Vanja C. Douglas

Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice

Basal cell carcinomas, the commonest human skin cancers, consistently have abnormalities of the hedgehog signaling pathway and often have PTCH gene mutations. We report here that Ptch+/– mice develop primordial follicular neoplasms resembling human trichoblastomas, and that exposure to ultraviolet radiation or ionizing radiation results in an increase in the number and size of these tumors and a shift in their histologic features so that they more closely resemble human basal cell carcinoma. The mouse basal cell carcinomas and trichoblastoma-like tumors resemble human basal cell carcinomas in their loss of normal hemidesmosomal components, presence of p53 mutations, frequent loss of the normal remaining Ptch allele, and activation of hedgehog target gene transcription. The Ptch mutant mice provide the first mouse model, to our knowledge, of ultraviolet and ionizing radiation-induced basal cell carcinoma-like tumors, and also demonstrate that Ptch inactivation and hedgehog target gene activation are essential for basal cell carcinoma tumorigenesis.

Do the Brain Attack Coalition's criteria for stroke centers improve care for ischemic stroke?

Background: In 2000, the Brain Attack Coalition (BAC) recommended 11 major criteria for the establishment of primary stroke centers. The BAC relied heavily on expert opinion because evidence supporting the criteria was sparse. Objective: To assess primary stroke center elements, based on the criteria proposed by the BAC, with a questionnaire at 34 academic medical centers. Methods: Patient characteristics and outcomes were collected for all patients (n = 16,853) admitted with ischemic stroke to each hospital from 1999 to 2001. Stroke center elements were evaluated as predictors of treatment with tissue plasminogen activator (tPA) and outcomes after adjustment for patient characteristics. Results: The in-hospital mortality rate was 6.3% (n = 1,062), and 2.4% (n = 399) of patients received tPA. None of the 11 major stroke center elements was associated with decreased in-hospital mortality or increased frequency of discharge home. However, four elements predicted increased tPA use, including written care protocols, integrated emergency medical services, organized emergency departments, and continuing medical/public education in stroke (each odds ratio [OR] > 2.0, p < 0.05). Use of tPA also tended to be greater at centers with an acute stroke team, a stroke unit, or rapid neuroimaging (each OR > 2.0, p < 0.10). Institutions with a greater number of major stroke center elements used tPA more frequently. Conclusions: Of the 11 stroke center elements recommended by the BAC, 7 were associated with increased tPA use. Institutions with a greater number of these seven features used tPA more often, suggesting these key elements may be most important for primary stroke center designation, at least in terms of identifying centers that deliver IV tPA frequently.

Head Computed Tomography Findings Predict Short-Term Stroke Risk After Transient Ischemic Attack

Background and Purpose— Current guidelines recommend the use of head CT in the evaluation of patients with transient ischemic attack (TIA), but data supporting its value are sparse. Methods— Patients who presented to 1 of 16 emergency departments of a large Northern California health maintenance organization and received a diagnosis of TIA from November 1997 through February 1998 were enrolled and followed up for 90 days. Clinical, demographic, and outcome data were obtained from computerized databases and medical records. Physicians blinded to patient characteristics and outcomes abstracted head CT findings from radiology reports. Abstracted findings included evidence of old or new infarct, periventricular white-matter disease, cerebral atrophy, cerebral vascular calcification, and nonischemic lesions. Results— Head CT was performed in 67% of eligible patients (n=322) diagnosed with TIA. Evidence of a new infarct was seen on head CT in 13 patients (4%). A nonischemic cause of TIA symptoms was found in 4 patients (1.2%). During follow-up, 10.9% of TIA patients experienced subsequent stroke. After adjustment for confounders, risk for stroke during follow-up was significantly higher in those with a new infarct on head CT compared with others with TIA (odds ratio, 4.06; 95% confidence interval, 1.16 to 14.14; P =0.028). Old infarction, periventricular white-matter disease, cerebral atrophy, and cerebral vascular calcification were not predictors of subsequent risk of stroke. Conclusions— Evidence of a new infarct on head CT in patients presenting with TIA is associated with increased short-term risk for stroke. Head CT appears to have prognostic value in patients with TIA and, for this reason alone, may be justified in their evaluation.

Alzheimer disease risk and genetic variation in ACE: A meta-analysis

Background: Numerous studies have tested for associations between common variants of the angiotensin-converting enzyme gene (ACE) and late-onset Alzheimer disease (AD), but results have been inconclusive. Methods: Relevant studies were systematically identified, and data were abstracted according to predefined criteria. Results: The odds ratio (OR) for AD in individuals with the I allele of the ACE D/I polymorphism compared with those with the DD genotype was 1.27 (95% CI, 1.10 to 1.47; p < 0.001). Heterogeneity between studies was significant (p < 0.001) but not in strata defined by race and age (p ≥ 0.10). The risk of AD associated with the I allele appeared to be higher among Asians (OR 2.44; 95% CI, 1.68 to 3.53) when compared with the risk among Caucasians (OR 1.18; 95% CI, 1.02 to 1.37) (p for comparison < 0.001), and in younger cases (mean age 65 to 74 years) (OR 1.54; 95% CI, 1.23 to 1.93) when compared with the risk in older cases (OR 1.13; 95% CI, 0.95 to 1.35) (p for comparison = 0.03). Conclusions: The I allele of the ACE D/I polymorphism is associated with an increased risk of late-onset AD. Further study of the pathogenetic characteristics of this allele and independent confirmation of the association in larger studies are warranted.

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.

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.

A Systematic Approach to the Diagnosis of Suspected Central Nervous System Lymphoma

Central nervous system (CNS) lymphoma can present a diagnostic challenge. Currently, there is no consensus regarding what presurgical evaluation is warranted or how to proceed when lesions are not surgically accessible. We conducted a review of the literature on CNS lymphoma diagnosis (1966 to October 2011) to determine whether a common diagnostic algorithm can be generated. We extracted data regarding the usefulness of brain and body imaging, serum and cerebrospinal fluid (CSF) studies, ophthalmologic examination, and tissue biopsy in the diagnosis of CNS lymphoma. Contrast enhancement on imaging is highly sensitive at the time of diagnosis: 98.9% in immunocompetent lymphoma and 96.1% in human immunodeficiency virus-related CNS lymphoma. The sensitivity of CSF cytology is low (2%-32%) but increases when combined with flow cytometry. Cerebrospinal fluid lactate dehydrogenase isozyme 5, β2-microglobulin, and immunoglobulin heavy chain rearrangement studies have improved sensitivity over CSF cytology (58%-85%) but have only moderate specificity (85%). New techniques of proteomics and microRNA analysis have more than 95% specificity in the diagnosis of CNS lymphoma. Positive CSF cytology, vitreous biopsy, or brain/leptomeningeal biopsy remain the current standard for diagnosis. A combined stepwise systematic approach outlined here may facilitate an expeditious, comprehensive presurgical evaluation for cases of suspected CNS lymphoma.

Utility of MRI in spinal arteriovenous fistula

Objective and background: Spinal arteriovenous fistula (SAVF) is a rare but treatable cause of myelopathy. The diagnostic accuracy of MRI for detecting SAVF is unknown. Our objective was to determine the sensitivity and specificity of MRI in the diagnosis SAVF and characterize its radiographic features. Methods: We conducted a retrospective case-control study of all SAVF treated at our institution from 1995 to 2010, including patients who presented with myelopathy, had MRIs available for review, and underwent either spinal angiogram or had another diagnosis confirming test. Two blinded board-certified radiologists reviewed a series of MRIs and listed the most likely diagnoses, radiologic findings, and recommended follow-up. Sensitivities and specificities of MRI compared to spinal angiogram were calculated. We additionally conducted a literature review of cases describing MRI findings in spinal dural and perimedullary arteriovenous fistula. Results: We identified 36 cases of SAVF (median age 56, 67% male) and 32 controls (median age 54, 44% male). MRI was sensitive in identifying SAVF as the primary diagnosis in 94% (radiologist A, 95% confidence interval [CI] 0.87–1.02) and 89% (radiologist B, 95% CI 0.79–0.99) of cases. The sensitivity of spinal cord T2 hyperintensity or flow voids was 100% and the specificity of T2 hyperintensity and flow voids was 97%. Conclusions: Among patients with myelopathy, spinal angiography is mandatory in the presence of both T2 hyperintensity and flow voids but may be unnecessary if both of these findings are absent. Neurology® 2012;79:25–30

Effect of a neurohospitalist service on outcomes at an academic medical center

Objective: To study the effect of a neurohospitalist service on length of stay, cost, patient satisfaction, and education at an academic medical center. Methods: This was a retrospective cohort study using administrative data, educational surveys, and standardized patient satisfaction surveys to compare outcomes in the 21 months before (n = 343) and 27 months after (n = 436) the introduction of a neurohospitalist service in October 2006 at a single tertiary care academic medical center. Results: The most common diagnoses treated in both periods were demyelinating disease, neuromuscular disease, seizure, CNS infection, and cerebrovascular disease. Mean length of stay was reduced during the neurohospitalist period compared with that during the preneurohospitalist period (4.6 days vs 6.3 days; p < 0.001), but there was no difference in median cost (

Diagnostic Yield of Electroencephalography in a General Inpatient Population

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