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PubMed2006

The value of animal models for drug development in multiple sclerosis.

The rodent model for multiple sclerosis, experimental allergic (autoimmune) encephalomyelitis (EAE), has been used to dissect molecular mechanisms of the autoimmune inflammatory response, and hence to devise and test new therapies for multiple sclerosis. Clearly, artificial immunization against myelin may not necessarily reproduce all the pathogenetic mechanisms operating in the human disease, but most therapies tested in multiple sclerosis patients are nevertheless based on concepts derived from studies in EAE. Unfortunately, several treatments, though successful in pre-clinical EAE trials, were either less effective in patients, worsened disease or caused unexpected, severe adverse events, as we review here. These discrepancies must, at least in part, be due to genetic and environmental differences, but the precise underlying reasons are not yet clear. Our understanding of EAE pathogenesis is still incomplete and so, therefore, are any implications for drug development in these models. Here, we suggest some potential explanations based on new thinking about key pathogenic concepts and differences that may limit extrapolation from EAE to multiple sclerosis. To try to circumvent these rodent-human dissimilarities more systematically, we propose that pre-clinical trials should be started in humanized mouse models.

Animals↗

PubMed2006

Longitudinal analysis of immune cell phenotypes in early stage multiple sclerosis: distinctive patterns characterize MRI-active patients.

To investigate whether peripheral immune abnormalities are associated with brain inflammation in multiple sclerosis, and whether differences in MRI activity are paralleled by changes in leukocyte composition, we conducted a prospective longitudinal study in patients at their clinical onset. Twenty patients presenting a first inflammatory event in the central nervous system suggestive of multiple sclerosis underwent, every 45 days for one year, immunophenotyping of 98 blood cell subsets together with brain MRI and clinical evaluation. Six patients showed intense MRI activity, six patients did not display MRI activity, while the remaining 8 patients had low (i.e. intermediate) MRI activity during the follow-up. Our results show that MRI-active and MRI-inactive patients display significant differences in ten lymphocyte subsets. Among these, there are both effector (CCR7-CD45RA-CD4+ alphabeta T cells, CCR5+ gammadelta T cells) and regulatory (DN CD28+ alphabeta T cells and CD25+CD8+ alphabeta T cells) lymphocytes pertaining to the innate and the acquired arms of the immune system. Moreover, these differences were, upon employment of a class prediction procedure based on "support vector machines" algorithm utilizing leave-one-out cross validation procedures, able to correctly assign patients to their respective MRI activity group. All 6 MRI-active and 6 MRI-inactive patients were correctly classified, and, upon application of a class prediction model in an unsupervised manner to the 8 patients with intermediate MRI activity, 6 were predicted as MRI-active and 2 as MRI-inactive patients. Also, when the mean values of the first three time points (T0, T1 and T2) were used for the prediction of all patients, the selected lymphocyte subsets correctly classified 90% of patients. Sensitivity was 91.7% and specificity was 87.5%. These results provide evidence showing that brain inflammation in multiple sclerosis is associated with distinct changes in peripheral lymphocyte subsets, and raise the possibility that the identified subsets may, after adequate validation, assist in the prediction of MRI activity in the early stages of multiple sclerosis.

Adult↗

PubMed2006

Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis.

In multiple sclerosis, the relationship between conventional MRI findings and the clinical evolution of the disease is weak. Magnetization transfer (MT) MRI can provide markers reflecting the more disabling features of multiple sclerosis pathology. The aim of the present study was to assess the value of MT MRI quantities and their short-term changes in predicting the long-term accumulation of disability in multiple sclerosis patients. Conventional and MT MRI scans of the brain were obtained at baseline and after 12 months in 73 patients, who were followed prospectively with clinical visits for a median period of 8 years. At baseline and at 12 months, T2-hyperintense and T1-hypointense lesion volume, normalized brain volume [with grey (GM) and white matter (WM) fractions] and average lesion MT ratio (MTR) were measured. At the two time points, metrics derived from the MTR histograms of the whole-brain parenchyma, GM and normal-appearing WM were also computed. A multivariate analysis, adjusted for follow-up duration, was performed to establish which variables were significant predictors of long-term neurological deterioration. At the end of follow-up, 44 patients (60%) showed a significant disability worsening. A multivariable model included baseline GM MTR histogram peak height [P = 0.029, odds ratio (OR) = 0.97], and average lesion MTR percentage change after 12 months (P = 0.016, OR = 0.88) as independent predictors of disability worsening at 8 years (r2 = 0.28). The discriminating ability of such a model in predicting the individual patients' outcome was 66%. MT MRI provides useful prognostic markers for the prediction of the long-term evolution of multiple sclerosis. This study also suggests that GM damage is one of the key factors associated with disability accumulation in this 'white matter' condition.

Brain↗

PubMed1994

9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene.

Tuberous sclerosis is an autosomal dominant disease whose characteristic feature is the development of multiple hamartomas in a variety of organs and tissues. Two major loci have been identified so far: TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3. Loss of heterozygosity at 16p13.3-associated markers has been recently observed in hamartomatous lesions of some tuberous sclerosis patients. Here we report the first evidence of loss of heterozygosity at the TSC1 critical region in a giant cell astrocytoma of a familial tuberous sclerosis case. Segregation analysis showed that the 9q34 haplotype lost carried the putative normal TSC1 gene. These data support the hypothesis of both a germline and somatic loss-of-function mutation for the development of tuberous sclerosis hamartomas and suggest a tumor-suppressor-like activity also for the TSC1 gene product. Finally, the possible significance of a second small region of loss of heterozygosity at 9p21, found in the same astrocytoma, is discussed.

Astrocytoma↗

PubMed1987

A cohort study of amyotrophic lateral sclerosis and parkinsonism-dementia on Guam and Rota.

A prospective study of the incidence of new cases of amyotrophic lateral sclerosis and parkinsonism-dementia was conducted by follow-up of 899 Chamorros in the Mariana Islands who participated in a baseline medical examination and interview in 1968. During a 15-year follow-up period, 28 new neurologically confirmed cases occurred, including 23 with parkinsonism-dementia and five with amyotrophic lateral sclerosis. The low incidence of amyotrophic lateral sclerosis was consistent with the reported disappearance of this disease from the Mariana Islands. However, the continuing high incidence of parkinsonism-dementia was not in agreement with a similarly reported disappearance nor with the hypothesis of a common cause of both diseases. Of 23 selected baseline examination variables, only the preference for traditional Chamorro food was significantly associated with an increased risk of parkinsonism-dementia. A review of the accumulated epidemiologic data on these neurologic diseases in the Mariana Islands did not support the current hypothesis that a chronic nutritional deficiency of calcium is a cause of both amyotrophic lateral sclerosis and parkinsonism-dementia.

Adult↗

PubMed1987

Force-time measurements of knee muscle functions of subjects with multiple sclerosis.

The purpose of this study was to determine whether the time-rate of muscle tension development, the muscle tension-maintaining capacity, and the reciprocal inhibition time of muscles in subjects with multiple sclerosis were significantly different from those of healthy subjects. An isokinetic dynamometer was used to evaluate the quadriceps femoris and hamstring muscles of 15 Experimental Group subjects with multiple sclerosis and 17 healthy Control Group subjects. The muscles were tested isometrically at 45 degrees of knee flexion and isokinetically at speeds of 30 degrees/sec and 90 degrees/sec. The subjects with multiple sclerosis demonstrated a significant (p less than .001) slowing of the time-rate of muscle tension development and a significant (p less than .005) decrease in muscle tension-maintaining capacity when compared with healthy subjects. The difference in the reciprocal inhibition time of muscles of the Experimental and Control Groups was not significant. When the reciprocal inhibition time of muscles was expressed as a percentage of the total torque curve, however, a significant prolongation (p less than .001) was observed in the subjects with multiple sclerosis.

Adolescent↗

PubMed2004

Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis.

OBJECTIVE: To determine serum levels of soluble cytotoxic T-lymphocyte associated molecule-4 (sCTLA-4) and clinical association in patients with systemic sclerosis (SSc). METHODS: Serum sCTLA-4 levels from 32 patients with diffuse cutaneous SSc (dSSc) and 27 patients with limited cutaneous SSc (lSSc) were examined by enzyme-linked immunosorbent assay (ELISA). For a longitudinal study, 211 sera from 30 SSc patients were analysed (follow-up 2.1-7.0 yr). RESULTS: Serum sCTLA-4 levels were elevated in dSSc patients compared with normal controls (n = 41), lSSc patients and patients with active systemic lupus erythematosus (SLE) (n = 23). By contrast, sCTLA-4 levels in patients with lSSc or SLE were normal. SSc patients with elevated sCTLA-4 levels had a shorter disease duration and more frequent presence of digital pitting scars, contracture of phalanges, diffuse pigmentation, pulmonary fibrosis and decreased percentage vital capacity (%VC) than those with normal sCTLA-4 levels. sCTLA-4 levels correlated positively with the extent of skin fibrosis, serum IgG levels and anti-topoisomerase I antibody levels. In a longitudinal study, sCTLA-4 levels decreased on a parallel with improvement of skin sclerosis in five dSSc patients. Skin sclerosis did not improve in two of six dSSc patients with high sCTLA-4 levels throughout the follow-up, while the remaining four patients showed improvement of skin sclerosis. CONCLUSION: These results suggest that sCTLA-4 correlates with disease severity and activity of SSc and that sCTLA-4 plays a role in immunological abnormalities of SSc, since sCTLA-4 may augment humoral immune responses as well as T-cell responses by interfering with B7-CTLA-4 interactions that induce negative signals in T and B cells.

Antigens, CD↗

PubMed2003

Oxidative Stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis.

PURPOSE OF REVIEW: Amyotrophic lateral sclerosis, or Lou Gehrig disease, is a progressive neurodegenerative disease of adult onset characterized by a loss of motor neurons in the spinal cord and motor cortex. In the last several years, substantial progress has been made in defining the pathogenesis of motor neuron injury and relationships between disease mechanisms and the selective vulnerability of the motor neuron in both familial and sporadic forms of amyotrophic lateral sclerosis. RECENT FINDINGS: Current theories have shifted from a neuron-centered pathology to a focus on the interaction between motor neurons and glia, and their respective contributions to pathways implicated in amyotrophic lateral sclerosis. Although multiple mechanisms clearly can contribute to the pathogenesis of motor neuron injury, recent advances suggest that oxidative stress may play a significant role in the amplification, and possibly the initiation, of disease. SUMMARY: This article reviews the clinical aspects of amyotrophic lateral sclerosis and potential mechanisms of disease pathogenesis in the context of recent data supporting a major role for oxidative stress throughout the disease course. Evidence suggesting an important role for intercellular signaling is emphasized.

Amyotrophic Lateral Sclerosis↗

PubMed2000

Multiple sclerosis with very late onset: a report of a case with onset at age 82 years and review of the literature.

This is a report of a patient with late-onset multiple sclerosis at age 82 years. The lesion involved was located on the spinal cord. Multiple sclerosis mainly affects young adults, making late onset of multiple sclerosis a rarity, particularly for cases after age 80 years. Common characteristics of late-onset multiple sclerosis reported in other publications are predominant involvement of the spinal cord and a progressively worsening course with a serious prognosis. In this case, magnetic resonance imaging revealed a large area of high signal intensity in the cervical and upper thoracic spinal cord on T2-weighted images. An increased immunoglobulin G level in cerebrospinal fluid also played a diagnostic role in ruling out cervical spondylotic myelopathy. Spontaneous improvement occurred 2 months after the onset. Unlike other patient described in the literature, the clinical course of this man was not as bleak.

Age of Onset↗

PubMed1995

Trauma, axonal injury, and amyotrophic lateral sclerosis: a clinical correlate of a neuropharmacologic model.

Axonal injury induces cell death in selectively vulnerable motor neurons of immature animals. This extensively studied animal model of trauma-induced motor neuron death is being used to develop the theoretical basis for the therapeutic use of neurotrophic factors to "rescue" dying neurons in amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Antecedent trauma has been implicated as a precipitating factor for amyotrophic lateral sclerosis in susceptible individuals. The animal model of trauma-induced motor neuron death provides support for the concept that motor neurons in individuals susceptible to amyotrophic lateral sclerosis may be selectively vulnerable to trauma producing axonal injury. The case histories of six young adult men who developed amyotrophic lateral sclerosis after trauma with axonal injury are presented.

Adult↗

PubMed1988

Radiologic and pathologic patterns of end-plate-based vertebral sclerosis.

Degenerative spondyloarthropathy is the result of a number of related pathologic processes, including loss of disc elasticity, repetitive mild trauma, and osteoporosis. The effects are manifested microscopically in a number of patterns reflecting alterations in stress, healing microfractures, and bone-cartilage interactions along the vertebral end-plate. The microscopic changes lead in turn to radiographically evident vertebral body sclerosis. The resultant sclerosis is not always in the classic band-like pattern along the vertebral end-plate, and the atypical patterns may be difficult to recognize as degenerative in origin. In a detailed analysis of clinical and postmortem material, we have categorized both the pathologic and radiographic patterns of benign non-Pagetic vertebral body sclerosis. This radiographic classification provides a unified framework for clinical recognition of the various patterns of degenerative sclerosis.

Adult↗

PubMedDate not supplied

Special considerations in the management of a patient with multiple sclerosis and a burn injury.

The purposes of this report were to describe a successful treatment of a burn injury in a patient with multiple sclerosis as well as to outline specific aspects of therapy that contributed to minimizing the risk of complications in this challenging patient. Multiple sclerosis is the leading cause of neurologic morbidity and death among young adults. It is an inflammatory disease of the central nervous system that involves the autonomic and somatic components and is characterized by a primary destruction of myelin. The demyelinated nerves exhibit an increased temperature sensitivity that accounts for the adverse effects of elevated core temperature on the neurologic signs and symptoms of this disease. Because burn injury, infection, and vigorous exercise elicit an elevation of core temperature with an accompanying deterioration in neurologic function, lowering the elevated core body temperature is mandatory. The dysautonomias of multiple sclerosis may be as devastating as their somatic counterparts and may have life-threatening implications. In recent years, advances in our understanding of the pathophysiology of central nervous system dysfunction have enabled physicians to improve dramatically the management of symptoms in multiple sclerosis without significantly altering the progressive long-term course of the disease.

Body Temperature↗

PubMed1994

Contributions of neuroimaging to diagnosis and monitoring of multiple sclerosis.

Recent advances in magnetic resonance neuroimaging have resulted in an increased ability to distinguish acute, potentially reversible lesions from chronic, irreversible lesions in multiple sclerosis. Refinements of magnetic resonance imaging techniques, such as fluid-attenuated inversion recovery, diffusion imaging, and magnetization transfer imaging, as well as magnetic resonance spectroscopic imaging, are providing increased sensitivity and allowing detection of changes in multiple sclerosis white matter that appears normal on standard spin-echo magnetic resonance images. Increased neuroimaging specificity and sensitivity enhance the ability to diagnose, monitor, and understand the progression of multiple sclerosis. Magnetic resonance spectroscopy and magnetic resonance spectroscopic imaging detect metabolites in vivo and have even greater potential for elucidating the biochemical pathology of demyelination in multiple sclerosis.

Brain↗

PubMed1998

Recent advances in immunology in multiple sclerosis.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system that is of possible autoimmune origin. This article is divided into three parts, reviewing recent advances in three selected topics regarding the immunology of multiple sclerosis. The first part addresses the consequences of T cell and oligodendrocyte death in the inflammatory lesions. The second covers the recent experimental evidence favouring the involvement of infectious agents in the pathophysiology of central nervous system autoimmune diseases. The third part concerns the mode of action of interferon-beta in multiple sclerosis. These new advances have lead to a better understanding of the immunopathology of multiple sclerosis and therefore open new therapeutic possibilities.

Cell Death↗

PubMed2000

The value of new magnetic resonance techniques in multiple sclerosis.

Cell-specific magnetic resonance imaging, magnetization transfer imaging, proton magnetic resonance spectroscopy and diffusion-weighted imaging have all recently been applied to the study of multiple sclerosis. These techniques can give more accurate and pathologically specific estimates of the multiple sclerosis lesion burden than conventional magnetic resonance. Their extensive application should improve the understanding of the mechanisms leading to multiple sclerosis-related irreversible disability and help in the diagnostic work-out of patients with suspected multiple sclerosis.

Humans↗

PubMed2000

The management of multiple sclerosis patients.

The management of individuals with multiple sclerosis must be considered under the following headings: administration and follow-up of adequate disease-modifying treatment, symptomatic relief and neurorehabilitation. Neurorehabilitation deserves a four-step strategy: multidisciplinary assessment, identification of areas of potential functional improvement, setting of goals of short/long-term duration, and measurement of outcomes. The patient's perspective is important to evaluate through questionnaires about quality of life. Well organized disability services with multidisciplinary specialists are probably cost effective and efficient. Determining the actual economic impact of multiple sclerosis and defining the most cost-effective type of care for persons with multiple sclerosis is a need in all countries faced with the limitation of healthcare resources. In persons with multiple sclerosis the range of main symptoms includes the loss of mobility and spasticity, pain, tremor, abnormal eye movements, paroxysmal symptoms, bladder and bowel dysfunction, sexual disturbances, fatigue and depression. Current palliative treatments, which are reviewed, are partly successful depending on the type of symptoms under consideration.

Humans↗

PubMed2000

Recent advances in amyotrophic lateral sclerosis.

The mechanisms by which mutations of the SOD1 gene cause selective motor neuron death remain uncertain, although interest continues to focus on the role of peroxynitrite, altered peroxidase activity of mutant SOD1, changes in intracellular copper homeostasis, protein aggregation, and changes in the function of glutamate transporters leading to excitotoxicity. Neurofilaments and peripherin appear to play some part in motor neuron degeneration, and amyotrophic lateral sclerosis is occasionally associated with mutations of the neurofilament heavy chain gene. Linkage to several chromosomal loci has been established for other forms of familial amyotrophic lateral sclerosis, but no new genes have been identified. In the clinical field, interest has been shown in the population incidence and prevalence of amyotrophic lateral sclerosis and the clinical variants that cause diagnostic confusion. Transcranial magnetic stimulation has been used to detect upper motor neuron damage and to explore cortical excitability in amyotrophic lateral sclerosis, and magnetic resonance imaging including proton magnetic resonance spectroscopy and diffusion weighted imaging also provide useful information on the upper motor neuron lesion. Aspects of care including assisted ventilation, nutrition, and patient autonomy are addressed, and underlying these themes is the requirement to measure quality of life with a new disease-specific instrument. Progress has been made in developing practice parameters. Riluzole remains the only drug to slow disease progression, although interventions such as non-invasive ventilation and gastrostomy also extend survival.

Amyotrophic Lateral Sclerosis↗

PubMed2001

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

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

Axons↗