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Best Advances of 2014: Picks from the Neurology Today Editorial Advisory Board

doi: 10.1097/01.NT.0000459771.19184.b3

At Neurology Today, we strive to cover important news that has an impact on clinical practice. But with the constant deluge of new research, it can be difficult to separate the truly revolutionary from the merely interesting. To that end, we asked members of our editorial advisory board — all leaders in their respective fields — to reflect on the most important advances, policies, and professionalism issues in neurology this year. Read on to find out what they picked as the most noteworthy research of 2014 — and why they think it is important.

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The Pick: Sigsbee, B, Bernat, JL. Physician burnout: A neurologic crisis. Neurology 2014; Epub 2014 Nov 5.

Results: The article describes a number of factors contributing to burnout among neurologists. Bruce Sigsbee, MD, FAAN, and James L. Bernat, MD, FAAN, report that neurologists frequently experience burnout, a syndrome characterized by loss of enthusiasm for work (emotional exhaustion), feelings of cynicism (depersonalization), and a low sense of personal accomplishment. Burnout is associated with work–life imbalance, work–home conflicts, substance abuse, depression, and suicide. Burned-out physicians may abandon clinical medicine or choose early retirement. Burnout is more common in physicians than other workers. Neurology is the only medical specialty that has both one of the highest rates of burnout and the poorest work–life balance.

Why It's Important: In an accompanying editorial to the study by Drs. Sigsbee and Bernat, Dr. Busis wrote: “Drs. Sigsbee and Bernat highlight an important problem that has been barely mentioned in the neurologic literature...The guiding principle of today's health care policy is the triple aim: increasing quality of care, decreasing costs, and improving the patient experience. Paradoxically, it ignores what should be a core strategy: ensuring the well-being and engagement of physicians and other health care providers. This omission commoditizes health care. The triple aim can only be achieved if physicians are mentally and physically capable of providing the best care for their patients...We must be proactive to prevent burnout and related problems from developing in the first place. We need to revise the structure, processes, and desired outcomes of our health care system to value the health of physicians and other health care providers as well as patients.”

See the Neurology Today article on this study, “Why Are Neurologists Burned Out?”

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The Pick: Sumowski JF, Rocca MA, Leavitt VM, et al. Brain reserve and cognitive reserve against cognitive decline over 4.5 years. Neurology 2014; 82: 1776-1783.

Results: In a longitudinal study, the investigators examined whether larger maximal lifetime brain growth (MLBG) — brain reserve — protects against cognitive decline over time (4.5 years) for patients with multiple sclerosis (MS). They found that larger MLBG protects against decline in cognitive efficiency, and greater intellectual enrichment protects against decline in cognitive efficiency and memory.

Why It's Important: Cognitive impairment is prevalent in MS patients, especially cognitive inefficiency and memory decline, but as this paper points out, it is difficult to predict who will better withstand the disease-associated burdens of brain atrophy and lesions. This paper lays a good foundation in support of the goal of maximizing lifelong brain health. For example, it suggests that early intervention cognitive rehabilitation may help prevent or delay the onset of functional impairment in patients who have lower brain reserve, and should stimulate more conversation about treatment paradigms for MS.

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The Pick: Paul BD, Sbodio JI, Xu R, et al. Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington's disease. Nature 2014; 509:96-100.

Results: This paper presents compelling evidence from cell culture, several Huntington's disease (HD) transgenic animal models, and from human HD tissue, that transcriptional down-regulation of cystathionine gamma-lyase (CSE) by mutant huntingtin underlies the pathogenesis of HD neurodegeneration. Furthermore, the study also demonstrates that treatment of HD transgenic mice with cysteine and N-acetylcysteine delays the onset of motor abnormalities and reverses declines in overall brain weight and striatal volume.

Why It's Important: The molecular mechanisms underlying the pathogenesis of the HD gene mutation remain ill-defined. This study suggests that CSE and the cysteine biosynthesis pathway may be central to the HD neurodegenerative process. Importantly, if correct, these findings point to novel therapies that could be quickly moved to human clinical trials.

See the Neurology Today article on this study, “Cysteine Supplementation Reverses Abnormalities in Huntington's Disease Cell and Animal Models,”

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The Picks: Srivastava S, Cohen JS, Vernon H, et al. Clinical whole exome sequencing in child neurology practice. Ann Neurol 2014; 76:473-483

Fogel BL, Lee H, Deignan JL, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol 2014; 71(10):1237-1246.

Novarino G, Fenstermaker AG, Zaki MS, et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 2014; 343(6170):506-511.

Results: Using whole exome sequencing, Siddharth Srivastava, MD, and colleagues were able to make a specific diagnosis in 41 percent of 78 patients with childhood neurodevelopmental disabilities. Using the same strategy, Bren Fogel, MD, PhD, and colleagues made a genetic diagnosis in 21 percent of 76 patients with progressive cerebellar ataxia and identified clinically relevant genetic information in 60 percent of these patients. Gaia Novarino, PhD, and others had similar success with autosomal recessive cases of hereditary spastic paraplegia. Note that each group of investigators was studying difficult selected cases that had previously escaped diagnosis through more traditional methods, including more routine single-gene analysis.

Why It's Important: These three studies all make the important point that whole exome sequencing has arrived in the clinical diagnosis of neurological diseases. These are not trivial academic findings because they have implications for genetic counseling, determinations of prognosis, management issues, and potential entry into treatment trials. Positive results can also avoid more invasive procedures such as muscle biopsy. Three challenges remain. First, the cost of exome sequencing will hopefully decrease. Second, insurance companies and Medicare/Medicaid need to be convinced that this testing is clinically relevant and a standard of practice. The recent American Academy of Neurology guidelines for evaluation of muscular dystrophy is an important step in this direction. Third, interpretation of test results can be either straightforward or highly equivocal and problematic. Medical geneticists, testing laboratories, and clinicians will need to sort out these often difficult and challenging problems of interpretation. Genetic counselors will be required to accurately present this information to the patients and families.

See the Neurology Today article, “Novel Gene Discovery Method Implicates New Genes for Hereditary Spastic Paraplegia — Links to Other Neurodegenerative Diseases,” Also, see the Neurology Today article, “AAN Issues Guideline on Diagnosing, Treating Limb-Girdle Muscular Dystrophies,”

EDITOR'S NOTE: The editorial advisory board recommended studies that were due to be published later this month and thus were embargoed at press time. Look for these recommendations in the next issue of Neurology Today.

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The Pick: Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: A practical clinical definition of epilepsy. Epilepsia 2014; 55(4):475-482.

Results: The International League Against Epilepsy published a position paper that states that epilepsy can be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 hours apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60 percent) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years.

Why It's Important: This study expands the group of people who are considered to have epilepsy, and now includes some patients after a single seizure. The definition is now predicated on the likelihood of having a recurrent seizure, rather than the absolute number of seizures that have occurred. In addition, for the first time, there is a definition of the “resolution” of epilepsy (although this is not the same as a cure).

The Picks: Olson H, Shen Y, Avallone J, et al. Copy number variation plays an important role in clinical epilepsy. Ann Neurol 2014; 75(6):943-958.

EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet 2014; 95(4):360-70.

International League Against Epilepsy Consortium on Common Epilepsies. Genetic determinants of common epilepsies: A meta-analysis of genome-wide association studies. Lancet Neurol 2014 13(9):893-903.

Results: These papers address new findings of genetic contributions to epilepsy. We find that it is a complex area, and rather than single gene mutations, there are genetic contributions to a multifactorial etiologic puzzle. Also, de novo mutations are common.

Why It's Important: These three papers are indicative of how rapidly we are learning about the genetic underpinnings of epilepsy, due to large consortia addressing this question.

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The Pick: Cook D, Rocker G. Dying with dignity in the intensive care unit. N Engl J Med 2014; 370: 2506-2514.

Results: The paper offers guidelines for integrating palliative care into intensive care and for maintaining a focus on the goals of care for patients in the intensive care unit (ICU).

Why It's Important: The transition from aggressive to palliative goals for ICU patients is often a struggle in practice with ambivalence shown by both physicians and family members. This article provides practical advice to improve quality ICU care by showing how to integrate both goals.

The Pick: Gold KJ, Goldman EB, Kamil LH, et al. No appointment necessary? Ethical challenges in treating friends and family. N Engl J Med 2014; 371: 1254-1258.

Results: The paper offers guidelines for handling common informal requests from friends or family members for diagnosis and treatment of their ailments and prescription writing.

Why It's Important: All physicians receive requests from family members and friends for treatment or prescriptions. Physicians are often unclear about ethical, legal, and prudential boundaries of acceptable medical care in these situations. This article offers guidelines for physicians when faced with these requests for informal medical care.

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The Pick: Ebinger M, Kunz A, Wendt M, et al. Effects of golden hour thrombolysis: a prehospital acute neurological treatment and optimization of medical care in stroke (PHANTOM-S) substudy. JAMA Neurol 2014; Epub 17 Nov 2014.

Results: The study showed that a specialized stroke ambulance equipped with a CT scanner and staffed by a neurologist, a paramedic, and a radiology technician could treat stroke patients more quickly and efficiently than could hospital care. It found that thrombolytic treatment with tissue plasminogen activator (tPA) during the “golden hour” — the 60-minute window after stroke symptoms begin — carried no higher risk for seven- or 90-day mortality. Rates of golden hour thrombolysis increased six-fold when the mobile stroke unit was in use, and patients who received swift treatment were found to be less likely to have prolonged hospital or nursing home stays.

Why It's Important: This is the first study to provide any information on outcomes of patients treated with tPA within the first hour after symptom onset, a time interval where we would expect much better outcomes than with standard treatment within three hours; no patients were treated in that 60-minute time window in previous efficacy studies so we had no data. It is now possible to achieve treatment in this time frame and obtain the data as a result of pre-hospital delivery of treatment via the mobile stroke unit concept. More study is needed to determine clinical outcomes with such an approach.

See the Neurology Today article, “Stroke Ambulances Make Headway in Early tPA Administration, But Long-Term Outcomes Data Are Needed” on page 1 of this issue.

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The Pick: Jüttler E, Unterberg A, Woitzik J, et al. Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke. N Engl J Med 2014; 370(12):1091-1100.

Results: Investigators randomly assigned 112 patients 61 years of age or older with malignant middle-cerebral-artery infarction to either conservative treatment in the intensive care unit (the control group) or hemicraniectomy; assignments were made within 48 hours after the onset of symptoms. The primary endpoint was survival without severe disability (defined by a score of 0 to 4 on the modified Rankin scale, which ranges from 0 [no symptoms] to 6 [death]) six months after randomization. Decompressive craniectomy increased survival without extreme disability in patients with large stroke with swelling; the proportion of patients who survived without severe disability was 38 percent in the hemicraniectomy group, as compared with 18 percent in the control group (odds ratio, 2.91; 95% confidence interval, 1.06 to 7.49; p=0.04). However, most survivors needed help with daily activities.

Why It's Important: This is a compelling study because we now have definitive evidence about how to counsel patients and proceed with decisions about surgery for swelling after ischemic stroke. The study also highlights that patients, especially those who are older, are at high risk for death and a lack of independence after this large stroke and that swelling is a serious problem. We need to urgently develop methods to monitor swelling and therapies to prevent and/or treat it when it occurs.

See the Neurology Today article on this study, “Decompressive Hemicraniectomy: To Halve or Not for Older Stroke Patients,”

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The Pick: Josephs KA, Whitwell JL, Weigand SD, et al. TDP-43 is a key player in the clinical features associated with Alzheimer's disease. Acta Neuropathol 2014; 127(6):811-824.

Results: In this autopsy-based study, subjects pathologically diagnosed with Alzheimer's disease were screened for brain TAR DNA-binding protein 43 (TDP-43) deposition. Fifty-seven percent were TDP-43 positive, and after accounting for the other known determinants of cognitive dysfunction in Alzheimer's disease, TDP-43 was found to be strongly associated with memory dysfunction and medial temporal lobe atrophy. TDP-43-positive subjects were ten times as likely to cognitively impaired, and the greater the TDP-43 burden, the greater the magnitude of cognitive impairment and medial temporal lobe atrophy.

Why It's Important: The TDP-43 protein, which has only recently been implicated in frontotemporal lobar degeneration and amyotrophic lateral sclerosis, may play a significant role in patients with Alzheimer's disease, either as part of the Alzheimer's disease process or as a separate neurodegenerative process. This reinforces the concept that Alzheimer's disease is a much more complex disease than was originally thought, and there may be more than one process that leads to Alzheimer's disease. This may also identify a new therapeutic target.

See the Neurology Today article on this study, “NEWS FROM THE ALZHEIMER'S ASSOCIATION INTERNATIONAL CONFERENCE: TDP-43 Emerges as a Major, and Perhaps Independent, Contributor to Memory Loss,”

The Picks: Porsteinsson AP, Drye LT, Pollock BG, et al. Effect of citalopram on agitation in Alzheimer's disease—The CitAD randomized controlled trial. JAMA 2014; 311(7):682-691.

Long KH, Moriarty JP, Mittelman MS, et al. Estimating the potential cost savings from the New York University Caregiver Intervention In Minnesota. Health Aff (Millwood) 2014; 33(4):596-604.

Results: The first study is a randomized, placebo-controlled, parallel group trial. It showed that citalopram significantly improved agitation and overall function compared with placebo over nine weeks in patients with agitation, but was associated with worsening of cognition and QT interval prolongation. The second study used a model to predict the effect of a previously proven caregiver intervention program (the NYU Caregiver Intervention) to patients and caregivers with dementia in Minnesota between 2010 and 2025. It found that approximately 5 percent more people with dementia would remain in their home, 19 percent fewer would die in institutions, and the intervention would save $996 million in direct costs.

Why It's Important: These studies both suggest that there are additional interventions that can be used to benefit patients and caregivers with dementia. While the study on citalopram identified issues with side effects, given the lack of efficacious treatments for patients with dementia and agitation, citalopram and perhaps other selective serotonin reuptake inhibitors (if this is a treatment effect) are now treatment options for this group of patients that are so difficult to help. The study of the caregiver intervention suggests that by using resources that may be currently available in the community, the health of patients and caregivers with dementia can be improved, and this also can lead to significant cost savings for a community.

See the Neurology Today article, “Dementia Caregiver Programs Could Yield Major Savings, Other Benefits,”

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The Picks: Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370:2467-2477.

Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478-2486.

Results: Investigators randomly assigned 572 patients 55 years of age or older, without known atrial fibrillation, who had had a cryptogenic ischemic stroke or transient ischemic attack within the previous six months to undergo additional noninvasive ambulatory electrocardiography monitoring with either a 30-day event-triggered recorder (intervention group) or a conventional 24-hour monitor (control group). David J. Gladstone, MD, PhD, and colleagues reported that among patients with cryptogenic ischemic stroke, event loop recording used during 30 days in a month detected atrial fibrillation in 16.1 percent of patients versus 3.2 percent of patients in the control group (absolute difference 12.9%; 95% CI, 8.0-17.6; p<0.001; number needed to screen: 8).

In the second trial, investigators conducted a randomized, controlled study of 441 patients to assess whether long-term monitoring with an insertable cardiac monitor (ICM) is more effective than conventional follow-up (control) for detecting atrial fibrillation in patients with cryptogenic stroke. Tommaso Sanna, MD, and colleagues report that among patients with cryptogenic ischemic stroke, implantable loop recording used during six months detected atrial fibrillation in 8.9 percent of patients versus 1.4 percent of patients in the control group (hazard ratio, 6.4; 95% CI, 1.9-21.7; p<0.001; number needed to screen: 3).

Why It's Important: These two trials are landmark studies that demonstrate that atrial fibrillation is more frequent after stroke than previously suspected. Moreover, they suggest that patients with cryptogenic stroke should be investigated thoroughly. The more atrial fibrillation is detected, the more patients will be given anticoagulation treatment and more recurrent strokes will be prevented.

The Pick: Derdeyn CP, Chimowitz MI, Lynn MJ, et al. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): The final results of a randomized trial. Lancet 2014; 383(9914):333-341.

Results: The study randomly assigned 451 patients with recent transient ischemic attack or stroke related to 70-99 percent stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification program) or aggressive medical management plus stenting with the Wingspan stent. During a median follow-up of 32.4 months, 34 of 227 patients in the medical management group (15 percent) and 52 of 224 patients in the stenting group (23 percent) had a primary endpoint event (stroke or death within 30 days after enrollment, ischemic stroke in the territory of the qualifying artery beyond 30 days of enrollment, or stroke or death within 30 days after a revascularization procedure of the qualifying lesion during follow-up). The cumulative probability of the primary endpoints was smaller in the medical management group versus the stenting group (p=0.0252).

Why It's Important: The study showed that patients with severe symptomatic intracranial atherosclerosis did not benefit from stenting using the specially designed Wingspan stent, and, in fact, that peri-procedural complications of stenting were higher than expected. Even more important was the finding that the patients randomized to intensive medical control of risk factors, including “coaching,” did much better than expected. This study has ushered in a new era of aggressive risk factor reduction for stroke prevention.

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THE PICK: Williams CM, Maher, et al. Efficacy of paracetamol for acute low-back pain: A double-blind, randomized controlled trial. Lancet 2014; 6736(14)60805-60809.

THE RESULTS: Acetaminophen/paracetamol is the recommended first-line analgesic for acute low-back pain; however, no high-quality evidence supports this recommendation. The authors did a multicenter, double-dummy, randomized, placebo-controlled trial across 235 primary care centers in Australia, enrolling 550 patients with acute lower back pain who were randomized to receive up to four weeks of regular doses of paracetamol; as-needed doses of paracetamol for pain relief, maximum 4000 mg paracetamol per day; or placebo. Neither regular or as-needed dosing affected recovery time compared with placebo.

WHY IT'S IMPORTANT: Given the significant hepatotoxicity associated with acetaminophen, this calls into question its utility as a first-line treatment for this indication, and adds weight to other findings of little or no benefit for it in osteoarthritis, dysmenorrhea, or rheumatoid arthritis.

THE PICK: Moriconi A, Cunha TM, Souza GR, et al. Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief. Proc Natl Acad Sci U S A 2014;111(47):16937-16942.

THE RESULTS: This paper suggests that C5a, the anaphylatoxin produced by complement activation, has potent nociceptive activity in several models of inflammatory and neuropathic pain by interacting with its selective GPCR C5aR. C5aR is widely expressed in immune cells, including neutrophils (polymorphonuclear cells), monocytes, microglia, and in non-immune cells, including neurons in the CNS and dorsal root ganglia.

WHY IT'S IMPORTANT: This paper is noteworthy because it demonstrated that ligands for a conserved site act as potent allosteric inhibitors of C5a-induced chemotaxis. Since the site is well conserved in both rat and mouse models, the results pave the way for the rational design of allosteric C5aR inhibitors with cross-species reactivity. These may become a new class of medications for multiple applications involving pain and inflammation.

© 2014 American Academy of Neurology