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Multiple Sclerosis Reviews: 2004

(137 References)

(2004). "Treatment optimization in multiple sclerosis: report of an international consensus meeting." Eur J Neurol 11(1): 43-7.

            Multiple sclerosis (MS) is a chronic disease for which there is currently no proven cure. Nevertheless, desperate views have changed to substantial optimism over recent years, as several lines of evidence have indicated that disease-modifying drugs (DMDs) have beneficial effects on neurological deterioration in MS. However, assessing the success of DMD therapy in an individual patient may not always be clear-cut for the doctor. In order to address this issue, an International Working Group of doctors experienced in treating patients with MS convened to discuss the optimization of DMD therapy, and the outcome of this consensus meeting is reported here. Participants developed statements that classify changes in relapses, disease progression and brain magnetic resonance imaging in a patient with MS who is taking DMD therapy, according to whether they are worthy of note, of some concern, or of serious concern and requiring a reassessment of current therapy. Based on these statements, the performance of standardized examinations to document changes in the disease enables a visual measure of the progress of an individual patient to be built up on an analogue model. This model provides a useful framework to help the neurologist to identify those patients for whom the therapeutic options should be reconsidered.

Abdel-Haq, N. M. and B. I. Asmar (2004). "Human herpesvirus 6 (HHV6) infection." Indian J Pediatr 71(1): 89-96.

            Human herpes virus-6 was first reported in 1986 and is the sixth member of the herpes virus family. HHV-6 consists of two closely related variants HHV-6A and HHV-6B. The majority of infections occur in healthy infants with most infections caused by HHV-6B. The virus preferentially infects CD4+T-lymphocytes and the surface marker CD46 acts as a co-receptor. Infection is followed by persistence and latency in different cells and organs including monocytes/macrophages, salivary glands, the brain and the kidneys. In this article we will discuss the clinical manifestations of HHV-6 infection in healthy children and the syndromes associated with HHV-6 reactivation in immunocompromised patients. Evidence of association between HHV-6 infection and different clinical entities such as multiple sclerosis, malignancy, infectious momononucleosis, drug hypersensitivity syndromes and skin eruptions is discussed. Published data on the use and efficacy of antiviral agents in complicated infections and infections in immunocompromised patients is presented.

Allcock, R. J., I. Forrest, et al. (2004). "A study of the prevalence of systemic sclerosis in northeast England." Rheumatology (Oxford) 43(5): 596-602.

            OBJECTIVES: We aimed to obtain an estimate of the prevalence and demographics of systemic sclerosis (SSc) and its subtypes at the turn of the millennium. METHODS: Case finding from multiple sources from a defined geographical area. Diagnosis confirmed by clinical examination. RESULTS: The crude prevalence of SSc in northeast England was 8.8 (95% CI: 6.8-10.8) per 100,000. The prevalence when adjusted for the entire UK is 8.2 (95% CI: 6.2-9.8) per 100,000. The ratio of women to men was 5.2:1. The median age of patients was 57.1 yr. The ratio of limited cutaneous SSc to diffuse cutaneous SSc was 4.7:1. Limited cutaneous SSc is associated with the presence of anticentromere antibodies; diffuse cutaneous SSc is associated with anti-Scl 70 antibodies, but either antibody was found in either form of SSc. CONCLUSIONS: SSc appears to be more common in northeast England than was found in the West Midlands in 1986. This may reflect changes in the diagnostic definition of SSc.

Althaus, H. H. (2004). "Remyelination in multiple sclerosis: a new role for neurotrophins?" Prog Brain Res 146: 415-32.

            Multiple sclerosis (MS) is a common neurological disease, which affects young adults. Its course is unpredictable and runs over decades. It is considered as an autoimmune disease, and is neuropathologically characterized by demyelination, variable loss of oligodendroglial cells, and axonal degeneration. Demyelination provides a permitting condition for axonal degeneration, which seems to be causative of permanent neurological deficits. Hence, the current treatment, which works preferentially immunmodulatory, should be complemented by therapeutics, which improves remyelination not only for restoring conduction velocity but also for preventing an irreversible axonal damage. One strategy to achieve this aim would be to promote remyelination by stimulating oligodendroglial cells remaining in MS lesions. While central nervous system neurons were already known to respond to neurotrophins (NT), interactions with glial cells became apparent more recently. In vitro and in vivo studies have shown that NT influence proliferation, differentiation, survival, and regeneration of mature oligodendrocytes and oligodendroglial precursors in favor of a myelin repair. Two in vivo models provided direct evidence that NT can improve remyelination. In addition, their neuroprotective and anti-inflammatory role would support a repair. Hence, a wealth of data point to NT as promising therapeutical candidates.

Attal, N. and D. Bouhassira (2004). "[Neuropathic pain: experimental advances and clinical applications]." Rev Neurol (Paris) 160(2): 199-203.

            Neuropathic pain is a clinical entity designating the different types of pain associated with a lesion of the nervous system including a wide range of pathological conditions from painful peripheral lesions (for example diabetic neuropathy, post-zoster pain, trauma-induced nerve injury) and central pain (particularly stroke-induced pain, spinal lesions, and multiple sclerosis). Despite this wide range of etiologies, neuropathic pain has well characterized clinical features which generally allow distinction from other types of pain: continuous often burn-like pain, paroxysmal pain (electrical discharge, knife stab), evoked pain, highly invalidating pain (allodynia, hyperalgesia), and associated dysethesia and/or paresthesia. Over the last ten Years, very little work has been published on neuropathic pain, which is now becoming a very active domain of research in neurobiology. Advances to date have not been spectacular although better tolerated agents have been recently marketed. Future progress should enable an appropriate response to the therapeutic challenge of neuropathic pain.

Ballabh, P., A. Braun, et al. (2004). "The blood-brain barrier: an overview: structure, regulation, and clinical implications." Neurobiol Dis 16(1): 1-13.

            The blood-brain barrier (BBB) is a diffusion barrier, which impedes influx of most compounds from blood to brain. Three cellular elements of the brain microvasculature compose the BBB-endothelial cells, astrocyte end-feet, and pericytes (PCs). Tight junctions (TJs), present between the cerebral endothelial cells, form a diffusion barrier, which selectively excludes most blood-borne substances from entering the brain. Astrocytic end-feet tightly ensheath the vessel wall and appear to be critical for the induction and maintenance of the TJ barrier, but astrocytes are not believed to have a barrier function in the mammalian brain. Dysfunction of the BBB, for example, impairment of the TJ seal, complicates a number of neurologic diseases including stroke and neuroinflammatory disorders. We review here the recent developments in our understanding of the BBB and the role of the BBB dysfunction in CNS disease. We have focused on intraventricular hemorrhage (IVH) in premature infants, which may involve dysfunction of the TJ seal as well as immaturity of the BBB in the germinal matrix (GM). A paucity of TJs or PCs, coupled with incomplete coverage of blood vessels by astrocyte end-feet, may account for the fragility of blood vessels in the GM of premature infants. Finally, this review describes the pathogenesis of increased BBB permeability in hypoxia-ischemia and inflammatory mechanisms involving the BBB in septic encephalopathy, HIV-induced dementia, multiple sclerosis, and Alzheimer disease.

Banwell, B. L. (2004). "Pediatric multiple sclerosis." Curr Neurol Neurosci Rep 4(3): 245-52.

            The onset of multiple sclerosis (MS) in childhood is being increasingly recognized. Despite this, there currently exist several barriers to the prompt diagnosis of MS in children. Many clinicians view MS as an exclusively adult-onset disease, and thus they may not entertain the diagnosis in a child. Also, the clinical and radiographic criteria for the diagnosis of MS have not been validated in a pediatric MS population. The available literature, as well as experience gained in a dedicated pediatric MS clinic, is used here to describe features of pediatric MS and contrast these with adult MS. The rationale and importance of future studies in pediatric MS is highlighted.

Bartosik-Psujek, H. and Z. Stelmasiak (2004). "[The formation and significance of antibodies to interferon beta during immunomodulating treatment of multiple sclerosis]." Neurol Neurochir Pol 38(1 Suppl 1): S53-6.

            Patients with multiple sclerosis receiving interferon beta (IFN) may develop neutralizing anti-interferon beta antibodies (NABs). The importance of NABs has not been completely explained, however it is generally reckoned that they might be one of the factors diminishing treatment efficacy. This paper presents the consequences of NABs formation during IFN therapy. Differences of immunogenicity between the interferon beta products with regard to their structure, formulation, dose, route of administration were presented and the influence of NABs on the biological and clinical activity of IFN beta therapy was shown.

Becanovic, K., M. Jagodic, et al. (2004). "Current gene-mapping strategies in experimental models of multiple sclerosis." Scand J Immunol 60(1-2): 39-51.

            Both family-based linkage analyses and population-based association studies have failed to identify disease-regulatory non-human leucocyte antigen genes of importance in multiple sclerosis (MS). Instead, investigators have employed experimental models, which offer major advantages in genetic studies. We summarize the current main methodologies used and the status of both the human and experimental approaches. Why is it important to find genes regulating MS? There is an immense number of cellular and molecular interactions defined in the immunological field and it is very difficult to unravel those that are critical to an inflammatory disease, such as MS, by classical hypothesis-driven research. Unbiased genetics defines evolutionary conserved gene polymorphisms and pathways regulated by these genes, which are central in the pathogenesis. These, in turn, are of interest as therapeutic targets and pharmacogenetic markers.

Bencsik, K. (2004). "Multiple sclerosis to date: diagnosis, epidemiology, new aspects of the pathomechanism and the therapy." Ideggyogy Sz 57(1-2): 41-50.

Benedict, R. H., D. A. Carone, et al. (2004). "Correlating brain atrophy with cognitive dysfunction, mood disturbances, and personality disorder in multiple sclerosis." J Neuroimaging 14(3 Suppl): 36S-45S.

            Neuropsychological impairment is a common feature of multiple sclerosis. Affected patients often have deficits in information-processing speed and memory and exhibit psychopathological states such as depression. A minority of patients have rarer affect/mood disorders such as euphoria sclerotica and pathological laughter/crying. Neuropsychological impairment is a major predictor of low quality of life, unemployment, and caregiver distress. Studies evaluating correlations between neuropsychological impairment and findings on magnetic resonance imaging show that neuropsychological dysfunction is associated with lesion burden and diffuse disease in normal-appearing brain tissue. However, measures of tissue atrophy including whole-brain and central atrophy are especially well correlated with and predictive of cognitive impairment. Moreover, recent studies have shown that conventional measures of brain atrophy explain more variance in neuropsychological dysfunction than do measures of lesion burden. In particular, neuropsychological outcomes correspond highly with linear measures of subcortical atrophy such as ventricle enlargement. Within the domain of emotional dysfunction, both lesion burden and atrophy are related to major depressive disorder. Brain atrophy also predicts euphoria and disinhibition. The preliminary data suggest that although lesion burden primarily predicts depressive disorder, both lesion burden and atrophy predict the presence of euphoria. Euphoria and disinhibition likely represent personality change associated with worsening cognition as the disease progresses. Taken together, this growing body of data on magnetic resonance imaging to neuropsychological correlations supports the clinical relevance and validity of brain atrophy as a measure of disease progression in multiple sclerosis. Continuing research focuses on the possible relationship between measures of regional brain atrophy and cognitive and emotional impairment.

Bennett, M. and R. Heard (2004). "Hyperbaric oxygen therapy for multiple sclerosis." Cochrane Database Syst Rev(1): CD003057.

            BACKGROUND: Multiple Sclerosis (MS) is a chronic, recurrent and progressive illness with no cure. On the basis of speculative pathophysiology, it has been suggested that Hyperbaric Oxygen Therapy (HBOT) may slow or reverse the progress of the disease. OBJECTIVES: The object of this review was to evaluate the efficacy and safety of HBOT in the treatment of MS. SEARCH STRATEGY: We searched the Cochrane MS Group trials register (July 2002), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2002), MEDLINE (January 1966 to October 2002) and the National Library of Medicine (NLM) database (July 2002), along with specialised hyperbaric resources and handsearching of relevant journals and proceedings. SELECTION CRITERIA: All randomised, controlled trials involving a comparison between HBOT and a sham therapy in MS were evaluated. DATA COLLECTION AND ANALYSIS: Two reviewers independently appraised all comparative trials identified, extracted data and scored them for methodological quality. MAIN RESULTS: We identified ten reports of nine trials that satisfied selection criteria (504 participants in total). Two trials produced generally positive results, while the remaining seven reported generally no evidence of a treatment effect. None of our three a priori subgroup analyses placed these two trials in the same group and were therefore unable to account for this difference. Three analyses (of 21) did indicate some benefit. For example, the mean Expanded Disability Status Scale (EDSS) at 12 months was improved in the HBOT group (group mean reduction in EDSS compared to sham -0.85 of a point, 95% confidence interval -1.28 to -0.42, P = 0.0001). Only the two generally positive trials reported on this outcome at this time (16% of the total participants in this review). REVIEWER'S CONCLUSIONS: We found no consistent evidence to confirm a beneficial effect of hyperbaric oxygen therapy for the treatment of multiple sclerosis and do not believe routine use is justified. The small number of analyses suggestive of benefit are isolated, difficult to ascribe with biological plausibility and would need to be confirmed in future well-designed trials. Such trials are not, in our view, justified by this review.

Bennetto, L. and N. Scolding (2004). "Inflammatory/post-infectious encephalomyelitis." J Neurol Neurosurg Psychiatry 75 Suppl 1: i22-8.

Benveniste, E. N., V. T. Nguyen, et al. (2004). "Molecular regulation of CD40 gene expression in macrophages and microglia." Brain Behav Immun 18(1): 7-12.

            Inflammatory events in the central nervous system (CNS) contribute to the disease process in a variety of neuroinflammatory diseases such as multiple sclerosis (MS), Alzheimer's Disease (AD), and cerebral ischemia, and activated macrophages/microglia are central to this response. Immunological activation of these cells leads to the production of a wide array of cytokines, chemokines, matrix metalloproteinases and neurotoxins, and ultimately to glial/neuronal injury and death. The CD40 molecule has an important role in promoting inflammatory responses by macrophages/microglia, since interaction with its cognate ligand, CD154, leads to secretion of cytokines and neurotoxins. Aberrant CD40 expression by macrophages/microglia, induced by cytokines such as IFN-gamma and TNF-alpha, contributes to neuroimmunologic cascades in the CNS. Strategies to suppress CD40 expression may attenuate inflammation and neuronal damage within the CNS, which will ultimately be of benefit in neuroinflammatory diseases. The mediators that regulate expression of CD40 in macrophages/microglia (both induction and inhibition) function at the level of gene transcription. In this review, we present an overview of the molecular basis of CD40 expression in macrophages/microglia. The signal transduction pathways and transcription factors employed by IFN-gamma and TNF-alpha to induce CD40 expression are described, as are the cis-elements in the CD40 promoter that are critical for CD40 transcription. Information is provided on the mechanism(s) underlying suppression of CD40 in macrophages/microglia by immunomodulatory agents such as IL-4, TGF-beta, neuropeptides, neurotrophins, and statins. A comprehensive assessment of CD40 production and function in macrophages/microglia will establish the foundation for future therapeutic manipulation of this critical immunoregulatory protein.

Bertolotto, A. (2004). "Neutralizing antibodies to interferon beta: implications for the management of multiple sclerosis." Curr Opin Neurol 17(3): 241-6.

            PURPOSE OF REVIEW: Antibodies against interferon-beta (IFN-beta) can appear in a relevant number of patients. The subset of antibodies that can neutralize IFN-beta activity are called neutralizing antibodies. This review focuses on their impact both on therapeutic efficacy and on bioactivity of IFN-beta, and on the management of antibody-positive patients. RECENT FINDINGS: When IFN-betas were first used, neutralizing antibodies were not considered important. However, recent clinical, biologic, and immunologic data have demonstrated that they reduce or abolish the therapeutic efficacy of IFN-beta in 10-20% of patients. Quantification of antibodies using various biologic methods make it difficult to compare among different laboratories, and hence, standardization of assay procedures is necessary. Despite these technical difficulties, data consistently show differences in immunogenicity among the different IFN-beta products and the negative effects of neutralizing antibodies on the clinical efficacy of IFN-betas. Because the therapeutic action of IFN-beta depends on activation of IFN-inducible genes, new methods for the quantification of the biologic activity of IFN-beta have been developed, and a good correlation has been found between the presence of neutralizing antibodies and abrogation of IFN-beta bioactivity. SUMMARY: Quantification of neutralizing antibodies and the in-vivo bioactivity of IFN-beta through IFN-beta-inducible gene products such as Myxovirus protein A, offer valuable information on IFN-beta therapy. Important questions such as the optimal therapeutic strategy for managing neutralizing antibodies positive patients require further study in clinical trials.

Besag, F. M. (2004). "Behavioral aspects of pediatric epilepsy syndromes." Epilepsy Behav 5 Suppl 1: S3-13.

            Apart from control of the seizures, two of the most important factors in determining how well a child with epilepsy progresses toward independence are cognition and behavior. The diagnosis of the correct epilepsy syndrome often provides information with regard to probability of good seizure control and intellectual outcome. However, relatively little has been published on the behavioral aspects of the various epilepsy syndromes. In West syndrome there is emerging evidence that early effective treatment might improve outcome in terms of both cognition and behavior. The work on this syndrome in children with tuberous sclerosis has demonstrated an association between temporal lobe tubers and autism. In Dravet syndrome, a variety of psychiatric disorders have been reported, including hyperactivity and autistic features. This is another epilepsy syndrome that tends to be resistant to treatment, implying that the prognosis has to be guarded. The behavioral problems reported with Lennox-Gastaut syndrome also include autistic features, as well as generally sluggish behavior. It is very likely that these characteristics largely reflect the effect of ongoing seizure activity. Autistic features, aggression, and hyperkinesis have been described with Landau-Kleffner syndrome. The behavior may improve dramatically with appropriate medical treatment or after multiple subpial transection. Although the syndrome of benign partial seizures with centrotemporal or rolandic spikes is said to have a very good prognosis, it is becoming increasingly evident that behavioral problems such as concentration difficulties, tempers, hyperactivity, and impulsivity might occur. Juvenile myoclonic epilepsy has been associated with very variable behavioral traits, sometimes with immature personality features and poor social adjustment suggesting frontal lobe dysfunction. Because many of the reports of behavioral disturbance associated with epilepsy syndromes are anecdotal and do not include validated measures of behavior it would be unwise to draw firm conclusions from them at this stage. Carefully conducted prospective studies, paying particular attention to any behavioral improvements that occur with successful treatment of the epilepsy, are required.

Bielekova, B. and R. Martin (2004). "Development of biomarkers in multiple sclerosis." Brain 127(Pt 7): 1463-78.

            Multiple sclerosis is a complex disease, as several pathophysiological processes (including inflammation, demyelination, axonal damage and repair mechanisms) participate in the disease process. Furthermore, as new pathological evidence reveals, these processes are not uniformly represented across patient populations but can selectively predominate in individual patients, thus contributing to the heterogeneity in phenotypic expression of the disease, its prognosis and response to therapies. While the armamentarium of available therapies for multiple sclerosis broadens, little is known about factors that predict treatment response in individual patients to a specific drug. More importantly, we are beginning to understand that, analogous to cancer therapy, the successful therapeutic strategy in multiple sclerosis might ultimately involve the combination of different therapeutics targeting several dominant pathophysiological processes. The development of these process-specific therapies will be impossible without the use of biomarkers that reflect the targeted process, can select patient population in which the targeted process is prevailing and can aid during the more rapid screening of therapeutic agents in the early phase of their development. This review summarizes the general concepts of biomarkers and their potential use as surrogate endpoints and tailors these concepts to specific applications in multiple sclerosis research.

Bo, L., J. J. Geurts, et al. (2004). "Magnetic resonance imaging as a tool to examine the neuropathology of multiple sclerosis." Neuropathol Appl Neurobiol 30(2): 106-17.

            Magnetic resonance imaging (MRI) has significantly extended the understanding of multiple sclerosis (MS), owing to its ability to sensitively depict the dynamics of the disease process in vivo. The subject of this review is the use of MRI in the post-mortem setting, with emphasis on how it may be used to improve the specimen selection process at autopsy. Lesions with active demyelination are highly interesting in the study of MS pathogenesis, but are rare in a typical autopsy material of chronic MS. The yield of MS lesions in autopsy specimen selection can be increased by the use of MRI-guided tissue sampling, as a significant proportion of abnormalities detected by post-mortem MRI are not macroscopically visible/palpable. The majority of these MRI abnormalities have been found to represent either discrete areas of microglial activation with no demyelination (so-called (p)reactive lesions), or active demyelinating MS lesions by further histopathological examination. The presence and extent of MS pathology outside of the focal demyelinated lesions is more readily appreciated by MRI-guided specimen sampling, as has been shown in the study of extensive areas of partial myelin loss in the spinal cord. A further advantage of MRI-guided specimen sampling is the ability to use three-dimensional and quantitative measures. The potential of correlating these with histopathological data may be further exploited in the future. The technical procedure for MRI-guided tissue sampling at autopsy is presented, and the limitations of the technique are discussed.

Boje, K. M. (2004). "Nitric oxide neurotoxicity in neurodegenerative diseases." Front Biosci 9: 763-76.

            Nitric oxide (nitrogen monoxide; NO) is a simple molecule with diverse biological functions. NO and related reactive nitrogen oxide species (RNOS) mediate intricate physiological and pathophysiological effects in the central nervous system. Depending on environmental conditions, NO and RNOS can initiate and mediate neuroprotection or neurotoxicity either exclusively or synergistically with other effectors. The focus of this review is limited to the neuroprotectant/neurotoxic role of NO in Acquired Immune Deficiency Syndrome (AIDS) Dementia Complex (aka HIV--Associated Dementia; HAD) Amyotrophic Lateral Sclerosis (aka Lou Gehrig's Disease), Alzheimer's Disease, Huntington's Disease, Multiple Sclerosis and Parkinson's Disease. This review will shed light on the question: "How important is NO in neurodegenerative diseases?"

Bomholt, S. F., M. S. Harbuz, et al. (2004). "Involvement and role of the hypothalamo-pituitary-adrenal (HPA) stress axis in animal models of chronic pain and inflammation." Stress 7(1): 1-14.

            Hypothalamo-pituitary-adrenal (HPA) axis changes have been reported in several disease states, including major depressive disorder, rheumatoid arthritis, multiple sclerosis and various other conditions associated with chronic pain. These observations suggest that stress and the HPA axis may play important roles in the pathology of these diseases. In order to contribute to a better understanding of the role that chronic stress may play in human pathology, this review article explores the involvement of the HPA axis in those animal models of chronic pain and inflammation that entail persistent rather than intermittent stress.

Brinar, V. V. (2004). "Non-MS recurrent demyelinating diseases." Clin Neurol Neurosurg 106(3): 197-210.

            The introduction of MRI has shown that the acute, recurrent (R), and multiphasic (M) forms of disseminated encephalomyelitis (DEM) are more common than suspected in adults, and that their MR images are sufficiently characteristic in most instances to make differentiation from multiple sclerosis (MS) possible. In addition, a number of clinical features of DEM are rarely seen in MS: fever, malaise, nausea, vomiting, positional vertigo, convulsions, aphasia, meningism, bilateral optic neuritis, and CSF leukocytosis and elevated protein. CSF oligoclonal bands are usually absent. It is remarkable that confusion between R- and MDEM and MS persists despite the numerous published reports on recurrent DEM dating back 70 years, many illustrating the characteristic MRIs. There are many case reports of DEM erroneously diagnosed as MS, Schilder's, Marburg's, Devic's, and Balo's disease, and, in particular brain tumors. It is probable that acute DEM is occasionally mistaken for a clinically isolated symptom of MS. Possible mechanisms for recurrence include localization at the site of a previous injury to the nervous system, or by the phenomenon of molecular mimicry. The importance of differentiating R- and MDEM from MS is greater today due to the recommendation that immunodulatory treatment be initiated in patients with a clinically isolated syndrome, or when the occurrence of a second clinical episode establishes the diagnosis of MS.

Brinar, V. V. (2004). "Diagnostic and therapeutic dilemmas." Clin Neurol Neurosurg 106(3): 180-6.

            Close blood relatives of MS patients have MRI changes suggestive of MS despite the absence of any symptoms. They have also been seen when an MRI is obtained for various reasons in unrelated persons. This raises questions regarding their clinical significance, if any, since typical MS plaques have been found at autopsy in eloquent parts of the nervous system in completely asymptomatic individuals. Do these people have MS and should immunomodulatory treatment be considered? Because they are not ill according to various dictionary definitions, no to both. A higher rate of MS in close blood relatives would be expected due to the known genetic susceptibility, but suggestive MRI changes are quite uncommon, even in unaffected twins. Finally, a review of the four published studies of MS lesions unexpectedly found at autopsy in neurologically asymptomatic persons revealed a prevalence of the disease of 0.1%, the same as the estimated prevalence of clinical MS in the United States.

Bruzzone, M. G., M. Grisoli, et al. (2004). "Neuroradiological features of vertigo." Neurol Sci 25 Suppl 1: S20-3.

            The diagnostic pathway in a patient with vertigo starts with the accurate evaluation of medical history followed by a general physical and neurological examination. This step can often lead to the identification of the correct cause of the disease or, at least, to a distinction between peripheral and central vertigo. Neuroradiological investigations have to be considered as elective diagnostic procedures and include: computed tomography (CT), magnetic resonance (MR), MR angiography (MRA), angiography. For the diagnosis of peripheral vertigo, benign paroxysmal positional vertigo, labyrinthitis, Meniere disease, perilymphatic fistula, local trauma, toxic labyrinthitis, acute otitis media and chronic middle ear effusion,the role of imaging techniques is controversial. CT and MR are performed to rule out other pathologies and to confirm the diagnosis. Increased resolution and application of special MR sequences enhancing the intralabyrinthine fluids have enabled more detailed analysis of labyrinthine structures and pathology. Both T2 and T1 contrast sequences are necessary. A high resolution CT study is required when otitis media is suspected and in the follow-up of post-traumatic vertigo. The causes of central vertigo are numerous and include: vertebro-basilar circulation vascular events, multiple sclerosis (MS), migraine-associated vertigo, cerebellar and brainstem tumors, CNS infections. Among them cerebrovascular ischemia and multiple sclerosis are the most frequent. In these situations imaging studies become mandatory. CT can diagnose most cerebellar hemorrhages and some cerebellar and brainstem acute ischemia, enhanced MR has proved to be the most sensitive tool to detect posterior fossa lesion. Diffusion-weighted MR can reveal acute ischemic changes before routine MR. There has been evidence that MR angiography, providing angiogram-like images of the intracranial vessels may sometimes avoid invasive angiography. MRA resolution is not as good as traditional angiography and may also be compromised by movements and other artifacts. Selective angiography of the posterior circulation is often indicated for therapeutic decisions.

Bryant, P. R., C. C. Geis, et al. (2004). "Stroke and neurodegenerative disorders. 4. Neurodegenerative disorders." Arch Phys Med Rehabil 85(3 Suppl 1): S21-33.

            This self-directed learning module highlights diagnosis, treatment, and rehabilitation issues in patients with neurodegenerative disorders, including multiple sclerosis (MS), Parkinson's disease, and amyotrophic lateral sclerosis (ALS). It is part of the study guide on stroke and neurodegenerative disorders in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on the differential diagnosis, diagnostic evaluation, medical management, and rehabilitation issues in MS. Similarly, the differential diagnosis treatment and rehabilitation in Parkinson's disease is discussed. Electrodiagnosis, pharmacologic treatment, and rehabilitation options for ALS are also discussed. OVERALL ARTICLE OBJECTIVES: To review the differential diagnosis, evaluation, medical treatment, and rehabilitation management of patients with MS, Parkinson's disease, and ALS.

Burgoon, M. P., D. H. Gilden, et al. (2004). "B cells in multiple sclerosis." Front Biosci 9: 786-96.

            The most common laboratory abnormality in multiple sclerosis (MS) is an increased amount of cerebrospinal fluid IgG and the presence of oligoclonal bands. Despite studies of the humoral response that suggest the involvement of an infectious agent or autoantigen in disease, the major targets of the oligoclonal response are still unknown. Identification of these targets will reveal valuable insights into the cause and pathogenesis of MS and is likely to lead to effective treatment.

Chaudhuri, A. and P. O. Behan (2004). "Fatigue in neurological disorders." Lancet 363(9413): 978-88.

            Chronic fatigue is a typical symptom of neurological diseases, and is most disabling in multiple sclerosis, postpoliomyelitis, poststroke, and in chronic fatigue syndrome. Disorders of neuromuscular junction transmission and metabolic diseases cause muscle fatigability, which is characterised by failure to sustain the force of muscle contraction (peripheral fatigue). Fatigue is also seen in diseases that affect the central, peripheral, and autonomic nervous systems (central fatigue). Enhanced perception of effort and limited endurance of sustained physical and mental activities are the main characteristics of central fatigue. Metabolic and structural lesions that disrupt the usual process of activation in pathways interconnecting the basal ganglia, thalamus, limbic system, and higher cortical centre are implicated in the pathophysiological process of central fatigue. A state of pre-existing relative hypocortisolaemia might sensitise the hypothalamic-pituitary-adrenal axis to development of persistent central fatigue after stress. The contributions of physiological, cognitive, and affective changes underlying fatigue are variable, and treatment is largely symptomatic and rehabilitative.

Christopherson, K. W., 2nd and R. A. Hromas (2004). "Endothelial chemokines in autoimmune disease." Curr Pharm Des 10(2): 145-54.

            Compelling evidence now exists supporting the involvement of chemokines in the pathogenesis of autoimmune diseases. Examples of chemokines and chemokine receptors being involved in mediating autoimmune disease exist for rheumatoid arthritis, multiple sclerosis, allograft rejection, systemic lupus erythematosus, psoriasis, atopic dermatitis, lichen planus, and graft-versus-host-disease. Expression of chemokines by endothelial cells appears to be an important step in the development of these diseases. Since chemokines are small molecular weight molecules that act through G-protein coupled receptors, they make attractive drug targets. Several antagonists of chemokine - chemokine receptor interactions have been used to successfully alleviate some or all of the symptoms associated with many of these diseases in animal models. Further investigation of the involvement of chemokines in the pathogenesis or progression of autoimmune diseases may lead to practical clinical advances in diagnosis, prognosis, and therapy of such diseases.

Confavreux, C. and S. Vukusic (2004). "Non-specific immunosuppressants in the treatment of multiple sclerosis." Clin Neurol Neurosurg 106(3): 263-9.

            Immunosuppressants have been proposed as disease-modifying treatments in multiple sclerosis (MS) for almost 40 years, but only one, mitoxantrone, has recently been approved, whereas beta-interferons and glatiramer acetate have been licensed since the mid-90s. Recent therapeutic trials of potent immunosuppressive agents such as Campath-1H, mitoxantrone and cyclophosphamide of MS patients with high relapse rates, rapid accumulation of disability and high degree of MRI activity, have resulted in strong suppression of clinical and MRI inflammatory activity, provided that profound and prolonged lymphopenia was achieved. Clinical experience during the past decades has amply demonstrated that some patients with MS respond to immunosuppressants. The odds ratios of relapsing-remitting MS patients to remain relapse-free after a 2-year period of treatment are similar for Betaseron, Avonex, Rebif, Copaxone, intravenous immunoglobulins or azathioprine compared to placebo. The risk of cancer induction is not significant for up to 10 years of daily usage of azathioprine. Currently available non-specific immunosuppressants are able to control inflammation and reduce relapses in MS, but cannot prevent neurodegeneration and the progression of irreversible disability; specific tools need to be developed for that purpose.

Coo, H. and K. J. Aronson (2004). "A systematic review of several potential non-genetic risk factors for multiple sclerosis." Neuroepidemiology 23(1-2): 1-12.

            We reviewed the literature published in the English language to determine the weight of evidence for several potential non-genetic risk factors for multiple sclerosis, including solar ultraviolet radiation (UVR), sex hormones and dietary fat/fatty acids. We ranked the plausibility of each factor and graded the methodological rigour of case-control and cohort studies to determine whether there was a sufficient number of high-quality studies to weigh the evidence. Based on our criteria, the plausibility for solar UVR and sex hormones is good and fair for dietary fat/fatty acids. However, the body of epidemiologic evidence is insufficient for these three sets of risk factors. We did not find a sufficient number of methodologically rigorous studies to weigh the evidence for any of the potential risk factors we examined.

Crino, P. B. (2004). "Malformations of cortical development: molecular pathogenesis and experimental strategies." Adv Exp Med Biol 548: 175-91.

            Malformations of cortical development (MCD) are developmental brain lesions characterized by abnormal formation of the cerebral cortex and a high clinical association with epilepsy in infants, children, and adults. Despite multiple anti-epileptic drugs (AEDs), treatment of epilepsy associated with MCD may require cortical resection performed to remove the cytoarchitecturally abnormal region of cortex. Single genes responsible for distinct MCD including lissencephaly, subcortical band heterotopia, and tuberous sclerosis, have been identified and permit important mechanistic insights into how gene mutations result in abnormal cortical cytoarchitecture. The pathogenesis of MCD such as focal cortical dysplasia, hemimegalencephaly, and polymicrogyria, remains unknown. A variety of new techniques including cDNA array analysis now allow for analysis of gene expression within MCD.

Dalakas, M. C. (2004). "Intravenous immunoglobulin in autoimmune neuromuscular diseases." Jama 291(19): 2367-75.

            CONTEXT: Intravenous immunoglobulin (IVIG) enhances immune homeostasis by modulating expression and function of Fc receptors, interfering with activation of complement and production of cytokines, providing anti-idiotypic antibodies, and affecting the activation and effector functions of T and B cells. These mechanisms may explain the effectiveness of IVIG in autoimmune neuromuscular disorders. OBJECTIVE: To systematically review the current status of the treatment of autoimmune neuromuscular diseases with IVIG, with emphasis on controlled trials. DATA SOURCES: Peer-reviewed publications identified through MEDLINE (1966-2003), EMBASE (1974-2003), and references from bibliographies of pertinent articles. Each autoimmune neuromuscular disease term was searched in combination with the term intravenous immunoglobulin. STUDY SELECTION AND DATA EXTRACTION: Criteria for selection of studies included controlled study design, English language, and clinical pertinence. Data quality was based on venue of publication and relevance to clinical care. DATA SYNTHESIS: Outcomes of controlled trials indicate that IVIG at a total dose of 2 g/kg is effective as first-line therapy in Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy and as second-line therapy in stiff-person syndrome, dermatomyositis, myasthenia gravis, and Lambert-Eaton myasthenic syndrome. In other controlled studies, IVIG produced a modest, variable, and transient but not statistically significant benefit in patients with inclusion body myositis and paraproteinemic anti-myelin-associated glycoprotein antibody demyelinating polyneuropathy. Intravenous immunoglobulin is not effective in patients with multiple sclerosis who have established weakness or optic neuritis. In myasthenia gravis, it should be reserved for difficult cases or before thymectomy in lieu of plasma exchange. CONCLUSION: Intravenous immunoglobulin is effective in many autoimmune neurologic diseases, but its spectrum of efficacy, especially as first-line therapy, and the appropriate dose for long-term maintenance therapy are not fully established. Further controlled studies of IVIG, combined with a dose-finding effect, pharmacoeconomics, and quality-of-life assessments, are warranted to improve the evidence base for clinical practice.

De Keyser, J., E. Zeinstra, et al. (2004). "Beta 2-adrenoceptor involvement in inflammatory demyelination and axonal degeneration in multiple sclerosis." Trends Pharmacol Sci 25(2): 67-71.

            Relapses of multiple sclerosis (MS) are considered to be the clinical expression of acute T-cell-mediated inflammatory demyelinating lesions disseminated in the CNS, whereas disease progression seems to result from widespread axonal degeneration. The pathophysiology of both disease components is incompletely understood. Astrocytes in MS lack beta(2)-adrenoceptors, which via cAMP-mediated processes inhibit the expression of major histocompatibility (MHC) class II molecules and stimulate glycogenolysis in normal conditions. In a pro-inflammatory CNS environment this beta(2)-adrenoceptor defect might allow astrocytes to transform into facultative antigen-presenting cells that can initiate the inflammatory cascade. The same receptor defect might impair astrocytic glycogenolysis, which normally generates lactate that is transported to axons as an energy source. Failure of axonal energy metabolism might result in axonal degeneration through mechanisms that involve intra-axonal accumulation of Ca(2+) ions and mitochondrial dysfunction. If this hypothesis is correct, therapies designed to elevate cAMP levels in astrocytes should reduce or prevent both relapses and progression of MS.

De Keyser, J., E. Zeinstra, et al. (2004). "Astrocytic beta2-adrenergic receptors and multiple sclerosis." Neurobiol Dis 15(2): 331-9.

            Despite intensive research, the cause and a cure of multiple sclerosis (MS) have remained elusive and many aspects of the pathogenesis are not understood. Immunohistochemical experiments have shown that astrocytic beta(2)-adrenergic receptors are lost in MS. Because norepinephrine mediates important supportive and protective actions of astrocytes via activation of these beta(2)-adrenergic receptors, we postulate that this abnormality may play a prominent role in the pathogenesis of MS. First, it may allow astrocytes to act as facultative antigen-presenting cells, thereby initiating T-cell mediated inflammatory responses that lead to the characteristic demyelinated lesions. Second, it may contribute to inflammatory injury by stimulating the production of nitric oxide and proinflammatory cytokines, and reducing glutamate uptake. Third, it may lead to apoptosis of oligodendrocytes by reducing the astrocytic production of trophic factors, including neuregulin, nerve growth factor and brain-derived neurotrophic factor. Fourth, it may impair astrocytic glycogenolysis, which supplies energy to axons, and this may represent a mechanism underlying axonal degeneration that is hold responsible for the progressive chronic disability.

de Seze, J. (2004). "[Can multiple sclerosis be diagnosed on a first demyelinating event?]." Presse Med 33(3): 174-9; discussion 192.

            Progression is required. The definition of multiple sclerosis (MS) relies on the notion of temporo-spatial dissemination of inflammatory demyelinating neurological episodes. Until recently, in order to retain the diagnosis of definite MS, two successive neurological episodes had to be observed in two different territories. Since the commercialisation of new immunomodulating treatments, and in particular the recent demonstration of their efficacy in delaying the onset of a second neurological episode, it has been necessary to draw-up new criteria. New criteria have recently been proposed by a group of experts and they emphasize the fundamental role played by magnetic resonance imaging. New priorities. With these new criteria, certain aspects have become front-line. This is the case of the necessity of foreseeing more exhaustive differential diagnoses of MS, so as to avoid the erroneous initiation of a specific treatment. There is also the problem of the selection of patients at high risk of a potentially progressive MS, not all patients necessarily require such treatment at the start. Updating. We successively present the recently revised diagnostic criteria in order to be able to diagnose MS after the first demyelinising episode, we then study the clinical and paraclinical predictive elements that provide supplementary support for MS and, notably, progressive MS. We also discuss the differential diagnoses to be excluded according to the clinical context and, lastly, we will attempt to assess the practical consequences of an early diagnosis, not only with regard to its announcement, but also with regard to the therapeutic decisions to be made.

Dietrich, J. B. (2004). "Endothelial cells of the blood-brain barrier: a target for glucocorticoids and estrogens?" Front Biosci 9: 684-93.

            Adhesion molecules are involved in the leukocyte recruitment of leukocytes at the blood-brain barrier. For this reason, it is important to understand how the regulation of their gene expression controls lymphocyte adhesion to endothelial cells in microvessels. Indeed, due to their specificity and diversity, adhesion molecules involved in extravasation play an essential role in the recruitment of activated leukocytes and activation of inflammation. Multiple sclerosis results from a chronic inflammation of the CNS which is mediated by infiltration of inflammatory cells from the immune system. Administration of glucocorticoids is a routine method to control multiple sclerosis since naturally derived or synthetic glucocorticoids are potent immunosuppressive and anti-inflammatory agents. Glucocorticoids also have beneficial effects in stabilizing the blood-brain barrier, as steroid hormones regulate the expression of adhesion molecule genes in endothelial cells. Other hormones such as estrogens modulate many endothelial cell biological activities, among them adhesion to leukocytes. They regulate expression of adhesion molecules genes on endothelial cells and are useful for the treatment of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The effects of glucocorticoids and estrogens on the expression of adhesion molecules on endothelial cells, including microvascular endothelial cells of the blood-brain barrier, are reviewed in this paper, as well as the involvement of these hormones in the therapy of experimental autoimmune encephalomyelitis and multiple sclerosis.

Dogan, R. N. and W. J. Karpus (2004). "Chemokines and chemokine receptors in autoimmune encephalomyelitis as a model for central nervous system inflammatory disease regulation." Front Biosci 9: 1500-5.

            This article focuses on the distinct role of chemokines and chemokine receptors during CNS inflammation in experimental autoimmune encephalomyelitis (EAE) as an animal model for multiple sclerosis (MS). We review the evidence that chemokines and chemokine receptors have an intrinsic role in regulating and amplifying the inflammatory reactions in EAE or MS leading to disease outcome. A variety of studies examining temporal chemokine expression patterns, using chemokine and chemokine receptor knockout mice as well as administering passive anti-chemokine antibodies indicates that these molecules are critical regulatory components for leukocyte recruitment and/or leukocyte retention in the CNS. Therefore, chemokine and chemokine receptor expression is tightly interrelated to composition of inflammatory cells in CNS lesions and the onset of clinical diseases and provide viable targets for therapeutic intervention.

Duran, M., J. R. Laporte, et al. (2004). "[News about therapeutic use of Cannabis and endocannabinoid system]." Med Clin (Barc) 122(10): 390-8.

            Growing basic research in recent years led to the discovery of the endocannabinoid system with a central role in neurobiology. New evidence suggests a therapeutic potential of cannabinoids in cancer chemotherapy-induced nausea and vomiting as well as in pain, spasticity and other symptoms in multiple sclerosis and movement disorders. Results of large randomized clinical trials of oral and sublingual Cannabis extracts will be known soon and there will be definitive answers to whether Cannabis has any therapeutic potential. Although the immediate future may lie in plant-based medicines, new targets for cannabinoid therapy focuses on the development of endocannabinoid degradation inhibitors which may offer site selectivity not afforded by cannabinoid receptor agonists.

Dyment, D. A., G. C. Ebers, et al. (2004). "Genetics of multiple sclerosis." Lancet Neurol 3(2): 104-10.

            Multiple sclerosis (MS) is probably aetiologically heterogeneous. Systematic genetic epidemiological and molecular genetic studies have provided important insights. Both genetic and non-genetic (environment, stochastic) factors may be involved in susceptibility as well as outcome, but we have yet to understand their relative roles. Any environmental factor is likely to be ubiquitous and act on a population-basis rather than within the family microenvironment. Taken together, the results of genome screening studies provide strong evidence for exclusion of a major locus in MS. There are, however, many genes that seem to be associated with MS. These include, but are in no way limited to, HLA classes I and II, T-cell receptor beta, CTLA4, ICAM1, and SH2D2A. The future of MS genetics, as for most common complex disorders, will be dependent on the resources available, ranging from biological samples and comprehensive databases of clinical and epidemiological information to the development of new technologies and statistical methods.

Edan, G. (2004). "[Aggressive multiple sclerosis. Definition and specific therapeutic indication]." Presse Med 33(3): 187-91; discussion 192.

            Introduction. On the 29th of October 2003, mitoxantrone was approved by the french health agency Afssaps (Agence francaise de securite sanitaire des produits de sante) for its use in the aggressive forms of multiple sclerosis (MS). It is the first immuno-suppressor having demonstrated particular efficacy in this progressive form of MS. Definition of aggressive MS. Agressive multiple sclerosis is defined as an MS that leads to the rapid accumumation of disabilities, whether these latter are the result of repeated relapses (at least 2 in the past 12 Months) or the continuous progression of a disability (increase in 2 points on the expanded disability status scale (EDSS) in the past 12 Months). The benefits of mitoxantrone. In cases of aggressive multiple sclerosis, mitoxantrone (20 mg IV), administered in Monthly cycles for 6 Months, clearly reduces the frequency of relapses, the appearance of new lesions on MRI and the progression of the disability. Precautions to be taken when using mitoxanthrone. The side effects however justify the fact that this drug is limited to the aggressive forms of MP. Cardiac toxicity limits the duration of the prescription and the maximum dose administered, requiring strict echocardiographical monitoring. Its unpredictable haematological toxicity can be devastating (risk of subsequent leukaemia). The benefit-risk ratio must be discussed with the patient and a Yearly echochardiography and three Monthly blood count must be continued during the 5 Years following withdrawal of mitoxantrone. The prescription of mitoxantrone is limited to the neurologists of departments specialized in neurology.

Etheridge, L. J., D. W. Beverley, et al. (2004). "The use of interferon beta in relapsing-remitting multiple sclerosis." Arch Dis Child 89(8): 789-91.

            The use of interferon beta-1a to treat multiple sclerosis in a child of 7 years of age is discussed. To date, there is only one other published report of the use of interferon beta in a child as young as this. One year after commencing treatment she had shown significant clinical improvement, with a marked reduction in number of relapses. In her second year of treatment she suffered a major relapse from which she slowly recovered.

Feinstein, A. (2004). "The neuropsychiatry of multiple sclerosis." Can J Psychiatry 49(3): 157-63.

            This review describes the many neuropsychiatric abnormalities associated with multiple sclerosis (MS). These may be broadly divided into 2 categories: disorders of mood, affect, and behaviour and abnormalities affecting cognition. With respect to the former, the epidemiology, phenomenology, and theories of etiology are described for the syndromes of depression, bipolar disorder, euphoria, pathological laughing and crying, and psychosis attributable to MS. The section discussing cognition reviews the prevalence and nature of cognitive dysfunction, with an emphasis on abnormalities affecting multiple domains of memory, speed of information processing, and executive function. The detection, natural history, and cerebral correlates of cognitive dysfunction are also discussed. Finally, treatment pertaining to all these disorders is reviewed, with the observation that translational research has been found wanting when it comes to providing algorithms to guide clinicians. Guidelines derived from general psychiatry still largely apply, although they may not always be most effective in patients with neurologic disorders. The importance of future research addressing this imbalance is emphasized, for neuropsychiatric sequelae add significantly to the morbidity associated with MS.

Flachenecker, P. and P. Rieckmann (2004). "Health outcomes in multiple sclerosis." Curr Opin Neurol 17(3): 257-61.

            PURPOSE OF REVIEW: Economic considerations are increasingly important in the evaluation of innovative medical technologies. In the past few years, evaluations of cost and cost-effectiveness analysis became a popular topic for multiple sclerosis research. Here, we review cost-of-illness and cost-utility studies in multiple sclerosis published during the past 2 years. RECENT FINDINGS: Despite differences in methodology, several cost-of-illness studies unequivocally demonstrated that indirect costs as a result of sick leave, premature retirement or loss of income made up almost half of the overall costs, and that total costs were higher in the more advanced stages of the disease. Cost-effectiveness studies of recombinant IFN-beta preparations demonstrated a marked variability in the incremental cost per quality-adjusted life-year, with amounts ranging from Euro 28 432 to US$338 738. For glatiramer acetate and mitoxantrone, only limited data are available, but even these few studies differed in their results. SUMMARY: Health outcome studies constitute a new and emerging field of multiple sclerosis research. All studies performed so far underscore the importance of indirect cost in multiple sclerosis. However, the marked differences in cost-effectiveness studies illustrate that the method of economic modeling has considerable impact on the results of these studies, which need standardization in order to evaluate properly the economic consequences of new and expensive therapies in multiple sclerosis.

Fox, R. J. and R. A. Rudick (2004). "Multiple sclerosis: disease markers accelerate progress." Lancet Neurol 3(1): 10.

Freedman, M. S., D. G. Patry, et al. (2004). "Treatment optimization in multiple sclerosis." Can J Neurol Sci 31(2): 157-68.

            The treatment of multiple sclerosis has finally become possible with the advent of the current disease-modifying therapies (DMTs) that have had a significant impact on those living with this disease. Though demonstrating clear efficacy on a number of short-term outcome measures, unfortunately, these agents are not "cures" and many patients with multiple sclerosis continue to experience disease activity in spite of treatment. Clinicians are becoming more comfortable initiating therapy with DMTs, but it is now important to focus attention on monitoring the results of the chosen therapy and deciding whether or not a patient is responding well to treatment. At present, however, clinicians lack criteria for defining optimal versus suboptimal responses to DMTs as well as evidence-based guidelines on how to improve treatment outcomes. Using a recently published model as a framework, The Canadian Multiple Sclerosis Working Group developed practical recommendations on how neurologists can assess the status of patients on DMTs and decide when it may be necessary to modify treatment in order to optimize outcomes. The Canadian Multiple Sclerosis Working Group's recommendations are based on monitoring relapses, neurological progression and MRI activity. Other possible causes of suboptimal treatment responses or treatment failure are also considered.

Ghoreschi, K. and M. Rocken (2004). "Immune deviation strategies in the therapy of psoriasis." Curr Drug Targets Inflamm Allergy 3(2): 193-8.

            The experience with biologicals in currently available animal models suggest that inflammatory autoimmune disease depend on IFN-gamma-producing T helper (Th) cells. Deletion of T cells improves most of these autoimmune diseases but bears the risks of general immunosuppression. Alternatively, selective deviation of the inflammatory, disease-inducing Th cells into an anti-inflammatory Th cell phenotype may be a promising strategy to treat inflammatory autoimmune diseases, such as psoriasis, rheumatoid arthritis, multiple sclerosis or autoimmune diabetes. The common feature of these organ-specific autoimmune diseases is the close association with IFN-gamma-producing Th1 cells, which recognize organ-specific antigens and orchestrate the cells and mediators that ultimately cause the tissue damage. Even though the autoantigens recognized in psoriasis remain enigmatic, it has been the first Th1-mediated autoimmune disease successfully treated in humans by immune deviation. The basis of such an immune intervention therapy has been established in experimental mice with model diseases of multiple sclerosis, rheumatoid arthritis or autoimmune diabetes. In all these autoimmune diseases clinical improvement was associated with the skewing of IFN-gamma producing autoantigen-specific Th1 cells into an IL-4 dominated Th2 phenotype. Such Th2 cells are still reactive to the autoantigen but provide a different cytokine pattern. The most powerful cytokines capable of inducing anti-inflammatory Th2 cells are IL-4 itself or IL-11. Interestingly, another agent that has been used for decades in the therapy of psoriasis in some European countries, fumaric acid esters (FAE), seems also to induce immune deviation. This review focuses on the potential immune deviating strategies based on the use of IL-4, IL-11 or FAE in the therapy of psoriasis, the effects of these agents on the immune system, potential risks and future perspectives for therapeutic intervention by immune deviation replacing immunosuppression.

Giesser, B. (2004). "Reproductive issues in persons with multiple sclerosis." Del Med J 76(3): 125-8.

Gilgun-Sherki, Y., E. Melamed, et al. (2004). "The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy." J Neurol 251(3): 261-8.

            Accumulating data indicate that oxidative stress (OS) plays a major role in the pathogenesis of multiple sclerosis (MS). Reactive oxygen species (ROS), leading to OS, generated in excess primarily by macrophages, have been implicated as mediators of demyelination and axonal damage in both MS and experimental autoimmune encephalomyelitis (EAE), its animal model. ROS cause damage to cardinal cellular components such as lipids, proteins and nucleic acids (e. g., RNA, DNA), resulting in cell death by necrosis or apoptosis. In addition, weakened cellular antioxidant defense systems in the central nervous system (CNS) in MS, and its vulnerability to ROS effects may increase damage. Thus, treatment with antioxidants might theoretically prevent propagation of tissue damage and improve both survival and neurological outcome. Indeed, several experimental studies have been performed to see whether dietary intake of several antioxidants prevents or reduces the progression of EAE. Although a few antioxidants showed some efficacy in these studies, little information is available on the effect of treatments with such compounds in patients with MS. Well-designed clinical studies using antioxidant intake, as well as investigations based on larger cohorts studied over a longer periods of time, are needed in order to assess whether antioxidant intake together with other conventional treatments, might be beneficial in treating MS.

Gladue, R. P., S. H. Zwillich, et al. (2004). "CCR1 antagonists for the treatment of autoimmune diseases." Curr Opin Investig Drugs 5(5): 499-504.

            Chemokines are 8- to 10-kDa proteins that regulate leukocyte infiltration into inflammatory sites. The therapeutic potential of inhibiting these proteins is supported by their increased expression in human diseases, numerous studies in animal models of disease and, in some cases, by human genetic association studies. These findings, combined with the ability of chemokines to interact with 7-transmembrane G protein-coupled receptors, render them attractive drug discovery targets. This article reviews the evidence that supports a role for the chemokine receptor CCR1 in the pathogenesis of autoimmune diseases, progress made in identifying low molecular-weight antagonists and the current status of agents undergoing clinical evaluation.

Gonsette, R. E. (2004). "A comparison of the benefits of mitoxantrone and other recent therapeutic approaches in multiple sclerosis." Expert Opin Pharmacother 5(4): 747-65.

            The approval by the FDA of four immunomodulators (three IFNs and glatiramer acetate) and one immunosuppressant (mitoxantrone; Novantrone) for the treatment of multiple sclerosis is definitely the most important progress in this field since the first description of the disease > 150 years ago. However, both types of immunotherapies raise specific problems. Immunomodulators benefit patients in the relapsing-remitting phase, or patients in the secondary-progressive phase showing clinical and/or radiological signs of active inflammatory processes. Their benefit is modest, but seems to persist with long-term administration, as their tolerance is acceptable. Mitoxantrone is a rescue therapy reserved to patients with an aggressive, rapidly progressive form of the disease. This immunosuppressant is effective on inflammatory processes and pathomechanisms responsible for disability progression. Unfortunately, its cardiotoxicity and potential leukaemogenicity prevent an administration beyond 2 or 3 years. Thus, there is a need to improve on the efficacy of immunomodulators and to reduce the toxicity of immunosuppressants. Combination therapies with immunomodulators and antioxidants or with neuroprotective drugs against excitotoxicity or Na + /Ca 2+ channellopathy are currently being investigated. With regard to immunosuppressants, the development of monoclonal antibodies with fully human protein sequences and the synthesis of a new molecule as effective as mitoxantrone but with a much lower toxicity (pixantrone) seem promising to halt or even to prevent disability progression.

Goodin, D. (2004). "Marijuana and multiple sclerosis." Lancet Neurol 3(2): 79-80.

Gray, O., G. V. McDonnell, et al. (2004). "Methotrexate for multiple sclerosis." Cochrane Database Syst Rev(2): CD003208.

            BACKGROUND: Methotrexate is a potent immunosuppressant which in theory could reduce relapse rates and delay disease progression in multiple sclerosis (MS). Subsequently, clinical trials of methotrexate have been conducted in people with MS. OBJECTIVES: To identify and summarise the evidence that methotrexate is beneficial and safe for people with MS. SEARCH STRATEGY: We searched the Cochrane MS Group trials register (searched December 2003), the Cochrane Central Register of Controlled Trails (The Cochrane Library Issue 4, 2003), MEDLINE (Pub Med) (January 1966 to June 2001), EMBASE (January 1988 to June 2001), and reference lists of articles. We also contacted trialists and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials of methotrexate for the prevention of relapses and disease progression in MS. DATA COLLECTION AND ANALYSIS: Two reviewers (OG, GM, ) independently selected articles for inclusion, assessed the trials' quality and extracted the data. Authors of one trial were contacted to obtaining missing information. MAIN RESULTS: One trial involving 60 participants with chronic progressive multiple sclerosis was included. The trial showed a non-significant reduction in sustained EDSS progression and number of relapses in favour of methotrexate therapy. There was no difference in time to first relapse and no data on relapse rate. Minor side-effects were reported frequently in both methotrexate (87.1%) and placebo groups (89.7%), but there were no major side-effects. REVIEWERS' CONCLUSIONS: In progressive MS, the single included trial reveals a non-significant trend in reduction of sustained EDSS progression and number of relapses in favour of methotrexate. A trial of methotrexate in relapsing remitting MS showed non-significant trends in favour of methotrexate but was excluded on methodological grounds. Before drawing further conclusions regarding the efficacy of methotrexate in MS, further trials are required.

Griffith, R. and M. Stevens (2004). "Legal requirements for safe handling in community care." Br J Community Nurs 9(5): 211-5.

            CASE STUDY: Andrea, a district nurse, together with home carers from the local social services department, has been caring for a wheelchair-bound patient with multiple sclerosis for 3 years. The patient requires assistance with going to the toilet and going to bed. She has always been reluctant to be moved using a hoist because of sudden spasms and this causes her great anxiety. Now the patient is refusing to be move mechanically and will only consent to being lifted manually. Andrea and the home care staff are concerned that this might place them at risk of injury and argue that it is against the trust and local authority moving and handling policy, which has a no-lift clause. Andrea would like to refuse to manually lift the patient but decides to check the legal position first.

Grigoriadis, N., T. Ben-Hur, et al. (2004). "Axonal damage in multiple sclerosis: a complex issue in a complex disease." Clin Neurol Neurosurg 106(3): 211-7.

            Multiple sclerosis is no longer considered to simply be an autoimmune demyelinating disease. Axonal destruction is another central pathological feature and a contributor to the accumulating disability of disease progression. The mechanism underlying axonal pathology has not been fully clarified but does not appear to be a simple one. The relationship between axonal damage and other components of the pathological features such as demyelination, inflammation and remyelination are under intense investigation. Experimental data suggest that therapeutic interventions such as the induction of rapid remyelination may lead to the protection of axons. In addition to immunomodulation, future strategies for neuroprotection may be of great importance.

Grimaud, J. and J. P. Auray (2004). "[Quality of life and economic cost of multiple sclerosis]." Rev Neurol (Paris) 160(1): 23-34.

            In multiple sclerosis, evaluation of quality of life is important because the patients are usually confronted with a decrease in physical, cognitive and social functioning. Apart from the personal suffering, the financial consequences for these patients and their family and the economic burden for society are enormous. Measurement of health related quality of life is important for the understanding of disease burden and the impact of specific MS treatments. Rising costs associated with new treatments and spending limits have prompted a search for gratter efficiency. Although health economics research can suggest ways to maximize health benefits within fixed budgets it is currently underused in MS. The purpose of this review of the literature is to explain some of the basic principles underlying both quality of life and economic evaluations, and analyse their contribution to understanding and managing patients with MS. Neurologists should not underestimate how dramatic their contributions can be to this maturing field that will influence the future of MS patients care.

Hafler, D. A. (2004). "Multiple sclerosis." J Clin Invest 113(6): 788-94.

            Multiple sclerosis is a complex genetic disease associated with inflammation in the CNS white matter thought to be mediated by autoreactive T cells. Clonal expansion of B cells, their antibody products, and T cells, hallmarks of inflammation in the CNS, are found in MS. This review discusses new methods to define the molecular pathology of human disease with high-throughput examination of germline DNA haplotypes, RNA expression, and protein structures that will allow the generation of a new series of hypotheses that can be tested to develop better understanding of and therapies for this disease.

Hahnel, S., G. Jost, et al. (2004). "[Current use and possible future applications of the magnetization transfer technique in neuroradiology]." Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 176(2): 175-82.

            Magnetization transfer (MT) imaging is a special MR technique used for selective suppression of the MR signal of protons bound on macromolecules. The most important applications in neuroradiology are (1) detection of subtle changes in otherwise normal-appearing cerebral white matter, for instance in multiple sclerosis (MS), Wallerian degeneration, and hydrocephalus, (2) differentiation of white matter lesions with high signal on T (2)-weighted MR-images, like MS plaques, brain infarctions, and brain edema, (3) follow-up of cerebral white matter diseases using volumetric MT techniques, and (4) improvement in delineating of contrast enhancing brain lesions, such as cerebral metastases. We describe the physical rationale of the MT technique and present the most important current and possible future applications of MT imaging to answer clinical and scientific questions in neuroradiology.

Halasz, P., J. Vajda, et al. (2004). "[Surgical treatment of epilepsy]." Ideggyogy Sz 57(5-6): 189-205.

            In this article the possibilities, indications, methods and results of surgery in epilepsy are summarized in general with the Hungarian experience emphasized. Surgery may provide effective treatment in about 5-10% of the epileptic population. Surgical solution nowadays became an essential treatment in medial temporal epilepsy, if hippocampal sclerosis or other lesion is present, in therapy resistant lesional extratemporal epilepsies and in catastrophic childhood epilepsies if the epileptic disorder is restricted to one hemisphere (Rasmussen syndrome, hemimegalencephaly, Sturge-Weber disease and posttraumatic or postencephalitic hemispherial epilepsies). The algorithms of the presurgical evaluation and the current methods for study the pacemaker area, forbidden zones, and hemispherial functions are treated. The currently used type and techniques of surgery, such as lesionectomy, temporal lobe resections, hemispherotomy, callosotomy, multiple subpial transsections and their indications are described. The newest surgical approaches, as deep brain stimulation, vagal nerve stimulation, and irradiation techniques are also briefly touched. Lastly, we deal with prognostical factors of the surgical outcome, reasons of surgical failures and complications. In a brief chapter the importance of postsurgical rehabilitation is emphasized.

Hawker, K. and E. Frohman (2004). "Multiple sclerosis." Prim Care 31(1): 201-26.

Hertz, L., Y. Chen, et al. (2004). "Astrocytic adrenoceptors: a major drug target in neurological and psychiatric disorders?" Curr Drug Targets CNS Neurol Disord 3(3): 239-67.

            Considerable attention has recently been paid to astrocyte functions, which are briefly summarized. A large amount of data is available about adrenoceptor expression and function in astrocytes, some of it dating back to the 1970's and some of it very recent. This material is reviewed in the present paper. The brain is innervated by noradrenergic fibers extending from locus coeruleus in the brain stem, which in turn is connected to a network of adrenergic and noradrenergic nuclei in the medulla and pons, contributing to the control of (nor)adrenergic, serotonergic, dopaminergic and cholinergic function, both in the central nervous system (CNS) and in the periphery. In the CNS astrocytes constitute a major target for noradrenergic innervation, which regulates morphological plasticity, energy metabolism, membrane transport, gap junction permeability and immunological responses in these cells. Noradrenergic effects on astrocytes are essential during consolidation of episodic, long-term memory, which is reinforced by beta-adrenergic activation. Glycogenolysis and synthesis of glutamate and glutamine from glucose, both of which are metabolic processes restricted to astrocytes, occur at several time-specific stages during the consolidation. Astrocytic abnormalities are almost certainly important in the pathogenesis of multiple sclerosis and in all probability contribute essentially to inflammation and malfunction in Alzheimer's disease and to mood disturbances in affective disorders. Noradrenergic function in astrocytes is severely disturbed by chronic exposure to cocaine, which also changes astrocyte morphology. Development of drugs modifying noradrenergic receptor activity and/or down-stream signaling is advocated for treatment of several neurological/psychiatric disorders and for neuroprotection. Astrocytic preparations are suggested for study of mechanism(s) of action of antidepressant drugs and pathophysiology of mood disorders.

Hobart, J. C., A. Riazi, et al. (2004). "Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome." Health Technol Assess 8(9): iii, 1-48.

            OBJECTIVES: To develop a patient-based, disease-specific measure of the health impact of multiple sclerosis (MS) for use in clinical trials and clinical practice. DATA SOURCES: People with MS. Members of the MS Society of Great Britain and Northern Ireland. METHODS: Standard psychometric methods were used to develop the Multiple Sclerosis Impact Scale (MSIS-29) in three stages. Stage 1 (item generation): questionnaire items were generated from 30 patient interviews on the impact of MS on their lives, expert opinion and literature review. Stage 2 (item reduction and scale generation): the questionnaire developed in stage 1 was administered by postal survey to 1530 randomly selected members of the MS Society. Standard item reduction techniques were used to develop a rating scale from the pool of questionnaire items. Stage 3 (psychometric evaluation): the questionnaire was evaluated for data quality, scaling assumptions, acceptability, reliability and validity in a separate postal survey of 1250 MS Society members. Responsiveness was evaluated in 55 people admitted to hospital for rehabilitation and intravenous steroid treatment of MS relapses. RESULTS: Stage 1 resulted in a 129-item questionnaire. Stage 2 resulted in a 29-item rating scale measuring the physical and psychological impact of MS. The MSIS-29 satisfied all recommended psychometric criteria for rigorous measurement. Data quality was excellent: missing data were low, item test-retest reliability was high and scale scores could be generated for over 98% of respondents. Item descriptive statistics, item convergent and discriminant validity, and factor analysis supported summing items to produce two summary scores. MSIS-29 physical and psychological scale scores showed good variability, low floor and ceiling effects, good internal consistency and test-retest reliability. Correlations with other measures and confirmation of hypotheses about group differences provided evidence for the validity of the MSIS-29 as a measure of the physical and psychological impact of multiple sclerosis. Effect sizes provided preliminary evidence for responsiveness. CONCLUSIONS: The 29-item MSIS-29 is a rigorous new measure of the physical and psychological impact of MS. All psychometric criteria were satisfied and there is preliminary evidence of responsiveness. The MSIS-29 is particularly appropriate for use in clinical trials to evaluate therapeutic effectiveness from the patient's perspective. Further critical evaluations of the MSIS-29 completed by people with neurologist-confirmed MS in different settings are suggested. Head-to-head comparisons of the psychometric properties of the MSIS-29 and other outcome measures for MS will help to determine the relative advantages of different instruments so that the choice of measures for studies can be evidence based.

Horstman, L. L., W. Jy, et al. (2004). "Endothelial microparticles as markers of endothelial dysfunction." Front Biosci 9: 1118-35.

            Endothelial microparticles (EMP) are small vesicles released from disturbed endothelial cells (EC). Owing to the central importance of EC injury in thrombotic and inflammatory conditions, assay of EMP as a marker of EC disturbance has come under intensive development by several laboratories. The review begins with established markers of EC injury, commonly soluble markers such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, von Willebrand factor (vWF), etc., pointing out that many of these are in fact mixtures of true soluble molecules with membrane-bound forms, for example, EMP. Assays of EMP from different labs are reviewed and standardization of assay is recommended. EMP are heterogeneous: those released in activation vs. apoptosis are distinctive in phenotypic markers and procoagulant properties. Application of EMP phenotype analysis can distinguish EC state of activation from apoptosis. Some EMP carry functional vWF with properties different from soluble vWF. Certain EMP bind to and activate monocytes; EMP-monocyte conjugates were found to be a marker of inflammatory disease such as multiple sclerosis (MS), and to enhance transendothelial migration of leukocytes in vitro. Clinical studies have revealed elevated plasma levels of EMP in lupus anticoagulant (LA), multiple sclerosis (MS), thrombotic thrombocytopenic purpura (TTP), coronary artery disease (CAD), hypertension, preeclampsia, and diabetes. Further refinement of EMP assay could open new windows for evaluating and monitoring endothelial injury in thrombotic and inflammatory disorders.

Hu, J. G., P. H. Lu, et al. (2004). "[Update on oligodendrocyte in biological function and associated neurological disorders]." Sheng Li Ke Xue Jin Zhan 35(1): 39-41.

Karin, N. (2004). "Induction of protective therapy for autoimmune diseases by targeted DNA vaccines encoding pro-inflammatory cytokines and chemokines." Curr Opin Mol Ther 6(1): 27-33.

            T-cell-mediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or type 1 diabetes result from an aggressive attack of self-components by autoimmune T-cells. Pro-inflammatory mediators, particularly cytokines and chemokines, direct the homing and effectorfunction of these cells. It has recently been demonstrated that the immune system, which can attack self-components, also generates 'beneficial' autoimmunity against pro-inflammatory mediators. During the course of an autoimmune condition, and to a much lesser extent in response to microbial inflammation, the immune system produces auto-antibodies to pro-inflammatory mediators. This reduces the harm from these diseases. We also discovered that targeted DNA vaccines could effectively amplify these responses to provide protective immunity. The underlying mechanism is partially understood. At the site of immunization, the relevant gene product is produced and then presented by dendritic cells/macrophages, which undergo activation due to an interaction of plasmid CpG with toll-like receptor 9 on the dendritic cell. This then activates CD4+ T-cells, which help the production of T-cell-dependent antibodies against the gene product of the vaccines. These antibodies neutralize their target product and suppress inflammation. This review explores this interesting concept and its therapeutic implications.

Kielian, T. and N. Esen (2004). "Effects of neuroinflammation on glia-glia gap junctional intercellular communication: a perspective." Neurochem Int 45(2-3): 429-36.

            Gap junctions serve as intercellular conduits that allow for the direct transfer of small molecular weight molecules (up to 1 kDa) including ions involved in cellular excitability, metabolic precursors, and second messengers. The observation of extensive intercellular coupling and large numbers of gap junctions in the central nervous system (CNS) suggests a syncytium-like organization of glial compartments. Inflammation is a hallmark of various CNS diseases such as bacterial and viral infections, multiple sclerosis, Alzheimer's disease, and cerebral ischemia. A general consequence of brain inflammation is reactive gliosis typified by astrocyte hypertrophy and proliferation of astrocytes and microglia. Changes in gap junction intercellular communication as reflected by alterations in dye coupling and connexin expression have been associated with numerous CNS inflammatory diseases, which may have dramatic implications on the survival of neuronal and glial populations in the context of neuroinflammation. A review of the effects of inflammatory products on glia-glia gap junctional communication and glial glutamate release is presented. In addition, the hypothesis of a "syncytial switch" based upon differential regulation of gap junction expression in astrocytes and microglia during normal CNS homeostasis and neuroinflammation is proposed.

Killestein, J., B. M. Uitdehaag, et al. (2004). "Cannabinoids in multiple sclerosis: do they have a therapeutic role?" Drugs 64(1): 1-11.

            This is an exciting time for cannabinoid research. Evidence suggests that cannabis (marijuana) can alleviate symptoms like muscle spasticity and pain in patients with multiple sclerosis (MS). Interest in the field of cannabinoids has been strengthened by the identification and cloning of cannabinoid receptors located in the central nervous system and the peripheral immune organs, and by the discovery of the endogenous cannabinoid ligands. Cannabinoids are also efficacious in animal models of MS. However, there have been only ten published clinical reports on the use of cannabis in MS, involving 78 individuals worldwide, and the results have been equivocal. Researchers encounter a number of difficulties in designing clinical studies that use cannabinoids. From the studies reporting the use of cannabinoids in MS patients with spasticity, the somewhat better designed studies failed to demonstrate objective improvement. Therefore, convincing evidence that cannabinoids are effective in MS is still lacking.

Kirk, S., J. A. Frank, et al. (2004). "Angiogenesis in multiple sclerosis: is it good, bad or an epiphenomenon?" J Neurol Sci 217(2): 125-30.

            Characteristic pathological features of multiple sclerosis (MS) include inflammation, demyelination and axonal and oligodendrocyte loss. In addition, lesions can also have a significant vascular component. In this review, morphological, biochemical and radiological evidence is presented suggesting angiogenesis as a potential focus for investigation in MS. We hypothesize that angiogenesis plays a significant role in the MS lesion, perpetuating disease progression. Thus, treatment strategies that inhibit angiogenesis may decrease clinical and pathological signs of disease. Several approaches for testing this hypothesis are outlined.

Klivenyi, P., J. Toldi, et al. (2004). "Kynurenines in neurodegenerative disorders: therapeutic consideration." Adv Exp Med Biol 541: 169-83.

Knechtle, S. J. (2004). "Present experience with Campath-1H in organ transplantation and its potential use in pediatric recipients." Pediatr Transplant 8(2): 106-12.

            Campath-1H is a humanized monoclonal antibody directed at CD52 expressed on lymphocytes and other cells of the immune system. It has been tested extensively in lymphoid malignancies, autoimmune diseases including rheumatoid arthritis, multiple sclerosis, and organ transplantation. Although its use in children has been limited to date, so far it appears to be well tolerated in children. Currently, studies are being implemented to further assess its safety and efficacy in pediatric organ transplantation. Immune cell depletion using Campath-1H appears to be particularly useful in organ transplantation in that lower doses of maintenance immunosuppressive drugs are needed. This feature is particularly attractive in children.

Lasky, J. (2004). "Pirfenidone." IDrugs 7(2): 166-72.

            Pirfenidone, an antifibrotic tissue growth antagonist, is in development for the potential treatment of fibrotic diseases including renal, liver and pulmonary fibrosis and for multiple sclerosis.

Lassmann, H. and R. M. Ransohoff (2004). "The CD4-Th1 model for multiple sclerosis: a crucial re-appraisal." Trends Immunol 25(3): 132-7.

Levine, S. M. and A. Chakrabarty (2004). "The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis." Ann N Y Acad Sci 1012: 252-66.

            Multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), are autoimmune disorders resulting in demyelination in the central nervous system (CNS). Pathologically, the blood-brain barrier becomes damaged, macrophages and T cells enter into the CNS, oligodendrocytes and myelin are destroyed, astrocytes and microglia undergo gliosis, and axons become transected. Data from several biochemical and pharmacological studies indicate that free radicals participate in the pathogenesis of EAE, and iron has been implicated as the catalyst leading to their formation. The primary focus of this article is the examination of the role of iron in the pathogenesis of MS and EAE. Particular attention will be paid to the role and distribution of iron and proteins involved with iron metabolism (e.g., transferrin, ferritin, heme oxygenase-1, etc.) in normal and disease states of myelin. Furthermore, therapeutic interventions aimed at iron, iron-binding proteins, and substrates or products of iron-catalyzed reactions leading to free radical production will be discussed.

Lie, R. K. (2004). "Research ethics and evidence based medicine." J Med Ethics 30(2): 122-5.

            In this paper, the author argues that the requirement to conduct randomised clinical trials to inform policy in cases where one wants to identify a cheaper alternative to known effective but expensive interventions raises an important ethical issue. This situation will eventually arise whenever there are resource constraints, and a policy decision has been made not to fund an intervention on cost effectiveness grounds. It has been thought that this is an issue only in extremely resource poor settings. This paper gives an example from the United Kingdom illustrating that this is also a problem faced by richer countries.

Lin, X., C. R. Tench, et al. (2004). "Measurement of spinal cord atrophy in multiple sclerosis." J Neuroimaging 14(3 Suppl): 20S-26S.

            In multiple sclerosis (MS), the spinal cord is a common area of involvement, and its dysfunction is likely to be responsible for much of motor disability. It has been reported that atrophy in the cervical spinal cord occurs early and is detectable in patients presenting with a clinically isolated syndrome. This finding has important implications for the early treatment of patients with MS because atrophy is thought to reflect destructive, irreversible pathology and subclinical impairment. Recent clinical trials of disease-modifying agents have included spinal cord imaging and, in particular, the measurement of atrophy as a secondary or exploratory measure of treatment efficacy. This review summarizes the underlying pathology responsible for spinal cord atrophy and the methods available to measure it. The relationships between spinal cord atrophy, other magnetic resonance imaging parameters, and clinical disability are also discussed.

Lopez Pison, J., O. Garcia Bodega, et al. (2004). "[Episodic disseminated inflammation of the central nervous system. Case mix review over a 13 year period]." Rev Neurol 38(5): 405-10.

            INTRODUCTION: Episodic disseminated inflammation of the central nervous system (CNS) presents in processes that are difficult to differentiate, such as acute disseminated encephalomyelitis (ADE) and its multiphasic variants, and multiple sclerosis (MS). Magnetic resonance imaging allows these problems to be identified more frequently than in the past. PATIENTS AND METHODS: We carried out a retrospective study of the cases of episodic disseminated inflammation of the CNS, according to clinical features and compatible neuroimaging, at the Neuropaediatric Unit of the Hospital Infantil Miguel Servet, between May 1990 and August 2003. RESULTS: Of the 6777 children evaluated over this period, 10 met the eligibility criteria, with a minimum age at onset of 2 years and 2 months. In four cases there was a history of an infectious process or vaccination. Clinical involvement was multisymptomatic, the most frequent being ataxia, dysmetry, tremor, drowsiness, paresis and cranial nerve involvement. Six of them had cerebrospinal fluid disorders and only two presented disorders in the fundus oculi. Five of them were given corticoid treatment. Progress was favourable, except in two cases: one due to the persistence of a corticoid dependent optical neuropathy and the other because of dyskinesia in the right hand. DISCUSSION: Diagnosis of ADE is established by signs of multifocal clinical involvement and neuroimaging, and depends on a compatible progression. Prognosis is generally good and corticoids seem to be effective, at least in shortening the time the clinical features last. It is not possible to completely differentiate it from MS, especially in recurring forms. Clinical and magnetic resonance controls must be carried out.

Lutton, J. D., R. Winston, et al. (2004). "Multiple sclerosis: etiological mechanisms and future directions." Exp Biol Med (Maywood) 229(1): 12-20.

            Multiple sclerosis (MS) is a complex human autoimmune-type disease with a predominantly unknown etiology. Immunologic destruction of myelin basic protein (MBP) throughout the nervous system is the major pathology of multiple sclerosis. This review will attempt to update new information about basic mechanisms and therapeutic management of the disease. The significance of the structure of MBP is discussed with respect to the contribution of such structures to the disease process. A number of MBP peptides that serve as the immunodominant antigens in MS patients have been identified. These peptides have been studied in animal models for their antigenic characteristics and ability to induce disease. Evidence for genetic contributions is reviewed with multigenerational twin studies providing the best evidence for susceptible haplotypes. The role of microorganisms/viruses and environmental agents are discussed as potential etiological factors but are now thought to be of minor importance to the primary causal development of the disease. Of major consideration are immunological mechanisms that contribute to the development of autoimmunity. In particular, antigen expression, cytokine and leukocyte interactions, and regulatory T-cells are discussed. Particular attention is given to regulatory T-cells (Treg), which help balance/modulate other T-cells such as Th1 and Th2 cells, and how such Treg regulate autoimmunity is addressed. The importance of the role of Tregs is exemplified by the demonstration that administration of oral antigens can induce specific Tregs that counteract experimental autoimmune encephalomyelitis in animal models. The significance of animal studies to human mul