Reviews & Analysis

In recent years, the central roles of neuronal and axonal damage, as well as axon–glial and axon–myelin interactions, in the pathogenesis and progression of multiple sclerosis (MS) have become increasingly apparent. Franklin et al. review advances in our understanding of the molecular mechanisms underlying these MS-related events, and discuss approaches towards axonal neuroprotection and repair, particularly through the regenerative process remyelination.

In this Review, von Geldern and Mowry discuss the potential effects of vitamin D and other dietary components on the disease course of multiple sclerosis (MS). Numerous studies have looked at the effects of nutrition on relapse rate and/or disease progression in this condition, and here the authors provide an overview of and a biological rationale for nutritional therapy in MS.

Whether dominantly inherited variants of Alzheimer disease (AD) and 'sporadic' forms exhibit similar pathophysiological and biomarker signatures remains unresolved. A landmark study has proposed a biomarker progression model of dominantly inherited AD, but a complex systems biology and physiology approach is required to translate these findings to sporadic disease.

Over the past few decades, considerable progress has been made in understanding the mechanisms underlying the relapsing–remitting stage of multiple sclerosis (MS), but the disease processes that drive progressive MS remain largely unresolved. In this Review, Lassmann and colleagues explore the current state of knowledge on the pathophysiology of progressive MS, and present a pathogenetic concept for this phase of the disease that involves oxidative stress and mitochondrial injury.

Multiple sclerosis is an inflammatory, demyelinating disease in which antigens of the myelin sheath have been considered the autoimmune target. A recent study suggests that the potassium channel KIR4.1 is another potential autoantigen in some patients with multiple sclerosis, and might also be a target in other demyelinating diseases.

Controversy exists over the treatment of brain arteriovenous malformations. A recent study suggests that, irrespective of clinical presentation, invasive treatment has no benefit over conservative management with regard to risk of seizure. Whether eradication is superior to medical management alone for those with seizures, headache and/or haemorrhage remains unsettled.

The understanding and treatment of medulloblastoma, the most common childhood malignant brain tumour, is rapidly evolving. Three complementary deep-sequencing studies that were recently published in Nature add to our knowledge of this disease, further refine risk stratification, and identify potential druggable targets.

Despite widespread damage associated with multiple sclerosis (MS) pathology, recovery of function can occur, driven by adaptive plasticity in brain networks. Tomassini et al. review the mechanisms underlying functional recovery in MS, and discuss interventions that might promote this process. Methodological considerations for imaging neuroplasticity using functional MRI are also highlighted.

Sepsis-associated encephalopathy (SAE) is a clinical syndrome that is associated with diffuse brain dysfunction and is secondary to infection in the body. Severity of SAE ranges from mild delirium to deep coma, and mortality reaches almost 70% in severe cases. In this Review, Gofton and Young provide an overview of the epidemiology and clinical presentation of SAE. They discuss current evidence relating to the pathophysiology and prognosis of SAE, and present a diagnostic approach and management strategy for patients with the disease.

Natural history of multiple sclerosis includes phases of relapse, remission and insidious progression. New data show that sustained improvements in disease, defined by reductions in EDSS scores, occur independent of relapses almost half as frequently as disease worsening. This finding might facilitate research into the biological processes involved in disease improvement.

The introduction of recombinant tissue-type plasminogen activator (tPA) revolutionized stroke treatment, but experimental studies have suggested potential toxic effects of this molecule on various components of the CNS. Two new studies have added further insight into the complex CNS effects of tPA following traumatic brain injury and brain ischaemia.

This Review discusses the concept of pharmacoresistant epilepsy and describes the identification and management of this frequently misdiagnosed condition, focusing on the underutilized role of surgical treatment. Wiebe and Jette present robust evidence of the safety and efficacy of epilepsy surgery in patients with confirmed pharmacoresistant epilepsy, and suggest that epilepsy surgery should be considered promptly for these individuals.

Cranial radiation therapy (CRT) is commonly used to treat brain tumours but, in paediatric patients, this therapeutic strategy can lead to subsequent neurocognitive impairment. Padovani et al. discuss both the mechanisms underlying the effect of CRT on cognitive function and factors that can affect outcome. New approaches to correct or avoid CRT-induced neurotoxicity are also considered.

Treatments for the hereditary optic neuropathies, including Leber hereditary optic neuropathy and dominant optic atrophy, are limited. In this Review, Nancy Newman summarizes the natural history of hereditary optic neuropathies, and the role of mitochondrial dysfunction in their pathogenesis. She highlights recent advances in the treatment of these disorders, and indicates how insights into the hereditary optic neuropathies could have therapeutic implications for other disorders of presumed mitochondrial dysfunction.

Understanding how genetic variation can confer susceptibility to neurological disease is an urgent priority. A new gene-expression study has explored the relationship between DNA sequence variation at the microtubule-associated protein tau (MAPT) locus and MAPT expression in the brain, providing an exciting new paradigm for the field.

High platelet reactivity persists in many patients receiving antiplatelet therapy for secondary prevention of ischaemic stroke. Patient-tailored antiplatelet therapy, guided by platelet function tests, is an appealing approach for prevention of recurrent vascular events. However, a recent study has demonstrated that this strategy is associated with worse clinical outcomes.

Around half of all stroke survivors exhibit spatial neglect—a failure to report, respond to or orientate to contralesional stimuli. Current therapeutic approaches for spatial neglect focus largely on visual perceptual processing, but many patients respond poorly to such approaches because their main impairments lie in spatial motor 'aiming' function. Here, Barrett et al. highlight a promising alternative approach—prism adaptation treatment—that specifically targets spatial motor deficits.

Megalencephaly syndromes are a spectrum of severe developmental neurological disorders associated with brain overgrowth. Two recent studies highlight the pathogenic role of somatic mutations in genes of the mTOR signalling pathway in the brains of patients with these conditions, providing hope for development of new treatments.

One of the main challenges associated with diagnosis of Alzheimer disease (AD) is the identification and validation of blood-based biomarkers. Three recent studies describe different approaches to blood-based biomarker research in AD, and provide hope for a simple, minimally invasive means of diagnosis.

Gene expression profiling (GEP) has advanced considerably in the past 5 years, and has been used to study differential gene expression associated with various neurological disorders. In their Review, Shaw and colleagues review recent GEP studies in amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. The findings have highlighted involvement of shared and distinct pathways across diseases, and point to possible biomarkers and therapeutic targets that could improve future diagnosis and treatment.