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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 multiple sclerosis is discussed. A potential role for natural antibodies and innate immune mechanisms to help provide resistance to disease development is also reviewed. Finally, a variety of therapeutic agents that have been and continue to be utilized for multiple sclerosis is reviewed. Trials with oral antigens, such as glatirmer acetate (copolymer 1) especially in combination with interferon-beta, have shown promise. Antibody therapy and bone marrow transplantation are also briefly discussed.


MacLean, R. (2004). "The challenge of managing patients with multiple sclerosis." Nurs Times 100(4): 42-4.

            Multiple sclerosis (MS) is the most common cause of neurological disability in young adults in the UK. It is variable in presentation and progression. Although there is no cure, there are many symptomatic treatments available. Nurses have a vital role in the ongoing assessment and management of people with MS.


Markovic-Plese, S., C. Pinilla, et al. (2004). "The initiation of the autoimmune response in multiple sclerosis." Clin Neurol Neurosurg 106(3): 218-22.

            Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Most evidence supports the autoimmune pathogenesis of the disease. According to this hypothesis, the activation of autoreactive T-cells is a central event in the development of autoimmune response in MS. We examined molecular events involved in the initiation of autoimmune response in MS. Recent studies in our laboratory have reported an unexpectedly high degree of T-cell receptor (TCR) degeneracy and molecular mimicry as a frequent phenomenon that might play a role in the initiation of autoimmune response in MS. This paper provides insights into the physiologic and pathologic role of autoreactive T-cells, and characterizes structurally and functionally the specific targets for new therapies of MS.


Martino, G. (2004). "How the brain repairs itself: new therapeutic strategies in inflammatory and degenerative CNS disorders." Lancet Neurol 3(6): 372-8.

            In the early 20th century, seminal work by Tello and Cajal showed that the CNS has the ability to regenerate itself after injury. In the most recent years, this pivotal observation has been rejuvenated by detailed in vitro and in vivo evidence supporting the idea of an innate self-maintenance programme to sustain brain homoeostasis and repair. These observations support the idea that chronic inflammatory and degenerative disorders of the brain might result from defective repair mechanisms rather than uncontrollable pathogenetic events. Investigation of the molecular and cellular events sustaining intrinsic brain-repair mechanisms and a better understanding of why they fail over time in chronic disorders might, therefore, provide an attractive conceptual framework within which to develop new and efficacious therapies for neurological diseases.


Masterman, T. and J. Hillert (2004). "The telltale scan: APOE epsilon4 in multiple sclerosis." Lancet Neurol 3(6): 331.


McCormack, P. L. and L. J. Scott (2004). "Interferon-beta-1b: a review of its use in relapsing-remitting and secondary progressive multiple sclerosis." CNS Drugs 18(8): 521-46.

            Interferon-beta-1b (Betaseron, Betaferon) is a non-glycosylated recombinant human interferon-beta approved for high-frequency, subcutaneous (SC) administration in the treatment of multiple sclerosis (MS). Its mechanism of action is unknown, but may involve modulation of the autoimmune pathogenic processes of MS. In a randomised, double-blind trial in patients with relapsing-remitting MS (RRMS), SC interferon-beta-1b 250 micro g (8 million International Units [MIU]) every other day reduced the annual relapse rate and increased the proportion of relapse-free patients compared with placebo. It also reduced relapse severity, hospitalisations, and disease activity assessed by magnetic resonance imaging (MRI), and increased the time to first relapse. Progression of disability showed a trend towards reduction relative to placebo and baseline, but did not reach statistical significance. SC interferon-beta-1b 250 micro g every other day was shown in a randomised trial to be superior to intramuscular (IM) interferon-beta-1a 30 micro g (6 MIU) once weekly with respect to reductions in relapse-related parameters, disability progression and MRI-assessed disease activity. In patients with secondary progressive MS (SPMS), SC interferon-beta-1b 250 micro g every other day slowed progression of the disease relative to placebo in one randomised, double-blind trial, but not in another. In both studies, interferon-beta-1b 250 micro g recipients had fewer relapses and less MRI-assessed disease activity than placebo recipients. The difference in primary outcome may reflect differences in patient entry criteria. Interferon-beta-1b is generally well tolerated and the common adverse events (e.g. injection site reactions, asthenia and an influenza-like symptom complex) are clinically manageable. In a randomised trial, the tolerability of SC interferon-beta-1b 250 micro g every other day was generally similar to that of IM interferon-beta-1a 30 micro g once weekly, except for higher incidences of injection site reactions and neutralising anti-interferon-beta antibodies with SC interferon-beta-1b. In conclusion, SC interferon-beta-1b 250 micro g every other day reduces the frequency and severity of relapses and MRI measures of disease activity and may delay the progression of disability in RRMS. The drug appeared to be more effective than, and as well tolerated as, IM interferon-beta-1a 30 micro g once weekly. Interferon-beta-1b also has positive effects on relapse rates and disease activity in patients with SPMS, although its effects on disease progression remain uncertain. The drug is generally well tolerated, and the common adverse events are clinically manageable. Thus, interferon-beta-1b is a valuable first-line therapy for patients with RRMS and a potentially useful option in those with SPMS.


McDonald, I. (2004). "Multiple sclerosis in its European matrix: some aspects of history, mechanisms and treatment." Can J Neurol Sci 31(1): 37-47.

            Susceptibility to multiple sclerosis is influenced by several genes which are relatively common in populations of European origin. Their precise identification is currently being intensively investigated. The pathophysiology of the main clinical features is better understood. Relapse results from abnormalities of conduction to which both demyelination and inflammation contribute. At the membrane level, remission depends on the formation of new sodium channels which restore conduction even in persistently demyelinated axons. Remyelination presumably contributes and synaptic reorganisation may also do so. Axonal degeneration contributes to irrecoverable deficit and progression of disability. These observations suggest new therapeutic strategies. The management of multiple sclerosis needs to be improved. Progress requires an ethically based partnership between patients, whose needs are paramount, the research and caring communities and the pharmaceutical industry.


Meier, D. S., H. L. Weiner, et al. (2004). "Magnetic resonance imaging surrogates of multiple sclerosis pathology and their relationship to central nervous system atrophy." J Neuroimaging 14(3 Suppl): 46S-53S.

            This article focuses on the various magnetic resonance imaging metrics currently used in multiple sclerosis and discusses how they relate to central nervous system atrophy. The authors discuss the significance of T2 lesion burden, gray matter damage, T1 hypointense lesions (black holes), contrast-enhanced lesions, magnetization transfer imaging, diffusion imaging, and magnetic resonance spectroscopy. These magnetic resonance imaging surrogates exhibit different sensitivities for each of the underlying pathogenic processes of multiple sclerosis. By exploiting the complementary nature and varying sensitivities of these magnetic resonance imaging surrogates, it is possible to create a more comprehensive picture of the degenerative process of multiple sclerosis.


Mestas, J. and C. C. Hughes (2004). "Of mice and not men: differences between mouse and human immunology." J Immunol 172(5): 2731-8.

            Mice are the experimental tool of choice for the majority of immunologists and the study of their immune responses has yielded tremendous insight into the workings of the human immune system. However, as 65 million years of evolution might suggest, there are significant differences. Here we outline known discrepancies in both innate and adaptive immunity, including: balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signaling pathway components, Thy-1, gammadelta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. We also provide examples, such as multiple sclerosis and delayed-type hypersensitivity, where complex multicomponent processes differ. Such differences should be taken into account when using mice as preclinical models of human disease.


Miller, A., L. Glass-Marmor, et al. (2004). "Bio-markers of disease activity and response to therapy in multiple sclerosis." Clin Neurol Neurosurg 106(3): 249-54.


Minagar, A., E. G. Toledo, et al. (2004). "Pathogenesis of brain and spinal cord atrophy in multiple sclerosis." J Neuroimaging 14(3 Suppl): 5S-10S.

            For more than a century, multiple sclerosis was viewed as a disease process characterized by oligodendrocyte and myelin loss, and research into the pathogenesis of multiple sclerosis was mainly focused on the mechanisms of inflammation. However, with development of more sophisticated neuroimaging and molecular biology techniques, attention has shifted to new aspects of pathogenesis of multiple sclerosis: axonal loss and neurodegeneration. Evidence is increasing that tissue destruction, primarily axonal loss and neurodegeneration, is a key element in the pathogenesis of multiple sclerosis. In addition, it is now known that brain and spinal cord atrophy begins early in the disease process of multiple sclerosis and advances relentlessly throughout the course of the disease. Cumulative data suggest that axonal loss is the major determinant of progressive neurologic disability in patients with multiple sclerosis. Magnetic resonance imaging and magnetic resonance spectroscopy in patients with multiple sclerosis for < 5 years indicate brain atrophy and loss of axonal integrity. Neurodegeneration and axonal loss in patients with multiple sclerosis are initially accompanied by a local response from oligodendrocyte progenitor cells and some remyelination. However, these repair mechanisms eventually fail, and patients typically develop generalized brain atrophy, cognitive decline, and permanent disability. Although the exact mechanisms underlying central nervous system atrophy in patients with multiple sclerosis are largely unknown, evidence exists that atrophy may represent an epiphenomenon related to the effects of dynamic inflammation within the central nervous system, including demyelination, axonal injury, neuronal loss, Wallerian degeneration, and possibly iron deposition. This article summarizes the potential mechanisms involved in central nervous system atrophy in patients with multiple sclerosis.


Mohr, D. C., S. L. Hart, et al. (2004). "Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis." Bmj 328(7442): 731.

            OBJECTIVE: To quantify the association between stressful life events and exacerbations of multiple sclerosis. DATA SOURCES: PubMed, PsychInfo, and Psychological Abstracts searched for empirical papers from 1965 to February 2003 with terms "stress", "trauma", and "multiple sclerosis". REVIEW METHODS: Three investigators independently reviewed papers for inclusion/exclusion criteria and extracted the relevant data, including methods, sample statistics, and outcomes. RESULTS: Of 20 studies identified, 14 were included. The meta-analysis showed a significant increase in risk of exacerbation in multiple sclerosis after stressful life events, with a weighted average effect size of d = 0.53 (95% confidence interval 0.40 to 0.65), P < 0.0001. The studies were homogenous, Q = 16.62, P = 0.22, I2 = 21.8%. Neither sampling nor study methods had any effect on study outcomes. CONCLUSIONS: There is a consistent association between stressful life events and subsequent exacerbation in multiple sclerosis. However these data do not allow the linking of specific stressors to exacerbations nor should they be used to infer that patients are responsible for their exacerbations. Investigation of the psychological, neuroendocrine, and immune mediators of stressful life events on exacerbation may lead to new behavioural and pharmacological strategies targeting potential links between stress and exacerbation.


Moore, R. J., R. M. Chamberlain, et al. (2004). "Apolipoprotein E and the risk of breast cancer in African-American and non-Hispanic white women. A review." Oncology 66(2): 79-93.

            The apolipoprotein genetic polymorphism (APO E) is part of a broader paradigm, highlighting the role of gene-environment interactions as risk factors for human diseases such as cardiovascular disease, Alzheimer's disease, dementia, atherosclerosis, multiple sclerosis, peripheral artery disease, diabetes, stroke, and most recently, cancer. APO E, a normal constituent of very-low-density lipoproteins and high-density lipoproteins, is involved in many functions, including lipid metabolism, cholesterol transport, tissue repair, immune response and regulation, as well as cell growth and differentiation. The location, frequency and functional effects of this gene have been reviewed elsewhere in terms of cardiovascular disease, Alzheimer's disease, neuromuscular disease, multiple sclerosis, stroke and diabetes. However, while the majority of studies have examined the significance of APO E as a molecular marker for a variety of diseases in multiethnic populations, few evaluate its role as a putative marker of cancer susceptibility. Fewer explore the importance of APO E on the risk of breast cancer, although some report an association. None have been designed to study its relevance as a marker of breast cancer risk in multiethnic populations. The purpose of this review was to evaluate the association between APO E and the risk for breast cancer in non-Hispanic white and African-American women.


Muhle, R., S. V. Trentacoste, et al. (2004). "The genetics of autism." Pediatrics 113(5): e472-86.

            Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Autism corresponds in this article to pervasive developmental disorder (PDD) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases, Tenth Revision. Except for Rett syndrome--attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene--the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause. Review of 2 major textbooks on autism and of papers published between 1961 and 2003 yields convincing evidence for multiple interacting genetic factors as the main causative determinants of autism. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that "idiopathic" autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of approximately 3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is approximately 2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affected. There are 3 main approaches to identifying genetic loci, chromosomal regions likely to contain relevant genes: 1) whole genome screens, searching for linkage of autism to shared genetic markers in populations of multiplex families (families with >1 affected family member; 2) cytogenetic studies that may guide molecular studies by pointing to relevant inherited or de novo chromosomal abnormalities in affected individuals and their families; and 3) evaluation of candidate genes known to affect brain development in these significantly linked regions or, alternatively, linkage of candidate genes selected a priori because of their presumptive contribution to the pathogenesis of autism. Data from whole-genome screens in multiplex families suggest interactions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31-q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a "chromosome 15 phenotype" was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABA(A) receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with autism than in nonautistic populations. In addition, animal models and linkage data from genome screens implicate the oxytocin receptor at 3p25-p26. Most pediatricians will have 1 or more children with this disorder in their practices. They must diagnose ASD expeditiously because early intervention increases its effectiveness. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in high-functioning children with a normal appearance and IQ and moderate social and language impairments. Genetic counseling justifies testing, but until autism genes are identified and their functions are understood, prenatal diagnosis will exist only for the rare cases ascribable to single-gene defects or overt chromosomal abnormalities. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for pediatricians to try to involve families with multiple affected members in formal research projects, as family studies are key to unraveling the causes and pathogenesis of autism. Parents need to understand that they and their affected children are the only available sources for identifying and studying the elusive genes responsible for autism. Future clinically useful insights and potential medications depend on identifying these genes and elucidating the influences of their products on brain development and physiology.


Munari, L., R. Lovati, et al. (2004). "Therapy with glatiramer acetate for multiple sclerosis." Cochrane Database Syst Rev(1): CD004678.

            BACKGROUND: Some clinical data have shown that glatiramer acetate (Copaxone), a synthetic amino acid polymer empirically found to suppress experimental allergic encephalomyelitis (EAE), an animal model of MS, might help improve the outcome of patients with multiple sclerosis (MS). OBJECTIVES: We performed a Cochrane review of all randomised, placebo-controlled trials of glatiramer acetate in MS, whatever the disease course. SEARCH STRATEGY: We searched the Cochrane MS Group trials register (June 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE (PubMed) (January 1966 to June 2003), EMBASE (January 1988 to June 2003) and hand searching of symposia reports (1990-2002) from the neurological Associations and MS Societies in both Europe and America. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing glatiramer acetate and placebo in patients with definite MS, whatever the administration schedule and disease course, were eligible for this review. DATA COLLECTION AND ANALYSIS: Both patients with relapsing-remitting (RR) and chronic progressive (CP) MS were analysed. Study protocols were comparable across trials as to patient entry criteria and outcome definition. No major flaws were found in methodological quality. However, efficacy of blinding should be balanced against well-known side effects, including injection-site reactions in glatiramer acetate-treated patients. MAIN RESULTS: A total of 646 patients contributed to this review, as it is summarised in Table 01. Glatiramer acetate did not show any significant effect on disease progression, measured as a sustained worsening in the Expanded Disability Status Scale (EDSS). On the other hand, a slight decrease in the mean EDSS score, driven by a major study, should be considered in the light of the limited validity of this outcome measure. No benefit was shown in CP MS patients (progression at two years: RR=0.69, 95% CI [0.33 to 1.46]). The frequency of reported adverse events does not support any major toxicity associated with glatiramer acetate administration. The most common systemic adverse event was a transient and self-limiting patterned reaction of flushing, chest tightness, sweating, palpitations, anxiety (relative risk = 3.40 (95% CI [2.22 to 5.21], p <0.00001]). Local injection-site reactions were observed in up to a half of patients treated with glatiramer acetate, thus making a blind assessment of outcomes questionable. REVIEWER'S CONCLUSIONS: Glatiramer acetate did not show any beneficial effect on the main outcome measures in MS, i.e. disease progression, and it does not substantially affect the risk of clinical relapses. Therefore its routine use in clinical practice is not currently supported. More investigations are needed. Further research should also develop more reliable measures of patient disability over time and include quality of life among primary outcomes.


Mycko, M. P., R. Papoian, et al. (2004). "Microarray gene expression profiling of chronic active and inactive lesions in multiple sclerosis." Clin Neurol Neurosurg 106(3): 223-9.

            Multiple sclerosis, a primary autoimmune disease of the central nervous system has been characterized by the presence of the demyelinating lesions (plaques) in the CNS. To further understand the gene transcription status of the two most common lesions, chronic active and chronic inactive, we have performed a cDNA microarray analysis of these two lesion type. Comparative analysis of differential gene expression of chronic active and inactive lesions have confirmed the existence of a significant difference in the transcriptional profiles of these two lesion types in both marginal and central areas. Different sets of genes were highlighted, including genes of inflammatory characteristics, apoptosis related and stress-induced, indicating their potential role in MS pathogenesis.


Nagata, K. (2004). "[Cigarette smoking and neurological disease]." No To Shinkei 56(3): 205-23.


Nelson, R. L. (2004). "Epidemiology of fecal incontinence." Gastroenterology 126(1 Suppl 1): S3-7.

            Nursing home residence is by far the most prominent association with fecal incontinence, with a prevalence approaching 50%. In one major survey, urinary incontinence was the greatest risk factor for developing fecal incontinence, and fecal incontinence was the greatest risk factor for developing urinary incontinence. Immobility, dementia, and the use of physical restraints were also important risk factors. Specific diseases associated with fecal incontinence include diabetes, multiple sclerosis, Parkinson's disease, stroke, and spinal cord injury. The surgical procedures lateral internal sphincterotomy for anal fissure, fistulotomy, and ileal pouch reconstruction can result in fecal incontinence. Children who are born with congenital abnormalities, such as imperforate anus, often experience soiling for many years. Future studies to determine the prevalence and etiology of fecal and urinary incontinence will need to first define these conditions and eliminate referral bias. Epidemiologic investigations of both disorders should be performed jointly because the conditions are so often comorbid.


Neuhaus, O., O. Stuve, et al. (2004). "Are statins a treatment option for multiple sclerosis?" Lancet Neurol 3(6): 369-71.

            BACKGROUND: Treatment options for multiple sclerosis (MS) are limited. The immunomodulatory drugs interferon beta and glatiramer acetate are only partly effective in reducing the relapse rate, slowing disease progression, and diminishing the number and volume of lesions on MRI. Mitoxantrone is an immunosuppressant approved for the treatment of active forms of relapsing-remitting or secondary progressive MS, but is dose-limited owing to its potential cardiotoxicity. Thus, identifying new effective therapeutic options with few side-effects is highly desirable. RECENT DEVELOPMENTS: Evidence has emerged that statins, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, have immunomodulatory effects. Recent reports showed that statins prevent and reverse chronic and relapsing experimental autoimmune encephalomyelitis, an animal model of MS. Furthermore, in vitro experiments with human immune cells have shown an immunomodulatory profile of statins comparable to that of interferon beta. An open label clinical trial of simvastatin for MS revealed a significant decrease in the number and volume of new MRI lesions and a favourable safety profile. WHERE NEXT?: The obvious advantage of statins over existing MS therapies is their oral route of dosing. Statins might be beneficial for MS patients as monotherapy or as an add-on to established disease modifying drugs. As the evidence of the benefit of statins in MS is currently insufficient, large controlled clinical trials are needed. The first of these trials is about to start.


Nishiyama, H. and Y. Kuroiwa (2004). "[Multiple sclerosis and cognitive impairment]." Nippon Rinsho 62 Suppl: 298-301.


Oleszak, E. L., J. R. Chang, et al. (2004). "Theiler's virus infection: a model for multiple sclerosis." Clin Microbiol Rev 17(1): 174-207.

            Both genetic background and environmental factors, very probably viruses, appear to play a role in the etiology of multiple sclerosis (MS). Lessons from viral experimental models suggest that many different viruses may trigger inflammatory demyelinating diseases resembling MS. Theiler's virus, a picornavirus, induces in susceptible strains of mice early acute disease resembling encephalomyelitis followed by late chronic demyelinating disease, which is one of the best, if not the best, animal model for MS. During early acute disease the virus replicates in gray matter of the central nervous system but is eliminated to very low titers 2 weeks postinfection. Late chronic demyelinating disease becomes clinically apparent approximately 2 weeks later and is characterized by extensive demyelinating lesions and mononuclear cell infiltrates, progressive spinal cord atrophy, and axonal loss. Myelin damage is immunologically mediated, but it is not clear whether it is due to molecular mimicry or epitope spreading. Cytokines, nitric oxide/reactive nitrogen species, and costimulatory molecules are involved in the pathogenesis of both diseases. Close similarities between Theiler's virus-induced demyelinating disease in mice and MS in humans, include the following: major histocompatibility complex-dependent susceptibility; substantial similarities in neuropathology, including axonal damage and remyelination; and paucity of T-cell apoptosis in demyelinating disease. Both diseases are immunologically mediated. These common features emphasize the close similarities of Theiler's virus-induced demyelinating disease in mice and MS in humans.


Olson, J. K., J. Ludovic Croxford, et al. (2004). "Innate and adaptive immune requirements for induction of autoimmune demyelinating disease by molecular mimicry." Mol Immunol 40(14-15): 1103-8.

            Molecular mimicry is the main postulated mechanism by which infectious agents induce autoimmune disease. A number of animal models have been utilized to establish a link between molecular mimicry and autoimmunity. However, a model of infectious disease whereby a natural pathogen expressing a known mimic epitope can induce autoimmunity to a known self-antigen leading to clinical autoimmune disease is still lacking. We have engineered a recombinant Theiler's murine encephalomyelitis virus (TMEV) to express an encephalitogenic myelin proteolipid protein PLP139-151 epitope (PLP-TMEV) and a PLP139-151 mimic peptide naturally expressed by Haemophilus influenzae (HI-TMEV). Infection of mice with either PLP-TMEV or HI-TMEV induces early-onset disease that is associated with the activation of cross-reactive PLP139-151-specific immunopathologic CD4+ Th1 cells. Based on results from this model, we hypothesize, due to the considerable degeneracy in the T cell repertoire, that induction of full-blown autoimmune disease via molecular mimicry is a tightly regulated process requiring multiple factors related to the pathogen expressing the potential mimic epitope. In this review, we will discuss how various factors related to the infectious environment control whether or not autoimmune disease is initiated. Contributing factors include the nature of the innate immune response to the pathogen which determines the immunopathologic potential of the induced cross-reactive T cells, the capacity of the mimic epitope to be processed and presented from its natural flanking sequences in the pathogen-encoded protein, the site(s) of the primary infection in the host and the ability of the pathogen to persist, and the potential requirement for multiple infections with the same or different pathogens.


Pelletier, D., K. Garrison, et al. (2004). "Measurement of whole-brain atrophy in multiple sclerosis." J Neuroimaging 14(3 Suppl): 11S-19S.

            Brain atrophy reflects the net result of irreversible and destructive pathological processes in multiple sclerosis (MS). The gross morphological changes can be accurately quantified using standard magnetic resonance imaging (MRI) acquisitions and various image analysis tools. The current methods used to assess whole-brain atrophy in patients with MS can be classified into 2 groups based on their reliance on segmentation and registration. Segmentation-based methods employed to measure whole-brain atrophy in MS include the brain parenchymal fraction, the index of brain atrophy, the whole-brain ratio, the brain to intracranial capacity ratio, fuzzy connectedness/Udupa's method, 3DVIEWNIX, the Alfano method, and SIENAX. Current registration-based methods used to measure whole-brain atrophy in MS include the brain boundary shift integral, SIENA, statistical parametric mapping, template-driven seg mentation, and voxel-based morphometry. Most of the methods presented here are sensitive to subtle changes in brain structures and have been successfully applied to MS as measures of whole-brain atrophy. Yet comparative studies of these methods are limited and are complicated by the lack of a gold standard for image acquisition, a segmentation algorithm, an image analysis method, or a reproducibility measure. Overall, the measure of whole-brain atrophy from MRI contributes to an appreciation of the dynamics of MS pathology and its relationship to the clinical course of MS. Determination of the relative reproducibility, precision, sensitivity, and validity of these methods will promote the use of whole-brain atrophy measures as components of comprehensive MRI-based outcome assessment in MS clinical trials.


Peppas, N. A., K. M. Wood, et al. (2004). "Hydrogels for oral delivery of therapeutic proteins." Expert Opin Biol Ther 4(6): 881-7.

            In recent years there has been significant new interest in the development of transmucosal (mostly oral) pharmaceutical formulations for the delivery of therapeutic proteins. Emphasis has been given to the molecular design of new carriers for the delivery of insulin, calcitonin and various types of interferons for the treatment of diabetes, osteoporosis, multiple sclerosis and cancer. Most popular carriers include advanced designs of swollen hydrogels prepared from neutral or intelligent polymeric networks. In this review, the most successful of such systems are presented and their promise in the field described.


Pershadsingh, H. A. (2004). "Peroxisome proliferator-activated receptor-gamma: therapeutic target for diseases beyond diabetes: quo vadis?" Expert Opin Investig Drugs 13(3): 215-28.

            The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals. Apart from improving insulin resistance, plasma lipids and systemic inflammatory markers, ameliorating atherosclerosis and preventing coronary artery restenosis in diabetic subjects, currently approved TZDs have been shown to improve psoriasis and ulcerative colitis in euglycaemic human subjects. These data imply that the activation of PPAR-gamma may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-gamma agonists may prove to be effective in treating diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR-gamma agonists are presently under development. Furthermore, of considerable interest is the recent discovery that a unique subset of currently prescribed antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR-gamma-modulating activity. These discoveries pave the way for the development of drugs for treating chronic multigenic cardiovascular and metabolic diseases, for which therapy is presently insufficient or non-existent. The potential utility of the currently available TZDs rosiglitazone and pioglitazone and PPAR-gamma-modulating angiotensin II Type 1 receptor antagonists in treating cardiovascular, metabolic and inflammatory diseases in insulin resistant and euglycaemic states is of immense clinical potential and should be investigated.


Phillips, C. J. (2004). "The cost of multiple sclerosis and the cost effectiveness of disease-modifying agents in its treatment." CNS Drugs 18(9): 561-74.

            Multiple sclerosis (MS) is one of the most common causes of neurological disability in young and middle-aged adults. The full economic cost of MS is substantial given that MS patients experience a major perturbation in their daily activities and the disease affects mainly young people who are obliged to restrict their levels of economic activity, either temporarily or permanently. A positive relationship exists between the direct and indirect costs of MS and its severity. Cost variations between countries exist because of differences in the costs of inpatient care, the number of ambulatory visits, drug usage and the extent and type of informal care.The development and availability of new agents has been accompanied by an increased optimism that treatment regimens for MS would be more effective. However, doubts have been expressed about the effectiveness of these treatments, which have compounded the problems associated with estimating the relative cost effectiveness of such interventions.In addition, variations in the utility scores associated with disease categories, the impact of relapses and the resulting utility losses, plus the speed of disease progression have all contributed to the difficulty of estimating the quality-adjusted life year (QALY) losses for a patient experiencing MS. Differences between studies with respect to the costs associated with each disability level, the timescale of the disease and the period over which costs and QALYs are to be measured, and the perspective employed in relation to costing have also resulted in a wide range of estimates being produced for the cost effectiveness of interferons and glatiramer acetate in the management of MS. These range from situations of cost savings, to over $US1.6 million (euro1.85 million) per QALY gained. Recent cost-effectiveness studies have benefited from more relevant and up-to-date data relating to disease progression and have generally produced more favourable cost-effectiveness ratios. However, the lack of homogeneity in the design of the studies partly accounts for the extent of variation in the estimates of cost effectiveness, and the difficulty of arriving at a consensus.The UK Department of Health has introduced a scheme that provides disease-modifying agents in the National Health Service for those patients with clinically active relapsing disease. Patients are monitored annually and payments to manufacturers are dependent on outcomes achieved. This initiative, although not without its detractors, will hopefully enhance the quantity and quality of evidence on the impact of drugs on disease progression and address some of the current difficulties with estimating the relative cost effectiveness of disease-modifying drugs in the treatment of patients with MS.


Pluchino, S., R. Furlan, et al. (2004). "Cell-based remyelinating therapies in multiple sclerosis: evidence from experimental studies." Curr Opin Neurol 17(3): 247-55.

            PURPOSE OF REVIEW: Spontaneous remyelination occurs in the central nervous system of patients with multiple sclerosis. However, this process is not robust enough to promote a functional and stable recovery of the myelin architecture. The development of cell-based therapies, aimed at promoting multifocal remyelination, is therefore foreseen. RECENT FINDINGS: Several experimental cell-based strategies aimed at replacing damaged myelin-forming cells have been developed in the last few years. However, most of these therapeutic approaches - although consistently able to form new myelin sheaths at the transplantation site - are unfeasible owing to the mutifocality of the demyelinating process in multiple sclerosis patients and the inability to grow and produce large numbers of differentiated myelin-forming cells in vitro. Stem cell-based therapies that partially overcome these limitations have been proposed recently. SUMMARY: Stem cell-based remyelinating therapies can be considered a plausible alternative strategy in immune-mediated demyelinating disorders. However, before any potential applications in patients with multiple sclerosis can be envisaged, it is necessary to confront the following preliminary, and still unsolved, questions: (1) the ideal stem cell source for transplantation; (2) the most appropriate route of stem cell administration; and, last but not least, (3) the best approach for achieving an appropriate, functional and long-lasting integration of transplanted stem cells into the host tissue.


Poser, C. M. (2004). "Multiple sclerosis trait: the premorbid stage of multiple sclerosis. A hypothesis." Acta Neurol Scand 109(4): 239-43.

            The unexpectedly low rate of concordance in monozygotic (MZ) twins with multiple sclerosis (MS) suggests that they share a systemic condition called the multiple sclerosis trait. This trait constitutes the premorbid stage of the disease and is quite distinct from asymptomatic MS. It results from the action of an antigenic challenge to the immune system of a genetically susceptible person but is short of producing lesions of the central nervous system parenchyma; in fact, the disease may never develop in people with the trait. An environmental triggering event is required to transform the trait into the disease. The discordance of clinical involvement and magnetic resonance images in MZ twins reflects differences in the effect of environmental influences.


Przedborski, S. (2004). "Programmed cell death in amyotrophic lateral sclerosis: a mechanism of pathogenic and therapeutic importance." Neurologist 10(1): 1-7.

            BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disease of adulthood. Mounting evidence indicates that molecular components of the programmed cell death (PCD) machinery are implicated in the demise of motor neurons in this illness. PCD, rather than being passive, is an active mechanism of cell death tightly regulated by multiple molecular pathways. REVIEW SUMMARY: Thus far, little is known about the etiology and the pathogenesis of ALS. However, several studies support the view that PCD is instrumental in ALS neurodegenerative process. Data from postmortem ALS specimens and from experimental models of ALS show that some dying motor neurons exhibit features reminiscent of apoptosis, a prominent morphologic form of PCD. In addition, many key molecular components of the PCD machinery are activated in ALS spinal cords. Supporting the significance of these alterations, genetic and pharmacological interventions aimed at mitigating these changes prolong survival and attenuate neurodegeneration in a mouse model of ALS. CONCLUSIONS: The morphologic evidence of PCD in ALS remains an equivocal. However, the molecular evidence of PCD involvement in ALS is compelling. Moreover, preclinical studies in mice demonstrate the beneficial effects of targeting PCD on ALS-like neurodegeneration. The neurologist needs to be familiar with the concept of PCD and the potential significance of targeting PCD as neuroprotective strategies for ALS.


Rastetter, W., A. Molina, et al. (2004). "Rituximab: expanding role in therapy for lymphomas and autoimmune diseases." Annu Rev Med 55: 477-503.

            Rituximab (Rituxan) is a human-mouse chimeric monoclonal antibody that targets the B-cell CD20 antigen and causes rapid and specific B-cell depletion. Rituximab was approved in the United States in 1997 to treat low-grade or follicular, relapsed or refractory, CD20-positive B-cell non-Hodgkin's lymphoma (NHL). Since then, further clinical experience with rituximab has been incorporated into the prescribing information, which now stipulates an extended eight-week schedule, treatment of patients with refractory or relapsed bulky disease measuring >10 cm, and retreatment of patients who responded to rituximab previously. In 1998, the European Union approved rituximab (MabThera) to treat stage III/IV, follicular, chemotherapy-resistant, or relapsed NHL. Recently, the European Union also approved the use of rituximab in combination with standard chemotherapy for aggressive NHL. Many clinical trials have evaluated rituximab, alone or with other therapies, in indolent and aggressive NHL as well as other B-cell lymphoproliferative disorders. New studies are evaluating rituximab's role in first-line therapy, maintenance therapy, and stem-cell transplantation procedures. The use of rituximab against autoimmune disorders, such as rheumatoid arthritis, immune thrombocytopenic purpura, autoimmune hemolytic anemia, systemic lupus erythematosus, and multiple sclerosis, is also under investigation.


Rudge, P. (2004). "Interferon antibodies: do they alter the beneficial effects of beta-interferon upon relapse rate in multiple sclerosis?" Mult Scler 10(2): 123-5.


Rudick, R. A. (2004). "Impact of disease-modifying therapies on brain and spinal cord atrophy in multiple sclerosis." J Neuroimaging 14(3 Suppl): 54S-64S.

            Brain and spinal cord atrophy occur early in the course of multiple sclerosis (MS) and continue throughout this lifelong illness, resulting in substantial parenchymal tissue loss at later disease stages. Treatments that slow or prevent atrophy may reduce disability progression in the long term. Disease-modifying agents (DMAs) such as interferon beta-1b (IFNbeta-1b), IFNbeta-1a, and glatiramer acetate inhibit inflammatory events believed to initiate and perpetuate the disease process. DMAs have been shown to inhibit aspects of MS related to brain inflammation such as relapses and gadolinium-enhanced lesions. Because brain inflammation has been linked to irreversible brain tissue injury, DMAs should be effective in reducing the rate of brain atrophy progression. Weekly IFNbeta-1a (Avonex or Rebif) has been shown to slow the rate of brain atrophy; a large study of a frequent injection regimen with IFNbeta-1a (Rebif) showed continued atrophy progression despite IFNbeta-1a at a rate similar to placebo-treated patients. It is not clear why weekly treatment regimens with lower total doses of IFNbeta-1a would show beneficial effects on brain atrophy compared with frequent injections with larger weekly doses. This article reviews results of clinical trials that have examined the effects of DMAs on brain and spinal cord atrophy in patients with MS. Some of these agents have demonstrated positive effects in well-controlled studies, suggesting that anti-inflammatory therapy can delay or prevent the emergence of irreversible central nervous system pathology.


Rumke, H. C. and H. K. Visser (2004). "[Childhood vaccinations anno 2004. II. The real and presumed side effects of vaccination]." Ned Tijdschr Geneeskd 148(8): 364-71.

            Vaccinations protect to a high degree against infectious diseases, but may cause side effects. In the Netherlands since 1962 the adverse events following immunizations are registered and analysed by the National Institute of Health and Environment (RIVM). Since 1983 a permanent Committee of the Dutch Health Council reviews adverse events reported to the RIVM. With the so-called killed vaccines the side effects are mainly local (redness, swelling, pain) or general (fever, listlessness, irritability, sleep and eating problems). They are seen mainly after DPT-IPV vaccination against diphtheria, pertussis, tetanus and poliomyelitis. Some side effects occur rarely (collapse reactions, discoloured legs, persistent screaming and convulsions) and very rarely serious neurological events are reported. After MMR vaccination against measles, mumps and rubella, cases of arthritis, thrombocytopenia and ataxia are reported sporadically. Usually, they have a spontaneous recovery. During recent years a scala of diseases or symptoms have been associated with vaccination (presumed side effects). Careful and extensive investigations have shown that such hypotheses could not be supported. Examples are allergic diseases as asthma, diabetes mellitus, multiple sclerosis (after hepatitis B vaccination), autism and inflammatory bowel disease (after MMR vaccination) and sudden infant death syndrome. The total number of cases where at least a possible relation between side effects and vaccination is observed--apart from local reactions and moderate general symptoms--is very rare (about 0.25 per 1000 vaccinations) and does not balance the benefits from vaccination. There appears increasing doubt about the use and safety of vaccinations. More research is needed about the motives of people to choose for and against vaccination. The education about vaccination for parents and professionals who are involved with vaccination has to be improved. Internet can play an important role.


Salem, M. L. (2004). "Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production." Curr Drug Targets Inflamm Allergy 3(1): 97-104.

            Estrogen appears to play a central role in the immune response and immune-mediated diseases. Estrogen receptors are expressed in a variety of immunocompetent cells, including CD4(+) and CD8(+) T cells and macrophages. Clinical observations indicate that some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, frequently remit during pregnancy but exacerbate, or have their onset during the postpartum period. Pharmacological levels of estrogen also appear to ameliorate certain autoimmune diseases. In addition, estrogen is known to suppress certain infectious diseases, as well as T cell-mediated responses toward oxazolone, keyhol lympet hemocyanin, Listeria soluble protein and purified protein derivatives. The immune basis for these phenomena is poorly understood. Based on a distinctive profile of cytokine production, data accumulated thus far have revealed modulatory effects for estrogen on the TH1-type and TH2-type cells, which represent two polarized forms of the effector specific immune response. Recent evidence indicates that estrogens inhibit the production of TH1 proinflammatory cytokines, such as IL-12, TNF-alpha and IFN-gamma, whereas they stimulate the production of TH2 anti-inflammatory cytokines, such as IL-10, IL-4, and TGF-beta. This can explain why estrogen suppresses and potentiates TH1- and TH2-mediated diseases, respectively. We hypothesize that exacerbation or suppression of inflammatory diseases by estrogen is mediated by skewing TH1-type to TH2-type response. This view represents a novel mechanism for the modulatory effect of estrogen on certain inflammatory diseases that can lead to beneficial or detrimental impacts depending on the type of immune involved. Such a concept is valuable when considering the application of combination therapies that include estrogen.


Salonia, A., R. M. Munarriz, et al. (2004). "Women's sexual dysfunction: a pathophysiological review." BJU Int 93(8): 1156-64.


Schipper, H. M. (2004). "Heme oxygenase-1: transducer of pathological brain iron sequestration under oxidative stress." Ann N Y Acad Sci 1012: 84-93.

            Mechanisms responsible for the pathological deposition of redox-active brain iron in human neurological disorders remain incompletely understood. Heme oxygenase-1 (HO-1) is a 32-kDa stress protein that degrades heme to biliverdin, free iron, and carbon monoxide. In this chapter, we review evidence that (1) HO-1 is overexpressed in CNS tissues affected by Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and other degenerative and nondegenerative CNS diseases; (2) the pro-oxidant effects of dopamine, hydrogen peroxide, beta-amyloid, and proinflammatory cytokines stimulate HO-1 expression in some of these conditions; and (3) upregulation of HO-1 in astrocytes exacerbates intracellular oxidative stress and promotes sequestration of nontransferrin-derived iron by the mitochondrial compartment. A model is presented implicating glial HO-1 induction as a "final common pathway" leading to pathological iron sequestration and mitochondrial insufficiency in a host of human CNS disorders.


Schwartz, M. (2004). "Vaccination for glaucoma: dream or reality?" Brain Res Bull 62(6): 481-4.

            Glaucoma is a neurodegenerative disease of the optic nerve, which continues to progress even if the primary cause of degeneration is identified and alleviated. At any given time the affected optic nerve contains fibers that are amenable to neuroprotection, and will escape degeneration provided that the proper pharmacological or other intervention is applied. Autoimmunity has long been viewed as a deleterious phenomenon that should be terminated or at least minimized in order to preserve health. We recently demonstrated, however, that T cells specific to self-proteins residing in the site of CNS insult can be protective. With the aim of boosting autoimmunity for neuroprotection without risking the induction of an autoimmune disease, we developed the use of Cop-1 (an FDA-approved drug for the treatment of multiple sclerosis) as an active vaccination for neuroprotection. Cop-1 is a synthetic polymer that weakly cross-reacts with a wide range of self-reacting T cells. Vaccination with Cop-1 resulted in significant neuroprotection in rat models of optic nerve crush and chronic glaucoma. Thus, boosting of a T cell-based mechanism, which we have termed 'protective autoimmunity', promotes recovery of the damaged optic nerve. Current studies in our laboratory are aimed at translating this treatment into a clinical therapy.


Scott, L. J. and D. P. Figgitt (2004). "Mitoxantrone: a review of its use in multiple sclerosis." CNS Drugs 18(6): 379-96.

            Mitoxantrone (Novantrone), a synthetic anthracenedione derivative, is an antineoplastic, immunomodulatory agent. Its presumed mechanism of action in patients with multiple sclerosis (MS) is via immunomodulatory mechanisms, although these remain to be fully elucidated. Intravenous mitoxantrone treatment improved neurological disability and delayed progression of MS in patients with worsening relapsing-remitting (RR) [also termed progressive-relapsing (PR) MS] or secondary-progressive (SP) disease. In a pivotal randomised, double-blind, multicentre trial, mitoxantrone 12 mg/m(2) administered once every 3 months for 2 years provided significant improvements in neurological disability ratings, including Kurtzke Expanded Disability Status Scale (EDSS), Ambulatory Index (AI) and Standardised Neurological Status (SNS) scores, compared with placebo. The drug also significantly reduced the mean number of corticosteroid-treated relapses and prolonged the time to the first treated relapse, with the beneficial effects on disease progression supported by magnetic resonance imaging. Post hoc analyses suggest that the benefits associated with mitoxantrone treatment may be sustained for at least 12 months after cessation of treatment, mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo.Concomitant intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g once every month for 6 months was more effective than intravenous methylprednisolone monotherapy in preventing the development of new gadolinium-enhanced lesions in patients with very active RRMS or SPMS.The drug was generally well tolerated in patients with MS. Adverse events were generally mild to moderate in severity and usually resolved upon discontinuation of treatment or with appropriate pharmacotherapy. At the recommended dosage, mitoxantrone appears to have a low potential to cause cardiotoxicity.In conclusion, intravenous mitoxantrone reduces the relapse rate and slows progression of the disease in patients with worsening RRMS, PRMS or SPMS; thus providing a new option for the management of these patients. The drug was generally well tolerated at the recommended dosage, although potential cardiotoxicity limits the total cumulative dose to 140 mg/m(2). Further studies are warranted to determine which patients with worsening RRMS, PRMS or SPMS are most likely to benefit from mitoxantrone treatment and to more fully define the long-term safety and tolerability of mitoxantrone, including the use of concomitant cardioprotectants to extend the therapeutic lifespan of the drug.Pharmacodynamic Profile. Mitoxantrone, a synthetic anthracenedione derivative, is an established cytotoxic, antineoplastic agent. Its presumed mechanism of action in multiple sclerosis (MS) is immunosuppression. In antineoplastic studies, the drug showed several immunomodulatory effects, inducing macrophage-mediated suppression of B-cell, T-helper and T-cytotoxic lymphocyte function. Currently, the pharmacodynamic properties of mitoxantrone have not been investigated to any extent in patients with MS. In one study, 6 months' treatment with intravenous mitoxantrone generally had no effect on the distribution of cytokine-positive peripheral blood monocyte cells in patients with MS. In an animal model of the disease, mitoxantrone suppressed the development and progression of both actively and passively induced acute experimental allergic encephalomyelitis (EAE). It appeared to be 10-20 times more effective than cyclophosphamide in the suppression of EAE. Moreover, mitoxantrone approximately doubled the mean time to onset of EAE versus control animals (279 vs 148 days after immunisation; p < 0.00005). In vitro, mitoxantrone 10 and 100 micro g/L inhibited myelin degradation by leucocytes and peritoneal macrophages derived from mice with acute EAE by approximately 60% and 100%.Pharmacokinetic Profile. Currently, there are no published pharmacokinetic data for intravenous mitoxantrone in pitoxantrone in patients with MS, paediatric patients or in those with renal impairment. All studies, to date, have been in patients with cancer receiving a single, approximately 30-minute intravenous infusion of mitoxantrone 5-14 mg/m(2). The drug exhibits triexponential pharmacokinetics, with a rapid initial distribution (alpha) phase, an intermediate distribution (beta) phase and a much slower elimination (gamma) phase. The mean half-life of the alpha phase appears to be 6-12 minutes and that of the beta phase 1.1-3.1 hours. Mitoxantrone has a high affinity for tissue, with a volume of distribution of up to 2248 L/m(2). Mitoxantrone persists for prolonged periods in tissues and was detectable in autopsy tissue from patients who last received the drug up to 272 days before death. At concentrations of 10-10000 ng/mL, the drug was 70-80 % bound to plasma proteins in dogs.Elimination of mitoxantrone occurs predominantly through biliary excretion and may be impaired in patients with hepatic dysfunction or third space abnormalities (e.g. ascites). The mean terminal elimination half-life of mitoxantrone ranged from 23 hours to 215 hours. Renal clearance accounts for 10 % of the total clearance of the drug. Total clearance of mitoxantrone ranged from 13 to 34.2 L/h/m(2) and renal clearance from 0.9 to 2.7 L/h/m(2). The drug appears to have a low potential for interaction with other concomitantly administered agents.Therapeutic Efficacy. Intravenous mitoxantrone (infusion of > or = 5 minutes), either as monotherapy or in combination with intravenous methylprednisolone, delayed the progression of the disease in patients with secondary-progressive (SP) or worsening relapsing-remitting (RR) MS (the latter is also termed progressive-relapsing MS) in comparative, randomised, multicentre trials.In a double-blind, monotherapy trial (Mitoxantrone In Multiple Sclerosis [MIMS] trial), mitoxantrone 12 mg/m(2) (n = 60) once every 3 months for 2 years significantly improved neurological disability relative to placebo (n = 64), as assessed by changes in mean Kurtzke Expanded Disability Status Scale (EDSS) score, mean Ambulatory Index (AI) score and mean Standardised Neurological Status (SNS) score. The drug also significantly reduced the mean number of corticosteroid-treated relapses per patient and prolonged the time to the first treated relapse. A Wei-Lachin multivariate analysis of these five efficacy variables indicated that the global difference between the two treatment groups was 0.30 (p < 0.0001). Mitroxantrone was also more effective than placebo according to secondary endpoints in this study, with fewer mitoxantrone recipients experiencing a relapse, a deterioration of > or =1 EDSS point or a confirmed deterioration in EDSS score over a 3-month period. Mitoxantrone recipients also showed less deterioration in quality-of-life ratings and had fewer hospital admissions, whereas more placebo recipients had new gadolinium-enhanced lesions at study end (the latter parameter was assessed using magnetic resonance imaging [MRI] in a subgroup of 110 patients, including 40 patients who received an exploratory 5 mg/m(2) dose). Furthermore, post hoc analyses indicated that the beneficial effects of mitoxantrone treatment on EDSS, SNS and AI scores were sustained for at least 12 months after cessation of treatment, with mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo.Preliminary data from a cost-minimisation analysis based on results from the MIMS trial indicated that approximately half of the cost of mitoxantrone was offset by cost savings in other areas associated with the treatment of MS (direct and indirect major costs), with a total annual incremental cost for mitoxantrone of dollar 1661 per patient.Combination therapy once-monthly with intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g was more effective than intravenous methylprednisolone 1g once every month in preventing the development of gadolinium-enhanced lesions in patients with very active RRMS or SPMS (double-blind assessment using MRI scans). After 6 months, significantly more combination therapy recipients had no new gadolinium-enhanced lesions (90.5% vs 31.3% with monotherapy; p < 0.001) [primary endpoint]. There were also significant reductions in both the mean number of new enhancing lesions and the total number of gadolinium-enhanced lesions in patients receiving combination therapy versus methylprednisolone monotherapy.Tolerability. Mitoxantrone was generally well tolerated in patients with MS. Treatment-emergent adverse events occurring significantly more frequently with mitoxantrone (12 mg/m(2) once every 3 months for 2 years) than placebo were nausea, alopecia, menstrual disorders, urinary tract infection, amenorrhoea, leucopenia and elevated gamma-glutamyltranspeptidase levels. Adverse events were usually mild to moderate in severity and generally resolved with discontinuation of treatment or when treated with appropriate pharmacotherapy. Eight percent of patients discontinued treatment in the mitoxantrone 12 mg/m(2) group due to an adverse event versus 3% of placebo recipients. The incidence of drug-related acute myelogenous leukaemia was very low (0.12%) in a cohort of 802 patients with MS receiving mitoxantrone.Evidence suggests that the risk of cardiotoxicity is low in patients with MS. After 1 year of monotherapy, 3.4% of mitoxantrone recipients had a reduction in left ventricular ejection fraction (LVEF) to < or =50% compared with 0% of placebo recipients; at the end of the second year, respective incidences were 1.9% and 2.9% (total cumulative dose of mitoxantrone per patient was 96 mg/m(2) after 2 years' treatment). (ABSTRACT TRUNCATED)


Sindern, E. (2004). "Role of chemokines and their receptors in the pathogenesis of multiple sclerosis." Front Biosci 9: 457-63.

            Multiple sclerosis (MS) is an autoimmune disease of the human central nervous system (CNS) of unknown etiology that causes demyelination and associated tissue injury. Trafficking of inflammatory T cells into the CNS is a crucial event in the pathogenesis of MS, a process in which chemokines and their receptors have been demonstrated to play an important role. Chemokines are key mediators of inflammation and have major effects on migration of cells to the sites of inflammation as well as activation of recruited and resident CNS cells. This paper summarizes recent and new information about the expression and function of elements of the chemokine system in MS and its animal model experimental allergic encephalomyelitis. Analysis of the chemokine system provides insights into mechanisms of CNS inflammatory reactions and may lead to new targets of therapeutic intervention in MS.


Siva, A., A. Altintas, et al. (2004). "Behcet's syndrome and the nervous system." Curr Opin Neurol 17(3): 347-57.

            PURPOSE OF REVIEW: Behcet's syndrome (BS) is a multi-system, vascular-inflammatory disease of unknown origin, involving the nervous system in a subgroup of patients. The syndrome is rare, but as patients with BS are young and frequently present with an acute or subacute brainstem syndrome or hemiparesis, as well as with other various neurological manifestations, the syndrome is often included in the differential diagnosis of multiple sclerosis, stroke of the young adult, and another wide range of neurological disorders. The present review summarizes the neurological involvement in BS, and emphasizes recent clinical concepts and ethiopathogenetic findings. RECENT FINDINGS: Over the last years the growing clinical and imaging evidence had suggested that neurological involvement in BS may be subclassified into two major forms: one, which is seen in the majority of patients, may be characterized as a vascular-inflammatory CNS disease, with focal or multifocal parenchymal involvement; the other, which has few symptoms and a better neurological prognosis, may be caused by isolated cerebral venous sinus thrombosis and intracranial hypertension. These two types rarely occur in the same individual, and their pathogenesis is likely to be different. A nonstructural vascular type headache is relatively common, whereas isolated behavioral syndromes and peripheral nervous system involvement are rare. SUMMARY: The involvement of the nervous system in BS is heterogeneous as clinical and imaging data reveal. Currently it is unknown which factors determine or have a role in the development of neurological involvement, but some progress has been achieved in understanding the neurological spectrum of the syndrome, which may lead to a better management of these patients.


Stangel, M. (2004). "Remyelinating and neuroprotective treatments in multiple sclerosis." Expert Opin Investig Drugs 13(4): 331-47.

            Multiple sclerosis (MS) is the most common cause of neurological disability in young adults. The pathological hallmark is multifocal demyelination and inflammation in the CNS. In addition, there is also a variable extent of axonal damage. Remyelination has been seen in up to 70% of lesions but repair is generally incomplete. The demonstration of neuropathological heterogeneity of MS lesions suggests different pathophysiological subtypes and it is therefore unlikely that there is a uniform cause of incomplete remyelination in MS. In recent years, a great body of knowledge has accumulated in order to better understand the regulatory mechanisms of remyelination. This has led to a number of approaches to promote repair mechanisms, most of which have been successful in animal experiments. Unfortunately, the translation of these experimental data into clinical treatments has proven difficult. More information on the pathogenesis of MS, the reason why repair mechanisms fail in MS and a better understanding of the regulation of remyelination are required. This will ultimately lead to a specific treatment tailored for the individual patient and will probably involve a combination of immunomodulation, remyelination and neuroprotection.


Stuve, O., T. Prod'homme, et al. (2004). "Statins as potential therapeutic agents in multiple sclerosis." Curr Neurol Neurosci Rep 4(3): 237-44.

            3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) are oral cholesterol-lowering drugs. Statins are well tolerated and have an excellent safety record. These agents competitively inhibit HMG CoA reductase, which is the enzyme that catalyzes the conversion of HMG CoA to L-mevalonate. Although L-mevalonate is a key intermediate in cholesterol synthesis, several of its metabolites are involved in post-translational modification of specific proteins involved in cell proliferation and differentiation. Thus, independent of their cholesterol-reducing properties, statins have important pleiotropic biologic effects. Recent reports indicate that statins have anti-inflammatory and neuroprotective properties. Whether statins will be of clinical benefit for patients with multiple sclerosis and other neurodegenerative diseases of the central nervous system will only be known after they are evaluated in prospective randomized clinical trials.


Sylvester, R. K., S. M. Lindsay, et al. (2004). "The conversion challenge: from intrathecal to oral morphine." Am J Hosp Palliat Care 21(2): 143-7.

            Numerous articles have described the methodologies used and outcomes achieved with the intrathecal (IT) administration of morphine for pain. However, only one case report has been published that describes converting a patient's IT morphine to an oral regimen. This case report describes the experience of converting a patient's IT morphine to oral morphine and discusses the scarcity of published data to validate suggested equianalgesic intraspinal morphine recommendations. The calculated equianalgesic oral to IT ratio in this case was 12:1. This is substantially lower than the 300:1 ratio published by Krames and the 90:1 ratio employed by a commercially available software program for calculating equianalgesic opioid doses. We recommend caution when applying existing guidelines for conversion of morphine from an IT to an oral regimen.


Szalai, A. J. and S. R. Barnum (2004). "Fc receptors and the common gamma-chain in experimental autoimmune encephalomyelitis." J Neurosci Res 75(5): 597-602.

            Fcgamma receptors (FcgammaRs), composed of a ligand-binding alpha-chain (FcRalpha) sometimes associated with the homodimeric, cell-signaling common gamma-chain (FcRgamma), comprise an important family of effector molecules linking humoral and cell-mediated adaptive immunity and regulating innate immunity. In peripheral autoimmune diseases, FcgammaRs contribute to inflammation and tissue damage through inappropriate activation of macrophages and neutrophils, release of cytokines and oxidants, and destruction of autoantibody-opsonized cells. In the central nervous system (CNS), the role of FcgammaRs in autoimmune disease such as multiple sclerosis (MS) remains largely unexplored despite extensive documentation of CNS-specific antibodies in cerebrospinal fluid and plaques. Several studies have now examined the role of FcgammaRs in experimental autoimmune encephalomyelitis (EAE), the animal model for MS, using mice genetically deficient in one or more FcgammaRs or in FcRgamma. These studies indicate that none of the FcgammaR alpha-chains are critical for EAE development and progression. In contrast, it is unequivocal that FcRgamma contributes to EAE, and surprisingly it seems that this effect is independent of FcgammaRs. Recent studies now indicate that FcRgamma expression in gammadelta T cells, most likely as a component of the TCR/CD3 signaling complex, is a critical requirement for EAE development. These studies support previous evidence implicating a pathogenic role for gammadelta T cells in EAE.


Szendrei, K. (2004). "[A novel analgesics made from Cannabis]." Ideggyogy Sz 57(1-2): 36-40.

            Bayer AG has recently announced that it acquired exclusive rights for the marketing of GW Pharmaceuticals' new medicine Sativex in Europe and in other regions. Sativex is a sublingual spray on Cannabis extract basis, and is equipped with an electronic tool to facilitate accurate dosing and to prevent misuses. It is standardized for the THC and CBD. The new analgesic is proposed for the treatment of muscle spasticity and pains accompanying multiple sclerosis and as an efficient analgetic for neurogenic pain not responding well to opioids and to other therapies available. The entirely new mechanism of action through the recently discovered cannabinoid receptor system may offer a real therapeutic potential to the drug. Although the Government of Netherlands has authorized the sale of pharmaceutical grade Cannabis herb by pharmacies in the Netherlands, the availability on the pharmaceutical market of the registered preparation may render requests for the authorization of the smoking of Cannabis herb (marihuana) by individuals suffering of multiple sclerosis, neurogenic pain, AIDS wasting syndrome unnecessary. Nevertheless, the "old chameleon" plant Cannabis appears to gradually regain its previous status in mainstream therapy and pharmacy. As long as the plant Cannabis and its products continue to be classified as narcotic drugs, medical use of the new preparation will need close supervision.


Tabakman, R., S. Lecht, et al. (2004). "Interactions between the cells of the immune and nervous system: neurotrophins as neuroprotection mediators in CNS injury." Prog Brain Res 146: 387-401.

            Inflammatory processes in the central nervous system (CNS) are considered neurotoxic, although recent studies suggest that they also can be beneficial and confer neuroprotection (neuroprotective autoimmunity). Cells from the immune system have been detected in CNS injury and found to produce and secrete a variety of neurotrophins such as NGF, BDNF, NT-3 and NT-4/5, and to express (similarly to neuronal cells), members of the tyrosine kinase (Trk) receptor family such as TrkA, TrkB and TrkC. Indeed, autocrine and paracrine interactions are observed at the site of CNS injury, resulting in a variety of homologic-heterologic modulations of immune and neuronal cell function. The end result of the inflammatory process, neurotoxicity and/or neuroprotection, is a function of the fine balance between the two cellular systems, i.e., of the complex signaling relationships between anti-inflammatory neuroprotective factors (neurotrophins and other chemical mediators) and proinflammatory neurotoxic factors (TNF, free radicals, certain cytokines, etc.). Autoimmune neuroprotection is a novel therapeutic approach aimed at shifting the balance between the immune and neuronal cells towards survival pathways in a variety of CNS injuries. This review focuses on data supporting this concept and its future therapeutical implications for optic nerve injury and multiple sclerosis.


Theoharides, T. C. and D. E. Cochrane (2004). "Critical role of mast cells in inflammatory diseases and the effect of acute stress." J Neuroimmunol 146(1-2): 1-12.

            Mast cells are not only necessary for allergic reactions, but recent findings indicate that they are also involved in a variety of neuroinflammatory diseases, especially those worsened by stress. In these cases, mast cells appear to be activated through their Fc receptors by immunoglobulins other than IgE, as well as by anaphylatoxins, neuropeptides and cytokines to secrete mediators selectively without overt degranulation. These facts can help us better understand a variety of sterile inflammatory conditions, such as multiple sclerosis (MS), migraines, inflammatory arthritis, atopic dermatitis, coronary inflammation, interstitial cystitis and irritable bowel syndrome, in which mast cells are activated without allergic degranulation.


Tishler, M. and Y. Shoenfeld (2004). "Vaccination may be associated with autoimmune diseases." Isr Med Assoc J 6(7): 430-2.


Trapp, B. D. (2004). "Pathogenesis of multiple sclerosis: the eyes only see what the mind is prepared to comprehend." Ann Neurol 55(4): 455-7.


van der Worp, H. B., J. van Gijn, et al. (2004). "[Treatment of optic neuritis]." Ned Tijdschr Geneeskd 148(2): 61-5.

            Optic neuritis manifests itself as a reversible loss of vision. It can be a clinically isolated incident or one of the (first) manifestations of multiple sclerosis (MS). Its differential diagnosis is extensive, and management of other disorders can differ radically. In a typical case, treatment with corticosteroids hastens recovery of vision but does not affect the eventual degree of recovery. There is a substantial risk of developing MS after isolated optic neuritis (approximately 50% within 20 years), especially if asymptomatic white matter lesions are found on MRI scanning of the brain. Intravenous treatment with methylprednisolone may delay the onset of MS somewhat, but after three years the benefit of this treatment is lost. Treatment with interferon beta-Ia in high-risk patients also slows down the progression to clinically definite MS, but the long-term benefits are uncertain. MR imaging of the brain has implications for prognosis but not for treatment.


Vandenbroeck, K., I. Alloza, et al. (2004). "Inhibiting cytokines of the interleukin-12 family: recent advances and novel challenges." J Pharm Pharmacol 56(2): 145-60.

            Interleukin-12 (IL-12) and the more recently discovered IL-23 and IL-27 constitute a unique family of structurally related, heterodimeric cytokines that regulate cell-mediated immune responses and T helper 1 (Th1)-type inflammatory reactions. Not surprisingly, the potentiality of treating conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA) through pharmacological interference with IL-12 pathways has received widespread attention. In this review we have examined over 50 substances with reported IL-12 inhibitory effects. We demonstrate that a majority of these belong to a limited number of major functional classes, each of which targets discrete events in the IL-12 biological pathway. Thus, most IL-12 inhibitory substances appear to work either through inhibition of transcription factor NF-kappa B activation, up-regulation of intracellular cAMP, blockage of posttranslational processing or interference with signal transduction pathways. In addition, cyclophilin-binding drugs, and generic inhibitors of nuclear histone deacetylases, and of ion channels, pumps and antiporters are emerging as potential leads to novel targets for interference with IL-12 production. Many inhibitors of NF-kappa B and of IL-12 signal transduction have been proven effective in limiting or preventing disease in experimental autoimmune encephalomyelitis (EAE) models of MS. The sharing of the p40 subunit, the IL-12R beta 1 and components of the signal transduction pathways between IL-12 and IL-23 raises the question as to whether the beneficial effects of various drugs previously ascribed to inhibition of IL-12 may, in fact, have been due to concurrent blockage of both cytokines, or of IL-23, rather than IL-12. Moreover, the homodimeric beta(2)-form of IL-12, though originally considered to display only antagonistic effects, is now emerging as a pronounced agonist in a variety of inflammatory processes. Reassessment of IL-12 inhibitory compounds is therefore needed to scrutinize their effects on IL-12 alpha beta, beta(2) and IL-23 formation. This is likely to open exciting perspectives to the identification of drugs that target these cytokines either indiscriminately or selectively. The functional diversity of presently available inhibitors should facilitate an unprecedented flexibility in designing future trials for the treatment of IL-12- and IL-23-mediated disorders.


Vermersch, P. (2004). "[Are there arguments for initiating an etiological treatment at the onset of the first demyelinating episode?]." Presse Med 33(3): 180-6; discussion 192.

            The arrival of immunomodulating treatments The pathology of multiple sclerosis (MS) took benefit from progresses of magnetic resonance-based and immunological studies, leading to the introduction of immunomodulatory agents and notably interferon beta (IFNbeta). The therapeutic impact of such treatments in the relapsing-remitting forms of the disease, and our improved knowledge on the natural history of the disease, raise the possibility of treating patients after the first demyelinating episode. This strategy may be more relevant in patients presenting poor prognostic criteria. Magnetic resonance imaging (MRI) data The clinical characteristics of the first episode do not help to predict the mean or long term progression. Magnetic resonance imaging has shown that the progression of the disease is partly infra-clinical. Other than data revealing demyelination involvement and inflammation, MRI has also provided arguments suggesting early axonal distress. In a patient, the presence of high lesion load at onset on weighted T2 sequences, of black holes and gadolinium enhancing lesions s on T1 sequences, or the presence of new lesions on MRI conducted a few Months later are all predictive factors of clinical progression and suggest that treatment should be initiated early. The interest of interferon beta Two clinical trials have shown that treatment with IFNbeta treatment after a first demyelinating event significantly decreased the risk of a second episode in the short term. The aim of such treatment would be to limit the irreversible axonal lesions, notably in the form of axonal sections often associated with inflammatory lesions. An early reduction in the inflammatory response could lead to a lesser number of axons and, consequently, reduced clinical disability.


Vial, T. and J. Descotes (2004). "Autoimmune diseases and vaccinations." Eur J Dermatol 14(2): 86-90.

            The potential association between vaccination and autoimmune diseases has been largely questioned in the past few years, but this assumption has mostly been based on case reports. The available evidence derived from several negative epidemiological studies is reassuring and at least indicates that vaccines are not a major cause of autoimmune diseases. However, there are still uncertainties as to whether a susceptible subpopulation may be at a higher risk of developing an autoimmune disease without causing an overall increase in the disease incidence. Based on selected examples, this review highlights the difficulties in assessing this issue. We suggest that a potential link between vaccines and autoimmune diseases cannot be definitely ruled out and should be carefully explored during the development of new candidate vaccines.


Villoslada, P. and C. P. Genain (2004). "Role of nerve growth factor and other trophic factors in brain inflammation." Prog Brain Res 146: 403-14.

            Inflammation in the brain is a double-edged process that may be beneficial in promoting homeostasis and repair, but can also result in tissue injury through the damaging potential of inflammatory mediators. Thus, control mechanisms that minimize the extent of the inflammatory reaction are necessary in order to help preserve brain architecture and restore function. The expression of neurotrophic factors such as nerve growth factor (NGF) is increased after brain injury, in part mediated by effects on astrocytes of pro-inflammatory mediators and cytokines produced by immune cells. Conversely, cells of the immune system express NGF receptors, and NGF signaling modulates immune function. Multiple sclerosis (MS) and the disease model experimental autoimmune encephalomyelitis are neurodegenerative disorders whereby chronic destruction of the brain parenchyma results from an autoaggressive, immune-mediated inflammatory process and insufficient tissue regeneration. Here, we review evidence indicating that the increased production of NGF and other trophic factors in central nervous system (CNS) during these diseases can suppress inflammation by switching the immune response to an anti-inflammatory, suppressive mode in a brain-specific environment. Thus, trophic factors networks in the adult CNS not only protects axons and myelin but appear to also actively contribute to the maintenance of the brain immune privilege. These agents may represent good targets for therapeutic intervention in MS and other chronic CNS inflammatory diseases.


Witowski, J., K. Ksiazek, et al. (2004). "Interleukin-17: a mediator of inflammatory responses." Cell Mol Life Sci 61(5): 567-79.

            Interleukin-17 (IL-17) is a prototype member of a new cytokine family with six species identified to date. IL-17 is secreted mainly by activated CD4(+) and CD8(+) T lymphocytes, while its receptor is distributed ubiquitously. IL-17 has been classified as a proinflammatory cytokine because of its ability to induce the expression of many mediators of inflammation, most strikingly those that are involved in the proliferation, maturation and chemotaxis of neutrophils. Increased levels of IL-17 have been associated with several conditions, including airway inflammation, rheumatoid arthritis, intraperitoneal abscesses and adhesions, inflammatory bowel disease, allograft rejection, psoriasis, cancer and multiple sclerosis. This review provides an overview of IL-17 activities, concentrating on those that lead to neutrophil recruitment.


Wolinsky, J. S. (2004). "Glatiramer acetate for the treatment of multiple sclerosis." Expert Opin Pharmacother 5(4): 875-91.

            Glatiramer acetate (Copaxone, Teva Pharmaceuticals Ltd) is a collection of immunomodulatory, synthetic polypeptides indicated for the treatment of relapsing-remitting multiple sclerosis (RR MS). Preclinical and clinical studies provide an evolving understanding of the mechanisms by which glatiramer acetate exerts both immunological and potential neuroprotective effects that account for its clinical efficacy. The results of pivotal controlled clinical trials and long-term data, derived from organised extension studies, are evaluated in detail and supportive data from open-label comparison, combination treatment and therapeutic switch studies are considered in order to determine the place of glatiramer acetate among other approved therapies for RR MS. The efficacy of glatiramer acetate is stable or may increase over time and the drug has a favourable side effect profile. Glatiramer acetate is an appropriate first-line immunomodulatory therapy for RR MS.


Woodward, S. (2004). "Current management of neurogenic bladder in patients with MS." Br J Nurs 13(7): 362-70.

            Multiple sclerosis (MS) is a common neurological problem and many sufferers are affected by urinary symptoms that negatively impact on their quality of life. Nurses are intimately involved in management of continence and other bladder problems with MS patients and need to be aware of appropriate assessment techniques and treatment options so that patients can be managed optimally. Nurses can have a significant role to play in reducing bladder symptoms and directly improving patients' quality of life. This article presents a review of current behavioural, pharmacological and surgical options for management of the neurogenic bladder in MS.


Yong, V. W. (2004). "Prospects for neuroprotection in multiple sclerosis." Front Biosci 9: 864-72.

            Axonal injury and neuronal loss are now recognised to be hallmarks of multiple sclerosis (MS) in addition to neuroinflammation and demyelination. This review discusses the factors that contribute to neural degeneration, and it emphasizes the need to confer neuroprotection in MS. The beneficial role of neuroinflammation is highlighted, and the possibility that glatiramer acetate enables neuroprotection in MS through beneficial inflammation is evaluated. Finally, the prospect of an experimental treatment, minocycline, in producing neuroprotection in MS is suggested.


Zhou, D. and B. Hemmer (2004). "Specificity and degeneracy: T cell recognition in CNS autoimmunity." Mol Immunol 40(14-15): 1057-61.

            T cells play a crucial role in the pathogenesis of most autoimmune disorders. However, target antigens and pathomechanisms leading to human autoimmune diseases are still largely unknown. Cross-recognition of T cells between self and foreign antigens has been considered as a driving force in generating autoimmunity. Here, we discuss the extent of degeneracy in T cell antigen recognition and hypothesize on the role of degenerate recognition in the pathogenesis of multiple sclerosis (MS), a candidate autoimmune disease of the central nervous system (CNS).


Ziemssen, T. (2004). "Neuroprotection and glatiramer acetate: the possible role in the treatment of multiple sclerosis." Adv Exp Med Biol 541: 111-34.


Zivadinov, R. and R. Bakshi (2004). "Central nervous system atrophy and clinical status in multiple sclerosis." J Neuroimaging 14(3 Suppl): 27S-35S.

            In this review, the authors focus on clinical aspects of central nervous system (CNS) atrophy in multiple sclerosis (MS), including the relationship between atrophy and disability, disease course, disease duration, quality of life, and fatigue. Cross-sectional studies have demonstrated a moderate but significant correlation between brain or spinal cord atrophy and physical disability in patients with MS. Longitudinal studies (>/= 5 years) have shown that CNS atrophy is a significant predictor of subsequent long-term neurologic deterioration. The clinical relevance of CNS atrophy is reinforced by studies showing that atrophy accounts for more variance than conventional lesion measures in predicting disability. Impaired quality of life and both urodynamic and sexual dysfunction, but not fatigue, are associated with brain atrophy. It is likely that once the level of CNS atrophy reaches a critical threshold, patients begin to suffer clinical impairment and disease progression. Longitudinal studies suggest that CNS atrophy may occur in patients with clinically isolated demyelinating syndromes who are at high risk for developing clinically definite MS. Longitudinal natural history studies in relapsing-remitting, secondary progressive, and primary progressive MS have suggested that patients develop CNS atrophy at a faster rate in the first few years of disease than later in the disease course. Similarly, long-term follow-up studies have shown a poor relationship between disease duration and the rate of brain atrophy. The authors conclude that measurement of atrophy of the CNS is emerging as a clinically relevant biomarker of the MS disease process.


Zivadinov, R. and R. Bakshi (2004). "Role of MRI in multiple sclerosis I: inflammation and lesions." Front Biosci 9: 665-83.

            Conventional magnetic resonance imaging (MRI) can improve accuracy in the diagnosis of multiple sclerosis (MS). Metrics derived from conventional MRI are now routinely used to detect therapeutic effects and extend clinical observations. Hyperintense lesions on T2-weighted MRI scans are related primarily to increased water content and thus cannot distinguish between inflammation, edema, demyelination, Wallerian degeneration, and axonal loss. In addition, T2-weighted and post-contrast images are not sufficiently sensitive to detect occult disease affecting normal appearing gray and white matter. They do not show a reliable correlation with clinical measures of disability and do not provide a complete assessment of therapeutic outcomes. In the past few years a host of advanced MRI techniques and analysis methods have been introduced for the assessment of MS. These MRI techniques appear to have better reliability as surrogate markers for monitoring the pathologic processes that most likely are related to disease activity and clinical progression. They are able to reveal a range of tissue changes that include edema, inflammation, demyelination, axonal loss, and neurodegeneration. Therefore, in a disease with a high degree of longitudinal variability of clinical signs and symptoms within and between patients, and with no current adequate biological markers of disease progression, non-conventional MRI techniques provide a powerful tool to non-invasively study pathological substrates of overt lesions and normal appearing brain tissue. In particular, the use of these techniques is promising in elucidating mechanisms underlying the accumulation of tissue damage, repair and functional reorganization of neural pathways in patients with MS.


Zivadinov, R. and R. Bakshi (2004). "Role of MRI in multiple sclerosis II: brain and spinal cord atrophy." Front Biosci 9: 647-64.

            A growing body of evidence indicates that irreversible tissue destruction including axonal and neuronal degeneration is a key component of the multiple sclerosis (MS) disease process. Magnetic resonance imaging (MRI) is a powerful technique that can be combined with semiautomated or automated computer assisted analysis approaches to detect progressive atrophy of the brain and spinal cord with high sensitivity and reproducibility. The pathophysiology of central nervous system (CNS) atrophy in MS is unknown but likely represents an epiphenomenon related to the effects of inflammation including chronic demyelination, axonal injury, neuronal loss and Wallerian degeneration. Other factors that may contribute to tissue atrophy include injury to the normal appearing gray and white matter by mechanisms such as loss of growth factors, altered electrical conduction and pathologic iron deposition. Prospective studies have suggested that atrophy in MS is predicted by previous inflammatory activity as measured by overt MRI lesions. Gadolinium (Gd)-enhancing lesions have shown a particularly strong predictive value in some but not all longitudinal studies of brain atrophy. Brain atrophy has also been related in cross-sectional and longitudinal studies to T2-hypointense lesions in deep grey matter, suggesting a link between tissue iron deposition and atrophy. The measurement of brain atrophy seems to be of growing clinical relevance as a biomarker of the MS disease process. Atrophy should now be included as a secondary endpoint in trials of therapies aimed at limiting disease progression. Currently available anti-inflammatory immunomodulatory agents and immunosuppressive treatments, while effective at preventing clinical deterioration, have shown at best partial effects in preventing CNS atrophy. Thus, there is a need to further validate atrophy as an outcome measure and ultimately develop treatment strategies that will protect against the destructive aspects of the disease process. This should in turn lead to better long term neurologic functioning and a better quality of life for patients with MS.

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