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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.
Early benefit of aspirin after TIA or ischemic stroke (July 2016)
The risk of recurrent ischemic stroke is highest in the first days and weeks after a transient ischemic attack (TIA) or ischemic stroke, but the benefit of aspirin in this time period has not been well studied. In a recent pooled analysis of data from over 15,000 subjects in 12 trials evaluating aspirin for secondary prevention, the benefit of aspirin was strongest in the early weeks after TIA or ischemic stroke . Compared with control (mostly placebo), aspirin reduced the relative risk of recurrent ischemic stroke within the first six weeks by 58 percent (1 versus 2.4 percent, absolute risk reduction 1.4 percent). The benefit of aspirin in this time frame was greatest for the subgroup of patients with TIA or minor stroke. These findings emphasize that aspirin should be started as early as possible after the diagnosis of TIA or ischemic stroke is confirmed. (See "Antiplatelet therapy for secondary prevention of stroke", section on 'Aspirin'.)
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'.)
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'.)
Daclizumab approved in the US for treating relapsing-remitting multiple sclerosis (June 2016)
Daclizumab, a humanized monoclonal antibody, was recently approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis . The approval was based upon evidence from two randomized controlled trials that daclizumab is effective for reducing relapse rates, and evidence from one trial that it may be effective for reducing disability progression. However, the clinical utility of daclizumab is likely to be limited by the risk of serious adverse events, including hepatotoxicity and infection, making it a second- or third-line agent for patients who have had an inadequate response to two or more disease-modifying agents for relapsing-remitting multiple sclerosis. Daclizumab will be available in the United States only through a restricted distribution program. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Daclizumab'.)
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'.)
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'.)
Whole brain radiation therapy and cognitive function in patients with limited number of brain metastases (August 2016)
Deferral of adjunctive whole brain radiation therapy (WBRT) in patients with a limited number of brain metastases who are eligible for surgery or stereotactic radiosurgery (SRS) has become more common over the last several years. This practice is supported by accumulating data from randomized trials showing that, although WBRT improves intracranial disease control, it does not appear to improve overall survival, and it is associated with early and delayed side effects that may worsen quality of life. A randomized trial of SRS plus WBRT versus SRS alone in 213 patients with brain metastases found that cognitive deterioration at three months was more common in patients who received WBRT (92 versus 64 percent), while overall survival was similar . Cognitive testing at 6 and 12 months and quality of life measures also favored SRS alone. Based on these results and other relevant studies, we suggest deferring adjunctive WBRT in most patients with a limited number of brain metastases. Such patients require serial neuroimaging after SRS alone to monitor for the development of new or progressive tumors. (See "Overview of the treatment of brain metastases", section on 'Role of adjunctive WBRT'.)
Radiation plus temozolomide in patients with 1p19q non-co-deleted anaplastic gliomas (July 2016)
Two previous randomized trials in patients with anaplastic oligodendroglial tumors found that postoperative treatment with radiation plus PCV (procarbazine, lomustine, and vincristine) improved survival compared with radiation alone. However, the benefit of PCV was primarily seen in patients whose tumors contained co-deletion of chromosomes 1p and 19q. The CATNON trial enrolled 748 patients with newly diagnosed anaplastic gliomas without 1p19q co-deletion and randomly assigned them to one of four treatment arms: radiation alone, radiation with concurrent temozolomide (TMZ), radiation with concurrent and 12 cycles of adjuvant TMZ, and radiation with 12 cycles of adjuvant TMZ . In an interim analysis with a median follow-up of over two years, patients who were randomized to receive 12 cycles of adjuvant TMZ had improved overall survival compared with those who received radiation without adjuvant TMZ (hazard ratio 0.65). Based on these results, we now recommend radiation plus chemotherapy in all patients with newly diagnosed anaplastic gliomas, rather than just those with 1p19q co-deleted tumors. The choice between PCV and TMZ should be individualized based on molecular characteristics of the tumor and patient preferences. (See "Management of anaplastic oligodendroglial tumors", section on 'CATNON'.)
Radiation plus temozolomide in older adults with glioblastoma (June 2016)
Shorter courses of radiation are increasingly used to treat older adults with glioblastoma, but the safety and efficacy of temozolomide in combination with such regimens have not been well studied. In a multinational phase III trial, 562 adults ≥65 years of age with a good performance status were randomly assigned to receive hypofractionated radiation (40 Gy in 15 fractions) plus concurrent and adjuvant temozolomide or radiation alone . Overall survival was significantly prolonged in patients assigned to combination therapy (9.3 versus 7.6 months), and quality of life outcomes were similar aside from an increase in nausea and constipation related to chemotherapy. The addition of temozolomide was especially beneficial in the subset of patients with O-6-methylguanine-DNA methyltransferase (MGMT) methylated tumors (13.5 versus 7.7 months). (See "Management of glioblastoma in older adults", section on 'Efficacy'.)
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'.)
Chronic sleep-wake disturbances after traumatic brain injury (July 2016)
Sleep-wake disturbances are very common in the weeks to months following traumatic brain injury (TBI), and a new study suggests that many of these symptoms persist long term. In a prospective case-control study in which 31 patients with TBI of any severity were evaluated at 18 months after injury, 67 percent of patients had evidence of excessive daytime sleepiness on objective testing, compared with only 19 percent of healthy controls . Patients also had persistent pleiosomnia (increased need for sleep), requiring an average of one more hour of sleep per 24 hours than controls. As in earlier studies, patients tended to underestimate their symptoms, emphasizing the importance of both subjective and objective sleep testing in patients with sleep-wake complaints after TBI. (See "Sleep-wake disorders in patients with traumatic brain injury", section on 'Natural history'.)
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