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Article first published online:
04 Aug 2022 | DOI: 10.1111/ene.14929

REVIEW ARTICLE

The contribution of neuropathology to multiple sclerosis research

Background and purpose

Neuropathology plays a major role in deciphering disease mechanisms in multiple sclerosis (MS). This review article describes recent advances in neuropathological research related to inflammatory demyelinating diseases.

Methods

A retrospective review of neuropathological studies published during the last two decades was conducted.

Results

The importance of neuropathology is generally seen in its contribution to the diagnosis of diseases of the nervous system and, in particular, in neuro‐oncology. However, when it also includes analysis of the global three‐dimensional extension of brain damage and the temporal sequence of lesion evolution and relates this to molecular changes in the lesions, it offers the potential to decipher disease pathogenesis and to contribute to the development of effective and causative treatments. In MS research, neuropathology has been essential in discriminating the disease from other inflammatory autoimmune or demyelinating diseases, such as neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD). It defined the hallmark of chronic progressive disease in MS patients as slowly expanding tissue damage, which occurs not only within and around lesions but also in the normal appearing white and gray matter. It showed that these changes occur in the course of a tissue‐resident immune response within the central nervous system, involving tissue‐resident effector memory cells and plasma cells. Molecular studies in neuropathologically defined micro‐dissected MS lesions identified a cascade of oxidative injury, mitochondrial damage and subsequent virtual hypoxia as a major pathway of tissue injury in MS.

Conclusions

The results of these studies were highly relevant for the identification of potential therapeutic targets in MS patients and the design of pivotal clinical trials.

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Authors:
Hans Lassmann

Article first published online:
23 Jun 2022 | DOI: 10.1111/ene.15360

CONSENSUS STATEMENT

Rapid screening for neglect following stroke: A systematic search and European Academy of Neurology recommendations

Background and purpose

Unilateral neglect is a common cognitive disorder following stroke. Neglect has a significant impact on functional outcomes, so it is important to detect. However, there is no consensus on which are the best screening tests to administer to detect neglect in time‐limited clinical environments.

Methods

Members of the European Academy of Neurology Scientific Panel on Higher Cortical Functions, neuropsychologists, occupational therapists, and researchers produced recommendations for primary and secondary tests for bedside neglect testing based on a rigorous literature review, data extraction, online consensus meeting, and subsequent iterations.

Results

A total of 512 articles were screened, and 42 were included. These reported data from 3367 stroke survivors assessed using 62 neglect screens. Tests were grouped into cancellation, line bisection, copying, reading/writing, and behavioral. Cancellation tasks were most frequently used (97.6% of studies), followed by bisection, copying, behavioral, and reading/writing assessments. The panel recommended a cancellation test as the primary screening test if there is time to administer only one test. One of several cancellation tests might be used, depending on availability. If time permits, one or more of line bisection, figure copying, and baking tray task were recommended as secondary tests. Finally, if a functional and ecological test is feasible, the Catherine Bergego Scale was recommended. Overall, the literature suggests that no single test on its own is sufficient to exclude a diagnosis of neglect. Therefore, the panel recommended that multiple neglect tests should be used whenever possible.

Conclusions

This study provides consensus recommendations for rapid bedside detection of neglect in real‐world, clinical environments.

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Authors:
Margaret Moore, Elise Milosevich, Roland Beisteiner, Audrey Bowen, Matthew Checketts, Nele Demeyere, Helena Fordell, Olivier Godefroy, Jan Laczó, Timothy Rich, Lindy Williams, Kate Woodward‐Nutt and Masud Husain

Article first published online:
30 Jun 2022 | DOI: 10.1111/ene.15381

GUIDELINES

European Academy of Neurology/Movement Disorder Society ‐ European Section guideline on the treatment of Parkinson's disease: I. Invasive therapies

Background and Purpose

This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist and general practitioners taking care of PD patients should know the therapies and their place in the treatment pathway.

Methods

Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging–guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health‐related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high‐class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered.

Results

Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN‐DBS is the best‐studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi‐DBS can also be offered. For early PD with early fluctuations, STN‐DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment‐resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication‐resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended.

Conclusions

Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups.

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Authors:
Günther Deuschl, Angelo Antonini, Joao Costa, Katarzyna Śmiłowska, Daniela Berg, Jean‐Christophe Corvol, Giovanni Fabbrini, Joaquim Ferreira, Tom Foltynie, Pablo Mir, Annette Schrag, Klaus Seppi, Pille Taba, Evzen Ruzicka, Marianna Selikhova, Nicholas Henschke, Gemma Villanueva and Elena Moro

Article first published online:
06 Jul 2022 | DOI: 10.1111/ene.15386

POSITION PAPER

The European Academy of Neurology Brain Health Strategy: One brain, one life, one approach

Background and purpose

Brain health is essential for health, well‐being, productivity and creativity across the entire life. Its definition goes beyond the absence of disease embracing all cognitive, emotional, behavioural and social functions which are necessary to cope with life situations.

Methods

The European Academy of Neurology (EAN) Brain Health Strategy responds to the high and increasing burden of neurological disorders. It aims to develop a non‐disease‐, non‐age‐centred holistic and positive approach (‘one brain, one life, one approach’) to prevent neurological disorders (e.g., Alzheimer's disease and other dementias, stroke, epilepsy, headache/migraine, Parkinson's disease, multiple sclerosis, sleep disorders, brain cancer) but also to preserve brain health and promote recovery after brain damage.

Results

The pillars of the EAN Brain Health Strategy are (1) to contribute to a global and international brain health approach (together with national and subspecialty societies, other medical societies, the World Health Organization, the World Federation of Neurology, patients' organizations, industry and other stakeholders); (2) to support the 47 European national neurological societies, healthcare and policymakers in the implementation of integrated and people‐centred campaigns; (3) to foster research (e.g., on prevention of neurological disorders, determinants and assessments of brain health); (4) to promote education of students, neurologists, general practitioners, other medical specialists and health professionals, patients, caregivers and the general public; (5) to raise public awareness of neurological disorders and brain health.

Conclusions

By adopting this ‘one brain, one life, one approach’ strategy in cooperation with partner societies, international organizations and policymakers, a significant number of neurological disorders may be prevented whilst the overall well‐being of individuals is enhanced by maintaining brain health through the life course.

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Authors:
Claudio L. A. Bassetti, Mathias Endres, Anja Sander, Michael Crean, Sumathi Subramaniam, Vanessa Carvalho, Giovanni Di Liberto, Oscar H. Franco, Yolande Pijnenburg, Matilde Leonardi and Paul Boon

Article first published online:
21 Jun 2022 | DOI: 10.1111/ene.15391

ORIGINAL ARTICLE

The characteristics of intracranial plaques of unilateral, anterior circulation embolic stroke of undetermined source: An analysis of different subtypes based on high‐resolution imaging

Background and purpose

The aim was to investigate the characteristics of non‐stenotic intracranial plaque (NSIP) in embolic stroke of undetermined source (ESUS) subtypes by high‐resolution magnetic resonance imaging.

Methods

Consecutive patients with ESUS who were mandatory for high‐resolution magnetic resonance imaging were retrospectively enrolled. Based on the location and arterial supply of the infarct, the ESUS were categorized into three types: cortical ESUS, subcortical ESUS and mixed ESUS. The NSIP parameters including plaque location, morphology (plaque distribution, remodeling index and plaque burden) and composition (thick fibrous cap, discontinuity of plaque surface, intraplaque hemorrhage and complicated plaque) were evaluated amongst the subtypes.

Results

Of 243 patients, there were 87 (35.8%) cortical ESUS, 127 (52.3%) subcortical ESUS and 29 (11.9%) mixed ESUS. Significant differences were found in plaque location ( < 0.001), plaque quadrant ( < 0.001), remodeling index ( < 0.001), plaque burden ( < 0.001), discontinuity of plaque surface ( < 0.001), intraplaque hemorrhage ( = 0.001) and complicated plaque ( < 0.001) of ipsilateral NISP amongst the different ESUS subtypes, except for fibrous cap ( = 0.135). However, no differences were found amongst contralateral NISP. In addition, the clinical characteristics of the differences between ESUS subtypes were striking, including age ( = 0.004), initial National Institutes of Health Stroke Scale ( < 0.001), coronary artery disease ( = 0.039), serum urea ( = 0.011) and creatinine ( = 0.002).

Conclusion

This is the first report of significantly heterogeneous characteristics of ipsilateral NSIP and clinical findings amongst ESUS subtypes, which may suggest their different underlying mechanisms.

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Authors:
Zi‐Yang Shang, Lin Tao, Xiao‐Qiu Li, Ben‐Qiang Yang, George Ntaios and Hui‐Sheng Chen

Article first published online:
05 Jun 2022 | DOI: 10.1111/ene.15409

ORIGINAL ARTICLE

Endovascular therapy versus no endovascular therapy in patients receiving best medical management for acute isolated occlusion of the posterior cerebral artery: A systematic review and meta‐analysis

Background and purpose

Endovascular therapy (EVT) is increasingly reported for treatment of isolated posterior cerebral artery (PCA) occlusions although its clinical benefit remains uncertain. This study‐level meta‐analysis investigated the functional outcomes and safety of EVT and best medical management (BMM) compared to BMM alone for treatment of PCA occlusion stroke.

Methods

We conducted a literature search in PubMed, Web of Science and Embase for studies in patients with isolated PCA occlusion stroke treated with EVT + BMM or BMM including intravenous thrombolysis. There were no randomized trials and all studies were retrospective. The primary outcome was modified Rankin Scale score of 0–2 at 3 months, while safety outcomes included mortality rate and incidence of symptomatic intracranial hemorrhage (sICH).

Results

Twelve studies with a total of 679 patients were included in the meta‐analysis: 338 patients with EVT + BMM and 341 patients receiving BMM alone. Good functional outcome at 3 months was achieved in 58.0% (95% confidence interval [CI] 43.83–70.95) of patients receiving EVT + BMM and 48.1% (95% CI 40.35–55.92) of patients who received BMM alone, with respective mortality rates of 12.6% (95% CI 7.30–20.93) and 12.3% (95% CI 8.64–17.33). sICH occurred in 4.2% (95% CI 2.47–7.03) of patients treated with EVT + BMM and 3.2% (95% CI 1.75–5.92) of patients treated with BMM alone. Comparative analyses were performed on studies that included both treatments and these demonstrated no significant differences.

Conclusions

Our results demonstrate that EVT represents a safe treatment for patients with isolated PCA occlusion stroke. There were no differences in clinical or safety outcomes between treatments, supporting randomization of future patients into distal vessel occlusion trials.

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Authors:
Anne Berberich, Stephanos Finitsis, Davide Strambo, Patrik Michel, Christian Herweh, Lukas Meyer, Uta Hanning, Daniel Strbian, Mohamad Abdalkader, Raul G. Nogueira, Volker Puetz, Daniel P. O. Kaiser, Marta Olive‐Gadea, Marc Ribo, Isabel Fragata, João Pedro Marto, Michele Romoli, Peter A. Ringleb, Thanh N. Nguyen and Simon Nagel

Article first published online:
17 Jun 2022 | DOI: 10.1111/ene.15410

ORIGINAL ARTICLE

Validation of new diagnostic criteria for fatigue in patients with Parkinson disease

Background and purpose

Although disabling fatigue is common in Parkinson disease (PD), available consensus‐based diagnostic criteria have not yet been empirically validated. The aim of this study was to evaluate the clinimetric properties of the criteria.

Methods

A sample of outpatients with PD was evaluated for demographic, clinical, behavioral, and cognitive features. Fatigue was diagnosed according to the new diagnostic criteria and was rated by means of the Parkinson Fatigue Scale (PFS) and Fatigue Severity Scale (FSS). Acceptability, concurrent and discriminant validity, and interrater reliability were evaluated with binary logistic regression analyses and Cohen kappa (κ).

Results

Of 241 included patients, 17 (7.1%) met the diagnostic criteria for PD‐related fatigue. Eight of nine symptoms described in Section A of the diagnostic criteria occurred in >50% of patients with fatigue. Acceptability (missing data = 0.8%) of the criteria was good, as was their concurrent validity with the PFS (odds ratio = 3.65) and FSS (odds ratio = 3.63). The discriminant validity of fatigue criteria with other PD‐related behavioral and cognitive features was good (odds ratio < 1.68). The interrater reliability was excellent (κ = 0.92).

Conclusions

This is the first study to test the clinimetric properties of case definition diagnostic criteria for PD‐related fatigue. Our results suggest that current diagnostic criteria may be useful in both clinical practice and research. Future longitudinal studies should examine their long‐term stability.

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Authors:
Mattia Siciliano, Benzi Kluger, Rosa De Micco, Carlo Chiorri, Valeria Sant'Elia, Marcello Silvestro, Alfonso Giordano, Gioacchino Tedeschi, Luca Passamonti, Luigi Trojano and Alessandro Tessitore

Article first published online:
06 Jun 2022 | DOI: 10.1111/ene.15411

ORIGINAL ARTICLE

A real‐world evidence study of nabiximols in multiple sclerosis patients with resistant spasticity: Analysis in relation to the newly described ‘spasticity‐plus syndrome’

Background and purpose

Nabiximols is a therapeutic option for patients with multiple sclerosis (MS) spasticity whose symptoms are poorly controlled by conventional oral first‐line medications. This study aimed to assess the relationship between changes in spasticity severity (measured on the 0–10 numeric rating scale [NRS]) and the presence of associated symptoms in patients treated with nabiximols, and to investigate the presence of the newly described ‘spasticity‐plus syndrome’.

Methods

We analyzed real‐world data from the Italian Medicines Agency e‐Registry on 1138 patients with MS spasticity who began treatment with nabiximols. Evaluation time points were baseline, 4 weeks, and 3, 6, 12 and 18 months after treatment start.

Results

Common symptoms associated with MS spasticity in this cohort were pain (38.4% at baseline), sleep disturbances (32.7%), and spasms/cramps (28.5%). Pain was frequently clustered with sleep disturbances (57.2% of pain cases) and spasms/cramps (43.9%). Approximately one‐third of patients with data at all evaluation time points maintained treatment at 18 months. Nabiximols reduced the baseline mean spasticity 0–10 NRS score by 24.6% at Week 4, and by 33.9% at 18 months in treatment continuers. Nabiximols resolved a range of MS spasticity‐associated symptoms at Week 4, and after 18 months in treatment continuers.

Conclusion

This real‐world analysis supports the concept of a spasticity‐plus syndrome and suggests that nabiximols can favorably impact a range of spasticity‐associated symptoms.

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Authors:
Francesco Patti, Clara Grazia Chisari, Óscar Fernández, Jorge Sarroca, Elena Ferrer‐Picón, Francisco Hernández Vicente and Carlos Vila Silván

Article first published online:
07 Jun 2022 | DOI: 10.1111/ene.15412

ORIGINAL ARTICLE

Sudomotor dysfunction in people with neuromyelitis optica spectrum disorders

Background and purpose

The aim was to determine the extent of sudomotor dysfunction in people with neuromyelitis optica spectrum disorder (pwNMOSD) and to compare findings with a historical cohort of people with relapsing–remitting multiple sclerosis (pwRRMS).

Methods

Forty‐eight pwNMOSD were enrolled from four clinical centers. All participants completed the Composite Autonomic Symptom Score 31 to screen for symptoms of sudomotor dysfunction. Sudomotor function was assessed using the quantitative sudomotor axon reflex test. The results were compared with a historical cohort of 35 pwRRMS matched for age, sex and disease duration.

Results

Symptoms of sudomotor dysfunction, defined by a score in the Composite Autonomic Symptom Score 31 secretomotor domain >0, were present in 26 (54%) of pwNMOSD. The quantitative sudomotor axon reflex test confirmed a sudomotor dysfunction in 25 (52.1%) of pwNMOSD; in 14 of them (29.2%) sudomotor dysfunction was moderate or severe. No difference was observed between pwNMOSD and pwRRMS in any of the studied parameters. However, symptomatic sudomotor dysfunction was more frequent in pwNMOSD ( = 8, 22.9%) compared to pwRRMS ( = 1, 3%; = 0.028). In a multivariable logistic regression analysis, statistically significant predictors for symptomatic sudomotor failure were age and diagnosis of neuromyelitis optica spectrum disorder.

Conclusions

Sudomotor dysfunction is common in pwNMOSD and more often symptomatic compared to pwRRMS.

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Authors:
Mario Habek, Marko Andabaka, Alessandra Fanciulli, Gregor Brecl Jakob, Jelena Drulović, Fabian Leys, Franziska Di Pauli, Harald Hegen, Michael Auer, Tatjana Pekmezović, Šarlota Mesaroš, Vanja Jovičević, Anamari Junaković, Gregor K. Wenning, Florian Deisenhammer, Tereza Gabelić, Barbara Barun, Ivan Adamec and Magdalena Krbot Skorić

Article first published online:
12 Jun 2022 | DOI: 10.1111/ene.15413

COMMENTARY

Brain health: The time has come

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Authors:
Vladimir Hachinski

Article first published online:
31 May 2022 | DOI: 10.1111/ene.15414

ORIGINAL ARTICLE

Stroke in the stroke unit: Recognition, treatment and outcomes in a single‐centre cohort

Background and purpose

In‐hospital strokes (IHS) are associated with longer diagnosis times, treatment delays and poorer outcomes. Strokes occurring in the stroke unit have seldom been studied. Our aim was to assess the management of in‐stroke‐unit ischaemic stroke (ISUS) by analysing ISUS characteristics, delays in diagnosis, treatments and outcomes.

Methods

Consecutive patients from the Acute Stroke Registry and Analysis of Lausanne (ASTRAL), from January 2003 to June 2019, were classified as ISUS, other‐IHS or community‐onset stroke (COS). Baseline and stroke characteristics, time to imaging and time to treatment, missed treatment opportunities, treatment rates and outcomes were compared using multivariate analysis with adjustment for relevant clinical, imaging and laboratory data available in ASTRAL.

Results

Amongst the 3456 patients analysed, 138 (4.0%) were ISUS, 214 (6.2%) other‐IHS and 3104 (89.8%) COS. In multivariate analysis, patients with ISUS more frequently had known stroke onset time than other‐IHS (adjusted odds ratio [aOR] 2.44; 95% confidence interval [CI] 1.39–4.35) or COS (aOR 2.56; 95% CI 1.59–4.17), had fewer missed treatment opportunities than other‐IHS (aOR 0.22; 95% CI 0.06–0.86) and higher endovascular treatment (EVT) rates than COS (aOR 3.03; 95% CI 1.54–5.88). ISUS was associated with a favourable shift in the modified Rankin Scale at 3 months in comparison with other‐IHS (aOR 1.73; 95% CI 1.11–2.69) or COS (aOR 1.46; 95% CI 1.00–2.12).

Conclusion

In‐stroke‐unit ischaemic stroke more frequently had known stroke onset time than other‐IHS or COS, fewer missed treatment opportunities than other‐IHS and a higher EVT rate than COS. This readiness to identify and treat patients in the stroke unit may explain the better long‐term outcome of ISUS.

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Authors:
João Pedro Marto, Alexander Salerno, Errikos Maslias, Dimitris Lambrou, Ashraf Eskandari, Davide Strambo and Patrik Michel

Article first published online:
06 Jun 2022 | DOI: 10.1111/ene.15415

ORIGINAL ARTICLE

Nonalcoholic fatty liver disease, serum cytokines, and dementia among rural‐dwelling older adults in China: A population‐based study

Background and purpose

Little is known about whether nonalcoholic fatty liver disease (NAFLD) is associated with dementia or the role of serum proinflammatory cytokines in the association. We aimed to investigate the interrelationships of NAFLD, serum cytokines, and dementia among rural‐dwelling older adults.

Methods

This population‐based cross‐sectional study included 5129 participants (aged ≥60 years; 61.79% women) who were living in rural communities and examined in March 2018–September 2018. NAFLD was defined through transabdominal ultrasound examination in the absence of hepatitis B or excessive alcohol consumption. Serum cytokines were measured in a subsample ( = 1686). Dementia, Alzheimer disease (AD), and vascular dementia (VaD) were diagnosed following international criteria. Data were analyzed with logistic regression and mediation models.

Results

Of the 5129 participants, 455 (8.87%) were detected with moderate‐to‐severe NAFLD, and 292 (5.69%) were diagnosed with dementia (188 with AD and 96 with VaD). The multivariable adjusted odds ratios associated with moderate‐to‐severe (vs. no‐to‐mild) NAFLD were 2.22 (95% confidence interval [CI] = 1.41–3.49) for all‐cause dementia, 1.88 (95% CI = 1.01–3.50) for AD, and 2.62 (95% CI = 1.33–5.17) for VaD. In the cytokine subsample, controlling for multiple potential confounders, moderate‐to‐severe NAFLD was significantly associated with higher levels of serum monocyte chemotactic protein‐1, interleukin‐17A, interleukin‐6 (IL‐6), interleukin‐8, and tumor necrosis factor‐α ( < 0.05). The mediation analysis showed that IL‐6 mediated 12.56% of the association between NAFLD and VaD.

Conclusions

Moderate‐to‐severe nonalcoholic fatty liver disease is associated with dementia and AD, especially with VaD, among rural‐dwelling Chinese older adults, in which the association with VaD is partly mediated by serum inflammatory cytokines.

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Authors:
Yongxiang Wang, Yuanjing Li, Keke Liu, Xiaolei Han, Yi Dong, Xiaojie Wang, Mingqi Wang, Lin Cong, Qinghua Zhang, Shi Tang, Tingting Hou, Cuicui Liu, Lin Song, Xiaojuan Han, Davide L. Vetrano, Yifeng Du and Chengxuan Qiu

Article first published online:
09 Jun 2022 | DOI: 10.1111/ene.15416

ORIGINAL ARTICLE

Penetrance of Parkinson disease G2385R‐associated variant in the Chinese population

Background and purpose

Penetrance estimates of the leucine‐rich repeat kinase 2 () variants for Parkinson disease (PD) vary widely. G2385R is one of the most common variants in Asian populations, and its penetrance is currently unknown. We aimed to estimate the penetrance of G2385R in the Chinese population.

Methods

The G2385R variant was tested by Sanger sequencing in 6386 participants older than 50 years, all from the community cohort established by Shanghai Ruijin Hospital in 2009–2011. G2385R carriers and matched noncarriers underwent a brief questionnaire survey (including sex, current age, PD diagnosis, and age at onset) and face‐to‐face PD assessment during 2020–2021. The penetrance of PD was estimated by the Kaplan–Meier method.

Results

A total of 396 G2385R carriers and 415 noncarriers were included, after excluding those with a baseline diagnosis of PD or unwilling to participate. In G2385R carriers, the penetrance of PD was 1.64% at 70 years, 10.26% at 80 years, and 18.49% at 90 years, and reached 25.90% at 95 years. The penetrance of PD in G2385R carriers was higher than in noncarriers ( = 0.0071). In noncarriers, only 0%, 3.72%, and 9.66% developed parkinsonism by 70, 80, and 90 years of age. Among carriers and noncarriers, there were no statistically significant differences in penetrance comparisons between males and females, or between urban and rural.

Conclusions

The lifetime penetrance of G2385R in the Chinese population was 25.9%. The penetrance modifier of G2385R in our study was age‐related. Further investigation of genetic and environmental modifiers affecting G2385R penetrance is warranted.

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Authors:
Pei Wang, Peijing Cui, Qi Luo, Jie Chen, Huidong Tang, Lina Zhang, Shengdi Chen and Jianfang Ma

Article first published online:
06 Jun 2022 | DOI: 10.1111/ene.15417

ORIGINAL ARTICLE

Glucose‐6‐phosphate dehydrogenase deficiency and intracranial atherosclerotic stenosis in stroke patients

Background and purpose

Intracranial atherosclerotic stenosis (ICAS) is a major cause of stroke in Asian countries. Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency, a hereditary enzyme defect prevalent in Asian countries, has been associated with atherosclerotic cardiovascular disease and worse poststroke outcomes. However, the impact of G6PD deficiency on ICAS remains unclear. We aimed to compare the risk of ICAS in stroke patients with and without G6PD deficiency in a Chinese cohort.

Methods

We prospectively and consecutively recruited stroke patients from four centers in China. All patients received intracranial artery assessment by magnetic resonance/computed tomography angiography or digital subtraction angiography, as well as G6PD enzyme evaluation. The prevalence, burden, and characteristics of ICAS were compared between patients with and without G6PD deficiency using multivariate regression analysis.

Results

Among 1593 patients, 116 (63.7%) of 182 patients with G6PD deficiency and 714 (50.6%) of 1411 patients with normal G6PD levels were identified as ICAS. Age, hypertension, diabetes, and G6PD deficiency were independent predictors of ICAS. Among patients with ICAS, G6PD‐deficient individuals were more likely to have multiple (≥2 segments) intracranial stenosis (odds ratio [OR] = 1.87, 95% confidence interval [CI] = 1.25–2.81, = 0.002). G6PD deficiency increased the risk of ICAS in patients who were male (OR = 1.82, 95% CI = 1.24–2.66, = 0.002), aged ≥70 years (OR = 2.40, 95% CI = 1.33–4.31, = 0.004), or hypertensive (OR = 1.88, 95% CI = 1.28–2.77, = 0.001).

Conclusions

Stroke patients with G6PD deficiency have a higher prevalence and ICAS burden than those with normal G6PD, particularly those who are male, older, and hypertensive.

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Authors:
Jianle Li, Yicong Chen, Zilin Ou, Yusheng Zhang, Zhijian Liang, Weisheng Deng, Hao Chen, Weixian Huang, Yingxin He, Shihui Xing, Jian Yu and Jinsheng Zeng

Article first published online:
07 Jun 2022 | DOI: 10.1111/ene.15418

ORIGINAL ARTICLE

The relationship of cerebrospinal fluid neurofilament levels with magnetic resonance imaging lesion location and disease activity in multiple sclerosis

Background and purpose

Neurofilament light chain (NfL) is an accepted biomarker of disease activity in multiple sclerosis (MS), but its relationship with magnetic resonance imaging (MRI) activity particularly in reference to lesion location and recurrent activity is not well understood.

Methods

In 139 MS patients who underwent lumbar punctures with follow‐up in 25, the relationship between cerebrospinal fluid (CSF) NfL and cranial MRI based on lesion location and lesion number was evaluated. Spearman rank correlation was used to assess the association between CSF NfL and MRI lesion location and lesion counts at baseline and follow‐up at 1 year. Multiple linear regression analysis was performed to assess which lesion location was most strongly associated with CSF NfL values.

Results

The associations between baseline CSF NfL and lesion location and follow‐up lesions were modest, whilst those between baseline MRI and follow‐up CSF NfL were greater: periventricular ( = 0.31, = 0.141), juxtacortical ( = 0.47, = 0.022), infratentorial ( = 0.71, ≤ 0.001) and cord lesions ( = 0.60, = 0.002). All associations, however, improved following adjustment for disease duration and type of MS. Modelling revealed 53% of (log) CSF NfL could be explained by variance in baseline MRI lesion location.

Conclusions

Baseline CSF NfL did not correlate with current or future MRI activity and lesion location. However, baseline MRI activity explained around 53% of the variation in the follow‐up CSF NfL, suggesting that the relationship between MRI and CSF NfL is mainly precedent rather than an association, that is one occurring before the other.

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Authors:
Ashok Adams, William Tilden, Jonathan Bestwick, David Holden, Lucia Bianchi, Ide Smets, Gavin Giovannoni and Sharmilee Gnanapavan

Article first published online:
10 Jun 2022 | DOI: 10.1111/ene.15419

ORIGINAL ARTICLE

Prospective longitudinal study on prognostic factors of visual recovery and structural change after a first episode of optic neuritis

Background and purpose

This study was undertaken to determine the role of optical coherence tomography (OCT) in predicting the final visual and structural outcome, and to evaluate the correlation between functional eye outcome and retinal changes, in patients with a first episode of optic neuritis (ON).

Methods

In this prospective study, consecutive adult patients with acute ON underwent ophthalmological evaluation at baseline and at 1 and 12 months, including OCT measurements of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell and inner plexiform layer, and inner nuclear layer thicknesses; high‐ and low‐contrast visual acuity; visual field assessment; and baseline brain magnetic resonance imaging Univariate and multivariate linear regressions were used to assess predictive factors of outcome. Correlations between 12‐month visual function and retinal structure were estimated by Spearman coefficients. Two groups of patients were analyzed, with or without multiple sclerosis (MS).

Results

Among 116 patients, 79 (68.1%) had MS, and 37 (31.9%) had ON not related to MS (including 19 idiopathic [i.e., isolated] ON, and 13 and five with myelin oligodendrocyte glycoprotein and aquaporin‐4 antibodies, respectively). We found no independent predictive factor of visual and retinal outcome. Analysis of the relationship between the visual field test (mean deviation) and pRNFL thickness demonstrated a threshold of 75.4 μm and 66.4 μm, below which the mean deviation was worse, for patients with MS ( = 0.007) and without MS ( < 0.001), respectively.

Conclusions

We found that inner retinal layer measurements during the first month are not predictive of final outcome. The critical threshold of axonal integrity, below which visual function is damaged, is different between patients with and without MS.

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Authors:
Romain Deschamps, Natalia Shor, Catherine Vignal, Jessica Guillaume, Marine Boudot de la Motte, Flore Salviat, Augustin Lecler, Romain Marignier, Rabih Hage, Sarah Coulette, Samuel Bidot, Antoine Gueguen, Martine Mauget‐Faysse, Caroline Bensa, Vivien Vasseur, Olivier Gout and Cedric Lamirel

Article first published online:
17 Jun 2022 | DOI: 10.1111/ene.15420

POSITION PAPER

European Academy of Neurology 2019 ‐ 2022

Background

The EAN was founded in 2014 with the mission of reducing the burden of neurological disorders.

Methods

In 2019 the society defined four strategic priorities: education, science, membership, and advocacy. This paper reviews the EAN development in the last 3 years.

Results

The outbreak of COVID‐19 pandemic in 2020 had a profound impact on the entire world and triggered profound changes in the EAN including the implementation of new digital technologies.

Conclusion

The ongoing pandemic and wars demonstrate the fragility of our political and health systems and the need for people centeredness, international collaborations, solidarity, and digitalization. The EAN will continue promoting excellence in neurological care, science and education as well as brain health for all.

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Authors:
Claudio L. A. Bassetti

Article first published online:
24 Jun 2022 | DOI: 10.1111/ene.15421

ORIGINAL ARTICLE

Disability progression in multiple sclerosis patients using early first‐line treatments

Background and purpose

Therapeutic management of relapsing–remitting multiple sclerosis (RRMS) has evolved towards early treatment. The objective was to assess the impact of early treatment initiation on disability progression amongst RRMS first‐line‐treated patients.

Methods

This study included all incident RRMS cases starting interferon or glatiramer acetate for the first time from 1 January 1996 to 31 December 2012 ( = 5279) from 10 MS expert Observatoire Français de la Sclérose en Plaques centres. The delay from treatment start to attaining an irreversible Expanded Disability Status Scale (EDSS) score of 3.0 was compared between the early group ( = 1882; treated within 12 months following MS clinical onset) and the later group using propensity score weighted Kaplan–Meier methods, overall and stratified by age.

Results

Overall, the restricted mean time before reaching EDSS 3.0 from treatment start was 11 years and 2 months for patients treated within the year following MS clinical onset and 10 years and 7 months for patients treated later. Thus, early treated patients gained 7 months (95% confidence interval [CI] 4–11 months) in the time to reach EDSS 3.0 compared to patients treated later (treatment start delayed by 28 months). The difference in restricted mean time was respectively 6 months (95% CI 1–10 months) and 14 months (95% CI 4–24 months) in the ≤40 years age group and in the >40 years age group, in favour of the early group.

Conclusions

Early treatment initiation resulted in a significant reduction of disability progression amongst patients with RRMS, and also amongst older patients.

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Authors:
Mathilde Lefort, Sandra Vukusic, Romain Casey, Gilles Edan, Emmanuelle Leray, François Cotton, Jérôme De Sèze, Pascal Douek, Francis Guillemin, David Laplaud, Christine Lebrun‐Frenay, Alexandre Pachot, Thibault Moreau, Javier Olaiz, Jean Pelletier, Claire Rigaud‐Bully, Bruno Stankoff, Hélène Zephir, Romain Marignier, Marc Debouverie, Jonathan Ciron, Aurélie Ruet, Nicolas Collongues, Catherine Lubetzki, Hélène Zephir, Pierre Labauge, Gilles Defer, Mikaël Cohen, Agnès Fromont, Sandrine Wiertlewsky, Eric Berger, Pierre Clavelou, Bertrand Audoin, Claire Giannesini, Olivier Gout, Eric Thouvenot, Olivier Heinzlef, Abdullatif Al‐Khedr, Bertrand Bourre, Olivier Casez, Philippe Cabre, Alexis Montcuquet, Abir Wahab, Jean‐Philippe Camdessanché, Serge Bakchine, Aude Maurousset, Haifa Ben Nasr, Karolina Hankiewicz, Corinne Pottier, Nicolas Maubeuge, Céline Labeyrie and Chantal Nifle

Article first published online:
11 Jun 2022 | DOI: 10.1111/ene.15422

ORIGINAL ARTICLE

Risk of intracranial meningioma with three potent progestogens: A population‐based case–control study

Background and purpose

A dose‐dependent association between the use of cyproterone acetate (CPA) and intracranial meningioma has been identified but data for other potent progestogens are scarce. The association was assessed between intracranial meningioma surgery and exposure to three potent progestogens: CPA (≥25 mg/day), nomegestrol acetate (NOMAC) (3.75–5 mg/day) and chlormadinone acetate (CMA) (2–10 mg/day).

Methods

In this nationwide population‐based case–control study, cases underwent surgery for intracranial meningioma in France from 2009 to 2018. They were matched to five control subjects for sex, year of birth and area of residence. Progestogen exposure was defined as progestogen use within the year before surgery for cases or the same date for their controls.

Results

In total, 25,216 cases were included (75% women, median age 58 years). Progestogen exposure was noted for 9.9% of cases (2497/25,216) and 1.9% (2382/126,080) of controls, with an odds ratio (OR) of 6.7 (95% confidence interval [CI] 6.3–7.1). The OR was 1.2 (1.0–1.4) for short‐term use (<1 year) and 9.5 (8.8–10.2) for prolonged use. A strong association was identified for prolonged use of CPA (OR = 22.7, 95% CI 19.5–26.4), NOMAC (OR = 6.5, 95% CI 5.8–7.2) and CMA (OR = 4.7, 95% CI 4.5–5.3). Progestogen exposure increased the risk of meningioma for all histological grades and anatomical sites, particularly for the anterior and middle skull base: OR = 35.7 (95% CI 26.5–48.2) and 23.9 (95% CI 17.8–32.2) for CPA. The estimated number of attributable cases was 2124 (95% CI 2028–2220) (212/year).

Conclusion

A strong association between prolonged exposure to potent progestogens and surgery for meningioma was observed. The risk increased from CMA to NOMAC to CPA. Individuals should be informed of this risk.

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Authors:
Léa Hoisnard, Moussa Laanani, Thibault Passeri, Lise Duranteau, Joël Coste, Mahmoud Zureik, Sébastien Froelich and Alain Weill

Article first published online:
20 Jun 2022 | DOI: 10.1111/ene.15423

ORIGINAL ARTICLE

Immunosuppressant and neuromyelitis optica spectrum disorder: optimal treatment duration and risk of discontinuation

Background and purpose

Preventing relapse by immunosuppressants (ISs) is critical for the prognosis of neuromyelitis optica spectrum disorder (NMOSD); however, the optimal duration of IS treatment is still under discussion. The objective was to explore the optimal duration of IS treatment and the risk of IS discontinuation for NMOSD.

Method

This cohort study was conducted at a major neurological center that housed the largest NMOSD database in South China. Eligible participants were patients with NMOSD undergoing IS treatment. The main outcome measures were changes in relapse risk based on IS treatment duration, clinical outcomes and predictors of relapse following IS discontinuation.

Results

In total, 343 patients were included in this study. The duration of IS treatment was strongly associated with a decrease in relapse risk (hazard ratio [HR] 0.53, < 0.001). Continuous IS treatment resulted in decreased relapse HRs within 5 years of receiving IS medication, with a mild rebound starting at 5 years. Rituximab reduced the risk of NMOSD relapse to approximately zero within 3 years. The rate of relapse after IS withdrawal was high (77.5%). As opposed to other ISs, a delayed relapse following rituximab withdrawal was observed in this study. Longitudinal extensive transverse myelitis (HR = 2.023, = 0.006) was associated with a higher risk of relapse after IS discontinuation.

Conclusions

Long‐term IS medication for NMOSD is generally suitable. Patients with longitudinal extensive transverse myelitis had a higher risk of relapse after IS discontinuation. Future studies should explore individualized strategies of rituximab maintenance treatment.

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Authors:
Rui Li, Cong Li, Qiao Huang, Zifeng Liu, Jingjing Chen, Bingjun Zhang, Chunxin Liu, Yaqing Shu, Yuge Wang, Allan G. Kermode and Wei Qiu

Article first published online:
11 Jun 2022 | DOI: 10.1111/ene.15425

ORIGINAL ARTICLE

Posterior circulation ischemic stroke not involving the brainstem is associated with cardiovascular autonomic dysfunction

Background and purpose

Ischemic stroke may induce cardiovascular autonomic dysfunction, but most previous studies have included patients with anterior circulation ischemic stroke or brainstem stroke. It remains unclear whether posterior circulation ischemic stroke (PCIS) without brainstem involvement also compromises cardiovascular autonomic modulation (CAM). Therefore, we aimed to assess CAM in PCIS patients with and without brainstem involvement.

Methods

In four subgroups of 61 PCIS patients (14 occipital lobe, 16 thalamic, 12 cerebellar, and 19 brainstem strokes) and 30 healthy controls, we recorded RR intervals (RRIs), systolic (SBP) and diastolic blood pressure (DBP), and respiration at supine rest during the first week after stroke onset. We calculated parameters reflecting total CAM (RRI‐standard deviation [RRI‐SD], RRI‐total powers), predominantly sympathetic CAM (RRI‐low‐frequency [LF] powers and SBP‐LF powers] and parasympathetic CAM (root mean square of successive RRI differences [RMSSD], RRI‐high‐frequency [HF] powers), sympathetic‐parasympathetic balance (RRI‐LF/HF ratios), and baroreflex sensitivity (BRS). Values were compared among the four PCIS groups and controls using one‐way ANOVA Kruskal–Wallis tests, with post‐hoc analyses. Significance was assumed for < 0.05.

Results

In each PCIS subgroup, values for RRI, RRI‐SD, RMSSD, RRI‐HF powers, and BRS were significantly lower, while SBP‐LF powers were higher than in the controls. Only in patients with occipital lobe stroke were RRI‐LF/HF ratios significantly higher than in controls. Otherwise, autonomic variables did not differ among the four PCIS subgroups.

Conclusions

During the first week after stroke onset, our PCIS patients with occipital lobe, thalamic, cerebellar, or brainstem strokes all had reduced cardiovagal modulation, compromised baroreflex, and increased peripheral sympathetic modulation. The RRI‐LF/HF ratios suggest that sympathetic predominance is slightly more prominent after occipital lobe stroke. PCIS may trigger cardiovascular autonomic dysfunction even without brainstem involvement.

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Authors:
Ruihao Wang, Martin Köhrmann, Rainer Kollmar, Julia Koehn, Stefan Schwab, Bernd Kallmünzer and Max J. Hilz

Article first published online:
13 Jun 2022 | DOI: 10.1111/ene.15427

ORIGINAL ARTICLE

Neurofilament light chain and total tau in the differential diagnosis and prognostic evaluation of acute and chronic inflammatory polyneuropathies

Background and Purpose

To investigate the diagnostic and prognostic value of axonal injury biomarkers in patients with inflammatory polyneuropathies.

Methods

Neurofilament light chain (NfL) and total tau (T‐tau) were measured in the cerebrospinal fluid (CSF) and plasma in 41 patients with Guillain–Barré syndrome (GBS), 32 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 10 with paraproteinemia‐related demyelinating polyneuropathy (PDN), and 8 with multifocal motor neuropathy (MMN), in comparison with 39 disease‐free controls and 59 other controls. Outcome was measured with the GBS‐disability score (GBS‐ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score.

Results

Neurofilament light chain levels in CSF and plasma were higher in GBS, CIDP, and PDN vs. disease‐free controls. Patients with MMN had higher NfL levels in plasma vs. disease‐free controls, but lower levels in CSF and plasma vs. patients with amyotrophic lateral sclerosis (ALS).

Conclusions

Acute and chronic inflammatory neuropathies are associated with an increase in levels of NfL in CSF and plasma, but NfL is validated as a prognostic biomarker only in GBS. NfL could be used in differentiating patients with MMN from ALS. T‐tau in plasma is a novel biomarker that could be used in a diagnostic assessment of patients with acute and chronic inflammatory polyneuropathies.

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Authors:
Ivan Kmezic, Kristin Samuelsson, Anja Finn, Zane Upate, Kaj Blennow, Henrik Zetterberg and Rayomand Press

Article first published online:
20 Jun 2022 | DOI: 10.1111/ene.15428

ORIGINAL ARTICLE

Mechanical thrombectomy failure in anterior circulation strokes: Outcomes and predictors of favorable outcome

Background and purpose

Despite continuous improvement and growing knowledge in the endovascular therapy of large vessel occlusion stroke (LVOS), mechanical thrombectomy (MT) still fails to obtain satisfying intracranial recanalization in 10% to 15% of cases. However, little is known regarding clinical and radiological outcomes among this singularly underexplored subpopulation undergoing failed MT. We aimed to investigate the outcome after failed MT and identify predictive factors of favorable outcome despite recanalization failure.

Methods

We conducted a retrospective analysis of consecutive patients prospectively included in the ongoing observational multicenter Endovascular Treatment in Ischemic Stroke registry from January 2015 to September 2020. Patients presenting with anterior circulation LVOS treated with MT but experiencing failed intracranial recanalization defined as final modified Thrombolysis In Cerebral Infarction (mTICI) score of 0, 1 and 2a were included. Clinical and radiological outcomes were assessed along with the exploration of predictive factors of Day‐90 favorable outcome.

Results

The study population comprised 533 patients. Mean age was 68.8 ± 16 years, and median admission National Institutes of Health Stroke Scale (NIHSS) and Alberta Stroke Program Early Computed Tomography Score (ASPECTS) were 17 (IQR 12–21) and 7 (IQR 5–8), respectively. Favorable outcomes were observed in 85 patients (18.2%) and 186 died (39.0%). The rate of symptomatic intracranial hemorrhage was 14.1%. In multivariable analysis, younger age (odds ratio [OR] 0.96, 95% CI 0.94–0.98, < 0.001), a lower admission NIHSS (OR 0.87, 95% CI 0.83–0.91, < 0.001), a lower number of MT passes (OR 0.77, 95% CI 0.77–0.87, < 0.001), a lower delta ASPECTS between initial and Day‐1 imaging (OR 0.83, 95% CI 0.71–0.98, = 0.026) and stroke etiology [significant difference among etiological subtypes ( = 0.024) with a tendency toward more favorable outcomes for dissection (OR 2.01, 95% CI 0.71–5.67)] were significantly associated with a 90‐day favorable outcome.

Conclusions

In this large retrospective analysis of a multicenter registry, we quantified the poor outcome after MT failure. We also identified factors associated with favorable outcome despite recanalization failure that might influence therapeutic management.

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Authors:
Gaultier Marnat, Benjamin Gory, Igor Sibon, Maeva Kyheng, Julien Labreuche, Grégoire Boulouis, Jean‐Sebastien Liegey, Jildaz Caroff, François Eugène, Olivier Naggara, Arturo Consoli, Mikael Mazighi, Benjamin Maier, Sebastien Richard, Christian Denier, Guillaume Turc, Bertrand Lapergue, Romain Bourcier, Adriana Tabarna, Adrienter Ter Schiphorst, Adrien Wang, Agnès Masson, Alain Meyer, Alain Viguier, Anne Claire Lukaszewicz, Anne‐Christine Januel, Anne‐Evelyne Vallet, Anne‐Laure Derelle, Anthony Le Bras, Arnaud Le Guen, Arturo Consoli, Augustin Lecler, Axelle Maurice, Aymeric Rouchaud, Barroso Bruno, Basile Kerleroux, Benjamin Daumas‐Duport, Benjamin Gory, Benjamin Maier, Benoît Guillon, Bernady Patricia, Bertrand Lapergue, Candice Sabben, Carlos Riquelme, Caroline Arquizan, Catherine Lamy, Cécile Preterre, Cédric Lenoble, Charbel Mounayer, Charlotte Barbier, Charlotte Rosso, Christian Denier, Christine Rodriguez‐Régent, Christophe Cognard, Chrysanthi Papagiannaki, Clément Tracol, Clothilde Isabel, Cyril Dargazanli, Dan Mihoc, David Higué, David Weisenburger‐Lile, Delvoye François, Denis Sablot, Denis Trystram, Eimad Shotar, Emmanuel Touze, Emmanuelle Schmitt, Eric Manchon, Evain Sarah, Evelyne Massardier, Fabrice Bonneville, Fatiha Bechiri, Federico Cagnazzo, Federico Di Maria, Fernando Pico, Flore Baronnet, Florent Gariel, Francis Turjman, Francisco Macian‐montoro, François Lun, Francois Mathias Merrien, François Rouanet, François Zhu, Frédéric Bourdain, Frédéric Clarençon, Frédéric Philippeau, Gaultier Marnat, Geoffroy Farouil, Georges Rodesh, Géraldine Buard, Gérard Audibert, Gioia Mione, Grégoire Boulouis, Grégory Gascou, Guillaume Bellanger, Guillaume Taylor, Guillaume Turc, Haja Rakotoharinandrasana, Hebert Solène, Hélène Caillez, Hélène Raoult, Hocine Redjem, Hubert Desal, Ian Seiler, Igor Sibon, Imad Derraz, Iona Podar, Ionel Alb, Irene Pierre‐Paul, Isabelle Mourand, Isabelle Quintana, Jean Darcourt, Jean Papaxanthos, Jean‐Christophe Ferre, Jean‐Christophe Gentric, Jean‐Christophe Lacour, Jean‐François Albucher, Jean‐Marc Olivot, Jean‐Philippe Desilles, Jean‐Sebastien Liegey, Jean‐Yves Gauvrit, Jérôme Berge, Jildaz Caroff, Julia Birchenall, Julie Gratieux, Julien Cogez, Julien Ognard, Julien Pottecher, Karine Blanc‐Lasserre, Kévin Premat, Laura Mechtouff, Laura Venditti, Laure Bottin, Laurent Derex, Laurent Lagoarde‐Segot, Laurent Spelle, Liang Liao, Lili Detraz, Lionel Calviere, Lisa Humbertjean, Lisa Papillon, Louis Fontaine, Louis Veunac, Lucas Corti, Lucas Gorza, Ludovic Lucas, Madalina Brezeanu, Malek Ben Maacha, Marc Braun, Marcela Voicu, Marie Reitter, Marion Boulanger, Marion Yger, Mathilde Poli, Matthieu Zuber, Maxime Gauberti, Maxime Tardieu, Maya Tchikviladze, Mélanie Pinault, Michel Piotin, Mikael Mazighi, Mikael Obadia, Monica Manisor, Monica Roy, Morgan Leguen, Nader Sourour, Nadia Ajili, Nicolas Gaillard, Nicolas Pangon, Nicolas Raposo, Norbert Nighoghossian, Oguzhan Coskun, Olivier Chassin, Olivier Heinzlef, Olivier Naggara, Omer Eker, Ovide Corabianu, Ozlem Ozkul Wermester, Pauline Bourst, Pauline Renou, Philippe Smadja, Philippe Tall, Philippe Tassan, Pierre Briau, Pierre‐Henri Lefèvre, Pierre‐Louis Alexandre, Raoul Pop, Raphael Blanc, Raynouard Igor, Regis Hubrecht, Remy Beaujeux, René Anxionnat, Roberto Riva, Romain Bourcier, Romain Schneckenburger, Romain Tonnelet, Roxana Gheoca, Roxanna Poll, Sabine Aptel, Sabrina Cochennec, Sabrina Debruxelles, Sarah Guy, Savatovsky Julien, Sebastian Richter, Sébastien Richard, Seners Pierre, Serge Bracard, Serge Evrard, Serge Timsit, Sergio Zimatore, Serkan Cakmak, Sharmila Sagnier, Simon Escalard, Solène de Gaalon, Sonia Alamowitch, Sophie Crozier, Sophie Guettier, Sophie Planel, Stanislas Smajda, Stéphane Olindo, Stéphane Vannier, Stéphanie Desmales, Stéphanie Lenck, Suzanna Saleme, Sylvie Marinier, Tae‐Hee Cho, Thiên‐Nga Chamaraux‐Tran, Thion Laurie‐Anne, Thomas de Broucker, Thomas Ronziere, Thomas Tourdias, Tristan Kerdraon, Valérie Domigo, Valerie Lauer, Valérie Wolff, Vanessa Chalumeau, Veronica Lassale, Veronique Quenardelle, Vincent Costalat, Vincent Degos, Wagih Ben Hassen, Wassim Farhat, Xavier Barreau and Yves Samson Anne Léger

Article first published online:
18 Jun 2022 | DOI: 10.1111/ene.15429

ORIGINAL ARTICLE

Use of antihypertensive medication and formation of de novo intracranial aneurysms

Background and purpose

Hypertension is a risk factor for subarachnoid hemorrhage and is also considered a risk factor for saccular intracranial aneurysm (sIA) formation. However, there is little direct evidence that antihypertensive medication will reduce sIA formation.

Methods

The impact of antihypertensive medication on de novo sIA formation was studied in an angiographically followed cohort of 1419 patients. Patients were identified from our population‐based Kuopio Intracranial Aneurysm Database, and data on the purchases of antihypertensive medication were obtained from a national registry. Univariate and multivariate analyses were used to investigate the risk factors.

Results

Of the 966 sIA patients who were prescribed with antihypertensive medication, 841 patients used the medication regularly; 20 of them had de novo sIA. One hundred and twenty‐five patients used the medication irregularly and 12 of them developed de novo sIAs. Four hundred and fifty‐three patients did not use antihypertensive medication even though 27 of them had a diagnosis of hypertension, and 10 of them developed de novo sIAs. In the multivariate analysis antihypertensive medication did not significantly reduce de novo sIA formation (hazard ratio [HR] 1.60, 95% confidence interval [CI] 0.84–3.06). Age at primary diagnosis (HR: 0.95, 95%: CI 0.93–0.98) and smoking history (HR: 5.53, 95% CI: 2.77–11.05) were significant risk factors for de novo sIA formation. Also, irregular usage of antihypertensive medication was a significant risk factor (HR: 3.84, 95% CI: 1.59–9.29) for de novo sIA formation.

Conclusions

Antihypertensive agents were not associated with a reduction of de novo sIA formation, but irregular use of antihypertensive agents was associated with an increased risk of de novo sIA formation.

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Authors:
Sari Räisänen, Jukka Huttunen, Terhi J. Huuskonen, Mikael von und zu Fraunberg, Timo Koivisto, Juha E. Jääskeläinen, Juhana Frösen and Antti Lindgren

Article first published online:
16 Jun 2022 | DOI: 10.1111/ene.15430

ORIGINAL ARTICLE

Levels and dynamics of estimated glomerular filtration rate and recurrent vascular events and death in patients with minor stroke or transient ischemic attack

Background and purpose

Impaired kidney function is associated with an increased risk of vascular events in acute stroke patients, when assessed by single measurements of estimated glomerular filtration rate (eGFR). It is unknown whether repeated measurements provide additional information for risk prediction.

Methods

The MonDAFIS (Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke) study randomly assigned 3465 acute ischemic stroke patients to either standard procedures or an additive Holter electrocardiogram. Baseline eGFR (CKD‐EPI formula) were dichotomized into values of < versus ≥60 ml/min/1.73 m. eGFR dynamics were classified based on two in‐hospital values as “stable normal” (≥60 ml/min/1.73 m), “increasing” (by at least 15% from baseline, second value ≥ 60 ml/min/1.73 m), “decreasing” (by at least 15% from baseline of ≥60 ml/min/1.73 m), and “stable decreased” (<60 ml/min/1.73 m). The composite endpoint (stroke, major bleeding, myocardial infarction, all‐cause death) was assessed after 24 months. We estimated hazard ratios in confounder‐adjusted models.

Results

Estimated glomerular filtration rate at baseline was available in 2947 and a second value in 1623 patients. After adjusting for age, stroke severity, cardiovascular risk factors, and randomization, eGFR < 60 ml/min/1.73 m at baseline (hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.40–3.54) as well as decreasing (HR = 1.79, 95% CI = 1.07–2.99) and stable decreased eGFR (HR = 1.64, 95% CI = 1.20–2.24) were independently associated with the composite endpoint. In addition, eGFR < 60 ml/min/1.73 at baseline (HR = 3.02, 95% CI = 1.51–6.10) and decreasing eGFR were associated with all‐cause death (HR = 3.12, 95% CI = 1.63–5.98).

Conclusions

In addition to patients with low eGFR levels at baseline, also those with decreasing eGFR have increased risk for vascular events and death; hence, repeated estimates of eGFR might add relevant information to risk prediction.

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Authors:
Serdar Tütüncü, Manuel C. Olma, Claudia Kunze, Michael Krämer, Joanna Dietzel, Johannes Schurig, Paula Filser, Waltraud Pfeilschifter, Gerhard F. Hamann, Thomas Büttner, Peter U. Heuschmann, Paulus Kirchhof, Ulrich Laufs, Darius G. Nabavi, Joachim Röther, Götz Thomalla, Roland Veltkamp, Kai‐Uwe Eckardt, Karl Georg Haeusler and Matthias Endres

Article first published online:
17 Jun 2022 | DOI: 10.1111/ene.15431

ORIGINAL ARTICLE

Prognostic value of glycemic gap in patients with spontaneous intracerebral hemorrhage

Background and purpose

Glycemic gap (GG), as a novel biomarker showing the acute glycemic change after the onset of acute illness, has been found to be associated with adverse outcomes in many diseases. This study aimed to explore the prognostic value of GG on long‐term outcomes of spontaneous intracerebral hemorrhage (sICH).

Methods

The current study included 528 patients from a multicenter, prospective, consecutive, observational cohort study. Poor clinical outcome was defined as modified Rankin Scale ≥ 3. GG was calculated using admission blood glucose minus hemoglobin A1c‐derived average blood glucose. Logistic regression analyses were performed to determine the association between GG and poor clinical outcomes at 30 days, 90 days, and 1 year.

Results

Glycemic gap was significantly associated with poor clinical outcomes at 30 days, 90 days, and 1 year ( < 0.05 for all models), where patients with higher GG were more likely to have poor clinical outcome. Restricted cubic splines revealed a positive association between GG and poor clinical outcome. In addition, patients with higher GG were more likely to have a higher 1‐year mortality rate. The addition of GG to the intracerebral hemorrhage score improved the discrimination and calibration properties for the prediction of poor clinical outcome.

Conclusions

Glycemic gap was independently associated with poor outcomes and may be a valuable prognostic factor in patients with sICH.

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Authors:
Chuanying Wang, Wenjuan Wang, Guangshuo Li, Anxin Wang, Xiaoli Zhang, Yunyun Xiong and Xingquan Zhao

Article first published online:
23 Jun 2022 | DOI: 10.1111/ene.15432

SHORT COMMUNICATION

Does prior use of antiplatelet therapy modify the effect of dual antiplatelet therapy in transient ischaemic attack/minor ischaemic stroke: A systematic review and meta‐analysis

Background and purpose

The purpose was to determine whether prior use of antiplatelet therapy modifies the effect of dual antiplatelet therapy in patients with acute minor ischaemic stroke or transient ischaemic attack.

Methods

A systematic review and meta‐analysis of randomized controlled trials was performed comparing dual antiplatelet therapy to aspirin that reported subgroup analysis by prior antiplatelet use, adhering to the Cochrane Collaboration Guidelines. A fixed‐effects meta‐analysis was used to estimate a pooled treatment effect overall in subgroups with prior aspirin therapy and without prior aspirin therapy. Difference in treatment effect was assessed by testing for interaction. The primary outcome measure was recurrent vascular events.

Results

Three eligible randomized controlled trials were identified, including 4831 participants with pre‐existing antiplatelet use and 16,236 participants without pre‐existing aspirin use. Recurrent vascular events occurred in 7.2% (95% confidence interval [CI] 4.3–10) of those without pre‐existing aspirin use versus 7.3% (95% CI 4.1–10) of those receiving prior aspirin therapy. Effect of dual antiplatelet therapy on the primary outcome measure was consistent in participants with no prior aspirin use (odds ratio 0.75, 95% CI 0.66–0.84) compared to those taking aspirin before randomization (odds ratio 0.79, 95% CI 0.63–0.998) ( interaction = 0.66). The number needed to treat in the aspirin‐naïve group was 55 (95% CI 37‐107) compared to 66 (95% CI 32 to –746) in those on prior aspirin therapy.

Conclusions

It was found that the effectiveness of dual antiplatelet therapy in patients with minor ischaemic stroke or high risk transient ischaemic attack does not significantly differ in patients with prior aspirin exposure; therefore there should be no influence on the decision to use dual antiplatelet therapy.

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Authors:
Aoibhin Clarke, Catriona Reddin, Robert Murphy and Martin J. O'Donnell

Article first published online:
20 Jun 2022 | DOI: 10.1111/ene.15433

ORIGINAL ARTICLE

Neurovascular disease in Switzerland: 10‐year trends show non‐traditional risk factors on the rise and higher exposure in women

Background and purpose

Effective risk factor modification is the prerequisite to prevent neurovascular disease such as stroke or vascular dementia. Non‐traditional vascular risk factors (nt‐vrfs) including stress significantly add to the risk of neurovascular disease arising from traditional vascular risk factors (t‐vrfs). In order to discover sex‐specific changes that may underlie previously reported inclines in the prevalence of neurovascular and cardiovascular disease in women, 10‐year trends in the prevalence of vrfs in Switzerland were assessed.

Methods

Anonymized data from 22,134 participants (51% women) of the governmental Swiss Health Survey, performed every 5 years (2007, 2012 and 2017), were obtained. Epidemiological parameters, t‐vrfs and nt‐vrfs were analyzed in a cross‐sectional study design.

Results

Over the observation period, the number of women having full‐time jobs increased considerably (2007 38%, 2012 39%, 2017 44%). This was accompanied by a substantial rise in the prevalence of nt‐vrfs in women and men including stress at work (2007, not available; 2012 women/men 58%/60%; 2017 women/men 66%/65%), low locus of control (women/men: 2007 21%/19%, 2012 22%/19%, 2017 25%/22%) and sleep disorders (women/men: 2007 30%/22%, 2012 28%/20%, 2017 32%/26%). Amongst t‐vrfs, only the prevalence of obesity and hypercholesterolemia increased over time in both sexes, whilst other t‐vrfs remained stable (hypertension [27%], diabetes [5%]) or decreased (smoking [9.4 cigarettes/day]).

Conclusions

A rise in women's economic participation alongside a higher affection with nt‐vrfs in the female Swiss population emphasizes the need to improve vascular risk stratification and implement effective preventive measures for neurovascular and cardiovascular disease.

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Authors:
Martin Hänsel, Klaus Steigmiller, Andreas R. Luft, Catherine Gebhard, Ulrike Held and Susanne Wegener

Article first published online:
22 Jun 2022 | DOI: 10.1111/ene.15434

ORIGINAL ARTICLE

Myopathy as a cause of fatigue in long‐term post‐COVID‐19 symptoms: Evidence of skeletal muscle histopathology

Background and purpose

Among post‐COVID‐19 symptoms, fatigue is reported as one of the most common, even after mild acute infection, and as the cause of fatigue, myopathy diagnosed by electromyography has been proposed in previous reports. This study aimed to explore the histopathological changes in patients with post‐COVID‐19 fatigue.

Methods

Sixteen patients (mean age = 46 years) with post‐COVID‐19 complaints of fatigue, myalgia, or weakness persisting for up to 14 months were included. In all patients, quantitative electromyography and muscle biopsies analyzed with light and electron microscopy were taken.

Results

Muscle weakness was present in 50% and myopathic electromyography in 75%, and in all patients there were histological changes. Muscle fiber atrophy was found in 38%, and 56% showed indications of fiber regeneration. Mitochondrial changes, comprising loss of cytochrome c oxidase activity, subsarcollemmal accumulation, and/or abnormal cristae, were present in 62%. Inflammation was found in 62%, seen as T lymphocytes and/or muscle fiber human leukocyte antigen ABC expression. In 75%, capillaries were affected, involving basal lamina and cells. In two patients, uncommon amounts of basal lamina were found, not only surrounding muscle fibers but also around nerves and capillaries.

Conclusions

The wide variety of histological changes in this study suggests that skeletal muscles may be a major target of SARS‐CoV‐2, causing muscular post‐COVID‐19 symptoms. The mitochondrial changes, inflammation, and capillary injury in muscle biopsies can cause fatigue in part due to reduced energy supply. Because most patients had mild–moderate acute affection, the new variants that might cause less severe acute disease could still have the ability to cause long‐term myopathy.

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Authors:
Eva K. Hejbøl, Thomas Harbo, Jane Agergaard, Line B. Madsen, Thomas H. Pedersen, Lars J. Østergaard, Henning Andersen, Henrik D. Schrøder and Hatice Tankisi

Article first published online:
23 Jun 2022 | DOI: 10.1111/ene.15435

ORIGINAL ARTICLE

Long‐term independence and quality of life after subthalamic stimulation in Parkinson disease

Background and purpose

Studies on long‐term nonmotor outcomes of subthalamic nucleus stimulation in Parkinson disease (PD) are scarce. This study reports on very long‐term non‐motor and motor outcomes in one of the largest cohorts of people with advanced PD, treated for >10 years with subthalamic nucleus stimulation. The main outcome was to document the evolution of independence in activities of daily living. The secondary outcomes were to measure the change in quality of life, as well as non‐motor and motor outcomes.

Methods

Patients were studied preoperatively, at 1 year, and beyond 10 years after subthalamic stimulation with an established protocol including motor, non‐motor, and neuropsychological assessments.

Results

Eighty‐five people with PD were included. Independence scores in the off‐medication condition (measured with the Schwab & England Activities of Daily Living Scale) as well as quality of life (measured with the Parkinson's Disease Questionnaire [PDQ]‐37) remained improved at longest follow‐up compared to preoperatively (respectively, < 0.001, = 0.015). Cognitive scores, measured with the Mattis Dementia Rating Scale, significantly worsened compared to before and 1 year after surgery ( < 0.001), without significant change in depression, measured with the Beck Depression Inventory. Motor fluctuations, dyskinesias, and off dystonia remained improved at longest follow‐up ( < 0.001), with a significant reduction in dopaminergic treatment (45%, < 0.001).

Conclusions

This study highlights the long‐term improvement of subthalamic stimulation on independence and quality of life, despite the progression of disease and the occurrence of levodopa‐resistant symptoms.

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Authors:
Anna Castrioto, Bettina Debû, Emilie Cousin, Pierre Pelissier, Eugénie Lhommée, Amélie Bichon, Emmanuelle Schmitt, Andrea Kistner, Sara Meoni, Eric Seigneuret, Stephan Chabardes, Paul Krack, Elena Moro and Valérie Fraix

Article first published online:
24 Jun 2022 | DOI: 10.1111/ene.15436

ORIGINAL ARTICLE

Association between liver fibrosis and incident dementia in the UK Biobank study

Background and purpose

There is growing recognition that chronic liver conditions influence brain health. The impact of liver fibrosis on dementia risk was unclear. We evaluated the association between liver fibrosis and incident dementia in a cohort study.

Methods

We performed a cohort analysis using data from the UK Biobank study, which prospectively enrolled adults starting in 2007, and continues to follow them. People with a Fibrosis‐4 (FIB‐4) liver fibrosis score >2.67 were categorized as at high risk of advanced fibrosis. The primary outcome was incident dementia, ascertained using a validated approach. We excluded participants with prevalent dementia at baseline. We used Cox proportional hazards models to evaluate the association between liver fibrosis and dementia while adjusting for potential confounders.

Results

Among 455,226 participants included in this analysis, the mean age was 56.5 years and 54% were women. Approximately 2.17% (95% confidence interval [CI] 2.13%–2.22%) had liver fibrosis. The rate of dementia per 1000 person‐years was 1.76 (95% CI 1.50–2.07) in participants with liver fibrosis and 0.52 (95% CI 0.50–0.54) in those without. After adjusting for demographics, socioeconomic deprivation, educational attainment, metabolic syndrome, hypertension, diabetes, dyslipidemia, and tobacco and alcohol use, liver fibrosis was associated with an increased risk of dementia (hazard ratio 1.52, 95% CI 1.22–1.90). Results were robust to sensitivity analyses. Effect modification by sex, metabolic syndrome, and apolipoprotein E4 carrier status was not observed.

Conclusion

Liver fibrosis in middle age was associated with an increased risk of incident dementia, independent of shared risk factors. Liver fibrosis may be an underrecognized risk factor for dementia.

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Authors:
Neal S. Parikh, Hooman Kamel, Cenai Zhang, Sonal Kumar, Russell Rosenblatt, Pascal Spincemaille, Ajay Gupta, David E. Cohen, Mony J. de Leon, Rebecca F. Gottesman and Costantino Iadecola

Article first published online:
20 Jun 2022 | DOI: 10.1111/ene.15437

ORIGINAL ARTICLE

Non‐invasive electrical stimulation in patients with neurodegenerative ataxia and spasticity: A systematic review and meta‐analysis of randomized controlled trials

Background and purpose

There are limited treatment options for patients with neurodegenerative ataxia and spasticity. Non‐invasive electrostimulation (NES) is receiving increasing interest because of its ease of implementation, cost‐effectiveness and safety. A meta‐analysis was conducted to evaluate the efficacy of NES.

Methods

MEDLINE and Embase were screened for studies using NES in ataxias and spasticity. Key outcome measurements of effectiveness included changes in (1) Modified Ashworth Scale (MAS) scores, (2) cerebellar brain inhibition (CBI), (3) the nine‐hole peg test (9HPT), (4) the 8‐m walking time (8MWT), (5) International Cooperative Ataxia Rating Scale (ICARS) score and (6) the Scale for Assessment and Rating of Ataxia (SARA) scores.

Results

Seven randomized controlled trials involving 203 patients were included. There were significant improvements in MAS (mean difference [MD] −0.42, 95% confidence interval [CI] −0.76 to −0.08, = 0.015), CBI (MD −0.35%, 95% CI −0.42 to −0.28, < 0.001), 8MWT (MD −1.88 s, 95% CI −3.26 to −0.49, = 0.008), ICARS (MD −7.84, 95% CI −11.90 to −3.78, < 0.001) and SARA (MD −3.01, 95% CI −4.74 to −1.28, < 0.001). There was almost no heterogeneity across all outcomes except for CBI ( = 79%). No significant changes in the 9HPT were observed comparing NES to a sham procedure (MD −3.52 s, 95% CI −9.15 to 2.10, = 0.220). Most included studies were at low risk of bias, and no severe adverse effects were reported.

Conclusion

It was demonstrated that NES is an effective treatment for improving coordination and balance and increased exercise capacity in patients with ataxia and spasticity. There was also a significant modulation of CBI in ataxic patients.

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Authors:
Aaron Shengting Mai, Jung Hahn Yong, Oliver Zi Hern Lim and Eng‐King Tan

Article first published online:
27 Jun 2022 | DOI: 10.1111/ene.15438

POSITION PAPER

Mapping of European activities on the integration of sex and gender factors in neurology and neuroscience

Background and purpose

Neurological disorders pose a profound unmet medical need for which new solutions are urgently needed. The consideration of both biological (sex) and socio‐cultural (gender) differences between men and women is necessary to identify more efficacious, safer and tailored treatments. Approaches for putting sex and gender medicine into practice have gathered momentum across Europe, but it is currently unclear to what extent they have been implemented in the field of neurology and neuroscience.

Methods

We mapped current activities in research, funding and education aimed at integrating sex and gender consideration in neuroscience and neurology in Europe. We examined and analyzed data gathered from literature searches, policy documents and reports by the European Commission and national funding agencies, web‐based searches, Web of Science, and searches of project databases of funding agencies. An informative/non‐systematic search was performed for sections on policies and funding, education, and basic research, while a systematic literature and database review was conducted for quantitative analysis of research output and funded projects in terms of sex and gender analysis.

Results

Our mapping shows that there is a growing interest in and attention given to sex and gender considerations in neurological fields, both from funding agencies and researchers. However, most activities, especially for education, are limited to the individual motivation of researchers and are not organically built within curricula and strategic research priorities.

Conclusion

We recommend actions that might help increase the consideration of sex and gender specifically in the field of neuroscience and neurology.

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Authors:
Nina B. Hentzen, Maria Teresa Ferretti, Antonella Santuccione Chadha, Joke Jaarsma, Marianne De Visser, Elena Moro, Anne Hege Aamodt, Gennarina Arabia, Selma Aybeck, Vanessa Carvalho, Riadh Goudier, Wolfgang Grisold, Elena R. Lebedeva, Magda Matczack, Melinda Magyari, Maria Judit Molnar, Martin Rakusa, Evelina Pajediene, Irene Tracy and Kristl Vonck

Article first published online:
06 Jul 2022 | DOI: 10.1111/ene.15439

SHORT COMMUNICATION

Treatment of COVID‐19‐induced refractory status epilepticus by tocilizumab

Background and purpose

COVID‐19 is a novel infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in which neurological complications have been increasingly recognized. Acute symptomatic epileptic seizures and status epilepticus are frequently reported neurological complications associated with this infection. The nervous system damage caused by SARS‐CoV‐2 may be mediated by the immune system. Interleukin 6 (IL‐6), an important component of the cytokine storm, is directly correlated with the severity of symptoms. Tocilizumab is an inhibitor of IL‐6 receptors, which blocks IL‐6‐mediated signal transduction and is used in the treatment of COVID‐19 and status epilepticus.

Case report

A patient with the Unverricht–Lundborg disease is presented who had developed refractory recurrent status epilepticus during COVID‐19 infection, which was finally controlled by treatment with tocilizumab.

Discussion

Tocilizumab, an IL‐6 inhibitor, may be considered as a treatment option in patients with status epilepticus and refractory seizures.

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Authors:
Esra Kochan Kizilkilic, Rumeysa Unkun, Ugur Uygunoglu, Sakir Delil and Cigdem Ozkara

Article first published online:
22 Jun 2022 | DOI: 10.1111/ene.15440

ORIGINAL ARTICLE

Valproate in status epilepticus: Correlation between loading dose, serum levels, and clinical response

Background and purpose

Intravenous valproate (VPA) is an established treatment of status epilepticus (SE), but optimal loading dose was not fully assessed. We aimed at analyzing the correlation between VPA loading dose and subsequent plasma levels with clinical response in SE.

Methods

This was a retrospective study in one referral center of all consecutive VPA‐naïve SE episodes treated with VPA between January 2013 and June 2019, in which total VPA trough plasma levels after intravenous loading dose were available. Response to VPA, defined as last antiseizure medication introduced before SE resolution (without the need for additional treatment), was correlated with VPA loading dose and trough level. Correlations were adjusted for other SE characteristics.

Results

Among 128 SE episodes, 53 (41%) responded to VPA. Median VPA loading dose was 25.2 mg/kg (range, 7–58 mg/kg). Loading doses and total plasma levels were not associated with the probability of response or mortality. Correcting for other possible confounders (number of previously tried treatment, demographics, SE severity) did not alter these findings. Only 3.8% of SE episodes that responded to VPA received >30 mg/kg.

Conclusions

A high loading dose (>30 mg/kg) is not associated with a greater response rate in patients with SE. Therefore, it seems to bring little benefit. If confirmed in further studies, a dosage of 25–30 mg/kg appears adequate in SE.

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Authors:
Sergiu Vijiala, Pascal André, Thierry Buclin, Laurent A. Decosterd, Andrea O. Rossetti and Jan Novy

Article first published online:
21 Jun 2022 | DOI: 10.1111/ene.15441

ORIGINAL ARTICLE

Risk factor management matters more than pharmaceutical cyclooxygenase‐2 inhibition in the prevention of de novo intracranial aneurysms

Background and purpose

Pathophysiological studies of saccular intracranial aneurysm (sIA) disease have shown that inflammation plays a crucial role in sIA development. Pharmaceutical inhibition of COX‐2–PGE2–NF‐κB signaling (COX‐2, cyclooxygenase‐2; PGE2, prostaglandin E2; NF‐κB, nuclear factor κB) has been shown in animal models to inhibit sIA formation and progression suggesting that use of medication inhibiting COX‐2 could reduce intracranial aneurysm formation also in patients.

Methods

The impact of COX‐2 inhibition on de novo sIA formation was studied in two cohorts: in a previously described angiographically followed cohort of 1419 sIA patients and in a cohort of 117 sIA patients treated with stenting or stent‐assisted embolization. Patients were identified from our population‐based Kuopio Intracranial Aneurysm Database. Data on the use of anti‐inflammatory medications and hospital diagnoses were obtained from national registries. Risk factors were identified by univariate and multivariate analyses.

Results

De novo sIA patients were younger and more often smokers. Use of COX‐2 selective inhibitors or nonsteroidal anti‐inflammatory drugs did not significantly reduce de novo sIA formation, but the percentage of patients with de novo sIA formation was smaller in patients with prescribed regular acetylsalicylic acid medication (1.1% vs. 3.6%). In the multivariate analysis, however, neither acetylsalicylic acid use nor other type of pharmaceutical inhibition of COX‐2 reduced the formation of de novo sIAs. The risk was mostly affected by age, smoking history and irregular usage of antihypertensive medication regardless of used COX‐2 inhibition level.

Conclusion

For the prevention of de novo sIA formation, risk factor management with focus on cessation of smoking and treating hypertension adequately seems more important than pharmaceutical COX‐2 inhibition.

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Authors:
Sari Räisänen, Jukka Huttunen, Terhi J. Huuskonen, Mikael von und zu Fraunberg, Timo Koivisto, Juha E. Jääskeläinen, Antti Lindgren and Juhana Frösen

Article first published online:
27 Jun 2022 | DOI: 10.1111/ene.15442

COMMENTARY

Machine‐learning in motor neuron diseases: Prospects and pitfalls

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Authors:
Peter Bede, Kai Ming Chang and Ee Ling Tan

Article first published online:
21 Jun 2022 | DOI: 10.1111/ene.15443

ORIGINAL ARTICLE

Olfactory outcomes in Zika virus‐associated Guillain–Barré syndrome

Background and purpose

Zika virus (ZIKV) infection has been associated with Guillain–Barré syndrome (GBS). However, little is known about the consequence of ZIKV infection on olfaction in humans.

Methods

Immediately before the COVID‐19 outbreak, we prospectively investigated the olfactory capacities of 19 patients with ZIKV‐associated GBS from the French West Indies and compared them to nine controls from the same population, with GBS of similar severity but independent of ZIKV infection. To provide further evidence that ZIKV infection induces smell alteration, we investigated the consequences of ZIKV infection on olfactory abilities using a mouse model.

Results

Patients with GBS‐ZIKA+ had poorer olfactory function than GBS‐non‐ZIKA, even 1–2 years after the acute phase. The proportion of patients with hyposmia was significantly higher in the GBS‐ZIKA+ than in the GBS‐non‐ZIKA group (68.4% vs. 22.2%, = 0.042). These deficits were characterized by lower threshold and identification scores and were independent from GBS severity. Additionally, ZIKV infection was found to impair olfaction in immunodeficient mice infected with ZIKV. High viral load was observed in their olfactory system and downstream brain structures. ZIKV promoted both cellular damage in the olfactory neuroepithelium and protracted inflammation of the olfactory bulb, likely accounting for smell alteration.

Conclusions

Patients with ZIKV‐related GBS had poorer long‐term olfactory function than patients with GBS‐non‐ZIKA, and ZIKV‐infected mice are hyposmic. These observations suggest that ZIKV belongs on the list of viruses affecting the olfactory system. Clinical evaluation of the olfactory system should be considered for ZIKV‐infected patients.

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Authors:
Françoise Lazarini, Annie Lannuzel, André Cabié, Vincent Michel, Yoann Madec, Hugo Chaumont, Isabelle Calmont, Mathilde Favrat, Xavier Montagutelli, Emmanuel Roze, Pierre‐Marie Lledo, Sylvie Abel, Ornella Cabras, Athéna Marquise, Mathilde Pircher, Aïssatou Signate, Christelle Celeste, Angela Lackmy, Guillaume Lepage, Quentin Lobjois, Aimée Petit, Benoît Tressières, Natacha Teissier, Tan‐Phuc Buivan, Laurine Conquet, Hélène Laude, Estelle Mottez, Fabien Taieb and Marie‐Noëlle Ungeheuer

Article first published online:
30 Jun 2022 | DOI: 10.1111/ene.15444

COMMENTARY

Another benefit of stroke unit care

Abstract

Patients who are already in a stroke unit for a first cerebral event or a situation entailing high risk for stroke are treated with shorter delays, fewer missed treatment opportunities, and better outcomes compared to those who are in another type of medical ward or at home.

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Authors:
Didier Leys

Article first published online:
10 Jul 2022 | DOI: 10.1111/ene.15480

European Journal of Neurology

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Brain health: The time has come

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