Background and purpose

To better characterize the effects of tafamidis in non‐Val30Met patients with transthyretin familial amyloid polyneuropathy, this analysis compared the neurological results from a 12‐month, open‐label study of non‐Val30Met versus Val30Met patients at month 12 from the 18‐month, double‐blind, placebo‐controlled registration study. A baseline covariate adjusted analysis was used to control for differences in baseline neurological severity.

Methods

Neurological function was assessed using the Neuropathy Impairment Score – Lower Limbs (NIS‐LL) in three cohorts: Val30Met tafamidis (=64), Val30Met placebo (=61) and non‐Val30Met tafamidis (=21). The change in NIS‐LL from baseline to month 12 for Val30Met and non‐Val30Met tafamidis‐treated patients was compared with the change from baseline at month 12 for Val30Met placebo‐treated patients using a mixed‐effects model for repeated measures (MMRM).

Results

The baseline adjusted mean (standard error) change in NIS‐LL values at month 12 was similar for Val30Met [1.60 (0.78)] and non‐Val30Met [1.62 (1.43)] tafamidis‐treated patients and less than that observed in the Val30Met placebo‐treated group [4.72 (0.77); =0.0055 for Val30Met and =0.0592 for non‐Val30Met]. Based on the MMRM, the magnitude of change in both tafamidis‐treated cohorts was similar across the range of observed baseline NIS‐LL values, and was consistently less than that observed in the Val30Met placebo‐treated group at month 12.

Conclusions

This baseline‐adjusted analysis demonstrated that tafamidis treatment delayed neurological progression comparably in Val30Met and non‐Val30Met patients across a range of baseline NIS‐LL values. Neurological progression in these two genotype groups may be more similar than previously considered.

Background and purpose

Apathy is an important neuropsychiatric feature of Parkinson's disease (PD), which often emerges before the onset of motor symptoms. Patients with rapid eye movement sleep behaviour disorder (RBD) have a high probability of developing PD in future. Neuropsychiatric problems are common in RBD, but apathy has not previously been detailed in this key prodromal population.

Methods

Eighty‐eight patients with polysomnographically proven RBD, 65 patients with PD and 33 controls were assessed for apathy using the Lille Apathy Rating Scale. Cognition and depression were also quantified. The sensitivity of the Unified Parkinson's Disease Rating Scale screening questions for apathy and depression was calculated.

Results

A total of 46% of patients with RBD were apathetic, compared with 31% of patients with PD in our sample. Most patients with RBD with depression were apathetic but more than half of apathetic patients were not depressed. The sensitivity of the single Unified Parkinson's Disease Rating Scale screening question was only 33% for mild apathy and 50% for severe apathy.

Conclusions

Apathy is common in RBD and is underestimated by a single self‐report question. Recognition of apathy as a distinct neuropsychiatric feature in RBD could aid targeted treatment interventions and might contribute to the understanding of prodromal PD.

Background and purpose

Cortical insular damage is associated with cardiac arrhythmias and an increased risk of death. We investigated the influence of insular damage on the outcome of patients with acute intracerebral hemorrhage as well as the frequency and predictors of new‐onset atrial fibrillation (nAF).

Methods

We studied consecutive patients with intracerebral hemorrhage from 2013 to 2016. We identified those patients who underwent continuous electrocardiographic monitoring (≥24 h), known atrial fibrillation and recent ischemic stroke. We prospectively collected demographic data, vascular risk factors, neurological severity, vital signs, radiological data, nAF and mortality at 3 months. Bivariate and multivariate regression analyses were performed.

Results

We evaluated 347 patients whose mean age was 73.5 ± 14.0 years (50.7% of them were men). We selected 183 patients to study the frequency and risk factors of nAF (mean age, 69.1 ± 14.7 years; 52.5% of them were men). We observed that 11/183 (6.0%) had nAF. Insular damage [odds ratio (OR), 7.6; 95% confidence interval (CI), 2.1–27.7] was associated with nAF. A total of 138/347 patients died within the first 3 months and insular damage was detected in 99/347 of them. Predictors of death were age (OR, 1.07; 95% CI, 1.04–1.10), blood glucose (OR, 1.00 per mg/dL;, 95% CI, 1.00–1.01), Glasgow Coma Scale score (OR, 0.85; 95% CI, 0.77–0.92), hematoma volume (OR, 1.02 per mL; 95% CI, 1.01–1.04), intraventricular hemorrhage (OR, 1.93; 95% CI, 1.03–3.64) and insular damage (OR, 3.98; 95% CI, 2.00–7.90).

Conclusions

The frequency of nAF in our patients was 6.0%. Insular damage was a risk factor for nAF and an independent predictor of death at 3 months.

Background and purpose

Our earlier study showed that structured education of general practitioners (GPs) improved their practice in headache management. Here the duration of this effect was assessed.

Methods

In a follow‐up observational study in southern Estonia, subjects were the same six GPs as previously, managing patients presenting with headache as the main complaint. Data reflecting their practice were collected prospectively during a 1‐year period commencing 2 years after the educational intervention. The primary outcome measure was referral rate (RR) to neurological services. Comparisons were made with baseline and post‐intervention data from the earlier study.

Results

In 366 patients consulting during the follow‐up period, the RR was 19.9%, lower than at baseline (39.5%;  < 0.0001) or post‐intervention (34.7%;  < 0.0001). The RR was diagnosis‐dependent: the biggest decline was for migraine. Use of headache diagnostic terms showed changes generally favouring specific terminology. In particular, the proportion of patients given migraine diagnoses greatly increased whilst use of the inappropriate M79.1 (Pericranial) myalgia almost disappeared. Requests for investigations, which had fallen from 26% (of patients seen) at baseline to 4% post‐intervention, resurged to 23% (mostly laboratory investigations; requests for X‐rays continued to dwindle). Initiation of treatment by the GPs remained at the post‐intervention level of just over 80% (up from baseline 58%).

Conclusions

Improvements in GPs’ practice after a structured educational programme mostly last for ≥3 years, some showing further betterment. A few measures suggest the beginnings of a decline towards baseline levels. This policy‐informing evidence for continuing medical education indicates that the educational programme needs repeating every 2–3 years.

Background and purpose

In the era of neurological subspecialization, most neurologists will have a field of specialist interest. The aim of this cross‐sectional multinational study was to identify the key areas of interest among trainees or junior specialists, assess the potential influence of an interest in research and consider the results in light of population needs.

Methods

A total of 300 residents and junior neurologists who received a bursary to attend the European Academy of Neurology conference were invited to participate in this study. Demographic and work‐related characteristics, as well as main subspecialty of choice, were examined via an anonymous electronic questionnaire. Participants holding a higher degree (PhD/MD) or working in research posts were considered research oriented.

Results

In total, 191 neurologists in training or junior specialists responded (response rate 63.7%). Full data were available for 187 participants (59.4% females). The study sample had a mean age of 30.5 ± 3.4 (range 25–45) years. The most popular subspecialty was movement disorders (18.2%), followed by multiple sclerosis (11.2%) and epilepsy (10.2%). This did not differ significantly between the participants who were or were not research oriented.

Conclusions

There is a potential mismatch between the interests of trainees and the future needs of the populations they serve, which is important to identify for workforce planning.

Abstract

Click to view the accompanying paper in this volume.

Background and purpose

The aim was to validate the Parkinson's Disease Composite Scale (PDCS).

Methods

The study included 194 Parkinson's disease (PD) patients in five countries. Investigators completed the following scales: PDCS, the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), Parkinson's Disease Sleep Scale Version 2, Montreal Cognitive Assessment, the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's Disease and the Clinical Impression of Severity Index for PD (CISI‐PD). For test−retest analysis, a second administration of the PDCS was carried out in 61 stable patients (as per the CISI‐PD) in 7–14 days after the first evaluation. The PDCS is a novel scale for PD with a total of 17 items divided into four domains: motor, non‐motor, treatment complications and disability.

Results

Parkinson's Disease Composite Scale mean and median values were close. Skewness values were into the criterion limits (−1 to +1). The complete range of scores was covered for 14 of the 17 items (83.4%). A floor effect of 25.26% and 28.25% was observed in the complications and disability level dimensions due to the proportion of patients free of these difficulties. No relevant floor or ceiling effect was observed for the PDCS total score (1.03% and 0.52%, respectively). The stability of the scale appeared excellent with most items meeting weighted kappa and intraclass correlation coefficient values >0.80. The convergent validity of the PDCS with corresponding scores of the MDS‐UPDRS showed high correlation values ( ≥ 0.60). The internal validity was into acceptable limits, with the majority of values higher than the minimal 0.30 threshold. The standard error of measurement suggested a satisfactory precision (SEM 3.81, <30% of the PDCS total score standard deviation).

Conclusion

The PDCS appears to be a feasible, acceptable, reproducible and valid scale.

Background and purpose

The aim was to describe the clinical, radiological and pathological features of an autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy.

Methods

Data from 19 patients with positive GFAP‐immunoglobulin G in cerebrospinal fluid (CSF) were retrospectively analyzed.

Results

The main disease manifestations included myelitis (68.4%), headache (63.2%), abnormal vision (63.2%), fever (52.6%), ataxia (36.8%), psychosis (31.6%), dyskinesia (15.8%), dementia (15.8%) and seizure (10.5%). Seventeen patients had brain abnormalities (89.5%), of which eight (42.1%) revealed the characteristic radial enhancing and laminar patterns. Cortical abnormalities were found in four patients (21.1%). Other abnormalities were found in the hypothalamus, midbrain, pons, medulla cerebellum, meninges and skull. Eleven patients had longitudinally extensive spinal cord lesions. CSF abnormalities were detected in all patients. Pathological examinations of four patients revealed extensive inflammation, with prominent perivascular B cells and T cells. Abundant antibody‐secreting cells were noted in the interstitial and perivascular spaces. Immunohistochemical analysis showed loss of astrocytes and neurons.

Conclusion

The present patients with positive GFAP‐immunoglobulin G are highly similar to autoimmune GFAP astrocytopathy, described in a recent report. The features of the neuropathology and immunopathology of GFAP astrocytopathies were perivascular inflammation and loss of astrocytes and neurons.

Background and purpose

The Toronto Clinical Neuropathy Score (TCNS) is a valid and reliable scale for the diagnosis and staging of diabetic sensorimotor polyneuropathy. In this study, we aimed to explore the performance of the TCNS in non‐diabetic polyneuropathies.

Methods

We performed a prospective study from November 2016 to May 2017 of patients with non‐diabetic polyneuropathy. Patients had clinical, electrophysiological and functional assessments of their polyneuropathy, and the findings were correlated with the TCNS.

Results

The TCNS correlated with all clinical, electrophysiological and disability measures of polyneuropathy, mostly at a moderate level (e.g. = −0.58 for sural nerve action potential amplitude). Higher TCNS severity grades were associated with worse polyneuropathy on all measures in the lower limbs, and with worse electrophysiological parameters and vibration perception thresholds in the upper limbs. The scale also showed excellent reliability and accuracy (kappa, 0.92–0.93 for inter‐ and intra‐observer reliability; area under the receiver operating characteristics curve, 0.93).

Conclusion

The TCNS is a valid and reliable scale for a wide spectrum of polyneuropathies, and might be useful in clinical practise and research for the diagnosis and staging of polyneuropathy.

Background and purpose

Natural history studies in spinal muscular atrophy (SMA) have primarily focused on infants and children. Natural history studies encompassing all age groups and SMA types are important for the interpretation of treatment effects of recently introduced survival motor neuron gene‐augmenting therapies.

Methods

We conducted a cross‐sectional study to investigate muscle strength, Hammersmith Functional Motor Scale (Expanded) score and the patterns of muscle weakness in relation to age and SMA type.

Results

We included 180 patients with SMA types 1–4 in the age range 1–77.5 years with median disease duration of 18 (range 0–65.8) years. With the exception of the early phases of disease in which children with SMA types 2 and 3 may achieve new motor skills and show a temporary increase in muscle strength, cross‐sectional data suggested that declining muscle strength and loss of motor skills over time are characteristic of all SMA types. Mean loss of strength was at least 1 point on the Medical Research Council score and 0.5 point on the Hammersmith Functional Motor Scale (Expanded) score per year. Trend lines compatible with deterioration of motor function and muscle strength started in childhood and continued into adulthood. The age at loss of specific motor skills was associated with disease severity. Triceps, deltoid, iliopsoas and quadriceps were the weakest muscles in all patients. Hierarchical cluster analysis did not show a segmental distribution of muscle weakness as suggested previously.

Conclusions

Progressive muscle weakness and loss of motor function are characteristic of all SMA types and all ages.

Background and purpose

Myasthenia gravis (MG) is an autoimmune disorder characterized by fatigable muscle weakness due to antibody‐mediated impairment of neuromuscular transmission. The aim of this study was to investigate the incidence and prevalence of MG in Latvia, and to characterize this population by well‐established clinical parameters such as age at onset, presence of associated antibodies and thymus pathology.

Methods

All prevalent cases on 1 January 2015 and cases of patients newly presenting with MG symptoms from 1 January 2010 to 31 December 2014 were selected from the database of the Neuromuscular Disease Clinic of Pauls Stradins Clinical University Hospital and Children's Clinical University Hospital. Crude rates were calculated based on population data. These were directly age‐standardized to the European and World Health Organization world standard populations. The analysis of clinical characteristics was carried out in a cohort of patients who had undergone a complete set of electrophysiological, serological and radiological investigations ( = 153; 68%).

Results

During the study period 99 incident and 226 prevalent cases were identified. The total crude MG incidence was 9.7 per million person‐years. The prevalence of MG on 1 January 2015 was 113.8 per million. 54.2% of patients tested positive for acetylcholine receptor antibodies, 7.8% for muscle specific kinase antibodies and 1.3% for lipoprotein related protein 4 antibodies.

Conclusions

This is the first study of MG in Latvia and the second population‐based study of MG in Eastern Europe. Our epidemiological results are similar to those in some other European and Northern American countries, and show high prevalence and increasing incidence of late‐onset MG.

Background and purpose

We have previously shown that patients with multiple sclerosis receiving immunomodulatory treatment have reduced seroprotection rates after influenza immunization. The aim of this study was to further investigate the influence of immunomodulatory therapies on the antibody response and seroprotection rates in patients immunized with seasonal influenza vaccine in 2012/2013 compared with healthy controls.

Methods

Ninety patients receiving fingolimod, glatiramer acetate, interferon beta‐1a/1b, natalizumab or no therapy were compared with 62 healthy controls. All subjects received the inactivated split virus vaccine in 2012 and serum samples were collected pre‐vaccination and 3, 6 and 12 months post‐vaccination. The vaccine responses were evaluated by the hemagglutination inhibition assay and adjusted for age and gender.

Results

No significant differences in rates of protection against H1N1 for interferon beta‐1a/1b and glatiramer acetate were observed as compared with controls at 3, 6 and 12 months. Fingolimod provided reduced protection at all time points post‐vaccination, whereas natalizumab displayed reduced protection at 3 and 6 months. Patients without immunomodulation did not display protection rates that were significantly different from the controls at 3 and 12 months.

Conclusion

These findings suggest that patients with multiple sclerosis receiving fingolimod or natalizumab should be considered for a second dose of the vaccine in cases of insufficient protection. Our results further indicate that new immunomodulatory treatment regimens should be systematically evaluated for their influence on influenza‐specific vaccine responses.

Background and purpose

The reduction of delay between onset and hospital arrival and adequate pre‐hospital care of persons with acute stroke are important for improving the chances of a favourable outcome. The objective is to recommend evidence‐based practices for the management of patients with suspected stroke in the pre‐hospital setting.

Methods

The GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to define the key clinical questions. An expert panel then reviewed the literature, established the quality of the evidence, and made recommendations.

Results

Despite very low quality of evidence educational campaigns to increase the awareness of immediately calling emergency medical services are strongly recommended. Moderate quality evidence was found to support strong recommendations for the training of emergency medical personnel in recognizing the symptoms of a stroke and in implementation of a pre‐hospital ‘code stroke’ including highest priority dispatch, pre‐hospital notification and rapid transfer to the closest ‘stroke‐ready’ centre. Insufficient evidence was found to recommend a pre‐hospital stroke scale to predict large vessel occlusion. Despite the very low quality of evidence, restoring normoxia in patients with hypoxia is recommended, and blood pressure lowering drugs and treating hyperglycaemia with insulin should be avoided. There is insufficient evidence to recommend the routine use of mobile stroke units delivering intravenous thrombolysis at the scene. Because only feasibility studies have been reported, no recommendations can be provided for pre‐hospital telemedicine during ambulance transport.

Conclusions

These guidelines inform on the contemporary approach to patients with suspected stroke in the pre‐hospital setting. Further studies, preferably randomized controlled trials, are required to examine the impact of particular interventions on quality parameters and outcome.

Background and purpose

Embolic strokes of undetermined source (ESUS) are a recent entity, not yet thoroughly investigated in young stroke patients. The clinical characteristics and long‐term risks of vascular events and all‐cause mortality between young‐onset ESUS and other aetiological subgroups were compared.

Methods

Patients with ESUS were identified amongst the 1008 patients aged 15−49 years with first‐ever ischaemic stroke in Helsinki Young Stroke Registry, and primary end‐points were defined as recurrent stroke, composite vascular events and all‐cause mortality. Cumulative 15‐year risks for each end‐point were analysed with life tables and adjusted risks were based on Cox proportional hazard analyses.

Results

Of the 971 eligible patients, 203 (20.9%) were classified as ESUS. They were younger (median age 40 years, interquartile range 32–46 vs. 45 years, 39–47), more often female (43.3% vs. 35.7%) and had fewer cardiovascular risk factors than other modified TOAST groups. With a median follow‐up time of 10.1 years, ESUS patients had the second lowest cumulative risk of recurrent stroke and composite vascular events and lowest mortality compared to other TOAST groups. Large‐artery atherosclerosis and small vessel disease carried significantly higher risk for recurrent stroke than did ESUS, whilst no difference appeared between cardioembolism from high‐risk sources and ESUS.

Conclusions

In our cohort, ESUS patients were younger and had milder cardiovascular risk factor burden and generally better long‐term outcome compared to other causes of young‐onset stroke. The comparable risk of recurrent stroke between ESUS and high‐risk sources of cardioembolism might suggest similarities in their pathophysiology.

Background and purpose

This cross‐sectional study aims to compare gait changes after the cerebrospinal fluid (CSF) tap test between normal pressure hydrocephalus patients with and without brain comorbidities (NPH+ and NPH− respectively) and then to identify significant contributors to a poor CSF tap test amongst individuals with NPH+.

Methods

Gait changes (during the single task and the dual task of backward counting) were quantified before and 24 h after the CSF tap test with an optoelectronic system in 52 NPH patients (77.4 ± 6.0 years; 34.6% women). Changes after the CSF tap test in stride time variability (STV, %) were our main outcome. CSF Alzheimer's disease biomarkers, cerebrovascular white matter changes assessed with brain imaging and neurodegenerative diseases with parkinsonian syndrome represented the three individual brain comorbidities.

Results

Brain comorbidities were frequently identified, NPH+ patients representing 40 patients of our sample (76.9%). NPH− patients improved their STV better in the single task (delta of STV = −58.6% ± 54.3% vs. −14.1% ± 62.0%; = 0.031) and in the dual task (delta of STV =−32.2% ± 33.7% vs. 6.3% ± 58.4%; = 0.028) after the CSF tap test than NPH+ patients. Amongst NPH+ individuals, only comorbid Alzheimer's disease was associated with STV increase (i.e. deterioration of gait) in the dual task [ 38.4; 95% confidence interval (5.64; 71.24); = 0.023] after the CSF tap test, whilst it was borderline in the single task [ 35.0; 95% confidence interval (−1.97; 71.90); = 0.063].

Conclusions

Brain comorbidities affect gait improvement after the CSF tap test in NPH patients; this influence is driven by Alzheimer's disease‐related pathology.

Abstract

Cerebral microbleeds (CMBs) are small foci of (acute, subacute or chronic) blood products, best seen using magnetic resonance imaging (MRI) techniques sensitive to iron deposits (i.e. gradient‐echo T2*‐weighted and susceptibility‐weighted imaging), frequently encountered in small vessel disease (SVD) (with hypertensive vasculopathy and cerebral amyloid angiopathy as the most frequent conditions) and also in other disorders. In this review, the MRI characteristics of CMBs and the associated MRI abnormalities encountered in common and less common SVD and non‐SVD conditions are the main focus. Identification of the origin of CMBs depends on their localization, the presence of other associated MRI abnormalities, and the patient's history and clinical state.

Background and purpose

Studies showed that β‐cell dysfunction is associated with increased risk of cardiovascular disease and subclinical carotid atherosclerosis. This study aimed to investigate the association between β‐cell function and prognosis of non‐diabetic patients with ischaemic stroke.

Methods

Ischaemic stroke patients without diabetes in the Abnormal Glucose Regulation in Patients with Acute Stroke across China registry were included in this analysis. Homeostasis assessment of β‐cell function (HOMA‐β) was performed and classified into four groups according to quartiles. The outcomes included stroke recurrence, poor functional outcome and all‐cause mortality.

Results

In a total of 1244 patients, the average age was 62.3 years; 63.1% patients were male. At 1 year, the first quartile of HOMA‐β (<54.0) was associated with increased stroke recurrence (adjusted hazard ratio 2.04, 95% confidence interval 1.32–3.17, =0.001), poor functional outcome (adjusted odds ratio 3.04, 95% confidence interval 1.90–4.88, <0.001) and mortality (adjusted hazard ratio 4.12, 95% confidence interval 2.24−7.59, <0.001) compared with the fourth quartile of HOMA‐β (≥166.3) after adjustment for insulin resistance and other potential covariates. The second and third quartiles of HOMA‐β were significantly associated with an increased risk of poor functional outcome. Multivariable regression analysis with restricted cubic splines showed an L‐shaped association between HOMA‐β and outcomes at 1 year.

Conclusions

Our study shows that lower HOMA‐β level is associated with poor outcomes at 1 year in non‐diabetic patients with ischaemic stroke.

Background and purpose

Forced vital capacity (FVC) <80% is one of the key indications for starting non‐invasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). It was hypothesized that a very early start of NIV could lengthen the free interval before death compared to later‐start NIV; as a secondary outcome, the survival rate of patients on NIV without tracheotomy was also evaluated.

Methods

This retrospective study was conducted on 194 ALS patients, divided into a later group (LG) with FVC <80% at NIV prescription ( = 129) and a very early group (VEG) with FVC ≥80% at NIV prescription ( = 65). Clinical and respiratory functional data and time free to death between groups over a 3‐year follow‐up were compared.

Result

At 36 months from diagnosis, mortality was 35% for the VEG versus 52.7% for the LG ( = 0.022). Kaplan−Meier survival curves adjusted for tracheotomy showed a lower probability of death ( = 0.001) for the VEG as a whole ( = 0.001) and for the non‐bulbar (NB) subgroup ( = 0.007). Very early NIV was protective of survival for all patients [hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.28–0.74;  = 0.001] and for the NB subgroup (HR 0.43; 95% CI 0.23–0.79;  = 0.007), whilst a tracheotomy was protective for all patients (HR 0.27; 95% CI 0.15–0.50;  = 0.000) and both NB (HR 0.26; 95% CI 0.12–0.56;  = 0.001) and bulbar subgroups (HR 0.29; 95% CI 0.11–0.77;  = 0.013). Survival in VEG patients on NIV without tracheotomy was three times that for the LG (43.1% vs. 14.7%).

Conclusion

Very early NIV prescription prolongs the free time from diagnosis to death in NB ALS patients whilst tracheotomy reduces the mortality risk in all patients.

Abstract

Deep brain stimulation (DBS) is an established therapy for appropriately selected patients with movement disorders and neuropsychiatric conditions. Although the exact mechanisms and biology of DBS are not fully understood, it is a safe and well‐tolerated therapy for many refractory cases of neuropsychiatric disease. Increasingly, DBS has been explored in other conditions with encouraging results. In this paper, available data is reviewed and new DBS targets, challenges and future directions in neurological disorders are explored. A detailed search of the medical literature discussing the potential use of DBS for neurological disorders excluding accepted indications was conducted. All reports were analyzed individually for content and redundant articles were excluded by examining individual abstracts. The level of evidence for each indication was summarized. Multiple studies report promising preliminary data regarding the safety and efficacy of DBS for a variety of neurological indications including chronic pain, tinnitus, epilepsy, Tourette syndrome, Huntington's disease, tardive dyskinesia and Alzheimer's disease. The initial results of DBS studies for diverse neurological disorders are encouraging but larger, controlled, prospective, homogeneous clinical trials are necessary to establish long‐term safety and effectiveness. The field of neuromodulation continues to evolve and advances in DBS technology, stereotactic techniques, neuroimaging and DBS programming capabilities are shaping the present and future of DBS research and use in practice.

Background and purpose

Serum neurofilaments are markers of axonal injury. We addressed their diagnostic and prognostic role in acute ischemic stroke (AIS) and transient ischemic attack (TIA).

Methods

Nested within a prospective cohort study, we compared levels of serum neurofilament light chain (sNfL) drawn within 24 h from symptom onset in patients with AIS or TIA. Patients without magnetic resonance imaging on admission were excluded. We assessed whether sNfL was associated with: (i) clinical severity on admission, (ii) diagnosis of AIS vs. TIA, (iii) infarct size on admission magnetic resonance diffusion‐weighted imaging (MR‐DWI) and (iv) functional outcome at 3 months.

Results

We analyzed 504 patients with AIS and 111 patients with TIA. On admission, higher National Institutes of Health Stroke Scale (NIHSS) scores were associated with higher sNfL: NIHSS score < 7, 13.1 pg/mL [interquartile range (IQR), 5.3–27.8]; NIHSS score 7–15, 16.7 pg/mL (IQR, 7.4–34.9); and NIHSS score > 15, 21.0 pg/mL (IQR, 9.3–40.4) ( = 0.01). Compared with AIS, patients with TIA had lower sNfL levels [9.0 pg/mL (95% confidence interval, 4.0–19.0) vs. 16.0 pg/mL (95% confidence interval, 7.3–34.4), < 0.001], also after adjusting for age and NIHSS score ( = 0.006). Among patients with AIS, infarct size on admission MR‐DWI was not associated with sNfL, either in univariate analysis ( = 0.15) or after adjusting for age and NIHSS score on admission ( = 0.56). Functional outcome 3 months after stroke was not associated with sNfL after adjusting for established predictors.

Conclusions

In conclusion, among patients admitted within 24 h of AIS or TIA onset, admission sNfL levels were associated with clinical severity on admission and TIA diagnosis, but not with infarct size on MR‐DWI acquired on admission or functional outcome at 3 months.

Background and purpose

Despite the important role of imaging in diagnosing idiopathic normal‐pressure hydrocephalus (iNPH), a structured overall assessment of radiological signs is still lacking. The purpose of this study was to construct a radiological scale, composed of morphological signs of iNPH, and compare it with clinical symptoms.

Methods

In this prospective, population‐based study of iNPH, 168 individuals (93 females) [mean age 75 (range 66–92) years] underwent computed tomography of the brain and a neurological examination with assessment of clinical symptoms according to Hellström's iNPH scale. Two radiologists, blinded to clinical data, independently evaluated and measured eight radiological parameters, i.e. Evans’ index, callosal angle, size of temporal horns, narrow high‐convexity sulci, dilated Sylvian fissures, focally dilated sulci, peri‐ventricular hypodensities and bulging of the lateral ventricular roof.

Results

In a linear regression model, all parameters except ventricular roof bulging were significantly associated with clinical iNPH symptoms. The seven remaining parameters were summarized into a total iNPH Radscale score ranging from 0 to 12. There was a significant correlation ( = 0.55, <0.001) between the total iNPH Radscale score and clinical symptoms. The inter‐rater agreement for the included radiological parameters was high (intraclass correlation, 0.74–0.97).

Conclusion

The iNPH Radscale may become a valuable diagnostic screening tool, allowing a structured radiological assessment. A high iNPH Radscale score together with clinical symptoms should raise suspicion of iNPH, motivating further evaluation for shunt surgery.

Background and purpose

Non‐alcoholic fatty liver disease (NAFLD) is closely correlated to visceral obesity, dyslipidaemia, insulin resistance and type 2 diabetes mellitus. We sought to assess the association between a specific stroke subgroup, brainstem infarctions (BSIs) and NAFLD. Furthermore, we evaluated whether NAFLD is an independent risk factor in patients with BSIs.

Methods

Non‐alcoholic fatty liver disease was assessed in 306 patients with radiologically confirmed BSIs via liver ultrasound. Differences between patients with and without NAFLD were compared. Data associated with stroke severity and progression after admission were collected.

Results

Non‐alcoholic fatty liver disease was found in 130 (42.5%) patients with acute BSIs; 58 (19.0%) had National Institutes of Health Stroke Scale scores >7 and 57 (18.6%) had progression after admission. Initial National Institutes of Health Stroke Scale scores, incidence of progression and stroke severity, and modified Rankin Scale scores at discharge were significantly higher in patients with NAFLD than in those without NAFLD. NAFLD was associated with stroke severity [Cox regression: hazard ratio (HR), 2.243; 95% confidence interval (CI), 1.254–4.013, < 0.01]. This risk remained statistically significant after controlling for age, gender, diabetes mellitus and C‐reactive protein (HR, 2.327; 95% CI, 1.252–4.324, < 0.01). In addition, NAFLD was associated with progression (HR, 2.155; 95% CI, 1.201–3.865, < 0.05) and remained significant after controlling for age, gender, diabetes mellitus, fibrinogen and C‐reactive protein (HR, 2.378; 95% CI, 1.260–4.486, < 0.01).

Conclusions

These results suggest that NAFLD is a potential risk factor when evaluating the severity and progression of acute BSIs. This relationship is independent of classic risk factors and metabolic syndrome features.

Background and purpose

Juvenile‐ or adult‐onset forms of severe 5,10‐methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting as complicated hereditary spastic paraplegia have rarely been described.

Methods

Two siblings with mental retardation developed a progressive spastic paraparesis in their late teens. Their diagnostic assessment included extensive neurophysiologic, neuroimaging and metabolic studies.

Results

Brain magnetic resonance imaging showed occipital white matter alterations, and electromyography documented a mixed polyneuropathy. Severe hyperhomocisteinemia (>150 μmol/L) associated with the characteristic amino acid profile suggested a diagnosis of severe MTHFR deficiency, confirmed by direct sequencing. Treatment with betaine and vitamins benefitted patients' symptoms and diagnostic features.

Conclusions

Severe MTHFR deficiency can be a rare, treatable cause of autosomal recessive complicated hereditary spastic paraplegia. Its screening should be part of the diagnostic flowchart for these disorders.

Abstract

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Since the 1970s, intravenous (IV) phenytoin (PHT) has traditionally been used as second‐stage treatment for convulsive status epilepticus (SE) after failure of benzodiazepines. The aim of this review was to critically assess the evidence supporting the use of IV PHT as treatment of convulsive SE in patients of any age. In particular, we critically appraised the results of randomized controlled trials (RCTs) evaluating IV PHT as treatment of convulsive SE. A systematic search of the literature was carried out to identify RCTs evaluating IV PHT as treatment of convulsive SE in patients of any age. Eight RCTs (544 patients allocated to IV PHT) were included. The included studies differed in almost every single characteristic considered. Six RCTs (472 patients) used IV PHT without demonstrating refractoriness of SE to benzodiazepines. Only two RCTs (72 patients) used IV PHT as second‐line treatment for benzodiazepine‐resistant convulsive SE. Overall, most evidence from RCTs supports the use of IV PHT immediately after IV diazepam, even if seizures have not recurred. The recommendation derived from RCTs supporting the use of IV PHT as second‐line treatment in benzodiazepine‐resistant convulsive SE is weak. This is emblematic of the lack of robust evidence from large RCTs to inform clinical practice on how to treat SE after failure of first‐line drugs. IV PHT given immediately after first‐line benzodiazepines could prolong their short antiepileptic effect and prevent seizure recurrence.

Background and purpose

Dimethyl fumarate (DMF) is an oral treatment for relapsing‐remitting multiple sclerosis (MS) with anti‐inflammatory and possible neuroprotective properties. Its effect on white matter and gray matter pathology is still not fully understood. The aim of the study was to characterize the effect of DMF on normal‐appearing white matter (NAWM) and thalamic pathology longitudinally.

Methods

In this observational, longitudinal, 24‐month magnetic resonance imaging study, 75 patients with relapsing‐remitting MS treated with DMF and 40 age‐ and sex‐matched healthy individuals were enrolled. Regional diffusion tensor imaging metrics and tract‐based spatial statistics analyses were used to assess differences between groups. Mean diffusivity, axial diffusivity, radial diffusivity and fractional anisotropy were measured in the thalamus and NAWM. Baseline differences and changes over time were evaluated within and between study groups.

Results

At baseline, patients with MS showed significantly increased diffusivity and decreased fractional anisotropy in the thalamus (< 0.001 for mean diffusivity, axial diffusivity and radial diffusivity) and NAWM (all  < 0.016) compared with healthy individuals. No significant within‐group difference was found in diffusion tensor imaging measures over 24 months in either group. Healthy individuals showed a significantly greater rate of increased diffusivity parameters in the thalamus and NAWM compared with patients with MS, over 24 months ( < 0.05).

Conclusions

The lack of changes in diffusion tensor imaging metrics in patients with MS over 24 months possibly indicates a neuroprotective role of DMF. These findings provide additional evidence of the beneficial effect of DMF on MS‐related pathology.

Background and purpose

Celiac disease (CD) is associated with an increased risk of developing epilepsy, a risk that persists after CD diagnosis. A significant proportion of patients with CD have persistent villous atrophy (VA) on follow‐up biopsy. The objective of this study was to determine whether persistent VA on follow‐up biopsy affected long‐term epilepsy risk and epilepsy‐related hospital emergency admissions.

Methods

This was a nationwide cohort study. We identified all people in Sweden with histological evidence of CD who underwent a follow‐up small intestinal biopsy (1969–2008). We compared those with persistent VA with those who showed histological improvement, assessing the development of epilepsy and related emergency hospital admissions (defined according to relevant International Classification of Diseases codes in the Swedish Patient Register). Cox regression analysis was used to assess outcome measures.

Results

Villous atrophy was present in 43% of 7590 people with CD who had a follow‐up biopsy. The presence of persistent VA was significantly associated with a reduced risk of developing newly‐diagnosed epilepsy (hazard ratio, 0.61; 95% confidence interval, 0.38–0.98). On stratified analysis, this effect was primarily amongst males (hazard ratio, 0.35; 95% confidence interval, 0.15–0.80). Among the 58 patients with CD with a prior diagnosis of epilepsy, those with persistent VA were less likely to visit an emergency department with epilepsy (hazard ratio, 0.37; 95% confidence interval, 0.09–1.09).

Conclusions

In a population‐based study of individuals with CD, persisting VA on follow‐up biopsy was associated with reduced future risk of developing epilepsy but did not influence emergency epilepsy‐related hospital admissions. The mechanism as to why persistent VA confers this benefit requires further exploration.