What made a difference this past year in neurology — in the clinic, at the bench, and in the pipeline for new drugs? What were some of the important developments in policy and practice? We asked the editorial board of Neurology Today — all leaders in their respective subspecialties — to highlight the most noteworthy research, policies, and professional issues that stood out from the rest during the past 12 months. Here, in the “Best Advances of 2018,” our editorial team describes developments that were both incremental and transformational this past year.
For more information and related commentary on these advances, read our past coverage in Neurology Today.
The Pick: Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: Toward a biological definition of Alzheimer's disease https://linkinghub.elsevier.com/retrieve/pii/S1552-5260(18)30072-4. Alzheimers Dement 2018; 14(14):535-562.
The Findings: This paper represents the most current understanding of Alzheimer's disease (AD) as an aberrant biological process of the brain that can be detected with various fluid — cerebrospinal fluid and blood — and imaging biomarkers. Importantly, this research framework proposes that AD, even in the absence of clinical symptoms, can be identified by these biomarkers, thereby moving the diagnosis from that of a clinical syndrome to that of a collection of related diagnostic markers.
Why It's Important: First, although this framework is intended for use for research purposes, many of the tools used to measure the biomarkers used in this context are currently available in the clinic. Thus, it is already possible to consider the clinical applications of this framework and it will likely influence diagnostic recommendations in the near future. Second, this paper clearly emphasizes the increasing importance placed on AD prevention by identifying the earliest traces of the disease. For neurologists, where the reliance on the clinical manifestations of a disease remains so important, this paper represents a movement into the brave new world of defining a disease before it can be recognized by its impact on brain function. Third, the direction that this framework takes remains controversial in the dementia field, suggesting there is more come in the near future. Stay tuned.
The Pick: Olsson B, Portelius E, Cullen NC, et al. Association of cerebrospinal fluid neurofilament light protein levels with cognition in patients with dementia, motor neuron disease, and movement disorders https://jamanetwork.com/journals/jamaneurology/fullarticle/2716834. JAMA Neurol 2018; Epub 2018 Dec 3.
The Findings: This paper highlights the role that neurofilament light chain (NfL) is likely to play in neurodegenerative disorders. Although NfL has been identified as a marker of disease activity in multiple sclerosis and cerebral trauma, this paper and others over the last two years strongly suggest that this is also a reliable marker of neurodegeneration. Therefore, it is increasingly likely that NfL can be used to predict disease progression, and potentially, therapeutic response in a number of neurodegenerative disorders.
Why It's Important: Multiple studies have demonstrated a strong correlation between blood and CSF NfL levels. This suggests that once methods for measuring serum NfL are validated, this could be an easily accessible and important diagnostic marker in neurodegenerative disorders.
Read the Neurology Today collection of articles on the role of neurofilament light protein in neurodegenerative disorders: http://bit.ly/NT-NfL.
The Pick: Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA https://www.nejm.org/doi/full/10.1056/NEJMoa1800410. New Engl J Med 2018; 379:215-225.
The Findings: Patients within 12 hours of high risk transient ischemic attack (TIA) or minor stroke (NIHSS < 3) were randomized to aspirin (50-325 mg daily) or the combination of aspirin and clopidogrel (75 mg daily after a loading dose of 600 mg) for 90 days. Patients with cardioembolic source or severe extra- or intra-cranial atherosclerosis were excluded. The dual antiplatelet (DAP) regimen proved superior with fewer recurrent ischemic events, especially recurrent ischemic stroke (5.0 percent with DAP vs. 6.5 percent with aspirin), at the cost of a slight increase in bleeding (0.9 percent with DAP vs. 0.4 percent with aspirin). Most of the recurrent ischemic events were prevented in the first week, and most of the bleeding occurred after three weeks.
Why It's Important: The benefit of DAP in preventing recurrent ischemic stroke in this study confirms the results of the CHANCE trial published in 2013 from a similar Asian cohort. CHANCE treated patients for 21 days, used a 300 mg clopidogrel loading dose, and did not find increased bleeding with DAP. Taken together, the data from these studies suggest that patients with minor stroke or high-risk TIA should receive DAP for 21 days to prevent early recurrent stroke. These data help us personalize secondary stroke prevention depending on stroke subtype. Data from other studies tell us that more prolonged DAP is useful for patients with severe intracranial atherosclerosis, that platelet monotherapy is sufficient for lacunes, that patients with cardioembolic stroke should be anticoagulated, and that patients with severe extracranial atherosclerosis should have endarterectomy or stenting. One caveat is that patients who carry the CYP2C19 loss of function allele may not respond to clopidogrel; ticagrelor is under investigation as an alternative.
The Picks: Albers GW, Marks, MP, Kemp, S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging https://www.nejm.org/doi/full/10.1056/NEJMoa1713973. N Engl J Med 2018; 378:708-718.
Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct https://www.nejm.org/doi/full/10.1056/NEJMoa1706442. N Engl J Med 2018; 378:11-21.
The Findings: GW Albers, et al, reported that patients, six to 16 hours after onset of middle cerebral artery stroke or internal carotid artery occlusion with substantial area of ischemic penumbra on CT or MRI, had much better outcome with thrombectomy than with medical management, with a modified Rankin Scale (mRS) score of 0-2 in 45 percent vs. 17 percent (p < 0.001), respectively. RG Nogueira, et al, found that among patients with acute stroke who had last been known to be well six to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone.
Why It's Important: Together, these two studies strongly support thrombectomy treatment up to 16-24 hours in carefully selected patients. Importantly, they reinforce the concept of “slow vs. fast progressors” based on an individual's collateral flow. While getting the artery open as fast as possible will result in better outcome in all patients, this is more important in fast progressors whose poor collaterals result in completion of the infarct within minutes of onset. The subjects in the Albers and Nogueira studies were “slow progressors” with sufficient collaterals to sustain tissue viability up to 24 hours. The caveat is that advanced imaging on CT or MRI is required to identify these patients. Also, the proportion of “slow progressors” within 6-24 hours is unknown but is probably well below 50 percent of patients. Nevertheless, because of the magnitude of benefit in treated patients, and poor outcome without treatment, these studies will change practice guidelines and will mandate changes in systems of care to identify and treat these patients.
The Pick: Hart RG, Sharma M, Mundl H, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source https://www.nejm.org/doi/full/10.1056/NEJMoa1802686. N Engl J Med 2018; 378:2191-2201.
The Findings: Patients with ischemic strokes that were thought to be embolic based on imaging and clinical features and the absence of other evident causes were randomly allocated to the factor Xa inhibitor rivaroxaban (15 mg) or aspirin (100 mg). After a median of 11 months follow up, the study was terminated because of lack of benefit (recurrent ischemic or hemorrhagic stroke or systemic embolism at 5.1 percent per year vs. 4.8 percent per year, respectively) and increased major bleeding (1.8 percent per year vs. 0.7 percent per year, respectively) in the rivaroxaban vs. aspirin group.
Why It's Important: Approximately 20 percent of ischemic strokes are non-lacunar on imaging and have no identifiable cause. It is possible that they are due to embolization to the brain. While anticoagulation is not routinely beneficial for stroke prevention, it is of proven benefit in patients with embolic strokes from an identifiable source such as atrial fibrillation. Hence, the rationale for testing anticoagulation in these suspected embolic strokes of undetermined source (ESUS). The failure of anticoagulation to reduce the roughly 5 percent yearly incidence of recurrent strokes might be due to several explanations: The strokes were not really embolic; the emboli were heterogeneous and not amenable to anticoagulation; or the dose of anticoagulant was too low since the 15 mg dose is lower than the approved 20 mg dose for atrial fibrillation. However, even the 15 mg dose was associated with higher bleeding. While further study of secondary stroke prevention in ESUS is needed, based on this study anticoagulation cannot be routinely recommended.
The Pick: Thomalla, G, Simonsen, CZ, Boutitie, F, et al. MRI-guided thrombolysis for stroke with unknown time of onset https://www.nejm.org/doi/full/10.1056/NEJMoa1804355. N Engl J Med 2018; 379:611-622.
The Findings: Patients with unknown time of onset or who woke up with stroke symptoms and who had positive DWI but no FLAIR abnormality on MRI (suggesting onset < 4.5 hours) had much better outcome with tPA vs no treatment (mRS 0-1 in 53 percent vs. 42 percent, p=0.02) without a significant increase in symptomatic intracerebral hemorrhage (2 percent).
Why It's Important: This study expands the number of stroke patients who can be effectively treated — in this case with tissue plasminogen activator (tPA). Many patients wake up with their stroke symptoms or present without reliable information on when symptoms first started. Such patients cannot be treated according to current guidelines, which require known onset by history within three to 4.5 hours. Since hyperintensity on the FLAIR MRI sequences do not appear until four to five hours after onset of arterial occlusion, the authors used the absence of FLAIR signal to select patients for treatment. They found much better outcome with tPA, without significant risk. This study will likely change practice with the caveats that emergent MRI is required to identify patients, and the study requires confirmation before providing level 1 evidence support in guidelines.
The Pick: McNeil JJ, Woods RL, Nelson WR, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly https://www.nejm.org/doi/full/10.1056/NEJMoa1805819. New Engl J Med 2018; Epub 2018 Sept 16.
McNeil JJ, Woods RL, Nelson MR, et al Effect of aspirin on disability-free survival in the healthy elderly https://www.nejm.org/doi/full/10.1056/NEJMoa1800722. New Engl J Med 2018; Epub 2018 Sept 16.
McNeil JJ, Nelson MR, Woods RL, et al Effect of aspirin on all-cause mortality in the healthy elderly https://www.nejm.org/doi/full/10.1056/NEJMoa1803955. New Engl J Med 2018; Epub 2018 Sept 16.
The Findings: Three separate papers evaluated primary prevention of vascular events and death in patients over 70 years old with no overt cardiovascular or cerebrovascular disease. The researchers found the use of aspirin at 100 mg daily conferred no benefit on disability-free survival, myocardial infarction, or stroke, and increased bleeding and all-cause mortality, especially cancer-related deaths.
Why It's Important: Because of its proven benefit for secondary stroke prevention, aspirin is often prescribed in the elderly. This series of papers together with previous studies provide convincing evidence that aspirin should not be routinely prescribed for primary prevention of stroke. If used, it should be confined to patients with significant vascular risk factors and lack of gastrointestinal or brain bleeding risk.
Read the Neurology Today article, “In the Clinic-Stroke: Thrombectomy Benefit Found to Extend to 24 Hours for Stroke Patients”: http://bit.ly/NT-thrombectomy.
Read the Neurology Today article, “For Your Patients-Stroke Prevention: Aspirin Use Shows No Benefit in Primary Prevention of Heart Attacks and Stroke in Healthy, Older Adults”: http://bit.ly/NT-aspirin-stroke.
The Pick: Schulz A, Ajayi T, Specchio N, et al, for the CLN2 Study Group. Study of intraventricular cerliponase alfa for CLN2 disease https://www.nejm.org/doi/full/10.1056/NEJMoa1712649. N Engl J Med 2018;378(20):1898-1907.
The Findings: Intraventricular infusion of cerliponase alfa in patients, 3—16 years old, with neuronal ceroid lipofuscinosis type 2 (CLN2) disease — a rare, autosomal recessive form of Batten's disease —resulted in a slower rate of decline in motor and language function than that in historical controls.
Why It's Important: This is a major innovative therapy for a previously untreatable disorder.
The Pick: Devinsky O, Patel AD, Cross JH, et al, for the GWPCARE3 Study Group. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome https://www.nejm.org/doi/full/10.1056/NEJMoa1714631. N Engl J Med 2018;378(20):1888-1897.
The Findings: Among children and adults with Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo.
Why It's Important: The study provides controlled information on the use of cannabidiol in patients with severe early-onset epilepsy who have treatment-resistant seizures. These patients have been difficult to treat but the topic and therapy are controversial.
Read the Neurology Today article, “In the Pipeline-Epilepsy: Cannabidiol Oil Reduces Drop Seizures in Lennox-Gastaut Syndrome,”: http://bit.ly/NT-CBD.
The Picks: Baud MO, Kleen JK, Mirro EA, et al. Multi-day rhythms modulate seizure risk in epilepsy. Nat Commun 2018: 9(1):88.
Karoly PJ, Goldenholz DM, Freestone DR, et al. Circadian and circaseptan rhythms in human epilepsy: A retrospective cohort study https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30274-6/fulltext. Lancet Neurol 2018; 17(11): 977-985.
The Findings: Using data from the responsive neurostimulator (RNS), an implanted device that treats epilepsy and records seizure activity, MO Baud, et al, were able to detect “waves” of interictal activity that occurred at regular intervals over months to years. Seizures were much more likely to occur during these “waves” and much less likely to occur at other times. The paper by PJ Karoly, et al, used seizure diary data alone and found recurring patterns (within the course of a day or over multiple days) that can be used to predict seizure occurrence.
Why It's Important: These studies open the door to seizure forecasting using devices. Efforts are ongoing to use both implanted and external devices for seizure forecasting. Even in the absence of the technology, using a consistent seizure diary might allow some patients to have a better day-by-day (or hour-by-hour) prediction if a seizure will occur. The cause of the cycling is at present unknown. Notably, although cycling has been attributed to catamenial exacerbation, 28-day cycling is seen in both genders.
The Finding: Myers CT, Hollingsworth G, Muir AM, e al. Parental mosaicism in “de novo” epileptic encephalopathies https://www.nejm.org/doi/full/10.1056/NEJMc1714579. N Engl J Med 2018; 378(17): 1646-1648.
The Findings: The investigators tested the frequency of low-level parental mosaicism in somatic tissue obtained from 120 triads of parents and their affected child with an apparent “de novo” pathogenic variant in one of the 33 genes causing epileptic encephalopathy. They excluded all families where standard sequencing had detected mosaicism. They used a coverage threshold for sequencing that would allow detection of a 1.0 percent minor allele frequency. They found mosaicism for their child's pathogenic variant in 10 parents (8.3%; 95% confidence interval, 3.4 to 13.3). The minor allele frequency was 1.4 percent—30.6 percent and was below what would be detected by means of Sanger sequencing in eight of the 10 parents.
Why It's Important: The study offers important insights for epileptic encephalopathies and other genetic conditions thought to be primarily derived from de novo mutations. Mutations that occur early may result in mosaicism for somatic or germ cells in a non-affected individual, who can then pass the gene on to their progeny. The study showed that the majority of mosaicism that was found was below the detection level of standard Sanger sequencing, and thus parents would be unaware that they have a risk of having another child with the same devastating disease. This has significant implications for genetic counseling and prenatal testing.
Read the Neurology Today collection of articles on epilepsy genetics and treatment targets: http://bit.ly/NT-epilepsy.
The Pick: White DB, Angus DC, Shields AM, et al for the PARTNER Investigators. A randomized trial of a family-support intervention in intensive care units https://www.nejm.org/doi/full/10.1056/NEJMoa1802637. N Engl J Med 2018;378(25):2365-2375.
The Findings: In a randomized trial of a “multicomponent family support intervention” in five intensive care units (ICUs), investigators measured the impact on surrogate decision-maker anxiety, depression, perceptions of communication, and patient centeredness, as well as length of ICU stay. They found no difference in psychological symptoms, but did find improvement in communication, patient centeredness, and length of stay.
Why It's Important: Interventions for surrogate wellness are rare and difficult to study as they are usually implemented in a stepwise fashion into normal practice leaving no ability to compare with a control group. Also, the metrics were relevant to the patient experience, which is growing in importance to medical centers.
The Pick: Lewis A, Bernat JL, Blosser S, et al. An interdisciplinary response to contemporary concerns about brain death determination http://n.neurology.org/content/interdisciplinary-response-contemporary-concerns-about-brain-death-determination. Neurology 2018;90(9):423-426.
The Findings: In response to recent lawsuits related to brain death determination, the AAN Ethics, Law, and Humanities Committee convened a multisociety quality improvement summit in October 2016 to address, and potentially correct, aspects of brain death determination within the purview of medical practice that may have contributed to these lawsuits. Participants reaffirmed the validity of determination of death by neurologic criteria and the use of the AAN practice guideline to determine brain death in adults; discussed the development of systems to ensure that brain death determination is consistent and accurate; reviewed strategies to respond to objections to determination of death by neurologic criteria; and outlined goals to improve public trust in brain death determination.
Why It's Important: I am one of the authors of this paper but I selected it because the frequency of cases questioning the validity of brain death are increasing. This is the first paper from the AAN Ethics, Law, and Humanities Committee to offer a response to support the current brain death criteria and outline a strategy to secure public support and understanding of neurologic determination of death.
Read the Neurology Today story, “New Consensus Statement Affirms AAN Brain Death Guideline, Calls for Consistency and Public Education”: http://bit.ly/NT-braindeath.
The Picks: Friedrich J, Kordasiewicz HB, O'Callaghan B, et al. Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles https://insight.jci.org/articles/view/123193. JCI Insight 2018; Epub 2018 Nov 2.
Niu C, Prakash TP, Kim A, et al. Antisense oligonucleotides targeting mutant ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7 http://stm.sciencemag.org/content/10/465/eaap8677?rss=1. Sci Transl Med 2018; 84(1):64-77.
The Findings: These pre-clinical studies in mice demonstrate efficacy of antisense oligonucleotide therapies in three of the most common dominant spinocerebellar ataxias (SCAs). All three studies demonstrate meaningful phenotypic rescue as well as improvement of markers of disease severity and/or progression.
Why It's Important: Chronic progressive neurogenetic diseases such as the dominant spinocerebellar ataxias have long eluded effective treatment, with current efforts limited to symptomatic management and no disease-modifying therapies available. These studies support developing human clinical trials for these disabling neurogenetic disorders.
Read the Neurology Today story, “Antisense Therapy Mitigates Vision Loss in Spinocerebellar Ataxia Mice, Pointing the Way to Clinical Trials”: http://bit.ly/NT-ASO-SCA.
The Pick: Wong JK, Cauraugh JH, Ho KWD, et al. STN vs. GPi deep brain stimulation for tremor suppression in Parkinson disease: A systematic review and meta-analysis https://www.prd-journal.com/article/S1353-8020(18)30376-6/abstract. Parkinsonism Relat Disord 2018; pii: S1353-8020(18)30376-6.
The Findings: The study showed that deep brain stimulation (DBS) is effective in reducing tremor in Parkinson's disease, with equivalent tremor control in the subthalamic nucleus (STN) and pars interna of the globus pallidus (GPi) targets.
Why It's Important: The findings of this systematic review and meta-analysis specifically address tremor suppression efficacy in STN vs GPi DBS. Importantly the effectiveness on tremor control in each target varied over time and should be taken into consideration when interpreting results in individual studies. The study results determined long-term tremor control can be accomplished with each target, which could allow for optimal DBS target selection based on other patient factors.
The Pick: Pen C, Gathagan RJ, Covell DJ, et al. Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies https://www.nature.com/articles/s41586-018-0104-4. Nature 2018; 557(7706):558-568.
Walker LC. Sabotage by the brain's supporting cells helps fuel neurodegeneration. Nature 2018; 557(7706):499-500.
The Findings: Multiple system atrophy (MSA) has a more malignant clinical course than other synucleinopathies such as Parkinson's disease (PD) and diffuse Lewy body disease (DLBD). All of these disorders have been attributed to misfolding and aggregation of alpha-synuclein, with seeding and proposed prion-like spread between cells. The primary site of alpha-synuclein aggregation is in oligodendrocytes in MSA (glial cytoplasmic inclusions) versus neurons in PD/DLBD (Lewy bodies and Lewy neurites). The abnormal alpha-synuclein protein “strains” are structurally and functionally distinct in MSA versus PD/DLBD, and much more toxic in MSA, even though the amino acid sequence of alpha-synuclein is usually the same in these disorders. In this study, the authors used an elegant combination of experiments to identify the underlying factors that lead to development of different strains of alpha-synuclein in MSA versus PD/DLBD. They demonstrate that the intracellular environment of oligodendrocytes is critical for the development of the highly toxic strain of alpha-synuclein that occurs in MSA, a strain that is about a thousand times more potent in inducing abnormal protein aggregation than the neuron-associated PD/DLBD strain. Further studies are needed to identify the oligodendrocyte-specific factors that induce the development of this highly toxic and aggressive MSA strain.
Why It's Important: This study provides novel insights about the pathogenesis of MSA and other synucleinopathies. These findings may help to facilitate the identification of targeted therapies for MSA, a relentlessly progressive disease for which there are currently no effective treatments.
The Pick: Corvol JC, Artaud F, Cormier-Dequaire F, et al. Longitudinal analysis of impulse control disorders in Parkinson disease http://n.neurology.org/content/91/3/e189.long. Neurology 2018; 91:e189-e201.
The Findings: Dopamine agonists (DAs) can cause potentially devastating impulse control disorders (ICDs) such as pathological gambling, compulsive eating, compulsive buying, and hypersexuality. Although ICDs generally improve with discontinuation of DA therapy, some patients develop dopamine agonist withdrawal syndrome, a severe, stereotyped drug withdrawal syndrome that does not respond to levodopa or other medications. As a result, these patients may never be able to taper DA therapy and can experience permanent ICDs.
Prior (mainly cross-sectional) studies in patients with Parkinson's disease (PD) have identified important clinical correlates of ICDs, including male sex and younger age, but have had conflicting findings regarding a potential relationship between ICDs and the dose or duration of dopaminergic therapy. In this study, the authors perform a multicenter longitudinal analysis of a cohort of subjects in France with early PD (≤5 year baseline disease duration) to evaluate the incidence of ICDs (diagnosed by semi-structured interview) and explore a potential dose-response relationship with dopaminergic medication use. In their analysis of subjects in the cohort with no baseline ICDs (n=306; 86.6 percent of whom had a history of DA use at least once since disease onset), they found a five-year cumulative incidence of ICDs of 46.1 percent overall [95% CI 37.4-55.7] and of 51.5 percent in those with any DA exposure [95% CI 41.8-62.1]. They also show a strong association between ICDs and both lifetime average daily DA dose and duration of DA therapy. In contrast, they did not detect a strong relationship between ICDs and levodopa exposure.
Why It's Important: This study confirms and expands prior findings that the cumulative incidence of DA-related ICDs is much higher than generally recognized and is related to the dosage and duration of DA treatment. Given the high incidence and potentially serious consequences of ICDs, clinicians and patients should weigh this information carefully when making treatment decisions.
Read the Neurology Today story, “For Your Patients-Parkinson's Disease: High-Dose, Long-Duration Use of Dopamine Agonists Increases Impulse Control Disorders in PD”: bit.ly/NT-ICD-PD.
The Pick: Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(17)30470-2/fulltext. Lancet Neurol 2018; 17(2):162-173.
The Findings: An international panel updated and recommended revisions to the 2010 McDonald criteria for diagnosis of multiple sclerosis (MS). Among them, the presence of CSF-specific oligoclonal bands allows a diagnosis of MS; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space.
Why It's Important: The updated McDonald criteria redefines the specifics through which an MS diagnosis can be made.
The Pick: Reindi M, Waters P. Myelin oligodendrocyte glycoprotein antibodies in neurological disease https://www.nature.com/articles/s41582-018-0112-x. Nat Rev Neurol 2018; Epub 2018 Dec 17.
The Finding: This review provides an overview of the research and current understanding of the anti-myelin oligodendrocyte glycoprotein (MOG) antibodies, which have been identified in patients with demyelinating phenotypes. The review also highlights differences between MOG-Ab-associated disease, neuromyelitis optical spectrum disorder, and MS and how best to treat MOG-Ab-associated disease.
Why It's Important: Anti-MOG antibodies have emerged as a clear separate diagnosis from MS, akin to the NMO spectrum disorder and extending that spectrum further. There have been numerous publications and poster presentations on this topic for the past year or two, but the review offers an excellent encapsulation of where the field is in this regard.
Read the Neurology Today article, “In the Clinic-MS: Updated McDonald Criteria Aim to Improve MS Diagnosis”: http://bit.ly/NT-McDonaldcriteria.
The Pick: Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke https://www.nejm.org/doi/full/10.1056/NEJMoa1716405. N Engl J Med 2018; 378: 1573-1582.
The Findings: This study showed that tenecteplase (TNK) may be superior to tPA in patients with suspected large artery occlusion with higher rates of reperfusion and improved functional outcome.
Why It's Important: The data in this study suggest that TNK may be an alternative to tPA. It also raises the possibility that medical therapies and approaches may obviate the need for thrombectomy in some cases.
Read the Neurology Today article, “Tenecteplase Found Non-Inferior to Alteplase for Large Strokes”: http://bit.ly/NT-TNK.
The Picks: Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis https://www.nejm.org/doi/full/10.1056/NEJMoa1716153. N Engl J Med 2018; 379(1): 11-21.
Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis https://www.nejm.org/doi/full/10.1056/NEJMoa1716793. N Engl J Med 20018; 379(1):22-31.
The Findings: The study by D Adams, et al, reported that patisiran led to improvements in polyneuropathy and other clinical measures in patients with hereditary transthyretin amyloidosis. Moreover, patisiran-treated patients scored better on assessments of walking, gait, and the ability to perform everyday activities. MD Benson, et al, reported that inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis; the most frequent serious adverse events in those taking inotersen were thrombocytopenia and glomerulonephritis but they were managed with enhanced monitoring.
Why It's Important: These two phase 3 studies are notable because they demonstrate the efficacy of two novel oligonucleotide-based therapies for hereditary amyloid neuropathy. Both drugs were subsequently approved by the US Food and Drug Administration.
Read the Neurology Today story, “In the Pipeline-Hereditary Transthyretin Amyloidosis Two Different Therapeutic Approaches Are Promising for hATTR”: http://bit.ly/NT-hATTTR.
The Picks: Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain https://www.nejm.org/doi/full/10.1056/NEJMoa1805453. N Engl J Med 2018;379(8)722-730.
Reungwetwattana T, Nakafawa K, Cho BC, et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer http://ascopubs.org/doi/abs/10.1200/JCO.2018.78.3118. J Clin Oncol 2018; Epub 2018 Aug 28.
Novello S, Mazieres J, Oh IJ, et al. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: Results from the phase IIII ALUR study https://academic.oup.com/annonc/article/29/6/1409/4970555. Ann Oncol 2018;29(6);1409-1416.
The Findings: HA Tawbi, et al, found that nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. T. Reungwetwattana, et al, reported that osimertinib has CNS efficacy in patients with untreated EGFR-mutated non-small-cell lung cancer. These results suggest a reduced risk of central nervous system (CNS) progression with osimertinib versus standard EGFR-tyrosine kinase inhibitors. Finally, the study by S. Novello, et al, found that alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated patients with advanced/metastatic anaplastic lymphoma kinase-positive non-small-cell lung cancer (NSCLC), with a favorable safety profile.
Why It's important: In 2018, these and other research studies continued to report advances for the management of CNS metastases from solid tumors such as mutation-driven NSCLC and melanoma. Use of immunotherapy and novel tyrosine kinase inhibitors in select patients now allow improved CNS control and deferral of radiation therapy.
Read the Neurology Today collection of articles on potential targets and treatments for glioblastoma: http://bit.ly/NT-glioblastoma.
POLICY & PRACTICE
The Pick: CY 2019 Medicare Physician Fee Schedule Final Rule
The Findings: In addition to the usual updates for physician reimbursement for services and procedures, the calendar year (CY) 2019 fee schedule reduces administrative burden related to documentation of evaluation and management (E/M) services and authorizes payments for non-face-to-face physician services performed using communication technology. It also proposes a dramatic flattening of the fee schedule for E/M services starting in CY 2021.
Why It's Important: Physicians will welcome the decreased administrative burden associated with medical documentation, which may improve physician professional satisfaction and decrease burnout and time spent on electronic health records after office hours. The increased willingness for the Centers for Medicare & Medicaid Services (CMS) to reimburse for non-face-to-face services will encourage more widespread adoption of various telehealth applications, which will increase patient access to care.
Most importantly, however, is that CMS listened to feedback from the AAN and most other medical organizations who opposed the flattening of the E/M fee schedule CMS originally proposed for calendar year 2019. Our advocacy efforts were successful. While virtually all physicians agree that the current system of E/M documentation and reimbursement is poorly designed, implementing the arbitrary and untested massive changes CMS proposed for CY 2019 was not the way to fix the problem. The proposed changes would have resulted in unintended consequences that would adversely affect patient care. The wise decision of CMS to delay major changes in E/M will give medical organizations and CMS enough time to work together to get E/M reform right. The AAN and other organizations are working diligently to achieve meaningful E/M reform as I write this.
Read the Neurology Today article, “Policy Watch: The CMS Decision on Payment to Physicians Is in. What's Next?”: http://bit.ly/NT-CMSDecision.
The Pick: The FDA approves the first blood test for brain bleeds after mild traumatic brain injury (TBI)/concussion.
The Findings: On Feb 14, 2018, the FDA approved what was described as a blood test that identifies biomarkers consistent with intracranial blood in the setting of mild TBI with a high degree of accuracy. The test measures blood levels of glial fibrillary acidic protein (GFAP) and ubiquitin c-terminal hydrolase-L1 (UCH-L1) and was widely publicized as a “concussion test” including in an FDA News Release where the test was described as an “aid in the evaluation of concussion in adults.”
Why It's Important: Because countless researchers have been studying biomarkers to identify concussion and providers and patients alike have been hopeful for a more reliable and objective test to identify concussion, it is not surprising that this story created a stir in the lay press and generated a great deal of interest from patients.
As a scientific community, one of our greatest responsibilities is to disseminate accurate unbiased information and to help interpret the results of studies and other impactful research. In the March 22, 2018 issue of Neurology Today, Drs. Javier Cárdenas and Tad Seifert provided expert commentary and provided clarity on the relevance of this test in the evaluation of TBI.
Important take home points were that this is not a test for “concussion” so much as it is a test for intracranial hemorrhage (ICH) in the setting of TBI and that the time it takes to obtain results do not make it an optimal screening test for use in an emergent setting at this time. Nonetheless, this test does have the potential to help mitigate the excessive number of imaging studies ordered on TBI patients by helping to identify those that have a higher likelihood of ICH and are more appropriate candidates for CT.
The Pick: Lumba-Brown B, Yeates KO, Sarmiento K, et al. Centers for Disease Control and Prevention guideline on the diagnosis and management of mild traumatic brain injury among children https://jamanetwork.com/journals/jamapediatrics/fullarticle/2698456. JAMA Pediatr 20018;172(11): e182853.
The Findings: The guideline includes 19 sets of recommendations on diagnosis, prognosis, and management/treatment of pediatric mild TBI. Prior to the release of this manuscript, there were reportedly no evidence-based guidelines on the evaluation and management of concussion in children and adolescents.
Why It's Important: Concussion continues to be a public health concern yet, in many respects, there appears to be a lack of consensus on best practices, especially in specific populations. This guideline includes critical appraisals of numerous diagnostic, treatment, and prognostic practices from which a number of recommendations were made. Importantly, the authors acknowledge that these guidelines are foundational and should be reviewed and changed over time as the science of TBI changes and new evidence is obtained.
The Pick: The FDA approves three calcitonin gene-related peptide (CGRP) antagonists for the prevention of migraine.
The Findings: CGRP antagonists represent a new class of medications and are also the first medications that have been designed specifically for the prevention of migraine. Erenumab, fremanezumab, and galcanezumab each obtained FDA approval and became commercially available in 2018 amid significant coverage in the lay-press, including a New York Times article on May 17, 2018.
Why It's Important: Until now, preventive treatments for migraine have been limited to medications such as antihypertensives, antidepressants, and anticonvulsants that were intended to treat other conditions whereas CGRP-antagonists are thought to specifically address the known role of CGRP in the pathophysiology of migraine.
Administered as injections, the existing body of evidence for the currently available CGRP-antagonists has been impressive demonstrating efficacy and tolerability compared to placebo. Despite the enthusiasm surrounding these three medications (and a fourth that is pending FDA approval), a number of issues have been raised including the cost of these new treatments, insurance coverage, and the need for long-term safety and efficacy data in a larger, “real-world” population of patients. Additionally, many providers agree that there are not yet enough data to help guide informed decision making with regard to which CGRP medication may be more appropriate for a specific patient with specific needs or co-morbidities or where these medications fit in treatment algorithms versus (or in combination with) other less-expensive, evidence-based treatments.
Another important issue that has been raised in the context of the release of these medications is patient access to treatment. Specifically, large insurers in at least two states have required that prescriptions for CGRP antagonists come from board-certified headache specialists of which there are less than 500 in the country, emphasizing disparities in access to subspecialty care and treatment.
Read the Neurology Today story, “In the Clinic-Traumatic Brain Injury: FDA Approves First Blood Test for Brain Bleeds After Mild TBI/Concussion”: http://bit.ly/NT-bloodtestTBI.
Read the Neurology Today story, “Practice Matters: The CGRP Inhibitors for Migraine Are Reaching the Market. Why Not All Neurologists May Be Able to Prescribe Them”: http://bit.ly/NT-CGRPantagonists.
The Pick: The announcement of the proposed slate of nominees for AAN officer and director positions for the 2019-2021 term:
President Elect: Orly Avitzur, MD, MBA, FAAN
Vice President: Ann H. Tilton, MD, FAAN
Secretary: Carlayne E. Jackson, MD, FAAN
Treasurer: Janis M. Miyasaki, MD, Med, FRCPC, FAAN
Brenda Banwell, MD, FAAN
Sarah M. Benish, MD, FAAN
Charlene Gamaldo, MD, FAAN
James N. Goldenberg, MD, CPI, FAPRCR, FAAN
Jonathan P. Hosey, MD, FAAN
Elaine C. Jones, MD, FAAN
Shannon M. Kilgore, MD, FAAN
Brett M. Kissela, MD, MS, FAAN
Thomas R. Vidic, MD, FAAN
Silver JK, Bank AM, Slocum CS, et al. Women physicians underrepresented in American Academy of Neurology awards. Neurology 2018; 91(7): e604-e614.
Graves JS, Brashear A. Gender bias in American Academy of Neurology recognition awards? Neurology 2018; 91(7):291-292.
McDermott M, Gelb DJ, Wilson K, et al. Sex differences in academic rank and publication rate at top-ranked US neurology programs. JAMA Neurol 2018; 75(8): 956-961.
Schor NF. The decanal divide: Women in decanal roles in US medical schools. Acad Med 2018; 93(2): 237-240.
The Findings: Social media discussions and a number of published studies and editorials in Neurology, JAMA Neurology, and Academic Medicine have called attention to the underrepresentation of female neurologists in leadership positions in academic neurology, disparities in publication rates at the top-ranked US neurology programs, and gender bias in AAN recognition awards.
Why It's Important: As an academic woman neurologist I was drawn to the 2018 publications and social media discussions around the gender disparity in medicine, including neurology. The statistics from these studies demonstrated that women in academic medicine were less likely to receive prestigious awards, academic rank promotions, leadership positions, and equal pay. The underrepresentation of women in leadership propagates downstream gender disparity. Those of us who have been in neurology practice fewer than 13 years have never had a female AAN President; the only female president served 2003-2005. The proposed slate of the AAN Board of Directors represents a welcome reversal of that trend.
Read the Neurology Today collection of articles on the gender gap in neurology: http://bit.ly/NT-gender-gap.