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Article first published online:
15 May 2021 | DOI: 10.1111/ene.14345

ORIGINAL ARTICLE

Correlation between total homocysteine and cerebral small vessel disease: A Mendelian randomization study

Background and purpose

Cerebral small vessel disease (CSVD) is a clinical imaging syndrome with diverse etiology. Total homocysteine (HCY) level might increase the risk of myocardial and cerebral infarction by damaging the vascular endothelium. We aimed to explore the correlation between total HCY and CSVD imaging burden, based on Mendelian randomization methods.

Methods

A total of 1,023 participants of the Shunyi study, a population‐based cohort study, were included. Vascular risk factors, total HCY levels and () gene mutations (C677T and A1298C) were examined. CSVD imaging markers, including lacunes, cerebral microbleeds, white matter hyperintensity, enlarged perivascular space and brain parenchymal fraction (BPF) were also assessed.

Results

Mutations of C677T were significantly correlated with increased total HCY levels (CC→TT: β = 0.28, < 0.0001), while mutations of A1298C were correlated with decreased total HCY levels (AA→AC: β = −0.13, < 0.0001; AA→CC: β = −0.25, = 0.004). In the Mendelian randomization study, the C677T genotype was significantly associated with lacunes (CC→CT: odds ratio [OR] 2.76, = 0.008; CC→TT: OR 2.50, = 0.018), and the A1298C genotype was significantly correlated with BPF (AA→CC: β = 1.32, = 0.015). Similarly, in multivariate regression analysis, total HCY levels were significantly correlated with lacunes (OR 2.14, < 0.0001) and negatively correlated with BPF (β = −0.55, = 0.004). Age, sex and vascular risk factors were adjusted for.

Conclusions

Total HCY level was correlated with imaging burden of CSVD, especially with lacunes and brain volume loss. For individuals with risk genetic predisposition, enhanced homocysteine‐lowering strategies might be necessary to reduce the risk and progress of CSVD.

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Authors:
Yuze Cao, Ning Su, Dingding Zhang, Lixin Zhou, Ming Yao, Shuyang Zhang, Liying Cui, Yicheng Zhu and Jun Ni

Article first published online:
16 Jan 2021 | DOI: 10.1111/ene.14708

SHORT COMMUNICATION

Detection of cutaneous prion protein deposits could help diagnose GPI‐anchorless prion disease with neuropathy

Background and purpose

To investigate prion protein (PrP) deposits in cutaneous tissues of patients of glycosylphosphatidylinositol (GPI)‐anchorless prion diseases with neuropathy.

Methods

Cutaneous tissue samples from three patients with GPI‐anchorless prion diseases were obtained, two cutaneous biopsy samples from the lower leg of Case 1 (Y162X) and Case 3 (D178fs25), and a cutaneous sample taken from the abdomen during an autopsy of Case 2 (D178fs25). We performed immunohistochemistry for PrP to look for abnormal PrP deposits.

Results

PrP deposits were observed in the dermal papilla, the sweat glands, the hair follicles, the arrector pili muscles, and peripheral nerves of all examined cases of GPI‐anchorless prion disease with neuropathy. The abnormal PrP accumulation was frequently localized at the basement membrane, and colocalized with laminin.

Conclusion

Immunohistochemical detection of PrP in cutaneous samples could be used to definitively diagnose GPI‐anchorless PrP disease with neuropathy.

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Authors:
Hiroyuki Honda, Kosuke Matsuzono, Kota Satoh, Masayoshi Fujisawa, Satoshi O. Suzuki, Chiaki Furuyama, Tetsuyuki Kitamoto, Shigeru Fujimoto, Koji Abe and Toru Iwaki

Article first published online:
22 Jan 2021 | DOI: 10.1111/ene.14720

SHORT COMMUNICATION

Is the Symbol Digit Modalities Test a useful outcome in secondary progressive multiple sclerosis?

Background

It is unclear which cognitive outcome measure is the most useful for clinical trials in multiple sclerosis. To investigate the usefulness of the Symbol Digit Modalities Test (SDMT) as a clinical outcome measure in secondary progressive multiple sclerosis (SPMS), we describe the frequency of worsening and improvement events in a large randomized controlled trial (RCT) dataset.

Methods

Using original trial data from the ASCEND trial ( = 889), a recent large RCT in SPMS, we describe worsening and similarly defined improvement with and without 3‐month confirmation on the SDMT in the whole trial cohort and unconfirmed worsening and improvement on the Paced Auditory Serial Addition Test (PASAT) in a smaller subset ( = 107).

Results

Somewhat unexpectedly, SDMT scores steadily increased throughout the 2 years of follow‐up in this trial. There were overall few SDMT worsening events throughout the trial (generally fewer than 10% of participants), but improvement events steadily increased from around 50% of participants with improvement at 12 weeks to more than 70% at 84 weeks and beyond. PASAT scores followed a similar pattern.

Conclusions

In this well‐characterized clinical trial cohort, the SDMT does not reflect the steady cognitive decline that patients with SPMS experience. Both SDMT and PASAT scores improve throughout follow‐up, possibly due to a practice effect. The SDMT may not be a useful outcome measure of disease progression in 2‐year clinical trials in SPMS.

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Authors:
Marcus W. Koch, Jop Mostert, Pavle Repovic, James D. Bowen, Bernard Uitdehaag and Gary Cutter

Article first published online:
24 Jan 2021 | DOI: 10.1111/ene.14732

SHORT COMMUNICATIONS

Central retinal artery occlusion as a neuro‐ophthalmological emergency: the need to raise public awareness

Background and purpose

Central retinal artery occlusion (CRAO) is a neuro‐ophthalmological emergency necessitating adequate and comprehensive diagnosis. Its optimal management and treatment, however, are still under debate. This study aimed at identifying respective areas for improvement.

Methods

We retrospectively analysed the medical records of patients with CRAO treated in our stroke unit between January 2016 and August 2020.

Results

During the observational period, 101 patients with CRAO were admitted. We observed an increase in the rate of patients primarily admitted to the stroke unit from 52.2% to 97.4%. In addition, the thrombolysis rate – with thrombolysis performed on an individual basis – rose from 0% to 14.1%, coinciding with the implementation of an in‐hospital management guideline. Almost 60% of all patients presented outside of the 4.5‐h time window for thrombolysis; by far the most common reason not to deliver intravenous thrombolysis in our cohort was a prehospital delay to presentation (58.8%), with 44.4% of patients having consulted a private‐practice ophthalmologist first. A total of 25 (32.5%) of 77 patients who underwent magnetic resonance imaging (MRI) had accompanying acute ischaemic stroke lesions on diffusion‐weighted MRI of the brain. A possible aetiology of CRAO was identified in 41.4% of patients.

Discussion

Public awareness of sudden unilateral visual loss as a presenting sign for stroke should be raised, increasing the chances for timely recognition in a hospital with ophthalmological expertise and a stroke centre. This is essential for ongoing and future prospective trials on this subject.

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Authors:
Carolin Hoyer, Christian Kahlert, Resul Güney, Frank Schlichtenbrede, Michael Platten and Kristina Szabo

Article first published online:
10 Feb 2021 | DOI: 10.1111/ene.14735

LETTER TO THE EDITOR

Letter to the Editor about the Ongre et al. publication: ‘Progression of fatigue in Parkinson's disease—a 9‐year follow‐up’ (Eur J Neurol 2020. doi: 10.1111/ene.14520)

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Authors:
Eva‐Juliane Vollstedt, Elena Warrlich, Björn Hauptmann, Henrike Hanssen, Christine Klein, Meike Kasten, Alexander Balck, Max Borsche, Norbert Brüggemann, Julia Graf, Jannik Prasuhn, Nathalie Schell, Vera Tadic, Tatiana Usnich and Raluca Modreanu

Article first published online:
20 Mar 2021 | DOI: 10.1111/ene.14740

SHORT COMMUNICATION

Endovascular treatment for basilar artery occlusion: A systematic review and meta‐analysis

Background and purpose

Independent randomized controlled clinical trials (RCTs) have provided robust evidence for endovascular treatment (EVT) as the standard of care treatment for acute large vessel occlusions in the anterior circulation. We examined available studies specific to posterior cerebral circulation ischemic strokes to see if any conclusions can be drawn regarding EVT options.

Methods

We performed a systematic literature search to identify studies evaluating the safety and efficacy of EVT versus standard medical treatment for patients with acute basilar artery occlusion (BAO). We extracted data for outcomes of interest and presented associations between the two groups with the use of risk ratios (RRs) or odds ratios (ORs), with corresponding 95% confidence intervals (CIs). We used a random‐effects model to pool the effect estimates.

Results

We identified five studies (two RCTs, three observational cohorts) including a total of 1098 patients. Patients receiving EVT had a higher risk of symptomatic intracranial hemorrhage (sICH) compared to those receiving non‐interventional medical management (RR 5.42, 95% CI 2.74–10.71). Nonsignificant trends towards modified Rankin Scale (mRS) scores 0–2 (RR 1.02, 95% CI 0.74–1.41), mRS scores 0–3 (RR = 0.97, 95% CI 0.64–1.47), overall functional improvement (OR 0.93, 95% CI 0.57–1.51), and all‐cause mortality (RR 1.03, 95% CI 0.78–1.35) at 3 months were seen.

Conclusion

Although EVT increases the probability of sICH, the available data do not exclude the possibility of improved functional outcomes over standard therapy. As larger studies are challenged by the perceived lack of equipoise in this vulnerable patient population, results of ongoing RCTs are expected to provide substantial input for future meta‐analyses.

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Authors:
Aristeidis H. Katsanos, Apostolos Safouris, Stavros Nikolakopoulos, Dimitris Mavridis, Nitin Goyal, Marios N. Psychogios, Georgios Magoufis, Christos Krogias, Luciana Catanese, Brian Van Adel, Guy Raphaeli, Amrou Sarraj, Marios Themistocleous, Evangelia Kararizou, Guillaume Turc, Adam Arthur, Andrei V. Alexandrov and Georgios Tsivgoulis

Article first published online:
12 Feb 2021 | DOI: 10.1111/ene.14751

ORIGINAL ARTICLE

Adaption and preliminary validation of the Addenbrooke's Cognitive Examination‐III as a screening test for mild cognitive impairment and dementia in hearing‐impaired individuals

Background

A large proportion of older adults assessed for cognitive impairment likely have hearing loss, potentially affecting accuracy of cognitive performance estimations. This study aimed to develop a hearing‐impaired version of the Addenbrooke's Cognitive Examination‐III (HI‐ACE‐III) and to assess whether the HI‐ACE‐III can accurately distinguish people with mild cognitive impairment (MCI) and dementia from cognitively intact controls.

Methods

The HI‐ACE‐III was developed by converting verbal instructions into a visual, timed PowerPoint presentation. Seventy‐four participants over the age of 60 years were classified into three groups: 29 had MCI, 15 had mild to moderate dementia and 30 were cognitively intact controls. Receiver operating characteristic (ROC) curves were graphed to test screening accuracy. Concurrent validity was examined through correlations between HI‐ACE‐III domain scores and relevant, visually presented standardized neuropsychological measures.

Results

ROC analysis for dementia revealed an area under the curve (AUC) of 0.99, achieving excellent sensitivity (100%) and good specificity (93.3%) at an optimum cut‐off of <87. The AUC for MCI was 0.86, achieving reasonable sensitivity (75.9%) and good specificity (86.7%) at an optimum cut‐off of <92. HI‐ACE‐III subtests shared anticipated and statistically significant correlations with established measures of cognitive functioning. Internal consistency of the HI‐ACE‐III was excellent as verified with Cronbach's alpha ( = 0.904).

Conclusions

Preliminarily, the HI‐ACE‐III showed good reliability, validity and screening utility for MCI and dementia in older adults in a hearing‐impairment context. The adapted HI‐ACE‐III may offer accurate and reliable indication of cognitive performance, supporting timely diagnosis and research examining links between hearing loss and cognitive decline.

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Authors:
Courtney North, Mary H. Heatley, Nattawan Utoomprurkporn, Doris Eva Bamiou, Sergi G. Costafreda and Joshua Stott

Article first published online:
13 Feb 2021 | DOI: 10.1111/ene.14753

LETTER TO THE EDITOR

Letter to the editor in response to the letter from the EPIPARK Study Group regarding the publication ʻProgression of fatigue in Parkinson's disease ‐ a 9‐year follow‐upʼ (Eur J Neurol 2021. doi:10.1111/ene.14520)

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Authors:
Solgunn Odinsen Ongre, Ingvild Dalen, Ole‐Bjørn Tysnes, Guido Alves and Karen Herlofson

Article first published online:
23 Feb 2021 | DOI: 10.1111/ene.14765

SHORT COMMUNICATION

False‐negative tests in Huntington's disease: A new variant within primer hybridization site

Background

Establishing the diagnosis of Huntington’s disease (HD) involves molecular genetic testing and estimation of the number of CAG repeats.

Material and Methods

We report a 42‐year‐old patient with clinical phenotype suggestive of HD, who was repeatedly negative on genetic testing for HD at a reference laboratory. He had positive history of similar symptoms in his father, but not in other family members. During a 2‐year follow‐up his symptoms slowly deteriorated (videos attached). The family history was misleading, as we discovered that patient’s father was adopted as infant. Having excluded HD‐like disorders and other causes of the symptoms we hypothesized that the primer could not bind to the mutated allele.

Results

The PCR reaction with primers HD1 and Hu3 revealed homozygosity of the other adjacent microsatellite tract consisting of the CCG repeats. The newly designed set of primers, located outside of the CAG tract (HD6extF, HD7extR) was used and enabled amplification of the mutant allele and detection of the abnormal range of CAG repeats.

Conclusions

As application of the novel primers led to the diagnosis of HD in other 5 patients previously tested negative, we propose their incorporation into routine genetic testing in patients suspected of HD displaying homoallelism in the standard protocol.

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Authors:
Jaroslaw Dulski, Anna Sulek, Magdalena Krygier, Wiktoria Radziwonik and Jaroslaw Slawek

Article first published online:
08 Mar 2021 | DOI: 10.1111/ene.14772

ORIGINAL ARTICLE

Exploratory pilot study of exogenous sustained‐release melatonin on nocturia in Parkinson's disease

Introduction

Nocturia is one of the commonest non‐motor symptoms in Parkinson's disease (PD). Nocturia has evolved from being understood as a symptom of urological disorders or neurogenic bladder dysfunction to being considered as a form of circadian dysregulation. Exogenous melatonin is known to help circadian function and can be an effective strategy for nocturia in PD.

Methods

In this open‐label, single‐site, exploratory, phase 2 pilot study, adults with PD and nocturia underwent assessments using standardized questionnaires, urodynamics studies and a bladder scan. This was followed by completion of a frequency volume chart (FVC) and 2‐week sleep diary. Sustained‐release melatonin 2 mg was then administered once‐nightly for 6 weeks. A repeat assessment using questionnaires, the FVC and sleep diary was performed whilst on treatment with melatonin. Companion or bed partners filled in sleep questionnaires to assess their sleep during the intervention.

Results

Twenty patients (12 males; mean age 68.2 [SD = 7.8] years; mean PD duration 8.0 [±5.5] years) with PD reporting nocturia were included. Administration of melatonin was associated with a significant reduction in the primary outcome bother related to nocturia measured using the International Consultation on Incontinence Questionnaire Nocturia (ICIQ‐N) ( = 0.01), number of episodes of nocturia per night ( = 0.013) and average urine volume voided at night ( = 0.013). No serious adverse events were reported. No significant improvement was noted in bed partner sleep scores.

Conclusions

In this preliminary open‐label study, administration of sustained‐release melatonin 2 mg was found to be safe for clinical use and was associated with significant improvements in night‐time frequency and nocturnal voided volumes in PD patients.

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Authors:
Amit Batla, Sara Simeoni, Tomoyuki Uchiyama, Lorenzo deMin, Joanne Baldwin, Charles Melbourne, Saiful Islam, Kailash P. Bhatia, Mahreen Pakzad, Sofia Eriksson and Jalesh N. Panicker

Article first published online:
14 Mar 2021 | DOI: 10.1111/ene.14774

ORIGINAL ARTICLE

Cardiovascular health and chronic axonal polyneuropathy: A population‐based study

Background and purpose

Chronic axonal polyneuropathy is a common, usually multifactorial, disease for which there is no treatment yet available. We investigated the association between cardiovascular health, defined by the health score of the American Heart Association, and chronic axonal polyneuropathy.

Methods

Between June 2013 and January 2017, we investigated participants of the Rotterdam Study, a population‐based cohort study. Participants were screened for polyneuropathy and categorized as having no, possible, probable or definite polyneuropathy. The cardiovascular health score (range 0–14; higher score reflecting better health) consisted of four health behaviours (diet, physical activity, smoking and body mass index) and three health factors (blood pressure, serum cholesterol and fasting glucose level).

Results

We included 1919 participants, of whom 120 (6.3%) had definite polyneuropathy. The median (interquartile range [IQR]) age was 69.0 (58.6–73.7) years and 53.4% were women. A higher cardiovascular health score was associated with a lower prevalence of definite polyneuropathy (per point increase: odds ratio [OR] 0.90, 95% confidence interval [CI] 0.84–0.96). Optimal cardiovascular health (score≥10) was strongly associated with a lower prevalence of definite polyneuropathy (OR 0.55, 95% CI 0.32–0.90). An increase in health factors and health behaviour scores separately was associated with a lower prevalence of polyneuropathy (per point increase: OR 0.82, 95% CI 0.71–0.95 and OR 0.86, 95% CI 0.78–0.96, respectively). The association between a lower cardiovascular health score and lower sural nerve amplitude was not significant after correction for covariates (difference 0.07µV, 95% CI −0.02–0.17).

Conclusions

Better cardiovascular health, consisting of both modifiable health behaviours and health factors, is associated with a lower prevalence of chronic axonal polyneuropathy.

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Authors:
Noor E. Taams, Fariba Ahmadizar, Rens Hanewinckel, Judith Drenthen, Trudy Voortman, M. Arfan Ikram, Maryam Kavousi and Pieter A. van Doorn

Article first published online:
12 Mar 2021 | DOI: 10.1111/ene.14777

SHORT COMMUNICATION

CD8 T‐cell predominance in autoimmune glial fibrillary acidic protein astrocytopathy

Background and objective

We aimed to report the pathological features of T lymphocytes in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP‐A).

Methods

A retrospective pathological analysis of patients with GFAP‐A was performed.

Results

Eight patients with GFAP‐immunoglobulin G (IgG) and pathological data were included. Their biopsy findings were similar, and all showed marked lymphocytic infiltration in the white matter, with perivascular predominance. The lymphocytic infiltration was predominantly composed of CD8 T lymphocytes rather than CD4 T lymphocytes, except in one patient who had overlapping positive myelin oligodendrocyte glycoprotein‐IgG. Unlike CD4 T cells, CD8 T cells were frequently observed adjacent to dystrophic neurons and astrocytes. There was also diffuse infiltration by CD68 and CD163 macrophages. CD8 astrocytes were identified in two samples, but no CD4 astrocytes were observed.

Conclusions

A predominance of CD8 T cells may be an important pathological and diagnostic feature in GFAP‐A.

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Authors:
Zhongmin Yuan, Huilu Li, Lu Huang, Congcong Fu, Yaotang Chen, Cheng Zhi, Wei Qiu and Youming Long

Article first published online:
06 Mar 2021 | DOI: 10.1111/ene.14778

LETTERS TO THE EDITOR

Minimal detectable change and minimal clinically important difference in spinal muscular atrophy patients

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Authors:
Juan F. Vázquez‐Costa and David Hervás

Article first published online:
04 Mar 2021 | DOI: 10.1111/ene.14780

ORIGINAL ARTICLE

Predictors of perfusion computed tomography alterations in stroke mimics attended as stroke code

Background and purpose

Stroke mimics (SMs) account for a significant number of patients attended as stroke code (SC) with an increasing number over the years. Recent studies show perfusion computed tomography (PCT) alterations in some SMs, especially in seizures. The objective of our study was to evaluate the clinical characteristics and PCT alterations in SMs attended as SC in order to identify potential predictors of PCT alterations in SMs.

Methods

A retrospective study was performed including all SC activations undergoing a multimodal CT study including non‐enhanced computed tomography (CT), CT angiography and PCT, as part of our SC protocol, over 39 months. Patients with a final diagnosis of SM after complete diagnosis work‐up were therefore selected. Clinical variables, diagnosis, PCT alteration patterns and type of map affected ( or time to peak, cerebral blood flow and cerebral blood volume) were registered.

Results

Stroke mimics represent up to 16% (284/1761) of SCs with a complete multimodal study according to our series. Amongst SMs, 26% (74/284) showed PCT alterations. PCT abnormalities are more prevalent in seizures and status epilepticus and the main pattern is alteration of the time to peak map, of unilateral hemispheric distribution or of non‐vascular territory. In our series, the independent predictors of alteration in PCT in SMs are aphasia, female sex and older age.

Conclusions

Perfusion computed tomography alterations can be found amongst almost a third of SMs attended as SC, especially older women presenting with aphasia with a final diagnosis of epileptic seizures and status epilepticus.

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Authors:
Alicia Gonzalez‐Martinez, Santiago Trillo, Carmen Benavides‐Bernaldo de Quirós, Laura Casado‐Fernández, María De Toledo, Antonio Barbosa‐Del Olmo, Lorena Vega Piris, Carmen Ramos, Rafael Manzanares‐Soler, Álvaro Ximénez‐Carrillo and José Vivancos

Article first published online:
13 Mar 2021 | DOI: 10.1111/ene.14783

ORIGINAL ARTICLE

Early apathetic, but not depressive, symptoms are associated with poor outcome after stroke

Background and purpose

Depression and apathy are frequent neuropsychiatric disturbances after stroke and may appear together. Despite the overlap in symptoms between poststroke depression and apathy, these two syndromes might be associated with different prognoses and benefit from different treatments. We aimed to disentangle the relationship between early depressive and apathetic symptoms and outcome after stroke.

Methods

Of 698 enrolled patients with ischemic stroke, we included 443 participants (median age = 69 years, 51% female) who underwent depressive and apathetic symptom assessment on Day 8 after stroke. We divided patients into four groups: without greater depressive and apathetic symptoms (Group 1), with only apathetic symptoms (Group 2), with only depressive symptoms (Group 3), and with both depressive and apathetic symptoms (Group 4).

Results

After adjusting for age and stroke severity, Group 2 and Group 4 had an increased risk of poor 3‐month outcome (odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.16–3.38, = 0.01 and OR = 1.58, 95% CI = 1.24–2.01, < 0.01, respectively). Group 2 and Group 4 also had an increased risk of poor 12‐month outcome (OR = 3.85, 95% CI = 2.19–6.78, < 0.01 and OR = 1.54, 95% CI = 1.22–1.96, < 0.01, respectively) and mortality (hazard ratio [HR] = 2.76, 95% CI = 1.19–6.41, = 0.02 and HR = 1.77, 95% CI = 1.32–2.38, < 0.01, respectively). Compared with Group 1, Group 3 did not have an increased risk of unfavorable outcomes.

Conclusions

Early apathetic, but not depressive, symptoms are related to worse outcomes after stroke. Our study underscores the importance of recognizing apathetic symptoms independently from depressive symptoms.

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Authors:
Anna Maria Lopatkiewicz, Joanna Pera, Agnieszka Slowik and Tomasz Dziedzic

Article first published online:
09 Mar 2021 | DOI: 10.1111/ene.14785

ORIGINAL ARTICLE

Association between neuropathy and B‐vitamins: A systematic review and meta‐analysis

Background

Peripheral neuropathy (PN) is common in patients with diseases that are in turn associated with deficiency of the B‐vitamins, and vitamin treatment has shown mixed results.

Methods

This systematic review and meta‐analysis studied the association between PN/pain and B‐vitamin biomarkers and investigated whether vitamin treatment can ameliorate the symptoms. PubMed and Web of Science were searched according to the study protocol.

Results

A total of 46 observational and seven interventional studies were identified and included in the data synthesis. The presence of PN was associated with lowered B12 levels (pooled estimate [95% CIs] = 1.51 [1.23–1.84], = 34, Cochran Test = 43.3%, = 0.003) and elevated methylmalonic acid (2.53 [1.39–4.60], = 9, = 63.8%, = 0.005) and homocysteine (3.48 [2.01–6.04], = 15, = 70.6%, < 0.001). B12 treatment (vs. the comparators) showed a non‐significant association with symptom improvement (1.36 (0.66–2.79), = 4, = 28.9%). Treatment with B1 was associated with a significant improvement in symptoms (5.34 [1.87–15.19], = 3, = 64.6%, = 0.059). Analysis of seven trials combined showed a non‐significant higher odds ratio for improvement under treatment with the B‐vitamins (2.58 [0.98–6.79], = 80.0%, < 0.001).

Conclusions

PN is associated with lowered plasma vitamin B12 and elevated methylmalonic acid and homocysteine. Overall, interventional studies have suggested that B‐vitamins could improve symptoms of PN. Available trials have limitations and generally did not investigate vitamin status prior to treatment. Well‐designed studies, especially in non‐diabetes PN, are needed. This meta‐analysis is registered at PROSPERO (ID: CRD42020144917).

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Authors:
Johannes Stein, Juergen Geisel and Rima Obeid

Article first published online:
15 Mar 2021 | DOI: 10.1111/ene.14786

ORIGINAL ARTICLE

The effect of intracranial stenosis on cognitive decline in a memory clinic cohort

Background and purpose

Intracranial stenosis (ICS) is a risk factor for cognitive impairment and dementia in cross‐sectional studies. However, data examining the effect of ICS on cognitive decline are limited. We investigated the effect of ICS on cognition over a period of 3 years in a memory clinic cohort.

Methods

Patients were recruited from the National University Hospital in Singapore. Data were collected using a standardised questionnaire, physical examination, and 3‐T magnetic resonance imaging (MRI) at baseline. ICS was defined as arterial narrowing that exceeded 50% of the luminal diameter in any intracranial vessel. Cognition was measured at baseline and annually for 3 years using the Mini‐Mental State Examination, the Montreal Cognitive Assessment, and a detailed neuropsychological test battery. The association between ICS and cognitive decline was analysed using generalised estimating equations.

Results

A total of 364 patients were included in the analysis. The mean (±SD) age was 71.9 (±8.0) years, and 164 (45.1%) patients were male. A total of 66 (18.1%) patients had ICS. ICS was associated with worse executive function (β = −0.37, 95% confidence interval = −0.68 to −0.05, = 0.022) and modified the effect of follow‐up time on memory ( = 0.005) and visuomotor speed ( = 0.047). These results remained significant after controlling for demographics, overall diagnosis, cardiovascular risk factors, and MRI markers of cerebrovascular disease.

Conclusions

Intracranial stenosis was independently associated with worse executive function across all time points, and cognitive decline in memory and visuomotor speed over 3 years of follow‐up. This suggests that ICS may be a useful indicator of vascular brain damage leading to cognitive decline and may warrant consideration of antiatherosclerotic treatment in clinical trials.

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Authors:
Mervyn Jun Rui Lim, Chuen Seng Tan, Bibek Gyanwali, Christopher Chen and Saima Hilal

Article first published online:
18 Mar 2021 | DOI: 10.1111/ene.14788

ORIGINAL ARTICLE

Tau protein as a diagnostic and prognostic biomarker in amyotrophic lateral sclerosis

Background and purpose

To test the hypothesis that total tau (tTau), tau phosphorylated at threonine 181 (pTau) and pTau/tTau ratio in the cerebrospinal fluid (CSF) are diagnostic and prognostic biomarkers of amyotrophic lateral sclerosis (ALS), we performed a retrospective observational study in a large cohort of ALS patients and controls.

Methods

We enrolled 196 ALS patients and 91 controls, who included patients with ALS‐mimicking diseases and those with non‐neurodegenerative diseases. All patients underwent lumbar puncture for CSF analysis at the time of the diagnostic evaluation or to first referral. We measured tTau and pTau levels in the CSF by chemiluminescence enzyme immunoassay.

Results

Patients with ALS showed significantly higher levels of CSF tTau and a lower pTau/tTau ratio than controls (tTau: 245 vs. 146 pg/ml; < 0.001; pTau/tTau ratio: 0.12 vs. 0.18; < 0.001, respectively). No differences in pTau levels were detected. Receiver‐operating characteristic curve analysis showed a good diagnostic accuracy of tTau and pTau/tTau ratio (tTau: area under the curve [AUC] 0.685, 95% confidence interval [CI] 0.616–0.754, = 0.039; pTau/tTau ratio: AUC 0.777, 95% CI 0.707–0.848, < 0.001). Among ALS patients, increased tTau levels were associated with advanced age of onset, increased revised amyotrophic lateral sclerosis functional rating scale (ALSFRS‐R) score (ΔFS) rate of progression, and spinal onset. Multivariate analysis showed that in ALS patients, this biomarker was an independent negative predictor of overall survival.

Conclusions

Our findings suggest that tTau and pTau/tTau ratio can be diagnostic biomarkers of ALS. In addition, CSF tTau level at diagnosis might play a relevant prognostic role in the disease.

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Authors:
Luisa Agnello, Tiziana Colletti, Bruna Lo Sasso, Matteo Vidali, Rossella Spataro, Caterina Maria Gambino, Rosaria Vincenza Giglio, Tommaso Piccoli, Giulia Bivona, Vincenzo La Bella and Marcello Ciaccio

Article first published online:
19 Mar 2021 | DOI: 10.1111/ene.14789

ORIGINAL ARTICLE

Untreated patients with multiple sclerosis: A study of French expert centers

Background and purpose

Disease‐modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment.

Methods

We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included.

Results

Of the 21,189 patients with MS (age 47.1 ± 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 ± 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7–31.9) were not receiving any DMT. Although patients with a relapsing‐remitting course ( = 11,693) were the most likely to receive DMT, 14.8% (95% CI 14.2–15.4) were still untreated (6.8% never treated). After multivariate analysis among patients with relapsing‐remitting MS, the main factors explaining never having been treated were: not having ≥9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44–0.61]) and lower EDSS score (OR 0.78 [95% CI 0.74–0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT.

Conclusion

A significant proportion of patients with MS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of patients with MS.

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Authors:
Xavier Moisset, Audrey‐Anne Fouchard, Bruno Pereira, Frédéric Taithe, Guillaume Mathey, Gilles Edan, Jonathan Ciron, Bruno Brochet, Jérôme De Sèze, Caroline Papeix, Patrick Vermersch, Pierre Labauge, Gilles Defer, Christine Lebrun‐Frenay, Thibault Moreau, David Laplaud, Eric Berger, Jean Pelletier, Bruno Stankoff, Olivier Gout, Eric Thouvenot, Olivier Heinzlef, Abdullatif Al‐Khedr, Bertrand Bourre, Olivier Casez, Philippe Cabre, Alexis Montcuquet, Alain Créange, Jean‐Philippe Camdessanché, Serge Bakchine, Aude Maurousset, Karolina Hankiewicz, Corinne Pottier, Nicolas Maubeuge, Dalia Dimitri Boulos, Chantal Nifle, Sandra Vukusic and Pierre Clavelou

Article first published online:
19 Mar 2021 | DOI: 10.1111/ene.14790

ORIGINAL ARTICLE

Delirium REduction after administration of melatonin in acute ischemic stroke (DREAMS): A propensity score–matched analysis

Background and purpose

Poststroke delirium (PSD) comprises a common and severe complication after stroke. However, treatment options for PSD remain insufficient. We investigated whether prophylactic melatonin supplementation may be associated with reduced risk for PSD.

Methods

Consecutive patients admitted to the Tübingen University Stroke Unit, Tübingen, Germany, with acute ischemic stroke (AIS), who underwent standard care between August 2017 and December 2017, and patients who additionally received prophylactic melatonin (2 mg per day at night) within 24 h of symptom onset between August 2018 and December 2018 were included. Primary outcomes were (i) PSD prevalence in AIS patients and (ii) PSD risk and PSD‐free survival in patients with cerebral infarction who underwent melatonin supplementation compared to propensity score–matched (PSM) controls. Secondary outcomes included time of PSD onset and PSD duration.

Results

Out of 465 (81.2%) patients with cerebral infarction and 108 (18.8%) transient ischemic attack (TIA) patients, 152 (26.5%) developed PSD (median time to onset [IQR]: 16 [8–32] h; duration 24 [8–40] h). Higher age, cerebral infarction rather than TIA, and higher National Institutes of Health Stroke Scale score and aphasia on admission were significant predictors of PSD. After PSM (164 melatonin‐treated patients with cerebral infarction versus 164 matched controls), 42 (25.6%) melatonin‐treated patients developed PSD versus 60 (36.6%) controls (odds ratio, 0.597; 95% confidence interval, 0.372–0.958; = 0.032). PSD‐free survival differed significantly between groups ( = 0.027), favoring melatonin‐treated patients. In patients with PSD, no between‐group differences in the time of PSD onset and PSD duration were noted.

Conclusions

Patients prophylactically treated with melatonin within 24 h of AIS onset had lower risk for PSD than patients undergoing standard care. Prospective randomized trials are warranted to corroborate these findings.

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Authors:
Annerose Mengel, Jan Zurloh, Christian Boßelmann, Bettina Brendel, Vera Stadler, Jennifer Sartor‐Pfeiffer, Andreas Meisel, Robert Fleischmann, Ulf Ziemann, Sven Poli and Maria‐Ioanna Stefanou

Article first published online:
21 Mar 2021 | DOI: 10.1111/ene.14792

ORIGINAL ARTICLE

Alterations of brain network topology and structural connectivity‐functional connectivity coupling in capsular versus pontine stroke

Background and purpose

This study was conducted to investigate whether capsular stroke (CS) and pontine stroke (PS) have different topological alterations of structural connectivity (SC) and functional connectivity (FC), as well as correlations of SC‐FC coupling with movement assessment scores.

Methods

Resting‐state functional magnetic resonance imaging and diffusion tensor imaging were prospectively acquired in 46 patients with CS, 36 with PS, and 29 healthy controls (HCs). Graph theoretical network analyses of SC and FC were performed. Patients with left and right lesions were analyzed separately.

Results

With regard to FC, the PS and CS groups both showed higher local efficiency than the HCs, and the CS group also had a higher clustering coefficient (Cp) than the HCs in the right lesion analysis. With regard to SC, the PS and CS groups both showed different normalized clustering coefficient (γ), small‐worldness (σ), and characteristic path length (Lp) compared with the HC group. Additionally, the CS group showed higher normalized characteristic path length (λ) and a lower Cp than the HCs and the PS group showed higher λ and lower global efficiency than the HCs in the right‐lesion analysis. However, γ, σ, Cp and Lp were only significantly different in the PS and CS groups compared with the HC group in the right‐lesion analysis. Importantly, the CS group was found to have a weaker SC‐FC coupling than the PS group and the HC group in the right‐lesion analysis. In addition, both patient groups had weaker structural‐functional connectome correlation than the HCs.

Conclusions

The CS and PS groups both showed FC and SC disruption and the CS group had a weaker SC‐FC coupling than the PS group in the right lesion analysis. This may provide useful information for individualized rehabilitative strategies.

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Authors:
Huiyou Chen, Wen Geng, Song’an Shang, Mengye Shi, Leilei Zhou, Liang Jiang, Peng Wang, Xindao Yin and Yu‐Chen Chen

Article first published online:
22 Mar 2021 | DOI: 10.1111/ene.14794

ORIGINAL ARTICLE

Antiherpetic medication and incident dementia: Observational cohort studies in four countries

Background and purpose

Several epidemiological studies from Taiwan, all using the same data resource, found significant associations between herpes virus infection, antiherpetic medication, and subsequent dementia. We conducted a multicenter observational cohort study using health registry data from Wales, Germany, Scotland, and Denmark to investigate potential associations between antiherpetic medication and incident dementia, and also to comprehensively investigate such associations broken down according to medication type and dose, type of herpes virus, and dementia subtype.

Methods

A total of 2.5 million individuals aged 65 years or more were followed up using linked electronic health records in four national observational cohort studies. Exposure and outcome were classified using coded data from primary and secondary care. Data were analyzed using survival analysis with time‐dependent covariates.

Results

Results were heterogeneous, with a tendency toward decreased dementia risk in individuals exposed to antiherpetic medication. Associations were not affected by treatment number, herpes subtype, dementia subtype, or specific medication. In one cohort, individuals diagnosed with herpes but not exposed to antiherpetic medication were at higher dementia risk.

Conclusions

Short‐term antiherpetic medication is not markedly associated with incident dementia. Because neither dementia subtype nor herpes subtype modified the association, the small but significant decrease in dementia incidence with antiherpetic administration may reflect confounding and misclassification.

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Authors:
Christian Schnier, Janet Janbek, Linda Williams, Tim Wilkinson, Thomas M. Laursen, Gunhild Waldemar, Hartmut Richter, Karel Kostev, Richard Lathe and Jürgen G Haas

Article first published online:
19 Mar 2021 | DOI: 10.1111/ene.14795

ORIGINAL ARTICLE

Misdiagnosis and diagnostic pitfalls of chronic inflammatory demyelinating polyradiculoneuropathy

Background and purpose

The aim of this study was to determine the frequency of over‐ and underdiagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to identify related diagnostic pitfalls.

Methods

We conducted a retrospective study in Dutch patients referred to the Erasmus University Medical Centre Rotterdam between 2011 and 2017 with either a diagnosis of CIDP or another diagnosis that was revised to CIDP. We used the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) 2010 diagnostic criteria for CIDP to classify patients into three groups: overdiagnosis, underdiagnosis, or confirmed diagnosis of CIDP. Clinical and laboratory features and treatment history were compared between groups.

Results

A referral diagnosis of CIDP was revised in 32% of patients (31/96; overdiagnosis). Of 81 patients diagnosed with CIDP, 16 (20%) were referred with another diagnosis (underdiagnosis). In the overdiagnosed patients, 20% of muscle weakness was asymmetric, 48% lacked proximal muscle weakness, 29% only had distal muscle weakness, 65% did not fulfil the electrodiagnostic criteria for CIDP, 74% had an elevated cerebrospinal fluid (CSF) protein level, and 97% had another type of neuropathy. In the underdiagnosed patients, all had proximal muscle weakness, 50% had a clinically atypical CIDP, all fulfilled the electrodiagnostic criteria for CIDP, and 25% had an increased CSF protein level.

Conclusion

Over‐ and underdiagnosis of CIDP is common. Diagnostic pitfalls include lack of attention to proximal muscle weakness as a diagnostic hallmark of CIDP, insufficient recognition of clinical atypical phenotypes, overreliance on CSF protein levels, misinterpretation of nerve conduction studies and poor adherence to electrodiagnostic criteria, and failure to exclude other causes of polyneuropathy.

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Authors:
Merel C. Broers, Carina Bunschoten, Judith Drenthen, Tiago A. O. Beck, Esther Brusse, Hester F. Lingsma, Jeffrey A. Allen, Richard A. Lewis, Pieter A. van Doorn and Bart C. Jacobs

Article first published online:
09 Apr 2021 | DOI: 10.1111/ene.14796

ORIGINAL ARTICLE

Effect of intravenous alteplase on post‐stroke depression in the WAKE UP trial

Background and purpose

The aim was to study the effect of intravenous alteplase on the development of post‐stroke depression (PSD) in acute stroke patients, and to identify predictors of PSD.

Methods

This post hoc analysis included patients with unknown onset stroke randomized to treatment with alteplase or placebo in the WAKE‐UP trial ( number, NCT01525290), in whom a composite end‐point of PSD was defined as a Beck Depression Inventory ≥10, medication with an antidepressant, or depression recorded as an adverse event. Multiple logistic regression was used to identify predictors of PSD at 90 days. Structural equation modelling was applied to assess the indirect effect of thrombolysis on PSD mediated by the modified Rankin Scale.

Results

Information on the composite end‐point was available for 438 of 503 randomized patients. PSD was present in 96 of 224 (42.9%) patients in the alteplase group and 115 of 214 (53.7%) in the placebo group (odds ratio 0.63; 95% confidence interval 0.43–0.94; = 0.022; adjusted for age and National Institutes of Health Stroke Scale at baseline). Prognostic factors associated with PSD included baseline medication with antidepressants, higher lesion volume, history of depression and assignment to placebo. While 65% of the effect of thrombolysis on PSD were caused directly, 35% were mediated by an improvement of the mRS.

Conclusions

Treatment with alteplase in patients with acute stroke resulted in lower rates of depression at 90 days, which were only partially explained by reduced functional disability. Predictors of PSD including history and clinical characteristics may help in identifying patients at risk of PSD.

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Authors:
Alina Königsberg, Susanne Sehner, Sönke Arlt, Bastian Cheng, Claus Z. Simonsen, Florent Boutitie, Joaquin Serena, Vincent Thijs, Martin Ebinger, Matthias Endres, Jochen B. Fiebach, Robin Lemmens, Keith W. Muir, Norbert Nighoghossian, Salvador Pedraza, Christian Gerloff and Götz Thomalla

Article first published online:
22 Mar 2021 | DOI: 10.1111/ene.14797

ORIGINAL ARTICLE

Sociability‐based fitness approach in Parkinson’s disease: Comparison with conventional rehabilitation

Background and purpose

The effect of a sociability‐based fitness approach on parkinsonian disability in patients with Parkinson's disease (PD) was assessed.

Methods

Eighty patients diagnosed with PD were randomly assigned to either the group‐based rehabilitation (GBR) group ( = 40) or the individual‐based rehabilitation (IBR) group ( = 40). The primary outcome was the difference between the two groups in the mean change from baseline to post‐training in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS). The secondary outcomes included the change in mental status and the difference in the mean change from baseline to month 3 and month 6 in the total score on the UPDRS.

Results

The mean (±SD) UPDRS scores were 72.0 ± 21.0 in the GBR group and 72.1 ± 18.6 in the IBR group. The UPDRS scores from baseline to post‐training were 22.8 ± 13.5 in the GBR group and 10.9 ± 8.8 in the IBR group (difference 11.8 points; 95% confidence interval [CI] 5.0–18.6; = 0.001). The difference between the groups from baseline to month 3 (difference 10.06 points; 95% CI 3.3–16.8) and the difference between the groups from baseline to month 6 (difference 11.7 points; 95% CI 4.9–18.5) were also significant ( = 0.004 and = 0.001, respectively). The scores of cognitive function and depression had not changed significantly.

Conclusions

Patients receiving GBR demonstrated significant improvements in parkinsonian symptoms, suggesting that the sociability‐based fitness can be applied to clinical treatment by sustaining the motivation in PD.

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Authors:
Takao Mitsui, Yoshiharu Arii, Ai Tsukamoto, Koichiro Taniguchi, Masaru Mabuchi, Arisa Shimizu, Nichika Sumitomo and Yukiko Kuroda Maki

Article first published online:
21 Mar 2021 | DOI: 10.1111/ene.14798

SHORT COMMUNICATION

The use of eye‐movement recording in patients with anti‐Hu antibody–associated paraneoplastic neurological syndromes to objectively determine extent and course of disease

Background and purpose

Paraneoplastic neurological syndromes with Hu‐antibodies (Hu‐PNS) are immune‐mediated disorders in patients with malignancies, most frequently small cell lung cancer, affecting both the peripheral and central nervous system (CNS). In Hu‐PNS, brainstem and cerebellar involvement are common. Here, we assessed whether eye‐movement disturbances can be used for diagnosis and monitoring of CNS involvement in Hu‐PNS.

Methods

Twenty‐nine patients with Hu‐PNS (17 females; mean age, 63.2 years,) and 14 healthy age‐matched controls (seven females; mean age, 60.2 years) were included. Saccadic and smooth pursuit eye movements in response to visual stimuli were recorded with video‐oculography. Eye movements were scored quantitatively (number of correction saccades, saccadic intrusions, and saccades during fixation period) and qualitatively by two eye‐movement experts. In 20 patients, up to three follow‐up measurements were made during subsequent hospital visits with fixed 4‐week intervals. Disease course was assessed using the modified Rankin Scale.

Results

Eye movements were disturbed in 26 of 29 Hu‐PNS patients, with horizontal eye movements being in general more impaired. Moreover, in 12 of the 14 Hu‐PNS patients without clinical CNS involvement, eye movements were disturbed. Changes in eye‐movement control over a period of up to 12 weeks were significantly correlated with the clinical response to treatment ( = 0.52, = 0.02).

Conclusions

Hu‐PNS often affects eye‐movement control, also in the absence of CNS signs or symptoms. Eye‐movement recordings in Hu‐PNS patients might be a useful tool to objectively monitor progression and treatment efficacy in Hu‐PNS patients.

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Authors:
Malou Janssen, Flip van Broekhoven, Peter Sillevis Smitt, Maarten Frens and Jos van der Geest

Article first published online:
20 Mar 2021 | DOI: 10.1111/ene.14799

ORIGINAL ARTICLE

First symptom guides diagnosis and prognosis in neurodegenerative diseases—a retrospective study of autopsy proven cases

Background and purpose

Clinical diagnostic criteria for neurodegenerative diseases have been framed based on clinical phenomenology. However, systematic knowledge about the first reported clinical symptoms in neurodegenerative diseases is lacking. Therefore, the aim was to determine the prevalence and clinical implications of the first clinical symptom (FS) as assessed by medical history in neuropathologically proven neurodegenerative diseases.

Methods

Neuropathological diagnoses from the Neurobiobank Munich, Germany, were matched with clinical records for analyses of the diagnostic and prognostic values of FSs.

Results

In all, 301 patients with the neuropathological diagnoses Alzheimer disease (AD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD) including the neuropathologically indistinguishable clinical phenotypes Parkinson disease and dementia with Lewy bodies, multiple system atrophy (MSA) and corticobasal degeneration (CBD) were studied. Memory disturbance was the most common FS in AD (34%), FTLD (19%) and LBD (26%), gait disturbance in PSP (35%) and MSA (27%) and aphasia and personality changes in CBD (20%, respectively). In a model adjusting for prevalence in the general population, AD was predicted by memory disturbance in 79.0%, aphasia in 97.2%, personality changes in 96.0% and by cognitive disturbance in 99.0%. Gait disturbance and tremor predicted LBD in 54.6% and 97.3%, coordination disturbance MSA in 59.4% and dysarthria FTLD in 73.0%. Cognitive FSs were associated with longer survival in AD (12.0 vs. 5.3 years; < 0.001) and FTLD (8.2 vs. 4.1 years; = 0.005) and motor FSs with shorter survival in PSP (7.2 vs. 9.7; = 0.048).

Conclusions

Assessing FSs in neurodegenerative diseases may be beneficial for accuracy of diagnosis and prognosis and thereby may improve clinical care and precision of study recruitment.

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Authors:
Jonathan Vöglein, Irena Kostova, Thomas Arzberger, Sigrun Roeber, Peer Schmitz, Mikael Simons, Viktoria Ruf, Otto Windl, Jochen Herms, Marianne Dieterich, Adrian Danek, Günter U. Höglinger, Armin Giese and Johannes Levin

Article first published online:
22 Mar 2021 | DOI: 10.1111/ene.14800

COMMENTARY

The challenge of detecting cognitive impairment in hearing‐impaired individuals

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Authors:
Luciana Vita and Diana Bruno

Article first published online:
24 Mar 2021 | DOI: 10.1111/ene.14802

ORIGINAL ARTICLE

Impact of the metabolic syndrome on peripheral nerve structure and function in type 2 diabetes

Background and purpose

There is a strong association between the metabolic syndrome in diabetes and the development of peripheral neuropathy; however, the pathophysiological mechanisms remain unknown.

Methods

Participants with type 2 diabetes and metabolic syndrome (T2DM/MetS, = 89) and type 2 diabetes alone (T2DM; = 59) underwent median nerve ultrasound and excitability studies to assess peripheral nerve structure and function. A subset of T2DM/MetS ( = 24) and T2DM ( = 22) participants underwent confocal microscopy to assess central and inferior whorl corneal nerve structure. Neuropathy severity was assessed using the modified Toronto Clinical Neuropathy Score (mTCNS). Diabetes groups were similar for age, sex distribution, diabetes duration, hemoglobin A, insulin treatment, and renal function. Sixty healthy controls similar for age and sex distribution were recruited for comparison.

Results

Participants with T2DM/MetS manifested with a greater mTCNS compared to T2DM ( < 0.05). Median nerve cross‐sectional area was larger in the T2DM/MetS group compared to the T2DM cohort ( < 0.05). Participants with T2DM/MetS had reductions in central (all < 0.01) and inferior whorl (all < 0.05) nerve measures. Compared to T2DM, the T2DM/MetS group demonstrated more severe changes in nerve excitability measures, which was due to reduced sodium channel permeability and sodium–potassium pump function. In comparison, only sodium channel permeability was reduced in the T2DM group.

Conclusions

Compared to participants with type 2 diabetes alone, those with diabetes and metabolic syndrome manifested greater alterations in peripheral nerve structure and function, which may be due to reduced function of the sodium–potassium pump.

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Authors:
Tushar Issar, Shyam S. Tummanapalli, Adeniyi A. Borire, Natalie C. G. Kwai, Ann M. Poynten, Ria Arnold, Maria Markoulli and Arun V. Krishnan

Article first published online:
21 Mar 2021 | DOI: 10.1111/ene.14805

ORIGINAL ARTICLE

Large vessel cardioembolic stroke and embolic stroke of undetermined source share a common profile of matrix metalloproteinase‐9 level and susceptibility vessel sign length

Background

Embolic stroke of undetermined source (ESUS) accounts for up to 25% of ischemic strokes. Identification of biomarkers that could improve the prediction of stroke subtype and subsequently of stroke prevention still remains a major issue.

Methods

The HIBISCUS‐STROKE cohort includes ischemic stroke patients with large vessel occlusion treated with mechanical thrombectomy following admission magnetic resonance imaging. Presence and length of susceptibility vessel sign (SVS) were assessed by gradient‐recalled echo T2*‐weighted imaging. Matrix metalloproteinase‐9 (MMP‐9) was measured on sera collected at admission. A multiple logistic regression model was performed to detect independent markers distinguishing cardioembolic (CE) from large‐artery atherosclerosis (LAA) subtype.

Results

A total of 147 patients were included, of them the etiology was distributed as follows: 86 (58.5%) CE, 26 (17.7%) LAA, and 35 (23.8%) ESUS. The optimal cutoff for differentiating CE from LAA subtype was 14.5 mm for SVS length (sensitivity, 79.7%; specificity, 72.7%) and 1110 ng/ml for admission MMP‐9 level (sensitivity, 85.3%; specificity, 52.2%). Multivariate analysis revealed that current smoking (odds ratio [OR] 0.07, 95% confidence interval [CI] 0.01–0.93), tandem occlusion (OR 0.01, 95% CI 0.01–0.21), SVS length (OR 0.78, 95% CI 0.63–0.97), and admission MMP‐9 level (OR 0.99, 95% CI 0.99–1.00) were inversely associated with CE subtype. SVS length and MMP‐9 level did not differ between ESUS and CE subtypes.

Conclusion

SVS length and admission MMP‐9 level may improve the prediction of CE subtype whose profile is close to ESUS, thus suggesting a common cardiac embolic source.

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Authors:
Hanan Alhazmi, Alexandre Bani‐Sadr, Thomas Bochaton, Alexandre Paccalet, Claire Crola Da Silva, Marielle Buisson, Camille Amaz, Roxana Ameli, Yves Berthezene, Omer Faruk Eker, Michel Ovize, Tae‐Hee Cho, Norbert Nighoghossian and Laura Mechtouff

Article first published online:
17 Apr 2021 | DOI: 10.1111/ene.14806

ORIGINAL ARTICLE

Magnitude of blood pressure change and clinical outcomes after thrombectomy in stroke caused by large artery occlusion

Background

Extremes of both high and low systolic blood pressure (SBP) after mechanical thrombectomy (MT) in large artery occlusion stroke are known predictors of unfavorable outcome. However, the effect of SBP change (∆SBP) during the first 24 h on thrombectomy outcomes remains unclear. We aimed to investigate the association between ∆SBP at different time intervals and thrombectomy outcomes.

Methods

We analyzed MT‐treated patients registered in the SITS International Stroke Thrombectomy Registry from January 1, 2014 to September 3, 2019. Primary outcome was 3‐month unfavorable outcome (modified Rankin scale scores 3–6). We defined ∆SBP as the mean SBP of a given time interval after MT (0–2, 2–4, 4–12, 12–24 h) minus admission SBP. Multivariable mixed logistic regression models were used to adjust for known confounders and center as random effect. Subgroup analyses were included to contrast specific subpopulations. Restricted cubic splines were used to model the associations.

Results

The study population consisted of 5835 patients (mean age 70 years, 51% male, median NIHSS 16). Mean ∆SBP was −12.3, −15.7, −17.2, and −16.9 mmHg for the time intervals 0–2, 2–4, 4–12 h, and 12–24 h, respectively. Higher ∆SBP was associated with unfavorable outcome at 0–2 h (odds ratio 1.065, 95% confidence interval 1.014–1.118), 2–4 h (1.140, 1.081–1.203), 4–12 h (1.145, 1.087–1.203), and 12–24 h (1.145, 1.089–1.203), for every increase of 10 mmHg. Restricted cubic spline models suggested that increasing ∆SBP was associated with unfavorable outcome, with higher values showing increased risk of unfavorable outcome.

Conclusion

SBP increase after thrombectomy in large artery occlusion stroke is associated with poor functional outcome.

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Authors:
Mohammad Anadani, Marius Matusevicius, Georgios Tsivgoulis, André Peeters, Ana Paiva Nunes, Michelangelo Mancuso, Christine Roffe, Adam de Havenon and Niaz Ahmed

Article first published online:
19 Mar 2021 | DOI: 10.1111/ene.14807

COMMENTARY

Progress towards optimizing blood pressure control after reperfusion therapy for acute ischemic stroke

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Authors:
Craig S. Anderson

Article first published online:
29 Mar 2021 | DOI: 10.1111/ene.14808

ORIGINAL ARTICLE

Vitamin D and white matter hyperintensities: results of the population‐based Heinz Nixdorf Recall Study and 1000BRAINS

Background and purpose

Cross‐sectional studies showed an inverse association between serum 25‐hydroxyvitamin D (25OHD) and white matter hyperintensities (WMHs) whereas the few longitudinal studies did not. The association between baseline 25OHD and WMHs at 10‐year follow‐up in the Heinz Nixdorf Recall Study plus 1000BRAINS was investigated.

Methods

Data of 505 participants (49% women, 56.2 ± 6.6 years) with 25OHD at baseline (2000–2003) and WMH volume and grade of WMHs using the Fazekas classification at 10‐year follow‐up were analysed. The association between deseasonalized 25OHD and the base‐10 logarithm of WMH volume was evaluated by multiple linear regression, adjusted for age, sex, education, smoking, alcohol consumption, sports, diabetes mellitus, systolic blood pressure and total cholesterol. β‐estimators were transformed back (10). Using multiple logistic regression, odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated to evaluate the association between deseasonalized 25OHD and Fazekas grades (0, absence and 1, punctate foci vs. 2, beginning and 3, large confluence).

Results

Mean 25OHD was 17.0 ± 8.2 ng/ml, and mean deseasonalized 25OHD was 16.9 ± 7.5 ng/ml. Mean WMH volume was 16.6 ± 17.4 ml, range 1–132 ml. Most grade 2–3 WMHs were found to be periventricular (39% of the participants), parietal (32%) and frontal (31%) (temporal 6%, occipital 3%). The linear regression showed an inverse association between 25OHD and WMH volume. On average, a 25OHD increase of 1 ng/ml was associated with a reduced WMH volume by a factor of 0.99 (95% CI 0.98; 1.00) (fully adjusted). There was also some indication for an inverse association between 25OHD and extent of periventricular (OR 0.98 [95% CI 0.96; 1.01]), frontal (0.99 [0.97; 1.02]) and parietal (0.98 [0.95; 1.00]) WMHs according to the Fazekas classification.

Conclusions

Lower 25OHD may be a risk factor for the occurrence of WMHs.

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Authors:
Sara Schramm, Lea Schliephake, Heiko Himpfen, Svenja Caspers, Raimund Erbel, Karl‐Heinz Jöckel and Susanne Moebus

Article first published online:
31 Mar 2021 | DOI: 10.1111/ene.14810

ORIGINAL ARTICLE

Chinese validation of the Rasch‐Built Overall Amyotrophic Lateral Sclerosis Disability Scale

Background and purpose

The Rasch‐Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) was developed using Rasch methodology. This scale has been demonstrated as a reliable outcome measure of amyotrophic lateral sclerosis (ALS) trials. To date, there are no similar interval‐weighted scales to assess disability in ALS patients. The current study aimed to validate a Chinese version of the ROADS via Rasch methodology.

Methods

The Chinese version of the ROADS was obtained through a standardized forward–backward translation and cultural adaptation. ALS patients were recruited from the Department of Neurology of Peking University Third Hospital in Beijing, China to complete the ROADS and the revised ALS Functional Rating Scale (ALSFRS‐R). Overall, 254 participants with ALS finished the Chinese scale. Rasch analysis was performed on the ROADS for validation and the ALSFRS‐R for comparison.

Results

The Chinese version of the ROADS was modified according to the statistical results. A final 28‐question scale was constructed that fulfilled all the requirements of the Rasch model with proper validity and reliability. Furthermore, the ROADS showed improved item targeting compared to the ALSFRS‐R. Conversely, the ALSFRS‐R did not fit the Rasch model expectations due to misfit values and disordered thresholds for all 12 items.

Conclusions

The Chinese adaptation of the ROADS is a linearly weighted scale that specifically captures overall disability in ALS patients. This scale indicates a wider range of item difficulties and better responsiveness than the ALSFRS‐R. The ROADS could be used as a valuable tool for use in ALS trials and in the clinic in Chinese settings.

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Authors:
Can Sun, Christina N. Fournier, Shan Ye, Nan Zhang, Yan Ma and Dongsheng Fan

Article first published online:
27 Mar 2021 | DOI: 10.1111/ene.14811

ORIGINAL ARTICLE

High incidence of stroke in young adults in Tartu, Estonia, 2013 to 2017: A prospective population‐based study

Background and purpose

Previous studies conducted elsewhere in the world have demonstrated an increase in the incidence of ischemic stroke (IS) in younger ages. We sought to determine stroke incidence and 28‐day case‐fatality rates in 15‐ to 54‐year‐old residents of Tartu, Estonia from 2013 to 2017.

Methods

All stroke cases that were the first ever in a lifetime (IS, nontraumatic intracerebral hemorrhage [ICH], and subarachnoid hemorrhage [SAH]) in 15‐ to 54‐year‐old residents of Tartu, Estonia were prospectively registered from January 1, 2013 to December 31, 2017. Several additional overlapping data sources were used for case ascertainment including other departments of the Tartu University Hospital and outpatient clinic, Estonian Cause of Death Registry, and the Estonian Electronic Health Record. All cases were thoroughly validated before inclusion.

Results

We identified 110 cases (43.6% female) of first‐ever stroke (IS 72.7%, ICH 12.7%, SAH 14.6%), out of which 85.5% were included prospectively. The mean age at onset was 44.3 ± 8.5 (SD) years. The mean age at onset was higher for men than for women ( = 0.046). The incidence of stroke standardized to the 1976 European standard population (EUR) was 46.1/100,000 (95% confidence interval [CI]: 37.4–54.8). IS incidence was 33.4/100,000 EUR (95% CI: 26–40.7). The total stroke incidence was higher in 45‐ to 54‐year‐old men than in women in the same age group (rate ratio, 2.24; 95% CI: 1.35–3.71). There were no more significant differences between sexes or age groups. The 28‐day case‐fatality rate was 10.9% for all strokes.

Conclusions

Our study shows higher crude incidence and case fatality of stroke in the young compared to studies from other high‐income countries.

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Authors:
Liisa Kõrv, Riina Vibo, Sandra Mallene and Janika Kõrv

Article first published online:
23 Mar 2021 | DOI: 10.1111/ene.14812

CASE STUDY

Neuropathy of the phrenic nerve associated with antiganglioside antibodies

Background and purpose

Antiganglioside antibodies have been implicated in several autoimmune‐mediated neuropathies, and binding of these antibodies can result in inflammatory changes of the nerves. Diaphragmatic paralysis is a rare condition, mostly arising from diseases affecting the phrenic nerve, neuromuscular junction, or skeletal muscle.

Objectives

In this case series, we identified five patients with diaphragmatic paralysis due to unilateral or bilateral neuropathy of the phrenic nerve associated with the presence of antiganglioside antibodies (immunoglobulin G anti‐GT1a antibodies and immunoglobulin M anti‐GM1 antibodies).

Discussion

The combination of an isolated phrenic nerve palsy with anti‐GM1 antibodies has only once been described. On the other hand, the association of anti‐GT1a antibodies with phrenic nerve palsy has never been reported before.

Conclusions

We report an association between phrenic nerve palsy and the presence of antiganglioside antibodies, but it remains unclear if there is a causal relationship. Further studies are needed to explore this matter.

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Authors:
Anouk Serrien, Katrien Sanders, Kristl G. Claeys, Koen Poesen, Dries Testelmans and Philip Van Damme

Article first published online:
15 May 2021 | DOI: 10.1111/ene.14814

LETTERS TO THE EDITOR

Response to Carvalho et al.: Diagnosis of monogenic small‐vessel disease – “real‐ world” application of the consensus recommendation of the European Academy of Neurology

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Authors:
Michelangelo Mancuso and Hugh S. Markus

Article first published online:
22 Mar 2021 | DOI: 10.1111/ene.14817

LETTERS TO THE EDITOR

Diagnosis of monogenic small vessel disease—“real‐world” application of the consensus recommendation of the European Academy of Neurology

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Authors:
Vanessa Carvalho, Paulo Ferreira, Maria João Lima, Margarida Calejo and Vitor Tedim Cruz

Article first published online:
24 Mar 2021 | DOI: 10.1111/ene.14818

LETTERS TO THE EDITOR

Reply to: Minimal detectable change and minimal clinically important differences in spinal muscular atrophy patients

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Authors:
Benjamin Stolte, Christoph Kleinschnitz and Tim Hagenacker

Article first published online:
21 Mar 2021 | DOI: 10.1111/ene.14819

ORIGINAL ARTICLE

Clinical characteristics and outcomes of thymoma‐associated myasthenia gravis

Background and purpose

Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG.

Methods

This multicenter study was based on data from a Spanish neurologist‐driven MG registry. All patients were aged >18 years at onset and had anti‐acetylcholine receptor antibodies. We compared the clinical data of thymomatous and nonthymomatous patients. Prognosis of patients with recurrent or nonresectable thymomas was assessed.

Results

We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma‐associated MG. Median follow‐up time was 4.6 years. At onset, thymoma‐associated MG patients were younger (52.0 vs. 60.4 years, < 0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95–4.68, < 0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15–2.21, = 0.005). Disease severity based on MGFA postintervention status (MGFA‐PIS) was higher in thymomatous patients at 1 year, 5 years, and the end of follow‐up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43–3.63, = 0.001; hazard ratio: 2.46, 95% CI: 1.47–4.14, = 0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long‐term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA‐PIS and higher mortality at the end of follow‐up.

Conclusions

Thymoma‐associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long‐term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.

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Authors:
Rodrigo Álvarez‐Velasco, Gerardo Gutiérrez‐Gutiérrez, Juan Carlos Trujillo, Elisabeth Martínez, Sonia Segovia, Marina Arribas‐Velasco, Guillermo Fernández, Carmen Paradas, Beatriz Vélez‐Gómez, Carlos Casasnovas, Velina Nedkova, Antonio Guerrero‐Sola, Alba Ramos‐Fransi, Alicia Martínez‐Piñeiro, Julio Pardo, Teresa Sevilla, María Teresa Gómez‐Caravaca, Adolfo López de Munain, Ivonne Jericó, Ana L. Pelayo‐Negro, María Asunción Martín, Yolanda Morgado, María Dolores Mendoza, Helena Pérez‐Pérez, Ricard Rojas‐García, Janina Turon‐Sans, Luis Querol, Eduard Gallardo, Isabel Illa and Elena Cortés‐Vicente

Article first published online:
30 Mar 2021 | DOI: 10.1111/ene.14820

ORIGINAL ARTICLE

Deep phenotyping of an international series of patients with late‐onset dysferlinopathy

Background

To describe the clinical, pathological, and molecular characteristics of late‐onset (LO) dysferlinopathy patients.

Methods

Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30 years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early‐onset (EO) dysferlinopathy (<30 years) were randomly selected from the COS study as a control group, and the North Star Assessment for Dysferlinopathy (NSAD) and Activity Limitation (ACTIVLIM) scores were used to assess functionality. Muscle biopsies obtained from 11 LO and 11 EO patients were revisited.

Results

Forty‐eight patients with LO dysferlinopathy were included (28 females). Median age at onset of symptoms was 37 (range 30–57) years and most patients showed a limb‐girdle ( = 26) or distal ( = 10) phenotype. However, compared with EO dysferlinopathy patients ( = 48), LO patients more frequently showed atypical phenotypes (7 vs. 1; = 0.014), including camptocormia, lower creatine kinase levels (2855 vs. 4394 U/L; = 0.01), and higher NSAD ( = 0.008) and ACTIVLIM scores ( = 0.016). Loss of ambulation in LO patients tended to occur later (23 ± 4.4 years after disease onset vs. 16.3 ± 6.8 years; = 0.064). Muscle biopsy of LO patients more frequently showed an atypical pattern (unspecific myopathic changes) as well as significantly less necrosis regeneration and inflammation. Although LO patients more frequently showed missense variants (39.8% vs. 23.9%; = 0.021), no differences in dysferlin protein expression were found on Western blot.

Conclusions

Late‐onset dysferlinopathy patients show a higher frequency of atypical presentations, are less severely affected, and show milder dystrophic changes in muscle biopsy.

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Authors:
Gorka Fernández‐Eulate, Giorgia Querin, Ursula Moore, Anthony Behin, Marion Masingue, Guillaume Bassez, Sarah Leonard‐Louis, Pascal Laforêt, Thierry Maisonobe, Philippe‐Edouard Merle, Marco Spinazzi, Guilhem Solé, Thierry Kuntzer, Anne‐Laure Bedat‐Millet, Emmanuelle Salort‐Campana, Shahram Attarian, Yann Péréon, Leonard Feasson, Julie Graveleau, Aleksandra Nadaj‐Pakleza, France Leturcq, Svetlana Gorokhova, Martin Krahn, Bruno Eymard, Volker Straub, Teresinha Evangelista and Tanya Stojkovic

Article first published online:
01 Apr 2021 | DOI: 10.1111/ene.14821

ORIGINAL ARTICLE

Somatic symptoms have negligible impact on Patient Health Questionnaire‐9 depression scale scores in neurological patients

Background and purpose

There is concern that the Patient Health Questionnaire‐9 (PHQ‐9) depression scale may be impacted by the presence of somatic symptoms (differential item functioning [DIF]) in patients with neurological conditions. We evaluated the PHQ‐9 for the presence and impact of DIF in large clinical samples of neurological patients.

Methods

We conducted a cross‐sectional study of patients seen at the Cleveland Clinic Cerebrovascular, Headache, Movement Disorder, and Neuromuscular clinics who completed the PHQ‐9 and patient‐reported disease severity measures as part of standard care between 29 July 2008 and 21 February 2013. We evaluated PHQ‐9 items for DIF with respect to disease‐specific severity for each condition. Salient DIF impact was characterized as a difference between DIF‐adjusted and unadjusted PHQ‐9 scores.

Results

Included in the study were 2112 patients with stroke, 8221 with migraine, 440 with amyotrophic lateral sclerosis (ALS), and 5022 with Parkinson disease (PD). Several PHQ‐9 items demonstrated DIF with respect to disease‐specific severity, although salient DIF was present in very few patients (stroke, = 0; migraine, = 1; ALS, = 13; PD, = 1).

Conclusions

PHQ‐9 items function consistently across disease severity, with salient levels of DIF impact found only for a very small proportion of people. These results suggest that the PHQ‐9 provides a consistent measure of depression severity among people with neurological conditions associated with somatic symptoms that overlap with depression.

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Authors:
Irene L. Katzan, Brittany Lapin, Sandra Griffith, Lara Jehi, Hubert Fernandez, Erik Pioro, Stewart Tepper and Paul K. Crane

Article first published online:
26 Mar 2021 | DOI: 10.1111/ene.14822

ORIGINAL ARTICLE

Worldwide barriers to genetic testing for movement disorders

Background and purpose

Despite enormous advances in identifying genetic variants responsible for many neurological diseases, access to genetic testing may be limited in clinical practice. The objective of this study was to assess worldwide access to genetic tests for movement disorders and factors impacting their utilization.

Methods

The Rare Movement Disorders Study Group of the International Parkinson and Movement Disorder Society designed an online survey electronically mailed to all 7815 members.

Results

Survey data completed by 1269 participants from 109 countries were analysed. Limited access to geneticists and genetic counsellors was reported in many world regions compared to Europe and North America. Availability of genetic testing was limited, with rates of access lower than 50%. Genetic testing for chorea was the most commonly available. For parkinsonism, dystonia, ataxia, hereditary spastic paraplegias and metabolic disorders, there was limited access to genetic testing in all countries compared to Europe and North America, with significant differences found for Africa, Central/South America, Asia. In many regions, genetic testing was supported by either private or public funding. Genetic testing was free of charge in Europe according to 63.5% of respondents. In North America, Africa, Central/South America, Asia and the Middle East access to free of charge genetic testing was by far significantly lower compared to Europe.

Conclusions

This survey highlights difficulties in accessing genetic testing and individuals with expertise in genetics at the worldwide level. In addition, major disparities in genetic testing amongst world regions are highlighted, probably due to a variety of factors including financial barriers.

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Authors:
Emilia M. Gatto, Ruth H. Walker, Claudio Gonzalez, Martin Cesarini, Giovanni Cossu, Christopher D. Stephen, Bettina Balint, Mayela Rodríguez‐Violante, Joseph Jankovic, Francesca Morgante, Hyder A. Jinnah, Alberto Albanese, Ignacio Amorin, Kailash Bhatia, Melanie Brandabur, Francisca Canals, Francisco Cardoso, Adriana Cardozo, Vanessa Carvalho, Anabel Chade, Pedro Chana, Alejandra Darling, Leonor Correia Guedes, Andrés De la Cerda, Marina de Koning‐Tijssen, Marcus V Della Coletta, Antoine Duquette, Alberto Espay, Jose Etcheverry, Joaquim Ferreira, Jennifer Friedman, Victor Fung, Christos Ganos, Pedro Garcia Ruiz, Oscar Gershanik, Kenneth B.V. Gross, Kim Han‐Joon, Ruyji Kaji, Katya Kotschet, Andres Lescano Da Rosa, Irene Litvan, Naomi Lubarr, Massimo Marano, Maria Josep Martí, Daniel Martinez Ramirez, Janis Miyasaki, Alexander Münchau, Daniela Muñoz Chesta, Pramod Pal, María Cecilia Peralta, Nicolás Phielipp, Giulietta Maria Riboldi, María Cruz Rodríguez Oroz, Federico Rodriguez‐Porcel, Harini Sarva, Ludger Schoels, Maria Stamelou and Claudia Uribe Roca

Article first published online:
09 Apr 2021 | DOI: 10.1111/ene.14826

ORIGINAL ARTICLE

Retinal layer thinning predicts treatment failure in relapsing multiple sclerosis

Background and purpose

Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) thinning are markers of neuroaxonal degeneration in multiple sclerosis (MS), which is reduced by disease‐modifying treatment (DMT). We aimed to investigate the potential of pRNFL and GCIPL thinning for prediction of DMT failure in relapsing MS (RMS).

Methods

In this 4‐year prospective observational study on 113 RMS patients, pRNFL and GCIPL were measured at DMT initiation and after 12 months (M12) and 24 months (M24). Treatment failure was defined as 6‐month confirmed Expanded Disability Status Scale (EDSS) progression and/or Symbol Digit Modalities Test (SDMT) worsening. Optimal cutoff values for predicting treatment failure were determined by receiver operating characteristic analyses and hazard ratios (HRs) by multivariable Cox regression adjusting for age, sex, disease duration, EDSS/SDMT, and DMT class.

Results

Thinning of GCIPL >0.5 μm/year at M24 showed superior value for treatment failure prediction (HR: 4.5, 95% confidence interval [CI]: 1.8–7.6, < 0.001; specificity 91%, sensitivity 81%), followed by GCIPL >0.5 μm at M12 (odds ratio [OR]: 3.9, 95% CI: 1.4–6.9, < 0.001; specificity 85%, sensitivity 78%), and pRNFL ≥2 μm/year at M24 (OR: 3.7, 95% CI: 1.1–6.5, = 0.023; specificity 84%, sensitivity 69%), whereas pRNFL at M12 was not predictive.

Conclusions

GCIPL, and to a lesser degree pRNFL, thinning predicts disability progression after DMT initiation and may be a useful and accessible biomarker of treatment failure in RMS.

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Authors:
Gabriel Bsteh, Harald Hegen, Patrick Altmann, Michael Auer, Klaus Berek, Franziska Di Pauli, Fritz Leutmezer, Paulus Rommer, Sebastian Wurth, Anne Zinganell, Tobias Zrzavy, Florian Deisenhammer and Thomas Berger

Article first published online:
02 Apr 2021 | DOI: 10.1111/ene.14829

ORIGINAL ARTICLE

Apolipoprotein E genotype predicts subarachnoid extension in spontaneous intracerebral haemorrhage

Background and purpose

Spontaneous intracerebral haemorrhage (ICH) with subarachnoid extension (SAHE) predicts poor outcomes and haematoma expansion in spontaneous ICH and is also a potential predictor of the severity of vascular amyloid deposition. The biological underpinnings of SAHE remain elusive. A study was conducted to identify risk factors associated with SAHE.

Methods

A retrospective analysis was performed of an ongoing prospective cohort of primary spontaneous supratentorial ICH patients admitted to Tongji Hospital. SAHE was rated on baseline noncontrast computed tomography images by investigators blinded to the clinical data.

Results

A total of 189 patients were enrolled. Apolipoprotein E (APOE) ε2 copies ( = 0.020), but not APOE ε4 copies ( > 0.2), were more common in patients with SAHE in univariate analysis. After controlling for confounding factors in multiple logistic regression, lobar haematoma (odds ratio [OR] 14.21, 95% confidence interval [CI] 5.89–34.33; < 0.001), large haematoma volume (OR 1.04, 95% CI 1.02–1.06; < 0.001) and APOE ε2 copies (OR 3.07, 95% CI 1.05–8.97; = 0.041) were three independent predictors of SAHE. For subgroup analysis stratified by location, APOE ε2 showed a possible association with SAHE in lobar ICH ( = 0.026) but not in deep ICH ( > 0.2). No significant association was found between APOE ε4 copies and either lobar ( > 0.2) or deep ICH ( > 0.2).

Conclusions

The APOE ε2 allele predicts SAHE in spontaneous supratentorial ICH. The association may predominantly apply to lobar ICH. Given the established relationship between the APOE ε2 allele and pathological cerebrovascular changes, our findings suggest that SAHE involves genetically driven vessel pathology.

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Authors:
Xiaodong Ye, Guo Li, Xiaoyan Liu, Guini Song, Yuchao Jia, Chunmei Wu, Xiong Wang, Shanshan Huang and Suiqiang Zhu

Article first published online:
04 Apr 2021 | DOI: 10.1111/ene.14830

ORIGINAL ARTICLE

Cerebral cavernous malformations: Prevalence of cardiovascular comorbidities and allergic diseases compared to the normal population

Background

To determine the prevalence of cardiovascular comorbidities and allergic diseases in patients with cavernous malformations of the central nervous system compared to the normal population.

Methods

Clinical and magnetic resonance imaging data of 1352 patients with cerebral cavernous malformations (CCM) from an observational, cross‐sectional, single‐institutional study were analyzed and compared to an age‐and‐gender stratified and matched sample from a population‐based, epidemiological study assessing cardiovascular risk factors in the local normal population of the same area (RECALL study).

Results

Of 1352 patients, 810 (60%) were female. Mean age was 40.4 ± 16 years. 221 patients (16%) suffered from familial disease. Presence of cardiovascular risk factors and intake of certain drugs in the overall cohort was mostly equal to the normal population reference sample ( = 786). The prevalence of allergic diseases was found to be significantly higher in all CCM patients compared to the normal population (30% vs. 20%, odds ratio [OR] 1.35 [1.12–1.63]) and in CCM cases compared to the normal population and familial cases (32% vs. 20% (OR 1.46 [1.19–1.78], = 0.0001) and 22% vs. 20%, respectively).

Conclusions

We present novel data on CCM using a large single‐institution and population‐based setup. The study elaborates disease characteristics of CCM patients in detail. For the first time, evidence for an unexplained high prevalence of allergic diseases in this patient population is described (differing between sporadic and familial cases), supporting the hypothesis that immune response is involved in the pathogenesis of CCM.

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Authors:
Philipp Dammann, Dino Vitali Saban, Annika Herten, Bixia Chen, Yuan Zhu, Alejandro Santos, Laurèl Rauschenbach, Karsten Wrede, Ramazan Jabbarli, Börge Schmidt, Karl‐Heinz Jöckel, Christoph Kleinschnitz, Michael Forsting and Ulrich Sure

Article first published online:
03 Apr 2021 | DOI: 10.1111/ene.14833

ORIGINAL ARTICLE

Analyses of peripheral blood dendritic cells and magnetic resonance spectroscopy support dysfunctional neuro‐immune crosstalk in Tourette syndrome

Background

Evidence supports that neurodevelopmental diseases, such as Tourette syndrome (TS), may involve dysfunctional neural‐immune crosstalk. This could lead to altered brain maturation and differences in immune and stress responses. Dendritic cells (DCs) play a major role in immunity as professional antigen‐presenting cells; changes in their frequency have been observed in several autoimmune conditions.

Methods

In 18 TS patients (15 on stable pharmacological treatment, three unmedicated) and 18 age‐matched healthy volunteers (HVs), we explored circulating blood‐derived DCs and their relationship with clinical variables and brain metabolites, measured via proton magnetic resonance spectroscopy (1H‐MRS). DC subsets, including plasmacytoid and myeloid type 1 and 2 dendritic cells (MDC1, MDC2), were studied with flow cytometry. 1H‐MRS was used to measure total choline, glutamate plus glutamine, total creatine (tCr), and total N‐acetylaspartate and N‐acetylaspartyl‐glutamate levels in frontal white matter (FWM) and the putamen.

Results

We did not observe differences in absolute concentrations of DC subsets or brain inflammatory metabolites between patients and HVs. However, TS patients manifesting anxiety showed a significant increase in MDC1s compared to TS patients without anxiety ( = 0.01). We also found a strong negative correlation between MDC1 frequency and tCr in the FWM of patients with TS ( = 0.0015), but not of HVs.

Conclusion

Elevated frequencies of the MDC1 subset in TS patients manifesting anxiety may reflect a proinflammatory status, potentially facilitating altered neuro‐immune crosstalk. Furthermore, the strong inverse correlation between brain tCr levels and MDC1 subset frequency in TS patients suggests a potential association between proinflammatory status and metabolic changes in sensitive brain regions.

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Authors:
Marianna Sarchioto, Franklyn Howe, Ingrid E. Dumitriu, Francesca Morgante, Jeremy Stern, Mark J. Edwards and Davide Martino

Article first published online:
16 Apr 2021 | DOI: 10.1111/ene.14837

ORIGINAL ARTICLE

Thrombolytic therapy for wake‐up stroke: A systematic review and meta‐analysis

Background and purpose

According to evidence‐based clinical practice guidelines, patients presenting with disabling stroke symptoms should be treated with intravenous tissue plasminogen activator (IV tPA) within 4.5 h of time last known well. However, 25% of strokes are detected upon awakening (i.e., wake‐up stroke [WUS]), which renders patients ineligible for IV tPA administered via time‐based treatment algorithms, because it is impossible to establish a reliable time of symptom onset. We performed a systematic review and meta‐analysis of the efficacy and safety of IV tPA compared with normal saline, placebo, or no treatment in patients with WUS using imaging‐based treatment algorithms.

Methods

We searched MEDLINE, Web of Science, and Scopus between January 1, 2006 and April 30, 2020. We included controlled trials (randomized or nonrandomized), observational cohort studies (prospective or retrospective), and single‐arm studies in which adults with WUS were administered IV tPA after magnetic resonance imaging (MRI)‐ or computed tomography (CT)‐based imaging. Our primary outcome was recovery at 90 days (defined as a modified Rankin Scale [mRS] score of 0–2), and our secondary outcomes were symptomatic intracranial hemorrhage (sICH) within 36 h, mortality, and other adverse effects.

Results

We included 16 studies that enrolled a total of 14,017 patients. Most studies were conducted in Europe (37.5%) or North America (37.5%), and 1757 patients (12.5%) received IV tPA. All studies used MRI‐based (five studies) or CT‐based (10 studies) imaging selection, and one study used a combination of modalities. Sixty‐one percent of patients receiving IV tPA achieved an mRS score of 0 to 2 at 90 days (95% confidence interval [CI]: 51%–70%, 12 studies), with a relative risk (RR) of 1.21 compared with patients not receiving IV tPA (95% CI: 1.01–1.46, four studies). Three percent of patients receiving IV tPA experienced sICH within 36 h (95% CI: 2.5%–4.1%; 16 studies), which is an RR of 4.00 compared with patients not receiving IV tPA (95% CI: 2.85–5.61, seven studies).

Conclusions

This systematic review and meta‐analysis suggests that IV tPA is associated with a better functional outcome at 90 days despite the increased but acceptable risk of sICH. Based on these results, IV tPA should be offered as a treatment for WUS patients with favorable neuroimaging findings.

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Authors:
Brian Mac Grory, Ian J. Saldanha, Eva A. Mistry, Christoph Stretz, Sven Poli, Marek Sykora, Lars Kellert, Katharina Feil, Shreyansh Shah, Ryan McTaggart, Derek Riebau, Shadi Yaghi, Kenneth Gaines, Ying Xian, Wuwei Feng and Matthew Schrag

Article first published online:
15 Apr 2021 | DOI: 10.1111/ene.14839

ORIGINAL ARTICLE

Risk factors for the progression of motoric cognitive risk syndrome to dementia: Retrospective cohort analysis of two populations

Background and purpose

Motoric cognitive risk syndrome (MCR) is a predementia syndrome characterized by cognitive complaints and slow gait. MCR is associated with increased risk of cognitive decline and incident dementia. Predictors of transition to dementia in MCR patients are still obscure.

Methods

We examined clinical, biological and lifestyle parameters related to conversion to dementia using Cox models in 439 older adults with prevalent MCR (mean age 79.87 ± 8.13 years, 70% women) from two cohorts, 268 from the Chicago‐based Rush Memory and Aging project (MAP) and 171 from the Religious Orders Study (ROS), which enrolled religious clergy across the United States.

Results

In the pooled sample, 439 (13.2%) had prevalent MCR (268 MAP and 171 ROS). There were 140 (31.9%) incident dementia cases over a median follow up of 4.0 years. Age predicted conversion from MCR to dementia in both cohorts. Male gender was a risk factor only in ROS. In the pooled data, only higher depressive symptoms were associated with higher risk of conversion to dementia (adjusted hazard ratio [aHR] 1.13, 95% CI 1.03–1.24). Lower cognitive activity participation (aHR 0.59, 95% CI 0.44–0.79) and apolipoprotein E ε4 allele (aHR 2.57, 95% CI 1.48–4.45) predicted conversion to dementia in MAP.

Conclusions

Depressive symptoms and other cohort‐specific risk factors were identified as predictors of transition to dementia in individuals with MCR. These findings suggest common pathological mechanisms underlying mood, gait and cognitive declines in aging, which could help develop preventive strategies.

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Authors:
Zeev Meiner, Emmeline Ayers, David A. Bennett, Cuiling Wang and Joe Verghese

Article first published online:
14 Apr 2021 | DOI: 10.1111/ene.14841

COMMENTARY

Post‐stroke depression: Can intravenous thrombolysis be effective?

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Authors:
Marina Diomedi and Ilaria Maestrini

Article first published online:
07 Apr 2021 | DOI: 10.1111/ene.14842

European Journal of Neurology

Issue Information

Issue Information

ORIGINAL ARTICLE

Background and purpose

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SHORT COMMUNICATION

Background and purpose

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LETTER TO THE EDITOR

Letter to the Editor about the Ongre et al. publication: ‘Progression of fatigue in Parkinson's disease—a 9‐year follow‐up’ (Eur J Neurol 2020. doi: 10.1111/ene.14520)

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Background

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LETTER TO THE EDITOR

Letter to the editor in response to the letter from the EPIPARK Study Group regarding the publication ʻProgression of fatigue in Parkinson's disease ‐ a 9‐year follow‐upʼ (Eur J Neurol 2021. doi:10.1111/ene.14520)

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Background and objective

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LETTERS TO THE EDITOR

Minimal detectable change and minimal clinically important difference in spinal muscular atrophy patients

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Background and purpose

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Background and purpose

Methods

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