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Background and PurposeThe lack of a robust diagnostic biomarker makes understanding depression from a neurobiological standpoint an important goal, especially in the context of brain imaging.MethodsIn this study, we aim to create novel image-based features for objective diagnosis of depression. Resting-state network time series are used to investigate neurodynamics with the help of wavelet coherence and Granger causality (G-causality). Three new features are introduced: total wavelet coherence, wavelet lead coherence, and wavelet coherence blob analysis. The fourth feature, pair-wise conditional G-causality, is used to establish the causality between resting-state networks. We use the proposed features to classify depression in adult subjects.ResultsWe obtained an accuracy of 86% in the wavelet lead coherence, 80% in Granger causality, and 86% in wavelet coherence blob analysis. Subjects with depression showed hyperconnectivity between the dorsal attention network and the auditory network as well as between the posterior default mode network and the dorsal attention network. Hypoconnectivity was found between the anterior default mode network and the auditory network as well as the right frontoparietal network and the lateral visual network. An abnormal co-activation pattern was found between cerebellum and the lateral motor network according to the wavelet coherence blob analysis.ConclusionBased on abnormal functional dynamics between brain networks, we were able to identify subjects with depression with high accuracy. The findings of this study contribute to the understanding of the impaired emotional and attention processing associated with depression, as well as decreased motor activity., BACKGROUND AND PURPOSE: The lack of a robust diagnostic biomarker makes understanding depression from a neurobiological standpoint an important goal, especially in the context of brain imaging.METHODS: In this study, we aim to create novel image-based features for objective diagnosis of depression. Resting-state network time series are used to investigate neurodynamics with the help of wavelet coherence and Granger causality (G-causality). Three new features are introduced: total wavelet coherence, wavelet lead coherence, and wavelet coherence blob analysis. The fourth feature, pair-wise conditional G-causality, is used to establish the causality between resting-state networks. We use the proposed features to classify depression in adult subjects.RESULTS: We obtained an accuracy of 86% in the wavelet lead coherence, 80% in Granger causality, and 86% in wavelet coherence blob analysis. Subjects with depression showed hyperconnectivity between the dorsal attention network and the auditory network as well as between the posterior default mode network and the dorsal attention network. Hypoconnectivity was found between the anterior default mode network and the auditory network as well as the right frontoparietal network and the lateral visual network. An abnormal co-activation pattern was found between cerebellum and the lateral motor network according to the wavelet coherence blob analysis.CONCLUSION: Based on abnormal functional dynamics between brain networks, we were able to identify subjects with depression with high accuracy. The findings of this study contribute to the understanding of the impaired emotional and attention processing associated with depression, as well as decreased motor activity.

Objectives Patients with Korsakoff syndrome (KS) may have a diminished pain perception. Information on KS and pain is scarce and limited to case descriptions. The present study is the first to investigate the underlying neural mechanisms of altered pain perception in patients with KS more systematically. Methods We conducted a literature search on neural correlates of pain perception in other neurocognitive disorders in which extensive research was done. Results The brain areas that are affected in KS showed considerable overlap with the neural correlates of pain perception in other neurocognitive disorders. We discussed which different aspects of disturbed pain perception could play a role within KS, based on distinct neural damage and brain areas involved in pain perception. Conclusions Combining current knowledge, we hypothesize that diminished pain perception in KS may be related to lesioned neural connections between cerebral cortical networks and relays of mainly the thalamus, the periaqueductal gray, and possibly lower brain stem regions projecting to the cerebellum. Based on these neural correlates of altered pain perception, we assume that increased pain thresholds, inhibition of pain signals, and disturbed input to cerebral and cerebellar cortical areas involved in pain processing, all are candidate mechanisms in cases of diminished pain perception in KS. We recommend that clinicians need to be alert for somatic morbidity in patients with KS. Due to altered neural processing of nociceptive input the clinical symptoms of somatic morbidity may present differently (i.e. limited pain responses) and therefore are at risk of being missed.

Background: Endovascular treatment (EVT) for acute ischemic stroke (AIS) is performed in intervention centers that provide the full range of neuro(endo)vascular care (level 1) and centers that only perform EVT for AIS (level 2). We compared outcomes between these center types and assessed whether differences in outcomes could be explained by center volume (CV). Patients and methods: We analyzed patients included in the MR CLEAN Registry (2014–2018), a registry of all EVT-treated patients in the Netherlands. Our primary outcome was the shift on the modified Rankin scale (mRS) after 90 days (ordinal regression). Secondary outcomes were the NIHSS 24–48 h post-EVT, door-to-groin time (DTGT), procedure time (linear regression), and recanalization (binary logistic regression). We compared outcomes between level 1 and 2 centers using multilevel regression models, with center as random intercept. We adjusted for relevant baseline factors, and in case of observed differences, we additionally adjusted for CV. Results: Of the 5144 patients 62% were treated in level 1 centers. We observed no significant differences between center types in mRS (adjusted(a)cOR: 0.79, 95% CI: 0.40 to 1.54), NIHSS (aβ: 0.31, 95% CI: −0.52 to 1.14), procedure duration (aβ: 0.88, 95% CI: −5.21 to 6.97), or DTGT (aβ: 4.24, 95% CI: −7.09 to 15.57). The probability for recanalization was higher in level 1 centers compared to level 2 centers (aOR 1.60, 95% CI: 1.10 to 2.33), and this difference probably depended on CV. Conclusions: We found no significant differences, that were independent of CV, in the outcomes of EVT for AIS between level 1 and level 2 intervention centers.

This study investigates the validity of Children's Time Awareness Questionnaire (CTAQ), a 20-item task for assessing children's time awareness. The CTAQ was administered to a group of typically developing children ( n = 107) and children with any developmental problems reported by parents (non-typically developing children, n = 28), aged 4-8 years old. We found some support for a one-factor structure (EFA), yet the explained variance is relatively low (21%). Our proposed structure of two additional subscales, i.e., "time words" and "time estimation," was not supported by (confirmatory and exploratory) factor analyses. In contrast, exploratory factor analyses (EFA) indicated a six-factor structure, which needs further investigation. We found low, yet non-significant correlations between CTAQ scales and caregiver reports on children's time awareness, planning and impulsivity, and no significant correlations between CTAQ scales and scores on cognitive performance tasks. As expected, we found that older children have higher CTAQ scores than younger children. Non typically developing children had lower scores on CTAQ scales, compared to typically developing children. The CTAQ has sufficient internal consistency. The CTAQ has potential to measure time awareness, future research is indicated to further develop the CTAQ and enhance clinical applicability.

BackgroundThe relationship between the interventionist’s experience and outcomes of endovascular thrombectomy (EVT) for acute ischemic stroke of the anterior circulation, is unclear.ObjectiveTo assess the effect of the interventionist’s level of experience on clinical, imaging, and workflow outcomes. Secondly, to determine which of the three experience definitions is most strongly associated with these outcome measures.MethodsWe analysed data from 2700 patients, included in the MR CLEAN Registry. We defined interventionist’s experience as the number of procedures performed in the year preceding the intervention (EXPfreq), total number of procedures performed (EXPno), and years of experience (EXPyears). Our outcomes were the baseline-adjusted National Institutes of Health Stroke Scale (NIHSS) score at 24–48 hours post-EVT, recanalization (extended Thrombolysis in Cerebral Infarction (eTICI) score ≥2B), and procedural duration. We used multilevel regression models with interventionists as random intercept. For EXPfreq and EXPno results were expressed per 10 procedures.ResultsIncreased EXPfreq was associated with lower 24–48 hour NIHSS scores (adjusted (a)β:−0.46, 95% CI −0.70 to −0.21). EXPno and EXPyears were not associated with short-term neurological outcomes. Increased EXPfreq and EXPno were both associated with recanalization (aOR=1.20, 95% CI 1.11 to 1.31 and aOR=1.08, 95% CI 1.04 to 1.12, respectively), and increased EXPfreq, EXPno, and EXPyears were all associated with shorter procedure times (aβ:−3.08, 95% CI−4.32 to −1.84; aβ:−1.34, 95% CI−1.84 to −0.85; and aβ:−0.79, 95% CI−1.45 to −0.13, respectively).ConclusionsHigher levels of interventionist’s experience are associated with better outcomes after EVT, in particular when experience is defined as the number of patients treated in the preceding year. Every 20 procedures more per year is associated with approximately one NIHSS score point decrease, an increased probability for recanalization (aOR=1.44), and a 6-minute shorter procedure time.

Background: Identification of risk factors and causes of stroke is key to optimize treatment and prevent recurrence. Up to one-third of young patients with stroke have a cryptogenic stroke according to current classification systems (Trial of ORG 10172 in Acute Stroke Treatment [TOAST] and atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection [ASCOD]). The aim was to identify risk factors and leads for (new) causes of cryptogenic ischemic stroke in young adults, using the pediatric classification system from the IPSS study (International Pediatric Stroke Study). Methods: This is a multicenter prospective cohort study conducted in 17 hospitals in the Netherlands, consisting of 1322 patients aged 18 to 49 years with first-ever, imaging confirmed, ischemic stroke between 2013 and 2021. The main outcome was distribution of risk factors according to IPSS classification in patients with cryptogenic and noncryptogenic stroke according to the TOAST and ASCOD classification. Results: The median age was 44.2 years, and 697 (52.7%) were men. Of these 1322 patients, 333 (25.2%) had a cryptogenic stroke according to the TOAST classification. Additional classification using the ASCOD criteria reduced the number patients with cryptogenic stroke from 333 to 260 (19.7%). When risk factors according to the IPSS were taken into account, the number of patients with no potential cause or risk factor for stroke reduced to 10 (0.8%). Conclusions: Among young adults aged 18 to 49 years with a cryptogenic ischemic stroke according to the TOAST classification, risk factors for stroke are highly prevalent. Using a pediatric classification system provides new leads for the possible causes in cryptogenic stroke, and could potentially lead to more tailored treatment for young individuals with stroke.

IntroductionThe efficacy and safety of local intra-arterial (IA) thrombolytics during endovascular thrombectomy (EVT) for large-vessel occlusions is uncertain. We analysed how often IA thrombolytics were administered in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry, whether it was associated with improved functional outcome and assessed technical and safety outcomes compared with EVT without IA thrombolytics.MethodsIn this observational study, we included patients undergoing EVT for an acute ischaemic stroke in the anterior circulation from the MR CLEAN Registry (March 2014–November 2017). The primary endpoint was favourable functional outcome, defined as an modified Rankin Scale score ≤2 at 90 days. Secondary endpoints were reperfusion status, early neurological recovery and symptomatic intracranial haemorrhage (sICH). Subgroup analyses for IA thrombolytics as primary versus adjuvant revascularisation attempt were performed.ResultsOf the 2263 included patients, 95 (4.2%) received IA thrombolytics during EVT. The IA thrombolytics administered were urokinase (median dose, 250 000 IU (IQR, 1 93 750–2 50 000)) or alteplase (median dose, 20 mg (IQR, 12–20)). No association was found between IA thrombolytics and favourable functional outcome (adjusted OR (aOR), 1.16; 95% CI 0.71 to 1.90). Successful reperfusion was less often observed in those patients treated with IA thrombolytics (aOR, 0.57; 95% CI 0.36 to 0.90). The odds of sICH (aOR, 0.82; 95% CI 0.32 to 2.10) and early neurological recovery were comparable between patients treated with and without IA thrombolytics. For primary and adjuvant revascularisation attempts, IA thrombolytics were more often administered for proximal than for distal occlusions. Functional outcomes were comparable for patients receiving IA thrombolytics as a primary versus adjuvant revascularisation attempt.ConclusionLocal IA thrombolytics were rarely used in the MR CLEAN Registry. In the relatively small study sample, no statistical difference was observed between groups in the rate of favourable functional outcome or sICH. Patients whom required and underwent IA thrombolytics were patients less likely to achieve successful reperfusion, probably due to selection bias.

BACKGROUND: Cognitive behavioral therapy (CBT) reduces anxiety symptoms in patients with Parkinson's disease (PD).OBJECTIVE: The objective of this study was to identify changes in functional connectivity in the brain after CBT for anxiety in patients with PD.METHODS: Thirty-five patients with PD and clinically significant anxiety were randomized over two groups: CBT plus clinical monitoring (10 CBT sessions) or clinical monitoring only (CMO). Changes in severity of anxiety symptoms were assessed with the Parkinson Anxiety Scale (PAS). Resting-state functional brain MRI was performed at baseline and after the intervention. Functional networks were extracted by an Independent Component Analysis (ICA). Functional connectivity (FC) changes between structures involved in the PD-related anxiety circuits, such as the fear circuit (involving limbic, frontal, and cingulate structures) and the cortico-striato-thalamo-cortical limbic circuit, and both within and between functional networks were compared between groups and regressed with anxiety symptoms changes.RESULTS: Compared to CMO, CBT reduced the FC between the right thalamus and the bilateral orbitofrontal cortices and increased the striato-frontal FC. CBT also increased the fronto-parietal FC within the central executive network (CEN) and between the CEN and the salience network. After CBT, improvement of PAS-score was associated with an increased striato-cingulate and parieto-temporal FC, and a decreased FC within the default-mode network and between the dorsal attentional network and the language network.CONCLUSION: CBT in PD-patients improves anxiety symptoms and is associated with functional changes reversing the imbalance between PD-related anxiety circuits and reinforcing cognitive control on emotional processing.

Arterial walls stiffen with age, cardiovascular risk factors, and various vascular diseases, which may lead to less damping of the arterial blood flow pulse, subsequent microvascular damage, and enlarged perivascular spaces (PVS). However, the exact interplay between these processes is unclear. This study aimed to investigate the relation between blood flow velocity pulsatility in the small lenticulostriate arteries and their supplying middle cerebral artery and the respective damping factor (DF), with the number of MRI-visible PVS in elderly subjects. Blood flow velocity waveforms were obtained in 45 subjects (median age [range]: 64 [48–81] years, 47% male) using 7T MRI. PVS were scored in the basal ganglia (BG) and centrum semiovale (CSO). Spearman correlation analyses were used to determine associations of the blood flow pulsatility and the DF, with PVS score, adjusted for age and sex. We found a significant association between a lower DF and a higher number of PVS in the BG ( rs = −0.352, P = 0.021), but not in the CSO. This finding supports the supposed pathophysiological mechanism in which excessive kinetic energy deposition leads to damage of small perforating arteries and contributes to the enlargement of PVS at the level of the BG, but possible other pathways might also be of influence.

Blood pressure variability (BPV) is related to cerebral white matter hyperintensities (WMH), but longitudinal studies assessing WMH progression are scarce. Patients with cardiovascular disease and control participants of the Heart-Brain Connection Study underwent 24-hour ambulatory blood pressure monitoring and repeated brain MRI at baseline and after 2 years. Using linear regression, we determined whether different measures of BPV (standard deviation, coefficient of variation, average real variability (ARV), variability independent of the mean) and nocturnal dipping were associated with WMH and whether this association was mediated or moderated by baseline cerebral perfusion. Among 177 participants (mean age: 65.9 ± 8.1 years, 33.9% female), the absence of diastolic nocturnal dipping was associated with higher WMH volume at baseline (β = 0.208, 95%CI: 0.025–0.392), but not with WMH progression among 91 participants with follow-up imaging. None of the BPV measures were associated with baseline WMH. Only 24-hour diastolic ARV was significantly associated with WMH progression (β = 0.144, 95%CI: 0.030–0.258), most profound in participants with low cerebral perfusion at baseline (p-interaction = 0.042). In conclusion, absent diastolic nocturnal dipping and 24-hour diastolic ARV were associated with higher WMH volume. Whilst requiring replication, these findings suggest that blood pressure patterns and variability may be a target for prevention of small vessel disease.

Aims To evaluate the clinical effectiveness of routine 24 h Holter monitoring to screen for conduction disturbances and arrhythmias in patients with myotonic dystrophy type 1 (DM1). Methods and results A retrospective two-centre study was conducted including DM1-affected individuals undergoing routine cardiac screening with at least one 24 h Holter monitoring between January 2010 and December 2020. For each individual, the following data were collected: Holter results, results of electrocardiograms (ECGs) performed at the same year as Holter monitoring, presence of cardiac complaints, and neuromuscular status. Holter findings were compared with the results of cardiac screening (ECG + history taking) performed at the same year. Cardiac conduction abnormalities and/or arrhythmias that would have remained undiagnosed based on history taking and ECG alone were considered de novo findings. A total 235 genetically confirmed DM1 patients were included. Abnormal Holter results were discovered in 126 (54%) patients after a mean follow-up of 64 ± 28 months in which an average of 3 ± 1 Holter recordings per patient was performed. Abnormalities upon Holter mainly consisted of conduction disorders (70%) such as atrioventricular (AV) block. Out of 126 patients with abnormal Holter findings, 74 (59%) patients had de novo Holter findings including second-degree AV block, atrial fibrillation/flutter and non-sustained ventricular tachycardia. Patient characteristics were unable to predict the occurrence of de novo Holter findings. In 39 out of 133 (29%) patients with normal ECGs upon yearly cardiac screening, abnormalities were found on Holter monitoring during follow-up. Conclusion Twenty-four hour Holter monitoring is of added value to routine cardiac screening for all DM1 patients.

PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

BACKGROUND: Chronic tinnitus can have an immense impact on quality of life. Despite recent treatment advances, many tinnitus patients remain refractory to them. Preclinical and clinical evidence suggests that deep brain stimulation (DBS) is a promising treatment to suppress tinnitus. In rats, it has been shown in multiple regions of the auditory pathway that DBS can have an alleviating effect on tinnitus. The thalamic medial geniculate body (MGB) takes a key position in the tinnitus network, shows pathophysiological hallmarks of tinnitus, and is readily accessible using stereotaxy. Here, a protocol is described to evaluate the safety and test the therapeutic effects of DBS in the MGB in severe tinnitus sufferers.METHODS: Bilateral DBS of the MGB will be applied in a future study in six patients with severe and refractory tinnitus. A double-blinded, randomized 2 × 2 crossover design (stimulation ON and OFF) will be applied, followed by a period of six months of open-label follow-up. The primary focus is to assess safety and feasibility (acceptability). Secondary outcomes assess a potential treatment effect and include tinnitus severity measured by the Tinnitus Functional Index (TFI), tinnitus loudness and distress, hearing, cognitive and psychological functions, quality of life, and neurophysiological characteristics.DISCUSSION: This protocol carefully balances risks and benefits and takes ethical considerations into account. This study will explore the safety and feasibility of DBS in severe refractory tinnitus, through extensive assessment of clinical and neurophysiological outcome measures. Additionally, important insights into the underlying mechanism of tinnitus and hearing function might be revealed.TRIAL REGISTRATION: ClinicalTrials.gov NCT03976908 (6 June 2019).

Psychiatric comorbidity is common in patients with chronic pain. In peripheral neuropathic pain, particularly anxiety and mood disorders are frequently present and associated with a high level of catastrophizing. Small fiber neuropathy (SFN) is a peripheral neuropathy dominated by pain. This study aimed to investigate the prevalence of and factors associated with anxiety and depressive symptoms in SFN. All consecutive patients diagnosed with SFN at Maastricht University Medical Center+, between September 2016 and October 2021, were included (n = 1310). Data on demographics, medical history, diagnostic tests, and questionnaires about pain, SFN-specific symptoms, and mental health were collected once. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression and the Pain Catastrophizing Scale (PCS) to measure the degree of catastrophizing. One-third of the patients had an abnormal HADS score (>= 11) on the subscales anxiety and/or depression (26.5% anxiety and 23.0% depression) indicating clinical relevance. Regression analysis showed that higher pain intensity, catastrophizing, and more SFN-related complaints were significantly associated with an abnormal HADS-score. In conclusion, the prevalence of reported anxiety or depressive symptoms in SFN is 36.3%. A multidisciplinary approach, not only focusing on pain relief, is therefore essential for the treatment of SFN.

PURPOSE: The aim of this longitudinal study was to assess trabecular bone scores (TBS) in institutionalized adults with refractory epilepsy and intellectual disability and to study the association of TBS and incident fractures during seven years of follow-up.METHODS: In 2009 and 2016, all institutionalized adult patients of a long-stay care facility in the Netherlands (n=261) were invited to undergo a dual-energy X-ray absorptiometry (DXA) including vertebral fracture assessment (VFA) and assessment of TBS. Vertebrae T4-L4 were analyzed using quantitative morphometry. New and worsening vertebral fractures (VFs) were considered as incident VFs. Data regarding clinical fractures were extracted from the medical files. Patients were treated with anti-osteoporosis medication according to the Dutch guideline.RESULTS: Baseline and follow-up DXA, VFA and TBS could be obtained in 136 patients (83 male) aged between 18 and 79 years old (44.7±15.5). At baseline, 36 patients (26.5%) were diagnosed with osteoporosis, 68 (50.0%) with osteopenia and 32 patients (23.5%) had a normal bone mineral density (BMD). As for TBS, 26 patients (19.1%) had a partially degraded microarchitecture and 26 patients (19.1%) a degraded microarchitecture. During seven years of follow-up, 80 patients (59%) sustained at least one fracture, of which 28 patients (35%) had one or more major osteoporotic fractures. Thirty-four patients (25.0%) had at least one new or worsening morphometric VF. Compared to baseline, TBS significantly decreased over seven years of follow-up in non-treated patients (-0.039±0.064, pCONCLUSION: In this study, we found a high incidence of fractures and TBS decreased significantly over seven years of follow-up in non-treated institutionalized adult patients with refractory epilepsy and intellectual disability, but TBS was not associated with incident fractures.

Objective As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. Methods This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p Results A cohort of 179 intracranial tumor patients was included [aged 19–85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20–30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. Interpretation Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.

INTRODUCTION: Parkinson's disease (PD) is a heterogeneous disorder with great variability in motor and non-motor manifestations. It is hypothesized that different motor subtypes are characterized by different neuropsychiatric and cognitive symptoms, but the underlying correlates in cerebral connectivity remain unknown. Our aim is to compare brain network connectivity between the postural instability and gait disorder (PIGD) and tremor-dominant (TD) subtypes, using both a within- and between-network analysis.METHODS: This cross-sectional resting-state fMRI study includes 81 PD patients, 54 belonging to the PIGD and 27 to the TD subgroup. Group-level spatial maps were created using independent component analysis. Differences in functional connectivity were investigated using dual regression analysis and inter-network connectivity analysis. An additional voxel-based morphometry analysis was performed to examine if results were influenced by grey matter atrophy.RESULTS: The PIGD subgroup scored worse than the TD subgroup on all cognitive domains. Resting-state fMRI network analyses suggested that the connection between the visual and sensorimotor network is a potential differentiator between PIGD and TD subgroups. However, after correcting for dopaminergic medication use these results were not significant anymore. There was no between-group difference in grey matter volume.CONCLUSION: Despite clear motor and cognitive differences between the PIGD and TD subtypes, no significant differences were found in network connectivity. Methodological challenges, substantial symptom heterogeneity and many involved variables make analyses and hypothesis building around PD subtypes highly complex. More sensitive visualisation methods combined with machine learning approaches may be required in the search for characteristic underpinnings of PD subtypes.

BACKGROUND: Whereas the treatment of motor symptoms in Huntington's disease (HD) receives much attention, less is known about the treatment of neuropsychiatric symptoms.OBJECTIVE: We aim to give an overview of psychotropic drug use in the treatment of neuropsychiatric symptoms across disease stages in HD.METHODS: We conducted a descriptive cross-sectional study of psychotropic drug prescriptions in a large longitudinal database of HD patients, Enroll HD. Across disease stages, the number of prescriptions per medication class, as well as the registered indications for these prescriptions were listed, and compared with that in gene negative participants.RESULTS: Of the 8967 included HD patients, 80% were using at least one psychotropic drug, compared to 27% of gene negative participants. In HD patients, 51% of all drug prescriptions was for psychotropic drugs. The average number of psychotropic drugs used per patient increased from 1.3 in the premanifest stage to 2.5 in stage 5. With progressing disease stages, the proportion of antidepressant drug prescriptions gradually decreased from 74.1% of all prescriptions to 27.3%, and antipsychotic drug prescriptions increased from 7.0% to 38.7%. In line with this, depression and anxiety as listed indications for prescription decreased with advancing disease stages (from 63.0% to 31.5% and from 30.0% to 15.4% respectively), whereas irritability and psychosis increased (from 3.1% to 28.6% and from 0.9% to 16.0% respectively).CONCLUSIONS: Psychotropic medication is widely prescribed in HD, for various indications. Antidepressant use decreases proportionally and antipsychotic use increases with advancing disease stages, suggesting a relative decrease in prevalence of anxiety and depression over disease stages on one hand, and a relative increase in prevalence of irritability and delusions on the other.

Contains fulltext : 287508.pdf (Publisher’s version ) (Closed access) BACKGROUND: Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset. METHODS: MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308. FINDINGS: On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1-4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65-1·47]). In the target population (n=291), the 90-day mRS score was 2 (2-4) in the glyceryl trinitrate group and 3 (1-4) in the control group (0·92 [0·59-1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53-2·14]) or serious adverse events (unadjusted OR 1·23 [0·76-1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78-44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18-4·17]). INTERPRETATION: We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting. FUNDING: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

Background Brain atrophy is suggested to impair the potential for functional recovery after acute ischemic stroke. We assessed whether the effect of endovascular treatment is modified by brain atrophy in patients with acute ischemic stroke due to large vessel occlusion. Methods We used data from MR CLEAN, a multicenter trial including patients with acute ischemic stroke due to anterior circulation large vessel occlusion randomized to endovascular treatment plus medical care (intervention) versus medical care alone (control). We segmented total brain volume (TBV) and intracranial volume (ICV) on baseline non-contrast computed tomography (n = 410). Next, we determined the degree of atrophy as the proportion of brain volume in relation to head size (1 − TBV/ICV) × 100%, analyzed as continuous variable and in tertiles. The primary outcome was a shift towards better functional outcome on the modified Rankin Scale expressed as adjusted common odds ratio. Treatment effect modification was tested using an interaction term between brain atrophy (as continuous variable) and treatment allocation. Results We found that brain atrophy significantly modified the effect of endovascular treatment on functional outcome (P for interaction = 0.04). Endovascular treatment led to larger shifts towards better functional outcome in the higher compared to the lower range of atrophy (adjusted common odds ratio, 1.86 [95% CI: 0.97–3.56] in the lowest tertile vs. 1.97 [95% CI: 1.03–3.74] in the middle tertile vs. 3.15 [95% CI: 1.59–6.24] in the highest tertile). Conclusion Benefit of endovascular treatment is larger in the higher compared to the lower range of atrophy, demonstrating that advanced atrophy should not be used as an argument to withhold endovascular treatment.

Pre-eclampsia is a hypertensive complication of pregnancy that is associated with an increased risk of long-term cardiovascular and cerebrovascular disorders. Although the underlying mechanism of persistent susceptibility to cerebral complications after pre-eclampsia remains largely unclear, impaired blood-brain barrier (BBB) integrity has been suggested to precede several cerebrovascular diseases. In this study, we aimed to investigate the integrity of the BBB years after pre-eclampsia.This was an observational study of premenopausal formerly pre-eclamptic women and controls with a history of normotensive pregnancy who underwent cerebral magnetic resonance imaging (MRI) at ultra-high field (7 Tesla) to assess the integrity of the BBB. Permeability of the BBB was determined by assessing leakage rate and fractional leakage volume of the contrast agent gadobutrol using dynamic contrast-enhanced MRI. BBB leakage measures were determined for the whole brain and lobar white and gray matter. Multivariable analyses were performed, and odds ratios were calculated to compare women with and those without a history of pre-eclampsia, adjusting for potential confounding effects of age, hypertension status at MRI and Fazekas score.Twenty-two formerly pre-eclamptic women (mean age, 37.8 ± 5.4 years) and 13 control women with a history of normotensive pregnancy (mean age, 40.8 ± 5.5 years) were included in the study. The time since the index pregnancy was 6.6 ± 3.2 years in the pre-eclamptic group and 9.0 ± 3.7 years in controls. The leakage rate and fractional leakage volume were significantly higher in formerly pre-eclamptic women than in controls in the global white (P = 0.001) and gray (P = 0.02) matter. Regionally, the frontal (P = 0.04) and parietal (P = 0.009) cortical gray matter, and the frontal (P = 0.001), temporal (P lt; 0.05) and occipital (P = 0.007) white matter showed higher leakage rates in formerly pre-eclamptic women. The odds of a high leakage rate after pre-eclampsia were generally higher in white-matter regions than in gray-matter regions.This observational study demonstrates global impairment of the BBB years after a pre-eclamptic pregnancy, which could be an early marker of long-term cerebrovascular disorders. © 2022 The Authors. Ultrasound in Obstetricsamp; Gynecology published by John Wileyamp; Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Learning disabilities (LDs) and working memory problems (WM) are common brain-related comorbidities in Duchenne muscular dystrophy (DMD). Despite growing evidence on the efficacy of computerized WM training in children with LDs, research in DMD is lacking. This exploratory study assessed whether training (1) improves dystrophin-associated WM problems in DMD, (2) effects are present at post-intervention, 3 and 8 months follow-up, and (3) improves problems that arise from their LDs. A single case non-concurrent multiple baseline across patients design evaluated the target behaviour i.e. parental reports of WM problems of four DMD participants with LDs. Additionally, participants completed cognitive tests of verbal and visual WM, academics, attention, processing speed and fluid reasoning. Parents and teachers completed behavioural questionnaires. Testing and questionnaires were administered at baseline, post-intervention (T2), 3 (T3) and 8 (T4) months follow-up. Positive effects on target behaviour were found for three of four participants, but parental bias cannot be ruled out. Short and long-term, near-and far transfer effects were found for verbal and visual WM (T2:n = 2, T3&T4:n = 1), reading (T2:n = 4,T3:n = 3,T4:n = 2), arithmetic (all T:n = 1), processing speed (all T:n = 4) and fluid reasoning (T2:n = 1,T3&T4:n = 2). Behavioural questionnaires displayed minimal changes (T2:n = 1,T3&T4:n = 2). Promising WM training results are shown in DMD that merit further research.

Netherlands Organization for Scientific Research [024.001.006]; National Institute on Deafness and Other Communication Disorders, USA [K01DC016904]; Center for Language and Brain NRU Higher School of Economics, RF Government [14.641.31.0004], Sierpowska, J., Rofes, A., Dahlslätt, K., Mandonnet, E., Ter Laan, M., Połczyńska, M., Hamer, P.D.W., Halaj, M., Spena, G., Meling, T.R., Motomura, K., Reyes, A.F., Campos, A.R., Robe, P.A., Zigiotto, L., Sarubbo, S., Freyschlag, C.F., Broen, M.P.G., Stranjalis, G., Papadopoulos, K., Liouta, E., Rutten, G.-J., Viegas, C.P., Silvestre, A., Perrote, F., Brochero, N., Cáceres, C., Zdun-Ryżewska, A., Kloc, W., Satoer, D., Dragoy, O., Hendriks, M.P.H., Alvarez-Carriles, J.C., Piai, V.

Blood-brain barrier (BBB) is known to be impaired in cerebral small vessel disease (SVD), and is measurable by dynamic-contrast enhancement (DCE)-MRI. In a cohort of 69 patients (42 sporadic, 27 monogenic SVD), who underwent 3T MRI, including DCE and cerebrovascular reactivity (CVR) sequences, we assessed the relationship of BBB-leakage hotspots to SVD lesions (lacunes, white matter hyperintensities (WMH), and microbleeds). We defined as hotspots the regions with permeability surface area product highest decile on DCE-derived maps within the white matter. We assessed factors associated with the presence and number of hotspots corresponding to SVD lesions in multivariable regression models adjusted for age, WMH volume, number of lacunes, and SVD type. We identified hotspots at lacune edges in 29/46 (63%) patients with lacunes, within WMH in 26/60 (43%) and at the WMH edges in 34/60 (57%) patients with WMH, and microbleed edges in 4/11 (36%) patients with microbleeds. In adjusted analysis, lower WMH-CVR was associated with presence and number of hotspots at lacune edges, and higher WMH volume with hotspots within WMH and at WMH edges, independently of the SVD type. In conclusion, SVD lesions frequently collocate with high BBB-leakage in patients with sporadic and monogenic forms of SVD.

Contains fulltext : 293770.pdf (Publisher’s version ) (Open Access) INTRODUCTION/AIMS: There is clear evidence for brain involvement in childhood myotonic dystrophy type 1 (DM1) from imaging studies and the prevalence of intellectual impairment and neurodevelopmental disorders. The cognitive profile of children with DM1 however is poorly understood. The aim of this study was to assess the cognitive profile of children with DM1. METHODS: Neuropsychological examination reports of 45 children aged 2-17 y were analyzed. All cognitive subtests used in this cohort were pooled in 10 cognitive domains. For every patient a composite z-score was calculated for every assessed domain. Composite scores were classified as average (z > -1), mild cognitive impairment (-1 ≥ z > -2), or major cognitive impairment (z ≤ -2). RESULTS: The nature and extent of neuropsychological examinations differed between centers and patients. The domains with the highest frequency of major cognitive impairment were social cognition (4/9 children tested; 44%), attention (13/32; 41%), and fine motor skills (3/10; 30%). Combining mild and major cognitive impairment, working memory (20/28; 71%), attention (21/32; 66%), and visuospatial functions (16/28; 57%) were the most frequently affected domains. Long-term memory was least affected, with mild impairment only in 5/29 (17%). DISCUSSION: Children with DM1 may have specific cognitive deficits, most frequently affecting working memory, attention, and visuospatial functions, in addition to the previously described global intellectual impairments. We recommend including a standardized neuropsychological examination in the standards of care for DM1 children. Early recognition of cognitive deficits and behavioral disorders in children with DM1 can improve their management. 01 juli 2023

Background: Hypertension alters the structure and function of cerebral blood vessels, and is an important risk factor for stroke and cerebral small vessel disease (cSVD). However, the pathophysiological process is not yet well understood. This study aimed to investigate the relationship between the pulsatility measures in small perforating arteries and hypertension, since hypertension-induced arterial stiffening may lead to a higher blood flow pulsatility and lower damping. Methods: We examined 28 patients with essential hypertension and 25 age- and sex-matched healthy controls (mean age: 63.4, range: 43–81 years, 26 males). Blood flow velocity waveforms were acquired in the lenticulostriate arteries (LSAs) and the middle cerebral artery using phase-contrast MRI at 7 Tesla. Several cSVD markers were scored. The velocity and pulsatility measures were compared between the hypertensives and controls. Results: A higher pulsatility index (PI) in the LSAs and a lower damping factor (DF) was found in the hypertensive compared to the normotensive group ( P =0.015, P =0.015, respectively), but no association was found for the PI in the middle cerebral artery. Higher systolic and mean arterial pressures were associated with higher PI in the LSA and DF. For diastolic blood pressure, only an association with a lower DF was found. Adjusting for cSVD score did not alter these relationships. Conclusions: This study shows a higher PI in the LSAs and a lower DF in subjects with hypertension, independent of cSVD presence. This supports the hypothesis that hypertension-induced arterial remodeling may alter the intracerebral blood flow velocity profiles, which could eventually contribute to cerebral tissue damage. Registration: URL: https://trialsearch.who.int/ ; Unique identifier: NL7537 and NL8798

BackgroundInternational consensus on IgM +/- anti-MAG +/- PNP (IgM PNP) is lacking. Despite increasing interest in clinical trials, validated disease-specific measures are needed to adequately capture limitations and changes over time. The IMAGiNe (IgM +/- anti-myelin associated glycoprotein [MAG] peripheral neuropathy) study surges as an international collaboration to create a standardized registry of patients with IgM +/- anti-MAG PNP. The consortium, which currently consists of 11 institutions from 7 countries, presents here the IMAGiNe study design and protocol. AimsFunctional outcome measures will be constructed at the level of impairment, as well as activity and participation. We aim to describe the natural history of the cohort, the role of anti-MAG antibodies, the presence of clinical subtypes, and potential biomarkers. MethodsThe IMAGiNe study is a prospective, observational cohort study with a 3-year follow-up. At each assessment, researchers collect clinical data and subjects complete a list of preselected outcome measures. Among these, the "Pre-Rasch-built Overall Disability Scale (Pre-RODS)" questionnaire will be submitted to Rasch analysis to assess classic and modern clinimetric requirements. ResultsThe final measures will include the IgM-PNP-specific RODS and Ataxia Rating Scale (IgM-PNP-ARS). Descriptions of the disease course, clinical heterogeneity, treatment regimes, variations in laboratory values, and antibody titers will help reach consensus on diagnosis and follow-up strategies. ConclusionThe constructed interval scales will be cross-culturally valid and suitable for use in future clinical trials and daily practice. The ultimate goals are to improve functional individualized assessment, reach international consensus, and lay the foundations for successful designs in future studies.

PURPOSE To examine whether nurse-led stroke aftercare is beneficial for long-term psychosocial outcome of community-dwelling persons with stroke. MATERIALS AND METHODS Comparative effectiveness research design in which a prospective stroke aftercare cohort (n = 87) was compared to care-as-usual (n = 363) at six- and 12-months post stroke. Changes over time in cognitive and emotional problems experienced in daily life, fatigue and stroke impact on daily life were examined for stroke aftercare only. Multilevel modelling was used to compare stroke aftercare to care-as-usual concerning anxiety and depression symptoms, social participation and quality of life, over time. RESULTS Sample characteristics did not differ between cohorts except for stroke type and on average, more severe stroke in the stroke aftercare cohort (p < 0.05). Following stroke aftercare, anxiety and emotional problems decreased significantly (p < 0.05), whereas care-as-usual remained stable over time in terms of anxiety. No significant changes over time were observed on the other outcome domains. CONCLUSIONS Nurse-led stroke aftercare showed to be beneficial for emotional well-being in comparison to care-as-usual. Providing psychoeducation and emotional support seem effective elements but adding other therapeutic elements such as self-management strategies might increase the effectiveness of nurse-led stroke aftercare.Implications for rehabilitationRoutine stroke follow-up care should pay attention to psychosocial and emotional outcome in a systematic manner, in addition to secondary prevention.Healthcare professionals such as (specialized) nurses are needed to appropriately address the hidden cognitive and emotional consequences of stroke.Providing psychoeducation and emotional support in stroke aftercare diminish insecurities and worries in community-dwelling persons with stroke, leading to better outcomes.

Clinical trials in chronic inflammatory demyelinating polyneuropathy (CIDP) often assess efficacy using the ordinal Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Here, data from the PATH study was reanalyzed using change in Inflammatory Rasch-built Overall Disability Scale (I-RODS) to define CIDP relapse instead of INCAT. The PATH study comprised an intravenous immunoglobulin (IVIG) dependency period and an IVIG (IgPro10 [Privigen]) restabilization period; subjects were then randomized to weekly maintenance subcutaneous immunoglobulin (SCIG; IgPro20 [Hizentra]) 0.2 g/kg or 0.4 g/kg or placebo for 24 weeks. CIDP relapse was defined as >= 1-point deterioration in adjusted INCAT, with a primary endpoint of relapse or withdrawal rates. This retrospective exploratory analysis redefined relapse using I-RODS via three different cut-off methods: an individual variability method, fixed cut-off of >= 8-point deterioration on I-RODS centile score or >= 4-point deterioration on I-RODS raw score. Relapse or withdrawal rates were 47% for placebo, 34% for 0.2 g/kg IgPro20 and 19% for 0.4 g/kg IgPro20 using the raw score; 40%, 28% and 15%, respectively using the centile score, and 49%, 40% and 27%, respectively using the individual variability method. IgPro20 was shown to be efficacious as a maintenance therapy for CIDP when relapse was defined using I-RODS. A stable response pattern was shown for I-RODS across various applied cut-offs, which could be applied in future clinical trials.

Intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy usually starts with a 2.0 g/kg induction dose followed by 1.0 g/kg maintenance doses every 3 weeks. No dose-ranging studies with intravenous immunoglobulin maintenance therapy have been published. The Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) study was a prospective, double-blind, randomized, parallel-group, multicentre, phase III study investigating the efficacy and safety of 10% liquid intravenous immunoglobulin (Panzyga®) in patients with active chronic inflammatory demyelinating polyneuropathy. Patients were randomized 1:2:1 to receive the standard intravenous immunoglobulin induction dose and then either 0.5, 1.0 or 2.0 g/kg maintenance doses every 3 weeks. The primary end point was the response rate in the 1.0 g/kg group, defined as an improvement ≥1 point in adjusted Inflammatory Neuropathy Cause and Treatment score at Week 6 versus baseline and maintained at Week 24. Secondary end points included dose response and safety. This trial was registered with EudraCT (Number 2015–005443-14) and clinicaltrials.gov (NCT02638207). Between August 2017 and September 2019, the study enrolled 142 patients. All 142 were included in the safety analyses. As no post-infusion data were available for three patients, 139 were included in the efficacy analyses, of whom 121 were previously on corticosteroids. The response rate was 80% (55/69 patients) [95% confidence interval (CI): 69–88%] in the 1.0 g/kg group, 65% (22/34; CI: 48–79%) in the 0.5 g/kg group, and 92% (33/36; CI: 78–97%) in the 2.0 g/kg group. While the proportion of responders was higher with higher maintenance doses, logistic regression analysis showed that the effect on response rate was driven by a significant difference between the 0.5 and 2.0 g/kg groups, whereas the response rates in the 0.5 and 2.0 g/kg groups did not differ significantly from the 1.0 g/kg group. Fifty-six per cent of all patients had an adjusted Inflammatory Neuropathy Cause and Treatment score improvement 3 weeks after the induction dose alone. Treatment-related adverse events were reported in 16 (45.7%), 32 (46.4%) and 20 (52.6%) patients in the 0.5, 1.0 and 2.0 g/kg dose groups, respectively. The most common adverse reaction was headache. There were no treatment-related deaths. Intravenous immunoglobulin (1.0 g/kg) was efficacious and well tolerated as maintenance treatment for patients with chronic inflammatory demyelinating polyneuropathy. Further studies of different maintenance doses of intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy are warranted.

To assess attainment of individual treatment goals one year after intrathecal baclofen (ITB) pump implantation in individuals with dyskinetic cerebral palsy (CP). A multi-center prospective cohort study was conducted including 34 non-walking individuals with severe dyskinetic CP, classified as Gross Motor Function Classification System (GMFCS) IV/V, aged 4–24 years, 12 months after pump implantation. The main outcome measure was Goal Attainment Scaling (GAS). Predictors of GAS results were analyzed. Complications were registered systematically. Seventy-one percent of individuals with dyskinetic CP fully achieved one or more treatment goals. One or more treatment goals were partially achieved in 97% of individuals. Two factors were found to be associated with attainment of goals: Dyskinesia Impairment Scale (DIS) score at baseline and the difference in pain score between baseline and follow-up. These two variables explain 30% of the variance in the outcome. Intrathecal baclofen is effective in achieving individual treatment goals in children and young adults with dyskinetic CP after nine to 12 months of ITB treatment. A positive outcome on treatment goals is, for a small part, associated with higher severity of dystonia at baseline and with improvement of pain during treatment. Dutch Trial Register, number NTR3642.Implications for rehabilitationIntrathecal baclofen treatment is effective in attainment of personal treatment goals, one year after pump implantation in patients with dyskinetic cerebral palsy.A positive outcome on treatment goals is, for a small part, related to higher severity of dystonia at the start and on improvement of pain during treatment. Intrathecal baclofen treatment is effective in attainment of personal treatment goals, one year after pump implantation in patients with dyskinetic cerebral palsy. A positive outcome on treatment goals is, for a small part, related to higher severity of dystonia at the start and on improvement of pain during treatment.

OBJECTIVE: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. METHODS: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. RESULTS: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. SIGNIFICANCE: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.

Contains fulltext : 293483.pdf (Publisher’s version ) (Open Access) BACKGROUND: Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD. METHODS: We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N = 2,258). Subsequently using Fisher's exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N = 23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N = 46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N = 46,350) and intracranial volume (N = 25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA. RESULTS: Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p = .0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p = .027), despite the absence of a significant genome-wide correlation (p = .81). CONCLUSIONS: This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD. 01 juli 2023

Contains fulltext : 291863.pdf (Publisher’s version ) (Open Access) Cine-MRI for adhesion detection is a promising novel modality that can help the large group of patients developing pain after abdominal surgery. Few studies into its diagnostic accuracy are available, and none address observer variability. This retrospective study explores the inter- and intra-observer variability, diagnostic accuracy, and the effect of experience. A total of 15 observers with a variety of experience reviewed 61 sagittal cine-MRI slices, placing box annotations with a confidence score at locations suspect for adhesions. Five observers reviewed the slices again one year later. Inter- and intra-observer variability are quantified using Fleiss’ (inter) and Cohen’s (intra) κ and percentage agreement. Diagnostic accuracy is quantified with receiver operating characteristic (ROC) analysis based on a consensus standard. Inter-observer Fleiss’ κ values range from 0.04 to 0.34, showing poor to fair agreement. High general and cine-MRI experience led to significantly (p < 0.001) better agreement among observers. The intra-observer results show Cohen’s κ values between 0.37 and 0.53 for all observers, except one with a low κ of −0.11. Group AUC scores lie between 0.66 and 0.72, with individual observers reaching 0.78. This study confirms that cine-MRI can diagnose adhesions, with respect to a radiologist consensus panel and shows that experience improves reading cine-MRI. Observers without specific experience adapt to this modality quickly after a short online tutorial. Observer agreement is fair at best and area under the receiver operating characteristic curve (AUC) scores leave room for improvement. Consistently interpreting this novel modality needs further research, for instance, by developing reporting guidelines or artificial intelligence-based methods.

Glioblastoma multiforme is the most common primary central nervous system tumor, with an incidence of 3 [...]

PURPOSE: 7T MRI enables measurements of blood flow velocity waveforms in small, perforating cerebral arteries. As these vessels can be tortuous, acquisition methods sensitive to flow in only one direction may not be sufficient to accurately determine the dynamic blood flow velocity. In this study, we compared 1D with 3D velocity encoding to measure the blood flow velocity and pulsatility in the lenticulostriate arteries (LSAs).METHODS: Blood flow velocity waveforms were measured in the LSAs of 18 subjects (age range: 20-74 years) using prospectively gated single-slice phase contrast (PC) MRI at 7T. For each subject, blood flow velocity waveforms were acquired in a single slice with one velocity encoding as well as three orthogonal velocity encodings. The peak velocity and pulsatility index (PI) were determined in the largest, perpendicularly planned LSA, one obliquely planned LSA and three smaller LSAs. The peak velocity and PI were compared between 1D and 3D measurements using Bland-Altman analysis, with the 95% limits of agreement (LOA) taken into account.RESULTS: For the largest, perpendicularly planned LSA, the peak velocity was slightly lower (0.2 cm/s, 1.7%) for 1D compared to 3D measurements, with an LOA range from the mean difference of (-0.27;0.27). The PI was slightly higher (0.01, 1.6%) for the 1D measurement, and an LOA range from the mean difference in PI of (-0.045;0.045). The obliquely planned LSA and three smaller LSAs demonstrated larger deviations (range mean percentage difference: 3.9-8.2%).CONCLUSION: 1D velocity encoding using 2D PC MRI provides sufficiently accurate dynamic velocity and pulsatility measurements in slices perpendicularly planned to single, large LSAs compared to 3D velocity encoding, while increasing errors are obtained with obliquely planned slices. A greater error is indicated when measuring multiple (possibly tortuous or obliquely planned) smaller LSAs in one scan using one-directional single-slice PC MRI.

INTRODUCTION: There are two treatment modalities for aneurysmal subarachnoid hemorrhage: endovascular treatment and neurosurgical clipping. Results of economic evaluations are needed to gain insight into the relationship between clinical effectiveness and costs of these treatment modalities. This important information can inform both clinical decision-making processes and policymakers in facilitating Value-Based Healthcare.EVIDENCE ACQUISITION: Databases (PubMed, Embase, Cochrane Library, the Centre for Reviews and Dissemination, EBSCO, and Web of Science) were searched for studies published until October 2020 that had performed economic evaluations in aneurysmal subarachnoid hemorrhage patients by comparing endovascular treatment with neurosurgical clipping. The quality of reporting and methodology of these evaluations was assessed using the associated instruments (i.e. CHEERS statement and CHEC-list, respectively).EVIDENCE SYNTHESIS: A total of six studies met the inclusion criteria. All included studies reported both effects and costs, however five did not relate effects to costs. Only one study related effects directly to costs, thus conducted a full economic evaluation. The reporting quality scored 81% and the methodological quality scored 30%.CONCLUSIONS: The quality of published cost-effectiveness studies on the treatment of aneurysmal subarachnoid hemorrhage is poor. Six studies reported both outcomes and costs, however only one study performed a full economic evaluation comparing endovascular treatment to neurosurgical clipping. Although the reporting quality was sufficient, the methodological quality was poor. Further research that relates health-related quality of life measures to costs of endovascular treatment and neurosurgical clipping is required-specifically focusing on both reporting and methodological quality. Different subgroup analyses and modeling could also enhance the findings.

(1) Background: Next to motor impairments, children with unilateral spastic cerebral palsy (CP) often experience sensory impairments. Intensive bimanual training is well known for improving motor abilities, though its effect on sensory impairments is less known. (2) Objective: To investigate whether bimanual intensive functional therapy without using enriched sensory materials improves somatosensory hand function. (3) Methods: A total of twenty-four participants with CP (12–17 years of age) received 80–90 h of intensive functional training aimed at improving bimanual performance in daily life. Somatosensory hand function was measured before training, directly after training, and at six months follow-up. Outcome measures were: proprioception, measured by thumb and wrist position tasks and thumb localization tasks; vibration sensation; tactile perception; and stereognosis. (4) Results: Next to improving on their individual treatment goals, after training, participants also showed significant improvements in the perception of thumb and wrist position, vibration sensation, tactile perception, and stereognosis of the more affected hand. Improvements were retained at six months follow-up. Conversely, proprioception measured by the thumb localization tasks did not improve after training. (5) Conclusions: Intensive functional bimanual training without environmental tactile enrichment may improve the somatosensory function of the more affected hand in children with unilateral spastic CP.

Personalized management of neuropathic pain is an unmet clinical need due to heterogeneity of the underlying aetiologies, incompletely understood pathophysiological mechanisms and limited efficacy of existing treatments. Recent studies on microRNA in pain preclinical models have begun to yield insights into pain-related mechanisms, identifying nociception-related species differences and pinpointing potential drug candidates. With the aim of bridging the translational gap towards the clinic, we generated a human pain-related integrative miRNA and mRNA molecular profile of the epidermis, the tissue hosting small nerve fibres, in a deeply phenotyped cohort of patients with sodium channel-related painful neuropathy not responding to currently available therapies. We identified four miRNAs strongly discriminating patients from healthy individuals, confirming their effect on differentially expressed gene targets driving peripheral sensory transduction, transmission, modulation and post-transcriptional modifications, with strong effects on gene targets including NEDD4. We identified a complex epidermal miRNA-mRNA network based on tissue-specific experimental data suggesting a cross-talk between epidermal cells and axons in neuropathy pain. Using immunofluorescence assay and confocal microscopy, we observed that Nav1.7 signal intensity in keratinocytes strongly inversely correlated with NEDD4 expression that was downregulated by miR-30 family, suggesting post-transcriptional fine tuning of pain-related protein expression. Our targeted molecular profiling advances the understanding of specific neuropathic pain fine signatures and may accelerate process towards personalized medicine in patients with neuropathic pain.Andelic et al. identify miRNA-driven epidermal regulatory mechanisms in SCN9A-related painful neuropathy not responding to currently available therapies. By revealing unique molecular signatures of neuropathic pain in deeply phenotyped patients, these findings could accelerate the development of personalized therapies.

Contains fulltext : 294518.pdf (Publisher’s version ) (Open Access) AIM: To study long-term disease course for females with early-onset dystrophinopathy, including common (female) symptoms, challenges in social participation, the need for care, and current healthcare management to support guideline development. METHOD: Twelve females with early-onset dystrophinopathy were followed for a median period of more than 17 years (range 1-36). RESULTS: One patient died owing to end-stage cardiac failure. Cardiac abnormalities were observed in three of the remaining 11 participants. Respiratory function was reduced in seven of 10 participants. Fatigue, myalgia, lower back pain, and arthralgia were reported in more than six of the participants. Functional status varied from exercise intolerance to wheelchair dependency. Most or all of the 10 participants reported restrictions in participation in work (n = 10), household duties (n = 10), sports (n = 9), and education (n = 8). Only a few participants received followed-up pulmonary (n = 2) or rehabilitation (n = 3) care. INTERPRETATION: Females with early-onset dystrophinopathy experience a wide range of impairments, comorbidities, limitations in activities, and restrictions in social participation. The whole spectrum should be acknowledged in the healthcare setting. Neuromuscular and cardiac follow-up are indispensable. Additional respiratory assessment and rehabilitation care are expected to improve health status and support daily activities and participation. WHAT THIS PAPER ADDS: No standard diagnostic procedures seem to exist for female patients suspected for dystrophinopathy. Female participants with early-onset dystrophinopathy experienced a broad scope of burdening symptoms, such as fatigue, myalgia, lower back pain, and arthralgia. None of participants worked full time, all felt restricted in paid work, and most felt restricted in education. Most participants showed decreased lung function, while only one was symptomatic. Availability of rehabilitation care may improve support for daily activities and participation for females with early-onset dystrophinopathy. 01 augustus 2023

Background and ObjectivesCauses of stroke in young adults differ from those in the elderly individuals, and in a larger percentage, no cause can be determined. To gain more insight into the etiology of (cryptogenic) stroke in the young population, we investigated whether trigger factors, such as short-lasting exposure to toxins or infection, may play a role.MethodsPatients aged 18–49 years with a first-ever ischemic stroke or intracerebral hemorrhage (ICH) in 17 participating centers in the Netherlands completed a questionnaire about exposure to 9 potential trigger factors in hazard periods and on a regular yearly basis. A case-crossover design was used to assess relative risks (RRs) with 95% confidence intervals (95% CIs) by the Mantel-Haenszel case-crossover method, for any stroke (ischemic stroke and ICH combined) and for different etiologic subgroups of ischemic stroke.ResultsOne thousand one hundred forty-six patients completed the questionnaire (1,043 patients with an ischemic stroke and 103 with an ICH, median age 44.0 years, 52.6% men). For any stroke, an increased risk emerged within 1 hour of cola consumption (RR 2.0, 95% CI 1.5–2.8) and vigorous physical exercise (RR 2.6, 95% CI 2.2–3.0), within 2 hours after sexual activity (RR 2.4, 95% CI 1.6–3.5), within 4 hours after illicit drug use (RR 2.8, 95% CI 1.7–4.9), and within 24 hours after fever or flu-like disease (RR 14.1, 95% CI 10.5–31.2; RR 13.9, 95% CI 8.9–21.9). Four trigger factors increased the risk of other determined and cryptogenic ischemic stroke, 3 that of cardioembolic stroke, 2 that of large vessel atherosclerosis and likely atherothrombotic stroke combined and stroke with multiple causes, and none that of stroke due to small vessel disease.DiscussionWe identified cola consumption, vigorous physical exercise, sexual activity, illicit drug use, fever, and flu-like disease as potential trigger factors for stroke in the young population and found differences in the type and number of trigger factors associated with different etiologic subgroups of ischemic stroke. These findings might help in better understanding the pathophysiologic mechanisms of (cryptogenic) stroke in the young population.

Introduction: Microvascular rarefaction, the functional reduction in perfused microvessels and structural reduction of microvascular density, seems to be an important mechanism in the pathophysiology of small blood vessel related disorders including vascular cognitive impairment (VCI) due to cerebral small vessel disease and heart failure with preserved ejection fraction (HFpEF). Both diseases share common risk factors including hypertension, diabetes mellitus, obesity, and ageing; in turn, these co-morbidities are associated with microvascular rarefaction. Our consortium aims to investigate novel non-invasive tools to quantify microvascular health and rarefaction in both organs, as well as surrogate biomarkers for cerebral and/or cardiac rarefaction (via sublingual capillary health, vascular density of the retina, and RNA content of circulating extracellular vesicles), and to determine whether microvascular density relates to disease severity. Methods/design: The clinical research program of CRUCIAL consists of four observational cohort studies. We aim to recruit 75 VCI patients, 60 HFpEF patients, 60 patients with severe aortic stenosis (AS) undergoing surgical aortic valve replacement as a pressure overload HFpEF model, and 200 elderly participants with mixed comorbidities to serve as controls. Data collected will include medical history, physical examination, cognitive testing, advanced brain and cardiac MRI, ECG, echocardiography, sublingual capillary health, optical coherence tomography angiography (OCTa), extracellular vesicles RNA analysis and myocardial remodelling-related serum biomarkers. The AS cohort undergoing surgery will also have myocardial biopsy for histological microvascular assessment. Discussion: CRUCIAL will examine the pathophysiological role of microvascular rarefaction in VCI and HFpEF using advanced brain and cardiac MRI techniques. Furthermore, we will investigate surrogate biomarkers for non-invasive, faster, easier, and cheaper assessment of microvascular density since these are more likely to be disseminated into widespread clinical practice. If microvascular rarefaction is an early marker of developing small vessel diseases, then measuring rarefaction may allow pre-clinical diagnosis, with implications for screening, risk stratification, and prevention. Further knowledge of the relevance of microvascular rarefaction and its underlying mechanisms may provide new avenues for research and therapeutic targets.

The aim of the study was to retrospectively evaluate the consistency of longitudinal findings on intellectual functioning in DMD boys and their relationship to behavioral and neuropsychiatric difficulties. The cohort included 70 patients of age 3 to 17 years with at least two assessments using the Wechsler scales. CBCL and clinical observation of behavior were also performed. Changes in total intelligence quotient were interpreted as stable or not stable using the reliable-change method. On the first assessment 43/70 had normal quotients, 18 borderline, 5 mild, and 4 moderate intellectual disability, while 27/70 had no behavioral disorders, 17 had abnormal CBCL, and 26 patients had clear signs of attention deficits despite normal CBCL. The remaining seven were untestable. The mean total intelligence quotient change in the cohort was −2.99 points (SD: 12.29). Stable results on TIQ were found in 63% of the paired assessments. A third of the consecutive cognitive assessments showed a difference of more than 11 points with changes up to 42 points. Boys with no behavioral/attention disorder had smaller changes than those with attention (p = 0.007) and behavioral disorders (p = 0.002). Changes in IQ may occur in Duchenne and are likely to be associated with behavioral or attention deficits.

Background: The clinical and economic benefit of endovascular treatment (EVT) in addition to best medical management in patients with stroke with mild preexisting symptoms/disability is not well studied. We aimed to investigate cost-effectiveness of EVT in patients with large vessel occlusion and mild prestroke symptoms/disability, defined as a modified Rankin Scale score of 1 or 2. Methods: Data are from the HERMES collaboration (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials), which pooled patient-level data from 7 large, randomized EVT trials. We used a decision model consisting of a short-run model to analyze costs and functional outcomes within 90 days after the index stroke and a long-run Markov state transition model (cycle length of 12 months) to estimate expected lifetime costs and outcomes from a health care and a societal perspective. Incremental cost-effectiveness ratio and net monetary benefits were calculated, and a probabilistic sensitivity analysis was performed. Results: EVT in addition to best medical management resulted in lifetime cost savings of $2821 (health care perspective) or $5378 (societal perspective) and an increment of 1.27 quality-adjusted life years compared with best medical management alone, indicating dominance of additional EVT as a treatment strategy. The net monetary benefits were higher for EVT in addition to best medical management compared with best medical management alone both at the higher (100 000$/quality-adjusted life years) and lower (50 000$/quality-adjusted life years) willingness to pay thresholds. Probabilistic sensitivity analysis showed decreased costs and an increase in quality-adjusted life years for additional EVT compared with best medical management only. Conclusions: From a health-economic standpoint, EVT in addition to best medical management should be the preferred strategy in patients with acute ischemic stroke with large vessel occlusion and mild prestroke symptoms/disability.

Thin-fiber neuropathy is characterized by neuropathic pain and autonomic dysfunction. The functions affected are automatic and cannot be actively and/or consciously influenced, such as heart rhythm, sweating pattern and problems with micturition (urination) and defecation (excretion). Currently, the diagnosis is made based on the clinical picture combined with an abnormal temperature threshold test and/or abnormal skin biopsy, without abnormalities on electromyography (EMG). Sometimes we see patients who do have the symptoms of neuropathic pain and autonomic symptoms appropriate to thin fiber neuropathy but unfortunately cannot diagnose it with the aforementioned examinations. Thus, at this time there is no gold standard. For this reason, research was conducted into techniques that can make an (additional) contribution to making this diagnosis. In addition, in this dissertation attention was paid to the genetic contribution to thin fiber neuropathy.

Background and Purpose: The benefit of endovascular treatment (EVT) for posterior circulation stroke (PCS) remains uncertain, and little is known on treatment outcomes in clinical practice. This study evaluates outcomes of a large PCS cohort treated with EVT in clinical practice. Simultaneous to this observational study, several intervention centers participated in the BASICS trial (Basilar Artery International Cooperation Study), which tested the efficacy of EVT for basilar artery occlusion in a randomized setting. We additionally compared characteristics and outcomes of patients treated outside BASICS in trial centers to those from nontrial centers. Methods: We included patients with PCS from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry: a prospective, multicenter, observational study of patients who underwent EVT in the Netherlands between 2014 and 2018. Primary outcome was a score of 0 to 3 on the modified Rankin Scale at 90 days. Secondary outcomes included reperfusion status and symptomatic intracranial hemorrhage. For outcome comparison between patients treated in trial versus nontrial centers, we used ordinal logistic regression analysis. Results: We included 264 patients of whom 135 (51%) had received intravenous thrombolysis. The basilar artery was most often involved (77%). Favorable outcome (modified Rankin Scale score 0–3) was observed in 115/252 (46%) patients, and 109/252 (43%) patients died. Successful reperfusion was achieved in 178/238 (75%), and symptomatic intracranial hemorrhage occurred in 9/264 (3%). The 154 nontrial patients receiving EVT in BASICS trial centers had similar characteristics and outcomes as the 110 patients treated in nontrial centers (modified Rankin Scale adjusted cOR: 0.77 [95% CI, 0.5–1.2]). Conclusions: Our study shows that high rates of favorable clinical outcome and successful reperfusion can be achieved with EVT for PCS, despite high mortality. Characteristics and outcomes of patients treated in trial versus nontrial centers were similar indicating that our cohort is representative of clinical practice in the Netherlands. Randomized studies using modern treatment approaches are needed for further insight in the benefit of EVT for PCS.

Objectives This study was undertaken to estimate the cost-effectiveness of deep brain stimulation (DBS) compared with vagus nerve stimulation (VNS) and care as usual (CAU) for adult patients with refractory epilepsy from a health care perspective using a lifetime decision analytic model. Methods A Markov decision analytic model was constructed to estimate the lifetime cost-effectiveness of DBS compared with VNS and CAU. Transition probabilities were estimated from a randomized controlled trial, and assumptions were made in consensus with an expert panel. Primary outcomes were expressed as incremental costs per quality-adjusted life-year (QALY) and per responder. Univariate and probabilistic sensitivity analyses were conducted to characterize parameter uncertainty. Results In DBS, 28.4% of the patients were responders, with an average of 21.38 QALYs per patient and expected lifetime health care costs of euro187 791. VNS had fewer responders (22.3%), fewer QALYs (20.70), and lower lifetime costs (euro156 871). CAU had the fewest responders (6.2%), fewest QALYs (18.74), and lowest total health care costs (euro64 670). When comparing with CAU, incremental cost-effectiveness ratios (ICERs) showed that costs per QALY gained were slightly lower for DBS (euro46 640) than for VNS (euro47 155). When comparing DBS with VNS, an incremental cost per additional QALY gained of euro45 170 was found for DBS. Sensitivity analyses showed that ICERs were heavily dependent on assumptions regarding loss to follow-up in the respective clinical trial. Significance This study suggests that, given current limited evidence, VNS and DBS are potentially cost-effective treatment strategies compared to CAU for patients with refractory epilepsy. However, results for DBS were heavily impacted by assumptions made to extrapolate nonresponse from the original trial. More stringent assumptions regarding nonresponse resulted in an ICER just above an acceptable willingness to pay threshold. Given the uncertainty surrounding the effectiveness of DBS and the large impact of assumptions related to nonresponse, further empirical research is needed to reduce uncertainty.

PURPOSE: To determine whether brivaracetam (BRV) provides an evident improvement in treatment efficacy and a reduction in treatment-emergent adverse events (TEAEs) in patients with refractory epilepsy, who previously failed treatment with levetiracetam (LEV).DESIGN: Retrospective analysis of data extracted from electronic patient files at Epilepsy Centre Kempenhaeghe (Heeze, the Netherlands) from the year 2000 until October 2020.METHODS: The inclusion criteria were met by 407 patients >18 years of age. During data collection, 26 patients were excluded due to too little follow-up information on the use of either LEV or BRV, and two more due to poor medication compliance, leaving a total of 379 patients for further analyses. All had used LEV before they started treatment with BRV. For every patient, data were collected including demographic information, efficacy (positive responder or non-responder) of LEV and BRV, and TEAEs occurring during LEV and BRV treatment.RESULTS: A total of 121 (29.8%) patients had discontinued BRV treatment before the end of data collection. At time of data collection the mean time since first seizure was 25.4 years. Of the 379 patients, 82.8% were diagnosed with focal epilepsy and 9.8% with generalized epilepsy. The median duration of treatment was 39 months for LEV and 20 months for BRV, the mean maximum dose was 1749.9 mg/day for LEV and 144.2 mg/day for BRV, and the mean number of concomitant AEDs was 1.4 at the start of LEV treatment and 2.0 at the start of BRV treatment. LEV was switched directly to BRV in 208 (54.9%) patients; 171 (45.1%) patients had an interval between discontinuation of LEV and the start of BRV. The mean duration of interval was 77.7 months. Of the patients who discontinued BRV, 30 (24.8%) switched back to LEV. Discontinuation of initial LEV treatment was due to TEAEs in 63.6% of patients, including 55.1% because of behavioural TEAEs. Discontinuation of BRV was due to inadequate efficacy in 24.0% of patients, to TEAEs in 47.1% and to both inadequate efficacy and TEAEs in 22.3%. Concerning efficacy, the analysis showed no significant difference between the positive responder rate of LEV and BRV (72.0% vs 69.1%, p>0.05). Of the patients who were positive responders to LEV treatment, 78.0% also had a positive response to BRV treatment. Of the non-responders to LEV treatment, 46.2% did have a positive response to BRV treatment. In comparison to LEV, patients reported significantly fewer TEAEs during BRV treatment (86.5% vs 61.7%, pCONCLUSION: Overall BRV was better tolerated than LEV, especially regarding the behavioural TEAEs. Efficacy analyses showed that patients are likely to have a positive response to BRV when they had a positive response to LEV. However, this is not always guaranteed. Lack of response to LEV does not preclude a positive response to BRV. All in all, BRV seems to be an interesting treatment option in patients previously treated with LEV.

BackgroundData on oral anticoagulant-related (OAC) intracerebral hemorrhage (ICH) incidence are scarce. Most studies on incidence time trends were performed before the introduction of Direct Oral Anticoagulants (DOACs). Between 2008 and 2018, the number of OAC-users in the Netherlands increased by 63%, with the number of DOAC-users almost equaling that of Vitamin K Antagonists (VKA)-users. We aimed to determine the recent total and OAC-related ICH incidence and assess changes over the last decade, including the effect of DOAC introduction.MethodsAll adult non-traumatic ICH patients presenting in any of three hospitals in the enclosed region of South-Limburg, the Netherlands, were retrospectively included, during two 3-year time periods: 2007–2009 and 2017–2019. OAC-related ICH was defined as ICH in patients using VKAs or DOACs. We calculated the incidence rate ratio (IRR) between the two study periods.ResultsIn the 2007–2009 period, we registered 652 ICHs of whom 168 (25.8%) were OAC-related (all VKA). In the 2017–2019 period, we registered 522 ICHs, 121 (23.2%) were OAC-related (70 VKA and 51 DOAC). In 2007–2009, the annual incidence of total ICH and OAC-related ICH was 40.9 and 10.5 per 100,000 person-years, respectively, which decreased to 32.4 and 7.5 per 100,000 person-years in 2017–2019. The IRR for total ICH and OAC-related ICH was 0.67 (95%-CI: 0.60–0.75) and 0.58 (0.46–0.73), respectively.ConclusionBoth total ICH and OAC-related ICH incidence decreased over the past decade in South-Limburg, the Netherlands, despite the aging population and increasing number of OAC-users. The introduction of DOACs, and possibly an improved cardiovascular risk management and change in OAC prescription pattern, could explain these findings.

BackgroundEarly neurological deterioration (END) after endovascular treatment (EVT) in patients with anterior circulation acute ischemic stroke (AIS) is associated with poor outcome. END may remain unexplained by parenchymal hemorrhage (UnEND). We aim to analyze the risk factors of UnEND in the medical management (MM) and EVT arms of the HERMES study.MethodsWe conducted a post-hoc analysis of anterior AIS patients who underwent EVT for proximal anterior occlusions. Risk factors of UnEND, defined as a worsening of ≥4 points between baseline National Institutes of Health Stroke Scale (NIHSS) and NIHSS at 24 hours without hemorrhage, were compared between both arms using mixed logistic regression models adjusted for baseline characteristics. An interaction analysis between the EVT and MM arms for risk factors of UnEND was conducted.ResultsAmong 1723 patients assessable for UnEND, 160 patients experienced an UnEND (9.3%), including 9.1% (78/854) in the EVT arm and 9.4% (82/869) in the MM arm. There was no significant difference in the incidence of UnEND between the two study arms. In the EVT population, independent risk factors of UnEND were lower baseline NIHSS, higher baseline glucose, and lower collateral grade. In the MM population, the only independent predictor of UnEND was higher baseline glucose. However, we did not demonstrate an interaction between EVT and MM for baseline factors as risk factors of UnEND. UnEND was, similarly in both treatment groups, a significant predictor of unfavorable outcome in both the EVT (pConclusionsUnEND is not an uncommon event, with a similar rate which ever treatment arm is considered. In the clinical scenario of AIS due to large vessel occlusion, no patient-related factor seems to increase the risk for UnEND when treated by EVT compared with MM.