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The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.
Anesthesia for patients with acute ischemic stroke undergoing mechanical thrombectomy (January 2017)
The type of anesthesia used for patients with acute ischemic stroke undergoing mechanical thrombectomy may affect outcomes, but data are limited and inconsistent. In a randomized trial testing general anesthesia versus conscious sedation in this setting, there was no significant difference between the two groups for the outcome of early neurologic improvement . Subjects assigned to general anesthesia were more likely to achieve functional independence at three months, but small patient numbers lower the confidence in this result. The findings of this trial conflict with earlier reports that general anesthesia was associated with worse outcomes. (See "Reperfusion therapy for acute ischemic stroke", section on 'Mechanical thrombectomy'.)
High-risk drug prescribing in adults with dementia (February 2017)
Older adults with dementia are at heightened risk for adverse drug effects from anticholinergic drugs, benzodiazepines, and opioids, among many others. Despite these risks, polypharmacy remains common in this population. In a study that included over 75,000 adults with dementia, 44 percent of patients were prescribed at least one potentially unsafe medication (mostly drugs with high anticholinergic activity), and rates were consistently higher in patients receiving care from multiple providers . These results highlight the need for careful monitoring of drug therapy in patients with dementia and the importance of communication among providers before starting new therapies. (See "Safety and societal issues related to dementia", section on 'Polypharmacy'.)
Postmenopausal estrogen and cognitive function (August 2016)
While limited observational and clinical trial data have suggested that early, but not late, postmenopausal exposure to estrogen provides protection against later cognitive impairment, a new randomized trial found no benefit of estrogen regardless of when it was started. In the Early versus Late Intervention Trial with Estradiol (ELITE), 643 postmenopausal women, stratified according to time since menopause (<6 years [early] versus >10 years [late]), received oral estradiol (with progesterone for women with a uterus) or placebo for a median of five years . When compared with placebo, estradiol, whether it was started early or late, had no effect on verbal memory, executive function, or global cognition. (See "Estrogen and cognitive function", section on 'Younger menopausal women'.)
Declining use of feeding tubes in advanced dementia (August 2016)
Patients with advanced dementia commonly have eating problems in the final stages of illness, and caregivers are faced with decisions about whether to continue oral feeding by hand or place a long-term feeding tube. The available evidence fails to demonstrate any health benefits of tube feeding over ongoing hand feeding, and an increasing number of consensus-based guidelines advocate against feeding tube placement in this setting. In keeping with these recommendations, a recent study in the United States found that the proportion of nursing home residents with advanced dementia who received a feeding tube within one year of the onset of feeding problems decreased by approximately 50 percent between the years 2000 and 2014 . Advance care planning is critical in the management of patients with dementia and should include preparatory discussions about eating problems and other common complications encountered in the advanced stages of the disease. (See "Palliative care of patients with advanced dementia", section on 'Oral versus tube feeding'.)
Ocrelizumab for relapsing multiple sclerosis (January 2017)
Two randomized, controlled trials in patients with relapsing-remitting multiple sclerosis (RRMS) have found that ocrelizumab, a recombinant anti-CD20 monoclonal antibody, is more effective than interferon beta-1a for reducing relapses and may also slow disability progression . In both trials, ocrelizumab significantly reduced the relapse rate and the mean number of gadolinium-enhancing brain lesions on MRI scan. In a pooled analysis, ocrelizumab also reduced the proportion of subjects with confirmed disability progression at 24 weeks. Infusion reactions were the most common adverse effect of ocrelizumab, and there were more neoplasms with ocrelizumab than with interferon beta-1a (0.5 versus 0.2 percent). The role of this agent in the early treatment of RRMS remains to be clarified, pending drug approval and further safety data on rates of infection and neoplasm. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Ocrelizumab'.)
Ocrelizumab for primary progressive multiple sclerosis (January 2017)
Ocrelizumab is the first drug to reduce the risk of disability progression among patients with primary progressive multiple sclerosis (PPMS), as shown by the double-blind, multicenter ORATORIO trial . Compared with placebo, ocrelizumab modestly reduced 24-week confirmed disability progression (30 versus 36 percent, absolute risk reduction 6 percent). In addition, ocrelizumab slowed deterioration from baseline to week 120 on the timed 25-foot walk and led to improvements on other endpoints. The role of this agent in treatment of PPMS remains to be clarified, pending drug approval and further safety data on rates of infection and neoplasm. (See "Treatment of progressive multiple sclerosis in adults", section on 'Ocrelizumab'.)
Thrombotic microangiopathy from interferon (October 2016)
Drug-induced thrombotic microangiopathy (DITMA) has been described with a number of chemotherapeutic, immunosuppressive, and other drugs. Unlike thrombotic thrombocytopenic purpura (TTP), DITMA is not associated with severely reduced ADAMTS13 activity, and the principal treatment is drug discontinuation rather than plasma exchange. A new report has provided strong evidence for interferon as a cause of TMA . Patients receiving interferon who develop signs of a TMA should have the drug discontinued promptly before organ failure develops. (See "Drug-induced thrombotic microangiopathy", section on 'Immunosuppressive agents'.)
No benefit of hypothermia in convulsive status epilepticus (January 2017)
Convulsive status epilepticus is prolonged and refractory to standard first-line medications in approximately one-third of patients, and outcomes associated with refractory status epilepticus are often poor. Induced hypothermia has been proposed as a potential neuroprotective strategy. However, in a randomized trial of 250 critically ill adults with convulsive status epilepticus, induced hypothermia did not improve 90-day mortality, functional outcomes, or rate of progression to refractory status epilepticus when added to standard first-line therapies . (See "Convulsive status epilepticus in adults: Treatment and prognosis", section on 'Others'.)
Intravenous carbamazepine approved for use in adults (November 2016)
An intravenous (IV) preparation of carbamazepine has been approved by the US Food and Drug Administration for use as short-term replacement therapy in adult patients on stable doses of oral carbamazepine who are transiently unable to ingest oral preparations . The recommended IV conversion dose is 70 percent of the total daily oral dose, divided into four equal doses and given every six hours. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine'.)
Everolimus for refractory epilepsy associated with tuberous sclerosis (September 2016)
Tuberous sclerosis complex (TSC) is characterized by the development of benign tumors in multiple organs, including the brain, and medically intractable epilepsy is a major cause of morbidity. The mammalian target of rapamycin (mTOR) pathway is over-activated in TSC, and mTOR inhibitors such as everolimus are known to have antitumor efficacy. Data on antiseizure effects have been limited, however. In the recent 18-week EXIST-3 trial, which enrolled over 360 subjects with TSC and treatment-resistant epilepsy, the proportion of subjects achieving a ≥50 percent reduction in seizure frequency was significantly greater for the low- and high-exposure everolimus groups compared with placebo (28, 40, and 15 percent, respectively) . The most common adverse events associated with everolimus were stomatitis, diarrhea, and pyrexia. While longer-term data are needed, these results suggest that everolimus is an effective and safe treatment option for patients with TSC and treatment-resistant epilepsy. (See "Tuberous sclerosis complex: Management", section on 'Refractory epilepsy'.)
Amitriptyline and topiramate for prevention of pediatric migraine (November 2016)
Amitriptyline and topiramate are commonly used as prophylactic agents for pediatric migraine, and two previous randomized trials found that topiramate was effective for this indication. However, neither amitriptyline nor topiramate was better than placebo for headache prevention in the 24-week CHAMP trial of children and adolescents (8 to 17 years of age) with episodic or chronic migraine . Adverse events were more common in the amitriptyline and topiramate groups. There is no single best preventive treatment for migraine in children, and choice of therapy should be individualized based on comorbidities and patient preferences. (See "Preventive treatment of migraine in children", section on 'Amitriptyline'.)
Complications of dopaminergic therapy for restless legs syndrome (August 2016)
The main complication of long-term dopaminergic therapy for restless legs syndrome/Willis-Ekbom disease (RLS/WED) is “augmentation,” or an increase in symptom severity with increasing doses of medication. This may present as earlier onset of symptoms during the day, increased intensity of symptoms, or spread to previously uninvolved body parts (eg, arms, trunk). New consensus-based guidelines on the identification and management of augmentation recommend avoiding dopaminergic drugs as first-line therapy for RLS/WED when possible, screening patients on dopaminergic therapy for augmentation as part of routine clinical follow-up (table 1), and using the lowest doses possible to control symptoms . Treatment options for augmentation reviewed in the guideline include altering the dopaminergic dosing schedule, switching to an extended release preparation, and transitioning to an alpha-2-delta calcium channel ligand (eg, gabapentin enacarbil, pregabalin). In addition, alternative causes of worsening symptoms should be sought, such as low iron stores, sleep deprivation, and certain drugs such as serotonergic antidepressants. (See "Treatment of restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in adults", section on 'Augmentation'.)
Nusinersen for spinal muscular atrophy (January 2017)
Nusinersen, an antisense oligonucleotide, is the first drug approved to treat spinal muscular atrophy (SMA) by the US Food and Drug Administration (FDA). In an interim analysis of the double-blind ENDEAR trial, which enrolled 82 infants with SMA, improvement in motor milestones was observed in 40 percent of patients treated with intrathecal nusinersen, versus none for those who received the sham procedure . The FDA based its approval upon data from this trial and open-label studies in older patients with SMA [14,15]. We recommend nusinersen for most infants with SMA and select children ages 2 to 12 years with SMA. (See "Spinal muscular atrophy", section on 'Nusinersen'.)
Diaphragmatic pacing harmful in patients with amyotrophic lateral sclerosis (January 2017)
Pacing the diaphragm in patients with amyotrophic lateral sclerosis (ALS) is controversial. A recent randomized trial of patients with early respiratory impairment from ALS reported that, compared with sham pacing, diaphragmatic pacing resulted in increased mortality and did not delay time to noninvasive ventilation . We continue to prefer to avoid diaphragmatic pacing in this population until future trials demonstrate a clear benefit. (See "Pacing the diaphragm: Patient selection, evaluation, implantation, and complications", section on 'Amyotrophic lateral sclerosis'.)
Thymectomy for myasthenia gravis (August 2016)
Lacking evidence from randomized trials, thymectomy for patients with nonthymomatous myasthenia gravis (MG) had been controversial. Now, the benefit of thymectomy is supported by the results of the multicenter, assessor-blinded MGTX trial, which enrolled 126 subjects with generalized acetylcholine receptor (AChR) antibody-associated MG and randomly assigned them to thymectomy plus alternate-day prednisone or alternate-day prednisone alone . Over a three-year period, thymectomy improved multiple clinical outcomes, including quantitative strength testing, average alternating-day prednisone requirements (44 versus 60 mg), need for azathioprine immunosuppression (17 versus 48 percent), and hospitalization for acute exacerbations (9 versus 37 percent). Based on these results and prior observational data, we recommend thymectomy for patients age <60 years with nonthymomatous, generalized acetylcholine receptor (AChR) antibody-associated MG. Thymectomy is also indicated in all patients with thymoma if resection is feasible. (See "Thymectomy for myasthenia gravis", section on 'Efficacy'.)
Potential interaction between high-dose methotrexate and levetiracetam (November 2016)
Levetiracetam is sometimes used for prophylaxis and treatment of seizures in patients undergoing high-dose methotrexate (MTX) treatment for brain or other central nervous system (CNS) cancers, including lymphomas. Health Canada has issued a safety review describing a potential interaction between the two drugs, noting 13 reports received by the levetiracetam manufacturer and concluding that concurrent use can lead to significantly elevated levels of MTX and increased risk of toxicity . The labeling is being revised to recommend careful MTX blood level monitoring. Additional details are available from Lexi-Interact, the drug interactions tool included within UpToDate. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Coadministered drugs that may interfere with excretion'.)
Eteplirsen for Duchenne muscular dystrophy (September 2016)
Small studies of eteplirsen, an exon 51 skipping drug, suggest that it can increase dystrophin production in skeletal muscle without drug-related adverse effects in patients with Duchenne muscular dystrophy (DMD) with an amenable dystrophin gene mutation. Based upon this finding, the US Food and Drug Administration granted accelerated approval of eteplirsen in September 2016 for the treatment patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping . The mutation is present in approximately 13 percent of patients with DMD. (See "Treatment of Duchenne and Becker muscular dystrophy", section on 'Eteplirsen'.)
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- Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med 2016; 21:1.
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