cover image European Journal of Neurology

European Journal of Neurology

2017 - Volume 24
Issue 2 | February 2017

Original Article

Background and purpose

Our aim was to determine the prognostic value of urine and blood heteroplasmy in patients with the m.3243A>G mutation.

Methods

Adults with the m.3243A>G mutation referred to our institution between January 2000 and May 2014 were retrospectively included. The relationship between their baseline clinical characteristics, their mutation load in urine and blood, and major adverse events (MAEs) during follow‐up, defined as medical complications requiring a hospitalization or complicated by death, was studied.

Results

Of the 43 patients (age 45.6 ± 13.3 years) included in the study, 36 patients were symptomatic, including nine with evidence of focal brain involvement, and seven were asymptomatic. Over a 5.5 ± 4.0 year mean follow‐up duration, 14 patients (33%) developed MAEs. Patients with MAEs had a higher mutation load than others in urine (60.1% ± 13.8% vs. 40.6% ± 26.2%, = 0.01) and in blood (26.9% ± 18.4% vs. 16.0% ± 12.1%, = 0.03). Optimal cutoff values for the prediction of MAEs were 45% for urine and 35% for blood. In multivariate analysis, mutation load in urine ≥45% [odds ratio 25.3; 95% confidence interval (CI) 1.1–567.8; = 0.04], left ventricular hypertrophy (odds ratio 16.7; 95% CI 1.3– 222.5; = 0.03) and seizures (odds ratio 48.3; 95% CI 2.5–933; = 0.01) were associated with MAEs.

Conclusions

Patients with the m.3243A>G mutation are at high risk of MAEs, which can be independently predicted by mutation load in urine ≥45%, a personal history of seizures, and left ventricular hypertrophy.

Original Article

Background and purpose

Proteinuria and estimated glomerular filtration rate (eGFR) are indicators of renal function. Whether proteinuria better predicts outcome than eGFR in stroke patients treated with intravenous thrombolysis (IVT) remains to be determined.

Methods

In this explorative multicenter IVT register based study, the presence of urine dipstick proteinuria (yes/no), reduced eGFR (<60 ml/min/1.73 m) and the coexistence of both with regard to (i) poor 3‐month outcome (modified Rankin Scale score 3–6), (ii) death within 3 months and (iii) symptomatic intracranial hemorrhage (ECASS‐II criteria) were compared. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals were calculated.

Results

Amongst 3398 patients, 881 (26.1%) had proteinuria and 623 (18.3%) reduced eGFR. Proteinuria [OR 1.65 (1.37–2.00) and OR 1.52 (1.24–1.88)] and reduced eGFR [OR 1.26 (1.01–1.57) and OR 1.34 (1.06–1.69)] were independently associated with poor functional outcome and death, respectively. After adding both renal markers to the models, proteinuria [OR 1.59 (1.31–1.93)] still predicted poor outcome whilst reduced eGFR [OR 1.20 (0.96–1.50)] did not. Proteinuria was associated with symptomatic intracranial hemorrhage [OR 1.54 (1.09–2.17)] but not reduced eGFR [OR 0.96 (0.63–1.62)]. In 234 (6.9%) patients, proteinuria and reduced eGFR were coexistent. Such patients were at the highest risk of poor outcome [OR 2.16 (1.54–3.03)] and death [OR 2.55 (1.69–3.84)].

Conclusion

Proteinuria and reduced eGFR were each independently associated with poor outcome and death but the statistically strongest association appeared for proteinuria. Patients with coexistent proteinuria and reduced eGFR were at the highest risk of poor outcome and death.

CME Article

Background and purpose

The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS.

Methods

We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified.

Results

Mean treatment duration was 60.4 ± 39.3 months, and mean follow‐up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal [0.09, 95% confidence interval (CI), 0.05–0.17 and 0.07, 95% CI, 0.05–0.11, respectively], relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09–0.16). Sixteen patients experienced a relapse and 19 had a gadolinium‐positive MRI scan without relapse during follow‐up. A gadolinium‐positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of <6 were positively associated with relapse and/or MRI activity after discontinuation ( = 0.0004 and = 0.03, respectively).

Conclusion

In this retrospective study, including a limited number of patients with SPMS, the annualized relapse rate remained stable after treatment withdrawal, relative to before treatment withdrawal. Further prospective studies are needed to confirm this result and provide evidence‐based guidelines for daily practice.

Original Article

Background and purpose

A single, oral dose of 3 mg/day tacrolimus, approved for myasthenia gravis (MG) treatment in Japan, was shown to reduce steroid dose and anti‐acetylcholine receptor (AChR) antibody titers as well as to improve MG symptoms. However, no studies have investigated the association between tacrolimus concentration and its clinical efficacy in MG. In this study, we aimed to determine the optimal tacrolimus concentration for MG treatment.

Methods

The trough tacrolimus concentration in 51 patients with MG (positive for anti‐AChR antibody, = 48; negative for anti‐AChR and anti‐muscle‐specific tyrosine kinase antibodies, = 3) who received 3 mg/day tacrolimus for more than 1 year was measured using a chemiluminescent enzyme immunoassay. The clinical characteristics of patients with MG as well as the dose of prednisolone used before and after tacrolimus treatment were evaluated retrospectively.

Results

The median trough tacrolimus concentration was 5.4 (range, 2.9–7.6) ng/mL, which was correlated with ‘minimal manifestation or better status’ ( = 0.0190, = 0.3273) and the reduction in anti‐AChR antibody 1 year after tacrolimus initiation ( = 0.0170, = 0.3465). When the cut‐off value for tacrolimus was defined as 4.8 ng/mL using a receiver operating characteristic curve, patients with adequate tacrolimus concentration (≥4.8 ng/mL) showed more reduction in anti‐AChR antibody titers and more improvement in MG‐related activities in daily life scores. More patients with adequate tacrolimus concentration achieved ‘minimal manifestation or better status’ compared with those with low tacrolimus concentration.

Conclusions

An adequate tacrolimus concentration is required for better MG prognosis.

Original Article

Background and purpose

Small vessel disease (SVD) and Alzheimer's disease (AD) are two common causes of cognitive impairment and dementia, traditionally considered as distinct processes. The relationship between radiological features suggestive of AD and SVD was explored, and the association of each of these features with cognitive status at 1 year was investigated in patients with stroke or transient ischaemic attack.

Methods

Anonymized data were accessed from the Virtual International Stroke Trials Archive (VISTA). Medial temporal lobe atrophy (MTA; a marker of AD) and markers of SVD were rated using validated ordinal visual scales. Cognitive status was evaluated with the Mini Mental State Examination (MMSE) 1 year after the index stroke. Logistic regression models were used to investigate independent associations between (i) baseline SVD features and MTA and (ii) all baseline neuroimaging features and cognitive status 1 year post‐stroke.

Results

In all, 234 patients were included, mean (±SD) age 65.7 ± 13.1 years, 145 (62%) male. Moderate to severe MTA was present in 104 (44%) patients. SVD features were independently associated with MTA ( < 0.001). After adjusting for age, sex, disability after stroke, hypertension and diabetes mellitus, MTA was the only radiological feature independently associated with cognitive impairment, defined using thresholds of MMSE ≤ 26 (odds ratio 1.94; 95% confidence interval 1.28–2.94) and MMSE ≤ 23 (odds ratio 2.31; 95% confidence interval 1.48–3.62).

Conclusion

In patients with ischaemic cerebrovascular disease, SVD features are associated with MTA, which is a common finding in stroke survivors. SVD and AD type neurodegeneration coexist, but the AD marker MTA, rather than SVD markers, is associated with post‐stroke cognitive impairment.

Original Article

Background and purpose

Large baseline hematoma volume (HV) and hematoma growth (HG) are related to poor outcome in patients with intracerebral hemorrhage (ICH). It remains controversial whether prior antiplatelet therapy (APT) influences baseline HV and HG, and the outcome following ICH.

Methods

We collected clinical and radiological data from a prospective cohort of patients diagnosed with ICH within 24 h of symptom onset. Prior APT was ascertained from the clinical history. In patients for whom a follow‐up computed tomography (CT) was available within 72 h, we assessed HG, defined as an increase of ≥33% and/or ≥12.5 mL in the HV. We assessed mortality and functional outcome during follow‐up with the Rankin scale. To perform a meta‐analysis, we searched for published studies reporting HG according to previous APT and pooled the available data.

Results

We included 223 patients (mean age 72.5 ± 13 years). Previous APT was reported in 74 patients (33.2%). The linear regression model showed that prior APT was independently associated with larger baseline HV. HG was detected in 49 of 130 patients (37.7%) and no differences related to prior APT were observed among our cohort. However, after pooling the data of seven studies in the meta‐analysis, prior APT showed an increase in HG frequency (odds ratio, 1.85; 95% confidence interval, 1.37–2.5). Patients who received APT presented with worse outcome during follow‐up, although this difference was not significant ( = 0.06).

Conclusions

In the current study, prior APT was related to larger baseline HV in patients with ICH. Data from the meta‐analysis also showed a higher risk of HG associated with APT.

Original Article

Background and purpose

Dravet syndrome (DS) is a severe, drug‐resistant epilepsy. Fenfluramine has been reported to have a long‐term clinically meaningful anticonvulsive effect in patients with DS.

Methods

This prospective, open‐label study assessed the safety and effectiveness of low‐dose fenfluramine in a new cohort of patients with DS. Following a 3‐month baseline period, fenfluramine was added to each patient's current antiepileptic drug regimen at a dose of 0.25–1.0 mg/kg/day (max. 20 mg/day). The incidence of major motor seizures (tonic, clonic, tonic–clonic, atonic and myoclonic seizures lasting >30 s) in both the baseline and treatment periods was assessed via a seizure diary. Periodic echocardiographic examinations during the treatment period were used to assess cardiovascular safety.

Results

Nine patients (aged 1.2–29.8 years) enrolled in the study and were treated with fenfluramine for a median duration of 1.5 (range, 0.3–5.1) years. Median frequency of major motor seizures was 15.0/month in the baseline period. All patients demonstrated a reduction in seizure frequency during the treatment period with a median reduction of 75% (range, 28–100%). Seven patients (78%) experienced a ≥50% reduction in major motor seizure frequency. The most common adverse events were somnolence ( = 5) and anorexia ( = 4). No evidence of cardiac valvulopathy or pulmonary hypertension was observed.

Conclusions

The effectiveness and safety of low‐dose fenfluramine as an add‐on therapy for DS in this new prospective cohort supports previous findings.

Original Article

Background and purpose

Clinically isolated syndrome (CIS) is a first demyelinating event of the central nervous system and can be a single event. After CIS, a chronic disease course with ongoing inflammation and relapses might occur, resulting in a diagnosis of multiple sclerosis (MS). As yet, there has been no prospective exploration of whether children and adults with CIS have the same disease course.

Methods

Patients with CIS, whose age ranged from 1 to 50 years, were prospectively followed. We divided the patients into three different age groups, i.e. 1–10, 11–17 and 18–50 years old. Demographic data, disease course, time to MS diagnosis and annualized relapse rates (ARRs) were compared among these groups.

Results

We included 383 patients with CIS, of whom 218 (56.9%) were diagnosed with MS. Children of between 11 and 17 years old had the highest rate of MS conversion (83.5% vs. 50.0% in the other age groups together, < 0.01) and the shortest time to MS diagnosis [median time 2.6 months (interquartile range, 0.6–6.0) vs. 8.2 months (interquartile range, 1.9–28.2) in the other age groups together, < 0.01). ARRs corrected for follow‐up were higher in children of <18 years old than in adults of ≥18 years old with MS (mean ARR, 0.65 vs. 0.43, < 0.01).

Conclusion

Children with CIS tend to have a more inflammatory disease course appearing from higher ARRs in all children and the highest rate of MS conversion in 11–17‐year‐old children. This supports early initiation of disease‐modifying therapy in children, perhaps even at the first event in children at high risk for MS in line with clinical practice in adults.

Original Article

Background and purpose

The effect of the triglyceride (TG) to high‐density lipoprotein cholesterol (HDL‐C) ratio (TG/HDL‐C) on clinical outcomes of acute ischaemic stroke (AIS) patients is unclear. This study sought to determine whether the TG/HDL‐C ratio in AIS patients is associated with worse outcomes at 3 months.

Methods

Acute ischaemic stroke patients who were admitted from 2011 to 2014 were enrolled in this study. TG, total cholesterol (TC), HDL‐C and low‐density lipoprotein cholesterol (LDL‐C) were collected on admission. Three end‐points were defined according to the modified Rankin scale (mRS) score at 3 months after symptom onset (excellent outcome, mRS 0–1; good outcome, mRS 0–2; and death, mRS 6).

Results

In all, 1006 patients were included (median age 68.5 years; 58.2% male). Higher TG, non‐HDL‐C and TG/HDL‐C were strongly associated with the three end‐points after adjustments: excellent [odds ratio (OR) = 1.39, OR 1.89 and OR 2.34, respectively] and good (OR 1.48, OR 2.90 and OR 4.12) outcomes, and death (OR 0.59, OR 0.29 and OR 0.26). According to receiver operating characteristic (ROC) analysis, the best discriminating factor was a TG/HDL‐C ≥ 0.87 for excellent outcomes [area under the ROC curve (AUC) 0.596; sensitivity 73.3%; specificity 42.7%] and non‐death (AUC 0.674; sensitivity 67.8%; specificity 60.6%) as well as a TG/HDL‐C ≥ 1.01 for a good outcome (AUC 0.652; sensitivity 61.6%; specificity 63.2%). Patients with a TG/HDL‐C < 0.87 had a 2.94‐fold increased risk of death (95% confidence interval 1.89–4.55) compared with patients with a TG/HDL‐C ≥ 0.87.

Conclusions

A lower TG/HDL‐C was independently associated with death and worse outcome at 3 months in AIS.

Original Article

Background and purpose

Paroxysmal atrial fibrillation (PAF) is often asymptomatic and increases the risk of ischaemic stroke. Detection of PAF is challenging but crucial because a change of treatment decreases the risk of ischaemic stroke. Post‐stroke investigations recommend at least 24‐h continuous cardiac rhythm monitoring. Extended monitoring detects more PAF but is limited by costs due to manual analysis. Interpretive software might be a reasonable screening tool. The aim was to validate the performance and utility of Pathfinder SL software compared to manual analysis.

Methods

In all, 135 ischaemic stroke patients with no prior history of PAF or atrial fibrillation and who had done a 7‐day continuous electrocardiogram monitoring (Holter) were included. Manual analysis was compared with Pathfinder SL software including a systematic control of registered events.

Results

Seventeen (12.6%) patients were diagnosed with PAF (atrial fibrillation > 30 s). Pathfinder SL software including a systematic control of events registered 16 (94.1%) patients with PAF. Manually 15 (88.2%) patients were detected with PAF. Pathfinder SL had a negative predictive value of 99% and sensitivity of 94%.

Conclusions

Pathfinder SL software including a systematic evaluation of events is an acceptable alternative compared to manual analysis in PAF detection following ischaemic stroke. It is less time consuming and therefore a reliable, cheaper alternative compared to manual analysis.

Original Article

Background and purpose

While impaired cognitive performance is common in multiple sclerosis (MS), it has been largely underdiagnosed. Here a magnetic resonance imaging (MRI) screening algorithm is proposed to identify patients at highest risk of cognitive impairment. The objective was to examine whether assessment of lesion burden together with whole brain atrophy on MRI improves our ability to identify cognitively impaired MS patients.

Methods

Of the 1253 patients enrolled in the study, 1052 patients with all cognitive, volumetric MRI and clinical data available were included in the analysis. Brain MRI and neuropsychological assessment with the Brief International Cognitive Assessment for Multiple Sclerosis were performed. Multivariable logistic regression and individual prediction analysis were used to investigate the associations between MRI markers and cognitive impairment. The results of the primary analysis were validated at two subsequent time points (months 12 and 24).

Results

The prevalence of cognitive impairment was greater in patients with low brain parenchymal fraction (BPF) (<0.85) and high T2 lesion volume (T2‐LV) (>3.5 ml) than in patients with high BPF (>0.85) and low T2‐LV (<3.5 ml), with an odds ratio (OR) of 6.5 (95% CI 4.4–9.5). Low BPF together with high T2‐LV identified in 270 (25.7%) patients predicted cognitive impairment with 83% specificity, 82% negative predictive value, 51% sensitivity and 75% overall accuracy. The risk of confirmed cognitive decline over the follow‐up was greater in patients with high T2‐LV (OR 2.1; 95% CI 1.1–3.8) and low BPF (OR 2.6; 95% CI 1.4–4.7).

Conclusions

The integrated MRI assessment of lesion burden and brain atrophy may improve the stratification of MS patients who may benefit from cognitive assessment.

Original Article

Background and purpose

In the world today 10–20 million people are still living with late effects of poliomyelitis (PM), but the long‐term consequences of the disease are not well known. The aim of this study was to describe lifelong morbidity and mortality among Danes who survived PM.

Methods

Data from official registers for a cohort of 3606 Danes hospitalized for PM in the period 1940–1954 were compared with 13 762 age‐ and gender‐matched controls.

Results

Compared with controls, mortality was moderately increased for both paralytic as well as non‐paralytic PM cases; Hazard Ratio, 1.31 (95% confidence interval, 1.18–1.44) and 1.09 (95% confidence interval, 1.00–1.19), respectively. Hospitalization rates were approximately 1.5 times higher among both paralytic and non‐paralytic PM cases as compared with controls. Discharge diagnoses showed a broad spectrum of diseases. There were no major differences in morbidities between paralytic and non‐paralytic PM cases.

Conclusions

Poliomyelitis has significant long‐term consequences on morbidity and mortality of both paralytic and non‐paralytic cases.

Letter to the Editor

Amiodarone‐induced gait unsteadiness is revealed to be bilateral vestibulopathy

Original Article

Background and purpose

The sleep‐onset rapid eye movement (REM) period (SOREMP), the hallmark of narcolepsy, may be a specific state and not the simple anticipation of REM sleep.

Methods

We analyzed the electroencephalographic spectral content in untreated patients with narcolepsy type 1 (NT1) during the sleep‐onset period (SOP) and during nocturnal REM sleep in two consecutive nocturnal recordings from 31 patients with NT1 (mean age 34 ± 15 years, 18 males) and a single nocturnal recording from 36 controls (mean age 38 ± 13 years, 21 males).

Results

The SOP‐1 and, more strikingly, SOP‐2 had significantly less delta and sigma activity in patients with NT1 in the SOREMP condition versus both controls and patients with NT1 without SOREMP. SOP‐2 also showed less theta and alpha activity. Conversely, sigma and beta activity were more represented during SOREMP compared with the nocturnal REM period in patients with NT1.

Conclusions

The analysis of the SOP supports the concept that SOREMP is a different state compared with both nocturnal REM sleep and non‐REM sleep onset.

Original Article

Background and purpose

Mild cognitive impairment (MCI) is associated with pronounced grey matter atrophy in various brain regions. However, the association between atrophy patterns and progression from no cognitive impairment (NCI) to Parkinson's disease (PD)‐MCI is not clearly known. We investigated the pattern and progression of atrophy in subcortical structures and its impact on cognition in patients with mild PD.

Methods

Sixty‐five patients with mild PD with baseline and longitudinal clinical and neuropsychological assessments, and structural magnetic resonance imaging scans were studied. Movement Disorder Society Task Force criteria were used to classify patients with PD into PD‐NCI ( = 54) and PD‐MCI ( = 11). Based on progression over time, those who remained without cognitive impairment were classified as PD‐stable ( = 42) and those who converted to MCI over 18 months were classified as PD‐converters ( = 12). FreeSurfer was used to measure cortical thickness and subcortical volumes at baseline and follow‐up.

Results

Parkinson's disease‐MCI showed baseline thalamus atrophy and progressive atrophy in the thalamus, caudate, presubiculum, cornu ammonis 1 and 2–3, and significant memory and executive dysfunction compared with PD‐NCI. PD‐converters had greater accumbens atrophy at baseline and progressive atrophy in the thalamus, caudate and accumbens with dysfunctions in memory and executive domains.

Conclusions

Progression of cognitive impairment in non‐demented PD is associated with a specific pattern of subcortical atrophy. Findings from this study will allow future studies to investigate in the role of subcortical structures as a biomarker for PD dementia.

Original Article

Background and purpose

Reduction of metaiodobenzylguanidine (MIBG) uptake has been observed in almost all patients with Parkinson's disease (PD), associated with hyposmia, orthostatic hypotension and rapid eye movement sleep behavioral disorder (RBD). In contrast, a subgroup of patients with PD with normal MIBG uptake have been reported to have milder disease and preserved cognition compared with those with lower MIBG. The aim of this study was to investigate whether non‐motor manifestations of PD differ between patients with normal and abnormal myocardial MIBG uptake.

Methods

Among 160 cases of PD, 44 had normal MIBG uptake. Twelve candidate non‐motor features were evaluated using questionnaires and laboratory tests.

Results

Patients with decreased MIBG uptake had more constipation, RBD, cognitive impairment, hyposmia and orthostatic hypotension than did those with normal MIBG uptake. On linear regression analysis, orthostatic hypotension, olfactory function and probable RBD were significantly associated with MIBG uptake in PD. The principal component analysis showed that the group with normal MIBG was not associated with non‐motor impairments.

Conclusions

These results suggest that patients with PD with normal MIBG scans have a relatively low disease burden compared with those with abnormal MIBG. Fewer synuclein pathologies in the myocardia and sympathetic ganglia in PD with preserved MIBG uptake might be associated with lower threshold patterns of Braak synuclein pathology for non‐motor manifestations compared with PD with decreased MIBG.

Short Communication

Background and purpose

Growth hormone (GH)/insulin‐like growth factor 1 (IGF‐1) axis abnormalities in multiple sclerosis (MS) suggest their role in its pathogenesis. Interferon β (IFN‐β) efficacy could be mediated also by an increase of IGF‐1 levels. A 2‐year longitudinal study was performed to estimate the prevalence of GH and/or IGF‐1 deficiency in clinically isolated syndrome (CIS) patients and their correlation with conversion to MS in IFN treated patients.

Methods

Clinical and demographic features of CIS patients were collected before the start of IFN‐β‐1b. IGF‐1 levels and GH response after arginine and GH releasing hormone + arginine stimulation tests were assessed. Clinical and magnetic resonance imaging evaluations were performed at baseline, 1 year and 2 years.

Results

Thirty CIS patients (24 female) were enrolled. At baseline, four patients (13%) showed a hypothalamic GH deficiency (GHD), whilst no one had a pituitary GHD. Baseline demographic, clinical and radiological data were not related to GHD, whilst IGF‐1 levels were inversely related to age ( < 0.001) and GH levels ( = 0.03). GH and IGF‐1 serum mean levels were not significantly modified after 1 and 2 years of treatment in the whole group, although 3/4 GHD patients experienced a normalization of GH levels, whilst one dropped out. After 2 years of treatment 13/28 (46%) patients converted to MS. The presence of GHD and GH and IGF‐1 levels were not predictive of relapses, new T2 lesions or conversion occurrence.

Conclusions

Growth hormone/IGF‐1 axis function was found to be frequently altered in CIS patients, but this was not related to MS conversion. Patients experienced an improvement of GHD during IFN therapy. Longer follow‐up is necessary to assess its impact on disease progression.

Original Article

Background and purpose

To determine whether iron deposition in deep brain nuclei assessed using high‐pass filtered phase imaging plays a role in motor disease severity in Parkinson's disease (PD).

Methods

Seventy patients with mild to moderate PD and 20 age‐ and gender‐matched healthy volunteers (HVs) underwent susceptibility‐weighted imaging on a 3 T magnetic resonance imaging scanner. Phase shifts (radians) in deep brain nuclei were derived from high‐pass filtered phase images and compared between groups. Analysis of clinical laterality and correlations with motor severity (Unified Parkinson's Disease Rating Scale, Part III, UPDRS‐III) were performed. Phase shifts (in radians) were compared between HVs and three PD subgroups divided according to UPDRS‐III scores using analysis of covariance, adjusting for age and regional area.

Results

Parkinson's disease patients had significantly ( < 0.001) higher radians than HVs bilaterally in the putamen, globus pallidus and substantia nigra (SN). The SN contralateral to the most affected side showed higher radians ( < 0.001) compared to the less affected side. SN radians positively correlated with UPDRS‐III and bradykinesia−rigidity subscores, but not with tremor subscores. followed by Bonferroni‐adjusted pairwise comparisons revealed that SN radians were significantly greater in the PD subgroup with higher UPDRS‐III scores compared to both lowest UPDRS‐III PD and HV groups ( < 0.001).

Conclusions

Increased nigral iron accumulation in PD appears to be stratified according to disease motor severity and correlates with symptoms related to dopaminergic neurodegeneration. This semi‐quantitative iron assessment could prove useful for objectively monitoring PD progression, especially in clinical trials concerning iron chelation therapies.

Letter to the Editor

Association of moyamoya disease with thyroid autoantibodies and thyroid function

Editorial

Abstract

Click to view the accompanying paper in this issue.

Editorial

Abstract

Click to view the accompanying paper in this issue.

Original Article

Background and purpose

In myotonic dystrophy type 1 (DM1), weakness of distal limb muscles affects quality of life. Non‐invasive evaluation of muscular involvement by muscle sonography could be useful for characterizing muscle‐specific involvement.

Methods

Sonography of the lower leg and forearm was performed in 19 patients with DM1 and 10 control subjects. The mean echo intensities (EIs) of seven limb muscles were obtained by computer‐assisted histogram analysis and compared within DM1 according to the overall clinical severity.

Results

The EIs of the muscles were significantly higher in DM1 than in the controls ( < 0.01), except for the soleus ( = 0.4). Comparison of adjacent muscles showed the following: (i) greater EIs in flexor digitorum profundus than flexor carpi ulnaris ( < 0.01) and flexor digitorum superficialis ( = 0.02), and (ii) greater EIs in the medial head of the gastrocnemius than the soleus ( < 0.00001). In a subgroup analysis of DM1 according to the modified Rankin Scale (mRS), the more severe subgroup (mRS = 4−5) had lower mean EIs than the less severe subgroup (mRS from 1−3) ( = 0.01) in the flexor digitorum superficialis but not in other muscles.

Conclusions

Preferential high echogenicity in the medial gastrocnemius and deep finger flexors is suggestive of DM1. Muscle echogenicity is not generally related to functional dysfunction in DM1.

Original Article

Background and purpose

Despite extensive studies on post‐stroke depression (PSD), the role of the total burden of cerebral small‐vessel disease (cSVD) in its pathogenesis remains unclear.

Methods

We conducted a magnetic resonance imaging (MRI)‐based cohort study to investigate the relationship between total MRI burden of cSVD and PSD among patients with first‐ever lacunar stroke. From June 2013 to January 2016, 374 patients were consecutively recruited. PSD was identified using the Chinese version of the Structured Clinical Interview for DSM‐IV. Brain MRI presence of silent lacunar infarcts, white‐matter lesions, cerebral microbleeds and enlarged perivascular spaces was summed to an ordinal score between 0 and 4. Multivariable logistic regression analysis was performed to determine the contribution of total MRI cSVD burden in the prediction of PSD.

Results

Ninety patients (24.1%) were diagnosed with PSD at 3 months after stroke. Only two MRI markers of cSVD, asymptomatic lacunar infarcts and white‐matter lesions, were related to PSD [odds ratio (OR), 3.167; 95% confidence interval (CI), 1.879–5.338; =0.001 and OR, 2.284; 95% CI, 1.403–3.713; =0.001, respectively]. Moreover, higher total MRI cSVD burden was an independent predictor for PSD (high tertile OR, 4.577; 95% CI, 2.400–8.728; =0.001) after adjusting for individual cSVD MRI marker and other potential confounders.

Conclusions

This study demonstrated that greater total MRI burden of cSVD may predict the presence of PSD in patients with acute lacunar stroke.

Original Article

Background and purpose

Chronic cluster headache is a rare, highly disabling primary headache condition. When medically intractable, occipital nerve stimulation can offer effective treatment. Open‐label series have provided data on small cohorts only.

Methods

We analyzed 51 subjects to evaluate the long‐term outcomes of highly intractable chronic cluster headache with occipital nerve stimulation. Patients with intractable chronic cluster headache were implanted with occipital nerve stimulators during the period 2007–2014. The primary endpoint was improvement in daily attack frequency. Secondary endpoints included attack severity, attack duration, quality‐of‐life measures, headache disability scores and adverse events.

Results

We studied 51 patients [35 males; mean age at implant 47.78 (range 31–70) years; mean follow‐up 39.17 (range 2–81) months]. Nineteen patients had other chronic headache types in addition in chronic cluster headache. At final follow‐up, there was a 46.1% improvement in attack frequency ( < 0001) across all patients, 49.5% ( < 0.001) in those with cluster headache alone and 40.3% ( = 0.036) in those with multiple phenotypes. There were no significant differences in response in those with or without multiple headache types. The overall response rate (defined as at least a 50% improvement in attack frequency) was 52.9%. Significant reductions were also seen in attack duration and severity. Improvements were noted in headache disability scores and quality‐of‐life measures. Triptan use of responders dropped by 62.56%, resulting in significant cost savings. Adverse event rates were highly favorable.

Conclusion

Occipital nerve stimulation appears to be a safe and efficacious treatment for highly intractable chronic cluster headache even after a mean follow‐up of over 3 years.

Original Article

Background and purpose

The objective of our study was to evaluate sex differences in the impact of weight and abdominal obesity on the risk of ischemic stroke.

Methods

We included 388 patients with ischemic stroke (aged <75 years) assessed consecutively in our hospital and 732 controls matched by age and sex. Vascular risk factors and anthropometric data (waist circumference, weight and height) were recorded. The impact of three anthropometric variables [body mass index (BMI), waist circumference and waist to height ratio] on ischemic stroke risk was calculated. These variables were divided into quartiles for a comprehensive comparison between cases and controls, stratified by sex and adjusted in logistic regression by age and vascular risk factors. Further logistic regression using dummy variables was performed to evaluate the association between BMI‐adjusted abdominal obesity and stroke risk.

Results

Increased BMI was not associated with increased stroke risk overall or in women, but was a protective factor in men [ = 0.03; odds ratio (OR), 0.59 (0.37–0.94)]. Abdominal obesity was a risk factor for stroke in women, in both waist circumference [ < 0.001; OR, 5.79 (3.10–10.85)] and waist to height ratio [ < 0.001; OR, 3.61 (1.99–6.54)] analyses, but was not significant in men. When considered independently of BMI, abdominal obesity was a risk factor in both sexes, but the strength of the association was significantly higher in women.

Conclusions

Increased BMI was related to a lower risk of stroke in men. Abdominal obesity was associated with ischemic stroke in women. The impact of abdominal obesity on stroke risk differs by sex.

Original Article

Background and purpose

Anxiety is common in Parkinson's disease (PD) and has a great influence on quality of life. However, little is known about risk factors for development of anxiety in PD. We investigated which factors were associated with longitudinal changes in severity of anxiety symptoms and development of future anxiety in patients who were not anxious at baseline.

Methods

Analyses were performed on data of the PROfiling PARKinson's disease (PROPARK) cohort, a 5‐year hospital‐based longitudinal cohort of over 400 patients with PD who have been examined annually. Linear mixed models were used to identify factors associated with longitudinal changes in Hospital Anxiety and Depression Scale – Anxiety (HADS‐A) scores. Survival analysis using data of patients who were not anxious at baseline was performed to identify predictors of future anxiety (i.e. HADS‐A ≥ 11).

Results

Of 409 patients who were included at baseline, 67 (16%) had anxiety, whereas 64 (19%) of the remaining 342 non‐anxious patients developed anxiety after a mean (SD) follow‐up of 2.6 (1.3) years. Seventy percent of the patients with anxiety were also depressed. Female gender, cognitive impairment, depressive symptoms, dysautonomia, insomnia and excessive daytime sleepiness (EDS) at baseline were associated with higher HADS‐A scores over time and, except for female gender and EDS, all of these variables were independent predictors of development of anxiety in patients who were not anxious at baseline.

Conclusions

Anxiety is highly prevalent in PD. Higher anxiety scores over time and future development of anxiety are associated with female gender, cognitive impairment, autonomic dysfunction, insomnia and EDS. Anxiety and depression usually coexist and share similar determinants, suggesting a common pathophysiological mechanism.

Original Article

Background and purpose

Subcutaneous immunoglobulin (SCIG) is effective as maintenance treatment in chronic inflammatory demyelinating polyneuropathy (CIDP). We investigated whether multiple subcutaneous infusions are as effective as conventional therapy with intravenous loading doses in treatment‐naive patients with CIDP.

Methods

Twenty patients fulfilling the clinical and electrophysiological criteria for CIDP were included and treated with either SCIG (0.4 g/kg/week) for 5 weeks or intravenous immunoglobulin (IVIG) (0.4 g/kg/day) for 5 days. After 10 weeks, patients were switched to the opposite treatment arm and followed for a further 10 weeks. All participants were evaluated at weeks 0, 2, 5 and 10 during both therapies. Primary outcome was combined isokinetic muscle strength (cIKS). Secondary outcomes were disability, clinical evaluation of muscle strength and the performance of various function tests.

Results

All participants received both therapies, 14 completing the protocol. Overall, cIKS increased by 7.4 ± 14.5% ( = 0.0003) during SCIG and by 6.9 ± 16.8% ( = 0.002) during IVIG, the effect being similar ( = 0.80). Improvement of cIKS peaked 2 weeks after IVIG and 5 weeks after SCIG. Disability improved during SCIG treatment only. Muscle strength determined by manual muscle testing improved after 5 and 10 weeks during SCIG but only after 5 weeks during IVIG. The remaining parameters improved equally during both treatments. Plasma immunoglobulin G levels at baseline and improvement of cIKS were related.

Conclusion

In treatment‐naive patients with CIDP, short‐lasting SCIG and IVIG therapy improve motor performance to a similar degree, but with earlier maximal improvement following IVIG than SCIG treatment.

Review Article

Abstract

Electroencephalographic (EEG) reactivity testing is often presented as a clear‐cut element of electrophysiological testing. Absence of EEG reactivity is generally considered an indicator of poor outcome, especially in patients after cardiac arrest. However, guidelines do not clearly describe how to test for reactivity and how to evaluate the results. In a quest for clear guidelines, we performed a systematic review aimed at identifying testing methods and definitions of EEG reactivity. We systematically searched the literature between 1970 and May 2016. Methodological quality of the studies was assessed using the QUality In Prognostic Studies tool. Quality of the descriptions of stimulus protocol and reactivity definition was rated on a four‐category grading scale based on reproducibility. We found that protocols for EEG reactivity testing vary greatly and descriptions of protocols are almost never replicable. Furthermore, replicable definitions of presence or absence of EEG reactivity are never provided. In order to draw firm conclusions on EEG reactivity as a prognostic factor, future studies should include a precise stimulation protocol and reactivity definition to facilitate guideline formation.

Original Article

Background and purpose

Ethnicity‐related differences in the incidence of acute disseminated encephalomyelitis (ADEM) and other demyelinating diseases including multiple sclerosis and neuromyelitis optica spectrum disorders have been reported. Little is reported on the influence of ethnicity and geographical location in ADEM.

Methods

Medical records of patients who presented with ADEM (ICD‐9 323.61 and 323.81) at large referral hospitals in China, Singapore and Japan (years 1992–2015) were retrospectively reviewed and data were collected in a centralized database. Presenting features and outcomes of ADEM were compared between this multi‐country Asian cohort and a uniformly collected US cohort using risk differences and risk ratios. Both cohorts were standardized to a 35% pediatric population to facilitate the comparison.

Results

There were 83 Asian patients (48 male, 16 pediatric) followed for a median of 2 (25th–75th percentile 1–10) months. Asian patients exhibited a 26% higher prevalence of spinal cord involvement on magnetic resonance imaging [95% confidence interval (CI) 0–52%; = 0.05; 63% vs. 37%], a 39% lower prevalence of preceding events (95% CI 12–65%; < 0.01; 33% vs. 72%) and a 23% lower prevalence of corpus callosum involvement (95% CI 7–39%; < 0.01; 8% vs. 31%). No difference was observed between the two cohorts in the probability of relapse over the first year after disease onset.

Conclusions

It is hypothesized that the high proportion of Asian patients with spinal cord lesions relates to genetic vulnerability or the higher incidence of neuromyelitis optica spectrum disorders in Asia or could be a spurious association. ADEM presentations most probably vary across geographical settings or ethnicities.

Letter to the Editor

Declining incidence of intracerebral hemorrhage

Original Article

Background and purpose

Epilepsy has been associated with cardiovascular comorbidity. Risk prediction equations are the standard tools in primary prevention of cardiovascular disease. Our aim was to compare the prevalence of cardiovascular risk factors (CVRFs), cardiovascular risk and statin use in people with epilepsy (PWE) and the general population.

Methods

The CVRFs and cardiovascular risk score were compared between 815 PWE from an outpatient register and 5336 participants from a general population cohort.

Results

People with epilepsy had less hypertension (43.3% vs. 50.4%), less diabetes (15.8% vs. 19.2%), more dyslipidemia (40.2% vs. 34.6%) and lower cardiovascular risk than the general population ( < 0.01). No etiology was associated with a worse CVRF profile or higher cardiovascular risk. Patients taking enzyme‐inducing antiepileptic drugs (EIAEDs) had more dyslipidemia than the general population (41.6% vs. 34.6%) but similar cardiovascular risk. Independently of risk or CVRFs, PWE had 60% more probability of receiving statins than the general population.

Conclusions

People with epilepsy had more dyslipidemia, related to EIAEDs, and lower cardiovascular risk but still took more statins than the general population. Physicians should use clinical judgement to decide on further treatment of CVRFs in PWE who are below the recommended risk threshold for treatment and should consider lipid abnormalities a potential side‐effect of EIAEDs. Other therapy options may need to be evaluated before starting lipid‐lowering treatment.

Original Article

Background and purpose

The presentation of Parkinson's disease patients with mutations in the gene (PD) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes.

Methods

An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PD patients from the MJFF Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor.

Results

Patients classified as diffuse/malignant presented with the highest levels of the pro‐inflammatory proteins interleukin 8 (IL‐8), monocyte chemotactic protein 1 (MCP‐1) and macrophage inflammatory protein 1‐β (MIP‐1‐β) paralleled by high levels of the neurotrophic protein brain‐derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis.

Conclusions

Inflammation seems to be associated with the presence of a specific clinical subtype in PD that is characterized by a broad and more severely affected spectrum of motor and non‐motor symptoms. The pro‐inflammatory metabolites IL‐8, MCP‐1 and MIP‐1‐β as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PD and predict progression.

Original Article

Background and purpose

We investigated changes in deep gray matter (DGM) volume and its relationship to cognition and clinical factors in a large cohort of patients with neuromyelitis optica spectrum disorder (NMOSD) and compared them with results from multiple sclerosis (MS).

Methods

Brain magnetic resonance imaging (3 Tesla) and clinical data from 91 patients with NMOSD, 52 patients with MS and 44 healthy controls (HCs) were prospectively evaluated. Differences in DGM volumes were compared among groups. The relationships between DGM atrophy and clinical variables were also analysed.

Results

Patients with NMOSD exhibited significantly reduced thalamic volumes compared with HCs ( = 0.029), although this atrophy was less severe than that seen in patients with MS ( < 0.001). DGM atrophy was restricted to the thalamus in NMOSD, but it was broadly distributed in MS. Patients with NMOSD with cognitive impairment (CI) exhibited more severe thalamic atrophy than those with cognitive preservation ( = 0.017) and HCs ( = 0.003), whereas patients with MS with CI revealed DGM atrophy across the entire structure, with the exception of the bilateral pallidum, left hippocampus and amygdala, relative to HCs. The Expanded Disability Status Scale score was correlated with thalamic atrophy in both NMOSD and MS. Patients with NMOSD with brain lesions demonstrated more severe thalamic atrophy than did those without brain lesions and HCs ( < 0.001).

Conclusions

The DGM atrophy was less severe and more selectively distributed in NMOSD than in MS. Thalamic atrophy was associated with clinical disability, including CI, in both NMOSD and MS.

Editorial

Abstract

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