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Article first published online:
05 Mar 2023 | DOI: 10.1111/ene.15395

REVIEW ARTICLE

Economic burden of Huntington disease in Europe and the USA: Results from the Huntington's Disease Burden of Illness study

Background and purpose

The prevalence of Huntington disease (HD) has increased over time; however, there is a lack of up‐to‐date evidence documenting the economic burden of HD by disease stage. This study provides an estimate of the annual direct medical, nonmedical, and indirect costs associated with HD from participants in the Huntington's Disease Burden of Illness (HDBOI) study in five European countries and the USA.

Methods

The HDBOI is a retrospective, cross‐sectional study. Data collection was conducted between September 2020 and May 2021. Participants were recruited by their HD‐treating physicians and categorized as early stage (ES), mid stage (MS), or advanced stage (AS) HD. Data were collected via three questionnaires: a case report form, completed by physicians who collected health care resource use associated with HD to compute direct medical cost, and optional patient and caregiver questionnaires, which included information used to compute nondirect medical and indirect costs. Country‐specific unit cost sources were used.

Results

HDBOI cost estimates were €12,663 ( = 2094) for direct medical costs, €2984 ( = 359) for nondirect medical costs, and €47,576 ( = 436) for indirect costs. Costs are higher in patients who are at later stages of disease; for example, direct medical costs estimates were €9220 ( = 846), €11,885 ( = 701), and €18,985 ( = 547) for ES, MS, and AS, respectively. Similar trends were observed for nondirect and indirect costs. Costs show large variations between patients and countries.

Conclusions

Cost estimates from the HDBOI study show that people with HD and their caregivers bear a large economic burden that increases as disease progresses.

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Authors:
Idaira Rodríguez‐Santana, Tiago Mestre, Ferdinando Squitieri, Rosa Willock, Astri Arnesen, Alison Clarke, Barbara D'Alessio, Alex Fisher, Rebecca Fuller, Jamie L. Hamilton, Hayley Hubberstey, Cath Stanley, Louise Vetter, Michaela Winkelmann, Maria Doherty, Yunchou Wu, Alan Finnegan and Samuel Frank

Article first published online:
08 Dec 2022 | DOI: 10.1111/ene.15645

REVIEW ARTICLE

Anti‐neurochondrin antibody as a biomarker in primary autoimmune cerebellar ataxia—a case report and review of the literature

Background and purpose

Neuronal autoantibodies can support the diagnosis of primary autoimmune cerebellar ataxia (PACA). Knowledge of PACA is still sparce. This article aims to highlight the relevance of anti‐neurochondrin antibodies and possible therapeutical consequences in people with PACA.

Methods

This is a case presentation and literature review of PACA associated with anti‐neurochondrin antibodies.

Results

A 33‐year‐old man noticed reduced control of the right leg in May 2020. During his first clinic appointment at our institution in September 2021, he complained about gait imbalance, fine motor disorders, tremor, intermittent diplopia and slurred speech. He presented a pancerebellar syndrome with stance, gait and limb ataxia, scanning speech and oculomotor dysfunction. Within 3 months the symptoms progressed. An initial cerebral magnetic resonance imaging, June 2020, was normal, but follow‐up imaging in October 2021 and July 2022 revealed marked cerebellar atrophy (29% volume loss). Cerebrospinal fluid analysis showed lymphocytic pleocytosis of 11 x 10/L (normal range 0–4) and oligoclonal bands type II. Anti‐neurochondrin antibodies (immunoglobulin G) were detected in serum (1:10,000) and cerebrospinal fluid (1:320, by cell‐based indirect immunofluorescence assay and immunoblot, analysed by the EUROIMMUN laboratory). After ruling out alternative causes and neoplasia, diagnosis of PACA was given and immunotherapy (steroids and cyclophosphamide) was started in January 2022. In March 2022 a stabilization of disease was observed.

Conclusion

Cerebellar ataxia associated with anti‐neurochondrin antibodies has only been described in 19 cases; however, the number of unrecognized PACAs may be higher. As anti‐neurochondrin antibodies target an intracellular antigen and exhibit a mainly cytotoxic T‐cell‐mediated pathogenesis, important therapeutic implications may result. Because of the severe and rapid clinical progression, aggressive immunotherapy was warranted. This case highlights the need for rapid diagnosis and therapy in PACA, as stabilization and even improvement of symptoms are attainable.

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Authors:
Anina Schwarzwald, Anke Salmen, Alejandro Xavier León Betancourt, Lara Diem, Helly Hammer, Piotr Radojewski, Michael Rebsamen, Nicole Kamber, Andrew Chan, Robert Hoepner and Christoph Friedli

Article first published online:
07 Dec 2022 | DOI: 10.1111/ene.15648

REVIEW ARTICLE

Comparative efficacy and safety of monoamine oxidase type B inhibitors plus channel blockers and monoamine oxidase type B inhibitors as adjuvant therapy to levodopa in the treatment of Parkinson's disease: a network meta‐analysis of randomized controlled trials

Background and purpose

The monoamine oxidase type B inhibitors plus channel blockers (MAO‐BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO‐BIs plus and conventional MAO‐BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD).

Method

Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta‐analysis was conducted.

Results

Thirty‐one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO‐BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26–4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45–3.87) for safinamide, 2.2 (0.98–3.64) for zonisamide and 2.04 (1.24–2.87) for rasagiline. No significant difference was detected amongst MAO‐BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1 mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO‐BIs plus had a higher probability of being safer agents compared to conventional MAO‐BIs.

Conclusions

Monoamine oxidase type B inhibitors plus, conventional MAO‐BIs and the corresponding doses are similar in efficacy in PD treatment. MAO‐BIs plus might be safer than conventional MAO‐BIs. Head‐to‐head comparisons are needed for further investigation.

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Authors:
Rui Yan, Huihui Cai, Yusha Cui, Dongning Su, Guoen Cai, Fabin Lin and Tao Feng

Article first published online:
11 Dec 2022 | DOI: 10.1111/ene.15651

EDITORIAL

Novel cognitive screening tests to address new clinical priorities and cultural diversity

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Authors:
Jordi A. Matias‐Guiu and Alfonso Delgado‐Álvarez

Article first published online:
08 Dec 2022 | DOI: 10.1111/ene.15653

CASE REPORT

Meningoencephalitis due to in an immunocompromised patient: Case report

Abstract

The first case of meningoencephalitis due to in an immunocompromised patient is reported. Clinical and radiological characteristics are described, as well as the treatment and prognosis of the patient.

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Authors:
Javier Martinez‐Poles, Ana Isabel Saldaña‐Díaz, Jaime Esteban, Mónica Lara‐Almunia, Anthony Tito Vizarreta Figueroa, Leticia Martín‐Gil, José Cebrián‐Escudero and José Fernández‐Ferro

Article first published online:
26 Dec 2022 | DOI: 10.1111/ene.15659

ORIGINAL ARTICLE

Characterizing mutations in Spain: The impact of genotype, age and sex in the natural history of the disease

Background and purpose

The aim of this study was to describe the frequency and distribution of mutations in Spain, and to explore factors contributing to their phenotype and prognosis.

Methods

Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic variants. Multivariable models were used to explore prognostic modifiers.

Results

In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all five exons of , including seven novel mutations. A total of 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry mutations. The frequency of this mutation varied considerably among regions, due to founder events. The most frequent mutation was p.Gly38Arg ( = 58), followed by p.Glu22Gly ( = 11), p.Asn140His ( = 10), and the novel p.Leu120Val ( = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp[Estimate] = 1.03 [0.01, 0.05], = 0.001) and poorer survival (hazard ratio 1.05 [1.01, 1.08], = 0.007), regardless of the underlying mutation. Female sex was independently associated with faster disease progression (exp[Estimate] = 2.1 [1.23, 3.65], = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs. 301 months).

Conclusions

These data may help to evaluate the efficacy of targeted treatments, and to expand the number of patients that might benefit from these treatments.

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Authors:
Juan F. Vázquez‐Costa, Daniel Borrego‐Hernández, Carmen Paradas, María Teresa Gómez‐Caravaca, Ricardo Rojas‐Garcia, Luis Varona, Mónica Povedano, Tania García‐Sobrino, Ivonne Jericó Pascual, Antonio Gutiérrez, Javier Riancho, Janina Turon‐Sans, Abdelilah Assialioui, Jordi Pérez‐Tur, Teresa Sevilla, Jesús Esteban Pérez, Alberto García‐Redondo, Alberto Andrés López, M. Dolores Calabria, Carmen Díaz‐Marín, Eva Fages Caravaca, Lucía Galán Dávila, Alberto García Martínez, Álvaro Gimenez‐Muñoz, Antonio Guerrero Sola, Javier Mascías Cadavid, Jesús S. Mora Pardina, José Luis Muñoz Blanco, Raúl Juntas‐Morales, Yolanda Morgado, Julio Pardo, Amador Valladares and Rosa Maria Vilar‐Ventura

Article first published online:
11 Jan 2023 | DOI: 10.1111/ene.15661

ORIGINAL ARTICLE

Quantitative proteomic analysis of cerebrospinal fluid from patients with idiopathic facial nerve palsy

Background and purpose

Idiopathic facial palsy (IFP) accounts for over 60% of peripheral facial palsy (FP) cases. The cause of IFP remains to be determined. Possible etiologies are nerve swelling due to inflammation and/or viral infection. In this study, we applied an integrative mass spectrometry approach to identify possibly altered protein patterns in the cerebrospinal fluid (CSF) of IFP patients.

Methods

We obtained CSF samples from 34 patients with FP. In four patients, varicella‐zoster virus was the cause (VZV‐FP). Among the 30 patients diagnosed with IFP, 17 had normal CSF parameters, five had slightly elevated CSF cell counts and normal or elevated CSF protein, and eight had normal CSF cell counts but elevated CSF protein. Five patients with primary headache served as controls. All samples were tested for viral pathogens by PCR and subjected to liquid chromatography tandem mass spectrometry and bioinformatics analysis and multiplex cytokine/chemokine arrays.

Results

All CSF samples, except those from VZV‐FP patients, were negative for all tested pathogens. The protein composition of CSF samples from IFP patients with normal CSF was comparable to controls. IFP patients with elevated CSF protein showed dysregulated proteins involved in inflammatory pathways, findings which were similar to those in VZV‐FP patients. Multiplex analysis revealed similarly elevated cytokine levels in the CSF of IFP patients with elevated CSF protein and VZV‐FP.

Conclusions

Our study revealed a subgroup of IFP patients with elevated CSF protein that showed upregulated inflammatory pathways, suggesting an inflammatory/infectious cause. However, no evidence for an inflammatory cause was found in IFP patients with normal CSF.

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Authors:
Ilias Masouris, Matthias Klein, Barbara Angele, Birgit Groß, Neha Goswami, Fathima Mashood, Manuela Gesell Salazar, Sören Schubert, Hans‐Walter Pfister, Uwe Koedel and Frank Schmidt

Article first published online:
01 Jan 2023 | DOI: 10.1111/ene.15663

ORIGINAL ARTICLE

The decline in stroke hospitalization due to COVID‐19 is unrelated to COVID‐19 intensity

Background and Purpose

During the coronavirus disease 2019 (COVID‐19) pandemic many countries reported a decline in stroke volumes. The aim of this study was to analyze if the decline was related to the intensity of the COVID‐19 pandemic.

Methods

The first pandemic year (1 March 2020 to 28 February 2021) overall and during the three COVID‐19 waves were compared with the preceding year. Volumes of acute ischaemic stroke (AIS), subarachnoid hemorrhage, intracerebral hemorrhage and recanalization treatments (intravenous thrombolysis [IVT] and mechanical thrombectomy [MT]) were obtained from the National Register of Reimbursed Health Services. Door‐to‐needle time, onset‐to‐door time and National Institutes of Health Stroke Scale at admission were obtained from the Registry of Stroke Care Quality.

Results

During the pandemic year compared to the preceding year there were 26,453 versus 28,771 stroke admissions, representing an 8.8% decline ( < 0.001). The declines (−10%, −11%, −19%) appeared in COVID‐19 waves (spring 2020, autumn 2020, winter 2021) except for an increase (2%) during summer 2020. Admissions for AIS declined by 10.2% ( < 0.001), whilst hemorrhagic stroke volumes were minimally decreased. The absolute volumes of IVT and MT decreased by 9.4% ( < 0.001) and 5.7% ( = 0.16), respectively. However, the proportions of ischaemic stroke patients receiving IVT (18% vs. 18%; = 0.72) and MT (6% vs. 6%; = 0.28) remained unchanged.

Conclusions

There was a decline in stroke admissions, but such decline was not related to COVID‐19 incidence. The frequency of use of recanalization procedures (IVT, MT) and times (onset‐to‐door time, door‐to‐needle time) in AIS were preserved in the Czech Republic during the first year of the pandemic.

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Authors:
Petra Sedova, Julia Anna Kent, Tomas Bryndziar, Jiri Jarkovsky, Ales Tomek, Martin Sramek, Ondrej Skoda, Tereza Sramkova, Kateřina Pokorová, Simona Littnerova, Robert D. Brown and Robert Mikulik

Article first published online:
28 Dec 2022 | DOI: 10.1111/ene.15664

ORIGINAL ARTICLE

Repetitive transcranial magnetic stimulation for hypokinetic dysarthria in Parkinson's disease enhances white matter integrity of the auditory–motor loop

Background and purpose

In our previous study, repeated sessions of repetitive transcranial magnetic stimulation (rTMS) over the auditory feedback area were shown to improve hypokinetic dysarthria (HD) in Parkinson's disease (PD) and led to changes in functional connectivity within the left‐sided articulatory networks. We analyzed data from this previous study and assessed the effects of rTMS for HD in PD on the diffusion parameters of the left anterior arcuate fasciculus (AAF), which connects the auditory feedback area with motor regions involved in articulation.

Methods

Patients were assigned to 10 sessions of real or sham 1‐Hz stimulation over the right posterior superior temporal gyrus. Stimulation effects were evaluated using magnetic resonance diffusion tensor imaging and by a speech therapist using a validated tool (Phonetics score of the Dysarthric Profile) at baseline, immediately after 2 weeks of stimulation, and at follow‐up visits at Weeks 6 and 10 after the baseline.

Results

Altogether, data from 33 patients were analyzed. A linear mixed model revealed significant time‐by‐group interaction ( = 0.006) for the relative changes of fractional anisotropy of the AAF; the value increases were associated with the temporal evolution of the Phonetics score ( = 0.367, = 0.028) in the real stimulation group.

Conclusions

Real rTMS treatment for HD in PD as compared to sham stimulation led to increases of white matter integrity of the auditory–motor loop during the 2‐month follow‐up period. The changes were related to motor speech improvements.

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Authors:
Lubos Brabenec, Patrik Simko, Alzbeta Sejnoha Minsterova, Milena Kostalova and Irena Rektorova

Article first published online:
28 Dec 2022 | DOI: 10.1111/ene.15665

ORIGINAL ARTICLE

Smartphone and custom‐made software to assess the effect of botulinum toxin in essential blepharospasm: Initial results

Background and purpose

It is challenging to assess essential blepharospasm (EB) patients objectively because they exhibit chaotic patterns of abnormal eyelid movements. Previously employed objective approaches used systems with low levels of accuracy systems or were too complex to be applied in routine clinical practice. We aimed to develop a practical tool using a smartphone camera and custom‐made software to objectively assess the therapeutic effects of botulinum toxin in blepharospasm patients.

Methods

Thirty‐four patients with EB were evaluated before and 15 days after receiving onabotulinumtoxinA injections. The control group was composed of 19 age‐matched healthy individuals. A smartphone (iPhone 6 S; Apple) was used to record spontaneous eyelid movements for 3 min, after which eyelid movement frequency was analysed using custom‐made software.

Results

Before treatment, eyelid movement frequency was significantly higher in the EB group (21.55 ± 13.30 movements/min) compared to the control group (8.26 ± 8.89 eyelid movements/min; < 0.001). The frequency of spontaneous eyelid movements was significantly reduced after treatment in the EB patients (8.46 ± 6.32 eyelid movements/min; < 0.001). After treatment, no statistically significant difference in eyelid movement rate was observed between the EB patients and the control group ( = 0.32).

Conclusions

Assessment of the spontaneous eyelid movements obtained with the smartphone camera and analysed with the custom‐made software enabled us to objectively measure the therapeutic effects of botulinum toxin in patients with blepharospasm. Further refinement of this system could enable customized and fine adjustments to botulinum toxin doses based on each patient's needs.

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Authors:
Cristina Yabumoto, Midori H. Osaki, Gustavo R. Gameiro, Suzana Matayoshi, Mauro Campos and Tammy H. Osaki

Article first published online:
12 Jan 2023 | DOI: 10.1111/ene.15666

ORIGINAL ARTICLE

Baseline free water within the visual processing system predicts future psychosis in Parkinson disease

Background and purpose

As psychosis is associated with decreased quality of life, increased institutionalization, and mortality in Parkinson disease (PD), it is essential to identify individuals at risk for future psychosis. This longitudinal study aimed to investigate whether diffusion tensor imaging (DTI) metrics of white matter hold independent utility for predicting future psychosis in PD, and whether they could be combined with clinical predictors to improve the prognostication of PD psychosis.

Methods

This study included 123 newly diagnosed PD patients collected in the Parkinson's Progression Markers Initiative. Tract‐based spatial statistics were used to compare baseline DTI metrics between PD patients who developed psychosis and those who did not during follow‐up. Binary logistic regression analyses were performed to identify the clinical and white matter markers predictive of psychosis.

Results

Among DTI measures, both higher baseline whole brain (odds ratio [OR] = 1.711, = 0.016) free water (FW) and visual processing system (OR = 1.680, < 0.001) FW were associated with an increased risk of future psychosis. Baseline FW remained a significant indicator of future psychosis in PD after controlling for clinical predictors. Moreover, the accuracy of prediction of psychosis using clinical predictors alone (area under the curve [AUC] = 0.742, 95% confidence interval [CI] = 0.655–0.816) was significantly improved by the addition of the visual processing system FW (AUC = 0.856, 95% CI = 0.781–0.912; Delong method, = 0.022).

Conclusions

Baseline FW of the visual processing system incurs an independent risk of future psychosis in PD, thus providing an opportunity for multiple‐modality marker models to include a white matter marker.

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Authors:
Guanglu Li, Jiajia Zhu, Xingqi Wu, Tingting Liu, Panpan Hu, Yanghua Tian and Kai Wang

Article first published online:
17 Jan 2023 | DOI: 10.1111/ene.15668

ORIGINAL ARTICLE

Sporadic Creutzfeldt–Jakob disease is associated with reorganization of metabolic connectivity in a pathological brain network

Background and purpose

Although sporadic Creutzfeldt–Jakob disease (sCJD) is a rare cause of dementia, it is critical to understand its functional networks as the prion protein spread throughout the brain may share similar mechanisms with other more common neurodegenerative disorders. In this study, the metabolic brain network associated with sCJD was investigated and its internal network organization was explored.

Methods

We explored 2‐[F]fluoro‐2‐deoxy‐‐glucose positron emission tomography (FDG‐PET) brain scans of 29 sCJD patients, 56 normal controls (NCs) and 46 other dementia patients from two independent centers. sCJD‐related pattern (CJDRP) was identified in a cohort of 16 pathologically proven sCJD patients and 16 age‐matched NCs using scaled subprofile modeling/principal component analysis and was prospectively validated in an independent cohort of 13 sCJD patients and 20 NCs. The pattern's specificity was tested on other dementia patients and its clinical relevance by clinical correlations. The pattern's internal organization was further studied using graph theory methods.

Results

The CJDRP was characterized by relative hypometabolism in the bilateral caudate, thalami, middle and superior frontal gyri, parietal lobe and posterior cingulum in association with relative hypermetabolism in the hippocampi, parahippocampal gyri and cerebellum. The pattern's expression significantly discriminated sCJD from NCs and other dementia patients ( < 0.005; receiver operating characteristic analysis CJD vs. NCs area under the curve [AUC] 0.90–0.96, sCJD vs. Alzheimer's disease AUC 0.78, sCJD vs. behavioral variant of frontotemporal dementia AUC 0.84). The pattern's expression significantly correlated with cognitive, functional decline and disease duration. The metabolic connectivity analysis revealed inefficient information transfer with specific network reorganization.

Conclusions

The CJDRP is a robust metabolic biomarker of sCJD. Due to its excellent clinical correlations it has the potential to monitor disease in emerging disease‐modifying trials.

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Authors:
Tomaž Rus, Jernej Mlakar, Luka Ležaić, An Vo, Nha Nguyen, Chris Tang, Michele Fiorini, Elena Prieto, Gloria Marti‐Andres, Javier Arbizu, David Eidelberg and Maja Trošt

Article first published online:
12 Jan 2023 | DOI: 10.1111/ene.15669

ORIGINAL ARTICLE

Eptinezumab improved patient‐reported outcomes and quality of life in patients with migraine and prior preventive treatment failures

Background and purpose

In the phase 3b, randomized, double‐blind, placebo‐controlled DELIVER clinical trial, eptinezumab reduced migraine frequency and headache in adults with two to four prior preventive treatment failures. Here, the effect of eptinezumab on coinciding patient‐reported outcomes is reported.

Methods

Adults were randomized to receive eptinezumab 100, 300 mg or placebo intravenously at weeks 12 and 24. The EQ‐5D‐5L, measuring overall patient health, and the six‐item Headache Impact Test were completed every 4 weeks. The Patient Global Impression of Change was completed at weeks 4, 12 and 24. Patient‐identified most bothersome symptom and the Migraine‐Specific Quality of Life Questionnaire were administered at weeks 12 and 24.

Results

Eptinezumab improved patient‐reported outcomes more than placebo, starting at week 4 and at all subsequent time points. By week 12, patients’ overall health (EQ‐5D‐5L visual analog scale score) improved with eptinezumab treatment (difference from placebo in change from baseline: 100 mg, 5.1, 95% confidence interval [CI] 2.2, 8.1, < 0.001; 300 mg, 7.5, 95% CI 4.5, 10.4, < 0.0001). At week 12, eptinezumab improved headache‐related quality of life (difference from placebo in change from baseline in Headache Impact Test total score: 100 mg, −3.8, 95% CI −5.0, −2.5, < 0.0001; 300 mg, −5.4, 95% CI −6.7, −4.2, < 0.0001), including each Migraine‐Specific Quality of Life Questionnaire domain ( ≤ 0.0001, all comparisons). Over twice as many patients receiving eptinezumab than placebo reported much or very much improvement on the Patient Global Impression of Change and patient‐identified most bothersome symptom.

Conclusion

Patients with two to four prior preventive treatment failures receiving eptinezumab versus placebo reported greater improvements in well‐being, quality of life and most bothersome symptoms compared to placebo.

Trial registration

ClinicalTrials.gov identifier: NCT04418765; EudraCT identifier: 2019‐004497‐25.

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Authors:
Peter J. Goadsby, Piero Barbanti, Giorgio Lambru, Anders Ettrup, Cecilie Laurberg Christoffersen, Mette Krog Josiassen, Ravinder Phul and Bjørn Sperling

Article first published online:
21 Jan 2023 | DOI: 10.1111/ene.15670

ORIGINAL ARTICLE

European Society for the Study of Tourette Syndrome 2022 criteria for clinical diagnosis of functional tic‐like behaviours: International consensus from experts in tic disorders

Background and purpose

In 2020, health professionals witnessed a dramatic increase in referrals of young people with rapid onset of severe tic‐like behaviours. We assembled a working group to develop criteria for the clinical diagnosis of functional tic‐like behaviours (FTLBs) to help neurologists, pediatricians, psychiatrists, and psychologists recognize and diagnose this condition.

Methods

We used a formal consensus development process, using a multiround, web‐based Delphi survey. The survey was based on an in‐person discussion at the European Society for the Study of Tourette Syndrome (ESSTS) meeting in Lausanne in June 2022. Members of an invited group with extensive clinical experience working with patients with Tourette syndrome and FTLBs discussed potential clinical criteria for diagnosis of FTLBs. An initial set of criteria were developed based on common clinical experiences and review of the literature on FTLBs and revised through iterative discussions, resulting in the survey items for voting.

Results

In total, 24 members of the working group were invited to participate in the Delphi process. We propose that there are three major criteria and two minor criteria to support the clinical diagnosis of FTLBs. A of FTLBs can be confirmed by the presence of all three major criteria. A of FTLBs can be confirmed by the presence of two major criteria and one minor criterion.

Conclusions

Distinguishing FTLBs from primary tics is important due to the distinct treatment paths required for these two conditions. A limitation of the ESSTS 2022 criteria is that they lack prospective testing of their sensitivity and specificity.

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Authors:
Tamara Pringsheim, Christos Ganos, Christelle Nilles, Andrea E. Cavanna, Donald L. Gilbert, Erica Greenberg, Andreas Hartmann, Tammy Hedderly, Isobel Heyman, Holan Liang, Irene Malaty, Osman Malik, Nanette Mol Debes, Kirsten Muller Vahl, Alexander Munchau, Tara Murphy, Peter Nagy, Tamsin Owen, Renata Rizzo, Liselotte Skov, Jeremy Stern, Natalia Szejko, Yulia Worbe and Davide Martino

Article first published online:
13 Jan 2023 | DOI: 10.1111/ene.15672

ORIGINAL ARTICLE

Amyotrophic lateral sclerosis regional progression intervals change according to time of involvement of different body regions

Background and purpose

The prediction of disease course is one of the main targets of amyotrophic lateral sclerosis (ALS) research, particularly considering its wide phenotypic heterogeneity. Despite many attempts to classify patients into prognostic categories according to the different spreading patterns at diagnosis, a precise regional progression rate and the time of involvement of each region has yet to be clarified. The aim of our study was to evaluate the functional decline in different body regions according to their time of involvement during disease course.

Methods

In a population‐based dataset of ALS patients, we analysed the functional decline in different body regions according to time and order of regional involvement. We calculated the regional progression intervals (RPIs) between initial involvement and severe functional impairment using the ALS Functional Rating Scale revised (ALSFRS‐r) subscores for the bulbar, upper limb, lower limb and respiratory/thoracic regions. Time‐to‐event analyses, adjusted for age, sex, ALSFRS‐r pre‐slope (ΔALSFRS‐R), cognitive status, and mutational status were performed.

Results

The duration of RPI differed significantly among ALS phenotypes, with the RPI of the first region involved being significantly longer than the RPIs of regions involved later. Cox proportional hazard models showed that in fact a longer time between disease onset and initial regional involvement was related to a reduced duration of the RPI duration in each different body region (bulbar region: hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.06–1.16, < 0.001; upper limb region: HR 1.16, 95% CI 1.06–1.28, = 0.002; lower limb region: HR 1.11, 95% CI 1.03–1.19, = 0.009; respiratory/thoracic region: HR 1.10, 95% CI 1.06–1.14, = 0.005).

Conclusions

We found that the progression of functional decline accelerates in regions involved later during disease course. Our findings can be useful in patient management and prognosis prediction.

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Authors:
Umberto Manera, Fabrizio D'Ovidio, Sara Cabras, Maria Claudia Torrieri, Antonio Canosa, Rosario Vasta, Francesca Palumbo, Maurizio Grassano, Fabiola De Marchi, Letizia Mazzini, Gabriele Mora, Cristina Moglia, Andrea Calvo and Adriano Chiò

Article first published online:
23 Jan 2023 | DOI: 10.1111/ene.15674

ORIGINAL ARTICLE

Analysis of co‐medication in people with dementia

Background and purpose

Dementia prevalence is increasing, with numbers projected to double by 2050. Risk factors for its development include age and cardiovascular comorbidities, which are found more often in patients with dementia and should be treated properly to improve outcomes. In this case–control study, we analysed a large population‐based prescription database to explore the patterns of co‐medication in patients with dementia.

Methods

Prescription claims covering >99% of the Austrian population from 2005 to 2016 were obtained. Patients who were treated with an approved antidementia drug (ADD) were included and co‐medication exposure was recorded. A group of people not taking ADDs was matched for age, sex and follow‐up duration as a control.

Results

We included 70,799 patients on ADDs who were exposed to a mean of 5.3 co‐medications while control patients were treated with a total of 5.2 co‐medications ( < 0.001). We found that patients on ADDs received less somatic (4.1 vs. 4.5) but more psychiatric medication (1.1 vs. 0.6; < 0.001 for both). Patients on ADDs were less likely to be treated for pain, cardiovascular conditions or hyperlipidemia. More than 50% of patients on ADDs were treated with antidepressants or antipsychotics. Greater number of co‐medications was associated with markers of more intensive antidementia treatment.

Conclusion

Patients on ADDs received more medications overall but were less frequently treated for somatic conditions known to be more prevalent in this group. Together, our data suggest that management of comorbidities in dementia could be improved to optimize outcome and quality of life.

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Authors:
Raphael Wurm, Tandis Parvizi, Stella Goeschl, Helena Untersteiner, Sara Silvaieh, Tanja Stamm, Hakan Cetin, Berthold Reichardt and Elisabeth Stögmann

Article first published online:
25 Jan 2023 | DOI: 10.1111/ene.15675

ORIGINAL ARTICLE

Clinical profiles and ethnic heterogeneity of sporadic fatal insomnia

Background and purpose

This study was undertaken to elucidate the clinical profile of sporadic fatal insomnia (sFI), assess the similarities and differences between sFI and fatal familial insomnia (FFI), and evaluate the influence of ethnicity on the phenotype of sFI patients.

Methods

The data of sFI and FFI patients were retrieved from our case series and through literature review. The clinical and diagnostic features of sFI and FFI were compared, as were the phenotypes of Asian and Caucasian sFI patients.

Results

We identified 44 sFI and 157 FFI cases. The prevalence of sleep‐related, neuropsychiatric, and autonomic symptoms among the sFI patients were 65.9%, 100.0%, and 43.2%, respectively. Compared to FFI, sFI exhibited longer disease duration and a higher proportion of neuropsychiatric symptoms, whereas FFI was characterized by a higher incidence of sleep‐related and autonomic symptoms in the early stages of the disease or throughout its course. In addition, a higher proportion of the sFI patients showed hyperintensity on magnetic resonance imaging (MRI) and periodic sharp wave complexes on electroencephalography compared to the FFI patients, especially those presenting with pathological changes associated with MM2‐cortical type sporadic Creutzfeldt–Jakob disease. The Asian sFI patients had a higher proportion of males and positivity for cerebrospinal fluid 14‐3‐3 protein, and fewer sleep‐related symptoms compared to Caucasian sFI patients. The age at onset and duration of sFI differed between ethnic groups, but the difference failed to reach statistical significance.

Conclusions

Despite its similarities to FFI, sFI is characterized by longer disease duration, higher proportion of neuropsychiatric symptoms, and hyperintensity on MRI, along with differences in the clinical characteristics based on ethnicity.

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Authors:
Zhongyun Chen, Min Chu, Jing Zhang, Yu Kong, Kexin Xie, Yue Cui, Hong Ye, Li Liu, Junjie Li, Lin Wang and Liyong Wu

Article first published online:
23 Jan 2023 | DOI: 10.1111/ene.15676

ORIGINAL ARTICLE

Chronic pain increases the risk of motoric cognitive risk syndrome at 4 years of follow‐up: evidence from the China Health and Retirement Longitudinal Study

Background and purpose

Slower gait speed and subjective cognitive concerns are characteristics of the motoric cognitive risk (MCR) syndrome. This study aimed to examine if changes in pain may be hallmarks of early MCR, through investigating the magnitude of the association of chronic pain and the risk of MCR at 4 years follow‐up.

Methods

In total, 3711 participants without dementia or any mobility disability aged ≥60 years were studied, including 1413 with chronic pain, enrolled in the China Health and Retirement Longitudinal Study, a prospective cohort study. MCR assessed at wave 1 (2011) and wave 3 (2015) was used as the exposure. Cox regression analysis was used to examine the longitudinal association between chronic pain and MCR after adjusting for individual factors, behaviors/physiology factors and societal factors. Four years later, the incident MCR was evaluated.

Results

After adjusting for individual factors, chronic pain was found to increase the risk of MCR development over time by about 1.5 times (hazard ratio 1.562, 95% confidence interval 1.228–1.986; < 0.001) and to be linked with incident MCR at baseline (odds ratio 1.397, 95% confidence interval 1.149–1.698; < 0.001). These associations remained substantial when behaviors/physiology factors and societal factors were taken into account in the analytical models.

Conclusions

The findings of our study imply that incident MCR may be exacerbated by chronic pain. Further exploration is required to find out whether chronic pain is a modifiable risk factor for MCR.

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Authors:
Haixu Liang and Ya Fang

Article first published online:
19 Jan 2023 | DOI: 10.1111/ene.15677

ORIGINAL ARTICLE

Response to erenumab assessed by Headache Impact Test‐6 is modulated by genetic factors and arterial hypertension: An explorative cohort study

Background and purpose

Response predictors to erenumab (ERE) in migraine patients would benefit their clinical management. We investigate associations between patients' clinical characteristics and polymorphisms at calcitonin receptor‐like receptor () and receptor activity‐modifying protein 1 () genes and response to ERE treatment measured as clinically meaningful improvement on the Headache Impact Test‐6 (HIT‐6) score.

Methods

This post hoc analysis of a prospective, multicenter, investigator‐initiated study involves 110 migraine patients starting ERE 70 mg/month. Demographics, medical history, and migraine‐related burden measured by HIT‐6 score were collected during 3 months before and after ERE start. Selected polymorphic variants of and genes were determined using real‐time polymerase chain reaction. Logistic regression models identified independent predictors for response to ERE, defined as HIT‐6 score improvement ≥ 8 points (HIT‐6 responders [HIT‐6 RESP] vs. HIT‐6 nonresponders).

Results

At Month 3, 58 (52.7%) patients were HIT‐6 RESP. Comorbid hypertension predicted a lower probability of being HIT‐6 RESP (odds ratio [OR] = 0.160, 95% confidence interval [CI] = 0.047–0.548, = 0.003). Compared to major alleles, minor alleles rs6710852G and rs6431564G conferred an increased probability of being HIT‐6 RESP (for each G allele: OR = 2.82, 95% CI = 1.03–7.73, = 0.043; OR = 2.10, 95% CI = 1.05–4.22, = 0.037). rs13386048A and rs12465864G decreased this probability (for each rs13386048A, OR = 0.53, 95% CI = 0.28–0.98, = 0.042; for each rs12465864G, OR = 0.32, 95% CI = 0.13–0.75, = 0.009). A genetic risk score based on the presence and number of identified risk alleles was independently associated with HIT‐6 RESP (OR = 0.49, 95% CI = 0.33–0.72, = 0.0003), surviving Bonferroni correction.

Conclusions

Response to ERE was associated with comorbid hypertension and specific allelic variants in and genes. Results require confirmation in future studies.

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Authors:
Chiara Zecca, Salvatore Terrazzino, Davide Para, Giovanna Campagna, Michele Viana, Christoph J. Schankin and Claudio Gobbi

Article first published online:
24 Jan 2023 | DOI: 10.1111/ene.15678

ORIGINAL ARTICLE

Retinal ganglion cell loss is associated with future disability worsening in early relapsing–remitting multiple sclerosis

Background and purpose

Thinning of the retinal combined ganglion cell and inner plexiform layer (GCIP) as measured by optical coherence tomography (OCT) is a common finding in patients with multiple sclerosis. This study aimed to investigate whether a single retinal OCT analysis allows prediction of future disease activity after a first demyelinating event.

Methods

This observational cohort study included 201 patients with recently diagnosed clinically isolated syndrome or relapsing–remitting multiple sclerosis from two German tertiary referral centers. Individuals underwent neurological examination, magnetic resonance imaging, and OCT at baseline and at yearly follow‐up visits.

Results

Patients were included at a median disease duration of 2.0 months. During a median follow‐up of 59 (interquartile range = 43–71) months, 82% of patients had ongoing disease activity as demonstrated by failing the no evidence of disease activity 3 (NEDA‐3) criteria, and 19% presented with confirmed disability worsening. A GCIP threshold of ≤77 μm at baseline identified patients with a high risk for NEDA‐3 failure (hazard ratio [HR] = 1.7, 95% confidence interval [CI] = 1.1–2.8, = 0.04), and GCIP measures of ≤69 μm predicted disability worsening (HR = 2.2, 95% CI = 1.2–4.3, = 0.01). Higher rates of annualized GCIP loss increased the risk for disability worsening (HR = 2.5 per 1 μm/year increase of GCIP loss, = 0.03).

Conclusions

Ganglion cell thickness as measured by OCT after the initial manifestation of multiple sclerosis may allow early risk stratification as to future disease activity and progression.

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Authors:
Josephine Wauschkuhn, Gilberto Solorza Buenrostro, Lilian Aly, Susanna Asseyer, Rebecca Wicklein, Julia Maria Hartberger, Klemens Ruprecht, Mark Mühlau, Tanja Schmitz‐Hübsch, Claudia Chien, Achim Berthele, Alexander U. Brandt, Thomas Korn, Friedemann Paul, Bernhard Hemmer, Hanna G. Zimmermann and Benjamin Knier

Article first published online:
29 Jan 2023 | DOI: 10.1111/ene.15681

LETTER TO THE EDITOR

High‐dose oral glutamine can reduce cerebrospinal fluid glutamate in mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes without a beneficial clinical or cerebral tissue effect

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Authors:
Josef Finsterer and Sounira Mehri

Article first published online:
22 Jan 2023 | DOI: 10.1111/ene.15682

LETTER TO THE EDITOR

Reply: High‐dose oral glutamine can reduce cerebrospinal fluid glutamate in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes without a beneficial clinical or cerebral tissue effect

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Authors:
María Paz Guerrero‐Molina, Cristina Domínguez‐González and Jesús González de la Aleja

Article first published online:
24 Jan 2023 | DOI: 10.1111/ene.15683

LETTER TO THE EDITOR

Sleep disorders and increased risk of dementia

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Authors:
Tomoyuki Kawada

Article first published online:
02 Feb 2023 | DOI: 10.1111/ene.15685

LETTER TO THE EDITOR

Autoantibody levels as biomarkers of disease activity in the management of myasthenia gravis

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Authors:
Hai‐Feng Li, Feng Gao and Xiang‐Jun Chen

Article first published online:
02 Feb 2023 | DOI: 10.1111/ene.15687

ORIGINAL ARTICLE

Long‐term favorable prognosis in late onset dominant distal titinopathy: Tibial muscular dystrophy

Background and purpose

Tibial muscular dystrophy (TMD) is a dominant late onset distal titinopathy. It was first described in Finnish patients 3 decades ago. TMD patients with several other mutations occur in many European populations. In this retrospective study, we were able to obtain longitudinal follow‐up data of the disease progression over 15 years in 137 TMD patients.

Methods

We retrieved clinical data retrospectively from three examinations spanning a period of 15 years. The data were analyzed in R. Frequencies, percentages, and median values were used to describe data. Probability values were determined with the chi‐squared test.

Results

In the cohort, the first symptoms were walking difficulties (97.8%) and weakness in distal lower limbs (98.5%). The progression of the weakness in distal lower limbs was moderate, and in the proximal lower limbs and proximal upper limbs it was mild. The distal upper limbs were not affected. Magnetic resonance imaging results indicated fatty degeneration preferentially in lower leg anterior muscles, gluteus minimus, and hamstring muscles. Serum creatine kinase values in the cohort were mostly normal (40.7%) or mildly elevated (53.7%). The data suggest that 50% of patients need walking aids by the age of 88 years.

Conclusions

Despite individual variability of severity, the overall disability due to walking difficulties and upper limb weakness remained moderate even at very advanced ages, and cardiomyopathy did not develop due to the titin defect alone. The acquired results promote the correct identification of TMD, and the obtained trajectories of disease evolution can be used as natural history data for any therapeutic intervention.

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Authors:
Victoria Lillback, Marco Savarese, Niina Sandholm, Peter Hackman and Bjarne Udd

Article first published online:
08 Feb 2023 | DOI: 10.1111/ene.15688

ORIGINAL ARTICLE

Independent effect of cardiometabolic syndromes and depression on dementia in Parkinson's disease: A 12‐year longitudinal follow‐up study of a nationwide cohort

Background

We aimed to investigate the incidence rate of Parkinson's disease dementia (PDD) according to age and disease duration by sex. Furthermore, we explored the effect of each cardiometabolic syndrome and depression on the incidence of PDD.

Methods

Using data from the Korean National Health Insurance Service, 79,622 patients with de novo Parkinson's disease (PD) aged ≥40 years between January 2002 and December 2010 were followed to December 2019. We analyzed the incidence of PDD according to age at PD diagnosis and disease duration. To determine cardiometabolic syndromes and depression that affected PDD, we used Fine and Gray competing regression after controlling for age and sex.

Results

During the 12.5‐year follow‐up period, the incidence of PDD increased with age at PD diagnosis (0.81–45.31 per 1000 person‐years among those aged 40–44 and over 80 years, respectively) and longer disease duration (22.68 per 1000 person‐years in 1–2 years to 34.16 per 1000 person‐years in 15–16 years). Hypertension (subdistribution hazard ratio [SHR] = 1.11; 95% confidence interval [CI] 1.07–1.16), diabetes (SHR = 1.09; 95% CI 1.05–1.14), dyslipidemia (SHR = 1.15; 95% CI 1.11–1.20), and depression (SHR = 1.36; 95% CI 1.30–1.41) independently increased the risk for PDD.

Conclusions

Our findings provide insights into cardiometabolic syndromes as modifiable risk factors for incident PDD. Furthermore, our results will help in designing public health policies with respect to controlling cardiometabolic syndromes and depression to prevent incident PDD in patients with PD.

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Authors:
Sung Hoon Kang, Yunjin Choi, Su Jin Chung, Chi Kyung Kim, Ji Hyun Kim, Kyungmi Oh, Joon Shik Yoon, Geum Joon Cho and Seong‐Beom Koh

Article first published online:
07 Feb 2023 | DOI: 10.1111/ene.15689

LETTER TO THE EDITOR

Reply to the Letter to the Editor in response to “Role of autoantibody levels as biomarkers in the management of patients with myasthenia gravis: A systematic review and expert appraisal”

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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:
14 Feb 2023 | DOI: 10.1111/ene.15690

ORIGINAL ARTICLE

Interplay between the catecholaminergic enzymatic axis and neurodegeneration/neuroinflammation processes in the Alzheimer's disease continuum

Background and Purpose

The locus coeruleus (LC) provides dopamine/noradrenaline (DA/NA) innervation throughout the brain and undergoes early degeneration in Alzheimer's disease (AD). We evaluated catecholaminergic enzyme levels in the cerebrospinal fluid (CSF) of a group of patients biologically defined as within the AD continuum (ADc) and explored their relationship with AD biomarkers and cytokine/growth factor levels to investigate their interplay with neurodegenerative and neuroinflammatory processes.

Methods

The CSF concentration of DA transporter (DAT), tyrosine‐hydroxylase (TH), DOPA‐decarboxylase (DDC), and dopamine‐β‐hydroxylase (DβH), as well as cytokine/growth factor levels, were analyzed in 41 ADc patients stratified according to CSF beta‐amyloid (Aβ) (A) and p‐tau (T) in AD pathological changes (A+ T‐) and AD (A+ T+) subgroups, as well as in 15 control subjects (A‐ T‐).

Results

The ADc group had lower CSF levels of DAT and TH but increased DβH levels to compensate for NA synthesis. DDC levels were higher in the A+ T+ subgroup but comparable with controls in the A+ T– subgroup, probably because the DA system is resilient to the degeneration of LC neurons in the absence of tau pathology. Adjusting for age, sex, APOE genotype, and cognitive status, a significant association was found between TH and Aβ ( = 0.25) and between DDC and p‐tau ( = 0.33). Finally, TH correlated with interleukin (IL)‐10 levels ( = 0.0008) and DβH with IL‐1β ( = 0.03), IL‐4 ( = 0.02), granulocyte colony‐stimulating factor ( = 0.007), and IL‐17 ( = 0.01).

Conclusions

Taken together, these findings suggest that catecholaminergic enzymes, functional markers of the catecholaminergic system, are closely linked to the neurodegenerative and neuroinflammatory processes in AD pathology.

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Authors:
Caterina Motta, Martina Assogna, Chiara Giuseppina Bonomi, Francesco Di Lorenzo, Marzia Nuccetelli, Nicola Biagio Mercuri, Giacomo Koch and Alessandro Martorana

Article first published online:
14 Feb 2023 | DOI: 10.1111/ene.15691

ORIGINAL ARTICLE

White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative

Background and purpose

The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years.

Methods

Ninety‐eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3–8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2‐year follow‐up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial–temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale.

Results

Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition ( < 0.05). Also, total WMH burden predicted the decline of executive function ( < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines ( < 0.05). WMH volumes at baseline did not predict motor decline.

Conclusion

White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid‐stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology.

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Authors:
Daniela Cristina Carvalho de Abreu, Frederico Pieruccini‐Faria, Yanina Sarquis‐Adamson, Alanna Black, Julia Fraser, Karen Van Ooteghem, Benjamin Cornish, David Grimes, Mandar Jog, Mario Masellis, Thomas Steeves, Nuwan Nanayakkara, Joel Ramirez, Christopher Scott, Melissa Holmes, Miracle Ozzoude, Courtney Berezuk, Sean Symons, Seyyed Mohammad Hassan Haddad, Stephen R. Arnott, Malcolm Binns, Stephen Strother, Derek Beaton, Kelly Sunderland, Athena Theyers, Brian Tan, Mojdeh Zamyadi, Brian Levine, Joseph B. Orange, Angela C. Roberts, Wendy Lou, Sujeevini Sujanthan, David P. Breen, Connie Marras, Donna Kwan, Sabrina Adamo, Alicia Peltsch, Angela K. Troyer, Sandra E. Black, Paula M. McLaughlin, Anthony E. Lang, William McIlroy, Robert Bartha and Manuel Montero‐Odasso

Article first published online:
14 Feb 2023 | DOI: 10.1111/ene.15692

ORIGINAL ARTICLE

Chronic inflammatory demyelinating polyradiculoneuropathy‐associated tremor: Phenotype and pathogenesis

Background and purpose

Tremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is underrecognized, and the pathophysiology remains incompletely understood. This study evaluated tremor in CIDP and tested the hypothesis, established in other demyelinating neuropathies, that tremor occurs due to mistimed peripheral inputs affecting central motor processing. Additionally, the tremor stability index (TSI) was calculated with the hypothesis that CIDP‐related tremor is more variable than other tremor disorders.

Methods

Consecutive patients with typical CIDP were prospectively recruited from neuromuscular clinics. Alternative causes of neuropathy and tremor were excluded. Cross‐sectional clinical assessment and extensive tremor study recordings were undertaken. Pearson correlation coefficient was used to compare nerve conduction studies and tremor characteristics, and ‐test was used for comparisons between groups.

Results

Twenty‐four patients with CIDP were included. Upper limb postural and action tremor was present in 66% and was mild according to the Essential Tremor Rating Assessment Scale. Tremor did not significantly impact disability. Surface electromyography (EMG) found high‐frequency spectral peaks in deltoid (13.73 ± 0.66 Hz), biceps brachii (11.82 ± 0.91 Hz), and extensor carpi radialis (11.87 ± 0.91 Hz) muscles, with lower peaks in abductor pollicis brevis EMG (6.07 ± 0.45 Hz) and index finger accelerometry (6.53 ± 0.42 Hz). Tremor was unchanged by weight loading but correlated with ulnar nerve F‐wave latency and median nerve sensory amplitude. TSI (2.3 ± 0.1) was significantly higher than essential tremor.

Conclusions

Postural tremor is a common feature in CIDP. Tremor was unaffected by weight loading, typical of centrally generated tremors, although there was a correlation with peripheral nerve abnormalities. The high beat‐to‐beat variability on TSI and gradation of peak frequencies further suggest a complex pathophysiology. These findings may assist clinicians with the diagnosis of neuropathic tremor.

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Authors:
Matthew Silsby, Alessandro F. Fois, Con Yiannikas, Karl Ng, Matthew C. Kiernan, Victor S. C. Fung and Steve Vucic

Article first published online:
12 Feb 2023 | DOI: 10.1111/ene.15693

ORIGINAL ARTICLE

Sexual dysfunction in female and male people with multiple sclerosis: disability, depression and hormonal status matter

Background and purpose

Sexual dysfunction (SD) in people with multiple sclerosis (pwMS) is common and an often underestimated issue in the care of pwMS. The objective of the study was to evaluate risk factors for SD in pwMS, correlate its prevalence with patient‐reported measures (quality of life and physical activity) and analyse its association with hormonal status.

Methods

Sexual dysfunction was determined in 152 pwMS using the Multiple Sclerosis Intimacy and Sexuality Questionnaire 19. A logistical regression model was used to identify independent risk factors for SD.

Results

The prevalence of SD in pwMS was 47%. Independent risk factors for the development of SD were ever‐smoking (odds ratio [OR] 3.4, = 0.023), disability as measured by the Expanded Disability Status Scale (OR 2.0, < 0.001), depression (OR 4.3, = 0.047) and bladder and bowel dysfunction (OR 8.8, < 0.001); the use of disease‐modifying treatment was associated with a lower risk for SD (OR 0.32, = 0.043). SD was associated with worse quality of life (Multiple Sclerosis Impact Scale 29: physical score 6.3 vs. 40.0; psychological score 8.3 vs. 33.3; both < 0.001) and lower physical activity (Baecke questionnaire, < 0.001). Laboratory analysis revealed significantly higher luteinizing hormone and follicle‐stimulating hormone levels and lower 17‐beta oestradiol, androstenedione, dehydroepiandrosterone sulfate, oestrone and anti‐Mullerian hormone levels in female pwMS with SD. In male pwMS and SD, there was a significant decrease in inhibin B levels.

Conclusions

Our findings highlight the requirement of a holistic approach to SD in MS including physical, neurourological and psychosocial factors. Active screening for SD, especially in patients with disability, depression or bladder and bowel dysfunction, is recommended.

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Authors:
Franziska Di Pauli, Anne Zinganell, Bettina Böttcher, Janette Walde, Michael Auer, Robert Barket, Klaus Berek, Alexander Egger, Andrea Griesmacher, Natasa Sukalo, Florian Deisenhammer and Harald Hegen

Article first published online:
05 Feb 2023 | DOI: 10.1111/ene.15696

ORIGINAL ARTICLE

Mediterranean diet is associated with a lower probability of prodromal Parkinson's disease and risk for Parkinson's disease/dementia with Lewy bodies: A longitudinal study

Background and purpose

Lifestyle factors have been implicated in the long‐lasting neurodegenerative process in prodromal Parkinson's disease (pPD). The aim was to investigate the associations between adherence to a Mediterranean diet (MeDi) and longitudinal changes of pPD probability and the development of Parkinson's disease (PD) or pPD in a Mediterranean older population.

Methods

Data from the Hellenic Longitudinal Investigation of Aging and Diet cohort (community‐dwelling individuals, aged ≥ 65 years) were used. A detailed food frequency questionnaire was used to evaluate dietary intake and calculate MeDi adherence score, ranging from 0 to 55, with higher scores indicating higher adherence. The probability of pPD was calculated according to the updated Movement Disorder Society research criteria.

Results

In all, 1047 non‐PD/dementia with Lewy bodies (DLB) participants were followed for 3 ± 1 years. MeDi adherence was associated with lower increase in pPD probability over time ( = −0.003, 95% confidence interval −0.006 to −0.001, = 0.010). Forty‐nine participants had incident possible/probable pPD (i.e., pPD probability ≥ 30%). Compared to the participants in the lowest quartile of MeDi adherence, those in the higher quartiles had an approximately 60%–70% lower risk for possible/probable pPD ( for trend 0.003). MeDi–pPD associations were driven by both motor and non‐motor pPD markers and not from risk markers. Also, 21 participants were diagnosed with PD/DLB at follow‐up. For each unit increase in the MeDi score, there was a 9%–10% lower risk for PD/DLB (hazard ratio 0.906 [95% confidence interval 0.823–0.997], = 0.044).

Conclusions

Mediterranean diet adherence is associated with lower increase in pPD probability over time and lower possible/probable pPD and PD/DLB incidence in older Mediterranean people. More studies are needed to confirm our results in other populations.

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Authors:
Maria I. Maraki, Mary Yannakoulia, Georgia Xiromerisiou, Leonidas Stefanis, Sokratis Charisis, Nikolaos Giagkou, Mary H. Kosmidis, Efthimios Dardiotis, Georgios M. Hadjigeorgiou, Paraskevi Sakka, Nikolaos Scarmeas and Maria Stamelou

Article first published online:
06 Feb 2023 | DOI: 10.1111/ene.15698

ORIGINAL ARTICLE

Temporal trends and outcomes in acute ischaemic stroke patients with a current or historical diagnosis of cancer

Background and purpose

The aim was to evaluate the temporal trends, characteristics and in‐hospital outcomes of patients hospitalized with acute ischaemic stroke (AIS) between those with and without current or historical malignancies.

Methods

Adult hospitalizations with a primary diagnosis of AIS were identified from the National Inpatient Sample database 2007–2017. Logistic regression was used to compare the differences in the utilization of AIS interventions and in‐hospital outcomes. For further analysis, subgroup analyses were performed stratified by cancer subtypes.

Results

There were 892,862 hospitalizations due to AIS, of which 108,357 (12.14%) had a concurrent diagnosis of current cancer (3.41%) or historical cancer (8.72%). After adjustment for confounders, patients with current malignancy were more likely to have worse clinical outcomes. The presence of historical cancers was not associated with an increase in poor clinical outcomes. Additionally, AIS patients with current malignancy were less likely to receive intravenous thrombolysis (adjusted odds ratio 0.66, 95% confidence interval 0.63–0.71). Amongst the subgroups of AIS patients treated with intravenous thrombolysis or mechanical thrombectomy, outcomes varied by cancer types. Notably, despite these acute stroke interventions, outcome remains poor in AIS patients with lung cancer.

Conclusions

Although AIS patients with malignancy generally have worse in‐hospital outcomes versus those without, there were considerable variations in these outcomes according to different cancer types and the use of AIS interventions. Finally, treatment of these AIS patients with a current or historical cancer diagnosis should be individualized.

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Authors:
Chi Peng, Fan Yang, Liwei Peng, Chenxu Zhang, Zhen Lin, Chenxin Chen, Huachen Gao, Jia He and Zhichao Jin

Article first published online:
14 Feb 2023 | DOI: 10.1111/ene.15699

ORIGINAL ARTICLE

Genotype–phenotype characteristics and baseline natural history of Chinese related neuropathy patients

Background and purpose

The aim was to characterize the phenotypic and genotypic features of myelin protein zero () related neuropathy and provide baseline data for longitudinal natural history studies or drug clinical trials.

Method

Clinical, neurophysiological and genetic data of 37 neuropathy patients with mutations were retrospectively collected.

Results

Nineteen different mutations in 23 unrelated neuropathy families were detected, and the frequency of mutations was 5.84% in total. Mutations , , and had not been reported previously. Hot spot mutation was detected in four unrelated families, and seven patients carried de novo mutations. The onset age indicated a bimodal distribution: prominent clustering in the first and fourth decades. The infantile‐onset group included 12 families, the childhood‐onset group consisted of two families and the adult‐onset group included nine families. The Charcot–Marie–Tooth Disease Neuropathy Score ranged from 3 to 25 with a mean value of 15.85 ± 5.88. Mutations that changed the cysteine residue (, , and ) in the extracellular region were more likely to cause severe early‐onset Charcot–Marie–Tooth disease type 1B (CMT1B) or Dejerine–Sottas syndrome. Nonsense‐mediated mRNA decay mutations , and were related to severe infantile‐onset CMT1B or Dejerine–Sottas syndrome; however, mutation was associated with a relatively milder childhood‐onset CMT1 phenotype.

Conclusion

Four novel mutations are reported that expand the genetic spectrum. De novo mutations accounted for 30.4% and were most related to a severe infantile‐onset phenotype. Genetic and clinical data from this cohort will provide the baseline data necessary for clinical trials and natural history studies.

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Authors:
Liu Lei, Li Xiaobo, Lin Zhiqiang, Xie Yongzhi, Huang Shunxiang, Zhao Huadong, Tang Beisha and Zhang Ruxu

Article first published online:
05 Feb 2023 | DOI: 10.1111/ene.15700

ORIGINAL ARTICLE

Cognitive phenotypes and factors associated with cognitive decline in a cohort of older patients with atrial fibrillation: The Strat‐AF study

Background and purpose

The multifactorial relationship between atrial fibrillation (AF) and cognitive impairment needs to be elucidated. The aim of this study was to assess, in AF patients on oral anticoagulants (OACs), the prevalence of cognitive impairment, defined according to clinical criteria or data‐driven phenotypes, the prevalence of cognitive worsening, and factors associated with cognitive outcomes.

Methods

The observational prospective Strat‐AF study enrolled AF patients aged ≥ 65 years who were receiving OACs. The baseline and 18‐month protocol included clinical, functional, and cognitive assessment, and brain magnetic resonance imaging. Cognitive outcomes were: empirically derived cognitive phenotypes; clinical diagnosis of cognitive impairment; and longitudinal cognitive worsening.

Results

Out of 182 patients (mean age 77.7 ± 6.7 years, 63% males), 82 (45%) received a cognitive impairment diagnosis, which was associated with lower education level and functional status, and higher level of atrophy. Cluster analysis identified three cognitive profiles: dysexecutive (17%); amnestic (25%); and normal (58%). Compared to the normal group, the dysexecutive group was older, and had higher CHADS‐VASc scores, while the amnestic group had worse cognitive and functional abilities, and medial temporal lobe atrophy (MTA). Out of 128 followed‐up patients, 35 (27%) had cognitive worsening that was associated with lower education level, worse cognitive efficiency, CHADS‐VASc score, timing of OAC intake, history of stroke, diabetes, non‐lacunar infarcts, white matter hyperintensities and MTA. In multivariate models, belonging to the dysexecutive or amnestic group was a main predictor of cognitive worsening.

Conclusions

In our cohort of older AF patients, CHADS‐VASc score, timing of OAC intake, and history of stroke influenced presence, type and progression of cognitive impairment. Empirically derived cognitive classification identified three groups with different clinical profiles and better predictive ability for cognitive worsening compared to conventional clinical diagnosis.

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Authors:
Emilia Salvadori, Eleonora Barucci, Carmen Barbato, Benedetta Formelli, Francesca Cesari, Stefano Chiti, Stefano Diciotti, Betti Giusti, Anna Maria Gori, Chiara Marzi, Francesca Pescini, Giovanni Pracucci, Enrico Fainardi, Rossella Marcucci and Anna Poggesi

Article first published online:
05 Feb 2023 | DOI: 10.1111/ene.15701

ORIGINAL ARTICLE

Performance validity tests in nonlitigant patients with functional motor disorder

Background and purpose

Performance validity tests (PVTs) are used in neuropsychological assessments to detect patterns of performance suggesting that the broader evaluation may be an invalid reflection of an individual's abilities. Data on functional motor disorder (FMD) are currently poor and conflicting. We aimed to examine the rate of failure on three different PVTs of nonlitigant, non‐compensation‐seeking FMD patients, and we compared their performance to that of healthy controls and controls asked to simulate malingering (healthy simulators).

Methods

We enrolled 29 nonlitigant, non‐compensation‐seeking patients with a clinical diagnosis of FMD, 29 healthy controls, and 29 healthy simulators. Three PVTs, the Coin in the Hand Test (CIH), the Rey 15‐Item Test (REY), and the Finger Tapping Test (FTT), were employed.

Results

Functional motor disorder patients showed low rates of failure on the CIH and REY (7% and 10%, respectively) and slightly higher rates on the FTT (15%, = 26), which implies a motor task. Their performance was statistically comparable to that of healthy controls but statistically different from that of healthy simulators ( < 0.001). Ninety‐three percent of FMD patients, 7% of healthy simulators, and 100% of healthy controls passed at least two of the three tests.

Conclusions

Performance validity test performance of nonlitigant, non‐compensation‐seeking patients with FMD ranged from 7% to 15%. Patients' performance was comparable to that of controls and significantly differed from that of simulators. This simple battery of three PVTs could be of practical utility and routinely used in clinical practice.

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Authors:
Ilaria A. Di Vico, Jon Stone, Laura Mcwhirter, Marianna Riello, Maria Elisabetta Zanolin, Michela Colombari, Mirta Fiorio and Michele Tinazzi

Article first published online:
05 Feb 2023 | DOI: 10.1111/ene.15703

ORIGINAL ARTICLE

Intracranial carotid artery calcification morphology differs in patients with lacunar and nonlacunar acute ischemic strokes

Background and purpose

Intracranial carotid artery calcifications (ICACs) are a common finding on noncontrast computed tomography (NCCT) and have been associated with an increased risk of ischemic stroke. However, no data are available about the association between ICAC patterns and stroke etiology. We investigated the association between ICAC patterns and etiological subtypes of ischemic stroke.

Methods

We retrospectively analyzed a single center cohort of patients admitted for ischemic stroke with known etiology. Each carotid artery was evaluated separately on NCCT scans to define the ICAC pattern (intimal, medial, mixed). The association between ICAC patterns and stroke etiology was investigated using logistic regression models adjusting for relevant confounders.

Results

A total of 485 patients were included (median age = 78 [interquartile range (IQR) = 70–85] years, 243 [50%] female, median National Institutes of Health Stroke Scale = 6 [IQR = 3–12]). Frequencies of ICAC patterns were: intimal, = 96 (20%); medial, = 273 (56%); mixed, = 51 (11%), indistinct/absent, = 65 (13%) patients. Intimal pattern was more frequent in lacunar compared with nonlacunar (33% vs. 16%, < 0.001) stroke etiology, whereas medial pattern was less frequent in lacunar compared with nonlacunar stroke (36% vs. 62%, < 0.001). After adjustment for confounders, intimal ICAC predominant pattern remained associated with lacunar stroke etiology in two multivariate models (Model 1: adjusted odds ratio [aOR] = 2.08, 95% confidence interval [CI] = 1.20–3.56; Model 2: aOR = 2.01, 95% CI = 1.16–3.46).

Conclusions

Our study suggests that intimal ICAC pattern is associated with lacunar stroke and may serve as a marker for lacunar stroke etiology, possibly strengthening the relation between endothelial dysfunction and lacunar stroke.

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Authors:
Federico Mazzacane, Beatrice Del Bello, Federica Ferrari, Alessandra Persico, Elisa Rognone, Anna Pichiecchio, Alessandro Padovani, Anna Cavallini, Andrea Morotti and Francesco Arba

Article first published online:
03 Feb 2023 | DOI: 10.1111/ene.15704

ORIGINAL ARTICLE

Observed associations between indicators of socioeconomic status and risk of multiple sclerosis in Sweden are explained by a few lifestyle‐related factors

Background and purpose

The association between socioeconomic status (SES) and the risk of multiple sclerosis (MS) is unclear. The aim was to study whether a potential association between indicators of SES and MS risk in Sweden is explained by lifestyle/environmental factors.

Methods

Using the Swedish MS registry and the Swedish patient registries, a register study was performed comprising all cases diagnosed with MS in Sweden between 1990 and 2018 ( = 24,729) and five randomly selected controls per case, matched by year and age at disease onset, sex and residential area at disease onset. Data from two matched case–control studies combined comprising data on environment/lifestyle factors (7193 cases, 9609 controls, inclusion period 2005–2018) were also utilized. For all participants, information regarding ancestry, formal education (available 1990–2018) and family income (available 1998–2018) was retrieved from the National Board of Health and Welfare.

Results

The registry study revealed no association between education and MS risk, whereas an income exceeding the upper quartile was associated with lower MS risk compared to having an income in the lowest quartile (odds ratio 0.86, 95% confidence interval 0.82–0.90). These findings were replicated in the crude analyses of the case–control study. However, after adjustment for confounding, no association was observed between income and risk of MS.

Conclusions

Education and income were not associated with occurrence of MS after adjustment for a few lifestyle‐related factors (smoking, alcohol consumption, body mass index and sun exposure habits), indicating that SES has no influence on MS risk besides its association with these lifestyle factors in the Swedish context.

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Authors:
Lars Alfredsson, Jan Hillert, Tomas Olsson and Anna Karin Hedström

Article first published online:
08 Feb 2023 | DOI: 10.1111/ene.15705

ORIGINAL ARTICLE

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis

Background and purpose

This study assessed the effect of patient characteristics on the response to disease‐modifying therapy (DMT) in multiple sclerosis (MS).

Methods

We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow‐up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12‐month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics.

Results

Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45–0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41–0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09–1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity.

Conclusions

DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

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Authors:
Ibrahima Diouf, Charles B. Malpas, Sifat Sharmin, Izanne Roos, Dana Horakova, Eva Kubala Havrdova, Francesco Patti, Vahid Shaygannejad, Serkan Ozakbas, Guillermo Izquierdo, Sara Eichau, Marco Onofrj, Alessandra Lugaresi, Raed Alroughani, Alexandre Prat, Marc Girard, Pierre Duquette, Murat Terzi, Cavit Boz, Francois Grand'Maison, Sherif Hamdy, Patrizia Sola, Diana Ferraro, Pierre Grammond, Recai Turkoglu, Katherine Buzzard, Olga Skibina, Bassem Yamout, Ayse Altintas, Oliver Gerlach, Vincent van Pesch, Yolanda Blanco, Davide Maimone, Jeannette Lechner‐Scott, Roberto Bergamaschi, Rana Karabudak, Gerardo Iuliano, Chris McGuigan, Elisabetta Cartechini, Michael Barnett, Stella Hughes, Maria José Sa, Claudio Solaro, Ludwig Kappos, Cristina Ramo‐Tello, Edgardo Cristiano, Suzanne Hodgkinson, Daniele Spitaleri, Aysun Soysal, Thor Petersen, Mark Slee, Ernest Butler, Franco Granella, Koen de Gans, Pamela McCombe, Radek Ampapa, Bart Van Wijmeersch, Anneke van der Walt, Helmut Butzkueven, Julie Prevost, L. G. F. Sinnige, Jose Luis Sanchez‐Menoyo, Steve Vucic, Guy Laureys, Liesbeth Van Hijfte, Dheeraj Khurana, Richard Macdonell, Riadh Gouider, Tamara Castillo‐Triviño, Orla Gray, Eduardo Aguera‐Morales, Abdullah Al‐Asmi, Cameron Shaw, Norma Deri, Talal Al‐Harbi, Yara Fragoso, Tunde Csepany, Angel Perez Sempere, Irene Trevino‐Frenk, Jan Schepel, Fraser Moore and Tomas Kalincik

Article first published online:
16 Feb 2023 | DOI: 10.1111/ene.15706

CASE REPORT

Ischaemic cerebral small vessel disease caused by adenosine deaminase 2 deficiency syndrome

Background and purpose

Only a small proportion of cerebral small vessel disease (cSVD), a frequent cause of stroke and cognitive or motor disability in adults, is attributable to monogenic conditions. The hereditary nature of a patient's cSVD may be masked by a mild or non‐informative phenotype, as single‐gene disorders have a variable mode of presentation, penetrance and disease severity.

Case description

An adult patient is here described with recurrent acute ischaemic strokes due to cSVD with no other phenotypic manifestation, in whom the pathogenic () missense variant in (), consistent with the diagnosis of adenosine deaminase 2 deficiency syndrome, was detected by targeted next‐generation sequencing.

Conclusions

Clinical suspicion of adenosine deaminase 2 deficiency syndrome may be overlooked in stroke patients in whom other specific disease features are lacking. This case enlarges the mode of presentation of the syndrome and highlights the diagnostic potential of next‐generation sequencing of known cSVD genes in young adults with recurrent small subcortical infarcts presenting with a lacunar syndrome.

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Authors:
Alessia Giossi, Silvia Clara Giliani, Massimo Gamba, Paola Toniati, Mauro Magoni and Alessandro Pezzini

Article first published online:
07 Feb 2023 | DOI: 10.1111/ene.15708

ORIGINAL ARTICLE

Quantitative muscle magnetic resonance imaging depicts microstructural abnormalities but no signs of inflammation or dystrophy in post‐COVID‐19 condition

Background and Purpose

Post‐COVID‐19 condition (PCC) has high impact on quality of life, with myalgia and fatigue affecting at least 25% of PCC patients. This case–control study aims to noninvasively assess muscular alterations via quantitative muscle magnetic resonance imaging (MRI) as possible mechanisms for ongoing musculoskeletal complaints and premature exhaustion in PCC.

Methods

Quantitative muscle MRI was performed on a 3 Tesla MRI scanner of the whole legs in PCC patients compared to age‐ and sex‐matched healthy controls, including a Dixon sequence to determine muscle fat fraction (FF), a multi‐echo spin‐echo sequence for quantitative water mapping reflecting putative edema, and a diffusion‐weighted spin‐echo echo‐planar imaging sequence to assess microstructural alterations. Clinical examination, nerve conduction studies, and serum creatine kinase were performed in all patients. Quantitative muscle MRI results were correlated to the results of the 6‐min walk test and standardized questionnaires assessing quality of life, fatigue, and depression.

Results

Twenty PCC patients (female: = 15, age = 48.8 ± 10.1 years, symptoms duration = 13.4 ± 4.2 months, body mass index [BMI] = 28.8 ± 4.7 kg/m) were compared to 20 healthy controls (female: = 15, age = 48.1 ± 11.1 years, BMI = 22.9 ± 2.2 kg/m). Neither FF nor T2 revealed signs of muscle degeneration or inflammation in either study groups. Diffusion tensor imaging (DTI) revealed reduced mean, axial, and radial diffusivity in the PCC group.

Conclusions

Quantitative muscle MRI did not depict any signs of ongoing inflammation or dystrophic process in the skeletal muscles in PCC patients. However, differences observed in muscle DTI depict microstructural abnormalities, which may reflect potentially reversible fiber hypotrophy due to deconditioning. Further longitudinal and interventional studies should prove this hypothesis.

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Authors:
Elena Enax‐Krumova, Johannes Forsting, Marlena Rohm, Peter Schwenkreis, Martin Tegenthoff, Christine H. Meyer‐Frießem and Lara Schlaffke

Article first published online:
15 Feb 2023 | DOI: 10.1111/ene.15709

COMMENTARY

Transcranial direct current stimulation and neurovascular modulation

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Authors:
Marom Bikson

Article first published online:
12 Feb 2023 | DOI: 10.1111/ene.15710

COMMENTARY

Brain‐specific biomarkers: on the winding path to accessibility and clinical relevance

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Authors:
Radu Tanasescu and Didier Leys

Article first published online:
08 Feb 2023 | DOI: 10.1111/ene.15712

ORIGINAL ARTICLE

Retinal layer thickness predicts disability accumulation in early relapsing multiple sclerosis

Background and purpose

This study was undertaken to investigate baseline peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) thickness for prediction of disability accumulation in early relapsing multiple sclerosis (RMS).

Methods

From a prospective observational study, we included patients with newly diagnosed RMS and obtained spectral‐domain optical coherence tomography scan within 90 days after RMS diagnosis. Impact of pRNFL and GCIPL thickness for prediction of disability accumulation (confirmed Expanded Disability Status Scale [EDSS] score ≥ 3.0) was tested by multivariate (adjusted hazard ratio [HR] with 95% confidence interval [CI]) Cox regression models.

Results

We analyzed 231 MS patients (mean age = 30.3 years, SD = 8.1, 74% female) during a median observation period of 61 months (range = 12–93). Mean pRNFL thickness was 92.6 μm (SD = 12.1), and mean GCIPL thickness was 81.4 μm (SD = 11.8). EDSS ≥ 3 was reached by 28 patients (12.1%) after a median 49 months (range = 9–92). EDSS ≥ 3 was predicted with GCIPL < 77 μm (HR = 2.7, 95% CI = 1.6–4.2, < 0.001) and pRNFL thickness ≤ 88 μm (HR = 2.0, 95% CI = 1.4–3.3, < 0.001). Higher age (HR = 1.4 per 10 years, < 0.001), incomplete remission of first clinical attack (HR = 2.2, < 0.001), ≥10 magnetic resonance imaging (MRI) lesions (HR = 2.0, < 0.001), and infratentorial MRI lesions (HR = 1.9, < 0.001) were associated with increased risk of disability accumulation, whereas highly effective disease‐modifying treatment was protective (HR = 0.6, < 0.001). Type of first clinical attack and presence of oligoclonal bands were not significantly associated.

Conclusions

Retinal layer thickness (GCIPL more than pRNFL) is a useful predictor of future disability accumulation in RMS, independently adding to established markers.

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Authors:
Gabriel Bsteh, Harald Hegen, Patrick Altmann, Michael Auer, Klaus Berek, Franziska Di Pauli, Lukas Haider, Barbara Kornek, Nik Krajnc, Fritz Leutmezer, Stefan Macher, Paulus Rommer, Lisa‐Maria Walchhofer, Karin Zebenholzer, Gudrun Zulehner, Florian Deisenhammer, Berthold Pemp and Thomas Berger

Article first published online:
16 Feb 2023 | DOI: 10.1111/ene.15718

European Journal of Neurology

ISSUE INFORMATION

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EDITORIAL

Novel cognitive screening tests to address new clinical priorities and cultural diversity

CASE REPORT

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