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- Pharmacological treatment of Parkinson disease: a review. [Journal Article]
- JAMA 2014 Apr 23-30; 311(16):1670-83.
Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life.To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea.References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic.Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, β-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies.Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established.
- Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. [Journal Article, Research Support, Non-U.S. Gov't]
- JAMA 2014 Apr 23-30; 311(16):1661-9.
Whether conservative management is superior to interventional treatment for unruptured brain arteriovenous malformations (bAVMs) is uncertain because of the shortage of long-term comparative data.To compare the long-term outcomes of conservative management vs intervention for unruptured bAVM.Population-based inception cohort study of 204 residents of Scotland aged 16 years or older who were first diagnosed as having an unruptured bAVM during 1999-2003 or 2006-2010 and followed up prospectively for 12 years.Conservative management (no intervention) vs intervention (any endovascular embolization, neurosurgical excision, or stereotactic radiosurgery alone or in combination).Cox regression analyses, with multivariable adjustment for prognostic factors and baseline imbalances if hazards were proportional, to compare rates of the primary outcome (death or sustained morbidity of any cause by Oxford Handicap Scale [OHS] score ≥2 for ≥2 successive years [0 = no symptoms and 6 = death]) and the secondary outcome (nonfatal symptomatic stroke or death due to bAVM, associated arterial aneurysm, or intervention).Of 204 patients, 103 underwent intervention. Those who underwent intervention were younger, more likely to have presented with seizure, and less likely to have large bAVMs than patients managed conservatively. During a median follow-up of 6.9 years (94% completeness), the rate of progression to the primary outcome was lower with conservative management during the first 4 years of follow-up (36 vs 39 events; 9.5 vs 9.8 per 100 person-years; adjusted hazard ratio, 0.59; 95% CI, 0.35-0.99), but rates were similar thereafter. The rate of the secondary outcome was lower with conservative management during 12 years of follow-up (14 vs 38 events; 1.6 vs 3.3 per 100 person-years; adjusted hazard ratio, 0.37; 95% CI, 0.19-0.72).Among patients aged 16 years or older diagnosed as having unruptured bAVM, use of conservative management compared with intervention was associated with better clinical outcomes for up to 12 years. Longer follow-up is required to understand whether this association persists.
- Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial. [Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.]
- JAMA 2014 Apr 23-30; 311(16):1652-60.
Benzodiazepines are considered first-line therapy for pediatric status epilepticus. Some studies suggest that lorazepam may be more effective or safer than diazepam, but lorazepam is not Food and Drug Administration approved for this indication.To test the hypothesis that lorazepam has better efficacy and safety than diazepam for treating pediatric status epilepticus.This double-blind, randomized clinical trial was conducted from March 1, 2008, to March 14, 2012. Patients aged 3 months to younger than 18 years with convulsive status epilepticus presenting to 1 of 11 US academic pediatric emergency departments were eligible. There were 273 patients; 140 randomized to diazepam and 133 to lorazepam.Patients received either 0.2 mg/kg of diazepam or 0.1 mg/kg of lorazepam intravenously, with half this dose repeated at 5 minutes if necessary. If status epilepticus continued at 12 minutes, fosphenytoin was administered.The primary efficacy outcome was cessation of status epilepticus by 10 minutes without recurrence within 30 minutes. The primary safety outcome was the performance of assisted ventilation. Secondary outcomes included rates of seizure recurrence and sedation and times to cessation of status epilepticus and return to baseline mental status. Outcomes were measured 4 hours after study medication administration.Cessation of status epilepticus for 10 minutes without recurrence within 30 minutes occurred in 101 of 140 (72.1%) in the diazepam group and 97 of 133 (72.9%) in the lorazepam group, with an absolute efficacy difference of 0.8% (95% CI, -11.4% to 9.8%). Twenty-six patients in each group required assisted ventilation (16.0% given diazepam and 17.6% given lorazepam; absolute risk difference, 1.6%; 95% CI, -9.9% to 6.8%). There were no statistically significant differences in secondary outcomes except that lorazepam patients were more likely to be sedated (66.9% vs 50%, respectively; absolute risk difference, 16.9%; 95% CI, 6.1% to 27.7%).Among pediatric patients with convulsive status epilepticus, treatment with lorazepam did not result in improved efficacy or safety compared with diazepam. These findings do not support the preferential use of lorazepam for this condition.clinicaltrials.gov Identifier: NCT00621478.
- Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. [Journal Article, Research Support, American Recovery and Reinvestment Act, Research Support, N.I.H., Extramural]
- JAMA 2014 Apr 23-30; 311(16):1641-51.
Acetazolamide is commonly used to treat idiopathic intracranial hypertension (IIH), but there is insufficient information to establish an evidence base for its use.To determine whether acetazolamide is beneficial in improving vision when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss.Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss who received a low-sodium weight-reduction diet. Participants were enrolled at 38 academic and private practice sites in North America from March 2010 to November 2012 and followed up for 6 months (last visit in June 2013). All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation (PMD) between -2 dB and -7 dB. The mean age was 29 years and all but 4 participants were women.Low-sodium weight-reduction diet plus the maximally tolerated dosage of acetazolamide (up to 4 g/d) or matching placebo for 6 months.The planned primary outcome variable was the change in PMD from baseline to month 6 in the most affected eye, as measured by Humphrey Field Analyzer. Perimetric mean deviation is a measure of global visual field loss (mean deviation from age-corrected normal values), with a range of 2 to -32 dB; larger negative values indicate greater vision loss. Secondary outcome variables included changes in papilledema grade, quality of life (Visual Function Questionnaire 25 [VFQ-25] and 36-Item Short Form Health Survey), headache disability, and weight at month 6.The mean improvement in PMD was greater with acetazolamide (1.43 dB, from -3.53 dB at baseline to -2.10 dB at month 6; n = 86) than with placebo (0.71 dB, from -3.53 dB to -2.82 dB; n = 79); the difference was 0.71 dB (95% CI, 0 to 1.43 dB; P = .050). Mean improvements in papilledema grade (acetazolamide: -1.31, from 2.76 to 1.45; placebo: -0.61, from 2.76 to 2.15; treatment effect, -0.70; 95% CI, -0.99 to -0.41; P < .001) and vision-related quality of life as measured by the National Eye Institute VFQ-25 (acetazolamide: 8.33, from 82.97 to 91.30; placebo: 1.98, from 82.97 to 84.95; treatment effect, 6.35; 95% CI, 2.22 to 10.47; P = .003) and its 10-item neuro-ophthalmic supplement (acetazolamide: 9.82, from 75.45 to 85.27; placebo: 1.59, from 75.45 to 77.04; treatment effect, 8.23; 95% CI, 3.89 to 12.56; P < .001) were also observed with acetazolamide. Participants assigned to acetazolamide also experienced a reduction in weight (acetazolamide: -7.50 kg, from 107.72 kg to 100.22 kg; placebo: -3.45 kg, from 107.72 kg to 104.27 kg; treatment effect, -4.05 kg, 95% CI, -6.27 to -1.83 kg; P < .001).In patients with IIH and mild visual loss, the use of acetazolamide with a low-sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function. The clinical importance of this improvement remains to be determined.clinicaltrials.gov Identifier: NCT01003639.
- Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative. [Journal Article, Research Support, Non-U.S. Gov't]
- JAMA 2014 Apr 23-30; 311(16):1632-40.
The benefits of intravenous tissue plasminogen activator (tPA) in patients with acute ischemic stroke (AIS) are time dependent and guidelines recommend a door-to-needle (DTN) time of 60 minutes or less. However, studies have found that less than 30% of US patients are treated within this time window. Target: Stroke was designed as a national quality improvement initiative to improve DTN times for tPA administration in patients with AIS.To evaluate DTN times for tPA administration and the proportion of patients with times of 60 minutes or less before and after initiation of a quality improvement initiative and to determine whether potential improvements in DTN times were associated with improvements in clinical outcomes.The Target: Stroke initiative disseminated 10 care strategies to achieve faster DTN times for tPA administration, provided clinical decision support tools, facilitated hospital participation, and encouraged sharing of best practices. This study included 71,169 patients with AIS treated with tPA (27,319 during the preintervention period from April 2003-December 2009 and 43,850 during the postintervention period from January 2010-September 2013) from 1030 Get With The Guidelines-Stroke participating hospitals (52.8% of total).The DTN times for tPA administration of 60 minutes or less and in-hospital risk-adjusted mortality, symptomatic intracranial hemorrhage, ambulatory status at discharge, and discharge destination.Median DTN time for tPA administration declined from 77 minutes (interquartile range [IQR], 60-98 minutes) during the preintervention period to 67 minutes (IQR, 51-87 minutes) during the postintervention period (P < .001). The DTN times for tPA administration of 60 minutes or less increased from 26.5% (95% CI, 26.0%-27.1%) of patients during the preintervention period to 41.3% (95% CI, 40.8%-41.7%) during the postintervention period (P < .001). The DTN times of 60 minutes or less increased from 29.6% (95% CI, 27.8%-31.5%) of patients in the quarter immediately before the intervention (fourth quarter of 2009) to 53.3% (95% CI, 51.5%-55.2%) in the final postintervention quarter (third quarter of 2013) (P < .001). The annual rate of improvement in DTN times of 60 minutes or less increased from 1.36% (95% CI, 1.04%-1.67%) per year preintervention to 6.20% (95% CI, 5.58%-6.78%) per year postintervention (P < .001). In-hospital all-cause mortality improved significantly from the preintervention to the postintervention period (9.93% vs 8.25%, respectively; adjusted odds ratio [OR], 0.89 [95% CI, 0.83-0.94], P < .001), symptomatic intracranial hemorrhage within 36 hours was less likely to occur (5.68% vs 4.68%; adjusted OR, 0.83 [95% CI, 0.76-0.91], P < .001), and discharge to home was more frequent (37.6% vs 42.7%; adjusted OR, 1.14 [95% CI, 1.09-1.19], P < .001).Implementation of a national quality improvement initiative was associated with improved timeliness of tPA administration following AIS on a national scale, and this improvement was associated with lower in-hospital mortality and intracranial hemorrhage, along with an increase in the percentage of patients discharged home.
- Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. [Journal Article, Research Support, Non-U.S. Gov't]
- JAMA 2014 Apr 23-30; 311(16):1622-31.
Time to thrombolysis is crucial for outcome in acute ischemic stroke.To determine if starting thrombolysis in a specialized ambulance reduces delays.In the Prehospital Acute Neurological Treatment and Optimization of Medical care in Stroke Study (PHANTOM-S), conducted in Berlin, Germany, we randomly assigned weeks with and without availability of the Stroke Emergency Mobile (STEMO) from May 1, 2011, to January 31, 2013. Berlin has an established stroke care infrastructure with 14 stroke units. We included 6182 adult patients (STEMO weeks: 44.3% male, mean [SD] age, 73.9 [15.0] y; control weeks: 45.2% male, mean [SD] age, 74.3 [14.9] y) for whom a stroke dispatch was activated.The intervention comprised an ambulance (STEMO) equipped with a CT scanner, point-of-care laboratory, and telemedicine connection; a stroke identification algorithm at dispatcher level; and a prehospital stroke team. Thrombolysis was started before transport to hospital if ischemic stroke was confirmed and contraindications excluded.Primary outcome was alarm-to-thrombolysis time. Secondary outcomes included thrombolysis rate, secondary intracerebral hemorrhage after thrombolysis, and 7-day mortality.Time reduction was assessed in all patients with a stroke dispatch from the entire catchment area in STEMO weeks (3213 patients) vs control weeks (2969 patients) and in patients in whom STEMO was available and deployed (1804 patients) vs control weeks (2969 patients). Compared with thrombolysis during control weeks, there was a reduction of 15 minutes (95% CI, 11-19) in alarm-to-treatment times in the catchment area during STEMO weeks (76.3 min; 95% CI, 73.2-79.3 vs 61.4 min; 95% CI, 58.7-64.0; P < .001). Among patients for whom STEMO was deployed, mean alarm-to-treatment time (51.8 min; 95% CI, 49.0-54.6) was shorter by 25 minutes (95% CI, 20-29; P < .001) than during control weeks. Thrombolysis rates in ischemic stroke were 29% (310/1070) during STEMO weeks and 33% (200/614) after STEMO deployment vs 21% (220/1041) during control weeks (differences, 8%; 95% CI, 4%-12%; P < .001, and 12%, 95% CI, 7%-16%; P < .001, respectively). STEMO deployment incurred no increased risk for intracerebral hemorrhage (STEMO deployment: 7/200; conventional care: 22/323; adjusted odds ratio [OR], 0.42, 95% CI, 0.18-1.03; P = .06) or 7-day mortality (9/199 vs 15/323; adjusted OR, 0.76; 95% CI, 0.31-1.82; P = .53).Compared with usual care, the use of ambulance-based thrombolysis resulted in decreased time to treatment without an increase in adverse events. Further studies are needed to assess the effects on clinical outcomes.clinicaltrials.gov Identifier: NCT01382862.
- Advancing neurotherapeutics in the 21st century. [Editorial, Introductory Journal Article]
- JAMA 2014 Apr 23-30; 311(16):1620-1.
- tPA for stroke: important progress in achieving faster treatment. [Comment, Editorial]
- JAMA 2014 Apr 23-30; 311(16):1615-7.
- A piece of my mind. Decisions. [Journal Article]
- JAMA 2014 Apr 23-30; 311(16):1613-4.