Showing papers in "Current Opinion in Neurology in 2003"

The epidemiology of epilepsy revisited

Abstract: Purpose of reviewEpidemiology is the study of the dynamics of a medical condition in a population. There are many shortcomings in the understanding of the epidemiology of epilepsy mostly caused by methodological problems. These include diagnostic accuracy, case ascertainment, and selection bias. In

Cognitive dysfunction in multiple sclerosis: a review of recent developments.

Abstract: Purpose of reviewNearly half of all patients diagnosed with multiple sclerosis will develop cognitive dysfunction, a symptom associated with significant decline in activities of daily living. The purpose of this review is to discuss recent literature investigating issues related to cognitive dysfunc

Radiation injury and neurogenesis.

Abstract: Purpose of reviewFor many cancers, survival depends on aggressive combined therapies, but treatment comes at a price. Children and adults who receive radiotherapy involving the brain frequently experience a progressive cognitive decline. The overt pathologies of radiation injury such as white matter

Upper and lower extremity robotic devices for rehabilitation and for studying motor control

Abstract: Purpose of reviewThe successful motor rehabilitation of stroke, traumatic brain-injured and spinal cord-injured patients requires an intensive and task-specific therapy approach. Budget constraints limit a hand-to-hand therapy approach, so that intelligent machines may offer a solution to promote mo

Dopamine: a key regulator to adapt action, emotion, motivation and cognition.

Abstract: Dopamine is expressed in restricted brain areas involved in numerous integrative functions contributing to automated behaviours that are highly adaptive. During ontogenesis, dopamine can have a trophic action, which influences cortical specification directly, especially in prefrontal areas. Such a role is attested by the close relationships existing between the development of dopamine cortical innervation and cognitive abilities. Interestingly, such a proposal is reinforced by phylogenetic data. During the last stages of evolution in mammals, the characteristic extension of dopamine cortical innervation is also correlated with the development of cognitive capacities. More generally, the contribution of dopamine will be to increase the processing of cortical information through basal ganglia, either during the course of evolution or development. In this respect, dysmaturation suspected in schizophrenia and attention deficit-hyperactivity disorder in children can emphasize such a defect in basal ganglia processing. Remarkably, these diseases are improved by dopamine antagonists and agonists, respectively. In this line of evidence, experimental studies showed that selective lesions of the dopamine neurones in rats or primates can actually provide motor, limbic and cognitive deficits, in later cases especially when the mesocorticolimbic dopamine pathways are altered. Data resulting from lesion studies also showed significant alteration in attentional processes, thus raising the question of the direct involvement of dopamine in regulating attention. Dopamine can act as a powerful regulator and integrator of different aspects of brain functions. For example, in Parkinson's disease, besides motor impairment, dopamine degeneration is also expressed by alterations of both limbic, executive and cognitive functions, both improved by dopamine receptor agonists and dopa therapy. Dopamine has thus to be considered as a key regulator that contributes to behavioural adaptation and to the anticipatory processes necessary for preparing voluntary action consequent upon intention. In this respect, the alteration of dopamine transmission with age could contribute to cognitive impairment. Therefore, to normalize dopamine transmission pharmacologically could actually improve the cognitive and limbic deficits during normal aging, as it does in psychiatric and neurological disorders.

Migrainous vertigo: development of a pathogenetic model and structured diagnostic interview.

Abstract: Purpose of reviewVestibular symptoms occur frequently in patients with migraine This review refines recently proposed diagnostic criteria for migraine-related vestibular symptoms, and develops a pathophysiological model for the interface between migraine and the vestibular systemRecent findingsThe

An update on falls.

Abstract: Purpose of reviewFalls among elderly persons create immense social problems because of their association with physical decline, serious psychosocial consequences, negative impact on the quality of life, and markedly reduced survival. In addition, falls pose high costs to the public health service. F

Do epileptic seizures damage the brain

Abstract: Purpose of reviewThe possibility that recurrent seizures in patients with poorly controlled epilepsy may produce neuronal damage and contribute to progressive functional and cognitive declines observed in some patients with epilepsy has major clinical and therapeutic implications for urgency of trea

Headaches caused by decreased intracranial pressure: diagnosis and management.

Abstract: Purpose of review More patients with spontaneous intracranial hypotension are now being diagnosed, and it is realized that most cases result from spontaneous cerebrospinal fluid leaks. A broader clinical and imaging spectrum of the disorder is recognized. This paper reviews new insights into the variability of clinical manifestations, imaging features, etiological factors, anatomy of leaks, and implications of these in patient management. Recent findings Spontaneous intracranial hypotension should not be equated with post-lumbar puncture headaches. In a substantial minority of patients, headaches are not orthostatic and may mimic other types of headache. Additional diverse neurological manifestations may dominate the clinical picture and patients may occasionally have no headache at all. Reports on unusual presentations of the disorder continue to appear in the literature. Furthermore, additional imaging features of cerebrospinal fluid leaks are recognized. High-flow and slow-flow leaks may present diagnostic challenges, and require modification of diagnostic studies aimed at locating the site of the leak. Stigmata of connective tissue abnormality, especially abnormalities of fibrillin and elastin, are seen in a notable minority of patients, pointing to weakness of the dural sac as one of the etiological factors. After treatment of spontaneous intracranial hypotension, surgically or by epidural blood patch, a rebound and self-limiting intracranial hypertension may sometimes develop. Summary In the past decade, interest in spontaneous intracranial hypotension has been rekindled, with a substantial growth of knowledge on various aspects of the disorder. We are in the learning phase, and new information will probably appear in the future, with notable diagnostic and therapeutic implications.

Channelopathies as a genetic cause of epilepsy.

Abstract: Purpose of reviewThis review describes the significant number of new gene associations with epilepsy syndromes that have emerged during the past year, together with additional mutations and new electrophysiological data relating to previously known gene associations.Recent findingsAutosomal dominant

Mechanisms of antiepileptic drug resistance.

Abstract: Purpose of reviewThe present review considers new developments in the study and our understanding of resistance to treatment with antiepileptic drugs in epilepsy.Recent findingsStudies suggest that mechanisms of resistance to drug treatment that operate in other diseases may also be relevant in human and animal drug-resistant epilepsy. Immunohistochemical and molecular genetic data show that there is overexpression of a number of genes and proteins that mediate nonspecific resistance to drug treatment. In particular, there is upregulation of P-glycoprotein and multidrug resistance-associated proteins 1 and 2. These proteins appear to be expressed in cerebral parenchymal cell populations that do not normally do so. Work in animal models suggests that these proteins are able to reduce the local concentration of antiepileptic drugs. Although these proteins are therefore good candidates for mediators of drug resistance, there is still limited proof that they are functionally important in human drug-resistant epilepsy.SummaryCareful attention needs to be given to the identification and confirmation of the practical importance of mechanisms postulated to underlie drug resistance in human epilepsy. If certain mechanisms are shown to be involved, then new therapeutic options for drug-resistant human epilepsy may be forthcoming.

Biopolymers and biodegradable smart implants for tissue regeneration after spinal cord injury.

Abstract: PURPOSE OF REVIEW: This article reviews recent experimental advances in the development of biosynthetic implants for repair of spinal cord injury.RECENT FINDINGS: Various important advances in the ...

Statins as potential therapeutic agents in neuroinflammatory disorders.

Abstract: Purpose of reviewMultiple sclerosis is a central nervous system inflammatory demyelinating disease that is thought to have an autoimmune pathogenesis. Recent results indicate that ‘statins’, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are the most commonly used oral cholesterol

Post-streptococcal autoimmune disorders of the central nervous system.

Abstract: Purpose of reviewAutoimmune disease has long been intertwined with investigations of infectious causes. Antibodies that are formed against an infectious agent can, through the process of molecular mimicry, also recognize healthy cells. When this occurs, the immune system erroneously destroys the hea

Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson's disease.

Abstract: Levodopa and the dopamine agonists are effective symptomatic treatments for Parkinson's disease, and all patients receive at least one of these agents during their illness. Long-term use of levodopa is commonly associated with motor complications such as dyskinesia, and both the dosing frequency and total daily dose of levodopa determine the rate of onset and severity. Dopamine agonists have gained popularity as first-line monotherapy in Parkinson's disease, as they effectively reverse motor deficits and reduce the risk of motor complications. Long-acting dopamine agonists providing continuous, rather than pulsatile, dopaminergic stimulation appear able to avoid dyskinesia induction. Current treatments act predominantly on D2 receptors, but drugs acting on both the D1 and D2 receptor families may produce an additive motor response, although this remains to be proven in patients with Parkinson's disease. Most currently used dopamine agonists are selective for D2-like receptors, with only pergolide and apomorphine potentially interacting with D1 receptor populations.

Molecular mechanisms of axonal damage in inflammatory central nervous system diseases.

Abstract: Purpose of review Axonal dysfunction and damage is an early pathological sign of autoimmune central nervous system disease, viral and bacterial infections, and brain trauma. Axonal injury has attracted considerable interest during the past few years because the degree of axonal damage appears to determine long-term clinical outcome. Recent findings Advanced magnetic resonance spectroscopic imaging techniques have suggested that axonal loss and dysfunction is responsible for the persistent neurological deficits that occur in patients with multiple sclerosis. Histopathological methods have shown that axonal damage is defined primarily by dysfunction of axonal transport, and finally by complete transection and degeneration of axons. Recent studies have demonstrated that the extent of axonal damage in the primary demyelinating lesion of multiple sclerosis patients is associated with the number of activated microglia/macrophages and cytotoxic CD8+ T lymphocytes. In addition, diffuse axonal dysfunction independent of demyelination develops in normal appearing white matter, possibly due to indirect effects of inflammation. Summary The fact that axonal damage in response to overt inflammatory reactions may occur gradually, leaving a window for therapeutical intervention, has important clinical implications. Determination of the exact molecular mechanism might help in finding new therapies for inflammatory axonal damage.

From fruit fly to bedside: translating lessons from Drosophila models of neurodegenerative disease

Abstract: Purpose of review Fly models have been developed for a variety of neurodegenerative disorders, and the field is beginning to harness the power of Drosophila genetics to dissect pathways of disease pathogenesis and identify targets for therapeutic intervention. In this review, we emphasize the most recent accomplishments and chart the potential rewards in translating lessons from Drosophila models to clinical therapeutics. Recent findings The conservation of human disease genes in the Drosophila genome forms the basis for several recent investigations of the normal biological functions of genes implicated in neurodegenerative disease. In addition, transgenic approaches continue to expand the list of diseases modeled in Drosophila that now includes Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and several spinocerebellar ataxias. Studies based on these models suggest that protein folding and degradation pathways play an important role in Parkinson’s disease and the polyglutamine repeat disorders, and that kinases and apoptotic pathways may modulate neurodegeneration in tauopathies. Summary Ongoing genetic studies with Drosophila neurodegenerative disease models promise to enhance our understanding of disease pathogenesis and generate target lists for future investigational research and drug development. The next challenge will be distilling a growing number of possible targets into a shortlist for fast-track drug design and clinical trials. With the advent of neurodegenerative disease models, the fruit fly is rapidly assuming a unique niche in bench to bedside research.

The electrophysiology of migraine.

Abstract: Purpose of reviewThe pathophysiology of migraine is far from being understood. Electrophysiological methods are useful to investigate peripheral and central mechanisms underlying this disorder. The purpose of this review is to highlight the results of electrophysiological studies published during th

Neonatal seizures and their treatment.

Abstract: Purpose of reviewNeonatal seizures continue to present a diagnostic and therapeutic challenge to paediatricians worldwide, and are a worrying sign for both parents and clinicians alike. The present review summarizes recent evidence regarding the diagnosis, aetiology and treatment of neonatal seizure

Progress towards understanding the neurobiology of Batten disease or neuronal ceroid lipofuscinosis.

Abstract: Purpose of reviewThe identification of genes mutated in the neuronal ceroid lipofuscinoses has accelerated research into the mechanisms that underlie these fatal autosomal recessive storage disorders, which are often referred to as Batten disease. This review summarizes progress in this field since

Cardiomyopathy in muscular dystrophies.

Abstract: Purpose of reviewThe association of cardiac complications in patients with muscular dystrophies has been known for a long time. However, until recently, the clinical and genetic heterogeneity of these conditions had hampered our abilities to recognize individual disease complications, especially in

The enigma of multiple sclerosis: inflammation and neurodegeneration cause heterogeneous dysfunction and damage

Abstract: Purpose of reviewThe demyelinating disease multiple sclerosis has an autoimmune inflammatory component, which has dominated the description of multiple sclerosis. A degenerative component to multiple sclerosis was always apparent, but was underappreciated until recently. Recent work has brought axon

Advances in magnetic resonance imaging of brain tumours.

Abstract: Purpose of review Magnetic resonance imaging (MRI) of brain tumours provides excellent anatomical detail of brain tumours and can also reveal the biology, cellular structure and vascular dynamics of a tumour, although the use of such features in routine clinical practice has yet to be realized In this review the latest advances in MRI of brain tumours are discussed and their clinical applications highlighted Recent findings A large international study is underway to develop more powerful methods for automated classification of MR spectra based on the acquisition of large datasets of tumour spectra Diffusion weighted imaging can help in the distinction between gliomas and abscesses, and perfusion weighted imaging can predict response to radiotherapy in low grade gliomas as well as distinguishing between different types of cerebral metastases Intraoperative MRI has now been shown to be technically feasible, safe and effective in obtaining histological information as well as increasing the likelihood of complete resection for pituitary tumours and gliomas Functional MRI and magnetic source imaging are alternative modalities that help the surgeon to avoid eloquent brain areas but may occasionally provide misleading information Diffusion tensor imaging can demonstrate the effect of a tumour on white matter tracts and provides complementary information to that from other techniques that reveal areas of eloquent cortex Summary Advances in MRI techniques are providing better diagnostic and therapeutic information, but can only ever be a surrogate marker of physiological and pathological processes; until it can routinely be used to image the brain at a cellular level, MRI will always be secondary to pathology in the final diagnostic evaluation

The current status of neuroimaging for epilepsy.

Abstract: Purpose of reviewNeuroimaging research continues apace and is being applied to further understanding of the epilepsies, and improve clinical management.Recent findingsStructural imaging has become more sensitive with developments of MRI hardware, acquisition and postprocessing methods. Tractography is being used to define critical pathways prior to surgery. Functional MRI for language lateralization is now a clinical tool. PET studies with specific ligands reveal neurochemical changes associated with specific epilepsy syndromes.SummaryMRI at 3T with FLAIR and multiple channel coils identifies and clarifies relevant abnormalities in 20% of patients with previously unremarkable scans. Voxel-based analysis of diffusion scans may identify abnormalities in group comparisons.Identification of relevant abnormalities using voxel-based methods in individual patients requires a careful balance of sensitivity and specificity, and has a 10-30% yield. The PROPELLER sequence improves the detail of hippocampal anatomy and correlation with histological slices shows the pathological basis of MRI signal changes. Tractography has shown the connections of the language cortex and visualizes specific tracts. Electroencephalograms with simultaneous functional MRI and perfusion have shown that perfusion changes are a major determinant of changes in blood-oxygen-level-dependent signal. Functional MRI of language and memory are becoming used as a predictor of deficits as a result of temporal lobe resection.Increased uptake of the PET tracer 11C-alpha-methyl tryptophan shows promise for localizing epileptogenic malformations of cortical development. Abnormalities of 5HT-1A receptor ligands have been reported in temporal lobe epilepsy, with controversial association with depression. Dopamine uptake abnormalities have been noted in autosomal dominant nocturnal frontal lobe epilepsy.

Gene expression changes after focal stroke, traumatic brain and spinal cord injuries.

Abstract: Purpose of review Large-scale gene expression profiling has recently been performed on stroke and spinal cord injuries. These studies provide insights into coordinated patterns of gene expression within the injury and the interrelationships of neurodegenerative and neural repair processes after injury. Recent findings The molecular signals for post-stroke angiogenesis begin within hours of initial cerebral ischemia, with sequential increases in message for initially destabilizing combinations of vascular growth factors and growth factor receptors, followed by growth factor combinations that promote endothelial cell division and stabilization. The overlap in molecular signaling between post-stroke angiogenesis, neurogenesis and axonal sprouting suggests a continuum of vascular and neural reorganization in the tissue adjacent to stroke. Inflammation after injury extends through early and late changes in the cytokine message. SOCS-3, a negative regulator of cytokine signaling, is increased after injury and may be neuroprotective. Components of an adult neuronal growth program have been identified in the peripheral nervous system during axonal regeneration, with overlap to axonal sprouting after stroke. The gene expression profile of the aged brain suggests an altered central nervous system environment that may exacerbate initial injury and impair neural reorganization after stroke and spinal cord injury. Summary When rigorously tested and independently validated, data from large-scale gene expression analyses provide new insights into the aggregate genetic control of stroke and spinal cord injury, and the interrelationship of important cellular events within the damaged region. These data also highlight novel genes in these processes, and suggest new directions in the investigation of tissue reorganization and repair after central nervous system injury.

New autoantibody mediated disorders of the central nervous system

Abstract: Purpose of review Recently, central nervous system disorders have been shown to be associated with autoantibodies. This review summarizes the recent findings and assesses the evidence that these conditions are caused by the antibodies, using the criteria established for peripheral nervous system autoimmune diseases. Recent findings Over the last few years, antibodies to voltage-gated calcium and potassium channels, and to glutamate receptors, have been detected in the serum and cerebrospinal fluid of patients with ataxia, limbic encephalitis and certain forms of epilepsy. Some of these patients respond to immunotherapies, suggesting that the antibodies are pathogenic, but there are few demonstrations using the passive transfer approach that antibodies present in the serum can penetrate the blood-brain barrier and affect central nervous system function. Some patients have antibodies to intracellular proteins such as glutamic acid decarboxylase or specific ribonuclear proteins. The pathogenicity of these antibodies must be in some doubt, although intravenous immunoglobulin therapy has been shown to be beneficial in stiff man syndrome, consistent with an autoimmune aetiology for the disease. In only a few conditions, has IgG derived from patients been shown to produce pathogenic effects in vivo or in vitro. Summary There is much that needs to be done to define the role of these antibodies and to determine how they affect central nervous system function in vivo. These studies must be carried out so that appropriate treatments can be provided for the growing number of patients with possible antibody-mediated conditions.

New CNS-active drugs which are second-generation valproic acid: can they lead to the development of a magic bullet?

Abstract: Purpose of review Valproic acid (VPA) is one of the four first line antiepileptic drugs (AEDs). VPA is also an effective drug in migraine prophylaxis and in treatment of bipolar disorders. The use of VPA is limited by its two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity, and it is the least potent of the established AEDs. Consequently, there is an incentive to develop a second-generation VPA. A successful, second-generation VPA would need to possess the following characteristics: broad-spectrum antiepileptic activity; better potency than VPA; and lack of teratogenicity and hepatotoxicity. These characteristics would give such a drug the potential to be utilized in epilepsy and other CNS disorders. Recent findings Intensive research has been carried out in order to develop a second-generation VPA that would be more potent and safer than VPA. Amide derivatives of VPA have shown particular value as potential follow-up compounds and have better in-vivo performance than VPA. Several CNS-active valproylamides are more potent as antiepileptics than VPA, they possess broad-spectrum antiepileptic activity, and have been found to be nonteratogenic in animal models. The amide analogues of VPA that emerged from structure-pharmacokinetic-pharmacodynamic relationship studies as promising second-generation compounds are: N-methyl-tetramethylcyclopropane carboxamide, (2S,3S)-valnoctamide, (R)-propylisopropyl acetamide and valproyl glycinamide. Summary At present there are three compounds in clinical trials in patients with epilepsy that can be regarded as second-generation VPA: valproyl glycinamide, 3-methylbutanamide or isovaleramide and SPD421 (DP-VPA). For any one of these second-generation valproic acids to become a successful follow-up compound to VPA, it has to fulfil the above criteria and also possess favorable pharmacokinetics.

Dopamine and cognitive function.

Abstract: PURPOSE OF REVIEW Although the cognitive deficits of idiopathic Parkinson's disease are now relatively well known, their neuropsychological and neurobiological basis are still discussed. RECENT FINDINGS As well as recent findings on cognitive changes and their underlying mechanisms, we will review new approaches concerning the effects of levo-dihydroxyphenylalanine, those of deep-brain stimulation and recent developments on personality disorders. SUMMARY Future research directions concern the relative influence of the striatofrontal loops in cognition and personality, and the respective contribution of subcortical and cortical lesions or dysfunctions, both in dementia and in specific cognitive and personality changes.

Functional imaging of cognition in Parkinson's disease

Abstract: Purpose of review Cognitive deficits that occur even early in the course of Parkinson's disease have received increasing attention in current imaging research. The exact physio-pathological processes mediating the deficits and the complex relationship of cognitive signs and antiparkinsonian treatment are not well understood. A clearer understanding of these mechanisms could potentially influence treatment choices, drug development and, ultimately, patient care. Recent findings Abnormal networks identified in studies of resting state metabolism in Parkinson's disease represent metabolic markers for remote effects of striato-nigral degeneration. These metabolic changes include subcortico-cortical networks, in particular cognitive cortico-striato-pallidal-thalamocortical loops. Recent brain studies focus on intervention-related brain changes. They illustrate different task-specific changes in brain activation with deep brain stimulation and with levodopa. Variable results of stimulation can be attributed to different effects on segregated cortico-striato-pallidal-thalamocortical loops during stimulation. By contrast, the heterogeneity observed in studies with levodopa possibly reflects the disease-stage and task-specific effects of levodopa. A decline in caudate dopamine modulated basal ganglia outflow appears to contribute to executive dysfunction and to brain activation changes in these loops at early Parkisnon's disease stages, while mesocortical degeneration mediated increases of inefficient dorsolateral prefrontal cortex activation may display a feature of more advanced disease stages only. Summary Despite evidence for the role of dopamine and cortico-striato-pallidal-thalamocortical loops in cognition, the specific contributions of mesocortical dopamine depletion and striatal dysfunction with downstream consequences on the loops remain to be separated. Additionally, more research is needed into the role of non-dopaminergic pathology in cognitive decline in Parkinson's disease.

Late complications in childhood central nervous system tumour survivors

Abstract: Purpose of review As the treatment of childhood brain tumours has improved, long-term survival has become more common. Cognitive, physical and psychological complications of the tumour and its treatment have been recognized more frequently in long-term survivors. This review highlights new studies on the cognitive and endocrine complications in survivors. Less-common late effects of treatment are also discussed. Recent findings Cognitive abnormalities and endocrine dysfunction are the most common complications in long-term survivors. Radiotherapy is the main cause of cognitive dysfunction, but intrathecal methotrexate and surgery are contributory factors. New studies have provided information on the frequency of endocrine complications and risk factors for the development of endocrine disorders. Endocrine complications are uncommon when the tumour has been treated with surgery alone. The risk of developing endocrine dysfunction is increased by radiotherapy, and some studies suggest that chemotherapy has an additional deleterious effect. Primary hypothyroidism may be caused by scattered irradiation from spinal and cranial radiotherapy. Direct involvement of the hypothalamus by the tumour, and hypothalamic damage secondary to surgery or radiotherapy, may cause obesity. Hypothalamic tumours also may be associated with hypersomnolence and other features consistent with narcolepsy. The pathogenesis of hypersomnolence in these patients has not been resolved. Long-term childhood brain-tumour survivors are 40 times more likely to develop a stroke than sibling controls. Superficial siderosis of the central nervous system can develop many years after curative treatment of a cerebellar tumour, but effective treatment for this disorder is not yet available. Summary An attempt to understand the factors that contribute to the long-term morbidity of childhood brain tumours can lead to changes in treatment that improve the quality of life in survivors. Prevention, early recognition and treatment of these complications are attainable goals.