cover image European Journal of Neurology

European Journal of Neurology

2020 - Volume 27
Issue 3 | March 2020
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Article first published online:
09 Feb 2020 | DOI: 10.1111/ene.13993

Original Article

Background and purpose

Assessing patients’ disability in multiple sclerosis (MS) requires time‐consuming batteries of hospital tests. MSCopilot is a software medical device for the self‐assessment of patients with MS (PwMS), combining four tests: walking, dexterity, cognition and low contrast vision. The objective was to validate MSCopilot versus the Multiple Sclerosis Functional Composite (MSFC).

Methods

This multicentre, open‐label, randomized, controlled, crossover study enrolled 141 PwMS and 76 healthy controls (HCs). All participants performed MSCopilot and MSFC tests at day 0. To assess reproducibility, 46 PwMS performed the same tests at day 30 ± 3. The primary end‐point was the validation of MSCopilot versus MSFC for the identification of PwMS against HCs, quantified using the area under the curve (AUC). The main secondary end‐point was the correlation of MSCopilot ‐scores with MSFC ‐scores.

Results

In all, 116 PwMS and 69 HCs were analysed. The primary end‐point was achieved: MSCopilot performance was non‐inferior to that of MSFC (AUC 0.92 and 0.89 respectively; = 0.3). MSCopilot and MSFC discriminated PwMS and HCs with 81% and 76% sensitivity and 82% and 88% specificity respectively. Digital and standard test scores were highly correlated ( = 0.81; < 0.001). The test–retest study demonstrated the good reproducibility of MSCopilot.

Conclusion

This study confirms the reliability of MSCopilot and its usability in clinical practice for the monitoring of MS‐related disability.

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Authors:
E. Maillart, P. Labauge, M. Cohen, A. Maarouf, S. Vukusic, C. Donzé, P. Gallien, J. De Sèze, B. Bourre, T. Moreau, C. Louapre, P. Mayran, S. Bieuvelet, M. Vallée, F. Bertillot, L. Klaeylé, A.‐L. Argoud, S. Zinaï and A. Tourbah
Article first published online:
19 Oct 2019 | DOI: 10.1111/ene.14091

Original Article

Background and purpose

Visual dysfunction is a non‐motor symptom of Parkinson disease (PD), but its prevalence is unknown as population‐based data on the epidemiology of visual symptoms in PD are lacking. The objective was to determine the prevalence of visual dysfunction in PD.

Methods

This was a cross‐sectional analysis of data from adults ≥50 years old in the Survey of Health, Ageing and Retirement in Europe (SHARE), a multinational population‐based health survey of adults living in one of 27 European countries and Israel. PD diagnosis was self‐reported. Impairment in overall, distance or near eyesight was defined as a score of 4 or 5 on a 1–5 scale. Adjusted logistic regression was used to determine the association between PD and self‐reported vision.

Results

There were 115 240 age‐eligible participants in the SHARE study (mean age 64.3 years, 54% female), of whom 1438 (1.25%) reported a diagnosis of PD. In adjusted logistic regression models, PD was associated with increased odds of impaired overall [odds ratio (OR) 2.67, 95% confidence interval (CI) 1.91–3.72], distance (OR 2.55, 95% CI 2.04–3.19) and near (OR 2.07, 95% CI 1.69–2.55) eyesight. Individuals with PD were also less likely to report having an eye examination within the previous 2 years (OR 0.59, 95% CI 0.38–0.92), but this did not remain statistically significant after adjusting for confounders (OR 0.76, 95% CI 0.47–1.24).

Conclusions

Visual dysfunction is significantly more common in PD than in the general adult population. Visual symptoms are a potentially under‐recognized and under‐treated source of reduced quality of life in PD patients that require further attention and study.

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Authors:
A. G. Hamedani and A. W. Willis
Article first published online:
19 Oct 2019 | DOI: 10.1111/ene.14092

Original Article

Background and purpose

Motoric cognitive risk syndrome (MCR), which is the juncture of subjective cognitive complaint and slow gait speed, is a pre‐dementia stage. The aims of the study are (i) to compare characteristics between individuals who have MCR defined using slow walking speed and/or increased five‐times‐sit‐to‐stand (FTSS) time as its motor component(s); and (ii) to characterize the association of MCR and its various motor components with incident dementia including Alzheimer disease and non‐Alzheimer dementia in the participants of the Epidémiologie de l’Ostéoporose (EPIDOS) study.

Methods

This prospective and observational cohort study selected 651 participants recruited from the EPIDOS study in Toulouse (France). MCR was defined as the association of subjective cognitive complaint and slow gait speed and/or increased FTSS time in participants without either dementia and mobility disabilities at baseline. Individuals with dementia were prospectively diagnosed during the physical and neuropsychological assessments included in the 7‐year follow‐up.

Results

The prevalence of MCR was around 7% when using an exclusive motor criterion, either slow gait speed or increased FTSS time, and was 20.9% when MCR subgroups were pooled. MCR was positively associated with incident dementia regardless of its type, and with Alzheimer disease in the slow gait speed MCR subgroup [odds ratio (OR) > 2.18 with ≤ 0.037] but not with non‐Alzheimer dementia. No significant association between incident dementia and MCR defined using increased FTSS time was shown.

Conclusions

Our findings confirm that MCR is associated with incident dementia and that slow gait speed is the appropriate motor criterion for detecting dementia risk.

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Authors:
O. Beauchet, H. Sekhon, C.P. Launay, Y. Rolland, A.‐M. Schott and G. Allali
Article first published online:
20 Oct 2019 | DOI: 10.1111/ene.14093

Original Article

Background and purpose

Heterozygous mutations in the gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive‐affective syndrome (CCAS), named SCA48.

Methods

Molecular screening was performed in a cohort of 235 unrelated patients with adult‐onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole‐exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel mutations. Clinico‐diagnostic findings were reviewed to define the phenotypic spectrum.

Results

Eight heterozygous mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions.

Conclusions

Our results support SCA48 as a significant cause of adult‐onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in .

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Authors:
M. Lieto, V. Riso, D. Galatolo, G. De Michele, S. Rossi, M. Barghigiani, S. Cocozza, G. Pontillo, R. Trovato, F. Saccà, E. Salvatore, A. Tessa, A. Filla, F. M. Santorelli, G. De Michele and G. Silvestri
Article first published online:
01 Nov 2019 | DOI: 10.1111/ene.14094

Original Article

Background and purpose

We hypothesized that combining intravenous immunoglobulin (IVIg) and intravenous methylprednisolone (IVMP) leads to more frequent remission compared with IVIg alone while maintaining the fast efficacy of IVIg. In this uncontrolled pilot study, we evaluated remission, rate of improvement and safety in patients with chronic inflammatory demyelinating polyradiculoneuropathy receiving induction treatment with combined IVIg and IVMP.

Methods

Consecutive treatment‐naive patients with chronic inflammatory demyelinating polyradiculoneuropathy were treated with IVIg infusions, consisting of a 2 g/kg loading dose and 1 g/kg maintenance treatment every 3 weeks, combined with 3‐weekly 1‐g IVMP infusions, for a total of 18 weeks. The cumulative steroid dose was 7 g. Primary outcome was remission at 1 year in patients who completed the treatment schedule. Remission was defined as improvement at 18 weeks without the need for further immune treatment between end of the treatment schedule and 1‐year follow‐up. Improvement was defined as a minimal clinically important difference on the Inflammatory Rasch‐Built Overall Disability Scale and/or an increase of ≥8 kPa in grip strength between baseline and week 18.

Results

A total of 20 patients were included; 17 completed the treatment schedule. A total of 13 (76%) of these patients improved at 18 weeks after start of treatment and 10 (59%) patients were in remission at 1 year. Serious adverse events were found in four patients.

Conclusions

Short‐term combined induction treatment with IVIg and IVMP induced remission in almost 60% of patients who completed the treatment schedule. Combined induction therapy was generally well tolerated. A randomized controlled trial is currently running to confirm efficacy and safety of IVMP as add‐on treatment to IVIg.

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Authors:
M. E. Adrichem, S. R. Bus, L. Wieske, H. Mohammed, C. Verhamme, R. Hadden, I. N. van Schaik and F. Eftimov
Article first published online:
07 Nov 2019 | DOI: 10.1111/ene.14096

Original Article

Background and purpose

Dermatomyositis (DM) with anti‐nuclear matrix protein‐2 (NXP‐2) antibodies usually shows multifocal ischaemic lesions in muscle. Here, we aimed to investigate the microarteriopathy underlying muscle ischaemia in anti‐NXP‐2‐positive DM.

Methods

A total of 16 patients diagnosed with anti‐NXP‐2‐positive DM were investigated by muscle biopsy. A total of 13 patients with DM with other myositis‐specific antibodies and 11 normal controls were included for comparison. Immunofluorescence assays were performed to localize endothelial cells, smooth muscle cells and pericytes, and to determine lesions in myofibers and microvessels by vascular endothelial growth factor and myxovirus resistance protein A (MxA). Electron microscopy was carried out to assess ultrastructure alterations.

Results

Subcutaneous edema, severe muscle weakness and dysphagia together with elevated creatine kinase, D‐dimer and triglyceride levels, and decreased albumin levels were found in anti‐NXP‐2‐positive DM. Muscle ischaemia included regional muscle edema, perifascicular atrophy, microinfarcts and focal punched‐out vacuoles. The density of arterioles was higher in anti‐NXP‐2‐positive DM (＜ 0.05). Perimysial arterioles with thickened vascular wall, thrombosis and lipid accumulation were found in the vascular wall of diseased perimysial arterioles. The frequency of diseased arterioles and thrombosis was higher in anti‐NXP‐2‐positive DM (< 0.05). Sarcoplasmic vascular endothelial growth factor and MxA expression was observed in multifocal ischaemic lesions. MxA was present in endothelial and smooth muscle cells of the diseased arterioles and pericytes. Electron microscopy confirmed damaged capillaries and tubuloreticular structures.

Conclusions

Our research suggested that perimysial arterioles were most commonly involved in anti‐NXP‐2‐positive DM, which led to muscle ischaemia.

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Authors:
Y. Liu, Y. Zheng, Q. Gang, Z. Xie, Y. Jin, X. Zhang, X. Deng, H. Hao, F. Gao, Z. Zhang, H. Xiong, W. Zhang, Z. Wang and Y. Yuan
Article first published online:
25 Oct 2019 | DOI: 10.1111/ene.14097

Original Article

Background and purpose

Although migraine is the second most disabling condition worldwide, there is poor awareness of it. The objective was to assess the awareness of migraine and previous diagnostic and therapeutic consultations and treatments in a large international population of migraineurs.

Methods

This was a multicentre study conducted in 12 headache centres in seven countries. Each centre recruited up to 100 patients referred for a first visit and diagnosed with migraine. Subjects were given a structured clinical questionnaire‐based interview about the perceptions of the type of headache they suffered from, its cause, previous diagnoses, investigations and treatments.

Results

In all, 1161 patients completed the study. Twenty‐eight per cent of participants were aware that they suffered from migraine. Sixty‐four per cent called their migraine ‘headache'; less commonly they used terms such as ‘cervical pain' (4%), tension headache (3%) and sinusitis (1%). Eight per cent of general practitioners and 35% of specialists (of whom 51% were neurologists and/or headache specialists) consulted for migraine formulated the correct diagnosis. Before participating in the study, 50% of patients had undergone X‐ray, computed tomography and/or magnetic resonance imaging of the cervical spine and 76% underwent brain and/or cervical spine imaging for migraine. Twenty‐eight per cent of patients had received symptomatic migraine‐specific medications and 29% at least one migraine preventive medication.

Conclusions

Although migraine is a very common disease, poor awareness of it amongst patients and physicians is still an issue in several countries. This highlights the importance of the promotion of migraine awareness to reduce its burden and limit direct and indirect costs and the risk of exposure to useless investigations.

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Authors:
M. Viana, F. Khaliq, C. Zecca, M. D. L. Figuerola, G. Sances, V. Di Piero, B. Petolicchio, M. Alessiani, P. Geppetti, C. Lupi, S. Benemei, R. Iannacchero, F. Maggioni, M. E. Jurno, S. Odobescu, E. Chiriac, A. Marfil, F. Brighina, N. Barrientos Uribe, C. Pérez Lago, C. Bordini, F. Lucchese, V. Maffey, G. Nappi, G. Sandrini and C. Tassorelli
Article first published online:
22 Oct 2019 | DOI: 10.1111/ene.14098

Original Article

Background and purpose

The aim was to evaluate whether the addition of evoked potentials (EPs) which evaluate brainstem function to the EP score improves its ability to predict disease progression in people with clinically isolated syndrome (pwCIS).

Methods

For 94 pwCIS, data on disease activity and progression after 2.9 (1.4–4.1) years of follow‐up were available. Baseline characteristics included magnetic resonance imaging (MRI) parameters, visual EPs, auditory EPs, somatosensory EPs of the median and tibial nerves, vestibular evoked myogenic potentials and tongue somatosensory EPs.

Results

A multivariable regression model including age, sex, total number of T2 lesions on baseline MRI and EP score >13 showed that the total number of T2 lesions on baseline MRI and EP score >13 increase the likelihood for sustained accumulation of disability (SAD). After controlling for age, sex and the total number of T2 lesions on baseline MRI, the hazard of SAD for participants with EP score >13 is 4.093 times that of participants with EP score ≤13. EP score >13 also increases the likelihood for progression measured with a composite measure of progression which uses the Expanded Disability Status Scale, the nine‐hole peg test and the timed 25‐ft walk (exp() = 5.577, 95% confidence interval 1.520–20.468,  = 0.01).

Conclusion

The addition of EPs that evaluate brainstem function to the EP score enables prediction of the progression of disability in pwCIS.

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Authors:
L. Crnošija, T. Gabelić, B. Barun, I. Adamec, M. Krbot Skorić and M. Habek
Article first published online:
25 Oct 2019 | DOI: 10.1111/ene.14100

Original Article

Background and purpose

Whether the Lewis–Sumner syndrome (L‐SS) is a distinct entity from other types of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP‐ot) remains controversial.

Method

The clinical/electrophysiological characteristics and long‐term outcomes of 45 L‐SS and 35 CIDP‐ot patients were retrospectively compared.

Results

The CIDP‐ot group was composed of 11 patients with a typical CIDP, 17 with a pure sensory form, four with a distal form and three with a pure motor form. In the L‐SS group, asymmetric ( < 0.001) and monomelic involvement ( = 0.04) of the upper limbs ( < 0.001) was significantly more frequent; paucisymptomatic forms (Overall Neuropathy Limitations Scale ≤ 1) were less frequent ( < 0.001); electroneuromyography showed that conduction block in intermediate nerve segments was the main demyelinating feature, with frequent F‐wave abnormalities on nerves without conduction block (44%). Long‐term prognosis was globally poorer in the L‐SS group with more frequent aggravation during treatment ( = 0.02), less frequent treatment withdrawal ( = 0.03) and longer time to achieve successful withdrawal (39 vs. 15 months).

Conclusions

Our study suggests that L‐SS patients have a less favourable therapeutic response rate and long‐term outcomes. Rapid differentiation of L‐SS from other forms of CIDP is important in order to anticipate a more complicated disease course management, with from one side the inefficacy or even harmfulness of corticosteroids and from the other side a difficult weaning procedure. A prospective study is necessary to confirm these results.

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Authors:
G. Fargeot, T. Maisonobe, D. Psimaras, R. Debs, T. Lenglet, D. Adams, C. Vandendries, C. Labeyrie and K. Viala
Article first published online:
24 Oct 2019 | DOI: 10.1111/ene.14101

Original Article

Background and purpose

Humanized monoclonal antibody galcanezumab, which binds to calcitonin‐gene‐related peptide, has shown efficacy for episodic and chronic migraine prevention. These analyses evaluated galcanezumab response for migraine headache prevention in patients who previously failed onabotulinumtoxinA (‘nonresponse’ or ‘inadequate response’ or safety reasons).

Methods

analyses included data from three double‐blind, placebo‐controlled, phase 3 episodic or chronic migraine studies; 2886 patients randomly received 120 or 240 mg galcanezumab or placebo. During double‐blind periods the study drug was administered subcutaneously once a month for 6 months in EVOLVE‐1 and ‐2 and for 3 months in REGAIN. The 120 mg groups received a 240 mg loading dose at month 1. Pooled analyses included 129 patients who failed onabotulinumtoxinA. Using mixed effect model repeat measurements, the least squares mean change from baseline in the number of migraine headache days (MHDs) was calculated for the first 3 months of treatment.

Results

For pooled analyses, significant decreases from baseline in the number of MHDs were observed for 120 mg (−3.91) and 240 mg (−5.27) galcanezumab overall versus placebo (−0.88) across 3‐month time points for patients who failed onabotulinumtoxinA. Corresponding data for patients with chronic migraine showed significant decreases: 120 mg (−3.18) and 240 mg (−4.26) galcanezumab versus placebo (0.16). Significant reductions in the number of MHDs per month with acute medication use included 120 mg galcanezumab (−4.35) and 240 mg galcanezumab (−4.55) versus placebo (−0.83). Estimates of ≥50% response during months 1–3 were 9.4% for placebo, 41.3% for 120 mg galcanezumab and 47.5% for 240 mg galcanezumab.

Conclusion

Galcanezumab is an option for prevention of migraine in patients who have previously failed onabotulinumtoxinA preventive therapy.

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Authors:
J. Ailani, E. Pearlman, Q. Zhang, A. J. Nagy, K. Schuh and S. K. Aurora
Article first published online:
10 Dec 2019 | DOI: 10.1111/ene.14102

Original Article

Background and purpose

Factors influencing the outcome after the critical care unit (CCU) for patients with status epilepticus (SE) are poorly understood. Survival for these patients was examined to establish (i) whether the risk of mortality has changed over time and (ii) whether admission to different unit types affects mortality risk over and above other risk factors.

Methods

The Intensive Care National Audit and Research Centre database and the Case Mix Programme database (January 2001 to December 2016) were analysed. Units were defined as neuro‐CCU (NCCU), general CCU with 24‐h neurological support (GCCU‐N) or general CCU with limited neurological support (GCCU‐L).

Results

There were 35 595 CCU cases of SE with a 3‐fold increase over time (4739 in 2001–2004 to 14 166 in 2013–2016). More recent admissions were older and were more often unsedated on admission. Mortality declined for all units although this was more marked for NCCUs (8.1% in 2001–2004 to 4.4% in 2013–2016 compared to 5.1% and 4.1% for GCCU‐L). Acute hospital mortality was two to three times higher than CCU mortality although this has also declined with time. GCCU‐L appeared to have lower mortality than NCCUs (odds ratio 0.84, 95% confidence interval 0.72, 0.98) but after adjustment for case mix there were no differences. Older age and markers of seriousness of morbidity were all associated with increased mortality risk.

Conclusions

The number of patients admitted to a CCU for SE is rising but critical care and acute hospital mortality is decreasing. Patients treated in an NCCU have higher mortality but this is explicable by more severe underlying disease.

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Authors:
M. S. Damian, Y. Ben‐Shlomo, R. Howard and D. A. Harrison
Article first published online:
06 Nov 2019 | DOI: 10.1111/ene.14106

Original Article

Background and purpose

The pathophysiological model of tics generally describes disruption of γ‐aminobutyric acid transmission, and taurine is found to be an agonist of γ‐aminobutyric acid receptors. The study aimed to evaluate the safety and efficacy of taurine as an add‐on treatment for tics.

Methods

Four hundred and four youngsters with tic disorders were randomly assigned to 12 weeks of either oral taurine or placebo. The Yale Global Tic Severity Scale was used to measure tic severity. The primary outcome measure was global severity scores reduced by more than 60% compared with baseline scores.

Results

Three hundred and eighty‐two patients were successfully treated. At week 4, no significant differences were found in the treatment effect and the total occurrence of adverse drug reactions between the taurine and placebo groups. At week 12, the proportion of significant improvement in tics was significantly higher in the taurine group than the placebo group (53.4% with taurine versus 34.5% without taurine; relative risk 1.546;  < 0.001), and no group differences were found in the total occurrence of adverse drug reactions.

Conclusions

Taurine is safe and effective for tics.

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Authors:
L. Ding, Z. Yang, G. Liu, N. Ran, M. Yi, H. Li, H. Zhao, L. Tang, H. Cheng, J. Zhao, Y. Zhang, X. Ji and S. Liu
Article first published online:
11 Nov 2019 | DOI: 10.1111/ene.14107

Original Article

Background

Spasticity is a frequent multifactorial manifestation of multiple sclerosis (MS), affecting mostly the chronic courses of the disease. Its impact on patient functioning and quality of life is profound. Treatment of spasticity includes oral and intrathecal anti‐spastic drugs, muscle injections with relaxant agents, physical therapy, electrical and magnetic stimulation and peripheral nerve stimulation, alone or in various combinations.

Methods

This Italian consensus on the treatment of spasticity in MS was produced by a large group of Italian MS experts in collaboration with neurophysiologists, experts in the production of guidelines and patients’ representatives operating under the umbrella of the Italian Neurological Society, the Associazione Italiana Sclerosi Multipla and the European Charcot Foundation. This guideline was developed in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A total of 11 questions were formulated following the PICO framework (patients, intervention, comparator, outcome). Controlled studies only were included in the analysis.

Results

Despite some consistent limitations due to the poor methodological quality of most studies, there was a consensus on a strong recommendation for the use of intrathecal baclofen, oromucosal spray of nabiximols and intramuscular injection of botulinum toxin. The level of recommendation was weak for oral baclofen, tizanidine, gabapentin, benzodiazepines and transcranial magnetic stimulation.

Conclusions

There is a clear need for new larger multicentre well‐designed clinical trials with a duration that allows the persistence of the effects and the long‐term safety of the interventions to be evaluated.

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Authors:
G. Comi, A. Solari, L. Leocani, D. Centonze, S. Otero‐Romero, Roberta Amadeo, Maria Pia Amato, Antonio Bertolotto, Laura Boffa, Giampaolo Brichetto, Mauro Comola, Angelo Ghezzi, Giacomo Lus, Maria Giovanna Marrosu, Franco Molteni, Francesco Patti, Carlo Pozzilli, Marco Rovaris, Francesco Saccà, Edoardo Sessa, Claudio Solaro, Maria Trojano, Carlo Trompetto and Mauro Zaffaroni
Article first published online:
03 Dec 2019 | DOI: 10.1111/ene.14110

Original Article

Background and purpose

Observational studies have implicated migraine as a risk factor for coronary artery disease (CAD) and atrial fibrillation (AF); however, it is unclear whether migraine is causal in this relationship. Potential causality between genetically instrumented liability to migraine and cardiovascular disease outcomes was investigated using two‐sample Mendelian randomization.

Methods

The exposure comprised 35 independent, genome‐wide significant genetic variants identified in the largest published genome‐wide association study of migraine ( = 59 674/ = 316 078). The outcome datasets included genome‐wide association studies of CAD (76 014/264 785), myocardial infarction (43 676/128 199), angina (10 618/326 065) and AF (60 620/970 216). Mendelian randomization estimates were calculated using inverse‐variance weighted regression, and were further assessed with conventional Mendelian randomization sensitivity analyses.

Results

Evidence was found for a protective effect of migraine liability on CAD (odds ratio 0.86, 95% confidence interval 0.76–0.96,  = 0.003), myocardial infarction (0.86, 0.74–0.96,  = 0.01) and angina (0.86, 0.75–0.99,  = 0.04), but not on AF (1.00, 0.95–1.05,  = 0.88). Analyses by migraine subtype showed an effect of liability to migraine without aura on CAD risk (0.91, 0.84–0.99,  = 0.014), but not of migraine with aura (1.00, 0.97–1.03,  = 0.89). Sensitivity analyses indicated minimal bias by horizontal pleiotropy, outliers, reverse causality or sample overlap.

Conclusions

A potentially protective effect of genetically instrumented liability to migraine on CAD risk was identified. Mechanistic research investigating this link is warranted.

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Authors:
I. Daghlas, Y. Guo and D. I. Chasman
Article first published online:
25 Nov 2019 | DOI: 10.1111/ene.14111

Original Article

Background and purpose

Elevated C‐reactive protein (CRP) is associated with an increased risk of ischaemic stroke (IS). However, the causality of this association is uncertain. The aim is to investigate whether genetically raised plasma CRP concentration levels are associated with IS on the basis of the Mendelian randomization method.

Methods

Based on the National Center for Biotechnology Information single nucleotide polymorphism (SNP) database, the Chinese online genetic database as well as previously published studies, four CRP‐associated SNP alleles (rs1130864, rs1205, rs876537 and rs3093059) with minor allele frequency ≥0.15 were selected and the concentration levels of CRP were measured in 378 first‐ever IS patients and 613 healthy controls.

Results

Three SNPs were chosen and used as instrumental variables. The adjusted odds ratios (ORs) [95% confidence interval (95% CI)] of IS per addition of the modelled allele were 1.07 (0.79–1.45) for rs876537, 0.99 (0.73–1.35) for rs1205 and 1.08 (0.71–1.65) for rs3093059. The OR (95% CI) of IS for plasma CRP ≥2.0 mg/l was 2.19 (1.06–4.53) compared with <2.0 mg/l. The adjusted OR (95% CI) of IS per genetically predicted 10% higher CRP concentration, based on the three SNPs as the instruments, was 1.02 (0.94–1.11). Furthermore, similar results were obtained with adjusted ORs (95% CI) of 1.00 (0.88–1.13) and 1.04 (0.93–1.16), respectively, for large‐artery atherosclerosis and small‐artery occlusion per genetically predicted 10% higher CRP concentration.

Conclusions

This Mendelian randomization study provides no clear support that elevated CRP concentration is causally associated with the risk of IS.

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Authors:
X. Zhang, A. Wang, J. Zhang, M. Singh, D. Liu, Y. Zuo, L. Wu, M. Song, W. Wang, V. Feigin, Y. Wang and D. Zheng
Article first published online:
26 Nov 2019 | DOI: 10.1111/ene.14113

Original Article

Background and purpose

Studies on using antiplatelet agents for secondary prevention in ischaemic stroke patients with renal dysfunction are limited. The Taiwan Stroke Registry database was used to compare the efficacy of antiplatelet agents.

Methods

From the Taiwan Stroke Registry data, 39 174 acute ischaemic stroke patients were identified and were classified into three groups by antiplatelet agent: aspirin, clopidogrel and dual antiplatelet therapy (DAPT) with a combination of aspirin and clopidogrel. The re‐stroke incidence and 1‐year mortality were stratified by estimated glomerular filtration rate (eGFR) levels at admission: ≥90, 60–89 and <60 ml/min/1.73 m or on dialysis.

Results

Compared to the aspirin group, the re‐stroke differences were not statistically significant for the clopidogrel group [adjusted subhazard ratio 0.95, 95% confidence interval (CI) 0.84–1.08] and the DAPT group (adjusted subhazard ratio 1.03, 95% CI 0.77–1.39) after controlling for the competing risk of death. The mortality rate increased as the eGFR level declined. In addition, compared to patients taking aspirin, there was no statistically significant difference in overall 1‐year mortality for the clopidogrel group (adjusted hazard ratio 1.11, 95% CI 0.95–1.29) and for the DAPT group (adjusted hazard ratio 1.01, 95% CI 0.67–1.54). The results were consistent in different subgroups stratified by eGFR levels.

Conclusions

There was no difference in the risks of recurrent stroke and 1‐year mortality amongst ischaemic stroke patients with or without renal dysfunction receiving antiplatelet agents with aspirin, clopidogrel or dual agents with a combination of aspirin and clopidogrel, regardless of their renal dysfunction status.

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Authors:
I.‐K. Wang, T.‐H. Yen, Y.‐C. Guo, Y. Sun, L.‐M. Lien, W.‐L. Chang, P.‐L. Chen, Y.‐C. Yang, F.‐C. Sung and C. Y. Hsu
Article first published online:
08 Dec 2019 | DOI: 10.1111/ene.14116

Original Article

Background and purpose

Biomarkers support the aetiological diagnosis of neurocognitive disorders . Incomplete evidence is available to drive clinical decisions; available diagnostic algorithms are generic and not very helpful in clinical practice. The aim was to develop a biomarker‐based diagnostic algorithm for mild cognitive impairment patients, leveraging on knowledge from recognized national experts.

Methods

With a Delphi procedure, experienced clinicians making variable use of biomarkers in clinical practice and representing five Italian scientific societies (neurology – Società Italiana di Neurologia per le Demenze; neuroradiology – Associazione Italiana di Neuroradiologia; biochemistry – Società Italiana di Biochimica Clinica; psychogeriatrics – Associazione Italiana di Psicogeriatria; nuclear medicine – Associazione Italiana di Medicina Nucleare) defined the theoretical framework, relevant literature, the diagnostic issues to be addressed and the diagnostic algorithm. An –1 majority defined consensus achievement.

Results

The panellists chose the 2011 National Institute on Aging and Alzheimer's Association diagnostic criteria as the reference theoretical framework and defined the algorithm in seven Delphi rounds. The algorithm includes baseline clinical and cognitive assessment, blood examination, and magnetic resonance imaging with exclusionary and inclusionary roles; dopamine transporter single‐photon emission computed tomography (if no/unclear parkinsonism) or metaiodobenzylguanidine cardiac scintigraphy for suspected dementia with Lewy bodies with clear parkinsonism (round VII, votes (yes‐no‐abstained): 3‐1‐1); F‐fluorodeoxyglucose positron emission tomography for suspected frontotemporal lobar degeneration and low diagnostic confidence of Alzheimer’s disease (round VII, 4‐0‐1); cerebrospinal fluid for suspected Alzheimer’s disease (round IV, 4‐1‐0); and amyloid positron emission tomography if cerebrospinal fluid was not possible/accepted (round V, 4‐1‐0) or inconclusive (round VI, 5‐0‐0).

Conclusions

These consensus recommendations can guide clinicians in the biomarker‐based aetiological diagnosis of mild cognitive impairment, whilst guidelines cannot be defined with evidence‐to‐decision procedures due to incomplete evidence.

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Authors:
M. Boccardi, V. Nicolosi, C. Festari, A. Bianchetti, S. Cappa, D. Chiasserini, A. Falini, U.P. Guerra, F. Nobili, A. Padovani, G. Sancesario, S. Morbelli, L. Parnetti, P. Tiraboschi, C. Muscio, D. Perani, F.B. Pizzini, A. Beltramello, G. Salvini Porro, M. Ciaccio, O. Schillaci, M. Trabucchi, F. Tagliavini and G.B. Frisoni
Article first published online:
18 Dec 2019 | DOI: 10.1111/ene.14117

Original Article

Background and purpose

It is well established that patient‐related constitutional features predispose to focal peripheral neuropathies. Some of these risk factors were investigated in common focal neuropathies encountered in patients referred for electromyography.

Methods

Gender, age, height and body mass index (BMI) were analysed retrospectively as risk factors for 11 focal neuropathies. In all, 9686 patients (age range 18–96 years; 58% women) were included from three different centres, with identical methods and equipment.

Results

High BMI was related to carpal tunnel syndrome (CTS), ulnar neuropathy at the elbow (UNE), combined CTS and UNE, meralgia paraesthetica and lumbar radiculopathy. In women, CTS and Morton's metatarsalgia were more common, whilst long thoracic neuropathies, suprascapular neuropathies and UNE were more common in men. Older age increased the risk for CTS, UNE, Morton's metatarsalgia and radiculopathies.

Conclusions

Age, gender and BMI are important risk factors for many common focal neuropathies.

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Authors:
C. Martínez‐Aparicio, S. K. Jääskeläinen, L. Puksa, F. Reche‐Lorite, P. Torné‐Poyatos, J. Paniagua Soto and B. Falck
Article first published online:
29 Nov 2019 | DOI: 10.1111/ene.14118

Original Article

Background and purpose

Existing research studies have demonstrated a relationship between magnetic resonance imaging (MRI) neuroimaging measures and walking speed in people with multiple sclerosis (PwMS). However, to date there are no data as to the brain structures involved in gait coordination and control in PwMS. Therefore, the aim of our study was to investigate the association between walk ratio, an indicator of gait coordination, and related brain structures in PwMS.

Methods

A brain MRI was performed by a 3.0‐T MR scanner in conjunction with a volumetric analysis based on three‐dimensional T1‐weighted images. Regions of interest were volumes of the hippocampus, amygdala, putamen, caudate, pallidum, thalamus, cerebellum and the corpus callosum regions. Walking speed and walk ratio, defined as step length divided by step rate, was measured whilst walking on an electronic walkway.

Results

In all, 343 PwMS (41.1 ± 13.4 years, 69.1% female, median Expanded Disability Status Scale 2.5) were included in the study. A significant association was found between the left cerebellum volume and walk ratio after controlling for age, gender, total cranial volume and disability;  = 0.379,  = 0.002. A similar association was found between the right cerebellum volume and walk ratio,  = 0.364,  = 0.002. No correlations were observed between walk ratio and the thalamus, basal ganglia, hippocampus, amygdala and the corpus callosum volumes. No association was found between walking speed and all brain measures.

Conclusions

The walk ratio should be considered when evaluating and assessing PwMS presenting with ataxia. Furthermore, it is also hypothesized that a low walk ratio indicates a lower cerebellum volume in the MS population.

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Authors:
A. Kalron, S. Menascu, U. Givon, M. Dolev and A. Achiron
Article first published online:
29 Nov 2019 | DOI: 10.1111/ene.14119

Letter to the Editor

Updates on migraine epidemiology

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Authors:
C. Mattiuzzi and G. Lippi
Article first published online:
28 Nov 2019 | DOI: 10.1111/ene.14120

Original Article

Background and purpose

Cerebrospinal fluid (CSF) kappa free light chains (FLCs) may be a more sensitive marker of intrathecal immunoglobulin (Ig)G synthesis compared with oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a multiple sclerosis (MS) diagnosis in a group of OCB‐negative patients with suspected MS.

Methods

The CSF and serum kappa and lambda FLCs were tested using the Freelite kit (serum) and Freelite Mx (CSF) assay (The Binding Site Group, Bimingham, UK) in 391 OCB‐negative patients with suspected/possible MS and in 54 OCB‐positive patients with MS.

Results

The CSF kappa FLC levels were below the detection limit (0.27 mg/L) in 61% of patients. Using quantitative data, we found the best kappa index cut‐off value for the prediction of MS to be 5.8. A kappa index ≥5.8 was present in 25% of OCB‐negative MS (23/92) and in 98% of OCB‐positive patients with MS. Using a qualitative approach and a kappa index cut‐off of 5.9, based on literature data, we likewise found that 24% of OCB‐negative patients with MS had a kappa index ≥5.9, compared with 5.4% of OCB‐negative patients without MS ( < 0.001). No reliable data could be obtained for the lambda index; lambda FLCs were below the detection limit (0.68 mg/L) in 90% of CSF samples.

Conclusions

The kappa index could contribute to the identification of OCB‐negative patients with a high probability of an MS diagnosis. Using more sensitive techniques might even improve the diagnostic performance of the kappa index and better define the role of the lambda index.

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Authors:
D. Ferraro, A. Trovati, R. Bedin, P. Natali, D. Franciotta, M. Santangelo, V. Camera, F. Vitetta, M. Varani, T. Trenti, M. Gastaldi, S. De Biasi, M. Nasi, M. Pinti, S. Meletti and P. Sola
Article first published online:
02 Dec 2019 | DOI: 10.1111/ene.14121

Short Communication

Background and purpose

The aim of this study was to assess the effectiveness of cladribine treatments in a population of patients with refractory myasthenia gravis (MG).

Methods

In a prospective open‐label study of cladribine in refractory MG, 13 patients received cladribine at baseline with repetitive cycles driven by clinical response. A Myasthenia Gravis Composite (MGC) score was obtained and a standard dose of steroids was administered.

Results

A total of 11 patients achieved significant clinical improvement in MGC score during their therapy. The mean MGC score declined from 15.1 to 6.3 points within 4 months of observation. The dosage of prednisolone declined from 9.5 to 1.9 mg. None of the patients required intravenous immunoglobulin or plasma exchange treatments and no adverse events occurred in the study period.

Conclusion

Cladribine seems to be a safe and effective emergency therapy in a population of patients with refractory MG.

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Authors:
K. Rejdak, S. Szklener, A. Korchut and D. Baranowski
Article first published online:
15 Dec 2019 | DOI: 10.1111/ene.14124

Original Article

Background and purpose

The long‐term outcomes and stroke recurrence after basilar artery occlusion (BAO) are largely unknown. We aimed to assess these variables in a comparatively large series of consecutive patients.

Methods

Adults with acute BAO were retrospectively identified from 1976 to 2011. Post‐discharge records were reviewed to assess for stroke recurrences, mortality and disability. Exploratory analysis of survival was carried out using Kaplan–Meier and log‐rank tests. Factors associated with survival time were determined using Cox models.

Results

A total of 86 patients (34% female, median age 72 [interquartile range (IQR), 60–79] years) with a median National Institutes of Health Stroke Scale score of 11 (IQR, 6–27) were included. Twenty‐nine patients (34%) died during the initial hospitalization. Median modified Rankin Scale (mRS) score at discharge among survivors was 4 (IQR, 2.5–5.5). At 1 and 5 years, 70% of survivors ad a mRS ≤3. Seventeen patients had recurrent strokes during the hospitalization and 12 patients had 19 recurrent strokes after discharge. The median survival time was 52 days (IQR, 6–1846). Older age per decade on admission [adjusted hazard ratios (aHR), 1.32; 95% confidence interval (CI), 1.05–1.66,  = 0.02] and a higher mRS at discharge (aHR, 4.48; 95% CI, 2.72–7.39,  < 0.0001) were associated with mortality. Patients who were not treated with any reperfusion therapy had a trend towards reduced mortality (aHR, 0.39; 95% CI, 0.14–1.08,  = 0.07).

Conclusions

Survivors from BAO had severe short‐term functional disability. Most deaths and stroke recurrences occurred within the first year following the initial event. The risk of death was higher in older and more disabled survivors. However, favorable long‐term recovery was possible.

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Authors:
M. A. Hawkes, E. Blaginykh, M. W. Ruff, T. Burrus, E. F. M. Wijdicks and A. A. Rabinstein
Article first published online:
08 Dec 2019 | DOI: 10.1111/ene.14126

Review Article

Background and purpose

In addition to lowering stroke risk, warfarin use is also associated with reduced stroke severity in patients with atrial fibrillation and acute ischaemic stroke. It was sought to determine whether the effect of non‐vitamin‐K oral anticoagulants (NOACs), compared to warfarin, differed by stroke severity.

Methods

Phase III randomized controlled trials with participants who were randomized to receive NOACs or warfarin for stroke prevention in the setting of non‐valvular atrial fibrillation were identified. Stroke was classified into two categories, fatal or disabling stroke and non‐disabling stroke, and meta‐analyses were completed for both outcomes and for comparative case fatality of stroke amongst trials.

Results

Five randomized controlled trials met our inclusion criteria. In clinical trials evaluating the NOACs usually prescribed in clinical practice (four trials), acute stroke was reported in 1403 (1.86%) participants, 787 (1.04%) in the NOAC group [386 (0.51%) fatal or disabling, 401 (0.53%) non‐disabling] and 616 (0.82%) in the warfarin group [367 (0.49%) fatal or disabling, 249 (0.33%) non‐disabling]. On meta‐analysis NOACs were significantly superior to warfarin for fatal or disabling stroke (odds ratio [OR] 0.77; 95% confidence interval [CI] 0.66–0.89,  = 21%) and non‐disabling stroke (OR 0.85; 95% CI 0.73–0.98,  = 2%). The case fatality of stroke was no different between groups (OR 0.90, 95% CI 0.75–1.13,  = 0%), but the point estimate favoured NOACs.

Conclusion

In phase III trials of NOACs, for prevention of stroke in atrial fibrillation, NOACs are associated with a lower risk of both fatal/disabling and non‐disabling stroke compared to warfarin.

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Authors:
M. Costello, R. Murphy, C. Judge, S. Ruttledge, S. Gorey, E. Loughlin, D. Hughes, A. Nolan, M. J. O’Donnell and M. Canavan
Article first published online:
08 Jan 2020 | DOI: 10.1111/ene.14134

Letter to the Editor

On the semantics of clinical trials. The case of a ‘pragmatic’ trial in Alzheimer’s disease

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Authors:
R. Dal‐Ré
Article first published online:
23 Dec 2019 | DOI: 10.1111/ene.14141

Editorial

Is decreased stroke severity in patients with atrial fibrillation receiving non‐vitamin K oral anticoagulant treatment the for warfarin?

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Authors:
A. H. Katsanos
Article first published online:
14 Jan 2020 | DOI: 10.1111/ene.14145

Short Communication

Background and purpose

Immune system dysfunction and inflammatory dysregulation have been shown in several animal models of fragile X syndrome (FXS). However, the phenotypical implications of this dysregulation have not been systematically evaluated in a large patient cohort.

Methods

Five thousand seven hundred thirty‐six FXS patients from a nationwide health insurance database were identified and compared to 573 600 age‐ and sex‐matched controls. The phenome‐wide association studies codes of FXS patients and those without FXS were compared and the false discovery rate was controlled at 0.05 using the Benjamini–Hochberg procedure.

Results

In addition to the commonly reported comorbidities of FXS, an over‐representation of infectious diseases, including otitis media, cellulitis and abscess of fingers or toes, viral enteritis, candidiasis and pneumonia, was discovered. In addition, there was an under‐representation of autoimmune disorders in FXS patients.

Conclusions

Our systematic comorbidity analyses identified immunologically‐based phenotypes associated with FXS. Our findings align with previous observations of compromised immunity and phagocytic defects in animal models of FXS. These results suggest the importance of immune‐related pathways in FXS patients and their relevance to the gene.

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Authors:
K.‐H. Yu, N. Palmer, K. Fox, L. Prock, K. D. Mandl, I. S. Kohane and D. Prilutsky
Article first published online:
17 Jan 2020 | DOI: 10.1111/ene.14146

Review Article

Background and purpose

Subthalamic deep brain stimulation (STN DBS) is an effective therapy against medication‐refractory motor complications in patients with Parkinson’s disease. However, it remains difficult to predict which baseline patient characteristics are associated with quality of life (QoL) after surgery. The objective was to identify preoperative factors associated with QoL after STN DBS by systematically reviewing publications of sufficient methodological quality.

Methods

Main databases were systematically searched up to March 2019 to identify studies that investigated factors associated with QoL after STN DBS in patients with idiopathic Parkinson’s disease.

Results

In all, 869 studies were identified, of which 18 fulfilled the inclusion criteria. Higher QoL after DBS appears to be associated with a large preoperative difference between ON and OFF motor function in some studies, although there was no clear association of severity of motor function or motor complications with postoperative QoL. Lower severity of dyskinesias was associated with greater postoperative QoL improvement but has been insufficiently studied. Higher baseline QoL was suggestive of higher postoperative QoL. Four studies suggested that older age at surgery is associated with a lower improvement, although six other studies reported no association. No or limited evidence was found for cognitive impairment or psychiatric dysfunction.

Conclusion

Various relative contraindications for STN DBS such as cognitive impairment and psychiatric dysfunction appear to be unrelated to postoperative QoL. However, the lack of clear correlations with disease‐related variables suggests that QoL may be individually influenced by other factors, indicating that an ideal preoperative patient profile with regard to QoL improvement cannot be readily provided.

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Authors:
V. J. Geraedts, S. Feleus, J. Marinus, J. J. van Hilten and M. F. Contarino
Article first published online:
24 Jan 2020 | DOI: 10.1111/ene.14147

Corrigendum

Patient and caregiver involvement in the formulation of guideline questions: findings from the European Academy of Neurology guideline on palliative care of people with severe multiple sclerosis

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Authors:
Article first published online:
09 Feb 2020 | DOI: 10.1111/ene.14149