S. Andrew Josephson

National Stroke Association guidelines for the management of transient ischemic attacks

Transient ischemic attacks are common and important harbingers of subsequent stroke. Management varies widely, and most published guidelines have not been updated in several years. We sought to create comprehensive, unbiased, evidence‐based guidelines for the management of patients with transient ischemic attacks.

Intermittent Atrial Fibrillation May Account for a Large Proportion of Otherwise Cryptogenic Stroke: A Study of 30-Day Cardiac Event Monitors

INTRODUCTION Despite extensive inpatient workup including telemetry monitoring, a significant proportion of stroke is classified as cryptogenic at hospital discharge. It is possible that a significant proportion of cryptogenic stroke is a result of intermittent atrial fibrillation (AF). Thirty-day cardiac event monitors (30-DEM) may increase the rate of AF detection compared with standard investigations that include a combination of electrocardiography, cardiac telemetry, and short-term Holter monitoring. METHODS Charts were reviewed of patients who were admitted to a university stroke center or who were evaluated in the outpatient clinic during a 9-month period to determine whether the cause of stroke was cryptogenic. As a matter of protocol, such patients typically underwent 30-DEM and the results of such monitoring were documented along with the duration of inpatient cardiac monitoring if relevant. RESULTS In all, 218 patients with a diagnosis of ischemic stroke or transient ischemic attack were identified. Of the strokes, 36 (16.5%) were classified as cryptogenic. Twenty patients with cryptogenic stroke or transient ischemic attack were evaluated with 30-DEM. Four (20%) were found to have AF, and all 4 patients were treated with warfarin. CONCLUSION The 30-DEM changed the medical treatment of 20% of patients with otherwise cryptogenic stroke because of the detection of intermittent AF despite no detection of AF on electrocardiography and inpatient telemetry monitoring in the majority of patients. Further prospective studies of extended cardiac event monitors in the setting of cryptogenic stroke are warranted.

Protein Biomarker Identification in the CSF of Patients With CNS Lymphoma

PURPOSE Elucidation of the CSF proteome may yield insights into the pathogenesis of CNS disease. We tested the hypothesis that individual CSF proteins distinguish CNS lymphoma from benign focal brain lesions. METHODS We used a liquid chromatography/mass spectrometry-based method to differentially quantify and identify several hundred CSF proteins in CNS lymphoma and control patients. We used enzyme-linked immunosorbent assay (ELISA) to confirm one of these markers in an additional validation set of 101 cases. RESULTS Approximately 80 CSF proteins were identified and found to be present at significantly different concentrations, both higher and lower, in training and test studies, which were highly concordant. To further validate these observations, we defined in detail the expression of one of these candidate biomarkers, antithrombin III (ATIII). ATIII RNA transcripts were identified within CNS lymphomas, and ATIII protein was localized selectively to tumor neovasculature. Determination of ATIII concentration by ELISA was significantly more accurate (> 75% sensitivity; > 98% specificity) than cytology in the identification of cancer. Measurement of CSF ATIII levels was found to potentially enhance the ability to diagnose and predict outcome. CONCLUSION Our findings demonstrate for the first time that proteomic analysis of CSF yields individual biomarkers with greater sensitivity in the identification of cancer than does CSF cytology. We propose that the discovery of CSF protein biomarkers will facilitate early and noninvasive diagnosis in patients with lesions not amenable to brain biopsy, as well as provide improved surrogates of prognosis and treatment response in CNS lymphoma and brain metastasis.

Subcortical Lacunes Are Associated With Executive Dysfunction in Cognitively Normal Elderly

Background and Purpose— The relationship between subcortical ischemic vascular disease (SIVD) and cognition in normal elderly is unclear, in part because of methodological inconsistencies across studies. To clarify this relationship, the current study investigated a well characterized cognitively normal elderly sample (≥55 years) with quantitative MRI and psychometrically robust neuropsychological measures within a multivariate model. Converging evidence suggests that SIVD selectively impairs frontal-executive tasks by disrupting frontal-subcortical circuits. We therefore hypothesized that MRI markers of SIVD would be selectively associated with worse executive functioning. Methods— We studied 94 participants who were cognitively and functionally normal. Volumetric measures of white matter signal hyperintensity (WMH), subcortical lacunes, hippocampal volume, and cortical gray matter were obtained to predict performance on composite measures of executive functioning and episodic memory. Results— Hierarchical regression demonstrated that after controlling for demographic variables, MMSE, and total intracranial volume, the total number of subcortical lacunes was the only significant predictor, with a greater number of lacunes associated with poorer executive performance. Hippocampal volume best predicted episodic memory performance. Conclusions— Results suggest that SIVD in the form of silent lacunes corresponds to poorer executive functioning even in otherwise normal elderly, which is consistent with the hypothesis that SIVD preferentially disrupts frontal-subcortical circuits. The clinical importance of these findings is highlighted by the fact that 33% of the normal elderly participants in this study had lacunar infarcts.

Higher ABCD2 Score Predicts Patients Most Likely to Have True Transient Ischemic Attack

Background and Purpose— Some patients diagnosed with transient ischemic attack (TIA) in the emergency department may actually have alternative diagnoses such as seizure, migraine, or other nonvascular spells. The ABCD2 score has been shown to predict subsequent risk of stroke in patients with TIA diagnosed by emergency physicians, but perhaps high ABCD2 scores simply separate those patients with true TIA from those with alternative diagnoses. We investigated this hypothesis in a cohort of patients with TIA identified in the emergency department whose records were reviewed by an expert neurologist. Methods— Among patients diagnosed by emergency physicians with TIA in 16 hospitals in the Kaiser-Permanente Medical Care Plan over a 1-year period ending February 1998 (before publication of prediction rules), an expert neurologist reviewed all records for those in which the diagnosis of TIA was considered questionable by a medical records analyst and determined whether the spell was likely to represent a true TIA. Subsequent strokes within 90 days were identified. ABCD2 scores were calculated for all patients and 2-sided Cochrane-Armitage trend tests were used to assess subsequent risk of stroke. Results— Of the 713 patients reviewed by the expert neurologist, 642 (90%) were judged to likely have experienced a true TIA. Ninety-day stroke risk was 24% (95% CI, 20% to 27%) in the group judged to have experienced a true TIA and 1.4% (0% to 7.6%) in the group judged to not have a true TIA (P<0.0001). ABCD2 scores were higher in those judged to have a true TIA compared with others (P=0.0001). In the group judged to have a true TIA, 90-day stroke risk increased as ABCD2 score increased (P<0.0001); there was no relationship between ABCD2 score and stroke risk in those judged unlikely to have had a TIA (P=0.73). Conclusions— Among patients diagnosed by emergency department physicians with TIA, higher ABCD2 score was associated with a greater likelihood that the diagnosis was confirmed on expert review. The predictive power of the ABCD2 model is therefore partially explained by identification of those patients likely to have experienced a true TIA, an important aspect of the score when used by nonneurologists. However, higher ABCD2 scores still remained predictive of 90-day stroke rate in the group of patients judged to have a true TIA by an expert neurologist.

Incidence of contrast nephropathy from cerebral CT angiography and CT perfusion imaging

The incidence of contrast-induced nephropathy was examined in 1,075 patients receiving routine CT angiography and CT perfusion brain imaging at a single institution. Fifty-two patients had a creatinine rise of ≥0.5 mg/dL. In four patients (0.37%), the administration of IV contrast medium possibly contributed to renal failure. Two patients (0.19%) received temporary hemodialysis during hospitalization. The incidence of contrast nephropathy in neurovascular patients is low.

CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma

Establishing the diagnosis of focal brain lesions in patients with unexplained neurologic symptoms represents a challenge. The goal of this study is to provide evidence supporting functional roles for CXC chemokine ligand (CXCL)13 and interleukin (IL)-10 in central nervous system (CNS) lymphomas and to evaluate the utility of each as prognostic and diagnostic biomarkers. We demonstrate for the first time that elevated CXCL13 concentration in cerebrospinal fluid (CSF) is prognostic and that CXCL13 and CXCL12 mediate chemotaxis of lymphoma cells isolated from CNS lymphoma lesions. Expression of the activated form of Janus kinase 1 supported a role for IL-10 in prosurvival signaling. We determined the concentration of CXCL13 and IL-10 in CSF of CNS lymphoma patients and control cohorts including inflammatory and degenerative neurologic disease in a multicenter study involving 220 patients. Bivariate elevated CXCL13 plus IL-10 was 99.3% specific for primary and secondary CNS lymphoma, with sensitivity significantly greater than reference standard CSF tests. These results identify CXCL13 and IL-10 as potentially important biomarkers of CNS lymphoma that merit further evaluation and support incorporation of CXCL13 and IL-10 into diagnostic algorithms for the workup of focal brain lesions in which lymphoma is a consideration.

NIH Stroke Scale Reliability in Ratings from a Large Sample of Clinicians

Objective: The NIH Stroke Scale (NIHSS) is widely used in stroke clinical care and trials. Certification in its use, most commonly through rating of video vignettes, is routinely required. To investigate the reliability of the NIHSS in a representative sample of raters, we examined the results of the most frequently used certification examination. Methods: At the invitation of the National Stroke Association, we analyzed the results of all raters who completed one of two multiple patient videotaped certification examinations from 1998 to 2004. Total scores for each vignette were calculated and ratings were compared based on percentile of responses and modified kappa scores. Results: There were 7,405 unique raters with 38,148 individual NIHSS item responses; median scores for each vignette ranged from 0 to 31. Total NIHSS scores varied widely between raters; scoring for 7 of the 11 patients (64%) had a four or more point difference in NIHSS score from the 5th to 95th percentile. The aphasia (kappa = 0.60) and facial palsy (0.65) items on the test contributed most to the variance in the total NIHSS score. Nurses agreed with the most common response on scoring more frequently than physicians (p < 0.0001). Taking the certification examination multiple times did not improve agreement. Conclusions: In a large diverse sample of clinicians, inter-rater reliability for individual elements of the NIHSS on videotaped vignettes was generally good, but overall scoring was inconsistent and could impact clinical trial results. Whether additional training, modification of examination elements, or clearer definitions for scoring could improve reliability requires further study.

Urinary Tract Infections Complicating Stroke Mechanisms, Consequences, and Possible Solutions

Background and Purpose— Hospital-acquired urinary tract infection (UTI) is a common complication in hospitalized patients. Recently, catheter-associated UTI has been identified by the Centers for Medicare and Medicaid Services as a preventable condition, and additional payments to hospitals for its treatment are now declined, increasing the need for prevention of this important complication. Summary of Review— This article explores in-depth the pathophysiology, risk factors for, and consequences of UTI after stroke and possible methods to reduce its incidence in the stroke population. Patients with stroke are particularly vulnerable to UTI due to increased risk from immunosuppression, bladder dysfunction, and increased Foley catheter use; and the fever and systemic inflammatory response associated with UTI may impair stroke recovery. UTI is associated with poorer neurological outcomes, longer hospital stays, and increased cost of care after stroke. Intervention strategies previously attempted in this and other populations include prophylactic antibiotics, antiseptic-impregnated catheters, and quality improvement interventions to reduce inappropriate catheterization. Conclusion— Patients with stroke have different risks for, consequences of, and barriers to reducing UTI than other hospitalized patients. Further research is needed to develop an effective approach to decreasing this important complication in the stroke population.

Presentation of reversible posterior leukoencephalopathy syndrome in patients on calcineurin inhibitors

BACKGROUND Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinico-radiologic diagnosis associated with numerous medical conditions including hypertension, immunosuppressant medications, and eclampsia. It is characterized by headache, altered mental status, seizures, visual disturbance, and neuroimaging consistent with posterior-predominant vasogenic edema. The objective of this study was to characterize the clinical spectrum and outcomes in a large series of RPLS patients, and to compare the presentation of patients taking calcineurin inhibitors (CNIs) to that of other RPLS patients. METHODS We reviewed records of patients seen by the neurology and transplant services over an 18-year period. Comorbid conditions, medications, blood pressure, laboratory testing, clinical outcomes, and radiographic findings were collected. RESULTS 84 episodes of RPLS were identified in 79 patients. Etiologies included CNIs (43%), hypertension (29%), renal disease (12%), preeclampsia/eclampsia (7%), and chemotherapy (5%). Patients on CNIs had lower blood pressures (p=0.002) and a lower prevalence of headache (p=0.02) compared to RPLS patients with other etiologies. Clinical recovery occurred in 65% of episodes, and radiographic resolution occurred in 67%. CONCLUSIONS Patients with CNI-induced RPLS have lower blood pressure than other RPLS patients, but otherwise present similarly. RPLS typically occurs within days to weeks of CNI initiation in patients without elevated medication levels. Clinical and radiographic recovery occurred in the majority of patients in this series, but one-third suffered residual neurologic deficits or death. These findings highlight the importance of prompt recognition and treatment of RPLS triggers to prevent permanent sequelae.