Neurology March 2013 Volume 80 Issue 13

Objective: Resting-state functional connectivity MRI (rs-fcMRI) may provide insight into the neurophysiology of HIV and aging.Methods: In this cross-sectional study, we used rs-fcMRI to investigate intra- and internetwork connectivity among 5 functional brain networks in 58 HIV-infected (HIV+) participants (44% receiving highly active antiretroviral therapy) and 53 HIV-uninfected (HIV-) controls. An analysis of covariance assessed the relationship among age, HIV laboratory markers, or degree of cognitive impairment and brain networks.Results: Individuals who were HIV+ had decreased rs-fcMRI intranetwork correlations in the default mode (DMN, p = 0.01), control (CON, p = 0.02), and salience (SAL, p = 0.02) networks, but showed no changes in the sensorimotor (SMN) or dorsal attention (DAN) network. Compared with HIV- controls, participants who were HIV+ had a significant loss of internetwork correlations between the DMN-DAN (p = 0.02), trending loss in DMN-SAL (p = 0.1) and CON-SMN (p = 0.1), and trending increase in CON-SAL (p = 0.1). Neither HIV markers (plasma HIV viral load or CD4+ cell count) nor degree of cognitive impairment correlated with rs-fcMRI measures. Aging correlated with a decrease in the magnitude of intranetwork functional connectivity within the DMN (p = 0.04) and SAL (p = 0.006) and with decreased magnitude of internetwork functional connectivity between DMN and SAL (p = 0.009) for both HIV+ and HIV- participants. No interaction was observed between HIV and aging.Conclusions: HIV and aging may cause independent decreases in rs-fcMRI. HIV may lead to a baseline decrease in brain function similar to deterioration that occurs with aging.(C)2013 American Academy of Neurology

Objective: To test the hypothesis that higher neuronal density in brainstem aminergic nuclei contributes to neural reserve.Methods: Participants are 165 individuals from the Rush Memory and Aging Project, a longitudinal clinical-pathologic cohort study. They completed a mean of 5.8 years of annual evaluations that included a battery of 19 cognitive tests from which a previously established composite measure of global cognition was derived. Upon death, they had a brain autopsy and uniform neuropathologic examination that provided estimates of the density of aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area plus summary measures of neuronal neurofibrillary tangles and Lewy bodies from these nuclei and medial temporal lobe and neocortex.Results: Neuronal densities in each nucleus were approximately normally distributed. In separate analyses, higher neuronal density in each nucleus except the ventral tegmental area was associated with slower rate of cognitive decline, but when modeled together only locus ceruleus neuronal density was related to cognitive decline (estimate = 0.003, SE = 0.001, p < 0.001). Higher densities of tangles and Lewy bodies in these brainstem nuclei were associated with faster cognitive decline even after controlling for pathologic burden elsewhere in the brain. Locus ceruleus neuronal density, brainstem tangles, and brainstem Lewy bodies had independent associations with rate of cognitive decline. In addition, at higher levels of locus ceruleus neuronal density, the association of Lewy bodies with cognitive decline was diminished.Conclusion: Density of noradrenergic neurons in the locus ceruleus may be a structural component of neural reserve.(C)2013 American Academy of Neurology

Objective: Prominent fibrinogen cleavage by recombinant tissue plasminogen activator and formation of fibrinogen degradation products with anticoagulant properties was proposed to amplify the risk of thrombolysis-related bleeding complications, but supportive evidence mainly derived from studies on myocardial infarction.Methods: This study included 547 consecutive stroke patients treated with recombinant tissue plasminogen activator, who underwent repeated assessment of fibrinogen levels before and 6 hours after thrombolysis. Symptomatic intracranial hemorrhages were ascertained using National Institute of Neurological Disorders and Stroke criteria.Results: Intracranial hemorrhage or systemic bleeding events manifested in 47 patients (8.6%). A decrease >=200 mg/dL in the fibrinogen level 6 hours after thrombolysis emerged as a significant and independent predictor for bleeding risk (multivariable odds ratio [95% confidence interval] 4.53 [2.39-8.60], p < 0.001). The population-attributable risk was 39.9% (95% confidence interval, 19.0-60.2) for any major bleeding, causality assumed, and surpassed 50% in patients with less severe strokes (NIH Stroke Scale score <=16). Quantification of fibrinogen depletion after stroke thrombolysis significantly improved routine risk prediction of bleeding complications as indicated by an increase in the C-statistics from 0.712 to 0.798 (p = 0.015) and a net reclassification index of 0.341 (p < 0.001). A prospective bicenter validation sample (n = 148) corroborates the key findings of this study and suggests positive and negative predictive values of fibrinogen depletion for any major bleeding of 29.2% and 93.5%.Conclusion: This study lends strong support to the concept that prominent fibrinogen turnover after IV stroke thrombolysis-a condition termed "early fibrinogen degradation coagulopathy"-is a relevant cause of major bleeding complications. Rigorous testing of more fibrin-specific thrombolytic agents in the setting of acute stroke is warranted.(C)2013 American Academy of Neurology

Objective: To identify clinical and nonclinical factors associated with time from epilepsy onset to surgical evaluation and treatment among a cohort of children having epilepsy surgery.Methods: Data were abstracted from records of 430 children (younger than 18 years) who had epilepsy neurosurgery at the University of California, Los Angeles from 1986 to 2010. Multivariable Cox proportional hazards models were used to analyze unique associations of clinical severity, pre-referral brain MRI, and sociodemographic characteristics with time to surgery.Results: Shorter time to surgery was associated with active (hazard ratio [HR] 5.67, 95% confidence interval [CI] 3.74-8.70) and successfully treated infantile spasms (HR 2.20, 95% CI 1.63-2.96); daily or more seizures (HR 2.09, 95% CI 1.58-2.76); MRI before referral regardless of imaging findings (HR 1.95, 95% CI 1.47-2.58); private insurance (HR 1.54, 95% CI 1.14-2.09); and Hispanic ethnicity (HR 1.38, 95% CI 1.01-1.87). There were race/ethnicity by insurance interactions (log-rank p = 0.049) with shortest time to surgery for Hispanic children with private insurance.Conclusions: Shorter intervals to surgical treatment were associated with greater epilepsy severity and insurance type, consistent with existing literature. However, associations of shorter times to treatment with having a brain MRI before referral and Hispanic ethnicity were unexpected and warrant further investigation. More knowledgeable referring providers and parents with greater help-seeking capability may explain obtaining an MRI before referral. Shorter intervals to surgery among Hispanic children may relate to the same factors yielding an increased volume of Hispanic children receiving surgery at the University of California, Los Angeles since 2000.(C)2013 American Academy of Neurology

Objective: To investigate the frequency of Coats syndrome and its association with D4Z4 contraction size in patients with facioscapulohumeral muscular dystrophy type 1 (FSHD1).Methods: We searched a North American FSHD registry and the University of Rochester (UR) FSHD research database, reviewed the literature, and sent surveys to 14 FSHD referral centers in the United States and overseas to identify patients with genetically confirmed FSHD1 with a diagnosis of Coats syndrome.Results: Out of 357 genetically confirmed patients in a North American FSHD registry and 51 patients in the UR database, 3 patients had a self-reported history of Coats disease (0.8%; 95% confidence interval 0.2%-2.2%). In total, we identified 14 patients with FSHD with known genetic contraction size and Coats syndrome confirmed by ophthalmologic examination: 10 from our survey and 4 from the literature. The median age at diagnosis of Coats syndrome was 10 years (interquartile range 14 years). The median D4Z4 fragment size was 13 kilobases (kb) (interquartile range 1 kb). One patient was mosaic (55% 11 kb, and 45% 78 kb).Conclusions: Coats syndrome is a rare extramuscular complication of FSHD1 associated with large D4Z4 contractions. Closer surveillance for retinal complications is warranted in patients with D4Z4 fragments <=15 kb.(C)2013 American Academy of Neurology

Objectives: To determine whether the previously demonstrated poor correlation between local faculty and external American Board of Psychiatry and Neurology (ABPN) examiners evaluating the Neurology Evaluation Exercise (NEX) is attributable to a difference between raters who know the residents and raters who do not, a difference between raters with ABPN experience and raters without it, or some other factor.Methods: Deidentified NEX encounters were videotaped at 2 neurology residency programs. Each video was graded by 1 local faculty examiner, 1 external faculty examiner with ABPN experience, and 1 external faculty examiner without ABPN experience, using the ABPN-sanctioned form. Acceptable/unacceptable rates were compared using Cohen [kappa] statistic.Results: Fifty-eight videotaped NEX encounters involving 20 residents were evaluated by 12 local faculty examiners, 13 ABPN examiners, and 10 external non-ABPN examiners. The level of agreement between groups failed to meet our target [kappa] of 0.7 (ABPN vs non-ABPN external examiners: [kappa] = 0.47 [95% confidence interval 0.21-0.73]; local vs non-ABPN external examiners: [kappa] = 0.37 [95% confidence interval 0.08-0.66]; local vs ABPN external examiners: [kappa] = 0.40 [95% confidence interval 0.14-0.67]). Local, non-ABPN, and ABPN examiners assigned a failing grade to 13 (22%), 11 (19%), and 16 (28%) of the NEX encounters, respectively.Conclusions: The disappointing correlation between local examiners, non-ABPN external examiners, and ABPN external examiners is not solely attributable to bias toward familiar residents. Inadequate training in NEX administration and scoring could be a factor. It is also possible that the NEX is not a valid tool. Further study is necessary.(C)2013 American Academy of Neurology