1. Sharrief A. Diagnosis and Management of Cerebral Small Vessel Disease. Continuum (Minneap Minn). 2023;29(2):501-518. doi:10.1212/CON.0000000000001232
Cerebral small vessel disease (CSVD) is one of the most common clinical conditions that a neuroimager will encounter. CSVD is associated with an increased risk of clinical ischemic and hemorrhagic stroke, silent infarcts, and cognitive decline and dementia. It has well-defined radiographic features and various clinical presentations. Despite its increasing prevalence with the aging population, few specific therapies exist to decrease its progression.
CSVD contributes to significant morbidity and mortality through its impact on stroke risk, cognitive decline, and dementia. Small vessel disease accounts for approximately 22% of ischemic stroke, and small vessel disease burden increases the risk of recurrent stroke following ischemic or hemorrhagic stroke. CSVD manifests as “silent” brain infarcts as well as clinically recognized small vessel ischemic strokes. Silent brain infarcts, which are also included in the classification of “covert cerebral small vessel disease,” are more common than acute ischemic stroke, with an estimated prevalence of 10% to 20% in adults. These lesions are often found incidentally but are associated with an increased risk of stroke and death, as well as other neurologic, neuropsychiatric, and cognitive symptoms, which are poorly recognized in clinical practice. CSVD accounts for most of the intracerebral hemorrhage (ICH) through arteriosclerosis (sometimes referred to as hypertensive arteriosclerosis) and cerebral amyloid angiopathy (CAA).
Age is the most common nonmodifiable risk factor for CSVD, and the aging of the population has led to the increased global prevalence of CSVD. Almost 100% of adults aged 90 and older have evidence of CSVD, with 36% of adults aged 80 to 90 demonstrating evidence of cerebral microbleeds.
Several modifiable clinical risk factors are associated with the development of CSVD. These include hypertension, obstructive sleep apnea, diabetes mellitus, hyperlipidemia, and tobacco use. Chronic kidney disease is associated with increased presence of cerebral microbleeds, white matter hyperintensities, and silent brain infarctions.
In 2013, a multidisciplinary group from the Centers for Standards in Neurodegeneration published a position paper describing the need for consistent terminology and setting the standard for describing CSVD. They described six radiographic phenotypes of CSVD: (1) recent small subcortical infarct, (2) white matter hyperintensity, (3) lacune of presumed vascular origin, (4) widened perivascular spaces, (5) cerebral microbleed, and (6) brain atrophy.
4 tables and 5 figures with this, including MR
2. Perneczky R, Jessen F, Grimmer T, et al. Anti-amyloid antibody therapies in Alzheimer’s disease. Brain. 2023;146(3):842-849. doi:10.1093/brain/awad005
New disease-modifying therapies (DMT) promise a step change in dementia care and prevention. At present, monoclonal antibodies (mAbs) targeting amyloid-β (Aβ) are the most prevalent drugs in phase III trials, with robust evidence on their engagement of the biological target in humans. However, clinical efficacy is less consistent across different agents, and the overall trial evidence so far indicated that successful Aβ clearance in early Alzheimer’s disease has at best very small effects on cognitive decline. The authors present this update which aims to elucidate the key reasons for those inconsistencies. To showcase the challenges with developing DMTs for Alzheimer’s disease, they start with an analysis of the three most recent anti-Aβ mAbs with completed phase III trials. They provide reasons why results of meta-analyses of the previous trials are less relevant in the appreciation of the new lecanemab data, including differences in drug dose, cohort characteristics, mAb specificity and adverse events.
Aducanumab, a human IgG1 mAb targeting amino acids of the Aβ peptide, is specific for Aβ plaques and on 7 June 2021, the US Food and Drug Administration (FDA) approved aducanumab for the treatment of Alzheimer’s disease. Significant side effects also occurred during treatment with aducanumab in the phase III trials. Of particular importance were amyloid-related imaging abnormalities with edema (ARIA-E) and/or microhemorrhages (ARIA-H) on brain MRI scans, with an incidence of 35% and 36% in the two phase III studies, and 25% of affected participants experiencing symptoms, particularly in carriers of the APOE ϵ4 allele.
While the primary aim of the phase III studies was to provide evidence for the clinical efficacy of aducanumab, the approval now granted is based on proof of meeting the surrogate biomarker end point of reducing Aβ plaques on PET. This accelerated approval route chosen by the FDA for aducanumab is intended for drugs targeting serious diseases, expected to have a significant added value over the available therapy, even if there is residual uncertainty about the ultimate clinical benefit. There must be substantial evidence for efficacy on a surrogate end point reflecting the underlying disease pathology, with no requirement for demonstration of any clinical benefit. While biomarker evidence was sufficient for approval by FDA, the European Medicines Agency was unlikely to follow the US decision, and the developer therefore withdrew the marketing authorization application; approval for the marketing of aducanumab will not be granted in the EU.
On September 27 2022, results were announced from CLARITY AD, a large worldwide clinical trial with 1795 participants with early Alzheimer’s disease, showing that lecanemab had achieved its primary end point, a statistically significant slowdown of clinical disease progression on the CDR-SB. In this phase III trial the treatment group received 10 mg/kg lecanemab intravenously every 2 weeks, with participants receiving either placebo or lecanemab in a 1:1 ratio.
Over the 18-month study period, both groups deteriorated on the Clinical Dementia Rating Scale-sum of the boxes (CDR-SB) and on other secondary clinical end points, as expected in Alzheimer’s disease. However, clinical deterioration in the lecanemab group was 27% slower compared to placebo after 18 months, resulting in a statistically highly significant difference.
1 table, 3 figures, no imaging
3. Haug CJ, Drazen JM. Artificial Intelligence and Machine Learning in Clinical Medicine, 2023. Drazen JM, Kohane IS, Leong TY, eds. New England Journal of Medicine. 2023;388(13):1201-1208. doi:10.1056/NEJMra2302038
What are the standards to which AI and machine learning–based interventional research should be held, if an app is going to be accepted as the standard that will shape, reform, and improve clinical practice? That research has three components. First, the research must be structured to answer a clinically meaningful question in a way that can influence the behavior of the health professional and lead to an improvement in outcomes for a patient. Second, the intervention must be definable, scalable, and applicable to the problem at hand. It must not be influenced by factors outside the domain of the problem and must yield outcomes that can be applied to similar clinical problems across a wide range of populations and disease prevalence. Can AI and machine learning–driven care meet these standards — ones that we demand from a novel therapeutic intervention or laboratory-based diagnostic test — or do we need to have a unique set of standards for this type of intervention? Third, when the results of the research are applied in such a way as to influence practice, the outcome must be beneficial for all patients under consideration, not just those who are like the ones with characteristics and findings on which the algorithm was trained. This raises the question of whether such algorithms should include consideration of public health (i.e., the use of scarce resources) when diagnostic or treatment recommendations are being made and the extent to which such considerations are part of the decision-making process of the algorithm. Such ethical considerations have engaged health professionals and the public for centuries.
3 figures
4. Sarraj A, Hassan AE, Abraham MG, et al. Trial of Endovascular Thrombectomy for Large Ischemic Strokes. New England Journal of Medicine. 2023;388(14):1259-1271. doi:10.1056/NEJMoa2214403
The authors performed a prospective, randomized, open-label, adaptive, international trial involving patients with stroke due to occlusion of the internal carotid artery or the first segment of the middle cerebral artery to assess endovascular thrombectomy within 24 hours after onset. Patients had a large ischemic-core volume, defined as an ASPECT score of 3 to 5 (range, 0 to 10, with lower scores indicating larger infarction) or a core volume of at least 50 ml on computed tomography perfusion or diffusion-weighted magnetic resonance imaging. Patients were assigned in a 1:1 ratio to endovascular thrombectomy plus medical care or to medical care alone. The primary outcome was the modified Rankin scale score at 90 days (range, 0 to 6, with higher scores indicating greater disability). Functional independence was a secondary outcome.
The trial was stopped early for efficacy; 178 patients had been assigned to the thrombectomy group and 174 to the medical-care group. The generalized odds ratio for a shift in the distribution of modified Rankin scale scores toward better outcomes in favor of thrombectomy was 1.51. A total of 20% of the patients in the thrombectomy group and 7% in the medical-care group had functional independence. Mortality was similar in the two groups. In the thrombectomy group, arterial access-site complications occurred in 5 patients, dissection in 10, cerebral-vessel perforation in 7, and transient vasospasm in 11. Symptomatic intracranial hemorrhage occurred in 1 patient in the thrombectomy group and in 2 in the medical-care group.
The results of the SELECT2 trial, which involved patients from broad geographic regions, showed that endovascular thrombectomy plus medical care resulted in better clinical outcomes than medical care alone in patients with a large ischemic core who presented within 24 hours after the time they were last known to be well.
2 figures, 3 tables
5. Schnurman Z, Benjamin CG, Miceli M, Sen C. Clival Chordomas in the Endoscopic Endonasal Era: Comparison With Management With Open Skull Base Approaches. Neurosurgery. 2023;92(4):756-761. doi:10.1227/neu.0000000000002286
The most significant surgical advancement for treating clival chordomas has been the increasing application of the endoscopic endonasal approach over the past 2 decades. Using a ventral, midline approach endoscopically, through the nasal passages, has been argued to be a more logical trajectory to reach clival chordomas, with the possibility of reducing extensive bone removal, brain retraction, and manipulation of cranial nerves that is inherent to larger open approaches.
The objective of this study was to compare a large series of patients treated by a single surgeon using primarily endoscopic endonasal approaches with previously published outcomes by the same surgeon using open skull base approaches. Between 2006 and 2020, 68 patients with skull base chordoma underwent resection using primarily endoscopic endonasal approaches. Outcomes and complications were compared with previously published results of resection of chordomas from 1991 to 2005 using open skull base approaches.
Compared with the prior cohort, the current principally endoscopic cohort demonstrated similar rates of OS and progression-free survival, but patients undergoing first-time resection had significantly higher rates of radical resection (82.9% compared with 64.3%) and required fewer staged surgeries.
There was no difference in survival rates for patients treated in the current era, primarily using endoscopic endonasal techniques, compared with previously published results using open skull-base approaches by the same surgeon. Although use of endoscopic endonasal approach resulted in higher rates of radical resection, patients undergoing first-time resection and fewer staged surgeries were required. The reason for the discrepancy in improvements in rates of radical resections between first-time resections and repeat resections is that repeat resections more frequently required open skull base approaches, with only 33% using the endoscopic endonasal approach alone, and 41% requiring open lateral approaches.
3 tables, 1 figure, no images
6. Lee BC, Tsai HH, Liu CJ, et al. Cerebral Venous Reflux and Cerebral Amyloid Angiopathy: An Magnetic Resonance Imaging/Positron Emission Tomography Study. Stroke. 2023;54(4):1046-1055. doi:10.1161/STROKEAHA.122.040503
Cerebral venous outflow alterations contribute to central nervous system pathology in aging and neurodegenerative disorders and are potentially linked to underlying cerebral microangiopathy. The authors investigated whether cerebral venous reflux (CVR) is more closely associated with cerebral amyloid angiopathy (CAA) than hypertensive microangiopathy in intracerebral hemorrhage (ICH) survivors. This cross-sectional study included 122 patients of spontaneous ICH with magnetic resonance and positron emission tomography imaging studies (2014–2022) in Taiwan. The presence of CVR was defined as abnormal signal intensity in the dural venous sinus or internal jugular vein on magnetic resonance angiography. Cerebral amyloid load was measured using the Pittsburgh compound B standardized uptake value ratio. Clinical and imaging characteristics associated with CVR were evaluated in univariable and multivariable analyses. In the subset of patients with CAA, they applied univariable and multivariable linear regression analyses to evaluate the association between CVR and cerebral amyloid retention.
Compared with patients without CVR (n=84), patients with CVR (n=38) were significantly more likely to have CAA-ICH (53.7% versus 19.8%) and had a higher cerebral amyloid load, 1.28 versus 1.06. In a multivariable model, CVR was independently associated with CAA-ICH (odds ratio, 4.81 after adjustment for age, sex and conventional small vessel disease markers. In CAA-ICH, higher PiB retention was observed in patients with CVR than patients without CVR. In multivariable analysis after adjustment for potential confounders, the presence of CVR was independently associated with a higher amyloid load.
They conclude that in spontaneous ICH, CVR is associated with CAA and a higher amyloid burden. The authors results suggest venous drainage dysfunction potentially plays a role in CAA and cerebral amyloid deposition.
3 tables, 3 figures, with MR imaging
7. Ioannidis JPA, Pezzullo AM, Boccia S. The Rapid Growth of Mega-Journals. JAMA. 2023;2015(5). doi:10.1001/jama.2023.3212
Mega-journals, those that publish large numbers of articles per year, are growing rapidly across science and especially in biomedicine. Although 11 Scopus-indexed journals published more than 2000 biomedical full papers (articles or reviews) in 2015 and accounted for 6% of that year’s literature, in 2022 there were 55 journals publishing more than 2000 full articles, totaling more than 300,000 articles (almost a quarter of the biomedical literature that year). In 2015, 2 biomedical research journals (PLoS One and Scientific Reports) published more than 3500 full articles. In 2022, there were 26 such prolific journals. The accelerating growth of mega-journals creates both threats and opportunities for biomedical science.
No figures or tables
8. Sabben C, Charbonneau F, Delvoye F, et al. Endovascular Therapy or Medical Management Alone for Isolated Posterior Cerebral Artery Occlusion: A Multicenter Study. Stroke. 2023;54(4):928-937. doi:10.1161/STROKEAHA.122.042283
The authors conducted a multicenter international observational study of consecutive stroke patients admitted within 6 hours from symptoms onset in 26 stroke centers with isolated occlusion of the first (P1) or second (P2) segment of the posterior cerebral artery and treated either with BMM+EVT or BMM alone. Propensity score with inverse probability of treatment weighting was used to account for baseline between-groups differences. The primary outcome was 3-month good functional outcome (modified Rankin Scale [mRS] score 0–2 or return to baseline modified Rankin Scale). Secondary outcomes were 3-month excellent recovery (modified Rankin Scale score 0–1), symptomatic intracranial hemorrhage, and early neurological deterioration.
Overall, 752 patients were included (167 and 585 patients in the BMM+EVT and BMM alone groups, respectively). Median age was 74 years, 329 (44%) patients were female, median National Institutes of Health Stroke Scale was 6, and occlusion site was P1 in 188 (25%) and P2 in 564 (75%) patients. Baseline clinical and radiological data were similar between the 2 groups following propensity score weighting. EVT was associated with a trend towards lower odds of good functional outcome and was not associated with excellent functional outcome. EVT was associated with a higher risk of symptomatic intracranial hemorrhage and early neurological deterioration.
More than one-third of this cohort was unable to live independently at 3 months (mRS above 2), and 57% of patients had some degree of disability (mRS above 1), in line with previous reports. This indicates that despite relatively low NIHSS scores on admission (median value of 6), proximal PCA occlusion stroke is a disabling condition.
In this observational study of patients with proximal posterior cerebral artery occlusion, EVT was not associated with good or excellent functional outcome as compared to BMM alone. However, EVT was associated with higher rates of symptomatic intracranial hemorrhage and early neurological deterioration. EVT should not be routinely recommended in this population, but randomization into a clinical trial is highly warranted.
3 figures, 3 tables, no imaging
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