Review Articles in 2016

The Glasgow Outcome Scale (GOS) is widely recommended as an outcome measure after traumatic brain injury. Following the 40^thanniversary of its original publication, McMillan and colleagues review the development of the GOS and its extension and refinement over the past four decades, and consider how it can contribute to further understanding of brain injury.

About 2% of the general population and 8% of people with migraine have chronic migraine, defined as ≥15 headache days per month. The condition can be disabling and has a severe impact on quality of life, yet it receives little attention. This Review summarizes the current understanding of the risk factors and pathophysiological mechanisms of migraine chronification, and discusses strategies to prevent and treat the disorder.

The archetypal vascular endothelial growth factor, VEGF, arose in evolution as a signal affecting neural cells, and was subsequently co-opted to regulate vascular function. Here, the authors review the roles of the VEGF family as both aetiological factors and therapeutic targets in neurological disease.

Overactivation of the mechanistic target of rapamycin (mTOR) signalling pathway contributes to neurological disorders, including neurodevelopmental disorders, tuberous sclerosis complex, epilepsy, and tumours of the CNS. In this Review, Peter Crino discusses the pathophysiological role of mTOR in neurological diseases and provides an overview of clinical trials that have assessed the efficacy of mTOR inhibitors in these diseases.

Premutation CGG expansions in theFMR1gene can lead to various premutation disorders throughout life and ultimately lead to fragile X-associated tremor/ataxia syndrome (FXTAS) in late life. In this Review, the authors summarize our current understanding of the clinical features and management of FXTAS, and consider how our advancing understanding of the pathogenic mechanisms could lead to new therapies.

Numerous genetic variants have been associated with late-onset Alzheimer disease (LOAD) but the determination of their effect has proven challenging. Here, Gaiteri and co-workers discuss how the analysis of molecular and brain networks and their combination into multiscale models can provide a more comprehensive and clinically relevant representation of the effects of LOAD-associated genetic variants

Skeletal muscle disorders of glycogenolysis and glycolysis account for most of the conditions collectively termed glycogen storage diseases. Godfrey and Quinlivan outline the distinguishing features of these disorders, and they describe a large European registry, EUROMAC, that has been established to pool and transfer knowledge regarding McArdle disease and other rare disorders of carbohydrate metabolism.

In modern X-ray therapy, healthy brain tissue that surrounds a CNS tumour receives low to medium dose irradiation, which has important long-term adverse effects such as cognitive toxicity, endocrinopathy, hearing loss and vasculopathic effects. Prolonged long-term survival in certain paediatric CNS tumours call for more attention in avoiding the long-term sequelae of radiotherapy. This Review discusses how proton therapy improves dose distribution and can help reduce long-term toxicities.

Extracellular vesicles (EVs) are released by most cell types, and they carry a cargo of protein and nucleic acid that reflects the cell of origin. Thompson and colleagues review current knowledge of the biology and function of EVs, including evidence for their involvement in neurodegenerative disease pathogenesis, and their potential as CNS-specific biomarkers.

Diagnosis of Creutzfeldt–Jakob disease (CJD) in living patients is challenging, but distinguishing this untreatable disease from treatable rapidly progressive dementias is essential, and will also help prevent iatrogenic transmission of CJD. In this Review, Zanusso et al. discuss novel techniques, such as ultrasensitive protein seeding assays and nasal brushings, that can aid antemortem diagnosis of CJD.

MRI-based visualization of demyelinated CNS lesions is pivotal to the diagnosis and monitoring of multiple sclerosis (MS). The authors describe how advanced multimodal neuroimaging techniques are providing valuable insights into lesion structure and blood–brain barrier dynamics, thereby narrowing the gap between the macroscopic view of the radiologist and the microscopic view of the pathologist. The findings in humans are compared with data from a primate model of MS — experimental autoimmune encephalomyelitis in the common marmoset.

The characteristic muscle weakness in myasthenia gravis (MG) is caused by antibodies against target molecules the neuromuscular junction. Here, Nils Gilhus and colleagues review how these antibodies and other biomarkers can be used to guide MG subgroup classification and treatment, as well as the best tests to detect these antibodies. Moreover, they discuss how the various antibodies are involved in MG pathogenesis.

In addition to the functional impairments that can arise after stroke, about one-third of stroke survivors experience neuropsychiatric disorders such as depression, anxiety or apathy. In this Review, Ferro and colleagues provide an update on the diagnosis and pathophysiology of the acute and long-term psychiatric consequences of stroke, and discuss available treatments and management strategies for these stroke-associated disorders.

Nonconvulsive status epilepticus has subtle symptoms and can be difficult to treat, meaning it is associated with considerable morbidity and mortality. In this Review, Sutter and colleagues discuss the epidemiology, clinical features and diagnosis of nonconvulsive status epilepticus, and discuss current recommendations for treatment.

The limb-girdle muscular dystrophies (LGMDs) comprise more than 30 genetically defined neuromuscular diseases that share the determining features of weakness and wasting of the pelvic and shoulder girdle muscles. Next-generation sequencing (NGS) technologies are continuing to expand the range of genes and phenotypes associated with the LGMDs. In this article, Thompson and Straub review the international collaborations that are addressing translational research issues in the LGMDs, and the lessons learned from large-scale NGS programmes.

Despite highly effective combination antiretroviral therapies, the prevalence of HIV-associated neurocognitive disorder (HAND) has not reduced. To date, clinical trials of HAND therapies have been unsuccessful, calling for better understanding of HAND pathogenesis to develop more-effective treatment strategies. In this Review, Justin McArthur and colleagues discuss recent proceedings in understanding the immunopathogenesis of HAND, drawing from human studies and animal models.

Epilepsy develops in many patients with glioma, and the two presentations are currently treated with independent therapies. In this Review, Huberfeld and Vecht provide an overview of the evidence that epilepsy and gliomas share pathogenic mechanisms that could be targeted to simultaneously manage seizures and target tumours. They consider the benefits and risks of using antiepileptic drugs to treat gliomas, and antitumour drugs to control epilepsy.

The range of immunomodulatory therapies to treat multiple sclerosis (MS) has widened markedly in recent years, and MS treatments have become more efficient. This improvement in efficacy has been accompanied by an increased risk of treatment-associated infections. In this Review, Winkelman et al. discuss the modes of action of the currently available MS therapies and detail the specific infections associated with each treatment. They consider how this information can influence the daily clinical use of MS therapies, so as to minimize the associated infectious risk.

Rare neurological diseases require widely distributed networks of centres, investigators and patients to foster multidisciplinary investigations and recruit sufficient numbers of patients for research studies and clinical trials. In this article, Jen and colleagues highlight the role of two networks, the Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and the Clinical Research Consortium for Studies of Cerebellar Ataxias (CRC-SCA), in bringing together the various stakeholders in patient-oriented research into rare neurological channelopathies.

Access to the brain remains a challenge in surgical and drug treatment of neurological disorders, but therapeutic use of ultrasound offers a realistic alternative to overcome the challenges. In this Review, the authors provide an overview of how ultrasound can be used for neurosurgery to ablate pathological tissue, for drug delivery by opening the blood–brain barrier, and for neuromodulation.