Journal Scan – This Month in Other Journals, May 2018

Nam K-W, Kim CK, Kim TJ, et al. FLAIR vascular hyperintensities predict early ischemic recurrence in TIA. Neurology. 2018;90(9):e738-e744. doi:10.1212/WNL.0000000000005034.

The authors set out to answer the question as to whether vascular hyperintensities on FLAIR images were associated with early recurrence of ischemic lesions in patients with lesion-negative TIA. This study selected 867 patients diagnosed with TIA within 24 hours of symptom onset who had been treated at two large centers in Seoul, Korea, between January 2010 and December 2015. All patients with TIA underwent brain MRI, MRA, echocardiography, and laboratory examinations within 24 hours of admission. Follow-up brain MRI was conducted during the acute phase of TIA for patients without contraindications. Kaplan-Meier and Cox regression analyses were used to compare the clinical outcomes at the 1-year follow-up between the FU-DWI (+) and FU-DWI (−) groups. Ipsilateral FLAIR vascular hyperintensity (FVH) was identified as an independent predictor of lesions on follow-up diffusion weighted images (FU-DWI [+]) in patients with lesion-negative TIA. Previous studies have indicated that early recurrence of ischemic lesions identified via MRI is associated with poor prognosis in patients with both TIA and mild ischemic stroke. This study suggests that FLAIR vascular hyperintensity can be used as a predictor of FU-DWI (+) in patients with isolated, lesion-negative TIA.

3 Figures and 2 Tables, but no MR images.

Sweeney MD, Sagare AP, Zlokovic B V. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14(3):133-150. doi:10.1038/nrneurol.2017.188.

In this long and extensive Review (256 references), the authors first briefly describe the molecular architecture and transport physiology of the BBB and then examine vascular pathology and neuroimaging, post-mortem and biomarker studies demonstrating BBB breakdown in several neurodegenerative diseases: Alzheimer disease (AD); Parkinson disease (PD); Huntington disease (HD); amyotrophic lateral sclerosis (ALS); and multiple sclerosis (MS), which is considered to be an autoimmune and neurodegenerative disorder, in addition to HIV‑1‑associated dementia and chronic traumatic encephalopathy (CTE). They focus on the pathogenetic mechanisms by which BBB breakdown leads to neurodegeneration and briefly note the implications of BBB dysfunction for therapeutic drug delivery. They also discuss future directions, gaps in the field and opportunities to control neurological disease by targeting the BBB.

Fun facts for the day: The human brain contains ~644 km of blood vessels that supply brain cells with oxygen, energy metabolites and nutrients and remove carbon dioxide and other metabolic waste products from the brain to the systemic circulation. Although representing only 2% of total body mass, the brain consumes ~20% of the body’s glucose and oxygen. Capillaries account for approximately 85% of cerebral vessel length and are a major site of the blood–brain barrier. In the human brain, capillaries provide approximately 12 m2 of endothelial cell surface area, which is available for transport of solutes from the blood to the brain and vice versa.

DCE-MRI studies have found increased BBB leakage of Gd in the basal ganglia in patients with PD compared with healthy controls. In patients with Huntington disease, DCE-MRI analysis reveals a positive correlation between increased BBB permeability in the caudate nucleus and increased disease burden score as well as with increased grey matter arterial cerebral blood volume. DCE-MRI studies have similarly established the presence of increased BBB permeability in white matter in MS, particularly in active MS lesions. To understand the pathogenetic role of BBB breakdown in the living human brain, future longitudinal DCE MRI studies are required to investigate the relationships between vascular changes, progression of neurological deficits in AD, PD, HD and MS and changes in brain structural and functional connectivity. Extending DCE MRI studies to patients with ALS, HIV‑1‑associated dementia and CTE will help identify whether regional BBB breakdown has a pathogenetic role in these neurodegenerative disorders. Damage to blood vessels can lead to pronounced BBB breakdown manifested as cerebral microbleeds which are frequently seen in AD, MCI and in APOE*ε4‑positive individuals (who have an increased genetic risk of AD). CAA is one of the main causes of vascular degeneration and lobar microbleeds in AD and contributes to BBB breakdown, infarcts, white matter changes and cognitive impairment. Microbleed location is related to its etiology: CAA causes lobar microbleeds, and hypertensive vasculopathy causes microbleeds in the basal ganglia, thalamus, cerebellum and brainstem. Microbleeds in AD are predominantly lobar (similar to CAA-associated microbleeds) and are mainly found in the occipital lobe. Cerebral microbleeds have been detected throughout deep grey matter regions (including the caudate, thalamus, putamen and globus pallidus), cortical regions and white matter in patients with PD by T2*-weighted and SWI-MRI. The incidence of microbleeds is higher in patients with PD dementia than in either PD patients without dementia or controls and is associated with the extent of white matter lesions.

4 Figures.

Bradbury LA, Hollis KA, Gautier B, et al. Diffusion-weighted Imaging Is a Sensitive and Specific Magnetic Resonance Sequence in the Diagnosis of Ankylosing Spondylitis. J Rheumatol. February 2018:jrheum.170312. doi:10.3899/jrheum.170312.

Disease activity measurement in AS is challenging. Currently the main approaches are to use patient self-completed questionnaires [such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)], blood tests [such as erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP)], and combinations of questionnaires and blood tests [such as the Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP and ASDAS-ESR]. Patient self-completed questionnaires such as these are subjective and influenced by variation such as patient reporter biases, coexistent fibromyalgia, and concomitant medicines such as analgesics; they were not developed for use in assessing patients with noninflammatory back pain. In the current study they investigated the discriminatory capacity of DWI in comparison with standard classification criteria for axSpA, and assessed its usefulness as an objective measure of disease activity both cross-sectionally and longitudinally in response to treatment with the TNFi adalimumab, in comparison with standard clinical measures used for treatment response assessment.

Three cohorts were studied prospectively: (1) 18 AS patients with Bath Ankylosing Spondylitis Disease Activity Index > 4, and erythrocyte sedimentation rate > 25 and/or C-reactive protein > 10 meeting the modified New York criteria for AS; (2) 20 cases of nonradiographic axial spondyloarthritis (nr-axSpA) as defined by the Assessment of Spondyloarthritis international Society (ASAS) criteria; and (3) 20 non-AS patients with chronic low back pain, aged between 18 and 45 years, who did not meet the imaging arm of the ASAS criteria for axSpA. Group 1 patients were studied prior to and following adalimumab treatment. Patients were assessed by DWI and conventional magnetic resonance imaging (MRI), and standard nonimaging measures.

At baseline, in contrast to standard nonimaging measures, DWI apparent diffusion coefficient (ADC) values showed good discriminatory performance [area under the curve (AUC) > 80% for Group 1 or 2 compared with Group 3]. They conclude that DWI is informative for diagnosis of AS and nonradiographic axial spondyloarthritis and has moderate utility in assessment of disease activity or treatment response, with performance similar to that of the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI score.

1 Figure, 5 Tables (no MR images)

Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018;378(7):625-635. doi:10.1056/NEJMoa1710504.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is characterized by atrophy and weakness of the skeletal muscles of the limbs and trunk and of the bulbar and respiratory muscles. It is caused by homozygous deletions or loss-of-function mutations in the gene encoding survival motor neuron 1 (SMN1) at locus 5q13, which result in insufficient expression of the survival motor neuron (SMN) protein.

A paralogous gene (paralogs are homologous genes that have evolved by duplication and code for protein with similar, but not identical functions), SMN2, also encodes the SMN protein, but the level of functional full-length SMN protein produced by SMN2 is only 5-10% of the level produced by SMN1. Nusinersen (new-sin-ER-sen)(marketed as Spinraza) is a modified antisense oligonucleotide drug that resists nucleases and binds to a specific sequence within the SMN2 pre–messenger RNA, thereby modifying the splicing of the SMN2 pre–messenger RNA to promote the expression of full-length SMN protein.

In this study, the authors conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least squares mean change from baseline in the Hammersmith Functional Motor Scale– Expanded (HFMSE) score at 15 months of treatment.

In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points, and the overall incidence of adverse events was similar. They conclude that among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group.

2 Figures, 3 Tables (no images)

See also:

Mendell, J. R., Al-Zaidy, S., Shell, R., Arnold, W. D., Rodino-Klapac, L. R., Prior, T. W., … Kaspar, B. K. (2017). Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. New England Journal of Medicine, 377(18), 1713–1722. https://doi.org/10.1056/NEJMoa1706198

Finkel, R. S., Mercuri, E., Darras, B. T., Connolly, A. M., Kuntz, N. L., Kirschner, J., … De Vivo, D. C. (2017). Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. New England Journal of Medicine, 377(18), 1723–1732. https://doi.org/10.1056/NEJMoa1702752

Walsh RR, Krismer F, Galpern WR, et al. Recommendations of the Global Multiple System Atrophy Research Roadmap Meeting. Neurology. 2018;90(2):74-82. doi:10.1212/WNL.0000000000004798.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals.

Imaging biomarker recommendations include:

  1. Develop standardized protocols for MRI-based diagnostics at conventional field strengths and explore sensitivity of multimodal approach (e.g PET/MRI) to disease progression and preclinical diagnosis.
  2. Develop multicenter task force to explore, assess, and implement functional imaging protocols with currently available tracers to evaluate MSA-related brain networks and dopaminergic integrity using existing PET and SPECT tracers.
  3. Develop sensitive and replicable imaging agents to assess molecular aspects of MSA pathology including synuclein aggregation and local CNS inflammatory activity in the brains of MSA patients.

2 Figures, 1 Table (no images)

Nawrocki T, Maldjian PD, Slasky SE, Contractor SG. Artificial Intelligence and Radiology: Have Rumors of the Radiologist’s Demise Been Greatly Exaggerated? Acad Radiol. 2018;(3):1-6. doi:10.1016/j.acra.2017.12.027.

To summarize: yes, they have been greatly exaggerated. The authors put forth several significant barriers to the widespread use of all-encompassing image interpretation with AI:

Machine learning has been successful with small images, and preliminary studies using machine learning on radiographic images have produced results limited to specific narrow tasks, such as differentiation of normal from abnormal chest radiographs in cases of tuberculosis. Application to more advanced imaging modalities, such as CT and MRI (with potentially hundreds of images per case), would require far more complex image processing and remains untested. As opposed to simple two-dimensional images, artificial intelligence will face formidable challenges when interpreting three-dimensional grayscale data where lesions are often subtle and the ranges for differential diagnosis are wider.

The authors note that mammographic CAD, which has been in existence for nearly 20 years, is the only machine learning application that is widely used in clinical diagnostic imaging at this time. Although CAD is being used extensively for mammographic interpretations, the ability of CAD to improve cancer detection rates remains controversial. When there is a difference of interpretation between the mammographer and the CAD system, only 2% of mammographers change their initial opinion, 36% sometimes change their opinion, and 62% rarely or never change their opinion.

A lack of large and well-annotated datasets for training artificial intelligence algorithms is a key obstacle to the use of these algorithms in medical imaging. Access to vast quantities of patient data and medical images is needed to provide educational material to the artificial intelligence software programs so the computer programs can “learn” to recognize abnormalities. Replacing radiologists will require thousands of well-functioning “narrow” algorithms, each of which is going to require a validated database that will require large capital investments. Additionally, it can be expected that different vendors would supply software for narrow applications using different systems that would not necessarily be compatible.

Regulatory approval allowing machines to do the work of trained radiologists is another major obstacle. The amount of testing and effort necessary to secure clearance from the U.S. Food and Drug Administration (FDA) for allowing machines to provide primary interpretations of imaging studies without a radiologist would be overwhelming.

The “black box” aspect of deep learning is also very much counter to the FDA’s requirements for documentation of the development process. In some cases, even the designers do not completely understand how deep learning algorithms are processing the data. The black box nature and the rapid growth of machine learning applications will make it difficult for the FDA to approve these applications in a timely fashion, given the volume and the complex nature of testing and verification involved.

They conclude that this technology, working alongside the radiologist, has the potential to improve accuracy, safety, efficiency, and productivity, particularly in terms of applications outside of image interpretation per se (radiomics, volume measurements).

5 Figures

Zalewski NL, Flanagan EP, Keegan BM. Evaluation of idiopathic transverse myelitis revealing specific myelopathy diagnoses. Neurology. 2018;90(2):e96-e102. doi:10.1212/WNL.0000000000004796.

The authors purpose was to evaluate specific myelopathy diagnoses made in patients with suspected idiopathic transverse myelitis (ITM).

A total of 226 patients 18 years and older were referred to Mayo Clinic Neurology for suspected ITM from December 1, 2010, to December 31, 2015. Electronic medical records were reviewed for detailed clinical presentation and course, laboratory and electrophysiologic investigations, and neuroimaging to determine the etiology. Current diagnostic criteria for ITM and alternative myelopathy diagnoses were applied. The diagnostic criteria for ITM were met in 41 of 226 patients (18.1%). In 158 patients (69.9%), an alternative specific myelopathy diagnosis was made: multiple sclerosis or clinically isolated syndrome, 75; vascular myelopathy, 41; neurosarcoidosis, 12; neuromyelitis optica spectrum disorder, 12; myelin oligodendrocyte glycoprotein myelopathy, 5; neoplastic, 4; compressive, 3; nutritional, 3; infectious, 2; and other, 2. A myelopathy was not confirmed in 27 patients. Time from symptom onset to final clinical diagnosis in patients without ITM was a median of 9 months.

This study demonstrates that most patients referred for evaluation of ITM do not meet the published diagnostic criteria for ITM and many are diagnosed with an alternative specific myelopathy.

The criteria are based on timing of clinical onset and progression to nadir, CSF abnormalities, and MRI features of gadolinium enhancement. Some patients in the study were referred with ITM despite time to nadir being faster than 4 hours or longer than 21 days. CSF pleocytosis and elevated IgG index or oligoclonal bands are nonspecific findings that occur in specific alternative myelopathy etiologies, characteristically MS, but also other inflammatory and noninflammatory myelopathies. Spinal cord MRI gadolinium enhancement occurs in many inflammatory and neoplastic causes of myelopathy and is increasingly recognized in noninflammatory etiologies including DAVF and spinal cord compression. The criteria do not acknowledge that particular patterns of MRI gadolinium enhancement and T2 hyperintensity may highly suggest a specific etiology.

Four Figures, 1 Table.

Matsuyama Y, Chiba K, Iwata H, Seo T, Toyama Y. A multicenter, randomized, double-blind, dose-finding study of condoliase in patients with lumbar disc herniation. J Neurosurg Spine. February 2018:1-13. doi:10.3171/2017.7.SPINE161327.

Chemonucleolysis involves the injection of an enzyme into the intervertebral disc to dissolve the nucleus pulposus, thereby reducing intradiscal pressure on the nerve root and improving LDH symptoms. This treatment is considered an intermediate treatment for LDH and falls between conservative treatment and surgical treatment. Condoliase (chondroitin sulfate ABC endolyase) is a pure mucopolysaccharidase derived from the gram-negative rod Proteus vulgaris. Condoliase has high substrate specificity for chondroitin sulfate and hyaluronic acid, which are glycosaminoglycans on proteoglycans that are abundant in the nucleus pulposus of the intervertebral disc, and lacks protease activity. Therefore, condoliase has the potential to become a safe and effective chemonucleolysis drug.

All eligible patients were randomly assigned to receive condoliase (1.25, 2.5, or 5 U) or placebo. The primary end point was a change in the worst leg pain from preadministration (baseline) to week 13. The secondary end points were changes from baseline in the following items: worst back pain, Oswestry Disability Index (ODI), SF-36, and neurological examination.

A total of 194 patients received an injection of condoliase or placebo. The mean change in worst leg pain from baseline to week 13 was -31.7 mm (placebo), -46.7 mm (1.25 U), -41.1 mm (2.5 U), and -47.6 mm (5 U). The differences were significant at week 13 in the 1.25-U group (-14.9 mm) and 5-U group (-15.9 mm) compared with the placebo group.

Back pain was the most common AE in the condoliase groups, with an incidence of 26.5% to 36.7%, and occurred within 1 week of administration in most cases and resolved within 1 month. Severity was mild to moderate in all patients. Allergy-like symptoms were observed in 4 patients in the condoliase groups. All 4 AEs were moderate, occurred within 2 days of administration, and resolved after drug treatment. Modic type 1 change and decrease in disc height were frequent imaging findings.

They conclude that condoliase significantly improved clinical symptoms in patients with LDH and was well tolerated. While all 3 doses had similar efficacy, the incidence of adverse drug reactions and decrease in disc height were dose dependent, thereby suggesting that 1.25 U would be the recommended clinical dose of condoliase.

6 Figures, 4 Tables.

Journal Scan – This Month in Other Journals, May 2018
Jeffrey Ross
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