Journal Scan – This Month in Other Journals, July 2017

Rabinstein AA. Treatment of Acute Ischemic Stroke. Continuum (Minneap Minn). 2017;23(1, Cerebrovascular Disease):62-81. doi:10.1212/CON.0000000000000420.

This is an excellent and comprehensive review of current acute stroke treatment.  The three main principles of acute stroke care are: (1) achieve timely recanalization of the occluded artery and reperfusion of the ischemic tissue, (2) optimize collateral flow, and (3) avoid secondary brain injury. The author states there is incontrovertible evidence that IV thrombolysis with rtPA and endovascular thrombectomy with a retrievable stent improve neurologic outcomes in patients with acute ischemic stroke. Both treatments should be administered as quickly as possible after stroke onset, can be combined, and are safe in appropriately selected candidates. IV thrombolysis with rtPA is proven to be effective in improving functional outcomes after an ischemic stroke up to 4.5 hours after symptom onset. IV rtPA infused within 3 hours of symptom onset increases the chances of functional independence at 3 months by one-third. The benefit is time dependent and much stronger when the drug is administered within the first 90 minutes after symptom onset.

Regarding mechanical thrombectomy, the six positive trials shared the requirement of CT angiograms for patient screening (only patients with documented internal carotid artery or proximal middle cerebral artery occlusions could be entered into the studies), emphasized the importance of prompt intervention, and almost exclusively used retrievable stents to achieve reperfusion. All of the trials enrolled patients with severe neurologic deficits and good prestroke functional status who presented mostly within 6 hours of symptom onset. Major early ischemic changes on the baseline CT scan were a reason for exclusion. Patients treated with mechanical thrombectomy had high rates of reperfusion and much better functional outcomes at 90 days. Mechanical thrombectomy was also proven to be quite safe, with a pooled rate of symptomatic ICH of 4.4% across all patients treated in the intervention arms of the five trials.

However, the best imaging modality to select patients for the intervention remains to be determined. All trials excluded patients with an ASPECTS score lower than 6 on baseline CT scan.

Regarding future directions, mobile stroke units are rapidly gaining acceptance. These are special ambulances equipped with a portable CT scanner and digital technology to enable telecommunication with a stroke specialist. They have been shown to allow safe initiation of IV thrombolysis while en-route to the stroke center. This option, although expensive, can be a very welcome solution for some heavily populated urban communities.

Coutinho JM, Liebeskind DS, Slater L-A, et al. Combined Intravenous Thrombolysis and Thrombectomy vs Thrombectomy Alone for Acute Ischemic Stroke. JAMA Neurol. 2017;74(3):268. doi:10.1001/jamaneurol.2016.5374.

It is not known whether intravenous thrombolysis (IVT) is of added benefit in patients undergoing mechanical thrombectomy (MT). This post hoc analysis used data from 291 patients treated with mechanical thrombectomy included in 2 large, multicenter, prospective clinical trials that evaluated mechanical thrombectomy for acute ischemic stroke (Solitaire With the Intention for Thrombectomy performed from January 1, 2010, through December 31, 2011, and Solitaire Flow Restoration Thrombectomy for Acute Revascularization from January 1, 2010, through December 31, 2012). Outcome measures included successful reperfusion, functional independence (modified Rankin Scale score of 0-2) and mortality at 90 days, symptomatic intracranial hemorrhage, emboli to new territory, and vasospasm. In multivariate analysis, no statistically significant association was observed between IVT and mechanical thrombectomy vs mechanical thrombectomy alone for any of the outcomes.

The authors point out that in a recent published pooled analysis of MR CLEAN, SWIFT PRIME, EXTEND-IA, ESCAPE, and REVASCAT (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke collaboration), no differences were found in clinical outcomes between IVT and mechanical thrombectomy and mechanical thrombectomy alone (Goyal M, Menon BK, van ZwamWH, et al; Lancet. 2016;387(10029):1723-1731).

Since no benefit or harm of treatment with IVT and mechanical thrombectomy compared with mechanical thrombectomy alone in patients with AIS and a proximal occlusion was observed, the authors believe that a randomized clinical trial directly comparing both strategies is warranted.

Interesting to see the debate regarding expansion and modifications of the use of IVT and MT, such as thrombectomy for M2 and distal clot, treatment for large ischemic cores, and do we need IVT at all?

Zhang S, Lai Y, Ding X, Parsons M, Zhang JH, Lou M. Absent Filling of Ipsilateral Superficial Middle Cerebral Vein Is Associated With Poor Outcome After Reperfusion Therapy. Stroke. 2017;48(4):907-914. doi:10.1161/STROKEAHA.116.016174.

The authors studied the effect of drainage of cortical veins, including the superficial middle cerebral vein (SMCV), vein of Trolard, and vein of Labbé on neurological outcomes after reperfusion therapy. 228 consecutive ischemic stroke patients who underwent pretreatment computed tomographic perfusion and 24-hour CTP or MR perfusion after intravenous thrombolysis were included. All patients underwent baseline CTP, including noncontrast CT (NCCT) and volume perfusion CT, and 24 hours CTP or magnetic resonance perfusion in accordance with routine stroke imaging protocol. Arterial input function and venous output function (VOF) were automatically selected by the software MIStar (MIStar; Apollo Medical Imaging Technology, Melbourne, Australia) from middle cerebral artery/anterior cerebral artery and superior sagittal sinus of nonischemic hemisphere, respectively. According to the venous output function curve, the venous peak phase was identified and selected to reconstruct the single-phase 3D CT venography (3D CTV) by the software NeuroDSA (Siemens, Munich, Germany).

They conclude that lack of superficial middle cerebral vein filling contributed to poor outcome after thrombolysis, especially when reperfusion was not achieved. The main deleterious effect of poor venous filling appears related to the development of brain edema.

Their result supports the independent impact of superficial middle cerebral vein drainage pattern on outcome, which is consistent with a previous finding that the occlusion of SMCV was the most important factor contributing to morbidity in patients undergoing pterional approach for aneurysm surgery. However, it differs from other papers, which demonstrated that the lack of all three veins, SMCV, VOT, and VOL filling, was related to poor outcome. This variance may be attributed to the assessment of dynamic CTA in this study, which improves the sensitivity for delayed contrast arrival in vessels, compared with conventional single-phase CTA done previously. Thus, late-filling cortical veins overlooked by conventional CTA could be detected by dynamic CTA.

4 Figures

Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic Stroke of Undetermined Source. Stroke. 2017;48(4):867-872. doi:10.1161/STROKEAHA.116.016414.

Embolic stroke of undetermined source (ESUS) designates patients with nonlacunar cryptogenic ischemic strokes in whom embolism is the likely stroke mechanism. The authors undertook a systematic literature review to assess the frequency of embolic stroke of undetermined source, patient features, and prognosis using PubMed from 2014 to present. Based on 9 studies, the reported frequency of embolic stroke of undetermined source ranged from 9%-25% of ischemic strokes, averaging 17%. From 8 studies involving 2045 embolic stroke of undetermined source patients, the mean age was 65 years and 42% were women; the mean NIH stroke score was 5 at stroke onset. Most (86%) embolic stroke of undetermined source patients were treated with antiplatelet therapy during follow-up.

The picture of ESUS patients that emerged from this study is of relatively young (compared with atrial fibrillation-associated stroke) patients with mild strokes and with lower frequencies of conventional vascular risk factors compared with non-embolic stroke of undetermined source patients with ischemic stroke. They speculate that ESUS is usually caused by relatively smaller emboli from valvular and arterial sources rather than larger emboli originating in the cardiac chambers, notably left atrial appendage thrombi in patients with atrial fibrillation that embolize to cause large, devastating strokes. Most minor risk emboli sources hypothesized to underlie most embolic stroke of undetermined source typically produce small emboli.

Sources of ESUS:

In mid-2014, 2 high-quality studies reported that episodes (usually brief, lasting several minutes) of previously unrecognized atrial fibrillation could be detected in 10% to 20% of patients with cryptogenic ischemic stroke if the duration of cardiac monitoring was prolonged beyond 24 hours of Holter ECG monitoring. This has been confirmed in other studies, with the frequency of detection of atrial fibrillation directly related to the duration of cardiac rhythm monitoring. Left atrial myopathy/dysfunction unassociated with atrial fibrillation may be a cause of embolic stroke of undetermined source. Other studies have emphasized a relationship of nonstenotic cervical carotid artery plaques with cryptogenic stroke and with embolic stroke of undetermined source. There has been additional emphasis on occult cancer in patients with cryptogenic stroke.

Therefore the interest in vessel wall imaging of the carotid bifurcations.  Show the unstable plaque or wall hemorrhage in these types of patients.

Hassan A, Mosley J, Singh S, Zinn PO. A Comprehensive Review of Genomics and Noncoding RNA in Gliomas. Top Magn Reson Imaging. 2017;26(1):1. doi:10.1097/RMR.0000000000000111.

Glioblastoma is the most malignant primary adult brain tumor. Despite our greater understanding of the biology of GBMs, clinical outcome of GBM patients remains poor, as their median survival with best available treatment is 12 to 18 months.

TP53 mutations, a major tumor suppressor gene, are mostly associated with gliomas (WHO grades II and III astrocytoma) that ultimately develop into IDH1/2 wild-type primary GBMs as well as secondary GBMs, as they are also positively correlated with IDH1/2 mutations. Among the 4 molecular subgroups, TP53 gene mutation is most closely associated with the proneural subgroup.

IDH1 mutation is significantly associated with secondary GBM and a better prognosis, where the patients with IDH1 mutation had increased median overall survival of 31 months versus 15 months in patients with WT IDH1. Expression of IDH1 mutation in primary human astrocytes has been shown to establish the phenotype like that seen in low-grade gliomas (LGGs).

Deletion of 1p/19q [loss of heterozygosity (LOH)] has been found to be a significant biomarker in cases of grade II-III oligodendrogliomas. However, 1p/19q deletions in GBM are found to be uncommon (<10%) in diffuse astrocytic gliomas. Codeletion in context of IDH1 mutation is most frequent in LGGs with the best progression-free and overall survival (median survival: 8 years).

NF1 is a tumor suppressor key negative regulator of Ras and mTOR signaling pathways. NF1 is predominantly mutated or deleted in approximately 18% of GBMs and mostly altered in the mesenchymal subgroup (53.8%) signature. Some of these mutations are also observed in patients with neurofibromatosis.

One frequently hypermethylated gene promoter in primary GBM (40%) is the gene called MGMT, which codes for O6-methylguanine-DNA methyltransferase, an enzyme responsible for restoration of guanine from O-6-methylaguanine. O-6-methylguanine results from exposure to DNA alkylating chemotherapeutic agents such as TMZ, which is the current standard chemotherapeutic agent for treatment of GBM. The extensive presence of O-6-methylguanine in genomic DNA leads to DNA strand breaks, apoptosis, and cell death. Therefore, the silencing of MGMT will significantly influence the response to chemotherapeutic agents such as TMZ, where tumors will be sensitive to TMZ when the MGMT promoter is hypermethylated.

Noncoding RNAs, particularly miRNAs and long noncoding RNAs (lncRNAs), have been implicated in multiple biological processes in normal and various disease including cancer contexts.

The ability of cancer cells to maintain proliferation over long period of time due to sustained proliferative signaling in tumor microenvironment is a fundamental feature of all cancers. In context of GBM, microRNAs are an integral part of the molecular mechanism for maintaining this proliferative signaling, where expression levels of a combination of overexpressed and repressed miRNAs promote GBM cell proliferation.

Cancer cell invasion is another hallmark of cancer. GBM tumors also have a significant number of invading cells into surrounding normal brain tissues, making complete resection of tumor impossible; this contributes significantly to tumor recurrence. A set of microRNAs have been implicated as modulators of cell invasion behavior.

GBM is a highly-vascularized tumor. Neovascularization is essential to provide oxygen and nutrients to the fast-growing tumor. A combination of pro- and anti-angiogenic miRNAs play a major role in regulating angiogenesis in GBM.

Much more to this review, so check it out.

Regev K, Healy BC, Khalid F, et al. Association Between Serum MicroRNAs and Magnetic Resonance Imaging Measures of Multiple Sclerosis Severity. JAMA Neurol. 2017;74(3):275. doi:10.1001/jamaneurol.2016.5197.

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression by binding to complementary sequences in untranslated messenger RNA (mRNA) regions, resulting in translational repression or mRNA degradation. Dysregulated miRNA expression links to a range of immunologic and other diseases. Due to their detectability and stability in plasma, serum, and cerebrospinal fluid as well as the development of sensitive methods for their detection and quantification, miRNAs are attractive biomarkers.

In this cross-sectional cohort study of 120 patients with MS, several key findings emerged:

1) Both protective and pathogenic associations were found between miRNAs and MRI;

2) A topographic specificity, different between the brain and spinal cord, was identified (a different set of miRNAs correlated with spinal cord vs brain atrophy);

3) A pathobiologic specificity was found with T2 lesions showing a different miRNA signature vs atrophy and destructive measures;

4) T2 lesions demonstrated the weakest link to both miRNA and disability.

Among the identified miRNAs, reduced expression of hsa.miR.143.3p correlated with increased T1:T2 ratio as a protective association. Previous studies indicate that hsa.miR.143.3p is inversely associated with brain tissue damage, with decreased levels in the serum in persons with Alzheimer disease, minimal cognitive impairment vascular dementia vs the levels in healthy individuals.

The pathogenic miRNA, hsa.miR.92a.3p, showed a pathogenic relationship with T1:T2 ratio in this study. This miRNA belongs to the miR17-92 cluster, which is overexpressed in B cells and plasma in patients with MS vs healthy individual serving as controls. In mice, miR17-92 favors proinflammatory T helper 17 polarization.

Another pathogenic miRNA in this study with regard to T1:T2 ratio (hsa.miR.486.5p) primarily targets phosphatase and tensin homologue (PTEN) and forkhead box protein O1 (aka forkhead in rhabdomyosarcoma). Both PTEN and FOXO1 are involved in the PI3K/Akt signaling pathway.

2 Figures, 3 Tables

Perry JR, Laperriere N, O’Callaghan CJ, et al. Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma. N Engl J Med. 2017;376(11):1027-1037. doi:10.1056/NEJMoa1611977.

Management of glioblastoma in patients 65 years of age or older is difficult given the poor prognosis, frequent coexisting conditions, and an increased risk of toxic effects from radiotherapy on the aging brain; however, phase 3 studies have shown the effectiveness of shorter courses of radiotherapy as compared with supportive care alone or standard radiotherapy (60 Gy over a period of 6 weeks).

The authors conducted a trial involving patients 65 years of age or older with newly diagnosed glioblastoma. Patients were randomly assigned to receive either radiotherapy alone (40 Gy in 15 fractions) or radiotherapy with concomitant and adjuvant temozolomide. Patients underwent randomization from November 2007 through September 2013. A total of 562 patients underwent randomization, 281 to each group. The median age was 73 years (range, 65-90). The median overall survival was longer with radiotherapy plus temozolomide than with radiotherapy alone (9.3 months vs. 7.6 months), as was the median progression-free survival (5.3 months vs. 3.9 months). Among 165 patients with methylated MGMT status, the median overall survival was 13.5 months with radiotherapy plus temozolomide and 7.7 months with radiotherapy alone.

They conclude that in elderly patients with glioblastoma, the addition of temozolomide to short-course radiotherapy resulted in longer survival than short-course radiotherapy alone.

Strand V, Singh JA. Evaluation and Management of the Patient With Suspected Inflammatory Spine Disease. Mayo Clin Proc. 2017;92(4):555-564. doi:10.1016/j.mayocp.2016.12.008.

This review presents an overview of the epidemiology, clinical characteristics, and burdens of AxSpA, followed by a case presentation outlining approaches to the evaluation and management of a patient with suspected inflammatory spine disease.

Spondyloarthritis (SpA) describes a heterogeneous group of chronic inflammatory rheumatic diseases, including ankylosing spondylitis (AS), psoriatic arthritis, enteropathic-related spondylitis, and nonradiographic axial SpA (AxSpA). All of these disorders are associated with familial clustering and human leukocyte antigen B27 positivity in a percentage of patients, but differing types of tissue inflammation and structural damage result in a variety of disease phenotypes. Spondyloarthritis can be divided into 2 subgroups: axial and peripheral according to the predominant location of arthritis.

Axial SpA can be further classified as AS or nonradiographic AxSpA. Ankylosing spondylitis is the classic form of the disease and presents with characteristic radiographic damage, and nonradiographic AxSpA presents without radiographic changes but with SIJ inflammation on MRI or CT. Extra-articular manifestations, including inflammatory bowel disease (IBD), acute anterior uveitis/iritis, aortic insufficiency, and enthesitis, are observed and can substantially affect the prognosis. Patients with AxSpA are also at increased risk for cardiovascular and other comorbidities, including ischemic heart disease, hypertension, diabetes mellitus, osteoporosis, and atrioventricular block.

Assessment of SpondyloArthritis International Society (ASAS) has developed and validated classification criteria for AxSpA that include patients with and without definite radiographic sacroiliitis. According to these criteria, AxSpA should be diagnosed in patients with sacroiliitis using radiography or MRI plus at least 1 clinical feature of SpA, or in patients with HLA-B27+ and at least 2 clinical features of SpA. Validated clinical disease features include inflammatory back pain, extraspinal manifestations, good response to nonsteroidal anti-inflammatory drug therapy, family history of SpA, HLA-B27+, and an elevated C-reactive protein level.

2 Figures, 2 Tables.  One very helpful table showing the different classification schemes (Rome criteria, New York criteria, ASAS).

Journal Scan – This Month in Other Journals, July 2017
Jeffrey Ross • Mayo Clinic, Phoenix

Dr. Jeffrey S. Ross is a Professor of Radiology at the Mayo Clinic College of Medicine, and practices neuroradiology at the Mayo Clinic in Phoenix, Arizona. His publications include over 100 peer-reviewed articles, nearly 60 non-refereed articles, 33 book chapters, and 10 books. He was an AJNR Senior Editor from 2006-2015, is a member of the editorial board for 3 other journals, and a manuscript reviewer for 10 journals. He became Editor-in-Chief of the AJNR in July 2015. He received the Gold Medal Award from the ASSR in 2013.

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