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PubMed2002

Pathogenesis of multiple sclerosis: an update on immunology.

Multiple sclerosis is characterized by demyelination and chronic inflammation of the central nervous system. Extensive studies in the animal model experimental autoimmune encephalomyelitis have suggested that multiple sclerosis is an autoimmune disorder mediated by myelin-specific CD4 T cells secreting T helper type 1 cytokines and tumor necrosis factor alpha. This concept has been widely used to develop new experimental therapies. However, recent findings in both experimental autoimmune encephalomyelitis and multiple sclerosis question a simple CD4 T helper type 1 T cell paradigm and provide evidence for the role of various immune cells in the pathogenesis of experimental autoimmune encephalomyelitis and multiple sclerosis. In this paper we review recent progress and discuss the implications for new therapeutic strategies.

Animals↗
PubMed2003

The tuberous sclerosis complex and its highly variable manifestations.

PURPOSE: Tuberous sclerosis is an autosomal dominant neurocutaneous syndrome affecting multiple organ systems and demonstrating highly variable clinical manifestations. Mutations in 2 tumor suppressor genes, TSC1 and TSC2, are linked to the evolution of the hamartomatous lesions. We describe the incidence and epidemiology, variable clinical manifestations and their relationships to renal pathology, and the management of morbid sequelae. MATERIALS AND METHODS: Using the search term tuberous sclerosis, we performed a MEDLINE search of the literature identifying 3,196 articles and selected those from urological, surgical, oncological, genetic and pediatric journals. Special focus was placed on the incidence and management of renal lesions and on different clinical manifestations and how they relate to renal tumors. RESULTS: Due to improved identification of the variable phenotypic expression, the reported incidence has increased. TSC1 and TSC2 mutations are related to various phenotypic manifestations and risks of malignancy, such as an increased incidence of the TSC2 mutation in patients with renal cell carcinoma. Renal sparing surgery and selective embolization techniques have mitigated the morbidity of the lesions. CONCLUSIONS: We now have a better understanding of the variability at the genotypic and phenotypic levels of the disease. We recommend that patients with tuberous sclerosis complex be evaluated by a multidisciplinary group of clinicians, including urologists, dermatologists, neurologists, pediatricians and geneticists. Close attention to these manifestations is necessary to ensure appropriate treatment of the sequelae of the tuberous sclerosis complex.

Cardiovascular Diseases↗
PubMed2003

Cognitive dysfunction in multiple sclerosis: a review of recent developments.

PURPOSE OF REVIEW: Nearly half of all patients diagnosed with multiple sclerosis will develop cognitive dysfunction, a symptom associated with significant decline in activities of daily living. The purpose of this review is to discuss recent literature investigating issues related to cognitive dysfunction in multiple sclerosis. RECENT FINDINGS: Recent studies, examined in this review, have provided increased understanding regarding specific cognitive processes affected in multiple sclerosis, as well as a characterization of its natural history. Studies have also continued to emphasize the extent to which cognitive deficits in the condition are associated with decline in daily living skills. Recent concerns regarding driving performance have been documented among cognitively impaired individuals. Studies have also examined correlates of cognitive dysfunction, with particular emphasis on neuroimaging techniques reflecting disease activity or lesion burden. With increased understanding of neurobiological correlates of cognitive deficits, investigators have begun to examine potential treatments for managing cognitive dysfunction. SUMMARY: This area of research has suggested that disease modifying medications can have an impact on magnetic resonance imaging disease activity by altering the cerebral demyelinating process resulting in a slower decline in cognitive functions over time and improved activities of daily living for patients with multiple sclerosis.

Activities of Daily Living↗
PubMed2005

Current trials in multiple sclerosis: established evidence and future hopes.

PURPOSE OF REVIEW: The aim of the present report is to briefly review multiple sclerosis therapeutic trials published or presented in 2004 to provide an up-to-date overview of the established evidence and new insights. RECENT FINDINGS: New data have come available that help us understand how currently approved disease modifying drugs can best be used. Nonetheless, their limited effectiveness - especially in progressive forms of multiple sclerosis - as well as the inconvenience and toxicity associated with their use, emphasize the need for new treatment strategies. A substantial number of reports on new emerging treatment modalities were published in 2004, and one of these modalities was newly approved by the US Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis. SUMMARY: Further advances have been made in the treatment of multiple sclerosis patients. On the one hand, we know better how and in whom to use existing medications. On the other hand, it is exciting to witness how increased insight in the pathophysiology of the disease and its symptoms has led to a series of new, innovative treatment modalities.

Adjuvants, Immunologic↗
PubMed2006

Emerging therapeutic targets in multiple sclerosis.

PURPOSE OF REVIEW: The aim of this review is to describe the recent findings regarding the pathogenesis of multiple sclerosis and their translation to new therapies. RECENT FINDINGS: Basic research is providing new insights into the immune elements involved in the pathogenesis of multiple sclerosis, both in the periphery as well as in the central nervous system. Unveiling the complex interplay of the molecules involved in the immunological cascade of the disease supplies new targets for the development of new immunotherapeutic strategies. Similarly, clinical studies and identification of distinct subgroups of patients based on their responsiveness to immunotherapies provides support for the existence of immunopathological disease subtypes that seem to require different therapeutic approaches. These studies extend the theoretical basis that facilitates development of neuroprotective and repair-promoting therapeutic strategies. SUMMARY: The application of novel and cutting-edge technologies in the fields of genomics and proteomics is providing a better understanding of the genetic and environmental factors involved in multiple sclerosis susceptibility and progression, as well as the detection of biomarkers for disease activity and response to therapy. Implementation of these facilitates identification of new targets for therapy towards tailoring treatment to the individual patient with multiple sclerosis.

Antigens↗
PubMed1989

Connective tissue disease mimicking multiple sclerosis.

Systemic lupus erythematosus, primary Sjögren's syndrome and systemic sclerosis may be associated with acute transverse myelitis and chronic relapsing neurological syndromes mimicking multiple sclerosis in the same individuals and/or their relatives. We now present three cases which suggest that there is a wide spectrum of connective tissue disorders mimicking multiple sclerosis and acute disseminated encephalomyelitis. These cases demonstrate that the diagnosis of multiple sclerosis should be kept under constant review by searching for the development of connective tissue disorders in the patients or their relatives.

Adult↗
PubMed1994

A population study of renal disease in patients with tuberous sclerosis.

OBJECTIVE: To establish the prevalence of renal disease, asymptomatic renal lesions and possible renal symptoms in a geographically defined population of individuals with tuberous sclerosis. PATIENTS AND METHODS: The study involved 131 patients (64 men, 67 women) with tuberous sclerosis who were resident in nine of the districts within the Wessex Region and three Bristol Health Districts and who had been identified by a prevalence study [1]. The patients' mean age was 22 years (range 6 months-74 years). Established renal disease was identified by history. Where possible individuals were seen and were examined. Specific enquiry was made for flank pain and macroscopic haematuria. Renal ultrasound, blood pressure measurement and urine analysis was offered to all individuals with tuberous sclerosis who were resident in the Bath Health District. RESULTS: Eight patients (6%) had a history of either renal polycystic kidney disease (two patients) or haemorrhage from renal angiomyolipomas (five female patients, one male patient). A further 21% of female and 3% of male patients had a history of severe flank pain or haematuria. Renal ultrasound screening revealed abnormalities in 10 of 21 individuals; angiomyolipomas > 1 cm were found in seven and were twice as common in female patients. CONCLUSIONS: Regular clinical review of individuals with tuberous sclerosis should include enquiry for renal symptoms and abdominal examination. Lesions > 4 cm are most likely to be symptomatic but longitudinal studies are needed before renal ultrasound screening of adolescents or adults can be recommended.

Adolescent↗
PubMed1976

Immunological status in tuberous sclerosis.

Cellular and humoral immunity, and lymphoid organ pathology, have been investigated in 10 institutionalized patients with tuberous sclerosis and 10 institutionalized matched controls without the disease. Type and incidence of infections and tumours were reviewed for each group, as was current medication. Elevated serum IgM levels were found in the patients with tuberous sclerosis, but no immunological deficiency of either cellular of humoral immunity was found, nor was there a difference in infection between the groups. Only patients with tuberous sclerosis had evidence of neoplasia. No morphological or histological abnormalities of lymph nodes, spleen or thymus were present. Explanations for the difference between tuberous sclerosis and ataxia telangiectasia are discussed, together with the effect of immuno-surveillance on the development of malignancy.

Adolescent↗
PubMed2000

Effect of theophylline and trimethobenzamide when given during kainate-induced status epilepticus: an improved histopathologic rat model of human hippocampal sclerosis.

PURPOSE: The most common pathology in temporal lobe epilepsy (TLE) is hippocampal sclerosis. It is controversial whether status epilepticus (SE) or prolonged seizures plus secondary cerebral injuries are pathogenic mechanisms of hippocampal sclerosis. This study addressed this question in rat models of TLE. METHODS: Hippocampal neuron densities and supragranular mossy fiber sprouting were determined in adult rats subjected to systemic kainate-induced SE (KA-only) and KA-induced SE followed 75 minutes later by theophylline (KA/Theo) or trimethobenzamide (KA/Tri). These drugs probably decrease seizure-induced cerebral hyperemia or hypertension. RESULTS: Compared with controls and KA-only rats, KA/Tri and KA/Theo rats showed decreased CA3b and CA1 neuron densities (i.e., greater Sommer's sector injury). In addition, KA/Tri rats showed that increased trimethobenzamide dosages were associated with decreased hilar, CA3c, CA3b, CA1, and subiculum neuron densities. There were no significant differences in supragranular mossy fiber sprouting between KA-only, KA/Tri, and KA/Theo rats. CONCLUSIONS: Pharmacologic manipulations during KA-induced SE are associated with differences in hippocampal pathology, especially in Sommer's sector, and the final pattern of damage and axon sprouting shows histopathologic similarities to that in patients with hippocampal sclerosis. Our findings support the hypothesis that secondary physiologic insults during SE that are likely to decrease seizure-induced cerebral hyperemia and hypertension may generate greater hippocampal neuronal injury compared with SE alone, and this may be a pathogenic mechanism of human hippocampal sclerosis in patients with TLE.

Animals↗
PubMed1977

The benign form of multiple sclerosis. Anatomo-clinical aspects.

The present paper is a study of three cases presenting the pathological aspect of chronic, non-evolutive multiple sclerosis, corresponding to a clinical picture of benign multiple sclerosis. The first case was discovered at autopsy, the second patient had two subclinical attacks of multiple sclerosis, with a twenty-year evolution (forme fruste), and in the third case the course of the chronic multiple sclerosis ran parallel to that of a cerebral and visceral arteriopathy. Anatomic study of the demyelinating lesions revealed their non-evolutive aspect and the presence within the plaques of lesions of the walls of small vessels with the perivascular adventitial fibrosis. The vascular changes appear to play a primordial role in the lack of evolution of the demyelinating areas, manifested clinically by a stationary, benign picture.

Brain↗
PubMed1997

Cerebrospinal fluid lactate and glutamine are reduced in multiple sclerosis.

OBJECTIVES: To analyse various metabolites in human cerebrospinal fluid from healthy controls and patients with multiple sclerosis. PATIENTS AND METHODS: Cerebrospinal fluid was obtained from patients by lumbar puncture, frozen, redissolved, and analysed for metabolites by proton nuclear magnetic resonance spectroscopy. RESULTS: Significantly lower values for lactate and glutamine were found in patients with multiple sclerosis in comparison with controls. No significant differences were found between patients with the relapsing-remitting and chronic progressive forms of the disease for any of the metabolites measured. CONCLUSION: There is a concomitant reduction in both lactate and glutamine in the cerebrospinal fluid of patients with multiple sclerosis compared to controls. This may be related to altered astrocytic metabolism during the disease. The results clearly show the diagnostic potential of magnetic resonance spectroscopy in diseases such as multiple sclerosis.

Adolescent↗
PubMed1997

Acute exacerbation of multiple sclerosis increases plasma levels of S-100 protein.

OBJECTIVES: To determine whether an increase in plasma concentration of S-100 protein can serve as a marker for acute exacerbation of multiple sclerosis. MATERIAL AND METHODS: The plasma level of S-100 protein was investigated in 28 patients suffering from multiple sclerosis. Of these, 17 patients were admitted for acute exacerbation and 11 patients had a stable disease with no clinical signs for acute exacerbation. S-100 protein concentrations in plasma were determined with an immunofluorometric sandwich assay. RESULTS: Plasma concentrations were significantly elevated in patients who were examined within 7 days after the onset of acute exacerbation (n = 6). S-100 levels of patients 8 to 28 days after the onset of acute exacerbation (n = 11) did not differ from healthy controls (n = 120). Eleven patients with multiple sclerosis without acute exacerbation had moderately elevated plasma levels. CONCLUSION: The plasma concentration of S-100 protein is a sensitive although unspecific indicator of neuronal damage and may be of use as a marker of disease activity in multiple sclerosis.

Acute Disease↗
PubMed1980

Detecting dentinal sclerosis in decalcified sections with the Pollak trichrome connective tissue stain.

The supply of young human teeth for controlled human pulp studies is inadequate. Dentinal sclerosis in older teeth modifies the expected pulpal responses. Decalcification, necessary to interpret pulpal responses, destroys the primary evidence of sclerosis. At present we are unable to detect the degree of sclerosis and the pulp response in the same preparation. Valid interpretations on older teeth cannot be accomplished until this problem is resolved. Fifty-seven teeth, normal and carious, representing a wide age span were fixed, embedded in Bioplastic and sectioned with the Bronwill Model No. 77 through the middle of the M-D plane on the labio-lingual plane to obtain an undecalcified ground section for examination with reflected and transmitted light and Faxitron 805 microradiography. The remaining portions of the tooth were decalcified, processed in paraffin and subjected to a variety of histochemical reactions including the Pollak trichrome stain. The Pollak trichrome and the Pollak trichrome solution No. 6 modification stains provided the greatest correlations with the sclerotic areas in the radiographs of the ground sections. Areas of dentin indicative of sclerosis prior to decalcification stained orange-red with the Pollak trichrome stain and deep orange with the Pollak trichrome solution No. 6 modification.

Dentin↗
PubMedDate not supplied

The accuracy of the dorsoproximal-dorsodistal projection in assessing third carpal bone sclerosis in standardbred trotters.

Thirty-five carpal joints from 20 standardbred trotters, age 1 to 7 years, all euthanized for nonorthopedic reasons, were examined to investigate the correlation between assessments of subchondral bone sclerosis in the third carpal bone from radiographs in the dorsoproximal-dorsodistal (DPr-DDi) projection and histomorphometric bone volume density measurements. The agreement between assessments of sclerosis from antemortem versus postmortem radiographs was also evaluated. Bones graded as sclerotic in the DPr-DDi projection had significantly higher bone volume density values for all areas of measurement than nonsclerotic bones. For sclerotic bones, grading of sclerosis was significantly associated with volume density measurements in the central cancellous bone only. There was a good agreement (Kw = 0.71) between assessments of radiographic bone sclerosis from antemortem versus postmortem radiographs.

Animals↗
PubMed1986

Breakdown of the blood-retinal barrier in multiple sclerosis measured by vitreous fluorophotometry.

Periphlebitis retinae in multiple sclerosis appears as transitory cellular infiltrations around veins in an otherwise normal retina. Similar cellular infiltrations have been found around veins in the central nervous system. In the present study the blood-retinal barrier has been investigated by vitreous fluorophotometry. Eight multiple sclerosis patients with actual periphlebitis retinae and 9 patients with previous but not active periphlebitis retinae were included in this study. Abnormal leakage of fluorescein was manifest in the group of multiple sclerosis patients with periphlebitis retinae. Permeability (1.8 +/- 0.2 X 10(-7) cm/sec; mean +/- SEM) but not in the control group as a whole permeability (1.3 +/- 0.1 X 10(-7) cm/sec; mean +/- SEM) compared to 17 normals (permeability 1.1 +/- 0.005). It is thus concluded that breakdown of the blood-retinal barrier may be transitory when connected with periphlebitis retinae in multiple sclerosis.

Adult↗
PubMed2003

When motor execution is selectively impaired: control of manipulative finger forces in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a degenerative motor neuron disorder with progressive and exclusive loss of motor neurons in the spinal cord, brainstem, and motor cortex. Five patients with amyotrophic lateral sclerosis, and 5 age-matched, healthy control subjects performed vertical point-to-point arm movements with an instrumented hand-held object. In between the movements, the object was held stationary. Compared with healthy controls, all patients generated greater grip forces during the phase of stationary holding of the object and greater ratios between grip and load force maximums during the arm movements. We conclude that in amyotrophic lateral sclerosis, the ability to scale the grip force magnitude efficiently according to the actual loading requirements is impaired. When performing upward movements, controls increased grip force in parallel with load force right from the movement onset; during downward movements, controls anticipated an early decrease of load force by constant or decreasing grip forces. In contrast, 3 of 5 patients showed an early increase of grip force during both upward and downward movements, indicating that in amyotrophic lateral sclerosis, the differential regulation of the grip force output according to the direction-dependent load force profile may be impaired. In motor neuron disease, the inaccurate grip force scaling and the impaired temporal coupling between grip and load force profiles may either directly result from deficient motor execution or be secondary to accompanying symptoms, such as dyscoordination of hand and finger muscles due to spasticity.

Aged↗
PubMed2004

Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis.

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

Humans↗
PubMed2004

Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial.

OBJECTIVE: To evaluate the effect of the oral synthetic delta-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis. DESIGN: Randomised double blind placebo controlled crossover trial. SETTING: Outpatient clinic, University Hospital of Aarhus, Denmark. PARTICIPANTS: 24 patients aged between 23 and 55 years with multiple sclerosis and central pain. INTERVENTION: Orally administered dronabinol at a maximum dose of 10 mg daily or corresponding placebo for three weeks (15-21 days), separated by a three week washout period. MAIN OUTCOME MEASURE: Median spontaneous pain intensity (numerical rating scale) in the last week of treatment. RESULTS: Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief score (numerical rating scale) was higher (3.0 (0 to 6.7) v> 0 (0 to 2.3), P = 0.035). The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change. CONCLUSIONS: Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.

Administration, Oral↗