cover image European Journal of Neurology

European Journal of Neurology

2022 - Volume 29
Issue 12 | December 2022
Previous Issue

ISSUE INFORMATION

Issue Information

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Article first published online:
02 Nov 2022 | DOI: 10.1111/ene.14932

SHORT COMMUNICATION

Background and purpose

Recently, p.Glu1121Ter in was identified as a potential cause of parkinsonism. However, no further replication has been conducted in a wider range of Parkinson's disease (PD) cohorts. We aimed to evaluate the genetic role of in PD.

Methods

We systematically analyzed the rare protein‐coding variants (minor allele frequency [MAF] < 0.01) in 1080 patients and 1051 healthy controls. Fisher's exact test was used to analyze the associations between each variant and risk of PD, while, at gene level, over‐representation of rare variants in patients was examined using the optimized sequence kernel association test (SKAT‐O).

Results

In total, 43 rare variants were identified in PD. No variant was significantly associated with risk of PD. Burden analysis showed enrichment of ultra‐rare variants (MAF < 0.001) of in PD One patient carried a variant (p.E1121D) in the same amino acid as that in the original study. Both patients showed worsened motor symptoms, and developed dyskinesia during follow‐up.

Conclusions

Our study explored the rare variant of in PD, and paves the way for future research on the genetic role of in PD.

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Authors:
Chunyu Li, Junyu Lin, Qirui Jiang and Huifang Shang
Article first published online:
29 Jul 2022 | DOI: 10.1111/ene.15512

ORIGINAL ARTICLE

Background and purpose

Reduced facial expression of emotions is a very frequent symptom of Parkinson's disease (PD) and has been considered part of the motor features of the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non‐motor symptoms of PD are poorly understood.

Methods

The clinical and structural brain correlates of hypomimia were studied. For this purpose, cross‐sectional data from the COPPADIS study database were used. Age, disease duration, levodopa equivalent daily dose, Unified Parkinson's Disease Rating Scale part III (UPDRS‐III), severity of apathy and depression and global cognitive status were collected. At the imaging level, analyses based on gray matter volume and cortical thickness were used.

Results

After controlling for multiple confounding variables such as age or disease duration, the severity of hypomimia was shown to be indissociable from the UPDRS‐III speech and bradykinesia items and was significantly related to the severity of apathy ( = 0.595;  < 0.0001). At the level of neural correlates, hypomimia was related to motor regions brodmann area 8 (BA 8) and to multiple fronto‐temporo‐parietal regions involved in the decoding, recognition and production of facial expression of emotions.

Conclusion

Reduced facial expressivity in PD is related to the severity of symptoms of apathy and is mediated by the dysfunction of brain systems involved in motor control and in the recognition, integration and expression of emotions. Therefore, hypomimia in PD may be conceptualized not exclusively as a motor symptom but as a consequence of a multidimensional deficit leading to a symptom where motor and non‐motor aspects converge.

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Authors:
Frederic Sampedro, Saul Martínez‐Horta, Andrea Horta‐Barba, Michel J. Grothe, Miguel A. Labrador‐Espinosa, Silvia Jesús, Astrid Adarmes‐Gomez, Fatima Carrillo, Arnau Puig‐Davi, Florinda Roldan‐Lora, Miquel Aguilar‐Barbera, Pau Pastor, Sonia Escalante Arroyo, Berta Solano Vila, Anna Cots‐Foraster, Javier Ruiz‐Martínez, Francisco Carrillo‐Padilla, Mercedes Pueyo‐Morlans, Isabel Gonzalez‐Aramburu, Jon Infante‐Ceberio, Jorge Hernandez‐Vara, Oriol de Fabregues‐Boixar, Teresa de Deus Fonticoba, Asuncion Avila, Juan Carlos Martínez‐Castrillo, Helena Bejr‐Kasem, Antonia Campolongo, Berta Pascual‐Sedano, Pablo Martínez‐Martín, Diego Santos‐García, Pablo Mir, Pedro J. Garcia‐Ruiz and Jaime Kulisevsky
Article first published online:
30 Jul 2022 | DOI: 10.1111/ene.15513

ORIGINAL ARTICLE

Background and purpose

Several smaller, community‐based studies have suggested a link between sleep disorders and dementia with a focus on sleep as a modifiable risk factor for dementia. Studies on neurodegenerative diseases are prone to reverse causation, and few studies have examined the association with long follow‐up time. Our aim was to explore the possible association between sleep disorders and late‐onset dementia in an entire population.

Methods

In a nationwide cohort with 40‐year follow‐up, associations between hospital‐based sleep disorder diagnoses and late‐onset dementia were assessed. Incidence rate ratios (IRR) were calculated using Poisson regression.

Results

The cohort consisted of 1,491,276 people. Those with any sleep disorder had a 17% higher risk of dementia (IRR 1.17, 95% confidence interval [CI] 1.11–1.24) compared to people with no sleep disorder, adjusted for age, sex, calendar year, highest attained educational level at age 50, and somatic and psychiatric comorbidity. The risk of dementia was significantly increased 0–5 years after sleep disorder diagnosis (IRR 1.35, 95% CI 1.25–1.47), whilst the association after 5 years or more was non‐significant (1.05, 95% CI 0.97–1.13).

Conclusions

Our findings show an increased short‐term risk of dementia following a hospital‐based sleep disorder diagnosis, whilst weaker evidence of a long‐term risk was found. This could potentially point towards sleep disorders as an early symptom of dementia. Further research is needed to distinguish sleep disorders as an early symptom of dementia, a risk factor, or both.

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Authors:
Line Damsgaard, Janet Janbek, Thomas Munk Laursen, Annette Erlangsen, Adam P. Spira and Gunhild Waldemar
Article first published online:
18 Aug 2022 | DOI: 10.1111/ene.15517

ORIGINAL ARTICLE

Background and purpose

In this retrospective study involving 14 university hospitals from France and Switzerland, the aim was to define the clinicopathological features of chronic neuropathies with anti‐disialosyl ganglioside immunoglobulin M (IgM) antibodies (CNDA).

Results

Fifty‐five patients with a polyneuropathy evolving for more than 2 months and with at least one anti‐disialosyl ganglioside IgM antibody, that is, anti‐GD1b, ‐GT1b, ‐GQ1b, ‐GT1a, ‐GD2 and ‐GD3, were identified. Seventy‐eight percent of patients were male, mean age at disease onset was 55 years (30–76) and disease onset was progressive (82%) or acute (18%). Patients presented with limb sensory symptoms (94% of cases), sensory ataxia (85%), oculomotor weakness (36%), limb motor symptoms (31%) and bulbar muscle weakness (18%). Sixty‐five percent of patients had a demyelinating polyradiculoneuropathy electrodiagnostic profile and 24% a sensory neuronopathy profile. Anti‐GD1b antibodies were found in 78% of cases, whilst other anti‐disialosyl antibodies were each observed in less than 51% of patients. Other features included nerve biopsy demyelination (100% of cases), increased cerebrospinal fluid protein content (75%), IgM paraprotein (50%) and malignant hemopathy (8%). Eighty‐six percent of CNDA patients were intravenous immunoglobulins‐responsive, and rituximab was successfully used as second‐line treatment in 50% of cases. Fifteen percent of patients had mild symptoms and were not treated. CNDA course was progressive (55%) or relapsing (45%), and 93% of patients still walked after a mean disease duration of 11 years.

Conclusion

Chronic neuropathies with anti‐disialosyl ganglioside IgM antibodies have a recognizable phenotype, are mostly intravenous immunoglobulins‐responsive and present with a good outcome in a majority of cases.

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Authors:
Claire Peillet, David Adams, Shahram Attarian, Françoise Bouhour, Cécile Cauquil, Julien Cassereau, Jean‐Baptiste Chanson, Pascal Cintas, Alain Creange, Emilien Delmont, Guillaume Fargeot, Steeve Genestet, Antoine Gueguen, Anne Laure Kaminsky, Thierry Kuntzer, Céline Labeyrie, Maud Michaud, Yann Pereon, Angela Puma, Karine Viala, Pascale Chretien, Clovis Adam and Andoni Echaniz‐Laguna
Article first published online:
29 Aug 2022 | DOI: 10.1111/ene.15523

LETTER TO THE EDITOR

Post‐COVID myopathy

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Authors:
Josef Finsterer and Fulvio A. Scorza
Article first published online:
26 Aug 2022 | DOI: 10.1111/ene.15524

LETTER TO THE EDITOR

Reply to “Post‐COVID myopathy”

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Authors:
Eva K. Hejbøl, Thomas Harbo, Jane Agergaard, Lars J. Østergaard, Henning Andersen, Henrik D. Schrøder and Hatice Tankisi
Article first published online:
22 Aug 2022 | DOI: 10.1111/ene.15525

CONSENSUS STATEMENT

Background and purpose

Patients with neuromuscular conditions are at increased risk of suffering perioperative complications related to anaesthesia. There is currently little specific anaesthetic guidance concerning these patients. Here, we present the European Neuromuscular Centre (ENMC) consensus statement on anaesthesia in patients with neuromuscular disorders as formulated during the 259th ENMC Workshop on Anaesthesia in Neuromuscular Disorders.

Methods

International experts in the field of (paediatric) anaesthesia, neurology, and genetics were invited to participate in the ENMC workshop. A literature search was conducted in PubMed and Embase, the main findings of which were disseminated to the participants and presented during the workshop. Depending on specific expertise, participants presented the existing evidence and their expert opinion concerning anaesthetic management in six specific groups of myopathies and neuromuscular junction disorders. The consensus statement was prepared according to the AGREE II (Appraisal of Guidelines for Research & Evaluation) reporting checklist. The level of evidence has been adapted according to the SIGN (Scottish Intercollegiate Guidelines Network) grading system. The final consensus statement was subjected to a modified Delphi process.

Results

A set of general recommendations valid for the anaesthetic management of patients with neuromuscular disorders in general have been formulated. Specific recommendations were formulated for (i) neuromuscular junction disorders, (ii) muscle channelopathies (nondystrophic myotonia and periodic paralysis), (iii) myotonic dystrophy (types 1 and 2), (iv) muscular dystrophies, (v) congenital myopathies and congenital dystrophies, and (vi) mitochondrial and metabolic myopathies.

Conclusions

This ENMC consensus statement summarizes the most important considerations for planning and performing anaesthesia in patients with neuromuscular disorders.

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Authors:
Luuk R. van den Bersselaar, Luc Heytens, Helga C. A. Silva, Jens Reimann, Giorgio Tasca, Óscar Díaz‐Cambronero, Nicoline Løkken, Anna Hellblom, Philip M. Hopkins, Henrik Rueffert, Börge Bastian, Juan Jesus Vilchez, Robyn Gillies, Stephan Johannsen, Francis Veyckemans, Tino Muenster, Andrea Klein, Ron Litman, Heinz Jungbluth, Sheila Riazi, Nicol C. Voermans and Marc M. J. Snoeck
Article first published online:
14 Sep 2022 | DOI: 10.1111/ene.15526

ORIGINAL ARTICLE

Background and purpose

Spinal–bulbar muscular atrophy (SBMA) (Kennedy's disease) is a motor neuron disease. Kennedy's disease is nearly exclusively caused by mutations in the androgen receptor encoding gene (). The results of studies aimed at identification of the genetic cause of a disease that best approximates SBMA in a pedigree (four patients) without mutations in are reported.

Methods

Clinical investigations included thorough neurological and non‐neurological examinations and testing. Genetic analysis was performed by exome sequencing using standard protocols. mutations were modeled on the crystal structure of UBA1.

Results

The clinical features of the patients are described in detail. A missense mutation in (c.T1499C; p.Ile500Thr) was identified as the probable cause of the non‐Kennedy SBMA in the pedigree. Like , is positioned on chromosome X. is a highly conserved gene. It encodes ubiquitin‐like modifier activating enzyme 1 (UBA1) which is the major E1 enzyme of the ubiquitin–proteasome system. Interestingly, mutations can also cause infantile‐onset X‐linked spinal muscular atrophy (XL‐SMA). The mutation identified here and the XL‐SMA causative mutations were shown to affect amino acids positioned in the vicinity of UBA1's ATP binding site and to cause structural changes.

Conclusion

was identified as a novel SBMA causative gene. The gene affects protein homeostasis which is one of most important components of the pathology of neurodegeneration. The contribution of this same gene to the etiology of XL‐SMA is discussed.

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Authors:
Marzieh Khani, Shahriar Nafissi, Hosein Shamshiri, Hamidreza Moazzeni, Hanieh Taheri, Mehdi Sadeghi, Najmeh Salehi, Fereshteh Chitsazian and Elahe Elahi
Article first published online:
13 Sep 2022 | DOI: 10.1111/ene.15528

ORIGINAL ARTICLE

Background and purpose

Although psychiatric diagnoses are recognized in idiopathic dystonia, no previous studies have examined the temporal relationship between idiopathic dystonia and psychiatric diagnoses at scale. Here, we determine rates of psychiatric diagnoses and psychiatric medication prescription in those diagnosed with idiopathic dystsuponia compared to matched controls.

Methods

A longitudinal population‐based cohort study using anonymized electronic health care data in Wales (UK) was conducted to identify individuals with idiopathic dystonia and comorbid psychiatric diagnoses/prescriptions between 1 January 1994 and 31 December 2017. Psychiatric diagnoses/prescriptions were identified from primary and secondary health care records.

Results

Individuals with idiopathic dystonia ( = 52,589) had higher rates of psychiatric diagnosis and psychiatric medication prescription when compared to controls ( = 216,754, 43% vs. 31%,  < 0.001; 45% vs. 37.9%,  < 0.001, respectively), with depression and anxiety being most common (cases: 31% and 28%). Psychiatric diagnoses predominantly predated dystonia diagnosis, particularly in the 12 months prior to diagnosis (incidence rate ratio [IRR] = 1.98, 95% confidence interval [CI] = 1.9–2.1), with an IRR of 12.4 (95% CI = 11.8–13.1) for anxiety disorders. There was, however, an elevated rate of most psychiatric diagnoses throughout the study period, including the 12 months after dystonia diagnosis (IRR = 1.96, 95% CI = 1.85–2.07).

Conclusions

This study suggests a bidirectional relationship between psychiatric disorders and dystonia, particularly with mood disorders. Psychiatric and motor symptoms in dystonia may have common aetiological mechanisms, with psychiatric disorders potentially forming prodromal symptoms of idiopathic dystonia.

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Authors:
Grace A. Bailey, Anna Rawlings, Fatemeh Torabi, William Owen Pickrell and Kathryn J. Peall
Article first published online:
11 Sep 2022 | DOI: 10.1111/ene.15530

ORIGINAL ARTICLE

Background and purpose

Sex is believed to drive heterogeneity in Alzheimer's disease (AD), although evidence in early‐onset AD (EOAD; <65 years) is scarce.

Methods

We included 62 EOAD patients and 44 healthy controls (HCs) with core AD cerebrospinal fluid (CSF) biomarkers, neurofilament light chain levels, neuropsychological assessment, and 3‐T magnetic resonance imaging. We measured cortical thickness (CTh) and hippocampal subfield volumes (HpS) using FreeSurfer. Adjusted linear models were used to analyze sex‐differences and the relationship between atrophy and cognition.

Results

Compared to same‐sex HCs, female EOAD subjects showed greater cognitive impairment and broader atrophy burden than male EOAD subjects. In a direct female‐EOAD versus male‐EOAD comparison, there were slight differences in temporal CTh, with no differences in cognition or HpS. CSF tau levels were higher in female EOAD than in male EOAD subjects. Greater atrophy was associated with worse cognition in female EOAD subjects.

Conclusions

At diagnosis, there are sex differences in the pattern of cognitive impairment, atrophy burden, and CSF tau in EOAD, suggesting there is an influence of sex on pathology spreading and susceptibility to the disease in EOAD.

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Authors:
José Contador, Agnès Pérez‐Millan, Nuria Guillén, Jordi Sarto, Adrià Tort‐Merino, Mircea Balasa, Neus Falgàs, Magdalena Castellví, Sergi Borrego‐Écija, Jordi Juncà‐Parella, Beatriz Bosch, Guadalupe Fernández‐Villullas, Oscar Ramos‐Campoy, Anna Antonell, Nuria Bargalló, Raquel Sanchez‐Valle, Roser Sala‐Llonch and Albert Lladó
Article first published online:
09 Sep 2022 | DOI: 10.1111/ene.15531

ORIGINAL ARTICLE

Background and Purpose

Clinical experience suggests that many patients with functional motor disorders (FMD), despite reporting severe balance problems, typically do not fall frequently. This discrepancy may hint towards a functional component. Here, we explored the role of the Shoulder‐Touch test, which features a light touch on the patient's shoulders, to reveal a possible functional etiology of postural instability.

Methods

We enrolled consecutive outpatients with a definite diagnosis of FMD. Patients with Parkinson's disease (PD) or progressive supranuclear palsy (PSP) with postural instability served as controls. Each patient underwent a clinical evaluation including testing for postural instability using the retropulsion test. Patients with an abnormal retropulsion test (score ≥ 1) also received a light touch on their shoulders to explore the presence (S‐Touch+) or absence (S‐Touch−) of an incongruent, exaggerated postural response, defined as taking three or more steps to recover or a fall if not caught by the examiner.

Results

From a total sample of 52 FMD patients, 48 patients were recruited. Twenty‐five patients (52%) had an abnormal retropulsion test. Twelve of these 25 patients (48%) had an S‐Touch+, either because of need to take two or more steps ( = 4) or a fall if not caught by the examiner ( = 8). None of the 23 PD/PSP patients manifested S‐Touch+. The sensitivity of the S‐Touch test was 48%, whereas its specificity was 100%.

Conclusion

The S‐Touch test has a high specificity, albeit with a modest sensitivity, to reveal a functional etiology of postural instability in persons with FMD.

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Authors:
Christian Geroin, Jorik Nonnekes, Roberto Erro, Serena Camozzi, Bastiaan R. Bloem and Michele Tinazzi
Article first published online:
08 Sep 2022 | DOI: 10.1111/ene.15532

ORIGINAL ARTICLE

Background and purpose

Fatigue is common following aneurysmal subarachnoid haemorrhage (aSAH) but little is known about its frequency, prognosis and impact on employment. The aim of this study was to assess the frequency of fatigue, whether it changes over time and the relationship to employment in the long term.

Methods

This was a retrospective observational study of aSAH cases and matched controls from the UK Biobank. The presence of fatigue was compared between cases and controls using the chi‐squared test. The change in frequency over time was assessed using Spearman's rank correlation coefficient. The effect of fatigue on employment was assessed using mediation analysis.

Results

Fatigue is more common following aSAH compared to matched controls (aSAH 18.7%; controls 13.7%;  = 13.0,  < 0.001) at a mean follow‐up of 123 months. Fatigue gradually improves over time with significant fatigue decreasing by 50% from ~20% in the first year to ~10% after a decade ( = 0.04). Fatigue significantly mediated 24.0% of the effect of aSAH status on employment.

Conclusions

Fatigue is common following aSAH and persists in the long term. It gradually improves over time but has a major impact on aSAH survivors, significantly contributing to unemployment following haemorrhage. Further work is required to develop treatments and management strategies for fatigue with a view to improving this symptom and consequently employment following aSAH.

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Authors:
Ben Gaastra, Harry Carmichael, Ian Galea and Diederik Bulters
Article first published online:
12 Sep 2022 | DOI: 10.1111/ene.15533

ORIGINAL ARTICLE

Background and purpose

Nerve conduction studies (NCS) are the current objective measure for diagnosis of peripheral neuropathy in type 2 diabetes but do not assess nerve structure. This study investigated the utility of peripheral nerve ultrasound as a marker of the presence and severity of peripheral neuropathy in type 2 diabetes.

Methods

A total of 156 patients were recruited, and nerve ultrasound was undertaken on distal tibial and distal median nerves. Neuropathy severity was graded using the modified Toronto Clinical Neuropathy Scale (mTCNS) and Total Neuropathy Score (TNS). Studies were undertaken by a single ultrasonographer blinded to nerve conduction results.

Results

A stepwise increase in tibial nerve cross‐sectional area (CSA) was noted with increasing TNS grade ( < 0.001) and each mTCNS quartile ( < 0.001). Regression analysis demonstrated a correlation between tibial nerve CSA and neuropathy severity ( < 0.001). Using receiver operator curve analysis, tibial nerve CSA of >12.88 mm yielded a sensitivity of 70.5% and specificity of 85.7% for neuropathy detection. Binary logistic regression revealed that tibial nerve CSA was a predictor of abnormal sural sensory nerve action potential amplitude (odds ratio = 1.239, 95% confidence interval [CI] = 1.142–1.345) and abnormal neuropathy score (odds ratio = 1.537, 95% confidence interval [CI] = 1.286–1.838).

Conclusions

Tibial nerve ultrasound has good specificity and sensitivity for neuropathy diagnosis in type 2 diabetes. The study demonstrates that tibial nerve CSA correlates with neuropathy severity. Future serial studies using both ultrasound and NCS may be useful in determining whether changes in ultrasound occur prior to development of nerve conduction abnormalities and neuropathic symptoms.

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Authors:
Roshan Dhanapalaratnam, Tushar Issar, Ann M. Poynten, Kerry‐Lee Milner, Natalie C. G. Kwai and Arun V. Krishnan
Article first published online:
14 Sep 2022 | DOI: 10.1111/ene.15534

ORIGINAL ARTICLE

Background and purpose

The aim was to investigate the effect of ε4 allele on cognitive decline in adAD. Presence of the ε4 allele reduces age of symptom onset, increases disease progression, and lowers cognitive performance in sporadic Alzheimer's disease (AD), while the impact of the ε4 allele in autosomal‐dominant AD (adAD) is incompletely known.

Methods

Mutation carriers (MCs;  = 39) and non‐carriers (NCs;  = 40) from six adAD families harbouring a mutation in the (28 MCs and 25 NCs) or the genes (11 MCs and 15 NCs) underwent repeated cognitive assessments. A timeline of disease course was defined as years to expected age of clinical onset (YECO) based on history of disease onset in each family. The MC and NC groups were comparable with regard to demographics and prevalence of the ε4 allele. The relationship between cognitive decline and YECO, YECO, education, , and ‐by‐YECO interaction was analysed using linear mixed‐effects models.

Results

The trajectory of cognitive decline was significantly predicted by linear and quadratic YECO and education in MCs and was determined by age and education in NCs. Adding ε4 allele (presence/absence) as a predictor did not change the results in the MC and NC groups. The outcome also remained the same for MCs and NCs after adding the ‐by‐YECO interaction as a predictor. Analyses of and MCs separately showed favourable ‐by‐YECO interaction in (less steep decline) and unfavourable interaction in (steeper decline), linked to the ε4 allele.

Conclusion

The ε4 allele influences cognitive decline positively in and negatively in mutation carriers with adAD, indicating a possible antagonistic pleiotropy.

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Authors:
Ove Almkvist, Charlotte Johansson, Jose Laffita‐Mesa, Steinunn Thordardottir and Caroline Graff
Article first published online:
11 Sep 2022 | DOI: 10.1111/ene.15536

ORIGINAL ARTICLE

Background and purpose

The insidious onset of Parkinson's disease (PD) makes early diagnosis difficult. Notably, idiopathic rapid eye movement sleep behavior disorder (iRBD) was reported as a prodrome of PD, which may represent a breakthrough for the early diagnosis of PD. However, currently there is no reliable biomarker for PD diagnosis. Considering that α‐synuclein (α‐Syn) and neuroinflammation are known to develop prior to the onset of clinical symptoms in PD, it was hypothesized that plasma total exosomal α‐Syn (t‐exo α‐Syn), neural‐derived exosomal α‐Syn (n‐exo α‐Syn) and exosomal apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain (ASC) may be potential biomarkers of PD.

Methods

In this study, 78 PD patients, 153 probable iRBD patients (pRBD) and 63 healthy controls (HCs) were recruited. α‐Syn concentrations were measured using a one‐step paramagnetic particle‐based chemiluminescence immunoassay, and ASC levels were measured using the Ella system.

Results

It was found that t‐exo α‐Syn was significantly increased in the PD group compared to the pRBD and HC groups ( < 0.0001), whilst n‐exo α‐Syn levels were significantly increased in both the PD and pRBD groups compared to HCs ( < 0.0001). Furthermore, although no difference was found in ASC levels between the PD and pRBD groups, there was a positive correlation between ASC and α‐Syn in exosomes.

Conclusions

Our results suggest that both t‐exo α‐Syn and n‐exo α‐Syn were elevated in the PD group, whilst only n‐exo α‐Syn was elevated in the pRBD group. Additionally, the adaptor protein of inflammasome ASC is correlated with α‐Syn and may facilitate synucleinopathy.

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Authors:
Yi‐Qun Yan, Jia‐Li Pu, Ran Zheng, Yi Fang, Lu‐Yan Gu, Tao Guo, Xiao‐Li Si, Cheng Zhou, Ying Chen, Yi Liu, Xiao‐Jun Guan, Xiao‐Jun Xu, Ya‐Ping Yan, Xin‐Zhen Yin, Min‐Ming Zhang, Zhi‐Hua Tao and Bao‐Rong Zhang
Article first published online:
15 Sep 2022 | DOI: 10.1111/ene.15537

ORIGINAL ARTICLE

Background and purpose

Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology‐driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences.

Methods

We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web‐based survey.

Results

We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head‐up tilt tests/laboratory/year is 105 (49–251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty‐five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100–360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4–110] inpatient stays/year). Forty‐one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe ( = 0.021).

Conclusions

This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.

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Authors:
Mario Habek, Fabian Leys, Magdalena Krbot Skorić, Diogo Reis Carneiro, Giovanna Calandra‐Buonaura, Jennifer Camaradou, Giacomo Chiaro, Pietro Cortelli, Cristian Falup‐Pecurariu, Roberta Granata, Pietro Guaraldi, Raimund Helbok, Max J. Hilz, Valeria Iodice, Jens Jordan, Evert C. A. Kaal, Anita Kamondi, Anne Pavy Le Traon, Isabel Rocha, Johann Sellner, Jean Michel Senard, Astrid Terkelsen, Gregor K. Wenning, Thomas Berger, Roland D. Thijs, Walter Struhal, Alessandra Fanciulli, Ivan Adamec, Arnaud Aerts, Leo L.R. Canta, Robert Shane Delamont, Frederik de Lange, Francesca Del Sorbo, Grazia Devigili, Rita Di Leo, Trang Dinh, Jacques‐Olivier Fortrat, Janne Gierthmühlen, Martin Hemels, Julia Köhn, Thomas Krøigård, Axel Lipp, Andrea Maier, Lucio Marinelli, Anna Mazzeo, Ivan Milenkovic, Maciej Motyl, Maria Grazia Natali Sora, Judith Navarro‐Otano, Kristian Bernhard Nilsen, Mario Oliveira, Petter Moe Omland, Giuseppe Pelliccioni, Yann Pereon, Roland Josef Resch, Camilla Rocchi, Frederic Roche, Joost Rutten, Beatriz Tijero Merino, Marcin Tutaj, A.M.H.G. van der Heijden‐Montfroy, Bas J.A. van Hoeve, Narender van Orshoven, Ruihao Wang and Werner J. Z’Graggen
Article first published online:
20 Sep 2022 | DOI: 10.1111/ene.15538

SHORT COMMUNICATION

Background and purpose

While levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), its use is associated with an increased risk of motor complications (MCs) in the first 5 years of treatment compared to dopamine agonist (DA) first therapy. It is not known whether this translates into true benefit later in the disease. We aimed to determine whether there is a difference in the time between initial levodopa versus DA treatment and the development of disabling MCs prompting deep brain stimulation (DBS) consideration.

Methods

This was a retrospective cohort study of patients with PD attending the DBS Clinic at Toronto Western Hospital, Canada between March 2004 and February 2022, who underwent globus pallidus interna (GPI) or subthalamic nucleus (STN) DBS in 2005 or later for disabling MCs.

Results

Of the 438 patients included in the study, 352 underwent STN DBS and 86 underwent GPi DBS. The median (range) disease duration was 9 (2–30) years. The majority of patients ( = 312) received levodopa first and 126 received a DA. There was no significant difference in disease duration or amantadine use between the two groups. The duration from the first treatment to assesment for DBS (levodopa: median 8 years, interquartile range [IQ] 4 years; DA: median 9, IQR 4 years) or DBS surgery (levodopa: median 10 years, IIQR 5 years; DA: median 10 years, IQR 5 years) did not differ.

Conclusion

To our knowledge, this is the only study to date to evaluate the duration between levodopa/DA‐first treatment and the development of MCs of sufficient severity to warrant consideration of DBS. No association was found. The results suggest that the development of disabling MCs warranting DBS is independent of the type of first dopaminergic treatment.

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Authors:
Diana A. Olszewska, Alfonso Fasano, Renato P. Munhoz, Carolina Candelaria Ramirez Gomez and Anthony E. Lang
Article first published online:
12 Sep 2022 | DOI: 10.1111/ene.15539

ORIGINAL ARTICLE

Background and purpose

There is some evidence that cytokines may play an important role in sleep deprivation; however, the underlying mechanisms are still unknown. So, the present study aimed to evaluate the relationship between NOD‐like receptor protein 1 (NLRP1) and NOD‐like receptor protein 3 (NLRP3) inflammasome activation of blood cells and serum levels of cytokines in individuals with chronic insomnia disorder (CID).

Methods

Blood samples were collected from 24 individuals with CID and 24 healthy volunteers. The inflammasome activation was evaluated using real‐time polymerase chain reaction of NLRP1, NLRP3, apoptosis‐associated speck‐like protein containing a caspase‐recruitment domain (ASC) and caspase‐1; western blot of NLRP1 and NLRP3; caspase‐1 activity assay; and serum levels of interleukin‐1β (IL‐1β), IL‐18 and other cytokines using enzyme‐linked immunosorbent assay. Reactive oxygen species generation in blood cells were detected by flow cytometry assay. Also, magnetic resonance imaging scans were obtained on a Siemens Magnetom Avanto 1.5 T MRI whole‐body scanner using an eight‐channel head coil.

Results

Increased activity of NLRP1 and NLRP3 inflammasomes in blood cells, increased serum levels of pro‐inflammatory cytokines and decreased serum levels of IL‐10 and transforming growth factor β in individuals with CID were found. Significant correlation was observed between increased serum concentration of IL‐1β and the severity of insomnia in individuals with CID. The levels of reactive oxygen species in blood cells were found to be correlated with IL‐1α and tumor necrosis factor α concentrations in sera from individuals with CID. Moreover, the individuals with CID demonstrated increased right cerebellum cortex and lateral ventricle mean diffusivity bilaterally compared to controls.

Conclusions

This study provided new insights on the pathogenesis of CID and the effects of cytokines on inflammasome activation.

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Authors:
Zahra Aghelan, Saeed Karima, Habibolah Khazaie, Seyed Hosein Abtahi, Ali Reza Farokhi, Masoumeh Rostampour, Fariborz Bahrehmand and Reza Khodarahmi
Article first published online:
12 Sep 2022 | DOI: 10.1111/ene.15540

ORIGINAL ARTICLE

Background and Purpose

Trochlear palsy is the most common cause of vertical diplopia. The etiologies of trochlear palsy have shown a large discrepancy among studies. This study aimed to establish the clinical features and underlying etiologies of isolated trochlear palsy by recruiting the patients from all departments in a referral‐based university hospital.

Methods

We reviewed the medical records of 1258 patients who had a confirmed diagnosis of isolated trochlear palsy at all departments of Seoul National University Bundang Hospital, Seongnam, South Korea, from 2003 to 2020. We also compared the proportion of etiologies with that of the patients pooled from previous studies.

Results

The most common etiology was congenital ( = 330, 32.4%), followed by idiopathic ( = 256, 25.1%), microvascular ( = 212, 20.8%), and traumatic ( = 145, 14.2%). These four etiologies explained 92.5% of isolated trochlear palsy. Patients were mostly managed by ophthalmologists ( = 841, 82.5%), followed by neurologists ( = 380, 37.3%), emergency physicians ( = 197, 19.3%), neurosurgeons ( = 75, 7.4%), and others ( = 18, 1.8%). The etiologic distribution of isolated trochlear palsy in the current study did not differ from that of 2664 patients pooled from the previous studies.

Conclusions

The proportion of etiologies of isolated trochlear palsy differs according to the age ranges of the patients and specialties involved in the management. The etiologic distribution of isolated trochlear palsy in the current study was comparable to the pooled result of previous reports.

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Authors:
Hyun‐Jae Kim, Hyo‐Jung Kim, Jeong‐Yoon Choi, Hee Kyung Yang, Jeong‐Min Hwang and Ji‐Soo Kim
Article first published online:
12 Sep 2022 | DOI: 10.1111/ene.15541

ORIGINAL ARTICLE

Background and purpose

Mos scales currently used to evaluate spinal muscular atrophy (SMA) patients have only been validated in children. The aim of this study was to assess the construct validity and responsiveness of several outcome measures in adult SMA patients.

Methods

Patients older than 15 years and followed up in five referral centres for at least 6 months, between October 2015 and August 2020, with a motor function scale score (Hammersmith Functional Motor Scale Expanded [HFMSE], Revised Upper Limb module [RULM]) were included. Bedside functional scales (Egen Klassification [EK2], Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS‐R]) were also collected when available. Spearman's rho correlations (rs) and Bangdiwala's concordance test (B) were used to evaluate the scales' construct validity. Monthly slopes of change were used to calculate their responsiveness of the scales.

Results

The study included 79 SMA patients, followed up for a mean of 16 months. All scales showed strong correlations with each other (rs > 0.70). A floor effect in motor function scales was found in the weakest patients (HFMSE < 5 and RULM < 10), and a ceiling effect was found in stronger patients (HFMSE > 60 and RULM > 35). The ALSFRS‐R (B = 0.72) showed a strong ability to discriminate between walkers, sitters and non‐sitters, and the HFMSE (B = 0.86) between walkers and sitters. The responsiveness was low overall, although in treated patients a moderate responsiveness was found for the ALSFRS‐R and HFMSE in walkers (0.69 and 0.61, respectively) and for EK2 in sitters (0.65) and non‐sitters (0.60).

Conclusions

This study shows the validity and limitations of the scales most frequently used to assess adult SMA patients. Overall, bedside functional scales showed some advantages over motor scales, although all showed limited responsiveness.

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Authors:
Juan F. Vázquez‐Costa, Mónica Povedano, Andrés E. Nascimiento‐Osorio, Antonio Moreno Escribano, Solange Kapetanovic Garcia, Raul Dominguez, Jessica M. Exposito, Laura González, Carla Marco, Julita Medina Castillo, Nuria Muelas, Daniel Natera de Benito, Nancy Carolina Ñungo Garzón, Inmaculada Pitarch Castellano, Teresa Sevilla and David Hervás
Article first published online:
13 Sep 2022 | DOI: 10.1111/ene.15542

ORIGINAL ARTICLE

Background and purpose

In the central nervous system, a multitude of changes have been described associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, such as microglial activation, perivascular lymphocyte cuffing, hypoxic‐ischaemic changes, microthrombosis, infarcts or haemorrhages. It was sought here to assess the vascular basement membranes (vBMs) and surrounding perivascular astrocytes for any morphological changes in acute respiratory syndrome (coronavirus disease 2019, COVID‐19) patients.

Methods

The light microscopy morphology of the vBMs and perivascular astrocytes from brains of 14 patients with confirmed SARS‐CoV‐2 infection was analysed and compared to four control patients utilizing fluorescent immunohistochemistry for collagen IV and astrocytes (GFAP), endothelia (CD31), tight junction 1 (TJ1) adhesion protein, as well as the aquaporin 4 (AQP4) water channel. On 2D and 3D deconvoluted images from the cortex and white matter, vessel densities, diameters, degree of gliosis, collagen IV/GFAP and GFAP/AQP4 colocalizations were calculated, as well as the fractal dimension of astrocytes and vBMs viewed in tangential planes.

Results

Fractal dimension analysis of the GFAP‐stained astrocytes revealed lower branching complexities and decreased GFAP/collagen IV colocalization for COVID‐19 patients. Interestingly, vBMs showed significantly increased irregularities (fractal dimension values) compared to controls. Vessel diameters were increased in COVID‐19 cases, especially for the white matter, TJ1 protein decreased its colocalization with the endothelia, and AQP4 reduced its co‐expression in astrocytes.

Conclusions

Our data on the irregularity of the basement membranes, loss of endothelial tight junction, reduction of the astrocyte end‐feet and decrease of AQP4 suggest subtle morphological changes of the blood–brain barrier in COVID‐19 brains that could be linked with indirect inflammatory signalling or hypoxia/hypercapnia.

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Authors:
Gabriela Camelia Rosu, Valentin Octavian Mateescu, Alexandra Simionescu, Anca‐Maria Istrate‐Ofiteru, George Cristian Curcă, Ionica Pirici, Laurentiu Mogoanta, Ion Mindrila, Samir Kumar‐Singh, Sorin Hostiuc and Daniel Pirici
Article first published online:
01 Oct 2022 | DOI: 10.1111/ene.15545

ORIGINAL ARTICLE

Background and purpose

Dizziness and vertigo are common symptoms after COVID‐19‐vaccination. We aimed to prospectively evaluate objective central or peripheral vestibular function in patients with dizziness, vertigo, and postural symptoms that started or worsened after COVID‐19‐vaccination.

Methods

Of 4137 patients who presented between January 2021 and April 2022 at the German Center for Vertigo and Balance Disorders, Ludwig Maximilian University of Munich, we identified 72 patients (mean age = 47 years) with enduring vestibular symptoms following COVID‐19 vaccination. All underwent medical history‐taking, and neurological and neuro‐otological workup with bithermal caloric test, video head‐impulse test, orthoptics, and audiometry. Diagnoses were based on international criteria. The distribution of diagnoses was compared to a cohort of 39,964 patients seen before the COVID‐19 pandemic.

Results

Symptom onset was within the first 4 weeks postvaccination. The most prevalent diagnoses were somatoform vestibular disorders (34.7%), vestibular migraine (19.4%), and overlap syndromes of both (18.1%). These disorders were significantly overrepresented compared to the prepandemic control cohort. Thirty‐six percent of patients with somatoform complaints reported a positive history of depressive or anxiety disorders. Nine patients presented with benign paroxysmal positional vertigo, three with acute unilateral vestibulopathy, and seven with different entities (vestibular paroxysmia, Ménière disease, polyneuropathy, ocular muscular paresis). Causally related central vestibular deficits were lacking. Novel peripheral vestibular deficits were found in four patients.

Conclusions

Newly induced persistent vestibular deficits following COVID‐19 vaccination were rare. The predominant causes of prolonged vestibular complaints were somatoform vestibular disorders and vestibular migraine, possibly triggered or aggravated by stress‐related circumstances due to the COVID‐19 pandemic or vaccination. An increase of other central or peripheral vestibular syndromes after COVID‐19 vaccination was not observed.

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Authors:
Johannes Gerb, Sandra Becker‐Bense, Andreas Zwergal and Doreen Huppert
Article first published online:
21 Sep 2022 | DOI: 10.1111/ene.15546

ORIGINAL ARTICLE

Background and purpose

Ictal respiratory disturbances have increasingly been reported, in both generalized and focal seizures, especially involving the temporal lobe. Recognition of ictal breathing impairment has gained importance for the risk of sudden unexpected death in epilepsy (SUDEP). The aim of this study was to evaluate the incidence of ictal apnea (IA) and related hypoxemia during seizures.

Methods

We collected and analyzed electroclinical data from consecutive patients undergoing long‐term video‐electroencephalographic (video‐EEG) monitoring with cardiorespiratory polygraphy. Patients were recruited at the epilepsy monitoring unit of the Civil Hospital of Baggiovara, Modena Academic Hospital, from April 2020 to February 2022.

Results

A total of 552 seizures were recorded in 63 patients. IA was observed in 57 of 552 (10.3%) seizures in 16 of 63 (25.4%) patients. Thirteen (81.2%) patients had focal seizures, and 11 of 16 patients showing IA had a diagnosis of temporal lobe epilepsy; two had a diagnosis of frontal lobe epilepsy and three of epileptic encephalopathy. Apnea agnosia was reported in all seizure types. Hypoxemia was observed in 25 of 57 (43.9%) seizures with IA, and the severity of hypoxemia was related to apnea duration. Apnea duration was significantly associated with epilepsy of unknown etiology (magnetic resonance imaging negative) and with older age at epilepsy onset ( < 0.001).

Conclusions

Ictal respiratory changes are a frequent clinical phenomenon, more likely to occur in focal epilepsies, although detected even in patients with epileptic encephalopathy. Our findings emphasize the need for respiratory polygraphy during long‐term video‐EEG monitoring for diagnostic and prognostic purposes, as well as in relation to the potential link of ictal apnea with the SUDEP risk.

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Authors:
Elisa Micalizzi, Anna Elisabetta Vaudano, Alice Ballerini, Francesca Talami, Giada Giovannini, Giulia Turchi, Maria Cristina Cioclu, Leandra Giunta and Stefano Meletti
Article first published online:
17 Sep 2022 | DOI: 10.1111/ene.15547

EDITORIAL

What if I could become the doctor I always wanted to be?

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Authors:
Peter P. Pramstaller, Peter Berlit, Claudio L. A. Bassetti and Christine Klein
Article first published online:
23 Sep 2022 | DOI: 10.1111/ene.15548

ORIGINAL ARTICLE

Background and purpose

Circulating metabolites have been implicated in stroke pathogenesis, but their genetic determinants are understudied. Using a Mendelian randomization approach, our aim was to provide evidence for the relationship of circulating metabolites and the risk of stroke and its subtypes.

Methods

Genetic instruments of 102 circulating metabolites were obtained from a genome‐wide association study, including 24,925 European individuals. Stroke was extracted from the MEGASTROKE dataset (67,162 cases; 454,450 controls) and a lacunar stroke dataset (7338 cases; 254,798 controls). The magnetic resonance imaging markers of cerebral small vessel disease and microstructural injury were evaluated by a genome‐wide association study of white matter hyperintensities ( = 18,381), fractional anisotropy ( = 17,663), mean diffusivity ( = 17,467) and brain microbleeds ( = 25,862). The inverse‐variance weighted method Mendelian randomization was used as the primary analytical method, and directional pleiotropy and heterogeneity were examined in sensitivity analyses.

Results

A genetic predisposition to a higher level of cholesterol in small and low‐density lipoprotein (LDL) was associated with risk of stroke (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.08–1.21,  = 5.98 × 10), especially for large‐artery atherosclerotic stroke (OR 1.34, 95% CI 1.19–1.52,  = 1.90 × 10). Total lipids in LDL particles were also associated with risk of stroke. A genetically determined higher cholesterol level in high‐density lipoprotein (HDL‐C) was associated with risk of intracerebral haemorrhage (OR 1.74, 95% CI 1.23–2.45,  = 1.66 × 10). No statistically significant association was found between genetic predisposition to circulating metabolites and magnetic resonance imaging markers of cerebral small vessel disease and microstructural injury.

Conclusions

Genetically determined levels of lipids in small LDL were associated with the risk of stroke, suggesting that a therapeutic strategy targeting small LDL levels may be crucial for stroke prevention. HDL‐C was positively associated with the risk of intracerebral haemorrhage.

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Authors:
Rong‐Ze Wang, Shu‐Yi Huang, Hong‐Qi Li, Yu‐Xiang Yang, Shi‐Dong Chen and Jin‐Tai Yu
Article first published online:
23 Sep 2022 | DOI: 10.1111/ene.15549

EDITORIAL

A call for translational science, longitudinal studies, and high‐quality clinical trials

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Authors:
Claudia Sommer
Article first published online:
21 Sep 2022 | DOI: 10.1111/ene.15550

ORIGINAL ARTICLE

Background and purpose

Epileptic seizures occur more often in patients with multiple sclerosis (MS) than in the general population. Their association with the prognosis of MS remains unclear. This study was undertaken to evaluate whether epileptic seizures may be a prognostic marker of MS disability, according to when the seizure occurs and its cause.

Methods

Data were extracted from a population‐based registry of MS in Lorraine, France. Kaplan–Meier curves and log‐rank tests were used to compare the probability of different levels of irreversible handicap during the course of MS in patients who experience epileptic seizures or do not, according to the chronology and the cause of the first epileptic seizure.

Results

Among 6238 patients, 134 had experienced at least one epileptic seizure (2.1%), and 82 (1.2%) had seizures secondary to MS. Patients with epileptic seizure as a first symptom of MS (14 patients) had the same disease progression as other relapsing–remitting MS patients. Patients who developed epileptic seizures during the course of MS (68 patients) had a higher probability of reaching Expanded Disability Status Scale = 3.0 ( = 0.006), 6.0 ( = 0.003), and 7.0 ( = 0.004) than patients without an epileptic background. Patients with a history of epileptic seizures unrelated to MS also had a worse prognosis than patients without an epileptic background.

Conclusions

Epileptic seizures might be viewed as a “classic MS relapse” in terms of prognosis if occurring early in MS, or as a marker of MS severity if developing during the disease. Epileptic diseases other than MS may worsen the course of MS.

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Authors:
Marion Selton, Guillaume Mathey, Marc Soudant, Philippe Manceau, René Anxionnat, Marc Debouverie and Jacques Jonas
Article first published online:
25 Sep 2022 | DOI: 10.1111/ene.15551

ORIGINAL ARTICLE

Background and purpose

GGC repeat expansions have been identified to be associated with essential tremor (ET). Our aim was to characterize ET patients with repeat expansions versus non‐expansions and describe distinctive clinical features of repeat expanded patients with long‐term follow‐up according to the new tremor classification.

Methods

Participants included 597 ET pedigrees, 412 sporadic cases and 1085 healthy controls. Repeat expansions of GGC in were screened, and comprehensive clinical features were investigated. A longitudinal clinical assessment and reclassification were performed in expanded patients.

Results

In total, 27 ET pedigrees (27/597) and three sporadic patients (3/412) were identified with pathogenic GGC repeat expansions (≥60 repeats). Intermediate‐length GGC repeats (41–59 repeats) were found in four sporadic ET cases and one control subject, and the frequency was higher than that in control participants (4/412 vs. 1/1085,  = 0.022). About 46 ET patients (43 familial cases from 27 pedigrees and three sporadic cases) with GGC repeat expansions had higher Essential Tremor Rating Assessment Scale I, Essential Tremor Rating Assessment Scale II and Non‐Motor Symptoms Scale scores and lower Mini‐Mental State Examination scores than the patients without expansions. Patients with pathogenic GGC repeats were reclassified as pure ET (25/46), ET‐plus (11/46) and ET‐neuronal intranuclear inclusion disease (10/46) subgroups at 2–8 years of follow‐up.

Conclusion

Our results further supported that GGC repeat expansions were associated with ET. Patients with pathogenic GGC repeats presented with more severe motor and non‐motor symptoms. Further long‐term follow‐up and subtype studies will help to define the role of in ET.

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Authors:
Xun Zhou, Hongyan Huang, Runcheng He, Sheng Zeng, Zhenhua Liu, Qian Xu, Jifeng Guo, Xinxiang Yan, Ranhui Duan, Jinchen Li, Beisha Tang, Yanming Xu and Qiying Sun
Article first published online:
25 Sep 2022 | DOI: 10.1111/ene.15552

ORIGINAL ARTICLE

Background and purpose

We evaluated the clinical and neurophysiological efficacy of rituximab (RTX) in a neurophysiologically homogeneous group of patients with monoclonal gammopathy and immunoglobulin M (IgM) anti‐myelin‐associated glycoprotein antibody (anti‐MAG) demyelinating polyneuropathy.

Methods

Twenty three anti‐MAG‐positive polyneuropathic patients were prospectively evaluated before and for 2 years after treatment with RTX 375 mg/m. The Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale (INCAT‐ds), modified INCAT sensory score (mISS), Medical Research Council sum score, Patients’ Global Impression of Change scale were used, IgM levels were assessed and extensive electrophysiological examinations were performed before (T0) and 1 year (T1) and 2 years (T2) after RTX treatment.

Results

At T1 and T2 there was a significant reduction from T0 both in mISS and in INCAT‐ds, with a  value < 0.001 in the inferential Friedman's test overall analysis. Ulnar nerve Terminal Latency Index and distal motor latency significantly changed from T0 to T1 and in the overall analysis ( = 0.001 and  = 0.002), and ulnar nerve sensory nerve action potential (SNAP) amplitude was significantly increased at T2 from T1, with a  value < 0.001 in the overall analysis. Analysis of the receiver‐operating characteristic curves showed that a 41.8% increase in SNAP amplitude in the ulnar nerve at T2 from T0 was a fair predictor of a mISS reduction of ≥2 points (area under the curve 0.85;  = 0.005; sensitivity: 90.9%, specificity: 83.3%).

Conclusions

This study suggests that RTX is effective in patients with clinically active demyelinating anti‐MAG neuropathy over 2 years of follow‐up, and that some neurophysiological variables might be useful for monitoring this efficacy.

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Authors:
Mattia Parisi, Irene Dogliotti, Michele Clerico, Davide Bertuzzo, Giulia Benevolo, Lorella Orsucci, Irene Schiavetti, Roberto Cavallo, Federica Cavallo, Simone Ragaini, Alessandra Di Liberto, Martina Ferrante, Giulia Bondielli, Carlo Alberto Artusi, Daniela Drandi, Leonardo Lopiano, Bruno Ferrero and Simone Ferrero
Article first published online:
25 Sep 2022 | DOI: 10.1111/ene.15553

ORIGINAL ARTICLE

Background and purpose

Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID‐19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID‐19 in MS patients and identify all factors associated with their manifestation.

Method

Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number.

Results

From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID‐19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98;  = 0.005) and more in smoker patients (OR 1.39;  = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24;  = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20;  = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24;  = 0.008). Some disease‐modifying therapies were associated with greater frequencies of certain COVID‐19 symptoms (association between anti‐CD20 therapies and increment in the number of concomitant symptoms: OR 1.29;  = 0.05). Differences in frequencies between the three waves were found for flu‐like symptoms (G1,  = 0.024), joint or muscle pain (G2,  = 0.013) and ageusia and anosmia (G5,  < 0.001). All cases should be referred to variants up to Delta.

Conclusion

Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID‐19 symptoms.

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Authors:
Irene Schiavetti, Luca Carmisciano, Marta Ponzano, Cinzia Cordioli, Eleonora Cocco, Girolama Alessandra Marfia, Matilde Inglese, Massimo Filippi, Marta Radaelli, Roberto Bergamaschi, Paolo Immovilli, Marco Capobianco, Nicola De Rossi, Giampaolo Brichetto, Cinzia Scandellari, Paola Cavalla, Ilaria Pesci, Paolo Confalonieri, Paola Perini, Maria Trojano, Roberta Lanzillo, Gioacchino Tedeschi, Giancarlo Comi, Mario Alberto Battaglia, Francesco Patti, Marco Salvetti, Maria Pia Sormani, Gianmarco Abbadessa, Umberto Aguglia, Lia Allegorico, Beatrice Maria Rossi Allegri, Anastasia Alteno, Maria Pia Amato, Pietro Annovazzi, Carlo Antozzi, Lucia Appendino, Sebastiano Arena, Viola Baione, Roberto Balgera, Valeria Barcella, Damiano Baroncini, Caterina Barrilà, Alessandra Bellacosa, Gianmarco Bellucci, Valeria Bergamaschi, Daiana Bezzini, Beatrice Biolzi, Alvino Bisecco, Simona Bonavita, Giovanna Borriello, Chiara Bosa, Antonio Bosco, Francesca Bovis, Marco Bozzali, Laura Brambilla, Vincenzo Brescia Morra, Maria Buccafusca, Elisabetta Bucciantini, Sebastiano Bucello, Maria Chiara Buscarinu, Maria Paola Cabboi, Massimiliano Calabrese, Francesca Calabria, Francesca Caleri, Federico Camilli, Luisa Maria Caniatti, Roberto Cantello, Ruggero Capra, Rocco Capuano, Patrizia Carta, Maria Grazia Celani, Maria Cellerino, Raffaella Cerqua, Clara Chisari, Raffaella Clerici, Marinella Clerico, Gaia Cola, Antonella Conte, Marta Zaffira Conti, Christian Cordano, Susanna Cordera, Francesco Corea, Claudio Correale, Salvatore Cottone, Francesco Crescenzo, Erica Curti, Alessandro d’Ambrosio, Emanuele D’Amico, Maura Chiara Danni, Alessia d’Arma, Vincenzo Dattola, Stefano de Biase, Giovanna De Luca, Stefania Federica De Mercanti, Paolo De Mitri, Nicola De Stefano, Fabio Maria Della Cava, Marco Della Cava, Sonia Di Lemme, Mario di Napoli, Alessia Di Sapio, Renato Docimo, Anna Dutto, Luana Evangelista, Salvatore Fanara, Roberta Fantozzi, Diana Ferraro, Maria Teresa Ferrò, Cristina Fioretti, Mario Fratta, Jessica Frau, Marzia Fronza, Roberto Furlan, Alberto Gajofatto, Antonio Gallo, Paolo Gallo, Claudio Gasperini, Anna Ghazaryan, Bruno Giometto, Francesca Gobbin, Flora Govone, Franco Granella, Erica Grange, Maria Grazia Grasso, Luigi M. E. Grimaldi, Angelica Guareschi, Clara Guaschino, Simone Guerrieri, Donata Guidetti, Ina Barbara Juergenson, Pietro Iaffaldano, Antonio Ianniello, Luigi Iasevoli, Daniele Imperiale, Maria Teresa Infante, Rosa Iodice, Aniello Iovino, Giovanna Konrad, Doriana Landi, Caterina Lapucci, Luigi Lavorgna, Maria Rita L’Episcopo, Serena Leva, Giuseppe Liberatore, Marianna Lo Re, Marco Longoni, Leonardo Lopiano, Lorena Lorefice, Matteo Lucchini, Giacomo Lus, Davide Maimone, Maria Malentacchi, Giulia Mallucci, Simona Malucchi, Chiara Rosa Mancinelli, Luca Mancinelli, Paolo Manganotti, Giorgia Teresa Maniscalco, Vittorio Mantero, Sabrina Marangoni, Damiano Marastoni, Fabiana Marinelli, Alessandro Marti, Filippo Boneschi Martinelli, Zoli Federco Masserano, Francesca Matta, Laura Mendozzi, Giuseppe Meucci, Silvia Miante, Giuseppina Miele, Eva Milano, Massimiliano Mirabella, Rosanna Missione, Marcello Moccia, Lucia Moiola, Sara Montepietra, Margherita MontiBragadin, Federico Montini, Roberta Motta, Raffaele Nardone, Carolina Gabri Nicoletti, Eduardo Nobile‐Orazio, Agostino Nozzolillo, Marco Onofrj, Riccardo Orlandi, Anna Palmieri, Damiano Paolicelli, Livia Pasquali, Luisa Pastò, Elisabetta Pedrazzoli, Maria Petracca, Alfredo Petrone, Carlo Piantadosi, Anna M. Pietroboni, Federica Pinardi, Emilio Portaccio, Mattia Pozzato, Carlo Pozzilli, Luca Prosperini, Alessandra Protti, Paolo Ragonese, Sarah Rasia, Sabrina Realmuto, Anna Repice, Eleonora Rigoni, Maria Teresa Rilla, Francesca Rinaldi, Calogero Marcello Romano, Marco Ronzoni, Marco Rovaris, Francesca Ruscica, Loredana Sabattini, Giuseppe Salemi, Lorenzo Saraceno, Alessia Sartori, Arianna Sartori, Elvira Sbragia, Giuditta Ilaria Scarano, Valentina Scarano, Maria Sessa, Caterina Sgarito, Grazia Sibilia, Gabriele Siciliano, Alessio Signori, Elisabetta Signoriello, Leonardo Sinisi, Francesca Sireci, Patrizia Sola, Claudio Solaro, Stefano Sotgiu, Maddalena Sparaco, Maria Laura Stromillo, Silvia Strumia, Emanuela Laura Susani, Giulietta Tabiadon, Francesco Teatini, Valentina Tomassini, Simone Tonietti, Valentina Torri, Carla Tortorella, Simona Toscano, Rocco Totaro, Maria Trotta, Gabriella Turano, Monica Ulivelli, Manzo Valentino, Giovanna Vaula, Domizia Vecchio, Marco Vercellino, Elena Pinuccia Verrengia, Marika Vianello, Eleonora Virgilio, Francesca Vitetta, Stefano Vollaro, Mauro Zaffaroni, Mauro Zampolini, Ignazio Roberto Zarbo, Antonio Zito and Luigi Zuliani
Article first published online:
23 Sep 2022 | DOI: 10.1111/ene.15554

COMMENTARY

Sleep disorders and increased risk of dementia

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Authors:
Luigi Ferini‐Strambi
Article first published online:
21 Sep 2022 | DOI: 10.1111/ene.15562

LETTER TO THE EDITOR

Response to Geroin et al.: Tapping into the mechanisms of abnormal functional postural control

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Authors:
Jan Coebergh, Ioanna Zimianiti, Toby J. Ellmers and Diego Kaski
Article first published online:
11 Oct 2022 | DOI: 10.1111/ene.15578