Review Articles in 2015

Hepatitis E virus (HEV) is the causative agent of hepatitis E, and extrahepatic manifestations, including various types of neurological injury, have also been reported in individuals with HEV infection. The most common neurological manifestations are Guillain–Barré syndrome (GBS), neuralgic amyotrophy, and encephalitis and/or myelitis. In this article, the authors review the reported cases of HEV-associated neurological injury, discuss the possible pathogenic mechanisms, and outline future directions and research questions.

Many neurological disorders, from traumatic brain injury to Alzheimer disease, affect social cognition, yet deficits in social cognition can be difficult to detect and diagnose effectively. In this Review, Henry and colleagues provide an overview of the clinical contexts in which social cognitive dysfunction arises and consider how tests can be used to detect it. Through examples of four conditions in which social cognitive dysfunction arises, they demonstrate the appropriate tests to use, and consider their clinical application beyond these disorders.

The most-established risk factors for intracerebral haemorrhage (ICH) are lifestyle-related, but several studies have reported familial aggregation of ICH. An understanding of the role of genetic risk factors in ICH could provide insight into ICH aetiopathogenesis, and improve prevention and patient-tailored management of ICH. This Review discusses the evidence for a genetic component in ICH, taking into account the strength of evidence and functional relevance to ICH for each genetic variant.

It is 40 years since the microtubule-associated protein tau was isolated and characterized, and 30 years since this protein was discovered to be abnormally hyperphoshorylated in the brains of patients with Alzheimer disease. To mark these important milestones, Iqbal and colleagues provide an overview of the pivotal discoveries in the tau research field over the past 40 years. They also review the current status of the field, focusing on the molecular biological insights that have established a key role for tau pathology in neurodegenerative disease, and the new therapeutic approaches that are emerging from this research.

Inflammation-driven synaptic dysfunction is emerging as a prominent pathogenic mechanism in multiple sclerosis (MS). Importantly, synaptic alterations and synaptic loss are potentially reversible, making them potential therapeutic targets. This Review draws on studies in patients with MS and in animal models of the disease to discuss the synaptic alterations in MS and the most promising drugs to restore synaptic function and intervene in the disease progression.

Harnessing self-protective pathways in the brain could protect against neurological disease, but pharmacological attempts at such an approach have failed. In this Review, Hess et al. consider the neurological potential of remote ischaemic conditioning (RIC), a procedure in which brief ischaemia induced by vascular occlusion in the limb activates self-protective pathways and protects distant organs against longer episodes of ischaemia. Clinical trials in cardiological settings have been successful, and trials in neurological conditions suggest that RIC is a feasible option for patients with ischaemic neurological conditions.

Myoclonus is characterized by sudden, involuntary jerks, and can be caused by a variety of acquired and genetic disorders. Identification of the aetiology of myoclonus is paramount, because treatment should be based on the underlying disorder. The authors propose a novel eight-step diagnostic algorithm for myoclonus, incorporating—for the first time—next-generation sequencing. The algorithm should aid clinical decision-making and facilitate mechanism-based treatment.

In our third and final installment from the MAGNIMS study group, Enzinger et al. consider how dramatic progress in MRI has enabled nonconventional structural imaging techniques to shed new light on the pathophysiology of multiple sclerosis. The authors discuss the present use of these techniques in the disease, and consider their future application to clinical research and practice.

Parkinson disease is defined by its motor symptoms, but onset of nonmotor symptoms, including constipation, can start much earlier. In this Review, Klingelhoefer and Reichmann present the evidence that the pathogenesis of Parkinson disease starts in the gut and is transferred to the CNS via trans-synaptic cell-to-cell transport that initiates a cascade of α-synuclein aggregation. They also consider how this process might be triggered by environmental factors, and how these earliest stages of pathogenesis might be targeted to delay or prevent disease progression.

Monoamine neurotransmitters are involved in many neurological functions, and defects in their synthesis, metabolism and transport leads to a variety of disorders with subtly different clinical manifestations that make them difficult to diagnose. The authors of this Review outline the clinical features, diagnosis and management of monoamine neurotransmitter disorders, and consider recent and future advances in knowledge and therapeutic options.

The diagnosis and monitoring of multiple sclerosis (MS) still relies largely on clinical manifestations and imaging. Blood-based or cerebrospinal fluid biomarkers to facilitate prognostic evaluation, staging and subtyping of MS, as well as to predict treatment response and adverse effects, are sorely needed. This comprehensive Review by Charlotte Teunissen and colleagues provides an update on advances in biomarker development and validation in MS, focusing on the clinical applications of MS biomarkers.

Cognitive dysfunction is frequently observed in patients with multiple sclerosis (MS), and can have a substantial impact on daily activities and quality of life. In this Review, Fielding and colleagues discuss how ocular motor measures in patients with MS might be used to characterize disruption to wide-ranging networks that support cognitive function, and to track disease progression and responses to novel therapies in these individuals.

Blood-derived biomarkers for gliomas would facilitate diagnostic and prognostic evaluation and assessment of treatment response. Extracellular vesicles, in particular, could be valuable, because they contain a variety of microRNAs, tumour DNA and metabolic markers that reflect the heterogeneous composition of the tumour. Here, Westphal and Lamszus provide an overview of the state of the art, prospects and challenges in development of circulating biomarkers for gliomas.

Dysregulation of the type I interferon pathway has been implicated in the pathogenesis of a spectrum of neuroinfectious and neuroinflammatory disorders. McGlasson et al. review the range of neurological diseases associated with type I interferon underactivity and overactivity, highlighting advances in our understanding of the molecular and cellular pathogenesis of these conditions. They also discuss the potential utility of type I interferon as a biomarker and therapeutic target in neuroinflammatory disease.

After an ischaemic or haemorrhagic stroke, microglial activation and the release of cell death products initiate a chain of inflammatory events that lead to vascular damage and oedema. Here, Shi and colleagues discuss the similarities between acute stroke and multiple sclerosis, and review past attempts to limit poststroke inflammation via immunotherapy. The authors then highlight gaps in our knowledge about the immune system's reaction to stroke, and discuss how best to move forward with this line of research.

Glioblastoma is the most common primary brain tumour in adults, and has a notoriously poor prognosis. Recent successes of immunotherapy in other cancer types have made immunotherapy—particularly the use of immune checkpoint modulators—an appealing strategy against glioblastoma. Here, Matthias Preusser and colleagues summarize current knowledge on immune checkpoint modulators, and evaluate their potential role in glioblastoma treatment in light of preclinical studies and emerging clinical data.

Following the success of pharmacological dopamine replacement in patients with Parkinson disease (PD), cell-based dopamine replacement strategies seemed the next logical step. In this Review, the authors outline the history of this therapeutic approach to PD, emphasizing the importance of obtaining robust preclinical data before proceeding to clinical trials. In addition, they discuss the challenges of bringing the new generation of stem cell-derived dopamine cells to the clinic.

Up to 12% of patients with Lyme disease develop neurological symptoms. This syndrome, Lyme neuroborreliosis, can manifest soon after the initial infection or months to years after the event. Koedel and colleagues discuss the diagnosis and treatment of early and late Lyme neuroborreliosis, and review the controversies surrounding post-treatment Lyme disease syndrome and chronic Lyme disease.

Restless legs syndrome that reduces quality of life and disturbs sleep requires pharmacological intervention. In the context of current guidelines and diagnostic criteria, Claudia Trenkwalder and colleagues summarize the treatments that are currently approved and used in clinical practice, including combination therapies. They also draw on their clinical experience to discuss and advise on the management of augmentation induced by dopaminergic drugs.

The elimination of amyloid-β (Aβ) from the brain is already impaired at the prodromal stage of Alzheimer disease (AD), so restoration of the clearance systems of the brain might delay the onset of AD. This Review provides a comprehensive update on the brain's clearance systems, including the recent discoveries of the glymphatic system and meningeal lymphatic vessels—findings that have important implications for understanding the disrupted elimination of toxic proteins in AD.