ICH volume, haematoma expansion and 3-month-mortality in patients on antiplatelet therapy. A systematic review and meta-analysis
Martina Goeldlin (Bern | CH)
Data on the influence of prior antiplatelet therapy (APT) on intracerebral haemorrhage (ICH) are conflicting. We aimed to summarize and meta-analyse the association of prior APT on characteristics of ICH and outcome.
We performed a systematic review and meta-analysis of all studies published on PubMed comparing ICH outcomes of patients on APT (APT-ICH) with patients not taking APT (non-APT-ICH). Primary outcomes were haematoma volume on admission (mean difference and 95%-CI), secondary haematoma expansion (HE), short-term- and 3-month mortality. Odds ratios (OR) were calculated with Maentel-Hanszel random-effects method and 95%-CI.
Out of 1205 identified studies, 28 on 31063 patients with APT-ICH and 62789 patients with non-APT-ICH matched our in- and exclusion criteria. Patients on APT were older (mean age difference 6.8 years, 95%-CI 5.71 - 7.90, p < 0.00001; I2 = 69%, p < 0.00001), had larger haematoma volume (mean difference 3.6 ml, 95% - CI 1.43 - 5.28, p = 0.0006; I2 = 60%, p < 0.0009), but there was no statistically significant difference in secondary haematoma expansion (OR 1.26, 95%-CI 0.83 - 1.91, p = 0.27; I2 = 65%, p = 0.001). Mortality in patients with APT-ICH was higher at short-term- (OR 2.02, 95%-CI 1.41 - 2.90, p = 0.001; I2 = 76%, p < 0.00001) and 3-month (OR 1.5, 95%-CI 1.24 - 1.81; p < 0.0001, I2= 70%, p < 0.001). We found insufficient data for functional outcome and comparison of single vs dual APT-ICH.
Prior APT is associated with predictors of poor outcome and mortality. Data on functional outcome and differences in single and dual APT-ICH are scarce and warrant further investigation along with the individual impact of APT therapy in the context of competing other predictors of poor outcome (i.e. age).
Role of Caveolin-1 in neovascularization and astrogliosis after stroke and effects of cavtratin as a neuroprotectant
Camille Blochet (Lausanne | CH)
Complex cellular and molecular events occur in the neurovascular unit after stroke and contribute to neuronal death, neurological deterioration and mortality. In the CNS, Caveolin-1 (Cav-1) is present in brain endothelial cells and astrocyte cultures. Cav-1 has a dual mode of action. On one hand, Cav-1 is associated with caveolae formation involved in endocytosis and transcytosis. On the other hand, Cav-1 can act through a scaffolding domain to modulate signaling pathways (1). Therefore, Cav-1 is likely to be an important player in the context of NVU dysfunction. However, its role after stroke is still controversial and the effect of Cavtratin, a cell-permeable peptide containing the scaffolding domain of Cav-1 has never been investigated (2).
The goal of the study was to investigate the role of Cav-1 in the acute phase after stroke and evaluate the potential neuroprotective effect of the Cavtratin peptide.
We first compared wild type (WT) and genetically modified Cav-1 knock-out (KO) mice in an ischemia-reperfusion model using transient Middle Cerebral Artery Occlusion (tMCAO). Outcome measures including lesion volume, behavioral tests, and immunofluorescence staining were collected at various time-points and up to 7 days after injury. We then performed blinded and randomized IP injections of Cavtratin or control scrambled peptide (dose 2.5 mg/kg) 3 hours after the reperfusion and evaluated the same outcome measures as above.
After tMCAO, Cav-1 expression was increased in new blood vessels within the lesion and we showed for the first time its presence in reactive astrocytes in the peri-lesion. Cav-1 KO mice displayed a more severe post-stroke outcome with larger lesions and worse behavioural scores than WT mice in all tests. Cav-1 KO mice exhibited reduced neovascularization and modified astrogliosis compared to WT mice 3 days post injury associated with aggravated functional deficits. Preliminary results of the outcomes after Cavtratin or control peptide injection show that mice injected with Cavtratin perform better in behavioral tests and display some features of neuroprotection.
Altogether, these results point towards a protective role of endogenous Cav-1 in the first days after ischemia by promoting both neovascularization and astrogliosis (3), and single injection of Cavtratin may facilitate the recovery post-stroke.
Genetic findings in children with CNS arteriovenous fistulas
Guillaume Saliou (Lausanne | CH)
Background and purpose:
To assess the spectrum of genetic anomalies in a cohort of children presenting at least one cerebral or spinal pial arteriovenous fistula (pial AVF) or a vein of Galen malformation (VGAM).
Materials and Methods:
We conducted a retroscpective analysis in 94 children known to have either with a pial AVF (n=43) or a VGAM (n=51), who were previously screened for Hemorrhagic Hereditary Telangiectasia (HHT) disease (ENG, ACVRL1 and SMAD4 mutations), Capillary malformation – arteriovenous malformation (CM-AVM) syndrome type 1 due to RASA1 mutation and type 2 due to EPHB4 mutation. The type of the shunt was thoroughly evaluated and then classified (pial AVF or VGAM). Arteriovenous shunts through the vein of Galen were classified as true VGAM only if the deep cerebral system was not draining together with the shunt but rather through an alternative venous pathway. Shunts that drained together with normal brain venous outflow through the vein of Galen were classified as pial AVF and not VGAM.
We identified a germline mutation in 28 probands. EPHB4 mutation was identified only in 5 of the 51 patients with VGAM. Hemorrhagic Hereditary Telangiectasia disease or RASA1 mutation were identified only in 23 of the 43 pial AVFs: eight mutations in ENG and one in ACVRL1 leading to a diagnosis of HHT and 14 in RASA1 leading to a diagnosis of CM-AVM1.
These results highlight the importance of genetic testing in this setting because of the high frequency of gene mutations in pediatric patients with cerebrospinal arteriovenous fistulas. EPHB4 mutation appears associated with true VAGM whereas HHT disease and RASA1 mutation appear associated with pial fistulas. More comprehensive studies are required to demonstrate a causal relationship.
Geometric morphometrics reveal altered corpus callosum shape in pyridoxine- dependent epilepsy
Gabriela Oesch (Zürich | CH)
Aim: To evaluate the features and maturational changes in overall callosal shape in patients with pyridoxine-dependent epilepsy (PDE).
Methods: Measurements were conducted through landmark based geometric morphometrics applied on cerebral MRIs of PDE patients and age-matched control subjects. The outline of the corpus callosum was manually traced in the midsagittal plane. 300 semi-landmarks along the outline were collected and underwent statistical generalized Procrustes analysis. An allometric regression was applied to evaluate the callosal shape due to growth over time.
Results: 38 subjects with PDE and 38 age- and gender-matched control subjects were included. Mean age at the time of the MRI in the patient group was 9.3 years (median 6.3 years, range 0.01- 48 years). Significant differences (p < 0.01) in the mean callosal shape between patients and controls were found. The allometric regression model revealed significant shape variations (p < 0.01) between the two study groups across the developmental course after controlling for the effect of callosal size on shape. This latter effect turned out to be significant as well (p < 0.001).
Conclusions: Patients with PDE show an altered callosal shape and variations in callosal ontogeny which are likely secondary to the underlying genetic defect with abnormal function of antiquitin, the product of the ALDH7A1 gene.
Flashing light therapy against photophobia in migraine – an fMRI study
Tuna Stefan Aslan (Wien | AT)
Photophobia is the most prevalent accompanying symptom of
migraine. Patients often tend to avoid bright light exposure as
it can trigger or worsen a migraine attack. However, a recent
study from Australia suggests that avoidance of aversive light
stimulus may potentiate photophobia, whereas systematic
exposure might induce better coping with the aversive
stimulus, possibly due to a habituation mechanism . This led
us to the hypothesis that photophobia might be treated in
some migraine patients using prolonged exposure to flickering
light stimulus. Despite behavioral indications for a possible
benefit thereof , neurophysiological studies using EEG and
fMRI have mostly shown a deficient interictal habituation to
repeated sensory stimuli in migraine patients . The current
study was set up to test repeated exposure to flashing light as
a therapeutic intervention against photophobia in migraine
Neuroimaging: The scans consisted of 10 subsequent runs, each one including
7 alternating blocks of flashing light (8 Hz) and darkness for
140 sec. The subjects were asked to fix their gaze to a cross
that was present throughout the runs. fMRI data were collected
using a 3T SIEMENS PRISMA system with a 64 channel head coil
and dedicated head fixation. Images were analyzed using
SPM12. We performed the within-subject contrast based on the
acquired data in the fMRI sessions following the Flash
("PostFlash") and the Dark ("PostDark") interventions.
Based on FWE < 0.05 correction 2 types of visual cortex
activity patterns were found:
-Habituation to “Flash”: This was found in 6 out of 11
healthy subjects and 2 out of 9 patients.
-No habituation to “Flash”: This was found in 3/9 patients
in line with the previously reported habituation
deficit in many migraine patients.
Other participants showed no significant differences in
the visual cortex between conditions.
Our initial results were in line with the neurophysiological
studies reporting deficient interictal habituation in migraine
patients and also revealed migraine patients demonstrating
an activation drop in the visual cortex following the “Flash”.
Previous literature suggests the existence of two subgroups
of migraine patients, with and without habituation to
sensory stimulation, which lends credibility to the observed
intragroup variability. The intragroup variability observed
underlines the necessity to analyze data individually in
Rare genetic variants in patients with cervical artery dissection
Christopher Tränka (Basel | CH)
Introduction: To identify pathogenic genetic variants associated with cervical artery dissection (CeAD).
Patients and methods: CeAD-patients with either a family history of CeAD (f-CeAD) or recurrent CeAD (r-CeAD) from the CeAD-databases of two experienced stroke centers were analyzed by whole exome sequencing.
Variants with allele frequency < 0.05 and classified as pathogenic by predicting algorithms (SIFT or Polyphen-2) or the ClinVar database were explored. First, we analyzed a panel of 30 candidate genes associated with arterial dissection (any site) or aneurysm according the OMIM (online Mendelian Inheritance of Men) database. Second, we performed a genome-wide search for pathogenic variants causing other vascular phenotypes possibly related to CeAD.
Findings were classified as CeAD-causing (pathogenic variants in genes from the arterial dissection or aneurysm panel) or suggestive (pathogenic variants in genes associated with other vascular phenotypes and variants of unknown significance in genes from the arterial dissection or aneurysm panel). All other variants were classified as benign/uncertain.
Results: Among 43 CeAD-patients, 28 patients (17 pedigrees) had f-CeAD and 15 had r-CeAD. No CeAD-causing variants were identified in r-CeAD patients. Among f-CeAD-patients, 5/17 pedigrees carried CeAD-causing variants in COL3A1, COL4A1, COL4A3, COL4A4, COL5A1, COL5A2 and FBN1. Suggestive variants in ABCC6, COL3A1, COL5A2, COL5A2, MEF2A, and RNF213 were detected in three pedigrees with f-CeAD and six patients with r-CeAD.
Discussion and Conclusion: CeAD-causing variants were rare and exclusively found in f-CeAD-patients, suggesting differences between the genetic architectures of f-CeAD and r-CeAD. The identified variants indicate a high genetic heterogeneity of the study sample.
Enlarging the Transient Global Amnesia Spectrum: Vascular and other atypical triggers and manifestations
Stefania Nannoni (Lausanne | CH)
Aims: Transient global amnesia (TGA) represents a benign syndrome usually easily distinguishable from stroke. It is often accompanied by an isolated hippocampus punctate lesion on diffusion-weighted imaging (HPDL). We report 13 unusual “TGA” cases associated with unusual triggers (such as acute strokes) or clinical aspects (such as focal neurological signs, or absence of amnestic manifestations).
Methods: Over 12-years, our comprehensive stroke center prospectively collected patients with clinically and/or radiologically defined TGA with A) acute vascular lesions, B) other neurological triggers, and C) unusual neurological manifestations. They were analyzed and grouped to redefine an enlarged “TGA spectrum”.
Results: We identified in group A) 5 patients with typical TGA (4 with HPDL) and radiological evidence of recent ischemic or hemorrhagic brain lesions (acute convexity subarachnoid hemorrhage, lenticular hemorrhage, 3 ischemic strokes in the middle cerebral artery territory), B) 4 patients with typical TGA (3 with HPDL) plus other transient neurological signs (aphasia, behavioral problems, minor lateralizing sensory-motor deficits), and C) 4 patients with HPDL but without clinical amnesia (but acute aphasia, minor lateralizing sensory-motor deficit, focal seizures with loss of awareness from anti-CASPR-2 encephalitis, and convulsive peri-coital syncope).
Conclusions: TGA can be triggered by acute vascular and other neurological events. Furthermore, TGA may present with additional focal neurological signs, or as HPDL with a non-amnestic syndrome. Therefore, TGA may better be considered as a “TGA spectrum”, with clinical and/or radiological manifestations being the common expression of acute stress to the brain.
Serum neurofilament light chain predicts brain volume loss in patients with atrial fibrillation
Alexandros Polymeris (Basel | CH)
Background and Aims
There is emerging evidence that atrial fibrillation (AF) is associated with cognitive dysfunction, increased risk for dementia and reduced brain volume independent of stroke, but the underlying mechanisms of these associations remain unclear. Here, we investigated the association of serum neurofilament light chain (sNfL), a neuroaxonal injury biomarker, with brain atrophy in AF patients.
Explorative analysis from the prospective observational Swiss-AF cohort study (NCT02105844), which recruited AF patients aged ≥ 65 years without recent stroke. We measured sNfL concentrations in duplicate at baseline using a single molecule array (SIMOA) assay. Brain MRI was obtained at baseline and after two years using a standardized protocol. This included a 3D T1-weighted MPRAGE sequence, on which we applied Structural Image Evaluation using Normalization of Atrophy (SIENA) with optimized parameters for brain extraction to calculate the two-year percentage whole brain volume change (PBVC). We further assessed the normalized brain volume using SIENAX, presence and volume of ischemic infarcts and white matter hyperintensities and count of microbleeds on appropriate sequences on the baseline MRI. We excluded patients with acute infarcts.
We included 232 consecutive Swiss-AF patients (median age 73, 75% male) for whom pilot data were available. In a simple linear regression model, baseline sNfL was significantly associated with two-year PBVC, with a 0.13% whole brain volume decrease per 10 pg/ml higher sNfL levels (95% CI [0.07, 0.19], p < .001). This association remained significant after adjustment for clinical parameters (age, sex, AF type, history of stroke and other vascular risk factors) and baseline MRI variables (aforementioned vascular brain lesions and normalized brain volume).
In AF patients, baseline sNfL was predictive of brain atrophy at two years independent of stroke history, cerebral infarcts and MRI markers of small vessel disease. This association might reflect a chronic neurodegenerative process in AF.
Migraine and cervicogenic headache: analysis of pathogenic interaction
Olga S. Khayrutdinova (Kazan | RU)
The main currently considered theory of migraine pathophysiology is trigeminovascular theory, in which the leading role was given to CGRP (calcitoningene related peptide), contained in the endings of trigeminal nerve and released intracranially during a migraine attack. In 2013 M. Shuelera et al pointed out the possible effect of pathological impulses from extracranial tissues to the onset of a migraine attack (Markus Schuelera et al. PAIN 2013:154: 1622-1631). According to their data it’s possible to suggest that therapy of cervical structures pathology in patients with migraine may favorably affect headache's course and the effectiveness of treatment.
Aim of the study is to evaluate the effect of the treatment of pathological impulses from cervical anatomical structures on the course of migraine and describe the effect of dimethylsulfoxide on the meningeal fibers of the trigeminal nerve on the model of migraine in rats.
Clinical part: Patients with cervicalgia and migraine were diagnosed by MRI of the cervical spine, history taking and neurological examination. After this they were treated by Comprehensive treatment received by patients includes: manual therapy, novocainic infiltration of the neck muscles, DMSO applications, triptans during migraine attack.
Experimental part: as an object of study in vitro was used an isolated rat skull preparation.Under visual control, the peripheral process of the trigeminal nerve was drawn into the glass electrode. Application of 0.1%, 1%, 10% of DMSO is carried out in the region of divergence of the middle meningeal artery.
1. In 61% of patients after the complex treatment described above, the intensity of migraine decreased (from 8.4 to 6.1 points VAS);
2. 69% of respondents noted a decrease of migraine attacks frequency (from 3.5 to 1.3 per month);
3. 82% noted an improvement in mood and quality of life in general.
4. 10% DMSO caused a dramatic change in the frequency of action potential from the first minutes of its presence in the solution (from 2.75 ± 0.76 s-1 to 16.57 ± 2.33 s-1) with next denervation.
Conclusion: the results of this study confirm the mutual influence of cervicogenic headache and migraine when they are combined in a patient. We noted the positive dynamics of the migraine course in patients during therapy aimed to eliminating of pathological impulses from cervical spine and dramatic action of 10% DMSO exposure to trigeminal nerve fibers with their subsequent denervation.
Effect of a motor-cognitive dual-task training for MS-related fatigue
Francesca Estrada Daniele (Brissago | CH)
Aim of the study:
To assess the effect of dual task training on MS-related fatigue.
Fatigue is one of the most common symptoms in people with MS (PwMS) where it represents the most impairing symptom for about 40% of them. Fatigue is now recognized as caused by a connectivity impairment in frontal and prefrontal areas, which results in increased activation. Dual tasks exercises are the best training to stimulate at the same time different cerebral areas and some studies found a correlation between dual tasks activities and fatigue onset in PwMS. Until now, the effect of dual task exercises on postural stability has been studied in stroke patients, Parkinson and MS patients but the effect of a dual task training on fatigue has never been explored.
Materials and Methods:
We enrolled 11 patients (8F, 3M) with a mean age of 53 years in this single group open label study. Inclusion criteria were:
Diagnosis of MS (any clinical course)
EDSS ≤ 6.5
Fatigue defined as cognitive and/or motor score in FSMC ≥ 22.
All patients performed a 2 weeks training program with 10 dual task exercise sessions in addition to the usual rehabilitative treatment in an in-patient clinical setting. Each session lasted 20 minutes and included the combination of cycling and cognitive tasks focussing on working memory.Outcome measures were:
FSMC (total, cognitive and motor) as main outcome
TUG (single and dual task)
Results & Discussion:
The positive predictive value for modifications in the final FSMC total score is the initial FSMC motor score (p < 0.05); the complete statistical analysis showed that after the dual task training we didn’t reach a significant improvement neither for the main and secondary outcome measures.
These preliminary data showed that motor FSMC score predicted the improvement of final global FSMC score, even if the global improvement on fatigue didn’t reach the statistically significance.
This may be explained by motor planning role of prefrontal region trained by cognitive training in the dual task exercise resulting in a better motor planning strategy which compensate functional disconnection due to MS probably responsible for fatigue in PwMS. Another easier explanation is that the aerobic exercise overwhelm the cognitive training of the dual task.
To verify these discordant explanations, it will be necessary to investigate a larger sample population, where dual task training would be compared with simple aerobic exercise.
Multimodal improvements after apomorphine treatment for chronic disorders of consciousness: preliminary results
Leandro R. D. Sanz (Liège | BE)
Aims: Treatment with apomorphine, a dopamine agonist, has exhibited behavioral effects on the recovery of patients with disorders of consciousness (DOC)[1,2], but its action on brain activity remains unknown. We report the preliminary results of a prospective open-label study using multimodal assessment methods, which aims to confirm the efficacy and investigate the mechanism of apomorphine treatment among post-coma patients.
Methods: Three patients with chronic DOC (1 female, 2 males; 47, 34 and 23 years old; 1 hemorrhage, 2 traumatic; 3.5, 4.5 and 3 months since onset) were administered subcutaneous apomorphine for 30 days. They were followed 30 days before initiation, during treatment and 30 days after withdrawal.Outcome measures included Coma Recovery Scale – Revised (CRS-R), positron emission tomography (PET)[4,5] and electroencephalography-based (EEG) measures such as functional connectivity and multivariate machine-learning classification[7,8].
Results: At baseline, patients 1 and 2 were diagnosed with the CRS-R as minimally conscious state (MCS) minus[9,10] (language-independent signs of consciousness), and patient 3 as MCS plus (language-related signs of consciousness). After the initiation of apomorphine, patient 1 improved to MCS plus, patient 2 remained in MCS minus but showed a new sign of consciousness and more consistent behaviors, and patient 3 emerged from the MCS.
PET revealed an improvement of global brain metabolism after compared to before apomorphine treatment for all three patients (difference of +43%, +26%, and +4% for patient 1, 2 and 3 respectively). Functional connectivity measured by EEG network centrality also increased after treatment for all patients in the alpha frequency bands. EEG multivariate classifier improved after treatment for two patients (difference of +25%, +20%, -1% for patient 1, 2, and 3 respectively) with significant increase in most individual EEG markers.
Conclusion: After treatment, patients showed multimodal improvements with more frequent conscious behaviors and increased brain activity measures compared to baseline observations. These results suggest that the action of apomorphine on the recovery of DOC patients may be associated with measurable neuroimaging changes. Additional results from the subsequent placebo-controlled randomized controlled trial will be necessary to confirm the efficacy and further define the neural effects of apomorphine treatment in severely brain-injured patients.
Treatment of therapy refractory chronic cluster headache with the CGRP antibody erenumab – A case report
Anna Lena Keck (Aarau | CH)
Lutz Achtnichts (Aarau | CH)
Cluster headache (CH) is a rare but severe headache disorder characterized by repeated unilateral head pain attacks accompanied by ipsilateral autonomic features. A minority of CH patients have the chronic form, without pain–free intervals between the headache attacks. Chronic CH is very disabling and the treatment is challenging. A recent study could show that Calcitonin gene-related peptide provokes cluster headache attacks in chronic cluster headache1. These results suggest that anti-CGRP drugs may be effective in cluster headache management. However evidence from clinical trials for anti-CGRP drugs in chronic CH is lacking. We report a case of a 36 year old female with chronic CH, who failed to respond to first, second, and third line therapies including also as well invasive treatment like sphenocath, nervous occipitalis infiltration and an implantation of a bilateral nervous occipitalis nerve stimulator. Under this treatment, she still had on average 4-5 attacks per day with intensities around the maximum mark on the visual-analogue-scale (VAS 8-10). We assessed her to a off-label treatment with erenumab.
We used a patient headache diary to assess the CH attacks frequency, intensity, duration and the medication use two months prior and four months after initiation of treatment.
After 2 months, Erenumab showed a marked reduction in cluster attack Intensity, duration and number of attacks per day. Furthermore, there was a drastic reduction in triptane and benzodiazepine use for acute attack treatment. After 4 month of treatment the effect was still present. Up to the present, no adverse effects of the erenumab treatment were observed.
These results suggest that anti-CGRP drugs might be effective in cluster headache management, however more reliable evidence is still lacking.