Increase In Lesion Volume Research Articles

Neuron-Specific Enolase, but Not S100B or Myelin Basic Protein, Increases in Peripheral Blood Corresponding to Lesion Volume after Cortical Impact in Piglets

A peripheral indicator of the presence and magnitude of brain injury has been a sought-after tool by clinicians. We measured neuron-specific enolase (NSE), myelin basic protein (MBP), and S100B, prior to and after scaled cortical impact in immature pigs, to determine if these purported markers increase after injury, correlate with the resulting lesion volume, and if these relationships vary with maturation. Scaled cortical impact resulted in increased lesion volume with increasing age. Concentrations of NSE, but not S100B or MBP, increased after injury in all age groups. The high variability of S100B concentrations prior to injury may have precluded detection of an increase due to injury. Total serum markers were estimated, accounting for the allometric growth of blood volume, and resulted in a positive correlation of both NSE and S100B with lesion volume. Even with allometric scaling of blood volume and a uniform mechanism of injury, NSE had only a fair to poor predictive value. In a clinical setting, where the types of injuries are varied, more investigation is required to yield a panel of serum markers that can reliably predict the extent of injury. Allometric scaling may improve estimation of serum marker release in pediatric populations.

Factors affecting diagnostic yield in needle biopsy for brain lesions

Introduction. We analyse the factors that are associated with the diagnostic yield of needle brain biopsy. Material and methods. We present a retrospective series of 124 consecutive biopsies in a 30-month period. Patients’ demographics (age, gender), lesion topography (side, location, depth), lesion characteristics (histology, volume, radiological enhancement), type of biopsy procedure (freehand, ultrasound guided, frameless and frame-based stereotactic) and the use of intraoperative histologic examination were correlated with the diagnostic rate. Descriptive statistics and a nominal logistic regression model were used to evaluate the factors influencing diagnostic yield. Results. 63 men and 61 women were included in the study with mean age 59.2 (range: 16–86). 55 were frame-based stereotactic biopsies, 33 were frameless stereotactic biopsies, 29 biopsies were performed under ultrasound guidance and 7 freehand. The diagnostic yield in our series is 93.5%. The gender, lesion topography, biopsy method, use of intraoperative histology and enhancement did not correlate with the diagnostic yield. Younger age had a negative impact on diagnostic yield. 6 out of 8 inconclusive biopsies were in non-glial lesions (p < 0.05). The odds of obtaining a positive diagnosis increased sevenfold with every cc increase in lesion volume. Conclusion. The age of the patient, the volume and the histology of the brain lesion had an impact on the diagnostic yield of needle biopsy. None of the other factors significantly influenced the diagnostic rate.

Long-Term (7-Year) Data from a Phase 2 Extension Study of Fingolimod in Relapsing Multiple Sclerosis (P01.129)

Objective: To report long-term outcomes and safety of fingolimod in relapsing multiple sclerosis (RMS) patients participating in a phase 2 study. Background After the 6-month (M) placebo controlled study in which fingolimod (1.25mg and 5mg dose groups) significantly reduced MRI and relapse activity compared to placebo all patients were invited to continue on fingolimod. The final analysis after 7 years is presented. Design/Methods: In the extension, placebo patients were re-randomized to fingolimod 1.25mg or 5mg (placebo/fingolimod group); fingolimod patients (1.25 or 5mg) continued with their core phase dose (fingolimod group). After the M24 visit, all patients received open-label, 1.25mg fingolimod and between M24-M60 were converted to 0.5mg. Results: Of 281 initially randomized patients 122 (43.4%) completed up to 7 years on study (core and extension). The overall ARR for the fingolimod group was 0.16 and for placebo/fingolimod 0.21. By study completion, 55-66% of fingolimod and 44% of placebo/fingolimod patients were relapse-free. The KM estimate of the proportion of patients who were free from 6-month confirmed disability progression ranged from 53-70% for both groups. At the end of study, 83% of all remaining patients were free of gadolinium-enhanced lesions. No increase in T2 lesion volume was observed. No chronic effects of fingolimod treatment were observed on heart rate or atrioventricular conduction. No cases of confirmed macular edema were observed. Twelve cases of skin malignancies have been reported (majority within the first 3 years): 5, basal cell carcinoma; 4, squamous cell carcinoma; 3, malignant melanoma. Conclusions: Long-term (>7 years) fingolimod treatment was associated with sustained low MRI and clinical disease activity in those remaining on therapy and was well tolerated with no new safety concerns arising with long-term dosing. Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Antel has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Biogen Idec, Novartis, Serono, Inc., Genzyme Corporation, Teva Neuroscience, and GlaxoSmithKline. Dr. Antel has received personal compensation in an editorial capacity for Multiple Sclerosis. Dr. Antel has received research support from Novartis. Dr. Montalban has received personal compensation for activities with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Montalban has received research support from Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. O9Connor has received personal compensation for activities with Abbott Labratories, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceuticals Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals as a consultant. Dr. O9Connor has received research support from Abbott Labratories, Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceutical Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals. Dr. De Vera has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Cremer has received personal compensation for activities with Novartis. Dr. Sfikas has received personal compensation for activities with Novartis as an employee. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations.

Comparison of a 1.5T Standard vs. 3T Optimized Protocols in Multiple Sclerosis Patients (P03.053)

Objective: To investigate the superiority of the 3T optimized vs. the 1.5T standardized protocols in detecting gadolinium enhancing (GD-E) lesions in patients with multiple sclerosis (MS). Background Use of post-contrast T1-weighted imaging (WI) is an important tool in diagnosing and predicting the course of MS. Application of optimized imaging strategies has the potential to increase detection of MRI disease activity. Design/Methods: A standard protocol was defined as a 1.5T scan with a single-dose of Gd and a 5-minute scanning delay after injection. An optimized protocol was defined as a 3T MRI scan, using a triple dose of Gd, 20 min scan delay, and using an off-resonance saturated magnetization transfer pulse to reduce the background signal. Fourteen relapsing-remitting MS patients and 3 healthy controls (HC) were scanned with 1.5T standardized and a 3T optimized protocols in random order over 72 hours. Results: There were 47 Gd-E lesions in the MS patients on 3T optimized and 34 on 1.5T standard protocols, a 38.2% increase. There was a significant increase in Gd-enhanced lesion volume (LV) detected with the optimized protocol (179.6%, p Conclusions: The 3T optimized protocol is a useful technique for increasing sensitivity of MRI to detect Gd-E lesions. Disclosure: Dr. Livshits has nothing to disclose. Dr. Hussein has nothing to disclose. Dr. Kennedy has nothing to disclose. Dr. Weinstock-Guttman has received personal compensation for activities with Acorda Therapeutics, Biogen Idec, Serono, Inc., Novartis, Pfizer Inc, Teva Neuroscience as a speaker and/or participant on an advisory board. Dr. Weinstock-Guttman has received research support from Acorda Therapeutics, Biogen Idec, Serono Inc., Novartis, Pfizer Inc, Teva Neuroscience, National Multiple Sclerosis Society, the National Institutes of Health, ITN, Teva Neuroscience, Aspreva-Roche, Acorda Therapeutics and Shire Pharmaceuticals. Dr. Hojnacki has received personal compensation for activities with Biogen Idec, Serono, Inc., Pfizer Inc, and Teva Neuroscience as a speaker and/or participant on scientific advisory boards. Dr. Zivadinov has received personal compensation for activities with Teva Neuroscience, Biogen Idec, EMD Serono, and Questcor Pharmaceuticals as a speaker and/or consultant. Dr. Zivadinov has received research support from Biogen Idec, Teva Neuroscience, Genzyme Corporation, Bracco, Questcor Pharmaceuticals and EMD Serono.

Protective effects of hydrogen-rich saline in a rat model of traumatic brain injury via reducing oxidative stress

BackgroundHydrogen gas (H2) has been considered as a novel antioxidant to selectively reduce the toxic reactive oxygen species (ROS) such as hydroxyl radical (•OH) without affecting the other signal ROS. Our recent study shows that H2 inhalation is beneficial to traumatic brain injury (TBI) via reducing oxidative stress. In contrast to H2, hydrogen-rich saline (HS) may be more suitable for clinical application. The present study was designed to investigate whether HS has a protective effect against TBI via reducing oxidative stress in rats. MethodsTBI model was induced by controlled cortical impact injury. Different dosages of HS were intraperitoneally administered at 5 min after TBI operation. We then measured the brain edema, blood-brain barrier (BBB) breakdown, neurological dysfunction and injury volume in all animals. In addition, the oxidative products and antioxidant enzymes in brain tissues were detected. ResultsTBI-challenged rats exhibited significant brain injuries characterized by the increase of BBB permeability, brain edema, and lesion volume as well as neurological dysfunction, which were dose-dependently ameliorated by HS treatment. Moreover, we found that HS treatment increased the endogenous antioxidant enzymatic activities and decreased the oxidative product levels in brain tissues of TBI-challenged rats. ConclusionHydrogen-rich saline can exert a protective effect against TBI via reducing oxidative stress. Molecular hydrogen may be a more effective therapeutic strategy for TBI patients.

Abstract 3804: Regression of DWI Lesion is Frequent and is Associated with Outcome after Endovascular Therapy for Acute Ischemic Stroke

Background: Hyperintensity on diffusion weighted imaging (DWI) on MRI obtained ultra-early is hypothesized to represent core ischemic lesion in patients with acute ischemic stroke. However, resolution of a part of DWI lesion is well known. We evaluated the evolution of the hyperintensity on DWI among acute stroke patients who underwent endovascular recanalization therapy. Methods: We reviewed prospective database of early MRI imaging in screening for endovascular therapy in acute stroke from May 2010 to July 2011. We included patients who had both pre-treatment and follow-up MRI. We assessed the change in DWI lesion volumes among these patients. Patients were divided into 2 groups: “growth group” (patients showing more than 10 % increase in lesion volumes), “non-growth group” (patients showing less than 10 % increase or decrease in lesion volumes). Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) score at arrival and discharge. We compared patient’s backgrounds, imaging findings, endovascular therapy, and Thrombolysis in Myocardial Infarct (TIMI) flow grade following endovascular therapy between “growth” and “non-growth” group. Results: Fifty four patients underwent acute endovascular therapy. Of these, 30 patients (56 %) had both pre-treatment and follow-up MRI. The median time between stroke onset to initial MRI was 257 minutes, and follow-up MRI were performed at median 2.5 days after endovascular therapy. Decrease of DWI lesion volume was seen in 5 patients (17 %) with median volume decrease of 15 ml among the 5 patients. Total of seven patients had decrease or &lt;10% growth of DWI lesion. There were no differences in pre-treatment NIHSS score or DWI lesion volume between the “non-growth” and “growth” groups. The “non-growth” group had a lower NIHSS score at discharge (median, 3 versus 14, p = 0.013) compared to that of growth group. TIMI recanalization grade 2 or 3 (88 % versus 87%, p = 1.000), or TIMI recanalization grade 3 (14 % versus 26 %, p = 1.000) were not different between the two groups. Conclusion: Patients without growth of DWI lesion may have good outcome. Decrease of DWI hyperintense lesion was observed in about one-fifth of patients who underwent endovascular therapy. However, that was not associated with the degree of recanalization.

Laser thermal therapy: Real‐time MRI‐guided and computer‐controlled procedures for metastatic brain tumors

We report the final results of a pilot clinical trial exploring the safety and feasibility of real-time magnetic resonance-guided laser-induced thermal therapy (MRgLITT) for treatment of resistant focal metastatic intracranial tumors. In patients with chemotherapy, whole-brain radiation, and radiosurgery resistant metastatic intracranial tumors, minimally invasive stereotaxic placement of a saline-cooled interstitial fiberoptic laser applicator under local anesthesia was followed by laser irradiation during continuous magnetic resonance imaging (MRI) scanning. A computer workstation extracted real-time temperature-sensitive information for feedback control over laser delivery. A total of 15 metastatic tumors were treated in 7 patients. Patients were followed with physical exam and imaging for 30 months. In all cases, the procedure was well tolerated, and patients were discharged home within 24 hours. Follow-up imaging at up to 30 months showed an acute increase in apparent lesion volume followed by a gradual and steady decrease. No tumor recurrence within thermal ablation zones was noted. Kaplan-Meier analysis indicated that the median survival was 19.8 months. Real-time magnetic resonance (MR) guidance of laser-induced thermal therapy (LITT) offers a high level of control. This tool therefore enables a minimally invasive option for destruction and treatment of resistant focal metastatic intracranial tumors. MR-guided LITT appears to provide a safe and potentially effective treatment for recurrent focal metastatic brain disease. A larger phase II and III series would be of interest to quantify potential median survival advantage.

Interleukin‐10 overexpression does not synergize with the neuroprotective action of RGD‐containing vectors after postnatal brain excitotoxicity but modulates the main inflammatory cell responses

Antiinflammatory cytokines such as interleukin-10 (IL-10) have been used to modulate and terminate inflammation and provide neuroprotection. Recently, we reported that the modular recombinant transfection vector NLSCt is an efficient tool for transgene overexpression in vivo, which induces neuroprotection as a result of its RGD-mediated integrin-interacting capacity. We here sought to evaluate the putative synergic neuroprotective action exerted by IL-10 overexpression using NLSCt as a transfection vector after an excitotoxic injury to the postnatal rat brain. For this purpose, lesion volume, neurodegeneration, astroglial and microglial responses, neutrophil infiltration, and proinflammatory cytokine production were analyzed at several survival times after intracortical NMDA injection in postnatal day 9 rats, followed by injection of NLSCt combined with the IL-10 gene, a control transgene, or saline vehicle solution. Our results show no combined neuroprotective effect between RGD-interacting vectors and IL-10 gene therapy; instead, IL-10 overexpression using NLSCt as transfection vector increased lesion volume and neuronal degeneration at 12 hr and 3 days postlesion. In parallel, NLSCt/IL-10 treated animals displayed increased density of neutrophils and microglia/macrophages, and a reduced astroglial content of GFAP and vimentin. Moreover, NLSCt/IL-10 treated animals did not show any variation in interleukin-1β or tumor necrosis factor-α expression but a slight increase in interleukin-6 content at 7 days postlesion. In conclusion, overexpression of IL-10 by using NLSCt transfection vector did not synergistically neuroprotect the excitotoxically damaged postnatal rat brain but induced changes in the astroglial and microglial and inflammatory cell response.

Isolated lateral thalamic infarction: the role of posterior cerebral artery disease

Lateral thalamic infarction (LTI) is usually caused by small vessel disease (SVD), i.e., occlusion of the deep perforator. However, focal atherosclerotic posterior cerebral artery disease (PCAD) may produce LTI via thrombotic occlusion of the perforator. We aimed to investigate the prevalence of PCAD in LTI and differences in clinical and imaging findings between LTIs associated with PCAD and SVD. We retrospectively evaluated 58 consecutive patients with isolated LTI who underwent diffusion-weighted imaging (DWI) and MR angiography (MRA) within 7 days after stroke onset. Patients were divided into two groups: those with PCAD and those with SVD. Clinical syndromes were divided into pure sensory stroke (PSS) and sensory stroke plus (SS-plus), i.e., the concomitant presence of motor dysfunction or ataxia. Clinical and imaging findings were compared between these two groups. Of the 58 patients, 13 (22.4%) had PCAD. PSS was more frequently associated with SVD than with PCAD (57.8% vs. 23.1%, P=0.032). Initial DWI lesion volume (cm³) was significantly larger in PCAD than in patients with SVD (0.38±0.13 vs. 0.33±0.22, P=0.025). Among the 23 patients (39.7%) who underwent follow-up DWI, patients with PCAD showed a significantly greater increase in subacute lesion volume than those with SVD (P=0.019). Although National Institutes of Health Stroke Scale scores did not differ at admission (P=0.185), they were significantly higher at discharge in PCAD than in patients with SVD (P=0.012). Our data suggest that PCAD is an important cause of LTI, being related to SS-plus, larger lesion volume, and worse clinical outcomes.

White Matter Damage and the Effect of Matrix Metalloproteinases in Type 2 Diabetic Mice After Stroke

Diabetes mellitus leads to a higher risk of ischemic stroke and worse outcome compared to the general population. However, there have been few studies on white matter (WM) damage after stroke in diabetes mellitus. We therefore investigated WM damage after stroke in mice with diabetes mellitus. BKS.Cg-m(+/+)Lepr(db)/J (db/db) type 2 diabetes mellitus mice and db(+) non-diabetes mellitus mice were subjected to middle cerebral artery occlusion. Functional outcome, immunostaining, zymography, Western blot, and polymerase chain reaction were used. After stroke, mice with diabetes mellitus exhibited significantly increased lesion volume and brain hemorrhagic and neurological deficits compared to mice without diabetes mellitus. Bielshowsky silver, luxol fast blue, amyloid precursor protein, and NG2 expression were significantly decreased, indicating WM damage, and matrix metalloproteinase (MMP)-9 activity was significantly increased in the ischemic brain of mice with diabetes mellitus. Subanalysis of similar lesions in mice with and without diabetes mellitus demonstrated mice with diabetes mellitus had significantly increased WM damage than in mice without diabetes mellitus (P<0.05). To investigate the mechanism underlying diabetes mellitus-induced WM damage, oxygen-glucose deprivation-stressed premature oligodendrocyte and primary cortical neuron cultures were used. High glucose increased MMP-2, MMP-9, cleaved caspase-3 levels, and apoptosis, as well as decreased cell survival and dendrite outgrowth in cultured primary cortical neuron. High glucose increased MMP-9, cleaved caspase-3 level, and apoptosis, and decreased cell proliferation and cell survival in cultured oligodendrocytes. Inhibition of MMP by GM6001 treatment significantly decreased high glucose-induced cell death and apoptosis in cultured primary cortical neuron and oligodendrocytes but did not alter dendrite outgrowth in primary cortical neuron. Mice with diabetes mellitus have increased brain hemorrhage and show more severely injured WM than mice without diabetes mellitus after stroke. MMP-9 upregulated in mice with diabetes mellitus may exacerbate WM damage after stroke in mice with diabetes mellitus.

Beneficial effects of hydrogen gas in a rat model of traumatic brain injury via reducing oxidative stress

Traumatic brain injury (TBI) is a leading cause of mortality and disability among the young population. It has been shown that hydrogen gas (H 2) exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical ( OH, the most cytotoxic ROS). Recently, we have found that H 2 inhalation significantly improved the survival rate and organ damage of septic mice. In the present study, we investigated the effectiveness of H 2 therapy on brain edema, blood–brain barrier (BBB) breakdown, neurological dysfunction and injury volume in TBI-challenged rats. In addition, we investigated the effects of H 2 treatment on the changes of oxidative products and antioxidant enzymes in brain tissue of TBI-challenged rats. Hydrogen treatment was given by exposure to 2% H 2 from 5 min to 5 h after sham or TBI operation, respectively. Here, we found that TBI-challenged rats showed significant brain injuries characterized by the increase of BBB permeability, brain edema and lesion volume as well as neurological dysfunction, which was significantly attenuated by 2% H 2 treatment. In addition, we found that the decrease of oxidative products and the increase of endogenous antioxidant enzymatic activities in the brain tissue may be associated with the protective effects of H 2 treatment in TBI-challenged rats. The present study supports that H 2 inhalation may be a more effective therapeutic strategy for patients with TBI.

Liver tumor laser ablation – increase in the subacute ablation lesion volume detected with post procedural MRI

The use of image-guided thermoablative methods in liver tumor treatment has expanded rapidly due to encouraging results and advanced imaging. However, little is known about the treatment-induced tissue response and effects on imaging findings during the subacute post procedural period. To study the development of subacute ablation zone volume with magnetic resonance imaging (MRI) after laser-mediated liver tumor thermal therapy. In all, 16 laser ablations were performed on 16 liver tumors resulting in 16 ablation zones in 11 consecutive patients. A low-field 0.23 T C-arm MRI scanner was used for imaging and procedural guidance. Repeated dynamic contrast-enhanced T1, contrast-enhanced T1 FSE, and T2 FSE studies of liver were performed at 0 and 72 h after the procedure. Ablation zone volumes were registered from the acquired image data. MRI scans showed a significant increase of ablation volume in all imaging sequences obtained at 72 h after the initial therapy. After laser ablation, there is a progressive perfusion decrease in the ablation site leading to an increase in the ablation volume. Post procedural baseline MRI at 72 h from the treatment provides more precise information about the ablation result than can be obtained with immediate post procedural MRI.

Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis

The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNβ-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg ( n = 589) or placebo ( n = 582) intravenously every 4 weeks plus IFNβ-1a 30 µg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNβ-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNβ-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNβ-1a and increased in those receiving IFNβ-1a alone (–277.5 mm 3 versus 525.6 mm 3; p < 0.001). Compared with IFNβ-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3 mm 3 versus 2210.5 mm 3; p < 0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; p < 0.001), and a slower rate of brain atrophy during the second year of therapy (–0.31% versus –0.40%; p = 0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNβ-1a alone.

The effect of acquisition time on visual and semi-quantitative analysis of F-18 FDG-PET studies in patients with head and neck cancer

To evaluate the impact of acquisition time on F-18 fluorodeoxyglucose positron emission tomography (PET) image quality, lesion detection rate, standard uptake and lesion volume measures. In 17 consecutively referred head and neck cancer patients, a 10-min acquisition of the head and neck was performed in list mode after completion of a whole-body PET-computed tomography scan. For each patient, 0.5, 1, 2, 3, 5, 7 and 10-min PET images were reconstructed. Image quality was scored on a 5-point scale. Lesions were visually identified and lesion locations were compared between scans with various acquisition times. Standard uptake values (SUVs) and lesion volumes were automatically obtained and compared. Image quality was scored excellent/good for 10 and 7-min scans; moderate for 5 and 3-min scans and poor/very poor for 2, 1 and 0.5-min scans. Lesion detection rate did not differ between scans with shorter acquisition times and the reference. Similarly, SUVmax was not significantly different between images with various scan times and the reference, except for the 0.5-min PET image (Wilcoxon, P = 0.04). Overall, lesion volume increased significantly with longer scan time (Friedman, P<0.0001). For individual lesions, however, the effect of scan time on volume was quite variable. The variability was significantly larger for images with scan times below 3 min than for images with scan times of > or = 3 min. Despite poor image quality for scans with short acquisition times, the lesion detection rate was not adversely affected. Increased scan time resulted in an increase in lesion volumes. This finding is of particular interest if PET images are implemented in radiation oncology treatment planning.

Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double‐blind placebo‐controlled multicenter trial

Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing-remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS (PPMS) through 96 weeks and safety through 122 weeks. Using 2:1 randomization, 439 PPMS patients received two 1,000 mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (4 courses). The primary endpoint was time to confirmed disease progression (CDP), a prespecified increase in Expanded Disability Status Scale sustained for 12 weeks. Secondary endpoints were change from baseline to week 96 in T2 lesion volume and total brain volume on magnetic resonance imaging scans. Differences in time to CDP between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2% rituximab; p = 0.14). From baseline to week 96, rituximab patients had less (p < 0.001) increase in T2 lesion volume; brain volume change was similar (p = 0.62) to placebo. Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010), those with gadolinium-enhancing lesions (HR = 0.41; p = 0.007), and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo. Adverse events were comparable between groups; 16.1% of rituximab and 13.6% of placebo patients reported serious events. Serious infections occurred in 4.5% of rituximab and <1.0% of placebo patients. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses. Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions.

Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis

Cigarette smoking has been linked to higher susceptibility and increased risk of progressive multiple sclerosis (MS). The effects of smoking on MRI characteristics of patients with MS have not been evaluated. To compare the MRI characteristics in cigarette smoker and nonsmoker patients with MS. We studied 368 consecutive patients with MS (age 44.0 +/-SD 10.2 years, disease duration 12.1 +/- 9.1 years) comprising 240 never-smokers and 128 (34.8%) ever-smokers (currently active and former smokers). The average number of packs per day smoked (+/-SD) was 0.95 +/- 0.65, and the mean duration of smoking was 18.0 +/- 9.5 years. All patients obtained full clinical and quantitative MRI evaluation. MRI measures included T1, T2, and gadolinium contrast-enhancing (CE) lesion volumes (LVs) and measures of central, global, and tissue-specific brain atrophy. The associations between smoking status and MRI measurements were assessed in regression analysis. Smoking was associated with increased Expanded Disability Status Scale (EDSS) scores (p = 0.004). The median EDSS scores (interquartile range) in the ever-smoker group and the active-smoker group were both 3.0 (2.0), compared with 2.5 (2.5) in never-smokers. There were adverse associations between smoking and the lesion measures including increased number of CE lesions (p < 0.001), T2 LV (p = 0.009), and T1 LV (p = 0.003). Smoking was associated with decreased brain parenchymal fraction (p = 0.047) and with increases in the lateral ventricle volume (p = 0.001) and third ventricle width (p = 0.023). Smoking is associated with increased blood-brain barrier disruption, higher lesion volumes, and greater atrophy in multiple sclerosis.

Basilar artery atherosclerotic disease is related to subacute lesion volume increase in pontine base infarction

Although basilar artery atherosclerotic disease (BAD) is frequent in patients with pontine base infarction, it remains unknown whether BAD is related to the lesion size or clinical outcome. We studied 56 patients with unilateral pontine base infarction who underwent (i) diffusion-weighted MRI within 48 h after stroke onset and (ii) follow-up MRI and MR angiography in the subacute stage. Neurologic progression was defined as increased National Institutes of Health Stroke Scale score by > or = 2 during admission. Clinical outcome was dichotomized as good and poor (> or = 3) according to the modified Rankin Scale at 1 month after stroke onset. Twenty-two patients (39%) had BAD and 15 patients (27%) had neurologic progression. Follow-up MRI performed at median 3.5 +/- 1.1 days after the initial MRI showed the lesion volume significantly increased (P < 0.001). The BAD was not significantly related to demographic characteristics, risk factors, initial and follow-up lesion volume, neurologic progression and clinical outcome, but was closely related to the subacute increase in lesion volume (P = 0.004 for 20% increase, P = 0.029 for 50% increase). BAD is related to subacute increase in lesion volume, but not to ultimate poor clinical outcome in patients with pontine base infarction.

Lesion volume increase is related to neurologic progression in patients with subcortical infarction

It remains unknown whether subacute lesion volume increase is related to neurologic progression (NP) and clinical outcome (CO) in patients with single subcortical infarct (SSI) in the middle cerebral artery (MCA) territory. We studied 77 patients who underwent diffusion-weighted MRI (DWI) within 48 h after stroke onset, which revealed unilateral SSI in the MCA territory, and follow-up DWI and MR angiography within 7 days of onset. Neurologic progression was defined as the increase of the National Institutes of Health Stroke Scale (NIHSS) score by ≥2 during the first week. Clinical outcome was dichotomized as good (≤2) and poor (≥3) according to the modified Rankin Scale at 1 month after the onset. Lesion volume increase was defined when the infarct volume in the follow-up MRI exceeds the initial one by either ≥30% or 50%. Fourteen patients (18.2%) had NP, and 17 (22.1%) had poor CO. Increase in lesion volume, found in 42 patients (54.5%) when defined by 50% increase and in 51 (66.2%) by 30%, was significantly associated with NP (50%, p=0.010; 30%, p=0.027) and poor CO (50%, p=0.040; 30%, 0.111). Multivariate logistic analyses revealed that lesion volume increase was independently related to NP (odd ratio, 8.48; 95% CI, 1.55–46.46) and that NP was the important predictor for poor CO (odd ratio, 39.69; 95% CI, 3.44–458.68). We conclude that subacute lesion volume growth is closely related to the NP and that the NP predicts subsequent poor CO.

Expediting MRI-Based Proof-of-Concept Stroke Trials Using an Earlier Imaging End Point

Before Phase III trials of acute stroke therapies, proof-of-concept MRI trials are increasingly used to gauge the likelihood of success. Given that animal models use infarct volume as the end point, Phase II trials have aimed to translate the findings using infarct growth. These trials could be expedited if subacute diffusion-weighted imaging lesion volume replaced late T2-weighted lesion volume as the primary end point. In the Echoplanar Imaging Thrombolytic Evaluation Trial, patients with acute ischemic stroke presenting within 3 to 6 hours were randomized to tissue plasminogen activator or placebo. We assessed correlations between acute (Day 1), subacute (Day 3 to 5) as well as late (Day 90) lesion volumes and clinical outcome (National Institutes of Health Stroke Scale). We compared lesion growth between placebo- and tissue plasminogen activator-treated patients. All 3 scans were performed in 72 of 101 patients (32 tissue plasminogen activator, 40 placebo). Median time to subacute imaging was 3 days (interquartile range, 2 to 4) and 90 days (interquartile range, 90 to 95) for the late scan. Increase in lesion volume from acute to subacute scans was smaller in the tissue plasminogen activator group compared with the placebo group (6.77 mL; interquartile range, 2.30 to 49.10; versus 30.00 mL; interquartile range, 7.19 to 85.93; P=0.03). Subsequent shrinkage did not reveal significant treatment effects. Correlation coefficient between acute and late lesion volumes was 0.81 (P<0.01). Subacute and late lesion volumes were strongly correlated (rho=0.94, P<0.01). Correlation coefficient for acute, subacute, and late lesion volume and late National Institutes of Health Stroke Scale score was 0.64 (P<0.01), 0.81 (P<0.01), and 0.77 (P<0.01), respectively. These findings suggest that subacute imaging at Day 3 after thrombolysis is an appropriate imaging end point for proof-of-concept MRI-based stroke treatment trials and can replace later MRI measurements.

Postmenopausal hormone therapy and subclinical cerebrovascular disease

The Women's Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials reported that conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increases risk for all-cause dementia and global cognitive decline. WHIMS MRI measured subclinical cerebrovascular disease as a possible mechanism to explain cognitive decline reported in WHIMS. We contacted 2,345 women at 14 WHIMS sites; scans were completed on 1,424 (61%) and 1,403 were accepted for analysis. The primary outcome measure was total ischemic lesion volume on brain MRI. Mean duration of on-trial HT or placebo was 4 (CEE+MPA) or 5.6 years (CEE-Alone) and scans were conducted an average of 3 (CEE+MPA) or 1.4 years (CEE-Alone) post-trial termination. Cross-sectional analysis of MRI lesions was conducted; general linear models were fitted to assess treatment group differences using analysis of covariance. A (two-tailed) critical value of alpha = 0.05 was used. In women evenly matched within trials at baseline, increased lesion volumes were significantly related to age, smoking, history of cardiovascular disease, hypertension, lower post-trial global cognition scores, and increased incident cases of on- or post-trial mild cognitive impairment or probable dementia. Mean ischemic lesion volumes were slightly larger for the CEE+MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Women assigned to CEE-Alone had similar mean ischemic lesion volumes compared to placebo. Conjugated equine estrogen-based hormone therapy was not associated with a significant increase in ischemic brain lesion volume relative to placebo. This finding was consistent within each trial and in pooled analyses across trials.