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Article first published online:
12 Aug 2021 | DOI: 10.1111/ene.14348

ORIGINAL ARTICLE

Association of with sporadic Alzheimer’s disease in southern Han Chinese

Background and purpose

The aim of this study was to discover the associations between and Alzheimer's disease (AD).

Methods

A total of 500 AD patients and 500 healthy controls were recruited in this study. Polymer chain reaction was used.

Results

There was a statistically significant difference between AD patients and controls in both the dominant and recessive models of rs2071746 after adjustment for age, gender and education (dominant model: = 0.047, odds ratio [OR] 1.34, 95% confidence interval [CI] 1.00–1.78, adjusted; recessive model: = 0.049, OR 1.34, 95% CI 1.00–1.80, adjusted). There was also a trend for an association between the dominant model and late‐onset AD after adjustment for age, gender and education (dominant model: = 0.084, OR 1.37, 95% CI 0.96–1.95, adjusted).

Conclusions

We found an association between the dominant and recessive models of rs2071746 and AD.

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Authors:
Bei Zhang, Hong‐Xiang Yu, Nan Zhi, Can Cui, Ying‐Ying Han, Min Hu, Hao Shen, Huan Bao and Gang Li

Article first published online:
23 Jun 2021 | DOI: 10.1111/ene.14870

GUIDELINES

European guideline and expert statements on the management of narcolepsy in adults and children

Background and aim

Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence‐based guidelines for the management of narcolepsy in both adults and children.

Methods

The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU‐NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach.

Results

A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults—scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults—SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children—scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children—SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient’s symptoms, comorbidities, tolerance and risk of potential drug interactions.

Conclusion

The management of narcolepsy involves non‐pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

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Authors:
Claudio L. A. Bassetti, Ulf Kallweit, Luca Vignatelli, Giuseppe Plazzi, Michel Lecendreux, Elisa Baldin, Leja Dolenc‐Groselj, Poul Jennum, Ramin Khatami, Mauro Manconi, Geert Mayer, Markku Partinen, Thomas Pollmächer, Paul Reading, Joan Santamaria, Karel Sonka, Yves Dauvilliers and Gert J. Lammers

Article first published online:
25 Jun 2021 | DOI: 10.1111/ene.14888

REVIEW ARTICLE

Rheumatoid meningitis: A systematic review and meta‐analysis

Background and purpose

Rheumatoid meningitis (RM) is a neurological complication of rheumatoid arthritis (RA). Current evidence is based on case reports and partial reviews.

Methods

This is a systematic review and meta‐analysis following the PRISMA statement. The aim is to describe the characteristics of the disease, including clinical, imaging and laboratory findings, treatment, outcomes and prognosis reported in the literature.

Results

In all, 103 studies with 130 cases were included. RM affected adults with an average age of 62 years, with or without a previous RA diagnosis. RA activity and time with the disease were associated with a worse prognosis. Most common clinical manifestations were transient focal neurological signs (64.6%), systemic symptoms (51.3%), episodic headache (50.4%) and neuropsychiatric alterations (47.7%). Joint manifestations were present in only 27.4% of cases. Brain magnetic resonance imaging showed unilateral or bilateral involvement, predominantly frontoparietal. Both pachymeninges and leptomeninges were affected, the latter more frequently (82.88%). The laboratory findings included increased levels of rheumatoid factor (89.71%), anti‐cyclic citrullinated peptide (89.47%), C‐reactive protein (82.54%) and erythrocyte sedimentation rate (81.81%). Cerebrospinal fluid analysis showed an increase in the protein level (76.14%), with pleocytosis (85.19%) of mononuclear predominance (89.19%). Biopsy was performed in 72.52% of the patients. Corticosteroid pulse therapy was the main induction therapy. Disease relapse occurred in 31.17% of patients, whilst 54.54% had a full recovery.

Conclusions

Rheumatoid meningitis must be considered in adult patients with or without RA diagnosis, high‐dose corticosteroid induction therapy should be installed and maintenance therapy plays a key role. It is not recommended to use anti‐TNF as an induction therapy. Nowadays, RM has a significantly better outcome. These findings may aid clinicians in timely RM diagnosis and treatment, thus improving its outcomes.

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Authors:
Eduardo Villa, Teresita Sarquis, José de Grazia, René Núñez, Pablo Alarcón, Rodrigo Villegas and Carlos Guevara

Article first published online:
29 Jun 2021 | DOI: 10.1111/ene.14904

ORIGINAL ARTICLE

A disease‐specific metabolic imaging marker for diagnosis and progression evaluation of semantic variant primary progressive aphasia

Background and purpose

The diagnosis and monitoring of semantic variant primary progressive aphasia (sv‐PPA) are clinically challenging. We aimed to establish a distinctive metabolic pattern in sv‐PPA for diagnosis and severity evaluation.

Methods

Fifteen sv‐PPA patients and 15 controls were enrolled to identify sv‐PPA‐related pattern (sv‐PPARP) by principal component analysis of F‐fluorodeoxyglucose positron emission tomography. Eighteen Alzheimer disease dementia (AD) and 14 behavioral variant frontotemporal dementia (bv‐FTD) patients were enrolled to test the discriminatory power. Correspondingly, regional metabolic activities extracted from the voxelwise analysis were evaluated for the discriminatory power.

Results

The sv‐PPARP was characterized as decreased metabolic activity mainly in the bilateral temporal lobe (left predominance), middle orbitofrontal gyrus, left hippocampus/parahippocampus gyrus, fusiform gyrus, insula, inferior orbitofrontal gyrus, and striatum, with increased activity in the bilateral lingual gyrus, cuneus, calcarine gyrus, and right precentral and postcentral gyrus. The pattern expression had significant discriminatory power (area under the curve [AUC] = 0.98, sensitivity = 100%, specificity = 94.4%) in distinguishing sv‐PPA from AD, and the asymmetry index offered complementary discriminatory power (AUC = 0.91, sensitivity = 86.7%, specificity = 92.9%) in distinguishing sv‐PPA from bv‐FTD. In sv‐PPA patients, the pattern expression correlated with Boston Naming Test scores at baseline and showed significant increase in the subset of patients with follow‐up. The voxelwise analysis showed similar topography, and the regional metabolic activities had equivalent or better discriminatory power and clinical correlations with Boston Naming Test scores. The ability to reflect disease progression in longitudinal follow‐up seemed to be inferior to the pattern expression.

Conclusions

The sv‐PPARP might serve as an objective biomarker for diagnosis and progression evaluation.

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Authors:
Jiaying Lu, Lin Huang, Yingru Lv, Shichun Peng, Qian Xu, Ling Li, Jingjie Ge, Huiwei Zhang, Yihui Guan, Qianhua Zhao, Qihao Guo, Keliang Chen, Ping Wu, Yilong Ma and Chuantao Zuo

Article first published online:
07 Jul 2021 | DOI: 10.1111/ene.14919

ORIGINAL ARTICLE

Diagnostic added value of interictal magnetic source imaging in presurgical evaluation of persons with epilepsy: A prospective blinded study

Background and purpose

In presurgical evaluation for epilepsy surgery, information is sourced from various imaging modalities to accurately localize the epileptogenic zone. Magnetoencephalography (MEG) is a newer noninvasive technique for localization. However, there is limited literature to evaluate if MEG provides additional advantage over the conventional imaging modalities in clinical decision making. The objective of this study was to assess the diagnostic added value of MEG in decision making before epilepsy surgery.

Method

This was a prospective observational study. Patients underwent 3 h of recording in a MEG scanner, and the resulting localizations were compared with other complimentary investigations. Added value of MEG (considered separately from high‐density electroencephalography) was defined as the frequency of cases in which (i) the information provided by magnetic source imaging (MSI) avoided implantation of intracranial electrodes and the patient was directly cleared for surgery, and (ii) MSI indicated additional substrates for implantation of intracranial electrodes. Postoperative seizure freedom was used as the diagnostic reference by which to measure the localizing accuracy of MSI.

Results

A total of 102 patients underwent epilepsy surgery. MEG provided nonredundant information, which contributed to deciding the course of surgery in 33% of the patients, and prevented intracranial recordings in 19%. A total of 76% of the patients underwent surgical resection in sublobes concordant with MSI localization, and the diagnostic odds ratio for good (Engel I) outcome in these patients was 2.3 (95% confidence interval 0.68, 7.86; = 0.183) after long‐term follow‐up of 36 months.

Conclusion

Magnetic source imaging yields additional useful information which can significantly alter as well as improve the surgical strategy for persons with epilepsy.

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Authors:
Manjari Tripathi, Kirandeep Kaur, Bhargavi Ramanujam, Vibhin Viswanathan, Kamal Bharti, Gaurav Singh, Vivek Singh, Ajay Garg, Chandra Sekhar Bal, Madhavi Tripathi, Mehar Chand Sharma, Ravindra Pandey, Deepa Dash, Pravat Mandal and Poodipedi Sarat Chandra

Article first published online:
10 Jul 2021 | DOI: 10.1111/ene.14935

GUIDELINES

European Academy of Neurology and European Federation of Neurorehabilitation Societies guideline on pharmacological support in early motor rehabilitation after acute ischaemic stroke

Background and purpose

Early pharmacological support for post‐stroke neurorehabilitation has seen an abundance of mixed results from clinical trials, leaving practitioners at a loss regarding the best options to improve patient outcomes. The objective of this evidence‐based guideline is to support clinical decision‐making of healthcare professionals involved in the recovery of stroke survivors.

Methods

This guideline was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. PubMed, Cochrane Library and Embase were searched (from database inception to June 2018, inclusive) to identify studies on pharmacological interventions for stroke rehabilitation initiated in the first 7 days (inclusive) after stroke, which were delivered together with neurorehabilitation. A sensitivity analysis was conducted on identified interventions to address results from breaking studies (from end of search to February 2020).

Results

Upon manually screening 17,969 unique database entries (of 57,001 original query results), interventions underwent meta‐analysis. Cerebrolysin (30 ml/day, intravenous, minimum 10 days) and citalopram (20 mg/day, oral) are recommended for clinical use for early neurorehabilitation after acute ischaemic stroke. The remaining interventions identified by our systematic search are not recommended for clinical use: amphetamine (5, 10 mg/day, oral), citalopram (10 mg/day, oral), dextroamphetamine (10 mg/day, oral), Di‐Huang‐Yi‐Zhi (2 × 18 g/day, oral), fluoxetine (20 mg/day, oral), lithium (2 × 300 mg/day, oral), MLC601(3 × 400 mg/day, oral), phosphodiesterase‐5 inhibitor PF‐03049423 (6 mg/day, oral). No recommendation ‘for’ or ‘against’ is provided for selegiline (5 mg/day, oral). Issues with safety and tolerability were identified for amphetamine, dextroamphetamine, fluoxetine and lithium.

Conclusions

This guideline provides information for clinicians regarding existing pharmacological support in interventions for neurorecovery after acute ischaemic stroke. Updates to this material will potentially elucidate existing conundrums, improve current recommendations, and hopefully expand therapeutic options for stroke survivors.

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Authors:
Ettore Beghi, Heinrich Binder, Codruta Birle, Natan Bornstein, Karin Diserens, Stanislav Groppa, Volker Homberg, Vitalie Lisnic, Maura Pugliatti, Gary Randall, Leopold Saltuari, Stefan Strilciuc, Johannes Vester and Dafin Muresanu

Article first published online:
21 Jun 2021 | DOI: 10.1111/ene.14936

ORIGINAL ARTICLE

High‐density lipoprotein cholesterol and brain aging amongst rural‐dwelling older adults: a population‐based magnetic resonance imaging study

Background and purpose

Current evidence supports the involvement of lipids in brain aging. A range of serum lipids is explored in association with brain structure and cognitive function amongst rural‐dwelling older adults.

Methods

This population‐based cross‐sectional study included 184 rural‐dwelling adults (age ≥ 65 years, 39.1% women) in Shandong, China. In 2014–2016, data on demographics, lifestyle, health conditions and serum lipids were collected. Volumes of gray matter, white matter, ventricles, hippocampus and white matter hyperintensity were automatically estimated on brain magnetic resonance imaging. Global cognitive function was assessed with the Mini‐Mental State Examination (MMSE), and mild cognitive impairment (MCI) was defined according to Petersen's criteria. Data were analyzed using the general linear regression, logistic regression and mediation models.

Results

Of the 184 participants, 47 were defined with MCI. Low high‐density lipoprotein cholesterol (HDL‐C; <1.55 vs. ≥1.55 mmol/l) was significantly associated with reduced volumes of total white matter (multi‐adjusted = −9.77, 95% confidence interval −19.48–0.06) and hippocampus (−0.23, −0.46–0.01), a lower MMSE score (−1.49, −2.67–0.31) and a higher likelihood of MCI (multi‐adjusted odds ratio 3.21, 95% confidence interval 1.42–7.29). The mediation effects of structural brain measures on the associations between a low level of HDL‐C and MMSE score or MCI were not statistically significant ( > 0.05).

Conclusions

This study suggests that low HDL‐C may be involved in structural brain aging and cognitive dysfunction amongst rural‐dwelling older adults in China, but the association of low HDL‐C with cognitive aging phenotypes appears not to be mediated by brain structure.

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Authors:
Mingqi Wang, Yuanjing Li, Lin Cong, Tingting Hou, Yishan Luo, Lin Shi, Liguo Chang, Chuanchen Zhang, Yongxiang Wang, Xiang Wang, Yifeng Du and Chengxuan Qiu

Article first published online:
06 Jul 2021 | DOI: 10.1111/ene.14939

REVIEW ARTICLE

Vestibular contributions to the Romberg test: Testing semicircular canal and otolith function

Abstract

Normal stance relies on three sensory inputs: vision, proprioception and vestibular function. The Romberg test, trying to stand with feet together and eyes closed, is familiar to every medical student as a test of distal proprioceptive impairment. It remains the best known of Romberg's many remarkable contributions to clinical neurology. In Romberg's time almost nothing was known about the function of the vestibular system. We now know that standing with the eyes closed on a compliant rather than a firm surface is more a test of vestibular than proprioceptive function. Peripheral vestibular function tests in clinical use today all rely on measurements of oligosynaptic brainstem reflexes. Short‐latency eye rotations in response to rapid, brief head rotations (head impulses) give an accurate, robust and reproducible measure of the function of any and each of the six semicircular canals. Short‐latency evoked potentials from sternomastoid and inferior oblique muscles in response to loud clicks or skull taps (vestibular evoked myogenic potentials) give an accurate and reproducible measure of the function of each and any of the four otolith organs. In the present paper, we briefly review what is now known about the anatomy and physiology of the peripheral receptors and brainstem pathways mediating these reflexes and examine how this knowledge can help interpret the Romberg test.

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Authors:
Gábor M. Halmágyi and Ian S. Curthoys

Article first published online:
23 Jun 2021 | DOI: 10.1111/ene.14942

ORIGINAL ARTICLE

Trends in the clinical features of amyotrophic lateral sclerosis: A 14‐year Chinese cohort study

Background and purpose

The aim was to determine the transitional patterns in the clinical characteristics, treatments and comorbidities in amyotrophic lateral sclerosis (ALS) patients over the past 14 years using data from a large clinical cohort in mainland China.

Methods

Sporadic ALS patients who visited the Peking University Third Hospital from January 2005 to December 2018 were included in this study. The 14 years were divided into three periods, and changes in the baseline characteristics of the participants were analyzed at 5‐year intervals.

Results

In total, 3410 patients with sporadic ALS were recruited: 2181 were men and 1229 were women. The proportion of patients with bulbar‐onset ALS increased from 13.0% in 2005–2009 to 19.5% in 2015–2018 ( < 0.001). The mean (standard deviation) age at onset increased from 49.5 (11.4) years in 2005–2009 to 53.0 (11.0) years in 2015–2018 ( < 0.001). ALS patients with diabetes or hypertension showed a delay in ALS onset, and the delay was even more apparent when the patients had both comorbidities. The proportion of riluzole users in 2015–2018 was approximately 2.5‐fold of that in 2005–2009 ( < 0.001).

Conclusions

In the context of a lack of clinical data on ALS in mainland China, this study evaluated a large cohort of patients diagnosed over a 14‐year period. The age at onset and percentage of patients who used riluzole both increased over the study period. Additionally, it was found that patients with comorbidities such as diabetes and hypertension had a delayed age of ALS onset.

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Authors:
Lu Chen, Lu Xu, Lu Tang, Kailin Xia, Danyang Tian, Gan Zhang, Yajun Wang, Zhou Yu, Jingyue Ma, Yixuan Zhang, Fan Wang, Can Sun, Gaoqi Zhang, Jiayu Fu, Lin Jiao, Mubalake Yilihamu, Shengfeng Wang, Siyan Zhan and Dongsheng Fan

Article first published online:
25 Jun 2021 | DOI: 10.1111/ene.14943

ORIGINAL ARTICLE

Sporadic Creutzfeldt–Jakob disease with extremely long 14‐year survival period

Background and purpose

Sporadic Creutzfeldt–Jakob disease is a rapidly progressing and highly variable neurodegenerative disease with heterogeneous clinical presentation and a median survival time from diagnosis to death of 4–6 months.

Methods

We report a rare case of a 61‐year‐old woman with a history of initially rapidly progressive dementia, with subsequent development of pyramidal and extrapyramidal signs and with an unusually long survival period of 14 years. Initial magnetic resonance imaging evaluation, single‐photon emission computed tomography, and electroencephalogram did not show relevant alterations.

Results

The postmortem examination of the brain showed diffuse spongiform change, gliosis, and neuronal loss along with abnormal immunostaining of prion protein in the grey matter, especially in the cerebellum. Indirect genetic analysis was negative.

Conclusions

This case is, to our knowledge, the sporadic Creutzfeldt–Jakob disease patient with the longest survival period ever documented. This surprisingly long duration highlights the importance of histopathological confirmation with brain autopsies for suspected cases, as the disease can easily be misdiagnosed in such slowly progressing cases.

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Authors:
Izaro Kortazar‐Zubizarreta, Rebeca Ruiz‐Onandi, Arrate Pereda, Yerai Vado, Gonzalo González‐Chinchon, Hasier Eraña, Guiomar Perez de Nanclares and Joaquín Castilla

Article first published online:
26 Jun 2021 | DOI: 10.1111/ene.14946

ORIGINAL ARTICLE

The association between cardiovascular risk burden and cognitive function amongst the old: a 9‐year longitudinal cohort study

Background and purpose

Cardiovascular risk burden in midlife has been linked to cognitive decline in later life, but whether this association still exists in older cohorts is unclear.

Methods

The association between the cardiovascular risk score and cognitive function was investigated using 9‐year follow‐up data. The risk score algorithms were from the Chinese guidelines on the prevention and treatment of dyslipidemia in adults (2016 revised), which were assessed at baseline and categorized into tertiles (low, middle and high). Full intelligence quotient (FIQ), verbal intelligence quotient (VIQ) and performance intelligence quotient (PIQ) were assessed at follow‐ups with the Wechsler Adult Intelligence Scale—Chinese, revised (WAIS‐RC). Data were analyzed using the linear mixed‐effects model.

Results

A total of 924 participants (mean age 78.06 ± 7.58 years) were included in our study. In all participants, the risk score ranged from 0.02 to 0.55 (mean score 0.16 ± 0.08). Compared with the low tertile, a higher risk score was associated with lower FIQ ( −0.094, 95% confidence interval [CI] −0.181, −0.007) and VIQ ( –0.100; 95% CI −0.192, −0.007) at the follow‐up. There is a more significant association between higher risk score and lower FIQ amongst females ( –0.263; 95% CI −0.462, −0.065) and VIQ ( −0.268; 95% CI −0.478, −0.057).

Conclusions

A higher cardiovascular risk score was associated with lower FIQ and VIQ. Higher cardiovascular risk burden increased the risk of cognition impairment and accelerated its progression over time. This study has implications for early detection of cognition impairment.

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Authors:
Xiaomin Wu, Hualou Wang, Chong Chen, Ying Xiong, Liping Zhu, Jingya Jia, Tong Yang and Fei Ma

Article first published online:
11 Jul 2021 | DOI: 10.1111/ene.14947

ORIGINAL ARTICLE

Genotype–phenotype correlation in French patients with gene‐related inherited neuropathy

Background and purpose

Preparations for clinical trials of unfolded protein response (UPR) inhibitors (such as Sephin1) that target the upregulated UPR in patients with Charcot–Marie–Tooth disease (CMT) carrying mutations are currently underway. The inclusion criteria for these trials are still being formulated. Our objective was to characterize the relation between genotypes and phenotypes in patients with CMT caused by mutations, and to refine the inclusion criteria for future trials.

Methods

Clinical and neurophysiological data of CMT patients with mutations were retrospectively collected at 11 French reference centers.

Results

Forty‐four mutations in were identified in 91 patients from 61 families. There was considerable heterogeneity. The same mutation was found to cause either axonal or demyelinating neuropathy. Three groups were identified according to the age at disease onset. CMT Examination Score (CMTES) tended to be higher in the early (≤22 years) and adult (23–47 years) onset groups (mean CMTESv2 = 10.4 and 10.0, respectively) than in the late onset group (>47 years, mean CMTESv2 = 8.6, = 0.47). There was a significant positive correlation between CMTESv2 and the age of patients in Groups I ( = 0.027) and II ( = 0.023), indicating that clinical severity progressed with age in these patients.

Conclusions

To optimize the selection of CMT patients carrying mutations for the upcoming trials, inclusion criteria should take into account the pathophysiology of the disease (upregulated UPR). Recruited patients should have a mild to moderate disease severity and a disease onset at between 18 and 50 years, as these patients exhibit significant disease progression over time.

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Authors:
Marie Subréville, Nathalie Bonello‐Palot, Douniazed Yahiaoui, Sadia Beloribi‐Djefaflia, Sara Fernandes, Tanya Stojkovic, Julien Cassereau, Yann Péréon, Andoni Echaniz‐Laguna, Marie‐Hélène Violleau, Antoine Soulages, Sarah Léonard Louis, Marion Masingue, Armelle Magot, Emilien Delmont, Sabrina Sacconi, David Adams, Céline Labeyrie, Steeve Genestet, Jean‐Baptiste Noury, Jean‐Baptiste Chanson, Nicolas Lévy, Raul Juntas‐Morales, Céline Tard, Guilhem Sole and Shahram Attarian

Article first published online:
29 Jun 2021 | DOI: 10.1111/ene.14948

ORIGINAL ARTICLE

Charcot–Marie–Tooth disease misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy: An international multicentric retrospective study

Background and purpose

Charcot–Marie–Tooth (CMT) disease, an untreatable hereditary polyneuropathy, may mimic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a treatable neuropathy.

Methods

In this retrospective study, we analyzed the characteristics of CMT patients misdiagnosed as CIDP at 16 university hospitals in three countries, compared these patients with a reference group of CIDP patients, and estimated the cost of misdiagnosis.

Results

Among 1104 CIDP cases, we identified 35 CMT patients misdiagnosed as CIDP (3.2%). All were initially diagnosed with definite or probable CIDP (European Federation of Neurological Societies/Peripheral Nerve Society criteria), and mutations in , , and 10 other CMT genes were found in 34%, 31%, and 35% of cases, respectively. In comparison with a reference group of 35 CIDP patients, CMT patients were younger (median age at disease onset = 39 vs. 56 years) and more frequently had motor weakness at disease onset (80% vs. 29%), hearing loss (14% vs. 0%), normal brachial plexus imaging (70% vs. 40%), lower cerebrospinal fluid protein content (median = 0.5 vs. 0.8 g/L), and lower treatment response (20% vs. 69%). Treatment cost in these 35 misdiagnosed patients was estimated at 4.6 million euros (M€), whereas the cost of CMT genetic analysis in 1104 patients was estimated at 2.7 M€.

Conclusions

In this study, 35 of 1104 (3.2%) patients initially diagnosed with CIDP had CMT. Importantly, the cost of treating these 35 misdiagnosed patients was significantly higher than the cost of performing CMT genetic analysis in 1104 patients (4.6 M€ vs. 2.7 M€), suggesting that CMT genetic investigations should be more widely used before diagnosing CIDP.

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Authors:
Fabien Hauw, Guillaume Fargeot, David Adams, Shahram Attarian, Cécile Cauquil, Jean‐Baptiste Chanson, Alain Créange, Thierry Gendre, Kumaran Deiva, Emilien Delmont, Bruno Francou, Steeve Genestet, Thierry Kuntzer, Philippe Latour, Gwendal Le Masson, Laurent Magy, Clotilde Nardin, François Ochsner, Guilhem Sole, Tanya Stojkovic, Thierry Maisonobe, Céline Tard, Peter Van den Berghe and Andoni Echaniz‐Laguna

Article first published online:
23 Jun 2021 | DOI: 10.1111/ene.14950

ORIGINAL ARTICLE

Clinical predictors and neural correlates for compromised swallowing safety in Huntington disease

Background and purpose

Dysphagia is one of the most common and important complications in Huntington disease (HD), frequently leading to aspiration pneumonia and mortality. Objective estimates of prevalence using instrumental diagnostics and data on neural correlates of dysphagia in HD are scarce or lacking entirely. Similarly, its correlation with other clinical markers is still not fully known. We aimed at defining clinical risk factors and neural correlates for compromised swallowing safety in HD more precisely.

Methods

Thirty‐four HD subjects (16 female, Shoulson & Fahn Stage I–IV, two premanifest) underwent a full clinical–neurological examination including the cranial nerves, the Unified Huntington’s Disease Rating Scale total motor score, and the Mini‐Mental State Examination. Fiberoptic endoscopic evaluation of swallowing (FEES) was performed by a trained speech and language therapist. Twenty‐six subjects additionally underwent a high‐resolution anatomical magnetic resonance imaging (MRI) scan (T1, 3‐T Siemens Prisma). Moreover, we correlated clinical and atrophy (MRI) measures with swallowing safety levels as judged by the validated Penetration–Aspiration Scale.

Results

FEES showed penetration or aspiration in 70.6%. Using partial correlation, no significant correlations were found between swallowing safety and any of the clinical markers after correcting for disease duration and CAG repeat length. Voxel‐based morphometry demonstrated atrophy associated with compromised swallowing safety in a network of parietothalamocerebellar areas related to sensorimotor communication, notably excluding striatum.

Conclusions

Our results characterise dysphagia in HD as a disorder of communication between sensory and motor networks involved in swallowing. This finding and high rates of silent aspiration argue in favor of instrumental swallowing evaluation early in the disease.

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Authors:
Beate Schumann‐Werner, Imis Dogan, Shahram Mirzazade, Bettina Mall, Rena Overbeck, Philipp Honrath, Jörg B. Schulz, Kathrin Reetz and Cornelius J. Werner

Article first published online:
24 Jun 2021 | DOI: 10.1111/ene.14953

ORIGINAL ARTICLE

Awakening to sleep disorders in Europe: Survey on education, knowledge and treatment competence of European residents and neurologists

Objectives

Sleep‐wake disorders are common in the general population and in most neurological disorders but are often poorly recognized. With the hypothesis that neurologists do not get sufficient training during their residency, the Young European Sleep Neurologist Association (YESNA) of the European Academy of Neurology (EAN) performed a survey on postgraduate sleep education.

Methods

A 16‐item questionnaire was developed and distributed among neurologists and residents across European countries. Questions assessed demographic, training and learning preferences in sleep disorders, as well as a self‐evaluation of knowledge based on five basic multiple‐choice questions (MCQs) on sleep‐wake disorders.

Results

The questionnaire was completed by 568 participants from 20 European countries. The mean age of participants was 31.9 years (SD 7.4 years) and was composed mostly of residents (73%). Three‐quarters of the participants reported undergraduate training in sleep medicine, while fewer than 60% did not receive any training on sleep disorders during their residencies. Almost half of the participants (45%) did not feel prepared to treat neurological patients with sleep problems. Only one‐third of the participants correctly answered at least three MCQs. Notably, 80% of participants favoured more education on sleep‐wake disorders during the neurology residency.

Conclusions

Education and knowledge on disorders in European neurological residents is generally insufficient, despite a strong interest in the topic. The results of our study may be useful for improving the European neurology curriculum and other postgraduate educational programmes.

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Authors:
Martin Rakusa, Mariusz Sieminski, Sofia Rakusa, Cristian Falup‐Pecurariu, Rolf Fronczek, Hildegard Hidalgo, Maria‐Lucia Muntean, Angelique Pijpers, Valerie Cochen De Cock, Fabio Pizza, Markus Schmidt, David R. Schreier, Elisa Baldin, Claudio L. A. Bassetti and Ulf Kallweit

Article first published online:
09 Jul 2021 | DOI: 10.1111/ene.14954

ORIGINAL ARTICLE

A cross‐sectional, prospective ocular motor study in 72 patients with Niemann‐Pick disease type C

Objective

To characterize ocular motor function in patients with Niemann‐Pick disease type C (NPC).

Methods

In a multicontinental, cross‐sectional study we characterized ocular‐motor function in 72 patients from 12 countries by video‐oculography. Interlinking with disease severity, we also searched for ocular motor biomarkers. Our study protocol comprised reflexive and self‐paced saccades, smooth pursuit, and gaze‐holding in horizontal and vertical planes. Data were compared with those of 158 healthy controls (HC).

Results

Some 98.2% of patients generated vertical saccades below the 95% CI of the controls’ peak velocity. Only 46.9% of patients had smooth pursuit gain lower than that of 95% CI of HC. The involvement in both downward and upward directions was similar (51°/s (68.9, [32.7–69.3]) downward versus 78.8°/s (65.9, [60.8–96.8]) upward). Horizontal saccadic peak velocity and latency, vertical saccadic duration and amplitude, and horizontal position smooth pursuit correlated best to disease severity. Compensating strategies such as blinks to elicit saccades, and head and upper body movements to overcome the gaze palsy, were observed. Vertical reflexive saccades were more impaired and slower than self‐paced ones. Gaze‐holding was normal. Ocular‐motor performance depended on the age of onset and disease duration.

Conclusions

This is the largest cohort of NPC patients investigated for ocular‐motor function. Vertical supranuclear saccade palsy is the hallmark of NPC. Vertical upward and downward saccades are equally impaired. Horizontal saccadic peak velocity and latency, vertical saccadic duration and amplitude, and horizontal position smooth pursuit can be used as surrogate parameters for clinical trials. Compensating strategies can contribute to establishing a diagnosis.

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Authors:
Tatiana Bremova‐Ertl, Larry Abel, Mark Walterfang, Ettore Salsano, Anna Ardissone, Věra Malinová, Miriam Kolníková, Jordi Gascón Bayarri, Ali Reza Tavasoli, Mahmoud Reza Ashrafi, Yasmina Amraoui, Eugen Mengel, Stefan A. Kolb, Andreas Brecht, Stanislavs Bardins and Michael Strupp

Article first published online:
12 Jul 2021 | DOI: 10.1111/ene.14955

ORIGINAL ARTICLE

Two healthy lifestyle scores are associated with lower subsequent fatigue risk using inverse probability weighting in an international longitudinal cohort of people with multiple sclerosis

Background and purpose

Several modifiable lifestyle factors have been associated with the onset and health outcomes of multiple sclerosis (MS), including clinically significant fatigue. A combined lifestyle score approach represents one method of assessing their relationship with clinical outcomes. The aim was to examine the association of two lifestyle scores with clinically significant fatigue and change thereof over 2.5 years' follow‐up using inverse probability treatment weighting (IPTW).

Methods

Data on sociodemographic, lifestyle, and clinical characteristics surveyed from an international cohort of people with MS at baseline and at 2.5‐year follow‐up were used. Fatigue was defined by the Fatigue Severity Scale (FSS >5) and healthy lifestyle by the Healthy Lifestyle Index Score (HLIS) and the Smoking, Nutrition, Alcohol Consumption and Physical Activity (SNAP) score. Analyses were by IPTW accounting for age, sex, MS type, disability, treated comorbidity number, immunomodulatory medication use, prescription antifatigue medication use, and ongoing relapse symptoms.

Results

In total, 1268 participants completed the FSS at both time points; approximately 62% had fatigue. Using doubly robust IPTW, high (>11/20) HLIS (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.81–0.98) and high (>3/5) SNAP (OR 0.82, 95% CI 0.73–0.90) were each associated with lower risk of fatigue at follow‐up. Evaluating change in fatigue, a higher SNAP score was associated with a lower risk of fatigue (OR 0.89, 95% CI 0.80–0.97) but the score for HLIS did not reach statistical significance (OR 0.93, 95% CI 0.85–1.01).

Conclusion

These results suggest a robust role for key lifestyle factors in preventing clinically significant fatigue and may represent a place for lifestyle modification in improving clinical outcomes in MS.

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Authors:
Tracey J. Weiland, Nupur Nag, Alysha De Livera, George A. Jelinek, Sandra L. Neate, William Bevens and Steve Simpson‐Yap

Article first published online:
13 Jul 2021 | DOI: 10.1111/ene.14956

ORIGINAL ARTICLE

Brain activity is contingent on neuropsychological function in a functional magnetic resonance imaging study of verbal working memory in amyotrophic lateral sclerosis

Background and purpose

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that causes progressive degeneration of neurons in motor and non‐motor brain regions, affecting multiple cognitive domains such as memory. A functional magnetic resonance imaging (fMRI) study was performed to explore working memory function in ALS.

Methods

To contribute to the growing research field that employs structural and functional neuroimaging to investigate the effect of ALS on different working memory components, the localization and intensity of alterations in neural activity was explored using fMRI. Being the first study to specifically address verbal working memory via fMRI in the context of ALS, the verbal ‐back task with 0‐back and 2‐back conditions was employed.

Results

Despite ALS patients showing unimpaired accuracies ( = 0.724) and reaction times ( = 0.0785), there was significantly increased brain activity of frontotemporal and parietal regions in the 2‐back minus 0‐back contrast in patients compared to controls (using nonparametric statistics with 5000 permutations and a threshold of 2.5).

Discussion

Increased brain activity of the frontotemporal and parietal regions during working memory performance was largely associated with better neuropsychological function within the ALS group, suggesting a compensatory effect during working memory execution. This study therefore adds to the current knowledge on neural correlates of working memory in ALS and contributes to a more nuanced understanding of hyperactivity during cognitive processes in fMRI studies of ALS.

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Authors:
Xenia Kobeleva, Judith Machts, Maria Veit, Stefan Vielhaber, Susanne Petri and Mircea Ariel Schoenfeld

Article first published online:
29 Jun 2021 | DOI: 10.1111/ene.14957

ORIGINAL ARTICLE

Permanent loss of independence in adult febrile‐infection‐related epilepsy syndrome survivors: an underestimated and unsolved challenge

Background and purpose

Febrile‐infection‐related epilepsy syndrome (FIRES) is an exceedingly rare and devastating subtype of new‐onset refractory status epilepticus, which causes refractory epilepsy and permanent neurocognitive impairment.

Methods

This was a long‐term follow‐up of adult FIRES survivors treated between 2005 and 2018 as part of the EpiCARE initiative, a European Reference Network for rare and complex epilepsies. Clinical, electroencephalography, imaging and functional outcome measures are described using the Scores of Independence for Neurologic and Geriatric Rehabilitation, the modified Rankin Scale and the Global Assessment of Severity of Epilepsy Scale.

Results

Six patients with refractory epilepsy following FIRES were evaluated. Despite general improvement after intensive care unit discharge, disease severity was still high at follow‐up in all patients. The functional outcome, as assessed by the modified Rankin Scale, was moderately impaired in 2/6 patients. In contrast, the Scores of Independence for Neurologic and Geriatric Rehabilitation indicated a loss of independence in 5/6, serious problems in memory and planning/problem‐solving in 4/6 and serious attentional problems in 3/6 patients.

Conclusions

Febrile‐infection‐related epilepsy syndrome survivors may regain vital functions and mobility but experience a significant loss of independence and participation due to recurring seizures, structural brain damage and neurocognitive decline. Minimization of disastrous outcomes through the systematic evaluation of rescue therapies within a network of specialized centres is crucial.

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Authors:
Robert Daniel Nass, Julia Taube, Tobias Bauer, Theodor Rüber, Rainer Surges and Christoph Helmstaedter

Article first published online:
02 Jul 2021 | DOI: 10.1111/ene.14958

ORIGINAL ARTICLE

Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis—a presymptomatic case–control study

Background and purpose

Epstein–Barr virus (EBV) and human herpesvirus 6A (HHV‐6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology.

Methods

A nested case–control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV‐6A was determined using a bead‐based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV‐6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP).

Results

Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56–0.88, = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV‐6A (AP 0.34, 95% CI 0.06–0.61) and EBV antigen EBNA‐1 (amino acid 385–420) at age 20–39 years (AP 0.37, 95% CI 0.09–0.65).

Conclusions

Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV‐6A seropositivity.

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Authors:
Viktor Grut, Martin Biström, Jonatan Salzer, Pernilla Stridh, Daniel Jons, Rasmus Gustafsson, Anna Fogdell‐Hahn, Jesse Huang, Nicole Brenner, Julia Butt, Noemi Bender, Anna Lindam, Lucia Alonso‐Magdalena, Martin Gunnarsson, Magnus Vrethem, Tomas Bergström, Oluf Andersen, Ingrid Kockum, Tim Waterboer, Tomas Olsson and Peter Sundström

Article first published online:
27 Jun 2021 | DOI: 10.1111/ene.14961

ORIGINAL ARTICLE

Clinical manifestations and long‐term outcome of early Lyme neuroborreliosis according to the European Federation of Neurological Societies diagnostic criteria (definite versus possible) in central Europe. A retrospective cohort study

Background and purpose

The characteristics and long‐term outcome of Lyme neuroborreliosis (LNB) according to diagnostic certainty (definite vs. possible) are incompletely understood.

Methods

In this retrospective cohort study of adults with definite or possible LNB, clinical and microbiological characteristics and long‐term outcome over 12 months were evaluated at a single medical center. Severity of acute disease and long‐term outcome were assessed using a composite clinical score encompassing clinical findings and symptoms and by the probability of incomplete recovery.

Results

Amongst 311 adult patients enrolled from 2008 to 2017, 139 (44.7%) had definite LNB and 172 (55.3%) had possible LNB. The most frequent LNB manifestation was cranial neuropathy with or without meningitis (53.4%). Patients with definite LNB more often had Bannwarth syndrome (53.2% vs. 18.6%), more severe disease (6 points vs. 4 points), longer pre‐treatment duration (median 21 days vs. 13.5 days), higher cerebrospinal fluid pleocytosis (median 139 × 10/L vs. 11 × 10/L) and higher rate of seropositivity (84.2% vs. 68.6%) than those with possible LNB. Ceftriaxone was prescribed more often than oral doxycycline in definite LNB than in possible LNB (96.4% vs. 65.7%). Unfavorable outcomes decreased during follow‐up, being higher in patients with more severe disease at enrollment and in those with possible LNB, but were not associated with antibiotic therapy.

Conclusions

Early LNB, most often presenting as cranial neuropathy, was definitively diagnosed in less than half of cases. A better diagnostic approach is needed to confirm borrelial etiology. Ceftriaxone was not superior to doxycycline in the treatment of early LNB, regardless of diagnostic certainty.

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Authors:
Daša Stupica, Fajko F. Bajrović, Rok Blagus, Tjaša Cerar Kišek, Stefan Collinet‐Adler, Anja Lah, Eva Levstek and Eva Ružić‐Sabljić

Article first published online:
01 Jul 2021 | DOI: 10.1111/ene.14962

LETTERS TO THE EDITOR

Rethinking neurological attitudes towards vasovagal syncope: The European Federation of Autonomic Societies (EFAS) recommendations regarding tilt table testing

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Authors:
J. Gert van Dijk, Roland D. Thijs, Michele Brignole, Cristian Falup‐Pecurariu, Alessandra Fanciulli, Roy Freeman, Pietro Guaraldi, Jens Jordan, Mario Habek, Max Hilz, Anne Pavy‐Le Traon, Iva Stankovic, Walter Struhal, Richard Sutton and Gregor Wenning

Article first published online:
01 Jul 2021 | DOI: 10.1111/ene.14963

SHORT COMMUNICATION

Prevalence of acute dizziness and vertigo in cortical stroke

Background and purpose

In posterior circulation stroke, vertigo can be a presenting feature. However, whether isolated hemispheric strokes present with vertigo is less clear, despite a few single case reports in the literature. Here, (a) the prevalence of vertigo/dizziness in acute stroke is explored and (b) the cortical distribution of the lesions in relation to both the known vestibular cortex and the evolution of the symptoms, are considered.

Methods

Structured interviews were conducted in 173 consecutive unselected patients admitted to the hyperacute stroke unit at the University College London Hospitals. The interview was used to evaluate whether the patient was suffering from dizziness and/or vertigo before the onset of the stroke and at the time of the stroke (acute dizziness/vertigo), and the nature of these symptoms.

Results

In all, 53 patients had cortical infarcts, of which 21 patients reported acute dizziness. Out of these 21, five patients reported rotational vertigo. Seventeen of the total 53 patients had lesions in known vestibular cortical areas distributed within the insular and parietal opercular cortices.

Conclusions

The prevalence of vertigo in acute cortical strokes was 9%, with no single locus of lesion overlap. There is growing evidence supporting a lateralized vestibular cortex, with speculation that cortical strokes affecting the right hemisphere are more likely to cause vestibular symptoms than left hemispheric strokes. A trend was observed for this association, with the right hemisphere affected in four of five patients who reported spinning vertigo at the onset of the stroke.

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Authors:
Yuk Man Chan, Yean Wong, Noorulain Khalid, Stephen Wastling, Andreas Flores‐Martin, Lucy‐Anne Frank, Nehzat Koohi, Qadeer Arshad, Indran Davagnanam and Diego Kaski

Article first published online:
02 Jul 2021 | DOI: 10.1111/ene.14964

ORIGINAL ARTICLE

Stressful life events can predict post‐stroke fatigue in patients with ischemic stroke

Objective

To investigate whether stressful life events (SLEs) can predict post‐stroke fatigue (PSF) in patients with acute ischemic stroke (AIS).

Methods

This prospective cohort study included data from patients with AIS who were followed up to 2‐year interview. PSF was assessed at admission and at 6 ( = 916), 12 ( = 880), and 24 ( = 857) months with the fatigue severity scale (FSS). SLEs were measured with the Social Readjustment Rating Scale questionnaire at 6, 12 and 24 months’ interview.

Results

A significant dose‐response association was found between SLEs and FSS score across all examined time‐points: compared with those did not experience SLEs, FSS score was higher for those experiencing SLEs ≥3 at 6 months ( 0.53, 95% CI 0.28–0.78), 12 months ( 0.54, 95% CI 0.30–0.78) and 24 months ( 0.48, 95% CI 0.29–0.68). Longitudinal analyses indicated a significantly positive relationship between the number of SLEs and FSS score (SLEs: ≥3 vs. 0, 0.14, 95% CI 0.09–0.19). Moreover, a distinct interaction of follow‐up time and SLE numbers on FSS score was observed ( < 0.05), which means elevated exposure to SLEs during follow‐up was associated with a lower rate of fatigue decline. A similar association was found in SLE load analysis.

Conclusion

Patients with severe fatigue were more likely to report increased number of SLEs in the previous 6 months, which could suggest that a non‐specific stressful event leads to an extra burden to an already vulnerable psychological system.

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Authors:
Chunrong Tao, Mengmeng Gu, Pengfei Xu, Jinjing Wang, Lulu Xiao, Wei Gui, Fengli Li, Shiyi Jiang, Xinfeng Liu, Wei Hu and Wen Sun

Article first published online:
07 Jul 2021 | DOI: 10.1111/ene.14977

ORIGINAL ARTICLE

Muscle involvement assessed by quantitative magnetic resonance imaging in patients with anoctamin 5 deficiency

Objective

Using magnetic resonance imaging (MRI) and stationary dynamometry, the aim was to investigate the muscle affection in paraspinal muscles and lower extremities and compare the muscle affection in men and women with anoctamin 5 (ANO5) deficiency.

Methods

Seventeen patients (seven women) with pathogenic ANO5‐mutations were included. Quantitative muscle fat fraction of back and leg muscles were assessed by Dixon MRI. Muscle strength was assessed by stationary dynamometer. Results were compared with 11 matched, healthy controls.

Results

Muscle involvement pattern in men with ANO5‐deficiency is characterized by a severe fat replacement of hamstrings, adductor and gastrocnemius muscles, while paraspinal muscles are only mildly affected, while preserved gracilis and sartorius muscles were hypertrophied. Women with ANO5‐myopathy, of the same age as male patients, were very mildly affected, showing muscle affection and strength resembling that found in healthy persons, with the exception of the gluteus minimus and medius and gastrocnemii muscles that were significantly replaced by fat. Although individual muscles showed clear asymmetric involvement in a few muscle groups, the overall muscle involvement was symmetric.

Conclusions

Patients with ANO5‐deficiency have relatively preserved paraspinal muscles on imaging and only mild reduction of trunk extension strength in men only. Our study quantifies the large difference in muscle affection in lower extremity between women and men with ANO5‐deficiency. The clinical notion is that affection may be very asymmetric in ANO5‐deficiency, but the present study shows that while this may be true for a few muscles, the general impression is that muscle affection is very symmetric.

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Authors:
Tahmina Khawajazada, Konni Kass, Karen Rudolf, Josefine de Stricker Borch, Aisha Munawar Sheikh, Nanna Witting and John Vissing

Article first published online:
11 Jul 2021 | DOI: 10.1111/ene.14979

SHORT COMMUNICATION

No evidence for a specific vitamin D deficit in benign paroxysmal positional vertigo

Background and purpose

The aim was to investigate whether there is a difference in serum 25‐hydroxyvitamin D (25(OH)D) concentration between patients with benign paroxysmal positional vertigo (BPPV), patients with other vestibular diseases and patients with other neurological non‐vestibular diseases presenting in a tertiary neurological academic outpatient clinic.

Methods

The serum 25(OH)D concentration was measured in 680 patients (368 male, mean age ± SD 58 ± 17 years, 661 Caucasian) without vitamin D supplementation. 158 patients had BPPV; 221 had other vestibular diseases (including 122 with peripheral vestibular disorders, such as unilateral vestibulopathy or Ménière's disease; 46 with central vestibular disorders, such as vestibular migraine or cerebellar dizziness; 53 with functional dizziness); and 301 patients with other neurological non‐vestibular diseases.

Results

There was no significant difference in the serum 25(OH)D concentration between patients with BPPV (mean ± SD 23.4 ± 9.4 ng/ml) and those with other vestibular disorders (24.9 ± 10.1 ng/ml, = 0.324). Patients with other neurological disorders had even lower concentrations (21.4 ± 10.6 ng/ml) than patients with BPPV ( < 0.005), patients with other vestibular disorders ( < 0.005) and all patients with vestibular disorders (24.9 ± 10.1 ng/ml, < 0.005).

Conclusion

Our analysis does not support the theory of a specific relationship between serum 25(OH)D concentration and the occurrence of BPPV or other vestibular disorders.

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Authors:
Nicolina Goldschagg, Daniel Teupser, Katharina Feil and Michael Strupp

Article first published online:
07 Jul 2021 | DOI: 10.1111/ene.14980

ORIGINAL ARTICLE

Dolichoarteriopathies of the extracranial internal carotid artery: The Plaque At RISK study

Background and purpose

Dolichoarteriopathies of the extracranial part of the internal carotid artery (ICA) are associated with cerebrovascular events, yet information on their prevalence and risk factors remains limited. The aim of the present study therefore was to study the prevalence and risk factors of dolichoarteriopathies in a sample of patients with cerebrovascular symptoms from the Plaque At RISK (PARISK) study.

Methods

In a random sample of 100 patients from the PARISK study, multidetector computed tomography angiography (MDCTA) was performed as part of clinical workup. On MDCTA, we evaluated the extracranial trajectory of the ICA by measuring the length (in millimeters), the tortuosity index (TI; defined as the ICA length divided by the shortest possible distance from bifurcation to skull base), and dolichoarteriopathy type (tortuosity, coiling or kinking). Next, we investigated the association between cardiovascular risk factors and these measurements using linear and logistic regression analyses.

Results

The mean (standard deviation) length of the ICA was 93 (± 14) mm, with a median (interquartile range) TI of 1.2 (1.1–1.3). The overall prevalence of dolichoarteriopathies was 69%, with tortuosity being the most common (72%), followed by coiling (20%), and kinking (8%). We found that age and obesity were associated with a higher TI: difference per 10‐year increase in age: 0.05 (95% confidence interval [CI] 0.02–0.08) and 0.16 (95% CI 0.07–0.25) for obesity. Obesity and hypercholesterolemia were associated with a more severe type of dolichoarteriopathy (odds ratio [OR] 2.07 [95% CI 1.04–4.12] and OR 2.17 [95% CI 1.02–4.63], respectively).

Conclusion

Dolichoarteriopathies in the extracranial ICA are common in patients with cerebrovascular symptoms, and age, obesity and hypercholesterolemia may play an important role in the pathophysiology of these abnormalities.

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Authors:
Kristine Dilba, Dianne H. K. van Dam‐Nolen, Geneviève A. J. C. Crombag, Anja G. van der Kolk, Peter J. Koudstaal, Paul J. Nederkoorn, Jeroen Hendrikse, Marianne Eline Kooi, Antonius F. W. van der Steen, Jolanda J. Wentzel, Aad van der Lugt and Daniel Bos

Article first published online:
07 Jul 2021 | DOI: 10.1111/ene.14982

REVIEW ARTICLE

Immunity and Gilles de la Tourette syndrome: A systematic review and meta‐analysis of evidence for immune implications in Tourette syndrome

Background and purpose

The neurobiology of Gilles de la Tourette syndrome (GTS) is known to involve corticostriatal loops possibly under genetic control. Less is known about possible environmental triggers of GTS. Specifically, immune‐related events following possible environmental inducers have been evoked, but important controversies still exist. In this systematic review and meta‐analysis, we looked for evidence in favor of such possibilities.

Methods

We performed a systematic review and meta‐analysis of all immunological data in PubMed.

Results

We found large discrepancies concerning immune dysfunctions in GTS, and meta‐analyzing cytokines data did not allow us to conclude there is an involvement of specific cytokines in GTS neurobiology. When looking specifically at pediatric autoimmune neuropsychiatric disorder associated with streptococcus/pediatric acute onset neuropsychiatric syndrome, we found some important evidence of a possible infectious involvement but in a limited number of studies. Our meta‐analysis found an increased level of anti‐streptolysin O antibodies in GTS patients, but the level of anti‐DNase B antibodies was not increased.

Conclusions

Too many questions still exist to allow us to definitively reach the conclusion that there is an infectious and immunological etiology in GTS. Much work is still needed to elucidate the possible role of immunology in GTS neurobiology and to favor immunological treatment rather than classical treatment.

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Authors:
Hugues Lamothe, Ryad Tamouza, Andreas Hartmann and Luc Mallet

Article first published online:
03 Jul 2021 | DOI: 10.1111/ene.14983

ORIGINAL ARTICLE

Contribution of sleep disturbances to fatigue in multiple sclerosis: a prospective study using clinical and polysomnographic parameters

Background and purpose

Fatigue is amongst the most frequent and disabling symptoms of multiple sclerosis and a close relation between fatigue and sleep quality has been hypothesized. In this study the contribution of sleep disturbances measured by clinical and polysomnographic parameters to fatigue in multiple sclerosis was investigated.

Methods

This was a prospective instrumental study performed at the Neurocenter of Southern Switzerland. Demographic data and clinical characteristics including fatigue (as measured by the modified fatigue impact scale [MFIS]), neurological disability, psychiatric symptoms, medications and sleep‐related variables were collected at baseline visit and by a home full‐night polysomnography. The associations between sleep‐related variables and the MFIS were tested using partial correlations adjusted by demographic and sleep‐unrelated clinical factors.

Results

Seventy‐six patients were included in the study, of whom 53 (69.7%) had an MFIS ≥38 points (median 49.5, interquartile range 31.0–62.0). MFIS scores were positively associated with age, neurological disability, symptoms of depression and anxiety, and use of benzodiazepines and selective serotonin reuptake inhibitors. When adjusting for these variables, the presence of restless legs syndrome (RLS) ( = 0.37, = 0.005) and periodic leg movements index ( = −0.33, = 0.014) were associated with MFIS. Excessive daytime sleepiness, total sleep time, sleep efficiency, respiratory disturbances, and percentage of time spent in the different sleep stages (N1, N2, N3 and rapid eye movement) were not associated with fatigue.

Conclusions

Multiple sclerosis patients with a diagnosis of RLS had significantly higher global fatigue scores compared to those without RLS. Future studies should investigate whether medical treatment of RLS can ameliorate fatigue.

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Authors:
Gianna C. Riccitelli, Giulio Disanto, Rosaria Sacco, Davide Sparasci, Leonardo Sacco, Anna Castelnovo, Silvia Miano, Mauro Manconi, Claudio Gobbi and Chiara Zecca

Article first published online:
30 Jun 2021 | DOI: 10.1111/ene.14984

ORIGINAL ARTICLE

Blood–brain barrier leakage and hemorrhagic transformation: The Reperfusion Injury in Ischemic StroKe (RISK) study

Background and purpose

In patients with acute ischemic stroke treated with reperfusion therapy we aimed to evaluate whether pretreatment blood–brain barrier (BBB) leakage is associated with subsequent hemorrhagic transformation (HT).

Methods

We prospectively screened patients with acute ischemic stroke treated with intravenous thrombolysis and/or endovascular treatment. Before treatment, each patient received computed tomography (CT), CT angiography, and CT perfusion. We assessed pretreatment BBB leakage within the ischemic area using the volume transfer constant (K) value. Our primary outcome was relevant HT, defined as hemorrhagic infarction type 2 or parenchymal hemorrhage type 1 or 2. We evaluated independent associations between BBB leakage and HT using logistic regression, adjusting for age, sex, baseline stroke severity, Alberta Stroke Program Early CT Score (ASPECTS) ≥ 6, treatment type, and onset‐to‐treatment time.

Results

We enrolled 171 patients with available assessment of BBB leakage. The patients' mean (±SD) age was 75.5 (±11.8) years, 86 (50%) were men, and the median (interquartile range) National Institutes of Health Stroke Scale score was 18 (12–23). A total of 32 patients (18%) received intravenous thrombolysis, 102 (60%) underwent direct endovascular treatment, and 37 (22%) underwent both. Patients with relevant HT ( = 31;18%) had greater mean BBB leakage (K 0.77 vs. 0.60; = 0.027). After adjustment in the logistic regression model, we found that BBB leakage was associated both with a more than twofold risk of relevant HT (odds ratio [OR] 2.50; 95% confidence interval [CI] 1.03–6.03 per K point increase; OR 2.34; 95% CI 1.06–5.17 for K values > 0.63 [mean BBB leakage value]) and with symptomatic intracerebral hemorrhage (OR 4.30; 95% CI 1.13–13.77 per K point increase).

Conclusion

Pretreatment BBB leakage before reperfusion therapy was associated with HT, and may help to identify patients at risk of HT.

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Authors:
Francesco Arba, Benedetta Piccardi, Vanessa Palumbo, Silvia Biagini, Francesco Galmozzi, Veronica Iovene, Alessio Giannini, Giuseppe Dario Testa, Alessandro Sodero, Mascia Nesi, Davide Gadda, Marco Moretti, Maria Lamassa, Francesca Pescini, Anna Poggesi, Cristina Sarti, Stefania Nannoni, Giovanni Pracucci, Nicola Limbucci, Sergio Nappini, Leonardo Renieri, Stefano Grifoni, Enrico Fainardi, Domenico Inzitari and Patrizia Nencini

Article first published online:
08 Jul 2021 | DOI: 10.1111/ene.14985

ORIGINAL ARTICLE

Systemic immune response against the oral pathogens and is associated with the formation and rupture of intracranial aneurysms

Background and purpose

Periodontal infections are associated with the formation and rupture of intracranial aneurysms (IAs). This study investigated the role of two key periodontal pathogens, and .

Methods

Immunoglobulin A (IgA) and IgG antibodies against . and . were measured with enzyme immune assay from the serum of 227 IA patients, of whom 64 also underwent clinical oral examination. As a control group, 1096 participants in a cross‐sectional health survey, Health 2000, underwent serological studies and oral examination. Logistic regression was used for multivariate analysis. Immunohistochemistry was performed to demonstrate bacteria‐derived epitopes in the IA wall.

Results

Widespread gingivitis and severe periodontitis were more common in IA patients than in controls (2× and 1.5×, respectively). IgA antibodies against . and . were 1.5× and 3–3.4× higher, respectively, in both unruptured and ruptured IA patients compared to controls (≤ 0.003). IgG antibodies against . were 1.8× lower in unruptured IA patients (< 0.001). In multivariate analysis, high IgA, but low IgG, antibody levels against . (odds ratio [OR] = 1.4, 95% confidence interval [Cl] = 1.1–1.8 and OR = 1.5, 95% Cl = 1.1–1.9; OR = 0.6, 95% Cl = 0.4–0.7 and OR = 0.5, 95% Cl = 0.4–0.7) and against . (OR = 2.3, 95% Cl = 1.7–3.1 and OR = 2.1, 95% Cl = 1.5–2.9; OR = 0.6, 95% Cl = 0.4–0.8 and OR = 0.6, 95% Cl = 0.5–0.9) were associated with the risk of IA formation and rupture. Immunohistochemistry showed . epitopes in the IA wall.

Conclusions

Exposure to the periodontal pathogens . and . and dysfunctional acquired immune response against them may increase the risk of IA formation and IA rupture.

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Authors:
Joona Hallikainen, Mikko Pyysalo, Sara Keränen, Jari Kellokoski, Timo Koivisto, Anna Liisa Suominen, Pirkko Pussinen, Tanja Pessi and Juhana Frösen

Article first published online:
08 Jul 2021 | DOI: 10.1111/ene.14986

ORIGINAL ARTICLE

Translational potential of the ghrelin receptor agonist macimorelin for seizure suppression in pharmacoresistant epilepsy

Background

Current drugs for epilepsy affect seizures, but no antiepileptogenic or disease‐modifying drugs are available that prevent or slow down epileptogenesis, which is characterized by neuronal cell loss, inflammation and aberrant network formation. Ghrelin and ghrelin receptor (ghrelin‐R) agonists were previously found to exert anticonvulsant, neuroprotective and anti‐inflammatory effects in seizure models and immediately after status epilepticus (SE). Therefore, the aim of this study was to assess whether the ghrelin‐R agonist macimorelin is antiepileptogenic in the pharmacoresistant intrahippocampal kainic acid (IHKA) mouse model.

Methods

SE was induced in C57BL/6 mice by unilateral IHKA injection. Starting 24 h after SE, mice were treated intraperitoneally with macimorelin (5 mg/kg) or saline twice daily for 2 weeks, followed by a 2‐week wash‐out. Mice were continuously electroencephalogram‐monitored, and at the end of the experiment neuroprotection and gliosis were assessed.

Results

Macimorelin significantly decreased the number and duration of seizures during the treatment period, but had no antiepileptogenic or disease‐modifying effect in this dose regimen. While macimorelin did not significantly affect food intake or body weight over a 2‐week treatment period, its acute orexigenic effect was preserved in epileptic mice but not in sham mice.

Conclusions

While the full ghrelin‐R agonist macimorelin was not significantly antiepileptogenic nor disease‐modifying, this is the first study to demonstrate its anticonvulsant effects in the IHKA model of drug‐refractory temporal lobe epilepsy. These findings highlight the potential use of macimorelin as a novel treatment option for seizure suppression in pharmacoresistant epilepsy.

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Authors:
An Buckinx, Anouk Pierre, Yana Van Den Herrewegen, Eckhard Guenther, Matthias Gerlach, Gaetan Van Laethem, Ron Kooijman, Dimitri De Bundel and Ilse Smolders

Article first published online:
09 Jul 2021 | DOI: 10.1111/ene.14992

ORIGINAL ARTICLE

Visuospatial dysfunction is associated with posterior distribution of white matter damage in non‐demented cerebral amyloid angiopathy

Background and purpose

Cerebral amyloid angiopathy (CAA) is a well‐recognized contributor to cognitive decline in the elderly. The posterior cortical predilection of CAA pathology would cause visuospatial dysfunction, which is still underexplored. We aimed to investigate whether the visuospatial dysfunction in CAA is associated with the posterior distribution of small vessel disease (SVD) imaging markers.

Methods

We recruited 60 non‐demented CAA cases from a Chinese prospective cohort and 30 cases with non‐CAA SVD as controls. We used the Visual Object and Space Perception (VOSP) battery to evaluate visuospatial abilities, and multivariable regression models to assess their associations with SVD imaging markers.

Results

There was visuospatial dysfunction, especially visual object perception impairment, in CAA compared to controls (‐score of VOSP: −0.11 ± 0.66 vs. 0.22 ± 0.54, = 0.023). The VOSP score in CAA was independently related to the fronto‐occipital gradient of white matter hyperintensity volumes (coefficient = 0.03, 95% confidence interval [CI] = 0.003–0.05, = 0.030) and mean fractional anisotropy values on diffusion tensor imaging (coefficient = 4.72, 95% CI = 0.97–8.48, = 0.015), but not the severity of global SVD imaging markers or the gradient of lobar cerebral microbleeds with adjustments for age and global cognition score.

Conclusions

This finding suggests that the damage of posterior white matter rather than global disease severity may be a major contributor to visuospatial dysfunction in CAA.

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Authors:
Ya Su, Jiayu Fu, Yanrong Zhang, Jiajie Xu, Qiang Dong and Xin Cheng

Article first published online:
08 Jul 2021 | DOI: 10.1111/ene.14993

ORIGINAL ARTICLE

Occult primary white matter impairment in Leber hereditary optic neuropathy

Background and purpose

Leber hereditary optic neuropathy (LHON) is a disease maternally inherited from mitochondria that predominantly impairs the retinal ganglion cells and their axons. To identify whether occult brain white matter (WM) impairment is involved, a voxel‐based analysis (VBA) of diffusion metrics was carried out in LHON patients with normal‐appearing brain parenchyma.

Methods

Fifty‐four symptomatic LHON patients (including 22 acute LHON with vision loss for ≤12 months, and 32 chronic LHON) without any visible brain lesions and 36 healthy controls (HCs) were enrolled in this study. VBA was applied to quantify the WM microstructural changes of LHON patients. Finally, the associations of the severity of WM impairment with disease duration and ophthalmologic deficits were assessed.

Results

Compared with the HCs, the average retinal nerve fiber layer (RNFL) thickness was significantly reduced in patients with chronic LHON, whereas it was increased in patients with acute LHON ( < 0.05, corrected). VBA identified significantly decreased fractional anisotropy widely in WM in both the acute and chronic LHON patients, including the left anterior thalamic radiation and superior longitudinal fasciculus, and bilateral corticospinal tract, dentate nuclei, inferior longitudinal fasciculus, forceps major, and optic radiation (OR; < 0.05, corrected). The integrity of most WM structures (except for the OR) was correlated with neither disease duration nor RNFL thickness ( > 0.05, corrected).

Conclusions

Occult primary impairment of widespread brain WM is present in LHON patients. The coexisting primary and secondary WM impairment may jointly contribute to the pathological process of LHON.

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Authors:
Ling Wang, Hao Ding, Bihong T. Chen, Ke Fan, Qin Tian, Miaomiao Long, Meng Liang, Dapeng Shi, Chunshui Yu and Wen Qin

Article first published online:
09 Jul 2021 | DOI: 10.1111/ene.14995

ORIGINAL ARTICLE

The risk of worsening of myasthenia by cardiovascular medication as reflected by reporting frequency

Background and purpose

Some groups of cardiovascular drugs (beta‐blocking drugs, Ca antagonists, antiarrhythmics) are listed as potentially worsening myasthenia. An empirical basis for alternative recommendations for antihypertensive and antiarrhythmic therapy in myasthenia patients has not yet been provided.

Methods

From the World Health Organization pharmacovigilance database, we retrieved total and myasthenia‐related counts of adverse drug reactions for various groups of drugs used in cardiovascular disease and drugs with related mechanism of action used in other indications. We calculated the reporting odds ratio as a measure of a disproportional fraction of myasthenia‐related events among all events. A 95% confidence interval of reporting odds ratio (ROR) >1 was taken as an indication for a higher risk. Because our approach involves a considerable number of tests, this situation is referred to as a signal that requires additional confirmation.

Results

A signal for an increased risk was noted for tizanidine, for alpha‐blocking drugs, for beta‐blocking drugs, and for Ca antagonists. ROR indicated a lower‐than‐average risk for salbutamol, angiotensin receptor antagonists, oral anticoagulants, thrombocytic function inhibitors, and heparins.

Conclusions

Angiotensin receptor antagonists, angiotensin‐converting enzyme inhibitors, and diuretics seem to be safe in antihypertensive therapy. Surprisingly, and yet requiring confirmation by case reports, alpha receptor–blocking drugs seem to carry a risk of myasthenia worsening. Amiodarone seems to be a safe alternative in antiarrhythmic therapy in patients with myasthenia.

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Authors:
Peter Trillenberg, Alexander Katalinic, Julia Thern and Tobias Graf

Article first published online:
09 Jul 2021 | DOI: 10.1111/ene.14996

ORIGINAL ARTICLE

Bruns' nystagmus revisited: A sign of stroke in patients with the acute vestibular syndrome

Objective

Gaze‐evoked nystagmus (GEN) is a central sign in patients with the acute vestibular syndrome (AVS); however, discriminating between a pathological and a physiologic GEN is a challenge. Here we evaluate GEN in patients with AVS.

Methods

In this prospective cross‐sectional study, we used video‐oculography (VOG) to compare GEN in the light (target at 15° eccentric) in 64 healthy subjects with 47 patients seen in the emergency department (ED) who had AVS; 35 with vestibular neuritis and 12 with stroke. All patients with an initial non‐diagnostic MRI received a confirmatory, delayed MRI as a reference standard in detecting stroke.

Results

Healthy subjects with GEN had a time constant of centripetal drift >18 s. VOG identified pathologic GEN (time constant ≤ 18 s) in 33% of patients with vestibular strokes, specificity was 100%, accuracy was 83%. Results were equivalent to examination by a clinical expert. As expected, since all patients with GEN had a SN in straight‐ahead position, they showed the pattern of a Bruns’ nystagmus.

Conclusions

One third of patients with AVS due to central vestibular strokes had a spontaneous SN in straight‐ahead gaze and a pathological GEN, producing the pattern of a Bruns’ nystagmus with a shift of the null position. The localization of the side of the lesion based on the null was not consistent, presumably because the circuits underlying gaze‐holding are widespread in the brainstem and cerebellum. Nevertheless, automated quantification of GEN with VOG was specific, and accurately identified patients in the ED with AVS due to strokes.

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Authors:
Georgios Mantokoudis, Athanasia Korda, David S. Zee, Ewa Zamaro, Thomas C. Sauter, Franca Wagner and Marco D. Caversaccio

Article first published online:
16 Jul 2021 | DOI: 10.1111/ene.14997

ORIGINAL ARTICLE

Plasma neurofilament light chain levels and cognitive testing as predictors of fast progression in Alzheimer’s disease

Background

Alzheimer's disease (AD) is characterized by a heterogeneous course. Predicting a fast rather than a slow decline over time is crucial to both provide a reliable prognosis and elaborate stricter enrolment criteria in clinical trials. Here we searched for independent predictors of cognitive decline rate to assess the risk of fast disease progression already at baseline.

Methods

Fifty‐three subjects with an “in‐vivo biomarker confirmed” diagnosis of AD were included. Neuropsychological assessment, plasma neurofilaments (NfL) concentrations and, in a subsample of 23 patients, brain magnetic resonance imaging were available. Patients were labelled FAST or SLOW depending on the Mini‐Mental State Examination (MMSE) points lost per year (FAST if more than 3 points). We adopted single logistic regression models to search for independent predictors of FAST progression.

Results

At baseline no differences were found between FAST and SLOW subgroups in demographics, MMSE scores, vascular burden and medial temporal lobe atrophy measurements. Higher plasma NfL concentrations and worse scores at semantic verbal fluency (SVF) and clock drawing test (CDT) were independent predictors of FAST decline, after controlling for age, education, sex and baseline disease severity stage. The regression model combining all the predictors correctly classified 80% of patients overall. The risk of FAST decline was 81.2% if all the three predictors were abnormal (i.e., SVF ≤21.5, CDT ≤5.5, NfL ≥22.19).

Conclusions

An easily applicable algorithm, including plasma NfL measurement and two neuropsychological tests worldwide adopted in clinical practice (SVF and CDT), may allow clinicians to reliably stratify AD patients in relation to the risk of fast cognitive decline.

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Authors:
Roberto Santangelo, Federica Agosta, Francesco Masi, Edoardo Gioele Spinelli, Giordano Cecchetti, Francesca Caso, Alessandra Mandelli, Rosalinda Cardamone, Alessandra Barbieri, Roberto Furlan, Giuseppe Magnani and Massimo Filippi

Article first published online:
23 Jul 2021 | DOI: 10.1111/ene.14999

ORIGINAL ARTICLE

Admission computed tomography radiomic signatures outperform hematoma volume in predicting baseline clinical severity and functional outcome in the ATACH‐2 trial intracerebral hemorrhage population

Background and purpose

Radiomics provides a framework for automated extraction of high‐dimensional feature sets from medical images. We aimed to determine radiomics signature correlates of admission clinical severity and medium‐term outcome from intracerebral hemorrhage (ICH) lesions on baseline head computed tomography (CT).

Methods

We used the ATACH‐2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage II) trial dataset. Patients included in this analysis ( = 895) were randomly allocated to discovery ( = 448) and independent validation ( = 447) cohorts. We extracted 1130 radiomics features from hematoma lesions on baseline noncontrast head CT scans and generated radiomics signatures associated with admission Glasgow Coma Scale (GCS), admission National Institutes of Health Stroke Scale (NIHSS), and 3‐month modified Rankin Scale (mRS) scores. Spearman's correlation between radiomics signatures and corresponding target variables was compared with hematoma volume.

Results

In the discovery cohort, radiomics signatures, compared to ICH volume, had a significantly stronger association with admission GCS (0.47 vs. 0.44, = 0.008), admission NIHSS (0.69 vs. 0.57, < 0.001), and 3‐month mRS scores (0.44 vs. 0.32, < 0.001). Similarly, in independent validation, radiomics signatures, compared to ICH volume, had a significantly stronger association with admission GCS (0.43 vs. 0.41, = 0.02), NIHSS (0.64 vs. 0.56, < 0.001), and 3‐month mRS scores (0.43 vs. 0.33, < 0.001). In multiple regression analysis adjusted for known predictors of ICH outcome, the radiomics signature was an independent predictor of 3‐month mRS in both cohorts.

Conclusions

Limited by the enrollment criteria of the ATACH‐2 trial, we showed that radiomics features quantifying hematoma texture, density, and shape on baseline CT can provide imaging correlates for clinical presentation and 3‐month outcome. These findings couldtrigger a paradigm shift where imaging biomarkers may improve current modelsfor prognostication, risk‐stratification, and treatment triage of ICH patients.

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Authors:
Stefan P. Haider, Adnan I. Qureshi, Abhi Jain, Hishan Tharmaseelan, Elisa R. Berson, Tal Zeevi, Shahram Majidi, Christopher G. Filippi, Simon Iseke, Moritz Gross, Julian N. Acosta, Ajay Malhotra, Jennifer A. Kim, Lauren H. Sansing, Guido J. Falcone, Kevin N. Sheth and Seyedmehdi Payabvash

Article first published online:
18 Jul 2021 | DOI: 10.1111/ene.15000

ORIGINAL ARTICLE

Charcot–Marie–Tooth disease due to mutations in Spain

Background and purpose

mutations have been described as a rare cause of axonal Charcot–Marie–Tooth disease (CMT2Z). The aim of this work was to determine the frequency and distribution of these mutations throughout Spain, to provide a comprehensive phenotypical description and, if possible, to establish a genotype–phenotype correlation.

Methods

Retrospectively, data on patients diagnosed with CMT2Z in Spain were collected and clinical, electrophysiological and muscle imaging information were analysed.

Results

Fifteen patients with CMT2Z were identified throughout Spain, seven of them belonging to a single kindred, whilst the rest were sporadic. The most common mutation was p.R252W, and four new mutations were identified. Eleven patients were categorized as having a scapuloperoneal phenotype, with asymmetric muscle weakness, early proximal upper limb involvement and frequent spontaneous muscular activity with distal sensory impairment and pes cavus, whilst two presented with a more classic length dependent sensory motor phenotype. This distinction was corroborated by the distribution of muscle fatty infiltration in muscle imaging. Two other patients were classified as having a neurodevelopmental phenotype consisting in congenital or early onset, delay in motor milestones, and global developmental delay in one of them. Nerve conduction studies revealed an unequivocally axonal neuropathy with frequent spontaneous activity, and serum creatine kinase levels were increased in 50% of the patients.

Conclusions

mutations are a rare cause of CMT in Spain, but in‐depth phenotyping reveals a recognizable phenotypic spectrum that will be clinically relevant for future identification of this disease.

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Authors:
Rafael Sivera, Vincenzo Lupo, Marina Frasquet, Herminia Argente‐Escrig, Jorge Alonso‐Pérez, Jordi Díaz‐Manera, Luis Querol, María del Mar García‐Romero, Samuel Ignacio Pascual, Tania García‐Sobrino, Carmen Paradas, Juan Francisco Vázquez‐Costa, Nuria Muelas, Elvira Millet, Juan Jesús Vílchez, Carmen Espinós and Teresa Sevilla

Article first published online:
18 Jul 2021 | DOI: 10.1111/ene.15001

ORIGINAL ARTICLE

Long‐term survival outcomes and prognostic factors related to ruptured intracranial aneurysms: A comparison of surgical and endovascular options in a propensity score–matched, nationwide population‐based cohort study

Background and purpose

To determine the long‐term survival outcomes of and prognostic factors for survival in patients with a ruptured intracranial aneurysm (RIA) who underwent endovascular coil embolization or surgical clipping.

Methods

We selected patients who had received a diagnosis of RIA between January 1, 2011 and December 31, 2017. Propensity score matching was performed, and Cox proportional hazards model curves were plotted to analyze all‐cause mortality in patients undergoing different treatments.

Results

The matching process yielded a final cohort of 8102 patients (4051 and 4051 in endovascular coil embolization and surgical clipping groups, respectively) who were eligible for inclusion. In multivariate Cox regression analyses, the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for endovascular coil embolization compared with surgical clipping were 0.87 (95% CI, 0.79–0.97). The aHRs for the ages of 65 to 74, 75 to 84, and ≥85 years compared with the ages of 20 to 64 years were 1.82 (95% CI, 1.60–2.07), 3.35 (95% CI, 2.93–3.84), and 6.99 (95% CI, 5.51–8.86), respectively. Surgical clipping; old age; male sex; treatment during 2011 to 2013; presence of diabetes, congestive heart failure, hypertension, chronic kidney disease, or end‐stage renal disease; history of stroke or transient ischemic attack; Charlson Comorbidity Index ≥2; attendance of nonacademic hospitals; and low income were significant independent prognostic factors for poor survival.

Conclusions

Compared with surgical clipping, endovascular coil embolization led to more favorable survival outcomes in patients with RIAs.

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Authors:
Yang‐Lan Lo, Ming‐Chang Li, Ying‐Hui Yu, Ho‐Min Chen and Szu‐Yuan Wu

Article first published online:
14 Jul 2021 | DOI: 10.1111/ene.15002

ORIGINAL ARTICLE

Motor unit number estimation in adult patients with spinal muscular atrophy treated with nusinersen

Background and purpose

The aim was to assess the organization and short‐term changes of motor units in adult patients with spinal muscular atrophy (SMA) treated with nusinersen.

Methods

In this single‐centre cross‐sectional and longitudinal study 15 adult patients with SMA type 3 were assessed and compared to 15 age‐matched healthy controls and nine patients with amyotrophic lateral sclerosis. Moreover, 10 patients with SMA were followed up after 4–8 months. All patients were investigated clinically and by the motor unit number estimation method MScanFit of the abductor pollicis brevis muscle.

Results

The number of motor units (< 0.001) was significantly lower in patients with SMA compared to healthy controls at study entry. Mean unit amplitude, median amplitude and largest unit (< 0.001) were significantly increased in patients with SMA. Patients with amyotrophic lateral sclerosis showed a significant reduction of compound muscle action potential (= 0.005) and number of motor units (= 0.03) compared to patients with SMA, accompanied by a larger median amplitude (= 0.03). A prospective analysis identified patients with the ability to walk to improve the number of motor units ( = 0.046) accompanied by a decreased median amplitude ( = 0.03). Electrophysiological measures showed a moderate to strong correlation with clinical scores.

Conclusion

Patients with SMA show loss of motor units in distal muscles. MScanFit variables indicate that compound muscle action potential amplitudes are maintained by collateral sprouting. Prospective analyses suggest that milder affected adult patients with SMA preferentially benefit from nusinersen treatment through recovery of smaller motor units. Correlations with clinical scores underline the potential of MScanFit as a surrogate marker.

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Authors:
Christian Schneider, Meike K. Wassermann, Nicolai B. Grether, Gereon R. Fink, Gilbert Wunderlich and Helmar C. Lehmann

Article first published online:
20 Jul 2021 | DOI: 10.1111/ene.15005

LETTERS TO THE EDITOR

Brain volume loss due to donanemab

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Authors:
Scott Ayton

Article first published online:
16 Jul 2021 | DOI: 10.1111/ene.15007

ORIGINAL ARTICLE

Early diagnosis of amyotrophic lateral sclerosis by threshold tracking and conventional transcranial magnetic stimulation

Background and purpose

Short‐interval intracortical inhibition by threshold tracking (T‐SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS) but has not been compared directly with conventional amplitude measurements (A‐SICI). This study compared A‐SICI and T‐SICI for sensitivity and clinical usefulness as biomarkers for ALS.

Methods

In all, 104 consecutive patients referred with suspicion of ALS were prospectively included and were subsequently divided into 62 patients with motor neuron disease (MND) and 42 patient controls (ALS mimics) by clinical follow‐up. T‐SICI and A‐SICI recorded in the first dorsal interosseus muscle (index test) were compared with recordings from 53 age‐matched healthy controls. The reference standard was the Awaji criteria. Clinical scorings, conventional nerve conduction studies and electromyography were also performed on the patients.

Results

Motor neuron disease patients had significantly reduced T‐SICI and A‐SICI compared with the healthy and patient control groups, which were similar. Sensitivity and specificity for discriminating MND patients from patient controls were high (areas under the receiver operating characteristic curves 0.762 and 0.810 for T‐SICI and A‐SICI respectively at 1–3.5 ms). Paradoxically, T‐SICI was most reduced in MND patients with the fewest upper motor neuron (UMN) signs (Spearman = 0.565, = 4.3 × 10).

Conclusions

Amplitude‐based measure of cortical inhibition and T‐SICI are both sensitive measures for the detection of cortical involvement in MND patients and may help early diagnosis of ALS, with T‐SICI most abnormal before UMN signs have developed. The gradation in T‐SICI from pathological facilitation in patients with minimal UMN signs to inhibition in those with the most UMN signs may be due to progressive degeneration of the subset of UMNs experiencing facilitation.

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Authors:
Hatice Tankisi, Christina S.‐Z. Nielsen, James Howells, Bülent Cengiz, Gintaute Samusyte, Martin Koltzenburg, Jakob U. Blicher, Anette T. Møller, Kirsten Pugdahl, Anders Fuglsang‐Frederiksen, Mamede de Carvalho and Hugh Bostock

Article first published online:
22 Jul 2021 | DOI: 10.1111/ene.15010

ORIGINAL ARTICLE

Cladribine suppresses disease activity in neuromyelitis optica spectrum disorder: a 2‐year follow‐up study

Background and purpose

Neuromyelitis optica spectrum disorder (NMOSD) is a difficult condition to treat. Cladribine selectively and transiently depletes B and T lymphocytes, leading to long‐lasting immune reconstitution. This report describes observations from 24 months of follow‐up after cladribine in NMOSD patients.

Methods

This is a retrospective analysis of a case series including 12 seropositive patients with NMOSD. Patients were given cladribine by subcutaneous injections in a series of several 2‐day cycles of 20 mg administered at intervals of 4–6 weeks. Thus, the full treatment course delivered a cumulative bioavailable dose similar to that approved for treatment of multiple sclerosis. Annualized relapse rate (ARR), disability (Expanded Disability Status Scale [EDSS] score) and safety in the 24 months preceding and the 24 months following the initiation of cladribine treatment were assessed.

Results

The mean ARR in the 24 months preceding cladribine treatment was 1.04 (95% confidence interval [CI] 0.67–1.62). The mean ARR in the 24 months following initiation of cladribine treatment was 0.21 (95% CI 0.08–0.56). The ratio in the rate of events post versus prior cladribine initiation was 0.20 (95% CI 0.07–0.59) and highly significant ( = 0.0073). The EDSS score did not change over the follow‐up period (2.5 ± 1.7; mean ± SD) compared to baseline (2.5 ± 1.5; mean ± SD). No serious adverse events considered to be linked to cladribine were observed during follow‐up.

Conclusions

Cladribine was safe in NMOSD patients over a 2‐year observation period. Cladribine treatment was associated with clinical stabilization, as evidenced by significantly decreased ARR and no progression of EDSS score.

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Authors:
Konrad Rejdak and Ewa Papuć

Article first published online:
26 Jul 2021 | DOI: 10.1111/ene.15012

SHORT COMMUNICATION

Prevalence of pediatric multiple sclerosis in Germany: A nationwide population‐based analysis

Background and purpose

Prevalence data are needed to reveal trends regarding the pediatric multiple sclerosis (MS) situation worldwide. The aim was to identify changes in MS diagnosis prevalence in pediatric patients over a 10‐year period in Germany.

Methods

This analysis is based on nationwide outpatient claims data of children aged <18 years covered by the German statutory health insurance ( = 11,381,939 in 2018). People with MS (PwMS) had ≥1 documented MS diagnosis (International Classification of Diseases, 10th Revision, German modification code G35.x). The annual pediatric MS diagnosis prevalence was analyzed regarding age, sex, and place of residence during 2009–2018.

Results

The prevalence of pediatric MS developed from 5.3 (2009) to 5.4 (2018)/100,000 insured population aged <18 years. The MS prevalence in patients aged 15–17 years showed a moderate increase over 10 years (19.6–22.7/100,000), whereas patients ≤14 years old showed a slight decrease (1.9–1.7/100,000). The sex ratio (female:male) in 2018 was relatively balanced in PwMS aged ≤14 years (1.32) but female‐dominated in those aged 15–17 years (2.47). The formerly different prevalence of pediatric MS between East and West Germany has converged since 2012.

Conclusions

So far, this is the largest study of pediatric MS prevalence in terms of source population size (87% of German children <18 years of age, = 11,381,939 in 2018) and study period (2009–2018) worldwide. The analyses revealed an increase in MS prevalence and a female‐dominated sex ratio in “older” adolescents compared to younger patients.

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Authors:
Niklas Frahm, Melanie Peters, Jörg Bätzing, David Ellenberger, Manas K. Akmatov, Judith Haas, Paulus S. Rommer, Alexander Stahmann, Uwe K. Zettl and Jakob Holstiege

Article first published online:
26 Jul 2021 | DOI: 10.1111/ene.15015

European Journal of Neurology

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