cover image European Journal of Neurology

European Journal of Neurology

2018 - Volume 25
Issue 12 | December 2018
Previous Issue

Original Article

Background

Few studies report on the experience of care for patients with Parkinson's disease (PD) from their own point of view.

Methods

An analysis was carried out of a survey in 11 European countries on self‐reported access to services and satisfaction with different aspects of care.

Results

In all, 1775 people with PD (PwP) participated with disease duration ranging from <1 to 42 years. When referred to a specialist most were seen within 3 months but medication reviews occurred every 3 months in only 10%, every 6 months in 37%, once a year in 40% and every 2 years or less frequently in 13%. Waiting times to therapists were usually ≥4 months. Satisfaction with care was highest for involvement of PwP in decisions (63% of respondents satisfied) and involvement of family/carer (62%) followed by communication with PwP (57%), information received (54%), frequency of treatment reviews (52%) and suitability of treatment for the individual condition and circumstances (52%), but lowest for availability and accessibility of treatment when needed (48%) and collaborations between healthcare professionals in delivering care (41% satisfied). The main factors associated with overall satisfaction scores with care were the overall satisfaction with initial consultation (= 0.26,  < 0.0001), the sensitivity with which the diagnosis was communicated, the quantity of information provided (both = 0.24,  < 0.0001) and the frequency of medication review (= 0.17,  < 0.0001).

Conclusion

More coordinated and responsive care, tailored to the individual, with regular and timely medication reviews and information provision, is likely to improve satisfaction with care in current healthcare pathways.

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Authors:
A. Schrag, K. Khan, S. Hotham, R. Merritt, O. Rascol and L. Graham
Article first published online:
16 Aug 2018 | DOI: 10.1111/ene.13738

Original Article

Background and purpose

To determine the association of differential leukocyte counts on admission with efficacy and safety outcomes in patients with acute ischaemic stroke (AIS) treated with intravenous thrombolysis (IVT).

Methods

Consecutive patients with AIS receiving IVT were evaluated at two stroke centers. Differential leukocyte counts and neutrophil:lymphocyte ratio (NLR) were determined during the initial 12 h of admission. Efficacy outcomes were favorable functional outcome (FFO) (modified Rankin Scale scores of 0–1) and functional independence (FI) (modified Rankin Scale scores of 0–2) at 3 months, whereas safety outcomes were symptomatic intracranial hemorrhage and 3‐month mortality.

Results

Among 657 IVT‐treated patients with AIS, the mean age was 64 ± 14 years, 50% were female and median National Institutes of Health Stroke Scale score was 7 points (interquartile range, 4–13). Lower neutrophil and leukocyte counts and NLR counts were observed in patients with 3‐month FFO and FI, whereas higher counts were observed in patients who died at 3 months. The best discriminative factors for 3‐month FFO and FI were NLR < 2.2 (sensitivity 51.4%, specificity 63.1%) and leukocyte count <8100/μL (sensitivity 57.5%, specificity 55.1%), respectively. After adjustment for potential confounders, NLR < 2.2 was associated with higher odds of FFO [odds ratio (OR), 1.56; 95% confidence interval (CI), 1.08–2.24; = 0.018], whereas leukocyte count <8100/μL demonstrated higher odds of 3‐month FI (OR, 1.69; 95% CI, 1.11–2.57; = 0.014) and lower odds of 3‐month mortality (OR, 0.31; 95% CI, 0.16–0.60; = 0.001). Combined neutrophil (<6800/μL) and leukocyte (<8100/μL) counts demonstrated a strong interaction for 3‐month FI (OR, 1.73; 95% CI, 1.13–2.67; interaction = 0.012).

Conclusions

Differential leukocyte counts on admission were independently associated with clinical outcomes in patients with AIS treated with IVT. These inflammatory biomarkers are potential targets for adjunctive neuroprotection in this stroke subgroup.

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Authors:
K. Malhotra, N. Goyal, J. J. Chang, M. Broce, A. Pandhi, A. Kerro, R. B. Shahripour, A. V. Alexandrov and G. Tsivgoulis
Article first published online:
01 Aug 2018 | DOI: 10.1111/ene.13741

Original Article

Background and purpose

Late‐onset multiple sclerosis (MS) has a prevalence of about 10–20% in natural history MS studies. Few data have been published about the long‐term disease trajectory in the cohort of late‐onset relapsing‐remitting MS (LORRMS). The aim of this study was to identify the risk factors for reaching an Expanded Disability Status Scale (EDSS) score of 6.0 in LORRMS (onset at >40 years of age) and young‐onset relapsing‐remitting MS (YORRMS) (onset between 18 and 40 years of age).

Methods

Clinical and radiological [magnetic resonance imaging (MRI) of the brain] follow‐up data were collected. Disability was assessed by EDSS score. A Cox proportional hazards model was used to evaluate the demographic and clinical predictors of reaching an EDSS score of 6.0 in the two cohorts.

Results

A total of 671 patients with relapsing‐remitting MS were enrolled, 143 (21.3%) with LORRMS and 528 (78.7%) with YORRMS. In LORRMS, age at onset was 47.8 ± 5.3 (mean ± SD) years and duration of follow‐up was 120.7 ± 52.7 months. In YORRMS, age at onset was 27 ± 2.7 years and duration of follow‐up was 149.9 ± 92.7 months. The survival curve analyses showed a higher probability of reaching an EDSS score of 6.0 for LORRMS in a shorter time (months) than for YORRMS (94.2 vs. 103.2 months; log‐rank 8.8; < 0.05). On MRI, YORRMS showed more brain inflammatory features than LORRMS. In the multivariate Cox model, age at onset [Exp(B) value, 6.5; 95% confidence interval, 1.9–22.6; < 0.001] and male gender [Exp(B) value, 1.7; 95% confidence interval, 1.0–2.8; < 0.05] were the strongest predictors of reaching an EDSS score of 6.0.

Conclusions

The male population with LORRMS reached severe disability faster than those with YORRMS, even when YORRMS showed more brain inflammatory features on MRI.

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Authors:
E. D'Amico, F. Patti, A. Zanghì, C. G. Chisari, S. Lo Fermo and M. Zappia
Article first published online:
03 Aug 2018 | DOI: 10.1111/ene.13745

Original Article

Background and purpose

Hemorrhagic transformation (HT) is a major complication of acute ischaemic stroke that is potentially related to clinical deterioration. The objective of this study was to assess whether chronic hyperglycemia is a predictive factor of HT in patients with acute anterior stroke.

Methods

Patients with acute anterior stroke were included in this study. Hemoglobin A1c (HbA1c) was measured in the morning after hospitalization. HT was detected by computed tomography scans or gradient echo magnetic resonance imaging performed 4 (±2) days after onset. Univariate and multivariate logistic regression analyses were used to assess the risks for HT and short‐term outcomes.

Results

Of the 426 patients included, 93 (21.8%) had HT: 61 (14.3%) presented with hemorrhagic infarction and 32 (7.5%) presented with parenchymal hematoma. A total of 54 patients received thrombolytic treatment and 18 (33.3%) were found to have HT. In the multivariate analysis, HbA1c [odds ratio (OR), 1.294; 95% confidence interval (CI), 1.097–1.528], infarction size (OR, 3.358; 95% CI, 1.748–6.449) and thrombolytic therapy (OR, 3.469; 95% CI, 1.757–6.847) were predictors of HT. The predictive effect of HbA1c on HT was still observed in both groups when patients were stratified according to the levels of fasting blood glucose. HbA1c was found to be a predictor of poor outcomes in the multilogistic regression analysis (OR, 1.482; 95% CI, 1.228–1.788).

Conclusions

Higher HbA1c was independently related to HT and poor neurological outcomes in patients with ischaemic stroke. These findings have significant implications for the treatment of diabetes and glucose management in patients with diabetes mellitus and/or acute ischaemic stroke.

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Authors:
G. Zhang, M. He, Y. Xu, X. Li, Z. Cai, Z. Guo, P. Meng, N. Ji, X. He and L. Pang
Article first published online:
31 Jul 2018 | DOI: 10.1111/ene.13747

Original Article

Background and purpose

Mitoxantrone (MITOX) has been used to treat patients with aggressive multiple sclerosis (MS) for decades. We aimed to describe the effectiveness and adverse events over 10 years post‐MITOX in patients with relapsing and progressive MS from an exhaustive real‐life database.

Methods

Data from patients who received MITOX before 1 January 2006 were collected from the MS Lorraine registry. Expanded Disability Status Scale (EDSS) scores and annual relapse rates (ARRs) year by year during follow‐up and the year prior to MITOX were compared. Time to the first relapse and a 1‐point increase in EDSS score were used in Cox multivariate models to find associations with potential predictive factors.

Results

A total of 411 patients were included. The ARR for the 155 relapsing patients had decreased from 2.0 (SD 1.20) the year before treatment to 0.3 (SD 0.31) by year 10 ( < 0.0001). The EDSS score increased from 2.8 (SD 1.44) to 4.8 (SD 1.90) by year 10 ( < 0.0001). A high ARR at MITOX initiation was associated with a longer time to a 1‐point increase in EDSS score (hazard ratio, 0.81; 95% confidence interval, 0.67–0.99; = 0.04). The EDSS score in 256 progressive patients increased from 5.0 (SD 1.33) to 6.5 (SD 1.26) by year 10 ( < 0.0001). We identified four cases of acute myeloid leukemias.

Conclusions

Patients with the most active forms of MS are the most likely to benefit from MITOX in the long term.

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Authors:
N. Chartier, J. Epstein, M. Soudant, C. Dahan, M. Michaud, S. Pittion‐Vouyovitch, F. Guillemin, M. Debouverie and G. Mathey
Article first published online:
03 Aug 2018 | DOI: 10.1111/ene.13748

Original Article

Background and purpose

Although the causes of multiple sclerosis (MS) remain partially unknown, environmental and genetic factors are thought to play a role in its aetiopathogenesis. Hypovitaminosis D, Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV‐6) infections have been described as possible MS triggers. Our aim was to analyse the possible link between 25‐hydroxyvitamin D [25(OH)D] and viruses in patients with MS.

Methods

We included 482 patients with MS in a 2‐year study. Serum samples were collected to analyse 25(OH)D levels and, according to sample availability, antibody titres against EBV and HHV‐6 by enzyme‐linked immunosorbent assay. DNA was extracted from blood in order to analyse EBV and HHV‐6 viral load by quantitative real‐time polymerase chain reaction and to genotype MS‐related single nucleotide polymorphisms (rs3135388, rs2248359 and rs12368653) when possible.

Results

The 25(OH)D levels were significantly higher in the first semester of the year than in the second. Carriers of the risk allele rs2248359‐C showed lower 25(OH)D levels than non‐carriers. For EBV, viral load was significantly higher when 25(OH)D levels were low, demonstrating an inverse correlation between 25(OH)D levels and EBV load.

Conclusions

The 25(OH)D levels could be involved in the regulation of EBV replication/reactivation in patients with MS.

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Authors:
S. Pérez‐Pérez, M. I. Domínguez‐Mozo, M. Á. García‐Martínez, Y. Aladro, M. Martínez‐Ginés, J. M. García‐Domínguez, C. López de Silanes, I. Casanova, I. Ortega‐Madueño, L. López‐Lozano, M. J. Torrejón, R. Arroyo and R. Álvarez‐Lafuente
Article first published online:
03 Aug 2018 | DOI: 10.1111/ene.13749

Original Article

Background and purpose

X‐linked Charcot–Marie–Tooth disease type 1 (CMTX1), caused by mutations in gap junction protein beta 1 (GJB1), is characterized by various central nervous system symptoms and gender differences of clinical severity. The aim of this study was to identify the frequency and mutation spectrum of CMTX1 patients in Japan and to demonstrate their phenotypic diversities.

Methods

Using three high‐throughput sequencing systems, targeted gene panel sequencing on 1483 unrelated index patients with suspected Charcot–Marie–Tooth (CMT) disease was performed. The peripheral and central nervous system involvements of all patients with variants were assessed retrospectively and a detailed gender comparison was conducted with the CMT examination score.

Results

Twenty‐three novel and 36 described variants were identified from 88 pedigrees, in which 34 female and 78 male patients were enrolled. Mean age at onset of the male patients was much younger than the females, 21.56 ± 17.63 years vs. 35.53 ± 23.72 years ( = 0.007). Male patients presented with more severe phenotypes in every examination item, but statistical differences were observed only in motor dysfunctions of the lower extremities and vibration sensation. No significant sensory difference was identified between genders, either clinically or electrophysiologically. Central nervous system dysfunctions were found in 15 patients from 12 pedigrees. Therein, six patients developed stroke‐like phenotypes, with dysarthria as the leading symptom.

Conclusions

A relatively lower frequency of CMTX1 (5.9%) was demonstrated and a broad mutation spectrum of was described. Detailed clinical differences between genders and various central nervous system symptoms were also illustrated, even in the same pedigree.

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Authors:
J.‐H. Yuan, Y. Sakiyama, A. Hashiguchi, M. Ando, Y. Okamoto, A. Yoshimura, Y. Higuchi and H. Takashima
Article first published online:
03 Aug 2018 | DOI: 10.1111/ene.13750

Original Article

Background and purpose

In patients with rheumatoid arthritis (RA), the serum C‐reactive protein (CRP) level is associated with ischaemic cerebrovascular disease (iCVD). Acute iCVD patients with RA were investigated, assessing changes of clinical characteristics and CRP with progress in RA treatment.

Methods

Patients hospitalized for acute iCVD from August 2002 to February 2018 were divided into two groups at February 2010. Patients with RA were retrospectively identified. The incidence of RA, the occurrence of acute exacerbation of inflammation due to causes other than synovitis preceding iCVD (non‐synovitis AEI) and serum CRP were compared.

Results

In the first and second periods, 23/1203 patients (1.9%) and 22/1094 patients (2.0%) respectively had acute iCVD with RA. Non‐synovitis AEI was significantly less frequent in the second period (5%,  = 1) than in the first period (35%,  = 8) ( < 0.05). CRP was significantly lower at iCVD onset in the second period [median and interquartile range 2.72 (0.89–4.5) mg/dl vs. 0.34 (0.12–1.19) mg/dl,  < 0.01]. Excluding nine patients with non‐synovitis AEI, CRP was still lower in the second period [1.21 (0.47–2.72) mg/dl vs. 0.33 (0.11–0.98) mg/dl,  < 0.01]. CRP levels before both iCVD and non‐synovitis AEI tended to be lower in the second period [1.53 (0.3–2.78) mg/dl vs. 0.69 (0.06–1.28) mg/dl,  = 0.059]. Two patients using tocilizumab developed iCVD despite persistently low CRP levels.

Conclusions

With progress in treatment, RA‐related inflammation was better suppressed and CRP decreased, but the prevalence of RA amongst acute iCVD patients was unchanged. Strategies for tighter control of inflammation are needed, and a new biomarker may be required in patients using tocilizumab.

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Authors:
H. Hashimoto, M. Kawamura, T. Yukami, M. Ishihara, Y. Bamba, S. Kaneshiro, H. Tsuboi and K. Yamamoto
Article first published online:
16 Aug 2018 | DOI: 10.1111/ene.13751

Original Article

Background and purpose

Creativity in Parkinson's disease (PD) is strongly related to dopaminergic activity and medication. We hypothesized that patients with PD, including those who are in the pre‐diagnostic phase of PD, are prone to choose highly structured ‘conventional’ professional occupations and avoid highly creative ‘artistic’ occupations.

Methods

At baseline of the population‐based Rotterdam Study, we asked 12 147 individuals aged ≥45 years about their latest occupation and categorized occupations according to the RIASEC model. Participants underwent baseline and follow‐up (median 11 years) examinations for PD. We determined associations of artistic (versus any other occupation) and conventional (versus any other occupation) occupations with PD. Additionally, we pooled our results with a recently published case–control study (Radboud Study).

Results

At baseline, conventional occupations were common [ = 4356 (36%)], whereas artistic occupations were rare [ = 137 (1%)]. There were 217 patients with PD, including 91 with prevalent PD and 126 with incident PD. The risk of PD varied substantially across occupational categories (chi‐square, 14.61; = 0.01). The penalized odds ratio (OR) of artistic occupations for PD was 0.19 [95% confidence interval (CI), 0.00–1.31; = 0.11], whereas the OR of conventional occupations for PD was 1.23 (95% CI, 0.95–1.66; = 0.10). The direction and magnitude of ORs were similar in cross‐sectional and longitudinal subsamples. Pooled ORs across the Rotterdam and Radboud Studies were 0.20 (95% CI, 0.08–0.52; < 0.001) for artistic and 1.23 (95% CI, 0.92–1.67; = 0.08) for conventional occupations.

Conclusions

The risk of PD varies substantially by choice of professional occupation. Our findings suggest that dopaminergic degeneration affects choice of occupation, which may start in the pre‐diagnostic phase of PD.

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Authors:
S. K. L. Darweesh, M. K. Ikram, M. J. Faber, N. M. de Vries, C. A. Haaxma, A. Hofman, P. J. Koudstaal, B. R. Bloem and M. A. Ikram
Article first published online:
06 Aug 2018 | DOI: 10.1111/ene.13752

Editorial

Abstract

Click to view the accompanying paper in this volume.

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Authors:
S. Lattanzi and M. Silvestrini
Article first published online:
18 Aug 2018 | DOI: 10.1111/ene.13754

Original Article

Background and purpose

Our aim was to study the quality of the literature search strategies used in recent systematic reviews and to develop and assess the diagnostic accuracy of six new search strategies (i.e. hedges).

Methods

Six neurological conditions were studied: migraine, stroke, dementia, epileptic seizures, Parkinson's disease and multiple sclerosis. Two reviewers independently assessed the quality of the search strategies used in systematic reviews published in 2015–2016. Complex hedges pertaining to the six conditions for use in Ovid MEDLINE were developed. Their diagnostic accuracy was compared to simple, single‐term keyword searches.

Results

Almost 60% of quality criteria for the overall literature search strategy used in 182 systematic reviews were not respected. Over 30% of search strategies relied on a single keyword to identify the neurological condition. The sensitivities of our complex hedges amongst 10 311 articles were between 83% and 95%, significantly higher than the simple keyword searches (as low as 48%). The specificities were greater than 97%.

Conclusions

There is great room for improvement in the search strategies used in systematic reviews of neurological conditions. Complex hedges were developed and validated to improve the accuracy of such searches. It is expected that this will lead to higher quality systematic reviews and meta‐analyses.

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Authors:
K.‐T. A. Bui, J. Abdaem, A. Muccilli, G. C. Gore and M. R. Keezer
Article first published online:
28 Aug 2018 | DOI: 10.1111/ene.13758

Short Communication

Background and purpose

In randomized trials magnesium supplementation did not improve clinical outcome after aneurysmal subarachnoid haemorrhage (aSAH) on handicap scales. After aSAH, many patients have cognitive problems that may not translate into handicap. The effect of magnesium on cognitive outcome after aSAH was studied.

Methods

In total, 209 patients who had been included in the Magnesium for Aneurysmal Subarachnoid Haemorrhage (MASH‐2) trial in the University Medical Centre of Utrecht were studied. Patients had been randomized to 64 mmol magnesium sulfate daily or placebo during hospitalization. Three months after aSAH patients underwent a neuropsychological examination (NPE) consisting of six neuropsychological tests or a brief cognitive assessment. Poisson and linear regression analyses were used to analyse the effect of magnesium on cognition.

Results

In the magnesium group 53 (49.5%) of the 107 patients and in the placebo group 51 (50.0%) of the 102 patients scored lower than the median cognitive score [relative risk 0.99, 95% confidence interval (CI) 0.76–1.30]. Linear regression analyses showed no significant relationship between intervention and cognition ( = 0.05, 95% CI −0.15 to 0.33).

Conclusions

Treatment with magnesium has no effect on cognitive outcome after aSAH.

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Authors:
I. M. C. Huenges Wajer, S. M. Dorhout Mees, W. M. van den Bergh, A. Algra, J. M. A. Visser‐Meily, G. J. E. Rinkel and M. J. E. van Zandvoort
Article first published online:
03 Sep 2018 | DOI: 10.1111/ene.13764

Letter to the Editor

involvement in myopathy

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Authors:
F. Lopes, M. Miguet, B. E. Mucha, J. Gauthier, V. Saillour, C.‐T. É. Nguyen, M. Vanasse, B. Ellezam, J. L. Michaud, J.‐F. Soucy and P. M. Campeau
Article first published online:
07 Nov 2018 | DOI: 10.1111/ene.13782

Editorial

Abstract

Click to view the accompanying paper in this volume.

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Authors:
M. Buttmann
Article first published online:
21 Sep 2018 | DOI: 10.1111/ene.13787

Review Article

Abstract

Females with myasthenia gravis (MG) worry about their disease having negative consequences for their children. Autoimmune disease mechanisms, treatment and heredity could all have an impact on the child. This is a subject review where Web of Science was searched for relevant keywords and combinations. Controlled and prospective studies were included, and also results from selected and unselected patient cohorts, guidelines, consensus papers and reviews. Neonatal MG with temporary muscle weakness occurs in 10% of newborn babies where the mother has MG, due to transplacental transfer of antibodies against acetylcholine receptor (AChR), muscle‐specific kinase (MuSK) or lipoprotein receptor‐related protein 4 (LRP4). Arthrogryposis and fetal AChR inactivation syndrome with contractures and permanent myopathy are rare events caused by mother's antibodies against fetal type AChR. The MG drugs pyridostigmine, prednisolone and azathioprine are regarded as safe during pregnancy and breastfeeding. Methotrexate, mycophenolate mofetil and cyclophosphamide are teratogenic. Mother's MG implies at least a 10‐fold increased risk for MG and other autoimmune diseases in the child. MG females should receive specific information about pregnancy and giving birth. First‐line MG treatments should usually be continued during pregnancy. Intravenous immunoglobulin and plasma exchange represent safe treatments for exacerbations. Neonatal MG risk means that MG women should give birth at hospitals experienced in neonatal intensive care. Neonatal MG needs supportive care, rarely also acetylcholine esterase inhibition or intravenous immunoglobulin. Women with MG should be supported in their wish to have children.

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Authors:
N. E. Gilhus and Y. Hong
Article first published online:
14 Sep 2018 | DOI: 10.1111/ene.13788

Letter to the Editor

Adult‐onset Rasmussen encephalitis treated with mitoxantrone

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Authors:
A. Stabile, F. Deleo, G. Didato, C. Pastori, C. Antozzi, M. de Curtis and F. Villani
Article first published online:
07 Nov 2018 | DOI: 10.1111/ene.13795

Letter to the Editor

Longitudinal brain magnetic resonance imaging and real‐time quaking induced conversion analysis in presymptomatic Creutzfeldt–Jakob disease

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Authors:
G. Novi, A. Canosa, F. Nobili, M. Bongianni, G. Zanusso, M. Balestrino and L. Roccatagliata
Article first published online:
07 Nov 2018 | DOI: 10.1111/ene.13807

Editorial

Progress in neurology 2017–2018

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Authors:
A. H. V. Schapira
Article first published online:
07 Nov 2018 | DOI: 10.1111/ene.13846