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Neurology Today:
doi: 10.1097/01.NT.0000425879.82089.02
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Best Advances of 2012: Picks from the Neurology Today Editorial Advisory Board

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Neurologists are barraged daily with notices about “groundbreaking” news in clinical and basic research as well as policies that shape practice. But how can clinicians truly decipher what is really important from what is being purported to be noteworthy? We asked the editorial advisory board of Neurology Today — leaders in the field — to help us decide. Following are their “picks” of the most important advances — papers, policies, and other developments — in neurology in 2012.

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MEDICAL ETHICS

JAMES L. BERNAT, professor of neurology and medicine, Dartmouth Medical School, Lebanon, NH.

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The Pick: Chung GS, Lawrence RE, Curlin FA, Meltzer DO, et al. Predictors of hospitalized patients' preferences for physician-directed medical decision making. J Med Ethics 2012; 38:77–82.

Results: In a study of over 8000 hospitalized patients, 97 percent wanted doctors to offer them treatment choices and consider their opinions but 67 percent preferred to leave medical decisions to the doctor.

Why It's Important: There is a debate in medical ethics between those who hold respect for autonomy as the highest ethic and those who hold physician beneficence as the highest ethic. The former group advocates that patients always should be in control of their medical decisions and that their physicians should simply follow. The latter group believes that physicians have a duty to compassionately guide patients to the right decision.

This study provides empirical data on what hospitalized patients really want. While nearly all patients want to know their treatment options and to make their physicians aware of their preferences, two-thirds of patients ultimately wish to cede the decision-making responsibility to their trusted physicians. Thus, neither unfettered autonomy nor beneficence emerges as the supreme ethic but a combination of the two is necessary.

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NEUROGENETICS

THOMAS BIRD, MD, professor of neurology, University of Washington VA Medical Center, Seattle, WA.

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The Picks: Guerreiro, R Wojtas A, Bras J, et al. TREM2 variants in Alzheimer's disease. N Eng J Med 2012: E-pub 2012 Nov. 14.

Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Eng J Med 2012: E-pub 2012 Nov. 14.

Results: Two groups working independently identified the same genetic risk factor for late onset Alzheimer's disease, namely a missense DNA change in the gene encoding TREM2 (triggering receptor expressed on myeloid cells 2 protein).

Why It's Important: Although this TREM2 genetic variant is rare in the general population, the finding underscores the value of large-scale genetic association studies in common diseases and emphasizes the importance of microglia and the inflammatory response pathway in the pathogenesis and potential treatment of Alzheimer's disease.

See the Neurology Today story about these studies: “New Genetic Variant Implicated in Alzheimer's Disease:” www.neurotodayonline.com.

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ELECTRONIC HEALTH RECORDS/PRACTICE MANAGEMENT

NEIL A. BUSIS, MD, chief, Division of Neurology, University of Pittsburgh Medical Center-Shadyside, Pittsburgh, PA.

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The Pick: The big news from technology is the evolving “meaningful use” standards for electronic health records (EHRs), well detailed at: http://healthit.hhs.gov/. Neurology Today associate editor Orly Avitzur, MD, has been covering this area for this publication since its inception. See her most recent story for the In Practice column, “Neurologists Meet Meaningful Use and Collect Incentive Dollars:” http://bit.ly/QNvxmk.

The Finding: To qualify for incentives for using EHRs, physicians must follow very strict and precise rules when they document their patient encounters. The learning curve is steep and it is more difficult to qualify for the incentives than one might think initially.

Why It's Important: The EHR vendors have to update or upgrade their software to allow users to qualify. Some users with EHRs that can't be upgraded will have to switch EHRs — either get the latest version of their current EHR or get a new one. This will have a substantial impact on neurologic care regardless of practice type or size.

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MOVEMENT DISORDERS

ANDREW S. FEIGIN, MD, associate professor of neurology & molecular medicine, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY.

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The Pick: Li F, Harmer P, Batya SS, et. al. Tai chi and postural stability in patients with Parkinson's disease. N Eng J Med 2012; 366:511–519.

The Finding: This controlled trial demonstrated that a tailored course of tai chi can improve postural stability and balance in patients with Parkinson's disease (PD).

Why It's Important: Accumulating evidence suggests that exercise based therapies may have both short and long-term benefits for patients with PD, but few rigorous clinical trials of these therapies have been conducted. This fairly large controlled trial compared tai chi to resistance training and stretching programs, and found improvement in an objective measure of postural stability in the tai chi group. Furthermore, these improvements appeared to result in fewer falls, a common and difficult to treat phenomenon in PD patients. Though the findings of this study are important in their own right, the fact that the study utilized a rigorous clinical trial design to study a non-medical therapy sets an important example, and hopefully will lead to more scientific evaluations of non-traditional treatments.

See the Neurology Today story about this study, “For Parkinson Disease Patients, Tai Chi Can Improve Balance and Reduce Falls:” http://bit.ly/11TmLXc.

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MULTIPLE SCEROSIS

JOHN R. CORBOY, MD, professor of neurology, University of Colorado School of Medicine, Aurora, CO.

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The Pick: Goodin DS, Reder TS, Knappertz V, et al. Survival in MS: A randomized cohort study 21 years after the pivotal IFNβ-1b trial. Neurology 2012; 78:1315–1322.

The Finding: The investigators show that 21-year follow-up data reveal that individuals treated with interferon (that is, not placebo for two years) had a lower mortality 20 years later compared with those who took placebo the first two years as part of a randomized controlled trial from the late 1980s and 1990s. Astonishingly, 21 years later, the authors tracked down all but six of the original 372 people from the trial. In addition, two MRI markers of disease severity that we use all the time in the office were also correlated with mortality.

Why It's Important: This study suggests that MRI changes, incredibly early in the course of the illness, are confirmed later to be associated with early mortality.

See the Neurology Today story about the study, “News from the ANA Annual Meeting: MS Death Rate Lower with Early Interferon Use, Study Shows:” http://bit.ly/SM8kRe

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EPILEPSY

JACQUELINE A. FRENCH, MD, professor of neurology, New York University Comprehensive Epilepsy Center, New York, NY.

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The Pick: Silbergleit R, Durkalski V, Barsan W, et al, for the NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366(7):591–600.

The Findings: This was a double-blind, randomized, noninferiority trial comparing intramuscular midazolam with intravenous lorazepam for children and adults in status epilepticus treated by paramedics prior to arrival at the hospital. The outcome measure was absence of seizures in the ER. Intramuscular midazolam was superior to intravenous lorazepam (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to 16.1; p<0.001 for both noninferiority and superiority). The difference mostly related to failure to initiate an IV infusion.

Why It's Important: This will save lives by improving treatment for status epilepticus. Also, it was the first epilepsy trial to use the NETT (Neurological Emergencies Treatment Trials ) Network, and it actually completed recruitment ahead of schedule, indicating that this type of trial (treating neurologic emergencies) is practical and feasible.

See the Neurology Today story, “En Route to the ER, an Autoinjector with Antiseizure Medications Found More Effective for Status Epilepticus,” http://bit.ly/Sk5GjF

The Pick: Engel J Jr, McDermott MP, Kieburtz K, et al, for the Early Randomized Surgical Epilepsy Trial (ERSET) Study Group. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 2012;307(9):922–30.

The Findings: This was a multicenter randomized, controlled trial of temporal lobectomy for patients with well-localized mesial temporal lobe epilepsy. Patients were randomized within two years of seizure onset, and had failed only two drugs. Recruitment was difficult, so only 38 participants were enrolled and randomized. Nonetheless, the results were overwhelmingly positive in favor of surgery: None of 23 patients in the medical group and 11 of 15 in the surgical group were seizure free during year two of follow-up (odds ratio = ∞; 95% CI, 11.8 to ∞; p < .001). Quality of life was also superior in the surgical group

Why It's Important: The study definitively demonstrated that patients with well-localized mesial temporal lobe epilepsy should be referred for surgery as early as possible, since the likelihood of seizure control with antiepileptic drugs is likely to be small. In prior studies, it has been noted that these patients are only referred for surgery after a substantial delay, often lasting decades. This delay undoubtedly leads to increased disability and potentially to increased risk of injury and death.

See Neurology Today story, “Earlier Epilepsy Surgery Recommended in Pharmacoresistant Patients, New Study Finds,” http://bit.ly/121x2Rg.

The Pick: Massively Parallel Sequencing in Epilepsy, Presented Dec 1, 2012 at the American Epilepsy Society annual meeting.

The Findings: The presentation described initial results on whole exome sequencing of the first 165 (of a total of approximately 425) infantile spasms and Lennox-Gastaut trios (probands and both parents) enrolled in the Epilepsy Phenome/Genome Project (EPGP),which is funded by the NINDS. The investigators, who were from both EPGP and the Epi4K Center Without Walls, identified 10 novel genes that have a high likelihood of being the cause of infantile spasms or Lennox-Gastaut, along with seven genes previously associated with these syndromes. Overall, they were able to identify the likely genetic basis of 15 percent of the cohort, a number that is expected to increase.

Why It's Important: Infantile spasms and Lennox-Gastaut are devastating pediatric epilepsy syndromes, mostly of unknown cause. The discovery of these genes underscores the fact that many patients with infantile spasms and Lennox-Gastaut have de novo — rather than inherited — mutations. Identification of these mutations could lead to specific therapeutic interventions based on genetic underpinnings, or could lead to screening tests to determine children at risk. More work needs to be done, but these results are very encouraging.

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NEUROCRITICAL CARE

KEVIN N. SHETH, MD assistant professor of neurology and neurosurgery, surgery, anesthesiology, and emergency medicine, University of Maryland, Baltimore, MD.

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The Pick: Lansberg MG, Straka M, Albers GW, et al, for the DEFUSE 2 study investigators. MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study. Lancet Neurol 2012:11(10):860–867.

The Advance: Whether endovascular stroke treatment improves clinical outcomes is unclear because of the paucity of data from randomized placebo-controlled trials. In the Lancet Neurology study, the DEFUSE 2 investigators aimed to establish whether MRI can be used to identify patients who are most likely to benefit from endovascular reperfusion: 110 patients had catheter angiography and of these 104 had an MRI profile and 99 could be assessed for reperfusion. Forty-six of 78 (59 percent) patients with target mismatch and 12 of 21 (57 percent) patients without target mismatch had reperfusion after endovascular treatment. Reperfusion was associated with increased good functional outcome at 90 days (OR 4ċ0, 95% CI 1ċ3–12ċ2) in the target mismatch group, but not in the no target mismatch group (1ċ9, 0ċ2–18ċ7). Target mismatch patients who had early reperfusion after endovascular stroke treatment had more favorable clinical outcomes. No association between reperfusion and favorable outcomes was present in patients without target mismatch.

Why It's Important: DEFUSE-2 strongly suggests that MRI based imaging is important, reliable, and practical for endovascular decision-making. The signal from point 1 can very strongly help to identify futile patients and suggests that MRI should be done prior to intra-arterial therapy.

The Pick: Nogueira RG, Lusep HL, Smith WS, et al, for the TREVO 2 Trialists. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): A randomised trial. Lancet 2012; 380(9849):1231–1240.

The Advance: Present mechanical devices are unable to achieve recanalization in up to 20–40 percent of large vessel occlusion stroke. In the Lancet study, the investigators compared efficacy and safety of the Trevo Retriever, a new stent-like device, with the US Food and Drug Administration-approved predecessor, the Merci Retriever. They randomly assigned 88 patients to the Trevo Retriever group and 90 patients to the Merci Retriever Group. Eighty-six percent in the Trevo group and 60 percent in the Merci group met the primary endpoint — thrombolysis in cerebral infarction scores of 2 or greater reperfusion with the assigned device alone — after the assigned device was used. There were no differences in incidence of the primary safety endpoint — a composite of procedure-related adverse events. The team concluded that patients who have had large vessel occlusion strokes but are ineligible for (or refractory to) intravenous tissue plasminogen activator should be treated with the Trevo Retriever in preference to the Merci Retriever.

Why It's Important: The Lancet study suggests that stent retrievers have made a big leap — from safety and efficacy perspectives. Perhaps potential endovascular patients need to get an MRI and if they have good target volume and are not futile, they should receive stent-based therapy.

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STROKE

JAMES C. GROTTA, MD, professor of neurology, University of Texas Medical School, Houston, TX.

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The Pick: Sandercock P, Wardlaw JM, Arauz A, et al, for the 3rd International stroke trial (IST-3). The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (The third international stroke trial [IST-3]): A randomised controlled trial. Lancet 2012;379:2352–2363.

The Finding: This was a large randomized trial of IV tissue plasminogen activator (tPA) given up to six hours after stroke in patients who did not qualify for tPA using standard criteria. Overall results were not positive, but patients treated within three hours did benefit, and patients over the age of 80 did as well as younger patients.

Why It's Important: This trial confirmed in real life situations in community hospitals that tPA is effective within three hours of stroke onset in a wider cohort of patients than is currently recommended by existing guidelines, especially for those over 80 years old. It also cast doubt on the benefit of treatment beyond three hours.

The Pick: Saver JL, Jahan R, Zaidat OO, et al, for the SWIFT Trialists. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): A randomised, parallel-group, non-inferiority trial. Lancet 2012;380(9849):1241–1249.

The Findings: This was a randomized comparison of a new “stent retriever” device versus older devices for endovascular thrombectomy in patients with acute ischemic stroke. The investigators found that the newer device opened more arteries, faster, and with better clinical outcomes.

Why It's Important: Many devices are now approved for thrombectomy but there is still uncertainty about clinical benefit. This has retarded enthusiasm for conducting randomized trials to evaluate efficacy, and cast doubt on the significance of trials that have been done so far because recanalization has often been delayed or incomplete. This new device (and others like it) will make it possible to open arteries faster and more completely and will become the new “gold standard” which will hopefully now be tested for efficacy compared to standard therapy.

See Neurology Today story, “News from the International Stroke Conference: Novel Clot Retrieval Device Outperforms Merci for Acute Ischemic Stroke,” http://bit.ly/HBa7TD.

The Pick: RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial data —reported at the Transcatheter Cardiovascular Therapeutics scientific symposium in November 2012.

The Findings: This was a randomized trial of patent foramen ovale (PFO) closure versus medical management for patients with PFO who have had a cryptogenic stroke — that is, no other cause was identified. While the primary outcome of recurrent stroke was just missed for significance — they showed the primary endpoint (all recurrent strokes) was similar between the PFO closure and medical therapy arms (1.8 vs. 3.3 percent, relative risk [RR] 0.53, 95 percent confidence interval [CI] 0.23–1.22, p = 0.16) — “on treatment” analysis confirmed a benefit favoring PFO closure (HR 0.37, 95 percent CI 0.14–0.96, p = 0.03), especially in patients with larger PFOs or with atrial septal aneurysm. There were low complication rates and high technical success rate.

Why It's Important: PFO is very common and most experienced clinicians are convinced that it is causally related to strokes in some patients. Previous studies of PFO closure had been negative, but had included transient ischemic attack patients and there was a high rate of complications and persistent shunt after the procedure. RESPECT was a better study in that it was confined to the subset of patients most likely to have PFO related stroke, and the device/procedure was technically successful and safe in almost all patients. The results are logical, and while the incidence of recurrent stroke was low in both groups, the preponderance of data supports PFO closure in selected patients (young cryptogenic stroke patients with large PFO or atrial septal aneurysm) in experienced hands.

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PAIN MANAGEMENT

ANNE LOUISE OAKLANDER, MD, PhD, associate professor of neurology, Harvard Medical School, Boston, MA.

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The Picks: All three papers report serious side effects of epidural steroid injections.

Kainer MA, Reagan DR, Jones TF, et al, for the Tennessee Fungal Meningitis Investigation Team. Fungal infections associated with contaminated methylprednisolone in Tennessee. N Engl J Med 2012;367 (23):2194–2203.

Al-Shoha A, Rao DS, Mandel S, et al. Effect of epidural steroid injection on bone mineral density and markers of bone turnover in postmenopausal women. Spine (Phila Pa 1976) 2012; 37 (25):E1567-E1571.

Cohen-Adad J, Buchbinder B, Oaklander A. Cervical spinal cord injection of epidural corticosteroids: Comprehensive longitudinal study including multiparametric magnetic resonance imaging. Pain 2012;153 (11):2292–2299.

The Findings: The report by MA Kainer is one of several published in the last few months documenting the US meningitis epidemic (541 cases, 36 deaths, at press time) caused by contaminated epidural steroid injections from a little-regulated compounding pharmacy in Framingham, MA. The report by A. Al-Shoha, et al, finds that a single epidural steroid injection suffices to significantly reduce bone marrow density in the hip six months later, and the paper by J Cohen-Adad, et al, finds that having epidural steroid injections injected into the spinal cord can cause long lasting spinal cord injury.

Why It's Important: These reports should curtail use of epidural steroid injections (ESI) for chronic back and/or neck pain. Since there is little (lumbar ESI) or no (cervical ESI) evidence of benefit as compared to placebo or oral steroids, the significant cost and risk of even rare serious adverse events argue against routine referral by neurologists and other physicians for ESI. Plus, all other spinally administered medications need closer regulation.

See Neurology Today coverage of the meningitis outbreak associated with epidural steroid injections: http://bit.ly/UOFIHU.

See more picks from the Neurology Today editorial advisory board in the next issue.

©2013 American Academy of Neurology

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