Is Autologous Stem Cell Transplantation a Safe and Effective Alternative to Whole Brain Radiation as Consolidation Therapy in Patients With Primary Central Nervous System Lymphoma?: A Critically Appraised Topic.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) is a promising alternative to whole brain radiation therapy (WBRT) in the treatment of primary central nervous system lymphoma (PCNSL). The objective of this study was to critically assess current evidence supporting the use of HD-ASCT as first-line consolidative therapy in PCNSL. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. RESULTS: A recent, open-label, noncomparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and toxicity of consolidative therapy with HD-ASCT and WBRT in PCNSL in 2 separate treatment arms. A total of 140 patients with newly diagnosed PCNSL between the ages of 18 and 60 years were included. The primary endpoint of 2-year progression-free survival was met in 63% of patients in the WBRT arm and 87% in the HD-ASCT arm. Notably, an overall improvement in neurocognitive scores was observed following HD-ASCT, while WBRT was associated with worsened cognitive outcomes. CONCLUSIONS: In young patients with newly diagnosed PCNSL, consolidative therapy with HD-ASCT appears to be associated with less neurocognitive toxicity and may be more effective than WBRT at preventing relapses, however, at the cost of a higher treatment-related mortality.

What is the Role of Tumor-treating Fields in Newly Diagnosed Glioblastoma?

Alternating electrical fields can disrupt mitosis leading to apoptosis of rapidly dividing cancer cells. The device that utilizes this mechanism is known as tumor-treating fields (TTFields). TTFields can be applied by ceramic transducer arrays on a shaved scalp to deliver the alternating electric activity to patients with glioblastoma (GBM). It has FDA approval for use in both recurrent and newly diagnosed GBM. The objective is to critically appraise the current evidence for the use of TTFields as adjunctive treatment to newly diagnosed GBM. The objective was addressed through the development of a structured, critically appraised topic. We incorporated a clinical scenario, background information, a structured question, literature search strategy, evidence summary, clinical bottom lines, and expert discussion. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of neurooncology. A randomized controlled trial was selected for critical appraisal. Patients with newly diagnosed GBM completing standard radiation and chemotherapy with temozolomide (TMZ) were subsequently randomized to receive maintenance TMZ with TTFields, or TMZ alone. With the addition of TTFields, median progression-free survival was 6.7 months compared with 4 months without the addition of TTFields (95% confidence interval, 0.52-0.76; P<0.001) and overall survival was 20.9 months compared with 16.0 months without the addition of TTFields (95% confidence interval, 0.53-0.76; P<0.001). TTFields may increase both progression-free and overall survival in patients receiving standard chemoradiation therapy for GBM.

Is Intravenous Thrombolysis Safe and Effective in Central Retinal Artery Occlusion? A Critically Appraised Topic.

BACKGROUND: Central retinal artery occlusion (CRAO) is a neurological and ophthalmologic emergency associated with poor visual recovery. There is a dilemma regarding the appropriate treatment, as formal guidelines are lacking. Despite being considered an ocular equivalent of cerebral infarction, the time window of intravenous (IV) thrombolysis administration for maximum efficacy and safety in CRAO remains uncertain. OBJECTIVE: To critically assess the current evidence regarding the safety and effectiveness of IV thrombolysis in the treatment of patients with CRAO. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, and content experts in the fields of vascular neurology and ophthalmology. RESULTS: A recent patient-level meta-analysis was selected for critical appraisal. The study compared the visual recovery rates after IV thrombolysis in CRAO against the natural history of this illness and conservative therapies (ocular massage, anterior chamber paracentesis, and/or hemodilution). Time to thrombolytic therapy administration had a significant impact on visual recovery in CRAO (P<0.001). IV thrombolysis within the first 4.5 hours after symptom onset resulted in recovery of vision in 50.0% of the patients [95% confidence interval (CI), 32.4%-67.6%]. The rate of visual recovery was nearly 3 times higher than in the natural history cohort [odds ratio, 4.7 (95% CI, 2.3-9.6); P<0.001], with a 32.3% absolute risk reduction and a number needed to treat of 4.0 (95% CI, 2.6-6.6). There was no significant difference in the recovery rate after thrombolysis compared with the natural history cohort for those patients treated after 4.5 hours. No major hemorrhages occurred after alteplase administration in this meta-analysis. CONCLUSIONS: IV thrombolysis in CRAO seems to be safe and effective within the first 4.5 hours of symptom onset. A clinical decision based on this meta-analysis alone cannot be made due to several limitations. A randomized controlled clinical trial of early IV alteplase administration in CRAO is necessary to provide evidence-based therapeutic guidance.

Is dabigatran cost effective compared with warfarin for stroke prevention in atrial fibrillation? A critically appraised topic.

BACKGROUND: Warfarin has provided protection against cardioembolic stroke in the setting of nonvalvular atrial fibrillation (NVAF) for the past 60 years. Dabigatran, the first oral direct thrombin inhibitor to be approved in the United States, promises to provide the same or better stroke protection with reduced risk of intracranial hemorrhage. However, it remains to be seen whether grand-scale adoption of dabigatran will be cost effective. OBJECTIVE: To critically assess current evidence regarding the cost effectiveness of dabigatran for preventing stroke in patients with NVAF compared with warfarin. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of vascular neurology. RESULTS: A cost-effectiveness analysis (CEA) that followed a hypothetical cohort of NVAF patients 65 years of age or older and CHADS2≥1 over their lifetime comparing dabigatran with adjusted-dose warfarin was reviewed. Assuming a willingness to pay a threshold of $50,000 per quality-adjusted life year (QALY), base case results favored high-dose (150 mg bid) dabigatran as a cost-effective alternative to warfarin. Sensitivity analysis asserted that the cost effectiveness of dabigatran improved if it could be obtained for ≤$13/d or if it was used in populations with high risk of stroke or intracranial hemorrhage. CONCLUSIONS: Dabigatran 150 mg bid ($12,286 per QALY) is a cost-effective alternative to International Normalized Ratio-adjusted warfarin for the prevention of ischemic stroke in patients 65 years of age or older with NVAF.

Do cannabinoids reduce multiple sclerosis-related spasticity?

BACKGROUND: The plant Cannabis sativa contains numerous cannabinoids, which are aromatic hydrocarbons that have central nervous system effects mediated through specific cannabinoid receptors. Some patients with multiple sclerosis (MS) report symptomatic relief from spasticity, pain, and other symptoms when using smoked cannabis, and small trials have suggested some symptomatic benefit. OBJECTIVE: Do cannabinoids improve spasticity in patients with MS? METHODS: We addressed the question through the development of a structured, critically appraised topic. Participants included consultant and resident neurologists, clinical epidemiologists, medical librarian, and clinical content experts in the field of MS. Participants started with a clinical scenario and a structured question, devised search strategies, located and compiled the best evidence, performed a critical appraisal, synthesized the results, summarized the evidence, provided commentary, and declared bottom-line conclusions. RESULTS: The largest randomized, placebo-controlled trial of oral cannabinoid therapy detected no improvement for MS-related spasticity as measured by the Ashworth scale. However, subjective participant reports indicated improvement in spasticity (P = 0.01), spasms (P = 0.038), sleep quality (P = 0.025), and pain (P = 0.002) without detriment to depression, fatigue, irritability, or walk time. A second randomized controlled trial, which used subjective participant report as the primary outcome, revealed the same discrepancy between subjective and objective spasticity outcome measures. CONCLUSION: Randomized controlled trials have failed to confirm objective evidence for a beneficial effect of cannabinoids on MS-related spasticity. However, improvement in subjective assessments of spasticity and other related symptoms have been consistently noted, raising questions about the sensitivity and validity of current objective outcome instruments. Further research is warranted with regards to both outcome instrument development and the effects of cannabinoids on MS-related spasticity.

Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression.

BACKGROUND: Neuromyelitis optica (NMO)-IgG is a specific autoantibody marker for NMO. It binds selectively to aquaporin 4 (AQP4), which is highly concentrated in astrocytic foot processes at the blood-brain barrier and is not restricted to optic nerve and spinal cord. Although it is conventionally believed that the brain is spared, brain imaging abnormalities are not uncommon in patients with NMO. OBJECTIVE: To investigate the location of brain lesions that are distinctive for NMO with respect to the localization of AQP4 in mammalian brain. DESIGN: Observational, retrospective case series. SETTING: Clinical serologic cohort of patients tested for NMO-IgG for whom brain MRI images were available. PATIENTS: We identified 120 patients seropositive for NMO-IgG for whom brain magnetic resonance images were available. MAIN OUTCOME MEASURE: Magnetic resonance imaging abnormalities. RESULTS: In 8 patients we observed recurring and distinctive magnetic resonance imaging abnormalities in the hypothalamic and periventricular areas that corresponded to brain regions of high AQP4 expression. CONCLUSION: The distribution of NMO-characteristic brain lesions corresponds to sites of high AQP4 expression.