The clinical spectrum of Erdheim-Chester disease: an observational cohort study.

Erdheim-Chester Disease (ECD) is a rare, potentially fatal, multi-organ myeloid neoplasm occurring mainly in adults. The diagnosis is established by clinical, radiologic, and histologic findings; ECD tumors contain foamy macrophages that are CD68+, CD163+, CD1a-, and frequently S100-. The purpose of this report is to describe the clinical and molecular variability of ECD. Sixty consecutive ECD patients (45 males, 15 females) were prospectively evaluated at the NIH Clinical Center between 2011 and 2015. Comprehensive imaging and laboratory studies were performed, and tissues were examined for BRAF V600E and MAPK pathway mutations. Mean age at first manifestations of ECD was 46 years; a diagnosis was established, on average, 4.2 years after initial presentation. Bone was the most common tissue affected, with osteosclerosis in 95% of patients. Other manifestations observed in one-third to two-thirds of patients include cardiac mass and periaortic involvement, diabetes insipidus, retro-orbital infiltration, retroperitoneal, lung, CNS, skin and xanthelasma, usually in combination. Methods of detection included imaging studies of various modalities. Mutation in BRAF V600E was detected in 51% of 57 biopsies. One patient had an ARAF D228V mutation, and one had an activating ALK fusion. Treatments included interferon alpha, imatinib, anakinra, cladribine, vemurafenib and dabrafenib with trametinib; eleven patients received no therapy. The diagnosis of ECD is elusive because of the rarity and varied presentations of the disorder. Identification of BRAF and other MAPK pathway mutations in biopsies improves ECD diagnosis, allows for development of targeted treatments, and demonstrates that ECD is a neoplastic disorder.

Intravenous rt-PA is not associated with increased risk of hemorrhage in patients with intracranial aneurysms.

BACKGROUND AND PURPOSE: The presence of an intracranial aneurysm is listed as an exclusion criterion for the administration of recombinant tissue-plasminogen activator (rt-PA). This study was designed to test the hypothesis that the administration of rt-PA is safe in patients who have an unruptured intracranial aneurysm. METHODS: We performed a retrospective analysis of all acute ischemic stroke patients treated with rt-PA at our tertiary care academic medical center from June 2006 to June 2010 who also received intracranial vessel imaging. Baseline clinical characteristics were prospectively determined. Identification of hemorrhage and the presence of aneurysm were obtained from radiology report, and neuro-imaging findings were confirmed by study investigators. Symptomatic intracerebral hemorrhage (sICH) was defined according to National Institutes of Neurological Disorders and Stroke criteria. RESULTS: Five percent of patients (8/172) had at least one intracranial aneurysm on vessel imaging. A total of seven patients (4 %) had sICH. There was no significant difference in intracranial aneurysms between patients with or without sICH [1/7 (14 %) vs. 7/165 (4.2 %), p = 0.29]. In one patient with sICH and an intracranial aneurysm, the location of hemorrhage was distant from the aneurysm. The only predictors found for sICH in our cohort were atrial fibrillation (p = 0.03) and infarct size (p = 0.0004). CONCLUSIONS: Incidental intracranial aneurysms are common in patients who were present with acute ischemic stroke and not associated with sICH in our population. The concern that these patients are at increased risk of hemorrhage after thrombolysis may not be warranted.

No increased risk of symptomatic intracerebral hemorrhage after thrombolysis in patients with European Cooperative Acute Stroke Study (ECASS) exclusion criteria.

BACKGROUND AND PURPOSE: The European Cooperative Acute Stroke Study (ECASS) III trial used additional exclusion criteria not present in current guidelines for thrombolytic therapy in the United States (age >80 years; National Institutes of Health Stroke Scale >25, combination of previous stroke and diabetes, aggressive measures required to control blood pressure [intravenous infusion], and oral anticoagulant treatment). We tested the hypothesis that thrombolysis is not safe in patients with 1 of the additional exclusion criteria. METHODS: All patients treated with intravenous tissue-type plasminogen activator for acute stroke at our center between June 2006 and June 2010 were identified (n=191), and stratified based on presence of each of the exclusion criteria. Primary outcomes were rate of symptomatic intracerebral hemorrhage and in-hospital mortality. Additionally, patients with and without symptomatic intracerebral hemorrhage were analyzed for differences in baseline characteristics. RESULTS: No exclusion criterion was associated with increased risk of symptomatic intracerebral hemorrhage. Symptomatic intracerebral hemorrhage was associated with atrial fibrillation (5 of 9 [55%], versus 35 of 182 [19.2%]; P=0.021), larger final infarct volume (mean 173 mL(3) versus 42 mL(3); P=0.0002), and elevated glucose (mean 166 mg/dL versus 127 mg/dL; P=0.038). There was higher mortality in patients >80 years (5 of 31 [16%] versus 6 of 160 [4%]; P=0.0186) and those with National Institutes of Health Stroke Scale >25 (2 of 5 [40%] versus 7 of 159 [4.4%]; P=0.025). CONCLUSIONS: In our cohort, none of the more stringent exclusion criteria from ECASS III were associated with increased risk of symptomatic intracerebral hemorrhage. Prospective randomized studies are needed clarify the safety and efficacy of tissue-type plasminogen activator in these patients through all treatment time windows.