Have clinicians adopted the use of brain MRI for patients with TIA and minor stroke?

Background: Use of MRI with diffusion-weighted imaging (DWI) can identify infarcts in 30%–50% of patients with TIA. Previous guidelines have indicated that MRI-DWI is the preferred imaging modality for patients with TIA. We assessed the frequency of MRI utilization and predictors of MRI performance.

Methods: A review of TIA and minor stroke patients evaluated at Veterans Affairs hospitals was conducted with regard to medical history, use of diagnostic imaging within 2 days of presentation, and in-hospital care variables. Chart abstraction was performed in a subset of hospitals to assess clinical variables not available in the administrative data.

Results: A total of 7,889 patients with TIA/minor stroke were included. Overall, 6,694 patients (84.9%) had CT or MRI, with 3,396/6,694 (50.7%) having MRI. Variables that were associated with increased odds of CT performance were age >80 years, prior stroke, history of atrial fibrillation, heart failure, coronary artery disease, anxiety, and low hospital complexity, while blood pressure >140/90 mm Hg and high hospital complexity were associated with increased likelihood of MRI. Diplopia (87% had MRI, p = 0.03), neurologic consultation on the day of presentation (73% had MRI, p < 0.0001), and symptom duration of >6 hours (74% had MRI, p = 0.0009) were associated with MRI performance.

Conclusions: Within a national health system, about 40% of patients with TIA/minor stroke had MRI performed within 2 days. Performance of MRI appeared to be influenced by several patient and facility-level variables, suggesting that there has been partial acceptance of the previous guideline that endorsed MRI for patients with TIA.

Neurology 2016

Endovascular treatment improves cognition after stroke A secondary analysis of REVASCAT trial

Objective: To investigate the effect of endovascular treatment on cognitive function as a prespecified secondary analysis of the REVASCAT (Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours) trial.

Methods: REVASCAT randomized 206 patients with anterior circulation proximal arterial occlusion stroke to Solitaire thrombectomy or best medical treatment alone. Patients with established dementia were excluded from enrollment. Cognitive function was assessed in person with Trail Making Test (TMT) Parts A and B at 3 months and 1 year after randomization by an investigator masked to treatment allocation. Test completion within 5 minutes, time of completion (seconds), and number of errors were recorded.

Results: From November 2012 to December 2014, 206 patients were enrolled in REVASCAT. TMT was assessed in 82 of 84 patients undergoing thrombectomy and 86 of 87 control patients alive at 3 months and in 71 of 79 patients undergoing thrombectomy and 72 of 78 control patients alive at 1 year. Rates of timely TMT-A completion were similar in both treatment arms, although patients undergoing thrombectomy required less time for TMT-A completion and had higher rates of error-free TMT-A performance. Thrombectomy was also associated with a higher probability of timely TMT-B completion (adjusted odds ratio 3.17, 95% confidence interval 1.51–6.66 at 3 months; and adjusted ratio 3.66, 95% confidence interval 1.60–8.35 at 1 year) and shorter time for TMT-B completion. Differences in TMT completion times between treatment arms were significant in patients with good functional outcome but not in those who were functionally dependent (modified Rankin Scale score >2). Poorer cognitive outcomes were significantly associated with larger infarct volume, higher modified Rankin Scale scores, and worse quality of life.

Conclusions: Thrombectomy improves TMT performance after stroke, especially among patients who reach good functional recovery.

Neurology 2016

Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB

Objective: To conduct a validation study of ¹²³I-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (¹²³I-FP-CIT) SPECT dopaminergic imaging in the clinical diagnosis of dementia with Lewy bodies (DLB) with autopsy as the gold standard.

Methods: Patients >60 years of age with dementia who had undergone ¹²³I-FP-CIT imaging in research studies and who had donated their brain tissue to the Newcastle Brain Tissue Resource were included. All had structured clinical research assessments, and clinical diagnoses were applied by consensus panels using international diagnostic criteria. All underwent ¹²³I-FP-CIT imaging at baseline, and scans were rated as normal or abnormal by blinded raters. Patients were reviewed in prospective studies and after death underwent detailed autopsy assessment, and neuropathologic diagnoses were applied with the use of standard international criteria.

Results: Fifty-five patients (33 with DLB and 22 with Alzheimer disease) were included. Against autopsy diagnosis, ¹²³I-FP-CIT had a balanced diagnostic accuracy of 86% (sensitivity 80%, specificity 92%) compared with clinical diagnosis, which had an accuracy of 79% (sensitivity 87%, specificity 72%). Among patients with DLB, 10% (3 patients) met pathologic criteria for Lewy body disease but had normal ¹²³I-FP-CIT imaging.

Conclusions: This large autopsy analysis of ¹²³I-FP-CIT imaging in dementia demonstrates that it is a valid and accurate biomarker for DLB, and the high specificity compared with clinical diagnosis (20% higher) is clinically important. The results need to be replicated with patients recruited from a wider range of settings, including movement disorder clinics and general practice. While an abnormal ¹²³I-FP-CIT scan strongly supports Lewy body disease, a normal scan does not exclude DLB with minimal brainstem involvement.

Classification of evidence: This study provides Class I evidence that ¹²³I-FP-CIT dopaminergic neuroimaging accurately identifies patients with DLB.

Neurology 2016

Antiepileptic drugs and hyponatremia in older adults: Two population-based cohort studies

Summary

Objective

To examine the 30-day risk of hospitalization with hyponatremia associated with carbamazepine, valproic acid (V), phenytoin (P), or topiramate (T) use compared to nonuse in the outpatient setting among older adults.

Methods

We conducted two population-based, retrospective cohort studies in Ontario, Canada, between 2003 and 2015 using administrative health care databases of older adults. The first study compared carbamazepine users to a propensity-score matched group of antiepileptic drug nonusers, whereas the second compared V-P-T users to a propensity-score matched group of antiepileptic nonusers. The primary outcome was hospitalization with hyponatremia within 30 days of an antiepileptic prescription.

Results

The baseline characteristics between matched groups were similar in both cohorts. Carbamazepine use versus nonuse was associated with a higher 30-day risk of hospitalization with hyponatremia (82/21,191 [0.39%] versus 30/63,573 [0.05%]; relative risk [RR] 8.20, 95% confidence interval [CI] 5.40–12.46). Similarly, V-P-T use versus nonuse was associated with a higher 30-day risk of hospitalization with hyponatremia (34/20,155 [0.17%] versus 26/40,310 [0.06%]; RR 2.62, 95% CI 1.57–4.36).

Significance

Older adults prescribed carbamazepine and V-P-T have a higher risk of being hospitalized with hyponatremia compared to other adults with similar indicators of baseline health who were not prescribed antiepileptic drugs. Physicians should be mindful of this risk; when a patient presents to a hospital with symptomatic hyponatremia these drugs should be considered as potential causes.

Epilepsia 2016

Use of Magnetic Resonance Imaging to Visualize Leptomeningeal Inflammation in Patients With Multiple Sclerosis A Review

Abstract

Importance  Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system traditionally characterized by an initial relapsing-remitting clinical course and focal inflammatory lesions that have a predilection for the periventricular white matter. Recently, however, histopathologic and imaging studies have illustrated a more complex pathologic substrate involving cortical demyelination, gray matter atrophy, and meningeal inflammation. Neuroimaging advances have facilitated improved detection of cortical pathology, but our understanding of the pathogenesis of cortical disease remains incomplete. The purpose of this review is to evaluate the current status and future prospects regarding the emerging role of magnetic resonance imaging to visualize leptomeningeal enhancement in patients with MS and place these findings in the proper pathobiologic and clinical context.

Observations  Cortical atrophy and demyelination along the subpial surface appear early in the disease course in patients with MS but accelerate in progressive stages. Histopathologic studies of patients have shown the presence of inflammatory infiltrates, in some cases with features of B cell–rich tertiary lymph follicles, along the cortical meningeal surface. Recent magnetic resonance imaging data demonstrate the ability to detect such inflammation using high-resolution gadolinium-enhanced contrast scans by the presence of leptomeningeal enhancement. Clinical and magnetic resonance imaging correlation studies indicate that leptomeningeal enhancement is most common in patients with progressive forms of MS and shows a relationship to subpial cortical lesions and cortical atrophy.

Conclusions and Relevance  A growing body of evidence suggests that gray matter demyelination, cortical atrophy, and leptomeningeal inflammation may be important components of progressive MS pathology and provide a new therapeutic target. Leptomeningeal enhancement may prove a useful surrogate marker for such pathology, perhaps improving our understanding of the natural history of progressive MS, although its ultimate effect on therapeutic development and clinical care requires further study.

JAMA Neurology 2016

Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains

Abstract

Importance  Cognitive impairment and dementia, including Alzheimer disease (AD), are common within the aging population, yet the factors that render the aging brain vulnerable to these processes are unknown. Perivascular localization of aquaporin-4 (AQP4) facilitates the clearance of interstitial solutes, including amyloid-β, through the brainwide network of perivascular pathways termed the glymphatic system, which may be compromised in the aging brain.

Objectives  To determine whether alterations in AQP4 expression or loss of perivascular AQP4 localization are features of the aging human brain and to define their association with AD pathology.

Design, Setting, and Participants  Expression of AQP4 was analyzed in postmortem frontal cortex of cognitively healthy and histopathologically confirmed individuals with AD by Western blot or immunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidic protein. Postmortem tissue and clinical data were provided by the Oregon Health and Science University Layton Aging and Alzheimer Disease Center and Oregon Brain Bank. Postmortem tissue from 79 individuals was evaluated, including cognitively intact “young” individuals aged younger than 60 years (range, 33-57 years), cognitively intact “aged” individuals aged older than 60 years (range, 61-96 years) with no known neurological disease, and individuals older than 60 years (range, 61-105 years) of age with a clinical history of AD confirmed by histopathological evaluation. Forty-eight patient samples (10 young, 20 aged, and 18 with AD) underwent histological analysis. Sixty patient samples underwent Western blot analysis (15 young, 24 aged, and 21 with AD).

Main Outcomes and Measures  Expression of AQP4 protein, AQP4 immunoreactivity, and perivascular AQP4 localization in the frontal cortex were evaluated.

Results  Expression of AQP4 was associated with advancing age among all individuals (R² = 0.17; P = .003). Perivascular AQP4 localization was significantly associated with AD status independent of age (OR, 11.7 per 10% increase in localization; z = −2.89; P = .004) and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden (R² = 0.15; P = .003) and increasing Braak stage (R² = 0.14; P = .006).

Conclusions and Relevance  In this study, altered AQP4 expression was associated with aging brains. Loss of perivascular AQP4 localization may be a factor that renders the aging brain vulnerable to the misaggregation of proteins, such as amyloid-β, in neurodegenerative conditions such as AD.

JAMA Neurology 2016

Imaging of Glial Cell Activation and White Matter Integrity in Brains of Active and Recently Retired National Football League Players

Abstract

Importance  Microglia, the resident immune cells of the central nervous system, play an important role in the brain’s response to injury and neurodegenerative processes. It has been proposed that prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury.

Objective  To measure translocator protein 18 kDa (TSPO), a marker of activated glial cell response, in a cohort of National Football League (NFL) players and control participants, and to report measures of white matter integrity.

Design, Setting, and Participants  This cross-sectional, case-control study included young active (n = 4) or former (n = 10) NFL players recruited from across the United States, and 16 age-, sex-, highest educational level–, and body mass index–matched control participants. This study was conducted at an academic research institution in Baltimore, Maryland, from January 29, 2015, to February 18, 2016.

Main Outcomes and Measures  Positron emission tomography–based regional measures of TSPO using [¹¹C]DPA-713, diffusion tensor imaging measures of regional white matter integrity, regional volumes on structural magnetic resonance imaging, and neuropsychological performance.

Results  The mean (SD) ages of the 14 NFL participants and 16 control participants were 31.3 (6.1) years and 27.6 (4.9) years, respectively. Players reported a mean (SD) of 7.0 (6.4) years (range, 1-21 years) since the last self-reported concussion. Using [¹¹C]DPA-713 positron emission tomographic data from 12 active or former NFL players and 11 matched control participants, the NFL players showed higher total distribution volume in 8 of the 12 brain regions examined (P < .004). We also observed limited change in white matter fractional anisotropy and mean diffusivity in 13 players compared with 15 control participants. In contrast, these young players did not differ from control participants in regional brain volumes or in neuropsychological performance.

Conclusions and Relevance  The results suggest that localized brain injury and repair, indicated by higher TSPO signal and white matter changes, may be associated with NFL play. Further study is needed to confirm these findings and to determine whether TSPO signal and white matter changes in young NFL athletes are related to later onset of neuropsychiatric symptoms.

JAMA Neurology 2016