cover image European Journal of Neurology

European Journal of Neurology

2018 - Volume 25
Issue 8 | August 2018

Original Article

Background and purpose

Chronic kidney disease and atrial fibrillation (AF) are two commonly coexisting risk factors of stroke. The aim of this study was to compare the association between impaired renal function and poor prognosis in ischaemic stroke patients with versus without AF.

Methods

Patients with ischaemic stroke in the China National Stroke Registry were included. Low estimated glomerular filtration rate (eGFR) on admission was defined as <60 ml/min/1.73 m. Outcomes included stroke recurrence, death, poor outcome defined as 3−6 on the modified Rankin Scale (mRS) and ordinal mRS at 12 months.

Results

Of 9154 patients included, 1143 (12.5%) patients had a low eGFR. Patients with a low eGFR had more presence of AF compared with those with an eGFR of ≥90 ml/min/1.73 m [21.5% vs. 6.9%; odds ratio (OR) 1.77, 95% confidence interval (CI) 1.43–2.20]. An interaction of eGFR category by AF was observed for poor outcome and ordinal mRS ( for interaction = 0.04 and 0.002). In patients with AF, the OR with 95% CI of low eGFR was 1.86 (1.19–2.92) for stroke recurrence, 2.87 (1.82–4.52) for death, 1.83 (1.09–3.05) for poor outcome and 2.20 (1.52–3.18) for ordinal mRS. In patients without AF, low eGFR was only associated with death and ordinal mRS (OR 1.61, 95% CI 1.28–2.02; common OR 1.20, 95% CI 1.04–1.38; respectively).

Conclusions

Stroke patients with lower eGFR had more presence of AF. The associations of low eGFR with risk of poor prognosis in stroke patients with AF were stronger than those without AF.

Original Article

Background and purpose

Educational intervention has proved to be effective in reducing drug abuse in uncomplicated medication‐overuse headache (MOH). This ancillary of the SAMOHA multicentre study aimed to assess any differences in phenotypic characteristics, type and amount of drugs overused, and comorbidities between patients with MOH who responded to simple advice and those who did not.

Methods

Demographic and clinical headache data of the last 3 months before enrollment of patients were collected and patients were then asked to fill out a daily headache diary for 4 weeks. Patients were then divided into two subgroups, i.e. those with confirmed MOH continued in the study [randomized (R) group], whereas those who did not still show any features of MOH dropped out of the study.

Results

A total of 88 (67.7%) patients still met the inclusion criteria after the baseline 4 weeks (R group). Conversely, 42 (32.3%) patients dropped out of the study. A detailed analysis of those who dropped out revealed that only 34 were not randomized at visit 2 because they no longer satisfied the inclusion criteria for MOH [screening failures (SF) group]. The SF group was significantly younger and had fewer years of migraine history than the R group. Moreover, the SF group had a significantly shorter history of chronicity compared with the R group.

Conclusions

Our findings suggest that in MOH trials, after an educational session, an observational period is needed in order to confirm the diagnosis of MOH and to avoid overestimation of the effect of other treatments used to manage MOH. Future research should focus mainly on those patients with MOH who do not respond to simple advice and with unsuccessful withdrawal.

Editorial

Abstract

Click to view the accompanying paper in this volume.

Review Article

Abstract

The aim of this study was to determine whether non‐invasive brain stimulation (NIBS) techniques improve fine motor performance in stroke. We searched PubMed, EMBASE, Web of Science, SciELO and OpenGrey for randomized clinical trials on NIBS for fine motor performance in stroke patients and healthy participants. We computed Hedges’ for active and sham groups, pooled data as random‐effects models and performed sensitivity analysis on chronicity, montage, frequency of stimulation and risk of bias. Twenty‐nine studies (351 patients and 152 healthy subjects) were reviewed. Effect sizes in stroke populations for transcranial direct current stimulation and repeated transcranial magnetic stimulation were 0.31 [95% confidence interval (CI), 0.08–0.55;  = 0.010; Tau, 0.09; , 34%; , 18.23;  = 0.110] and 0.46 (95% CI, 0.00–0.92;  = 0.05; Tau, 0.38; , 67%; , 30.45;  = 0.007). The effect size of non‐dominant healthy hemisphere transcranial direct current stimulation on non‐dominant hand function was 1.25 (95% CI, 0.09–2.41;  = 0.04; Tau, 1.26; , 93%; , 40.27;  < 0.001). Our results show that NIBS is associated with gains in fine motor performance in chronic stroke patients and healthy subjects. This supports the effects of NIBS on motor learning and encourages investigation to optimize their effects in clinical and research settings.

Original Article

Background and purpose

Human endogenous retroviruses (HERV) K/W seem to play a role in fostering and exacerbation of some neurological diseases, including amyotrophic lateral sclerosis (ALS). Given these findings, the immunity response against HERV‐K and HERV‐W envelope surface (env‐su) glycoprotein antigens in serum and cerebrospinal fluid (CSF) was investigated for ALS, multiple sclerosis (MS) and Alzheimer's disease patients and in healthy controls.

Methods

Four antigenic peptides derived respectively from HERV‐K and HERV‐W env‐su proteins were studied in 21 definite or probable ALS patients, 26 possible or definite relapsing−remitting MS patients, 18 patients with Alzheimer's disease and 39 healthy controls. An indirect enzyme‐linked immunosorbent assay was set up to detect specific antibodies (Abs) against env‐su peptides.

Results

Amongst the measured levels of Abs against the four different HERV‐K peptide fragments, only HERV‐K env‐su was significantly elevated in ALS compared to other groups, both in serum and CSF. Instead, amongst the Abs levels directed against the four different HERV‐W peptide fragments, only HERV‐W env‐su and HERV‐W env‐su were significantly elevated, in the serum and CSF of the MS group compared to other groups. In ALS patients, the HERV‐K env‐su Abs levels were significantly correlated with clinical measures of disease severity, both in serum and CSF.

Conclusions

Increased circulating levels of Abs directed against the HERV‐W env‐su and HERV‐W env‐su peptide fragments could serve as possible biomarkers in patients with MS. Similarly, increased circulating levels of Abs directed against the HERV‐K env‐su peptide fragment could serve as a possible early novel biomarker in patients with ALS.

Original Article

Background and purpose

Patients with multiple sclerosis (MS) have many pregnancy‐related doubts and fears. Careful counselling is thus important. Mitoxantrone (MITO) is used in patients with aggressive MS and may affect reproductive capacity. The aim of this study was to investigate pregnancy planning and outcomes in patients with MS treated with MITO, both before and after the treatment.

Methods

Patients with MS previously treated with MITO were recruited. Clinical, demographic and treatment data were recorded. A questionnaire regarding the planning and outcomes of all pregnancies was administered. Parametric and non‐parametric tests were performed using SPSS 22 software.

Results

A total of 238 patients (female/male, 158/80) were included; 106 subjects planned a pregnancy before MITO and 40 after MITO. Of these, respectively, 102 (97%) and 35 (85%) resulted in conception, 19 (19%) and 7 (18%) in miscarriage, 6 (6%) and 1 (3%) in abortion and 98 (96%) and 32 (91%) were full‐term pregnancies. A total of 96 patients (40%) planned a pregnancy only before MITO (and not after), whereas 30 (13%) planned a pregnancy only after MITO (and not before) ( < 0.01). A total of 103 patients did not plan a pregnancy before MITO and 198 did not plan a pregnancy after MITO. The reasons included lack of interest or a partner, fear of MS and infertility. All of the babies born were healthy until the end of follow‐up.

Conclusions

Mitoxantrone does not affect the ability to conceive or pregnancy outcomes. We found no differences in pregnancies, abortions or miscarriages before and after MITO. The tendency to plan pregnancies decreased significantly after MITO. Our findings may be useful for improving the quality of life of patients and the approach taken by neurologists.

Original Article

Background and purpose

Tacrolimus is beneficial for treatment of myasthenia gravis (MG) and has a narrow therapeutic range. Therefore, therapeutic drug monitoring is essential for tacrolimus to optimize dosage and prevent adverse reactions. However, no studies have explored the factors influencing tacrolimus blood concentration in patients with MG. Thus, we aimed to analyze these factors and discuss how to optimize tacrolimus dosage for MG treatment.

Methods

Data regarding clinical characteristics, therapeutic drugs and adverse reactions of patients with MG who received tacrolimus were collected from 2013 to 2015 at Beijing Hospital. Tacrolimus whole‐blood concentrations were measured by chemiluminescent microparticle immunoassay and CYP3A5*3 gene polymorphism was detected by digital fluorescence molecule hybridization fluorescence. Regression analysis was applied to analyze the factors influencing blood concentrations and adverse reactions.

Results

It was shown that there was a correlation between concentration and dosage. Furthermore, co‐administration of proton pump inhibitor and clarithromycin and CYP3A5*3 gene polymorphism could significantly increase the tacrolimus whole‐blood levels. Adverse reactions were related to blood concentration, CYP3A5 genetic polymorphisms and combined medication though logistic regression analysis.

Conclusions

The concentration of tacrolimus is affected by many factors. Therapeutic drug monitoring and detection of CYP3A5 gene polymorphism was essential for dosage optimization in patients with MG.

Original Article

Background and purpose

Treatments to facilitate recovery after traumatic brain injury (TBI) are urgently needed. We conducted a 9‐month pilot, randomized placebo‐controlled clinical trial to examine the safety and potential effects of the herbal supplement MLC901 (NeuroAiD II™) on cognitive functioning following TBI.

Methods

Adults aged 18–65 years at 1–12 months after mild or moderate TBI were randomized to receive MLC901 (0.8 g capsules 3 times daily) or placebo for 6 months. The primary outcome was cognitive functioning as assessed by the CNS Vital Signs online neuropsychological test. Secondary outcomes included the Cognitive Failures Questionnaire, the Rivermead Post‐concussion Symptom Questionnaire (neurobehavioral sequelae), Quality of Life after Brain Injury, Hospital Anxiety and Depression Scale, Modified Fatigue Impact Scale and extended Glasgow Outcome Scale (physical disability). Assessments were completed at baseline and at 3‐, 6‐ and 9‐month follow‐up. Linear mixed‐effects models were conducted, with the primary outcome time‐point of 6 months.

Results

A total of 78 participants [mean age 37.5 ± 14.8 years, 39 (50%) female] were included in the analysis. Baseline variables were similar between groups (treatment group, = 36; control group, = 42). Linear mixed‐effects models controlling for time, group allocation, repeated measurements, adherence and baseline assessment scores revealed significant improvements in complex attention ( = 0.04, = 0.6) and executive functioning ( = 0.04, = 0.4) at 6 months in the MLC901 group compared with controls. There were no significant differences between the groups for neurobehavioral sequelae, mood, fatigue, physical disability or overall quality of life at 6 months. No serious adverse events were reported.

Conclusions

MLC901 was safe and well tolerated post‐TBI. This study provided Class I/II evidence that, for patients with mild to moderate TBI, 6 months of MLC901 improved cognitive functioning.

Letter to the Editor

Blood–brain barrier permeability in a patient with Labrune syndrome due to mutations

Original Article

Background and purpose

The National Institute for Health and Care Excellence (NICE) in the UK recommends the use of OnabotulinumtoxinA (BoNTA, Botox) in the management of chronic migraine (CM) following specific guidelines within the National Health Service. In view of the lack of data on the efficacy of this therapy following implementation of these guidelines in clinical practice and on the evaluation of guidance compliance, we aimed to evaluate the effectiveness and safety of BoNTA in patients with CM following the NICE guidelines.

Methods

This was a prospective real‐life audit study.

Results

After two treatments, 127 of 200 patients (63.5%) obtained at least a 30% reduction in headache days. Those who continued the treatment up to 3 years reported a stable beneficial effect compared with baseline. Amongst responders, 68 patients (53.5%) were reclassified as episodic migraineurs. A total of 57 of these patients (83.8%) converted to an episodic migraine pattern at 6‐month follow‐up. The majority of those whose migraine became episodic after BoNTA extended the treatment intervals beyond 3 months (range 4–8 months) before noticing any worsening of headache. We observed no significant differences in the efficacy measures in patients treated with 155 U BoNTA compared with those treated with >155 U BoNTA.

Conclusions

When administered according to the NICE guidance, BoNTA produced a clinically meaningful effect in the long‐term management of CM with and without medication overuse headache. Treatment discontinuation when CM becomes episodic may be useful in clinical practice to identify those who may benefit from extended treatment intervals. Our clinical experience indicates a lack of additional benefit from using the ‘follow‐the‐pain’ paradigm.

Original Article

Background and purpose

Increased supratentorial white matter hyperintensities volume (S‐WMHV) has been reported to be a predictor of worse outcome in patients with acute ischemic stroke (AIS). However, few studies have focused on less common locations, such as brainstem white matter hyperintensities (B‐WMH), and their relationship to S‐WMHV. This study aimed to examine whether B‐WMH affect clinical outcome after AIS or transient ischemic attack (TIA).

Methods

Based on magnetic resonance imaging evidence, B‐WMH were evaluated in 313 prospectively identified patients with AIS/TIA and registered as absent or present. Standardized S‐WMHV was quantified using a validated volumetric image analysis and natural log‐transformed (Log_S‐WMHV). Poor outcome was defined as a modified Rankin Scale score of 3–6 at 3 months after the index event.

Results

Brainstem white matter hyperintensities were detected in 57 (18.2%) patients. In unadjusted analyses for outcome, the presence of B‐WMH was associated with worse outcome, compared with patients without B‐WMH ( = 0.034). In multivariate analysis controlling for age, atrial fibrillation, stroke severity, reperfusion therapies and Log_S‐WMHV, only B‐WMH [odds ratio (OR), 2.46; = 0.021] and stroke severity (OR, 1.23; < 0.001) remained independently associated with unfavourable 90‐day modified Rankin Scale score. Patients with B‐WMH were older (OR, 1.06; < 0.001) and tended to have more hyperlipidaemia (OR, 2.21; = 0.023) and peripheral arterial disease (OR, 2.57; = 0.031).

Conclusions

Brainstem white matter hyperintensities are an independent predictor of poor outcome after AIS/TIA and this relationship persists after adjustment for important prognostic factors. Our results also show that leukoaraiosis in this location identifies patients with a specific risk factor profile, suggesting differences in the underlying pathogenesis.

Original Article

Background and purpose

An external validation of the selection criteria of diffusion‐weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake‐up and late‐presenting strokes undergoing the Neurointervention with Trevo (DAWN) and the Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke (DEFUSE3) trials was conducted in a cohort of unknown onset stroke (UOS) patients treated with thrombectomy.

Methods

A validation cohort of UOS patients was selected from a prospectively collected thrombectomy database to match the inclusion criteria of DAWN and DEFUSE 3. Patients with an initial National Institutes of Health Stroke Scale (NIHSS) ≥10 were stratified according to the DAWN selection criteria. Patients ≤90 years old with an initial NIHSS ≥6 were stratified according to the DEFUSE 3 selection criteria. The proportions of patients with a modified Rankin Scale (mRS) ≤2 at 3 months follow‐up were compared between DAWN‐eligible patients and the DAWN trial thrombectomy group, and between DEFUSE 3‐eligible patients and the DEFUSE 3 trial thrombectomy group.

Results

Of the 60/102 (59%) DAWN‐eligible patients, 26 patients (43%) reached a mRS ≤2 at 3 months follow‐up [versus 52/107 patients (49%) in the DAWN trial thrombectomy group; = 0.52]. Of the 100/117 (85%) DEFUSE 3‐eligible patients, 48 patients (48%) reached a mRS ≤2 at 3 months follow‐up [versus 41/92 patients (45%) in the DEFUSE 3 trial thrombectomy group; = 0.67]. Of the DAWN‐ineligible and DEFUSE 3‐ineligible patients who underwent thrombectomy, 38% (16/42) and 41% (7/17) of patients reached a mRS ≤2, respectively.

Conclusion

The results of the DAWN and DEFUSE 3 trials were externally validated in a UOS cohort where the trials' selection criteria identified a similar proportion of responders to thrombectomy.

CME Article

Background and purpose

The aim was to report the clinical characteristics of 12 patients with limbic encephalitis (LE) who were antibody‐negative after a comprehensive immunological study.

Methods

The clinical records of 163 patients with LE were reviewed. Immunohistochemistry on rat brain, cultured neurons and cell‐based assays were used to identify neuronal autoantibodies. Patients were included if (i) there was adequate clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging information to classify the syndrome as LE, (ii) magnetic resonance images were accessible for central review and (iii) serum and CSF were available and were confirmed negative for neuronal antibodies.

Results

Twelve (7%) of 163 LE patients [median age 62 years; range 40–79; 9 (75%) male] without neuronal autoantibodies were identified. The most frequent initial complaints were deficits in short‐term memory leading to hospital admission in a few weeks (median time 2 weeks; range 0.5–12). In four patients the short‐term memory dysfunction remained as an isolated symptom during the entire course of the disease. Seizures, drowsiness and psychiatric problems were unusual. Four patients had solid tumors (one lung, one esophagus, two metastatic cervical adenopathies of unknown primary tumor) and one chronic lymphocytic leukemia. CSF showed pleocytosis in seven (58%) with a median of 13 white blood cells/mm (range 9–25). Immunotherapy included corticosteroids, intravenous immunoglobulins and combinations of both drugs or with rituximab. Clinical improvement occurred in six (54%) of 11 assessable patients.

Conclusions

Despite the discovery of new antibodies, 7% of LE patients remain seronegative. Antibody‐negative LE is more frequent in older males and usually develops with predominant or isolated short‐term memory loss. Despite the absence of antibodies, patients may have an underlying cancer and respond to immunotherapy.

Original Article

Background and purpose

Blood pressure (BP) levels in acute intracerebral hemorrhage (ICH) and mortality have not been thoroughly studied in the young.

Methods

The relationship between BP and mortality was assessed in consecutive patients with first‐ever, non‐traumatic acute ICH at ≤50 years of age, enrolled in the Helsinki ICH Young Study. BP parameters included systolic BP (SBP), diastolic BP (DBP), mean arterial pressure and pulse pressure (SBP − DBP) at admission and 24 h, and delta (admission–24 h) BP parameters. Outcome measures were 3‐month and long‐term mortalities, adjusted for demographics and ICH score parameters for short‐term and cardiovascular risk factors for long‐term prognostics. Cox regression models were used to assess independent BP parameters associated with mortality.

Results

Of our 334 patients (61% male), 92 (27%) had pre‐stroke hypertension and 54 (16%) used antihypertensive treatment. The follow‐up extended to 17 years with a median of 12 (interquartile range, 9.65–14.7) years. Both 3‐month ( = 56; 16%) and long‐term ( = 97; 29%) mortalities were associated with significantly higher admission SBP and mean arterial pressure levels, but not with 24‐h BP levels, compared with survivors. Patients with SBP ≥ 160 mmHg ( = 156; 46%) had a significantly higher mortality rate ( = 59, 17% vs. = 38, 11%; = 0.001) and died earlier (9.6; 95% confidence interval, 2.9–12.9 years vs. 11.3; 95% confidence interval, 8.1–13.9 years; P = 0.001) within the follow‐up period. In multivariable analyses, admission SBP ≥160 mmHg was independently associated with both 3‐month (hazard ratio, 2.50; 95% confidence interval, 1.19–5.24; < 0.05) and long‐term (hazard ratio, 2.02; 95% confidence interval, 1.18–3.43; < 0.01) mortalities.

Conclusions

In young patients with ICH, acute‐phase SBP levels ≥160 mmHg are independently associated with increased mortality.

Editorial

Abstract

Click to view the accompanying paper in this volume.

Editorial

Abstract

Click to view the accompanying paper in this volume.

Letter to the Editor

A novel prion protein gene‐truncating mutation causing autonomic neuropathy and diarrhea

Editorial

Abstract

Click to view the accompanying paper in this volume.

Letter to the Editor

Blood−brain barrier permeability in a patient with Labrune syndrome due to SNORD118 mutations: would this be the mechanism for progressive worsening?

Letter to the Editor

Brain comorbidities in normal pressure hydrocephalus and their impact on the cerebrospinal fluid tap test?

Short Communication

Background and purpose

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may share similar clinical findings and tests to distinguish between the two disorders could be useful. We evaluated the blink reflex and R2 blink reflex recovery cycle (R2BRRC), determining diagnostic sensitivity, specificity and positive and negative predictive value of R2BRRC in differentiating patients with PSP from those with CBS.

Methods

This was a prospective data collection study investigating blink reflex and R2BRRC at interstimulus intervals (ISIs) of 100, 150, 200, 300, 400, 500 and 750 ms in 12 patients with PSP, eight patients with CBS and 10 controls.

Results

Patients with PSP have earlier recruitment of R2BRRC as compared with patients with CBS (ISI: 100 ms, = 0.002; 150 ms, < 0.001; 200 ms, < 0.001; 300 ms, = 0.02) and controls (ISI: 100 ms, < 0.001; 150 ms, < 0.001; 200 ms, < 0.001; 300 ms, = 0.004). The presence of an early recovery of the R2 differentiated PSP from CBS with a specificity and sensitivity of 87.5% and 91.7%, respectively.

Conclusions

The R2BRRC curve might be considered to be a useful tool in differentiating patients with PSP from those with CBS.

Letter to the Editor

Functional eyelid opening apraxia: a kinematic study

Letter to the Editor

Brain comorbidities in normal pressure hydrocephalus