Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Tissue Plasminogen Activator Prescription and Administration Errors within a Regional Stroke System.

BACKGROUND: Intravenous (IV) tissue plasminogen activator (tPA) utilization in acute ischemic stroke (AIS) requires weight-based dosing and a standardized infusion rate. In our regional network, we have tried to minimize tPA dosing errors. We describe the frequency and types of tPA administration errors made in our comprehensive stroke center (CSC) and at community hospitals (CHs) prior to transfer. METHODS: Using our stroke quality database, we extracted clinical and pharmacy information on all patients who received IV tPA from 2010-11 at the CSC or CH prior to transfer. All records were analyzed for the presence of inclusion/exclusion criteria deviations or tPA errors in prescription, reconstitution, dispensing, or administration, and for association with outcomes. RESULTS: We identified 131 AIS cases treated with IV tPA: 51% female; mean age 68; 32% treated at the CSC, and 68% at CHs (including 26% by telestroke) from 22 CHs. tPA prescription and administration errors were present in 64% of all patients (41% CSC, 75% CH, P < .001), the most common being incorrect dosage for body weight (19% CSC, 55% CH, P < .001). Of the 27 overdoses, there were 3 deaths due to systemic hemorrhage or ICH. Nonetheless, outcomes (parenchymal hematoma, mortality, modified Rankin Scale score) did not differ between CSC and CH patients nor between those with and without errors. CONCLUSION: Despite focus on minimization of tPA administration errors in AIS patients, such errors were very common in our regional stroke system. Although an association between tPA errors and stroke outcomes was not demonstrated, quality assurance mechanisms are still necessary to reduce potentially dangerous, avoidable errors.

Neurosarcoidosis: Longitudinal experience in a single-center, academic healthcare system.

OBJECTIVE: To characterize patients with neurosarcoidosis within the University of Utah healthcare system, including demographics, clinical characteristics, treatment, and long-term outcomes. METHODS: We describe the clinical features and outcomes of patients with neurosarcoidosis within the University of Utah healthcare system (a large referral center for 10% of the continental United States by land mass). Patients were selected who met the following criteria: (1) at least one International Classification of Diseases Clinical Modification, 9th revision code 135 or International Classification of Diseases Clinical Modification, 10th revision code D86* (sarcoidosis) and (2) at least one outpatient visit with a University of Utah clinician in the Neurology Department within the University of Utah electronic health record. RESULTS: We identified 56 patients meeting the study criteria. Thirty-five patients (63%) were women, and most patients (84%) were white. Twelve patients (22%) met the criteria for definite neurosarcoidosis, 36 patients (64%) were diagnosed with probable neurosarcoidosis, and 8 patients (14%) were diagnosed with possible neurosarcoidosis. A total of 8 medications were used for the treatment of neurosarcoidosis. Prednisone was the first-line treatment in 51 patients (91%). Infliximab was the most effective therapy, with 87% of patients remaining stable or improving on infliximab. Treatment response for methotrexate and azathioprine was mixed, and mycophenolate mofetil and rituximab were the least effective treatments in this cohort. CONCLUSIONS: This is a comprehensive characterization of neurosarcoidosis within a single healthcare system at the University of Utah that reports long-term response to treatment and outcomes of patients with neurosarcoidosis. Our results suggest the use of infliximab as a first-line therapy for neurosarcoidosis.

Basilar artery occlusive disease in the New England Medical Center Posterior Circulation Registry.

BACKGROUND: Most reports on basilar artery (BA) occlusive disease have retrospectively described single cases or small patient series. OBJECTIVE: To assess clinical and vascular features, stroke mechanisms, etiologies, and outcome of moderate to severe BA occlusive disease among 407 patients in the New England Medical Center Posterior Circulation Registry, the largest prospective series of consecutively collected patients with posterior circulation ischemia to date. RESULTS: We studied 87 patients and identified 3 patient groups with distinct vascular, clinical, etiological, and prognostic characteristics: isolated BA disease (39 patients [44.8%]), BA involvement as part of widespread posterior circulation atherosclerosis (36 patients [41.4%]), and embolism to the BA (12 patients [13.8%]). Vascular risk factors were common and often multiple. Most patients (54 [62.1%]) had involvement of the midportion of the BA. Fifty-eight patients (66%) initially had transient ischemic attacks, of whom 34 (58.6%) progressed to stroke. Transient ischemic attacks were usually multiple, lasted for several months, and increased in frequency as the stroke approached. When an infarct was present, the middle posterior intracranial territory was most often involved (66 patients [75.9%]). Outcome was much better than previously assumed. The mortality rate was 2.3%, and 62 patients (almost 75%) had minor or no deficits at follow-up. Outcome was best among patients with widespread atherosclerotic disease and worst in 7; (58.3%, with major disability) of 12 patients with embolism to the BA. Distal territory involvement, embolism, BA occlusion, decreased level of consciousness, tetraparesis, and abnormal pupils were significant predictors of poor outcome. CONCLUSION: Inclusion of patients into 1 of the BA groups and early identification of predictive outcome factors guide diagnostic evaluation and treatment.

Outcome at 30 days in the New England Medical Center Posterior Circulation Registry.

BACKGROUND: Vertebrobasilar disease is generally considered a condition with a poor prognosis because of high rates of mortality and severe disability. OBJECTIVE: To compare the outcomes of 407 patients entered in the New England Medical Center Posterior Circulation Registry with the reported results of other studies. RESULTS: In contrast, among 407 patients prospectively and consecutively studied in the New England Medical Center Posterior Circulation Registry, we found a low mortality rate at 30 days after onset (3.6%) and relatively low rates of major disability (18% using a Modified Rankin Disability Scale score). Thirty days after stroke, 28% of the patients had no disability and 51% had only a minor disability. Stroke location, stroke mechanism, and arteries involved predicted outcome. Basilar artery involvement, embolic stroke mechanism, and multiple posterior circulation intracranial territory involvement correlated with poor outcome. Patients with lesions in the basilar artery were 5 times more likely to have a poor outcome independent of other factors. Lesions in the middle and distal territories were each associated with a poor outcome in one third of the patients. CONCLUSION: In contrast with previous reports, we found that vertebrobasilar occlusive disease consists of a variety of different stroke mechanisms and vascular lesions, many with a good prognosis.

Therapeutic hypothermia for status epilepticus: A report, historical perspective, and review.

Refractory status epilepticus is a disease associated with high morbidity and mortality, which does not always respond to standard treatments, and when they fail, alternative modalities become crucial. Therapeutic hypothermia slows nerve conduction in vitro, and has been shown to abort seizures in animal models. Therapeutic hypothermia has been experimentally used in humans since 1963 for a variety of intracranial pathologies. More recently there have been multiple reports demonstrating the effectiveness of therapeutic hypothermia in treating refractory status epilepticus. We report a case of super-refractory status epilepticus successfully treated with therapeutic hypothermia, complimented by a historical and literature review of this modality. While there is limited evidence, and some risks associated with therapeutic hypothermia, it should be considered as a reasonable and potentially effective treatment option for refractory status epilepticus.

Reproducibility of ABC/2 method to determine infarct volume and mismatch percentage with CT perfusion.

BACKGROUND: Our aim is to implement a simple, rapid, and reliable method using computed tomography perfusion imaging and clinical judgment to target patients for reperfusion therapy in the hyper-acute stroke setting. We introduce a novel formula (1-infarct volume [CBV]/penumbra volume [MTT] × 100%) to quantify mismatch percentage. METHODS: Twenty patients with anterior circulation strokes who underwent CT perfusion and received intravenous tissue plasminogen activator (IV tPA) were analyzed retrospectively. Nine blinded viewers determined volume of infarct and ischemic penumbra using the ABC/2 method and also the mismatch percentage. RESULTS: Interrater reliability using the volumetric formula (ABC/2) was very good (intraclass correlation [ICC] = .9440 and ICC = .8510) for hemodynamic parameters infarct (CBV) and penumbra (MTT). ICC coefficient using the mismatch formula (1-MTT/CBV × 100%) was good (ICC of .635). CONCLUSIONS: The ABC/2 method of volume estimation on CT perfusion is a reliable and efficient approach to determine infarct and penumbra volumes. The 1-CBV/MTT × 100% formula produces a mismatch percentage assisting providers in communicating the proportion of salvageable brain and guides therapy in the setting of patients with unclear time of onset with potentially salvageable tissue who can undergo mechanical retrieval or intraarterial thrombolytics.

New England Medical Center Posterior Circulation registry.

Among 407 New England Medical Center Posterior Circulation registry patients, 59% had strokes without transient ischemic attacks (TIAs), 24% had TIAs then strokes, and 16% had only TIAs. Embolism was the commonest stroke mechanism (40% of patients including 24% cardiac origin, 14% intraarterial, 2% cardiac and arterial sources). In 32% large artery occlusive lesions caused hemodynamic brain ischemia. Infarcts most often included the distal posterior circulation territory (rostral brainstem, superior cerebellum and occipital and temporal lobes); the proximal (medulla and posterior inferior cerebellum) and middle (pons and anterior inferior cerebellum) territories were equally involved. Severe occlusive lesions (>50% stenosis) involved more than one large artery in 148 patients; 134 had one artery site involved unilaterally or bilaterally. The commonest occlusive sites were: extracranial vertebral artery (52 patients, 15 bilateral) intracranial vertebral artery (40 patients, 12 bilateral), basilar artery (46 patients). Intraarterial embolism was the commonest mechanism of brain infarction in patients with vertebral artery occlusive disease. Thirty-day mortality was 3.6%. Embolic mechanism, distal territory location, and basilar artery occlusive disease carried the poorest prognosis. The best outcome was in patients who had multiple arterial occlusive sites; they had position-sensitive TIAs during months to years.