Showing papers in "Current Opinion in Neurology in 2001"

Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences.

Abstract: Renewed interest in axonal injury in multiple sclerosis has significantly shifted the focus of research into this disease toward neurodegeneration. During the past year magnetic resonance and morphologic studies have continued to confirm and extend the concept that axonal transection begins at disease onset, and that cumulative axonal loss provides the pathologic substrate for the progressive disability that most long-term MS patients experience. Although inflammation and chronic demyelination are probable causes of axonal transection, little is known about the molecular mechanisms that are involved. The view that MS can also be considered an inflammatory neurodegenerative disease has important clinical implications for therapeutic approaches, monitoring of patients, and future treatment strategies.

Cerebral ischemia and inflammation.

Abstract: Ischemic stroke triggers an inflammatory reaction in the affected area, which progresses for days to weeks after the onset of symptoms. There is evidence that selected aspects of such inflammatory processes contribute to the progression of ischemic brain injury, leading to worsening of the tissue damage and exacerbation of neurologic deficits. Therefore, interventions aimed at suppressing postischemic inflammation offer attractive therapeutic strategies for human stroke, with a potentially wide therapeutic window. A large body of work has addressed the inflammatory process in the postischemic brain. 1 2 3 4 5 In this chapter, we review the basic cellular and molecular features of postischemic inflammation, focusing on recent advances and insights on the potential mechanisms by which such inflammation influences stroke outcome. We then analyze the potential therapeutic implications of modulators of specific inflammatory targets from the perspective of near-future translational approaches.

The role of glial cells in Parkinson's disease.

Abstract: Parkinson's disease is a common neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta. The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Aside from these beneficial effects, the glial response can mediate a variety of deleterious events related to the production of reactive species, and pro-inflammatory prostaglandin and cytokines. This article reviews the potential protective and deleterious effects of glial cells in the substantia nigra pars compacta of Parkinson's disease.

Epidemiology of the Guillain-Barré syndrome.

Abstract: This review focuses on recent epidemiological findings on Guillain-Barre syndrome regarding incidence, antecedent events related to the disease, prognosis and prognostic indicators, and treatment. Moreover, this review summarizes recent observations on clinical variants of Guillain-Barre syndrome and their relationship with the prevailing clinical presentation of the disease. The epidemiological observations which have advanced the understanding of the pathogenesis of Guillain-Barre syndrome are also discussed.

Is robot-aided sensorimotor training in stroke rehabilitation a realistic option?

Abstract: Stroke is the leading cause of disability, despite continued advances in prevention and treatment techniques based on novel delivery of new fibrinolytic drugs. Improved medical treatment of the complications caused by acute stroke has contributed to decreased mortality, but 90% of the survivors have significant neurological deficits. Reducing the degree of permanent disability remains the goal of poststroke neuro-rehabilitation programs, and new approaches to impairment reduction through managing sensorimotor experience may contribute further to altering disability. Recent reports from a number of laboratories using enhanced sensorimotor training protocols, particularly those with robotic devices, have indicated modest success in reducing impairment and increasing motor power in the exercised limb of patients with stroke when compared with control individuals. Whether arming the therapist with new tools, especially robotic devices, to treat impairment is a realistic approach to modern interdisciplinary rehabilitation raises questions regarding the added value of impairment reduction, and under what conditions should scientific and clinical development of robotic studies continue.

The process of epileptogenesis: a pathophysiological approach.

Abstract: Several recent advances have contributed to our understanding of the processes associated with mesial temporal lobe epilepsy in humans and in experimental animal models. Common pathological features between the human condition and the animal models may indicate a fundamental involvement of the given

Progenitor cells and glioma formation.

Abstract: The gliomas are a collection of tumors that arise within the central nervous system and have characteristics similar to astrocytes, oligodendrocytes, or their precursors. Whether or not the glial characteristics of these tumors mean that they arise from the differentiated glia that they resemble or their precursors has been debated. Even under normal circumstances the cells within the central nervous system of an adult can trans-differentiate to other cell types. In addition, mutations found in gliomas further destabilize the differentiation status of these cells making a determination of what cell type gives rise to a given tumor histology difficult. Lineage tracing studies in animals can be used to correlate some specific cell characteristics with the histology of gliomas that arise from these cells. From these experiments it appears that undifferentiated cells are more sensitive to the oncogenic effects of certain signaling abnormalities than are differentiated cells, but that with the appropriate genetic abnormalities differentiated astrocytes can act as the cell-of-origin for gliomas. These data imply that small molecules that promote differentiation may be a rational component of glioma therapy in combination with other drugs aimed at specific molecular signaling targets.

Molecular genetics of human microcephaly.

Abstract: Human microcephaly comprises a heterogeneous group of conditions that are characterized by a failure of normal brain growth. Microcephaly can be caused by many injurious or degenerative conditions, or by developmental malformations in which the growth of the brain is impaired as a result of defects in pattern formation, cell proliferation, cell survival, cell differentiation, or cell growth. These latter forms of congenital microcephaly are frequently inherited, usually as recessive traits, and are associated with mental retardation and sometimes epilepsy. Some of the genes that cause congenital microcephaly are likely to control crucial aspects of neural development, and may also be involved in the evolutionary explosion of cortical size that characterizes primates. There has recently been a rapid advance in the use of genetic mapping techniques to identify genetic loci responsible for microcephaly. Although several loci have been mapped, the condition is clearly genetically and clinically heterogeneous.

Alpha-synuclein and the Lewy body disorders.

Abstract: alpha-Synuclein has risen to prominence during the past 5 years because of its association with several neurodegenerative diseases that have come to be known as the synucleinopathies. The clinical phenotype of the synucleinopathies is variable, with the most common being parkinsonism, autonomic dysfunction, and dementia. Progress has been made in clinical, neuropathologic and biochemical characterization of the synucleinopathies and their differentiation from other neurodegenerative disorders. At the molecular level, the synucleinopathies have conformational and post-translational modifications of synuclein that favor its fibrillization and aggregation in inclusions in neurons and glia. Whether inclusion body formation is an adaptive response or is directly related to degeneration of neuronal and glial cells is a topic of current research.

Psychiatric consequences of vestibular dysfunction.

Abstract: Anxiety and dizziness are co-morbid symptoms in a larger percentage of patients than would be expected from chance alone. Such patients have an increased handicap and poorer prognosis. In this review, we discuss the interface between vestibular disorders and anxiety disorders. The two conditions are functionally related via both somatopsychic and psychosomatic mechanisms, and are linked via overlapping neural circuits that include monoaminergic pathways and the parabrachial nucleus network. An alternative conceptualization to the common notion of 'psychogenic' dizziness is presented. Implications for patient management are discussed.

Homocysteine and stroke.

Abstract: During the past year epidemiological studies have linked elevated plasma total homocysteine concentrations with an increased risk of ischaemic stroke because of arterial disease. Laboratory studies have further explored the mitogenic effects of total homocysteine on vascular smooth muscle, and cytotoxic and thrombophilic effects on vascular endothelium. Also, a clinical trial has shown that lowering total homocysteine by means of multivitamin therapy decreases the rate of abnormal exercise electrocardiography tests. However, it remains to be determined whether lowering total homocysteine prevents hard clinical outcome events, such as stroke and other serious vascular events. An alternative explanation for the observed association between elevated total homocysteine and stroke is a confounding effect of factors associated with hyperhomocysteinaemia (e.g. cigarette smoking, renal impairment, an atherogenic diet, cystine deficiency, folate deficiency) or perhaps even the acute vascular events themselves, whereby the tissue damage temporarily increases total homocysteine levels. The results of ongoing clinical trials in stroke patients to determine the impact of multivitamin therapy on recurrent stroke and other serious vascular events are awaited.

Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations.

Abstract: Rett syndrome, a neurodevelopmental disorder that is a leading cause of mental retardation in females, is caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). MECP2 mutations have subsequently been identified in patients with a variety of clinical syndromes ranging from mild learning disability in females to severe mental retardation, seizures, ataxia, and sometimes neonatal encephalopathy in males. In classic Rett syndrome, genotype-phenotype correlation studies suggest that X chromosome inactivation patterns have a more prominent effect on clinical severity than the type of mutation. When the full range of phenotypes associated with MECP2 mutations is considered, however, the mutation type strongly affects disease severity. MeCP2 is a transcriptional repressor that binds to methylated CpG dinucleotides throughout the genome, and mutations in Rett syndrome patients are thought to result in at least a partial loss of function. Abnormal gene expression may thus underlie the phenotype. Discovering which genes are misregulated in the absence of functional MeCP2 is crucial for understanding the pathogenesis of this disorder and related syndromes.

Multiple sclerosis: recent developments in neuropathology, pathogenesis, magnetic resonance imaging studies and treatment.

Abstract: The cause of multiple sclerosis is generally considered to be entirely T cell mediated. However, recent reports of studies in a variety of animal models of inflammatory demyelinating disease, coupled with detailed pathological analysis and neuroimaging studies of multiple sclerosis patients, indicate that the events involved in the formation of the multiple sclerosis lesion may be more complicated. This complex pathogenesis is reflected in the variable response of multiple sclerosis patients to immunomodulatory therapy.

Memory and epilepsy: characteristics, course, and influence of drugs and surgery.

Abstract: Memory processing in humans is essential for consciousness, cognitive-behavioral development and individual biography. In epilepsy, declarative memory functions show characteristic patterns of impairment when mesiotemporal and associated neocortical structures are affected by lesions, ongoing epileptic activity, or the undesired effects of conservative or operative treatment. Major issues are thus the etiology, onset and course of memory impairment, as well as the prevention of further memory decline during treatment. New input in the field has resulted from improved imaging techniques, sophisticated experimental study designs, more selective surgical approaches, and new antiepileptic drugs.

Botulinum treatment of spasticity: why is it so difficult to show a functional benefit?

Abstract: Clinical experience seems to indicate that botulinum toxin injections can, in selected patients with upper motor neurone syndrome, reduce spasticity and improve voluntary movement and active function. However, double-blind placebo-controlled trials have had difficulty showing active functional improvement, despite the clear ability of botulinum toxin to reduce spasticity. This prompts a re-analysis of the basic assumption that spasticity impairs voluntary movement and a review of the methodology of the clinical trials. Motor dysfunction is usually caused by weakness and the other "negative" features of upper motor neurone syndrome, rather than muscle overactivity. Recent research has explored the pathophysiological basis of the voluntary movement disorder, in particular the role of the various forms of motor overactivity, which might be amenable to botulinum toxin treatment. The failure of double-blind placebo-controlled clinical trials to show improvement in active function is, to a large extent, a result of their methodology, especially patient selection, injection protocols, and the choice of outcome measures. Clinical trials need to be re-designed and based upon expert experience and a better understanding of the pathophysiology of the motor disorder.

Nitric oxide in primary headaches.

Abstract: The molecular mechanisms that underlie the primary headaches - migraine, cluster headache and tension-type headache - have not yet been clarified. On the basis of studies in headache induced by intravenous infusions of glyceryl trinitrate (an exogenous nitric oxide donor) and histamine (which libera

Radiation injury to the nervous system.

Abstract: This article reviews the current knowledge with regard to neurotoxicity of conventional radiation, including recent understanding of the pathophysiology, molecular biology, diagnostic evaluation and clinical presentations, as well as proposed treatment modalities and possible protective agents.

Parkin and Parkinson's disease.

Abstract: Parkin is the causative gene for an autosomal recessive form of Parkinson's disease. The gene was discovered in 1998. The parkin gene is a novel gene containing 12 exons spanning over 1.5 Mb and encodes a protein of 465 amino acids with a molecular mass of approximately 52,000 M(r). Various deletion mutations and point mutations have been discovered in patients with autosomal recessive Parkinson's disease. The substantia nigra and the locus coeruleus selectively undergo neurodegeneration without forming Lewy bodies. The parkin gene product, Parkin protein, has a unique structure with a ubiquitin-like domain in the amino-terminus and a RING finger motif in the carboxy terminus. The function of Parkin was not known until recently. During the year 2000, great progress was made in defining its function. First of all, Parkin was found to be a ubiquitin-protein ligase (E3), a component of the ubiquitin system, which is an important adenosine triphosphate-dependent protein degradation machinery. In addition, CDCrel-1, a synaptic vesicle associated protein, was found to be a substrate for Parkin as an E3. Although many studies still need to be performed to elucidate the molecular mechanism of the selective nigral neurodegeneration in this form of familial Parkinson's disease, it will not be too long before this is accomplished. In this review article, we evaluate the developments in this area published since 1 February 2000.

Vestibular evoked potentials.

Abstract: Loud clicks, short tone bursts, head taps and short duration transmastoid currents are all capable of activating vestibular receptors and evoking reflex changes in tonic electromyogram activity within the sternocleidomastoid muscles. Because they derive from averaged electromyograms, the responses are termed 'vestibular evoked myogenic potentials'. The earliest response ipsilateral to a loud click, p13n23, is dependent upon vestibular activation, specifically saccular afferents. These new techniques are beginning to be applied clinically. An important application is in suspected cases of the Tullio phenomenon, a condition that is characterized by a pathological reduction in click threshold. The techniques have also been applied in the assessment of otolith function, vestibular neuritis, Meniere's disease and vestibular nerve tumours (acoustic neuromas).

The role of rehabilitation in the recovery of walking in the neurological population.

Abstract: Recent studies demonstrate that neurological patients show great potential for recovery in both the early and late stages following injury. Enhancement of the recovery process could be achieved with new rehabilitation approaches alone or in combination with pharmacological intervention. These new ap

Brain stem gliomas.

Abstract: Brainstem gliomas are now regarded as a heterogeneous group of tumors that can be distinguished by age of onset, clinical and radiological presentation and biological behavior. This paper will focus on each subtype of tumor, in children and in adults, and on recent advances in diagnostic criteria and therapeutic options.

Immunological update on multiple sclerosis.

Abstract: The present review of the recent literature focuses on antigen-specific immune reactions in multiple sclerosis. New techniques have allowed precise quantitative analysis of the antigen-receptor repertoire of infiltrating T cells in the multiple sclerosis brain. Novel candidate autoantigens, includin

The genetics of late-onset Alzheimer's disease.

Abstract: Of late-onset Alzheimer's disease patients 50% do not carry an apolipoprotein E epsilon 4 allele, indicating that there must be other genetic or environmental risk factors for the disease. During the past few years, both genetic linkage and candidate gene studies have been undertaken in order to identify novel genetic risk factors for late-onset Alzheimer's disease. Previous genome screens implicated a region of chromosome 12 that contains the genes that encode both alpha(2)-macroglobulin and the low-density lipoprotein receptor-related protein. However, candidate gene studies have produced mixed results with respect to both of these genes. New linkage studies now provide strong evidence for Alzheimer's disease susceptibility loci on chromosomes 9 and 10. The locus on chromosome 10 very probably modifies risk for Alzheimer's disease by modulating beta-amyloid-42 levels.

Psychiatric issues in epilepsy.

Abstract: In recent years there has been considerable research interest at the interface between epilepsy and psychiatry. Topics of interest include the epidemiology of psychiatric co-morbidity in epilepsy; clinical syndromes at this interface and their classification; the relationship between cognitive dysfunction and psychiatric co-morbidity; biological mechanisms that mediate such co-morbidity, especially with developments in imaging and genetic research; the association between temporal lobe surgery, vagus nerve stimulation, and other non-pharmacological treatments, and the development of such co-morbidity; the contribution of anticonvulsant drugs towards the development of psychiatric co-morbidity; quality of life and other psychosocial issues; and non-epileptic attack disorder. In this review, papers on these psychiatric issues in epilepsy, with a focus on those published in the past year (October 1999 to October 2000) are critically evaluated, and some important current issues at this interface are considered in detail.

Recent advances in hereditary spastic paraplegia.

Abstract: The hereditary spastic paraplegias are a group of rare disorders that are characterized by great clinical and genetic heterogeneity. There has been an exponential increase in the number of HSP loci mapped in recent years, with nine out of the 17 loci reported during the past 2 years. Eight loci have now been identified for the autosomal-dominant form, and seven of these are associated with pure HSP. Spastic paraplegia-4 remains the most frequent locus, and is usually associated with a pure phenotype. Although the corresponding spastin gene was only recently identified, over 50 mutations have been described to date, which renders molecular diagnosis difficult. Five loci are known for autosomal-recessive HSP, and four of these are associated with complex forms, all with different phenotypes. Two genes have been identified: paraplegin and sacsin. Finally, three loci have been identified in X-linked HSP, two of which are complex forms. The genes that encode L1 and PLP were the first to be identified in HSP disorders. Surprisingly, the five genes encode proteins of different families, making understanding and diagnosis of HSP even more difficult. The discovery of new genes should hopefully help to clarify the pathophysiology of these disorders.

Autonomic dysfunction in movement disorders.

Abstract: Dysfunction of the autonomic nervous system is an under-recognised but important aspect of the aetiological and clinical manifestation of primary degenerative dysautonomias such as multiple system atrophy (MSA) and Parkinson's disease (PD). Although the clinical presentation of dysautonomia in these two disorders may overlap, yet pathological and in vivo imaging studies suggest considerable differences. Functional imaging studies suggest that selective cardiac sympathetic denervation may occur early in PD but not in other parkinsonian syndromes. The clinical implication of this apparently disease specific peripheral dysautonomia is unknown and would be the subject of much interest in future years. Dysautonomia in degenerative disorders also affect respiration, genitourinary function and sleep. Sleep related disorders such as rapid eye movement behaviour disorder and urinary voiding dysfunction appear to precede the development of PD related symptoms while patients with sporadic ataxia have been shown to progress to develop MSA. Dysautonomia has also been recognised in other movement disorders, examples being the combination of dystonia and complex regional pain syndrome with elevated HLA-DR13 and late onset Huntington's disease presenting with dominant parkinsonism and minimal chorea. These studies have helped progress in various diagnostic and management parameters in relation to autonomic dysfunction and movement disorders.

Assessment of cutaneous innervation by skin biopsies.

Abstract: Skin biopsies that are immunostained to identify nerve fibers provide a new tool for assessing the small caliber nociceptors that terminate in the epidermis, as well as other cutaneous nerve fibers. Skin biopsies can be performed in multiple sites and can be repeated over time, so that a spatiotemporal profile of epidermal innervation can be constructed. This approach may help assess the progression of fiber loss in disease and of regeneration and re-innervation with treatment.

Targeting the central nervous system inflammatory response in ischemic stroke.

Abstract: In experimental models of stroke, inflammation appears to contribute to cerebral ischemic injury. Clinical trials that are aimed at limiting the postischemic inflammatory response, however, have thus far had disappointing results. These clinical failures probably reflect the fact that there has been insufficient preclinical data and inadequate trial design, rather than provide evidence against a role for inflammation in ischemic brain injury.

Molecular mechanisms of cellular interactions in peripheral nerve regeneration.

Abstract: The peripheral nervous system, as opposed to the central nervous system, has the intrinsic capacity to regenerate. It was recognized long ago that this can be achieved only after an extensive clean-up procedure, the so-called Wallerian degeneration, in which myelin debris is removed and a suitable environment for growing axons is generated. Wallerian degeneration and the regeneration process itself both depend on direct cellular interactions as well as on long-range signals between all participating cell types. Elucidating the nature and functional consequences of these signals is a main goal in understanding peripheral nerve repair.

Classification of demyelinating diseases at the interface between etiology and pathogenesis.

Abstract: The classical demyelinating diseases include the 'autoimmune' inflammatory demyelinating diseases, the inflammatory demyelinating diseases of infectious aetiology, and the demyelinating or dysmyelinating diseases of genetic/hereditary background. In addition, primary demyelination is present in other conditions, such as brain ischaemia and intoxication. Irrespective of the primary aetiology, selective demyelination can be mediated through various pathogenetic pathways: the immune-mediated inflammatory pathway; the metabolic pathway; and the ischaemic/excitotoxic pathway. These pathways are only partly segregated with distinct aetiologies of demyelinating diseases, but they also reflect the way in which the patient copes with the disease-inciting event in relation to their particular genetic background. For future therapeutic strategies it will be important to interfere with the specific pathogenetic pathways of demyelination, which may be common to various demyelinating diseases, but may differ in subgroups of patients who suffer from a particular clinical demyelinating disease entity.