cover image European Journal of Neurology

European Journal of Neurology

2020 - Volume 27
Issue 10 | October 2020
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Article first published online:
15 Sep 2020 | DOI: 10.1111/ene.14000

Original Article

Background and purpose

Acute vestibular symptoms have a profound impact on patients’ well‐being. In this study, health‐related quality of life (HRQoL) and functional impairment were investigated prospectively in patients with different peripheral and central vestibular disorders during the acute symptomatic stage to decipher the most relevant underlying factors.

Methods

In all, 175 patients with acute vestibular disorders were categorized as central vestibular (CV,  = 40), peripheral vestibular (PV,  = 68) and episodic vestibular disorders (EV,  = 67). All patients completed scores to quantify generic HRQoL (European Quality of Life Score Five Dimensions Five Levels, EQ‐5D‐5L) and disease‐specific HRQoL (Dizziness Handicap Inventory, DHI). Vestibular‐ocular motor signs were assessed by video‐oculography, vestibular‐spinal control by posturography and verticality perception by measurement of subjective visual vertical.

Results

Patients with PV had a poorer HRQoL compared to patients with CV and EV (EQ‐5D‐5L/DHI: PV, 0.53 ± 0.31/56.1 ± 19.7; CV, 0.66 ± 0.28/43.3 ± 24.0; EV, 0.75 ± 0.24/46.7 ± 21.4). After adjusting for age, gender, cardiovascular risk factors and non‐vestibular brainstem/cerebellar dysfunction patients with PV persisted to have poorer generic and disease‐specific HRQoL (EQ‐5D‐5L −0.17, DHI +11.2) than patients with CV. Horizontal spontaneous nystagmus was a highly relevant factor for subgroup differences in EQ‐5D‐5L and DHI, whilst vertical spontaneous nystagmus, subjective visual vertical and sway path were not. EQ‐5D‐5L decreased significantly with more intense horizontal subjective visual vertical in CV (rho = −0.57) and PV (rho = −0.5) but not EV (rho = −0.13).

Conclusions

Patients with PV have the highest functional impairment of all patients with acute vestibular disorders. Vestibular‐ocular motor disturbance in the yaw plane has more impact than vestibular‐spinal or vestibular‐perceptive asymmetry in the roll and pitch plane, suggesting that horizontal visual stability is the most critical for HRQoL.

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Authors:
K. Möhwald, H. Hadzhikolev, S. Bardins, S. Becker‐Bense, T. Brandt, E. Grill, K. Jahn, M. Dieterich and A. Zwergal
Article first published online:
02 Jun 2020 | DOI: 10.1111/ene.14318

Original Article

Background and purpose

The objective of the study was to investigate the relationship between rs34043159 and Alzheimer’s disease (AD) in the Chinese population.

Methods

A total of 500 AD patients and 500 healthy controls were recruited. The SNaPshot technique was used to detect rs34043159.

Results

The dominant and recessive models of rs34043159 were associated with AD with or without adjustment of age, gender and education [dominant model, = 0.019, odds ratio (OR) 1.42, 95% confidence interval (CI) 1.06–1.89, adjusted; recessive model, = 0.011, OR 0.69, 95% CI 0.51–0.92, adjusted]. The recessive model of rs34043159 was associated with early‐onset AD (EOAD) with or without adjustment of age, gender and education (recessive model, = 0.038, OR 0.60, 95% CI 0.37–0.97, adjusted). The additive model was associated with late‐onset AD (LOAD) ( = 0.041). The dominant model of rs34043159 was associated with LOAD with or without adjustment of age, gender and education (dominant model, = 0.005, OR 1.68, 95% CI 1.17–2.44, adjusted).

Conclusion

An association between the dominant and recessive model of rs34043159 and AD was found. The recessive model of rs34043159 was associated with EOAD. The additive and dominant models of rs34043159 were associated with LOAD.

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Authors:
K. Chen, Y. Tang, X. Zhao, C. Hou, G. Li and B. Zhang
Article first published online:
24 Jun 2020 | DOI: 10.1111/ene.14319

Original Article

Background and purpose

Argyrophilic grain disease (AGD) is a limbic‐predominant 4R‐tauopathy. AGD is thought to be an age‐related disorder and is frequently detected as a concomitant pathology with other neurodegenerative conditions. There is a paucity of data on the clinical phenotype of pure AGD. In elderly patients, however, AGD pathology frequently associates with cognitive decline, personality changes, urine incontinence and cachexia. In this study, clinicopathological findings were analysed in individuals younger than 75.

Methods

Patients were identified retrospectively based on neuropathological examinations during 2006–2017 and selected when AGD was the primary and dominant pathological finding. Clinical data were obtained retrospectively through medical records.

Results

In all, 55 patients (2% of all examinations performed during that period) with AGD were identified. In seven cases (13%) AGD was the primary neuropathological diagnosis without significant concomitant pathologies. Two patients were female, median age at the time of death was 64 years (range 51–74) and the median duration of disease was 3 months (range 0.5–36). The most frequent symptoms were progressive cognitive decline, urinary incontinence, seizures and psychiatric symptoms. Brain magnetic resonance imaging revealed mild temporal atrophy.

Conclusions

Argyrophilic grain disease is a rarely recognized limbic tauopathy in younger individuals. Widening the clinicopathological spectrum of tauopathies may allow identification of further patients who could benefit from tau‐based therapeutic strategies.

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Authors:
R. Wurm, S. Klotz, J. Rahimi, R. Katzenschlager, E. Lindeck‐Pozza, G. Regelsberger, K. Danics, I. Kapas, Z. A. Bíró, E. Stögmann, E. Gelpi and G. G. Kovacs
Article first published online:
08 Jun 2020 | DOI: 10.1111/ene.14321

Original Article

Background and purpose

Idiopathic normal pressure hydrocephalus (iNPH) is a clinical entity without established pathological hallmarks. Previous autopsy studies reported that patients with an antemortem diagnosis of iNPH had a different postmortem diagnosis, commonly progressive supranuclear palsy (PSP). Disproportionately enlarged subarachnoid space hydrocephalus (DESH) has been reported as a characteristic feature of iNPH on magnetic resonance imaging (MRI). In addition, periventricular white matter hyperintensities (PVHs) are noted in most patients with iNPH; these PVHs are supposed to reflect transependymal movement of ventricular cerebrospinal fluid. It is hypothesized that PSP develops more iNPH‐like MRI features than other neurodegenerative disorders.

Methods

Thirty‐eight patients with a clinical diagnosis of PSP, 42 with Parkinson’s disease (PD) without dementia, 30 with PD with dementia (PDD) and 29 with Alzheimer’s disease (AD) were enrolled. The DESH score and PVH grade were measured using the conventional MRI sequence and were compared amongst the patient groups.

Results

Disproportionately enlarged subarachnoid space hydrocephalus score was significantly higher in patients with PSP than PD without dementia, and there was a trend that the DESH score was higher in patients with PSP than PDD or Alzheimer’s disease. PVH grade was significantly larger in patients with PSP than PD without dementia. In the components of the DESH score, callosal angle was significantly smaller in patients with PSP than in PD without dementia or PDD.

Conclusions

This study demonstrated that some PSP patients develop iNPH‐like MRI features, suggesting the presence of iNPH‐like features in the clinical spectrum of PSP. A clinical phenotype of PSP with hydrocephalus is proposed, which should be further investigated in future studies.

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Authors:
M. Ohara, T. Hattori and T. Yokota
Article first published online:
29 Jun 2020 | DOI: 10.1111/ene.14322

Original Article

Background and purpose

The best therapeutic approach for aggressive relapsing–remitting multiple sclerosis remains unknown. The objective was to compare the efficacy and safety of autologous haematopoietic stem cell transplantation (aHSCT) and alemtuzumab in aggressive relapsing–remitting multiple sclerosis.

Methods

The time to first relapse, time to confirmed disability worsening, time to first evidence of magnetic resonance imaging (MRI) activity and time to first evidence of disease activity were compared between the two treatment groups. Secondary outcomes included the 12, 24 and 36 month annualized relapse rate (ARR) and the 6‐month confirmed Expanded Disability Status Scale (EDSS) changes at months 12 and 24.

Results

Fifty‐seven patients treated with aHSCT ( = 25) or alemtuzumab ( = 32) were included. At baseline, aHSCT patients had a higher EDSS (median score 6 vs. 3;  < 0.001), higher ARR (mean ARR 3.2 vs. 1.7;  = 0.001) and a higher number of baseline T1 gadolinium‐enhancing lesions on MRI (mean number 15.5 vs. 1.6;  < 0.001). NEDA‐3 (no evidence of disease activity) status was more frequently achieved in aHSCT‐treated patients than in alemtuzumab‐treated patients [75% vs. 56% of patients at the end of the observation period; hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.08–0.84;  = 0.023]. aHSCT significantly reduced the risk of relapse (relapse‐free survival 84% vs. 69%; HR 0.13, 95% CI 0.02–0.63;  = 0.012) and MRI activity (MRI‐activity‐free survival 85% vs. 59%; HR 0.13, 95% CI 0.03–0.59;  = 0.009). The ARR at 36 months was significantly lower in the aHSCT group (0.05 vs. 0.35,  = 0.02). A significant effect of aHSCT in promoting EDSS improvement compared with alemtuzumab was noted ( = 0.035).

Conclusions

Alemtuzumab and aHSCT are effective treatment choices for aggressive multiple sclerosis. aHSCT seems to be superior to alemtuzumab in inducing complete disease control and in promoting short‐term disability improvement.

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Authors:
G. Boffa, C. Lapucci, E. Sbragia, R. Varaldo, A. M. Raiola, D. Currò, L. Roccatagliata, E. Capello, A. Laroni, M. Mikulska, F. Gualandi, A. Uccelli, E. Angelucci, G. L. Mancardi and M. Inglese
Article first published online:
16 Jun 2020 | DOI: 10.1111/ene.14324

Original Article

Background and purpose

Autoimmune encephalitis (AE) represents a complex syndrome with diverse clinical manifestations and therapeutic outcomes. The aim of this study was to report the clinical characteristics and the long‐term outcome of patients with paraneoplastic and idiopathic AE.

Methods

All patients with subacute encephalopathy admitted to the Neurology Department of our Institution from January 2012 to May 2019 were consecutively enrolled. Patients’ serum and cerebrospinal fluid were tested for neural‐specific autoantibodies by indirect immunofluorescence assays on mouse brain, rat neurons, cell‐based assays and immunoblots. Outcome was assessed by the modified Rankin Scale score.

Results

From 107 adult patients with subacute encephalopathy, 50 patients were finally diagnosed with AE. Neural antibodies (Abs) were detected in 45/50 patients (90%). Leucine‐rich glioma‐inactivated protein 1 immunoglobulin G was the most frequent (6/50, 12%) Ab specific to neural surface antigens detected in adults with AE. Paraneoplastic encephalitis was diagnosed in 16/50 patients (32%). The presence of bilateral temporal lobe lesions on magnetic resonance imaging and cerebrospinal fluid restricted oligoclonal bands was associated with a higher probability to detect cancer at the time of AE diagnosis. All patients with Abs to neural surface antigens had a good outcome at last follow‐up. Severe disability at AE onset and the lack of long‐term immunosuppression predicted a poor outcome.

Conclusions

Leucine‐rich glioma‐inactivated protein 1 immunoglobulin G was the most frequent Ab detected. Patients with bilateral temporal lobe lesions and oligoclonal bands have a higher probability to harbour an occult tumour. In these patients, a strict surveillance and monitoring for cancer detection is recommended.

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Authors:
R. Iorio, V. Damato, G. Spagni, G. Della Marca, C. Vollono, G. Masi, C. Papi, L. Campetella, G. Monte and A. Evoli
Article first published online:
19 Jun 2020 | DOI: 10.1111/ene.14325

Original Article

Background and purpose

Post‐hypoxic movement disorders and chronic post‐hypoxic myoclonus are rare complications after cardiac arrest in adults. Our study investigates the clinical spectrum, neuroimaging results, therapy and prognosis of these debilitating post‐hypoxic sequelae.

Methods

This retrospective study included 72 patients from the neurological intensive care unit at a university hospital, who were diagnosed with hypoxic‐ischaemic encephalopathy after cardiac arrest between January 2007 and September 2018. Clinical records were screened for occurrence of post‐hypoxic movement disorders and chronic post‐hypoxic myoclonus. Affected patients were further analysed for applied neuroprognostic tests, administered therapy and treatment response, and the outcome of these movement disorders and neurological function.

Results

Nineteen out of 72 screened patients exhibited post‐hypoxic motor symptoms. Basal ganglia injury was the most likely neuroanatomical correlate of movement disorders as indicated by T1 hyperintensities and hypometabolism of this region in magnetic resonance imaging and positron emission tomography computed tomography. Levomepromazine and intrathecal baclofen showed first promising and mostly prompt responses to control these post‐hypoxic movement disorders and even hyperkinetic storms. In contrast, chronic post‐hypoxic myoclonus best responded to co‐application of clonazepam, levetiracetam and primidone. Remission rates of post‐hypoxic movement disorders and chronic post‐hypoxic myoclonus were 58% and 50%, respectively. Affected patients seemed to present a rather good recovery of cognitive functions in contrast to the often more severe physical deficits.

Conclusions

Post‐hypoxic movement disorders associated with pronounced basal ganglia dysfunction might be efficiently controlled by levomepromazine or intrathecal baclofen. Their occurrence might be an indicator for a more unfavourable, but often not devastating, neurological outcome.

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Authors:
F. Scheibe, W. J. Neumann, C. Lange, M. Scheel, C. Furth, M. Köhnlein, P. Mergenthaler, J. Schultze‐Amberger, P. Triebkorn, P. Ritter, A. A. Kühn and A. Meisel
Article first published online:
26 Jun 2020 | DOI: 10.1111/ene.14326

Original Article

Background and purpose

Malignant middle cerebral artery infarction (MMI) is a severe complication of acute ischaemic stroke (AIS). The aim of our study was to assess whether successful reperfusion after endovascular therapy (EVT) in AIS with clinical and imaging predictors of MMI decreased its occurrence.

Methods

Data were collected between January 2014 and July 2018 in a monocentric prospective AIS registry of patients treated with EVT. Patients selected were <65 years old with severe anterior circulation AIS with a National Institutes of Health Stroke Scale score >15, baseline Diffusion‐Weighted Imaging‐Alberta Stroke Program Early Computed Tomography Score ≤ 6 and baseline diffusion‐weighted imaging lesion volume >82 mL within 6 h of symptom onset. Successful reperfusion was defined as a Thrombolysis in Cerebral Ischemia score ≥ 2b. Occurrence of MMI was the primary endpoint.

Results

A total of 66 EVT‐treated patients were included in our study. MMI occurred in 27 patients (41%). In unadjusted analysis, successful reperfusion was associated with fewer MMIs (31.8% vs. 65.0%;  = 0.015) and with more favorable outcome at 3 months (50% vs. 20%;  = 0.023). In multivariate analysis, successful reperfusion was associated with an adjusted odds ratio (95% confidence intervals) of 0.35 (0.10–1.12) for MMI and 2.77 (0.84–10.43) for 3‐month favorable outcome occurrence.

Conclusions

Early successful reperfusion performed in patients with AIS with clinical and imaging predictors of MMI was associated with decreased MMI occurrence. Reperfusion status might be considered in evaluating the need for craniectomy in patients with early predictors of MMI.

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Authors:
C. Sabben, J. P. Desilles, F. Charbonneau, J. Savatovsky, E. Morvan, A. Obadia, I. Raynouard, F. Fela, S. Escalard, H. Redjem, S. Smajda, G. Ciccio, R. Blanc, R. Fahed, C. Le Guerinel, N. Engrand, M. Ben Maacha, J. Labreuche, M. Mazighi, M. Piotin and M. Obadia
Article first published online:
18 Jun 2020 | DOI: 10.1111/ene.14330

Original Article

Background and purpose

OnabotulinumtoxinA is an effective preventive treatment for chronic migraine (CM). In CM, in addition to a reduction in headache frequency, a decreased reliance on oral prophylactics is also indicative of treatment effectiveness. This study aimed to quantify the change in the use of oral prophylactics after treatment with onabotulinumtoxinA in patients with CM.

Methods

This was a retrospective, multicentric, cross‐sectional study. Patients with CM (International Classification of Headache Disorders‐3beta) that had been treated with onabotulinumtoxinA were enrolled consecutively. We collected parameters related to each patient’s pre‐treatment situation, as well as their current situation, focusing on frequency and intensity of migraine, number of oral prophylactics and the respective cycle of onabotulinumtoxinA. Univariate and logistic regression analyses were performed.

Results

We included 542 patients, 90.0% of whom were taking oral preventive treatments. During treatment with onabotulinumtoxinA, 47.8% withdrew at least one prophylactic and 41.6% stopped using oral prophylactics altogether. Factors associated with a reduction or cessation of oral prophylactics were >50% improvement in frequency and intensity, remission to episodic migraine, use of topiramate as an initial treatment, increased number of infiltrations and shorter chronification period ( < 0.05). The multivariate analysis showed that a chronification period <20 months, more than five cycles of onabotulinumtoxinA, >50% improvement in pain intensity and topiramate as an initial treatment were predictors of a reduction in oral prophylactics (area under the curve, 70.3%;  < 0.001).

Conclusions

Our study demonstrated the efficacy and safety of onabotulinumtoxinA. This treatment reduced the use of oral prophylactics. Withdrawal of oral prophylactics was most likely to occur after five cycles of treatment.

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Authors:
A. Alpuente, V. J. Gallardo, M. Torres‐Ferrús, S. Santos‐Lasaosa, A. L. Guerrero, J. M. Laínez, J. Viguera, A. Gago‐Veiga, P. Irimia, M. Sánchez del Rio and P. Pozo‐Rosich
Article first published online:
17 Jun 2020 | DOI: 10.1111/ene.14331

Original Article

Background and purpose

Amyotrophic lateral sclerosis (ALS) is a motor neuron disorder, although extra‐motor degeneration is well recognized, especially in frontotemporal regions manifested as ALS with frontotemporal dementia (ALS‐FTD). Previous neuroimaging studies of the brains of ALS‐FTD patients have measured abnormalities of either grey matter (GM) or white matter (WM) structures but not of both together. Therefore, the aim was to evaluate both GM and WM in the same ALS‐FTD patient using functional and structural neuroimaging. By doing so, insights could be gained into whether neurodegeneration in ALS‐FTD is primarily a neuronopathy or axonopathy.

Methods

After high‐resolution brain 2‐deoxy‐2‐[F]fluoro‐D‐glucose (F‐FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were obtained in ALS‐FTD patients and in age‐ and sex‐matched neurological controls, changes in metabolic rate, cortical thickness (CT) and WM network analysis using graph theory were analyzed.

Results

Significant reductions in F‐FDG PET metabolism, CT and WM connections were observed in motor and extra‐motor brain regions of ALS‐FTD patients compared to controls. Both CT and underlying WM networks were abnormal in frontal, temporal, parietal and occipital lobes of ALS‐FTD patients with 86 of 90 brain regions showing reductions of CT.

Conclusion

Abnormalities in significantly fewer WM networks underlying the affected cortical regions suggest that neurodegeneration in brains of ALS‐FTD patients is primarily a ‘neuronopathy’ rather than an ‘axonopathy.’

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Authors:
V. Rajagopalan and E. P. Pioro
Article first published online:
27 Jun 2020 | DOI: 10.1111/ene.14332

Original Article

Background and purpose

Acute ischaemic stroke (AIS) is a vital cause of mortality and morbidity in China. Many AIS patients develop early neurological deterioration (END). This study aimed to construct a nomogram to predict END in AIS patients.

Methods

Acute ischaemic stroke patients in Nanjing First Hospital were recruited as the training cohort. Additional patients in Nantong Third People’s Hospital were enrolled as the validation cohort. Multivariate logistic regression was utilized to establish the nomogram. Discrimination and calibration performance of the nomogram were tested by concordance index and calibration plots. Decision curve analysis was employed to assess the utility of the nomogram.

Results

In all, 1889 and 818 patients were recruited in the training and validation cohorts, respectively. Age [odds ratio (OR) 1.075; 95% confidence interval (CI) 1.059–1.091], diabetes mellitus (OR 1.673; 95% CI 1.181–2.370), atrial fibrillation (OR 3.297; 95% CI 2.005–5.421), previous antiplatelet medication (OR 0.473; 95% CI 0.301–0.744), hyper‐sensitive C‐reactive protein (OR 1.049; 95% CI 1.036–1.063) and baseline National Institutes of Health Stroke Scale (OR 1.071; 95% CI 1.045–1.098) were associated with END and incorporated in the nomogram. The concordance index was 0.826 (95% CI 0.785–0.885) and 0.798 (95% CI 0.749–0.847) in the training and validation cohorts. By decision curve analysis, the model was relevant between thresholds of 0.06 and 0.90 in the training cohort and 0.08 and 0.77 in the validation cohort.

Conclusions

The nomogram composed of hyper‐sensitive C‐reactive protein, age, diabetes mellitus, atrial fibrillation, previous antiplatelet medication and baseline National Institutes of Health Stroke Scale may predict the risk of END in AIS patients.

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Authors:
P. Gong, X. Zhang, Y. Gong, Y. Liu, S. Wang, Z. Li, W. Chen, F. Zhou, J. Zhou, T. Jiang and Y. Zhang
Article first published online:
16 Jun 2020 | DOI: 10.1111/ene.14333

Original Article

Background and purpose

The silent progression of patients with multiple sclerosis (MS) has been reported. The aim of this study was to investigate the association between brain atrophy rates and disease‐modifying drugs (DMDs) in patients with MS during their relapse‐free period.

Methods

Patients with relapsing‐remitting MS were classified into two groups on the basis of clinical records, i.e. a first‐generation DMD group treated with interferon‐beta‐1a, interferon‐beta‐1b or glatiramer acetate and a second‐generation DMD group treated with dimethyl fumarate, fingolimod or natalizumab. Brain volume was calculated with SPM12.

Results

A total of 45 patients with relapsing‐remitting MS were enrolled in the first‐generation ( = 22) or second‐generation ( = 23) DMD group. The annualized relapse rate was lower in the first‐generation than in the second‐generation DMD group (median 0.26 vs. 0.59;  < 0.001). The annualized atrophy rate of the normalized brain volume was not different between the first‐ and second‐generation DMD groups after analysis of covariance (median 0.13% vs. 0.59%;  = 0.17).

Conclusions

The median annualized atrophy rate of normalized brain volume in the first‐generation DMD group was similar to the previously reported annual brain atrophy rate of healthy controls, which may suggest that treatment with a first‐generation DMD need not be changed when patients with MS are clinically inactive.

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Authors:
H. Masuda, M. Mori, S. Hirano, A. Uzawa, T. Uchida, R. Ohtani, R. Aoki and S. Kuwabara
Article first published online:
25 Jun 2020 | DOI: 10.1111/ene.14335

Original Article

Background and purpose

The intracerebral hemorrhage (ICH) score is the most widely used and validated prognostic model for estimating 30‐day mortality in ICH. However, the score was developed and validated in an ICH population probably not using oral anticoagulants (OACs). The aim of this study was to determine the performance of the ICH score for predicting the 30‐day mortality rate in the full range of ICH scores in patients using OACs.

Methods

Data from admitted patients with ICH were collected retrospectively in two Dutch comprehensive stroke centers. The validity of the ICH score was evaluated by assessing both discrimination and calibration in OAC and OAC‐naive patient groups.

Results

A total of 1752 patients were included of which 462 (26%) patients were on OAC. The 30‐day mortality was 54% for the OAC cohort and 34% for the OAC‐naive cohort. The 30‐day mortality was higher in the OAC cohort for ICH score 1 (33% vs. 12.5%; odds ratio, 3.4; 95% confidence intervals, 1.1–10.4) and ICH score 2 (53% vs. 26%; odds ratio, 3.2; 95% confidence intervals, 1.2–8.2) compared with the predicted mortality rate of the original ICH score. Overall, the discriminative ability of the ICH score was equally good in both cohorts (area under the curve 0.83 vs. 0.87, respectively).

Conclusions

The ICH score underestimated the 30‐day mortality rate for lower ICH scores in OAC‐ICH. When estimating the prognosis of ICH in patients using OAC, this underestimation of mortality must be taken into account.

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Authors:
M. O. Fakiri, M. Uyttenboogaart, R. Houben, R. J. van Oostenbrugge, J. Staals and G.J. Luijckx
Article first published online:
16 Jun 2020 | DOI: 10.1111/ene.14336

Original Article

Background and purpose

As a major antioxidant, uric acid (UA) is known to be associated with the clinical progression of Parkinson’s disease (PD). This study investigated whether baseline UA levels are associated with the risk for levodopa‐induced dyskinesia (LID) in PD in a sex‐dependent manner.

Methods

In all, 152 patients with PD (78 males and 74 females) who were followed up for >2 years were enrolled. The effect of baseline serum UA levels on LID‐free survival was assessed by Cox regression, separately for sex, whilst being adjusted for potential confounding factors. The optimal UA level cut‐off value to determine the high‐risk group for LID was set using Contal and O’Quigley’s method.

Results

Levodopa‐induced dyskinesia developed in 23 (29.5%) male patients and 30 (40.5%) female patients. Cox regression showed a significant interaction between UA level and sex. Higher UA levels were associated with a higher risk for LID in male PD patients (hazard ratio 1.380; 95% confidence interval 1.038–1.835;  = 0.027), although this relationship was not observed in female PD patients. The optimal UA level cut‐off for LID in male PD was 7.2 mg/dl, and the high UA group had a 5.7‐fold higher risk of developing LID than the low UA group.

Conclusions

Contrary to a presumptive beneficial role of UA, the present study demonstrated that higher UA levels are associated with increased risk of LID occurrence in male patients with PD, suggesting a sex‐dependent role of UA in LID.

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Authors:
J. H. Jung, S. J. Chung, H. S. Yoo, Y. H. Lee, K. Baik, B. S. Ye, Y. H. Sohn and P. H. Lee
Article first published online:
16 Jun 2020 | DOI: 10.1111/ene.14337

Original Article

Background and purpose

To clarify the causal associations of interleukin‐1 receptor antagonist (IL‐1ra) and interleukin‐2 receptor alpha subunit (IL‐2rα) with the risk of amyotrophic lateral sclerosis (ALS).

Methods

A two‐sample Mendelian randomization study design was employed. Single‐nucleotide polymorphisms associated with IL‐1ra ( = 2) and IL‐2rα ( = 1) at the genome‐wide significance level were used as unbiased instrumental variables. Summary‐level data for ALS were obtained from Project MinE, an international collaboration consortium with 12 577 ALS cases and 23 475 controls of European descent.

Results

Genetic predisposition to higher levels of IL‐1ra was significantly associated with lower odds of ALS. For a 1‐SD increase of circulating IL‐1ra levels, the odds ratio of ALS was 0.64 (95% confidence intervals, 0.46–0.88;  = 0.005). There was a borderline inverse association between IL‐2rα levels and ALS (odds ratio, 0.91; 95% confidence intervals, 0.83–1.00;  = 0.058).

Conclusions

Interleukin‐1 receptor antagonist levels were inversely associated with ALS, suggesting that interleukin‐1 inhibitors may lower the risk of this always fatal disease. The role of IL‐2rα levels in ALS needs further verification in causal inference studies with larger sample sizes.

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Authors:
S. Yuan, P. M. Roos and S. C. Larsson
Article first published online:
08 Jun 2020 | DOI: 10.1111/ene.14338

Original Article

Background and purpose

To reduce the diagnostic gap of dementia, three strategies can be employed for case finding of cognitive impairment in ambulatory care settings, namely using informant report, brief cognitive test or a combination of informant report and brief cognitive test. The right strategy to adopt across different healthcare settings remains unclear. This diagnostic study compared the performance of the three strategies for detecting dementia (primary aim), as well as for detecting both mild cognitive impairment (MCI) and dementia (secondary aim).

Methods

Participants aged ≥65 years ( = 11 057) were recruited from Alzheimer’s Disease Centers across the USA. Participants provided data on an informant report (Functional Activities Questionnaire), brief cognitive test (four‐item short variant of Montreal Cognitive Assessment) and a combined measure with informant report and brief cognitive test (sum of Functional Activities Questionnaire and Montreal Cognitive Assessment short variant). They also received standardized assessments (clinical history, physical examination and neuropsychological testing) to diagnose MCI and dementia. Areas under the receiver operating characteristic curve (AUCs) of the three strategies were compared using the DeLong method, with AUC > 90% indicating excellent performance.

Results

All three strategies had excellent performance in detecting dementia, although informant report [AUC, 95.9%; 95% confidence intervals (CI), 95.4–96.3%] was significantly better than brief cognitive test (AUC, 93.0%; 95% CI, 92.4–93.6%) and the combined measure had the best performance (AUC, 97.0%; 95% CI, 96.7–97.4%). However, to detect both MCI and dementia, only the combined measure had excellent performance (AUC, 93.0%; 95% CI, 92.5–93.4%), whereas stand‐alone informant report or brief cognitive test performed suboptimally (AUC < 90%). Performance of the three strategies was not affected by participants’ age, educational attainment or underlying prevalence of MCI and dementia.

Conclusions

For case finding of dementia in ambulatory care settings, informant reports would suffice as first‐line measures and brief cognitive tests may optionally be added on, in services with available resources, to further improve the accuracy of detection. For case finding of both MCI and dementia, a combination of informant reports and brief cognitive tests remains the most appropriate strategy.

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Authors:
T. M. Liew
Article first published online:
16 Jun 2020 | DOI: 10.1111/ene.14353

Original Article

Background and purpose

Little evidence exists to describe the incidence and risk factors for dementia in developing countries. This study aimed to examine the incidence and factors associated with the risk of developing dementia in a Thai general population.

Methods

Data on 206 073 men and women aged ≥50 years participating in the Health Check Ubon Ratchathani Project in 2006 were merged with diagnostic information from the hospital’s electronic medical records in the following 6 years (2006–2012). The incidence of physician‐diagnosed dementia over 6 years was examined. Factors associated with the risk of developing dementia were examined using multivariate Cox proportional hazard regression.

Results

Over a total time at risk of 1 196 433 person‐years, 480 individuals developed dementia; the incidence rate was 0.40 [95% confidence interval (CI) 0.37–0.44] per 1000 person‐years. Dementia incidence rose exponentially with increasing age to 1.37 (95% CI 1.07–1.75) per 1000 person‐years in those aged 80–84 years and dropped after the age of 85 years. Factors independently associated with the risk of developing dementia included increasing age, diabetes and lack of physical exercise. The risk of dementia rose by 7% for every 1 year of age older [adjusted hazard ratio (aHR) 1.07, 95% CI 1.06–1.08]. Diabetes increased the risk of dementia by 51% (aHR 1.51, 95% CI 1.12–2.03). Compared to no physical exercise, having 3–5 days/week and> 5 days/week of physical exercise reduced the risk of dementia by 37% and 59% (aHR 0.63, 95% CI 0.50–0.79, and 0.41, 95% CI 0.26–0.66, respectively).

Conclusions

Dementia incidence in a Thai population was lower than Western populations and its independent risk factors included increasing age, diabetes and a lack of physical exercise. Adequate physical exercise may counterbalance the ageing process, the main drive of dementia.

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Authors:
P. Boongird, P. Chamnan, S. Laptikultham, P. Krittayapoositpot, W. Nitiyanant, W. Aekplakorn and A. Mangklabruks
Article first published online:
18 Jun 2020 | DOI: 10.1111/ene.14354

Original Article

Background and purpose

Neurological manifestations have been identified in the context of autoimmune hepatitis (AIH). Previous case reports highlighted the association between AIH and sensory neuronopathy (SN). Despite that, little is known about the frequency of AIH‐related SN and its clinical/neurophysiological profile. Moreover, it is not clear whether SN is an AIH‐specific manifestation or related to chronic liver damage.

Methods

Seventy consecutive AIH patients were enrolled and their characteristics were compared with 52 consecutive patients with chronic active hepatitis B. All subjects underwent clinical and neurophysiological evaluation. Further comparisons were performed between AIH SN and AIH non‐SN patients.

Results

Mean ages and male:female proportions in the AIH and chronic active hepatitis B groups were 42.2 ± 16.3/51.7 ± 13.6 years and 14:56/29:23, respectively. The frequencies of carpal tunnel syndrome, radiculopathy and polyneuropathy were similar between groups. In contrast, SN was identified only in AIH patients (5/70 vs. 0/52,  = 0.04); the overall prevalence of AIH‐related SN was 7% with an average profile of a woman in her 40s with asymmetric onset of sensory deficits that chronically evolved to disabling proprioceptive ataxia associated with marked dysautonomia. Neurological disability and hepatocellular damage did not follow in parallel. Anti‐fibroblast growth factor receptor type 3 antibodies were found in 3/5 (60%) of the patients with AIH‐related SN. Clinical or demographic predictors of SN in the context of AIH could not be identified.

Conclusion

Sensory neuronopathy, but not other peripheral nervous system diseases, is a specific AIH neurological manifestation. It is often disabling and, in contrast to hepatocellular injury, does not respond to immunosuppression.

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Authors:
A. R. M. Martinez, F. D. de Lima, M. P. Martins, I. E. Pereira, N. Miotto, D. F. C. Mazo, A. G. Vigani, L. B. E. da Costa, R. S. B. Stucchi, J. R. S. Almeida, A. Nucci and M. C. França
Article first published online:
25 Jun 2020 | DOI: 10.1111/ene.14355

Letters To The Editor

Non‐vitamin‐K oral anticoagulants may not significantly reduce the risk of fatal or disabling stroke compared with warfarin

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Authors:
F. Zheng, L. Luo, J. Wang, T. Huang, J. Huang, C. Wang, W. Hu and B. Krischek
Article first published online:
11 Jun 2020 | DOI: 10.1111/ene.14356

Short Communication

Background and purpose

It is currently unknown whether mechanical thrombectomy (MT) for ischaemic stroke patients with low initial Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is clinically beneficial or even harmful. The purpose of this study was to investigate whether failed or incomplete MT in acute large vessel occlusion stroke with an initial ASPECTS ≤ 5 is associated with worse clinical outcome compared to patients not undergoing MT.

Methods

This observational cohort study included a consecutive sample of patients with anterior circulation stroke and initial ASPECTS ≤ 5 admitted between March 2015 and August 2019. Failed recanalization was defined as Thrombolysis in Cerebral Infarction (TICI) score 0–2a, and incomplete recanalization as TICI 2b. Clinical outcome was assessed using the modified Rankin Scale (mRS) at 90 days defining very poor clinical outcome as mRS > 4.

Results

One hundred and seventy patients were included. Ninety‐nine patients underwent MT and 71 patients received best medical treatment only. Clinical outcome after failed or incomplete MT (TICI 0–2b) was significantly better compared to patients with medical treatment only (median mRS 5, interquartile range 4–6 vs 5–6,  = 0.03). In multivariable logistic regression analysis, failed or incomplete MT (TICI 0–2b) showed a significantly reduced likelihood for very poor outcome (odds ratio 0.39, 95% confidence interval 0.19–0.83,  = 0.01). Failed MT (TICI 0–2a) was not associated with a worse outcome compared to best medical treatment.

Conclusions

Patients with failed or incomplete recanalization results (TICI 0–2b) showed a reduced likelihood for very poor outcome compared with those who did not receive MT. Evidence from randomized trials is needed to confirm that even failed or incomplete MT is not harmful in these patients.

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Authors:
G. Broocks, F. Flottmann, M. Schönfeld, M. Bechstein, P. Aye, H. Kniep, T. D. Faizy, R. McDonough, G. Schön, M. Deb‐Chatterji, G. Thomalla, P. Sporns, J. Fiehler, U. Hanning, A. Kemmling and L. Meyer
Article first published online:
26 Jun 2020 | DOI: 10.1111/ene.14358

Original Article

Background and purpose

The differentiation of Alzheimer’s disease (AD) dementia from vascular dementia (VaD) and mixed‐type dementia (mixed dementia) requires stepwise analysis and usually occurs late in the disease process. Early diagnosis and therapy monitoring would benefit greatly from the identification of biomarkers of neurodegeneration, especially blood biomarkers. To this end, the aim of the present pilot study was to investigate differences in the distribution of peripheral T‐cell populations in patients with AD compared to VaD and mixed dementia.

Methods

Flow cytometry was performed on blood samples from 11 patients with AD, six with VaD and six with mixed dementia, as well as 17 healthy control subjects (HCs). CD4+ and CD8+ T cells were typed for expression of CD45, CD27, CD28, CD25, FoxP3, CCR4 and CCR6; the other leukocytes were also assessed. Functionally, immune cell uptake of the β‐amyloid (Aβ) toxic fragment (Aβ) was also evaluated.

Results

A higher proportion of CD4+CD28− memory T cells and a reciprocal reduction of CD4+CD28+CD27+ naïve T lymphocytes was detected in all patient groups relative to controls. Significantly fewer CD4+CD25+FoxP3 regulatory T cells were present in patients with VaD, and significantly more CCR6+ and CCR4+ CD4+ T cells in those with AD. Higher CCR6+ T‐cell frequencies were also present in patients with mixed dementia, potentially due to the inflammation and immune cell chemoattraction triggered by Aβ.

Conclusions

The present study was a comprehensive investigation comparing different kinds of dementia, revealing differentially expressed peripheral markers that are potentially useful for early AD, VaD and mixed dementia diagnoses, and that would assist in proper treatments for these disparate diseases. Validation is now required.

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Authors:
C. D’Angelo, D. Goldeck, G. Pawelec, L. Gaspari, A. Di Iorio and R. Paganelli
Article first published online:
11 Jul 2020 | DOI: 10.1111/ene.14360

Case Study

Background

Charcot‐Marie‐Tooth disease (CMT) constitutes a group of heterogeneous hereditary motor and sensor neuropathies. Mutations in the periaxin () gene cause CMT4F with an autosomal recessive early‐onset demyelinating neuropathy and are extremely rare in a non‐Romani white population.

Methods

We report on a 66‐year‐old Italian man presenting with slowly progressive and late‐onset demyelinating CMT. The molecular analysis was performed using a custom panel containing 39 genes associated with the CMT phenotype.

Results

The patient harbored a homozygous PRX 71‐nucleotide deletion (c.3286_3356del71, I1096fsX17).

Conclusions

This is the first report that describes such a genetic mutation in a population of non‐Romani origin.

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Authors:
L. Citrigno, S. Zoccolella, P. Lastella, I. L. Simone and M. Muglia
Article first published online:
15 Sep 2020 | DOI: 10.1111/ene.14362

Short Communication

Background and purpose

Multiple studies have suggested an immunomodulatory role of cholesterol. We investigated whether cholesterol levels are associated with the risk of infectious complications (ICs) in acute ischemic stroke patients.

Methods

A single‐center prospective cohort was analyzed. Total (TOTc), low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol levels were measured within 24 h from admission. The outcome of interest was the occurrence of any IC (pneumonia, urinary tract infection, sepsis, other infection) during hospitalization. Predictors of ICs were investigated with multivariable logistic regression.

Results

A total of 603 patients were included (median age 78 years, 49.3% males), of whom 134 (22.2%) developed an IC. Subjects with ICs had lower TOTc compared with patients without ICs (median 157 vs. 173 mg/dL;  < 0.001). When TOTc was stratified in quartiles, we observed a linear decrease in the prevalence of ICs with higher TOTc levels (Q1, <144 mg/dL, 32.7%; Q2, 145–168 mg/dL, 24.7%; Q3, 169–197 mg/dL, 17.8%; Q4, >197 mg/dL, 13.3%  < 0.001). The inverse relationship between TOTc and ICs remained significant after adjustment for confounders in logistic regression [odds ratio (OR) for 10 mg/dL increase, 0.92; 95% confidence intervals (CI), 0.87–0.97;  = 0.001]. This association was also confirmed for low‐density lipoprotein cholesterol (OR, 0.93; 95% CI, 0.88–0.99;  = 0.013) and high‐density lipoprotein cholesterol (OR, 0.85; 95% CI, 0.73–0.98;  = 0.026) and was not mediated by statin treatment.

Conclusion

Higher cholesterol levels are independently associated with lower risk of ICs in ischemic stroke patients. Further studies are needed to confirm our findings and characterize the biological mechanisms underlying this association.

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Authors:
F. Mazzacane, E. Leuci, A. Persico, G. Micieli, E. Candeloro, A. Cavallini and A. Morotti
Article first published online:
16 Jun 2020 | DOI: 10.1111/ene.14364

Letters to the Editor

Response to letter: non‐vitamin‐K oral anticoagulants may not significantly reduce the risk of fatal or disabling stroke compared with warfarin

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Authors:
M. Costello, C. Judge, M. J. O’Donnell and M. Canavan
Article first published online:
09 Jul 2020 | DOI: 10.1111/ene.14366

Short Communications

Background and purpose

Visual snow manifests as a pan‐field, dynamic visual disturbance described as continuous television static‐like tiny flickering dots. Current diagnostic criteria further require at least two additional symptoms for visual snow syndrome (VSS) from: palinopsia (afterimages and trailing); entoptic phenomena (floaters, blue field entoptic phenomenon, photopsia, self‐light of the eye); photophobia and nyctalopia. Our objective was to compare the phenotype of VSS in an Italian and British population.

Methods

Patients with VSS were characterized clinically using the current criteria. An online survey was prepared in collaboration with the patient group Eye‐on‐Vision. Patients were directed to the site if they contacted us by email asking to be involved in research. After data collection, we compared the phenotypic characteristics of a subgroup of British versus Italian patients taking part in the survey. As we expected more responses from the UK, we matched 100 UK patients for gender and age with our Italian cohort.

Results

Patients were enrolled from the UK ( = 100) and Italy ( = 100). The populations had similar demography. After multiple correction testing there were no differences in VSS features between the two groups. The same was true for the prevalence of migraine and previous use of recreational drugs.

Conclusion

This is the first study comparing the phenotype of VSS between two distinct populations. Our findings suggest that the visual snow phenotype, as well as migraine comorbidity, is similar across the two groups.

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Authors:
M. Viana, F. Puledda and P. J. Goadsby
Article first published online:
23 Jul 2020 | DOI: 10.1111/ene.14369

Original Article

Background and purpose

Hidden hearing loss has been reported in patients with Charcot‐Marie‐Tooth (CMT) disease; however, the auditory‐processing deficits have not been widely explored. We investigated the psychoacoustic and neurophysiological aspects of auditory processing in patients with CMT disease type 1A (CMT1A) and type 2A (CMT2A).

Methods

A total of 43 patients with CMT1A and 15 patients with CMT2A were prospectively enrolled. All patients with CMT disease had normal sound‐detection ability by using pure‐tone audiometry. Spectral‐ripple discrimination, temporal modulation detection and auditory frequency‐following response were compared between CMT1A, CMT2A and control groups.

Results

Although all participants had normal audiograms, patients with CMT disease had difficulty understanding speech in noise. The psychoacoustic auditory processing was somewhat different depending on the underlying pathophysiology of CMT disease. Patients with CMT1A had degraded auditory temporal and spectral processing. Patients with CMT2A had no reduced spectral resolution, but they showed further reduced temporal resolution than the patients with CMT1A. The amplitudes of the frequency‐following response were reduced in patients with CMT1A and CMT2A, but the neural timing remained relatively intact.

Conclusions

When we first assessed the neural representation to speech at the brainstem level, the grand average brainstem responses were reduced in both patients with CMT1A and CMT2A compared with healthy controls. As the psychoacoustic aspects of auditory dysfunctions in CMT1A and CMT2A were somewhat different, it is necessary to consider future auditory rehabilitation methods based on their pathophysiology.

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Authors:
J. E. Choi, H. Y. Seol, J. M. Seok, S. H. Hong, B.‐O. Choi and I. J. Moon
Article first published online:
30 Jun 2020 | DOI: 10.1111/ene.14370

Short Communication

Background and purpose

Diagnostic uncertainty is common in the emergency evaluation of neurological conditions such as acute confusional states, particularly for non‐neurologists. We aimed to investigate the clinical recognition process of transient global amnesia (TGA) before arrival at the hospital and in the emergency department (ED).

Methods

In this retrospective observational study, medical records of 365 patients with TGA were analysed concerning mode of arrival, symptoms and suspected diagnosis made by pre‐hospital medical care providers and the ED neurologist.

Results

More than half of the 248 patients who were evaluated before arrival at the hospital ( = 157, 63.3%) received a diagnosis of suspected stroke, whereas TGA was considered in only 16 patients (6.5%), with recognition of acute amnesia in 150 patients (60.5%) and disturbed orientation in 86 patients (34.7%). Repetitive questions by the patient were noted in 28 patients (11.3%). In contrast, in 355 patients (97.3%), TGA was considered the primary diagnosis by the ED neurologist. Diagnosis in the ED was achieved by documenting ongoing impairment of episodic verbal memory (100.0%), repetitive questions as a prominent ancillary finding (95.5%) and the lack of focal neurological symptoms (100.0%) or by carefully obtaining collateral history suggestive of anterograde memory disturbance (89.9%) and/or repetitive questions (85.7%).

Conclusion

Recognizing TGA crucially depends on identifying isolated anterograde episodic long‐term memory disturbance or its observable effects such as repetitive questions and actions.

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Authors:
C. Hoyer, A. Ebert, A. Pooyeh, P. Eisele, A. Gass, M. Platten and K. Szabo
Article first published online:
22 Jun 2020 | DOI: 10.1111/ene.14371

Short Communication

Background and purpose

Stroke is a dreaded complication in patients with cancer. Besides paraneoplastic coagulopathy, chemotherapy, radiotherapy and tumor‐directed invasive procedures, circulating cancer cells may contribute to thrombus formation and embolic stroke. However, the incidence of tumor cells within the blood clots of cancer patients with stroke is unknown and the role of circulating tumor cells in the formation of cerebrovascular thrombi remains unclear.

Methods

All patients who had undergone cerebrovascular thrombectomy at the University Hospital Zurich between 2014 and 2017 were screened for history of cancer. Clinical information was retrieved from the local stroke registry and the electronic charts and thrombi underwent a thorough histopathological re‐review.

Results

Thirty‐two of 182 patients (18%) with thrombectomy had a history of cancer. The majority of patients had advanced stage cancer. However, even after extensive histopathological re‐review, only one specimen revealed tumor cells in the thrombus: a 75‐year‐old patient with acute occlusion of the middle cerebral artery who had been diagnosed with non‐small‐cell lung cancer 8.1 months prior to stroke.

Conclusions

The presence of cancer cells in clots from cerebrovascular thrombectomy, indicative of a direct involvement of circulating tumor cells in the causation of stroke, is rare.

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Authors:
F. Wolpert, Z. Kulcsár, M. Hänsel, E. Rushing, K. Seystahl, J. Schweizer, P. Roth, A.R. Luft, S. Wegener and M. Weller
Article first published online:
10 Jul 2020 | DOI: 10.1111/ene.14372

Letters To The Editor

What is the pattern of the neuropathy associated with anti‐FGFR3 antibodies?

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Authors:
Y. Tholance, C. P. Moritz, J. P. Camdessanché and J. C. Antoine
Article first published online:
01 Jul 2020 | DOI: 10.1111/ene.14376

Letters To The Editor

Quantitative MRI as an imaging marker of concussion: evidence from studying repeated events

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Authors:
M. Pedersen, M. Makdissi, D. M. Parker, T. Barbour, D. F. Abbott, P. McCrory and G. D. Jackson
Article first published online:
29 Jun 2020 | DOI: 10.1111/ene.14377

Editorial

Stem cell transplantation and alemtuzumab – options for ‘early reprogramming’ in multiple sclerosis?

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Authors:
S. Pfeuffer and S. G. Meuth
Article first published online:
12 Jul 2020 | DOI: 10.1111/ene.14378

Commentary

Neural autoantibodies and autoimmune encephalitis – the conjunction of both counts

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Authors:
C. G. Bien
Article first published online:
01 Jul 2020 | DOI: 10.1111/ene.14379

Letters To The Editor

Reply to: What is the pattern of the neuropathy associated with anti‐FGFR3 antibodies?

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Authors:
B. Roy, S. Kovvuru, Y. C. Castillo, A. Huttner and R. J. Nowak
Article first published online:
30 Jun 2020 | DOI: 10.1111/ene.14381

Original Article

Background and purpose

Liver fibrosis, a common yet often subclinical manifestation of chronic liver disease, may have an unrecognized role in cognitive impairment. We evaluated the association between a validated liver fibrosis index and cognitive measures among older adults.

Methods

We examined the association between liver fibrosis and cognitive performance among participants aged 60 years and older in the US National Health and Nutrition Examination Survey. Liver fibrosis was measured with the validated Fibrosis‐4 (FIB‐4) liver fibrosis score. The outcomes were performance on four standardized cognitive tests of immediate and delayed verbal learning, verbal fluency, and attention/concentration. We used linear regression to evaluate the association between FIB‐4 score and performance on cognitive tests while adjusting for potential confounders. In sensitivity analyses, we examined this association in participants without known liver disease.

Results

Among 3217 adult participants, the mean age was 69 years, and 54% were women. Standard liver chemistries were largely in the normal range. However, 5.0% [95% confidence interval (CI) 4.0–6.0] had liver fibrosis based on a validated cut‐off. In adjusted linear regression models, higher liver fibrosis scores were associated with worse immediate recall (β −0.39; 95% CI −0.58, −0.21), language fluency (β −0.46; 95% CI −0.72, −0.21), and attention/concentration (β −1.34; 95% CI −2.25, −0.43), but not delayed recall (β −0.10; 95% CI −0.20, 0.01). Results were similar when limiting the study population to participants without known clinical liver disease.

Conclusion

Liver fibrosis, including subclinical liver fibrosis, may be an independent risk factor for cognitive impairment among older adults.

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Authors:
N. S. Parikh, S. Kumar, R. Rosenblatt, C. Zhao, D. E. Cohen, C. Iadecola and H. Kamel
Article first published online:
20 Jul 2020 | DOI: 10.1111/ene.14384

Original Article

Background and purpose

Dysphagia, dysarthria and aphasia are common symptoms following acute stroke; however, limited data are available from recent prospective clinical trials. The aim of this study was to determine the incidence and associated factors of dysphagia, dysarthria and aphasia following a first acute ischaemic stroke in patients admitted to a comprehensive stroke center.

Methods

All first ischaemic stroke patients admitted to the Stroke Unit of Ghent University Hospital within 48 h after symptom onset were enrolled in this prospective study between March 2018 and October 2019. Dysphagia and communication screenings were performed within 3 days after admission. When dysphagia, dysarthria and/or aphasia were assumed, standardized assessments were performed. Incidence rates were calculated as point estimates (%) with 95% confidence intervals (CI). Associated factors were calculated via multivariate binary logistic regression analyses.

Results

Dysphagia, dysarthria and aphasia were present in 23% (95% CI, 17–31), 44% (95% CI, 37–52) and 23% (95% CI, 17–30), respectively of 151 first ischaemic stroke patients [67 female, mean age 67 (SD 14) years]. Separate multivariate binary logistic regression analyses showed that dysphagia, dysarthria and aphasia were significantly associated with age‐adjusted stroke severity at baseline [odds ratio (OR), 1.16; 95% CI, 1.09–1.23; OR, 1.13; 95% CI, 1.07–1.20 and OR, 1.11; 95% CI, 1.05–1.17 respectively]. Corrected for stroke severity, the risk for aphasia increased by 4% per year of age (OR, 1.04; 95% CI, 1.00–1.07). Adjusted for age and stroke severity, aphasia was significantly associated with large artery atherosclerosis as stroke etiology (OR, 3.91; 95% CI, 1.18–12.98).

Conclusions

This trial showed a high incidence of dysphagia, dysarthria and aphasia following acute ischaemic stroke. Stroke severity was an associated factor for all three symptoms.

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Authors:
E. De Cock, K. Batens, D. Hemelsoet, P. Boon, K. Oostra and V. De Herdt
Article first published online:
30 Jun 2020 | DOI: 10.1111/ene.14385

Original Article

Background and purpose

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviours during REM sleep. Several studies showed that iRBD is a prodromal stage of synucleinopathies. Therefore, identifying iRBD in the general population is of utmost importance. In this study, we explore whether the assessment of rest–activity rhythm features can distinguish patients with iRBD from patients with disorders characterized by other pathological motor activity during sleep and healthy controls.

Methods

Nineteen patients with video‐polysomnographic diagnosis of iRBD, 39 patients with other disorders with motor activity during sleep [19 with restless leg syndrome (RLS) and 20 with untreated sleep apnea syndrome (SAS)] and 16 healthy controls underwent 2‐week actigraphy and video‐polysomnography, and completed REM sleep behavior disorder screening questionnaires. Non‐parametric analyses were applied to assess the rest–activity rhythm features.

Results

Patients with iRBD showed lower sleep efficiency, increased estimated wake after sleep onset and increased frequency of prolonged activity bouts compared to those with RLS and controls, while no difference emerged compared with SAS patients. Moreover, patients with iRBD presented increased occurrence of estimated nap in comparison to those with RLS, those with SAS and controls. The I < O, a 24‐h measure that expresses the relationship between nocturnal and diurnal motor activity intensity, distinguished patients with iRBD from those with RLS, those with SAS and controls, with an area under the curve greater than that of REM sleep behavior disorder screening questionnaires. An I < O of 98.32 shows the best balance between sensitivity (63.2%) and specificity (89.1%).

Discussion

The I < O index distinguished iRBD patients from those with other pathological motor activity during sleep and controls, confirming its use as an objective measure suitable to screen large at‐risk populations.

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Authors:
M. Filardi, A. Stefani, E. Holzknecht, F. Pizza, G. Plazzi and B. Högl
Article first published online:
07 Jul 2020 | DOI: 10.1111/ene.14386

Letters To The Editor

Serum neurofilament light chain level as a biomarker of neurodegeneration and predictor of white‐matter abnormality progression

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Authors:
J. K. Murthy and S. Das
Article first published online:
04 Jul 2020 | DOI: 10.1111/ene.14389

Review Article

Abstract

Livedo is a net‐like violaceous skin pattern. It can be classified as physiological or pathological. The physiological livedo reticularis usually appears in cold conditions, whereas the pathological and irregular livedo, which persists in warm temperatures, is often labeled as ‘livedo racemosa’. Some neurological pathologies are associated with livedo, most commonly those with an inflammatory component or those derived from systemic disorders. The present review summarizes the most important central and peripheral neurological diseases in pediatric and adult age groups associated with livedo, providing physicians with an overview of the clinical presentation, etiology, diagnosis and management of these conditions.

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Authors:
F. Mitri, A. Enk, A. Bersano and M. Kraemer
Article first published online:
02 Jul 2020 | DOI: 10.1111/ene.14390

Review

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra‐motor manifestations are increasingly recognized. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. ALS often has a focal onset but subsequently spreads to different body regions, where failure of respiratory muscles typically limits survival to 2–5 years after disease onset. In up to 50% of cases, there are extra‐motor manifestations such as changes in behaviour, executive dysfunction and language problems. In 10%–15% of patients, these problems are severe enough to meet the clinical criteria of frontotemporal dementia (FTD). In 10% of ALS patients, the family history suggests an autosomal dominant inheritance pattern. The remaining 90% have no affected family members and are classified as sporadic ALS. The causes of ALS appear to be heterogeneous and are only partially understood. To date, more than 20 genes have been associated with ALS. The most common genetic cause is a hexanucleotide repeat expansion in the gene, responsible for 30%–50% of familial ALS and 7% of sporadic ALS. These expansions are also a frequent cause of frontotemporal dementia, emphasizing the molecular overlap between ALS and FTD. To this day there is no cure or effective treatment for ALS and the cornerstone of treatment remains multidisciplinary care, including nutritional and respiratory support and symptom management. In this review, different aspects of ALS are discussed, including epidemiology, aetiology, pathogenesis, clinical features, differential diagnosis, investigations, treatment and future prospects.

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Authors:
P. Masrori and P. Van Damme
Article first published online:
07 Jul 2020 | DOI: 10.1111/ene.14393

Review

Abstract

Approximately 89% of patients with Parkinson’s disease (PD) suffer from dysarthria. Lee Silverman Voice Treatment (LSVT), a behavioral therapy, aims to improve speech and voice functions. The objective was to assess the effectiveness of LSVT compared with other/no speech interventions for dysarthria in patients with PD. Electronic databases, including PubMed, Embase and the Cochrane Library, were searched. The publication date of all included studies was before 6 March 2020. Only randomized controlled trials (RCTs) that evaluated the LSVT intervention compared with other/no speech intervention were considered. The data obtained from the included studies were described and the mean differences were calculated. Eight RCTs were included in this meta‐analysis comparing LSVT with other/no speech interventions. In the comparison of LSVT versus no intervention, vocal intensity for sustained ‘Ah’ phonation, reading the ‘Rainbow passage’, monologue and describing a picture increased by 8.87, 4.34, 3.25 and 3.31 dB, respectively, after 1 month of therapy. Compared with the respiratory therapy group, the LSVT group also showed significant improvement in vocal intensity for sustained ‘Ah’ phonation, reading the ‘Rainbow passage’ and monologue immediately after treatment (13.39, 6.66 and 3.19 dB). Positive improvement still existed after 24 months. There was no difference in the therapeutic effect between face‐to‐face and online LSVT. The effectiveness of LSVT for dysarthria in patients with PD was verified in these trials. However, future RCTs with sufficient participants are essential to evaluate the effectiveness of LSVT for dysarthria.

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Authors:
F. Yuan, X. Guo, X. Wei, F. Xie, J. Zheng, Y. Huang, Z. Huang, Z. Chang, H. Li, Y. Guo, J. Chen, J. Guo, B. Tang, B. Deng and Q. Wang
Article first published online:
12 Aug 2020 | DOI: 10.1111/ene.14399

Guidelines

Background and purpose

Dementia is one of the most common disorders and is associated with increased morbidity, mortality and decreased quality of life. The present guideline addresses important medical management issues including systematic medical follow‐up, vascular risk factors in dementia, pain in dementia, use of antipsychotics in dementia and epilepsy in dementia.

Methods

A systematic review of the literature was carried out. Based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, we developed a guideline. Where recommendations based on GRADE were not possible, a good practice statement was formulated.

Results

Systematic management of vascular risk factors should be performed in patients with mild to moderate dementia as prevention of cerebrovascular pathology may impact on the progression of dementia (Good Practice statement). Individuals with dementia (without previous stroke) and atrial fibrillation should be treated with anticoagulants (weak recommendation). Discontinuation of opioids should be considered in certain individuals with dementia (e.g. for whom there are no signs or symptoms of pain or no clear indication, or suspicion of side effects; Good Practice statement). Behavioral symptoms in persons with dementia should not be treated with mild analgesics (weak recommendation). In all patients with dementia treated with opioids, assessment of the individual risk–benefit ratio should be performed at regular intervals. Regular, preplanned medical follow‐up should be offered to all patients with dementia. The setting will depend on the organization of local health services and should, as a minimum, include general practitioners with easy access to dementia specialists (Good Practice statement). Individuals with dementia and agitation and/or aggression should be treated with atypical antipsychotics only after all non‐pharmacological measures have been proven to be without benefit or in the case of severe self‐harm or harm to others (weak recommendation). Antipsychotics should be discontinued after cessation of behavioral disturbances and in patients in whom there are side effects (Good Practice statement). For treatment of epilepsy in individuals with dementia, newer anticonvulsants should be considered as first‐line therapy (Good Practice statement).

Conclusion

This GRADE‐based guideline offers recommendations on several important medical issues in patients with dementia, and thus adds important guidance for clinicians. For some issues, very little or no evidence was identified, highlighting the importance of further studies within these areas.

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Authors:
K. S. Frederiksen, C. Cooper, G. B. Frisoni, L. Frölich, J. Georges, M. G. Kramberger, C. Nilsson, P. Passmore, L. Mantoan Ritter, D. Religa, R. Schmidt, E. Stefanova, A. Verdelho, M. Vandenbulcke, B. Winblad and G. Waldemar
Article first published online:
26 Jul 2020 | DOI: 10.1111/ene.14412

Short Communication

Background and purpose

Clinical trials (CTs) aimed at vulnerable groups, such as patients with mental disorders, create ethical complexity. The patient information sheet (PIS) should provide all of the information about the CT that is relevant to the subject's decision to participate. After being informed, the subject will decide freely whether to take part in the CT and will read and sign the informed consent form (ICF). The objective was to assess the quality of PISs/ICFs from a hospital neurology service. The assessment was made using validated and reliable checklists of the information included in the PISs/ICFs of CTs with medicinal products.

Methods

The study comprised analyses of compliance with the checklists of 21 PISs and ICFs reviewed/approved during 2016–2017 by a medicinal research ethics committee.

Results

All PISs/ICFs were from multicenter CTs sponsored by pharmaceutical companies in different therapeutic areas, mainly Parkinson’s (52.4%) and Alzheimer’s (38.1%) diseases. The PISs from the neurology service demonstrated good compliance (≥80%) with the checklist, whereas ICFs should be improved. Sponsors omitted some relevant information, such as the study title or that the participant be informed of any information arising from the research that may be relevant to the subject’s health, although this information may be in the PIS.

Conclusions

The PISs/ICFs of CTs of medicinal products that are currently used need improvement. PISs and ICFs should be separate documents for each CT. In particular, the PISs/ICFs should consider the criteria related to the decision of participants, protect their rights and ensure that the information received is complete.

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Authors:
A. G. Jaramillo Vélez, M. Aguas Compaired, M. Granados Plaza, E. L. Mariño and P. Modamio
Article first published online:
20 Jul 2020 | DOI: 10.1111/ene.14420

Review Article

Background and purpose

Advance care planning allows people to plan for their future care needs and can include medical, psychological and social aspects. However, little is known on the use, experience of and attitudes towards advance care planning in patients with parkinsonian disorders, their family carers and healthcare professionals.

Methods

A systematic search of online databases was conducted in April 2019 using a narrative synthesis approach with thematic analysis and tabulation to synthesize the findings.

Results

In all, 507 articles were identified and 27 were included. There were five overarching themes: (i) what is involved in advance care planning discussions, (ii) when and how advance care planning discussions are initiated, (iii) barriers to advance care planning, (iv) the role of healthcare professionals and (v) the role of the family carer. This evidence was used to highlight eight effective components to support optimal advance care planning in parkinsonian disorders: advance care planning discussions should be individualized in content, timing and approach; patients should be invited to discuss advance care planning early and regularly; palliative care services should be introduced early; a skilled professional should deliver advance care planning; support to family carers should be offered in the advance care planning process; healthcare professionals should be educated on parkinsonian disorders and palliative care; advance care planning should be clearly documented and shared with relevant services; and healthcare professionals should be enabled to conduct effective advance care planning.

Conclusions

These components can inform best practice in advance care planning in patients with parkinsonian disorders.

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Authors:
D. Nimmons, L. Hatter, N. Davies, EL Sampson, K. Walters and A. Schrag
Article first published online:
30 Jul 2020 | DOI: 10.1111/ene.14424

Original Article

Background and purpose

Post‐stroke fatigue (PSF) is a common neuropsychiatric affective symptom occurring after stroke. Evidence indicates activated inflammatory pathways are involved in modulating the stroke and fatigue. High‐sensitivity C‐reactive protein (hs‐CRP) is one of the most sensitive indicators of inflammation. Our aim was to estimate the association between plasma hs‐CRP and PSF after acute ischaemic stroke.

Methods

In all, 212 acute ischaemic stroke patients were consecutively recruited within the first 14 days after stroke onset and followed up for 6 months. Plasma hs‐CRP levels were assayed by enzyme linked immunosorbent assay. Fatigue severity was assessed using the Fatigue Scale for Motor and Cognitive Functions. A score ≥ 43 is defined as PSF.

Results

Sixty‐eight stroke patients (32.1%) were diagnosed with PSF at 6 months’ follow‐up. In the patients with PSF, plasma hs‐CRP levels were significantly higher compared with those in non‐PSF patients ( = −8.524,  ≤ 0.001). In multivariate analyses, plasma levels of hs‐CRP were independently associated with PSF at 6 months (odds ratio 3.435, 95% confidence interval 2.222–5.309;  ≤ 0.001) after adjusting other recorded variables. Based on the receiver operating characteristic curve, the optimal cut‐off value of plasma hs‐CRP levels as an indicator for the prediction of PSF was projected to be 0.52 mg/dl, which yielded a sensitivity of 77.9% and a specificity of 74.3%, with the area under the curve 0.794 (95% confidence interval 0.725–0.864;  ≤ 0.001).

Conclusion

Elevated plasma hs‐CRP levels at admission were associated with PSF 6 months after stroke, suggesting that these alterations might predict the development of PSF in stroke patients.

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Authors:
X. Liu, B. Wang, X. Wang, M. Tian, X. Wang and Y. Zhang
Article first published online:
08 Aug 2020 | DOI: 10.1111/ene.14430

Letters To The Editor

Herpes simplex virus encephalitis after temporal lobe resection: an infrequent but treatable complication of epilepsy surgery

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Authors:
J. Martínez‐Poles, R. Toledano, Á. Aledo‐Serrano, K. Korn, R. Coras, I. Blümcke, I. García‐Morales, J. Álvarez‐Linera and A. Gil‐Nagel
Article first published online:
05 Sep 2020 | DOI: 10.1111/ene.14475