Magnetic Resonance Imaging Pilot Study of Intravenous Glyburide in Traumatic Brain Injury.

Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10 h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6-10, and 14 had contusions. There were no differences in adverse events (AEs) or severe adverse events (ASEs) between groups. The magnetic resonance imaging (MRI) percent change at 72-168 h from screening/baseline was compared between the glyburide and placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo versus 136% with glyburide (p = 0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with glyburide (p = 0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular, and intracellular water, respectively. The percent change with time for each measure was compared in lesions (n = 14) versus uninjured white matter (n = 24) in subjects receiving placebo (n = 20) or glyburide (n = 18). For placebo, the percent change in lesions for all three measures was significantly different compared with uninjured white matter (analysis of variance [ANOVA], p < 0.02), consistent with worsening of edema in untreated contusions. In contrast, for glyburide, the percent change in lesions for all three measures was not significantly different compared with uninjured white matter. Further study of IV glyburide in contusion TBI is warranted.

Three-year follow-up of prospective trial of focused ultrasound thalamotomy for essential tremor.

OBJECTIVE: To test the hypothesis that transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) thalamotomy is effective, durable, and safe for patients with medication-refractory essential tremor (ET), we assessed clinical outcomes at 3-year follow-up of a controlled multicenter prospective trial. METHODS: Outcomes were based on the Clinical Rating Scale for Tremor, including hand combined tremor-motor (scale of 0-32), functional disability (scale of 0-32), and postural tremor (scale of 0-4) scores, and total scores from the Quality of Life in Essential Tremor Questionnaire (scale of 0-100). Scores at 36 months were compared with baseline and at 6 months after treatment to assess for efficacy and durability. Adverse events were also reported. RESULTS: Measured scores remained improved from baseline to 36 months (all p < 0.0001). Range of improvement from baseline was 38%-50% in hand tremor, 43%-56% in disability, 50%-75% in postural tremor, and 27%-42% in quality of life. When compared to scores at 6 months, median scores increased for hand tremor (95% confidence interval [CI] 0-2, p = 0.0098) and disability (95% CI 1-4, p = 0.0001). During the third follow-up year, all previously noted adverse events remained mild or moderate, none worsened, 2 resolved, and no new adverse events occurred. CONCLUSIONS: Results at 3 years after unilateral tcMRgFUS thalamotomy for ET show continued benefit, and no progressive or delayed complications. Patients may experience mild degradation in some treatment metrics by 3 years, though improvement from baseline remains significant. CLINICALTRIALSGOV IDENTIFIER: NCT01827904. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with severe ET, unilateral tcMRgFUS thalamotomy provides durable benefit after 3 years.

Disseminated cryptococcosis associated with administration of eculizumab.

PURPOSE: A case report of fatal disseminated cryptococcosis in a patient treated with eculizumab is presented along with a review of literature suggesting a possible etiologic mechanism. SUMMARY: A 23-year-old man with a history of minimal change nephrotic syndrome was hospitalized for acute kidney injury and abdominal pain and swelling. He was found to have disseminated pneumococcal disease, including peritonitis, bacteremia, and pulmonic endocarditis. The patient developed evidence of microangiopathic hemolytic anemia, leading to a diagnosis of atypical hemolytic uremic syndrome, and was started on eculizumab. The patient initially improved but developed septic shock 18 days after the first dose of eculizumab. All subsequent blood, respiratory, and intraabdominal cultures grew Cryptococcus neoformans. Twenty-eight days after the initial dose of eculizumab, the patient died. Autopsy findings demonstrated disseminated cryptococcosis, with infection noted in lung, myocardial, kidney, and liver tissues. Considering the complement-dependent nature of host defenses against Cryptococcus species and available evidence regarding C. neoformans pathogenicity from studies of murine models, it was hypothesized that the patient's cryptococcosis and death were secondary to administration of eculizumab and consequent blockage of the C5 component of the complement cascade. Eculizumab is known to predispose recipients to infections with encapsulated organisms; however, this was believed to be the first reported case of infection with an encapsulated yeast possibly due to eculizumab use. Patients receiving eculizumab should be monitored closely for invasive cryptococcal infections. CONCLUSION: A 23-year-old man developed fatal disseminated cryptococcosis after treatment with eculizumab.