ene.15867

ORIGINAL ARTICLE

Optimal cut‐off value of the modified Toronto Clinical Neuropathy Score in the diagnosis of polyneuropathy

Background and purpose

The modified Toronto Clinical Neuropathy Score (mTCNS) is a valid and reliable scale for the diagnosis and staging of diabetic sensorimotor polyneuropathy (DSP). The aim of this study was to determine the optimal diagnostic cut‐off value of the mTCNS in diverse polyneuropathies (PNPs).

Methods

Demographics and mTCNS values were retrospectively extracted from an electronic database of 190 patients with PNP and 20 normal controls. Sensitivity, specificity, and likelihood ratios and area under the receiver‐operating characteristic (ROC) curve were determined for each diagnosis and different cut‐off values of the mTCNS. Patients underwent clinical, electrophysiological and functional assessments of their PNP.

Results

Forty‐three percent of PNP was related to diabetes or impaired glucose tolerance. mTCNS was significantly higher in patients with PNP than in those without (15.27 ± 8 vs. 0.79 ± 1.4; = 0.001). The cut‐off value for diagnosing PNP was ≥3 (sensitivity 98.4%, specificity 85.7%, positive likelihood ratio 6.88). The area under the ROC curve was 0.987.

Conclusion

A value of 3 or more on the mTCNS is recommended for the diagnosis of PNP.

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Authors:
Juan Francisco Idiaquez, Monica Alcantara and Vera Bril

Article first published online:
30 May 2023 | DOI: 10.1111/ene.15870

COMMENTARY

Neuropathic pain ‐ Still a challenge to assess

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Authors:
Kristin Ørstavik

Article first published online:
01 Jun 2023 | DOI: 10.1111/ene.15889

European Journal of Neurology

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ORIGINAL ARTICLE

Background and purpose

Methods

Results

Conclusions

ORIGINAL ARTICLE

Background and purpose

Methods