cover image European Journal of Neurology

European Journal of Neurology

2018 - Volume 25
Issue 2 | February 2018
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Original Article

Background and purpose

New diagnostic criteria of multiple sclerosis (MS) increase the number of patients being diagnosed with MS whilst a substantial part might not convert to clinically definite MS (CDMS). The diagnostic accuracy of the McDonald 2005 and 2010 criteria for conversion to CDMS was evaluated in an unselected cohort of patients in whom an MS diagnostic work‐up was decided.

Methods

Clinical, magnetic resonance imaging and cerebrospinal fluid data were analysed for all patients who presented with symptoms suspicious for MS at the university based MS outpatient clinic between 2006 and 2010 ( = 165).

Results

Follow‐up was available for 131 patients. During the mean follow‐up period of 2 years, 19% of patients developed CDMS whereas 64% of the patients fulfilling McDonald 2010 criteria did not convert to CDMS.

Conclusion

The low clinical conversion rate indicates that the new diagnostic criteria may increase the incidence of MS cases with a less active disease course.

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Authors:
S. C. Rosenkranz, B. Kaulen, A. Neuhaus, S. Siemonsen, S. Köpke, M. Daumer, J.‐P. Stellmann and C. Heesen
Article first published online:
02 Dec 2017 | DOI: 10.1111/ene.13476

Editorial

Abstract

Click to view the accompanying paper in this volume.

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Authors:
A. Carotenuto
Article first published online:
24 Nov 2017 | DOI: 10.1111/ene.13482

Letter to the Editor

CLIPPERS mimickers: relapsing brainstem encephalitis associated with anti‐MOG antibodies

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Authors:
G. Berzero, G. Taieb, R. Marignier, N. Younan, J. Savatovsky, D. Leclercq and D. Psimaras
Article first published online:
22 Jan 2018 | DOI: 10.1111/ene.13483

Original Article

Background and purpose

Acute convexity subarachnoid hemorrhage (cSAH) and cortical superficial siderosis (cSS) are neuroimaging markers of cerebral amyloid angiopathy (CAA) that may arise through similar mechanisms. The prevalence of cSS in patients with CAA presenting with acute cSAH versus lobar intracerebral hemorrhage (ICH) was compared and the physiopathology of cSS was explored by examining neuroimaging associations.

Methods

Data from 116 consecutive patients with probable CAA (mean age, 77.4 ± 7.3 years) presenting with acute cSAH ( = 45) or acute lobar ICH ( = 71) were retrospectively analyzed. Magnetic resonance imaging scans were analyzed for cSS and other imaging markers. The two groups’ clinical and imaging data were compared and the associations between cSAH and cSS were explored.

Results

Patients with cSAH presented mostly with transient focal neurological episodes. The prevalence of cSS was higher amongst cSAH patients than amongst ICH patients (88.9% vs. 57.7%; < 0.001). In multivariable logistic regression analysis, focal [odds ratio (OR) 6.73; 95% confidence interval (CI) 1.75–25.81; = 0.005] and disseminated (OR 11.68; 95% CI 3.55–38.35; < 0.001) cSS were independently associated with acute cSAH, whereas older age (OR 0.93; 95% CI 0.87–0.99; = 0.025) and chronic lobar ICH count (OR 0.45; 95% CI 0.25–0.80; = 0.007) were associated with acute lobar ICH.

Conclusions

Amongst patients with CAA, cSS is independently associated with acute cSAH. These findings suggest that cSAH may be involved in the pathogenesis of the cSS observed in CAA. Longitudinal studies are warranted to assess this potential causal relationship.

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Authors:
N. Raposo, L. Calviere, V. Cazzola, M. Planton, S. Patsoura, M. Wargny, J. F. Albucher, A. Sommet, J. M. Olivot, F. Chollet, J. Pariente, F. Bonneville and A. Viguier
Article first published online:
23 Nov 2017 | DOI: 10.1111/ene.13484

Original Article

Background and purpose

Identification of patients with familial hypercholesterolaemia (FH) is a prerequisite for the appropriate management of their excess cardiovascular risk. It is currently unknown how many patients with acute ischaemic stroke or transient ischaemic attack (TIA) are affected by FH and whether systematic screening for FH is warranted in these patients.

Methods

The prevalence of a clinical diagnosis of FH was estimated in a large representative series of patients with acute ischaemic stroke or TIA (ABCD2 score ≥ 3) using the Dutch Lipid Clinic Network Algorithm (DLCNA; possible FH ≥3, probable/definite FH ≥6).

Results

Out of 1054 patients included in the present analysis, 14 had probable/definite FH (1.3%; 95% confidence interval 0.6–2.0) and 107 possible FH (10.2%; 8.4–12.0) corresponding to an overall prevalence of potential FH of 11.5%. Prevalences were even higher in patients with stroke/TIA manifestation before age 55 in men or 60 in women (3.1%, 0.6–5.6; and 13.1%, 8.3–17.9) and those with a prior history of cardiovascular disease (2.6%, 0.9–4.3; and 15.1%, 11.3–18.9). Of note, in two‐thirds of our patients with probable/definite and possible FH, stroke or TIA was the initial clinical disease manifestation.

Conclusions

The frequency of potential FH, based on clinical criteria, in patients with acute ischaemic stroke or TIA was 11.5% and that of probable/definite FH (1.3%) was similar to recently reported counts for patients with acute coronary syndrome (1.6%). FH screening using the DLCNA is feasible in clinical routine and should be considered as part of the usual diagnostic work‐up.

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Authors:
T. Toell, L. Mayer, R. Pechlaner, S. Krebs, K. Willeit, C. Lang, C. Boehme, B. Prantl, M. Knoflach, J. Ferrari, P. Fuchs, W. Prokop, A. Griesmacher, W. Lang, S. Kiechl and J. Willeit
Article first published online:
14 Dec 2017 | DOI: 10.1111/ene.13485

Original Article

Background and purpose

Lithuania is one of the countries with the highest incidence of tick‐borne encephalitis (TBE) in Europe. The aim of this study was to describe the epidemiological patterns of TBE in Lithuania, and characterize clinical features in adults in the light of the high incidence in recent years.

Methods

Surveillance data available on the website of the Centre for Communicable Diseases and AIDS of Lithuania were used to describe the epidemiological patterns of TBE. The retrospective study included 712 patients hospitalized in the Centre for Infectious Diseases and the Centre for Neurology of Vilnius University in the years 2005–2014.

Results

Tick‐borne encephalitis incidence rates have been increasing by 8.5% per year for the 45‐year period from 1970 to 2014. The joinpoint model finds two joinpoints at 1991 and 1994, with a significant decrease of 8.4% per year ( < 0.05) prior to the joinpoint at 1991, and a rise of 195.2% afterwards. TBE presented with meningoencephalitis in 556 cases (81.3%). A total of 129 patients (18%) had a severe case of the disease. The most common neurological signs were ataxia (579, 81.3%), meningeal signs (474, 66.5%) and tremor (338, 47.5%). Limb paresis was observed in 6.3% of patients. Five patients (0.7%) died, and 544 patients (76.7%) were discharged with sequelae.

Conclusions

Intensified efforts in promoting TBE vaccination will be needed in the light of the high incidence and expanded spatial distribution. Significant prognostic factors for severe cases of the disease were age above 61 and delayed immune response of specific immunoglobulin G.

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Authors:
D. Radzišauskienė, K. Žagminas, L. Ašoklienė, A. Jasionis, R. Mameniškienė, A. Ambrozaitis, L. Jančorienė, D. Jatužis, I. Petraitytė and E. Mockienė
Article first published online:
06 Dec 2017 | DOI: 10.1111/ene.13486

Original Article

Background and purpose

The quality of clinical practice guidelines on dystonia has not yet been assessed. Our aim was to appraise the methodological quality of guidelines worldwide and to analyze the consistency of their recommendations.

Methods

We searched for clinical practice guidelines on dystonia diagnosis/treatment in the National Guideline Clearinghouse, PubMed, National Institute for Health and Care Excellence, Guidelines International Network and Web of Science databases. We also searched for guidelines on homepages of international neurological societies. We asked for guidelines from every Management Committee member of the BM1101 Action of the Cooperation between Science and Technology European framework and every member of the International Parkinson and Movement Disorders Society with special interest in dystonia.

Results

Fifteen guidelines were evaluated. Among guidelines on treatment, only one from the American Academy of Neurology could be considered as high quality. Among guidelines on diagnosis and therapy, the guideline from the European Federation of Neurological Societies was recommended by the appraisers. Clinical applicability and reports of editorial independence were the greatest shortcomings. The rigor of development was poor and stakeholder involvement was also incomplete in most guidelines. Discrepancies among recommendations may result from the weight given to consensus statements and expert opinions due to the lack of evidence, as well as inaccuracy of disease classification.

Conclusions

The quality of appraised guidelines was low. It is necessary to improve the quality of guidelines on dystonia, and the applied terminology of dystonia also needs to be standardized.

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Authors:
G. Tamás, C. Abrantes, A. Valadas, P. Radics, A. Albanese, M. A. J. Tijssen and J. J. Ferreira
Article first published online:
22 Dec 2017 | DOI: 10.1111/ene.13488

Original Article

Background and purpose

A direct aspiration first pass technique (ADAPT), involving the first‐line use of a large‐bore distal aspiration catheter, is a new strategy in the mechanical thrombectomy of acute ischemic stroke caused by large‐vessel occlusion. However, its impact on reperfusion rates, clinical outcomes and complication rates has not been fully examined.

Methods

We conducted a systematic review of the literature searching multiple databases for reports on thrombectomy of acute stroke with ADAPT and performed meta‐analyses of clinical and radiographic outcomes.

Results

We selected 16 articles that included a total of 1378 patients treated with ADAPT. The mean admission National Institutes of Health Stroke Scale score was 17 and pre‐treatment intravenous thrombolysis was used in 51% of cases. The successful recanalization (thrombolysis in cerebral ischemia 2b‐3) rate was 66% [95% confidence interval (CI), 59–72%] with ADAPT and a rescue stent retriever was used in 31% of cases (95% CI, 24–37%) yielding an overall thrombolysis in cerebral ischemia 2b‐3 rate of 89% (95% CI, 85–92%). We found a pooled estimate of 50% (95% CI, 45–54%) for functional independence (modified Rankin Scale score 0–2) at 90 days, 15% (95% CI, 10–21%) for mortality within 90 days and 5% (95% CI, 3–7%) for symptomatic intracranial hemorrhage.

Conclusions

ADAPT therapy is associated with similar reperfusion rates, clinical outcomes and complication rates compared with thrombectomy with stent retrievers. However, the major limitations of current evidence (i.e. retrospective studies and selection bias) indicate a need for adequately powered, multicenter randomized controlled trials to determine the best strategy.

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Authors:
B. Gory, X. Armoiry, R. Sivan‐Hoffmann, M. Piotin, M. Mazighi, B. Lapergue, R. Blanc and F. Turjman
Article first published online:
24 Nov 2017 | DOI: 10.1111/ene.13490

Editorial

Abstract

Click to view the accompanying paper in this volume.

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Authors:
A. Fromm
Article first published online:
02 Dec 2017 | DOI: 10.1111/ene.13492

Original Article

Background and purpose

Clinical trials have shown that robust collateral flow has a relationship with good clinical outcome; however, different stroke subtypes were lumped together. This study explored the relationship between baseline collaterals and the onset‐to‐imaging time (OIT) and the correlation between pre‐treatment collateral status and clinical outcome amongst different subtypes.

Method

Prospectively collected data from consecutive acute ischaemic stroke patients with acute middle cerebral artery occlusion who received reperfusion therapy were reviewed. The regional leptomeningeal score (20 points) was based on the scoring extent of contrast opacification in the six Alberta Stroke Program Early CT Score (ASPECTS) cortical regions (M1–6), parasagittal anterior cerebral artery territory and the basal ganglia by perfusion‐derived dynamic four‐dimensional computed tomography angiography (4D CTA). Stroke subtype was determined by the TOAST classification criteria. A 3‐months modified Rankin Scale score of 0–2 was defined as a good outcome.

Results

The analysis included 158 patients: 30 (19.0%) patients had large artery atherosclerotic stroke (LAA), 87 (55.1%) cardioembolic stroke (CE) and 41 (25.9%) stroke of undetermined etiology. Baseline collateral was negatively correlated with OIT ( = 0.0205) in the CE group after adjusting for female sex, smoking, hyperlipidemia, baseline National Institutes of Health Stroke Scale (NIHSS) and baseline mismatch ratio, but not in the LAA group. Baseline collateral showed a strong relationship with good clinical outcome after adjusting for recanalization, baseline NIHSS, age and female sex (odds ratio 1.120, confidence interval 1.013–1.238, = 0.027) in all patients and in the CE group (odds ratio 3.223, confidence interval 1.212–8.570, = 0.019), but not in the LAA patients.

Conclusions

Based on 4D CTA, sustained good leptomeningeal collaterals may predict good outcome in CE but not in LAA patients. Moreover, the extent of collaterals was associated with OIT in the CE patients, which indicates prompt reperfusion therapy in this group of patients.

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Authors:
X. Zhang, M. Zhang, W. Ding, S. Yan, D. S. Liebeskind and M. Lou
Article first published online:
11 Dec 2017 | DOI: 10.1111/ene.13493

Original Article

Background and purpose

The aim of our study was to describe, by a case‐control and cross‐sectional design, the correlation between clinical impairment and age in Charcot‐Marie‐Tooth type 1A (CMT1A) patients.

Methods

Seventy CMT1A patients and 70 sex‐ and age‐matched healthy controls were enrolled. Motor performance was assessed through the 10‐m walk test, the 6‐min walk test and the 9‐hole peg test of the dominant and non‐dominant side, and muscle strength was measured by using the Medical Research Council score. In the CMT1A group, disability and quality of life were evaluated using the Charcot‐Marie‐Tooth Neuropathy Score (CMTNS) and the Short Form 36 (SF‐36) questionnaire. Cross‐sectional relationships between age and all clinical measures were analyzed and differences in the slopes between cases and controls were calculated. The occurrence of a structural change in the age‐related progression of clinical measures was explored.

Results

The deterioration of motor performance correlated with age in both groups with a greater slope in CMT1A patients than controls. The deterioration of CMTNS and SF‐36 correlated with age in the CMT1A group. The deterioration of all clinical measures with the exception of the SF‐36 questionnaire showed a structural change at the 50th year of age. The rate of deterioration was no different between patients and controls until 50 years of age, whereupon it became significantly greater in CMT1A patients.

Conclusion

Our study supports that the disease progression in CMT1A patients is an age‐related process and the 50th year of age represents a critical moment after which the clinical decline becomes faster.

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Authors:
S. Tozza, D. Bruzzese, C. Pisciotta, R. Iodice, M. Esposito, R. Dubbioso, L. Ruggiero, A. Topa, E. Spina, L. Santoro and F. Manganelli
Article first published online:
14 Dec 2017 | DOI: 10.1111/ene.13494

Review Article

Abstract

The carbohydrate‐binding molecule galectin‐3 has garnered significant attention recently as a biomarker for various conditions ranging from cardiac disease to obesity. Although there have been several recent studies investigating its role in stroke and other cerebrovascular diseases, awareness of this emerging biomarker in the wider neurology community is limited. We performed a systematic search in PubMed, Embase, Scopus, CINAHL, Clinicaltrials.gov and the Cochrane library in November and December 2016 for articles related to galectin‐3 and cerebrovascular disease. We included both human and pre‐clinical studies in order to provide a comprehensive view of the state of the literature on this topic. The majority of the relevant literature focuses on stroke, cerebral ischemia and atherosclerosis, but some recent attention has also been devoted to intracranial and subarachnoid hemorrhage. Higher blood levels of galectin‐3 correlate with worse outcomes in atherosclerotic disease as well as in intracranial and subarachnoid hemorrhage in human studies. However, experimental evidence supporting the role of galectin‐3 in these phenotypes is not as robust. It is likely that the role of galectin‐3 in the inflammatory cascade within the central nervous system following injury is responsible for many of its effects, but its varied physiological functions and multiple sites of expression mean that it may have different effects depending on the nature of the disease condition and the time since injury. In summary, experimental and human research raises the possibility that galectin‐3, which is closely linked to the inflammatory cascade, could be of value as a prognostic marker and therapeutic target in cerebrovascular disease.

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Authors:
A. Venkatraman, S. Hardas, N. Patel, N. Singh Bajaj, G. Arora and P. Arora
Article first published online:
02 Dec 2017 | DOI: 10.1111/ene.13496

Original Article

Background and purpose

The most common neurological manifestation of antiphospholipid syndrome (APS) is ischaemic stroke. Identifying patients with APS at high risk for developing any thrombotic event remains a major challenge. In this study, the aim was to identify predictive factors of ischaemic stroke in a cohort of primary APS (PAPS) patients who presented with new onset symptoms suggestive of acute stroke.

Methods

This prospective multicentre study included 36 consecutive PAPS patients who presented with new onset symptoms suggestive of an acute stroke. Patients were prospectively followed up for 12 months.

Results

In 10 (28%) out of 36 PAPS patients [mean age 41 years (SD 13.4), 70% female], the suspicion of an acute stroke was confirmed by brain magnetic resonance imaging. Sixty per cent of these patients were <50 years old. Eight of the 10 patients had a history of previous venous thrombosis and were receiving vitamin K antagonist (VKA), with international normalized ratio target 2–3; one patient had a history of a previous arterial event receiving treatment with VKA target international normalized ratio 2–3 plus low dose aspirin; and one patient had a history of previous pregnancy morbidity receiving only low dose aspirin. Time in the therapeutic range for patients receiving VKA was 77.7% (SD 6.6%). Hypercholesterolaemia was significantly higher in patients with confirmed stroke compared to those without ( < 0.05). Similarly, a significantly higher rate of anti‐β2 glycoprotein‐I (β2GPI) antibodies (immunoglobulin G/immunoglobulin M; < 0.05) and higher adjusted global APS score (aGAPSS) values were found in patients with a confirmed stroke [mean aGAPSS 8.9 (SD 4.7) vs. mean aGAPSS 6.4 (SD 2.5); < 0.05].

Conclusions

Patients with PAPS, including young patients, have a high risk of recurrent thrombosis despite anticoagulation treatment. A careful risk assessment is mandatory to identify patients at risk for recurrence.

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Authors:
M. Radin, K. Schreiber, I. Cecchi, D. Roccatello, M. J. Cuadrado and S. Sciascia
Article first published online:
02 Dec 2017 | DOI: 10.1111/ene.13499

Original Article

Background and purpose

Biomarker changes in cognitively impaired patients with small vessel disease are largely unknown. The rate of amyloid/lacune progression, cortical thinning and cognitive decline were evaluated in subcortical vascular mild cognitive impairment (svMCI) patients.

Methods

Seventy‐two svMCI patients were divided into early stage (ES‐svMCI, = 39) and late stage (LS‐svMCI, = 33) according to their Clinical Dementia Rating Sum of Boxes score. Patients were annually followed up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and underwent a second [C] Pittsburgh compound B (PiB) positron emission tomography scan within a mean interval of 32.4 months.

Results

There was no difference in the rate of increase in PiB uptake or lacune number between the ES‐svMCI and LS‐svMCI. However, LS‐svMCI showed more rapid cortical thinning and cognitive decline than did the ES‐svMCI.

Conclusions

We suggest that, whilst the rate of change in pathological burden did not differ between ES‐svMCI and LS‐svMCI, cortical thinning and cognitive decline progressed more rapidly in the LS‐svMCI.

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Authors:
J. Lee, S. W. Seo, J.‐J. Yang, Y. K. Jang, J. S. Lee, Y. J. Kim, J. Chin, J. M. Lee, S. T. Kim, K.‐H. Lee, J. H. Lee, J. S. Kim, S. Kim, H. Yoo, A. Y. Lee, D. L. Na and H. J. Kim
Article first published online:
21 Dec 2017 | DOI: 10.1111/ene.13500

Editorial

Abstract

Click to view the accompanying paper in this volume.

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Authors:
W. J. Brownlee
Article first published online:
02 Dec 2017 | DOI: 10.1111/ene.13501

Letter to the Editor

F‐NaF PET‐MRI: an innovative tool to assess carotid artery plaque vulnerability

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Authors:
L. Mechtouff, M. Sigovan, N. Costes, P. Douek, D. Collet‐Benzaquen, N. Nighoghossian and Y. Berthezene
Article first published online:
22 Jan 2018 | DOI: 10.1111/ene.13502

Original Article

Background and purpose

Constipation is a common non‐motor symptom of Parkinson's disease (PD). Deposition of α‐synuclein inclusions that spread from the gut to the substantia nigra through the vagus nerve has recently been speculated to be a pre‐motor and early stage of PD. The aim of the study was to investigate whether constipation is associated with dopaminergic pathology on dopamine transporter (DAT) single‐photon emission computed tomography in early drug‐naïve patients with PD. Our hypothesis was that constipation is associated with other signs of pre‐motor PD and is independent of DAT pathology. We then investigated for associations with motor and non‐motor symptoms, and with cerebrospinal fluid biomarkers of PD pathology.

Methods

Using the Parkinson's Progression Markers Initiative database, we investigated the prevalence of constipation and the association between constipation and clinical features, striatal [I]Ioflupane uptake and non‐imaging (cerebrospinal fluid and serum) biomarkers. Constipation was evaluated using Movement Disorder Society‐Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part I item 1.11.

Results

One third (132/398) of patients with PD had constipation. Higher severity of constipation correlated with older age ( = 0.728, < 0.001), higher MDS‐UPDRS total score ( = 0.285, < 0.001), worse postural instability ( = 0.190, = 0.012), rapid eye movement sleep behaviour disorder ( = 0.228, < 0.0001) and depression ( = 0.187, = 0.024). No correlation was found with cerebrospinal fluid, serum and imaging markers of PD pathology.

Conclusions

Constipation was not associated with DAT pathology but with rapid eye movement sleep behaviour disorder and depression, which are speculated to be pre‐motor symptoms of PD. This confirms the hypothesis that constipation may be a pre‐motor sign of PD due to an impairment of non‐dopaminergic pathways.

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Authors:
G. Pagano, T. Yousaf, H. Wilson, F. Niccolini, S. Polychronis, K. R. Chaudhuri and M. Politis
Article first published online:
11 Dec 2017 | DOI: 10.1111/ene.13503

Original Article

Background and purpose

The present study was conducted to accurately determine the presence of mild cognitive impairment, which is often difficult to evaluate using only simple tests. Our approach focused on discrepancy analysis of fluid intelligence relative to crystallized intelligence using internationally recognized neuropsychological tests.

Methods

One‐hundred and five patients diagnosed with asymptomatic carotid artery stenosis were assessed. The neuropsychological tests included the two subtests (information and picture completion) of Wechsler Adult Intelligence Scale‐Revised (WAIS‐R‐two‐subtests): crystallized intelligence tests and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (immediate memory, visuospatial/constructional, language, attention, delayed memory and total score) as fluid intelligence tests. Discrepancy analysis was used to assess cognitive impairment. The score for RBANS was subtracted from the score for WAIS‐R‐two‐subtests, and if the score difference was greater than the 5% confidence limit for statistical significance, it was defined as a decline in cognitive function.

Results

The WAIS‐R‐two‐subsets was within normal limits when compared with the standardized values. However, all RBANS domains showed significant declines. Frequencies of decline in each RBANS domain were as follows: 69 patients (66%) in immediate memory, 26 (25%) in visuospatial/constructional, 54 (51%) in language, 63 (60%) in attention, 54 (51%) in delayed memory and 78 (74%) in the total score. Moreover, 99 patients (94%) showed decline in at least one RBANS domain.

Conclusions

Cognitive function is only preserved in a few patients with asymptomatic carotid artery stenosis. Mild cognitive impairment can be precisely detected by performing the discrepancy analysis between crystallized and fluid intelligence tests.

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Authors:
A. Takaiwa, N. Kuwayama, N. Akioka, D. Kashiwazaki and S. Kuroda
Article first published online:
23 Nov 2017 | DOI: 10.1111/ene.13504

Original Article

Background and purpose

The prevalence of multiple sclerosis (MS) is considered to be lower in East Asia than in Western countries. An increasing trend has been reported globally for the prevalence of MS. We investigated the changes in the prevalence and clinical characteristics of MS in the Tokachi province of Hokkaido, northern Japan from 2001 to 2016.

Methods

Prevalence was determined on 31 March 2016. Data‐processing sheets were collected from all MS‐related institutions in Tokachi province. We applied Poser's diagnostic criteria for MS as used in our previous three studies. Cases of neuromyelitis optica spectrum disorders were excluded.

Results

In 2016, the crude MS prevalence was 18.6/100 000 (95% confidence interval, 14.3–23.8) in northern Japan. Over the last 15 years, the prevalence of MS in the same area was 8.1, 12.6 and 16.2 in 2001, 2006 and 2011, respectively. The female:male ratio was 3.57, which increased from 2.63 in 2001. The ratios of primary progressive, relapsing–remitting and secondary progressive MS types were 2%, 84% and 14%, respectively.

Conclusion

Our results demonstrated a consistent increase in MS prevalence among the northern Japanese population, particularly in females, and relatively lower rates of progressive MS in northern Japan than in Western countries.

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Authors:
H. Houzen, K. Kondo, K. Horiuchi and M. Niino
Article first published online:
24 Nov 2017 | DOI: 10.1111/ene.13506

Original Article

Background and purpose

Intravenous thrombolysis (IVT) is the only approved pharmacological treatment for acute ischemic stroke. Off‐label IVT for ischemic stroke is common. We aimed to analyse its safety in a large database.

Methods

This was a retrospective analysis of the safe implementation of treatments in stroke (SITS) thrombolysis registry with regard to 11 off‐label criteria according to the European licence for alteplase. Symptomatic intracranial haemorrhage (SICH) according to SITS was defined as primary safety endpoint and SICH according to the European Cooperative Acute Stroke Study (ECASS II) definition and the National Institute of Neurological Disorders and Stroke definition as secondary safety endpoints. Multivariable logistic regression analyses after replacing missing values using multiple imputations were performed.

Results

Patients from 793 centres in 44 countries were included, mainly (95%) in Europe. A total of 56 258 patients who were treated with intravenous alteplase were included. Median age was 71 (IQR 61–78) years and median National Institutes of Health Stroke Scale score was 12 (IQR 7–17). A total of 16 740 (30%) patients received off‐label IVT and 1037 (1.8%) patients suffered from SICH according to the SITS definition (SICH SITS). Median percentage of missing values per variable was 0.4%. The only two off‐label criteria constituting independent positive and negative predictors for SICH SITS were high blood pressure (odds ratio, 1.39; 95% confidence interval, 1.08–1.80; = 0.012) and minor stroke (odds ratio, 0.51; 95% confidence interval, 0.33–0.78; = 0.002). Very severe stroke, previous stroke and diabetes, age and high glucose levels were additional independent predictors of SICH according to the ECASS II and National Institute of Neurological Disorders and Stroke definitions.

Conclusions

Thrombolysis appears to be safe with regard to SICH for most of the off‐label criteria, especially for minor stroke, but is risky in patients with high blood pressure. Individual risk–benefit evaluation should be performed.

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Authors:
S. Mundiyanapurath, K. Hees, N. Ahmed, N. Wahlgren, L. Uhlmann, M. Kieser, P. A. Ringleb, W. Hacke and S. Nagel
Article first published online:
02 Dec 2017 | DOI: 10.1111/ene.13507

Original Article

Background and purpose

Small fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals.

Methods

A total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings.

Results

No associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients.

Conclusions

Based on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral.

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Authors:
B. T. A. de Greef, J. G. J. Hoeijmakers, C. M. L. Gorissen‐Brouwers, M. Geerts, C. G. Faber and I. S. J. Merkies
Article first published online:
18 Dec 2017 | DOI: 10.1111/ene.13508

Original Article

Background and purpose

Facial‐sparing scapular myopathy (SHD) is the most common atypical form of facioscapulohumeral muscular dystrophy (FSHD), clinically defined as without apparent facial muscle weakness on neurological examination. The clinical profiles and genetic features of SHD are limited.

Methods

A cohort of 21 Chinese patients with SHD were confirmed by molecular genetic analysis based on pulsed‐field gel electrophoresis. The clinical assessments and methylation analysis were noted.

Results

The patients had FSHD‐related fragments with 4qA haplotype ranging from 18 kb to 33 kb (mean 26.3 ± 4.6 kb). The mean onset age was 25.52 ± 8.3 years. Over half of the patients had scapular winging and asymmetry weakness consistent with FSHD, without facial symptoms during their visit. Their facial electromyogram results were almost normal or mild myogenic damage, as well as the myopathology and serum creatine kinase. A conflict was unexpectedly found in intergenerational DR1 methylation analysis.

Conclusion

Facial‐sparing scapular myopathy is characterized as mild myopathic symptoms and chronic progression of weakness. The diagnosis should be accurately confirmed through FSHD‐sized fragment detection and 4qA/B variant determination. Although the next generations of SHD had more severe muscular symptoms, local hypomethylation within D4Z4 was not found as a modifier for clinical heterogeneity.

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Authors:
J.‐J. He, X.‐D. Lin, F. Lin, G.‐R. Xu, L.‐Q. Xu, W. Hu, D.‐N. Wang, H.‐X. Lin, M.‐T. Lin, N. Wang and Z.‐Q. Wang
Article first published online:
21 Dec 2017 | DOI: 10.1111/ene.13509

Editorial

Abstract

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Authors:
G. Tsivgoulis and V‐A. Lioutas
Article first published online:
02 Dec 2017 | DOI: 10.1111/ene.13511

Original Article

Background and purpose

Idiopathic intracranial hypertension (IIH) is characterized by abnormally elevated intracranial pressure (ICP) without identifiable etiology. Recently, however, a subset of patients with presumed IIH have been found with isolated internal jugular vein (IJV) stenosis in the absence of intracranial abnormalities.

Methods

Fifteen consecutive patients were screened from 46 patients suspected as IIH and were finally confirmed as isolated IJV stenosis. The stenotic IJV was corrected with stenting when the trans‐stenotic mean pressure gradient (∆MPG) was equal to or higher than 5.44 cmHO. Dynamic magnetic resonance venography, computed tomographic venography and digital subtraction angiography of the IJV, ∆MPG, ICP, Headache Impact Test 6 and the Frisén papilledema grade score before and after stenting were compared.

Results

All the stenotic IJVs were corrected by stenting. ∆MPG decreased and the abnormal collateral veins disappeared or shrank immediately. Headache, tinnitus, papilledema and ICP were significantly ameliorated at 14 ± 3 days of follow‐up (all < 0.01). At 12 ± 5.6 months of outpatient follow‐up, headache disappeared in 14 out of 15 patients (93.3%), visual impairments were recovered in 10 of 12 patients (83.3%) and tinnitus resolved in 10 out of 11 patients (90.9%). In 12 out of 15 cases, the Frisén papilledema grade scores declined to 1 (0–2). The stented IJVs in all 15 patients kept to sufficient blood flows on computed tomographic venography follow‐up without stenting‐related adverse events.

Conclusions

Non‐thrombotic IJV stenosis may be a potential etiology of IIH. Stenting seems to be a promising option to address the issue of intracranial hypertension from the etiological level, particularly after medical treatment failure.

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Authors:
D. Zhou, R. Meng, X. Zhang, L. Guo, S. Li, W. Wu, J. Duan, H. Song, Y. Ding and X. Ji
Article first published online:
07 Dec 2017 | DOI: 10.1111/ene.13512

Original Article

Background and purpose

Calculation of the cerebrospinal fluid:serum glucose (CSF:S) ratio is part of the routine cerebrospinal fluid (CSF) work‐up. Reference values have been defined for lumbar CSF, but are lacking for ventricular CSF. The objective of this study was to investigate whether the CSF:S ratio is similar in lumbar and ventricular compartments, and to determine cut‐off values for CSF:S ratio in ventricular CSF.

Methods

We included CSF samples that were collected by either lumbar puncture or ventricular drainage, with a red blood cell count <500/μL, normal white blood cell count and age‐related normal total protein content, with simultaneously withdrawn serum sample and time to laboratory processing of ≤2 h. This resulted in 1808 sample pairs. Glucose concentrations in CSF and serum were measured by enzymatic spectrophotometry.

Results

The CSF:S ratio was similar in ventricular and lumbar compartments after controlling for age, sex, time between sample withdrawal and laboratory processing, CSF white blood cell and red blood cell count, CSF total protein and serum glucose concentration using a multiple linear regression model. Lower limits for CSF:S ratio in the ventricular compartment, defined as 5 percentile, were 0.51 for patients with serum glucose concentration < 100 mg/dL, 0.45 for those with serum glucose concentration ≥ 100 mg/dL and <150 mg/dL, and 0.36 for those with serum glucose concentration ≥150 mg/dL.

Conclusions

The CSF:S ratio was similar in the ventricular and lumbar compartments, and depended mainly on time to laboratory processing and absolute serum glucose levels. Previously established lower limits for CSF:S ratio in lumbar CSF can be also applied for ventricular CSF.

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Authors:
H. Hegen, J. Walde, M. Auer and F. Deisenhammer
Article first published online:
28 Nov 2017 | DOI: 10.1111/ene.13513

Letter to the Editor

Miller Fisher syndrome associated with a Zika virus infection

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Authors:
N. Gibelin, J. Romero, V. Gregoire and M. Kaidomar
Article first published online:
22 Jan 2018 | DOI: 10.1111/ene.13514

Editorial

Abstract

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Authors:
V. Rajajee
Article first published online:
11 Dec 2017 | DOI: 10.1111/ene.13516

Original Article

Background and purpose

Remote intracerebral hemorrhage (rICH) is infrequent after intravenous thrombolysis (IVT) and its mechanism remains poorly understood. We aimed to assess its frequency and possible relationship with the severity of white matter hyperintensity (WMH) in patients with acute ischemic stroke.

Methods

We prospectively analyzed data from consecutive patients with acute ischemic stroke with magnetic resonance imaging and IVT. WMH volume was quantitatively measured. rICH was defined as intracranial hemorrhage that appears in brain regions without visible ischemic changes on 24‐h follow‐up imaging. Unfavorable outcome was defined as a modified Rankin scale score of 3–6 at 3 months. Logistic regression analysis was used to determine the impact of WMH volume on hemorrhage, including rICH and local parenchymal hemorrhage, as well as clinical outcome.

Results

Of a total of 503 patients analyzed, 17 (3.4%) patients developed rICH. Logistic regression analysis indicated that patients with rICH had significantly larger whole‐brain corrected WMH volume (cWMHv) than those without rICH (22.90 vs. 4.42 mL; odds ratio, 1.562/10 mL; 95% confidence interval, 1.215–2.009; = 0.001). Not only the corrected peri‐ventricular WMH volume ( = 0.001), but also the corrected deep WMH volume ( = 0.013) was associated with the occurrence of rICH. cWMHv was also independently associated with local parenchymal hemorrhage ( = 0.025). rICH was not related to unfavorable outcome ( = 0.323), whereas cWMHv ( = 0.006) was associated with unfavorable outcome.

Conclusion

An increased occurrence rate of rICH after IVT is related to more extensive WMH, which may suggest underlying whole‐brain vascular injury in patients with WMH.

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Authors:
Y. Chen, S. Yan, M. Xu, G. Zhong, D. S. Liebeskind and M. Lou
Article first published online:
07 Dec 2017 | DOI: 10.1111/ene.13517

Original Article

Background and purpose

The main aim of this study was to identify which patients with glioblastoma multiforme (GBM) have a higher risk of presenting seizures during follow‐up.

Methods

Patients with newly diagnosed GBM were reviewed ( = 306) and classified as patients with (Group 1) and without (Group 2) seizures at onset. Group 2 was split into patients with seizures during follow‐up (Group 2A) and patients who never had seizures (Group 2B). The anatomical location of GBM was identified and compared by voxel‐based lesion symptom mapping (discovery set). Seizure‐susceptible brain regions obtained were assessed visually and automatically in external GBM validation series ( = 85).

Results

In patients with GBM who had no seizures at onset, an increased risk of presenting seizures during follow‐up was identified in the superior frontal and inferior occipital lobe, as well as in inferoposterior regions of the temporal lobe. Conversely, those patients with GBM located in medial and inferoanterior temporal areas had a significantly lower risk of suffering from seizures during follow‐up. Additionally, the seizure‐susceptible brain region maps obtained classified patients in the validation set with high positive and negative predictive values.

Conclusions

Tumor location is a useful marker to identify patients with GBM who are at risk of suffering from seizures during follow‐up. These results may help to support the use of antiepileptic prophylaxis in a selected GBM population and to improve stratification in antiepileptic clinical trials.

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Authors:
N. Cayuela, M. Simó, C. Majós, X. Rifà‐Ros, J. Gállego Pérez‐Larraya, P. Ripollés, N. Vidal, J. Miró, F. Gil, M. Gil‐Gil, G. Plans, F. Graus and J. Bruna
Article first published online:
11 Dec 2017 | DOI: 10.1111/ene.13518

Original Article

Background and purpose

Distal hereditary motor neuropathy (dHMN) due to sigma non‐opioid intracellular receptor 1 () gene mutation (OMIM 601978.0003) is a rare neuromuscular disorder characterized by prominent amyotrophic distal limb weakness and co‐existing pyramidal signs initially described in a Chinese family recently. We report an extended consanguineous Omani family segregating dHMN with pyramidal signs in an autosomal recessive pattern and describe a novel mutation in the gene underlying this motor phenotype. We also provide an update on the reported phenotypic profile of mutations.

Methods

We utilized homozygosity mapping and whole‐exome sequencing of leucocyte DNA obtained from three affected members of an Omani family who manifested with a length‐dependent motor neuropathy and pyramidal signs.

Results

We identified a novel C>T transition at nucleotide position 238 (c.238C>T) in exon 2 of the gene. Sanger sequencing and segregation analysis confirmed the presence of two copies of the variant in the affected subjects, unlike the unaffected healthy parents/sibling who carried, at most, a single copy. The T allele is predicted to cause a truncating mutation (p.Gln80*), probably flagging the mRNA for nonsense‐mediated decay leading to a complete loss of function, thereby potentially contributing to the disease process.

Conclusions

Our finding expands the spectrum of mutations causing recessive dHMN and indicates that this disorder is pan‐ethnic. mutation should be included in the diagnostic panel of a dHMN, especially if there are co‐existing pyramidal signs and autosomal recessive inheritance.

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Authors:
R. Nandhagopal, D. Meftah, S. Al‐Kalbani and P. Scott
Article first published online:
12 Dec 2017 | DOI: 10.1111/ene.13519

Original Article

Background and purpose

Leptomeningeal collateral (LMC) status governs the prognosis of large artery occlusive stroke, although factors determining LMC status are not fully elucidated. The aim was to investigate metrics affecting LMC status in such patients by using computational fluid dynamics (CFD) models based on computed tomography angiography (CTA).

Methods

In this cross‐sectional study, patients with recent ischaemic stroke or transient ischaemic attack attributed to atherosclerotic M1 middle cerebral artery (MCA) stenosis (50%–99%) were recruited. Demographic, clinical and imaging data of these patients were collected. Ipsilesional LMC status was graded as good or poor by assessing the laterality of anterior and posterior cerebral arteries in CTA. A CFD model based on CTA was constructed to reflect focal hemodynamics in the distal internal carotid artery, M1 MCA and A1 anterior cerebral artery. Pressure gradients were calculated across culprit MCA stenotic lesions in CFD models. Predictors for good LMC status were sought in univariate and multivariate analyses.

Results

Amongst the 85 patients enrolled (mean age 61.5 ± 10.9 years), 38 (44.7%) had good ipsilesional LMC status. The mean pressure gradient across MCA lesions was 14.8 ± 18.1 mmHg. Advanced age ( = 0.030) and a larger translesional pressure gradient ( = 0.029) independently predicted good LMCs. A lower fasting blood glucose level also showed a trend for good LMCs ( = 0.058).

Conclusions

Our study suggested a correlation between translesional pressure gradient and maturation of LMCs in intracranial atherosclerotic disease. Further studies with more exquisite and dynamic monitoring of cerebral hemodynamics and LMC evolution are needed to verify the current findings.

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Authors:
X. Leng, L. Lan, H. L. Ip, F. Fan, S. H. Ma, K. Ma, H. Liu, Z. Yan, J. Liu, J. Abrigo, Y. O. Y. Soo, D. S. Liebeskind, K. S. Wong and T. W. Leung
Article first published online:
18 Dec 2017 | DOI: 10.1111/ene.13521

Original Article

Background and purpose

OnabotulinumtoxinA is a treatment specifically approved for the prophylaxis of chronic migraine in adults. The aim of this study was to assess the effectiveness of OnabotulinumtoxinA in chronic migraine after 1 year of treatment in a real‐life setting and to identify clinical predictors of outcome.

Methods

We designed a prospective multicentre study performed in 13 hospitals in Spain. Patients underwent a complete medical history and examination. They were treated with OnabotulinumtoxinA every 12 weeks for 1 year. Data about outcome, adverse events, abortive medication use, emergency room use and disability were collected at 3 and 12 months.

Results

A total of 725 subjects completed the study. At 12 months, 79.3% showed >50% reduction in number of headaches per month and 94.9% reported no adverse events. Unilaterality of pain, fewer days of disability per month and milder headache at baseline were correlated with good outcome. Duration of disease <12 months increased the chances of response to treatment with OnabotulinumtoxinA (odds ratio, 1.470; 95% confidence interval, 1.123–2.174; = 0.045).

Conclusions

This study confirmed the effectiveness of treatment with OnabotulinumtoxinA after 1 year of treatment. The chances of a good outcome may be increased by starting treatment in the first 12 months after chronic migraine diagnosis.

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Authors:
C. Domínguez, P. Pozo‐Rosich, M. Torres‐Ferrús, N. Hernández‐Beltrán, C. Jurado‐Cobo, C. González‐Oria, S. Santos, M. J. Monzón, G. Latorre, L. C. Álvaro, A. Gago, M. Gallego, V. Medrano, M. Huerta, J. García‐Alhama, R. Belvís, Y. Leira and R. Leira
Article first published online:
18 Dec 2017 | DOI: 10.1111/ene.13523

Editorial

Abstract

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Authors:
H. Milionis
Article first published online:
15 Dec 2017 | DOI: 10.1111/ene.13525

Short Communication

Background and purpose

encodes Ca1.1, a voltage sensor for muscle excitation−contraction coupling, which activates the ryanodine receptor 1 (RYR1) leading to calcium release from the sarcoplasmic reticulum. mutations cause hypokalemic periodic paralysis, malignant hyperthermia and congenital myopathy. mutations result in congenital myopathy, malignant hyperthermia and rhabdomyolysis.

Methods

The aim was to describe a novel phenotype associated with a variant at a site previously linked to hypokalemic periodic paralysis.

Results

The patient presented with fluctuating asymptomatic creatine kinase elevation after an episode of rhabdomyolysis but has no history of periodic paralysis. His muscle biopsy showed core‐like structures occurring mainly in type 2 fibers. He carries a novel Ca1.1 variant (p.Arg528Leu) affecting a highly conserved amino acid. Different mutations at the same location cause hypokalemic periodic paralysis.

Conclusion

This case underscores the similarity between the phenotypes caused by mutations in two functionally linked proteins, RYR1 and Ca1.1.

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Authors:
C. Anandan, M. A. Cipriani, R. S. Laughlin, Z. Niu and M. Milone
Article first published online:
26 Dec 2017 | DOI: 10.1111/ene.13528

Letter to the Editor

Optic nerve sheath diameter measurement in patients with idiopathic normal‐pressure hydrocephalus

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Authors:
M. De Bernardo and N. Rosa
Article first published online:
22 Jan 2018 | DOI: 10.1111/ene.13530

Letter to the Editor

Congenital myasthenic syndrome due to mutations mimicking congenital myopathy in an Irish family

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Authors:
P. Bogdanova‐Mihaylova, R. P. J. Murphy, M. D. Alexander, J. C. McHugh, A. Reghan Foley, F. Brett and S. M. Murphy
Article first published online:
22 Jan 2018 | DOI: 10.1111/ene.13532

EAN Guidelines/CME Article

Background and purpose

Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is therefore a need for a reference tool compiling current data to aid professionals in treatment decisions. The objective was to develop an evidence‐based clinical practice guideline for the pharmacological treatment of people with MS.

Methods

This guideline has been developed using the GRADE methodology and following the updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. Literature searches up to December 2016 were performed and the evidence is presented narratively and, when possible, combined in a meta‐analysis. The quality of evidence was rated into four categories – very high, high, low and very low − according to the risk of bias. The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk−benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique.

Results

A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease‐modifying drugs approved by the European Medicine Agency at the time of publication. A total of 21 recommendations were agreed by the guideline working group members after three rounds of consensus.

Conclusion

The present guideline, which includes descriptions of the evidence together with recommendations, will enable homogeneity of treatment decisions across Europe.

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Authors:
X. Montalban, R. Gold, A. J. Thompson, S. Otero‐Romero, M. P. Amato, D. Chandraratna, M. Clanet, G. Comi, T. Derfuss, F. Fazekas, H. P. Hartung, E. Havrdova, B. Hemmer, L. Kappos, R. Liblau, C. Lubetzki, E. Marcus, D. H. Miller, T. Olsson, S. Pilling, K. Selmaj, A. Siva, P. S. Sorensen, M. P. Sormani, C. Thalheim, H. Wiendl and F. Zipp
Article first published online:
19 Jan 2018 | DOI: 10.1111/ene.13536

Letter to the Editor

Pyridostigmine bromide versus fludrocortisone in the treatment of orthostatic hypotension in Parkinson's disease – reply

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Authors:
S. R. Schreglmann, F. Büchele, G. Kägi and C. R. Baumann
Article first published online:
22 Jan 2018 | DOI: 10.1111/ene.13541

Editorial

Abstract

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Authors:
A. Daniele and F. Panza
Article first published online:
27 Dec 2017 | DOI: 10.1111/ene.13542

Letter to the Editor

Corpus callosum agenesis, myopathy and pinpoint pupils: consider Stormorken syndrome

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Authors:
A. Alonso‐Jiménez, C. Ramón, O. Dols‐Icardo, C. Roig, E. Gallardo, J. Clarimón, C. Núñez‐Peralta and J. Díaz‐Manera
Article first published online:
22 Jan 2018 | DOI: 10.1111/ene.13545

Calendar

Calendar

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Article first published online:
22 Jan 2018 | DOI: 10.1111/ene.13561