The daily barrage of “groundbreaking” news in neurology research makes it challenging for clinicians to decipher what is truly important for their practice. We asked members of our editorial advisory board — all leaders in the field — to help separate the “wheat from the chaff,” so to speak, in highlighting the most important advances, policies, and developments this year. Read on to find out what they “picked” — and why — as most noteworthy in 2013.
The Pick: Strand JJ, Kamdar MM, Carey EC. Top 10 things palliative care clinicians wished everyone knew about palliative care. Mayo Clin Proc 2013; 88(8): 859–865.
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Results: Palliative care physicians at large academic medical centers summarized the essential elements of palliative medicine that all physicians should know. They debunk common misconceptions, show how integrating palliative care into the management of chronic and terminal illness improves the quality of care, and argue for incorporating palliative care earlier into the care plan of patients with serious illnesses.
Why It's Important: All neurologists should incorporate the principles and practice of palliative care in their management of neurological patients with chronic and terminal illnesses. This article provides the evidence for doing so and shows how it improves the quality of care we give our patients, particularly in the areas of complex symptom management — for example, treating non-pain symptoms such as nausea, delirium, and fatigue; communication (that is, responding to emotion and demonstrating empathy); establishing goals of care; and facilitating medical decision-making.
The Picks: Guerreiro R, Wojtas A, Brás J, et al. TREM2 variants in Alzheimer's disease. N Engl Med 2013; 368(2): 117–127.
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Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 2013; 368(2): 107–116.
Results: Using different approaches, two groups independently found that a variant (R47H) in the TREM2 (triggering receptor expressed on myeloid cells 2 protein) gene is a rare but strong genetic risk factor for late-onset Alzheimer's disease (AD) in the general population.
Why It's Important: Among other things, the TREM2 protein is involved with phagocytosis by microglia. Relating a variant in this gene/protein to AD strongly supports the involvement of microglia and the immune system in the pathogenesis of this important disease and also adds another factor to genetic risk for AD.
The Pick: Broderick JP, Palesch YY, Demchuk AM, et al. Interventional Management of Stroke (IMS) III Investigators: Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013; 368(13):1265. [This paper was also one of Dr. Grotta's best paper selections for 2013.]
Figure. KEVIN N. SHE...Image Tools
The Results: This study of endovascular therapy for ischemic stroke had been funded by the National Institute for Neurological Disorders and Stroke and running for several years. It was stopped early at an interim analysis because of futility to achieve very good functional outcome compared with treatment with tissue plasminogen activator (tPA) alone. Investigators reported similar mortality findings in the endovascular-therapy and intravenous tPA groups at 90 days (19.1 percent and 21.6 percent, respectively; p = 0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of tPA (6.2 percent and 5.9 percent respectively; p = 0.83).
Why It's Important: The study has had, and continues to have, major implications for the utility and practice of intra-arterial therapy across the country and has potential implications for referral patterns and reimbursement. At the same time, there has been a lot of excitement in this area because of the new-generation stent retrievers, for which the trials have been rather promising. We will continue to learn a great deal about the importance of speed, technology, and patient selection through secondary analyses of these findings. This story will continue to unfold.
See the Neurology Today article on this study: “NEWS FROM THE INTERNATIONAL STROKE CONFERENCE: No Improvement Found in Stroke Outcomes with Endovascular Treatment”: http://bit.ly/YQXWub.
The Picks: Yosef N, Shalek AK, Gaublomme JT, et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature 2013; 496(7446):461–468.
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Wu C, Yosef N, Thalhamer T, et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 2013:496(7446): 513–517.
Kleinewietfeld M, Manzel A, Titze J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 2013;496(7446): 518–522.
Results: These three studies published in the same issue of Nature describe the molecular pathways that can precipitate autoimmune disease, and identify a high-salt diet as a potential risk factor for developing multiple sclerosis. In the first study, the investigators developed a functional model of how TH17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases, are regulated. In the second study, the investigators found that mouse cells cultured in high-salt conditions had higher expression of serum glucocorticoid kinase 1 (SGK1) and produced more TH17 cells — thus, providing an insight into a molecular mechanism by which a high-salt diet triggers TH17 development and promotes tissue inflammation. The third study found that mice fed with a high-salt diet develop a more severe form of experimental autoimmune encephalomyelitis, an animal model for MS, in line with augmented CNS infiltrating and peripherally induced antigen-specific TH17 cells. They concluded that increased dietary salt intake “might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.”
Why It's Important: The three studies suggest a possible mechanism by which salt may enhance autoimmunity. Whether a high-salt diet is responsible for disease progression or worsening will need to be the focus for future studies. But if proven, neurologists could begin to counsel patients on the merits of following a low-salt diet.
The Picks: Ash PE, Bieniek KF, Petrucelli L, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013; 77(4): 639–646.
Figure. DAVID GILL, ...Image Tools
Mori K, Weng SM, Edbauer D, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 2013; 339(6125): 1335–1338.
The Results: These two articles, published concurrently in two different journals, looked at the effect of the C9ORF72 (chromosome 9 open reading frame 72) mutations, which are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). This gene mutation is an “über” long repeat and may contain hundreds to thousands of GGGGCC repeats. These repeats are transcribed into RNA, but are also translated into proteins despite not having a start signal. This process, called “repeat-associated nonstandard” translation, produces dipeptide proteins and accumulates into inclusions.
Why It's Important: This finding is noteworthy because it not only provides an explanation for the pathophysiology of this gene mutation, but also suggests that there may be a new mechanism of disease at work in patients with the gene mutation.
The Pick: Monsell SE, Mock C, Roe CM, et al. Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology. Neurology 2013;80(23):2121-2129.
The Results: This autopsy-based study looked at subjects with and without symptoms of AD who had varying degrees of AD neuropathologic changes. Among the findings, expression of AD symptoms was affected more by neurofibrillary tangle scores than neuritic plaque burden, and symptomatic patients tended to be older, have a history of recent depression, and have higher Hachinski Ischemic Scores, suggestive of vascular dementia (although cerebrovascular pathology was not associated with symptoms). There was also an effect of apolipoprotein E (APOE) allelic status even after the amount of amyloid-beta neuropathology was taken into account.
Why It's Important: This finding is noteworthy because it not only provides an explanation for the pathophysiology of this gene mutation (APOE), but also suggests that there may be a new mechanism of disease at work in patients with the gene mutation.
The Pick: Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral hemorrhage (STICH II): A randomized trial. Lancet 2013; 382: 397–408.
Figure. JAMES C. GRO...Image Tools
Results: Previous studies have suggested that superficial lobar hematomas might benefit from surgical evacuation. Those results prompted this randomized study comparing early evacuation versus medical therapy. While there was no benefit overall, post-hoc analysis suggested that surgery reduced mortality and improved outcome in those patients with larger hematomas who were deteriorating due to mass effect. [174 (59 percent) of 297 patients in the early surgery group had an unfavorable outcome versus 178 (62 percent) of 286 patients in the initial conservative treatment group (absolute difference 3.7% [95 percent CI –4.3 to 11.6], odds ratio 0.86 [0.62 to 1.20]; p=0.367).]
Why It's Important:
This study likely adds the final needed piece of evidence to recommend against the routine evacuation of intracerebral hematomas. However, if the patient is deteriorating due to the mass effect of a superficial lobar hemorrhage, surgical evacuation should still be considered. Furthermore, studies of minimally invasive clot extraction are now under way.
The Pick: Toledo JB, Arnold SE, Raible K, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre. Brain 2013; 136: 2697–2706.
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Results: In a series of 6205 autopsy cases of dementia, all types of dementias were found to have a vascular component, ranging from 60 percent in frontotemporal dementias to 80 percent in AD. In every case, the presence of vascular disease decreased the threshold of the presentation of dementia.
Why It's Important: Vascular disease is highly treatable, and identifying the vascular component could prevent, delay, or mitigate dementia. Even a small delay in the onset would make a huge difference. For instance, delaying the onset of AD by one year would cut the prevalence by 20 percent; delaying it by five years would cut the prevalence of dementia in half.
The Picks: The implementation of the Patient Protection and Affordable Care Act (PPACA).
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Feig AB, Ding EL. Evidenced Formal Coverage Index and universal healthcare enactment: A prospective longitudinal study of economic, social, and political predictors of 194 countries. Health Policy 2013; 113(1):50–60.
Results: Mexico, Turkey, and the US — three of 34 member countries of the Organisation for Economic Co-operation and Development, whose mission is to promote policies that improve the economic and social well-being of people around the world — are ranked number 2, 3, 4, respectively, in inequality. Among all countries, the lack of universal coverage is also correlated with income inequality, as well as low levels of income and education, ethnic fractionalization, and governance by dictatorship or other non-democratic forms of government.
Why It's Important: The PPACA is the biggest US health policy change in 50 years. In adding an additional layer of expense by mandating private health insurance, however, it may prove too expensive to fully implement. A simpler and less expensive alternative — expansion of Medicare (the “public option”) — was opposed by members of both parties who were heavily influenced by the health insurance lobbies' efforts against it. Although the overall number of insured may increase under the PPACA, the lack of health insurance for those still unable to afford it will remain a shameful and serious public health issue.
The Pick: Aviles-Olmos I, Dickson J, Kefalopoulou1 Z, et al. Exenatide and the treatment of patients with Parkinson's disease. J Clin Invest 2013; 123(6):2730–2736.
Figure. ANDREW S. FE...Image Tools
This study utilized a novel approach to early phase clinical trial design to provide preliminary evidence that an established diabetes drug, exenatide — a glucagon-like peptide-1 receptor agonist — is a well-tolerated and possibly effective treatment for Parkinson's disease. The investigators reported that exenatide-treated patients had a mean improvement at 12 months on the Movement Disorders Society Unified Parkinson's Disease Rating Scale of 2.7 points, compared with a mean decline of 2.2 points in control patients (p = 0.037).
Why It's Important:
Disease modifying therapies are desperately needed for neurodegenerative disorders, yet developing such drugs presents many daunting challenges. Though early phase clinical trials can establish preliminary safety data, providing compelling preliminary efficacy data in a cost-effective manner has been a vexing problem. This study highlights two important approaches to addressing this challenge. First, repurposing existing drugs approved for other indications may hasten the drug development process because a wealth of safety and tolerability data already exist. Second, the study utilized a novel non-placebo controlled design that involved the use of a parallel best medical therapy group, a two month washout period at the end of the 12-month treatment period, and perhaps most importantly, blinded video assessments by independent raters. Though this study does not provide conclusive evidence of efficacy, the data are compelling and may increase confidence in committing to a multi-million dollar definitive phase 3 efficacy trial.
The Pick: Cook MJ, O'Brien TJ, Himes D, et al. Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: A first-in-man study. Lancet Neurol 2013; 12(6):563–571.
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The Results: This study investigated the seizure advisory system for patients with treatment-resistant epilepsy. The system uses an implanted device with an audio channel and an individualized computer algorithm to provide patients with real-time information about whether they are at risk for a seizure within the next half hour. Fifteen patients were implanted with the device. In conjunction with EEG, the seizure advisory system created a well-documented diary of confirmed clinical seizures for the implanted patients.
Why It's Important: The results prove that seizure prediction — a problem many researchers are working on — is feasible. Of equal importance, the device picked up a large number of clinical seizures that were not recorded on the seizure diaries maintained by patients. In fact, very little correlation was found between the seizures that patients reported and the confirmed seizures captured by the device. This finding highlights the fact that many patients with treatment-resistant epilepsy are unable to report accurate seizure counts, which has both clinical and research implications.
The Pick: Neligan A, Haliasos N, Solomon JK, et al. A survey of adult and pediatric epilepsy surgery in the United Kingdom. Epilepsia 2013; 54(5): e62–e65.
The Results: The Society of British Neurologic Surgeons surveyed every adult and pediatric epilepsy surgery center in the United Kingdom (n=23) to determine the number of epilepsy surgeries being performed in 2011. They compared this to the (previously published) numbers that had been performed in 2003. The results indicate that the number of all resective epilepsy surgeries decreased while the number of vagus nerve stimulators implanted increased. The number of temporal lobe resections — the most common type of surgery — went from 318 in 2000 to 182 in 2011 (a decrease of 43 percent). The number of surgeries for mesial temporal sclerosis went from 208 to 118, while surgeries for non-lesional temporal lobe epilepsy rose.
Why It's Important: This is the first country-wide study to confirm several other surveys in the United States, Sweden, and Germany, indicating a drop in epilepsy surgery, temporal lobe epilepsy surgery in particular. This is striking, as it follows the publication of both a randomized controlled trial that demonstrated the effectiveness of epilepsy surgery — Wiebe S, Blume WT, Eliasziw M, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001; 345: 311-318 — and widely disseminated evidence based guidelines endorsing temporal lobectomy (Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Neurology 2003; 60: 538–547). The fact that these data represent an entire country eliminates one previously suggested cause for the drop in epilepsy surgery, namely an increase in smaller epilepsy centers reducing referrals to larger academic centers. Other theories explaining the drop include a reduction in the number of suitable epilepsy surgery candidates, perhaps due to better treatment of febrile status epilepticus (a presumed cause of mesial temporal sclerosis), and a reduction in the number of serious traumatic brain injuries. Unfortunately, studies do not indicate a reduction in the number of treatment-resistant epilepsies, indicating that many patients with treatment-resistant epilepsy are not candidates for surgery.
HEALTH POLICY/PRACTICE MANAGEMENT
The Pick: Moses H III, Matheson DHM, Yoshimura S, et al. The anatomy of health care in the United States. JAMA 2013; 310 (18):1947–1963.
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The Results: Publicly available data were used to identify health care trends, principally from 1980 to 2011, in the source and use of funds; the people receiving and organizations providing care; and the resulting value created and health outcomes. The authors found that since 2000, price (especially of hospital charges, professional services, drugs and devices, and administrative costs) — not demand for services or aging of the population — produced 91 percent of cost increases; personal out-of-pocket spending on insurance premiums and co-payments declined, from 23 percent to 11 percent; and chronic illnesses accounted for 84 percent of costs overall among the entire population, not only of the elderly. Three factors have produced the most change, the authors assert: consolidation, with fewer general hospitals and more single-specialty hospitals and physician groups; information technology, in which investment has occurred but value is elusive; and a trend toward the patient as consumer, whereby influence is sought outside traditional channels using social media, informal networks, new public sources of information, and self-management software.
Why It's Important: This is the best available overview of the current state of affairs and future challenges to our health care system. Also of interest is the fact that Dr. Moses, the lead author, is a neurologist.
The Pick: Han L, Ma C, Dong X, et al. A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 2013; 16 (2):174–182.
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The Results: This paper identified a unique subset of unmyelinated sensory neurons that only innervate the skin and appear to specifically mediate itch. They express the mas-related G-protein A3 receptor — believed to regulate nociceptor function and/or development — as well as markers of nociceptive neurons. This suggests that there are distinct neuronal pathways for itch.
Why It's Important: This may allow the development of new treatments for neuropathic itch, a sometimes disabling condition triggered by many neurological conditions including shingles, peripheral neuropathy, and stroke. Treatments for dermatological itch, such as antihistamines, are ineffective for neuropathic itch.
The Picks: Zhang XY, Wen J, Liu JY. Gain-of-function mutations in SCN11A cause familial episodic pain. Am J Hum Genet 2013; 93 (5): 957–966.
Leipold E, Liebmann L, Kurth I, et al. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat Genet 2013; 45(11):1399–404.
The Results: These new studies show that mutations in SCN11A (sodium channel, voltage-gated, type XI, alpha subunit), which encodes the Nav1.9 voltage-gated sodium channel, underlie newly characterized congenital neuropathies characterized by combinations of insensitivity to pain, spontaneous neuropathic pain, and recurrent tissue damage and mutilation.
Why It's Important: By implicating a new sodium channel gene — Nav1.9 encoded for by the SCN11A gene — as a contributor to pain sensation, these papers identify a potential cause of painful neuropathy and a potential new target for therapy development.
The Picks: Üçeyler N, Zeller D, Sommer C, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013; 136(Pt 6):1857–1867.
Oaklander AL, Herzog ZD, Klein MM, et al. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain 2013; 154(11): 2310–2316.
Albrecht PJ, Hou Q, Rice FL, et al. Excessive peptidergic sensory innervation of cutaneous arteriole-venule shunts (AVS) in the palmar glabrous skin of fibromyalgia patients: Implications for widespread deep tissue pain and fatigue. Pain Med 2013;14 (6):895–915.
Serra J, Collado A, Bostock H, et al. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 2013; E-pub 2013 Nov. 16.
The Results: These three independent papers identify pathological and physiological evidence that fibromyalgia overlaps substantially with small-fiber polyneuropathy and appears to originate in many patients in the peripheral nervous system. It may thus have similar causes or respond to similar treatments used for other painful polyneuropathies.
Why It's Important: These papers identify the first objective abnormalities associated with fibromyalgia and suggest that many fibromyalgia patients may in fact have a neurological disease.