Review Articles

Small-fiber neuropathy is a condition that has been underdiagnosed in the past, partly because small nerve fibers cannot be observed using routine neurophysiological tests. Skin biopsy is a safe, minimally invasive tool that can provide important diagnostic information on small nerve fibers, and in this article Lauria and Devigili discuss how this approach is being applied to the diagnosis and monitoring of peripheral neuropathies.

Findings in animal models of Huntington's disease and levodopa-induced dyskinesia indicate that corticostriatal long-term potentiation is abnormally stable in these conditions, causing persistent inhibition of the output nuclei of the basal ganglia, which leads to involuntary movements. In this article, Centonze et al. review evidence that repetitive transcranial magnetic stimulation can interfere with the maintenance of corticostriatal long-term potentiation in humans, and might, therefore, be useful as an antidyskinetic treatment.

Huntington's disease (HD) accounts for around 90% of cases of chorea of genetic etiology, but a number of other distinct genetic disorders can present with a clinical picture indistinguishable from HD. In this article, Schneider et al. review the clinical features and genetic bases of these HD-like syndromes, discussing the clinical clues that should prompt further investigations in patients presenting with these conditions.

Activation of the ligand-inducible transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) has been shown to suppress inflammation in peripheral macrophages and in models of human autoimmune disease. As Heneka et al. discuss in this Review, PPARγ is now being investigated as a potential therapeutic target in CNS disorders with an inflammatory component, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis.

In children, nonconvulsive status epilepticus (NCSE) is associated with various conditions, including acute neurological injuries and specific childhood epilepsy syndromes, and it can also be observed in individuals with learning difficulties. In this article, Korff and Nordli review various aspects of NCSE, including clinical and electroencephalographic features, prognosis, and treatment recommendations. They also highlight the need for further research into NCSE in pediatric populations.

In this Review, Sacktor et al. summarize our current understanding of HIV-associated cognitive impairment in resource-limited settings, focusing specifically on the countries of sub-Saharan Africa. They also consider the potential impact of HIV-1 clade diversity on HIV-associated neurological disease.

Charcot–Marie–Tooth disease is the most common inherited disease of the PNS. This Review summarizes our current understanding of the genetic and molecular mechanisms that underlie the demyelinating forms of Charcot–Marie–Tooth disease. The authors also discuss how knowledge of these mechanisms is guiding the development of strategies to diagnose and treat these conditions in the clinic.

The emerging field of neuroprosthetics is focused on the development of therapeutic interventions that restore lost neural function by stimulating sensory or motor pathways, or by harnessing activity recorded from remnant neural pathways to control an external device. As Richard Normann discusses in this Review, penetrating microelectrode arrays are providing unprecedented selective access to the neurons of the CNS and PNS, and are likely to form the basis for new therapies for disorders of the nervous system.

Last year's Nobel Prize in Physiology or Medicine was won by Andrew Fire and Craig Mello for their discovery of RNA interference, an evolutionarily conserved cellular pathway that regulates endogenous gene expression. In this Review, Gonzalez and Paulson discuss how RNA interference is being exploited experimentally to suppress the expression of dominantly acting genes that cause incurable neurodegenerative disorders, and highlight the questions that need to be answered before human clinical trials of this technology can commence.

Alzheimer's disease is characterized pathologically by the deposition in the brain of amyloid-β peptides generated through proteolysis of amyloid precursor protein (APP). In this article, Cheng et al. review evidence that amyloidogenic processing of APP takes place predominantly in cholesterol-rich membrane microdomains known as lipid rafts. They also discuss potential new therapeutic strategies based on the targeting of APP processing in lipid rafts.

The use of brain stimulation for the treatment of neurological diseases such as chronic pain, Parkinson's disease, stroke and epilepsy has attracted growing attention. In this article, Fregni and Pascual-Leone review the recent literature regarding the use of two noninvasive brain stimulation techniques: repetitive transcranial magnetic stimulation and transcranial direct current stimulation. The authors discuss the underlying principles and present examples illustrating the therapeutic potential of these two techniques.

Baló's concentric sclerosis (BCS) is a demyelinating disorder characterized by white matter lesions consisting of rings of demyelination alternating with rings of relatively intact myelin. In this Review, Mowryet al.discuss how advanced neuroimaging techniques have contributed to our understanding of the pathogenesis of BCS, as well as enabling clinicians to distinguish BCS from other demyelinating disorders such as multiple sclerosis. The authors explore these themes further in a Case Study in this issue.

Diabetic neuropathy—the most common neuropathy in industrialized countries—encompasses a broad range of clinical manifestations. In this Review, Gérard Said discusses the clinical, pathological and therapeutic aspects of various forms of diabetic neuropathy, including length-dependent diabetic polyneuropathy and focal diabetic neuropathies. The author also addresses the diagnosis of nondiabetic neuropathies in patients with diabetes.

Around a third of patients with epilepsy have refractory epilepsy; that is, they continue to have seizures despite trying a range of antiepileptic drugs. Recent basic research has explored the underlying causes of refractory epilepsy, and in this article Sanjay Sisodiya discusses the two main hypotheses that have emerged from these studies. He also considers how knowledge of the molecular basis of refractoriness might guide the development of new therapies.

Cerebral vasospasm is the classic cause of delayed neurological deterioration after subarachnoid hemorrhage (SAH). Surprisingly, however, patient outcome after SAH was not improved in recent trials of the endothelin antagonist clazosentan, which prevents vasospasm. In light of this result, Macdonald et al. highlight the need for reconsideration of the pathophysiology of SAH.

Inborn errors of metabolism account for around a third of all genetic diseases. They can affect many organs, but in most cases they involve the nervous system. This Review focuses on treatable inborn errors of metabolism that can be diagnosed in a neurology department, and proposes guidelines to help neurologists to avoid overlooking treatable metabolic diseases.

Children with sickle cell disease present with a variety of neurological syndromes, including ischemic and hemorrhagic stroke. In this Review, Fenella Kirkham describes the clinical and pathological features of stroke in individuals with sickle cell disease, and considers strategies for prevention and management of stroke in this patient population.

Stenting is being used increasingly for the treatment of carotid artery stenosis, but it is still unknown whether it is as safe and successful as carotid endarterectomy—the standard treatment for symptomatic patients with more than 50% carotid stenosis. This Review summarizes current knowledge on the effectiveness of both procedures, and provides an updated meta-analysis based on data from randomized trials.

Melatonin has been used successfully to treat insomnia, but has not received regulatory approval by the FDA because it can be sold freely as a food supplement. This has prompted a search by pharmaceutical companies for patentable melatonin receptor ligands, and the melatonin receptor agonist ramelteon has received particular attention. This Review describes the pharmacology and metabolism of ramelteon, assesses evidence from animal models and clinical studies that supports its efficacy in treating insomnia, and discusses its possible mechanism of action.

In recent years, considerable progress has been made towards understanding the mechanisms that underlie autoimmune inflammatory diseases of the PNS, such as Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy. As Meyer zu Hörste et al. discuss in this Review, many promising therapeutic approaches for these conditions have been established in animal models, but attempts to transfer this knowledge to the clinic have met with limited success to date.