Reviews & Analysis

Patients with epilepsy have a higher mortality rate than the general population. A recent population-based study has found that external causes of death, such as suicide and accidental deaths of various types, account for 16% of the deaths in these patients, and that psychiatric comorbidity contributes significantly to their occurrence.

A recent study has examined potential predictive markers of Alzheimer disease (AD) and stroke. The results challenge some current assumptions, suggesting that stroke might often follow a decade of deterioration in brain structure and function, and that cognitive and MRI markers of AD differ in older and younger individuals.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) study protocol currently precludes disclosure of test results to participants. A survey among ADNI investigators, however, demonstrates that most want this policy changed, in light of the approval of ¹⁸F-florbetapir as a PET amyloid ligand. Should we tell the study participants if they want to know?

Identification of the key factors involved in glioblastoma oncogenesis is a necessary precursor to the development of efficient and personalized, targeted therapy. Combining data from high-throughput genetic screening, bioinformatic analysis and functional studies, a multicentre research collaboration has identified new driving mutations in glioblastoma, including novel tumour suppressor and fusion oncogenes.

New research indicates that next-generation sequencing (NGS) can improve the diagnostic yield in a highly selected group of patients with ataxia, following comprehensive exclusion work-up of other causes. However, routine practical application of NGS will depend on refinement of current technologies to facilitate data interpretation, and cost-effectiveness analysis in different patient groups.

An evidence-based guideline update on vagus nerve stimulation for treatment of epilepsy supports consideration of its use in children, in patients with Lennox–Gastaut syndrome, and to improve mood in adults. Its efficacy may also increase over prolonged treatment. These conclusions are tentative, however, highlighting our knowledge gaps.

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.

In patients with chronic epilepsy, MRI-based detection of an underlying brain lesion can offer the potential for surgical treatment, but a substantial proportion of patients have normal MRI scans. A recent study has shown that repeat neuroimaging with improved MRI technology can enable detection of previously unidentified epileptogenic lesions.

Gene therapy approaches for glioblastoma multiforme (GBM) have been under investigation in clinical trials since the 1990s, but the results to date have been disappointing. A recently published phase III trial of adenovirus-based gene therapy for GBM has demonstrated modest—but possibly clinically relevant—improvements in patient survival.

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.

Patients with transient ischaemic attack or minor ischaemic stroke have a high risk of early recurrence. A new study in Chinese patients suggests that this risk is reduced following treatment with clopidogrel plus aspirin compared with aspirin alone. However, whether the findings can be extrapolated to other populations remains unclear.

The heterogeneity of traumatic spinal cord injury necessitates large clinical trials to differentiate natural improvements from enhanced recovery due to therapeutic intervention. Recent development of an imaging biomarker to visualize changes in the corticospinal motor system could offer the opportunity to directly visualize anatomical evidence of repair, regeneration and plasticity.

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.

A Task Force of the International League Against Epilepsy has proposed a new pathology-based classification of three types of hippocampal sclerosis—the most frequent brain lesion in drug-resistant temporal lobe epilepsy. This classification is designed to be reproducible across centres, thereby aiding communication of histopathological findings.

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.

Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is an effective treatment for acute ischaemic stroke, although its use for patients with mild forms of this condition remains controversial. Here, Guerrero and Savitz outline the potential risks and benefits of rtPA in this patient population, and explain why they believe patients with mild ischaemic stroke should receive this treatment.

The month of birth effect describes the apparent association between month of birth and future risk of multiple sclerosis, whereby people born in spring months have slightly increased risk. A recent analysis of the available data, however, suggests that this relationship is spurious because studies have not adequately controlled for confounders.