1. Catapano JS, Labib MA, Srinivasan VM, et al. Saccular aneurysms in the post–Barrow Ruptured Aneurysm Trial era. J Neurosurg 2021;137(July):1–8
The Barrow Ruptured Aneurysm Trial (BRAT) was a single-center trial that compared endovascular coiling to microsurgical clipping in patients treated for aneurysmal subarachnoid hemorrhage (aSAH). However, because patients in the BRAT were treated more than 15 years ago, and because there have been advances since then—particularly in endovascular techniques—the relevance of the BRAT today remains controversial. Some hypothesize that these technical advances may reduce retreatment rates for endovascular intervention. In this study, the authors analyzed data for the post-BRAT (PBRAT) era to compare microsurgical clipping with endovascular embolization (coiling and flow diverters) in the two time periods and to examine how the results of the original BRAT have influenced the practice of neurosurgeons at the study institution.
Of the 1014 patients with aSAH during the study period, 798 (79%) were confirmed to have saccular aneurysms. Neurological outcomes at ≥ 1-year follow-up did not differ between patients treated with microsurgery (n = 451) and those who received endovascular (n = 347) treatment (p = 0.51). The number of retreatments was significantly higher among patients treated endovascularly (32/347, 9%) than among patients treated microsurgically (6/451, 1%). The retreatment rate after endovascular treatment was lower in the post BRAT era (9%) than in the BRAT (18%).
Similarly to the BRAT results, the post BRAT-era results showed no significant difference in neurological outcomes between endovascular and microsurgical intervention for saccular aneurysms. Hence, in quaternary centers with expert neurosurgeons, neurological outcomes in aSAH patients are likely associated with the inherent risk of the hemorrhage and, to a lesser extent, with the specific treatment modality. For example, in the present analysis, the average aneurysm size was 5.5 mm, and 35% of aneurysms were < 5 mm in size. The substantial number of small aneurysms argues for more aggressive treatment of these lesions, particularly in patients at an increased risk for aneurysm rupture.
In patients with saccular aneurysms in the BRAT, endovascular surgery was found to be associated with a retreatment rate of 18% compared with only 0.4% in the microsurgery cohort. The PBRAT-era analysis found similar results, with a significantly higher percentage of endovascular patients than microsurgery patients requiring retreatment. However, the percentage of endovascular patients in the post BRAT era requiring retreatment was half that in the BRAT study (9% vs 18%). In patients with anterior circulation aneurysms, only 7% of endovascular patients required retreatment in the post BRAT era cohort. The substantial decrease in retreatment is likely due to the advances in endovascular techniques over the past decade, especially improved coil and catheter technology.
2 figures, 5 tables, no imaging
2. Kresbach C, Neyazi S, Schüller U. Updates in the classification of ependymal neoplasms: The 2021 WHO Classification and beyond. Brain Pathol 2022;(February):1–11
Clinically, ependymomas represent a very heterogeneous group of tumors from rather benign subependymomas to very aggressive and often deadly childhood ependymomas of the posterior fossa. Newly identified biological markers and classification schemes, e. g. based on global DNA methylation profiling, have led to the definition of 10 types of ependymal tumors and an improved prediction of patients’ outcome by applying the new classification system. While the exact genetic basis for several ependymoma types still remains unclear, the knowledge about ependymoma driving events has significantly increased within the last decade and contributed to a classification based on molecular characteristics and localization rather than histological features alone. Convincing evidence is now pointing towards gene fusions involving ZFTA or YAP1 causing the development of supratentorial ependymomas. Also, H3, EZHIP, or TERT mutations have been detected in a fraction of infratentorial ependymal tumors. Finally, MYCN amplifications have recently been identified in spinal ependymomas, in addition to the previously known mutations in NF2.
A major improvement presented by the 2021 WHO Classification is the taxonomy within the tumor family of ependymoma. Whereas the previous edition primarily defined ependymoma subtypes based on clinico-pathological characteristics (with the exception of RELA-fusion positive ependymoma), the current update mainly comprises molecular subtypes instead. More precisely, the types of subependymomas (SE), myxopapillary ependymomas (MPE), and RELA-fusion positive (now: ZFTA-fusion positive) ependymomas have been maintained in the 2021 classification, although some changes have been applied. The previously used terms of ependymoma and anaplastic ependymoma are not used to define an entity anymore. Instead, PFA and PFB ependymoma in the posterior fossa, YAP1-fusion positive ependymoma in the cerebrum, and spinal ependymoma as well as spinal ependymoma, MYCN-amplified, in the spinal cord have been newly defined. This not only provides an objective molecular basis for the diagnosis and classification of ependymomas, but is also intended to better predict the clinical outcome of the patients.
4 figures with histology
3. Whitfield BT, Huse JT. Classification of adult-type diffuse gliomas: impact of the World Health Organization 2021 update. Brain Pathol 2022;(February):1–12
WHO 2021 expands upon the trend started in 2016, using key molecular biomarkers to define neoplastic entities and greatly reducing the dependency on morphologic features for tumor classification. Terminology around tumor grading has also been simplified, with molecular features dictating classification and joint histopathologic and molecular analysis determining grade. The classification of diffuse gliomas under the 2021 update is dependent largely on isocitrate dehydrogenase (IDH1/2) mutation status and 1p/19q codeletion status, resulting in 3 primary disease groups: IDH-mutant, 1p/19q codeleted oligodendroglioma; IDH-mutant, non-codeleted astrocytoma; and IDH-wildtype glioblastoma.
Astrocytoma, IDH-mutant is now the preferred designation for all adult-type gliomas that are IDH1-or IDH2-mutant with absence of 1p/19q codeletion. These diffusely infiltrating gliomas frequently harbor inactivating mutations in TP53 and ATRX and can be defined as either CNS WHO grade 2, grade 3, or grade 4. Designations such as diffuse astrocytoma, IDH-mutant; anaplastic astrocytoma, IDH-mutant; and glioblastoma, IDH-mutant are no longer preferred, having been replaced with astrocytoma, IDH-mutant grade 2, grade 3, and grade 4, respectively.
WHO 2021 reserves the term glioblastoma specifically for IDH-wildtype tumors, with IDH-mutant glioblastoma having been effectively renamed astrocytoma, WHO grade 4. Microvascular proliferation and/or necrosis are both sufficient to establish a diagnosis of glioblastoma in an IDH-wildtype, H3-wildtype diffuse glioma. However, WHO 2021 also delineates multiple defining molecular features for IDH-wildtype glioblastoma, namely TERT promoter mutation, epidermal growth factor receptor (EGFR) amplification, and combined chromosome 7 gain/chromosome 10 loss.
7 figures with histology
4. Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. J Prev Alzheimer’s Dis 2022;9:197–210. (Journal of Prevention of Alzheimer’s Disease)
EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease, funded by Biogen. These studies involved 348 sites in 20 countries. Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50–85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia, of which 1812 (55.2%) completed the study. Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of −0.39 for high-dose aducanumab vs placebo, 22% decrease]) but not in ENGAGE (difference of 0.03, 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer’s disease pathophysiology.
In summary, the authors state that ENGAGE did not meet its primary. or secondary endpoints, and the EMERGE high-dose aducanumab group met all primary and secondary endpoints. EMERGE is the first phase 3 trial to demonstrate an association between reduction of biomarkers of AD pathology and a statistically significant slowing of clinical decline, supporting the possibility that removal of Aβ from the brain (together with modification of downstream biomarkers of disease) may be associated with a clinical benefit in patients with early AD.
2 tables, 2 figures
5. Ayton S. Ventricular enlargement caused by aducanumab. Nat Rev Neurol 2022;18(July):383–84. (Nature News and Views section i.e., commentary)
Now for another view of the data:
The author states that the long- awaited publication of two discordant phase III trials has done little to unify an Alzheimer disease (AD) research field divided by the controversial FDA approval of the therapeutic monoclonal antibody aducanumab (marketed as Aduhelm by Biogen). Brain volumetric data from the EMERGE and ENGAGE trials importantly show that aducanumab treatment causes enlargement of the lateral ventricles — a measure of neurodegeneration. Aducanumab is highly effective at lowering the amyloid- β (Aβ) plaque burden in the brain, but the EMERGE and ENGAGE studies were terminated after failing a prespecified futility analysis. Some 6 months later, however, Biogen presented additional evidence that high- dose aducanumab produced significant slowing of cognitive decline compared with placebo in the EMERGE study (a 22% decrease) — a result that was not replicated in the ENGAGE study (a 2% increase). On the basis of these findings, Biogen submitted an application for FDA approval. Despite severe criticisms from an external advisory review and the FDA’s own statistical review, accelerated approval was granted on the basis of “substantial evidence of effectiveness on the surrogate end point of reduction in brain amyloid plaque [that] is reasonably likely to predict clinical benefit”.
As Aduhelm is currently being prescribed to patients with AD, it is imperative that the label is updated with a warning regarding the risk of brain tissue loss. The volumetric data should now be explored further (for example, looking at different brain structures and subgroup analysis), and longer- term studies of changes in brain volume should be conducted to evaluate whether aducanumab causes progressive brain damage. These investigations are especially relevant given the growing calls to treat people in the earliest possible (pre-symptomatic) stages of AD.
6. Ho CY, Salimian M, Hegert J, et al. Postmortem assessment of olfactory tissue degeneration and microvasculopathy in patients with COVID-19. JAMA Neurol 2022;79:544–53
In addition to respiratory illnesses, various nonrespiratory manifestations of COVID-19 have also been reported. One of the most prevalent nonrespiratory symptoms is olfactory dysfunction. Olfactory dysfunction of variable severity, including anosmia, hyposmia, and parosmia, reportedly affect 30% to 70% of patients with COVID-19. The prevalence of olfactory dysfunction has prompted US Centers for Disease Control and Prevention to list new loss of smell as a cardinal symptom of COVID-19 on its webpage. Olfactory dysfunction occurs early in the course of infection and has no direct association with disease severity or viral loads. In one study, it was recorded as the first presenting symptom among approximately 12% of patients. In most cases, the symptoms spontaneously resolve within 3 to 4 weeks. A subset of patients nevertheless developed persistent olfactory impairment up to 12 months post infection, suggesting that injury to the olfactory system may be severe or permanent.
In this cohort study of 23 deceased patients with COVID-19 and 14 matched controls, more severe axon pathology, axon losses, and microvascular pathology were noted in olfactory tissue from patients with COVID-19 than that from the control individuals. The olfactory pathology was particularly severe in patients with reported smell alterations but were not associated with the clinical severity, timing of infection, or the presence of SARS-CoV-2 in the olfactory tissue.
To the author’s knowledge, this cohort study was the first to examine the ultrastructural changes of olfactory bulb and olfactory tract in COVID-19 infection. Previous studies of olfactory bulb have been limited to conventional histologic examination without providing appropriate controls or information regarding patients’ smell function. Results from this study not only confirmed at an ultrastructural level the previously reported radiological abnormalities in olfactory bulb but also demonstrated how the pathologic findings were associated with smell alterations in patients with COVID-19. Consistent with findings reported by other groups, this study also did not find evidence of viral infection in olfactory bulb from most patients with COVID- 19. Therefore, the axon and microvascular pathology in olfactory bulb and olfactory tract were most likely not caused by direct viral injury.
1 table, 4 figures including electron microscopy
7. Agosti E, Graepel S, Lanzino G. Principles and strategies for step-by-step AVM excision. Neurosurg Focus 2022;53:E5. Available from: https://thejns.org/view/journals/neurosurg-focus/53/1/article-pE5.xml
Dr. Yasargil has been quoted as saying that “the secret of AVM surgery is in the ventricle.” Conically shaped AVMs whose tips extend very near to the ventricle receive vascular supply from deep choroidal feeders through brain parenchyma closest to the ependyma. Control and coagulation of these feeders is much easier on the ventricle side before they enter the white matter. Additionally, when the AVM is near the ependyma of the ventricle, there is almost always a deep-draining vein. These deep-draining veins must be identified, isolated, and coagulated, together with the deep feeders. This deep venous drainage in large AVMs may not be visible on the preoperative angiogram as it is overshadowed by the much higher flow in the more superficial and larger veins. This deep venous component must be suspected when the AVM comes close to the ependyma of the ventricle and can be inferred from close analysis of the T2-weighted thin slices of the axial MRI. As the dissection proceeds circumferentially, the main draining vein is maintained in continuity until the very end. However, secondary drainage veins can be sacrificed before full circumferential dissection is completed, to facilitate progression of the resection and better access to deeper portions of the AVM. Because the AVM is mostly disconnected, flow into the main draining vein may slow down to the point at which portions of the AVM may thrombose. This can be perceived as increased tension in the nidus, which may, in turn, become more difficult to retract and manipulate. To prevent the risk of massive bleeding, the main draining vein is not sacrificed until all incoming feeders have been severed and the nidus has been completely disconnected from the surrounding parenchyma.
3 artful graphics of AVM resection
8. Kontakis M, Marques C, Löfgren H, et al. Artificial disc replacement and adjacent-segment pathology: 10-year outcomes of a randomized trial. J Neurosurg Spine 2021;36:1–9. Available from: https://thejns.org/view/journals/j-neurosurg-spine/aop/article-10.3171-2021.9.SPINE21904/article-10.3171-2021.9.SPINE21904.xml
Artificial disc replacement (ADR) is designed to preserve motion and thus protect against adjacent segment pathology (ASP) and act as an alternative treatment to fusion surgery. The question remains, how well do ADR devices perform after 10 years of follow-up compared with fusion surgery in terms of patient satisfaction, sustainability, and protection against ASP?
This was the 10-year follow-up study of 153 participants who underwent ADR or fusion surgery after anterior decompression due to cervical degenerative radiculopathy. Ten participants were lost to follow-up, which left 143 participants (80 underwent ADR and 65 underwent anterior cervical discectomy and fusion). There were no differences between groups in terms of patient-reported outcome measures. Nineteen (24%) participants in the ADR group compared with 9 (14%) in the fusion group underwent secondary surgical procedures. The higher reoperation rate of the ADR group was mainly due to 11 female participants with device loosening. The rates of reoperation due to adjacent segment pathology were similar between groups, which was confirmed with MRI assessment of adjacent segment pathology that also showed no differences between the groups. This is the first 10-year follow-up study to compare ADR and fusion surgery after anterior decompression for cervical degenerative radiculopathy and to provide MRI information for assessment of adjacent segment pathology. Even though PROMs were similar between the ADR and fusion surgery groups at the 10-year follow-up evaluation, there were more reoperations in the ADR group due to implant loosening. The rates of reoperation for adjacent segment pathology were similar between groups, and preserved motion did not prevent adjacent segment pathology as assessed on MRI.
3 figures, 5 tables, no imaging
The American Society of Neuroradiology is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Visit the ASNR Education Connection website to claim CME credit for this podcast.
