cover image European Journal of Neurology

European Journal of Neurology

2023 - Volume 30
Issue 1 | January 2023
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Article first published online:
14 Dec 2022 | DOI: 10.1111/ene.15392

REVIEW ARTICLE

Background and purpose

Primary Sjögren syndrome (pSS) is a chronic, systemic, autoimmune disorder characterized by lymphocytic infiltrates of the exocrine organs, leading to sicca symptoms and parotid enlargement. pSS has been linked to various neurological manifestations, including peripheral neuropathy (PN). We aimed to provide a comprehensive analysis of the currently available evidence regarding pSS‐related PN.

Methods

A literature search in the PubMed database was performed, and 49 papers were eligible to be included in this systematic review and meta‐analysis.

Results

The pooled prevalence of PN in pSS is estimated to be 15.0% (95% confidence interval = 10.7%–20.7%). The mean age of pSS patients at PN diagnosis is 59 years. Among the patients with pSS and PN, 83% are females. Neuropathic symptoms usually precede or lead to the pSS diagnosis at a 2:1 ratio in patients with pSS‐related PN. The commonest type of pSS‐related PN is distal axonal polyneuropathy (80% of patients with pSS‐related PN), followed by sensory ganglionopathy. Peripheral and cranial mononeuropathies—particularly trigeminal—are also frequent. Risk factors for developing PN include increasing age and presence of vasculitis. Immune‐mediated pathogenetic mechanisms are discussed. Glucocorticoids are the most commonly used treatment option for managing pSS‐related PN, when associated with vasculitis, followed by the use of intravenous immunoglobulin.

Conclusions

PN is very common in pSS patients. Evidence on long‐term prognosis of PN in pSS is limited, and further research is needed. Research into the use of immunosuppressive medication in nonvasculitic neuropathies in the context of pSS merits further consideration.

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Authors:
Andreas Liampas, Konstantinos Parperis, Maria Faidra Erotocritou, Antonios Nteveros, Marianna Papadopoulou, Christos Moschovos, Mohammed Akil, Stefano Coaccioli, Georgios M. Hadjigeorgiou, Marios Hadjivassiliou and Panagiotis Zis
Article first published online:
23 Sep 2022 | DOI: 10.1111/ene.15555

ORIGINAL ARTICLE

Background and purpose

Human neuropathological studies indicate that the pontine nucleus Locus Coeruleus (LC) undergoes significant and early degeneration in Alzheimer's disease. This line of evidence alongside experimental data suggests that the LC functional/structural decay may represent a critical factor for Alzheimer's disease pathophysiological and clinical progression. In the present prospective study, we used Magnetic Resonance Imaging (MRI) with LC‐sensitive sequence (LC‐MRI) to investigate the LC involvement in Alzheimer's disease progression, and whether specific LC‐MRI features at baseline are associated with prognosis and cognitive performance in amnestic Mild Cognitive Impairment.

Methods

LC‐MRI parameters were measured at baseline by a template‐based method on 3.0‐T magnetic resonance images in 34 patients with Alzheimer's disease dementia, 73 patients with amnestic Mild Cognitive Impairment, and 53 cognitively intact individuals. A thorough neurological and neuropsychological assessment was performed at baseline and 2.5‐year follow‐up.

Results

In subjects with Mild Cognitive Impairment who converted to dementia ( = 32), the LC intensity and number of LC‐related voxels were significantly lower than in cognitively intact individuals, resembling those observed in demented patients. Such a reduction was not detected in Mild Cognitive Impairment individuals, who remained stable at follow‐up. In Mild Cognitive Impairment subjects converting to dementia, LC‐MRI parameter reduction was maximal in the rostral part of the left nucleus. Structural equation modeling analysis showed that LC‐MRI parameters positively correlate with cognitive performance.

Conclusions

Our findings highlight a potential role of LC‐MRI for predicting clinical progression in Mild Cognitive Impairment and support the key role of LC degeneration in the Alzheimer clinical .

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Authors:
Alessandro Galgani, Francesco Lombardo, Nicola Martini, Andrea Vergallo, Luca Bastiani, Harald Hampel, Hana Hlavata, Filippo Baldacci, Gloria Tognoni, Daniele De Marchi, Irene Ghicopulos, Sara De Cori, Francesca Biagioni, Carla Letizia Busceti, Roberto Ceravolo, Ubaldo Bonuccelli, Dante Chiappino, Gabriele Siciliano, Francesco Fornai, Nicola Pavese and Filippo Sean Giorgi
Article first published online:
03 Oct 2022 | DOI: 10.1111/ene.15556

ORIGINAL ARTICLE

Background and purpose

Incongruent beliefs about self‐localization in space markedly disturb patients' behavior. Spatial delusions, or reduplicative paramnesias, are characterized by a firm conviction of place reduplication, transformation, or mislocation. Evidence suggests they are frequent after right hemisphere lesions, but comprehensive information about their clinical features is lacking.

Methods

We prospectively screened 504 acute right‐hemisphere stroke patients for the presence of spatial delusions. Their behavioral and clinical features were systematically assessed. Then, we analyzed the correlation of their duration with the magnitude of structural disruption of belief‐associated functional networks. Finally, we described the syndrome subtypes and evaluated whether the clinical categorization would be predicted by the structural disruption of familiarity‐associated functional networks using an unsupervised ‐means clustering algorithm.

Results

Sixty patients with spatial delusions were identified and fully characterized. Most (93%) localized the misidentified places closer to home than the hospital. The median time duration was 3 days (interquartile range = 1–7 days), and it was moderately correlated with the magnitude of structural–functional decoupling of belief‐associated functional networks ( = 0.39,  = 0.02; beta coefficient regressing for lesion volume = 3.18,  = 0.04). Each clinical subtype had characteristic response patterns, which were reported, and representative examples were provided. Clustering based on structural disruption of familiarity‐ and unfamiliarity‐associated functional networks poorly matched the clinical categorization (lesion: Rand index = 0.47; structural disconnection: Rand index = 0.51).

Conclusions

The systematic characterization of the peculiar clinical features of stroke‐associated spatial delusions may improve the syndrome diagnosis and clinical approaches. The novel evidence about their neural correlates fosters the clarification of the pathophysiology of delusional misidentifications.

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Authors:
Pedro N. Alves, Ana C. Fonseca, Teresa Pinho‐e‐Melo and Isabel P. Martins
Article first published online:
29 Sep 2022 | DOI: 10.1111/ene.15557

ORIGINAL ARTICLE

Background and purpose

Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily‐ON therapeutic condition.

Methods

We performed a pre‐/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily‐ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed.

Results

We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2 ± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean = 2.3 at T1, 1.7 at T2, 1.2 at T3;  = 0.013). Posture and speech features did not show significant changes, whereas stride length ( = 0.049), turn duration ( = 0.001), and turn velocity ( = 0.024) significantly improved on doubling the levodopa infusion rate.

Conclusions

In a short‐term evaluation, the increase of LCIG dose can improve "dopa‐resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia.

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Authors:
Gabriele Imbalzano, Domiziana Rinaldi, Giovanna Calandra‐Buonaura, Manuela Contin, Federica Amato, Giulia Giannini, Luisa Sambati, Claudia Ledda, Alberto Romagnolo, Gabriella Olmo, Pietro Cortelli, Maurizio Zibetti, Leonardo Lopiano and Carlo Alberto Artusi
Article first published online:
12 Oct 2022 | DOI: 10.1111/ene.15558

ORIGINAL ARTICLE

Background and purpose

Data on pregnancy outcomes following fetal exposure to disease‐modifying drugs (DMDs) in women with multiple sclerosis (MS) are sparse although growing.

Methods

Data from the Danish Multiple Sclerosis Registry were linked with nationwide registries enabling an investigation of adverse pregnancy outcomes in newborns of women with MS following fetal exposure to injectable first‐line treatments, dimethyl fumarate, glatiramer acetate, or natalizumab. Logistic regression models accounting for clustered data were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for individual and composite adverse outcomes after adjusting for relevant covariates.

Results

A total of 1009 DMD‐exposed pregnancies were compared with 1073 DMD‐unexposed pregnancies as well as 91,112 pregnancies from the general population. No association of an increased risk of any perinatal outcome was found when comparing newborns with fetal exposure with the general population, including preterm birth (OR = 1.19, 95% CI = 0.86–1.64), small for gestational age (OR = 1.38, 95% CI = 0.92–2.07), spontaneous abortion (OR = 1.04, 95% CI = 0.84–1.27), congenital malformation (OR = 0.99, 95% CI = 0.68–1.45), low Apgar score (OR = 0.62, 95% CI = 0.23–1.65), stillbirth (OR = 1.05, 95% CI = 0.33–3.31), placenta complication (OR = 0.53, 95% CI = 0.22–1.27), and any adverse event (OR = 1.10, 95% CI = 0.93–1.30). Similar results were found when comparing DMD‐exposed pregnancies with DMD‐unexposed pregnancies.

Conclusions

We found no increased association of adverse pregnancy outcomes in newborns with fetal exposure to DMDs when compared with either DMD‐unexposed pregnancies or the general population.

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Authors:
Johanna Balslev Andersen, Finn Sellebjerg and Melinda Magyari
Article first published online:
01 Oct 2022 | DOI: 10.1111/ene.15559

ORIGINAL ARTICLE

Background and purpose

Upper limb (UL) function is often affected in people with multiple sclerosis (PwMS) and is typically assessed through objective measures, including the Nine Hole Peg Test (9‐HPT), Box and Block Test (BBT), and Hand Grip Strength (HGS). It is important to include the subjective perspective of PwMS in the assessment. This study aims to evaluate associations between Manual Ability Measure‐36 (MAM‐36) and 9‐HPT, BBT, and HGS in MS.

Methods

The cross‐sectional study included five Italian centers. Inclusion criteria were age ≥ 18 years, MS diagnosis, and stable disease course. Exclusion criteria were bilateral UL paralysis, and concomitant orthopedic or neurological diseases.

Results

A total of 199 PwMS were included: 128 female, mean age = 50.7 ± 13.0 years, 119 relapsing–remitting MS (RRMS), 31 primary and 49 secondary progressive MS, mean disease duration = 14.0 ± 10.4, years, mean Expanded Disability Status Scale (EDSS) = 4.6 ± 2.0.

Conclusions

Correlations between objective measures and MAM‐36 were small to moderate, meaning that objective measures do not match subjects' perception of UL function. The combination of 9‐HPT and HGS measures can help improve the assessment of UL function in activities of daily living.

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Authors:
Claudio Solaro, Rachele Di Giovanni, Erica Grange, Giampaolo Brichetto, Margit Mueller, Andrea Tacchino, Rita Bertoni, Francesco Patti, Angelo Pappalardo, Luca Prosperini, Letizia Castelli, Rosalba Rosato, Davide Cattaneo and Davide Marengo
Article first published online:
28 Sep 2022 | DOI: 10.1111/ene.15560

ORIGINAL ARTICLE

Background and purpose

Neuromyelitis optica spectrum disorder (NMOSD) is a severe neurological inflammatory disease mainly caused by pathogenic aquaporin‐4 antibodies (AQP4‐IgG). The safety and efficacy of the neonatal Fc receptor antagonist batoclimab addition to conventional intravenous methylprednisolone pulse (IVMP) therapy in patients with NMOSD acute attacks was assessed.

Methods

In an open‐label, dose‐escalation phase 1b study, NMOSD patients with acute myelitis and/or optic neuritis received four doses of weekly subcutaneous injections of either 340 mg or 680 mg batoclimab with concurrent IVMP and were followed up for 27 weeks. The primary end‐points were safety and tolerability. Secondary end‐points included pharmacodynamics and efficacy, with key efficacy assessment at week 4.

Results

In total nine NMOSD patients were enrolled, including two and seven in the 340 and 680 mg groups. Five patients had acute myelitis, while the remaining four had unilateral optic neuritis. Batoclimab add‐on therapy had an overall good safety profile without serious adverse events. In the 680 mg group, mean immunoglobulin G (IgG) reached its maximum reduction at the last dose (day 22). In the meantime, AQP4‐IgG was undetectable in six of seven subjects whose baseline AQP4‐IgG titers ranged from 1:32 to 1:320. Expanded Disability Status Scale score was reduced by 1.3 ± 0.4 at week 4 (2.7 ± 1.3) compared with baseline (4.0 ± 1.0).

Conclusions

Batoclimab add‐on therapy to IVMP is safe and tolerated in patients with NMOSD. Preliminary evidence suggests a beneficial neurological effect. A randomized controlled trial would be needed to prove the efficacy.

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Authors:
Yuge Wang, Xiaonan Zhong, Honghao Wang, Yu Peng, Fudong Shi, Dongmei Jia, Huan Yang, Qiuming Zeng, Chao Quan, Jingzi ZhangBao, Michael Lee, Jun Qi, Xiaoxiang Chen and Wei Qiu
Article first published online:
25 Sep 2022 | DOI: 10.1111/ene.15561

ORIGINAL ARTICLE

Background and Purpose

To evaluate the 1‐year effectiveness and tolerability of galcanezumab in real life and the prognostic indicators of persistent response.

Methods

High‐frequency episodic migraine (HFEM) and chronic migraine (CM) patients treated with galcanezumab who completed a 1‐year observation were enrolled. The primary outcomes assessed during the 12 months (V1–V12) were the change in monthly migraine days (MMDs) from baseline and the response rates ≥50% in MMDs (MMD ≥50% RR). The secondary outcomes were changes in pain intensity (numerical rating scale [NRS]) and in monthly acute medication intake (MAMI).

Results

We enrolled 191 patients (77.5% CM). Twenty‐three patients (12%) dropped out, two for nonserious adverse events. At least 40% of patients took add‐on standard preventives from baseline to V12. At V12, MMDs were reduced by 6.0 days in HFEM and by 11.9 days in CM patients (both  < 0.00001); NRS and MAMI were also decreased in both groups ( < 0.00001). One‐hundred eight (56.5%) patients presented MMD ≥50% RR for 9 cumulative months (interquartile range=8): we defined this value as the cutoff for a persistent response. Persistent responders were less likely to have a higher body mass index (BMI) ( = 0.007) but more frequently had a good response to triptans ( = 0.005) and MMD ≥50% RR at V1 ( < 0.0000001). Patients without a persistent response were on add‐on therapy for longer periods of time ( < 0.001).

Conclusions

Galcanezumab was effective and well‐tolerated in the 1‐year term, with most patients presenting MMD ≥50% RR for at least 9 months. Triptan response, lower BMI, and MMD ≥50% RR in the first month emerged as predictive factors for a persistent response.

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Authors:
Fabrizio Vernieri, Nicoletta Brunelli, Marilena Marcosano, Cinzia Aurilia, Gabriella Egeo, Carlo Lovati, Valentina Favoni, Armando Perrotta, Ilaria Maestrini, Renata Rao, Luigi d'Onofrio, Cinzia Finocchi, Marco Aguggia, Francesco Bono, Angelo Ranieri, Maria Albanese, Vittorio Di Piero, Sabina Cevoli, Claudia Altamura, Piero Barbanti, Carmelina Maria Costa, Luisa Fofi, Francesca Schiano Di Cola, Florindo d’Onofrio, Davide Bertuzzo, Fabio Bombardieri, Roberta Messina, Bruno Colombo, Massimo Filippi, Alberto Doretti, Gianluca Demirtzidis and Stefano Messina
Article first published online:
26 Sep 2022 | DOI: 10.1111/ene.15563

ORIGINAL ARTICLE

Background and purpose

Post‐stroke seizures (PSSs) are some of the most common complications of stroke and are associated with poor outcomes in patients. Endovascular treatment (EVT) is the standard of care for patients with acute ischaemic stroke related large‐vessel occlusion. However, whether EVT increases the risk of PSSs remains controversial; the association between PSSs and EVT is poorly understood.

Methods

PubMed, Embase and the Cochrane Library were searched for relevant studies published from 1995 to 6 December 2021. The overall incidence of PSSs in patients treated with EVT and the separate incidence for all included studies in each subgroup, stratified by the type of treatment or time of onset, were calculated. The pooled odds ratio and confidence interval were calculated to quantify the effects of EVT on PSS occurrence.

Results

In all, 946 studies were screened and 16 articles were included, with a total sample size of 12,664 patients; 7836 patients received EVT, of whom 460 had PSS. The pooled incidence of PSS after EVT was 5.8%, which was similar to patients treated with mechanical thrombectomy (5.3%), intra‐arterial thrombolysis (6.8%) or bridging therapy (5.4%). The cumulative incidence of post‐stroke epilepsy (6.0%) was almost twice that of acute symptomatic seizures (3.6%). The pooled odds ratio for the relationship between EVT and PSS was 1.91 (95% confidence interval 0.98–3.73).

Conclusions

The cumulative incidence of stroke patients treated with EVT who developed seizures was 5.8%, and EVT was non‐significantly associated with the occurrence of seizures after stroke.

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Authors:
Fangzhou Liu, Deng Chen, Yaoqi Fu, Haijiao Wang and Ling Liu
Article first published online:
13 Oct 2022 | DOI: 10.1111/ene.15564

REVIEW ARTICLE

Background and purpose

Although myasthenia gravis (MG) is recognized as an immunoglobulin G autoantibody‐mediated disease, the relationship between autoantibody levels and disease activity in MG is unclear. We sought to evaluate this landscape through systematically assessing the evidence, testing the impact of predefined variables on any relationship, and augmenting with expert opinion.

Methods

In October 2020, a forum of leading clinicians and researchers in neurology from across Europe (Expert Forum for Rare Autoantibodies in Neurology in Myasthenia Gravis) participated in a series of virtual meetings that took place alongside the conduct of a systematic literature review (SLR).

Results

Forty‐two studies were identified meeting inclusion criteria. Of these, 10 reported some correlation between a patient's autoantibody level and disease severity. Generally, decreased autoantibody levels (acetylcholine receptor, muscle‐specific kinase, and titin) were positively and significantly correlated with improvements in disease severity (Quantitative Myasthenia Gravis score, Myasthenia Gravis Composite score, Myasthenia Gravis Activities of Daily Living score, Myasthenia Gravis Foundation of America classification). Given the limited evidence, testing the impact of predefined variables was not feasible.

Conclusions

This first SLR to assess whether a correlation exists between autoantibody levels and disease activity in patients with MG has indicated a potential positive correlation, which could have clinical implications in guiding treatment decisions. However, in light of the limited and variable evidence, we cannot currently recommend routine clinical use of autoantibody level testing in this context. For now, patient's characteristics, clinical disease course, and laboratory data (e.g., autoantibody status, thymus histology) should inform management, alongside patient‐reported outcomes. We highlight the need for future studies to reach more definitive conclusions on this relationship.

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Authors:
Andreas Meisel, Fulvio Baggi, Anthony Behin, Amelia Evoli, Anna Kostera‐Pruszczyk, Renato Mantegazza, Raul Juntas Morales, Anna Rostedt Punga, Sabrina Sacconi, Michael Schroeter, Jan Verschuuren, Louise Crathorne, Kris Holmes and Maria‐Isabel Leite
Article first published online:
07 Oct 2022 | DOI: 10.1111/ene.15565

ORIGINAL ARTICLE

Background and purpose

A clinical risk score for sudden unexpected death in epilepsy (SUDEP) in patients with drug‐resistant focal epilepsy could help improve prevention.

Methods

A case–control study was conducted including (i) definite or probable SUDEP cases collected by the French National Sentinel Mortality Epilepsy Network and (ii) control patients from the French national research database of epilepsy monitoring units. Patients with drug‐resistant focal epilepsy were eligible. Multiple logistic regressions were performed. After sensitivity analysis and internal validation, a simplified risk score was developed from the selected variables.

Results

Sixty‐two SUDEP cases and 620 controls were included. Of 21 potential predictors explored, seven were ultimately selected, including generalized seizure frequency (>1/month vs. <1/year: adjusted odds ratio [AOR] 2.6, 95% confidence interval [CI] 1.25–5.41), nocturnal or sleep‐related seizures (AOR 4.49, 95% CI 2.68–7.53), current or past depression (AOR 2.0, 95% CI 1.19–3.34) or the ability to alert someone of an oncoming seizure (AOR 0.57, 95% CI 0.33–0.98). After internal validation, a clinically usable score ranging from −1 to 8 was developed, with high discrimination capabilities (area under the receiver operating curve 0.85, 95% CI 0.80–0.90). The threshold of 3 has good sensitivity (82.3%, 95% CI 72.7–91.8), whilst keeping a good specificity (82.7%, 95% CI 79.8–85.7).

Conclusions

These results outline the importance of generalized and nocturnal seizures on the occurrence of SUDEP, and show a protective role in the ability to alert someone of an oncoming seizure. The SUDEP‐CARE score is promising and will need external validation. Further work, including paraclinical explorations, could improve this risk score.

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Authors:
Chris Serrand, Sylvain Rheims, Marie Faucanié, Arielle Crespel, Vera Dinkelacker, William Szurhaj, Arnaud Biraben, Fabrice Bartolomei, Nathalie de Grissac, Elizabeth Landré, Marie Denuelle, Laurent Vercueil, Cécile Marchal, Louis Maillard, Philippe Derambure, Sophie Dupont, Vincent Navarro, Thibault Mura, Audrey Jaussent, Valérie Macioce, Philippe Ryvlin and Marie‐Christine Picot
Article first published online:
27 Sep 2022 | DOI: 10.1111/ene.15566

LETTER TO THE EDITOR

Hearing impairment and development of parkinsonism and possible rapid eye movement sleep behaviour disorder: A CLSA prospective population‐based study

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Authors:
Chun W. Yao, Aliya Szpindel, Amélie Pelletier and Ronald B. Postuma
Article first published online:
01 Oct 2022 | DOI: 10.1111/ene.15567

POSITION PAPER

Background and purpose

Functional neurological disorders (FNDs) have attracted much attention from the neurological medical community over the last decades as new developments in neurosciences have reduced stigma around these by showing brain network dysfunctions. An overlap with other neurological conditions such as multiple sclerosis (MS) is well known by clinicians but there is a lack of clinical and fundamental research in this field to better define diagnosis and therapeutic decisions, as well as a lack of deep understanding of the underlying pathophysiology.

Aim

We aimed to provide a critical commentary on the state of knowledge about the borderland between FNDs and MS.

Methods

We based our commentary on a joint point of view between an FND specialist and an MS expert.

Results

A brief review of the previous literature and relevant new studies covering the overlap between FNDs and MS is presented, along with suggestions for future research directions.

Conclusion

There are clear diagnostic criteria for both FNDs and MS and a strict application of these will help better diagnosis and prevent unnecessary treatment escalation in MS or absence of referral to multimodal therapy in FND. Better teaching of younger neurologists is needed as well as prospective research focusing on pathophysiology.

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Authors:
Selma Aybek and Andrew Chan
Article first published online:
01 Oct 2022 | DOI: 10.1111/ene.15568

ORIGINAL ARTICLE

Background and purpose

Mild behavioral impairment (MBI) has been increasingly regarded as the neurobehavioral axis of predementia risk states, but a specific investigation of its detection as a potential marker of prodromal dementia in motor neuron diseases (MNDs) is still lacking. The aims of our study were therefore to explore MBI in MNDs both at onset and over the disease course, and to evaluate its relationship with baseline and longitudinal cognitive features.

Methods

Sixty MND patients with cognitive/behavioral, mood, and motor examinations were recruited and followed longitudinally for up to 15 months. Associations between baseline MBI symptoms and clinical features were tested using the Spearman correlation coefficient. Based on longitudinal data, relative deltas of variation for each cognitive measure were generated, and linear regression models were then used to evaluate the role of baseline MBI symptoms in predicting longitudinal rates of cognitive decline.

Results

At disease onset, the most impaired MBI domain was affective/emotional dysregulation, followed by impulse dyscontrol, apathy, and social inappropriateness. Greater MBI symptoms correlated with more severe baseline motor, cognitive/behavioral, and mood disturbances ( values from <0.001 to 0.05). Longitudinally, the greatest decline was observed in the affective/emotional dysregulation domain, followed by impulse dyscontrol, apathy, and social inappropriateness. Greater MBI symptoms at onset were significant predictors of more severe longitudinal cognitive decline in both amyotrophic lateral sclerosis (ALS)‐specific and ALS‐nonspecific functions ( values from <0.001 to 0.03).

Conclusions

MBI represents a valuable clinical marker of incident cognitive decline in MNDs, and its evaluation has good potential for detecting dementia in its preclinical/prodromal phase.

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Authors:
Pilar M. Ferraro, Ester Gervino, Emiliano De Maria, Giuseppe Meo, Marta Ponzano, Matteo Pardini, Alessio Signori, Angelo Schenone, Luca Roccatagliata and Claudia Caponnetto
Article first published online:
02 Oct 2022 | DOI: 10.1111/ene.15570

ORIGINAL ARTICLE

Background and purpose

Nuclear factor erythroid 2‐related factor 2 (NRF2; encoded by the gene) has been implicated in outcome following aneurysmal subarachnoid haemorrhage (aSAH) through its activity as a regulator of inflammation, oxidative injury and blood breakdown product clearance. The aim of this study was to identify whether genetic variation in is associated with clinical outcome following aSAH.

Methods

Ten tagging single nucleotide polymorphisms (SNPs) in were genotyped and tested for association with dichotomized clinical outcome, assessed by the modified Rankin scale, in both a discovery and a validation cohort. functional analysis was performed using a range of bioinformatic tools.

Results

One SNP, rs10183914, was significantly associated with outcome following aSAH in both the discovery ( = 1007) and validation cohorts ( = 466). The risk of poor outcome was estimated to be 1.33‐fold (95% confidence interval 1.12–1.58) higher in individuals with the T allele of rs10183914 ( = 0.001). functional analysis identified rs10183914 as a potentially regulatory variant with effects on transcription factor binding in addition to alternative splicing with the T allele, associated with a significant reduction in the intron excision ratio ( = 1.3 × 10).

Conclusions

The SNP, rs10183914, is significantly associated with outcome following aSAH. This is consistent with a clinically relevant pathophysiological role for oxidative and inflammatory brain injury due to blood and its breakdown products in aSAH. Furthermore, our findings support NRF2 as a potential therapeutic target following aSAH and other forms of intracranial haemorrhage.

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Authors:
Ben Gaastra, Poppy Duncan, Mark K. Bakker, Isabel C. Hostettler, Varinder S. Alg, Henry Houlden, Ynte M. Ruigrok, Ian Galea, Will Tapper, David Werring and Diederik Bulters
Article first published online:
02 Oct 2022 | DOI: 10.1111/ene.15571

LETTER TO THE EDITOR

European Psychiatric Association–European Academy of Neurology statement on post‐COVID syndrome

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Authors:
Claudio L. A. Bassetti, Raimund Helbok, Kristina Adorjan and Peter Falkai
Article first published online:
07 Oct 2022 | DOI: 10.1111/ene.15572

ORIGINAL ARTICLE

Background and purpose

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials.

Methods

This was a phase II, multicentre, randomized, double‐blind, placebo‐controlled, parallel‐group trial. Participants diagnosed with definite, probable or probable laboratory‐supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non‐infusion days, followed by an additional 24 weeks off‐treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale—Revised), a measure of self‐sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire‐40, ALSAQ‐40) and survival. Tolerability and safety were assessed.

Results

Seventy‐four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ‐40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, = 0.0101; ALSAQ‐40, difference –0.19 per week, standard error 0.10, = 0.0319). Adverse events were similar in the two arms. In a analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60.

Conclusions

The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.

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Authors:
Ettore Beghi, Elisabetta Pupillo, Elisa Bianchi, Valentina Bonetto, Silvia Luotti, Laura Pasetto, Caterina Bendotti, Massimo Tortarolo, Francesca Sironi, Laura Camporeale, Alexander V. Sherman, Sabrina Paganoni, Ada Scognamiglio, Fabiola De Marchi, Paolo Bongioanni, Renata Del Carratore, Claudia Caponnetto, Luca Diamanti, Daniele Martinelli, Andrea Calvo, Massimiliano Filosto, Alessandro Padovani, Stefano Cotti Piccinelli, Claudia Ricci, Stefania Dalla Giacoma, Nicoletta De Angelis, Maurizio Inghilleri, Rossella Spataro, Vincenzo La Bella, Giancarlo Logroscino, Christian Lunetta, Claudia Tarlarini, Jessica Mandrioli, Ilaria Martinelli, Cecilia Simonini, Elisabetta Zucchi, Maria Rosaria Monsurrò, Dario Ricciardi, Francesca Trojsi, Nilo Riva, Massimo Filippi, Isabella Laura Simone, Gianni Sorarù, Cristina Spera, Lucia Florio, Sonia Messina, Massimo Russo, Gabriele Siciliano, Amelia Conte, Maria Valeria Saddi, Nicola Carboni, Letizia Mazzini, Gabriele Enia, Andrea Zucchella, Lorenzo Pinzani, Lorena De Giorgi, Celeste Nicoletti, Elisa Semprucci, Emilio Davide Arippol, Giorgia Giussani, Monica Graziani, Cinzia Ferrari, Roberto Cantello, Enrica Bersano, Cristina Dolciotti, Silvia Maria Masciandaro, Ilaria Da Prato, Corrado Cabona, Giuseppe Meo, Mauro Ceroni, Beatrice Dal Fabbro, Adriano Chiò, Cristina Moglia, Umberto Manera, Giuseppe Fuda, Federico Casale, Giovanni De Marco, Paolina Salamone, Fabio Giannini, Silvia Bocci, Marco Ceccanti, Chiara Cambieri, Laura Libonati, Federica Moret, Vittorio Frasca, Tiziana Coletti, Rosanna Tortelli, Rosa Capozzo, Francesca Gerardi, Valeria Sansone, Nicola Fini, Giulia Gianferrari, Annalisa Gessani, Yuri Falzone, Paride Schito, Laura Pozzi, Teuta Domi, Eustachio D’Errico, Antonella Morea, Gianmarco Milella, Matteo Gizzi, Francesca Paci, Simonetta Ferracchiato, Michele Zarrelli, Nino Desina, Alessandra Govoni, Erika Schirinzi, Costanza Simoncini, Mario Sabatelli, Daniela Bernardo, Giulia Bisogni, Giovanna Piras, Maria Monne and Elisabetta Manca
Article first published online:
07 Oct 2022 | DOI: 10.1111/ene.15573

ORIGINAL ARTICLE

Background and purpose

The purpose of this study was to investigate the 5‐year risk of a third bleeding event in cavernous malformations (CMs) of the central nervous system.

Methods

Patients with cerebral or spinal CMs treated between 2003 and 2021 were screened using our institutional database. Patients with a complete magnetic resonance imaging dataset, clinical baseline characteristics, and history of two bleeding events were included. Patients who underwent surgical CM removal were excluded. Neurological functional status was obtained using the modified Rankin Scale score at the second and third bleeding. Kaplan–Meier and Cox regression analyses were performed to determine the cumulative 5‐year risk for a third haemorrhage.

Results

Forty‐two patients were included. Cox regression analysis adjusted for age and sex did not identify risk factors for a third haemorrhage. 37% of patients experienced neurological deterioration after the third haemorrhage ( = 0.019). The cumulative 5‐year risk of a third bleeding was 66.7% (95% confidence interval [CI] 50.4%–80%) for the whole cohort, 65.9% (95% CI 49.3%–79.5%) for patients with bleeding at initial diagnosis, 72.7% (95% CI 39.3%–92.7%) for patients with a developmental venous anomaly, 76.9% (95% CI 55.9%–90.3%) for patients with CM localization to the brainstem and 75% (95% CI 50.6%–90.4%) for patients suffering from familial CM disease.

Conclusions

During an untreated 5‐year follow‐up after a second haemorrhage, a significantly increased risk of a third haemorrhage compared to the known risk of a first and second bleeding event was identified. The third bleeding was significantly associated with neurological deterioration. These findings may justify a surgical treatment after a second bleeding event.

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Authors:
Alejandro N. Santos, Laurèl Rauschenbach, Hanah Hadice Gull, Angelina Olbrich, Kirstin Lahl, Marvin Darkwah Oppong, Thiemo F. Dinger, Christoph Rieß, Bixia Chen, Annika Lenkeit, Börge Schmidt, Yan Li, Ramazan Jabbarli, Karsten H. Wrede, Ulrich Sure and Philipp Dammann
Article first published online:
13 Oct 2022 | DOI: 10.1111/ene.15574

ORIGINAL ARTICLE

Background and purpose

Advanced analysis of electroencephalography (EEG) data has become an essential tool in brain research. Based solely on resting state EEG signals, a data‐driven, predictive and explanatory approach is presented to discriminate painful from non‐painful diabetic polyneuropathy (DPN) patients.

Methods

Three minutes long, 64 electrode resting‐state recordings were obtained from 180 DPN patients. The analysis consisted of a mixture of traditional, explanatory and machine learning analyses. First, the 10 functional bivariate connections best differentiating between painful and non‐painful patients in each EEG band were identified and the relevant receiver operating characteristic was calculated. Later, those connections were correlated with selected clinical parameters.

Results

Predictive analysis indicated that theta and beta bands contain most of the information required for discrimination between painful and non‐painful polyneuropathy patients, with area under the receiver operating characteristic curve values of 0.93 for theta and 0.89 for beta bands. Assessing statistical differences between the average magnitude of functional connectivity values and clinical pain parameters revealed that painful DPN patients had significantly higher cortical functional connectivity than non‐painful ones ( = 0.008 for theta and  = 0.001 for alpha bands). Moreover, intra‐band analysis of individual significant functional connections revealed a positive correlation with average reported pain in the previous 3 months in all frequency bands.

Conclusions

Resting state EEG functional connectivity can serve as a highly accurate biomarker for the presence or absence of pain in DPN patients. This highlights the importance of the brain, in addition to the peripheral lesions, in generating the clinical pain picture. This tool can probably be extended to other pain syndromes.

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Authors:
Leah Shafran Topaz, Alex Frid, Yelena Granovsky, Rabab Zubidat, Shoshana Crystal, Chen Buxbaum, Noam Bosak, Rafi Hadad, Erel Domany, Tayir Alon, Lian Meir Yalon, Merav Shor, Mogher Khamaisi, Irit Hochberg, Nataliya Yarovinsky, Zeev Volkovich, David L. Bennett and David Yarnitsky
Article first published online:
26 Oct 2022 | DOI: 10.1111/ene.15575

ORIGINAL ARTICLE

Background

Quantitative lesion net water uptake (NWU) has been described as an imaging biomarker reflecting vasogenic edema as an early indicator of infarct progression. We hypothesized that edema formation measured by NWU is higher in children compared to adults but despite this functional outcome may be better in children.

Methods

This study analyzed children enrolled in the Save ChildS Study who had baseline and follow‐up computed tomography available and the data were compared to adult patients.

Results

Some 207 patients, of whom 13 were children and 194 were adults, were analyzed. Median NWU at baseline was 7.8% (IQR: 4.3–11.3), and there were no significant differences between children and adults (7.5% vs. 7.8%;  = 0.87). The early edema progression rate was 3.0%/h in children and 2.3%/h in adults. Median ΔNWU was 15.1% in children and 10.5% in adults. Children had significantly more often excellent (mRS 0–1; children 10/13 = 77% vs. adults 28/196 = 14%;  < 0.0001) and favorable clinical outcomes (mRS 0–2, 12/13 = 92% vs. 39/196 = 20%;  < 0.0001).

Conclusions

In this study, clinical outcomes in children with large vessel occlusion strokes were better than in adults despite similar clinical and imaging characteristics and similar edema formation. This may be impacted by the generally better outcomes of children after strokes but may demonstrate that the degree of early ischemic changes using Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and edema progression rate may not be a reason for exclusion from endovascular thrombectomy.

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Authors:
Peter B. Sporns, Thilo Rusche, Sarah Lee, Uta Hanning, Lukas Meyer, Tobias Faizy, Jens Fiehler, Marios Psychogios, Andre Kemmling and Gabriel Broocks
Article first published online:
12 Oct 2022 | DOI: 10.1111/ene.15576

ORIGINAL ARTICLE

Background and purpose

Measures of atrophy in the whole brain can be used to reliably assess treatment effect in clinical trials of patients with multiple sclerosis (MS). Trials assessing the effect of treatment on grey matter (GM) and white matter (WM) atrophy are very informative, but hindered by technical limitations. This study aimed to measure GM and WM volume changes, using a robust longitudinal method, in patients with relapsing MS randomized to cladribine tablets 3.5 mg/kg or placebo in the CLARITY study.

Methods

We analysed T1‐weighted magnetic resonance sequences using SIENA‐XL, from 0 to 6 months (cladribine,  = 267; placebo,  = 265) and 6 to 24 months (cladribine,  = 184; placebo,  = 186). Mean percentage GM and WM volume changes (PGMVC and PWMVC) were compared using a mixed‐effect model.

Results

More GM and WM volume loss was found in patients taking cladribine versus those taking placebo in the first 6 months of treatment (PGMVC: cladribine: −0.53 vs. placebo: −0.25 [ = 0.045]; PWMVC: cladribine: −0.49 vs. placebo: −0.34 [ = 0.137]), probably due to pseudoatrophy. However, over the period 6 to 24 months, GM volume loss was significantly lower in patients on cladribine than in those on placebo (PGMVC: cladribine: −0.90 vs. placebo: −1.27 [ = 0.026]). In this period, volume changes in WM were similar in the two treatment arms ( = 0.52).

Conclusions

After a short period of pseudoatrophy, treatment with cladribine 3.5 mg/kg significantly reduced GM atrophy in comparison with placebo. This supports the relevance of GM damage in MS and may have important implications for physical and cognitive disability progression.

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Authors:
Rosa Cortese, Marco Battaglini, Maria Pia Sormani, Ludovico Luchetti, Giordano Gentile, Maira Inderyas, Nektaria Alexandri and Nicola De Stefano
Article first published online:
11 Oct 2022 | DOI: 10.1111/ene.15579

COMMENTARY

Long‐term consequences of subarachnoid haemorrhage: Is it time for new strategies?

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Authors:
Alessandro Pezzini
Article first published online:
06 Oct 2022 | DOI: 10.1111/ene.15580

ORIGINAL ARTICLE

Background and purpose

Growing evidence shows that ALS patients feature a disturbed energy metabolism. However, these features have rarely been investigated in the presymptomatic stage.

Methods

A total of 60 presymptomatic ALS mutation carriers and 70 age‐ and gender‐matched controls (non‐mutation carriers from the same families) were recruited. All subjects underwent assessments of their metabolic profiles under fasting conditions at enrollment, including body mass index (BMI), blood pressure and serum levels of blood glucose, total cholesterol, triglycerides, high‐density lipoprotein (HDL) and low‐density lipoprotein.

Results

All mutations combined, no differences between presymptomatic ALS gene carriers and controls were found. From a cardiovascular point of view, presymptomatic chromosome 9 open reading frame 72 () gene carriers showed lower cardiovascular risk profiles compared to healthy controls, including lower BMI (median 22.9, interquartile range [IQR] 20.6–26.1 kg/m vs. 24.9, IQR 22.7–30.5 kg/m;  = 0.007), lower systolic blood pressure (120, IQR 110–130 mmHg vs. 128, IQR 120–140 mmHg;  = 0.02), lower fasting serum glucose (89.0, IQR 85.0–97.0 mg/dl vs. 96.0, IQR 89.3–102.0 mg/dl;  = 0.005) and higher HDL (1.6, IQR 1.3–1.8 mmol/l vs. 1.2, IQR 1.0–1.4 mmol/l;  = 0.04). However, presymptomatic superoxide dismutase 1 () gene mutation carriers showed higher cardiovascular risk profiles compared to healthy controls, including higher BMI (28.0, IQR 26.1–31.5 kg/m vs. 24.9, IQR 22.7–30.5 kg/m;  = 0.02), higher fasting serum glucose (100.0, IQR 94.0–117.0 mg/dl vs. 96.0, IQR 89.3–102.0 mg/dl;  = 0.04) and lower HDL (1.2, IQR 1.0–1.4 mmol/l vs. 1.4, IQR 1.2–1.7 mmol/l;  = 0.01). These features were most prominent in patients carrying gene mutations associated with slow disease progression.

Conclusions

This study identified distinct metabolic profiles in presymptomatic ALS gene carriers, which might be associated with disease progression in the symptomatic phase.

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Authors:
Kailin Xia, Simon Witzel, Christina Witzel, Veronika Klose, Dongsheng Fan, Albert C. Ludolph and Johannes Dorst
Article first published online:
17 Oct 2022 | DOI: 10.1111/ene.15584

LETTER TO THE EDITOR

Reply to the Letter to the Editor in response to “Integrated evaluation of a panel of neurochemical biomarkers to optimize diagnosis and prognosis in amyotrophic lateral sclerosis”

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Authors:
Nilo Riva and Angelo Quattrini
Article first published online:
08 Oct 2022 | DOI: 10.1111/ene.15586

ORIGINAL ARTICLE

Background

In a recent trial, hydroxychloroquine (HCQ) treatment reduced the expected rate of disability worsening at 18 months in primary progressive multiple sclerosis (PPMS). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers in multiple sclerosis.

Methods

We measured NfL and GFAP levels in serum samples from 39 patients with inactive PPMS included in a phase II clinical trial of HCQ treatment in PPMS at multiple time points over 18 months, and investigated the association of these biomarkers with clinical disability at screening and during follow‐up. Screening and 12‐month retinal nerve fiber layer (RNFL) thickness was also recorded and analyzed.

Results

NfL and GFAP levels increased over time, but only significantly from screening to month 6. NfL and GFAP levels did not significantly increase from month 6 up to month 18. At screening, NfL and GFAP levels did not correlate with the Expanded Disability Status Scale (EDSS), and GFAP but not NfL modestly correlated with Timed 25‐Foot Walk test (T25FW). Screening NfL and GFAP levels did not predict disability worsening (≥20% worsening on the T25FW) at month 18. RNFL thickness decreased significantly from screening to month 12 and independently predicted disability worsening.

Conclusions

In this cohort of people with inactive PPMS, HCQ treatment attenuated the increase of NfL and GFAP after 6 months of treatment and up to 18 months of follow‐up, suggesting a treatment effect of HCQ over these biomarkers. RNFL thickness, a marker of neuroaxonal atrophy, was associated with disability worsening, and should be explored further as a prognostic marker in this population.

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Authors:
Carlos Camara‐Lemarroy, Claudia Silva, Jit Gohill, V. Wee Yong and Marcus Koch
Article first published online:
25 Oct 2022 | DOI: 10.1111/ene.15588

ORIGINAL ARTICLE

Background and purpose

Weight loss in patients with amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. Decreased hypothalamic volume is proposed to contribute to weight loss due to loss of appetite and/or hypermetabolism. We aimed to investigate the relationship between hypothalamic volume and body mass index (BMI) in ALS and Alzheimer's disease (AD), and the associations of hypothalamic volume with weight loss, appetite, metabolism and survival in patients with ALS.

Methods

We compared hypothalamic volumes from magnetic resonance imaging scans with BMI for patients with ALS ( = 42), patients with AD ( = 167) and non‐neurodegenerative disease controls ( = 527). Hypothalamic volumes from patients with ALS were correlated with measures of appetite and metabolism, and change in anthropomorphic measures and disease outcomes.

Results

Lower hypothalamic volume was associated with lower and higher BMI in ALS (quadratic association; probability of direction = 0.96). This was not observed in AD patients or controls. Hypothalamic volume was not associated with loss of appetite ( = 0.58) or hypermetabolism ( = 0.49). Patients with lower BMI and lower hypothalamic volume tended to lose weight ( = 0.08) and fat mass ( = 0.06) over the course of their disease, and presented with an increased risk of earlier death (hazard ratio [HR] 3.16,  = 0.03). Lower hypothalamic volume alone trended for greater risk of earlier death (HR 2.61,  = 0.07).

Conclusion

These observations suggest that lower hypothalamic volume in ALS contributes to positive and negative energy balance, and  is not universally associated with loss of appetite or hypermetabolism. Critically, lower hypothalamic volume with lower BMI was associated with weight loss and earlier death.

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Authors:
Jeryn Chang, Thomas B. Shaw, Cory J. Holdom, Pamela A. McCombe, Robert D. Henderson, Jurgen Fripp, Markus Barth, Christine C. Guo, Shyuan T. Ngo and Frederik J. Steyn
Article first published online:
08 Nov 2022 | DOI: 10.1111/ene.15589

LETTER TO THE EDITOR

“Integrated evaluation of a panel of neurochemical biomarkers to optimize diagnosis and prognosis in amyotrophic lateral sclerosis”

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Authors:
Ali Aamir, Hussain Haider Shah and Tehreem Mansure
Article first published online:
27 Oct 2022 | DOI: 10.1111/ene.15590

ORIGINAL ARTICLE

Background and purpose

Spontaneous intracranial hypotension (SIH) is an important etiology of infratentorial superficial siderosis (iSS) of the central nervous system. However, the prevalence of iSS amongst patients with SIH is unknown and the imaging findings of iSS might represent a late stage of disease. The aim was to identify cerebrospinal fluid (CSF) biomarkers of iSS in patients with SIH.

Methods

Consecutive patients evaluated for SIH at our institution between May 2017 and January 2019 were included. Lumbar CSF samples were analyzed for the presence of ferritin and bilirubin. Magnetic resonance imaging was assessed for the presence of iSS.

Results

Twenty‐four patients with SIH were included. CSF samples were positive for bilirubin in 2/19 (10.5%). CSF ferritin was elevated in 7/23 (30.4%). Signs of iSS on imaging were present in four patients (16.7%). All patients with imaging signs of iSS demonstrated elevated CSF ferritin. Ferritin level was significantly higher amongst patients demonstrating iSS compared to those without (median 45.0 vs. 11.0 μg/l;  = 0.003). Symptom duration was longer in patients with iSS than in patients without iSS (median 40 months vs. 9 months,  = 0.018).

Conclusion

Cerebrospinal fluid alterations indicative of iSS are prevalent amongst patients with SIH. It is speculated that a preclinical phase without symptoms or imaging signs but during which elevated biomarkers of the disease are apparent from CSF analysis might exist. It is suggested that measurement of CSF ferritin is incorporated in the work‐up of patients with SIH to identify those at risk of developing iSS.

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Authors:
Levin Häni, Christian Fung, Christopher Marvin Jesse, Christof Schild, Eike Immo Piechowiak, Tomas Dobrocky, Andreas Raabe and Jürgen Beck
Article first published online:
19 Oct 2022 | DOI: 10.1111/ene.15591

ORIGINAL ARTICLE

Background and purpose

Cholesterol is vital in neuronal function; however, the influence of cholesterol levels on parkinsonism is unclear. This study investigated the relationship between baseline total cholesterol (TC) levels, dopamine loss, and motor symptoms in drug‐naïve Parkinson disease (PD).

Methods

This cross‐sectional study enrolled 447 drug‐naïve patients with PD who underwent dopamine transporter (DAT) imaging. Multivariate linear regression was used to investigate the effect of cholesterol levels on Unified Parkinson's Disease Rating Scale Part III (UPDRS‐III) total score and each subscore after adjusting for the covariates. An interaction analysis was performed to examine the interaction between TC levels and statin use on the UPDRS‐III scores.

Results

No significant correlation was found between TC levels and DAT availability after adjusting for potential confounders. Multivariate linear regression showed that TC levels were significantly and negatively associated with the UPDRS‐III total score ( = −0.116,  = 0.013) and bradykinesia subscore ( = −0.145,  = 0.011). Dichotomized analysis according to TC levels showed that TC levels were significantly associated with UPDRS‐III total score, and rigidity, bradykinesia, and axial subscores only in the low TC group. There was an interaction effect between TC levels and statin use for the axial subscores ( = −0.523,  = 0.025). Subgroup analysis showed that TC levels were significantly and negatively associated with the axial subscore in statin users; however, no association was found in statin nonusers.

Conclusions

This study suggests that TC levels affect parkinsonian motor symptoms, especially in subjects with low cholesterol status, whereas the severity of axial motor symptoms is negatively associated with TC levels only in statin users.

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Authors:
Seong Ho Jeong, Hye Sun Lee, Seok Jong Chung, Han Soo Yoo, Jin Ho Jung, Kyoungwon Baik, Jong Sam Baik, Young H. Sohn and Phil Hyu Lee
Article first published online:
25 Oct 2022 | DOI: 10.1111/ene.15592

POSITION PAPER

Background and Purpose

Multiple sclerosis (MS) is an unpredictable disease characterised by a highly variable disease onset and clinical course. Three main clinical phenotypes have been described. However, distinguishing between the two progressive forms of MS can be challenging for clinicians. This article examines how the diagnostic definitions of progressive MS impact clinical research, the design of clinical trials and, ultimately, treatment decisions.

Methods

We carried out an extensive review of the literature highlighting differences in the definition of progressive forms of MS, and the importance of assessing the extent of the ongoing inflammatory component in MS when making treatment decisions.

Results

Inconsistent results in phase III clinical studies of treatments for progressive MS, may be attributable to differences in patient characteristics (e.g., age, clinical and radiological activity at baseline) and endpoint definitions. In both primary and secondary progressive MS, patients who are younger and have more active disease will derive the greatest benefit from the available treatments.

Conclusions

We recommend making treatment decisions based on the individual patient's pattern of disease progression, as well as functional, clinical and imaging parameters, rather than on their clinical phenotype. Because the definition of progressive MS differs across clinical studies, careful selection of eligibility criteria and study endpoints is needed for future studies in patients with progressive MS.

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Authors:
Carlo Pozzilli, Maura Pugliatti, Patrick Vermersch, Nikolaos Grigoriadis, Mona Alkhawajah, Laura Airas and Celia Oreja‐Guevara
Article first published online:
25 Oct 2022 | DOI: 10.1111/ene.15593

ORIGINAL ARTICLE

Background

Collateral therapeutics exert a promising protective effect on the outcome of acute ischemic stroke. Cerebral blood flow (CBF) may be modulated by different head positioning. The current study aimed to determine the effect of head‐down tilt (HDT) on stroke in a rodent model.

Methods

The model of middle cerebral artery occlusion and reperfusion (MCAO/R) was used in this study. Neurological deficit scoring, 2,3,5‐triphenyltetrazolium chloride staining, brain water content, perivascular aquaporin protein‐4 (AQP4) localization, pericyte marker platelet‐derived growth factor receptor β (PDGFRβ), and CBF velocity were evaluated at 24 h after MCAO/R and HDT treatment.

Results

In the rat model of MCAO/R, brain infarct volume and neurological deficit score were significantly alleviated in the −30° and −60° groups compared to those in the lying flat (0°) group. Compared with the 0° group, an increase in CBF velocity was detected in the −30° group through two‐photon microscopy imaging at 24 h after MCAO/R. Compared with the SHAM group, a decrease in PDGFRβ was observed in both the MCAO/R and HDT treatment (−30°) groups. The integrated optical density of PDGFRβ was found to be higher in the HDT treatment (−30°) group than in the MCAO/R group. An impairment in perivascular AQP4 polarity and an increase in brain water content were observed after MCAO/R, which were not exacerbated by HDT treatment (−30°).

Conclusions

Our findings suggest that HDT treatment at certain degrees may exert a neuroprotective effect after MCAO/R through improving CBF velocity and the protection of pericytes.

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Authors:
Zi‐Ai Zhao, Nan‐Nan Zhang, Yu Cui and Hui‐Sheng Chen
Article first published online:
28 Oct 2022 | DOI: 10.1111/ene.15597

LETTER TO THE EDITOR

Letter to the editor re “Minor stroke in large vessel occlusion: A matched analysis of patients from the German Stroke Registry—Endovascular Treatment and patients from the Safe Implementation of Treatments in Stroke—International Stroke Thrombolysis Register”

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Authors:
Ajay Malhotra, Mihir Khunte, Xiao Wu and Mahla Radmard
Article first published online:
28 Oct 2022 | DOI: 10.1111/ene.15598

REVIEW ARTICLE

Background and purpose

The aim was to systematically review the effectiveness and safety of telemedicine combined with usual care (in‐person visits) compared to usual care for the therapeutic management and follow‐up assessment of neurological diseases.

Methods

The electronic databases MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials were searched (June 2021). Randomized controlled trials (RCTs) on patients of any age with neurological diseases were considered. Two reviewers screened and abstracted data in duplicate and independently and assessed risk of bias using the Cochrane risk‐of‐bias tool for randomized trials (RoB 2). When possible, pooled effect estimates were calculated.

Results

Of a total of 3018 records initially retrieved, 25 RCTs ( = 2335) were included: 11 ( = 804) on stroke, four ( = 520) on Parkinson's disease, three ( = 110) on multiple sclerosis, two ( = 320) on epilepsy, one ( = 63) on dementia, one ( = 23) on spina bifida, one ( = 40) on migraine, one ( = 22) on cerebral palsy and one ( = 433) on brain damage. Types of telemedicine assessed were online visits (11 studies), tele‐rehabilitation (seven studies), telephone calls (three), smartphone apps (two) and online computer software (two). The evidence was quite limited except for stroke. Compared to usual care alone, telemedicine plus usual care was found to improve depressive symptoms, functional status, motor function, executive function, generic quality of life, healthcare utilization and healthy lifestyle in patients in post‐stroke follow‐up.

Conclusions

Well‐designed and executed RCTs are needed to confirm our findings on stroke and to have more scientific evidence available for the other neurological diseases.

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Authors:
Beatriz León‐Salas, Yadira González‐Hernández, Diego Infante‐Ventura, Aythami de Armas‐Castellano, Javier García‐García, Miguel García‐Hernández, Montserrat Carmona‐Rodríguez, Javier Olazarán, José Luis Dobato, Leticia Rodríguez‐Rodríguez and María M. Trujillo‐Martín
Article first published online:
14 Nov 2022 | DOI: 10.1111/ene.15599

LETTER TO THE EDITOR

Response to the letter to the editor regarding “Minor stroke in large vessel occlusion: A matched analysis of patients from the German Stroke Registry–Endovascular Treatment (GSR‐ET) and patients from the Safe Implementation of Treatments in Stroke–International Stroke Thrombolysis Register (SITS‐ISTR)”

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Authors:
Katharina Feil, Marius Matusevicius, Niaz Ahmed and Lars Kellert
Article first published online:
27 Oct 2022 | DOI: 10.1111/ene.15600

ORIGINAL ARTICLE

Background and purpose

Myotonic dystrophy type 1 (DM1) is a hereditary and multisystemic disease that is characterized by heterogeneous manifestations. Although muscular impairment is central to DM1, a premanifest DM1 form has been proposed for those characterized by the absence of muscle signs in precursory phases. Nevertheless, subtle signs and/or symptoms related to other systems, such as the central nervous system (CNS), may emerge and progress gradually. This study aimed to validate the premanifest DM1 concept and to characterize and track affected individuals from a CNS centred perspective.

Methods

Retrospective data of 120 participants (23 premanifest DM1, 25 manifest DM1 and 72 healthy controls) were analysed transversally and longitudinally (over 11.17 years). Compiled data included clinical, neuropsychological and neuroradiological (brain volume and white matter lesion, WML) measures taken at two time points.

Results

Manifest DM1 showed significantly more molecular affectation, worse performance on neuropsychological domains, lower grey and white matter volumes and a different pattern of WMLs than premanifest DM1. The latter was slightly different from healthy controls regarding brain volume and WMLs. Additionally, daytime sleepiness and molecular expansion size explained 50% of the variance of the muscular deterioration at follow‐up in premanifest individuals.

Conclusions

Premanifest DM1 individuals showed subtle neuroradiological alterations, which suggests CNS involvement early in the disease. Based on follow‐up data, a debate emerges around the existence of a ‘non‐muscular DM1’ subtype and/or a premanifest phase, as a precursory stage to other DM1 manifestations.

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Authors:
Joana Garmendia, Garazi Labayru, Miren Zulaica, Jorge Villanúa, Adolfo López de Munain and Andone Sistiaga
Article first published online:
31 Oct 2022 | DOI: 10.1111/ene.15604

LETTER TO THE EDITOR

Secondary hypokalemic periodic paralysis in Crohn disease: Two case reports

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Authors:
Francisco de Assis Aquino Gondim, Antônio Miguel Furtado Leitão, José Marcelino Aragão Fernandes, Davi Farias de Araújo, Marcellus Henrique Loiola Ponte Souza and Lúcia Libanez Bessa Campelo Braga
Article first published online:
01 Nov 2022 | DOI: 10.1111/ene.15610