Reviews & Analysis

Studies into the relationship between diabetes and amyotrophic lateral sclerosis (ALS) have produced conflicting results. In young patients, diabetes is a consistent risk factor for ALS; in older patients, diabetes protects against ALS in Europe, but increases the risk of ALS in Asia. Environment and genotype might both contribute to this variation.

The detection of an unruptured intracranial aneurysm poses a dilemma for the patient and the physician: an aneurysm rupture is a catastrophic event, but preventive repair is not without risks. The recently updated AHA/ASA guidelines provide some foundation for decision-making by summarizing the available evidence, but several clinically relevant questions remain uncertain.

Glioblastoma is the most common primary brain tumour in adults, and has a notoriously poor prognosis. Recent successes of immunotherapy in other cancer types have made immunotherapy—particularly the use of immune checkpoint modulators—an appealing strategy against glioblastoma. Here, Matthias Preusser and colleagues summarize current knowledge on immune checkpoint modulators, and evaluate their potential role in glioblastoma treatment in light of preclinical studies and emerging clinical data.

Following the success of pharmacological dopamine replacement in patients with Parkinson disease (PD), cell-based dopamine replacement strategies seemed the next logical step. In this Review, the authors outline the history of this therapeutic approach to PD, emphasizing the importance of obtaining robust preclinical data before proceeding to clinical trials. In addition, they discuss the challenges of bringing the new generation of stem cell-derived dopamine cells to the clinic.

A large study corroborates the link between depression and increased risk of subsequent Parkinson disease (PD), but whether depression is a risk factor for or a prodromal symptom of PD remains a conundrum. Consideration of nonbiological risk factors and disorders associated with depression aside from PD could elucidate this complex relationship.

Cognitive impairment is a major sequela after stroke. A recent study shows that cognitive impairment is prevalent after ischaemic stroke, even in patients with good functional recovery, and that compromise in different cognitive domains predicts future functional disability. Here, we reflect on how poststroke cognitive impairment is measured and conceptualized.

Up to 12% of patients with Lyme disease develop neurological symptoms. This syndrome, Lyme neuroborreliosis, can manifest soon after the initial infection or months to years after the event. Koedel and colleagues discuss the diagnosis and treatment of early and late Lyme neuroborreliosis, and review the controversies surrounding post-treatment Lyme disease syndrome and chronic Lyme disease.

Restless legs syndrome that reduces quality of life and disturbs sleep requires pharmacological intervention. In the context of current guidelines and diagnostic criteria, Claudia Trenkwalder and colleagues summarize the treatments that are currently approved and used in clinical practice, including combination therapies. They also draw on their clinical experience to discuss and advise on the management of augmentation induced by dopaminergic drugs.

Bevacizumab is approved for use in recurrent glioblastoma, but whether it benefits patients with newly diagnosed glioblastoma remains unclear. Two new studies further question the use of the bevacizumab in this context, but leave much to be clarified about its optimal clinical application.

Multiple system atrophy (MSA) carries a universally poor prognosis, but the natural history of the disease is not well established. A new study prospectively followed a cohort of patients with MSA across multiple centres in the USA. The results provide valuable insight into progression and survival in patients with MSA.

The elimination of amyloid-β (Aβ) from the brain is already impaired at the prodromal stage of Alzheimer disease (AD), so restoration of the clearance systems of the brain might delay the onset of AD. This Review provides a comprehensive update on the brain's clearance systems, including the recent discoveries of the glymphatic system and meningeal lymphatic vessels—findings that have important implications for understanding the disrupted elimination of toxic proteins in AD.

The use of MRI in patients with multiple sclerosis (MS) is commonplace in clinical settings. However, the precise implementation of MRI in the diagnosis of MS is highly variable, which is problematic in the context of the substantial technical advances of the past decade. In these Evidence-based Guidelines, members of the MAGNIMS study group present a standardized approach to the use of MRI in the diagnosis of MS.

A surprisingly high rate of nonconvulsive seizures and status epilepticus is found during continuous EEG monitoring in critically ill patients. A recent analysis of data regarding hospitalization and mortality in patients with status epilepticus emphasizes the relevance not only of how status epilepticus is defined, but also of how it is detected.

Loss of hypocretin neurons is a hallmark finding in narcolepsy; recent findings have implicated also increased number of histamine neurons in this disorder. This Review provides an overview of coregulation of sleep and wakefulness by hypocretin and histamine. The authors also review the changes in hypocretin and histamine systems in narcolepsy and neurodegenerative diseases (such as Alzheimer disease, Parkinson disease and Huntington disease) and discuss novel therapeutic approaches for manipulation of the histamine system in these diseases.

The use of infant formula as a substitute for or supplementation to breast milk has increased dramatically since the middle of the 20^th century. Such formula is typically supplemented with high levels of iron, yet the long-term effects of high exposure to iron during infancy are poorly understood. In this Perspectives article, Hare et al. discuss evidence that iron overload in infancy increases the risk of neurodegenerative disorders, such as Parkinson disease, in old age. They also consider methods for accurate measurement of past iron exposure that could be used to further investigate the risks.

Dopa-responsive dystonia is a highly treatable movement disorder that usually presents in childhood, but the heterogeneity of its aetiology and presentation can lead to delayed diagnosis. In this Review, Wijemanne and Jankovic summarize the diversity of conditions that present with dopa-responsive dystonia, consider the differential diagnosis for the symptoms, and outline the tests that can be used to ensure an early and accurate diagnosis that enables appropriate treatment to be started as early as possible.

A recent study has identified a variant of the SLC9A9 gene that is associated with the clinical response to IFN-β treatment. IFN-β induces SLC9A9 expression, resulting in inhibition of proinflammatory T lymphocytes. The findings suggest a key role for this gene in determining the response to IFN-β in patients with multiple sclerosis.

Current rehabilitative strategies for children with unilateral cerebral palsy (UCP) focus on activity-based tasks, but a greater understanding of the condition and the way in which the brain responds to therapy could enable the development of more-effective approaches. In this Review, the authors first discuss current rehabilitative strategies and the factors that are crucial to their success. They then consider in detail how neuroimaging is informing us about the neurobiology of UCP and the neuroplasticity in the brains of children with the condition, and how this knowledge could transform therapy.

A subset of patients with multiple sclerosis (MS) demonstrate rapid accumulation of disability, and symptoms that are refractory to standard disease-modifying therapies. Rush and colleagues present criteria for identifying patients with so-called aggressive MS, and outline the efficacy of various therapies in this group of patients. The authors emphasize the need to act quickly with these patients, and propose a treatment algorithm to aid clinical decision-making.

MRI studies in multiple sclerosis (MS) have mainly focused on brain lesions because of the technical challenges in spinal cord imaging. However, spinal cord abnormalities correlate with disability in MS, and have important diagnostic and prognostic implications. This Review provides an update on technical advances in spinal cord MRI, and discusses the clinical relevance of recent insights into spinal cord pathology in MS.