May 2019 (9 papers)

1. Ebeling PR, Akesson K, Bauer DC, et al. The Efficacy and Safety of Vertebral Augmentation: A Second ASBMR Task Force Report. J Bone Miner Res. 2019;34(1):3-21. doi:10.1002/jbmr.3653.

Two placebo-controlled trials of percutaneous vertebroplasty published in 2009 questioned the value of this procedure, and an additional three trials, all in participants with acute symptoms (for up to 9 weeks), have now confirmed the findings of these earlier trials. No placebo-controlled trials of balloon kyphoplasty have been performed and evidence of the value of this procedure is reliant on low quality evidence from trials that have compared kyphoplasty with usual care or head-to-head comparisons with vertebroplasty. In addition, there have been few trials of other nonpharmacological approaches to reduce pain in patients with vertebral fractures.

The American Society for Bone and Mineral Research (ASBMR) leadership charged this Task Force to address key questions on the efficacy and safety of vertebral augmentation and other nonpharmacological approaches for the treatment of pain after VF. This report details the findings and recommendations of this Task Force.

For patients with acutely painful VF, percutaneous vertebroplasty provides no demonstrable clinically significant benefit over placebo. Results did not differ according to duration of pain. There is also insufficient evidence to support kyphoplasty over nonsurgical management, percutaneous vertebroplasty, vertebral body stenting, or KIVA®. There is limited evidence to determine the risk of incident VF or serious adverse effects (AE) related to either percutaneous vertebroplasty or kyphoplasty. No recommendation can be made about harms, but they cannot be excluded.

For patients with painful VF, it is unclear whether spinal bracing improves physical function, disability, or quality of life. Exercise may improve mobility and may reduce pain and fear of falling but does not reduce falls or fractures in individuals with VF. General and intervention-specific research recommendations stress the need to reduce study bias and address methodological flaws in study design and data collection. This includes the need for larger sample sizes, inclusion of a placebo control, more data on serious AE, and more research on nonpharmacologic interventions. Routine use of vertebral augmentation is not supported by current evidence. Anti-osteoporotic medications reduce the risk of subsequent vertebral fractures by 40–70%.

In making quality, informed patient care decisions, clinicians will need to balance the limited findings on the safety and efficacy of other nonpharmacologic interventions with good clinical judgment. Fully disclosing the evidence to patients will ensure that they can make the best evidence-informed decisions about their care.

2. Clarke BL, Khosla S. Is It Time to Stop (or Pause) Vertebral Augmentation? J Bone Miner Res. 2019;34(1):1-2. doi:10.1002/jbmr.3651.
Commentary on the Ebeling Taskforce paper:
Despite the absence of clear evidence for efficacy and potential safety concerns, an estimated 81,690 patients underwent vertebroplasty and 169,413 patients underwent kyphoplasty in the United States between 2006 and 2014.

The Task Force is to be commended for the comprehensive and thoughtful nature of their review of the evidence, which included a systematic review of the existing literature and meta analyses. Their conclusions are clear. Vertebroplasty provides no clinically significant benefit in terms of pain control over placebo or sham procedures based on five randomized placebo controlled trials. Kyphoplasty provided weak evidence of benefit in one clinical trial showing reduced pain compared with nonsurgical treatment, but lack of placebo-controlled trials, along with absence of any benefits of kyphoplasty over vertebroplasty when the two have been directly compared in a small number of heterogeneous head-to-head trials, argues against the routine use of this procedure also.

Although disheartening to patients and physicians, the Task Force report also provides some guidance for next steps, including future clinical trials. Given the current body of evidence, the Task Force recommends against additional trials of vertebroplasty unless these are large and adequately powered to alter the conclusion based on current evidence that this procedure is no more effective than placebo. Importantly, the Task Force recommends that this procedure be discontinued in clinical practice.

3. Nakagawa D, Nagahama Y, Policeni BA, et al. Accuracy of detecting enlargement of aneurysms using different MRI modalities and measurement protocols. J Neurosurg. 2018;130(February):1-7. doi:10.3171/2017.9.JNS171811.

Three silicone flow phantom models, each with 8 aneurysms of various sizes at different sites, were used in this study. The aneurysm models were identical except for an incremental increase in the sizes of the 8 aneurysms, which ranged from 0.4 mm to 2 mm. The phantoms were imaged on 1.5-T and 3-T MRI units with both time-of-flight (TOF) and contrast-enhanced MR angiography. Three independent expert neuroradiologists measured the aneurysms in a blinded manner using different measurement approaches (Huston, Cloft, Wintermark).

The aims of this study were to determine 1) whether the observers could accurately detect any increase in aneurysm dimension using different reading protocols; 2) the minimum incremental increase that can be reliably detected with a high agreement rate; 3) the effect of different imaging machines and MRI sequences (TOF vs Gd) on the detection rate; and 4) whether the location of the aneurysm affects the detection rate.

The results of this study suggest that 1) aneurysm dimensions that were increased in the phantom models were detected very reliably by the individual observers, and the agreement rate among the 3 observers was significantly high; 2) aneurysm dimensions that were kept fixed in the phantom models were occasionally miscalculated by the individual observers; 3) the detection rate of at least 1 increase in any aneurysm dimension did not depend on the choice of MRI modality; 4) the location of the aneurysm affected the detection rate of aneurysm enlargement; and 5) different measurement protocols did not affect the detection rate of at least 1 increase in any aneurysm dimension for each MRI modality.

This is the first study in the literature to identify the smallest incremental aneurysm enlargement that could be reliably detected using different MRA and reading protocols by expert neuroradiologists. The observers consistently and blindly were able to reliably detect incremental growth, even aneurysm dimension increases as small as 0.4 mm. The margin error of misreading size was within 0.1–0.3 mm in most of the misread aneurysm dimensions.

Aneurysm dimension were detected by our observers, especially using 1.5-T MRA with Gd, 3-T TOF MRA, and 3-T MRA with Gd. The use of 1.5-T TOF MRA exacerbated the misreading. Thus, based on this data, 3.0-T imaging may provide the best assessment of size variation. If using 1.5-T MRA, the additional use of Gd improved the detection of size variation in our model.

4. Lang M, Silva D, Dai L, et al. Superiority of constructive interference in steady-state MRI sequencing over T1-weighted MRI sequencing for evaluating cavernous sinus invasion by pituitary macroadenomas. J Neurosurg. 2018;130(February):1-8. doi:10.3171/2017.9.JNS171699.

VIBE and CISS images of 98 patients with pituitary macroadenoma were retrospectively analyzed and graded using the modified Knosp classification. The Knosp grades were correlated to surgical findings of cavernous sinus invasion (CSI), which were determined intraoperatively using 0° and 30° endoscopes. The predictive accuracies for CSI according to the Knosp grades derived from the CISS and VIBE images were compared using receiver operating characteristic (ROC) curves.

Lots of numbers reported in this paper, but briefly….if grades 3A, 3B, and 4 were considered to be “invasive grades,” the sensitivity and specificity were 74.1% and 92.3% for the VIBE sequences, respectively, and 77.8% and 95.9% for the CISS sequences, respectively. Of 196 assessments (both the left and right sides of 98 macroadenomas), 45 cases (23.0%) had different Knosp grades when scored using VIBE versus CISS images.

In this patient cohort, the Knosp grades determined from the CISS sequences were overall better correlated with the risk of CSI than the VIBE sequences. This might be due to increased overlap between gadolinium enhancement of the tumor and blood in the cavernous sinus on VIBE images, whereas contrast was not used for CISS imaging. The comparison between the ROC curves and AUCs provided further confirmation of the CISS sequence’s superiority.

5 figures, 3 tables.

5. Rahman S, Copeland WC. POLG-related disorders and their neurological manifestations. Nat Rev Neurol. 2019;15(1):40-52. doi:10.1038/s41582-018-0101-0.

POLG is one of several nuclear genes that are associated with mtDNA depletion or deletion disorders. In 2001, Van Goethem et al. published a seminal paper describing four mutations in POLG that were associated with either autosomal dominant or autosomal recessive progressive external ophthalmoplegia (PEO). Between 2003 and 2005, several reports identified POLG mutations in patients with ataxia. Also in this time frame, Alpers–Huttenlocher syndrome (AHS) was found to be caused by recessive mutations in POLG. The high frequency of POLG mutations in the Norwegian and Finnish populations led to calls to include POLG testing as a first- line diagnostic in ataxia syndromes. These reports were the first of many to identify disease associated mutations in the POLG gene. Pathogenic variants in POLG are now known to cause a spectrum of overlapping phenotypes, including some that were clinically defined long before their molecular basis was known. This article reviews these clinical disorders and symptoms associated with POLG- related disorders.

Common PLOG related disorders include:
Neonatal or infancy- Myocerebrohepatopathy spectrum (MCHS) (Depletion)
Infancy or childhood- Alpers–Huttenlocher syndrome (AHS) (Depletion)
Adolescent or young adult –
Ataxia neuropathy spectrum (ANS) including mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) (Deletions)
Myoclonic epilepsy myopathy sensory ataxia (MEMSA) including mitochondrial spinocerebellar ataxia with epilepsy (SCAE) (Deletions)
Progressive external ophthalmoplegia (PEO) with or without sensory ataxia
neuropathy dysarthria and ophthalmoplegia (SANDO) (Deletions)

2 figures, 4 tables (no MRI)

6. Begoli E, Bhattacharya T, Kusnezov D. The need for uncertainty quantification in machine-assisted medical decision making. Nat Mach Intell. 2019;1(1):20-23. doi:10.1038/s42256-018-0004-1.

Uncertainty quantification (UQ) extends the traditional discipline of statistical error analysis to also capture uncertainties due to possibly incomplete, inaccurate and contradictory input data, missing and undetected mechanisms and dependencies, expert judgment, and variations between reasonable model forms and modelling strategies. Advances in UQ now provide measures of confidence necessary to inform national and international security decisions. A notable example is the US support of a nuclear test moratorium since 1992, whereby it is annually providing detailed measures of confidence in the safety, security and performance of the nuclear stockpile.

The authors see at least four overlapping groups of challenges associated with the uncertainty quantification of the data-driven approaches such as deep learning (DL).

1. Absence of theory: unlike the physical world, which is governed by the well-understood laws of physics, the domains where the DL is usually applied, such as medicine, do not have ‘hard laws’. Although we use compensating mathematical techniques that take certain assumptions in order to account for the random noise, or some other well-known problem in working with the data, we are ultimately operating without the fundamental, underlying mathematical model.

2. Absence of causal models: in addition to the absence of underlying mechanistic theory, one also has to contend with the fact that DL is essentially exploiting correlations in the data, without paying attention to any causal link.

3. Sensitivity to imperfect data: DL learns from data, and often uses subtle multivariate correlations to improve its predictions. Real-world data are usually imperfect—typically containing missing elements and errors—and these imperfections have patterns that can confound prediction. Specific Uncertainty quantification methods, therefore, need to be developed to quantify the sensitivity of models to imperfect data.

4. Computational expense: the training of the DL models is computationally expensive, and any further re-computation and re-evaluation of the models, aimed, for example, at the calculation of uncertainty bounds, might currently be prohibitively expensive. Fortunately, computing capacity in support of DL is growing exponentially.

7. Zalewski NL, Rabinstein AA, Krecke KN, et al. Characteristics of Spontaneous Spinal Cord Infarction and Proposed Diagnostic Criteria. JAMA Neurol. 2019;76(1):56. doi:10.1001/jamaneurol.2018.2734.

An institution-based search tool was used to identify patients evaluated at Mayo Clinic, Rochester, Minnesota, from January 1997 to December 2017 with a spontaneous SCI. Participants were 18 years and older with a diagnosis of spontaneous SCI (n = 133), and controls were selected from a database of alternative myelopathy etiologies for validation of the proposed diagnostic criteria (n = 280).

Of 133 included patients with a spontaneous SCI, the median (interquartile range) age at presentation was 60 years, and 101 (76%) had vascular risk factors. Rapid onset of severe deficits reaching nadir within 12 hours was typical (102 [77%]); some had a stuttering decline (31 [23%]). Sensory loss occurred in 126 patients (95%), selectively affecting pain/temperature in 49 (39%). Initial magnetic resonance imaging (MRI) spine results were normal in 30 patients (24%). Characteristic MRI T2-hyperintense patterns included owl eyes (82 [65%]) and pencil-like hyperintensity (50 [40%]); gadolinium enhancement (37 of 96 [39%]) was often linear and located in the anterior gray matter. Confirmatory MRI findings included diffusion-weighted imaging/apparent diffusion coefficient restriction (19 of 29 [67%]), adjacent dissection/occlusion (16 of 82 [20%]), and vertebral body infarction (11 [9%]).

Physicians should request DWI in patients with acute myelopathy in an attempt to confirm the diagnosis of SCI; however, DWI has incomplete sensitivity in SCI given limitations of spatial resolution and susceptibility artifacts, as has been shown in definite cases of periprocedural SCI. Classic findings of owl eyes or pencil-like hyperintensity are helpful in suspecting SCI but are neither specific nor required for the diagnosis. A variety of other T2-hyperintensity patterns can also be seen, as previously characterized in the periprocedural setting. Magnetic resonance imaging is often normal acutely in SCI (24%), and thus repeating imaging days later is recommended.

2 Figures, 2 Tables, 1 box for diagnostic criteria

8. Sadigh G, Jalilvand A, Singh K, Duszak R. Pirated Manuscripts From Radiology’s Most Impactful Journals: An International Analysis of Copyright-Infringing Downloads. J Am Coll Radiol. 2019;16(1):108-114. doi:10.1016/j.jacr.2018.07.005.

Sci-Hub, the world’s largest scholarly literature pirate website (permitting unauthorized duplication of copyrighted content) was founded in 2011, and since then, its very existence has proven (to say the least) quite controversial.

The authors retrieved request event details for all articles downloaded from Sci-Hub between September 1, 2015, and February 28, 2016, from the website’s publicly accessible server logs. Focusing on high-impact factor radiology journals, they then targeted journals with a 2015 Thomson Reuters impact factor of 2 or greater, and the journal category of “radiology, nuclear medicine and medical imaging” using the Thomson Reuter’s Journal Citation Reports search tool.

The large majority of these downloaded manuscripts were review articles (26 of 30; 87%) and most were published in RadioGraphics (60%). The three most frequently downloaded articles were from European Radiology, RadioGraphics, and NeuroImage. By country, download requests were most frequent from China (17,973 of 105,075; 17.1%), India (7,965; 7.6%), and Iran (6,402; 6.0%) (Fig. 2A). However, downloads on a per capita basis were most common in Portugal (210.8 per one million population), Chile (135.4), and Tunisia (113.8). Only 4.2% (4,450 of 105,075) of all download requests were from the United States.

The reasons for this country to country variation—or US state to state variation, is unknown, but most likely relates to a lack of institutional subscriptional access to relevant scientific journals by many users.

The authors opine that in many ways, Sci-Hub is to the scholarly publishing industry as Napster was to the record industry. They believe that it would be wise for Elsevier and other publishers to study the history of what did—and did not—work in other industries. The sustainability of many academic journals may be at stake.

Personally it is difficult for me to equate human healthcare and the curation of the medical literature which involves life and death vs decisions to the music industry.

For an alternative view to open access for everyone, I point you to this tangentially related reference:
Leopold SS, Haddad FS, Sandell LJ, Swiontkowski M. Editorial: Clinical Orthopaedics and Related Research, The Bone & Joint Journal, The Journal of Orthopaedic Research, and The Journal of Bone and Joint Surgery Will Not Accept Clinical Research Manuscripts Previously Posted to Preprint Servers. Clin Orthop Relat Res. 2019;477(1):1-4. doi:10.1097/CORR.0000000000000565.

9. Debette S, Schilling S, Duperron M-G, Larsson SC, Markus HS. Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury. JAMA Neurol. 2019;76(1):81. doi:10.1001/jamaneurol.2018.3122.

Large-scale brain imaging studies in the general population have shown that radiological evidence of covert vascular brain injury (VBI) is much more frequent than clinical stroke and is highly prevalent in community-dwelling older persons. Such incidental findings are also often detected on MRI performed in routine clinical practice, and how they should be interpreted and acted on presents a common clinical challenge. Individual studies have suggested that MRI markers of covert VBI predict an increased risk of stroke, dementia, and death, but other studies did not show any association. Better understanding of the association of specific MRI markers of VBI with outcomes is crucial to optimize prevention strategies.

The authors asked the question: What is the clinical and therapeutic significance of MRI markers of covert vascular brain injury (white matter hyperintensities of presumed vascular origin, magnetic resonance imaging–defined covert brain infarcts, cerebral microbleeds, and perivascular spaces) in community-dwelling older adults?

In this systematic review and meta-analysis of more than 16,000 participants, there was evidence that white matter hyperintensities, brain infarcts, and cerebral microbleeds have a major clinical significance in community-dwelling older adults; they were associated with an increased risk of stroke (both hemorrhagic and ischemic for all markers), dementia, and death.

From a practical perspective, the discovery of these MRI markers should prompt detailed assessment of a person’s risk for stroke and dementia and careful evaluation of the benefit–risk ratio for available preventive strategies. Randomized clinical trials are required to determine whether specific therapies, particularly aspirin therapy and intensive blood pressure lowering, are beneficial when these MRI markers are noted as incidental findings.

3 Figures, 1 table