Review Articles in 2015

Loss of hypocretin neurons is a hallmark finding in narcolepsy; recent findings have implicated also increased number of histamine neurons in this disorder. This Review provides an overview of coregulation of sleep and wakefulness by hypocretin and histamine. The authors also review the changes in hypocretin and histamine systems in narcolepsy and neurodegenerative diseases (such as Alzheimer disease, Parkinson disease and Huntington disease) and discuss novel therapeutic approaches for manipulation of the histamine system in these diseases.

Dopa-responsive dystonia is a highly treatable movement disorder that usually presents in childhood, but the heterogeneity of its aetiology and presentation can lead to delayed diagnosis. In this Review, Wijemanne and Jankovic summarize the diversity of conditions that present with dopa-responsive dystonia, consider the differential diagnosis for the symptoms, and outline the tests that can be used to ensure an early and accurate diagnosis that enables appropriate treatment to be started as early as possible.

Current rehabilitative strategies for children with unilateral cerebral palsy (UCP) focus on activity-based tasks, but a greater understanding of the condition and the way in which the brain responds to therapy could enable the development of more-effective approaches. In this Review, the authors first discuss current rehabilitative strategies and the factors that are crucial to their success. They then consider in detail how neuroimaging is informing us about the neurobiology of UCP and the neuroplasticity in the brains of children with the condition, and how this knowledge could transform therapy.

A subset of patients with multiple sclerosis (MS) demonstrate rapid accumulation of disability, and symptoms that are refractory to standard disease-modifying therapies. Rush and colleagues present criteria for identifying patients with so-called aggressive MS, and outline the efficacy of various therapies in this group of patients. The authors emphasize the need to act quickly with these patients, and propose a treatment algorithm to aid clinical decision-making.

MRI studies in multiple sclerosis (MS) have mainly focused on brain lesions because of the technical challenges in spinal cord imaging. However, spinal cord abnormalities correlate with disability in MS, and have important diagnostic and prognostic implications. This Review provides an update on technical advances in spinal cord MRI, and discusses the clinical relevance of recent insights into spinal cord pathology in MS.

Spinal muscular atrophy (SMA) is the most common genetic cause of infant death. No disease-modifying treatments are available for SMA, but the increasingly precise understanding of SMA aetiopathogenesis has led to the development of promising therapeutic strategies. Here, Farevelli et al. provide an overview of established data and novel insights into SMA pathogenesis, and discuss preclinical evidence and recent advances from ongoing clinical trials.

Despite the increasing prevalence of neurodegenerative diseases in our ageing population, disease-modifying therapies remain elusive. As the mechanisms underlying neurodegeneration are poorly understood, these diseases are not especially amenable to target-based drug screening strategies. Here, Khurana et al. present phenotypic screening as an alternative drug discovery approach, and discuss how insights from a simple eukaryote, baker's yeast, are driving research in patient-derived neurons.

Vascular parkinsonism can result from a variety of vascular disorders, and most frequently manifests as an impairment of gait known as lower body parkinsonism. In this Review, Amos Korczyn summarizes the current understanding of clinical and pathogenetic aspects of vascular parkinsonism, including knowledge gained from neuroimaging, and considers current and future therapy for this condition. He also considers whether similarities between vascular parkinsonism and Binswanger disease mean that they should be considered as manifestations of the same pathology.

Central poststroke pain is not a rare consequence of stroke, but current pharmacological treatment options are limited and have little benefit. In this Review, the authors reconsider central poststroke pain as a network reorganization disorder, providing a framework to better understand the pathogenesis of the condition. In this context, they discuss the use of invasive and noninvasive neurostimulation to provide pain relief through modulation of network nodes, either as an alternative to or in combination with pharmacological treatments.

Management of multiple sclerosis (MS) and neuromyelitis optica (NMO) in women of fertile age must carefully weigh the risk to the fetus against the risk that rebound of disease activity might cause to the mother. Vukusic and Marignier summarize the currently available safety data on disease-modifying drugs for MS and NMO. Moreover, they outline goals for counselling in women with MS or NMO who wish to have children.

Amyotrophic lateral sclerosis (ALS) involves a complex interaction between genetic susceptibility and environmental insults. In this Review, Paez-Colasante and colleagues discuss various disease mechanisms that might apply to ALS, with particular emphasis on epigenetic factors. To date, only one treatment even modestly improves survival in patients with ALS, and the authors discuss several potential new therapeutic targets.

At present, direct electrical stimulation (DES) is the only technique that allows directin vivomapping of white matter tracts in humans. In this Review, Hugues Duffau discusses the insights into functional connectivity that have been gained from DES during awake surgery for brain lesions. In addition, the author considers the clinical implications of a paradigmatic shift from a localizationist model to a hodotopical model of cerebral processing.

The effects of statin treatment on the development of cognitive impairment, dementia and Alzheimer disease are unclear. In this Review, the authors systematically evaluate the findings from randomized controlled trials and observational studies that have investigated the association of statin use with cognition—including consideration of probable sources of bias—so as to summarize the current evidence and make recommendations for future work.

Migraine affects up to 25% of women of reproductive age. Suboptimally treated migraine during pregnancy can negatively affect both mother and fetus, but few data exist on the safety of many commonly used pharmacotherapies for migraine. This Review summarizes current evidence on the safety of the most common antimigraine drugs during pregnancy and breastfeeding, and provides treatment recommendations for clinical practice.

White matter hyperintensities (WMHs) are frequently seen on brain MRI in older people, and are thought to result from chronic ischaemia associated with cerebral small vessel disease. Prins and Scheltens provide a timely Review on WMHs, including their relationship with cognitive decline and dementia. The authors also discuss how WMHs might provide a therapeutic target to prevent the onset and progression of dementia.

Age related hearing impairment (ARHI, also known as presbycusis) is an important frailty marker, and could be a reversible risk factor for dementia and Alzheimer disease. Poor verbal communication and depletion of cognitive reserve might causally link ARHI to cognitive decline and frailty; hearing aids and cognitive training might, thus, provide a strategy to delay or prevent cognitive deterioration. In this Review, Panza and colleagues discuss the interplay between cognitive impairment, ARHI and frailty in older age.

The past 20 years have seen remarkable progress in research into multiple sclerosis (MS), resulting in a veritable armamentarium of treatment options. Ransohoff and colleagues reflect on three major eras of drug development to date. The authors also offer guidance on how best to select between various therapeutics, and look to the future of MS research.

Neuroinflammation during critical phases of brain development can increase the risk of neurological and neuropsychiatric disorders, even in adulthood. In this Review, Hagberg et al. review the mechanisms through which inflammation can exacerbate perinatal brain injury, and outline how understanding the interplay between inflammation and brain injury can aid the identification of new strategies to alleviate neurological and neuropsychiatric morbidity.

Mounting evidence suggests that autoantibodies contribute to the pathogenesis of demyelination in the PNS and CNS, and that such autoantibodies might impair saltatory conduction mediated by the node of Ranvier. In this Review, the authors provide a detailed description of the molecular anatomy of the node of Ranvier, discuss nodal, paranodal and juxtaparanodal proteins as likely autoantigens, and examine the role of autoantibodies in the pathogenesis of demyelinating disease.

Perihaematomal oedema (PHO) is an important pathophysiological marker of secondary injury following intracerebral haemorrhage. In this Review, the authors consider PHO in a novel framework and highlight the clinical relevance of the condition, both as a therapeutic target and as a surrogate marker for novel interventions that target secondary injury.