Review Articles in 2014

Brain imaging and histopathological studies have suggested that iron plays a crucial part in the pathophysiology of multiple sclerosis (MS). In this Review, Yong and colleagues discuss the growing evidence of widespread dysregulation of iron metabolism associated with MS, from focal iron deposits around grey matter lesions to iron deficits in white matter that might interfere with remyelination and other cellular repair processes. The authors then outline several potential mechanisms for treating iron dysregulation that balance the trophic and toxic properties of this molecule.

Correct diagnosis of chronic neuropathies is paramount, because acquired neuropathies are frequently immune-mediated and, thus, amenable to treatment. Distinction between different types of neuropathies, however, is not trivial. In this Review, Norman Latov discusses clinical presentation, differential diagnosis and treatment of chronic acquired demyelinating neuropathies, and suggests a diagnostic pathway for clinical practice.

The DNA repair proteinO⁶-methylguanine-DNA methyltransferase (MGMT) might interfere with alkylating agent chemotherapy in patients with glioma or glioblastoma. In this Review, Wick and colleagues discuss how epigenetic silencing of the MGMT gene via promotor methylation is associated with improved response to chemotherapy, and with improved survival, in patients with glioblastoma and other gliomas. The authors also highlight the usefulness of MGMTpromotor methylation as a biomarker for both clinical practice and the design of treatment trials.

Pruritus is a very common condition, with almost one-third of the global population experiencing itch in a given week. Its origin is not always in the skin: damage to neurons or glia can induce neuropathic pruritus, which is often associated with neuropathic pain. Neuropathic pruritus is often difficult to treat and—if chronic—can severely impair quality of life. Here, Laurent Misery and colleagues review the role of the nervous system and neuropathic syndromes in pruritus, summarize the currently available therapeutic options, and propose therapeutic strategies for managing neuropathic pruritus.

Cataplexy is the pathognomonic symptom of narcolepsy, a condition that is caused by depletion of orexin neurons. Cataplectic attacks are characterized by sudden involuntary muscle weakness or paralysis, often triggered by strong emotions. In this article, Dauvilliers et al. review the latest understanding of potential mechanisms underlying narcolepsy and cataplexy, the utility of experimental models, and the need for early diagnosis and therapy.

Central and peripheral neurological disorders can present with autonomic failure or hyperactivity, which can affect the sympathetic, parasympathetic and/or enteric nervous systems. This Review outlines the clinical approach to patients with generalized autonomic failure, focusing predominantly on classification and diagnosis, but also touching briefly on treatment and management. A systematic approach to diagnosis is essential to enable detection of treatable, potentially disabling or life-threatening conditions.

The fusion oncogene first discovered in patients with sarcomas,FUS, encodes a protein that pathologically accumulates in multiple neurodegenerative disorders. In this Review, Deng and colleagues discuss the involvement of various FUS mutations in amyotrophic lateral sclerosis, frontotemporal lobar degeneration and essential tremor, with particular emphasis on pathogenetic mechanisms. The authors argue that FUShas a general role in the neurodegenerative processes, and might therefore be a promising therapeutic target.

Despite varying aetiology, the clinical signs and symptoms of chronic distal symmetrical sensory peripheral neuropathies are similar. Gary Bennett and colleagues argue that this similarity arises from a common cause: mitochondrial injury. Various chemotherapeutic drugs, HIV-associated viral proteins and excess glucose can hamper mitochondrial function, thereby causing a chronic neuronal energy deficit, which manifests as spontaneous discharges and compartmental neuronal degeneration. Pharmacological protection from mitochondrial injury during chemotherapy, HIV treatment or in patients with diabetes could thus be used as an intervention for these potentially debilitating neuropathies.

Ophthalmic findings are common features of neurodegenerative disorders, and have emerged as potentially useful biomarkers of disease progression in several conditions. Kersten et al. describe the various afferent visual system and other ophthalmic features of inherited neurodegenerative disorders, focusing on the expanding role of optical coherence tomography in diagnostic imaging of the retina and optic nerve head. They also discuss the ophthalmic manifestations and treatment implications of mitochondrial dysfunction—a feature of many inherited neurodegenerative diseases.

The average age of ischaemic stroke onset is decreasing, owing to a rise in the incidence of stroke among individuals under 50 years of age. In this article, the authors review the current literature on risk factors for and aetiology of 'young' ischaemic stroke. In addition, they discuss the lifelong implications of stroke in young adults, not only in terms of cardiovascular disease recurrence, but also with respect to psychosocial consequences, including cognitive and social impairments, mood disorders and fatigue.

Sudden unexpected death in epilepsy (SUDEP) is cited as the cause of nearly 2,000 deaths per year in the USA alone, and accounts for as many as 15% of epilepsy-related deaths. Controversy prevails over the relative contributions of cardiac failure and respiratory arrest to SUDEP. Here, the authors discuss the mechanisms that cause cardiac, respiratory and arousal abnormalities during the ictal and postictal periods, and highlight possible preventive interventions that might reduce the risk of SUDEP.

The aetiology of most epilepsies used to be regarded as unknown, but in the past few years, massively parallel gene-sequencing techniques and clinical genetic studies have revealed that many forms of epilepsy—including those formerly labelled as idiopathic or acquired—are likely to have a genetic basis. Increased understanding of the genetic architecture of epilepsies has important implications for genetic testing, treatment selection and counselling. Furthermore, understanding the genetic background of epilepsies can guide neurobiological research for novel therapies.

The use of deep brain stimulation as a treatment for various refractory neurological disorders is increasing—perhaps faster than our understanding of this surgical technique. Electrical neuromodulation has been explored in people with epilepsy since the 1950s, and stimulation sites, parameters and results have varied. In this article, Fisher and Velasco review the use of neurostimulation as a treatment for epilepsy, from early experiments in animal models and humans to recent randomized controlled trials.

Wilmshurst et al. discuss how appropriate terminology can aid in the diagnosis and treatment of paediatric epilepsies. Furthermore, they give an update on key changes to the organization and terminology of epilepsies by the International League Against Epilepsy and an overview of the challenges in implementing new guidelines to treat paediatric patients particularly in low-income countries.

Great progress has been made in elucidating the acute inflammatory components of multiple sclerosis (MS), but the pathophysiological mechanisms of the concomitant neurodegeneration are poorly understood. Friese and colleagues review the current state of knowledge regarding the pathological mechanisms of neuroaxonal dysfunction and injury in MS, highlighting evidence that axonal and neuronal impairment are early and independent contributors to disease progression.

As a response to accumulation of debris and abnormally folded proteins during neurodegeneration, microglia multiply and adopt a chronically activated state. This process, referred to as priming, makes microglia susceptible to a secondary inflammatory stimulus, often arising from a systemic disorder with an inflammatory component, such as diabetes. Primed microglia react to the secondary inflammatory stimulus with an exaggarated response, which can further exacerbate neurodegeneration.

Huntington disease (HD) is considered to be a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, enabling the entire disease course to be studied. Ross et al. describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments. Building on this information, they review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials.

Neurological prognostication in patients who remain in hypoxic–ischaemic coma after cardiac arrest has always been challenging, and has become even more so since the advent of therapeutic hypothermia (TH). In this Review, Greer et al. consider how neurological outcomes and prognostic indicators might be influenced by the use of TH, and discuss advances in neuroimaging and electrophysiology that are expected to aid neuroprognostication in this patient population.

Chronic pain is a common problem that incurs substantial costs to the individual and society as a whole. The efficacy of currently available medications is limited, prompting the exploration of alternative therapeutic approaches. Here, Jensen et al. summarize the state of knowledge regarding the efficacy and mechanisms of four different neuromodulatory interventions—hypnosis, meditation training, noninvasive brain stimulation, and neurofeedback—for the treatment of chronic pain.

Migraine is the most common neurological disorder in the general population. In this article, de Tommaso et al. review the EEG findings that indicate altered sensory processing and dysfunctional recruitment of networks in the migrainous brain. The authors propose that thalamocortical dysrhythmia may underlie the altered synchronicity and sensory processing in migraine.