Reviews & Analysis

A recent study has identified mutations in the ubiquilin 2 gene in patients with dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS–dementia. The results suggest that ubiquilin 2 inclusions and impairment of the protein degradation pathway contribute to the pathogenesis of ALS and possibly other neurodegenerative disorders.

Until the early 1990s, the prevailing view was that amyotrophic lateral sclerosis (ALS) was rarely familial, but subsequent genetic discoveries have overturned this idea. Andersen and Al-Chalabi document the rapidly changing genetic landscape in ALS, highlighting the lack of a clear distinction between heritable and apparently sporadic ALS, and providing recommendations for genetic counseling.

Research into amyotrophic lateral sclerosis (ALS) has improved our understanding of the molecular mechanisms underlying disease pathogenesis, but diagnosis of patients with ALS has remained difficult. Bowseret al. highlight recent discoveries of biomarkers for ALS—from proteins in biofluids to neurophysiological and neuroimaging findings—and discuss the benefits and limitations of these biomarkers as diagnostic and prognostic indicators of disease.

Amyotrophic lateral sclerosis is a devastating neurodegenerative motor neuron disease that results in progressive loss of bulbar and limb function. In this Review, Hardiman et al. provide an overview of the clinical aspects of the disease, discussing epidemiology, clinical presentation, diagnosis and management, with an emphasis on recent key advances.

Clinical trials for amyotrophic lateral sclerosis have failed to yield a single new drug over the past 17 years. In their Opinion article, Gordon and Meininger provide insights into possible reasons for the lack of success, such as the heterogeneity of the disease, limitations of preclinical models, and the choice of clinical end points. They also present possible strategies to address the ongoing challenges, including appropriate dose selection and development of suitable biomarkers.

Glial cell line-derived neurotrophic factor (GDNF) has proved efficacious in treatment of neurodegeneration in toxin-induced models of Parkinson disease (PD), but clinical trials have been equivocal. Do the results of a recent study—suggesting that GDNF is ineffective in an α-synuclein-overexpression PD model—exclude GDNF as a therapy for PD?

Intracranial arterial aneurysms can pose life-threatening risks to patients, so understanding the cause and the progression of these lesions is important for choosing the right treatment. This Review argues that aneurysms are a symptom of an underlying vascular disease rather than constituting a disease on their own. The authors classify intracranial aneurysms by vessel wall pathology and demonstrate that knowledge of the morphology and pathology of this structure is important in determining the therapeutic approach.

Neurostimulation therapy is often needed for patients with neuropathic pain that is refractory to medical treatment. In this Review, Nguyenet al. compare and contrast the evidence for efficacy of motor cortex stimulation and deep brain stimulation, highlighting the brain-targeting strategies, mechanisms of action and future therapeutic potentials of both treatments in patients with chronic neuropathic pain.

For patients with transient cerebral ischemia, prompt diagnostic evaluation and rapid initiation of treatments markedly reduces the incidence of subsequent acute stroke. However, controversy exists about which patients to evaluate, and where and how quickly to perform the testing. Do current guidelines provide the best answers?

Perinatal brain injury is associated with a substantial risk of long-term disability. A recent study has shown that the severity of injury to the deep nuclear gray matter and brainstem, determined by early MRI, correlates with the risk of death and/or cerebral palsy at 2 years.

Bacterial meningitis, one of the infections most feared by parents, and on the mind of every pediatrician who evaluates a febrile child, is an important cause of morbidity and mortality in childhood. New vaccines have the potential to prevent the majority of these cases and could transform child health.

Treatment of Parkinson disease (PD) with dopaminergic medication is associated with the development of impulse control disorders (ICDs). A new study suggests that, irrespective of medication, patients with PD are more likely to make impulsive decisions. How and why might the risk of ICDs be increased in patients with this disease?

Neurocysticercosis (caused by infection with the tapewormTaenia solium) is a major cause of acquired seizures and epilepsy worldwide. Nash and Garcia describe the different types of neurocysticercosis infection and discuss the role of the host inflammatory response in disease pathology. They also highlight recent advances in the diagnosis and treatment of the disease, including the limitations of current therapies.

Neuropathy is the most common complication of diabetes and considerably reduces patient quality of life, yet no disease-modifying therapies are currently available and symptomatic treatments generally provide only partial relief. Vincent and colleagues provide an update on the cellular mechanisms that lead to diabetic neuropathy, which involves a complex interplay between oxidative and inflammatory pathways in neurons, Schwann cells and the microvascular endothelium. The authors highlight potential new therapeutic targets and discuss drug candidates that are in development for this debilitating diabetic complication.

Research has shown that Huntington disease, a progressive and fatal neurodegenerative disorder resulting from polyglutamine expansion in the huntingtin protein, is associated with changes in cellular cholesterol metabolism. Drawing on data from clinical and animal studies, Karasinska and Hayden discuss the roles of cholesterol in the CNS and describe the current state of knowledge of cholesterol dysregulation in Huntington disease.

The diagnosis of rapidly progressive dementias (RPDs), particularly sporadic Jakob–Creutzfeldt disease (sCJD), can prove challenging. Treatable RPDs can mimic sCJD, which is currently untreatable. A recent review of a large cohort of patients with suspected CJD highlights the extent of misdiagnosis and possible sources of error.

Early supported discharge (ESD) is a model of stroke care that decreases the inpatient length of stay and provides superior functional benefit compared with inpatient rehabilitation. Recently published consensus guidelines from a panel of ESD trialists provide a practical blueprint for implementing the ESD model and measuring its effectiveness.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic autoimmune neuropathy. In this Review, Marinos Dalakas provides an update on the diagnosis of this disease, including recently devised consensus criteria. CIDP treatments—primarily corticosteroids, intravenous immunoglobulin and plasmapheresis—and ongoing challenges in trial design are discussed, together with potential therapeutic approaches that are emerging from advances in our understanding of the underlying immunopathology of this disease.

Pain is common in patients with multiple sclerosis (MS) and can be difficult to diagnose and manage. Solaro and Messmer Uccelli provide a summary of the available data on pharmacological approaches to pain management in MS, including the different treatment options for neuropathic and nociceptive pain, and highlight the need for further clinical trials in this field.

Othello syndrome, as demonstrated by Shakespeare's fictional character of that name, describes individuals with severe delusional jealousy. Retrospective analysis of data from patients with this syndrome suggests that it is frequently associated with neurological disorders, particularly those affecting the right frontal lobe. What are the implications of these findings?