Future targets for migraine treatment beyond CGRP.

BACKGROUND: Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine. FINDINGS: We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results. CONCLUSION: While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.

Visual cortex changes in children with sickle cell disease and normal visual acuity: a multimodal magnetic resonance imaging study.

The visual system is primarily affected in sickle cell disease (SCD), and eye examination is recommended starting in late childhood. So far, to our knowledge, all studies have focused on the retina, neglecting the changes that might be present in the cortical portion of the visual system. We performed a multimodal magnetic resonance imaging (MRI) evaluation of the visual cortex in 25 children with SCD (mean age: 12·3 ± 1·9 years) and 31 controls (mean age: 12·7 ± 1·6 years). At ophthalmologic examination, 3/25 SCD children had mild visual acuity deficits and 2/25 had mild tortuosity of the retinal vessels. None showed optic pathway infarcts at MRI or Transcranial Doppler abnormal blood velocities, and 6/25 disclosed posterior cerebral artery stenosis (five mild and one severe) at MR-angiography. Compared to controls, SCD children had increased posterior pericalcarine cortical thickness, with a different trajectory of cortical maturation and decreased connectivity within medial and ventral visual neural networks. Our findings suggest that SCD affects the development and the tuning of the visual cortex, leading to anatomical and functional changes in childhood even in the absence of retinopathy, and set the basis for future studies to determine if these changes can represent useful predictors of visual impairment in adulthood, biomarkers of disease progression or treatment response.

Intravenous thrombolysis for ischemic stroke in the Veneto region: the gap between eligibility and reality.

Intravenous thrombolysis (IVT) is the treatment of choice for most patients with acute ischemic stroke. According to the recently updated guidelines, IVT should be administered in absence of absolute exclusion criteria. We aimed to assess the proportion of ischemic strokes potentially eligible and actually treated with IVT, and to explore the reasons for not administering IVT. We prospectively collected and analyzed data from 1184 consecutive ischemic stroke patients admitted to the 22 Stroke Units (SUs) of the Veneto region from September 18th to December 10th 2017. Patients were treated with IVT according to the current Italian guidelines. For untreated patients, the reasons for not administering IVT were reported by each center in a predefined model including absolute and/or relative exclusion criteria and other possible reasons. Out of 841 (71%) patients who presented within 4.5 h of stroke onset, 704 (59%) had no other absolute exclusion criteria and were therefore potentially eligible for IVT according to the current guidelines. However, only 323 (27%) patients were eventually treated with IVT. Among 861 (73%) untreated patients, 480 had at least one absolute exclusion criterion, 283 only relative exclusion criteria, 56 only other reasons, and 42 a combination of relative exclusion criteria and other reasons. Our study showed that only 46% (323/704) of the potentially eligible patients were actually treated with IVT in the SUs of the Veneto region. All healthcare professionals involved in the acute stroke pathway should make an effort to bridge this gap between eligibility and reality.

Transcranial Sonography in Neurodegenerative Diseases with Cognitive Decline.

Transcranial sonography (TCS) of the brain parenchyma detects alterations in the substantia nigra (SN), raphe nuclei and basal ganglia; this technique has been established as a tool for the early diagnosis of Parkinson's disease and differential diagnosis from atypical parkinsonian syndromes. Here, we aimed to review the main applications of TCS in neurodegenerative diseases presenting with dementia syndrome, focusing on Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration, idiopathic normal pressure hydrocephalus, and atypical and secondary parkinsonisms. The finding of bilaterally marked hyperechogenicity of the SN appears as a characteristic feature of DLB, while it is found only in a minority of AD patients. SN hyperechogenicity is also detected in most patients with corticobasal degeneration and in about one third of patients with progressive supranuclear palsy, in which is constantly associated with hyperechogenic alterations of the basal ganglia. In conclusion, TCS is a valid supportive tool in the diagnostic workup of patients with dementia due to different neurodegenerative conditions. A promising new application is the differentiation of DLB from AD even at the early stages of these diseases.

Prognostic Role of Microembolic Signals After Endovascular Treatment in Anterior Circulation Ischemic Stroke Patients.

BACKGROUND: Endovascular treatment (EVT) is an effective therapy for acute ischemic stroke due to large artery occlusion of the anterior circulation. Yet some patients do not experience clinical improvement despite successful recanalization and reperfusion. The reasons are unknown, but one possible explanation is microvessel obstruction downstream. The aim of this study was to assess the presence of microembolic signals (MES) with transcranial Doppler and define their role as predictors of clinical outcome in stroke patients after EVT. MATERIALS AND METHODS: We enrolled 40 consecutive patients (23 men, mean age 65.8 ± 7.6 years) with an acute ischemic stroke caused by large artery occlusion of the anterior circulation who underwent EVT. Presence and rate of MES were assessed by 60-minute transcranial Doppler monitoring at the end of the procedure and after 15 days from stroke onset. RESULTS: MES were detected in 65% (26/40) of patients after EVT. Ipsilateral carotid occlusion (P = 0.05), ≥50% ipsilateral carotid stenosis (P = 0.05), incomplete recanalization (P = 0.03), and inadequate collaterals (P = 0.04) were associated with a significantly higher MES count, which was correlated with a worse functional prognosis (P = 0.03), higher mortality (P = 0.02), higher distal embolization burden even outside the original ischemic territory (P = 0.02), and higher risk of cardiovascular events (P = 0.04). CONCLUSIONS: MES monitoring in stroke patients after EVT provides useful prognostic information, sheds light on the lack of clinical improvement despite successful recanalization, and might guide medical treatment in higher risk patients.

Stentriever Thrombectomy Failure: A Challenge in Stroke Management.

BACKGROUND AND OBJECTIVE: Stentriever thrombectomy failure in patients with acute ischemic stroke caused by anterior circulation large artery occlusion is not a rare event. The purpose of this study was to investigate whether other procedures (tirofiban, permanent stenting) are able to recanalize the occluded vessel and determine a better outcome without increasing mortality and intracranial hemorrhage rates. METHODS: Among 513 patients consecutively admitted with anterior circulation stroke, 109 underwent stentriever thrombectomy. Modified Thrombolysis in Cerebral Ischemia (mTICI) 2b-3 recanalization was achieved in 60 patients (55.0%, group 1). Only 3 of 19 patients (group 2) obtained additional recanalization with intra-arterial infusion of tirofiban. The remaining 46 either underwent permanent stenting (n = 23, group 3) or were left nonrecanalized (n = 23, group 4). The rate of mTICI 2b-3 and clinical outcomes were analyzed in the different groups. RESULTS: A successful recanalization (mTICI 2b-3) was achieved in 17 patients of group 3 (73.9%). A significantly better outcome was observed in group 3 (modified Rankin Scale [mRS] score, 0-2) than in group 4 at 3 months (56.5% vs. 17.4%). Symptomatic intracranial hemorrhage rates were not different between group 3 and group 4 (4.3% vs. 4.3%), whereas there was a significantly higher mortality in group 4 than in group 3 (39.1% vs. 4.3%). On multivariate analysis, permanent stenting was the only factor independently associated with favorable outcome and mortality. CONCLUSIONS: Permanent stenting might be a feasible solution in patients with acute large artery occlusion after stentriever thrombectomy failure.

Safety and Tolerability of SonoVue® in Patients with Large Artery Anterior Circulation Acute Stroke.

BACKGROUND AND PURPOSE: Ultrasound contrast agents (UCAs) are routinely used to improve the visualization of intracranial arteries. Since a higher rate of intracranial hemorrhage (ICH) has been observed in patients undergoing sonothrombolysis in combination with UCAs, we conducted this study with the aim of assessing safety and tolerability of SonoVue® in patients with acute ischemic stroke due to anterior circulation large artery occlusion (LAO) and eligible to intravenous thrombolysis and/or mechanical thrombectomy. METHODS: Among 474 patients consecutively admitted to our Stroke Unit with anterior circulation ischemic stroke, SonoVue® was administered during transcranial ultrasound evaluation to 48 patients with suspected LAO for diagnostic confirmation (group I) and to 44 patients with inadequate temporal bone window. Forty-eight stroke patients with LAO diagnosed only by computed tomography (CT) angiography /magnetic resonance (MR) angiography and matched for age, gender, and National Institutes of Health Stroke Scale score with group I represented the control group (group II). Thrombolysis, thrombectomy, or combined treatment were offered to all eligible patients. Brain MR imaging/CT was performed in both groups in case of neurological deterioration or after 1 week to check for ICH. RESULTS: SonoVue® did not cause any serious adverse event; only mild and transient side effects were reported in six cases (6.5%). Among patients in groups I and II, there were 31 (32.3%) secondary cerebral bleedings with no statistically significant difference between the groups, but only 2 (2.1%) were symptomatic. CONCLUSIONS: According to our study, SonoVue® can be safely administered to acute ischemic stroke patients with suspected anterior circulation LAO and/or inadequate temporal bone window.

LDL density and oxidation are modulated by PON1 promoter genotype in patients with Alzheimer's disease.

Cholesterol metabolism alteration is a hot topic in the field of Alzheimer's disease (AD). However, data on plasma lipoproteins cholesterol distribution and oxidation in AD and their possible genetic determinants are lacking. The paraoxonase-1 (PON1) gene -107C/T promoter polymorphisms have been found associated with AD. One of the fundamental functions of PON1 enzyme is the inhibition of low-density lipoproteins (LDL) oxidation. We therefore evaluated plasma lipoprotein profile and LDL density and oxidation in late-onset AD patients and healthy elderly subjects, without neuroimaging evidence of cerebrovascular lesions and not on lipid-lowering treatment, and their interaction with PON1 -107C/T and apolipoprotein E (APOE) genotypes. Mean plasma total cholesterol and LDL levels were higher in AD than controls (p < 0.05). Lipoproteins cholesterol distribution shifted toward a greater prevalence of smaller, denser LDL (sd-LDL, p < 0.05) only in AD patients with PON1 -107TT genotype, who also showed increased plasma levels of oxidized LDL (ox-LDL, p = 0.02). A significant association was observed between sd-LDL and ox-LDL levels (p < 005) in AD patients. APOE genotype did not modulate lipoprotein distribution. Increased levels of sd-LDL and ox-LDL particles in the AD PON1 TT patients could be explained by the combined effect of an AD-related pro-oxidant milieu and an ineffective PON1 gene polymorphism-related antioxidant capacity. The functional correlate of the association between PON1 -107C/T polymorphism and AD may be the abnormal modulation of LDL oxidation. Ox-LDL may amplify the processes of endothelial injury promoted by vascular amyloid deposition, which represents one of the potential pathways explaining the cross-road between vascular and neurodegenerative pathomechanisms in AD.

Clinical and cognitive correlates of visual hallucinations in dementia with Lewy bodies.

BACKGROUND: The presence of recurrent complex visual hallucinations (VHs) is a core feature of dementia with Lewy bodies (DLB). The aim of this study was to investigate which clinical and neuropsychological characteristics are associated with VHs and their predictive value over a 1 year follow-up. METHODS: 81 DLB patients, 41 with (VH+) and 36 without (VH-) VHs, and 45 patients with Alzheimer's disease (AD), were enrolled. All participants underwent extensive neuropsychological testing. Visual-spatial and perceptual abilities were evaluated with the Visual and Object Space Perception (VOSP) battery. Fluctuations in attention, rapid eye movement sleep behaviour disorder (RBD) symptoms, extrapyramidal signs and behavioural disturbances were studied with dedicated clinical scales. RESULTS: The presence of VHs was associated with older age and later disease onset, but not with disease duration or with fluctuations, RBD or parkinsonism severity. Cognitive correlates of VHs were deficits in visual attention (digit cancellation: p<0.005) and executive functions (clock drawing: p<0.05; digit span forward: p<0.05) on a background of a slightly worse global cognitive performance (Mini-Mental State Examination: p=0.05). Visual-perceptual and visual-spatial deficits were significantly worse in DLB than in AD patients (VOSP subtests scores 1, 6, 7 and 8) but were not different in DLB VH+ and VH-, except for subtest 6. Poor performance in the visual attention task was an independent predictor of VHs. DISCUSSION: Impairment of visual-spatial and perceptual abilities in DLB represents a disease related cognitive signature, independent of the presence of VHs, for which it may represent a predisposing condition. Visual attention, instead, is the main cognitive determinant for the genesis of VHs.