Reviews & Analysis

Treatment of older patients with glioblastoma must take into account reduced treatment benefits and increased treatment-related toxicity, as this group of frail patients has a particularly poor prognosis. A new systematic review provides guidance for treating elderly patients, but decision-making in clinical practice faces many challenges.

The list of vascular, lifestyle-related and other risk factors and biomarkers associated with dementia development has constantly grown over the past few years. A recent study emphasizes the importance of risk prediction models for identification of individuals with increased risk of future cognitive impairment who could benefit from preventive interventions.

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.

Class I evidence supports the efficacy of surgical treatment in patients with temporal lobe epilepsy that is refractory to antiseizure medications. One major concern, however, is the risk of memory decline, particularly after temporal lobe resection in the language-dominant hemisphere. A new study evaluates a noninvasive technique to predict these memory deficits.

Primary CNS lymphoma (PCNSL) is uniquely responsive to initial radiotherapy or chemotherapy, but the best therapeutic approach remains uncertain. Recently updated results from a phase III trial do not support the use of radiotherapy in PCNSL, although the analyses had several disappointing limitations.

The symptoms and neuropathology of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) can show a high degree of overlap, and few effective treatments exist for these conditions. In this Perspectives article, Ittner and colleagues describe recent failures in the translation of data from mouse models into clinical trials for patients with FTD and/or ALS. The authors summarize the strengths and weaknesses of several available mouse models, and make recommendations for improving future research practice.

Seizures after neonatal hypoxia are difficult to treat. A recent antiepileptic safety and dose-finding study examined phenobarbital plus bumetanide, but was stopped owing to apparent futility and increased risk of hearing loss. However, this decision could have been overcautious: 0.2 mg/kg bumetanide reduced seizure burden, and might not have increased hearing loss.

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.

A new study shows that in patients with multiple sclerosis who exhibit active disease despite disease-modifying therapy, a switch to fingolimod is more effective than continuation of IFN-β or glatiramer acetate for preventing relapses and worsening of disability. These data support the utility of treatment escalation to improve disease control.

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.

Local synthesis of IgG in the CNS is present in >90% of patients with multiple sclerosis (MS), and is considered a hallmark of the disease. A recent study has discovered genetic factors associated with intrathecal production of these antibodies, and suggests excessive IgG synthesis as an indicator of an aggressive disease.

In a long-term clinical trial, a responsive neurostimulation system was shown to reduce seizures and improve quality of life in patients with drug-resistant epilepsy. Furthermore, these effects persisted over an extended time period. Will neurostimulation close the treatment gap for patients with refractory epilepsy?

A long-term outcome analysis in patients with lacunar stroke enrolled in the Secondary Prevention of Small Subcortical Strokes trial highlights the relevance of functional disability after small-vessel strokes. These data support the emerging 'burden of disease' concept in individuals with cerebral microangiopathy, and the role of MRI in outcome prediction.

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 apolipoprotein E ε4 (APOE^*ε4) allele is a well-established risk factor for cognitive decline, particularly among white individuals. A recent study highlights factors associated with cognitive resilience in both black and white APOE^*ε4 carriers. Despite racial differences in the frequency and impact of APOE^*ε4, resilience factors are similar across races.

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.

A recent review and meta-analysis on pharmacotherapy for neuropathic pain provides a precise update on treatment efficacy and adverse effects. The authors offer revised evidence-based recommendations for first-line therapies and subsequent options, but we still a need to improve individual treatment decisions, including nonpharmacological therapies, in affected patients.