Review Articles in 2013

In this Review, Paul Matthews and colleagues outline the potential benefits of a stratified approach to health-care delivery in neurology, including reduced risk of adverse events from medicines, and lower treatment costs. They provide examples of neurological diseases in which stratified medicine is already improving treatment, and consider challenges to implementation of these approaches.

Subarachnoid haemorrhage (SAH) has a high case fatality. In addition to neurological injury occurring at the time of haemorrhage, delayed neurological deterioration can occur days later owing to processes such as cerebral vasospasm and microthrombosis, which culminate in delayed cerebral ischaemia. R. Loch Macdonald reviews the pathophysiology of these delayed complications of SAH, and outlines existing treatments and drugs in development for this indication.

Primary cilia are hair-like, non-motile sensory organelles that are found on the surface of almost all cells in vertebrates. Defects in these organelles can lead to a wide array of disorders known as ciliopathies. In this Review, Valente et al. focus on ciliopathies with major neurological involvement, describing their clinical features and known pathogenetic mechanisms, and discussing the possible aetiologies of associated brain malformations.

Effective treatments are lacking for most neurological disorders, and progress in developing new therapeutic agents has been frustratingly slow. Howells and colleagues explore the barriers to the development of treatments for these conditions, focusing predominantly on the stroke field. They highlight the current deficiencies and conflicts of interest in preclinical and clinical research, and suggest ways in which scientific rigour might be improved.

Notable failures of amyloid-β-targeted therapies in late-stage clinical trials for Alzheimer disease (AD) suggest the need for a reassessment of the amyloid cascade hypothesis of AD pathology. Here, Giacobini and Gold discuss the limitations of focusing on amyloid-β, and suggest a shift towards tau-directed therapy. They outline the rationale for such an approach and summarize results in animal models that show promise for translation to the clinic.

Rodent models of nerve injury are frequently used to study peripheral nerve regeneration, but translating the findings to clinical applications has been difficult, in part because in axons in humans generally need to regenerate over much longer distances, leaving the distal nerves and muscle tissue denervated for long periods of time. In this Review, Scheib and Höke discuss the challenges and advances in the study of peripheral nerve regeneration, and suggest that chronic rodent models of nerve injury more closely mimic the chronic denervation condition that is commonly present in human nerve injuries.

Current approaches to rehabiliation of motor and language function after stroke focus on compensation rather than repair of the underlying damage, often with limited clinical benefit. Here, Steven Small and colleagues propose a new model for poststroke therapy that aims to rebuild brain circuits underlying the impaired functional domains. They describe experience with action observation therapy, which harnesses the putative mirror neuron system in humans to improve motor performance and language skills.

In addition to difficulties in movement, patients with Parkinson disease (PD) exhibit changes in somatosensory function, which might contribute substantially to disability by interfering with signals that are required for the preparation and execution of voluntary movement. In this article, Conte et al. review the evidence for disrupted tactile, nociceptive, thermal and proprioceptive sensations in PD, and the effects of dopaminergic therapy and deep brain stimulation on these sensations.

Intravenous thrombolytic therapy is the only approved treatment for acute ischaemic stroke, but the majority of patients do not benefit from, or are ineligible to receive, such treatment. Angiographically guided recanalization of the occluded vessel through use of a stent retrieval device offers the potential to effectively restore blood flow in patients with ischaemic stroke, and has shown promise in early-stage trials. Jansen and Rohr review advances in such neurothrombectomy techniques and summarize completed and ongoing trials. The authors outline important considerations when selecting patients for this intervention.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in relentlessly progressive paralysis and, ultimately, death. Considerable progress has been made in elucidating the genetic causes of ALS, but the contribution of environmental factors has been more difficult to determine. Al-Chalabi and Hardiman outline the current state of knowledge regarding the environmental and genetic epidemiology of ALS, and propose a disease model in which environmental risks and time act on a pre-existing genetic load.

Parkinson disease (PD) pathogenesis involves dysfunction and eventual death of midbrain dopaminergic neurons. Emerging evidence points to a role for the transcription factor NURR1 in this process. In this Review, the authors describe findings from animal and human studies that support this concept, outline possible underlying mechanisms involving oxidative stress and interaction with α-synuclein, and highlight the potential of NURR1 as a therapeutic target.

Cortical spreading depression (CSD) is a wave of activity that propagates across the brain surface, and has long been presumed to be the physiological substrate of the migraine aura. Despite substantial evidence from animal models, however, the relationship between CSD and migraine in humans remains uncertain. Charles and Baca review our current understanding of the role of CSD in migraine, and highlight the unresolved issues in this field of investigation.

Charcot–Marie–Tooth disease (CMT) encompasses a group of inherited motor and sensory neuropathies. Over the past two decades, considerable advances have been made in identification of the causative genes. Here, Rossor et al. outline the role of next-generation sequencing in enabling rapid, parallel screening of multiple CMT-associated genes, and propose a diagnostic algorithm for application of genetic screening when CMT is suspected.

Neuropathic pain is a common feature of many nervous system disorders, and carries a substantial morbidity burden. In this Review, Cruccu and colleagues describe the distinct pathological mechanisms that are thought underlie the various types of neuropathic pain, such as ongoing burning sensations and allodynia. The authors argue that a symptom-based framework could be used to tailor diagnostic and treatment approaches.

Sepsis-associated encephalopathy (SAE) is a severe neurological consequence of sepsis that carries a high risk of mortality. Although the signs and symptoms of SAE are well-recognized, the underlying pathomechanisms of sepsis-associated neurological dysfunction are poorly understood. In this Review, Stubbs et al. discuss how imaging can provide insight into the pathophysiology of SAE, outlining current approaches to diagnostic imaging in research and clinical studies, and highlighting how 'next-generation' imaging technologies might improve understanding, diagnosis and management of SAE.

The concept of lysosomal storage disorders (LSDs) has existed for over 50 years, but our understanding of the causes and pathobiology of these diseases have come to light only recently, following advances in genetic technology. In this Review, Rose-Mary Boustany summarizes current understanding of known LSDs, highlighting existing treatment approaches for patients with these often devastating disorders, and outlining the barriers to development of novel therapies.

Determination of prognosis in patients with status epilepticus (SE)—a life-threatening state of ongoing or repetitive seizures—is difficult, and current outcome prediction scales do not take into account novel outcome markers, such as EEG and imaging findings. Here, Sutter et al. review the available data on major prognostic determinants of outcome in SE, and propose a novel paradigm for assessment of these predictive factors over the course of the seizure.

The pathophysiological processes underlying onset and progression of amyotrophic lateral sclerosis (ALS) remain poorly understood. Unlike conventional imaging techniques, which provide information only at a gross structural level, advanced imaging modalities have shed light on the microstructural changes that accompany this disease. Eva Feldman and colleagues describe how advanced neuroimaging studies have delineated key factors, such as white matter tract integrity and brain metabolism, that are altered in ALS, and consider how such insights could aid diagnosis and treatment.

As the range of therapeutic options for multiple sclerosis (MS) continues to expand, the ability to select the most appropriate treatment for each patient becomes increasingly important. In this Review, Sormani and De Stefano assess the studies that have attempted to classify patients with MS on the basis of their response to IFN-β treatment. The authors also discuss the development and use of scoring systems that combine different clinical and MRI markers to aid definition of an early response to this drug.

The majority of patients with multiple sclerosis (MS) will at some point experience the progressive form of the disease, involving relentless functional decline and axonal degeneration. No cure for progressive MS is currently available, and clinical trials in this patient population are problematic. Koch and colleagues describe current limitations of trials in progressive MS, such as lack of suitable outcome measures, and present approaches to address these challenges.