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John Hughlings Jackson (1835–1911) was the pre-eminent British neurologist of the last 3 decades of the 19th century whose most seminal contributions related to the understanding of epileptic seizures. Jackson instructed that his personal papers should be destroyed at his death, and consequently, few examples of his handwriting now survive. We discovered a series of marginalia in Jackson's handwriting annotating one of his papers, “On temporary mental disorders after epileptic paroxysms,” first published in 1875 in the West Riding Lunatic Asylum Medical Reports. Two of the most extensive annotations indicate Jackson's later understanding of “epileptic vertigo” and of “mental automatisms.” We contextualize the changes in Jackson's thinking suggested by these emendations. These marginalia give insights into Jackson's continuing effort to understand epilepsy and its implications for brain function, an issue that was then, as now, one of the fundamental problems in neurology.

We read with great interest the recent paper by Jones et al., in which the authors compared the presence of infarcts in children vs patients with sickle cell disease (SCD).1

We thank Luwen et al. for their insightful comments on our recent paper.1Owing to the length and figure limits for our chosen submission category, we omitted some of the case's history and diagnostic features from the paper. Our patient presented with progressive hypersomnia, cognitive decline, intermittent horizontal binocular double vision, and tremors over the course of 9 months. Magnetic resonance imaging (MRI) of the patient's brain with and without gadolinium contrast showed multiple multifocal confluent bilateral cerebral and cerebellar enhancing and nonenhancing white matter abnormalities. Vitreous biopsy flow cytometry and next-generation sequencing (NGS) of the vitreous sample detected CD20+, MYD88+ diffuse large B-cell lymphoma.

At Neurology®, we aim to publish manuscripts that address research questions that are important to patients, trainees, clinicians, and researchers; use appropriate and robust methods; and are transparently reported. To help us decide which papers to publish, we rely on the advice of internal and external peer reviewers who are experts in the topic under study. In addition, because of the complexity of the methods used or the implications of the findings for patient care, we have asked methods experts, including Richard J. Kryscio, PhD, Neurology's Associate Editor for Biostatistics since 2006 and Sue Leurgans, PhD, and V. Shane Pankratz, PhD, biostatistics section editors, to evaluate some of the manuscripts that we receive. Their advice, along with that of many other methods reviewers, has been invaluable to us as we make editorial decisions and, we hope, to the authors, as they improve the quality of the papers, whether they are eventually published in Neurologyor elsewhere. We wish to express our gratitude to Drs. Kryscio, Leurgans, and Pankratz for their dedication to evaluating these manuscripts for a period of many years.

The editors and editorial team of Neurology®express our thanks to the dedicated peer reviewers who have contributed time and expertise over the past 6 months. Decisions about which papers to publish are informed by their evaluation of the novelty, accuracy, interpretation, and implications of research questions, methods, and results. The high quality and success of this journal owe much to their continuing dedication.

Between April 1, 2015, and September 30, 2015, Neurology® received 2,642 new and 567 revised manuscripts (compared to 2,366 new and 646 revised manuscripts during the same period in 2014). We received 4,645 peer reviews during this same interval (compared to 4,438 during the same period in 2014). Average time from submission to first decision for papers chosen for review was 36 days. We are able to accept only a minority of submitted papers and must make difficult decisions regarding which articles will most benefit our readers and improve patient care. Your thoughtful comments regarding the uniqueness of study populations, novel methods, studies that are especially educational, or new strategies for diagnosing and treating neurologic disease are tremendously helpful and highly appreciated. We are also grateful for your cooperation in returning reviews in a timely manner.

Peer review serves 2 primary objectives. First, it helps editors decide which papers to publish. Second, and just as importantly, peer review improves the quality of the manuscripts that we publish in Neurology® (and, we hope, of the manuscripts that we do not accept and are published elsewhere).

E.C. Seguin was one of the early, influential 19th-century neurologists who participated in the development of neurology as a specialty in the United States. Born in France, but raised from early childhood in the United States, Seguin published widely, developed a high-profile New York City practice, and was named Clinical Professor of Diseases of the Mind and Nervous System at the College of Physicians and Surgeons (New York) in 1874. Typical of the era, he studied neurologic disorders, but also several conditions that today would be considered in the realm of psychiatry. One of his seminal papers was titled “The treatment of mild cases of melancholia at home” (1876). Contrary to the widespread practice of isolating patients in either rest homes or asylums, Seguin introduced and formalized treatment of depression within the household. Against this academic backdrop, Seguin returned home on October 31, 1882, to discover that his own wife, afflicted with long-standing depression and treated at home, had committed suicide after murdering their 3 children. The grim dichotomy between the confidently written paper and the reality of the treatment failure is a neurologic lesson in humility regarding diseases and their unpredictable outcomes.

The use of prescription medication to augment cognitive or affective function in healthy persons—or neuroenhancement—is increasing in adult and pediatric populations. In children and adolescents, neuroenhancement appears to be increasing in parallel to the rising rates of attention-deficit disorder diagnoses and stimulant medication prescriptions, and the opportunities for medication diversion. Pediatric neuroenhancement remains a particularly unsettled and value-laden practice, often without appropriate goals or justification. Pediatric neuroenhancement presents its own ethical, social, legal, and developmental issues, including the fiduciary responsibility of physicians caring for children, the special integrity of the doctor–child–parent relationship, the vulnerability of children to various forms of coercion, distributive justice in school settings, and the moral obligation of physicians to prevent misuse of medication. Neurodevelopmental issues include the importance of evolving personal authenticity during childhood and adolescence, the emergence of individual decision-making capacities, and the process of developing autonomy. This Ethics, Law, and Humanities Committee position paper, endorsed by the American Academy of Neurology, Child Neurology Society, and American Neurological Association, focuses on various implications of pediatric neuroenhancement and outlines discussion points in responding to neuroenhancement requests from parents or adolescents. Based on currently available data and the balance of ethics issues reviewed in this position paper, neuroenhancement in legally and developmentally nonautonomous children and adolescents without a diagnosis of a neurologic disorder is not justifiable. In nearly autonomous adolescents, the fiduciary obligation of the physician may be weaker, but the prescription of neuroenhancements is inadvisable because of numerous social, developmental, and professional integrity issues.

John Hughlings Jackson articulated a neurologic method of systematically evaluating the anatomy, physiology, and pathology of every patient with neurologic disease. He used this mode of analysis to develop a theory of the physiology of epilepsy. We examined an example of his method in a newly discovered, unpublished manuscript containing his suggestions for the treatment of epilepsy based on his physiologic ideas. He had his private papers destroyed at the time of his death, but the Rockefeller Library of the University College London Institute of Neurology, Queen Square, contains a collection of his papers probably saved from destruction by his collaborator James Taylor. Among these articles is an 1899 memorandum, labeled “For Private Circulation” and entitled “A Suggestion for the Treatment of Epilepsy.” In it, Hughlings Jackson claimed that focal discharging lesions cause both focal and generalized epilepsy, and that the cells in the lesion discharge their energy more easily than normal tissue. Citing microscopic evidence that such lesions are congested and inflamed, and that tuberculin destroys such tissue in the lung, he reasoned that destroying these unstable neurons with tuberculin would improve epilepsy. In this private manuscript, Hughlings Jackson uses an unusually detailed analysis of the pathology, anatomy, and physiology of epilepsy to predict a scientific approach to its treatment.

Soon after the successful introduction of large oral doses of levodopa or of levodopa plus a decar-boxylase inhibitor, such as carbidopa or benserazide, for the treatment of Parkinson's disease, it became evident that several disturbing side effects were limiting the therapeutic eficacy of this amino acid. This paper discusses novel practical approaches for the management of these levodopa-related complications. These approaches include therapeutic strategies for controlled delivery of levodopa to the brain (controlled-release preparations), rescue treatment with subcutaneous, intranasal, or sublingual administration of the dopamine agonist apomorhine, and the administration of an atypical neuroleptic, such as clozapine. Other approaches for prolonging the response of levodopa that are being used or investigated are also reviewed in this paper. These include the use of levodopa prodrugs and blocking the degradation in the brain with inhibitors of monoamine oxidase-B and catechol-O-methyltransferase.

In previous papers of this series, we explored the epidemiology of MS, examining the effects of race, sex, geography, latitude and climate, migration, age at onset, population ancestry, and individual ethnicity on the risk of MS, using an unusually large cohort of MS cases and pre-illness matched controls comprising US veterans of World War II (WWII) and the Korean Conflict (KC). In this paper, we examine primarily the effect of other factors on the risk of MS in this cohort and their relation to those previously studied. We found here that latitude tier of residence at entry into active duty (EAD), years of education, and socioeconomic class (coded from occupation) were similarly associated with MS risk among white men, black men, and white women. Higher levels of each factor showed increased MS risk. Multivariate analyses indicated that for white male WWII subjects an urban address, 9 or more years of education, uncorrected visual acuity less than 20/20 at EAD, a more northern latitude, and a higher proportion of the subject's EAD state population reporting Swedish ancestry each significantly increased the risk of MS. White male KC subjects showed roughly the same patterns, except that uncorrected visual acuity less than 20/20 was associated with lower MS risk (ancestry/ethnicity was not studied). For black male WWII and KC subjects combined, a similar analysis (omitting ancestry/ethnicity) showed that only latitude at EAD and 9 or more years of education were independently associated with a significantly higher MS risk, and for WWII plus KC white women (also without ancestry/ethnicity), only latitude was a significant risk factor in these multivariate analyses. The smaller number of subjects, especially in these last two groups, limited the power to detect statistically significant risks in these last analyses. Similarities to white men of WWII in univariate analyses for all other groups suggest that findings for the former would otherwise apply to the latter. Although the interpretations of these associations may be obscure, in addition to geography, age, sex, and race, per se, higher socioeconomic status is significantly associated with higher MS risk in black and white men and in white women in the United States.

Tao et al.1have described an interaction between elevated plasma C-reactive protein (CRP) levels and APOEε4 burden in data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). They concluded that “CRP released during peripheral inflammation could be a mediator in APOEε4–related AD neurodegeneration and serve as a drug target for AD.”1We demonstrated CRP's mediation in data from the Texas Alzheimer's Research and Care Consortium (TARCC), a larger, ethnically diverse, and similarly well-characterized cohort, in 2017.2The TARCC measures blood-based protein biomarkers in serum by the same methodology and vendor as the ADNI. In our paper, we tested N = 120 serum proteins, and only CRP had an unequivocal mediation effect on the association of APOEwith prospectively measured and highly adjusted dementia severity.

Neurology® received 2,659 new and 629 revised manuscripts between April 1, 2017, and September 30, 2017 (compared to 2,565 new and 650 revised manuscripts during the same period in 2016). We received 4,566 peer reviews (compared to 4,461 during the same period in 2016) for these papers. Only a minority of submitted and reviewed manuscripts can be published. We must often make difficult decisions regarding which articles we believe will most benefit readers and improve patient care and highly appreciate your thoughtful comments regarding uniqueness of study populations, novel methods, studies that are especially educational, or new strategies for diagnosing and treating neurologic disease. We understand that the obligations for your time are many and thank you for your cooperation in returning reviews within a timely manner.

We cannot adequately convey our gratitude for the dedication of Neurology's peer reviewers. Peer review is an essential mechanism for assessing quality of research and conferring credibility to the content we publish, and authors benefit greatly by receiving your feedback on their work. Listing your names in this message cannot fully reflect our appreciation for your efforts in reviewing papers.

We read with interest the paper by Pallud et al.1in which patients with isocitrate dehydrogenase wild-type glioma who took levetiracetam during the whole standard chemoradiation protocol experienced relevant improvement in survival.

Between April 1, 2016, and September 30, 2016, Neurology®received 2,565 new and 650 revised manuscripts (compared to 2,366 new and 646 revised manuscripts during this same period in 2015). We received 4,461 peer reviews (compared to 4,645 during the same period in 2015) for these papers. We can accept only a minority of submitted manuscripts and must often make extremely difficult decisions regarding which articles we believe will most benefit readers and improve patient care. Your thoughtful comments regarding uniqueness of study populations, novel methods, studies that are especially educational, or new strategies for diagnosing and treating neurologic disease are highly appreciated. We thank you also for your cooperation in returning reviews in a timely manner.

Submissions to the journal are increasing steadily. During the 6-month interval from October 1, 2015, through March 31, 2016, Neurology®received 2,608 new and 608 revised manuscripts (compared to 2,476 new and 600 revised manuscripts during this same period in 2014-2015). We received 4,344 peer reviews (compared to 4,264 during the same period in 2014-2015) for these papers. We can only accept a minority of the manuscripts submitted to us, as we are limited in the number of pages we can publish, and must often make extremely difficult decisions regarding which articles we believe will most benefit readers and improve patient care. You, our reviewers, make these decisions much easier when you make specific comments regarding uniqueness of study populations, novel methods, studies that are especially educational, or new strategies for diagnosing and treating neurologic disease. In addition, the constructive feedback for authors of manuscripts submitted to the Resident and Fellow Section of Neurologyis especially helpful to junior authors in improving their clinical and scientific writing abilities. Our gratitude for your dedication to reviewing for Neurologycannot be adequately conveyed.

Six hundred of 912 papers submitted were accepted for presentation at the 1983 Annual Meeting of the AAN. A statistical study of scoring by individual members of the Committee showed significant mean score differences. A normalization procedure for scoring was compared with the actual meeting scores and selections. A substantial difference in 3 of 19 program categories and lesser changes in 14 others occurred. It is no longer feasible for each submission to be evaluated by all committee members. Four readers per paper and normalization of scores will result in a program reflecting the broad interests of the Academy membership.

The recent American Academy of Neurology position paper by Franklin, “Opioids for chronic noncancer pain,” suggests that the benefits of opioid treatment are very likely to be substantially outweighed by the risks and recommends avoidance of doses above 80–120 mg/day morphine equivalent. However, close reading of the primary literature supports a different conclusion: opioids have been shown in randomized controlled trials (RCTs) to be highly effective in the treatment of chronic nonmalignant pain; long-term follow-up studies have shown that this effectiveness can be maintained; and effectiveness has been limited in many clinical trials by failure to take into account high variability in dose requirements, failure to adequately treat depression, and use of suboptimal outcome measures. Frequency of side effects in many RCTs has been inflated by overly rapid dose titration and failure to appreciate the high interindividual variability in side effect profiles. The recent marked increase in incidence of opioid overdose is of grave concern, but there is good reason to believe that it has been somewhat exaggerated. Potential causes of overdose include inadequately treated depression; inadequately treated pain, particularly when compounded by hopelessness; inadvertent overdose; concurrent use of alcohol; and insufficient practitioner expertise. Effective treatment of pain can enable large numbers of patients to lead productive lives and improve quality of life. Effective alleviation of suffering associated with pain falls squarely within the physician's professional obligation. Existing scientific studies provide the basis for many improvements in pain management that can increase effectiveness and reduce risk. Many potentially useful areas of further research can be identified.

During the 6-month interval from October 1, 2014, through March 31, 2015, Neurology®received 2,476 new and 600 revised manuscripts (compared to 2,457 new and 594 revised manuscripts during this same period in 2013–2014). We received 4,264 peer reviews (compared to 4,282 during the same period in 2013–2014). We are only able to accept a minority of papers submitted as we are limited in the number of pages we can publish, and we must make difficult decisions regarding which articles we believe will most benefit readers and improve patient care. We encourage reviewers to make specific comments regarding uniqueness of study populations, novel methods, studies that are especially educational, or new strategies for diagnosing and treating neurologic disease. In addition, the constructive feedback for authors of manuscripts submitted to the Resident & Fellow Section of Neurologyis immensely helpful to junior authors in improving their clinical and scientific writing abilities. Our gratitude for your dedication to reviewing for Neurologycannot be adequately conveyed.

Dr. Li et al. investigated the safety and efficacy of normobaric hyperoxia (NBO) combined with endovascular treatment (EVT), compared with EVT alone, in 86 patients with acute ischemic stroke and large vessel occlusion in the anterior circulation in a single-center, proof-of-concept, assessor-blinded, randomized, controlled pilot study. NBO consisted of giving 100% oxygen through a face mask (10L/min for 4 hours) before vascular recanalization. The researchers found that the infarct volume at 24–48 hours was significantly smaller in the NBO group. In addition, the NBO group had a significantly lower median mRS at 90 days. The paper generated considerable interest from the readership, and several responses were received. In one response, Dr. Yin et al. propose that hyperbaric oxygen therapy (HBOT) could promote greater oxygen diffusion into ischemic tissues as a potential neuroprotective treatment. They suggest that HBOT, delivered in single or multiple sessions to mitigate adverse effects of prolonged exposure, would be a helpful comparator with NBO in future trials. Responding to this comment, the authors cite previous studies suggesting that a single round of HBOT delivered alone or after NBO may be more effective than NBO alone in treating transient ischemia in animal models. However, repeated daily HBOT had no additional benefit in those studies. They speculate that a single round of HBOT with EVT may be optimal. Nevertheless, they emphasize the ease of delivery of NBO compared with the need for a special pressuring device to deliver HBOT, which may result in treatment delays and may be more difficult to achieve while undergoing EVT.

Dr. Siow et al. explored the associations between human glymphatic function—assessed using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index—with sleep, neuropsychological performance, and cerebral gray matter volumes in a cross-sectional study of 84 participants aged 60 years or older. They found that age, N2 stage sleep duration, and apnea-hypopnea index were independently associated with DTI-APLS and that higher DTI-APLS was associated with better neuropsychological test performance and higher gray matter volume, implying that DTI-APLS may be a potential biomarker for cognitive disorders. Nonetheless, the reproducibility of this new MRI technique to assess interstitial fluid dynamics remains under investigation. In response, Dr. Kawada seeks to clarify the selection of independent variables for the multivariable models presented in the paper. Responding to these comments, the authors note that among baseline demographic and clinical variables, only age and pulse rate had a significant association with DTI-APLS. They also report the adjusted R2of the model as requested by Dr. Kawada. The glymphatic system has emerged as an important frontier in the study of sleep, cognition, and neurodegenerative diseases, and we can expect to see further insights from in-vivo glymphatic imaging in the coming years.

Ramos et al. reported a case of a 48-year-old patient with undiagnosed ankylosing spondylitis who experienced pathologic cervical fracture, spinal cord injury, vertebral artery dissection, and cerebellar strokes after spinal manipulative therapy. In response, Drs. Trager and García astutely note that a virtually identical case report was published in the journal Internal and Emergency Medicine. The editors investigated the concerns of duplicate publication and confirmed that this was the case. We contacted the authors of both papers and the editor of Internal and Emergency Medicine, and both journals issued a notice of duplicate publication explaining the outcome of the investigation.1In addition, Drs. Trager and García express concerns that the patient's care was discordant with chiropractic standards and question whether the initial treating provider was a formally trained, licensed chiropractor. In another response, Dr. Kolberg et al. report that the Brazilian Chiropractic Association found no evidence that the provider in question was a formally trained chiropractor (the editors have not investigated this). They call for the regulation of the chiropractic profession in Brazil, arguing that spinal manipulation is safe when performed by a trained chiropractor. Whereas such dramatic adverse outcomes after spinal manipulation may indeed be rare, the potential cerebrovascular risks of spinal manipulation are well appreciated by neurologists. Nevertheless, we may expect that such reports continue to generate debate about the role of such manipulation, particularly in the cervical area.

Hospitals and physicians' practices are rapidly implementing the electronic health record (EHR) because it offers many demonstrated advantages over paper records. Issues of misuse of the EHR previously identified include breaches in confidentiality and privacy and inappropriate record sharing. I describe a separate set of ethical and quality problems of the EHR that result from its otherwise beneficial timesaving features that inadvertently enable carelessness and harmful shortcuts. These problems include copying and pasting data obtained from other clinicians, authorship ambiguities, inadvertent inclusion of unobtained data in templated notes, misleading history and physical examinations, failure to review prepopulated data, inadequate discharge summaries, impairments to patient–physician communication, and the transformation of the purpose of the medical record to billing documentation. I offer a brief analysis and recommendations to mitigate these problems.

In recent years, criteria for the diagnosis of multiple sclerosis (MS) have changed, mainly due to the incorporation of new MRI criteria. While the new criteria are a logical step forward, they are complex and—not surprisingly—a good working knowledge of them is not always evident among neurologists and neuroradiologists. In some circumstances, several MRI examinations are needed to achieve an accurate and prompt diagnosis. This provides an incentive for continued efforts to refine the incorporation of MRI-derived information into the diagnostic workup of patients presenting with a clinically isolated syndrome. Within the European multicenter collaborative research network that studies MRI in MS (MAGNIMS), a workshop was held in London in November 2007 to review information that may simplify the existing MS diagnostic criteria, while maintaining a high specificity that is essential to minimize false positive diagnoses. New data that are now published were reviewed and discussed and together with a new proposal are integrated in this position paper.