Showing papers in "Nature Reviews Neurology in 2011"
TL;DR: An overview of the criteria used in the diagnosis of Alzheimer disease is provided, highlighting how this disease is related to, but distinct from, normal aging.
Abstract: The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques-which are frequently surrounded by dystrophic neurites-and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis.
1,496 citations
TL;DR: This work focuses on the rapidly growing body of evidence that supports the involvement of inflammatory mediators—released by brain cells and peripheral immune cells—in both the origin of individual seizures and the epileptogenic process.
Abstract: Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis.
1,401 citations
TL;DR: Current evidence linking late-life and earlier-life depression and dementia, and the primary underlying mechanisms and implications for treatment are summarized and analyzed.
Abstract: Depression is highly common throughout the life course and dementia is common in late life. Depression has been linked with dementia, and growing evidence implies that the timing of depression may be important in defining the nature of this association. In particular, earlier-life depression (or depressive symptoms) has consistently been associated with a more than twofold increase in dementia risk. By contrast, studies of late-life depression and dementia risk have been conflicting; most support an association, yet the nature of this association (for example, if depression is a prodrome or consequence of, or risk factor for dementia) remains unclear. The likely biological mechanisms linking depression to dementia include vascular disease, alterations in glucocorticoid steroid levels and hippocampal atrophy, increased deposition of amyloid-β plaques, inflammatory changes, and deficits of nerve growth factors. Treatment strategies for depression could interfere with these pathways and alter the risk of dementia. Given the projected increase in dementia incidence in the coming decades, understanding whether treatment for depression alone, or combined with other regimens, improves cognition is of critical importance. In this Review, we summarize and analyze current evidence linking late-life and earlier-life depression and dementia, and discuss the primary underlying mechanisms and implications for treatment.
846 citations
TL;DR: The only clinical feature that distinguishes recognized hereditary from apparently sporadic ALS is a lower mean age of onset in the former, and all the clinical features reported in hereditary cases have also been observed in sporadic cases.
Abstract: Hereditary amyotrophic lateral sclerosis (ALS) encompasses a group of genetic disorders characterized by adult-onset loss of the lower and upper motor neuron systems, often with involvement of other parts of the nervous system. Cases of hereditary ALS have been attributed to mutations in 12 different genes, the most common being SOD1, FUS and TARDBP-mutations in the other genes are rare. The identified genes explain 25-35% of cases of familial ALS, but identifying the remaining genes has proved difficult. Only a few genes seem to account for significant numbers of ALS cases, with many others causing a few cases each. Hereditary ALS can be inherited in an autosomal dominant, autosomal recessive or X-linked manner, and families with low disease penetrance are frequently observed. In such families, the genetic predisposition may remain unnoticed, so many patients carry a diagnosis of isolated or sporadic ALS. The only clinical feature that distinguishes recognized hereditary from apparently sporadic ALS is a lower mean age of onset in the former. All the clinical features reported in hereditary cases (including signs of extrapyramidal, cerebellar or cognitive involvement) have also been observed in sporadic cases. Genetic counseling and risk assessment in relatives depend on establishing the specific gene defect and the disease penetrance in the particular family.
615 citations
TL;DR: Ongoing research on the cellular pathways highlighted in this Review is predicted to open the door to new therapeutic interventions to slow disease progression in ALS.
Abstract: Amyotrophic lateral sclerosis (ALS) is a genetically diverse disease. At least 15 ALS-associated gene loci have so far been identified, and the causative gene is known in approximately 30% of familial ALS cases. Less is known about the factors underlying the sporadic form of the disease. The molecular mechanisms of motor neuron degeneration are best understood in the subtype of disease caused by mutations in superoxide dismutase 1, with a current consensus that motor neuron injury is caused by a complex interplay between multiple pathogenic processes. A key recent finding is that mutated TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions in ALS, providing a possible link between the genetic mutation and the cellular pathology. New insights have also indicated the importance of dysregulated glial cell-motor neuron crosstalk, and have highlighted the vulnerability of the distal axonal compartment early in the disease course. In addition, recent studies have suggested that disordered RNA processing is likely to represent a major contributing factor to motor neuron disease. Ongoing research on the cellular pathways highlighted in this Review is predicted to open the door to new therapeutic interventions to slow disease progression in ALS.
544 citations
TL;DR: Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting, and Riluzole remains the only effective drug, and extends the average survival of patients by 3–6 months.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom onset. The incidence of ALS in Europe is 2-3 cases per 100,000 individuals in the general population, and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia. Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely used assessment tool; scores are used to predict survival, and have been employed extensively in clinical trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3-6 months. Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical need for patients with this devastating condition.
527 citations
TL;DR: This Review aims to provide a focused overview of neuroplasticity associated with poststroke motor impairment, and the latest experimental interventions being developed to manipulate neuro plasticity to enhance motor rehabilitation.
Abstract: Approximately one-third of patients with stroke exhibit persistent disability after the initial cerebrovascular episode, with motor impairments accounting for most poststroke disability. Exercise and training have long been used to restore motor function after stroke. Better training strategies and therapies to enhance the effects of these rehabilitative protocols are currently being developed for poststroke disability. The advancement of our understanding of the neuroplastic changes associated with poststroke motor impairment and the innate mechanisms of repair is crucial to this endeavor. Pharmaceutical, biological and electrophysiological treatments that augment neuroplasticity are being explored to further extend the boundaries of poststroke rehabilitation. Potential motor rehabilitation therapies, such as stem cell therapy, exogenous tissue engineering and brain–computer interface technologies, could be integral in helping patients with stroke regain motor control. As the methods for providing motor rehabilitation change, the primary goals of poststroke rehabilitation will be driven by the activity and quality of life needs of individual patients. This Review aims to provide a focused overview of neuroplasticity associated with poststroke motor impairment, and the latest experimental interventions being developed to manipulate neuroplasticity to enhance motor rehabilitation.
502 citations
TL;DR: It is indicated that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP 7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology.
Abstract: This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder-isolated distal motor neuropathy-has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot-Marie-Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.
470 citations
TL;DR: The emerging cellular mechanisms that are activated in the diabetic milieu of hyperglycemia, dyslipidemia and impaired insulin signaling are discussed, thereby identifying promising therapeutic targets, including mitochondrial function and inflammation.
Abstract: In patients with diabetes, nerve injury is a common complication that leads to chronic pain, numbness and substantial loss of quality of life. Good glycemic control can decrease the incidence of diabetic neuropathy, but more than half of all patients with diabetes still develop this complication. There is no approved treatment to prevent or halt diabetic neuropathy, and only symptomatic pain therapies, with variable efficacy, are available. New insights into the mechanisms leading to the development of diabetic neuropathy continue to point to systemic and cellular imbalances in metabolites of glucose and lipids. In the PNS, sensory neurons, Schwann cells and the microvascular endothelium are vulnerable to oxidative and inflammatory stress in the presence of these altered metabolic substrates. This Review discusses the emerging cellular mechanisms that are activated in the diabetic milieu of hyperglycemia, dyslipidemia and impaired insulin signaling. We highlight the pathways to cellular injury, thereby identifying promising therapeutic targets, including mitochondrial function and inflammation.
436 citations
TL;DR: This Review will begin with a focus on the problem of memory impairment in temporal lobe epilepsy, including findings demonstrating that anatomical abnormalities extend far outside the temporal lobe, and that cognitive impairments extend beyond memory function.
Abstract: Cognitive impairment, particularly memory disruption, is a major complicating feature of epilepsy. This Review will begin with a focus on the problem of memory impairment in temporal lobe epilepsy (TLE). We present a brief overview of anatomical substrates of memory disorders in TLE, followed by a discussion of how our understanding of these disorders has been improved by studying the outcomes of anterior temporal lobectomy. The clinical efforts made to predict which patients are at greatest risk of experiencing adverse cognitive outcomes following epilepsy surgery are also considered. Finally, we examine the vastly changing view of TLE, including findings demonstrating that anatomical abnormalities extend far outside the temporal lobe, and that cognitive impairments extend beyond memory function. Linkage between these distributed cognitive and anatomical abnormalities point to a new understanding of the anatomical architecture of cognitive impairment in epilepsy. Clarifying the origin of these cognitive and anatomical abnormalities, their progression over time and, most importantly, methods for protecting cognitive and brain health in epilepsy, present a challenge to neurologists.
377 citations
TL;DR: It is found that the heterogeneity in neuropsychological presentation among patients with MS reflects the influence of many factors, including genetics, sex, intelligence, disease course, comorbid neuropsychiatric illness, and health behaviors.
Abstract: Cognitive impairment is common in multiple sclerosis (MS), especially when assessed by neuropsychological tests that emphasize mental processing speed, episodic memory, and some aspects of executive function. In this Review, we question why some MS patients develop severe impairment in cognitive abilities, while cognitive ability remains intact in others. We find that the heterogeneity in neuropsychological presentation among patients with MS reflects the influence of many factors, including genetics, sex, intelligence, disease course, comorbid neuropsychiatric illness, and health behaviors. Neuropsychological deficits are also robustly correlated with brain MRI metrics. Male patients with early evidence of cerebral gray matter atrophy are most prone to impairment, whereas high premorbid intelligence improves the neuropsychological prognosis. Routine evaluation of cognition is useful for helping patients to navigate problems related to activities of daily living and work disability and, if reliable methods are employed, cognitive decline can be detected and included among the many clinical signs of disease progression or treatment failure. Pharmacological treatments for neuropsychological impairment are on the horizon, although presently no firm medical indications exist for the condition.
TL;DR: This Review examines alcohol-related brain damage from the perspective of THE AUTHORS and KS, exploring the clinical presentations, postmortem brain pathology, in vivo MRI findings and potential molecular mechanisms associated with these conditions.
Abstract: One of the sequelae of chronic alcohol abuse is malnutrition. Importantly, a deficiency in thiamine (vitamin B(1)) can result in the acute, potentially reversible neurological disorder Wernicke encephalopathy (WE). When WE is recognized, thiamine treatment can elicit a rapid clinical recovery. If WE is left untreated, however, patients can develop Korsakoff syndrome (KS), a severe neurological disorder characterized by anterograde amnesia. Alcohol-related brain damage (ARBD) describes the effects of chronic alcohol consumption on human brain structure and function in the absence of more discrete and well-characterized neurological concomitants of alcoholism such as WE and KS. Through knowledge of both the well-described changes in brain structure and function that are evident in alcohol-related disorders such as WE and KS and the clinical outcomes associated with these changes, researchers have begun to gain a better understanding of ARBD. This Review examines ARBD from the perspective of WE and KS, exploring the clinical presentations, postmortem brain pathology, in vivo MRI findings and potential molecular mechanisms associated with these conditions. An awareness of the consequences of chronic alcohol consumption on human behavior and brain structure can enable clinicians to improve detection and treatment of ARBD.
TL;DR: Identifying ways to induce a sustained behavioral change, using specifically tailored programs that address potential barriers such as depression, apathy and postural instability, may lead to an improved quality of life in individuals with PD.
Abstract: Parkinson disease (PD) is a neurodegenerative disorder characterized by progressive motor and nonmotor impairments. These impairments incline many patients towards a sedentary lifestyle, which has many deleterious consequences. Accumulating evidence suggests that patients with PD might benefit from physical activity and exercise in a number of ways, from general improvements in health to disease-specific effects and, potentially, disease-modifying effects (suggested by animal data). Many issues remain to be addressed, including the need to perform clinical trials to demonstrate these presumed benefits of physical activity and exercise in patients with PD. These trials must also address safety issues, such as an increased risk of falls and cardiovascular complications in more-active patients. Identifying ways to induce a sustained behavioral change, using specifically tailored programs that address potential barriers such as depression, apathy and postural instability, may lead to an improved quality of life in individuals with PD.
TL;DR: Optimize respiratory management, including noninvasive nocturnal ventilation together with careful orthopedic management, are the current mainstays of treatment and have already led to a considerable improvement in life expectancy for children with Ullrich congenital muscular dystrophy.
Abstract: The collagen VI-related myopathy known as Ullrich congenital muscular dystrophy is an early-onset disease that combines substantial muscle weakness with striking joint laxity and progressive contractures. Patients might learn to walk in early childhood; however, this ability is subsequently lost, concomitant with the development of frequent nocturnal respiratory failure. Patients with intermediate phenotypes of collagen VI-related myopathy display a lesser degree of weakness and a longer period of ambulation than do individuals with Ullrich congenital muscular dystrophy, and the spectrum of disease finally encompasses mild Bethlem myopathy, in which ambulation persists into adulthood. Dominant and recessive autosomal mutations in the three major collagen VI genes-COL6A1, COL6A2, and COL6A3-can underlie this entire clinical spectrum, and result in deficient or dysfunctional microfibrillar collagen VI in the extracellular matrix of muscle and other connective tissues, such as skin and tendons. The potential effects on muscle include progressive dystrophic changes, fibrosis and evidence for increased apoptosis, which potentially open avenues for pharmacological intervention. Optimized respiratory management, including noninvasive nocturnal ventilation together with careful orthopedic management, are the current mainstays of treatment and have already led to a considerable improvement in life expectancy for children with Ullrich congenital muscular dystrophy.
TL;DR: Advances in the understanding of the underlying immunopathology in CIDP have identified new targets for future therapeutic efforts, including T cells, B cells, and transmigration and transduction molecules, including new target antigens.
Abstract: Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic autoimmune neuropathy. Despite clinical challenges in diagnosis-owing in part to the existence of disease variants, and different views on how many electrophysiological abnormalities are needed to document demyelination-consensus criteria seem to have been reached for research or clinical practice. Current standard of care involves corticosteroids, intravenous immunoglobulin (IVIg) and/or plasmapheresis, which provide short-term benefits. Maintenance therapy with IVIg can induce sustained remission, increase quality of life and prevent further axonal loss, but caution is needed to avoid overtreatment. Commonly used immunosuppressive drugs offer minimal benefit, necessitating the development of new therapies for treatment-refractory patients. Advances in our understanding of the underlying immunopathology in CIDP have identified new targets for future therapeutic efforts, including T cells, B cells, and transmigration and transduction molecules. New biomarkers and scoring systems represent emerging tools with the potential to predict therapeutic responses and identify patients with active disease for enrollment into clinical trials. This Review highlights the recent advances in diagnosing CIDP, provides an update on the immunopathology including new target antigens, and discusses current treatments, ongoing challenges and future therapeutic directions.
TL;DR: Progress in biomarker development to differentiate CBD from other disorders has been slow, but is essential in improving diagnosis and in development of disease-modifying therapies.
Abstract: Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disorder with onset in the 5(th) to 7(th) decade of life. It is associated with heterogeneous motor, sensory, behavioral and cognitive symptoms, which make its diagnosis difficult in a living patient. The etiology of CBD is unknown; however, neuropathological and genetic evidence supports a pathogenetic role for microtubule-associated protein tau. CBD pathology is characterized by circumscribed cortical atrophy with spongiosis and ballooned neurons; the distribution of these changes dictates the patient's clinical presentation. Neuronal and glial tau pathology is extensive in gray and white matter of the cortex, basal ganglia, diencephalon and rostral brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques. The classic clinical presentation, termed corticobasal syndrome (CBS), comprises asymmetric progressive rigidity and apraxia with limb dystonia and myoclonus. CBS also occurs in conjunction with other diseases, including Alzheimer disease and progressive supranuclear palsy. Moreover, the pathology of CBD is associated with clinical presentations other than CBS, including Richardson syndrome, behavioral variant frontotemporal dementia, primary progressive aphasia and posterior cortical syndrome. Progress in biomarker development to differentiate CBD from other disorders has been slow, but is essential in improving diagnosis and in development of disease-modifying therapies.
TL;DR: The disease is thought to result from an underlying genetic predisposition, a susceptibility to mechanical injury of the brachial plexus, and an immune or autoimmune trigger for the attacks.
Abstract: Neuralgic amyotrophy--also known as Parsonage-Turner syndrome or brachial plexus neuritis--is a distinct and painful peripheral neuropathy that causes episodes of multifocal paresis and sensory loss in a brachial plexus distribution with concomitant involvement of other PNS structures (such as the lumbosacral plexus or phrenic nerve) in a large number of patients. The phenotype can be limited or extensive and the amount of disability experienced also varies between patients, but many are left with residual disabilities that affect their ability to work and their everyday life. Both idiopathic and hereditary forms exist. The latter form is genetically heterogeneous, but in 55% of affected families, neuralgic amyotrophy is associated with a point mutation or duplication in the SEPT9 gene on chromosome 17q25. The disease is thought to result from an underlying genetic predisposition, a susceptibility to mechanical injury of the brachial plexus (possibly representing disturbance of the epineurial blood-nerve barrier), and an immune or autoimmune trigger for the attacks. The precise pathophysiological mechanisms are still unclear; treatment is empirical, and preventive measures are not yet available. This Review provides an overview of the current clinical and pathophysiological concepts and research topics in neuralgic amyotrophy.
TL;DR: By revealing dysplastic lesions that previously eluded visual assessments, quantitative structural MRI methods have clearly demonstrated an increased diagnostic yield of epileptic lesions, and have provided successful surgical options to an increasing number of patients with 'cryptogenic' epilepsy.
Abstract: Nearly one-third of patients with focal epilepsy experience disabling seizures that are refractory to pharmacotherapy. Drug-resistant focal epilepsy is, however, potentially curable by surgery. Although lesions associated with the epileptic focus can often be accurately detected by MRI, in many patients conventional imaging based on visual evaluation is unable to pinpoint the surgical target. Patients with so-called cryptogenic epilepsy represent one of the greatest clinical challenges in many tertiary epilepsy centers. In recent years, it has become increasingly clear that epilepsies that are considered cryptogenic are not necessarily nonlesional, the primary histopathological substrate being subtle cortical dysplasia. This Review considers the application of new advances in brain imaging, such as MRI morphometry, computational modeling and diffusion tensor imaging. By revealing dysplastic lesions that previously eluded visual assessments, quantitative structural MRI methods such as these have clearly demonstrated an increased diagnostic yield of epileptic lesions, and have provided successful surgical options to an increasing number of patients with 'cryptogenic' epilepsy.
TL;DR: It is suggested that WMLs may exacerbate or contribute to some motor and cognitive deficits associated with PD, and existing and emerging methods for studying white matter pathology in vivo are reviewed, and future research directions are proposed.
Abstract: Pure vascular parkinsonism without evidence of nigral Lewy body pathology may occur as a distinct clinicopathological entity, but a much more frequent occurrence is the comorbid presence of age-associated white matter lesions (WMLs) in idiopathic Parkinson disease (PD). WMLs are associated with motor and cognitive symptoms in otherwise normal elderly individuals. Comorbid WMLs are, therefore, expected to contribute to clinical symptoms in PD. Studies of WMLs in PD differ with regard to methods of assessment of WML burden and the patient populations selected for analysis, but converging evidence suggests that postural stability and gait motor functions are predominantly affected. WMLs are described to contribute to dementia in Alzheimer disease, and emerging but inconclusive evidence indicates similar effects in PD. In this article, we review the literature addressing the occurrence and impact of WMLs in PD, and suggest that WMLs may exacerbate or contribute to some motor and cognitive deficits associated with PD. We review existing and emerging methods for studying white matter pathology in vivo, and propose future research directions.
TL;DR: The evidence in favor of MCS is sufficient to include it in the range of therapeutic options for refractory neuropathic pain, and the respective efficacies and mechanisms of action of DBS and MCS are discussed.
Abstract: Neurostimulation therapy is indicated for neuropathic pain that is refractory to medical treatment, and includes stimulation of the dorsal spinal cord, deep brain structures, and the precentral motor cortex. Spinal cord stimulation is validated in the treatment of selected types of chronic pain syndromes, such as failed back surgery syndrome. Deep brain stimulation (DBS) has shown promise as a treatment for peripheral neuropathic pain and phantom limb pain. Compared with DBS, motor cortex stimulation (MCS) is currently more frequently used, mainly because it is more easily performed, and has a wider range of indications (including central poststroke pain). Controlled trials have demonstrated the efficacy of MCS in the treatment of various types of neuropathic pain, although these trials included a limited number of patients and need to be confirmed by large, controlled, multicenter studies. Despite technical progress in neurosurgical navigation, results from studies of MCS are variable, and validated criteria for selecting good candidates for implantation are lacking. However, the evidence in favor of MCS is sufficient to include it in the range of therapeutic options for refractory neuropathic pain. In this Review, the respective efficacies and mechanisms of action of DBS and MCS are discussed.
TL;DR: A newly recognized form of IMNM that is associated with statin use and the production of autoantibodies that recognize 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the pharmacological target of statins is focused on.
Abstract: The different autoimmune myopathies-for example, dermatomyositis, polymyositis, and immune-mediated necrotizing myopathies (IMNM)-have unique muscle biopsy findings, but they also share specific clinical features, such as proximal muscle weakness and elevated serum levels of muscle enzymes. Furthermore, around 60% of patients with autoimmune myopathy have been shown to have a myositis-specific autoantibody, each of which is associated with a distinct clinical phenotype. The typical clinical presentations of the autoimmune myopathies are reviewed here, and the different myositis-specific autoantibodies, including the anti-synthetase antibodies, dermatomyositis-associated antibodies, and IMNM-associated antibodies, are discussed in detail. This Review also focuses on a newly recognized form of IMNM that is associated with statin use and the production of autoantibodies that recognize 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the pharmacological target of statins. The contribution of interferon signaling to the development of dermatomyositis and the potential link between malignancies and the initiation of autoimmune myopathies are also assessed.
TL;DR: The importance of calcified granulomas with perilesional edema as foci of seizures and epilepsy in populations where neurocysticercosis is endemic is newly recognized, and indicates that treatment with anti-inflammatory agents could have a role in controlling or preventing epilepsy in patients.
Abstract: Neurocysticercosis is a parasitic disease caused by the larval (cystic) form of the pork cestode tapeworm, Taenia solium, and is a major cause of acquired seizures and epilepsy worldwide. Development of sensitive and specific diagnostic methods, particularly CT and MRI, has revolutionized our knowledge of the burden of cysticercosis infection and disease, and has led to the development of effective antihelminthic treatments for neurocysticercosis. The importance of calcified granulomas with perilesional edema as foci of seizures and epilepsy in populations where neurocysticercosis is endemic is newly recognized, and indicates that treatment with anti-inflammatory agents could have a role in controlling or preventing epilepsy in these patients. Importantly, neurocysticercosis is one of the few diseases that could potentially be controlled or eliminated-an accomplishment that would prevent millions of cases of epilepsy. This Review examines the rationale for treatment of neurocysticercosis and highlights the essential role of inflammation in the pathogenesis of disease, the exacerbation of symptoms that occurs as a result of antihelminthic treatment, and the limitations of current antihelminthic and anti-inflammatory treatments.
TL;DR: The clinical features that can help clinicians differentiate between PNES and epileptic seizures are reviewed, and no single feature is pathognomonic for PNES.
Abstract: Psychogenic nonepileptic seizures (PNES) resemble epileptic seizures and are often misdiagnosed and mistreated as the latter. Occasionally, epileptic seizures are misdiagnosed and mistreated as PNES. 70% of PNES cases develop between the second and fourth decades of life, but this disease can also affect children and the elderly. At least 10% of patients with PNES have concurrent epileptic seizures or have had epileptic seizures before being diagnosed with PNES. Psychological stress exceeding an individual's coping capacity often precedes PNES. Clinicians can find differentiating between PNES and epileptic seizures challenging. Some clinical features can help distinguish PNES from epileptic seizures, but other features associated with PNES are nonspecific and occur during both types of seizures. Diagnostic errors often result from an overreliance on specific clinical features. Note that no single feature is pathognomonic for PNES. When typical seizures can be recorded, video-EEG is the diagnostic gold standard for PNES, and in such cases a diagnosis can be made with high accuracy. When video-EEG reveals no epileptiform activity before, during or after the ictus, thorough neurological and psychiatric histories can be used to confirm the diagnosis of PNES. In this article, we review the clinical features that can help clinicians differentiate between PNES and epileptic seizures.
TL;DR: Progress in basic neuroscience research is reviewed and its translational impact on the neurorehabilitation of language disorders after stroke is reviewed to provide a new opportunity for investigating fast plastic neuronal changes in the areas of the brain associated with language processing.
Abstract: The treatment of aphasias-acquired language disorders-caused by stroke and other neurological conditions has benefitted from insights from neuroscience and neuropsychology. Hebbian mechanisms suggest that massed practice and exploitation of residual neurological capacities can aid neurorehabilitation of patients with poststroke aphasia, and progress in basic neuroscience research indicates that the language system of the human brain is functionally interwoven with perceptual and motor systems. Intensive speech and language therapies, including constraint-induced aphasia therapy, that activate both the linguistic and concordant motor circuits utilize the knowledge gained from these advances in neuroscience research and can lead to surprisingly rapid improvements in language performance, even in patients with chronic aphasia. Drug-based therapies alone and in conjunction with behavioral language therapies also increase language performance in patients with aphasia. Furthermore, noninvasive transcranial magnetic stimulation and electrical stimulation techniques that target neuronal activity within perilesional areas might help patients with aphasia to regain lost language functions. Intensive language-action therapies that lead to rapid improvements in language skills might provide a new opportunity for investigating fast plastic neuronal changes in the areas of the brain associated with language processing. Here, we review progress in basic neuroscience research and its translational impact on the neurorehabilitation of language disorders after stroke.
TL;DR: It is demonstrated that aneurysms represent a symptom of an underlying vascular disease rather than constituting a disease on their own, and that understanding the morphology and pathology of this structure is important in determining the therapeutic approach.
Abstract: An aneurysm is a focal dilatation of an arterial blood vessel. Luminal forces, such as high blood flow, shear stress and turbulence, are implicated in the pathogenesis of intracranial aneurysms, and luminal characteristics, such as sac size and morphology, are usually essential to the clinical decision-making process. Despite frequent clinical emphasis on the vessel lumen, however, the pathology underlying the formation, growth and rupture of an aneurysm mainly resides in the vessel wall. Research on the morphology and histopathology of the vessel wall reveals that intracranial aneurysms do not constitute a single disease, but are a shared manifestation of a wide range of diseases, each of which has a unique natural history and optimum therapy. This Review classifies intracranial aneurysms by vessel wall pathology, and demonstrates that understanding the morphology and pathology of this structure is important in determining the therapeutic approach. The article concludes that aneurysms represent a symptom of an underlying vascular disease rather than constituting a disease on their own.
TL;DR: This endophenotypic approach—the focus of this Review—simplifies the connection between genes and behavior and is needed for complex disorders like chronic pain.
Abstract: Pain is a complex, multidimensional experience that has defied our understanding for centuries. Through the advent of noninvasive neuroimaging techniques, we have been able to examine the human brain and its response to nociceptive inputs. As a result, our knowledge of which brain regions are critical for generating an acute pain experience has grown, as has our understanding of how cognitive, emotional, contextual and various physiological factors influence the pain experience. Furthermore, we have been able to identify key processes within the brain that underpin the transition to and maintenance of chronic pain states, as well as highlight the dramatic consequences of chronic pain on the brain's structure and neurochemistry. Building upon this knowledge, we are now in a position to consider whether any of these brain imaging 'phenotypes' of acute or chronic pain should be considered as useful endophenotypes; thereby enabling us to relate the complex genetics that underpin everyday pain sensitivity or chronic pain states to intermediate biomarkers. This endophenotypic approach-the focus of this Review-simplifies the connection between genes and behavior and is needed for complex disorders like chronic pain.
TL;DR: Tests are being tested to enhance thrombolytic efficacy, attempts are underway to reduce the risk of symptomatic intracerebral hemorrhage, and improvements in prehospital management strategies are being introduced.
Abstract: Around 15 years have now elapsed since thrombolysis was first shown to be effective for treating acute ischemic stroke, but therapeutic uptake has been modest. As outlined in this Review, research efforts are being directed towards rectifying this situation in a number of ways. First, strategies to enhance thrombolytic efficacy are being tested; these include intravenous and intra-arterial bridging protocols, sonothrombolysis, and the use of alternative thrombolytic agents. Second, means of extending the 4.5-h therapeutic time window up to 6 h, or even up to 9 h in patients selected on the basis of imaging, are being investigated in clinical trials. Prolongation of the time window using neuroprotection to 'freeze' penumbral tissue is also being attempted. Third, attempts are underway to reduce the risk of symptomatic intracerebral hemorrhage (currently affecting about 7% of cases) by refining imaging selection criteria, and through the use of alternative thrombolytic agents, lower doses of tissue plasminogen activator, blood-based biomarkers, and neuroprotectants. Last, in an effort to include more people within the currently accepted therapeutic time window, improvements in prehospital management strategies are being introduced. Elimination of prehospital and in-hospital delays is an urgent priority.
TL;DR: Tourette syndrome is a hereditary, childhood-onset neurodevelopmental disorder that was first clearly described in France in 1885 and is characterized by sudden, rapid, recurrent, nonrhythmic movements or sounds, often preceded by premonitory sensations or urges.
Abstract: Tourette syndrome is a hereditary, childhood-onset neurodevelopmental disorder that was first clearly described in France in 1885. This disorder is characterized by sudden, rapid, recurrent, nonrhythmic movements (motor tics) or sounds (vocal or phonic tics), often preceded by premonitory sensations or urges. Some individuals also have psychiatric comorbidities, notably attention-deficit hyperactivity disorder or obsessive-compulsive disorder. Tourette syndrome occurs worldwide, in all races and ethnicities, in both sexes and in children as well as in adults. Estimates of its prevalence in children vary, with rates of up to 1% being reported, but rates of 0.3-0.8% are thought to accurately reflect the occurrence of the disorder. Research has led to progress in many aspects of Tourette syndrome, although many questions and unmet needs remain. For example, except for rare cases, the genetic basis remains elusive. The anatomical and neuronal changes in the brain that underlie Tourette syndrome are also unclear, although the evidence increasingly implicates alterations in basal ganglia function. Treatment is often unnecessary for individuals with mild tics, but for those with moderate to severe forms of the syndrome, some drugs are available, albeit frequently ineffective. Behavioral and surgical therapies, in particular deep brain stimulation, are currently undergoing development and show promising results. This Review examines the history of Tourette syndrome and describes its clinical presentation. The article also provides an overview of the epidemiology and pathophysiology of this disorder. Current treatment strategies and potential future therapies are also discussed.
TL;DR: The signs and symptoms that suggest various etiologies and differential diagnoses of LETM are described, and illustrated by educational case studies.
Abstract: Longitudinal extensive transverse myelitis (LETM) is defined as a spinal cord lesion that extends over three or more vertebrae, as seen on MRI of the spine. The clinical presentation of a patient with LETM is often dramatic and can consist of paraparesis or tetraparesis, sensory disturbances, and gait, bladder, bowel and/or sexual dysfunction. LETM is a characteristic feature of neuromyelitis optica, but such spinal lesions can also occur in various other autoimmune and inflammatory diseases that involve the CNS--such as multiple sclerosis, sarcoidosis or Sjogren syndrome--or in infectious diseases with CNS involvement. Patients with a neoplastic disorder or traumatic spinal cord injury can also present with longitudinal spinal lesions. In this Review, the signs and symptoms that suggest various etiologies and differential diagnoses of LETM are described, and illustrated by educational case studies. The best therapeutic options for patients with each diagnosis are also discussed.
TL;DR: More evidence is needed to better understand the underlying dilatatory artheriopathy that causes this disease, and to determine whether patients with dolichoectasia might benefit from early diagnosis.
Abstract: Dolichoectasia is an arterial disease that causes dilatation and/or tortuosity of the affected vessel. The prevalence of dolichoectasia increases with age, and this disease is also associated with other traditional cardiovascular risk factors. Multiple pathophysiological processes might lead to the development of dolichoectatic vessels, and activation of metalloproteinases and irregular turbulent blood flow seem to cause irreversible disruption of the internal elastic lamina. Intracranial dolichoectasia commonly presents with ischemic or hemorrhagic stroke, and/or cranial neuropathies. The posterior circulation is more frequently affected by the dolichoectatic process than the anterior circulation. A positive diagnosis of dolichoectasia requires visual assessment of vessel shape and, if the posterior circulation is affected, application of Smoker's criteria. Reproducible criteria that aid diagnosis of dolichoectasia in the anterior circulation are lacking. No specific treatment for dolichoectasia exists, and the surgical and medical therapies that have been used to treat this condition have not been systematically evaluated. More evidence is needed to better understand the underlying dilatatory artheriopathy that causes this disease, and to determine whether patients with dolichoectasia might benefit from early diagnosis. In this article, we provide a comprehensive review of current knowledge regarding dolichoectasia, and highlight gaps in our knowledge to aid future research.