Reviews & Analysis

In this article, Nonnekes and colleagues offer a new approach to the diagnosis of neurological disorders associated with altered gait, balance and posture. Their method takes the presenting sign or signs as the starting point of a focused differential diagnosis, which triggers a tailored search into the underlying neurological syndrome.

The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer immunotherapy, but these agents carry a high risk of immune-related adverse events. Here, the authors introduce the mechanisms of action of ICIs and review their adverse effects on the CNS, which result in conditions such as paraneoplastic neurological syndromes and multiple sclerosis.

Sadnicka and colleagues present task-specific dystonia in the context of motor skill learning in health. Their framework integrates established risk factors for task-specific dystonia with mechanisms of motor skill learning, to indicate how disrupted neural representations of motor skills might arise.

Comorbidity is common in multiple sclerosis (MS). In this Opinion article, Ruth Ann Marrie discusses how comorbidity affects diagnosis, progression, mortality, and health-related quality of life in patients with MS, and how clinicians should incorporate the prevention and management of comorbidities when treating MS.

The recently revised 5th edition of the WHO classification of brain tumours 'blue book' will have a major impact in stratifying diagnosis and treatment. However, low-grade neuroepithelial tumours (LEATs), which present with early-onset focal epilepsy, lack integrated clinicopathological and molecular genetic diagnostic tools. The Neuropathology Task Force of the International League against Epilepsy will critically discuss this issue, as well as offer perspectives on how to decipher and validate clinically meaningful LEAT entities using the current WHO approach.

Drawing on data from social network studies, Dhand and colleagues suggest that focusing on a patient's personal network can help identify individuals at risk of poor health outcomes. The authors provide an overview of the terminology used in social network studies, discuss social network structures that put patients at risk, and suggest how social network research might be applied in the neurology clinic.

Participants in collision sports show a high incidence of concussion and can have deleterious long-term consequences for brain function. Here, Rebekah Mannix and colleagues discuss the benefits and risks associated with the practice of contact sports and examine how this balance affects policies regarding the practice of collision sports.

Suspected non-Alzheimer disease pathophysiology (SNAP) is a biomarker-based concept that applies to individuals with normal levels of amyloid-β biomarkers in the brain, but in whom biomarkers of neurodegeneration are abnormal. Clinically normal and mildly impaired individuals with SNAP are at increased risk of poor clinical and cognitive outcomes. In this Perspectives article, Clifford Jack and colleagues describe the available data on SNAP and address topical controversies in the field.

Rupture of an unruptured intracranial aneurysm (UIA) is the most common cause of subarachnoid haemorrhage (SAH), and at least one in 20–30 adults is estimated to carry an asymptomatic UIA. However, the likelihood and epidemiology of UIA rupture and the associated risk factors are poorly understood. In this Perspectives article, Korja and Kaprio discuss possible misconceptions in the epidemiology of UIAs and SAH, and suggest options to improve the quality of future research.

The risk factors for cardiovascular disease are largely the same as those that harm brain health, and—importantly—these shared risk factors are modifiable. This Perspectives article discusses how the conceptual shift from avoiding vascular risk factors to promoting brain health creates opportunities for reducing morbidity and mortality associated with poor brain health.

The term 'preclinical Alzheimer disease (AD) treatment' refers to interventions that are initiated in cognitively unimpaired at-risk individuals, and are intended to postpone, reduce the risk of, or prevent the clinical onset of AD. In this article, the authors review emerging strategies for the accelerated evaluation of preclinical AD treatments, and discuss the work that has set the stage for implementing these strategies. In particular, they highlight the role of the Collaboration for Alzheimer's Prevention (CAP)—an initiative that is designed to help stakeholders advance AD prevention research in a coordinated, transparent and effective way.

The use of infant formula as a substitute for or supplementation to breast milk has increased dramatically since the middle of the 20^th century. Such formula is typically supplemented with high levels of iron, yet the long-term effects of high exposure to iron during infancy are poorly understood. In this Perspectives article, Hare et al. discuss evidence that iron overload in infancy increases the risk of neurodegenerative disorders, such as Parkinson disease, in old age. They also consider methods for accurate measurement of past iron exposure that could be used to further investigate the risks.

The symptoms and neuropathology of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) can show a high degree of overlap, and few effective treatments exist for these conditions. In this Perspectives article, Ittner and colleagues describe recent failures in the translation of data from mouse models into clinical trials for patients with FTD and/or ALS. The authors summarize the strengths and weaknesses of several available mouse models, and make recommendations for improving future research practice.

The randomized controlled trial represents the gold standard in clinical trial design, but large phase III studies are difficult and expensive to conduct in neurological diseases. In this Perspectives article, Koch and colleagues argue that the futility trial, a phase II design first developed in the oncology field, should be used more widely by neurologists. The authors describe how futility trials could be employed in Parkinson disease, stroke, multiple sclerosis and other conditions.

The short-term safety and efficacy of IFN-β in patients with multiple sclerosis are well established, but less is known about this drug when taken over years and decades. Sormani and Bruzzi discuss the difficulties associated with designing studies of the long-term treatment effects of IFN-β. They then present techniques that have been employed to minimize potential sources of bias. The authors conclude that long-term use of IFN-β reduces clinical progression, but important questions relating to mortality warrant further investigation.

After brain injuries, microglia and macrophages can aid or hinder tissue repair depending on polarization toward specific cell phenotypes. This Perspectives article describes the phenotypic dynamics and different functions of these cells after acute CNS injury and argues that therapeutic approaches should focus on subtle adjustment of the balance between their phenotypes.

More than 80% of patients with the demyelinating disorder neuromyelitis optica (NMO) experience pain from this condition, which severely affects their quality of life. NMO-associated pain is largely refractory to contemporary pain therapy, suggesting that the mechanisms underlying pain in NMO differ from those underlying other causes of pain. In this article, Bradl and colleagues explore the mechanisms underlying pain in patients with NMO, and attempt to identify molecular and cellular targets for therapy.

Several distinct autoimmune neuropathies can be referred to collectively as Guillain–Barré syndrome (GBS). Wakerley and colleagues argue that confusing terminology hinders diagnosis, and they present a revised classification of 'classic' GBS, Miller Fisher syndrome and related conditions. This new approach to diagnosis might facilitate work-up, thereby helping to identify the correct treatment as quickly as possible.

Preimplantation genetic diagnosis (PGD) facilitates conception of a healthy child by couples at risk of having offspring with an inherited debilitating or fatal neurological disorder. PGD has been carried out for various conditions, including spinal muscular atrophy, Huntington disease, fragile X syndrome, and chromosomal and mitochondrial disorders. This article aims to assist neurologists in counselling and treatment of individuals who wish to explore the option of PGD, and advocates the formulation of guidelines for the responsible integration of PGD into preventative neurology.

Genetic testing has the potential to revolutionize care for individuals with epilepsy, but its advent is bringing to light important new issues, particularly surrounding the benefits and risks of testing, and the optimal provision of genetic services. Poduri and colleagues describe these challenges, and call for mechanisms to be established to address them.