Bellwald S, Weber R, Dobrocky T, et al. Direct Mechanical Intervention Versus Bridging Therapy in Stroke Patients Eligible for Intravenous Thrombolysis. Stroke. 2017;48(12):3282-3288. doi:10.1161/STROKEAHA.117.018459.
The authors assessed whether direct MT is equally effective as bridging thrombolysis treatment consisting of intravenous thrombolysis plus MT in intravenous thrombolysis eligible patients.
They compared clinical and radiological outcomes at 3 months in 249 bridging patients with 111 patients receiving direct MT for large-vessel occlusion anterior circulation stroke from 2 prospective registries.
Functional outcome, mortality, and intracerebral hemorrhage did not differ, neither in univariate nor after multivariate and propensity score matching. However, in patients with internal carotid artery occlusion, mortality in the direct MT cohort was significantly lower.
There are several observational studies comparing direct MT in intravenous thrombolysis ineligible patients with bridging thrombolysis. Some of these studies suggested that pretreatment with intravenous thrombolysis before MT may increase recanalization rates and facilitate the endovascular procedure; however, there were considerable between-study variance. However, these findings could not be supported by post hoc analyses of recent randomized controlled trials, neither in a pooled post hoc analysis of SWIFT-PRIME and STAR nor in a post hoc analysis of MR CLEAN. Furthermore, a recent meta-analysis of 5 randomized controlled trials suggested that the treatment effect size of MT does not differ between patients receiving intravenous thrombolysis and those treated with MT alone.
The conclusion of this study, involving matched-pair analysis based on 2 large registries, was that there was no difference in outcome in intravenous thrombolysis eligible patients with LVO anterior circulation stroke treated with direct mechanical intervention compared with those treated with bridging thrombolysis except for a higher mortality in patients with ICA occlusions.
In their individual patient data comparison of bridging therapy with direct MT, they included intravenous thrombolysis eligible patients only. Some data of these patients have been published in previous reports; however, because of the small simple size and because of the local setting, it was difficult to translate the data in a general setting and to perform subgroup analysis in patients with ICA occlusion. They could not observe any increase in mortality when withholding IVT before MT: neither in univariate analysis nor in multivariate and propensity score matching, there was any difference in mortality between both groups. In the subset of patients with ICA occlusion, there was no difference in the univariate comparison, but in the multivariate matching analysis, mortality rate was significantly lower in the direct MT group. This finding was confirmed after 2:1 matching and propensity score matching.
3 Tables, 1 figure
Arnoux A, Triquenot-Bagan A, Andriuta D, et al. Imaging Characteristics of Venous Parenchymal Abnormalities. Stroke. 2017;48(12):3258-3265. doi:10.1161/STROKEAHA.117.017937.
The authors describe the patterns of parenchymal lesions associated with CVT and to determine the lesion sites in 44 consecutively hospitalized patients with CVT and parenchymal lesions on magnetic resonance imaging. The diagnosis of CVT was confirmed by magnetic resonance imaging/magnetic resonance venography. MR imaging patterns for CVT were retrospectively analyzed with regard to the lesion’s type, shape, and site.
The most frequent stroke subtype was hemorrhagic ischemia (in 56.8% of cases), followed by intracerebral hematoma (in 22.72% of cases) and nonhemorrhagic ischemia (in 20.45% of cases). Although there were no significant differences between these 3 groups with regard to the clinical and radiological characteristics, they observed a nonsignificant trend (P=0.08) toward a shorter time interval between hospital admission and MRI for nonhemorrhagic stroke.
The CVT parenchymal abnormalities were centered on 6 main foci and were related to the site of venous occlusion:
(1) the inferior parietal lobule (n=20; 44.5%), associated mainly with occlusion of the transverse sinus (n=10) or pure cortical veins (n=10);
(2) the inferior and posterior temporal regions (n=10; 22.75%), associated mainly with occlusion of the transverse sinus (n=9);
(3) the parasagittal frontal region (n=6; 13.6%), associated mainly with occlusion of the superior sagittal sinus (n=4) or the transverse sinus (n=4);
(4) the thalamus (n=5; 11.3%) associated with occlusion of the straight sinus (n=5);
(5) the cerebellar hemisphere (n=2; 4.5%), associated in both cases with occlusion of the transverse sinus; and
(6) the deep hemispheric regions (n=3; 6.8%), associated with occlusion of the superior sagittal sinus in all cases.
3 Figures, 1 table
Didn’t we already know this?
Hwang MH, Cho DH, Baek SM, et al. Spine-on-a-chip: Human annulus fibrosus degeneration model for simulating the severity of intervertebral disc degeneration. Biomicrofluidics. 2017;11(6):64107. doi:10.1063/1.5005010.
This is complicated, so best to just go and read this one. My short summary is as follows:
The aim of the study was to confirm the molecular regulation of the catabolic and inflammatory response of human AF cells in specific concentrations of IL-1b and macrophage-mediated IVD degeneration and to validate the availability of a newly developed microfluidic-based gradient spine-on-a-chip. The authors created an “IVD co-culturing microfluidic gradient platform” composed of three distinct chambers connected with a micro-patterned gradient channel using standard photolithographic techniques. The chambers enabled three types of cells (IVD, neuronal, and vascular cells) to be cultured. The 1st and 2nd chambers were directly connected through a microchannel. The 2nd and 3rd chambers were connected through arrays of thin hydrogel channels for studying the paracrine signaling between 2nd and 3rd chamber cells without direct contact. Micropatterned gradient channels were connected to the 1st chamber for pro-inflammatory gradient stimulation.
The authors conclude that increasing the concentration of inflammatory initiator caused modulated expression of pain-related factors, angiogenesis molecules, and catabolic enzymes. Also, accumulated macrophage derived soluble factors resulted in morphological changes in human AF cells and kinetic alterations such as velocity, dendritic length, cell area, and growth rate, similar to that reported within degenerative IVD.
5 figures
Boulouis G, Lauer A, Siddiqui AK, et al. Clinical Imaging Factors Associated With Infarct Progression in Patients With Ischemic Stroke During Transfer for Mechanical Thrombectomy. JAMA Neurol. 2017;2114(11):1361-1367. doi:10.1001/jamaneurol.2017.2149.
The question that the authors asked is: Among patients with ischemic stroke transferred for mechanical thrombectomy, what baseline clinical imaging factors portend an unfavorable evolution to a point at which the patient may not derive clinical benefit from mechanical thrombectomy at arrival?
A significant proportion of patients with ischemic stroke are initially evaluated at referring hospitals (RHs) that are prepared for acute stroke cases. These patients may receive intravenous thrombolysis before being transferred (drip and ship) to a thrombectomy-capable stroke center (TCSC) for endovascular treatment evaluation. For those patients clinically eligible at the referring hospitals (ie, favorable imaging profile, National Institutes of Health Stroke Score [NIHSS]≥6, and able to reach a thrombectomy-capable stroke center within 6 hours of symptom onset), clinical stroke severity is known to be a determinant of infarct progression. Other potential clinical or imaging factors that determine infarct progression are poorly understood. Adequacy of leptomeningeal collateral blood vessels is known to influence infarct progression in patients with ischemic stroke, but their role in predicting eligibility for mechanical thrombectomy has not been studied in the common setting of transferred patients. The ability to determine infarct evolution has the potential to allow optimized resource use within stroke networks by better selecting patients most likely to remain eligible and limiting futile transfers for thrombectomy.
The authors sought to determine the clinical and imaging factors associated with evolution to an unfavorable imaging profile in patients transferred from referring hospitals to a thrombectomy-capable stroke center and to specifically evaluate the influence of the adequacy of leptomeningeal flow on infarct progression in these patients.
A total of 316 patients were included in the analysis. In multivariable models, higher National Institutes of Health Stroke Score, lower baseline ASPECTSs, and no or poor collateral blood vessel status were associated with ASPECTS decay, with collateral blood vessel status demonstrating the highest adjusted odds ratio of 5.14
They conclude that in patients with ischemic stroke transferred for thrombectomy, poor collateral blood flow and stroke clinical severity are the main determinants of ASPECTS decay. Their findings suggest that in certain subgroups vascular imaging, including collateral assessment, can play a crucial role in determining the benefits of transfer for thrombectomy.
3 Tables, 1 figure
Donofrio PD. Guillain-Barré Syndrome. Contin Lifelong Learn Neurol. 2017;23:1295-1309. doi:10.1212/CON.0000000000000513.
This is an excellent review article on the current state of Guillain-Barre´ syndrome (GBS), including its clinical presentation, evaluation, pathophysiology, and treatment.
GBS is an acute/subacute-onset polyradiculoneuropathy typically presenting with sensory symptoms and weakness over several days, often leading to quadriparesis. Approximately 70% of patients report a recent preceding upper or lower respiratory tract infection or gastrointestinal illness. Approximately 30% of patients require intubation and ventilation because of respiratory failure. Nerve conduction studies in the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) form of GBS typically show evidence for a multifocal demyelinating process, including conduction block or temporal dispersion in motor nerves. CSF analysis commonly shows an elevated protein, but this elevation may not be present until the third week of the illness. Patients with AIDP are treated with best medical management and either IV immunoglobulin (IVIg) or plasma exchange.
Imaging is primarily performed to exclude other causes of quadriparesis particularly transverse myelitis, or a subacute compressive myelopathy. As many as 95% of children with GBS show enhancement of the lumbar roots secondary to the inflammatory process, which can help confirm the diagnosis.
6 Tables.
Payoux P, Salabert AS. New PET markers for the diagnosis of dementia. Curr Opin Neurol. 2017;30(6):1. doi:10.1097/WCO.0000000000000489.
Amyloid, tau, and neuroinflammation markers are likely to be in this order, the next PET tracers available for clinical use.
Regarding amyloid imaging, the 11C-Pittsburgh compound B (PIB)-PET is the best-known compound but since it is labelled with a short half-life isotope (11C: 20 min) its use was restrained to research field. Numerous studies have demonstrated that this compound binds b-amyloid fibrils in several cortical regions of Alzheimer’s disease patients; these studies paved the way for developing several amyloid plaque PET tracers, labelled with fluorine-18 (18F: half-life of 110 min), which allows for marketing these ligands and for broader diffusion to PET facilities in clinical settings.
Three radiopharmaceuticals have been authorized by the European Medicines Agency and the US FDA (18F-florbetapir, 18F-florbetaben, 18F-flutemetamol) with diagnostic performances considered as equivalent.
For all the amyloid tracers, PET findings were reported to be highly informative for the diagnosis of Alzheimer’s disease, especially regarding their negative predictive value. A negative test, with extremely low or undetectable amyloid plaque density, is considered exclude a diagnosis of Alzheimer’s disease; by contrast, a moderate-to-high amyloid plaque density could be in favor of the diagnosis. However, a positive scan is not sufficient to diagnose Alzheimer’s disease especially in elderly study participants.
The Society of Nuclear medicine and Molecular Imaging and the Alzheimer’s Association delineated ‘appropriate use criteria’ in 2013 involving three clinical circumstances in which amyloid PET is recommended to clarify the diagnosis in: ‘Patients with persistent or progressive unexplained mild cognitive impairment’, ‘Patients satisfying core clinical criteria for possible Alzheimer’s disease (i.e. atypical clinical course or etiologically mixed presentation)’, and ‘Patients with atypically young-onset dementia’.
The second group is those agents targeting tau. This is way complicated so I refer you to the paper, but needless to say, these agents are pure research at the moment.
The third group of agents includes the markers of neuroinflammation. The translocator protein (TSPO), also described as a peripheral benzodiazepine receptor, is an 18-kDa protein highly hydrophobic with five transmembrane domain protein mainly situated in the outer mitochondrial membrane. Classically not present in healthy brain parenchyma, TSPO has been widely identified in microglial cells in dementia neuropathology that involves neuroinflammatory processes and microglial activation.
For dementia, TSPO tracers have been evaluated in Alzheimer’s disease and frontotemporal lobar degeneration (FTLD).
In mild and early forms of Alzheimer’s disease, detection of increased 11C-(R)-PK11195 binding has suggested that microglial activation is an early event in the pathogenesis of the disease.
A longitudinal study based on 30 study participants (eight mild cognitive impairment, eight Alzheimer’s disease, and 14 controls) has demonstrated that microglial activation was increased in the mild cognitive impairment cohort compared with controls.
3 Tables.
Zamboni P, Tesio L, Galimberti S, et al. Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis. JAMA Neurol. November 2017:1-9. doi:10.1001/jamaneurol.2017.3825.
Chronic cerebrospinal venous insufficiency (CCSVI) is a nosological hypothesis that was discussed for the first time by the World Consensus Conference on Venous Malformations in Monte Carlo in September 2009. The Chronic cerebrospinal venous insufficiency hypothesis suggests that inadequate blood flow from the CNS is caused by stenotic and/or malformative alterations of the main vessels draining blood from the brain and spine such as internal jugular veins (IJVs) and the azygos vein (AV).
A highly significant correlation between chronic cerebrospinal venous insufficiency and MS has been reported by Zamboni et al (Zamboni, P. et al. (2009). Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry, 80, 392–399) in a cohort of patients evaluated by echo-color Doppler ultrasonography.
Zamboni et al also led a pilot study enrolling 65 patients to assess the efficacy of percutaneous transluminal angioplasty of stenotic IJV and AV in the treatment of chronic cerebrospinal venous insufficiency (Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg 2009;50:1348–58). The authors of this study stated that the percutaneous treatment positively influenced the clinical condition and the quality of life of patients with MS when compared with the preoperative assessment.
Many studies have since come out against this hypothesis, it the point of societies making consensus statements not to perform angioplasty in this population (Baracchini, C. et al (2012). CCSVI and MS: a statement from the European Society of neurosonology and cerebral hemodynamics. Journal of Neurology), but the topic remains controversial.
So, on to this study: Chronic cerebrospinal venous insufficiency (CCSVI) is defined by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial. The authors analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have chronic cerebrospinal venous insufficiency on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6 MS centers in Italy. The trial began in August 2012 and concluded in March 2016.
Two primary end points were assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, post void residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on MRI, including the proportion of lesion-free patients.
Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups. To maintain patient blinding, surgeons were trained to deliver a catheter venography intervention that simulated venous PTA. This involved sudden acceleration of the catheter as it passed through the internal jugular vein together with a comment from the radiologist suggesting that venous PTA had been performed.
Venous PTA did not reduce the mean number of new combined brain lesions on magnetic resonance imaging at 12 months. However, there was a tendency for more patients to become free of new lesions after venous PTA mainly because of a reduction in new lesions appearing 6 to 12 months after randomization. They conclude that venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS.
So can we put this theory to rest? No venous PTA in MS.
Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. November 2017:NEJMoa1706442. doi:10.1056/NEJMoa1706442.
The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. The authors postulate that patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy.
Patients were eligible for inclusion in the trial if they had evidence of occlusion of the intracranial internal carotid artery, M1, or both on CT angiography or MRA. In addition, patients had to have a mismatch between the severity of the clinical deficit and the infarct volume, which was defined according to the following criteria: those in Group A were 80 years of age or older, had a score of 10 or higher on the National Institutes of Health Stroke Scale (NIHSS; scores range from 0 to 42, with higher scores indicating a more severe deficit), and had an infarct volume of less than 21 ml; those in Group B were younger than 80 years of age, had a score of 10 or higher on the NIHSS, and had an infarct volume of less than 31 ml; and those in Group C were younger than 80 years of age, had a score of 20 or higher on the NIHSS, and had an infarct volume of 31 to less than 51 ml.
Infarct volume was assessed with the use of diffusion-weighted MRI or perfusion CT and was measured with the use of automated software (RAPID, iSchemaView).
Patients were randomly assigned from 26 sites, in a 1:1 ratio, to thrombectomy plus standard medical care (the thrombectomy group) or to standard medical care alone (the control group). Randomization was performed with the use of a central, Web-based procedure, with block minimization processes to balance the two treatment groups, and was stratified according to mismatch criteria (Group A, Group B, or Group C), the interval between the time that the patient was last known to be well and randomization (6 to 12 hours or >12 to 24 hours), and the occlusion site (intracranial internal carotid artery or the first segment of the middle cerebral artery).
The DAWN trial showed that, among patients with stroke due to occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, outcomes for disability and functional independence at 90 days were better with thrombectomy plus standard medical care than with standard medical care alone. For every 2 patients who underwent thrombectomy, 1 additional patient had a better score for disability at 90 days (as compared with the results in the control group); for every 2.8 patients who underwent thrombectomy, 1 additional patient had functional independence at 90 days.
3 Tables, 2 figures (no images).
