cover image European Journal of Neurology

European Journal of Neurology

2016 - Volume 23
Issue 5 | May 2016
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CME Article

Background and purpose

The full spectrum of causes of convexal subarachnoid hemorrhage (cSAH) requires further investigation. Therefore, our objective was to describe the spectrum of clinical and imaging features of patients with non‐traumatic cSAH.

Methods

A retrospective observational study of consecutive patients with non‐traumatic cSAH was performed at a tertiary referral center. The underlying cause of cSAH was characterized and clinical and imaging features that predict a specific etiology were identified. The frequency of future cSAH or intracerebral hemorrhage (ICH) was determined.

Results

In all, 88 patients [median age 64 years (range 25–85)] with non‐traumatic cSAH were identified. The most common causes were reversible cerebral vasoconstriction syndrome (RCVS) (26, 29.5%), cerebral amyloid angiopathy (CAA) (23, 26.1%), indeterminate (14, 15.9%) and endocarditis (9, 10.2%). CAA patients commonly presented at an older age than RCVS patients (75 years versus 51 years, < 0.0001). Thirteen patients (14.7%) had recurrent cSAH, and 12 patients (13.6%) had a subsequent ICH. However, the risk was high amongst those with CAA compared to those caused by RCVS, with recurrent cSAH in 39.1% and subsequent lobar ICH in 43.5% of CAA cases.

Conclusions

Our study demonstrates the clinical diversity of cSAH. Older age, sensorimotor dysfunction and stereotyped spells suggest CAA as the underlying cause. Younger age and thunderclap headache predict RCVS. Yet, various other causes also need to be considered in the differential diagnosis.

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Authors:
J. Graff‐Radford, J. E. Fugate, J. Klaas, K. D. Flemming, R. D. Brown and A. A. Rabinstein
Article first published online:
22 Feb 2016 | DOI: 10.1111/ene.12926

Letter to the Editor

Slowly progressive LGI1 encephalitis with isolated late‐onset cognitive dysfunction: a treatable mimic of Alzheimer's disease

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Authors:
J. Marquetand, M. van Lessen, B. Bender, M. Reimold, G. Elsen, W. Stoecker and M. Synofzik
Article first published online:
15 Apr 2016 | DOI: 10.1111/ene.12939

Original Article

Background and purpose

Non‐motor symptoms (NMSs) are common amongst patients with Parkinson's disease (PD); however, little is known about their influence on the health‐related quality of life (QoL) over a defined follow‐up period. The study was aimed to establish the impact of NMSs on the QoL of patients with PD over a 2‐year follow‐up period.

Method

A total of 227 newly referred PD patients were prospectively recruited between 2013 and 2014. The Non‐Motor Symptoms Scale was used to evaluate NMSs burden whilst QoL was assessed with the Parkinson's Disease Questionnaire‐39 items. Motor disabilities were assessed using the Part III (motor) Unified Parkinson's Disease Rating Scale (UPDRSm).

Results

The mean age was 64.37 (10.18) years; 59.9% were males and a majority (89.0%) were ethnic Chinese. Almost 65% were unemployed and 84.6% had attained no more than secondary level of education. In the univariate analysis, total NMSs burden, age, gender, subsequent visit, Hoehn and Yahr staging, disease duration and UPDRSm score were individually predictive of change in the Parkinson's Disease Questionnaire Summary Index score from baseline to follow‐up visit. However, in the multivariate analysis, total NMSs burden significantly predicted the QoL scores whilst motor scores did not. Specifically, NMS domains 2 (sleep/fatigue), 3 (mood/apathy) and 5 (attention/memory) were most significantly predictive of QoL change.

Conclusion

Unlike motor disabilities, NMSs burden, in particular sleep, mood and attention, have a significant impact on the QoL of PD patients over a 2‐year follow‐up period.

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Authors:
K. M. Prakash, N. V. Nadkarni, W.‐K. Lye, M.‐H. Yong and E.‐K. Tan
Article first published online:
25 Jan 2016 | DOI: 10.1111/ene.12950

Original Article

Background and purpose

Combining different therapies may improve disease control in patients with relapsing−remitting multiple sclerosis (RRMS). This study assessed the efficacy and safety of minocycline added to subcutaneous (sc) interferon (IFN) β‐1a therapy.

Methods

This was a double‐blind, randomized, placebo‐controlled multicentre study. Within 3 months (±1 month) of starting sc IFN β‐1a 44 μg three times weekly, patients with RRMS were randomized to minocycline 100 mg twice daily or placebo, added to sc IFN β‐1a, for 96 weeks. The primary efficacy endpoint was the time to first qualifying relapse. Secondary efficacy endpoints were the annualized relapse rate for qualifying relapses, the number of new/enlarging T2‐weighted lesions and change in brain volume [magnetic resonance imaging (MRI) was performed only in a few selected centres]. In addition, a number of tertiary efficacy endpoints were assessed.

Results

One hundred and forty‐nine patients received minocycline and 155 received placebo; MRI data were available for 23 and 27 patients, respectively. The time to first qualifying relapse did not differ significantly for minocycline versus placebo (hazard ratio 0.85; 95% confidence interval 0.53, 1.35; log‐rank = 0.50; 0.48). There were no statistically significant differences between the two groups on other efficacy endpoints, although some numerical trends in favour of minocycline were observed. No unexpected adverse events were reported, but more patients discontinued because of adverse events with minocycline versus placebo.

Conclusion

Minocycline showed no statistically significant beneficial effect when added to sc IFN β‐1a therapy.

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Authors:
P. S. Sørensen, F. Sellebjerg, J. Lycke, M. Färkkilä, A. Créange, C. G. Lund, M. Schluep, J. L. Frederiksen, E. Stenager, C. Pfleger, E. Garde, E. Kinnunen and K. Marhardt
Article first published online:
05 Feb 2016 | DOI: 10.1111/ene.12953

Original Article

Background and propose

Familial Creutzfeldt−Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the gene. The typical presenting symptoms include cognitive decline, behavioral changes and gait disturbances; however, some patients may have an unusual presentation such as a stroke‐like presentation, alien hand syndrome or visual disturbances. The aim of this paper is to describe uncommon presentations in our series of consecutive patients with E200K fCJD.

Methods

The study group included consecutive fCJD patients followed up as part of a longitudinal prospective study ongoing since 2003 or hospitalized since 2005. The clinical diagnosis of probable CJD was based on accepted diagnostic criteria and supported by typical magnetic resonance imaging, electroencephalographic findings, elevated cerebrospinal fluid tau protein levels and by genetic testing for the E200K mutation. Disease symptoms and signs were retrieved from the medical files.

Results

The study population included 77 patients (42 men) with a mean age of disease onset of 60.6 ± 7.2 years. The most prevalent presenting symptoms were cognitive decline followed by gait impairment and behavioral changes. However, six patients had an unusual presentation including auditory agnosia, monoparesis, stroke‐like presentation, facial nerve palsy, pseudobulbar syndrome and alien hand syndrome.

Conclusions

Our case series illustrates the wide phenotypic variability of the clinical presentation of patients with fCJD and widens the clinical spectrum of the disease. A high level of clinical suspicion may prove useful in obtaining early diagnosis and therefore avoiding costly and inefficient diagnostic and therapeutic strategies.

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Authors:
O. S. Cohen, I. Kimiagar, A. D. Korczyn, Z. Nitsan, S. Appel, C. Hoffmann, H. Rosenmann, E. Kahana and J. Chapman
Article first published online:
25 Jan 2016 | DOI: 10.1111/ene.12955

Original Article

Background and purpose

There is an urgent need for early predictive markers for the course of disease in prodromal α‐synucleinopathies such as idiopathic rapid eye movement (REM) sleep behaviour disorder. Autonomic cardiac/vascular dysfunction is a prominent feature in advanced α‐synucleinopathies, but its diagnostic value as an early neurodegenerative marker remains unclear. The latter may be complicated since synuclein‐mediated neurodegeneration may involve central and peripheral components of the autonomic nervous system.

Methods

The diagnostic value of autonomic symptoms and central and peripheral autonomic markers of blood pressure and heart rate regulation were prospectively evaluated in 20 subjects with idiopathic REM sleep behaviour disorder and 20 age‐matched healthy controls.

Results

Although subjects with REM sleep behaviour disorder showed no clinical autonomic symptoms, blood pressure ( ≤ 0.035) and heart rate response ( ≤ 0.065) were slightly diminished during orthostatic challenge. Autonomic dysregulation was distinctively reflected in lower resting heart rate (all components, ≤ 0.05) and blood pressure variability (low frequency component, ≤ 0.024) indicating peripheral cardiac/vascular denervation. In contrast, baroreflex sensitivity and central cardiac autonomic outflow (sympathovagal balance) were well preserved indicating intact central autonomic regulation. Heart rate variability [very low frequency component, receiver operating characteristic (ROC) area under the curve (AUC) 0.80, ≤ 0.001] and blood pressure variability (low frequency component ROC AUC 0.73, ≤ 0.01) but not baroreflex sensitivity and sympathovagal balance showed an excellent diagnostic accuracy in identifying subjects with REM sleep behaviour disorder and healthy controls.

Conclusions

Cardiac/vascular dysfunction in prodromal α‐synucleinopathy arises from peripheral rather than from central autonomic degeneration. Autonomic indices encoded in heart rate and blood pressure variability are precise functional markers of early synuclein‐mediated neurodegeneration.

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Authors:
C. Dahms, A. Guenther, M. Schwab, T. Schultze, S. Nowack, D. Hoyer, J. Ehrhardt, O. W. Witte, G. Mayer and S. Rupprecht
Article first published online:
04 Feb 2016 | DOI: 10.1111/ene.12957

Original Article

Background and purpose

Based on a tight network of stroke units (SUs) and interventional centres, endovascular treatment of acute major intracranial vessel occlusion has been widely implemented in Austria. Documentation of all patients in the nationwide SU registry has thereby become mandatory.

Methods

Demographic, clinical and interventional characteristics of patients who underwent endovascular treatment for acute ischaemic stroke in 11 Austrian interventional centres between 1 October 2013 and 30 September 2014 were analysed.

Results

In total, 301 patients (50.5% women; median age 70.5 years; median National Institutes of Health Stroke Scale score 17) were identified.193 patients (64.1%) additionally received intravenous thrombolysis. The most frequent vessel occlusion sites were the M1 segment of the middle cerebral artery ( = 161, 53.5%), the intracranial internal carotid artery ( = 60, 19.9%) and the basilar artery ( = 40, 13.3%). Stent retrievers were used in 235 patients (78.1%) and adequate reperfusion (modified Thrombolysis in Cerebral Infarction scores 2b and 3, median onset to reperfusion time 254 min) was achieved in 242 patients (81.4%). Symptomatic intracranial haemorrhage occurred in 7%. 43.8% of patients ( = 132) had good functional outcome (modified Rankin Scale score 0–2) and the mortality rate was 20.9% ( = 63) after 3 months. Compared to the anterior circulation, vertebrobasilar stroke patients had higher mortality. Patients with secondary hospital transportation had better outcomes after 3 months than in‐house treated patients.

Conclusion

Our results document nationwide favourable outcome and safety rates of endovascular stroke treatment comparable to recent randomized trials. The ability to provide such data and the need to further optimize such an approach also underscore the contribution of respective registries.

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Authors:
W. Serles, T. Gattringer, S. Mutzenbach, L. Seyfang, J. Trenkler, M. Killer‐Oberpfalzer, H. Deutschmann, K. Niederkorn, F. Wolf, A. Gruber, K. Hausegger, J. Weber, S. Thurnher, E. Gizewski, J. Willeit, R. Karaic, E. Fertl, C. Našel, M. Brainin, J. Erian, S. Oberndorfer, F. Karnel, W. Grisold, E. Auff, F. Fazekas, H.‐P. Haring and W. Lang
Article first published online:
03 Feb 2016 | DOI: 10.1111/ene.12958

Original Article

Background and purpose

Apathy is the most commonly reported behavioural change in amyotrophic lateral sclerosis (ALS). However, the degree to which it affects prognosis and overlaps with depression in this population is unknown. The present study examined the relationship between level of apathy, mortality and survival time and whether apathy was linked to specific symptom clusters of depression.

Methods

A cohort of 76 consecutive ALS patients attending specialized multidisciplinary clinics were classified according to level of apathy. The effects of clinical factors and apathy on survival time were analysed using univariate and multivariate methods.

Results

The majority of patients with moderate to severe apathy died during the study ( = 0.003) and had a median survival time of 21.7 months, considerably shorter than patients with mild apathy (46.9 months) and no apathy (51.9 months) ( = 0.0001). Apathy remained a significant predictor of survival even after controlling for clinical factors and symptom duration at the time of study entry (hazard ratio 3.8, 95% confidence interval 1.9–7.5, = 0.0001). Depression with demoralization was not associated with level of apathy ( = 0.172) whereas depression with anhedonia was more common in patients with apathy than in those without apathy ( = 0.006).

Conclusions

The presence of severe apathy is an independent, negative prognostic factor in ALS.

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Authors:
J. Caga, M. R. Turner, S. Hsieh, R. M. Ahmed, E. Devenney, E. Ramsey, M. C. Zoing, E. Mioshi and M. C. Kiernan
Article first published online:
29 Jan 2016 | DOI: 10.1111/ene.12959

Original Article

Background and purpose

The role of chitinases and chitinase‐like proteins in multiple sclerosis (MS) is currently unknown; however, cerebrospinal fluid (CSF) levels of chitinase 3‐like 1 (CHI3L1) predict prognosis in early MS. Whether this applies to other chitinases and chitinase‐like proteins is yet to be established. Our objective was to investigate the potential of chitinase 3‐like 2 (CHI3L2) and chitotriosidase as prognostic biomarkers in optic neuritis (ON) as the first demyelinating episode and to evaluate the ability of CHI3L2 to predict long‐term MS risk and disability.

Methods

In a prospective cohort of 73 patients with ON as a first demyelinating episode and 26 age‐matched healthy controls levels of CHI3L2 and chitotriosidase in CSF were explored by enzyme‐linked immunosorbent assay. Associations with magnetic resonance imaging white matter lesions, CSF oligoclonal bands, immunoglobulin G index and leukocyte count were investigated. Long‐term MS risk and disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite components) were examined in a retrospective cohort of 78 patients with ON as the first demyelinating episode (mean follow‐up 14 years). The predictive ability of CHI3L2 was compared with CHI3L1.

Results

Cerebrospinal fluid levels of CHI3L2 and chitotriosidase were significantly elevated in patients with ON and were associated with MS risk measures. CHI3L2 levels predicted MS development after ON (hazard ratio 1.95, = 0.00039, Cox regression) and cognitive impairment by the Paced Auditory Serial Addition Test ( = 0.0357, linear regression) at follow‐up. In a multivariate analysis of MS risk, CHI3L2 performed better than CHI3L1.

Conclusions

CHI3L2 and chitotriosidase are promising biomarkers in patients with a first demyelinating episode. Our findings thus support a role for these proteins as biomarkers in early MS.

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Authors:
M. Møllgaard, M. Degn, F. Sellebjerg, J. L. Frederiksen and S. Modvig
Article first published online:
12 Feb 2016 | DOI: 10.1111/ene.12960

Original Article

Background and Purpose

Acute hydrocephalus is an early and common complication of aneurysmal subarachnoid hemorrhage (SAH). However, considerably fewer patients develop chronic hydrocephalus requiring shunt placement. Our aim was to develop a risk score for early identification of patients with shunt dependency after SAH.

Methods

Two hundred and forty‐two SAH individuals who were treated in our institution between January 2008 and December 2013 and survived the initial impact were retrospectively analyzed. Clinical parameters within 72 h after the ictus were correlated with shunt dependency. Independent predictors were summarized into a new risk score which was validated in a subsequent SAH cohort treated between January and December 2014.

Results

Seventy‐five patients (31%) underwent shunt placement. Of 23 evaluated variables, only the following five showed independent associations with shunt dependency and were subsequently used to establish the Chronic Hydrocephalus Ensuing from SAH Score (CHESS, 0–8 points): Hunt and Hess grade ≥IV (1 point), location of the ruptured aneurysm in the posterior circulation (1 point), acute hydrocephalus (4 points), the presence of intraventricular hemorrhage (1 point) and early cerebral infarction on follow‐up computed tomography scan (1 point). The CHESS showed strong correlation with shunt dependency ( = 0.0007) and could be successfully validated in both internal SAH cohorts tested. Patients scoring ≥6 CHESS points had significantly higher risk of shunt dependency ( < 0.0001) than other patients.

Conclusion

The CHESS may become a valuable diagnostic tool for early estimation of shunt dependency after SAH. Further evaluation and external validation will be required in prospective studies.

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Authors:
R. Jabbarli, A.‐M. Bohrer, D. Pierscianek, D. Müller, K. H. Wrede, P. Dammann, N. El Hindy, N. Özkan, U. Sure and O. Müller
Article first published online:
26 Feb 2016 | DOI: 10.1111/ene.12962

Original Article

Background and purpose

Progressive multifocal leucoencephalopathy‐associated immune reconstitution inflammatory syndrome (PML‐IRIS) is the paradoxical worsening or unmasking of preexisting infection with JC virus attributable to a rapid recovery of the immune system after highly active antiretroviral therapy (HAART) initiation. We investigated the incidence and factors associated with PML‐IRIS in HIV‐infected patients. We also studied its influence on mortality of PML and the effect of corticosteroid therapy.

Methods

Single‐center retrospective analysis of HIV‐infected patients diagnosed with PML from 1996 to 2012 who received HAART.

Results

Among 59 PML patients treated with HAART, 18 (30.51%) developed PML‐IRIS (five delayed PML‐IRIS, 13 simultaneous PML‐IRIS). Patients who developed IRIS had lower CD4 counts prior to treatment (102 vs. 68.5, < 0.05) and experienced a greater decline in HIV‐RNA levels in response to HAART (2.5log vs. 2.95log, < 0.05). Gadolinium enhancement on MRI was observed in 31.25% of PML‐IRIS cases versus 2.56% of PML non‐IRIS ( < 0.01). Survival rates were higher in patients with PML‐IRIS compared to those with PML non‐IRIS. Eight patients received corticosteroids, five of which had a good outcome. Patients who died were severely ill when treatment was initiated whereas patients who survived were treated before major neurological deterioration occurred.

Conclusions

Nearly one‐third of HIV‐infected patients with PML develop IRIS after initiating HAART. Patients severely immunocompromised who experience a rapid virological response to HAART have a higher risk for PML‐IRIS. There was a trend for lower mortality in patients with IRIS. Early treatment with corticosteroids might be useful.

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Authors:
S. Sainz‐de‐la‐Maza, J. L. Casado, M. J. Pérez‐Elías, A. Moreno, C. Quereda, S. Moreno and I. Corral
Article first published online:
23 Feb 2016 | DOI: 10.1111/ene.12963

Original Article

Background and purpose

Acute stroke patients with severely impaired oral intake are at risk of malnutrition and dehydration. Rapid identification of these patients is necessary to establish early enteral tube feeding. Whether specific lesion location predicts early tube dependency was analysed, and the neural correlates of impaired oral intake after hemispheric ischaemic stroke were assessed.

Methods

Tube dependency and functional oral intake were evaluated with a standardized comprehensive swallowing assessment within the first 48 h after magnetic resonance imaging proven first‐time acute supratentorial ischaemic stroke. Voxel‐based lesion symptom mapping (VLSM) was performed to compare lesion location between tube‐dependent patients versus patients without tube feeding and impaired versus unimpaired oral intake.

Results

Out of 119 included patients 43 (36%) had impaired oral intake and 12 (10%) were tube dependent. Both tube dependency and impaired oral intake were significantly associated with a higher National Institutes of Health Stroke Scale score and larger infarct volume and these patients had worse clinical outcome at discharge. Clinical characteristics did not differ between left and right hemispheric strokes. In the VLSM analysis, mildly impaired oral intake correlated with lesions of the Rolandic operculum, the insular cortex, the superior corona radiata and to a lesser extent of the putamen, the external capsule and the superior longitudinal fascicle. Tube dependency was significantly associated with affection of the anterior insular cortex.

Conclusions

Mild impairment of oral intake correlates with damage to a widespread operculo‐insular swallowing network. However, specific lesions of the anterior insula lead to severe impairment and tube dependency and clinicians might consider early enteral tube feeding in these patients.

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Authors:
M. Galovic, N. Leisi, M. Müller, J. Weber, B. Tettenborn, F. Brugger, E. Abela, B. Weder and G. Kägi
Article first published online:
22 Feb 2016 | DOI: 10.1111/ene.12964

Original Article

Background

Tremor in dystonia has been described as a postural or kinetic abnormality. In recent series, however, patients with idiopathic adult‐onset dystonia also displayed rest tremor.

Methods

The frequency and distribution of rest tremor were studied in a cohort of 173 consecutive Italian patients affected by various forms of idiopathic adult‐onset dystonia attending our movement disorder clinic over 8 months.

Results

Examination revealed tremor in 59/173 patients (34%): 12 patients had head tremor, 34 patients had arm tremor, whilst 13 patients presented tremor in both sites. Head tremor was postural in all patients, whereas arm tremor was postural/kinetic in 28 patients, only at rest in one and both postural/kinetic and at rest in 18 patients. Patients with tremor were more likely to have segmental/multifocal dystonia. Patients who had rest tremor (either alone or associated with action tremor) had a higher age at dystonia onset and a greater frequency of dystonic arm involvement than patients with action tremor alone or without tremor.

Conclusions

Both action and rest tremor are part of the tremor spectrum of adult‐onset dystonia and are more frequently encountered in segmental/multifocal dystonia. The higher age at dystonia onset and the greater frequency of arm dystonia in patients with rest tremor may have pathophysiological implications and may account, at least in part, for the previous lack of identification of rest tremor as one possible type of tremor present in dystonia.

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Authors:
A. F. Gigante, A. Berardelli and G. Defazio
Article first published online:
24 Feb 2016 | DOI: 10.1111/ene.12966

Original Article

Background and purpose

Young ischaemic stroke patients often suffer from cognitive impairment after stroke. However, the risk factors of cognitive impairment are still unclear. This study examined the impact of vascular risk factors (VRFs) on cognitive impairment in first‐ever young ischaemic stroke patients.

Methods

Subjects were divided into low (0–1 VRF, = 27), medium (2–3 VRFs, = 45) and high‐risk (≥4 VRFs, = 12) groups according to their number of VRFs. The following VRFs were collected: hypertension, diabetes mellitus, dyslipidaemia, atrial fibrillation, obesity, smoking, excess alcohol consumption, coronary heart disease and hyperhomocysteinaemia. A battery of cognitive assessments was executed 2 weeks after stroke. Differences of cognitive performances between groups were compared. The correlation between VRFs and cognitive function was investigated with an emphasis on discovering the main VRFs.

Results

Eighty‐four patients were enrolled in this study eventually. Compared with the low‐risk group, the high‐risk group had significantly worse performance in most of the cognitive domains. VRFs had a correlation with general cognition, executive function, attention and verbal fluency. After adjusting the covariates, VRFs showed a linear correlation with global cognitive function ( = 0.640, = 0.000), verbal fluency ( = 0.372, = 0.000), delayed memory ( = 0.327, = 0.002), visual attention ( = 0.290, = 0.007) and executive function ( = 0.266, = 0.015). Amongst all the VRFs, hypertension, hyperlipidaemia, smoking and hyperhomocysteinaemia were the main influencing VRFs.

Conclusion

Vascular risk factors aggravate cognitive impairment after young ischaemic stroke. Effective management of VRFs in young adults is urgent and this may reduce the cognitive impairment.

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Authors:
D. Lu, S. Ren, J. Zhang and D. Sun
Article first published online:
25 Feb 2016 | DOI: 10.1111/ene.12967

Original Article

Background and purpose

The association of serum uric acid, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and longitudinal cognitive decline was evaluated using the AD Neuroimaging Initiative database.

Methods

In 271 healthy subjects, 596 mild cognitive impairment patients and 197 AD patients, serum uric acid and CSF AD biomarkers were measured at baseline, and Mini‐Mental State Examination and AD Assessment Scale − Cognitive Subscale (ADAS‐cog) were assessed serially (mean duration, 2.9 years). The effect of uric acid on longitudinal cognitive decline was evaluated using linear mixed effect models for Mini‐Mental State Examination and ADAS‐cog scores in female and male subjects separately, with possible confounders controlled (model 1). To determine the effects of uric acid independent of CSF biomarker (Aβ or tau) and to test whether the detrimental effects of CSF biomarker differ according to uric acid, CSF biomarker and its interaction with uric acid were further included in model 1 (model 2).

Results

Higher levels of uric acid were associated with slower cognitive decline, particularly in the mild cognitive impairment and dementia subgroups, and more prominently in female subjects. Model 2 with CSF Aβ showed that higher levels of uric acid were associated with a slower cognitive decline and alleviated the detrimental effect of Aβ on cognitive decline. Model 2 with CSF tau showed that higher levels of uric acid alleviated the detrimental effect of tau on cognitive decline in female subjects but not in male subjects.

Conclusion

Higher levels of uric acid had protective effects on longitudinal cognitive decline independent of and interactively with CSF AD biomarkers.

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Authors:
B. S. Ye, W. W. Lee, J. H. Ham, J. J. Lee, P. H. Lee and Y. H. Sohn
Article first published online:
24 Feb 2016 | DOI: 10.1111/ene.12969

Original Article

Background and purpose

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immunomediated condition affecting the peripheral nervous system where probably macrophages are the primary effector cells for demyelination. Reactive oxygen species (ROS), catalyzed by the NOX family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzymes, can induce peroxidation and are potentially injurious to myelin. Our aim was to assess the activity of NOX2, an isoform of NOX, in a series of CIDP patients and to analyze the effect of intravenous immunoglobulin (IVIg) on NOX2.

Methods

Thirty CIDP patients treated with IVIg and 30 control subjects were enrolled. To evaluate NOX2 activity, neutrophil and monocyte oxidative burst was measured directly in fresh whole blood using the Phagoburst™ assay, a fluorescence‐activated cell sorting method. The mean fluorescence intensity, emitted in response to different stimuli, leads to the production of ROS and corresponds to the percentage of oxidizing cells and their enzymatic activity.

Results

Mean fluorescence intensity values for granulocyte and monocyte burst in patients (mean 633.3, SD 191; mean 111.8, SD 28.5) were different from those measured in healthy controls (granulocytes, mean 436.6, SD 137.0, = 0.0003; monocytes, mean 78.2, SD 17.3, = 0.000001). Moreover, IVIg administration increased both granulocyte ( = 0.005) and monocyte ( = 0.0009) burst.

Conclusion

Our findings demonstrate that oxidative burst is significantly increased in CIDP patients and that treatment with IVIg enhances oxidative values, thus representing a possible IVIg therapeutic effect linked to a regulatory effect of ROS. Based on this, the development of treatments targeting the specific activation of NOX may be beneficial in autoimmune disorders.

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Authors:
G. Marrali, P. Salamone, F. Casale, G. Fuda, P. Cugnasco, C. Caorsi, A. Amoroso, A. Calvo, L. Lopiano, D. Cocito and A. Chiò
Article first published online:
29 Feb 2016 | DOI: 10.1111/ene.12971

Letter to the Editor

Toe pseudoathetosis in vitamin B12 deficiency

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Authors:
G. Sciacca, F. Le Pira, G. Mostile, A. Nicoletti and M. Zappia
Article first published online:
15 Apr 2016 | DOI: 10.1111/ene.12972

Original Article

Background and purpose

Trace elements (TEs) may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and volcanic degassing is the major natural source of TEs. Mount Etna, in the province of Catania, is the largest active volcano in Europe. Our aim was to assess the incidence of ALS in the province of Catania during 2005–2010 and its spatial distribution with respect to volcanic gas deposition.

Methods

Cases from all neurological centres of the province of Catania and of the boundary provinces were retrospectively collected. Patients who had onset during 2005–2010 and fulfilled the El Escorial revised diagnostic criteria were included. The incidence of ALS was estimated for the entire province and separately for the population living on the eastern and western flank of Mount Etna, respectively, the most and least exposed areas to volcanogenic TEs, considered as a possible risk factor for ALS.

Results

One hundred and twenty‐six (57 men) ALS patients were enrolled. The mean annual crude incidence rate was 2.0/100 000 person‐years (95% confidence interval 1.7–2.4). A higher incidence rate was found in the population living on the eastern flank compared to the western flank (2.4/100 000 and 0.9/100 000 respectively) with a relative risk of 2.75 (95% confidence interval 1.64–4.89; < 0.001).

Conclusions

The incidence of ALS in the province of Catania is close to those reported worldwide. The incidence was higher amongst the population living on the eastern flank of Mount Etna, which could be interpreted as a possible role of volcanogenic TEs. Further research on TEs and genetic factors is necessary to support this assumption.

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Authors:
A. Nicoletti, R. Vasta, V. Venti, G. Mostile, S. Lo Fermo, F. Patti, R. Scillieri, D. De Cicco, P. Volanti, R. Marziolo, D. Maimone, M. Fiore, M. Ferrante and M. Zappia
Article first published online:
29 Feb 2016 | DOI: 10.1111/ene.12973

Original Article

Background and purpose

Deficits in cognition have been reported in Parkinson's disease (PD) already in the early and even in the pre‐motor stages. Whilst substantia nigra hyperechogenicity measured by transcranial B‐mode sonography (TCS) represents a strong PD marker and is associated with an increased risk for PD in still healthy individuals, its association with cognitive performance in prodromal PD stages is not well established.

Methods

Two different cohorts of healthy elderly individuals were assessed by TCS and two different neuropsychological test batteries covering executive functions, verbal memory, language, visuo‐constructional function and attention. Cognitive performance was compared between individuals with hyperechogenicity (SN+) and without hyperechogenicity (SN−).

Results

In both cohorts, SN+ individuals performed significantly worse than the SN− group in tests assessing verbal memory (word list delayed recall = 0.05, logical memory II < 0.017). Significant differences in Mini‐Mental State Examination score (cohort 1, = 0.02) and executive function tests (cohort 2, Stroop Color−Word Reading, = 0.004) could only be shown in one of the two cohorts. No between‐group effects were found in other cognitive tests and domains.

Conclusions

These results indicate that individuals with the PD risk marker SN+ perform worse in verbal memory compared to SN− independent of the assessment battery. Memory performance should be assessed in detail in individuals at risk for PD.

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Authors:
R. Yilmaz, S. Behnke, I. Liepelt‐Scarfone, B. Roeben, C. Pausch, A. Runkel, S. Heinzel, R. Niebler, U. Suenkel, G. W. Eschweiler, W. Maetzler and D. Berg
Article first published online:
24 Feb 2016 | DOI: 10.1111/ene.12974

Original Article

Background and purpose

Preventing behavioural crises appears to be crucial to promote quality of life of the patient−caregiver dyad, to reduce inappropriate hospitalizations and to delay institutionalization. The Alzheimer Cooperative Valuation in Europe promotes mobile care to prevent patients from severe behavioural and psychological symptoms in dementia. This study assessed the potential efficacy of a mobile team for Alzheimer's disease on hospitalization sparing and behavioural disorder reduction.

Methods

A cohort study was set up from 1 January 2012 to 31 December 2013 by the Clinical and Research Memory Centre of Lyon (France). It included patients with behavioural and psychological symptoms living at home or in a nursing home. An interview explored the alternative patient pathways used by general practitioners (GPs) if the mobile team had not existed (hospitalization sparing). The Neuropsychiatry Inventory score was assessed at inclusion and 30 days later. The sample included 424 consecutive patients with Alzheimer's disease or related disorders and behavioural disorders at any cognitive and functional stage of the disease, taken in charge by the mobile team.

Results

Amongst the 424 patients (84.0 ± 7.2 years), 220 (51.9%) hospitalizations were considered by their GPs and 181 (82.3%) were avoided. The Neuropsychiatric Inventory score declined after mobile team intervention (45.8–29.9, < 0.001). Sleep and appetite disorders, endangered situation and caregiver burnout were associated with higher risk of hospitalization at 30 days.

Conclusions

The mobile team for Alzheimer's disease allows a high proportion of hospitalizations related to behavioural disorders to be avoided and may help to reduce behavioural disorders.

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Authors:
P. Krolak‐Salmon, C. Roubaud, H. Finne‐Soveri, N. Riolacci‐Dhoyen, G. Richard, I. Rouch, A. Leperre‐Desplanques and V. Dauphinot
Article first published online:
06 Mar 2016 | DOI: 10.1111/ene.12975

Letter to the Editor

A Japanese CADASIL kindred with a novel two‐base mutation

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Authors:
S. Suda, S. Okubo, M. Ueda, K. Sowa, A. Abe, J. Aoki, K. Muraga, K. Suzuki, Y. Sakamoto, I. Mizuta, T. Mizuno and K. Kimura
Article first published online:
15 Apr 2016 | DOI: 10.1111/ene.12977

Letter to the Editor

The optimal approach to detect atrial fibrillation in potential cardioembolic stroke

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Authors:
Y. Kim and S.‐H. Lee
Article first published online:
15 Apr 2016 | DOI: 10.1111/ene.12980

Review Article

Abstract

Genetic screens steadily reveal more loci that show robust associations to complex human diseases, including multiple sclerosis (MS). Although some of the identified genetic variants are easily interpreted into a biological function, most of the genetic associations are frequently challenging to interpret. Underlying these difficulties is the fact that chip‐based assays typically detect single nucleotide polymorphisms (SNPs) representative of a stretch of DNA containing many genomic variants in linkage disequilibrium. Furthermore, a large proportion of the SNPs with strongest association to MS are located in regions of the DNA that do not directly code for proteins. Here we discuss challenges faced by MS researchers to follow up the large‐scale genetic screens that have been published over the past years in search of functional consequences of the identified MS‐associated SNPs. We discuss experimental design, tools and methods that may provide the much‐needed biological insights in both disease etiology and disease manifestations.

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Authors:
S. D. Bos, T. Berge, E. G. Celius and H. F. Harbo
Article first published online:
07 Mar 2016 | DOI: 10.1111/ene.12981

Editorial

Abstract

Click to view the accompanying paper in this issue.

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Authors:
G. Deuschl
Article first published online:
14 Mar 2016 | DOI: 10.1111/ene.12985

Calendar

Calendar

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Article first published online:
15 Apr 2016 | DOI: 10.1111/ene.13032