Jay Mandrekar

Inflammatory cortical demyelination in early multiple sclerosis

BACKGROUND Cortical disease has emerged as a critical aspect of the pathogenesis of multiple sclerosis, being associated with disease progression and cognitive impairment. Most studies of cortical lesions have focused on autopsy findings in patients with long-standing, chronic, progressive multiple sclerosis, and the noninflammatory nature of these lesions has been emphasized. Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease. METHODS We evaluated the prevalence and character of demyelinating cortical lesions in patients with multiple sclerosis. Cortical tissues were obtained in passing during biopsy sampling of white-matter lesions. In most cases, biopsy was done with the use of stereotactic procedures to diagnose suspected tumors. Patients with sufficient cortex (138 of 563 patients screened) were evaluated for cortical demyelination. Using immunohistochemistry, we characterized cortical lesions with respect to demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and a topographic association between cortical demyelination and meningeal inflammation. Diagnoses were ascertained in a subgroup of 77 patients (56%) at the last follow-up visit (at a median of 3.5 years). RESULTS Cortical demyelination was present in 53 patients (38%) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81% of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72% of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study. CONCLUSIONS In this cohort of patients with early-stage multiple sclerosis, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. (Funded by the National Multiple Sclerosis Society and the National Institutes of Health.).

Predictors of neurologic outcome in hypothermia after cardiac arrest.

To evaluate the predictive value of neurologic prognostic indicators for patients treated with hypothermia after surviving cardiopulmonary arrest.

Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study

BACKGROUND Complement activation after binding of an IgG autoantibody to aquaporin 4 (AQP4) is thought to be a major determinant of CNS inflammation and astrocytic injury in neuromyelitis optica. The aim of this study was to investigate the use of eculizumab--a therapeutic monoclonal IgG that neutralises the complement protein C5--in neuromyelitis optica spectrum disorders. METHODS Between Oct 20, 2009, and Nov 3, 2010, we recruited patients from two US centres into an open-label trial. Patients were AQP4-IgG-seropositive, aged at least 18 years, had a neuromyelitis optica spectrum disorder, and had at least two attacks in the preceding 6 months or three in the previous 12 months. Patients received meningococcal vaccine at a screening visit and 2 weeks later began eculizumab treatment. They received 600 mg intravenous eculizumab weekly for 4 weeks, 900 mg in the fifth week, and then 900 mg every 2 weeks for 48 weeks. The coprimary endpoints were efficacy (measured by number of attacks [new worsening of neurological function lasting for more than 24 h and not attributable to an identifiable cause]) and safety. Secondary endpoints were disability (measured by expanded disability status scale), ambulation (Hauser score), and visual acuity. At follow-up visits (after 6 weeks and 3, 6, 9, and 12 months of treatment; and 3 and 12 months after discontinuation), complete neurological examination was undertaken and an adverse event questionnaire completed. This trial is registered with ClinicalTrials.gov, number NCT00904826. FINDINGS We enrolled 14 patients, all of whom were women. After 12 months of eculizumab treatment, 12 patients were relapse free; two had had possible attacks. The median number of attacks per year fell from three before treatment (range two to four) to zero (zero to one) during treatment (p<0·0001). No patient had worsened disability by any outcome measure. Median score on the expanded disability status scale improved from 4·3 (range 1·0-8·0) before treatment to 3·5 (0-8·0) during treatment (p=0·0078). Two patients improved by two points and three improved by one point on the Hauser score; no change was recorded for the other patients. Visual acuity had improved in at least one eye by one point in four patients, and by two points in one patient; no change was recorded for other patients. One patient had meningococcal sepsis and sterile meningitis about 2 months after the first eculizumab infusion, but resumed treatment after full recovery. No other drug-related serious adverse events occurred. Eight attacks in five patients were reported within 12 months of eculizumab withdrawal. INTERPRETATION Eculizumab seems to be well tolerated, significantly reduce attack frequency, and stabilise or improve neurological disability measures in patients with aggressive neuromyelitis optica spectrum disorders. The apparent effects of eculizumab deserve further investigation in larger, randomised controlled studies. FUNDING Alexion Pharmaceuticals.

Continuous EEG in therapeutic hypothermia after cardiac arrest: Prognostic and clinical value

Objectives: To determine the prognostic value of an EEG grading scale and clinical outcome of treated seizures detected with continuous EEG (cEEG) during therapeutic hypothermia (TH) and rewarming post cardiac arrest (CA). Methods: Our cohort study retrospectively reviewed the electronic medical records and cEEGs of all patients undergoing TH after CA under protocol over 2 years. cEEG was initiated during TH and continued until restoration of normothermia (NT). EEGs were graded 1–3 (3 = most severe) using a departmentally developed EEG severity grading scale by 2 authors blinded to clinical outcome. Outcome was measured using the Cerebral Performance Category scale; grades 1–2 were considered a “good” outcome, 3–5 “poor.” Results: Fifty-four patients were included; 51 remained on cEEG through NT. Nineteen died. EEG severity grading during both TH and NT statistically correlated with outcome (grade 1 = good, grade 3 = poor). Other EEG features correlating with poor outcome included seizures, nonreactive background, and epileptiform discharges. Changes in EEG grade during monitoring did not statistically correlate with outcome. Five patients had seizures; all occurred in patients with grade 3 EEG backgrounds and all had a poor outcome. Conclusion: Grades 1 and 3 on our EEG severity grading scale during TH and NT correlated with outcome. Treating seizures did not improve outcome in our cohort.

Beneficial Plasma Exchange Response in Central Nervous System Inflammatory Demyelination

BACKGROUND Plasma exchange (PLEX) is a beneficial rescue therapy for acute, steroid-refractory central nervous system inflammatory demyelinating disease (CNS-IDD). Despite the approximately 45% PLEX response rate reported among patients with CNS-IDD, determinants of interindividual differences in PLEX response are not well characterized. OBJECTIVE To perform an exploratory analysis of clinical, radiographic, and serological features associated with beneficial PLEX response. DESIGN Historical cohort study. SETTING Neurology practice, Mayo Clinic College of Medicine, Rochester, Minnesota. Patients All Mayo Clinic patients treated with PLEX between January 5, 1999, and November 12, 2007, for a steroid-refractory CNS-IDD attack. MAIN OUTCOME MEASURE The PLEX response in attack-related, targeted neurological deficit(s) assessed within the 6-month period following PLEX. RESULTS We identified 153 patients treated with PLEX for a steroid-refractory CNS-IDD, of whom 90 (59%) exhibited moderate to marked functional neurological improvement within 6 months following treatment. Pre-PLEX clinical features associated with a beneficial PLEX response were shorter disease duration (P = .02) and preserved deep tendon reflexes (P = .001); post-PLEX variables included a diagnosis of relapsing-remitting multiple sclerosis (P = .008) and a lower Expanded Disability Status Scale score (P < .001) at last follow-up. Plasma exchange was less effective for patients with multiple sclerosis who subsequently developed a progressive disease course (P = .046). Radiographic features associated with a beneficial PLEX response were presence of ring-enhancing lesions (odds ratio = 4.00; P = .03) and/or mass effect (odds ratio = 3.00; P = .02). No association was found between neuromyelitis optica-IgG serostatus and PLEX response. CONCLUSIONS We have identified clinical and radiographic features that may aid in identifying patients with fulminant, steroid-refractory CNS-IDD attacks who are more likely to respond to PLEX.

Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque

An extensive analysis of white matter plaques in a large sample of multiple sclerosis (MS) autopsies provides insights into the dynamic nature of MS pathology.

Percutaneous Ablation of Renal Masses Measuring 3.0 cm and Smaller: Comparative Local Control and Complications After Radiofrequency Ablation and Cryoablation

OBJECTIVE The purpose of this article is to compare the efficacy and complication rates of percutaneous radiofrequency ablation (RFA) and cryoablation in the treatment of renal masses measuring 3.0 cm and smaller. MATERIALS AND METHODS A retrospective review was performed of 385 patients with 445 tumors measuring 3.0 cm or smaller treated with thermal ablation from 2000 through 2010. Two hundred fifty-six tumors in 222 patients were treated with RFA (mean [± SD] tumor size, 1.9 ± 0.5 cm), and 189 tumors in 163 patients were treated with cryoablation (mean tumor size, 2.3 ± 0.5 cm). Major complications and efficacy as measured by technical success and local tumor recurrence rates were recorded. RESULTS There were five (1.1%) technical failures, including one (0.4%) among tumors treated with RFA and four (2.1%) among tumors treated with cryoablation (p = 0.17). Of the 218 tumors treated with RFA and with follow-up beyond 3 months, seven (3.2%) developed local tumor recurrence, at a mean of 2.8 years after treatment (range, 1.2-4.1 years). Of the 145 tumors treated with cryoablation and with follow-up beyond 3 months, four (2.8%) developed local tumor recurrence at a mean of 0.9 years after treatment (range, 0.3-1.6 years). For biopsy-proven renal cell carcinoma, estimated local recurrence-free survival rates at 1, 3, and 5 years after RFA were 100%, 98.1%, and 98.1%, respectively, compared with 97.3%, 90.6%, and 90.6%, respectively, after cryoablation (p = 0.09). Major complications occurred after 4.3% (10/232) of RFAs and 4.5% (8/176) of cryoablation procedures (p = 0.91). CONCLUSION RFA and cryoablation are both effective in the treatment of renal masses measuring 3 cm or smaller. Major complications with either procedure are infrequent.

Incidence of traumatic brain injury across the full disease spectrum: A population-based medical record review study

Background: Extremely few objective estimates of traumatic brain injury incidence include all ages, both sexes, all injury mechanisms, and the full spectrum from very mild to fatal events. Methods: We used unique Rochester Epidemiology Project medical records-linkage resources, including highly sensitive and specific diagnostic coding, to identify all Olmsted County, MN, residents with diagnoses suggestive of traumatic brain injury regardless of age, setting, insurance, or injury mechanism. Provider-linked medical records for a 16% random sample were reviewed for confirmation as definite, probable, possible (symptomatic), or no traumatic brain injury. We estimated incidence per 100,000 person-years for 1987–2000 and compared these record-review rates with rates obtained using Centers for Disease Control and Prevention (CDC) data-systems approach. For the latter, we identified all Olmsted County residents with any CDC-specified diagnosis codes recorded on hospital/emergency department administrative claims or death certificates during 1987–2000. Results: Of sampled individuals, 1257 met record-review criteria for incident traumatic brain injury; 56% were ages 16–64 years, 56% were male, and 53% were symptomatic. Mechanism, sex, and diagnostic certainty differed by age. The incidence rate per 100,000 person-years was 558 (95% confidence interval = 528–590) versus 341 (331–350) using the CDC data-system approach. The CDC approach captured only 40% of record-review cases. Seventy-four percent of missing cases presented to the hospital/emergency department; none had CDC-specified codes assigned on hospital/emergency department administrative claims or death certificates; and 66% were symptomatic. Conclusions: Capture of symptomatic traumatic brain injuries requires a wider range of diagnosis codes, plus sampling strategies to avoid high rates of false-positive events.

Post–Cardiac Arrest Mortality Is Declining A Study of the US National Inpatient Sample 2001 to 2009

Background— Despite several advances in postresuscitation care over the past decade, population-based mortality rates for patients hospitalized with cardiac arrest in the United States have not been studied over this time period. The aim of this study was to determine the annual in-hospital mortality rates of patients with cardiac arrest from 2001 to 2009. Methods and Results— The US mortality rates for hospitalized patients with cardiac arrest were determined using the 2001 to 2009 US National Inpatient Sample, a national hospital discharge database. Using the International Classification of Diseases, 9th Edition, code 427.5, we identified patients hospitalized in the United States with cardiac arrest from 2001 to 2009. The main outcome measure was in-hospital mortality. A total of 1 190 860 patients were hospitalized with a diagnosis of cardiac arrest in the United States from 2001 to 2009. The in-hospital mortality rate decreased each year from 69.6% in 2001 to 57.8% in 2009. In multivariable analysis, when controlling for age, sex, race, and comorbidities, earlier year was a strong independent predictor of in-hospital death. The mortality rate declined across all analyzed subgroups, including sex, age, race, and stratification by comorbidity. Conclusions— The in-hospital mortality rate of patients hospitalized with cardiac arrest in the United States decreased by 11.8% from 2001 to 2009.Background— Despite several advances in postresuscitation care over the past decade, population-based mortality rates for patients hospitalized with cardiac arrest in the United States have not been studied over this time period. The aim of this study was to determine the annual in-hospital mortality rates of patients with cardiac arrest from 2001 to 2009. Methods and Results— The US mortality rates for hospitalized patients with cardiac arrest were determined using the 2001 to 2009 US National Inpatient Sample, a national hospital discharge database. Using the International Classification of Diseases , 9th Edition, code 427.5, we identified patients hospitalized in the United States with cardiac arrest from 2001 to 2009. The main outcome measure was in-hospital mortality. A total of 1 190 860 patients were hospitalized with a diagnosis of cardiac arrest in the United States from 2001 to 2009. The in-hospital mortality rate decreased each year from 69.6% in 2001 to 57.8% in 2009. In multivariable analysis, when controlling for age, sex, race, and comorbidities, earlier year was a strong independent predictor of in-hospital death. The mortality rate declined across all analyzed subgroups, including sex, age, race, and stratification by comorbidity. Conclusions— The in-hospital mortality rate of patients hospitalized with cardiac arrest in the United States decreased by 11.8% from 2001 to 2009. # Clinical Perspective {#article-title-18}

COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score.

OBJECTIVE To develop a concise and statistically robust instrument to assess autonomic symptoms that provides clinically relevant scores of autonomic symptom severity based on the well-established 169-item Autonomic Symptom Profile (ASP) and its validated 84-question scoring instrument, the Composite Autonomic Symptom Score (COMPASS). PATIENTS AND METHODS We assessed the internal consistency of COMPASS using Cronbach α coefficients based on the ASP of 405 healthy control subjects recruited and seen in the Mayo Clinic Autonomic Disorders Center between March 1, 1995, and March 31, 2010. Applying a simplified scoring algorithm, we then used exploratory factor analysis with orthogonal rotation and eigenvalue calculations to extract internally consistent domains and to reduce dimensionality. This analysis was followed by expert revisions to eliminate redundant content and to retain clinically important questions and final assessment of the new instrument. RESULTS The new simplified scoring algorithm alone resulted in higher Cronbach α values in all domains. Factor analysis revealed 7 domains with a total of 54 questions retained. Expert revisions resulted in further reduction of questions and domains with a remaining total of 31 questions in 6 domains (COMPASS 31). Measures of internal consistency were much improved compared to those for COMPASS. Following appropriate weighting, this instrument provides an autonomic symptom score from 0 to 100. CONCLUSION COMPASS 31 is a refined, internally consistent, and markedly abbreviated quantitative measure of autonomic symptoms. It is based on the original ASP and COMPASS, applies a much simplified scoring algorithm, and is suitable for widespread use in autonomic research and practice.