Reviews & Analysis

In the past two decades, there has been concern that levodopa—the gold-standard therapy for Parkinson disease (PD)—may be toxic to dopaminergic neurons. However, findings from a recent study suggest that chronic use of levodopa does not enhance progression of PD pathology. Can we make sense of this controversy?

Neurological markers are used to predict outcomes in patients resuscitated after cardiac arrest, and are crucial in informing treatment decisions in comatose patients. A multicenter study reports that therapeutic hypothermia in cardiac arrest alters the reliability of several recommended prognostic parameters, and the authors highlight challenges to optimization of prognostic paradigms.

Depression is a common symptom in patients with Parkinson disease (PD), and is found at higher rates in these individuals than in healthy populations or patients with other neurodegenerative disorders. Aarsland et al. discuss both the course of depression and the mechanisms that may contribute to the enhanced susceptibility to depression in patients with PD. Management strategies to control depression in these individuals are also highlighted.

The discovery of mutations that contribute to movement disorders has facilitated the identification of converging pathways and novel therapeutic targets. Successful translation of these research findings into clinical practice will require identification of early markers of disease progression, and recent research indicates that progress is being made in this area.

Defects in autophagy—a process that enables the degradation of unwanted or damaged intracellular proteins and organelles—are associated with the accumulation of aggregate-prone proteins. Defects in neuronal autophagy may have a role in neurodegenerative disease that are associated with aberrant protein accumulation, such as Alzheimer disease and Parkinson disease. Rubinsztein and Harris discuss how defects in autophagic pathways might cause these diseases and highlight how autophagy-modulating drugs might be used as therapy.

The first-in-human phase I trial of stem cell transplantation for amyotrophic lateral sclerosis was approved by the FDA in 2009 and is ongoing. In their Perspectives article, Eva Feldman and colleagues, who are conducting the trial, discuss the preclinical research supporting this therapeutic approach, key aspects of the trial design to overcome translational issues, and ongoing challenges to address in future studies.

A new cross-sectional study proposes three subtypes of Alzheimer disease: hippocampal-sparing, typical and limbic-predominant, associated with average lifespans of 72, 79 and 86 years, respectively. A longitudinal view suggests that age might be a major neuropathological determinant, with typical cases having younger onset and limbic-predominant cases having older onset.

Spinal angiography has historically been associated with a high risk of complications, but up-to-date safety reports are lacking. A recent retrospective review found a low complication rate of catheter angiography of the spine, and suggests that MRI performs poorly as an alternative approach to the diagnosis of spinal vascular disorders.

Cases of postural tachycardia syndrome (PoTS) have been described dating back to the 19^thcentury; however, the condition remains poorly understood, and the diagnosis is not readily made. Mathias and colleagues provide a comprehensive Review detailing the characteristics and possible pathophysiological mechanisms of PoTS, as well as investigation and treatment.

Lesion activity detected on MRI scans has become an accepted surrogate for disease activity in relapsing–remitting multiple sclerosis (MS). Barkhof and colleagues provide key recommendations for efficient use of MRI in clinical trials for relapse-onset MS, including practical issues related to acquisition, analysis and reporting of MRI data, approaches to optimization of trial design, and safety considerations.

Now that antipsychotic medication is all but proscribed for the treatment of distress and disturbed behavior in people with dementia in care homes, the drive to identify effective alternative approaches is pressing. A study from Norway suggests that paracetamol may be effective in many cases, but some caution is required.

Multifocal motor neuropathy (MMN) is a rare inflammatory disorder that features slowly progressive, asymmetric distal limb weakness. Leonard van den Berg and colleagues describe the diagnostic criteria for MMN, which are important for distinguishing this disease from mimic disorders such as amyotrophic lateral sclerosis. The authors also discuss the pathophysiology of MMN, emphasizing the role of GM1-specific autoantibodies, and outline current treatment options and possible new therapeutic strategies.

Tourette syndrome, characterized by motor or vocal tics, is a multifactorial neurodevelopmental disorder that affects up to 1% of children and adults worldwide. In this Review, McNaught and Mink describe the history of Tourette syndrome and its clinical presentation, and provide an overview of its epidemiology and pathophysiology. Current treatment strategies and potential future therapies are also discussed.

Neuropsychological assessment can identify deficits in brain function that assist in the diagnosis of patients with dementing illness. Fields et al. highlight the unique properties of neuropsychological measurements, including their role as biomarkers of dementia, in differentiating diseases with similar topographies, and in predicting the risk of dementia. Prediction of functional decline on the basis of these measurements will assist in planning of the future care requirements for patients at risk of dementia.

An improved understanding of the cellular events that lead to motor neuron injury in amyotrophic lateral sclerosis (ALS) could highlight promising new therapeutic strategies. Pamela Shaw and colleagues provide a comprehensive overview of the numerous molecular mechanisms that are involved in ALS, including oxidative stress, mitochondrial dysfunction and excitotoxicity. They discuss features specific to motor neurons that might render this cell type vulnerable to damage, and highlight important links between cellular events and clinical features of the disease.

Most patients who present with longitudinal extensive transverse myelitis (LETM) are diagnosed with neuromyelitis optica (NMO). Trebst et al. use case studies of patients without NMO who presented with spinal lesions to show the variety of different etiologies that can underlie LETM. The authors highlight the diagnostic indicators and difficulties encountered in making differential diagnoses in these patients.

Combination therapy is a rational strategy to optimize therapeutic benefits and minimize risks associated with treatment of patients with multiple sclerosis (MS). A recent study reporting negative results of combination therapy in MS should not discourage investigators from future attempts to identify optimal combinations for the treatment of this disease.

Clazosentan—a drug previously demonstrated to reduce angiographic vasospasm in patients with aneurysmal subarachnoid hemorrhage—had no significant effect on vasospasm-related morbidity and mortality in the CONSCIOUS-2 trial. A multifactorial cause for delayed ischemic neurological deficits might partly account for these negative findings.

A recent clinical trial showed no beneficial effects of statin treatment in patients with Alzheimer disease (AD) and normal cholesterol levels. Other studies show that the effects of statins can vary depending on cholesterol levels and stage of disease, so statins should not be ruled out as an AD therapy.

Rituximab is an immunosuppressive monoclonal antibody therapy that is used in some cases to help prevent relapses of neuromyelitis optica, an inflammatory CNS demyelinating disease. A new study provides evidence supporting efficacy and a strategy for optimizing the timing of repeated courses of treatment for the individual patient.