cover image European Journal of Neurology

European Journal of Neurology

2019 - Volume 26
Issue 4 | April 2019
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Short Communication

Background

Prevalence and time of occurrence of prodromal symptoms of Parkinson's disease (PD) in relation to the onset of classical motor manifestation varies between patients. Possible modifying factors might be different genetic architectures predisposing to varying burden of manifestations.

Objectives

To characterize the prodromal phase in PD patients with heterozygous mutations in the gene compared to PD patients without GBA mutation.

Methods

In a retrospective design, 151 participants [47 PD patients carrying a mutation (PD), 52 idiopathic PD patients (PD), 52 healthy elderly (CON)] underwent a validated structured interview designed to assess prevalence and time of occurrence of prodromal symptoms.

Results

PD showed a higher prevalence of prodromal symptoms and almost simultaneous occurrence of non‐motor and early motor symptoms shortly before PD diagnosis whereas PD reported a longer prodromal phase starting with non‐motor symptoms.

Conclusion

The short and severe prodromal phase in PD might call for shorter assessment intervals in yet premanifest mutation carriers.

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Authors:
M. Zimmermann, A. Gaenslen, K. Prahl, K. Srulijes, A.‐K. Hauser, C. Schulte, I. Csoti, D. Berg and K. Brockmann
Article first published online:
14 Sep 2018 | DOI: 10.1111/ene.13776

Letter to the Editor

Prolonged survival in a patient with a novel pyrroline‐5‐carboxylase reductase 2 genetic variant

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Authors:
C. Spagnoli, E. Pavlidis, G. G. Salerno, L. Koskinen, H. Kääriäinen, D. Frattini, J. W. Koskenvuo and C. Fusco
Article first published online:
04 Mar 2019 | DOI: 10.1111/ene.13817

Letter to the Editor

Lung function, sleep‐disordered breathing and stroke

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Authors:
T. Kawada
Article first published online:
04 Mar 2019 | DOI: 10.1111/ene.13834

Original Article

Background and purpose

Chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) are rare autoimmune diseases. Guidelines were published in 2010 for their diagnosis and treatment. In France, intravenous immunoglobulins (IVIGs) are mainly used for the first‐line treatment. The burden of healthcare costs is often underlined but rarely studied. The aim of this survey was to compare to guidelines, the daily practice of French neurologists with IVIGs for CIDP and MMN treatment.

Methods

This was a retrospective observational study consisting of an online questionnaire performed between March and May 2014. A total of 49 questionnaires were included, a quarter of which were from neurologists working in neuromuscular reference centers (NRCs).

Results

A total of 182 patient case reports were studied. Patients were referred to an NRC for initial diagnosis in approximately 30% of cases in CIDP and 50% of cases in MMN. The initial management of IVIG (frequency, dose and duration) was not different between NRCs and non‐NRCs. Guidelines were followed and neurologists were relatively at ease in diagnosing and treating patients.

Conclusions

This was the first national study to describe the implementation of the European Federation of Neurological Sciences/Peripheral Nerve Society guidelines in the daily management of IVIGs in patients with MMN and CIDP in France. Efforts are needed to improve long‐term tailored treatment and home treatment to reduce economic costs.

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Authors:
C. Rosier, N. Graveline, A. Lacour, J.‐C. Antoine and J.‐P. Camdessanché
Article first published online:
15 Nov 2018 | DOI: 10.1111/ene.13841

Original Article

Background and purpose

GLORIA, a registry conducted with 375 advanced Parkinson's disease patients treated with levodopa‐carbidopa intestinal gel (LCIG) for 24 months in routine clinical care, demonstrated significant reductions from baseline in ‘off’ time and ‘on’ time with dyskinesia and improvements in the Non‐Motor Symptom Scale (NMSS) total and individual domain scores, and in Parkinson's Disease Questionnaire 8 item (PDQ‐8) total score.

Methods

Associations between baseline NMSS burden (NMSB), the multi‐domain NMSS total score and the PDQ‐8 total score were investigated for 233 patients. Baseline NMSB was assigned to five numerical categories defined by the NMSS total cutoff scores (0–20, 21–40, 41–60, 61–80 and >80). Pearson and Spearman correlations were calculated at month 24.

Results

The response of LCIG was assessed using validated criteria after 24 months. The proportion of patients decreasing ≥ 30 NMSS score points was 47% in the most affected NMSB category (NMSS total score > 80). A positive association was noted between baseline NMSB and NMSS total score (0.57,  < 0.0001), as well as between NMSS total score and PDQ‐8 total score (0.46,  < 0.0001). Associations between improvements of the NMSS domain sleep/fatigue and PDQ‐8 total score (0.32,  = 0.0001) as well as between the NMSS domain mood/cognition and PDQ‐8 total score (0.37,  < 0.0001) were also shown.

Conclusions

This analysis demonstrated positive associations between NMSS baseline burden and improvements of non‐motor symptoms. Improvements of non‐motor symptoms were associated with improved quality of life in advanced parkinsonian patients during a 2‐year treatment with LCIG and reflect the long‐term non‐motor efficacy of this treatment.

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Authors:
K. Ray Chaudhuri, A. Antonini, W. Z. Robieson, O. Sanchez‐Soliño, L. Bergmann and W. Poewe
Article first published online:
26 Dec 2018 | DOI: 10.1111/ene.13847

Letter to the Editor

Cost‐conscious high‐quality care and guideline development education: a strange contradiction or simple solution?

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Authors:
H. J. M. Majoie, J. van Gaalen, D. M. L. Verstegen, G. A. P. G. van Mastrigt, J. Kleijnen, P. Alonso‐Coello, G. Gartlehner, K. Ritchie, D. Service, M. Leone and S. M. A. A. Evers
Article first published online:
04 Mar 2019 | DOI: 10.1111/ene.13855

Original Article

Background and purpose

Alcoholic beverages are frequently reported migraine triggers. We aimed to assess self‐reported alcohol consumption as a migraine attack trigger and to investigate the effect on alcohol consumption behavior in a large migraine cohort.

Methods

We conducted a cross‐sectional, web‐based, questionnaire study among 2197 patients with migraine from the well‐defined Leiden University MIgraine Neuro‐Analysis (LUMINA) study population. We assessed alcoholic beverage consumption and self‐reported trigger potential, reasons behind alcohol abstinence and time between alcohol consumption and migraine attack onset.

Results

Alcoholic beverages were reported as a trigger by 35.6% of participants with migraine. In addition, over 25% of patients with migraine who had stopped consuming or never consumed alcoholic beverages did so because of presumed trigger effects. Wine, especially red wine (77.8% of participants), was recognized as the most common trigger among the alcoholic beverages. However, red wine consistently led to an attack in only 8.8% of participants. Time of onset was rapid (<3 h) in one‐third of patients and almost 90% had an onset <10 h independent of beverage type.

Conclusions

Alcoholic beverages, especially red wine, are recognized as a migraine trigger factor by patients with migraine and have a substantial effect on alcohol consumption behavior. Rapid onset of provoked migraine attacks in contrast to what is known about hangover headache might point to a different mechanism. The low consistency of provocation suggests that alcoholic beverages acting as a singular trigger is insufficient and may depend on a fluctuating trigger threshold.

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Authors:
G. L. J. Onderwater, W. P. J. van Oosterhout, G. G. Schoonman, M. D. Ferrari and G. M. Terwindt
Article first published online:
18 Dec 2018 | DOI: 10.1111/ene.13861

Original Article

Background and purpose

Dysphagia occurs in up to 50% of all patients with acute stroke. There is debate regarding which is the most effective screening tool in identifying aspiration in patients with acute stroke. We assessed the accuracy of the Sapienza Global Bedside Evaluation of Swallowing after Stroke (GLOBE‐3S), which combines the Toronto Bedside Swallowing Screening Test (TOR‐BSST©) with oxygen desaturation and laryngeal elevation measurement during swallowing.

Methods

We prospectively enrolled consecutive patients with stroke within 72 h of symptom onset. All patients with stroke firstly underwent a standard neurological examination, then the GLOBE‐3S evaluation and finally the fiberoptic endoscopic evaluation of swallowing (FEES). Two different assessors, a neurologist and a speech pathologist, blind to both the clinical data and each other's evaluation, administered the GLOBE‐3S and FEES examination. We assessed the accuracy of the GLOBE‐3S in detecting post‐stroke swallow impairment with aspiration using the FEES as the standard.

Results

We enrolled 50 patients with acute stroke, 28 of whom (56%) had swallowing impairment with aspiration at FEES evaluation. A total of 33 patients (66%) failed the GLOBE‐3S evaluation. The GLOBE‐3S reached a sensitivity of 100% and a specificity of 77.3% (negative predictive value, 100%; positive likelihood ratio, 4.34). The median time required for the GLOBE‐3S to be performed was 297 s.

Conclusions

GLOBE‐3S is quick to perform at the bedside and can accurately identify aspiration in patients with acute stroke. By including the measurement of laryngeal elevation and monitoring of oxygen desaturation, it could represent a highly sensitive instrument to avoid the misdiagnosis of silent aspirators.

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Authors:
M. Toscano, A. Viganò, A. Rea, A. Verzina, T. Sasso D'Elia, F. Puledda, L. Longo, V. Mancini, M. Ruggiero, T. B. Jannini, G. Giuliani, F. Albino, M. Altieri, E. Vicenzini, F. Fattapposta, F. Pauri, P. Giacomini, G. Ruoppolo and V. Di Piero
Article first published online:
03 Dec 2018 | DOI: 10.1111/ene.13862

Original Article

Background and purpose

Multiple sclerosis (MS) is a chronic neurological disease associated with substantial disability and morbidity. The objective of our study was to assess the long‐term consequences of MS clinical course on sick leave and disability pension.

Methods

Patients with relapsing‐remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS) were identified through the Swedish Multiple Sclerosis Registry. We calculated the mean annual prevalence and number of sick leave and disability pension days by clinical course, age and year pre‐ and post‐diagnosis, and compared outcomes using Welch's ‐tests and ANOVA models, mixed‐effects regression and survival analysis.

Results

The sample included 5371 patients (4568 with RRMS, 390 with SPMS and 413 with PPMS). The mean annual number of days with sick leave and disability pension ranged from 101 at 1 year after diagnosis to 164 after 11 years for patients with RRMS. Corresponding estimates for PPMS were 188 and 311 days. Higher levels of absenteeism were observed in patients with PPMS versus RRMS 7 years before diagnosis for sick leave ( < 0.025) and 10 years before diagnosis for disability pension ( < 0.034). Differences between SPMS and PPMS were minor.

Conclusions

Patients with RRMS had substantially lower levels of sick leave and disability pension over time compared with their counterparts with SPMS and PPMS, whereas labour‐force absenteeism was similar for patients with SPMS and PPMS. These findings contribute to the understanding of the impact of MS on socioeconomic outcomes and help inform the discussion on the clinical classification of different courses of the disease.

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Authors:
A. Castelo‐Branco, E. Landfeldt, A. Svedbom, E. Löfroth, A. Kavaliunas and J. Hillert
Article first published online:
10 Jan 2019 | DOI: 10.1111/ene.13863

Original Article

Background and purpose

Several clinical trials have demonstrated that dual antiplatelet therapy (DAPT) benefited patients with transient ischaemic attack (TIA) with an ABCD2 score ≥4. The present study aimed to investigate whether the ABCD3‐I score could be a more appropriate tool for selection of patients with TIA to receive DAPT in real‐world settings.

Methods

We derived data from the TIA database of The First Affiliated Hospital of Zhengzhou University. The predictive outcome was ischaemic stroke at 90 days. The additive interaction effect was presented by the attributable proportion due to interaction. Kaplan–Meier curves were plotted to present cumulative stroke rates in different risk categories with monotherapy and DAPT. Cox proportional hazards regression was used to determine risk factors associated with stroke.

Results

Among 785 patients, the mean (SD) age was 56.95 (12.73) years and 77 patients (9.8%) had an ischaemic stroke at 90 days. A total of 55.8% of patients (attributable proportion due to interaction; 95% confidence interval, 20.8%–90.9%) were attributed to additive interaction of ABCD3‐I score and antiplatelet therapy. Kaplan–Meier curves showed a significant difference between patients receiving monotherapy and DAPT in high‐risk patients with TIA ( = 0.021). DAPT reduced 90‐day stroke risk in high‐risk patients with TIA as assessed independently by ABCD3‐I score (adjusted hazard ratio, 0.43; 95% confidence interval, 0.20–0.92,  = 0.031). The benefit did not exist in low‐ and medium‐risk patients by ABCD3‐I score (patients with ABCD2 score ≥ 4 or <4).

Conclusions

High‐risk patients with TIA assessed by ABCD3‐I score received the most pronounced clinical benefit from early use of DAPT in real‐world clinical experience.

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Authors:
B. Song, R. Hu, L. Pei, Y. Cao, P. Chen, S. Sun, X. Wang, X. Tian, Y. Guo and Y. Xu
Article first published online:
17 Dec 2018 | DOI: 10.1111/ene.13864

Original Article

Background and purpose

Studies in women with epilepsy (WWE) regarding pregnancy and labour complications have disclosed contradictory results. Our purpose was to investigate whether WWE have a higher risk of acute caesarean section (CS) or pregnancy complications than women without epilepsy or women with other chronic diseases and, if we found a higher risk, to explore potential explanations.

Methods

The study used prospectively registered obstetric data from the Oppland Perinatal Database in the period 2001–2011, containing information on 18 244 births, including 110 singleton pregnancies in mothers with validated epilepsy. Data regarding epilepsy were collected retrospectively from medical records.

Results

Epilepsy was a significant risk factor for acute CS, breech presentation and low birth weight in offspring [odds ratio (OR), 1.93, 95% confidence interval (CI), 1.2–3.1; OR, 2.29, 95% CI, 1.2–4.6 and OR, 2.10, 95% CI, 1.0–4.2, respectively]. In multivariate logistic regression analysis, antiepileptic drug exposure was an independent risk factor for acute CS (OR, 2.00; 95% CI, 1.06–3.77) and polytherapy was a significant risk factor for breech presentation (OR, 5.37; 95% CI, 1.13–25.57). Seizure frequency during pregnancy had no influence on the complication rate.

Conclusions

We found that WWE using antiepileptic drugs during pregnancy had increased rates of acute CS, breech presentation and low birth weight, and that seizure frequency during pregnancy did not influence the complication rate.

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Authors:
A. H. Farmen, J. H. Grundt, J. O. Nakling, P. Mowinckel, K. O. Nakken and M. I. Lossius
Article first published online:
10 Dec 2018 | DOI: 10.1111/ene.13865

Original Article

Background and purpose

Natalizumab (NTZ) is a highly effective treatment for relapsing‐remitting multiple sclerosis (MS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease‐modifying treatments (DMTs) are administered. In this study, for the first time, the safety and efficacy of autologous hematopoietic stem‐cell transplantation (aHSCT) performed following NTZ discontinuation were retrospectively compared with conventional DMTs.

Methods

Patients with relapsing‐remitting MS treated with NTZ who discontinued the drug after at least six administrations and with at least 6 months of follow‐up were included. Patients underwent aHSCT after a minimum of 6 months following NTZ withdrawal, receiving meanwhile cyclophosphamide or corticosteroids, or other DMTs approved for MS (control group) after an adequate wash‐out period. Both hematological and neurological follow‐up were assessed according to standard policies.

Results

A total of 52 patients were included, 11 who received aHSCT and 41 who received DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life‐threatening complications, including progressive multifocal leukoencephalopathy, were observed. At 3 years following NTZ discontinuation, no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared with 11.5% of those in the DMT group ( = 0.0212). Disease reactivation in the patients with aHSCT was observed only during wash‐out/bridging therapy and 100% of the cases were free from disease activity after aHSCT.

Conclusions

These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash‐out period. aHSCT after 6 months from NTZ withdrawal appears to be safe.

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Authors:
A. Mariottini, C. Innocenti, B. Forci, E. Magnani, C. Mechi, A. Barilaro, R. Nistri, A. Fani, R. Saccardi, L. Massacesi and A. M. Repice
Article first published online:
14 Dec 2018 | DOI: 10.1111/ene.13866

Original Article

Background and purpose

The usefulness of plexus magnetic resonance imaging (MRI) in the diagnosis of chronic inflammatory demyelinating polyradiculopathy (CIDP) without definite European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria is currently unclear.

Methods

Data from consecutive patients with clinical manifestations suggesting CIDP, with or without (CIDP‐D and CIDP‐ND, respectively) definite EFNS/PNS electrodiagnostic criteria, and referred for plexus MRI in our imaging centre were retrospectively analysed. An expert committee of neurologists compared the level of suspicion of CIDP in CIDP‐ND patients to the blinded/unblinded MRI findings. Plexus MRI was reviewed by a neuroradiologist blinded to the final diagnosis.

Results

In all, 38 patients were assessed with suspected CIDP‐ND [7/38 (18%) probable; 13/38 (34%) possible; 18/38 (47%), no EFNS/PNS electrodiagnostic criteria], plus 10 with CIDP‐D. Thirty‐six of the 38 (95%) fulfilled clinical criteria of CIDP variants, including pure sensory neuropathy in 22/36 (61%). Plexus MRI showed abnormalities in 22/38 (58%) patients including increased nerve signal intensity on T2‐weighted images in 22/22 (100%), nerve enlargement in 20/22 (91%) and contrast enhancement in 8/22 (36%). Plexus MRI enabled the expert committee's final diagnosis to be adjusted in 7/38 (18%) patients, and in conjunction with nerve conduction studies was a supportive criterion to classify 7/24 (29%) patients as definite CIDP. MRI abnormalities were more asymmetrical ( = 0.03) and less diffuse ( = 0.1) in CIDP‐ND than in CIDP‐D.

Conclusions

Our observations suggest that plexus MRI makes a valuable contribution to the diagnosis of CIDP‐ND patients. Further studies are needed to investigate inter‐rater reliability of clinical and imaging criteria of CIDP in these patients, and the impact on outcomes.

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Authors:
G. Fargeot, K. Viala, M. Theaudin, M.‐A. Labeyrie, R. Costa, J. M. Léger, D. Adams, C. Vandendries and C. Labeyrie
Article first published online:
10 Dec 2018 | DOI: 10.1111/ene.13868

Original Article

Background and purpose

Patients with a history of brain radiotherapy can experience acute stroke‐like syndromes related to the delayed effects of brain radiation, including stroke‐like migraine attacks after radiation therapy syndrome, peri‐ictal pseudoprogression and acute late‐onset encephalopathy after radiation therapy syndrome. The aim of this study was to collect evidence on the long‐term outcome and treatment of these conditions, whose knowledge is undermined by their rarity and fragmented description.

Methods

Cases were collected, both prospectively and retrospectively, amongst six neuro‐oncology departments. Inclusion criteria were as follows: (i) history of brain radiotherapy (completed at least 6 months before the acute episode); (ii) new onset of acute/subacute neurological symptoms; (iii) exclusion of all etiologies unrelated to brain irradiation. A review of current literature on stroke‐like syndromes was performed to corroborate our findings.

Results

Thirty‐two patients with acute neurological conditions attributed to the delayed effects of radiation were identified, including 26 patients with stroke‐like syndromes. Patients with stroke‐like syndromes commonly presented with a mosaic of symptoms, including focal deficits (77%), encephalopathy (50%), seizures (35%) and headache (35%). Seventy‐three percent of them had acute consistent magnetic resonance imaging alterations. Treatment included high‐dose steroids in 65% of cases. Twenty‐two patients recovered completely (85%). Sixteen patients (62%) experienced relapses (median follow‐up 3.5 years). A literature review identified 87 additional stroke‐like cases with similar characteristics.

Conclusions

Stroke‐like events related to brain irradiation may be associated with permanent sequelae. Steroids are often administered on empirical grounds, as they are thought to accelerate recovery. Relapses are common, highlighting the need to elaborate adequate prevention strategies.

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Authors:
A. L. Di Stefano, G. Berzero, F. Ducray, M. Eoli, A. Pichiecchio, L. M. Farina, V. Cuccarini, M. C. Brunelli, L. Diamanti, S. Condette Auliac, A. Salmaggi, A. Silvani, B. Giometto, A. Pace, A. Vidiri, F. Bourdain, S. Bastianello, M. Ceroni and E. Marchioni
Article first published online:
10 Jan 2019 | DOI: 10.1111/ene.13870

Original Article

Background and purpose

Cognitive enhancers are commonly prescribed to people with Alzheimer's disease and related dementias to improve cognition and function. However, their effectiveness for individuals in the pre‐stages of dementia, particularly in functional motor outcomes, remains unknown. We aimed to determine the efficacy of donepezil, a cognitive enhancer that improves cholinergic neurotransmission, on gait performance in mild cognitive impairment (MCI).

Methods

This was a double‐blind, placebo‐controlled trial including 60 older adults with MCI, randomized to receive donepezil (10 mg/daily, maximal dose) or placebo. Primary outcome was gait speed (cm/s) under single and three dual‐task conditions (counting backwards by 1 or 7 and naming animals) measured using an electronic walkway. Dual‐task gait cost (DTC), a valid measure of motor–cognitive interaction, was calculated as the percentage change between single () and dual‐task () gait speeds: [( − )/] × 100. Secondary outcomes included attention, executive function, balance and falls.

Results

After 6 months, the donepezil group experienced an improvement in dual‐task gait speed (range 4–11 cm/s), although this was not statistically significant. The donepezil group showed a significant reduction in DTC (improvement) by counting backwards by 1 and 7 compared with placebo (10.25% vs. 1.75%, = 0.048; 21.38% vs. 14.64%, = 0.037, intention‐to‐treat analysis). Per‐protocol analyses showed that all three DTCs improved in the donepezil group, along with a non‐significant reduction of rate of falls.

Conclusions

Donepezil treatment improved dual‐task gait speed and DTC in elderly patients with MCI. Our results support the concept of reducing falls in MCI by targeting the motor–cognitive interface.

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Authors:
M. Montero‐Odasso, M. Speechley, H. Chertkow, Y. Sarquis‐Adamson, J. Wells, M. Borrie, L. Vanderhaeghe, G. Y. Zou, S. Fraser, L. Bherer and S. W. Muir‐Hunter
Article first published online:
26 Dec 2018 | DOI: 10.1111/ene.13872

Editorial

Abstract

Click to view the accompanying paper in this volume.

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Authors:
Y. A. Rajabally, P. van den Bergh, Adrian Fowle, Jean‐Marc Leger, Eduardo Nobile‐Orazio, Antonino Uncini and Pieter van Doorn
Article first published online:
11 Jan 2019 | DOI: 10.1111/ene.13873

Original Article

Background and purpose

Diffusion‐weighted imaging (DWI) commonly detects acute ischaemic lesions in patients with acute intracerebral hemorrhage (ICH), especially with cerebral amyloid angiopathy (CAA). We investigated the relationship between cortical superficial siderosis (cSS), a neuroimaging marker of CAA, and DWI lesions in patients with acute ICH.

Methods

We conducted a retrospective analysis of prospectively collected data from consecutive patients with acute supratentorial ICH who underwent brain magnetic resonance imaging within 10 days after symptom onset. Magnetic resonance imaging scans were analyzed for DWI lesions, cSS and other markers for small‐vessel disease. Univariate and multivariate analyses were performed to assess the association between cSS and DWI lesions.

Results

Among 246 ICH survivors (mean age 71.4 ± 12.6 years) who were enrolled, 126 had lobar ICH and 120 had deep ICH. Overall, DWI lesions were observed in 38 (15.4%) patients and were more common in patients with lobar ICH than deep ICH (22.2% vs. 8.3%; =0.003). In multivariate logistic regression analysis, the extent of white matter hyperintensities [odds ratio (OR), 1.29; 95% confidence interval (CI), 1.05–1.58; =0.02] and cSS severity (focal cSS: OR, 3.54; 95% CI, 1.28–9.84; disseminated cSS: OR, 4.41; 95% CI, 1.78–10.97; =0.001) were independently associated with the presence of DWI lesions.

Conclusions

Diffusion‐weighted imaging lesions are more frequently observed in patients with acute lobar ICH than in those with deep ICH. cSS severity and white matter hyperintensity extent are independent predictors for the presence of DWI lesions, suggesting that CAA may be involved in the pathogenesis of DWI lesions associated with acute ICH.

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Authors:
P. Revel‐Mouroz, A. Viguier, V. Cazzola, L. Calviere, S. Patsoura, V. Rousseau, A. Sommet, J. F. Albucher, C. Cognard, J. M. Olivot, F. Bonneville and N. Raposo
Article first published online:
18 Dec 2018 | DOI: 10.1111/ene.13874

Original Article

Background and purpose

Fingolimod is a drug approved for treatment of relapsing‐remitting multiple sclerosis (RRMS) that exerts its effects via sequestering lymphocytes within the lymph nodes. The drug, acting on the sphingosine‐1‐phosphate pathway, is involved in a plethora of processes and, to date, its mechanism of action is not completely understood.

Methods

Gene expression levels of NR4A in blood obtained from HCs, treatment‐naive (T0) and Fingolimod‐treated patients with RRMS were evaluated to determine their contribution to drug response.

Results

Gene expression levels of NR4A were down‐regulated in T0 patients compared with HCs. Patients treated with Fingolimod for >2 years were characterized by higher levels of NR4A2 compared with the T0 group, approaching those of HCs. NR4A1 and NR4A3 levels were not altered.

Conclusions

Involvement of the NR4A family in the pathogenesis of multiple sclerosis and a role of Fingolimod in the recovery from NR4A2 deficit can be hypothesized based on our data.

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Authors:
F. Montarolo, S. Perga, S. Martire, F. Brescia, M. Caldano, M. Lo Re, G. Panzica and A. Bertolotto
Article first published online:
22 Dec 2018 | DOI: 10.1111/ene.13875

Original Article

Background and purpose

International recommendations advocate that carotid endarterectomy (CEA) should be performed within 2 weeks from the index event in symptomatic carotid artery stenosis (sCAS) patients. However, there are controversial data regarding the safety of CEA performed during the first 2 days of ictus. The aim of this international, multicenter study was to prospectively evaluate the safety of urgent (0–2 days) in comparison to early (3–14 days) CEA in patients with sCAS.

Methods

Consecutive patients with non‐disabling (modified Rankin Scale scores ≤2) acute ischaemic stroke or transient ischaemic attack due to sCAS (≥70%) underwent urgent or early CEA at five tertiary‐care stroke centers during a 6‐year period. The primary outcome events included stroke, myocardial infarction or death during the 30‐day follow‐up period.

Results

A total of 311 patients with sCAS underwent urgent ( = 63) or early ( = 248) CEA. The two groups did not differ in baseline characteristics with the exception of crescendo transient ischaemic attacks (21% in urgent vs. 7% in early CEA; = 0.001). The 30‐day rates of stroke did not differ ( = 0.333) between patients with urgent (7.9%; 95% confidence interval 3.1%–17.7%) and early (4.4%; 95% confidence interval 2.4%–7.9%) CEA. The mortality and myocardial infarction rates were similar between the two groups. The median length of hospitalization was shorter in urgent CEA [6 days (interquartile range 4–6) vs. 10 days (interquartile range 7–14);  < 0.001].

Conclusions

Our findings highlight that urgent CEA performed within 2 days from the index event is related to a non‐significant increase in the risk of peri‐procedural stroke. The safety of urgent CEA requires further evaluation in larger datasets.

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Authors:
A. Roussopoulou, G. Tsivgoulis, C. Krogias, A. Lazaris, K. Moulakakis, G. S. Georgiadis, R. Mikulik, J. D. Kakisis, C. Zompola, S. Faissner, M. Chondrogianni, C. Liantinioti, T. Hummel, A. Safouris, P. Matsota, K. Voumvourakis, M. Lazarides, G. Geroulakos and S. N. Vasdekis
Article first published online:
26 Dec 2018 | DOI: 10.1111/ene.13876

Original Article

Background and purpose

The spasticity phenomenon is a significant factor in the development of disability. Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment method for this disorder. Our aim was to compare the effects of two protocols of rTMS – the high‐frequency (HF) rTMS (20 Hz) and the intermittent theta‐burst stimulation (iTBS) – on the level of spasticity and concomitant symptoms in patients with secondary progressive multiple sclerosis with an analysis of the duration of the effects up to 12 weeks after the stimulation course.

Methods

Thirty‐four patients with secondary progressive multiple sclerosis and lower spastic paraparesis were randomized into three groups: (i) HF‐rTMS (20 Hz); (ii) iTBS; (iii) sham stimulation. Spasticity and spasticity‐associated symptoms were assessed by the Modified Ashworth Scale, the Subjective Evaluating Spasticity Scale (SESS), the numerical analog scale, the Modified Fatigue Impact Scale and the pain level scale.

Results

The Modified Ashworth Scale was significantly reduced after the stimulation course in the HF‐rTMS and iTBS groups. The SESS was reduced post‐intervention and at the two follow‐ups in the iTBS group, whilst HF‐rTMS produced an SESS reduction only at the 2‐week follow‐up, with no effects in the sham group. Conversely, reduction in pain and fatigue was found in the HF‐rTMS group.

Conclusions

The results show that HF‐rTMS and iTBS significantly reduce spasticity measured by the Modified Ashworth Scale, in contrast to sham stimulation. Some evidence was found in favor of a longer‐lasting effect of iTBS on the SESS and of a reduction in pain and fatigue after HF‐rTMS.

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Authors:
J. Korzhova, I. Bakulin, D. Sinitsyn, A. Poydasheva, N. Suponeva, M. Zakharova and M. Piradov
Article first published online:
15 Jan 2019 | DOI: 10.1111/ene.13877

Original Article

Background and purpose

mutations are the most common cause of hereditary spastic paraplegia (SPG4‐HSP), which is characterized by progressive lower limb weakness, spasticity and hyperreflexia. There are few studies about non‐motor manifestations in this disease and none about autonomic involvement. Therefore, the aim was to determine the frequency and pattern of autonomic complaints in patients with SPG4‐HSP, as well as to determine the clinical relevance and the possible factors associated with these manifestations.

Methods

Thirty‐four molecularly confirmed SPG4 patients were recruited in a multicenter cross‐sectional study, of whom 26 underwent detailed neurophysiological testing (heart rate variability, sympathetic skin response and the Quantitative Sudomotor Axonal Reflex Test). The Scales for Outcomes in Parkinson's Disease – Autonomic Questionnaire (SCOPA‐AUT) was applied to quantify the severity of autonomic symptoms. Results were compared with 44 age‐ and gender‐matched healthy controls using non‐parametric tests. values <0.05 were considered significant.

Results

In the SPG4‐HSP group, there were 18 men with a mean age of 47.7 ± 12.6 years. SCOPA‐AUT scores were similar between patients and controls (0.238). Only the urinary domain subscore was significantly higher amongst patients (4 vs. 2.5, 0.05). Absent sympathetic skin response in the hands and feet was more frequent amongst patients (20% vs. 0%,  < 0.001, and 64% vs. 0%,  = 0.006, respectively). Quantitative Sudomotor Axonal Reflex Test responses were also smaller throughout all recording regions in the SPG4‐HSP group.

Conclusion

Our results indicate that SPG4‐HSP patients have sudomotor dysfunction caused by damaged small post‐ganglionic cholinergic fibers. Damage in SPG4‐HSP extends to the peripheral nervous system.

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Authors:
C. González‐Salazar, K. A. G. Takazaki, A. R. M. Martinez, L. R. Pimentel‐Silva, L. A. Jacinto‐Scudeiro, É. Y. Nakagawa, C. E. Fujiwara Murakami, J. A. M. Saute, J. L. Pedroso, O. G. P. Barsottini, H. A. G. Teive and M. C. França Jr
Article first published online:
10 Jan 2019 | DOI: 10.1111/ene.13878

Review Article

Abstract

In experimental stroke models pretreatment with the newly introduced antidiabetic agents, glucagon‐like peptide 1 receptor (GLP‐1R) agonists, has been shown to exert neuroprotective effects. Published evidence with regard to the effect of treatment with GLP‐1R agonists on the risk of stroke was evaluated. Data from prospective randomized placebo‐controlled trials up to October 2018 involving GLP‐1R agonists which reported cardiovascular outcomes as primary end‐points of efficacy and/or safety were meta‐analysed. Five eligible multicentre randomized placebo‐controlled trials (ELIXA, LEADER, SUSTAIN, EXSCEL and HARMONY) were included. The pooled analysis ( = 42 358) showed a significant reduction by 13% in the risk of total stroke from treatment with GLP‐1R agonists versus placebo (risk ratio 0.87, 95% confidence interval 0.78–0.98,  = 0.021) with no significant heterogeneity between trials ( = 4.094,  = 0.393,  = 2.307%). When only fatal stroke was included (this applied for the ELIXA, LEADER, EXSCEL and HARMONY trials), active treatment was associated with a non‐significant reduction by 16% compared with placebo (risk ratio 0.84, 95% confidence interval 0.60–1.17,  = 0.29). The findings of this meta‐analysis support the evidence from earlier experimental studies calling attention to potential ‘stroke protective’ effects from treatment with GLP‐1R.

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Authors:
F. Barkas, M. Elisaf and H. Milionis
Article first published online:
30 Jan 2019 | DOI: 10.1111/ene.13905

Review

Abstract

John Cunningham virus (JCV) infection of the central nervous system causes progressive multifocal leukoencephalopathy (PML) in patients with systemic immunosuppression. With the increased application of modern immunotherapy and biologics in various immune‐mediated disorders, the PML risk spectrum has changed. Thus, new tools and strategies for risk assessment and stratification in drug‐associated PML such as the JCV antibody indices have been introduced. Imaging studies have highlighted atypical presentations of cerebral JCV disease such as granule cell neuronopathy. Imaging markers have been developed to differentiate PML from new multiple sclerosis lesions and to facilitate the early identification of pre‐clinical manifestations of PML and its immune reconstitution inflammatory syndrome. PML can be diagnosed either by brain biopsy or by clinical, radiographic and virological criteria. Experimental treatment options including immunization and modulation of interleukin‐mediated immune response are emerging. PML should be considered in any patient with compromised systemic or central nervous system immune surveillance presenting with progressive neurological symptoms.

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Authors:
T. Bartsch, T. Rempe, F. Leypoldt, C. Riedel, O. Jansen, D. Berg and G. Deuschl
Article first published online:
08 Feb 2019 | DOI: 10.1111/ene.13906

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Article first published online:
04 Mar 2019 | DOI: 10.1111/ene.13938