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Best Papers of 2011: Picks from the Neurology Today Editorial Advisory Board


When there are almost daily announcements about major neurology “advances,” how do you choose the wheat from the chaff? Neurology Today asked its editorial advisory board — all leaders and experts in the field — to help us decide. We asked them to select their favorite “picks” for the most noteworthy studies in 2011.

Read on to find out why they chose these studies and what they had to say about why they are “game changers” and important to the field. [Note: These are presented not in the order of importance, but by the alphabetical order of the editorial advisory board members.]

  1. Cruse D. Chennu S, Chatelle C, et al. Bedside detection of awareness in the vegetative state: A cohort study. Lancet 2011; E-pub 2011 Nov. 9.
  2. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72(2): 257-68. E-pub 2011 Sep 21.
  3. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72(2):245-256. E-pub 2011 Sep 21.
  4. Murff HJ, FitzHenry F, Speroff T, et al. Automated identification of postoperative complications within an electronic medical record using natural language processing. JAMA 2011;306(8):848-855.
  5. Lucchinetti CF, Popescu BFG, Ransohoff RM, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011; 365:2188-2197.
  6. Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: A meta-analysis of placebo-controlled randomised trials. Lancet Neurol 2011;10(11):961-968.
  7. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011;365:993-1003.
  8. Granger CB, Alexander JH, Wallentin L, et al, for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992.
  9. Connolly SJ, Eikelboom J, Yusuf S, et al, for the AVERROES Sterring Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364(9): 806-817.
  10. Emery EC, Young GT, McNaughton PA, et al. HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science 2011; 333(6048):1462-1466.
  11. Cooper DJ, Rosenfeld JV, Wolfe R, et al, for the DECRA Trial Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. N Eng J Med 2011; 364: 1493-1502.


James L. Bernat, MD, professor of neurology and medicine, Dartmouth Medical School: In the Lancet, D Cruse, and colleagues reported that bedside EEG responses to commands (“motor imagery”) were shown to detect presence of awareness of self in several patients diagnosed in a vegetative state who showed no evidence for awareness on a thorough neurological examination.

This study supplements published fMRI studies that, in a few clinically diagnosed vegetative state patients, show patterns of response to questions that indicate awareness. But, unlike the fMRI protocols that can be performed in only a few medical centers, this EEG protocol could be conducted at most medical centers.


Thomas Bird, MD, professor of neurology, University of Washington VA Medical Center, Seattle, WA: In back-to-back papers in the same issue of Neuron, M DeJesus-Hernandez, and colleagues, and AE Renton and colleagues, report the discovery of a novel expanded hexanucleotide repeat in a gene of unknown function on chromosome 9 (C9ORF72) in kindreds with familial frontotemporal dementia (FTD), familial amyotrophic lateral sclerosis (ALS) and sporadic cases of both diseases.

These findings are noteworthy and exciting because this new mutation appears to be the most common cause of familial FTD and ALS and also appears to be responsible for perhaps 4 percent of sporadic ALS cases. These findings will impact genetic testing and counseling of these diseases, raise important questions about genetic factors in sporadic ALS, and provide an entirely new focus for identifying a novel protein and mechanism underlying these common and severe neurodegenerative diseases.


Neil A. Busis, MD, chief, Division of Neurology, University of Pittsburgh Medical Center-Shadyside, Pittsburgh, PA: In the Journal of the American Medical Association, H. J. Murff and colleagues reported that among patients undergoing inpatient surgical procedures at VA medical centers, natural language processing analysis of electronic medical records to identify postoperative complications had higher sensitivity and lower specificity compared with patient safety indicators based on discharge coding.

As noted in an accompanying editorial, US health care is entering a new era — moving from a cottage industry to one in which health care systems will be key to delivering safe, effective, and efficient care. Electronic health records will play a central role in this transformation. Currently, the electronic health record remains a tool with vast potential but a limited set of current capabilities. Natural language processing has the potential for many new applications such as automated quality assessment to assisting in the performance of comparative effectiveness research. The promise of natural language process has been on the horizon for some time. The study by HJ Murff et al, suggests that these benefits may be closer than ever, but only if the power of computing is harnessed to understand the vast amount of written data that currently needs a pair of eyes and a human brain to comprehend it.


John Corboy, MD, professor of neurology, University of Colorado School of Medicine, CU Anschutz Medical Campus, Aurora, CO: C Lucchinetti and colleagues report that in a cohort of patients with early-stage multiple sclerosis (MS), cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation.

Cortical demyelination was present in 53 patients (38 percent) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81 percent of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72 percent of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82 percent) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41 percent) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study.

This study may help redefine the nature of how we think of the pathogenesis of MS. (Watch for the story in the next issue of Neurology Today.)


Andrew S. Feigin, MD, associate professor of neurology & molecular medicine, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY: Like Dr. Bird, Dr. Feigin also cited the study by AE Renton et al, adding that a hexanucleotide repeat expansion within a non-translated portion of DNA (an intron) is the most common mutation responsible for familial ALS and can also underlie FTD; (in this study, approximately 30 percent of sporadic FTD patients had this expansion).

This finding suggests that abnormalities of RNA metabolism may be an underlying cause for several neurodegenerative disorders, and this could lead to novel therapies for some of these disorders.


Jacqueline A. French, MD, professor of neurology, New York University Comprehensive Epilepsy Center, New York, NY: P. Ryvlin et al, provided a meta-analysis of patients randomized to placebo or active drug in 112 add-on antiepileptic drug (AED) studies of refractory partial-onset seizures. They reported five-fold more cases of sudden unexpected death (SUDEP) in the patients randomized to add-on placebo vs efficacious doses of a new drug. Rates of definite or probable SUDEP per 1000 person-years were 0 9 (95% CI 0 2-2 7) in patients who received efficacious AED doses and 6 9 (3 8-11 6) in those allocated to placebo. Confidence intervals were not overlapping.

This is a surprising finding, considering all patients had chronic epilepsy, and most had failed many AEDs before being randomized into their respective studies, and were already receiving one to three background drugs. Yet, they still gained substantial protection from the new drug that was added.

The results are game changing for several reasons. The first is that this is the first study that provides compelling evidence that SUDEP risk can be changed by adjusting treatment. The second is that it indicates that treatment-resistant patients should be encouraged to continue trying new therapies. Finally, it raises significant concerns about studies in uncontrolled patients that include long placebo periods, even if the study has an add-on design.


James C. Grotta, MD, professor of neurology, University of Texas Medical School, Houston, TX: In the New England Journal of Medicine study by MI Chimowitz et al, patients with severe intracranial arterial stenosis causing transient ischemic attack (TIA) or stroke were randomized to medical therapy with or without stenting. The study was stopped early by the Data and Safety Monitoring Board because of a high rate of early stroke and death in the stenting group, which made it impossible for the stenting group to be associated with lower long term recurrent stroke risk compared to patients treated with medical therapy alone. Medical therapy included short-term use of aspirin and clopidogrel (Plavix) as well as active intervention by a health management group to encourage medication compliance and achievement of clinical benchmarks.

First, the study showed that intracranial stenting was associated with higher risk than previously anticipated even though the procedure was carried out in “expert” centers. Thus, improved stenting methodology is needed before intracranial stenting is done outside of clinical trials. Second, the rate of recurrent stroke in the medical group was much lower than expected in this very high risk patient cohort, indicating that “aggressive” medical therapy as used in this study is very effective in stroke prevention.


Vladimir Hachinski, MD, professor of neurology, University of Western Ontario, London, Ontario: In the New England Journal of Medicine, CB Granger et al, compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause.

In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. This is a game changer because it shows that apixaban can be used in a larger number of patients within the limits of increased costs.


Donald J. Iverson, MD, Humboldt Neuro-logical Medical Group, Eureka, CA: In the New England Journal of Medicine, SJ Connolly et al, reported data from a double-blind study, which randomly assigned 5,599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism.

In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. This study is a game-changer because it has been a long wait for an alternative to warfarin and all of its hassles (blood monitoring and drug interactions). Unfortunately, though, the lack of an antidote for apixaban may limit its acceptance for widespread usage.


Anne Louise Oaklander, MD, PhD, associate professor of neurology, Harvard Medical School, Boston, MA: In this report in Science, E. C. Emery et al, offer insights into the important role of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels in inflammatory and neuropathic pain. Overactivity of primary sensory neurons is a hallmark of neuropathic pain, and ion channels known as HCN channels are newly implicated, specifically HCN2. While other channels respond to membrane depolarization, HCN channels are activated by hyperpolarization. After action potential firing, HCN channels open to depolarize the membrane in preparation for another round of action potentials, which puts them in a position to regulate the repetitive neuronal firing that drives neuropathic pain.

In a mouse model of neuropathic pain (and of inflammatory pain), knocking out HCN2 in nociceptive neurons protected animals from developing hypersensitivity to heat, cold, or touch.

These dramatic behavioral effects suggest that HCN2, and the nociceptors that express them are at the root of neuropathic pain. If the role of HCN2 in people is confirmed, HCN2 could offer a novel target for developing new pain treatments. The HCN2 knockout mice retained normal baseline sensitivity to pain, suggesting that blocking HCN2 might block neuropathic pain while preserving acute pain responses for protection.


Kevin N. Sheth, MD, assistant professor of neurology and neurosurgery, surgery, anesthesiology, and emergency medicine, University of Maryland, Baltimore, MD: In this New England Journal of Medicine study, D. James Cooper et al, randomized patients with severe diffuse traumatic brain injury and intracranial hypertension refractory (defined as ICP > 20 mm Hg for greater than 15 minutes) to standard of care medical therapy versus early bifrontal temporoparietal decompressive craniectomy. In addition, patients with focal hematomas and prior evacuation were excluded. Patients who underwent surgical decompression had fewer episodes and duration of intracranial hypertension; however, they had worse scores by six-month functional outcomes. Rates of death were similar in both groups.

First, this study was an important milestone for a deadly condition and a potential treatment with considerable practice variability. There have previously been no randomized controlled trials evaluating decompressive craniectomy in adults with traumatic brain injury. The study showed that the surgical procedure used, early and aggressively, in a specific group of patients with diffuse injuries, did not result in improved overall outcomes for patients. The results also draw attention to our current ability to measure and interpret intracranial pressure in a meaningful way. While the surgical decompression should not be abandoned on the basis of this study alone, clearly, further study is required to identify those circumstances when it may be beneficial.wzThis kind of important comparative effectiveness study is hopefully a preamble to similar future studies in neurocritical care.