cover image European Journal of Neurology

European Journal of Neurology

2020 - Volume 27
Issue 12 | December 2020
Previous Issue

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Article first published online:
08 Nov 2020 | DOI: 10.1111/ene.14002

Letters To The Editor

Response to: migraine symptoms and the role of the autonomic dysfunction

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Authors:
K. M. Linstra, R. Fronczek and G. M. Terwindt
Article first published online:
22 Jun 2020 | DOI: 10.1111/ene.14374

Letters to the Editor

A novel Col4A1 mutation: recognizing an uncommon cause of stroke

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Authors:
S. Portela Sánchez, J. M. Velázquez Pérez, P. Simón Campo, J. A. Guzmán De Villoria, J. García Planells and J. M. García Domínguez
Article first published online:
31 Jul 2020 | DOI: 10.1111/ene.14413

Original Article

Background and purpose

Limited data are available in the literature for upper limb impairment in multiple sclerosis (MS). This study aimed to report the distribution of values of hand grip strength (HGS), of the box and block test (BBT) and of the nine‐hole peg test (9HPT) correlated with demographic and clinical data in subjects with MS.

Methods

This study involved five Italian neurological centres. The inclusion criteria were age ≥ 18, MS diagnosis, stable disease phase, right‐hand dominance. All subjects underwent HGS, BBT and 9‐HPT evaluation.

Results

In all, 202 subjects with MS were enrolled: 137 females; mean age 48.4 years; mean Expanded Disability Status Scale (EDSS) 4.17; mean disease duration 14.12 years; disease course 129 relapsing–remitting, 21 primary progressive and 52 secondary progressive MS subjects; mean right HGS 25.3 kg, left 23.2 kg; mean right BBT 45.7 blocks, left 44.9 blocks; mean right 9‐HPT 30.7 s, left 33.4 s. All results were statistically significantly different compared to healthy controls. HGS, BBT and 9‐HPT were associated with age, EDSS and disease duration, whilst disease course correlated with BBT and 9‐HPT. The BBT and 9‐HPT scores significantly differed according to level of disability (EDSS ≤3.0, 3.5–5.5, ≥6.0).

Conclusion

Hand grip strength and BBT value distribution in a large MS population is reported. Correlations between HGS, BBT and 9‐HPT were generally low.

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Authors:
C. Solaro, R. Di Giovanni, E. Grange, M. Mueller, M. Messmer Uccelli, R. Bertoni, G. Brichetto, A. Tacchino, F. Patti, A. Pappalardo, L. Prosperini, L. Castelli, R. Rosato, D. Cattaneo and D. Marengo
Article first published online:
01 Aug 2020 | DOI: 10.1111/ene.14427

Letters To The Editor

A neurological point of view on the European Society of Cardiology guidelines: the interactions between direct oral anticoagulants and antiepileptic drugs

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Authors:
M. Puma, I. Maestrini, M. Altieri and V. Di Piero
Article first published online:
27 Jul 2020 | DOI: 10.1111/ene.14428

Original Article

Background and purpose

The existence of contraindications to intravenous thrombolysis (IVT) is considered a criterion for direct transfer of patients with suspected acute stroke to thrombectomy‐capable centers in the prehospital setting. Our aim was to assess the utility of this criterion in a setting where routing protocols are defined by the Madrid – Direct Referral to Endovascular Center (M‐DIRECT) prehospital scale.

Methods

This was a analysis of the M‐DIRECT study. Reported contraindications to IVT were retrospectively collected from emergency medical services reports and categorized into late window, anticoagulant treatment and other contraindications. Final diagnosis and treatment rates were compared between patients with and without reported IVT contraindications and according to anticoagulant treatment or late window categories.

Results

The M‐DIRECT study included 541 patients. Reported IVT contraindications were present in 227 (42.0%) patients. Regarding final diagnosis no significant differences were found between patients with or without reported IVT contraindications: ischaemic stroke (any) 65.6% vs. 62.1%, ischaemic stroke with large vessel occlusion (LVO) 32.2% vs. 28.3%, hemorrhagic stroke 15.4% vs. 15.6%, stroke mimic 18.9% vs. 22.3% respectively. Amongst patients with LVO, endovascular thrombectomy (EVT) was performed less often in the presence of IVT contraindications (56.2% vs. 74.2%). M‐DIRECT‐positive patients had higher rates of LVO and EVT compared with M‐DIRECT‐negative patients independent of reported IVT contraindications.

Conclusions

Reported IVT contraindications alone do not increase EVT likelihood and should not be considered to determine routing in urban stroke networks.

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Authors:
J. Rodríguez‐Pardo, S. Secades‐García, N. Riera‐López, M. Alonso de Leciñana, V. Real‐Martínez, J. Carneado‐Ruiz, J. Díaz‐Guzmán, E. Díez‐Tejedor, J. Egido‐Herrero, A. Gil‐Núñez, M. C. Matute‐Lozano, S. Trillo, R. Vera‐Lechuga, J. Vivancos‐Mora, Á. Ximénez‐Carrillo and B. Fuentes
Article first published online:
01 Aug 2020 | DOI: 10.1111/ene.14429

Original Article

Background and purpose

Migraine is a common and costly neurological disorder. The aims of this study were to quantify the costs of chronic (CM) and episodic migraine (EM) in Spain, evaluating the impact of psychiatric comorbidities and disability, and to estimate the economic savings associated with reducing the number of migraine‐days by 50%.

Methods

This was an observational, cross‐sectional analysis of data from migraine patients who participated in the Spanish Migraine Atlas. The participants were invited to complete a structured questionnaire including the following scales: the Headache Needs Assessment, the Hospital Anxiety and Depression Scale, and the Migraine Disability Assessment Scale (MIDAS).

Results

A total of 475 patients were included, of whom 187 had CM (39.4%). Total costs per patient/year were: €16 578.2 ± €34 568.1 for CM and €6227.8 ± €6515.7 for EM. A higher degree of disability, according to MIDAS, significantly increased the total cost of migraine, while the presence of psychiatric comorbidity increased costs for EM patients only. A reduction of 1 migraine‐day per month decreased average total costs by €744.14 per patient/year for EM and €663.20 per patient/year for CM, while a reduction in the number of migraine‐days by 50% would result in economic savings of €2232.44 per patient/year ( = 0.927) for EM and €6631.99 per patient/year ( = 0.886) for CM.

Conclusions

The costs associated with migraine were driven by migraine frequency and the degree of disability, whereas psychiatric comorbidity only influenced the cost of EM. These results highlight the need to optimize migraine management to reduce the economic migraine burden. Future studies are needed to confirm our results.

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Authors:
P. Irimia, M. Garrido‐Cumbrera, S. Santos‐Lasaosa, O. Braçe, I. Colomina, C. Blanch and P. Pozo‐Rosich
Article first published online:
08 Aug 2020 | DOI: 10.1111/ene.14431

Original Article

Background and purpose

The patient's perspective is becoming increasingly important for endpoints in studies on multiple sclerosis. However, relapse data generated from the patient's perspective in combination with independent documentation by the physician are scarce. Our objective was to compare self‐reported relapses by the patient to physician‐documented relapses within a routine clinical practice setting of quarterly visits.

Methods

Two‐year data ( = 1921 patients) were extracted from two prospective, non‐interventional, multicentre cohort studies in Germany. The number of relapses independently reported by patients and physicians was analysed. In addition, inter‐rater reliability and measures of validity were evaluated. Patterns of associations were investigated in subgroup analysis of sociodemographic, clinical and patient‐reported outcome measures.

Results

Patients and physicians showed good overall agreement [κ = 0.78, 95% confidence interval (CI) 0.76–0.80]. Nevertheless, patients reported, on average, more relapses than physicians during follow‐up (0.55 vs. 0.44;  < 0.001). Corresponding annualized relapse rates were 0.38 (95% CI 0.36–0.39) and 0.30 (95% CI 0.29–0.31), respectively. Differences between physicians and patients were particularly pronounced in patient groups with greater disability levels, decreased health‐related quality of life or treatment satisfaction. The positive predictive value was 74.01% (95% CI 71.85–76.07), and the negative predictive value was 98.86% (95% CI 98.67–99.03).

Conclusion

Some disagreement on the occurrence of relapses appears in specific patient subgroups, where factors such as pseudo‐relapses or confounding factors may have promoted over‐ or under‐reporting.

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Authors:
D. Schriefer, R. Haase, B. Ettle and T. Ziemssen
Article first published online:
02 Aug 2020 | DOI: 10.1111/ene.14432

Commentary

Visual snow syndrome: is it normal or a disorder – and what to do with patients?

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Authors:
C. J. Schankin, F. Puledda and P. J. Goadsby
Article first published online:
08 Aug 2020 | DOI: 10.1111/ene.14436

Original Article

Background and purpose

Ischaemic and hemorrhagic strokes are dreaded complications of infective endocarditis (IE). The timing of valve surgery for IE patients with stroke remains uncertain. The aim was to study perioperative neurological complications in relation to surgical timing.

Methods

The study cohort consisted of patients diagnosed with acute IE from January 2010 to December 2016. Early surgery was defined as valve surgery within 14 days of IE diagnosis, and late surgery as after 14 days. Neurological complications that occurred within 14 days post‐surgery were considered perioperative and classified as new ischaemic stroke or hemorrhagic stroke, expansion of an existing intracranial hemorrhage and new‐onset seizures. Perioperative neurological complications were compared by surgical timing and other variables, including pre‐surgical imaging.

Results

Overall, 183 patients underwent valve surgery: 92 had early surgery at a median of 8 days (interquartile range 6–11); 91 had late surgery at a median of 28 days (interquartile range 19–50). Twenty patients (10.9%) had 24 complications: 11 ischaemic, six intraparenchymal hemorrhages, three subarachnoid hemorrhages (SAHs) and four new‐onset seizures. Rates of neurological complications were similar for early and late surgery groups (10.9% vs. 11%). Enterococcal IE was more common amongst patients with perioperative neurological complications (35% vs. 12.3%,  < 0.01). An acute infarct was present on pre‐surgical magnetic resonance imaging of 134 patients (74%) and was not associated with perioperative neurological complications. Thirty‐five patients (19.3%) had intracranial hemorrhage on pre‐surgical imaging. SAH on pre‐surgical imaging was associated with developing SAH perioperatively (66.7% vs. 13.5%,  < 0.01).

Conclusion

Early valve surgery for patients with IE complicated by stroke was not associated with perioperative neurological complications.

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Authors:
L. Q. Zhang, S.‐M. Cho, C. J. Rice, J. Khoury, R. J. Marquardt, A. B. Buletko, J. Hardman, D. Wisco and K. Uchino
Article first published online:
23 Aug 2020 | DOI: 10.1111/ene.14438

Original Article

Background and purpose

The incidence of moyamoya disease (MMD) in Europe is not well known. In those affected, the risk of brain hemorrhage is considered low. The present study aimed to investigate the incidence and clinical presentation of MMD in the Danish population.

Methods

Eligible patients were identified in the Danish National Patient Register from 1994 to 2017. We collected clinical and radiological data from individual patient records from neurological, neurosurgical and paediatric units across Denmark. The diagnosis was validated according to established criteria. We also extracted basic demographic data on the cohort from the Danish Civil Registration System.

Results

A total of 52 patients fulfilled the diagnostic criteria for MMD. Most patients were native Danes and only 15% had an East Asian background. The ratio of female to male patients was 1.8, and the incidence had two peaks: one in childhood and another in young middle age. Until 2007, MMD was only diagnosed sporadically. From 2008 onwards, the incidence rate was 0.07 per 100 000 person‐years (95% confidence interval 0.05–0.09 per 100 000 person‐years). The most common mode of presentation was ischaemic stroke (33%), followed by hemorrhage (23%), headache (17%) and transient ischaemic attack (14%).

Conclusions

Moyamoya disease is rare in Denmark, but is associated with a considerable risk of hemorrhage. Thus, MMD should be considered in the evaluation for ischaemic as well as hemorrhagic stroke paediatric and middle‐aged Caucasians.

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Authors:
P. Birkeland, V. Tharmabalan, J. Lauritsen, V. Ganesan, C. R. Bjarkam and P. von Weitzel‐Mudersbach
Article first published online:
08 Aug 2020 | DOI: 10.1111/ene.14439

LETTER TO THE EDITOR

Toward a unified European curriculum – reforming national residency programme in Slovenia

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Authors:
M. Rakusa and U. Rot
Article first published online:
06 Aug 2020 | DOI: 10.1111/ene.14441

Original Article

Background and purpose

Primitive reflexes may reoccur in various neurodegenerative diseases. However, little is known about their structural and functional correlates in the human brain. Notably, the neural mechanisms underlying a positive palmomental reflex (PMR) are poorly understood. As recent studies link Alzheimer's disease (AD)‐related primitive reflexes to a dysfunction of the corticostriatal motor circuit (CMC), we conducted the present study to investigate functional and structural correlates of a positive PMR. We hypothesized an involvement of frontostriatal structures and an impairment of the CMC.

Methods

Using whole‐brain resting‐state functional connectivity (FC), hypothesis and FC result‐based probabilistic tractography, and voxel‐based morphometry analyses, we compared two groups of AD patients with either positive ( = 12) or negative PMR ( = 12).

Results

No significant differences in grey matter volume or structural connectivity (SC) could be observed between the PMR‐positive and PMR‐negative groups. In contrast, the PMR‐positive group showed a decreased seed‐to‐voxel FC between the bilateral supplementary motor area and parts of the right‐hemispherical caudate nucleus and thalamus and a decreased region of interest (ROI)‐to‐ROI FC between the left putamen and the left superior frontal gyrus.

Conclusion

Data suggest that dysfunction of the CMC reflected by decreased FC underlies a positive PMR in patients with AD. The lack of significant grey matter or SC differences might reflect that changes in FC appear before changes in SC in the structures of the CMC and brain atrophy.

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Authors:
H. Gramespacher, N. Richter, S. Edwin Thanarajah, H. I. L. Jacobs, K. N. H. Dillen, N. Nellessen, B. von Reutern, J. Dronse, J. Kukolja, G. R. Fink and O. A. Onur
Article first published online:
20 Aug 2020 | DOI: 10.1111/ene.14443

Letters To The Editor

Neurology practice during the COVID‐19 outbreak and post‐pandemic era: experiences and challenges

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Authors:
Y. Tang, Y. Xing, L. Cui, C. Wu, X. Wen, H. Song, L. Wu, H. Chang, J. Song, Y. Wang and G. Zhao
Article first published online:
09 Aug 2020 | DOI: 10.1111/ene.14445

Original Article

Background and purpose

The aim was to define the radiological picture of facioscapulohumeral muscular dystrophy 2 (FSHD2) in comparison with FSHD1 and to explore correlations between imaging and clinical/molecular data.

Methods

Upper girdle and/or lower limb muscle magnetic resonance imaging scans of 34 molecularly confirmed FSHD2 patients from nine European neuromuscular centres were analysed. T1‐weighted and short‐tau inversion recovery (STIR) sequences were used to evaluate the global pattern and to assess the extent of fatty replacement and muscle oedema.

Results

The most frequently affected muscles were obliquus and transversus abdominis, semimembranosus, soleus and gluteus minimus in the lower limbs; trapezius, serratus anterior, latissimus dorsi and pectoralis major in the upper girdle. Iliopsoas, popliteus, obturator internus and tibialis posterior in the lower limbs and subscapularis, spinati, sternocleidomastoid and levator scapulae in the upper girdle were the most spared. Asymmetry and STIR hyperintensities were consistent features. The pattern of muscle involvement was similar to that of FSHD1, and the combined involvement of trapezius, abdominal and hamstring muscles, together with complete sparing of iliopsoas and subscapularis, was detected in 91% of patients. Peculiar differences were identified in a rostro‐caudal gradient, a predominant involvement of lower limb muscles compared to the upper girdle, and in the higher percentage of STIR hyperintensities in FSHD2.

Conclusion

This multicentre study defines the pattern of muscle involvement in FSHD2, providing useful information for diagnostics and clinical trial design. Both similarities and differences between FSHD1 and FSHD2 were detected, which is also relevant to better understand the pathogenic mechanisms underlying the FSHD‐related disease spectrum.

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Authors:
G. Giacomucci, M. Monforte, J. Diaz‐Manera, K. Mul, R. Fernandez Torrón, L. Maggi, C. Marini Bettolo, J. R. Dahlqvist, J. Haberlova, P. Camaño, M. Gros, T. Tartaglione, L. Cristiano, S. Gerevini, P. Calandra, G. Deidda, E. Giardina, S. Sacconi, V. Straub, J. Vissing, B. Van Engelen, E. Ricci and G. Tasca
Article first published online:
14 Aug 2020 | DOI: 10.1111/ene.14446

Original Article

Background and purpose

Blood pressure (BP) variability has been associated with worse neurological outcomes in acute ischaemic stroke (AIS) patients receiving treatment with intravenous thrombolysis (IVT). However, no study to date has investigated whether pulse pressure (PP) variability may be a superior indicator of the total cardiovascular risk, as measured by clinical outcomes.

Methods

Pulse pressure variability was calculated from 24‐h PP measurements following tissue plasminogen activator bolus in AIS patients enrolled in the Combined Lysis of Thrombus using Ultrasound and Systemic Tissue Plasminogen Activator for Emergent Revascularization (CLOTBUST‐ER) trial. The outcomes of interest were the pre‐specified efficacy and safety end‐points of CLOTBUST‐ER. All associations were adjusted for potential confounders in multivariable regression models.

Results

Data from 674 participants was analyzed. PP variability was identified as the BP parameter with the most parsimonious fit in multivariable models of all outcomes, and was independently associated (< 0.001) with lower likelihood of both 24‐h neurological improvement and 90‐day independent functional outcome. PP variability was also independently related to increased odds of any intracranial bleeding (= 0.011) and 90‐day mortality (< 0.001). Every 5‐mmHg increase in the 24‐h PP variability was independently associated with a 36% decrease in the likelihood of 90‐day independent functional outcome (adjusted odds ratio 0.64, 95% confidence interval 0.52–0.80) and a 60% increase in the odds of 90‐day mortality (adjusted odds ratio 1.60, 95% confidence interval 1.23–2.07). PP variability was not associated with symptomatic intracranial bleeding at either 24 or 36 h after IVT administration.

Conclusions

Increased PP variability appears to be independently associated with adverse short‐term and long‐term functional outcomes of AIS patients treated with IVT.

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Authors:
A. H. Katsanos, A. V. Alexandrov, P. Mandava, M. Köhrmann, L. Soinne, A. D. Barreto, V. K. Sharma, R. Mikulik, K. W. Muir, T. Rothlisberger, J. C. Grotta, C. R. Levi, C. A. Molina, M. Saqqur, L. Palaiodimou, T. Psaltopoulou, M. R. Vosko, T. Moreira, J. B. Fiebach, M. Rubiera, E. C. Sandset, A. de Havenon, T. A. Kent, A. W. Alexandrov, P. D. Schellinger and G. Tsivgoulis
Article first published online:
17 Aug 2020 | DOI: 10.1111/ene.14447

Original Article

Background and purpose

Urinary liver‐type fatty‐acid binding protein (L‐FABP), which is a biomarker of kidney tubule injury, has been studied extensively and established as a risk marker of acute kidney injury (AKI). The aim of this study was to investigate whether kidney tubule injury is associated with the development of AKI and mortality in patients with acute ischaemic stroke.

Methods

Acute ischaemic stroke patients hospitalized in the stroke care unit (SCU) within 24 h after symptom onset were prospectively investigated. AKI was defined on the basis of Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Baseline urinary L‐FABP was measured on admission. We evaluated the associations among urinary L‐FABP, incidence of AKI, and 90‐day mortality adjusted for renal function, albuminuria and other potentially predictive variables, using multivariable analysis.

Results

In total, 527 acute ischaemic stroke patients (342 men, median age 74 years) were enrolled in the study. Twenty‐seven patients (5.1%) experienced AKI within 7 days of admission. In the univariate analysis, high urinary L‐FABP level had positive associations with AKI [53.8 μg/g creatinine (Cr) vs. 3.9 μg/g Cr;  < 0.001] and 90‐day mortality (15.5 μg/g Cr vs. 4.0 μg/g Cr;  < 0.001). In the multivariate analysis, elevated urinary L‐FABP level (per 10‐μg/g Cr increase) was independently associated with AKI (odds ratio 1.225, 95% confidence interval (CI) 1.083–1.454;  = 0.003) and 90‐day mortality (hazard ratio 1.091, 95% CI 1.045–1.138;  < 0.001).

Conclusion

Urinary biomarkers of kidney tubule injury are independently associated with the development of AKI and 90‐day mortality in patients with acute ischaemic stroke treated at the SCU.

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Authors:
T. Shimoyama, T. Sato, Y. Sakamoto, K. Nagai, J. Aoki, S. Suda, Y. Nishiyama and K. Kimura
Article first published online:
16 Aug 2020 | DOI: 10.1111/ene.14448

Letters To The Editor

Response to: ‘Patients with breakthrough tick‐borne encephalitis suffer a more severe clinical course and display extensive MRI changes’

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Authors:
H.‐J. Schmitt, W. Erber and F. Khan
Article first published online:
30 Aug 2020 | DOI: 10.1111/ene.14449

Original Article

Background and purpose

Dementia disorders predispose for lethal complications and decrease life expectancy. A more profound knowledge regarding end‐stage conditions in dementia could therefore ameliorate treatment and care of these patients.

Methods

Autopsy reports on 207 deceased individuals with clinically diagnosed neurocognitive disorder/dementia and on 200 neurocognitively healthy individuals of the same age range were studied. Autopsy results, especially cause of death, were compared between the dementia and the control groups.

Results

The two most frequent causes of death in the dementia population were pneumonia (34.3%) and acute myocardial infarction (30.4%). This result differed from that of the control group, in which acute myocardial infarction (42.5%) accounted for most events of deaths, followed by circulatory failure (12.5%). The leading cause of death varied amongst dementia subtypes. Further, in Alzheimer’s disease pneumonia was more frequent in severe/advanced cases whilst acute myocardial infarction was more common in milder cases.

Conclusions

Cause of death differed between the demented and the general population of the same age and between subtypes of dementia. Alzheimer’s disease severity was reflected in different final conditions. The findings have relevance for the final stage care and treatment in dementia disorders.

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Authors:
A. N. W. Degerskär and E. M. Englund
Article first published online:
31 Aug 2020 | DOI: 10.1111/ene.14450

ORIGINAL ARTICLE

Background and purpose

Neuromodulation is a promising approach to increasing motor recovery in stroke; however, to date, there is a scarcity of evidence documenting the clinical potential of transcranial direct current stimulation (tDCS) administered in the acute phase of stroke. The present study aims to examine the clinical effects of a treatment involving the application of tDCS in the acute stage post‐stroke.

Methods

This was a randomized, double‐blind, sham‐controlled trial. A cohort of 32 stroke patients with severe motor impairment underwent 5 days of treatment with real or sham bi‐hemispheric tDCS over the motor cortex. During the treatment, tDCS was applied twice per day (two daily applications each of 15 min), starting 48 to 72 h after stroke onset.

Results

We found statistically significant improvements after both real and sham tDCS treatments in primary (hand grip strength, Motricity Index) and secondary (National Institutes of Health Stroke Scale score, Barthel Index) outcomes. Patients receiving real tDCS showed a larger improvement of upper‐limb muscle strength at the end of treatment phase; this advantage was no longer present after 6 months.

Conclusions

Transcranial direct current stimulation may be used to accelerate the rate of upper‐limb motor recovery during the spontaneous recovery period.

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Authors:
N. Bolognini, C. Russo, M. I. Souza Carneiro, A. Nicotra, E. Olgiati, V. Spandri, E. Agostoni, A. Salmaggi and G. Vallar
Article first published online:
16 Aug 2020 | DOI: 10.1111/ene.14451

Original Article

Background and purpose

Hypomimia is a prominent clinical feature in people with Parkinson’s disease (PD), but it remains under‐investigated. We aimed to examine the clinical correlates of hypomimia in PD and to determine whether this is a levodopa‐responsive sign.

Methods

We included 89 people with PD. Hypomimia was assessed from digital video recordings by movement disorder specialists. Clinical evaluation included use of the Unified Parkinson’s Disease Rating Scale part III (UPDRS‐III), and assessment of motor and non‐motor symptoms using standardized clinical scales. The relationships between hypomimia and other clinical data were analysed using Mann–Whitney ‐tests and regression analysis.

Results

Hypomimia occurred in up to 70% of patients with PD. Patients with hypomimia had worse UPDRS‐III 'off‐medication' scores, mainly driven by bradykinesia and rigidity subscores. Patients with hypomimia also had worse apathy than patients without hypomimia. Finally, we found that hypomimia was levodopa‐responsive and its improvement mirrored the change by levodopa in axial motor symptoms.

Conclusion

Our study provides novel information regarding the clinical correlates of hypomimia in people with PD. A better understanding of hypomimia may be relevant for improving treatment and quality of life in PD.

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Authors:
L. Ricciardi, A. De Angelis, L. Marsili, I. Faiman, P. Pradhan, E. A. Pereira, M. J. Edwards, F. Morgante and M. Bologna
Article first published online:
20 Aug 2020 | DOI: 10.1111/ene.14452

Original Article

Background and purpose

Haemorrhagic transformation (HT) is one of the main risks of intravenous thrombolysis (IVT) for acute ischaemic stroke. Contraindications serve to exclude patients at high risk of HT after IVT. One of these contraindications is a stroke within the preceding 3 months. It is unclear if this contraindication should include recent clinically silent infarcts (RSIs). The aim of this study was to investigate whether RSIs are associated with a higher risk of HT and a worse clinical outcome after IVT for acute ischaemic stroke.

Methods

In a retrospective monocentric cohort study, all patients who received IVT for acute ischaemic stroke based on magnetic resonance imaging were assessed over 5 years. RSIs were defined as lesions with diffusion restriction and positive signal on fluid attenuated inversion recovery sequences. Patients with RSIs (RSI+) were compared to patients without RSIs (RSI−) regarding HT after IVT and clinical outcome.

Results

In all, 981 patients who had received IVT for acute ischaemic stroke demonstrated by magnetic resonance imaging were identified. RSIs were detected in 115 patients (11.5%). HT after IVT was observed in 32 (28.3%) RSI+ and 56 (25.8%) RSI− patients ( = 0.624). Symptomatic intracerebral haemorrhage was noted in two (1.8%) RSI+ and five (2.3%) RSI− patients ( = 1.000). No differences in clinical outcome were observed.

Conclusions

The detection of RSIs in patients treated with IVT for acute ischaemic stroke was not associated with a higher risk of HT or a worse clinical outcome. The results of this study argue against considering RSIs as a contraindication for IVT.

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Authors:
S. Stösser, L. Ullrich, J. Kassubek, A. C. Ludolph, M. Schocke and H. Neugebauer
Article first published online:
13 Aug 2020 | DOI: 10.1111/ene.14453

Original Article

Background and purpose

Unexpected stressful life events may alter immune function and affect susceptibility to autoimmune diseases including multiple sclerosis (MS). Current results from epidemiological investigations examining the role of stress in MS remain inconsistent. The aim was to conduct the hitherto largest population‐based case–control study on this topic.

Methods

Extensive questionnaire information collected on lifestyle environmental factors available for 2930 incident MS cases and 6170 controls were used to assess the association of 10 major life events that had occurred before disease onset with the risk of MS by unconditional logistic regressions, adjusting for potential confounders. Stratified analyses were also performed by sex and time.

Results

Compelling evidence was found for a link between major life events and risk of MS – most events significantly increased disease risk by 17%–30%. It was further observed that women were affected to a greater extent than men under certain stressful scenarios, and that most events that happened recently (≤5 years prior to MS onset) had significant effects on MS, indicating a critical window in disease development.

Conclusion

Stressful life events may have an adverse effect on the risk of MS. Research into the mechanisms of this observation may give important clues to triggering pathogenetic events in MS.

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Authors:
X. Jiang, T. Olsson, J. Hillert, I. Kockum and L. Alfredsson
Article first published online:
23 Aug 2020 | DOI: 10.1111/ene.14458

Letters to the Editor

Response to Finsterer and colleagues on ‘Prospective studies on the efficacy of rituximab for myasthenia gravis are warranted’

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Authors:
A. Dos Santos, Y. Pereon, S. Wiertlewski and A. Magot
Article first published online:
04 Sep 2020 | DOI: 10.1111/ene.14460

Letters To The Editor

Prospective studies on the efficacy of rituximab for myasthenia gravis are warranted

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Authors:
J. Finsterer, F. A. Scorza and C. A. Scorza
Article first published online:
24 Aug 2020 | DOI: 10.1111/ene.14461

Original Article

Background and purpose

Charcot–Marie–Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of whilst point mutations in and other genes are rare causes. Recently, mutations have been reported in CMT1 families.

Methods

Individuals with ‐associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients’ visits at our centres or primary care sites.

Results

Nineteen CMT1 families containing 38 carriers of three different missense variants were identified and a mutational hotspot at c.1117C>T (p.Arg373Cys) was confirmed. Compared to patients with the common duplication, individuals with variants had a later age of diagnosis (third to fifth decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits.

Conclusions

Our study confirms the relevance of mutations in CMT1. It is proposed to include in the genetic work‐up of individuals suspected with CMT1, particularly when diagnosis is established beyond the first and second decade and comparably moderate motor deficits contrast with early and marked sensory involvement. ‐associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme.

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Authors:
D. Safka Brozkova, T. Stojkovic, J. Haberlová, R. Mazanec, R. Windhager, P. Fernandes Rosenegger, S. Hacker, S. Züchner, A. Kochański, S. Leonard‐Louis, B. Francou, P. Latour, J. Senderek, P. Seeman and M. Auer‐Grumbach
Article first published online:
05 Sep 2020 | DOI: 10.1111/ene.14463

Original Article

Background and purpose

Spain has been one of the countries more heavily stricken by SARS‐CoV‐2, which has had huge implications for stroke care. The aim was to analyse the impact of the COVID‐19 epidemic outbreak on reperfusion therapies for acute ischaemic stroke in the northwest of Spain.

Methods

This was a Spanish multicentre retrospective observational study based on data from tertiary hospitals of the NORDICTUS network. All patients receiving reperfusion therapy for ischaemic stroke between 30 December 2019 and 3 May 2020 were recorded, and their baseline, clinical and radiological characteristics, extra‐ and intra‐hospital times of action, Code Stroke activation pathway, COVID‐19 status, reperfusion rate, and short‐term outcome before and after the setting of the emergency state were analysed.

Results

A total of 796 patients received reperfusion therapies for ischaemic stroke. There was a decrease in the number of patients treated per week (46.5 patients per week vs. 39.0 patients per week,  = 0.043) and a delay in out‐of‐hospital (95.0 vs. 110.0 min,  = 0.001) and door‐to‐needle times (51.0 vs. 55.0,  = 0.038). Patients receiving endovascular therapy obtained less successful reperfusion rates (92.9% vs. 86.6%,  = 0.016). COVID‐19 patients had more in‐hospital mortality.

Conclusion

A decrease in the number of patients benefiting from reperfusion therapies was found, with a delay in out‐of‐hospital and door‐to‐needle times and worse reperfusion rates in northwest Spain. COVID‐19 patients had more in‐hospital mortality.

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Authors:
H. Tejada Meza, Á. Lambea Gil, A. Sancho Saldaña, M. Martínez‐Zabaleta, E. Garmendia Lopetegui, E. López‐Cancio Martínez, M. Castañón Apilánez, M. Herrera Isasi, J. Marta Enguita, B. Gómez‐Vicente, J.F. Arenillas, N. Arenaza Basterrechea, J.J. Timiraos Fernández, J. Sánchez Herrero, J.L. Maciñeiras Montero, M. Castellanos Rodrigo, D. Fernández‐Coud, I. Casado Menéndez, M.T. Temprano Fernández, M. Freijo, A. Luna, E.J. Palacio Portilla, Y. Jiménez López, E. Rodríguez‐Castro, M. Rodríguez‐Yáñez, J. Tejada García, I. Beltrán Rodríguez, F. Julián‐Villaverde, M.P. Moreno García, J.M. Trejo Gabriel‐Galán, A. Echavarría Iñiguez, C. Pérez Lázaro, M.P. Navarro Pérez and J. Marta Moreno
Article first published online:
04 Sep 2020 | DOI: 10.1111/ene.14467

Original Article

Background and purpose

Diabetic polyneuropathy (DPN) is a common complication of diabetes. Using the Toronto criteria for diabetic polyneuropathy and the grading system for neuropathic pain, the performance of neuropathy scales and questionnaires were assessed by comparing them to a clinical gold standard diagnosis of DPN and painful DPN in a cohort of patients with recently diagnosed type 2 diabetes.

Methods

A questionnaire on neuropathy and pain was sent to a cohort of 5514 Danish type 2 diabetes patients. A sample of 389 patients underwent a detailed clinical examination and completed neuropathy questionnaires and scales.

Results

Of the 389 patients with a median diabetes duration of 5.9 years, 126 had definite DPN (including 53 with painful DPN), 88 had probable DPN and 53 had possible DPN. There were 49 patients with other causes of polyneuropathy, neuropathy symptoms or pain, 10 with subclinical DPN and 63 without DPN. The sensitivity of the Michigan Neuropathy Screening Instrument questionnaire to detect DPN was 25.7% and the specificity 84.6%. The sensitivity of the Toronto Clinical Neuropathy Scoring System, including questionnaire and clinical examination, was 62.9% and the specificity was 74.6%.

Conclusions

Diabetic polyneuropathy affects approximately one in five Danish patients with recently diagnosed type 2 diabetes but neuropathic pain is not as common as previously reported. Neuropathy scales with clinical examination perform better compared with questionnaires alone, but better scales are needed for future epidemiological studies.

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Authors:
S. S. Gylfadottir, M. Itani, T. Krøigård, A. G. Kristensen, D. H. Christensen, S. K. Nicolaisen, P. Karlsson, B. C. Callaghan, D. L. Bennett, H. Andersen, H. Tankisi, J. S. Nielsen, N. T. Andersen, T. S. Jensen, R. W. Thomsen, S. H. Sindrup and N. B. Finnerup
Article first published online:
09 Sep 2020 | DOI: 10.1111/ene.14469

Original Article

Background and purpose

The prevalence of fatigue and its relation with clinical, neuropsychological and brain magnetic resonance imaging (MRI) variables in a large cohort of multiple sclerosis (MS) patients was investigated.

Method

The Modified Fatigue Impact Scale and its subdomains were collected from 725 healthy controls and 366 MS patients [238 relapsing–remitting (RRMS) and 128 progressive (PMS)]. For the Modified Fatigue Impact Scale global and subdomains, MS patients were classified as fatigued (F‐MS) or non‐fatigued (NF‐MS) according to cut‐off values provided by logistic regression models with a specificity of 90% (i.e. a 10% false‐positive rate in classifying healthy controls). MS patients underwent neurological, neuropsychological and MRI evaluations. Clinical and MRI measures were compared between F‐MS and NF‐MS patients using age‐, sex‐ and phenotype‐adjusted linear models. Heterogeneities between phenotypes were tested with specific interaction terms.

Results

Global fatigue affected 174 (47.5%) MS patients, being more prevalent in PMS (PMS 64.1% vs. RRMS 38.7%,  < 0.001). For all dichotomizations, F‐MS were older ( from <0.001 to 0.012) and more depressed ( < 0.001) than NF‐MS patients. Compared to NF‐MS, cognitive F‐MS patients had lower education ( = 0.035). Compared to NF‐MS, patients with global and physical fatigue had higher Expanded Disability Status Scale only for RRMS ( < 0.001). Only RRMS patients with physical fatigue had lower brain ( = 0.05), white matter ( = 0.039) and thalamic volumes ( = 0.022) compared to NF‐MS patients.

Conclusions

In MS, fatigue is associated with older age, lower education and higher depression. Only in RRMS, fatigue is associated with Expanded Disability Status Scale and brain atrophy. A plateauing effect of disability and structural damage can explain the lack of associations in PMS.

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Authors:
O. Marchesi, C. Vizzino, A. Meani, L. Conti, G. C. Riccitelli, P. Preziosa, M. Filippi and M. A. Rocca
Article first published online:
06 Sep 2020 | DOI: 10.1111/ene.14471

Original Article

Background and purpose

In patients with spinal muscular atrophy (SMA), functional disease scores are frequently used to evaluate the course of the disease and the efficacy of treatment. The aim of the present study was to propose minimal clinically important difference (MCID) values for motor scores in order to estimate the degree of change within a functional score that can be considered clinically meaningful.

Methods

To estimate the MCID, distribution‐based approaches were used. For each assessment [Revised Upper Limb Module (RULM), Hammersmith Functional Motor Scale Expanded (HFMSE) and 6‐min walk test (6MWT)] and subgroup (SMA type 2, SMA type 3, ambulatory and non‐ambulatory), the following MCID values based on a cohort of 51 adults with SMA were calculated: standard error of measurement (SEm), one‐half of standard deviation (1/2 SD) and one‐third of standard deviation (1/3 SD) of patients' baseline scores.

Results

For the overall cohort, the SEm, 1/2 SD and 1/3 SD MCID values were 2.9, 6.4 and 4.3 for the RULM and 4.3, 10.6 and 7.0 for the HFMSE, respectively. Subgroup analysis led to generally lower standard deviations and consecutively lower MCID values due to the significantly different motor functions of the groups. The respective MCID values for the 6MWT were 55.5 m, 71.1 m and 47.8 m.

Conclusions

Our data provide MCID values for functional motor scores commonly used in adults with SMA in order to distinguish statistical effects from ‘real’ changes. A complementary systematic consensus process could help to further adjust the MCID values we propose.

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Authors:
B. Stolte, J.‐M. Bois, S. Bolz, K. Kizina, A. Totzeck, M. Schlag, C. Kleinschnitz and T. Hagenacker
Article first published online:
06 Sep 2020 | DOI: 10.1111/ene.14472

Letters To The Editor

Movement disorders as a new neurological clinical picture in severe SARS‐CoV‐2 infection

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Authors:
P. Cuhna, B. Herlin, K. Vassilev, A. Kas, S. Lehericy, Y. Worbe, E. Apartis, M. Vidailhet and S. Dupont
Article first published online:
14 Sep 2020 | DOI: 10.1111/ene.14474

Original Article

Background and purpose

Monitoring of the disease course of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) remains challenging because nerve conduction studies do not adequately correlate with functional disability. The prognostic value of pathological spontaneous activity (PSA) in needle electromyography (EMG) in different CIDP subgroups in a longitudinal context has, to date, not been analysed. We aimed to determine whether PSA was a prognostic marker or a marker of disease activity in a cohort of patients with CIDP.

Methods

A total of 127 patients with CIDP spectrum disorder were retrospectively analysed over 57 ± 47 months regarding the occurrence of PSA (fibrillations and positive sharp waves). The presence of PSA at diagnosis, newly occurring PSA, and continuously present PSA were longitudinally correlated with clinical disability using the Inflammatory Neuropathy Cause and Treatment Overall Disability Sum Score (INCAT‐ODSS) and CIDP subtype.

Results

Pathological spontaneous activity occurred in 49.6% of all CIDP patients at first diagnosis. More frequent evidence of PSA was significantly associated with a higher INCAT‐ODSS at the last follow‐up. Continuous and new occurrence of PSA were associated with higher degree of disability at the last follow‐up. The majority of patients with sustained evidence of PSA were characterized by an atypical phenotype, higher degree of disability, and the need for escalation of treatment.

Conclusions

Pathological spontaneous activity was associated with a higher degree of disability and occurred more frequently in atypical CIDP variants according to the longitudinal data of a large cohort of patients with CIDP. Our results showed that EMG examination was an adequate marker for disease progression and should be evaluated during the disease course.

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Authors:
T. Grüter, J. Motte, A. L. Fisse, Y. Bulut, N. Köse, D. Athanasopoulos, S. Otto, M. ‐S. Yoon, C. Schneider‐Gold, R. Gold and K. Pitarokoili
Article first published online:
09 Sep 2020 | DOI: 10.1111/ene.14476

Original Article

Background and purpose

The aim was to describe the profiles of hemorrhagic patterns of moyamoya disease (MMD) and analyze the risk factors in a large population.

Methods

A total of 335 conservatively managed MMD patients with hemorrhage in our hospital were included in this cross‐sectional study. The correlation between clinical and angiographic characteristics and hemorrhagic patterns (anterior or posterior hemorrhage) was assessed in the hemorrhagic hemisphere by univariate and multivariate logistic regression models. In addition, stratified analysis was performed.

Results

The 335 hemorrhagic hemispheres (patients) comprised 179 (53.4%) anterior and 156 (46.6%) posterior hemorrhages. For all cases, age at onset [odds ratio (OR) 0.98; 95% confidence interval (CI) 0.96–1.00;  = 0.048] and choroidal anastomosis (OR 1.87; 95% CI 1.19–2.94; 0.007) were found by multivariate regression analysis to be negatively and positively associated with a significantly increased risk of posterior hemorrhage, respectively. After stratified analysis, hypertension (OR 0.37; 95% CI 0.14–0.97; 0.043) was identified by multivariate regression analysis as a risk factor for anterior hemorrhage in patients without dilation of choroidal anastomosis. On the other hand, choroidal anastomosis (OR 2.62; 95% CI 1.02–6.72; 0.045) and involvement of the posterior cerebral artery (OR 3.39; 95% CI 1.20–9.63; 0.022) were associated with significantly increased risk of posterior hemorrhage in children and young adults (<30 years of age).

Conclusions

A dynamic change in hemorrhagic patterns in MMD patients with increasing age at onset was observed. Choroidal anastomosis is a predictor of posterior hemorrhage. Hypertension is a risk factor for anterior hemorrhage in patients without extreme dilation of choroidal anastomosis.

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Authors:
Q. Zhang, M. Zhao, P. Ge, X. Liu, R. Wang, Y. Zhang, D. Zhang and J. Zhao
Article first published online:
12 Oct 2020 | DOI: 10.1111/ene.14477

Short Communications

Aim

The aim of this paper is to describe the clinical features of COVID‐19‐related encephalopathy and their metabolic correlates using brain 2‐desoxy‐2‐fluoro‐D‐glucose (FDG)‐positron‐emission tomography (PET)/computed tomography (CT) imaging.

Background and purpose

A variety of neurological manifestations have been reported in association with COVID‐19. COVID‐19‐related encephalopathy has seldom been reported and studied.

Methods

We report four cases of COVID‐19‐related encephalopathy. The diagnosis was made in patients with confirmed COVID‐19 who presented with new‐onset cognitive disturbances, central focal neurological signs, or seizures. All patients underwent cognitive screening, brain magnetic resonance imaging (MRI), lumbar puncture, and brain 2‐desoxy‐2‐fluoro‐D‐glucose (FDG)‐positron‐emission tomography (PET)/computed tomography (CT) (FDG‐PET/CT).

Results

The four patients were aged 60 years or older, and presented with various degrees of cognitive impairment, with predominant frontal lobe impairment. Two patients presented with cerebellar syndrome, one patient had myoclonus, one had psychiatric manifestations, and one had status epilepticus. The delay between first COVID‐19 symptoms and onset of neurological symptoms was between 0 and 12 days. None of the patients had MRI features of encephalitis nor significant cerebrospinal fluid (CSF) abnormalities. SARS‐CoV‐2 RT‐PCR in the CSF was negative for all patients. All patients presented with a consistent brain FDG‐PET/CT pattern of abnormalities, namely frontal hypometabolism and cerebellar hypermetabolism. All patients improved after immunotherapy.

Conclusions

Despite varied clinical presentations, all patients presented with a consistent FDG‐PET pattern, which may reflect an immune mechanism.

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Authors:
C. Delorme, O. Paccoud, A. Kas, A. Hesters, S. Bombois, P. Shambrook, A. Boullet, D. Doukhi, L. Le Guennec, N. Godefroy, R. Maatoug, P. Fossati, B. Millet, V. Navarro, G. Bruneteau, S. Demeret and V. Pourcher
Article first published online:
22 Sep 2020 | DOI: 10.1111/ene.14478

Original Article

Background and purpose

Stroke has detrimental effects in multiple health domains not captured by routine scales. The International Consortium for Health Outcome Measurement has developed a standardized set for self‐reported assessment to overcome this limitation. The aim was to assess this set in acute stroke care.

Methods

Consecutive patients with acute ischaemic stroke, transient ischaemic attack or intracerebral hemorrhage were enrolled. Demographics, living situation and cardiovascular risk factors were collected from medical records and interviews. The Patient‐reported Outcomes Measurement Information System 10‐Question Short Form (PROMIS‐10) and the Patient Health Questionnaire‐4 (PHQ‐4) were conducted 90 days after admission. Linear and logistic regression analyses were used to identify predictors of outcome. The study is registered at ClinicalTrials.gov, NCT03795948.

Results

In all, 1064 patients were enrolled; mean age was 71.6 years, 51% were female, and median National Institutes of Health Stroke Scale (NIHSS) on admission was 3. Diagnosis was acute ischaemic stroke in 74%, transient ischaemic attack in 20% and intracerebral hemorrhage in 6%. 673 patients were available for outcome evaluation at 90 days; of these 90 (13%) had died. In survivors, scores of PROMIS‐10 physical and mental health were 40.3 ± 6.17 and 44.3 ± 8.63, compared to 50 ± 10 in healthy populations. 16% reported symptoms indicating depression or anxiety on the PHQ‐4. Higher NIHSS, prior stroke and requiring help pre‐stroke predicted lower values in physical and mental health scores. Higher NIHSS and diabetes were associated with anxiety or depression.

Conclusions

Integrated in the routine of acute stroke care, systematic assessment of patient‐reported outcomes reveals impairments in physical and mental health. Main predictors are severity of stroke symptoms and comorbidities such as hypertension and diabetes.

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Authors:
D. L. Rimmele, L. Lebherz, M. Frese, H. Appelbohm, H.‐J. Bartz, L. Kriston, C. Gerloff, M. Härter and G. Thomalla
Article first published online:
07 Sep 2020 | DOI: 10.1111/ene.14479

Original Article

Background and purpose

There is a lack of comparative safety data on the risk of pseudotumor cerebri syndrome (PTCS) associated with different hormonal contraceptives. We sought to quantify the risk of PTCS associated with eight different types of hormonal contraceptives compared with oral levonorgestrel.

Methods

We conducted a retrospective cohort study, with a case–control analysis of 4 871 504 women aged 15–45 years in the period 2008–2015, using IQVIA Ambulatory Electronic Medical Records data in the USA. Patients who used nine different contraceptive agents including intrauterine levonorgestrel, medroxyprogesterone injection, etonogestrel/ethinyl estradiol vaginal ring and combination oral contraceptives (COCs) that contained ethinyl estradiol and the progestins levonorgestrel, norgestimate, desogestrel, norethindrone and drospirenone, were included. Diagnosis of PTCS was defined using the first International Classification of Diseases, 9th or 10th revision, code for intracranial hypertension in patients who had also received an imaging code in the 30 days prior to the index date.

Results

A total of 3323 PTCS cases and 13 292 matched controls were identified. No increase in risk was found when analysing intrauterine levonorgestrel or COCs containing desogestrel, norethindrone, drospirenone, norgestimate or norgestrel versus COC levonorgestrel. The adjusted incidence rate ratio for etonogestrel/etonogestrel/ethinyl estradiol vaginal ring and medroxyprogesterone suspension compared with levonorgestrel COC was 4.45 [95% confidence interval (CI) 1.98–9.96] and 2.20 (95% CI 1.33–3.64), respectively.

Conclusions

This study found an elevated risk for PTCS among users of etonogestrel vaginal ring and medroxyprogesterone suspension when compared with oral levonorgestrel. Future studies are needed to confirm these findings.

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Authors:
M. Etminan, F. Khosrow‐Khavar, M. Sodhi, B. Carleton, L. A. Magee, H. Tremlett, A. Kezouh and C. Sheldon
Article first published online:
04 Sep 2020 | DOI: 10.1111/ene.14480

Letters To The Editor

Neurexin‐3α‐associated autoimmune encephalitis: a case report of full recovery after rituximab therapy

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Authors:
P. A. Loehrer, C. I. Bien, A.‐E. Dusoi, L. Timmermann and O. J. Simon
Article first published online:
21 Sep 2020 | DOI: 10.1111/ene.14481

Original Article

Background and purpose

The importance of upper limb function in multiple sclerosis (MS) is increasingly recognized, especially for the evaluation of patients with progressive MS with reduced mobility. Two sensor‐engineered gloves, able to measure quantitatively the timing of finger opposition movements, were previously used to assess upper limb disability in MS. The aims of the present study were: (1) to confirm the association between glove‐derived variables and standard measures of MS disability in a larger cohort; (2) to assess the correlation with quantitative magnetic resonance imaging (MRI) and quality of life (QoL) measures; and (3) to determine if the glove‐derived variables offer advantages over the standard measure for assessing upper limb function in MS, namely, the Nine‐Hole Peg Test (9HPT).

Methods

Sixty‐five patients with MS, stable on disease‐modifying treatment, were evaluated at baseline using the glove, and through clinical examination (Expanded Disability Status Scale, Symbol Digit Modalities Test, Timed 25‐Foot Walk Test and 9HPT), MRI evaluation and QoL questionnaires. Correlations between the glove‐derived variables and clinical, MRI and QoL variables were assessed using Spearman's rank correlation coefficient analysis.

Results

Glove‐derived variables significantly differed between patients with relapsing‐remitting and those with progressive MS, with similar or slightly higher correlations of the 9HPT with clinical variables. We found greater correlations of the QoL physical component with glove‐derived variables than with the 9HPT, and a significant correlation of its mental component with the glove‐derived variables but not with the 9HPT.

Conclusion

The study results, confirming previous findings and showing advantages over the 9HPT, encourage the investigation of sensitivity to change in glove‐derived variables in a longitudinal setting.

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Authors:
L. Carmisciano, A. Signori, M. Pardini, G. Novi, C. Lapucci, L. Nesi, E. Gallo, A. Laroni, M. Cellerino, R. Meli, E. Sbragia, L. Filippi, A. Uccelli, M. Inglese and M. P. Sormani
Article first published online:
09 Sep 2020 | DOI: 10.1111/ene.14482

Original Article

Background and purpose

The purpose was to evaluate, in a consecutive series of patients with isolated acute retinal ischaemia, the proportion of patients with acute silent brain infarcts (SBIs) on diffusion‐weighted imaging (DWI) and to assess risk of recurrence within 3 months.

Methods

In all, 103 consecutive patients with isolated acute retinal ischaemia (central retinal artery occlusion, branch retinal artery occlusion or transient monocular vision loss) were included between January 2015 and December 2016. They all had cerebral magnetic resonance imaging including DWI as well as a standardized aetiological workup and 3 months of follow‐up. The presence of DWI‐positive cerebral lesions was recorded. Main clinical and radiological characteristics between DWI‐positive and DWI‐negative patients were compared.

Results

Of the 103 patients (including 42 transient monocular vision loss), 20 (19.5%) had SBIs on DWI, which were ipsilateral to the acute retinal ischaemia in 30% and involved different and/or multiple vascular territories in 70% of cases. Ipsilateral carotid stenosis and occlusion were respectively identified in 17 and eight patients whereas cardioaortic embolism was found in 19 patients. Overall, patients with and without acute SBIs were comparable. The topography of SBIs was related to the aetiology of the acute retinal ischaemia. At 3 months of follow‐up, one patient suffered from ischaemic stroke and five had recurrent retinal ischaemia.

Conclusions

Irrespective of the baseline characteristics of the patients, SBIs are present in about 20% of patients with isolated acute retinal ischaemia and may be of interest in the aetiological workup. Overall risk of recurrence is low, favoured by rapid aetiological workup and appropriate treatment.

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Authors:
X. Ayrignac, C. Zagroun, A. Coget, S. Azakri, N. Menjot de Champfleur, A. L. Montcriol, P. Labauge, I. Mourand, A. Ducros, V. Daïen and C. Arquizan
Article first published online:
06 Sep 2020 | DOI: 10.1111/ene.14485

Original Article

Background and purpose

Acquired hepatocerebral degeneration (AHD) and hepatic encephalopathy (HE) are neurological complications of chronic liver disease (CLD) with portosystemic shunt. While HE is common, AHD is a rare entity, and the clinical imaging relationships observed in small series lack validation in large patient cohorts. The aim of this study was to characterize a cohort of AHD patients and to explore possible associations with HE coexistence.

Methods

We performed a retrospective analysis of patients with a working AHD diagnosis, between 2008 and 2019. Clinical, laboratory, imaging and neuropsychological results at first neurological observation were reviewed and compared between the 'AHD' group and the 'AHD with HE' group.

Results

A total of 76 patients were recruited. The most frequent neurological manifestations were neuropsychiatric (93.4%) and extrapyramidal (84.2%). Only 38% of patients had hypermanganesemia. Compared with the AHD group, the AHD with HE group had more hyperkinetic movement disorders (71.4% vs. 38.5%;  = 0.05), a higher number of patients on the dementia spectrum (57.7% vs. 20%;  = 0.04), higher median ammonia levels ( = 0.014) and more widespread cortico‐subcortical and pyramidal involvement on brain magnetic resonance imaging. Nineteen patients underwent liver transplantation, with significantly improved survival ( = 0.006).

Discussion

Hepatic encephalopathy and AHD often coexist in the same patient. Seventy‐six patients with CLD and AHD were evaluated, making this one of the largest reported AHD cohorts. Blood manganese level was a weak diagnostic marker in AHD. Early liver function restoration through liver transplantation improved survival. Our report provides a detailed description of the phenotype and long‐term outcome of AHD, with relevance for diagnosis and treatment.

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Authors:
M. J. Malaquias, C. M. Pinto, C. Ramos, S. Ferreira, J. Gandara, A. Almeida, S. Cavaco, H. P. Miranda and M. Magalhães
Article first published online:
09 Sep 2020 | DOI: 10.1111/ene.14486

Case Study

Facial nerve palsy: an atypical clinical manifestation of COVID‐19 infection in a family cluster

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Authors:
C. Derollez, T. Alberto, I. Leroi, M.‐A. Mackowiak and Y. Chen
Article first published online:
08 Nov 2020 | DOI: 10.1111/ene.14493

Corrigendum

Using machine learning to predict stroke‐associated pneumonia in Chinese acute ischaemic stroke patients

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Authors:
Article first published online:
08 Nov 2020 | DOI: 10.1111/ene.14495

Short Communication

Background and purpose

Cranial nerve palsy is occasionally present in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), but its prevalence, characteristics and relations with the CIDP subtypes have rarely been investigated. The aim of this study was to systematically assess cranial nerve involvement in typical and atypical CIDP.

Methods

Clinical data were reviewed in 132 consecutive patients with CIDP, including typical CIDP ( = 89), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) ( = 31), distal acquired demyelinating symmetric (DADS) ( = 9) and others ( = 3).

Results

The frequency of cranial nerve palsy was 11% in typical CIDP, 48% in MADSAM and 11% in DADS. Facial and bulbar palsy was most frequently present (9%), followed by ocular motor nerve palsy (5%). Bilateral involvement was seen in all typical CIDP and DADS patients, whereas 80% of MADSAM patients had unilateral palsy. The presence of cranial nerve involvement was associated with more severe limb muscle weakness in typical CIDP, but not in MADSAM. Cranial nerve palsy fully recovered in 90% of typical CIDP and in 67% of MADSAM patients.

Conclusion

Amongst the CIDP subtypes, cranial palsy is frequent and unilateral in MADSAM, and less frequent and bilateral in typical CIDP and DADS. In typical CIDP, facial and bulbar palsy reflects more severe and extensive inflammation.

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Authors:
K. Shibuya, A. Tsuneyama, S. Misawa, T. Suichi, Y. Suzuki, Y. Kojima, K. Nakamura, H. Kano, M. Prado and S. Kuwabara
Article first published online:
23 Sep 2020 | DOI: 10.1111/ene.14497

Case Study

Abstract

Rituximab (RTX), a chimeric anti‐CD20 monoclonal antibody, has demonstrated good efficacy as treatment in patients with resistant chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but it is highly immunogenic due to its structure. Ocrelizumab (OCR) is a humanized anti‐CD20 antibody, with higher tolerability and a lower immunogenic profile compared to RTX. We present a case of refractory CIDP effectively treated with OCR, switched from RTX after the development of anti‐drug antibodies. A 25‐year‐old man was admitted to our clinic for the onset of distal upper and lower limb weakness and numbness, with electrodiagnostic criteria of CIDP. After several attempted standard CIDP treatments, RTX was introduced due to poor control of clinical relapses. Unfortunately, the patient developed a high anti‐drug antibody titer after RTX infusion, with no control of disease. OCR was started as an off‐label treatment, resulting in partial recovery from the last recurrence and achieving good prevention of new relapses with no adverse events. We suggest that OCR should be considered as another therapeutic option in refractory CIDP. In the literature, this is the first case of CIDP treated with OCR, demonstrating good efficacy for its anti‐CD20 effect and better tolerability because of its lower immunogenicity.

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Authors:
S. Casertano, E. Signoriello, F. Rossi, A. Di Pietro, F. Tuccillo, S. Bonavita and G. Lus
Article first published online:
08 Nov 2020 | DOI: 10.1111/ene.14498

Letter To The Editor

Migraine symptoms and the role of autonomic dysfunction

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Authors:
A. Celikbilek
Article first published online:
21 Sep 2020 | DOI: 10.1111/ene.14504

Short Communication

Background and purpose

Mutations in the gene are the most common cause of autosomal‐dominant Alzheimer’s disease and have been associated with the earliest disease onset. We describe an unusual presentation of the rare mutation with a late age of onset, and we provide for the first time pathological evidence for this mutation.

Methods

A 71‐year‐old female patient with progressive cognitive decline in the past 3 years and positive family history for dementia underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid‐positron emission tomography (PET) and extensive genetic screening with a next‐generation sequencing technique.

Results

The diagnostic workup revealed mixed behavioural and amnestic disease features on neuropsychological tests, magnetic resonance imaging, and 18‐fluorodeoxyglucose (FDG)‐PET. Amyloid‐PET detected amyloid deposition in the frontal areas, in the parietal lobes and the precunei. The genetic screening revealed the presence of the rare mutation in the gene.

Conclusions

Extensive genetic screening is also advisable for late‐onset presentations of Alzheimer’s disease, especially in the presence of a positive family history or atypical clinical features.

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Authors:
M. Scarioni, A. Arighi, C. Fenoglio, F. Sorrentino, M. Serpente, E. Rotondo, M. Mercurio, G. Marotta, A. A. Dijkstra, Y. A. L. Pijnenburg, E. Scarpini and D. Galimberti
Article first published online:
12 Oct 2020 | DOI: 10.1111/ene.14506

Short Communications

Background and purpose

Investigating mutation carriers with Dutch‐type hereditary (D‐) cerebral amyloid angiopathy (CAA), offers the possibility to identify markers in pre‐ and symptomatic stages of CAA. Optical coherence tomography (OCT) has shown potential to detect retinal changes in several neurodegenerative diseases. The aim of the present exploratory study was to investigate thinning of retinal layers as a possible (early) biomarker in D‐CAA mutation carriers.

Methods

Twenty‐one D‐CAA mutation carriers ( = 8 presymptomatic,  = 13 symptomatic, median age 50 years) and nine controls (median age 53 years) were scanned using spectral‐domain OCT. Symptomatic mutation carriers were defined as having a history of ≥1 symptomatic intracerebral hemorrhage. D‐CAA mutation carriers and controls were recruited from our D‐CAA cohort and a healthy control cohort. Total peripapillary retinal nerve fiber layer (pRNFL) thickness, six regions of pRNFL, total macular volume (TMV), and individual macular region thickness were measured and analysed, adjusted for age.

Results

The overall median (interquartile range) thickness of pRNFL was lower in symptomatic, but not presymptomatic D‐CAA mutation carriers compared with controls [91 (86–95) µm vs. 99 (87–108) µm;  = 0.006]. Both presymptomatic [111 (93–122) µm vs. 131 (123–143) µm;  < 0.001] and symptomatic carriers [119 (95–128) µm vs. 131 (123–143) µm;  = 0.034] had a thinner temporal‐superior quadrant of the pRNFL versus controls. TMV or individual macular layer thickness did not differ between carriers and controls.

Conclusions

Thinning of the retinal nerve fiber layer may be a candidate marker of disease in hereditary CAA. Further studies are needed to determine whether retinal thinning is present in sporadic CAA and estimate its value as a marker for disease progression.

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Authors:
E. S. van Etten, I. de Boer, S.R. Steenmeijer, M. Al‐Nofal, M. J. H. Wermer, I. C. Notting and G. M. Terwindt
Article first published online:
05 Oct 2020 | DOI: 10.1111/ene.14507

Short Communications

Background and purpose

Comorbidity of acute ischaemic stroke with Covid‐19 is a challenging condition, potentially influencing the decision of whether to administer intravenous thrombolysis (IVT). We aimed to assess the 1‐month outcome in ischaemic stroke patients with Covid‐19 infection who received IVT alone or before thrombectomy (bridging therapy).

Methods

As a collaboration initiative promoted by the Italian Stroke Organization, all Italian stroke units ( = 190) were contacted and invited to participate in data collection on stroke patients with Covid‐19 who received IVT.

Results

Seventy‐five invited centers agreed to participate. Thirty patients received IVT alone and 17 received bridging therapy between 21 February 2020 and 30 April 2020 in 20 centers ( = 18, Northern Italy;  = 2, Central Italy). At 1 month, 14 (30.4%) patients died and 20 (62.5%) survivors had a modified Rankin Scale (mRS) score of 3 to 5. At 24 to 36 hours, asymptomatic intracerebral hemorrhage (ICH) was reported in eight (17.4%) patients and symptomatic ICH (sICH) in two (4.3%) patients. Causes of death were severe ischaemic stroke ( = 8), a new ischaemic stroke ( = 2), acute respiratory failure ( = 1), acute renal failure ( = 1), acute myocardial infarction ( = 1), and endocarditis ( = 1). In survivors with a 1‐month mRS score of 3 to 5, baseline glucose level was higher, whereas endovascular procedure time in cases of bridging therapy was longer. Baseline National Institutes of Health Stroke Scale glucose and creatinine levels were higher in patients who died.

Conclusions

Intravenous thrombolysis for patients with stroke and Covid‐19 was not a rare event in the most affected areas by pandemic, and rates of 1‐month unfavorable outcomes were high compared to previous data from the pre–Covid‐19 literature. However, risk of sICH was not increased.

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Authors:
M. Cappellari, A. Zini, D. Sangalli, A. Cavallini, M. Reggiani, F. N. Sepe, N. Rifino, G. Giussani, D. Guidetti, M. Zedde, S. Marcheselli, M. Longoni, S. Beretta, V. Sidoti, D. M. Papurello, A. Giossi, P. Nencini, M. Plocco, M. Balestrino, E. Rota and D. Toni
Article first published online:
15 Oct 2020 | DOI: 10.1111/ene.14511

Short Communication

Background and purpose

Mutations in the early growth response 2 gene () cause demyelinating, but also axonal, neuropathies differing in severity and age of onset. Except for one family, all reported cases have autosomal dominant inheritance and mutations are localized within the three zinc finger (ZNF) DNA‐binding domain. The aim of this study was to provide a clinical and molecular analysis of a novel recessive mutation in EGR2.

Methods

Clinical and electrophysiological assessments of three affected patients, from a consanguineous family, were performed. Genetic analyses of were carried out by Sanger sequencing. Functional effects of clinical recessive mutations were assessed using a mammalian two‐hybrid assay.

Results

A novel missense mutation (c.791C>T; p.P264L) in the homozygous state was detected outside the ZNF domains of the gene. Three affected siblings presented with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. Respiratory compromise and cranial nerve dysfunction were also found. Our data indicate that the p.P264L mutation prevents interaction of EGR2 transcription factor with NAB corepressors, suggesting that a disruption of the NAB‐EGR2 protein interactions can result in dramatic neuropathy.

Conclusion

Mutations in, or next to, the R1 domain of EGR2 should be considered with extreme caution for genetic counseling, since these could cause a severe neuropathy with an autosomal recessive manner of transmission.

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Authors:
V. Lupo, S. Won, M. Frasquet, M. S. Schnitzler, S. S. Komath, S. I. Pascual‐Pascual, C. Espinós, J. Svaren and T. Sevilla
Article first published online:
27 Sep 2020 | DOI: 10.1111/ene.14512

Short Communication

Background and purpose

Endovascular therapy (EVT) has become standard care for acute ischaemic stroke caused by large‐vessel occlusion in the anterior circulation. However, access to this treatment in Europe remains poor. The lack of operators is a contributing factor and there is on‐going discussion as to whether other specialists, including neurologists, could contribute to the EVT workforce. The question remains whether the next generation of neurologists to become ‘interventional neurologists’. The aim of this study was to address this question.

Methods

We conducted a short survey within the National Representatives Network (a division of the Resident and Research Fellow Section, European Academy of Neurology) in order to determine the interest of future neurologists in performing EVT.

Results

A total of 1218 responses from 27 European countries were received, with some variation in the number of respondents and results among individual countries. In total, 568 neurology trainees (47%) stated that they would want to be an ‘interventional neurologist’.

Conclusion

Our findings suggest that neurologists could make a significant contribution to the workforce performing EVT and have important implications for the development and uptake of training programmes in Europe.

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Authors:
D. R. Schreier, F. Di Lorenzo, F. Iodice and S. Shribman
Article first published online:
04 Oct 2020 | DOI: 10.1111/ene.14519

Case Study

Background

Coronavirus disease 2019 (COVID‐19) typically presents with respiratory illness ranging in severity. Neurological complications of the disease remain largely unknown. Herein, we discuss the case of a woman diagnosed with COVID‐19 meningitis following two positive cerebrospinal fluid (CSF) RT‐PCR assays, and highlight the importance of recognizing the neurological manifestations of the disease.

Case report

The patient was a 49‐year‐old woman with a history of hypertension who presented with non‐specific symptoms (fever, headache, malaise, nausea/vomiting). Chest computed tomography (CT) revealed a lack of pulmonary involvement and oropharyngeal/nasopharyngeal RT‐PCR was negative for COVID‐19. A lumbar puncture was performed on the third day of admission and the CSF analysis elucidated a viral pattern, but the CSF bacterial culture and RT‐PCR assay for herpes simplex virus were both negative. Surprisingly, the CSF RT‐PCR for COVID‐19 was positive. The diagnosis of COVID‐19 meningitis was made and the patient was treated solely with Kaletra, with a second CSF analysis confirming our unique finding 1 week later. The patient's clinical characteristics improved progressively, and she was discharged in excellent general condition after 21 days.

Conclusion

In contrast to what was originally believed, the SARS‐CoV‐2 can cause meningitis in isolation, perhaps by crossing the blood‐brain barrier. Hence, it seems essential that physicians maintain a high index of suspicion for neurological involvement among COVID‐19 patients, with early CSF analysis and brain imaging sometimes being indicated.

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Authors:
Z. Khodamoradi, S. A. Hosseini, M. H. Gholampoor Saadi, Z. Mehrabi, M. R. Sasani and S. Yaghoubi
Article first published online:
08 Nov 2020 | DOI: 10.1111/ene.14536