Multiple Sclerosis References 2003; Authors: E-F
(56 References)
Egner, A., V. L. Phillips, et al. (2003). "Depression, fatigue, and health-related quality of life among people with advanced multiple sclerosis: Results from an exploratory telerehabilitation study." NeuroRehabilitation 18(2): 125-33.
This study reports on secondary data, depression, fatigue and health-related quality of life (HRQOL), collected on people with advanced multiple sclerosis (MS) as part of a larger study of the impact of a telerehabilitation intervention on people with severe mobility impairment. People with spinal cord injuries (SCIs) (n=111) and the prevention of pressure sores were the primary group of interest of the project. The focus here is on data collected from people with advanced MS (n=27), who were included as an exploratory cohort, as they experience increased risk of pressure ulcer development as their level of mobility declines. The study consisted of a nine-week intervention with three randomized groups: video, telephone, and standard care. Aside from information on pressure sores, data were also collected on fatigue, depression, and HRQOL for a two-year follow-up period. For the video group HRQOL scores trended higher and fatigue and depression scores lower for 24 months. Fatigue scores were significantly lower for the video group at month six, 12, and 18. In the sample overall, fatigue symptoms were far more prominent than depressive symptoms and affected 100% higher rates of depression than women. At baseline, controlling for Extended Disability Status Score (EDSS), depression and fatigue were correlated. However, contrary to indications from previous cross-sectional studies, no consistent relationship was observed over time between the two. Telerehabilitation interventions for people with advanced MS warrant further investigation. Findings here suggest that such interventions may be beneficial, although the results need affirmation through larger samples. In addition, the higher prevalence of male depression merits serious attention.
Ehde, D. M., M. P. Jensen, et al. (2003). "Chronic pain secondary to disability: a review." Clin J Pain 19(1): 3-17.
BACKGROUND: Until recently, very little has been written regarding chronic pain as a secondary problem in persons who already have a physical disability, despite the potential for pain to increase the negative impact of what may already be a very disabling condition. The purpose of this review is to summarize what is currently known concerning the nature and scope of chronic pain as a secondary condition to disability, specifically spinal cord injury, acquired amputations, cerebral palsy, multiple sclerosis, neuromuscular disease, and postpolio syndrome. METHOD: What is known concerning the frequency, severity, impact, and treatment of pain in these specific conditions is reviewed, as are the factors that contribute to, or are associated with, adjustment to chronic pain in these disability groups. The authors conclude with several research questions that emerge from this knowledge, the answers to which will contribute to the long-term goal of the reduction of pain and suffering in persons with disabilities. CONCLUSIONS: The existing literature clearly documents that many persons with disabilities experience chronic pain. Many questions remain unanswered regarding the scope, severity, and treatment of chronic pain in these groups.
Eikelenboom, M. J., A. Petzold, et al. (2003). "Multiple sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy." Neurology 60(2): 219-23.
OBJECTIVE: To evaluate markers of axonal damage in CSF and serum of patients with different subtypes of MS in relation to measures of disease progression on MRI. METHODS: In 51 patients with MS (21 relapsing-remitting, 20 secondary progressive, 10 primary progressive), levels of heavy and light neurofilaments (NfH and NfL) and antibodies to neurofilaments (anti-NfL and -NfH) as well as the total immunoglobulin G (IgG) were analyzed. MRI analysis included T2 hyperintense, T1 hypointense, and gadolinium enhancing lesions and markers of cerebral atrophy (ventricular and parenchymal fractions). RESULTS: For the total group, correlations were found between the anti-NfL index and the parenchymal fraction (PF) (r = -0.51, p < 0.001), T2 lesion load (r = 0.41, p < 0.05), ventricular fraction (r = 0.37, p < 0.05), and T1 lesion load (r = 0.37, p < 0.05). For the anti-NfH index, a correlation was found with the PF (r = -0.39, p < 0.05). No correlations were found between the IgG index and MRI measures. CONCLUSIONS: Intrathecal production of anti-NfL antibodies may serve as a marker of tissue damage, particularly axonal loss, in MS.
Einarsson, U., K. Gottberg, et al. (2003). "Multiple sclerosis in Stockholm County. A pilot study exploring the feasibility of assessment of impairment, disability and handicap by home visits." Clin Rehabil 17(3): 294-303.
OBJECTIVE: A pilot study performed within Stockholm County to evaluate the feasibility of collecting data using a comprehensive evaluation package administered in the home environment to assess impairment, disability and handicap in order to explore the consequences of multiple sclerosis (MS). DESIGN: Home visits to 26 purposefully selected MS patients with different levels of disability, in both ordinary and sheltered living. The comprehensive evaluation package included: biographical data, Mini-Mental State Examination, Free Recall and Recognition of 12 Random Words Test, Symbol Digit Modalities Test, Beck Depression Index, Lindmark Motor Capacity Assessment, time to walk 10 metres, Nine-hole Peg Test, Barthel ADL Index, Katz Extended ADL Index, Frenchay Activities Index, Sickness Impact Profile and frequency of falls and injurious falls. RESULTS: This pilot study demonstrates that the proposed methods can be used to evaluate MS patients differing in levels of disability and forms of living. The data collection method, based on home visits, was well accepted by the patients, their spouses and salaried personal assistants and could be performed within 2-2 1/2 hours. CONCLUSIONS: The evaluation package used in this pilot study is suitable for use in population-based studies and it should provide comprehensive information on the impact and consequences of MS on patients, and should contribute to the identification of areas in which the provision of rehabilitation and health care services needs to be improved.
Elliott, P. J., T. M. Zollner, et al. (2003). "Proteasome inhibition: a new anti-inflammatory strategy." J Mol Med 81(4): 235-45.
The ubiquitin-proteasome pathway has a central role in the selective degradation of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. Consequently proteasome inhibition is a potential treatment option for cancer and inflammatory conditions. Thus far, proof of principle has been obtained from studies in numerous animal models for a variety of human diseases including cancer, reperfusion injury, and inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis. Two proteasome inhibitors, each representing a unique chemical class, are currently under clinical evaluation. Velcade (PS-341) is currently being evaluated in multiple phase II clinical trials for several solid tumor indications and has just entered a phase III trial for multiple myeloma. PS-519, representing another class of inhibitors, focuses on the inflammatory events following ischemia and reperfusion injury. Since proteasome inhibitors exhibit anti-inflammatory and antiproliferative effects, diseases characterized by both of these processes simultaneously, as is the case in rheumatoid arthritis or psoriasis, might also represent clinical opportunities for such drugs.
Embrey, N. and C. Lowndes (2003). "Benchmarking best practice in relapse management of multiple sclerosis." Nurs Stand 17(22): 38-42.
The Midlands multiple sclerosis (MS) nurse group developed a benchmark for relapse management in MS, using the framework outlined in the DoH document Essence of Care (DoH 2001). The authors discuss the benchmarking process and demonstrate how specialist nurses can collaboratively establish best practice and influence the quality of care. The potential benefits of applying the benchmarking process to relapse management are discussed. Good practice for management of patients with relapsing MS has been developed.
Enzinger, C., S. Ropele, et al. (2003). "Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele." Arch Neurol 60(1): 65-70.
BACKGROUND: In multiple sclerosis (MS), the epsilon4 allele of apolipoprotein E (APOE epsilon4) has been associated with more rapid clinical worsening and more severe tissue damage on magnetic resonance imaging. OBJECTIVE: To use proton magnetic resonance spectroscopy ((1)H-MRS) to further explore the biochemical changes in the brains of patients with MS associated with APOE epsilon4. DESIGN: A 2-year clinical and (1)H-MRS follow-up cohort study. SETTING: The MS outpatient clinic, Department of Neurology, and Magnetic Resonance Center of Karl-Franzens University. PATIENTS: We performed (1)H-MRS of the central portion of both hemispheres and APOE genotyping in 72 patients (52 women and 20 men; mean +/- SD age, 34.8 +/- 8.8 years) with clinically definite relapsing-remitting MS. Repeated studies were performed in 44 patients after a mean +/- SD interval of 34 +/- 9 months. MAIN OUTCOME MEASURE: Levels of N-acetylaspartate as measured by (1)H-MRS. RESULTS: Patients with MS and an epsilon4 allele (n = 19) had a significantly lower mean +/- SD N-acetylaspartate-creatine ratio than those without an epsilon4 allele (n = 53) (1.73 +/- 0.26 vs 1.89 +/- 0.24; P =.04) despite the absence of significant differences in age at onset, disease duration, Expanded Disability Status Scale score, and number of previous relapses between subgroups. During follow-up, the drop in the N-acetylaspartate-creatine ratio of epsilon4 carriers was also significantly larger (-0.31 vs -0.10; P =.01). This was paralleled by a higher number of relapses (mean +/- SD, 4.1 +/- 2.7 vs 1.7 +/- 1.6; P =.02) and a faster although nonsignificant progression of disability (mean +/- SD (Delta)Expanded Disability Status Scale score, 0.9 +/- 1.8 vs 0.3 +/- 1.1; P =.19). CONCLUSIONS: The APOE epsilon4 allele has a negative effect on the course of MS, and increasing axonal damage may be an important mechanism.
Eriksen, E., R. Haugstad, et al. (2003). "Interferon-beta Treatment in Multiple Sclerosis; Patients' Experience in the First 100 Patients." Acta Neurol Scand 107(6): 429-30.
Eriksson, M., O. Andersen, et al. (2003). "Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis." Mult Scler 9(3): 260-74.
This paper extends on previous data on prognosis in multiple sclerosis (MS), to encompass the entire course of the disease. The first episode suggestive of MS [the clinically isolated syndrome (CIS)] was included as a starting point, and the speed of secondary progression as an end point. Primary progressive MS was not included. Unique preconditions, with one neurological service covering the Goteborg district, allowed for establishing a strictly population-based, essentially untreated 15-year incidence cohort of 308 MS patients who were followed for 25 years. Survival analysis was performed as Kaplan-Meyer graphs, and independent predictors were ascertained by Cox regression analysis. A matrix of several predictors and end points was created. From CIS, a higher risk of developing clinically definite MS (CDMS), secondary progressive course and Disability Status Scale 7 (DSS7) was predicted by efferent tract lesions. However, less than 25% had reached DSS7 25 years after CIS with pure afferent lesions or other favorable predictors. During the first five years, higher relapse frequency, as well as incomplete remission of early bouts, predicted higher risks of secondary progressive course and DSS7 during follow-up to 25 years. However, these early predictors were unable to predict the rate of progression, which seems to contain an element of the disease process unassociated with its early events. Only late predictors, such as a shorter time from onset to secondary progression (1-10 years) and a higher number of functional systems involved at onset of progression predicted a faster progression rate. Predictors from this study could be used to refine historically controlled trials.
Evans, J. P., M. H. Brown, et al. (2003). "Revising the troublesome stoma: combined abdominal wall recontouring and revision of stomas." Dis Colon Rectum 46(1): 122-6.
PURPOSE: Despite preoperative siting and maturation of stomas, some patients may have poor stoma function because of redundant pannus, scars, creases, and parastomal or incisional hernias. In these patients, a combined abdominoplasty and stoma revision may be helpful. The object of this manuscript is to report our preliminary results. METHODS: Eight patients (mean age, 48 years; female/male ratio, 7/1) undergoing this procedure are reported. Five patients had inflammatory bowel disease, two had malignancies, and one had multiple sclerosis with bladder and bowel involvement. Patients were contacted at two months to two years follow-up to assess functional outcome and satisfaction with the procedure. RESULTS: Indications for surgery were difficulty maintaining an appliance (n = 7), frequent stool leakage (n = 6), and skin irritation (n = 4). Multiple surgeries (n = 4), skin creases (n = 3), scarring (n = 2), large weight loss (n = 4), and hernias (n = 5) were contributing factors. At surgery five patients had hernias repaired (3 parastomal, 2 incisional), three had stomas resited, and three underwent resections for Crohn's disease. One patient developed a seroma postoperatively. At follow-up six patients were able to maintain an appliance for at least four days, whereas one changed the appliance every three days because of personal preference. None experience stool leakage. All reported a dramatic improvement in body image. CONCLUSION: Combined stoma revision and abdominoplasty can be performed safely and leads to improved functional results and outcome.
Fagius, J. (2003). "[Disease-modifying treatment of MS--progress with complications]." Lakartidningen 100(13): 1164, 1167-8.
Fassas, A. (2003). "Intense immunosuppression and autologous hematopoietic stem cell transplantation for multiple sclerosis." Haematologica 88(3): 244-5.
Fazakerley, J. K. and R. Walker (2003). "Virus demyelination." J Neurovirol 9(2): 148-64.
A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent demyelinating diseases are progressive multifocal leukoencephalopathy, caused by JC papovirus destruction of oligodendrocytes, and subacute sclerosing panencephalitis, an invariably fatal childhood disease caused by persistent measles virus. The most common neurological disease of young adults in the developed world, multiple sclerosis, is also characterized by lesions of inflammatory demyelination; however, the etiology of this disease remains an enigma. A viral etiology is possible, because most demyelinating diseases of known etiology in both man and animals are viral. Understanding of the pathogenesis of virus-induced demyelination derives for the most part from the study of animal models. Studies with neurotropic strains of mouse hepatitis virus, Theiler's virus, and Semliki Forest virus have been at the forefront of this research. These models demonstrate how viruses enter the brain, spread, persist, and interact with immune responses. Common features are an ability to infect and persist in glial cells, generation of predominantly CD8(+) responses, which control and clear the early phase of virus replication but which fail to eradicate the infection, and lesions of inflammatory demyelination. In most cases demyelination is to a limited extent the result of direct virus destruction of oligodendrocytes, but for the most part is the consequence of immune and inflammatory responses. These models illustrate the roles of age and genetic susceptibility and establish the concept that persistent CNS infection can lead to the generation of CNS autoimmune responses.
Feindel, W. (2003). "Osler and the "medico-chirurgical neurologists": Horsley, Cushing, and Penfield." J Neurosurg 99(1): 188-99.
Sir Victor Horsley's lecture "On the Technique of Operations on the Central Nervous System," delivered in Toronto in 1906, set the stage for an appraisal of Sir William Osler as a protagonist for the emerging specialty of neurosurgery. During his time at McGill University from 1871 to 1884, Osler performed more than 1000 autopsies. Hispathological reports covered the topics of cerebral aneurysm, apoplectic hemorrhage, vascular infarction, subdural hematoma, meningitis, multiple sclerosis, cerebral abscess, and brain tumor. He wrote about cerebral localization and anatomy and the relationships between the morphological characteristics of the brain and intelligence and criminality. During his continuing career at Philadelphia and Baltimore, Osler published widely on problems in clinical neurology, including monographs on cerebral palsies and chorea as well as chapters on disorders of the nervous system in the first five editions of his popular textbook, The Principles and Practice of Medicine. He became familiar with many of the outstanding figures in medical neurology of his time. Regarding neurosurgery, Osler commended the pioneer operation for a brain tumor in 1884 by Rickman Godlee and the surgery for epilepsy in 1886 by Horsley. In 1907, in discussing the state of brain surgery as reviewed by Horsley, William Macewen, and others, Osler made a plea for "medico-chirurgical neurologists, properly trained in the anatomical, physiological, clinical and surgical aspects of the subject." He played a significant role as a referring physician, mentor, and friend to his young colleague Harvey Cushing (later to become Osler's Boswell), who was breaking new ground in neurosurgery at Johns Hopkins Hospital. Beyond that Osler became an inspiring hero figure for his Oxford student Wilder Penfield, who a few decades later would establish a neurological institute at McGill University where medico-chirurgical neurology would flourish.
Feinstein, D. L. (2003). "Therapeutic potential of peroxisome proliferator-activated receptor agonists for neurological disease." Diabetes Technol Ther 5(1): 67-73.
Activation of peroxisome proliferator-activated receptors (PPARs) mediates the insulin-sensitizing effects of thiazolidinediones used for treatment of type 2 diabetes, owing to changes in the transcription and expression of genes influencing carbohydrate and lipid metabolism. However, PPAR activation can have additional effects upon cellular physiology, including anti-proliferative and anti-inflammatory. These effects are observed in many cell types, including brain glial cells and blood lymphocytes, cells whose activation contributes to the initiation and progression of damage occurring in neurological diseases such as Alzheimer's disease (AD) and multiple sclerosis (MS). In view of the need for development of additional therapeutic options, several recent studies have tested the possibility that PPAR agonists would be neuroprotective in these diseases. This paper will summarize data from cell culture experiments and from studies in animal models, demonstrating that PPARgamma agonists can exert neuroprotective effects, thereby providing the basis for the design of clinical trials to test the safety and efficacy of thiazolidinediones in neuroinflammatory conditions such as AD and MS.
Feki, I., F. Belahsen, et al. (2003). "[Subacute myelitis revealed by human immunodeficiency virus infection]." Rev Neurol (Paris) 159(5 Pt 1): 577-80.
A 35 year-old heterosexual man had a six months history of cervical myelitis with progressive paraplegia, leg weakness and paresthesia of the four extremities. Spinal cord MRI showed a high T2 signal intramedullary lesion wide from the bulbo-medullary junction to D4. Post gadolinium T1 sequence revealed an enhancement in front of C3-C4 vertebrae. VIH serology was positive. Corticosteroid treatment achieved a marked improvement. In addition to vacuolar myelopathy, well-known at the advanced stages of the HIV infection (AIDS), myelitis and clinical pictures simulating multiple sclerosis were described during early stages of the infection. These inflammatory lesions of the central nervous system and sometimes of the peripheral nervous system seems to be related to the immune response dysfunction induced by the VIH.
Fernandez, O., T. Arbizu, et al. (2003). "Clinical benefits of interferon beta-1a in relapsing-remitting MS: a phase IV study." Acta Neurol Scand 107(1): 7-11.
OBJECTIVE: To evaluate the efficacy and safety of IFNbeta-1a (Avonex, Biogen, Inc., Cambridge, MA, USA) in patients with relapsing-remitting multiple sclerosis (MS). METHODS: In this multicenter, open-label, prospective clinical trial, 96 patients with relapsing-remitting MS received IFNbeta-1a 30 mcg intramuscularly once weekly for 2 years. Outcome variables included: change from baseline in mean number of exacerbations, proportion of exacerbation-free patients, and mean Expanded Disability Status Scale (EDSS) scores at Years 1 and 2. RESULTS: IFNbeta-1a significantly (P < 0.0001) reduced exacerbation rate at Years 1 and 2 of treatment. The percentage of exacerbation-free patients was 53% during Year 1 and 33% during Year 2. Mean EDSS scores were 2.96 +/- 1.26 at baseline, 2.89 +/- 1.42 at Year 1, and 3.00 +/- 1.62 at Year 2 (P = 0.116). EDSS scores improved in 35.4%, remained stable in 28.1%, and worsened in 36.5% of patients. IFNbeta-1a treatment was well tolerated. CONCLUSION: This study confirms and extends the beneficial clinical profile for IFNbeta-1a in relapsing MS.
Ferrari, R. (2003). "Acute cervical hyperextension-hyperflexion injury may precipitate and/or exacerbate symptomatic multiple sclerosis." Eur J Neurol 10(1): 109-10.
Feve, A. (2003). "[Spasticity and botulinum toxin in 2003. An update]." Neurochirurgie 49(2-3 Pt 2): 265-70.
After the spastic foot in cerebral palsy, there are now wider indications for botulinum toxin injections in spasticity. Post stroke upper limb spasticity has been usefully treated by botulinum toxin in several studies, including double blind placebo-controlled studies. Two serotypes and one serotype B are marketed, with various properties. Botulinum toxin has been studied in multiple etiologies of spasticity. In multiple sclerosis, few studies revealed an efficacy in angulations and comfort. In spinal cord injuries, gait and sphincter disorders can be improved. In post stroke spasticity, lower limb angulations are improved, but gait remained difficult to evaluate. In upper limb spasticity, angulation, function and quality of life were improved in double blind, placebo controlled studies. Comparisons of costs and efficacy are made between botulinum toxin and the other antispastic methods.
Feys, P., W. F. Helsen, et al. (2003). "Intention tremor during manual aiming: a study of eye and hand movements." Mult Scler 9(1): 44-54.
Accurate goal-directed movements toward a visual target require a precise coordination of both the oculomotor and limb motor systems. Intention tremor and eye movement deficits are frequently observed in multiple sclerosis (MS). The goal of this study was to examine the characteristics of intention tremor and simultaneously produced eye movements during rapid goal-directed movements. Eye and hand movements were synchronously measured in 16 MS patients with intention tremor and 16 control subjects. Manual performances of the patient group were characterized by a delayed onset, slower execution and aiming inaccuracies. In line with the clinically defined picture of intention tremor differences between patients and control subjects were most pronounced toward the end of the movement. Dependent variables were obviously greater in MS patients compared with control subjects, and correlated well with clinical outcome measures. The application of an inertial load to the limb did not show any effect on intention tremor. In addition to impaired limb coordination, evidence has been found that eye movements, too, were abnormal in patients compared with control subjects. Moreover, eye and hand movement deficits seemed to be closely related, suggesting a common underlying command structure. Inaccurate eye movements were likely to hamper an accurate motor performance of the hand.
Feys, P. G., A. Davies-Smith, et al. (2003). "Intention tremor rated according to different finger-to-nose test protocols: a survey." Arch Phys Med Rehabil 84(1): 79-82.
OBJECTIVES: To investigate the dependence of intention tremor rating scores on different finger-to-nose test (FNT) protocols, varying in arm position and the time the finger has to be kept on the nose, and to examine their relevance to function. DESIGN: Observational survey. Video recordings were made while patients performed the FNTs and functional tasks such as pouring water. SETTING: Three European rehabilitation centers in Belgium, Finland, and England. PARTICIPANTS: Twenty-six multiple sclerosis patients with intention tremor (avg age, 44.1y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Six examiners rated the degree of intention tremor by using the Fahn Tremor Rating Scale. RESULTS: Interrater reliability for rating intention tremor during the FNTs was high (kappa=.65-.74). Both the required arm position and time constraints affected the magnitude of intention tremor rating scores (mean rank, 2.27-2.95) and their functional relevance (rho=.70-.84). Intention tremor was scored the highest when the arm was lifted to 90 degrees of abduction at the shoulder and the subject was required to stabilize the finger on the nose. However, its functional relevance was lower compared with a more "functionally" executed FNT. CONCLUSIONS: The rating of intention tremor during the FNT depends on test instructions. A standardized protocol is needed.
Filion, L. G., D. Matusevicius, et al. (2003). "Monocyte-derived IL12, CD86 (B7-2) and CD40L expression in relapsing and progressive multiple sclerosis." Clin Immunol 106(2): 127-38.
Multiple sclerosis has been postulated to be an autoimmune disease in which Th1 immune responses predominate. This response is associated with an increased production of IFNgamma and IL12 produced by T cells and by cells of the monocyte (MO) lineage, respectively. An increased expression of costimulatory molecules by T cells and antigen-presenting cells is also observed. We hypothesized that in relapsing-remitting MS (RRMS) (with or without of IFNbeta treatment) and in secondary progressive patients (SPMS) IL12 and costimulatory molecules (CD80 [B7-1], CD86 [B7-2], CD28, CD40, CD40L) would be differentially produced or expressed by MO or T cells. We performed cross-sectional and longitudinal flow cytometric studies (at monthly intervals) on peripheral blood mononuclear cells (PBMC) or on MO from SPMS or untreated and IFNbeta-treated patients with RRMS. We determined that CD86 and CD40L expression was highest on MO derived from SPMS patients compared to those from RRMS or from healthy controls (HC). In vitro culture of PBMC with recombinant human IL10, a cytokine that may be increased in response to treatment with IFNbeta and that down-regulates CD86 expression, reduced the expression of CD86 on MO derived from RRMS patients to a much higher degree compared to cells derived from SPMS or HC. In vitro secreted IL12 levels from freshly isolated MO from SPMS patients were more than 10-fold higher than either the treated or the untreated RRMS or HC. RRMS patients treated with IFNbeta demonstrated slightly lower levels of MO IL12 secretion. Our data suggest that a key mechanism in the pathogenesis of MS is the increased expression of CD86 and CD40L and the increased production of IL12 during disease progression. Part of the mechanism of action of IFNbeta may be to reduce MO CD86 and CD40L expression and IL12 secretion; failure to do so might signify either a lack of response or a transition to a more progressive phase of illness.
Filion, L. G., G. Graziani-Bowering, et al. (2003). "Monocyte-derived cytokines in multiple sclerosis." Clin Exp Immunol 131(2): 324-34.
MS is an inflammatory, presumably autoimmune, disease mediated by the activation of T cells, B cells and monocytes (MO). Inflammation is thought to occur early during the relapsing-remitting phase of MS (RRMS), whereas in the later phases of MS such as secondary progressive MS (SPMS), inflammation tends to diminish. Our objective was to compare the types and amounts of proinflammatory and regulatory cytokines produced by MO from relapsing-remitting patients with or without treatment with IFN-beta (RRMS+ therapy, RRMS- therapy), respectively, from secondary progressive patients (SPMS) and from healthy controls (HC). MO were isolated by a density-gradient technique and three different techniques (RNase protection assay, ELISA and intracellular cytokine staining) were used to assess cytokine levels. An increase in IL6, IL12 and TNF-alpha was observed by all three methods for RRMS- therapy and for SPMS patients compared to HC and RRMS+ therapy patients. We conclude that proinflammatory and regulatory monokines can be derived from MO of MS patients and that these levels are modulated by IFN-beta therapy. Although it is believed that inflammation tends to diminish in SPMS patients, our data show that inflammatory cytokines continue to be released at high levels, suggesting that IFN-beta or IL10 treatment may be beneficial for this group.
Filippi, M. and M. A. Rocca (2003). "Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging." Curr Opin Neurol 16(3): 275-82.
PURPOSE OF REVIEW: This review is intended to provide an up-to-date summary of the main functional magnetic resonance imaging studies conducted in patients with multiple sclerosis, and to show how such studies are changing our views on the ability of the multiple sclerosis brain to limit the clinical consequences of irreversible structural tissue damage. RECENT FINDINGS: Brain cortical reorganization is a common phenomenon occurring in patients with multiple sclerosis, independent of disease duration and clinical phenotype, which can be elicited by macroscopic lesions, as well as by the presence of 'occult' multiple sclerosis-related damage of the brain and cervical cord. An increased recruitment of the cerebral networks involved in the performance of given tasks might represent a first step in cortical reorganization with the potential to maintain a normal level of function in the course of multiple sclerosis. The progressive failure of these mechanisms, because of accumulating tissue damage, might, on the one hand, result in the activation of previously silent 'second-order' compensatory areas, and, on the other, contribute to the accumulation of irreversible disability. SUMMARY: Functional magnetic resonance imaging has the potential to provide important information about cortical reorganization following multiple sclerosis-related tissue damage, which should improve our understanding of the factors associated with the accumulation of irreversible disability in this disease. The enhancement of any beneficial effects of this cortical adaptive plasticity should be considered as a potential target of therapy for multiple sclerosis.
Filippi, M., M. A. Rocca, et al. (2003). "The use of quantitative magnetic-resonance-based techniques to monitor the evolution of multiple sclerosis." Lancet Neurol 2(6): 337-46.
Conventional MRI can improve accuracy in the diagnosis of multiple sclerosis (MS) and monitor the efficacy of experimental treatments. However, conventional MRI provides only gross estimates of the extent and nature of tissue damage associated with this disease. Other quantitative magnetic-resonance-based techniques have the potential to overcome the limitations of conventional MRI and, as a consequence, to improve our understanding of the natural history of MS. Magnetisation-transfer, diffusion-weighted, and functional MRI-as well as proton magnetic-resonance spectroscopy-are helping us to elucidate the mechanisms that underlie injury, repair, and functional adaptation in patients with MS. These techniques are substantially changing our understanding of how MS causes irreversible disability and should be used more extensively in clinical trials and in studies of disease progression.
Filippi, M. (2003). "MRI-clinical correlations in the primary progressive course of MS: new insights into the disease pathophysiology from the application of magnetization transfer, diffusion tensor, and functional MRI." J Neurol Sci 206(2): 157-64.
Despite patients with primary progressive multiple sclerosis (PPMS) experience a progressive disease course from onset, the burden and activity of lesions on conventional magnetic resonance imaging (MRI) scans of the brain are lower than in all other main clinical phenotypes of MS. This review outlines the major contributions given by magnetization transfer MRI, diffusion tensor MRI and functional MRI to the understanding of the pathophysiology of PPMS and provides evidence that, at least, three factors might explain this clinical/MRI discrepancy: (a) the presence of a diffuse tissue damage at a microscopic level; (b) a prevalent involvement of the cervical cord, and (c) an impairment of the adaptive capacity of the cortex to limit the functional consequences of subcortical structural damage.
Filippi, M., M. Bozzali, et al. (2003). "Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis." Brain 126(Pt 2): 433-7.
Although axonal pathology is recognized as one of the major pathological features of multiple sclerosis, it is less clear how early in its course it occurs and how it correlates with MRI-visible lesion loads. To assess this early axonal pathology, we quantified the concentration of whole-brain N-acetylaspartate (WBNAA) in a group of patients at the earliest clinical stage of the disease and compared the results with those from healthy controls. Conventional brain MRI and WBNAA using unlocalized proton magnetic resonance spectroscopy were obtained from 31 patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis and paraclinical evidence of dissemination in space, and from 16 matched controls. An additional conventional MRI scan was obtained in all patients 4-6 months later to detect dissemination of lesions in time. The mean WBNAA concentration was significantly lower in patients compared with the controls (P < 0.0001). It was not significantly different between patients with and without enhancing lesions at the baseline MRI or between patients with and without lesion dissemination in time. No correlation was found between WBNAA concentrations and lesion volumes. Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis. This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention.
Filippi, M. (2003). "Magnetization transfer MRI in multiple sclerosis and other central nervous system disorders." Eur J Neurol 10(1): 3-10.
The present review summarizes the major contributions given by magnetization transfer-magnetic resonance imaging to provide an accurate in vivo picture of the heterogeneity of central nervous system pathology and, ultimately, to improve our ability to monitor the evolution of various neurological conditions.
Filippini, G., L. Munari, et al. (2003). "Interferons in relapsing remitting multiple sclerosis: a systematic review." Lancet 361(9357): 545-52.
BACKGROUND: Recombinant interferons have been approved by many national regulatory agencies for treatment of relapsing remitting multiple sclerosis, but widespread discussion continues about their true effectiveness, benefits, side-effects, and costs. METHODS: With the Cochrane Collaboration methodology, we reviewed all published, randomised, placebo-controlled trials of recombinant interferons undertaken in patients with relapsing remitting multiple sclerosis between 1993 and 2002. Our primary aim was to find out whether recombinant interferons reduced the number of patients who had clinical exacerbations and disease progression, compared with placebo. FINDINGS: The seven trials that met our criteria included 1215 randomised patients: data from 667 (55%) were available for analysis at 1 year's and from 919 (76%) at 2 years' follow-up. Interferon seemed to reduce the number of patients who had exacerbations during the first year of treatment (relative risk 0.73, 95% CI 0.54-0.99), but results at 2 years' follow-up were not robust and were difficult to interpret because of the many dropouts. Although the number of patients who had exacerbations (0.81, 0.74-0.89) or progressed (0.70, 0.55-0.88) during the first 2 years fell significantly in the protocol analysis, results were inconclusive after sensitivity analyses for exacerbations (1.11, 0.73-1.68) and disease progression (1.31, 0.60-2.89). Data were insufficient to establish whether steroid use and admissions to hospital were reduced in the interferon group. Similarly, MRI outcome data could not be analysed quantitatively. Side-effects were common, and acute toxic effects adversely affected quality of life. INTERPRETATION: Recombinant interferons slightly reduce the number of patients who have exacerbations during first year of treatment. Their clinical effect beyond 1 year is uncertain and new trials are needed to assess their long-term effectiveness and side-effects.
Filippovich, A. N. (2003). "[Diagnosis of multiple sclerosis in the initial stage of the disease]." Zh Nevrol Psikhiatr Im S S Korsakova 103(2): 49-50.
Finesilver, C. (2003). "Multiple sclerosis." Rn 66(4): 36-43; quiz 44.
Firouzi, R., A. Rolland, et al. (2003). "Multiple sclerosis-associated retrovirus particles cause T lymphocyte-dependent death with brain hemorrhage in humanized SCID mice model." J Neurovirol 9(1): 79-93.
A retroviral element (multiple sclerosis-associated retrovirus, MSRV) defining a family of genetically inherited endogenous retroviruses (human endogenous retrovirus type W, HERV-W) has been characterized in cell cultures from patients with multiple sclerosis. Recently, MSRV retroviral particles or the envelope recombinant protein were shown to display superantigen activity in vitro, but no animal model has yet been set up for studying the pathogenicity of this retrovirus. In the present study, the pathogenicity of different sources of MSRV retroviral particles has been evaluated in a hybrid animal model: severe combined immunodeficiency (SCID) mice grafted with human lymphocytes and injected intraperitoneally with MSRV virion or mock controls. MSRV-injected mice presented with acute neurological symptoms and died within 5 to 10 days post injection. Necropsy revealed disseminated and major brain hemorrhages, whereas control animals did not show abnormalities (P <.001). In ill animals, reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed circulating MSRV RNA in serum, whereas overexpression of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma was evidenced in spleen RNA. Neuropathological examination confirmed that hemorrhages occurred prior to death in multifocal areas of brain parenchyma and meninges. Further series addressed the question of immune-mediated pathogenicity, by inoculating virion to SCID mice grafted with total and T lymphocyte-depleted cells in parallel: dramatic and statistically significant reduction in the number of affected mice was observed in T-depleted series (P <.001). This in vivo study suggests that MSRV retroviral particles from MS cultures have potent immunopathogenic properties mediated by T cells compatible with the previously reported superantigen activity in vitro, which appear to be mediated by an overexpression of proinflammatory cytokines.
FitzGerald, U. F., T. Gilbey, et al. (2003). "Transcription factor expression and cellular redox in immature oligodendrocyte cell death: effect of Bcl-2." Mol Cell Neurosci 22(4): 516-29.
Multiple sclerosis (MS) is characterized by the progressive damage or loss of oligodendrocytes. In an effort to better understand the causes of oligodendrocyte destruction in MS plaques, we treated immature oligodendrocytes with glucose oxidase, ceramide, or brefeldin A. These treatments model the different mechanisms by which oligodendrocytes are thought to die. We report that the AP-1 and Egr-1 transcription factors are induced within an hour of treatment. Of the AP-1 proteins studied, c-Jun was expressed at the highest level, followed by JunD, c-Fos, and Fra-2, although different treatments induced slightly different levels of expression. Bcl-2 overexpression protects against all treatments, to differing degrees. Although Bcl-2 did not have a dramatic effect on AP-1 or Egr-1 induction within the first 3 h, it caused a lowering of steady-state redox levels with a concomitant increase in cellular glutathione. We propose that the lowering of cellular redox and the upregulation of glutathione are responsible in part for the protective properties of Bcl-2.
Flodin, U., A. M. Landtblom, et al. (2003). "Multiple sclerosis in nurse anaesthetists." Occup Environ Med 60(1): 66-8.
BACKGROUND: Volatile anaesthetics are chemically related to organic solvents used in industry. Exposure to industrial solvents may increase the incidence of multiple sclerosis (MS). AIM: To examine the risk among nurse anaesthetists of contracting MS. METHODS: Nurses with MS were identified by an appeal in the monthly magazine of the Swedish Nurse Union and a magazine of the Neurological Patients Association in Sweden. Ninety nurses with MS responded and contacted our clinic. They were given a questionnaire, which was filled in by 85 subjects; 13 of these were nurse anaesthetists. The questionnaire requested information about work tasks, exposure, diagnosis, symptoms, and year. The number of active nurse anaesthetists was estimated based on information from the National Board of Health and Welfare and The Nurse Union. Incidence data for women in the region of Gothenburg and Denmark were used as the reference to estimate the risk by calculation of the standardised incidence ratio (SIR). RESULTS: Eleven of the 13 nurse anaesthetists were exposed to anaesthetic gases before onset of MS. Mean duration of exposure before diagnosis was 14.4 years (range 4-27 years). Ten cases were diagnosed in the study period 1980-99, resulting in significantly increased SIRs of 2.9 and 2.8 with the Gothenburg and the Danish reference data, respectively. CONCLUSION: Although based on crude data and a somewhat approximate analysis, this study provides preliminary evidence for an excess risk of MS in nurse anaesthetists. The risk may be even greater than observed, as the case ascertainment might have been incomplete because of the crude method applied. Further studies in this respect are clearly required to more definitely assess the risk.
Flores, N., C. Duran, et al. (2003). "NFkappaB and AP-1 DNA binding activity in patients with multiple sclerosis." J Neuroimmunol 135(1-2): 141-7.
Current evidence suggests that multiple sclerosis (MS) results from an autoimmune response mediated by T lymphocytes, which would be activated in the peripheral blood and migrate into the central nervous system. NFkappaB and AP-1 are two main transcription factors involved in T-cell activation. To investigate possible alterations in the activity of these factors in MS individuals, we have assayed NFkappaB and AP-1 DNA binding activity in peripheral blood mononuclear cells (PBMC). Binding activity was analyzed by gel mobility shift assay in MS patients compared with controls. No significant differences were found between the two groups, indicating no evidence of abnormalities associated with MS in NFkappaB or AP-1 binding activities in PBMC, both basally and after PMA+anti-CD3 antibody induction.
Folgar, S., E. M. Gatto, et al. (2003). "Parkinsonism as a manifestation of multiple sclerosis." Mov Disord 18(1): 108-10.
We describe a 48-year-old patient, with a diagnosis of relapsing-remitting multiple sclerosis, who presented to our service with a parkinsonian syndrome that markedly improved after corticosteroid treatment. To the best of our knowledge, only 12 cases of parkinsonism have been reported from 1970 to the present, of which only 8 seemed secondary to MS, i.e., those presenting conclusive imaging evidence or unequivocal response to corticosteroids.
Forbes, A., A. While, et al. (2003). "Impact of clinical nurse specialists in multiple sclerosis--synthesis of the evidence." J Adv Nurs 42(5): 442-62.
BACKGROUND: Multiple sclerosis is a chronic neurological condition demanding a broad range of interventions and support. Multiple sclerosis nurse specialists are emerging as a leading force in providing care to this group of patients. AIM: This review aimed to identify and synthesize the evidence on the role of clinical nurse specialists in meeting the care needs of people with multiple sclerosis. METHODS: A systematic review of the literature addressing the role of the multiple sclerosis nurse specialist was undertaken. The review examined both the appropriateness and effectiveness of the multiple sclerosis nurse specialist role. The content of each item identified in the review was analysed, examining the structure, process and outcomes variables associated with the role. Materials containing an explicit methodology were critically appraised using established schedules and graded as strong, moderate or weak. The data were then synthesized in tables, thematically and using a quasi-judicial approach called the 'System of Reasoning'. FINDINGS: Fifty-five items were examined and most (53%; n = 18) were descriptive in nature. There was insufficient evidence to demonstrate that the multiple sclerosis nurse role makes a difference to care. However, evidence was found to support current descriptions of the role - meaning? and there appeared to be a good fit between the role and the care needs of people with multiple sclerosis. CONCLUSION: A systematic overview of the attributes of the multiple sclerosis nurse role is provided which should help service providers, nurses and other professionals consider how multiple sclerosis nurse specialists roles can contribute to the care of people with this condition. While there is little current evidence of effectiveness for the multiple sclerosis nurse specialist role, there is evidence for its appropriateness, although more rigorous primary research is required to test this.
Foster, S. C., C. Daniels, et al. (2003). "Dysregulation of the hypothalamic-pituitary-gonadal axis in experimental autoimmune encephalomyelitis and multiple sclerosis." J Neuroimmunol 140(1-2): 78-87.
The ability of sex hormones to regulate cytokine production is well established, but the ability of cytokines to regulate sex hormone production has only begun to be investigated. We measured sex hormones in mice with passive experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS) patients with sexual dysfunction. Abnormally low serum testosterone levels were found in male mice with EAE and in male MS patients, while serum estrogen levels in female mice with EAE were normal. An inverse relationship between cytokine and testosterone levels in male mice with EAE, coupled with an increase in serum luteinizing hormone (LH) levels, suggests that inflammatory cytokines suppress testosterone production by a direct effect on testicular Leydig cells. Gender differences in the sensitivity of the hypothalamic-pituitary-gonadal (HPG) axis to inflammation may be an important factor regulating the duration and severity of central nervous system (CNS) autoimmunity.
Foxman, B. (2003). "Epidemiology of urinary tract infections: incidence, morbidity, and economic costs." Dis Mon 49(2): 53-70.
Urinary tract infections (UTIs) are considered to be the most common bacterial infection. According to the 1997 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, UTI accounted for nearly 7 million office visits and 1 million emergency department visits, resulting in 100,000 hospitalizations. Nevertheless, it is difficult to accurately assess the incidence of UTIs, because they are not reportable diseases in the United States. This situation is further complicated by the fact that accurate diagnosis depends on both the presence of symptoms and a positive urine culture, although in most outpatient settings this diagnosis is made without the benefit of culture.Women are significantly more likely to experience UTI than men. Nearly 1 in 3 women will have had at least 1 episode of UTI requiring antimicrobial therapy by the age of 24 years. Almost half of all women will experience 1 UTI during their lifetime. Specific subpopulations at increased risk of UTI include infants, pregnant women, the elderly, patients with spinal cord injuries and/or catheters, patients with diabetes or multiple sclerosis, patients with acquired immunodeficiency disease syndrome/human immunodeficiency virus, and patients with underlying urologic abnormalities. Catheter-associated UTI is the most common nosocomial infection, accounting for >1 million cases in hospitals and nursing homes. The risk of UTI increases with increasing duration of catheterization. In noninstitutionalized elderly populations, UTIs are the second most common form of infection, accounting for nearly 25% of all infections.There are important medical and financial implications associated with UTIs. In the nonobstructed, nonpregnant female adult, acute uncomplicated UTI is believed to be a benign illness with no long-term medical consequences. However, UTI elevates the risk of pyelonephritis, premature delivery, and fetal mortality among pregnant women, and is associated with impaired renal function and end-stage renal disease among pediatric patients. Financially, the estimated annual cost of community-acquired UTI is significant, at approximately $1.6 billion.
Franciotta, D., E. Zardini, et al. (2003). "Interferon gamma and interleukin 4 producing T cells in peripheral blood of multiple sclerosis patients undergoing immunomodulatory treatment." J Neurol Neurosurg Psychiatry 74(1): 123-6.
Intracellular cytokine flow cytometry was used to analyse the percentages of interferon (IFN) gamma and interleukin (IL)-4 producing T cells in the peripheral blood of multiple sclerosis patients, before and after immunomodulatory treatment, and of healthy controls. After six months of treatment, different doses of IFN beta1a (Avonex or Rebif) decreased CD4(+) (Th1, Th2) and CD8(+) (Tc1) cells to a similar extent, without affecting the Th1/Th2 ratio. These T cell subsets were unmodified after nine months of glatiramer acetate (Copaxone) treatment, and after six day courses of high dose 6-methylprednisolone. The data suggest that IFN beta1a produces sustained downmodulation of IFN gamma and IL-4 producing T cells in vivo, which may contribute to its therapeutic efficacy; that glatiramer acetate possibly acts without altering non-specific cellular immunity; and that glucocorticoid induced lymphocytopenia does not affect the percentages of Th1, Th2, and Tc1 cells; at least in the periphery, none of the treatments caused a Th1 to Th2 shift that could account for their respective therapeutic effects.
Francis, G., H. Panitich, et al. (2003). "Re: Vartanian T. An examination of the results of the EVIDENCE, INCOMIN, and phase III studies of interferon beta products in the treatment of multiple sclerosis. Clin Ther. 2003;25:105-118." Clin Ther 25(6): 1888-90.
Franklin, R. J. (2003). "Remyelination by transplanted olfactory ensheathing cells." Anat Rec 271B(1): 71-6.
The olfactory ensheathing cells (OECs) of the peripheral olfactory system associate with the axons of the first cranial nerve. These axons are not myelinated by OECs because of their very small diameter. However, when OECs are transplanted into areas where they encounter larger-diameter axons, such as in a model of primary demyelination, these cells assume a myelinating phenotype. Myelinating OECs very closely resemble myelinating Schwann cells by all criteria currently examined, including morphology, ultrastructure, biochemistry, and transcriptional regulation. Indeed, it is currently impossible to reliably distinguish myelinating OECs and myelinating Schwann cells that have been transplanted into experimental models of CNS demyelination. This article describes recent studies on the myelinating properties of transplanted OECs, focusing on their intrinsic myelinating potential and how this can be augmented by the presence of meningeal cells. The relative merits of OECs compared with Schwann cells when transplanted into astrocyte-containing lesions in the CNS are discussed together with their potential role in transplanted-mediated repair of demyelinating disease such as multiple sclerosis. Anat Rec (Part B: New Anat) 271BB:71-76, 2003. Copyright 2003 Wiley-Liss, Inc.
Fraser, C., O. Hadjimichael, et al. (2003). "Predictors of adherence to glatiramer acetate therapy in individuals with self-reported progressive forms of multiple sclerosis." J Neurosci Nurs 35(3): 163-70.
The purpose of this study was to evaluate psychological, biophysical, and sociodemographic variables as predictors of adherence to glatiramer acetate (Copaxone) therapy in individuals with self-reported progressive forms of multiple sclerosis (MS). The literature lends support for self-efficacy, self-esteem, hope, and disability to be predictors of adherence. Therefore the hypotheses for this study were (a) higher self-efficacy will be a significant predictor of adherence, (b) higher self-esteem will be a significant predictor of adherence, (c) higher hope will be a significant predictor of adherence, and (d) a lower level of disability will be a significant predictor of adherence. The MS Self-Efficacy Scale (MSSE), Rosenberg Self-Esteem Scale, Herth Hope Index, and Performance Scales; a sociodemographic questionnaire; and an information sheet regarding consent to participate in the study were mailed to 1,200 potential participants. A total of 594 individuals responded, and for the evaluation of predictors of adherence in individuals with self-reported progressive forms of MS, 199 met the criteria. Logistic regression analysis revealed four significant predictors of adherence: the MSSE Control subscale, MSSE Function subscale, perceived support of the physician, and perceived support of the spouse. The higher the score on the MSSE Control subscale, the more likely the individual will adhere to glatiramer acetate therapy. The higher the score on the MSSE Function subscale, the more likely the individual will adhere to glatiramer acetate therapy. The MSSE Control and Function subscales show promise of being useful to predict adherence.
Fredrikson, S., Q. Cheng, et al. (2003). "Elevated suicide risk among patients with multiple sclerosis in Sweden." Neuroepidemiology 22(2): 146-52.
Results from previous studies of suicide risk among patients with multiple sclerosis (MS) are inconsistent. This may be explained partly by differences in methodology and study populations. The purpose of our study was to investigate suicide risk among hospital patients with MS in Sweden. During the period 1969-1996, 12,834 cases were recorded in the Swedish Hospital Inpatient Register, with 77,377 hospital admissions, in which MS was a primary or secondary diagnosis at discharge. The mean follow-up time for the whole cohort was 9.9 (SD 7.3) years. When the data for these MS patients were linked to the Swedish Causes of Death Register for the same period, 5,052 (39.4%) were found to have died. Among the 5,052 deaths, suicide was an underlying cause of death in 90 cases (1.8%). The mean period between the initial admission date with an MS diagnosis at discharge and the date of death for the 90 MS suicide cases was 5.8 (SD 5.1) years. This was significantly shorter (p = 0.002) than the mean of 7.9 (SD 6.4) years for MS cases who died due to other causes. Suicide risk, calculated as the standardized mortality ratio (SMR), was significantly elevated (SMR = 2.3) among both male and female MS cases compared with the general population. Suicide risk was particularly high in the first year after initial admission with an MS diagnosis, and among younger male MS cases. The mean age at the time of suicide was 44.5 (SD 12.4) years, and 58% of the suicides were committed within 5 years after the first admission with an MS diagnosis. The crude suicide rate among MS patients during the study period was 71 per 100,000 person-years. The rate was significantly higher (p < 0.001) in males (114) than in females (47), with an odds ratio of 2.4 (95% CI: 1.6-3.8). These findings have implications for suicide preventive measures in neurological practice.
Freedman, M., J. King, et al. (2003). "Interferons in relapsing remitting multiple sclerosis." Lancet 361(9371): 1822-3; author reply 1823-4.
Freire-Garabal, M., M. J. Nunez, et al. (2003). "Administration of the 5-hydroxytryptamine(1A) receptor antagonist WAY100635 suppresses acute experimental allergic encephalomyelitis in Lewis rats." Neurosci Lett 342(1-2): 33-6.
Experimental allergic encephalomyelitis (EAE) is a T-cell inflammatory disease of the central nervous system (CNS) widely considered as an animal model of multiple sclerosis. In Lewis rats, myelin basic protein-complete Freund's adjuvant (MBP-CFA)-induced EAE is an acute monophasic disease from which animals recover fully. In our experiments, daily treatment (since day 1 after MBP-CFA inoculation) with the 5-hydroxytryptamine((1A)) (5-HT(1A)) receptor agonist (R)-(+)-8-hydroxy-2-(Dipropylamino)-tetralin (R(+)-8-OH-DPAT) resulted in a dose-related enhancement of neurological and histological signs in EAE-induced rats. This effect of R(+)-8-OH-DPAT was reduced by the co-administration of the 5-HT(1A) receptor antagonist (N-[2-(4-[2-mehoxyphenil]-1-piperazinyl)-ethyl]-N-2-pyridinylcyclohexaneca rboxamide (WAY100635) at the peak of the acute disease. Moreover, treatment with WAY100635 since inoculation resulted in a delayed onset of the first clinical signs, milder disease and earlier regression of neurological signs along with a decrease in inflammation in the CNS.
French, L. E. and J. Tschopp (2003). "Protein-based therapeutic approaches targeting death receptors." Cell Death Differ 10(1): 117-23.
Death receptors (DRs) are a growing family of transmembrane proteins that can detect the presence of specific extracellular death signals and rapidly trigger cellular destruction by apoptosis. Eight human DRs (Fas, TNF-R1, TRAMP, TRAIL-R1, TRAIL-R2, DR-6, EDA-R and NGF-R) have been identified. The best studied to date is Fas (CD95). Expression and signaling by Fas and its ligand (FasL, CD95L) is a tightly regulated process essential for key physiological functions in a variety of organs, including the maintenance of immune homeostasis. Recently, strong evidence has shown that dysregulation of Fas expression and/or signaling contributes to the pathogenesis of tissue destructive diseases such as graft-versus-host disease, toxic epidermal necrolysis, multiple sclerosis and stroke. With these new developments, strategies for modulating the function of Fas signaling have emerged and provided novel protein-based therapeutic possibilities that will be discussed herein. Selective triggering of DR-mediated apoptosis in cancer cells is an emerging approach that is being intensely investigated as a mode of cancer therapy. Local administration of Fas agonists, and more promisingly, systemic use of soluble recombinant forms of TRAIL have shown efficacy in preclinical models of the disease. Developments in this field that may have important clinical implications for the treatment of cancer are reviewed.Cell Death and Differentiation (2003) 10, 117-123. doi:10.1038/sj.cdd.4401185
Frohman, E. M. (2003). "Multiple sclerosis." Med Clin North Am 87(4): 867-97, viii-ix.
Multiple sclerosis (MS) is the most common disabling neurologic disease of young people affecting between 350 and 450,000 individuals in the United States. Substantial advances have been made in the diagnostic assessment and treatment interventions over the last 10 years such that we are now able effectively to treat both the disease process and the associated symptomatic complaints associated with MS. Most patients consult with their primary care physician at the time when the first clinical manifestations of MS emerge. These physicians play a central role in the early identification and treatment of patients with MS. This article emphasizes the expanding diagnostic and therapeutic capabilities evolving for the MS patient and the crucial role played by primary care physicians in collaboration with neurologists in the coordination of the initial diagnostic and treatment plan.
Frohman, E. M., P. D. Kramer, et al. (2003). "Benign paroxysmal positioning vertigo in multiple sclerosis: diagnosis, pathophysiology and therapeutic techniques." Mult Scler 9(3): 250-5.
OBJECTIVE: To report on the most common causes of vertigo in patients with multiple sclerosis (MS) and emphasize appropriate diagnostic techniques and treatment interventions. BACKGROUND: True vertigo is estimated to occur in about 20% of MS patients. Lesions within the vestibular nuclei and in the root entry zone of cranial nerve VIII represent the most common locations where demyelinating activity can provoke vertigo in patients with MS. However, other causes of vertigo should be explored in MS patients in order to avoid unnecessary treatment with corticosteroids and vestibular suppressants. Recently, we reviewed our four-year experience with new onset vertigo in our university-based MS population and found that benign paroxysmal positioning vertigo (BPPV) to be the most common cause. All patients diagnosed with BPPV were treated successfully with particle repositioning maneuvers. The remaining patients were treated with conventional therapies appropriate for the specific diagnosis. CONCLUSIONS: Empiric treatments with corticosteroids and/or vestibular suppressants should not be employed until all MS patients undergo a careful bedside examination, which includes diagnostic positional and, if indicated, particle repositioning maneuvers. Here we emphasize the pathophysiology of BPPV and illustrate the proper techniques for the diagnostic and therapeutic maneuvers.
Frohman, E. M., P. O'Suilleabhain, et al. (2003). "A new measure of dysconjugacy in INO: the first-pass amplitude." J Neurol Sci 210(1-2): 65-71.
BACKGROUND: The ratios of abducting to adducting eye movements (versional dysconjugacy index, VDI) for saccadic velocity and acceleration have been useful measures by which to objectively characterize internuclear ophthalmoparesis (INO). Amplitude measures of dysconjugacy have been less useful, given that many patients maintain the ability to ultimately reach a centrifugal fixation target and that traditional amplitude measures of VDI have focused on this 'final amplitude' (FA) position. METHODS: We utilized infrared oculography to define a new amplitude measure of dysconjugacy in 42 multiple sclerosis (MS) patients with INO. The first-pass amplitude (FPA)-VDI is the ratio of abduction/adduction eye movement amplitudes computed at the time when the abducting eye initially achieves the centrifugal horizontal fixation target. RESULTS: FPA-VDI values were significantly more sensitive and specific than FA-VDI values in demonstrating dysconjugacy in INO, and there was a 14-fold increase in dysconjugacy as measured by FPA-VDI Z-scores when compared to FA-VDI Z-scores. CONCLUSION: Consideration of velocity (pulse) and amplitude (step) components of dysconjugacy in patients with INO can provide a greater understanding of the dynamic aspects of this syndrome. We propose to characterize the relationship between the pathophysiology of INO and neuroradiologic measures of tissue injury in MS.
Frohman, E. M. and T. C. Frohman (2003). "Horizontal monocular saccadic failure: an unusual clinically isolated syndrome progressing to multiple sclerosis." Mult Scler 9(1): 55-8.
This paper describes an unusual clinically isolated syndrome of inflammatory demyelination that was characterized by a right VI nerve palsy and right internuclear ophthalmoparesis (INO), along with an unusual form of dissociated nystagmus. Magnetic resonance imaging (MRI) revealed an isolated lesion within the right dorsomediolateral pontine tegmentum. Four years later, the subject developed a partial sensory transverse myelitis, confirming clinically definite multiple sclerosis (MS). This paper extends the range of isolated syndromes associated with MS.
Frost, E. E., J. A. Nielsen, et al. (2003). "PDGF and FGF2 regulate oligodendrocyte progenitor responses to demyelination." J Neurobiol 54(3): 457-72.
Acute demyelination of adult CNS, resulting from trauma or disease, is initially followed by remyelination. However, chronic lesions with subsequent functional impairment result from eventual failure of the remyelination process, as seen in multiple sclerosis. Studies using animal models of successful remyelination delineate a progression of events facilitating remyelination. A universal feature of this repair process is extensive proliferation of oligodendrocyte progenitor cells (OPs) in response to demyelination. To investigate signals that regulate OP proliferation in response to demyelination we used murine hepatitis virus-A59 (MHV-A59) infection of adult mice to induce focal demyelination throughout the spinal cord followed by spontaneous remyelination. We cultured glial cells directly from demyelinating and remyelinating spinal cords using conditions that maintain the dramatically enhanced OP proliferative response prior to CNS remyelination. We identify PDGF and FGF2 as significant mitogens regulating this proliferative response. Furthermore, we demonstrate endogenous PDGF and FGF2 activity in these glial cultures isolated from demyelinated CNS tissue. These findings correlate well with our previous demonstration of increased in vivo expression of PDGF and FGF2 ligand and corresponding receptors in MHV-A59 lesions. Together these studies support the potential of these pathways to function in vivo as critical factors in regulating remyelination.
Fujino, M., N. Funeshima, et al. (2003). "Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment." J Pharmacol Exp Ther 305(1): 70-7.
Experimental autoimmune encephalomyelitis (EAE) is a T-cell-dependent autoimmune disease that reproduces the inflammatory demyelinating pathology of multiple sclerosis (MS). We investigated the efficacy and mechanism of immunosuppression against EAE by administering 2-amino-[2-(4-octylphenyl) ethyl]-1,3-propanediol hydrochloride (FTY720) in Lewis rats immunized with myelin basic protein together with complete Freund's adjuvant. FTY720 treatment almost completely protected the rats against disease. The protection by FTY720 was associated with a dramatic reduction in the number of lymphocytes staining for T-cell receptors in the spinal cord as examined by immunohistochemistry. The mRNA expression of Th1 cytokines interleukin (IL)-2, IL-6, and interferon-gamma in the spinal cord was also reduced dramatically as assessed by reverse-transcription polymerase chain reaction. Furthermore, lymphocytes isolated from the spleen of FTY720-treated rats were transferred into naive recipient rats against EAE manifestation by reducing both disease incidence and clinical score. These results suggested that the protective anti-inflammatory effect of treatment with FTY720 was, to a large extent, due to the inhibition of encephalitogenic T-cell responses and/or their migration into the central nervous system and may be a potential candidate for use in treating patients with MS.
Furlan, R., S. Pluchino, et al. (2003). "Gene therapy-mediated modulation of immune processes in the central nervous system." Curr Pharm Des 9(24): 2002-8.
Selective interference with immune processes in the central nervous system (CNS) is a very difficult task because of the limitations associated with the delivery of immuno modulatory molecules across the blood brain barrier. Systemic administration of immune-mediators, either by conventional routes or by intramuscularly or intravenous gene therapy, is hampered by severe side effects and alters immune-system functions also in peripheral organs. To overcome these problems, different gene therapy strategies have been developed to deliver immuno modulatory molecules directly within the central nervous system. The use of engineered CNS antigen-specific circulating cells as selective delivery vehicles, the direct injection of gene vectors into the brain parenchyma, or also the ependymal route, have been proposed as possible alternative gene therapy protocols to selectively interfere with immuno-pathological processes in the CNS. We will review the use of these CNS-targeted gene therapy protocols for the treatment of experimental autoimmune encephalomyelitis (EAE), the prototypical experimental immune-mediated disease of the CNS, and therefore discuss the relevance of these results for the therapy of multiple sclerosis (MS) the most common, immune-mediated, demyelinating disease of the CNS in humans.
Furlan, R., S. Pluchino, et al. (2003). "The therapeutic use of gene therapy in inflammatory demyelinating diseases of the central nervous system." Curr Opin Neurol 16(3): 385-92.
PURPOSE OF REVIEW: Gene therapy protocols aimed to deliver therapeutic molecules into the central nervous system may represent an alternative therapeutic strategy in patients affected by inflammatory demyelinating diseases of the central nervous system where systemic therapies have shown limited therapeutic efficacy possibly owing to the blood-brain barrier, a major obstacle for the entry of therapeutic molecules into the central nervous system. RECENT FINDINGS: Among inflammatory demyelinating diseases of the central nervous system, gene therapy approaches have been so far developed almost exclusively for multiple sclerosis. However, the chronic/relapsing nature of the disease, the restriction to the central nervous system of the pathological process as well as the necessity to inhibit the ongoing inflammatory process but also to foster endogenous remyelinating pathways, have posed several questions which still need to be properly addressed for the development of a successful gene therapy strategy in multiple sclerosis patients. SUMMARY: The gene therapy approaches for multiple sclerosis have been so far developed and tested only in rodents and monkeys with experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The results of these studies clearly indicate that the delivery of therapeutic genes within the central nervous system is superior to the peripheral delivery. In particular, the intracerebral delivery of genes coding for anti-inflammatory and/or neurotrophic molecules, using gene vectors derived from non-replicative viruses, showed to inhibit not only the detrimental function of blood-borne mononuclear effector cells but also to foster proliferation and differentiation of surviving oligodendrocytes within demyelinated areas. Here, we summarize the most recent findings of this novel area of research.
Furlan, R., A. Bergami, et al. (2003). "Activation of invariant NKT cells by alphaGalCer administration protects mice from MOG35-55-induced EAE: critical roles for administration route and IFN-gamma." Eur J Immunol 33(7): 1830-8.
Invariant NKT (inv. NKT) cells co-express an invariant alpha beta T cell receptor and the NK receptor NK1.1 and, upon CD1d-restricted recognition of the glycosphingolipid antigen alpha-galactosyl ceramide (alphaGalCer), secrete large amounts of regulatory cytokines. We investigated whether alphaGalCer-dependent activation of inv. NKT cells protects from experimental autoimmune encephalomyelitis (EAE), an immune-mediated disease of the central nervous system mimicking multiple sclerosis, induced in C57BL/6 mice by the myelin oligodendrocyte glycoprotein (MOG) encephalitogenic peptide aa 35-55. alphaGalCer was administered at the time of immunization s.c., mixed with complete Freund's adjuvant and MOG35-55 peptide, or administered i.p., diluted in PBS. EAE onset was delayed and disease severity was decreased only when alphaGalCer was s.c. administered. The protective effect of s.c. administration of alphaGalCer was associated with a markedly enhanced IFN-gamma production by liver-confined inv. NKT cells which, in turn, suppressed Th1-cytokine production and fostered secretion of IL-10 from MOG35-55-specific T cells. In vivo neutralization of IFN-gamma, but notIL-4, reversed the protective effect induced by s.c. administration of alphaGalCer, further confirming the critical regulatory role exerted by IFN-gamma-producing inv. NKT cells. Our results indicate that alphaGalCer, properly administered, may elicit an inv. NKT-cell-mediated suppressive effect on the effector function of encephalitogenic T cells; this effect is able to ameliorate autoimmunedemyelination.