1. Mehran R, Dangas GD, Weisbord SD. Contrast-associated acute kidney injury. N Engl J Med 2019;380(22):2146–55. doi:10.1056/NEJMra1805256

This review summarizes the pathophysiology of contrast-associated acute kidney injury, the diagnostic criteria, and risk stratification; discusses current controversies regarding the incidence of this condition; and focuses on studies that have provided the evidence that forms the basis for preventive care.

Multiple studies have compared the risk of acute kidney injury after procedures performed with and those performed without intravascular administration of contrast material. A meta-analysis by McDonald et al. that involved 25,950 patients showed no significant difference in the risk of acute kidney injury between patients who underwent procedures with intravenous administration of iodinated contrast material and those who underwent procedures without it (6.4% and 6.5%, respectively). The incidence rates of dialysis and death were also similar in the two groups. Another meta-analysis showed a lower risk of acute kidney injury among patients with acute ischemic stroke who underwent CT with intravenous administration of contrast material, as compared with patients who underwent CT without the use of contrast material. Other studies have reported similar findings.

The incidence of severe acute kidney injury due to contrast material is quite low. A study that prospectively assessed the development of contrast-associated acute kidney injury among patients with chronic kidney disease who were undergoing nonemergency coronary angiography showed that 1.2% of the patients had a post procedure increase in the plasma creatinine level that was 50% or more of the baseline value, and none had an increase of 100% or more or required dialysis. In a meta-analysis of studies involving patients who underwent contrast-enhanced CT, the rate of post-procedure dialysis was just 0.3%. Although currently available data are insufficient to declare that contrast agents are not nephrotoxic, severe acute kidney injury characterized by substantial decrements in kidney function, the need for renal replacement therapy, or both appears to be very infrequent after intravascular contrast administration. Accordingly, a prudent approach to the care of patients undergoing contrast-enhanced procedures involves judicious implementation of evidence-based preventive care for patients identified as being at highest risk for acute kidney injury.

1. Volume expansion with isotonic saline…good (intravenous infusion of isotonic saline for 1 to 3 hours before and 6 hours after the procedure).
2. Isotonic sodium bicarbonate provides no benefit relative to isotonic saline.
3. Acetylcysteine is not recommended for the prevention of acute kidney injury or longer-term adverse events after angiographic procedures.
4. A preemptive temporary suspension of metformin therapy has been advocated, not because this medication augments the risk of kidney injury but rather out of concern about the development of lactic acidosis, should severe acute kidney injury occur.
5. Given the prevalence of diabetes, the widespread use of metformin, and practical issues related to the temporary discontinuation of the medication, additional data are needed before firm, evidence-based recommendations can be provided regarding the discontinuation of metformin in patients undergoing contrast-enhanced procedures.

3 figures, 72 references

2. Nelson PT, Dickson DW, Trojanowski JQ, et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain 2019;142(6):1503–27. doi:10.1093/brain/awz099

This is a 24 page report on TDP-43 encephalopathy (aka Transactive response DNA binding protein of 43 kDa) proteinopathy ) (TDP-43), that in limbic brain structures is commonly observed in subjects past 80 years of age. This proteinopathy has been associated with substantial cognitive impairment that mimicked Alzheimer’s disease clinical syndrome in retrospective studies.

Historically, the first-recognized pathological manifestation of limbic-predominant age-related TDP-43 encephalopathy was profound hippocampal neuron loss and gliosis, collectively termed hippocampal sclerosis. In a 1994 study identified 13 elderly subjects with dementia and hippocampal sclerosis, yet who lacked substantial Alzheimer’s disease neuropathological change. Other larger autopsy series that included subjects with dementia and hippocampal sclerosis were later reported.

Despite evidence from many sources attesting to the public health impact of age-related TDP-43 proteinopathy, there is as yet no consensus-based nomenclature. The authors propose new terminology: limbic-predominant age-related TDP-43 encephalopathy (LATE). Guidelines are suggested for the autopsy evaluation and staging of LATE neuropathological change (LATE-NC). They review the medical literature pertaining to LATE, including cognitive manifestations, neuroimaging, public health impact, and genetics. The importance of LATE as a contributing factor in neurodegeneration is stressed, as are the needs for specific LATE biomarker development, TDP-43 focused drug discovery, and eventual clinical trials.

1. LATE neuropathological change is present in >20% (up to 50%) of individuals past age 80 years according to large community-based autopsy series.
2. LATE is associated with substantial disease-specific cognitive impairment, usually an amnestic dementia syndrome (‘dementia of the Alzheimer’s type’).
3. MRI studies have provided a complementary window into brain changes in LATE, highlighting brain atrophy both within and outside of the medial temporal lobes of brains with autopsy-verified LATE neuropathological change.
4. A common finding in MRI studies is that hippocampal atrophy is greater in cases with LATE neuropathological change than in those with pure Alzheimer’s disease.

5 figures, 2 tables

3. Rubin DB, Danish HH, Ali AB, et al. Neurological toxicities associated with chimeric antigen receptor T-cell therapy. Brain 2019;142(5):1334–48. doi:10.1093/brain/awz053

Chimeric antigen receptor (CAR) T cells have emerged in recent years as a powerful treatment for relapsed and refractory hematological malignancies. Impressive therapeutic response rates, however, are accompanied by significant and often treatment-limiting toxicity. Toxicity predominately occurs as two related but distinct syndromes: cytokine release syndrome (CRS) and neurotoxicity.

CRS is a multi-system clinical syndrome characterized by fever, hypotension, hypoxia, and in more severe cases multisystem organ dysfunction. CRS is caused by the widespread release of pro-inflammatory cytokines by the activated CAR T cells. CRS is extremely common; in some trials, 100% of patients experienced at least some symptoms of CRS. Treatment with tocilizumab, which blocks the IL-6 signal receptor pathway, can effectively mitigate the symptoms of CRS without impairing the antitumor efficacy of the CAR T cells.

In contrast, the neurotoxicity associated with CAR T-cell therapy remains idiosyncratic and poorly characterized. In the literature, patients are described as variably suffering from encephalopathy, confusional state, delirium, or mental-status changes. Other neurotoxicities, including aphasia, tremor, ataxia, seizure, and cerebral edema, have all also been reported with varying frequency.

The authors characterized the neurological toxicity associated with chimeric antigen receptor T-cell therapy in a consecutive series of 100 patients up to 2 months post transfusion, 28 of whom were obtained from chart review and the others by prospective observation. The underlying neoplasms were lymphoma (74%), myeloma (14%), leukemia (10%), and sarcoma (2%). The median age of the cohort was 64.5 years old and 39% of patients were female. The most commonly occurring neurological symptoms were encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%). Focal neurological deficits are frequently observed after chimeric antigen receptor T-cell therapy and are associated with regional EEG abnormalities, FDG-PET hypometabolism, and elevated velocities on transcranial Doppler ultrasound. In contrast, structural imaging was typically normal.

Specifically, non-contrast head CT was the most commonly obtained neurodiagnostic study. Ninety-nine CT scans were obtained in 48 patients. Four abnormal findings were noted: the two cases of subarachnoid hemorrhage, one of the two ischemic strokes, and a case of diffuse cerebral edema. MRI was obtained in 29 cases. The only acute intracranial findings noted on MRI were two cases of ischemic stroke, two cases of subarachnoid hemorrhage, and a case of bilateral intralabyrinthine cochlear hemorrhages.

Five patients died after receiving CAR T cells; only one death was directly related to neurotoxicity. This patient, a 21-year-old male treated for relapsed B-cell acute lymphoblastic leukemia, developed acute obtundation progressing to coma and brain death on post-transfusion Day 5. On head CT, he was found to have diffuse cerebral edema. The other patients all died from disease progression or CRS.

6 figures, 2 tables

4. Herrera-Perez D, Haslam A, Crain T, et al. A comprehensive review of randomized clinical trials in three medical journals reveals 396 medical reversals. Elife 2019;8:1–19. doi:10.7554/eLife.45183

Low-value medical practices are medical practices that are either ineffective or that cost more than other options but only offer similar effectiveness. Such practices can result in physical and emotional harm, undermine public trust in medicine, and have both an opportunity cost and a financial cost. Medical reversals are a subset of low-value medical practices and are defined as practices that have been found, through randomized controlled trials, to be no better than a prior or lesser standard of care. It can, however, be difficult to identify medical reversals. For example, Cochrane reviews provide high-quality evidence on medical practices, but each review focuses on only one practice and many practices have not been reviewed by Cochrane. The Choosing Wisely initiative in the US maintains a list of low-value medical practices, but it relies on medical organizations to report such practices and often includes only those practices where there is a high degree of consensus.

The authors report how a systematic search of randomized controlled trials in three leading medical journals – the Journal of the American Medical Association (JAMA), the Lancet, and the New England Journal of Medicine (NEJM) –identified 396 medical reversals.

Most studies (92%, n = 366) were conducted on populations in high-income counties, whereas 8% (n = 30) were done in low- or middle-income countries, including, but not limited to China, India, Malaysia, Ghana Tanzania, and Ethiopia. Cardiovascular disease was the most common medical category (20%, n = 80), followed by public health/preventive medicine (12%, n = 48), and critical care (11%, n = 45). Regarding the type of intervention, medication was the most common (33%, n = 129), followed by a procedure (20%, n = 81), vitamin/supplement (13%, n = 53), device (9%, n = 35) and system intervention (8%, n = 30).

One topic of interest they touch on:

The treatment of symptomatic lumbar stenosis has included epidural glucocorticoid injections. This treatment is frequently prescribed by physicians to treat lumbar stenosis and other conditions, with an estimated 25% of the Medicare population and 74% of patients at the Veteran’s Administration being prescribed this treatment. As the usage of glucocorticoid injections increased to treat various ailments, so did the cost. From 1994 to 2001 there was a 271% growth in usage of the treatment, and the cost went from $24 million to over $175 million. The LESS trial (N = 441) was designed to compare the effectiveness of epidural injections of glucocorticoids plus anesthetic vs. injections of anesthetic alone. At six weeks after randomization, there were no significant differences in RMDQ scores (used to measure functional disability), or pain intensity, between the patients treated with glucocorticoids plus lidocaine and those in the lidocaine alone group. This is a reversal of administering epidural glucocorticoid injections in patients who have lumbar central spinal stenosis and moderate-to- severe leg pain and disability.

2 figures, 2 tables, a bunch of supplementary files

5. Fujihara K. Neuromyelitis optica spectrum disorders: still evolving and broadening. Curr Opin Neurol 2019;32(3):385–94. doi:10.1097/WCO.0000000000000694

In the 2015 diagnostic criteria, neuromyelitis optica spectrum disorders (NMOSD) is stratified by aquaporin- 4 (AQP4)-antibody serostatus and encompasses brain syndrome as well as optic neuritis and acute myelitis, making earlier diagnosis possible compared with the previous criteria. The clinical spectrum of myelin oligodendrocyte glycoprotein (MOG)-antibody detected in some cases with AQP4-antibody-seronegative NMOSD is somewhat different from AQP4-antibody-seropositive NMOSD.

Pathologically, AQP4-antibody-seropositive NMOSD is an autoimmune astrocytopathic disease whereas MOG antibody-seropositive NMOSD is an inflammatory demyelinating disease (myelin oligodendrocyte glycoprotein (MOG) is a minor myelin protein localized at the outermost layer of the myelin sheath. MOG has been used as an immunogen to induce experimental autoimmune encephalomyelitis (EAE) in rodents for more than 30 years).

After disease-modifying drugs (DMD) for multiple sclerosis were approved, in the beginning the patients with NMOSD were also treated with DMD for multiple sclerosis. However, such DMD for multiple sclerosis as interferon-beta, natalizumab and fingolimod were ineffective in or exacerbated AQP4-antibody-seropositive NMOSD.

Current treatment of NMOSD includes:

(1) High-dose intravenous methylprednisolone is the first-line therapy in the acute phase of NMOSD. Plasma exchange may be needed as a rescue therapy in cases refractory to HIMP.

(2) Long-term immunosuppression is needed to prevent relapses of NMOSD.

Immunosuppression but not disease-modifying drugs for multiple sclerosis is the treatment of choice for NMOSD.

6. Hanseeuw BJ, Betensky RA, Jacobs HIL, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease. JAMA Neurol 2019;76(8):915–24. doi:10.1001/jamaneurol.2019.1424

Prospective cohort study was conducted between 2010 and 2017 at the Harvard Aging Brain Study, Boston, Massachusetts. The study enrolled 279 clinically normal participants. An additional 90 individuals were approached but declined the study or did not meet the inclusion criteria. In this report, the authors analyzed data from 60 participants who had multiple Aβ and tau PET observations available on October 31, 2017.

A median of 3 Pittsburgh compound B–PET (Aβ, 2010-2017) and 2 flortaucipir-PET (tau, 2013-2017) images were collected. They used initial PET and slope data, assessing the rates of change in Aβ and tau, to measure cognitive changes. Cognition was evaluated annually using the Preclinical Alzheimer Cognitive Composite (2010-2017). Annual consensus meetings evaluated progression to mild cognitive impairment.

Seventeen participants (28%) exhibited an initial high Aβ burden. An antecedent rise in Aβ was associated with subsequent changes in tau. Tau changes were associated with cognitive changes, covarying baseline Aβ and tau. Tau changes were greater in the participants who progressed to mild cognitive impairment (n = 6) than in those who did not.

The conclude that they identified sequential changes in normal older adults, from Aβ to tau to cognition, after which the participants with high Aβ with greater tau increase met clinical criteria for mild cognitive impairment. These findings highlight the importance of repeated tau-PET observations to track disease progression and the importance of repeated amyloid-PET observations to detect the earliest AD pathologic changes.

3 figures, 2 tables

7. Zaro-Weber O, Fleischer H, Reiblich L, et al. Penumbra detection in acute stroke with perfusion magnetic resonance imaging: validation with 15 O-positron emission tomography. Ann Neurol 2019;85(6):875–86. doi:10.1002/ana.25479

Ten patients (group A) with acute and subacute ischemic stroke underwent perfusion-weighted (PW)/diffusion-weighted MRI and consecutive full quantitative 15O-PET within 48 hours of stroke onset. Penumbra as defined by 15O-PET cerebral blood flow (CBF), oxygen extraction fraction, and oxygen metabolism was used to validate a wide range of established PW measures (eg, time-to-maximum [Tmax]) to optimize penumbral tissue detection. Validation was carried out using a voxel-based receiver-operating-characteristic curve analysis.

The perfusion-weighted map Tmax (area-under-the-curve = 0.88) performed best in detecting penumbral tissue up to 48 hours after stroke onset. The optimal threshold to discriminate penumbra from oligemia was Tmax >5.6 seconds with a sensitivity and specificity of >80%.

From a clinical point of view, these results are important because the optimal perfusion-weighted maps and penumbra thresholds validated against full quantitative PET up to 48 hours of stroke onset are pivotal to detect penumbral tissue and can help the clinician to decide on revascularization or other options of treatment in acute stroke beyond the established time windows. This is particularly true because recent clinical stroke studies (DEFUSE-3 and DAWN) have shown a clinical benefit of endovascular revascularization based on mismatch detection within 24 hours of stroke onset.

3 figures, 3 tables including PET and MR

8. Chua MMJ, Silveira L, Moore J, et al. Flow diversion for treatment of intracranial aneurysms: mechanism and implications. Ann Neurol 2019;85(6):793–800. doi:10.1002/ana.25484

Flow diverters (FDs) are new generation stents characterized by low porosity and aptly named for their intended mechanism of action, that is, vessel reconstruction with a reduction of flow into the intracranial aneurysm and subsequent redirection along the path of the parent vessel. At this time, FDs require the use of dual antiplatelet therapy to prevent in-stent thrombosis. Flow diversion is increasingly used to treat intracranial aneurysms, as it may be used without coiling in many situations, thus eliminating the need for microcatheter manipulation with the aneurysm. The Pipeline embolization device (PED; Medtronic, Irvine, CA) was approved by the FDA in 2011 for indication of “large or giant wide-neck intracranial aneurysms in the internal carotid artery (ICA) from the petrous to the superior hypophyseal segments.” Recently, the FDA indication for PED use has expanded to include all wide-neck intracranial aneurysms regardless of size and location in the ICA. Although the ICA remains the most frequent indication for FD use, there are several publications citing their off-label use in other locations. FDs in other unique rupture situations such as blister and dissecting aneurysms have demonstrated value.

There are risks associated with FD use, with morbidity and mortality rates as high as 5% and 4% respectively due to FD-treatment–related complications with 76% complete aneurysm occlusion rate. These complications may include acute infarction due to vessel perforation, ischemic stroke (due to in-stent thrombus formation), delayed rupture after treatment, and/or intraparenchymal hemorrhage. Furthermore, higher rates of complications are correlated with larger aneurysms, likely due to these being less stable and also tending to be more technically challenging to approach.

2 figures