cover image European Journal of Neurology

European Journal of Neurology

2021 - Volume 28
Issue 3 | March 2021
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Article first published online:
08 Feb 2021 | DOI: 10.1111/ene.14342

ORIGINAL ARTICLE

Background and purpose

This was an investigation of the differential effects of early intensive versus guideline‐recommended blood pressure (BP) lowering between lacunar and non‐lacunar acute ischaemic stroke (AIS) in the BP arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED).

Methods

In 1,632 participants classified as having definite or probable lacunar ( = 454 [27.8%]) or non‐lacunar AIS according to pre‐specified definitions based upon clinical and adjudicated imaging findings, mean BP changes over days 0–7 were plotted, and systolic BP differences by treatment between subgroups were estimated in generalized linear models. Logistic regression models were used to estimate the BP treatment effects on 90‐day outcomes (primary, an ordinal shift of modified Rankin scale scores) across lacunar and non‐lacunar AIS after adjustment for baseline covariables.

Results

Most baseline characteristics, acute BP and other management differed between lacunar and non‐lacunar AIS, but mean systolic BP differences by treatment were comparable at each time point (all  > 0.12) and over 24 h post‐randomization (−5.5, 95% CI −6.5, −4.4 mmHg in lacunar AIS vs. −5.6, 95% CI −6.3, −4.8 mmHg in non‐lacunar AIS,  = 0.93). The neutral effect of intensive BP lowering on functional outcome and the beneficial effect on intracranial haemorrhage were similar for the two subgroups (all  > 0.19).

Conclusions

There were no differences in the treatment effect of early intensive versus guideline‐recommended BP lowering across lacunar and non‐lacunar AIS.

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Authors:
Zien Zhou, Chao Xia, Cheryl Carcel, Sohei Yoshimura, Xia Wang, Candice Delcourt, Alejandra Malavera, Xiaoying Chen, Grant Mair, Mark Woodward, John Chalmers, Andrew M. Demchuk, Richard I. Lindley, Thompson G. Robinson, Mark W. Parsons, Joanna M. Wardlaw and Craig S. Anderson
Article first published online:
01 Dec 2020 | DOI: 10.1111/ene.14598

ORIGINAL ARTICLE

Background

Apart from inflammation and neurodegeneration, the individual clinical course of multiple sclerosis (MS) might be determined by differential adaptive capacities of the central nervous system. It has been postulated that the retention of adaptive training effects may be impaired in persons with MS (PwMS).

Objective

To investigate motor adaptation and consolidation capacities of people with MS in a visual motor adaptation task (VAT).

Methods

A total of 23 PwMS (Expanded Disability Status Scale (EDSS) score < 6) and 20 matched healthy controls were recruited. All participants completed three sessions of a VAT where a clockwise rotation angle of 30° was introduced as perturbation during the active learning part of the paradigm. The training session (T) was repeated after 24 h (T) and 72 h (T). Directional errors and parameters of adaptation and retention were evaluated.

Results

PwMS showed similar adaptation and online learning abilities as controls. However, the retention ratio was significantly lower in patients compared to controls at T1 ( = 0.036) and T2 ( = 0.039). There was no significant correlation between the overall adaptation or retention ratio and the EDSS score, respectively.

Conclusion

Our findings indicate intact adaptation, but limited consolidation, in patients with mild‐to‐moderate MS. Future studies are needed to define the neurobiological substrates of this plasticity and the extent to which it can influence clinical outcomes.

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Authors:
Carine Nguemeni, Luis Nakchbandi, György Homola and Daniel Zeller
Article first published online:
05 Dec 2020 | DOI: 10.1111/ene.14599

ORIGINAL ARTICLE

Background and purpose

Elevated cerebrospinal fluid (CSF) total protein in patients with acute ascending paresis is indicative of Guillain–Barré syndrome (GBS). Recent studies showed that the outdated, but still widely used upper reference limit (URL) for CSF total protein of 0.45 g/L leads to false‐positive results, mainly as a result of lack of age‐adjustment. The objective of this study was to assess the frequency of increased CSF total protein in adult GBS patients according to a new age‐dependent URL.

Methods

Patients with GBS treated at the Medical University of Innsbruck between 2000 and 2018 were included in this study. Demographic, clinical, electrophysiological and CSF data were obtained from patients' medical charts. Frequency of increased CSF total protein depending on disease duration was compared using the conventional URL of 0.45 g/L and the age‐dependent URL.

Results

Ninety‐seven patients with GBS aged 57 ± 18 years, comprising 38% women, underwent CSF sampling within a median of 6 days after symptom onset. The median CSF total protein concentration was 0.65 g/L and correlated with disease duration. Overall, 74% of patients had elevated CSF total protein levels using the conventional URL, as opposed to 52% applying the age‐dependent URL. At 0–3, 4–7, 8–14 and >14 days after disease onset, elevated CSF total protein was found in 46%, 84%, 78% and 100% of patients using the conventional URL, and in 32%, 53%, 65% and 64% of patients using the age‐dependent URL. In multivariate analysis, significant predictors of elevated CSF total protein were disease duration and the demyelinating GBS variant. Similar results were obtained for CSF/serum albumin quotient (Q).

Conclusion

Fewer true‐positives for CSF total protein and Q must be considered in suspected GBS, especially in the early disease course.

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Authors:
Harald Hegen, Felix Ladstätter, Gabriel Bsteh, Michael Auer, Klaus Berek, Franziska Di Pauli, Janette Walde, Julia Wanschitz, Anne Zinganell and Florian Deisenhammer
Article first published online:
30 Nov 2020 | DOI: 10.1111/ene.14600

ORIGINAL ARTICLE

Background and purpose

Spinocerebellar ataxia type 2 (SCA2) is the second most common type of spinocerebellar ataxia in China. However, data on the clinical and genetic features of Chinese SCA2 patients are scarce. This study aims to provide a comprehensive description of in the Chinese SCA2 cohort.

Methods

A total of 135 patients with SCA2 from 92 families and 104 unrelated normal controls were recruited from three medical centers between 2008 and 2020. Sanger sequencing and TA cloning were used to determine the CAG repeat length and intrinsic structure. The clinical data of patients with SCA2, including electromyography, magnetic resonance imaging, positron‐emission tomography, and clinical scale scores, were recorded.

Results

The mean ± SD age at onset of SCA2 patients was 32.6 ± 11.9 years and the corresponding CAG repeat length was 42.1 ± 3.6. CAG repeat length accounted for 64% of the age‐at‐onset variance. We observed that patients had a significantly lower proportion of (CAG)CAA(CAG)CAA(CAG) within normal alleles than normal controls (48.8% vs. 64.9%;  = 0.003), while the distribution of the proportion of (CAG)CAA (CAG) was the opposite. Peripheral neuropathy was frequent, occurring in 75.9% of the patients. Parkinsonism was relatively common, with a frequency of 11.8%. Two patients with parkinsonism had a significantly more severe reduction in dopamine transporter levels in the bilateral striatum than the one patient with pure ataxia. An infant‐onset case of SCA2 with more than 180 CAG repeats was characterized by global development delay, hypotonia and hearing impairment.

Conclusions

This study describes the genetic profile and clinical characteristics of the largest SCA2 cohort to date in the Chinese population and analyzes inter‐population differences. Many aspects of this study population were different from other populations with SCA2.

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Authors:
Lu Yang, Yi Dong, Yin Ma, Wang Ni and Zhi‐Ying Wu
Article first published online:
01 Dec 2020 | DOI: 10.1111/ene.14601

CASE STUDY

Background

Mutations in are associated with a wide phenotypic spectrum including generalized dystonia with whispering dysphonia (DYT‐).

Methods

We report the case of a 44‐year‐old patient with DYT‐ with a clinical presentation of disabling progressive dystonia, with a prominent laryngeal, cervical and facial involvement.

Results

Bipallidal deep brain stimulation (DBS) resulted in a 55% reduction of dystonia severity assessed by the Burke–Fahn−Marsden scale score 6 months after surgery. The effect was obvious on the cervical and facial components of dystonia.

Conclusion

We suggest that bipallidal DBS should be considered in patients with disabling dystonia related to variants.

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Authors:
Cécile Delorme, Emmanuel Roze, Carine Karachi, Marie Vidailhet and Elodie Hainque
Article first published online:
08 Feb 2021 | DOI: 10.1111/ene.14602

ORIGINAL ARTICLE

Background

Dysphagia frequently occurs in patients with Parkinson’s disease (PD) and is associated with severe complications. However, the underlying pathology is poorly understood at present. This study investigated the effect of cognitive and motor dual‐task interference on oropharyngeal swallowing in PD.

Methods

Thirty PD patients (23 men, mean age 65.90 ± 9.32 years, mean Hoehn and Yahr stage 2.62 ± 0.81, mean UPDRS 18.00 ± 7.18) were examined using flexible endoscopic evaluation of swallowing (FEES). FEES was performed during three paradigms: at baseline without interference, during a cognitive dual‐task, and during a motor dual‐task. Oropharyngeal swallowing function was rated using a score which was validated to detect changes in PD related dysphagia. The three paradigms were compared using a two‐way‐repetitive‐measures‐ and a post‐hoc‐analysis.

Results

Mean swallowing score in baseline FEES was 10.67 ± 5.89. It significantly increased (worsened) to 15.97 ± 7.62 ( < 0.001) in the motor dual‐task and to 14.55 ± 7.49 ( < 0.001) in the cognitive dual‐task. Premature bolus spillage and pharyngeal residue both significantly increased during both of the dual‐task conditions whereas penetration/aspiration events did not change.

Conclusion

Oropharyngeal swallowing in patients with PD is not purely reflexive but requires mental capacity. Additional allocation of attentional resources in the central control of swallowing seems to be an effective compensatory mechanism in PD‐related dysphagia: The proposed dual‐task protocol may be useful to challenge swallowing functional reserve. Conversely, as a therapeutic strategy, it could be beneficial to focus attention on swallowing and to avoid dual‐task situations.

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Authors:
Bendix Labeit, Inga Claus, Paul Muhle, Liesa Regner, Sonja Suntrup‐Krueger, Rainer Dziewas and Tobias Warnecke
Article first published online:
02 Dec 2020 | DOI: 10.1111/ene.14603

ORIGINAL ARTICLE

Background and purpose

Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the central nervous system from the John Cunningham virus (JCV), is a side effect of natalizumab (NTZ) treatment for relapsing–remitting multiple sclerosis (RRMS), potentially leading to a substantial increase of physical and mental disability. Nevertheless, data of neuropsychological impairment during the NTZ‐PML disease course are missing. Our objective was to evaluate the neuropsychological disease course of NTZ‐PML patients and to compare neuropsychological deficits of NTZ‐PML patients with two different non‐PML multiple sclerosis (MS) cohorts.

Methods

Neuropsychological examinations of 28 NTZ‐PML patients performed during different phases of the disease ([i] at PML diagnosis, [ii] during immune reconstitution inflammatory syndrome [IRIS], and [iii] post‐IRIS/PML) were retrospectively analyzed and compared to those of NTZ‐treated RRMS or secondary progressive MS patients with and without immunotherapy.

Results

Compared to controls, NTZ‐PML patients performed worse in neuropsychological examinations during all stages of disease, mainly affecting visuospatial ability and working memory. Furthermore, failure to eliminate the JCV from the central nervous system was associated with a progredient decline of cognition, especially working memory.

Conclusions

Working memory and visuospatial abilities are the core neuropsychological deficits of NTZ‐PML patients in long‐term follow‐up. Our findings should be implemented in neurorehabilitation strategies.

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Authors:
Markus Kinner, Christian Prehn, Ruth Schneider, Christoph Schroeder, Eva Kolb, Ralf Gold, Robert Hoepner and Andew Chan
Article first published online:
08 Dec 2020 | DOI: 10.1111/ene.14604

REVIEW ARTICLE

Background and purpose

Respiratory dysfunction in Parkinson’s disease (PD) is often an underdiagnosed and untreated impairment associated with the disease. Clinically, a reactive approach to respiratory morbidity is taken, rather than preventative approaches that address underlying impairment/s. This systematic review identifies the current evidence to support nonpharmacological interventions to improve respiratory impairments in individuals with PD.

Methods

The relevant literature was searched using a customised and systematic strategy. Randomised and nonrandomised control trials of nonpharmacological interventions targeting respiratory outcome measures in PD were included. Outcomes of interest were respiratory morbidity and mortality, respiratory muscle strength, spirometry measures, lung volumes, peak cough flow, and perception of dyspnoea.

Results

Nonpharmacological interventions included: functional training, generalised strength training, respiratory muscle strength training, aerobic exercise, qigong, yoga, breath stacking, incentive spirometry and singing. Methodological quality of included studies varied. Meta‐analyses of nonpharmacological interventions demonstrated significant effects for inspiratory muscle strength (mean difference [MD] 19.68; confidence interval [CI] 8.49, 30.87;  = 3.45;  = 0.0006;  = 2%), expiratory muscle strength (MD 18.97; CI 7.79, 30.14;  = 3.33;  = 0.0009;  = 23%) and peak expiratory flow (MD 72.21; CI 31.19, 113.24;  = 3.45;  = 0.0006;  = 0%). Best‐evidence synthesis identified level 1 evidence supporting nonpharmacological interventions for improving peak cough flow and perceived dyspnoea. No studies were identified reporting outcomes of respiratory rate, inspiration:expiration ratio or respiratory morbidity or mortality in PD.

Conclusions

Nonpharmacological interventions improved respiratory muscle strength and peak expiratory flow in PD. Additional trials targeting respiratory dysfunction and longitudinal studies examining the relationship between respiratory dysfunction and morbidity and mortality rates in PD are required.

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Authors:
L. McMahon, C. Blake and O. Lennon
Article first published online:
01 Dec 2020 | DOI: 10.1111/ene.14605

SHORT COMMUNICATION

Background and purpose

At high altitude the brain is exposed to hypoxic stress, which may result in neurological conditions, with acute mountain sickness (AMS) being the most common. We aimed to test the hypothesis that rapid ascent to high altitude alters neuro‐axonal integrity, which can be detected by increased concentration of serum neurofilament light (sNfL) in the blood and may even be exaggerated in people with AMS.

Methods

Serum neurofilament light was measured using a single‐molecule array (Simoa, Quanterix, Lexington, MA, USA) assay at low altitude (423 m) in 47 healthy study participants and 44 h after rapid and active ascent to high altitude (4559 m). Peripheral oxygen saturation (SpO) and partial pressures of oxygen (pO) were obtained at low and high altitude. The Acute Mountain Sickness‐Cerebral (AMS‐C) scoring system was used to assess AMS incidence and AMS severity.

Results

There was an increase in sNfL from its baseline value compared with its value at high altitude (6.34 ± 1.96 vs. 7.19 ± 3.14 pg/ml;  = 0.014), but sNfL level did not correlate with SpO ( = −0.19;  = 0.066) or pO ( = −0.19;  = 0.068). The incidence of AMS at high altitude was 62%. Neither at low altitude ( = 0.706) nor at high altitude ( = 0.985) was there a difference in sNfL between participants with and without AMS as measured 3 days after rapid ascent and 44 h of high‐altitude exposure. Altitude sNfL did not correlate with AMS‐C, either overall or with single‐item scores such as headache severity.

Conclusions

Rapid ascent of healthy people to high altitude provokes an increase in sNfL 44 h after arrival at 4559 m, which is not related to the magnitude of hypoxemia or AMS incidence and severity, suggesting that neuro‐axonal injury does not directly contribute to AMS.

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Authors:
Mahdi Sareban, Marc Moritz Berger, Daniela Pinter, Arabella Buchmann, Franziska Macholz, Peter Schmidt, Lisa Schiefer, Magdalena Schimke, Josef Niebauer, Jürgen Michael Steinacker, Gunnar Treff and Michael Khalil
Article first published online:
26 Nov 2020 | DOI: 10.1111/ene.14606

REVIEW

Background and purpose

Several studies suggested a role or iron in the pathogenesis or Parkinson's disease (PD), and substantia nigra iron concentrarions have been found increased in PD. However, the results on cerebrospinal (CSF) and serum/plasma iron levels in PD patients have been controversial. The aim of this systematic review and meta‐analysis was to establish the CSF and serum/plasma levels of iron and iron‐related proteins (ferritin, transferrin, lactoferrin, haptoglobin, and hepcidine) levels, and the urine levels of iron, in patients with PD.

Methods

Four databases (PubMed, EMBASE, MedLine, and Web of Science – Core Collection) were reviewed for studies published from 1966 to October 5, 2020. References of interest were identified. A meta‐analysis of eligible studies was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) and Meta‐analysis of Observational Studies in Epidemiology (MOOSE) guidelines, using the R software package .

Results

A non‐significant trend towards higher CSF iron levels and marginally significantly lower serum/plasma iron levels was observed in patients with PD compared with age‐ and sex‐matched controls. CSF and serum/plasma ferritin and transferrin concentrations, and serum/plasma lactoferrin and haptoglobin concentrations did not differ significantly between PD patients and controls.

Conclusion

The findings of this study suggest an association between decreased serum/plasma iron levels and, possibly, higher CSF iron levels with risk of PD.

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Authors:
Félix Javier Jiménez‐Jiménez, Hortensia Alonso‐Navarro, Elena García‐Martín and José A. G. Agúndez
Article first published online:
01 Dec 2020 | DOI: 10.1111/ene.14607

ORIGINAL ARTICLE

Background and purpose

Cardiovascular risk factors and comorbidities can affect the prognosis of multiple sclerosis (MS). The Framingham risk score is an algorithm that can estimate the 10‐year risk of developing macrovascular disease. Our objectives were to evaluate the possible association between the Framingham risk score at baseline and MS relapses, disability, and disease‐modifying therapy (DMT) choices over a 5‐year follow‐up.

Methods

This is a retrospective cohort study including 251 MS subjects. At baseline, we calculated the Framingham risk score considering the following variables: age, sex, diabetes, smoking, systolic blood pressure, and body mass index. MS outcomes including relapses, disability, and treatments were collected over 5 years. Cox proportional regression models were employed to estimate hazard ratios (HRs).

Results

A one‐point increase in the Framingham risk score was associated with 31% higher risk of relapse (HR = 1.31; 95% confidence interval [CI] = 1.03, 1.68), 19% higher risk of reaching of EDSS 6.0 (HR = 1.19; 95% CI = 1.05, 3.01), and 62% higher risk of DMT escalation (HR = 1.62; 95% CI = 1.22, 3.01).

Conclusions

Higher cardiovascular risk was associated with higher risk of relapses, disability, and DMT escalation in MS. Early identification, correction, and treatment of cardiovascular comorbidities should be carefully considered within MS management.

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Authors:
Martina Petruzzo, Antonio Reia, Giorgia T. Maniscalco, Fabrizio Luiso, Roberta Lanzillo, Cinzia Valeria Russo, Antonio Carotenuto, Lia Allegorico, Raffaele Palladino, Vincenzo Brescia Morra and Marcello Moccia
Article first published online:
21 Nov 2020 | DOI: 10.1111/ene.14608

Original Article

Background and purpose

Texture analysis of magnetic resonance imaging (MRI) brain scans have been proposed as a promising tool in the early diagnosis of Alzheimer’s disease (AD), but its biological correlates remain unknown. In this study, we examined the relationship between MRI texture features and AD pathology.

Methods

The study included 150 participants who had a 3.0T T1‐weighted image, amyloid‐β positron emission tomography (PET), and tau PET within 3 months of each other. In each of six brain regions (hippocampus, precuneus, and entorhinal, middle temporal, posterior cingulate and superior frontal cortices), linear regression analyses adjusting for age and sex was performed to examine the effects of regional amyloid‐β and tau burden on regional texture features. We also compared neuroimaging measures based on pathological severity using ANOVA.

Results

In all regions, tau burden ( < 0.05), but not amyloid‐β burden, were associated with a certain texture feature that varied with the region’s cytoarchitecture. Specifically, autocorrelation and cluster shade were associated with tau burden in allocortical and periallocortical regions, whereas entropy and contrast were associated with tau burden in neocortical regions. Mean signal intensity of each region did not show any associations with AD pathology. The values of the region‐specific textures also varied across groups of varying pathological severity.

Conclusions

Our results suggest that textures of T1‐weighted MRI reflect changes in the brain that are associated with regional tau burden and the local cytoarchitecture. This study provides insight into how MRI texture can be used for detection of microstructural changes in AD.

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Authors:
Subin Lee and Ki Woong Kim
Article first published online:
28 Nov 2020 | DOI: 10.1111/ene.14609

ORIGINAL ARTICLE

Background and purpose

Cortical microinfarcts (CMIs) are frequently found in the brains of patients with advanced cerebral amyloid angiopathy (CAA) at autopsy. The small vessel disease (SVD) score for CAA (i.e., the CAA‐SVD score) has been proposed to evaluate the severity of CAA‐associated vasculopathic changes by a combination of magnetic resonance imaging (MRI) markers. The aim of this study was to examine the association between total CAA‐SVD score and features of CMIs on 3‐Tesla MRI.

Methods

Eighty patients with probable CAA were retrospectively analyzed. Lobar cerebral microbleeds, cortical superficial siderosis, enlargement of perivascular space in the centrum semiovale and white matter hyperintensity were collectively assessed, and the total CAA‐SVD score was calculated. The presence of CMI was also examined.

Results

Of the 80 patients, 13 (16.25%) had CMIs. CMIs were detected more frequently in the parietal and occipital lobes. A positive correlation was found between total CAA‐SVD score and prevalence of CMI ( = 0.943;  = 0.005). Total CAA‐SVD score was significantly higher in patients with CMIs than in those without ( = 0.009). In a multivariable logistic regression analysis, the presence of CMIs was significantly associated with total CAA‐SVD score (odds ratio 2.318 [95% confidence interval 1.228–4.376];  = 0.01, per each additional point).

Conclusions

The presence of CMIs with a high CAA‐SVD score could be an indicator of more severe amyloid‐associated vasculopathic changes in patients with probable CAA.

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Authors:
Yuichiro Ii, Hidehiro Ishikawa, Akihiro Shindo, Hirofumi Matsuyama, Keita Matsuura, Kana Matsuda, Kimiko Yoshimaru, Masayuki Satoh, Ryota Kogue, Maki Umino, Masayuki Maeda and Hidekazu Tomimoto
Article first published online:
27 Nov 2020 | DOI: 10.1111/ene.14610

ORIGINAL ARTICLE

Background and purpose

Retinal pathological changes may precede or accompany the deterioration of brain tissue in Parkinson's disease (PD). The purpose of this meta‐analysis was to assess the usefulness of optical coherence tomography (OCT) measurements as potential imaging biomarkers for PD.

Methods

PubMed, Embase, Web of Science and Cochrane Library databases were systematically searched for observational studies (published prior to 30 May 2020) comparing the OCT measurements between PD patients and healthy controls (HCs). Our main end‐points were peripapillary retinal nerve fiber layer (pRNFL) thickness, macular ganglion cell complex thickness, macular thickness and macular volume. Pooled data were assessed by use of a random‐effects model.

Results

A total of 36 observational studies were identified that included 1712 patients with PD (2548 eyes) and 1778 HCs (2646 eyes). Compared with the HC group, the PD group showed a significant reduction in mean pRNFL thickness (weighted mean difference [WMD] −3.51 μm, 95% confidence interval [CI] −4.84, −2.18;  = 0.000), all quadrants at the pRNFL (WMD range −7.65 to −2.44 μm, all  < 0.05), macular fovea thickness (WMD −5.62 μm, 95% CI −7.37, −3.87;  = 0.000), all outer sector thicknesses at the macula (WMD range −4.68 to −4.10 μm, all  < 0.05), macular volume (WMD −0.21 mm, 95% CI −0.36, −0.06;  < 0.05) and macular ganglion cell complex thickness (WMD −4.18 μm, 95% CI −6.07, −2.29;  < 0.05).

Conclusions

Our pooled data confirmed robust associations between retinal OCT measurements and PD, highlighting the usefulness of OCT measurements as potential imaging biomarkers for PD.

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Authors:
Wen‐Chuan Zhou, Jin‐Xin Tao and Jing Li
Article first published online:
01 Dec 2020 | DOI: 10.1111/ene.14613

ORIGINAL ARTICLE

Background

Social deprivation may have a deleterious influence on post‐stroke outcomes, but available data in the literature are mixed.

Aim

The aim of this cohort study was to evaluate the impact of social deprivation on 1‐year survival in patients with first‐ever stroke.

Methods

Social deprivation was assessed at individual level with the EPICES score, a validated multidimensional questionnaire, in 1312 patients with ischemic stroke and 228 patients with spontaneous intracerebral hemorrhage, who were prospectively enrolled in six French study centers. Baseline characteristics including stroke severity and pre‐stroke functional status were collected. Multivariable Cox models were generated to evaluate the associations between social deprivation and survival at 12 months in ischemic stroke and intracerebral hemorrhage separately.

Results

A total of 819 patients (53.2%) were socially deprived (EPICES score ≥ 30.17). In ischemic stroke, mortality at 12 months was higher in deprived than in non‐deprived patients (16% vs. 11%,  = 0.006). In multivariable analyses, there was no association between deprivation and death occurring within the first 90 days following ischemic stroke (adjusted hazard ratio [aHR] 0.81, 95% CI 0.54–1.22,  = 0.32). In contrast, an excess in mortality was observed between 90 days and 12 months in deprived compared with non‐deprived patients (aHR 1.97, 95% CI 1.14–3.42,  = 0.016). In patients with intracerebral hemorrhage, mortality at 12 months did not significantly differ according to deprivation status.

Conclusions

Social deprivation was associated with delayed mortality in ischemic stroke patients only and, although the exact underlying mechanisms are still to be identified, our findings suggest that deprived patients in particular may benefit from an optimization of post‐stroke care.

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Authors:
Yannick Béjot, Abderrahmane Bourredjem, Emmanuelle Mimeau, Julien Joux, Annie Lannuzel, Caroline Misslin‐Tritsch, Claire Bonithon‐Kopp, Devi Rochemont, Mathieu Nacher, André Cabie, Marie‐Laure Lalanne Mistrih and Isabelle Fournel
Article first published online:
25 Nov 2020 | DOI: 10.1111/ene.14614

ORIGINAL ARTICLE

Background and purpose

Melkersson‐Rosenthal syndrome (MRS) is a rare neuro‐mucocutaneous disease. In addition to the traditional clinical triad, there is also a diversity of clinical signs, and it may be related to other systemic diseases.

Methods

In the present study, we report a case of MRS with endocrine disorders that exhibits extraordinary therapeutic efficiency by using hydroxychloroquine (HCQ), explore whether there is an internal connection between MRS and endocrine disorders, and discuss the mechanism of the therapeutic efficiency of using HCQ. The hypothesis proposed for the first time is that MRS may essentially be a systemic granulomatous disease.

Results

The physical examination revealed orofacial swelling and fissured tongue. The histopathologic examination showed epithelioid granulomas. Combined with the other examination, this case was diagnosed as incomplete MRS. HCQ and local drugs were introduced. The patient achieved clinical recovery and psychological cure by the 18‐week follow‐up, and the 1‐year follow‐up found no reactivation of MRS. Moreover, the levels of cortisol and adrenocorticotropic were within normal ranges.

Conclusions

After the drug therapy was targeted at granuloma, not only did all of the symptoms related to MRS disappear, but the endocrine system also returned to normal. It is speculated that the endocrine disorder in this patient may be related to MRS. We further propose the first‐time hypothesis that MRS may essentially be a systemic granulomatous disease. It provides a new medication method with high‐level efficiency.

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Authors:
Shimeng Wang, Hongmei Wang, Xueke Shi, Fanglong Wu, Ling Lv, Mingjia Hu, Wanxin Sun, Lanyan Wu and Hongmei Zhou
Article first published online:
14 Dec 2020 | DOI: 10.1111/ene.14615

Original Article

Background and purpose

Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. Due to vast heterogeneity, clinical examination and protein‐based analyses often fail to identify the genetic causes of these diseases. The aim of this study was to genetically diagnose a cohort of 36 difficult‐to‐diagnose CMD and CM cases of Indian origin using next‐generation sequencing methods.

Methods

Whole‐exome sequencing (WES) was performed to identify pathogenic mutations in previously reported CMD and CM‐related genes using variant calling and stringent variant filtration process. Subsequently, homology modelling and molecular dynamics simulations (MDS) studies were undertaken for a number of novel and missense variants.

Results

A total of 33 and 21 rare and deleterious mutations were identified in 28 genes previously reported in CMD and CM based on OMIM, ClinVar and Orphanet, respectively. We could accurately diagnose 54% patients ( = 12/22) in the CMD group and 35% patients ( = 5/14) in the CM group. Furthermore, MDS studies for mutations located in LMNA, LAMA2 and RYR1 suggest that the wild‐type proteins are more stable than their mutant counterparts, implying a potential mechanism of pathogenesis.

Conclusion

The WES findings led us to identify reported as well as novel variants for the first time in Indian patients with CMD and CM. This allowed us to achieve an accurate genetic diagnosis, which was difficult using conventional diagnostic tools. Transferring these WES findings to clinical practice will help guide clinical care of the affected patients and inform genetic counselling.

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Authors:
Shamita Sanga, Arnab Ghosh, Krishna Kumar, Kiran Polavarapu, Veeramani Preethish‐Kumar, Seena Vengalil, Saraswati Nashi, Mainak Bardhan, Gautham Arunachal, Sanita Raju, Narayanappa Gayathri, Nidhan K. Biswas, Saikat Chakrabarti, Atchayaram Nalini, Sudipto Roy and Moulinath Acharya
Article first published online:
26 Nov 2020 | DOI: 10.1111/ene.14616

SHORT COMMUNICATIONS

Background and purpose

Progressive multifocal leukoencephalopathy (PML) is a severe infection caused by the polyomavirus JC that develops in the central nervous system (CNS) of immunosuppressed patients. The infection frequently starts in the brain hemispheres and can spread into other CNS regions such as the brainstem. Initial isolated PML brainstem lesions are exceptional. We aimed to describe the challenging diagnosis of PML with isolated brainstem lesions at the time of disease onset.

Methods

We describe a case of PML starting with an isolated brainstem lesion and reviewed clinical, radiological, and biological features of all the reported cases of isolated brainstem PML.

Results

Isolated brainstem PML at disease onset is extremely rare. In addition to our case, only nine PML cases presenting with strictly isolated radioanatomical brainstem location at the time of disease onset were retrieved through the literature. All patients share similar brain magnetic resonance imaging features, without contrast enhancement. Eight patients presented with initial clinical worsening, but full recovery occurred in three patients, partial recovery in two, and death in three. Even if prognosis is reserved because of the surrounding vital structures in the brainstem, clinical recovery may occur.

Conclusions

This case report and literature review emphasize that isolated brainstem lesion is an atypical presentation of PML at disease onset.

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Authors:
Gautier Breville, Igor J. Koralnik and Patrice H. Lalive
Article first published online:
01 Dec 2020 | DOI: 10.1111/ene.14617

LETTERS TO THE EDITOR

Cognitive frailty and falls

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Authors:
Liang Xu
Article first published online:
22 Nov 2020 | DOI: 10.1111/ene.14620

SHORT COMMUNICATION

Background

The hexanucleotide expansion mutation is the most common cause of genetic frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and combined FTD‐ALS. Its underlying neuropathology combines TDP‐43 pathology and dipeptide repeat protein (DPR) deposits and may also associate with other neurodegeneration‐associated protein aggregates. Herein we present a unique combination of mutation with sporadic Creutzfeldt−Jakob disease (CJD) in a 74‐year‐old patient with rapidly progressive dementia.

Methods

Detailed neuropathological examination including immunohistochemistry for several proteinopathies. Genetic analysis was conducted by repeat primed polymerase chain reaction (PCR). Furthermore, we analyzed additional mutation carriers for prion−protein (PrP) deposits in brain tissue and screened the cerebellar cortex of other CJD cases for p62/DPR neuronal inclusions to assess the frequency of combined pathologies.

Results

Postmortem brain examination of a patient with a rapidly progressive neurological deterioration of 8 months’ duration confirmed the diagnosis of CJD. She harbored valine homozygosity at codon 129. In addition, a frontotemporal lobar degeneration (FTLD)‐pattern with TDP‐43 protein aggregates and p62+/C9RANT+ positive inclusions along with a high degree of Alzheimer‐related pathology (A3B3C3) were identified. The suspected expansion mutation was confirmed by repeat‐primed PCR. Screening of 13 cases showed no pathological PrP aggregates and screening of 100 CJD cases revealed no other expansion mutation carriers.

Conclusion

A combination of a expansion mutation‐related FTLD with sporadic CJD in the same patient is rare. While the rarity of both diseases makes this concurrence most likely to be coincidental, questions regarding a potential link between these two neurodegenerative pathologies deserve further studies.

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Authors:
Sigrid Klotz, Theresa König, Marcus Erdler, Andreas Ulram, Anita Nguyen, Thomas Ströbel, Alexander Zimprich, Elisabeth Stögmann, Günther Regelsberger, Romana Höftberger, Herbert Budka, Gabor G. Kovacs and Ellen Gelpi
Article first published online:
01 Dec 2020 | DOI: 10.1111/ene.14621

ORIGINAL ARTICLE

Background and purpose

β‐Amyloid formation has been suggested to form part of the brain's response to bacterial infection. This hypothesis has been based on experimental animal studies and autopsy studies in humans. We asked if β‐amyloid accumulates locally around a bacterial brain abscess in living human patients. Furthermore, because brain abscess patients may suffer from chronic cognitive symptoms after abscess treatment, we also asked if a brain abscess precipitates accumulation of β‐amyloid in the neocortex in a manner that could explain abscess‐related cognitive complaints.

Methods

In a prospective study, we investigated 17 brain abscess patients (age 24–72 years) with F‐flutemetamol positron emission tomography on one occasion 1 to 10 months after brain abscess treatment to visualize β‐amyloid accumulation.

Results

F‐flutemetamol uptake was reduced in the edematous brain tissue that surrounded the abscess remains. On this background of reduced F‐flutemetamol signal, three out of 17 patients showed a distinctly increased F‐flutemetamol uptake in the tissue immediately surrounding the abscess remains, suggesting accumulation of β‐amyloid. These three patients underwent F‐flutemetamol positron emission tomography significantly earlier after neurosurgical treatment ( = 0.042), and they had larger abscesses ( = 0.027) than the rest of the patients. All 17 patients suffered from mental fatigue or some subjective cognitive symptom, such as attention difficulties or memory problems, but in none of the patients was there an increase in neocortical F‐flutemetamol signal.

Conclusions

β‐Amyloid may accumulate locally around the abscess remains in some patients with a brain abscess.

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Authors:
Ane Gretesdatter Rogne, Ebba Gløersen Müller, Eirin Udnæs, Solrun Sigurdardottir, Rune Raudeberg, James Patrick Connelly, Mona‐Elisabeth Revheim, Bjørnar Hassel and Daniel Dahlberg
Article first published online:
27 Nov 2020 | DOI: 10.1111/ene.14622

ORIGINAL ARTICLE

Background and purpose

Among stroke patients, low serum 25‐hydroxyvitamin D predicts poor outcomes. In mice, higher omega‐3 (n‐3) fatty acid intake diminishes brain damage after stroke. In this study, we tested whether vitamin D or n‐3 fatty acids supplementation prior to stroke reduces the risk of functional limitations and physical disability after stroke.

Methods

We used data from VITAL (the VITamin D and OmegA‐3 TriaL) which randomized middle‐aged and older men and women without cardiovascular disease to vitamin D (2000 IU/day) and/or marine n‐3 fatty acids (1 g/day) and followed them for incident stroke events. Individuals experiencing a non‐fatal stroke were mailed questionnaires assessing functional limitations (the physical performance scale adapted from Nagi) and physical disability (the modified Katz Activities of Daily Living and Rosow‐Breslau Functional Health scales). We used logistic regression to analyze associations between randomized treatment and limitations on each scale.

Results

A total of 290 individuals experienced their first stroke during the trial, of whom 197 stroke survivors completed the stroke outcomes questionnaire a median of 1.4 years after diagnosis. We observed no associations between randomized treatment to vitamin D and functional limitations (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.52, 1.97) or physical disability (Rosow‐Breslau scale: OR 0.92, 95% CI 0.50, 1.67; Katz scale: OR 1.03, 95% CI 0.31, 3.42). Those randomized to n‐3 fatty acids had a non‐significantly lower risk of functional limitations (OR 0.55, 95% CI 0.28, 1.09) and physical disability (Rosow‐Breslau scale: OR 0.56, 95% CI 0.31, 1.02; Katz sclae: OR 0.32, 95% CI 0.50, 1.67).

Conclusion

Vitamin D or omega‐3 fatty acid supplementation prior to stroke did not result in significantly improved post‐stroke outcomes.

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Authors:
Pamela M. Rist, Julie E. Buring, Nancy R. Cook, JoAnn E. Manson and Kathryn M. Rexrode
Article first published online:
24 Nov 2020 | DOI: 10.1111/ene.14623

LETTER TO THE EDITOR

Sulfate reducing gut bacteria and Parkinson's disease

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Authors:
Kari Erik Murros
Article first published online:
26 Nov 2020 | DOI: 10.1111/ene.14626

ORIGINAL ARTICLE

Background and purpose

To determine how the coverage of specialized allied health services for patients with Parkinson's disease (PD) has developed in the Netherlands since the publication of trials that demonstrated cost‐effectiveness.

Methods

We used healthcare expenditure‐based data on all insured individuals in the Netherlands to determine the annual proportion of patients with PD who received either specialized or generic allied health services (physiotherapy, occupational therapy, speech–language therapy) in 2 calendar years separated by a 5‐year interval (2012 and 2017). Specialized allied health services were delivered through the ParkinsonNet approach, which encompassed professional training and concentration of care among specifically trained professionals.

Results

Between 2012 and 2017, there was an increase in the number of patients with any physiotherapy (from 17,843 [62% of all patients with PD that year] to 22,282 [68%]), speech–language therapy (from 2171 [8%] to 3378 [10%]), and occupational therapy (from 2813 [10%] to 5939 [18%]). Among therapy‐requiring patients, the percentage who were treated by a specialized therapist rose substantially for physiotherapy (from 36% in 2012 to 62% in 2017; χ = 2460.2;  < 0.001), speech–language therapy (from 59% to 85%; χ = 445.4;  < 0.001), and occupational therapy (from 61% to 77%; χ = 231.6;  < 0.001). By contrast, the number of patients with generic therapists did not change meaningfully. By 2017, specialized care delivery had extended to regions that had been poorly covered in 2012, essentially achieving nationwide coverage.

Conclusions

Following the publication of positive trials, specialized allied healthcare delivery was successfully scaled for patients with PD in the Netherlands, potentially serving as a template for other healthcare innovations for patients with PD elsewhere.

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Authors:
Bastiaan R. Bloem, Marietta Eimers, Mirte S. van Galen, Marten Munneke and Sirwan K. L. Darweesh
Article first published online:
02 Dec 2020 | DOI: 10.1111/ene.14627

ORIGINAL ARTICLE

Background

The data on long‐term outcome after basilar artery occlusion (BAO) are scarce. Little is known about BAO survivors´ outcome over decades.

Aim

We set out to investigate long‐term survival and causes of death in BAO patients with up to two decades of follow‐up. We also evaluated differences in outcome trends.

Methods

Two hundred and seven BAO patients treated with intravenous thrombolysis (IVT) at the Department of Neurology, Helsinki University Hospital, between 1995 and 2016, were analyzed. Short‐term outcome was assessed by modified Rankin Scale (mRS) at 3 months. Long‐term cumulative survival rate was analyzed using Kaplan−Meier analysis. Factors associated with mortality were analyzed with Cox regression.

Results

Moderate outcome (mRS 0–3) was achieved in 41.1% and good outcome (mRS 0–2) in 30.4% of patients at 3 months. Three‐month mortality was 39.6%, of which 89% died within the first month. The median follow‐up time in 3‐month survivors was 8.9 years (maximum 21.8 years). Total mortality during follow‐up was 52.2%. Cumulative mortality rate was 25.7%. Older age, coronary artery disease and more extensive ischemic changes on admission brain imaging were independently associated with long‐term mortality. After the acute phase, the rate of other vascular causes of death increased in relation to stroke.

Conclusions

The described evolution of a large, single‐center BAO cohort shows a trend towards a higher rate of good and/or moderate outcome during later years in IVT‐treated patients. Survivors showed relative longevity, and the rate of cardiac and other vascular causes of death increased in relation to stroke sequelae over the long term.

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Authors:
Juhani Ritvonen, Tiina Sairanen, Heli Silvennoinen, Pekka Virtanen, Oili Salonen, Perttu J. Lindsberg and Daniel Strbian
Article first published online:
01 Dec 2020 | DOI: 10.1111/ene.14628

ORIGINAL ARTICLE

Background and Purpose

The aim of this meta‐analysis study was to assess the predictive effects of p.R4810K on phenotype in moyamoya disease (MMD).

Methods

Electronic databases (e.g., Pubmed and EMBASE) were searched, and relevant articles published up to August 2020 were retrieved. Review Manager 5.3 and Stata 12.0 were used for all statistical analyses. Pooled odds ratios, with 95% confidence intervals, and three comparison models were evaluated to analyze the association between pR4810K variant and clinical characteristics of MMD patients using a fixed‐effects model.

Results

A total of 2798 patients with MMD were selected and the effects of the heterozygous or homozygous p.R4810K variant on 18 clinical features were identified. There were more patients aged <15 years in the GA and AA groups (AA vs GA:  = 0.009; AA vs GG:  = 0.003; GA vs GG:  = 0.001). Among homozygous patients, the majority experienced MMD onset before the age of 4 years (AA vs. GA:  < 0.00001; AA vs GG:  < 0.00001). The frequency of infarctions and transient ischemic attack was significantly higher in homozygotes and heterozygotes，respectively. However, the frequency of intracerebral/intraventricular hemorrhage was lower in patients with the GA than the GG genotype. More MMD patients with AA and GA genotypes had a family history of the disease ( = 0.003,  < 0.00001, respectively). Posterior cerebral artery involvement was more common in patients with the GA genotype ( < 0.00001).

Conclusion

The homozygous or heterozygous variant may be an efficient biomarker with which to classify different clinical phenotypes of MMD.

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Authors:
Yue Wang, Luping Yang, Xiaotong Wang, Fanxin Zeng, Kaili Zhang, Qian Zhang, Mengwei Liu, Shan Liu, Mengke Shang, Qian Li, Yuetian Yang, Man Liang and Wanyang Liu
Article first published online:
02 Dec 2020 | DOI: 10.1111/ene.14635

ORIGINAL ARTICLE

Background and purpose

The Unruptured Intracranial Aneurysm Treatment Score (UIATS) was built to harmonize the treatment decision making on unruptured intracranial aneurysms. Therefore, it may also function as a predictor of aneurysm progression. In this study, we aimed to assess the validity of the UIATS model to identify aneurysms at risk of growth or rupture during follow‐up.

Methods

We calculated the UIATS for a consecutive series of conservatively treated unruptured intracranial aneurysms, included in our prospectively kept neurovascular database. Computed tomography angiography and/or magnetic resonance angiography imaging at baseline and during follow‐up was analyzed to detect aneurysm growth. We defined rupture as a cerebrospinal fluid or computed tomography–proven subarachnoid hemorrhage. We calculated the area under the receiver operator curve, sensitivity, and specificity, to determine the performance of the UIATS model.

Results

We included 214 consecutive patients with 277 unruptured intracranial aneurysms. Aneurysms were followed for a median period of 1.3 years (range 0.3–11.7 years). During follow‐up, 17 aneurysms enlarged (6.1%), and two aneurysms ruptured (0.7%). The UIATS model showed a sensitivity of 80% and a specificity of 44%. The area under the receiver operator curve was 0.62 (95% confidence interval 0.46–0.79).

Conclusions

Our observational study involving consecutive patients with an unruptured intracranial aneurysm showed poor performance of the UIATS model to predict aneurysm growth or rupture during follow‐up.

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Authors:
Rob Molenberg, Marlien W. Aalbers, Aryan Mazuri, Gert Jan Luijckx, Jan D. M. Metzemaekers, Rob J. M. Groen, Maarten Uyttenboogaart and J. Marc C. van Dijk
Article first published online:
03 Dec 2020 | DOI: 10.1111/ene.14636

ORIGINAL ARTICLE

Background and purpose

The aim of this study was to evaluate brain metabolic correlates of apathy in amyotrophic lateral sclerosis (ALS).

Methods

A total of 165 ALS patients underwent F‐2‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography (F‐FDG‐PET) and Frontal Systems Behaviour Scale (FrSBe) evaluation. FrSBe provides “before” and “after” apathy subscores, referring to premorbid and morbid conditions. “After” apathy subscore and “before‐after” gap, i.e. the difference between “before” and “after” subscores, were regressed against whole‐brain metabolism. Among patients with a pathological “after” apathy subscore (i.e., ≥65), we compared patients with “before” apathy subscores ≥65 and <65, and patients with “before‐after” gaps of <22 and ≥22.

Results

In the whole sample, the “after” apathy subscore negatively correlated with metabolism in the dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), ventrolateral prefrontal cortex (VLPFC), premotor cortex (PMC) and anterior cingulate cortex (ACC), and insula bilaterally. A positive correlation was found in the cerebellum and pons. The “before‐after” gap negatively correlated with metabolism in bilateral DLPFC, DMPFC and PMC, and left VLPFC and ACC, and positively correlated with cerebellar and pontine clusters. Among patients with an “after” apathy subscore ≥65, we found no difference between those with “before” apathy subscores ≥65 and <65. Patients with a “before‐after” gap ≥22, compared to patients with a gap <22, showed relative hypometabolism in bilateral DLPFC and DMPFC, and left ACC and PMC, and relative cerebellar and pontine hypermetabolism.

Conclusion

No studies on brain F‐2‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography correlates of apathy have been performed in ALS. We found that FrSBe “after” apathy subscore correlated with metabolic changes in brain regions known as neuroanatomical correlates of apathy. Furthermore, our findings support the relevance of the gap between premorbid and morbid conditions to detect behavioural changes due to the neurodegenerative process underlying ALS.

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Authors:
Antonio Canosa, Veria Vacchiano, Fabrizio D'Ovidio, Andrea Calvo, Cristina Moglia, Umberto Manera, Rosario Vasta, Rocco Liguori, Vincenzo Arena, Maurizio Grassano, Francesca Palumbo, Laura Peotta, Barbara Iazzolino, Marco Pagani and Adriano Chiò
Article first published online:
03 Dec 2020 | DOI: 10.1111/ene.14637

REVIEW

Background and purpose

Minocycline is a broad‐spectrum antibiotic, effective as a chronic treatment for recurrent bacterial infections. Beyond its antibiotic action, minocycline also has important anti‐inflammatory, antioxidant and antiapoptotic properties. Its efficacy has therefore been evaluated in many neurodegenerative and psychiatric diseases that have an inflammatory basis. Our aim was to review preclinical and clinical studies performed in neurological and psychiatric diseases whose treatment involved the use of minocycline and thereby to discern the possible beneficial effect of minocycline in these disorders.

Methods

Completed and ongoing preclinical studies and clinical trials of minocycline for both neurodegenerative diseases and psychiatric disorders, published from January 1995 to January 2020, were identified through searching relevant databases (, ). A total of 74 preclinical studies and 44 clinical trials and open‐label studies were selected.

Results

The results of the nearly 20 years of research identified are diverse. While minocycline mostly proved to be effective in animal models, clinical results showed divergent outcomes, with positive results in some studies counterbalanced by a number of cases with no significant improvements. Specific data for each disease are further individually described in this review.

Conclusions

Despite minocycline demonstrating antioxidant and anti‐inflammatory effects, discrepancies between preclinical and clinical data indicate that we should be cautious in analyzing the outcomes. Improving and standardizing protocols and refining animal models could help us to determine if minocycline really is a useful drug in the treatment of these pathologies.

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Authors:
Diego Romero‐Miguel, Nicolás Lamanna‐Rama, Marta Casquero‐Veiga, Vanessa Gómez‐Rangel, Manuel Desco and María Luisa Soto‐Montenegro
Article first published online:
24 Dec 2020 | DOI: 10.1111/ene.14642

CASE STUDY

Abstract

We report the first case of formation of a small 4‐ × 3‐mm symptomatic aneurysm with subsequent subarachnoid haemorrhage (SAH) within 15 days. A pre‐existing aneurysm was excluded by magnetic resonance angiography, as well as conventional angiography. In this case, there was no history of SAH, which is in contrast to other reported cases of aneurysms that developed after previous aneurysm rupture.

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Authors:
Justine Münsterberg, Bernd Eckert and Joachim Röther
Article first published online:
08 Feb 2021 | DOI: 10.1111/ene.14645

Original Article

Background and purpose

Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood.

Methods

We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near‐normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy‐targeted next generation sequencing panel.

Results

We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the ( = 2), ( = 1), ( = 1), and ( = 1) genes, which are typically associated with severe early‐onset HLDs, and in the gene ( = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing and a pathogenic variant were found in two patients, both females, with early‐onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in ( = 1) and ( = 1) and potentially relevant variants of unknown significance in ( = 1), which are genes associated with severe, early‐onset diseases with central hypomyelination/dysmyelination.

Conclusions

A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease‐causing genes, including genes associated with severe early‐onset HLDs, and genes causing peroxisome biogenesis disorders.

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Authors:
Daniela Di Bella, Stefania Magri, Chiara Benzoni, Laura Farina, Carmelo Maccagnano, Elisa Sarto, Marco Moscatelli, Silvia Baratta, Claudia Ciano, Sylvie H. M. J. Piacentini, Lara Draghi, Elena Mauro, Davide Pareyson, Cinzia Gellera, Franco Taroni and Ettore Salsano
Article first published online:
03 Dec 2020 | DOI: 10.1111/ene.14646

LETTER TO THE EDITOR

Expanding the genotypic and phenotypic spectrum of Beta‐propeller protein‐associated neurodegeneration

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Authors:
Edoardo Monfrini, Pierluigi Tocco, Sara Bonato, Mattia Tosi, Valentina Melzi, Emanuele Frattini, Giulia Franco, Stefania Corti, Giacomo Pietro Comi, Nereo Bresolin and Alessio Di Fonzo
Article first published online:
30 Dec 2020 | DOI: 10.1111/ene.14679

ORIGINAL ARTICLE

Background and purpose

Natural killer (NK) cells may play a role in multiple sclerosis (MS). Ratios of NK cells to CD4 T cells have been proposed as a biomarker for the therapeutic effect of stem cell transplantation in MS. The objectives here were to explore the relevance of this ratio in MS patients by analysing NK and T cell subsets, as well as their prognostic value for disease activity.

Methods

Baseline peripheral blood mononuclear cells of 50 relapsing–remitting MS patients, participating in our vitamin D supplementation study (SOLARIUM), were analysed with flow cytometry. Disease activity was measured as new magnetic resonance imaging lesions, relapses and mean plasma neurofilament light chain levels after 48 weeks of follow‐up.

Results

The proportion of NK cells correlated negatively with CD4 T cells ( = −0.335,  = 0.001) and interleukin 17A (IL‐17A) CD4 T cells ( = −0.203,  = 0.043). Participants with magnetic resonance imaging activity or relapses displayed lower NK/IL‐17ACD4 T cell ratios ( =0.025 and  = 0.006, respectively). The NK/IL‐17ACD4 T cell ratio correlated negatively with neurofilament light chain levels ( = −0.320,  = 0.050). Vitamin D supplementation did not affect these ratios.

Conclusions

Our data suggest a protective role of an expanded NK cell compartment compared to the CD4 T cell subset fractions in relapsing–remitting MS patients. NK/CD4 T cell ratios may be a prognostic biomarker for disease activity in MS.

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Authors:
Max Mimpen, Anne‐Hilde Muris, Linda Rolf, Oliver Gerlach, Jens Kuhle, Raymond Hupperts, Joost Smolders and Jan Damoiseaux
Article first published online:
30 Dec 2020 | DOI: 10.1111/ene.14680

ORIGINAL ARTICLE

Background

Brown−Vialetto−Van Laere syndrome (BVVLS) and Fazio−Londe disease (FLD) are rare neurological disorders presenting with pontobulbar palsy, muscle weakness and respiratory insufficiency. Mutations in (hRFVT‐2) or (hRFVT‐3) genes can be responsible for these disorders with an autosomal recessive pattern of inheritance. The aim of this study was to screen for mutations in and among Indian families diagnosed with BVVLS and FLD.

Methods

and were screened in one FLD and three BVVLS patients by exon‐specific amplification using PCR and sequencing. predictions using bioinformatics tools and confocal imaging using HEK‐293 cells were performed to determine the functional impact of identified mutations.

Results

Genetic analysis of a mother and son with BVVLS was identified with a novel homozygous mutation c.710C>T (p.Ala237Val) in . This variant was found to have an autosomal pseudodominant pattern of inheritance, which was neither listed in the Exome Variant Server or in the 1000 Genomes Project database. analysis and confocal imaging of the p.Ala237Val variant showed higher degree of disorderness in hRFVT‐3 that could affect riboflavin transport. Furthermore, a common homozygous mutation c.62A>G (p.Asn21Ser) was identified in other BVVLS and FLD patients. Despite having different clinical phenotypes, both BVVLS and FLD can be attributed to this mutation.

Conclusion

A rare and peculiar pattern of autosomal pseudodominant inheritance is observed for the first time in two genetically related BVVLS cases with Indian origin and a common mutation c.62A>G (p.Asn21Ser) in can be responsible for both BVVLS and FLD with variable phenotypes.

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Authors:
Santhalingam Gayathri, Vykuntaraju K. Gowda, Tamilarasan Udhayabanu, Benjamin O'Callaghan, Stephanie Efthymiou, Perumal Varalakshmi, Naveen Benakappa, Henry Houlden and Balasubramaniem Ashokkumar
Article first published online:
05 Jan 2021 | DOI: 10.1111/ene.14682

ORIGINAL ARTICLE

Background and purpose

To evaluate the association between plasma fibroblast growth factor 21 (FGF‐21) and clinical outcomes in patients with acute ischemic stroke.

Methods

A total of 3412 acute ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke with plasma FGF‐21 measurements were included in this analysis. The primary outcome was a combination of death or major disability (modified Rankin Scale score ≥3) within 1 year after stroke.

Results

During the 1‐year of follow‐up, 745 (21.83%) patients experienced the primary outcome; 550 had a major disability and 195 died. After multivariate adjustment, higher plasma FGF‐21 was significantly associated with increased risk of the primary outcome (odds ratio = 1.52, 95% confidence interval = 1.11–1.29). Each 1‐SD increase of log‐transformed FGF‐21 (0.67 pg/ml) was associated with 19%, 3%, and 33% increased risk of the primary outcome, major disability, and death, respectively. The addition of FGF‐21 to the conventional risk factors significantly improved prediction of the primary outcome in ischemic stroke patients (net reclassification index = 10.8%,  = 0.011; integrated discrimination improvement = 0.3%,  = 0.038).

Conclusions

Higher plasma FGF‐21 was associated with poor prognosis in acute ischemic stroke patients, suggesting that FGF‐21 may be a prognostic marker for ischemic stroke.

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Authors:
Xiaowei Zheng, Zhengbao Zhu, Daoxia Guo, Chongke Zhong, Tan Xu, Yanbo Peng, Aili Wang, Hao Peng, Zhong Ju, Deqin Geng, Yonghong Zhang and Jiang He
Article first published online:
05 Jan 2021 | DOI: 10.1111/ene.14683

ORIGINAL ARTICLE

Abstract

No studies have prospectively investigated headache at onset of first‐ever ischemic stroke along with a large concurrent control group. Our aims were to answer two important questions: (i) Are headaches at stroke onset causally related to the stroke, and what are their typical clinical characteristics? (ii) What etiology of stroke is associated with these headaches?

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Authors:
Elena R. Lebedeva, Anton V. Ushenin, Natalia M. Gurary, Tatiana S. Tsypushkina, Denis V. Gilev, Nadezda V. Kislyak and Jes Olesen
Article first published online:
05 Jan 2021 | DOI: 10.1111/ene.14684

ORIGINAL ARTICLE

Background and purpose

Patients with a chronic illness, such as multiple sclerosis (MS), and their natural caregivers have a specific experience of healthcare and health services. These experiences need to be assessed to evaluate the quality of care. Our objective was to develop a French‐language questionnaire to evaluate the quality of care as experienced by MS patients and their natural caregivers.

Methods

Eligible patients had been diagnosed with MS according to the McDonald criteria. Eligible caregivers were individuals designated by the patients. The MusiCare questionnaire was developed in two standard phases: (i) item generation, based on interviews with patients and caregivers; and (ii) validation, consisting of validity, reliability, external validity, reproducibility, and responsiveness measures.

Results

In total, 1088 patients ( = 660) and caregivers ( = 488) were recruited. The initial 64‐item version of MusiCare was administered to a random subsample ( = 748). The validation process generated a 35‐item questionnaire. Internal consistency and scalability were satisfactory. Testing of the external validity revealed expected associations between MusiCare scores and sociodemographic and clinical data. The questionnaire showed good reproducibility and responsiveness.

Conclusions

The availability of a reliable and validated French‐language self‐report questionnaire probing the experience of the quality of care for MS will allow the feedback of patients and caregivers to be incorporated into a continuous healthcare quality‐improvement strategy.

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Authors:
David Veillard, Karine Baumstarck, Gilles Edan, Marc Debouverie, Sandrine Wiertlewski, Jérôme De Sèze, Pierre Clavelou, Jean Pelletier, Christophe Verny, Karine Chauvin, Marie Elisabeth Cosson, Anderson Loundou and Pascal Auquier
Article first published online:
05 Jan 2021 | DOI: 10.1111/ene.14685

ORIGINAL ARTICLE

Background and purpose

Up to 30% of infective endocarditis (IE) patients have ischemic stroke as a complication. Standard treatment with mechanical thrombectomy (MT) with or without intravenous thrombolysis for large vessel occlusion (LVO) has not been evaluated formally in these patients.

Methods

Patients enrolled in the German Stroke Registry–Endovascular Treatment (GSR‐ET) between June 2015 and December 2019 were analyzed. Patients with stroke due to IE and patients with cardioembolic stroke and atrial fibrillation (AF) were compared using propensity score matching. Successful reperfusion was defined as modified Thrombolysis in Cerebral Infarction score = 2b–3. Modified Rankin Scale (mRS) = 0–2 at 3 months indicated good outcome.

Results

Of 6635 patients, 55 patients (age = 69.0 ± 13.3 years, 43.6% female, median premorbid mRS (pmRS) = 1, interquartile range [IQR] = 0–1, National Institutes of Health Stroke Scale [NIHSS] = 15, IQR = 10–21) presented with septic embolic stroke due to IE and were compared to 104 patients (age = 66.5 ± 13.4 years, 39.4% female, pmRS = 0, IQR = 0–2, NIHSS = 16, IQR = 10–20) with cardioembolic stroke due to AF. Successful recanalization was achieved in 74.5% of endocarditis patients compared to 87.5% of controls ( = 0.039). Intracranial hemorrhage rates were comparable (30.9% vs. 21.6%,  = 0.175). Good functional outcome was 20.0% in patients with IE compared to 43.3% in matched patients ( = 0.006), with a significantly higher mortality (60.0% vs. 28.8%,  < 0.001). IE was strongly associated with poor outcome (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.11–0.87,  = 0.03 for good outcome) and mortality (OR = 4.49, 95% CI = 1.80–10.68,  = 0.001).

Conclusions

Although MT results in high successful recanalization rates with acceptable safety profile, patients with LVO stroke due to IE have poor outcome.

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Authors:
Katharina Feil, Clemens Küpper, Steffen Tiedt, Konstantinos Dimitriadis, Moriz Herzberg, Franziska Dorn, Thomas Liebig, Marianne Dieterich, Lars Kellert, Tobias Boeckh‐Behrens, Silke Wunderlich, Alexander Ludolph, Karl‐Heinz Henn, Arno Reich, Anastasios Mpotsaris, Martin Wiesmann, Ulrike Ernemann, Sven Poli, Christian H Nolte, Eberhard Siebert, Sarah Zweynert, Georg Bohner, Laszlo Solymosi, Gabor Petzold, Waltraud Pfeilschifter, Fee Keil, Joachim Röther, Bernd Eckert, Jörg Berrouschot, Albrecht Bormann, Anna Alegiani, Jens Fiehler, Christian Gerloff, Götz Thomalla, Sven Thonke, Christopher Bangard, Christoffer Kraemer, Martin Dichgans, Marios Psychogios, Jan Liman, Martina Petersen, Florian Stögbauer, Peter Kraft, Mirko Pham, Michael Braun, Gerhard F Hamann, Christian Roth, Klaus Gröschel, Timo Uphaus and Volker Limmroth
Article first published online:
06 Jan 2021 | DOI: 10.1111/ene.14686

LETTERS TO THE EDITOR

A rare cause of midbrain haemorrhage

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Authors:
Kristin S. Lange, Guillaume Taieb, Pierre Lepretre, Elisa De La Cruz, Caroline Arquizan and Nicolas Gaillard
Article first published online:
30 Dec 2020 | DOI: 10.1111/ene.14688

ORIGINAL ARTICLE

Background and purpose

Charcot‐Marie‐Tooth (CMT) disease is a chronic, slowly progressing disorder. The lack of specific disease progression biomarkers limits the execution of clinical trials. However, neurofilament light chain (NfL) has been suggested as a potential biomarker for peripheral nervous system disorders.

Methods

Ninety‐six CMT disease patients and 60 healthy controls were enrolled in the study. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Blood plasma NfL concentrations were measured using the single‐molecule array NfL assay.

Results

The NfL concentration was significantly higher in the CMT disease patient group than in the controls ( < 0.001). Of the CMT disease patients, those with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (CMT1A and other CMT disease types) ( = 0.0498). The NfL concentration had a significant but weak correlation with the CMTNSv2 ( = 0.25,  = 0.012). In one CMT disease patient with an extremely elevated NfL level, overlap with chronic inflammatory demyelinating polyneuropathy was suspected. Receiver operating characteristic analysis showed that an NfL concentration of 8.9 pg/ml could be used to discriminate CMT disease patients from controls, with an area under the curve of 0.881.

Conclusions

Our study confirmed that the plasma NfL concentration is significantly higher in CMT disease patients than in controls. Plasma NfL concentration was found to significantly, albeit weakly, reflect the clinical severity of CMT disease. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT disease; however, several issues need to be addressed first.

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Authors:
Elina Millere, Dmitrijs Rots, Joel Simrén, Nicholas J. Ashton, Einars Kupats, Ieva Micule, Viktorija Priedite, Natalja Kurjane, Kaj Blennow, Linda Gailite, Henrik Zetterberg and Viktorija Kenina
Article first published online:
06 Jan 2021 | DOI: 10.1111/ene.14689

CASE STUDY

Abstract

Neurological immune‐mediated side effects are rare but often severe complications of immune checkpoint inhibitor (ICI) treatment. This report describes a severe case of nivolumab/ipilimumab‐associated glutamic acid decarboxylase 65–positive autoimmune encephalitis. It proposes neurofilament light chain levels, a biomarker indicating axonal damage, in the cerebrospinal fluid and serum as a putative novel biomarker for this diagnostically and therapeutically challenging entity with an often unfavorable outcome. Additionally, we provide an overview of previous reports of patients developing autoimmune encephalitis under ICI treatment.

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Authors:
Johannes Piepgras, Aneka Müller, Falk Steffen, Johannes Lotz, Carmen Loquai, Frauke Zipp, Christian Dresel and Stefan Bittner
Article first published online:
08 Feb 2021 | DOI: 10.1111/ene.14692

EDITORIAL

Hypomyelinating leukodystrophies in adults

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Authors:
Fanny Mochel
Article first published online:
06 Jan 2021 | DOI: 10.1111/ene.14694

ORIGINAL ARTICLE

Background and purpose

Disease‐modifying therapies provide new horizons for hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN) to slow neuropathic progression. Initiating treatment at the earliest time requires biomarkers reflecting both small‐ and large‐fiber degeneration in carriers.

Methods

This study included examinations of pathology (intraepidermal nerve fiber [IENF] density), physiology (nerve conduction studies, autonomic function test, and nerve excitability), and psychophysics (thermal thresholds) in carriers to compare to healthy controls and asymptomatic diabetic patients.

Results

There were 43 carriers (44.2 ± 11.4 years, p.Ala117Ser in 42 carriers), 43 controls (43.4 ± 12.7 years) including 26 noncarrier families, and 50 asymptomatic diabetic patients (58.1 ± 9.5 years). Carriers had lower IENF densities than controls and similar densities as diabetic patients. Median nerve conduction parameters, especially distal motor latency, were the most frequent neurophysiological abnormality in carriers, could differentiate carriers from controls and diabetic patients, were correlated with IENF densities in carriers but not in controls and diabetic patients, and were correlated with nerve excitability parameters in carriers but not in controls. Fifteen carriers (34.9%) with electrophysiological evidence of median nerve entrapment at the wrist had lower IENF densities and more abnormal conduction parameters than carriers without. We defined nerve dysfunction index—the ratio of median distal motor latency to IENF density—which differentiated carriers from controls.

Conclusions

In late‐onset ATTRv‐PN carriers with predominant p.Ala117Ser, median conduction parameters were the most common neurophysiological abnormalities and served as surrogate signatures of small‐ and large‐fiber impairment. Combination of median distal motor latency and IENF density can reflect early neuropathy in carriers.

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Authors:
Ming‐Chang Chiang, Ti‐Yen Yeh, Jia‐Ying Sung, Hsueh‐Wen Hsueh, Yi‐Hui Kao, Sung‐Ju Hsueh, Kai‐Chieh Chang, Fang‐Ping Feng, Yea‐Huey Lin, Chi‐Chao Chao and Sung‐Tsang Hsieh
Article first published online:
09 Jan 2021 | DOI: 10.1111/ene.14698

ORIGINAL ARTICLE

Background and purpose

Soluble suppression of tumorigenicity 2 (sST2) might be related to stroke and depression, but the association of sST2 with poststroke depression (PSD) is unclear. The study aimed to prospectively assess the association between plasma sST2 levels and PSD.

Methods

A total of 635 acute ischemic stroke patients with sST2 measurements from the China Antihypertensive Trial in Acute Ischemic Stroke were included in this analysis. We used the 24‐item Hamilton Rating Scale for Depression to assess depression at 3 months, and PSD was defined as a score of ≥8. Logistic regression analysis was performed to estimate the risk of PSD associated with sST2, and net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to assess the predictive value of sST2.

Results

Two hundred fifty (39.4%) patients developed depression at 3 months after ischemic stroke. Patients with PSD had higher sST2 levels than patients without PSD (172.7 vs. 153.8 pg/ml;  = 0.003). After adjustment for age, sex, education, National Institutes of Health Stroke Scale score, and other covariates, the odds ratio for the highest quartile of sST2 compared with the lowest quartile was 1.84 (95% confidence interval, 1.10–3.08) for PSD. Adding sST2 to a conventional model notably improved risk prediction for PSD (category‐free NRI = 19.34%, 95% confidence interval = 4.39%–34.28%,  = 0.017; IDI = 1.20%, 95% confidence interval = 0.25%–2.15%,  = 0.014).

Conclusions

Increased plasma sST2 levels in the acute phase of ischemic stroke were significantly associated with the increased risk of PSD, independently of conventional risk factors.

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Authors:
Yaling Lu, Sifan Qian, Haichang Chen, Pengcheng Yuan, Rui Zhang, Aili Wang, Jintao Zhang, Zhong Ju, Yonghong Zhang, Tan Xu and Chongke Zhong
Article first published online:
11 Jan 2021 | DOI: 10.1111/ene.14699

Thanks to reviewers

Thank you to our peer reviewers in 2020

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Article first published online:
08 Feb 2021 | DOI: 10.1111/ene.14731