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PubMed2002

Genetic analysis of multiple sclerosis.

The increased recurrence risk within families indicates a role for genetic factors in the etiology of multiple sclerosis. Genes may influence susceptibility to the development of multiple sclerosis and the subsequent course of the disease. To date, associations have only been demonstrated consistently with class II major histocompatibility complex (MHC) alleles. The relatively low yield from additional candidate gene studies is only modestly advanced by several whole-genome linkage analyses, and by the first in a series of planned whole-genome linkage disequilibrium screens for allelic associations. The aims of linkage and association are to narrow the search for chromosomal regions encoding genes for multiple sclerosis and, with information from the human gene project, suggest new positional candidates. In time, it is expected that these genes will include some that confer susceptibility to the general process of autoimmunity, others that are specific for multiple sclerosis in all populations, some that act only in defined ethic groups, and those that determine particular phenotypes or shape the clinical course. These genetic analyses are predicated on the assumption that multiple sclerosis is one disease; a major part of future studies will be to resolve the question of disease heterogeneity in multiple sclerosis. When eventually in place, the potential of this genetic knowledge for improved understanding of the pathogenesis of multiple sclerosis and designing novel treatments is considerable.

DNA Mutational Analysis↗

PubMed1999

Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis.

The elective treatment of patients with multiple sclerosis, using a humanized anti-leukocyte (CD52) monoclonal antibody (Campath-1H), has illuminated mechanisms that underlie the clinical course of the disease. Twenty-seven patients were studied clinically and by magnetic resonance imaging (MRI) before and for 18 months after a single pulse of Campath-1H. The first dose of monoclonal antibody was associated with a transient rehearsal of previous symptoms caused by the release of mediators that impede conduction at previously demyelinated sites; this effect remained despite selective blockade of tumor necrosis factor-alpha. Disease activity persisted for several weeks after treatment but thereafter radiological markers of cerebral inflammation were suppressed for at least 18 months during which there were no new symptoms or signs. However, about half the patients experienced progressive disability and increasing brain atrophy, attributable on the basis of MRI spectroscopy to axonal degeneration, which correlated with the extent of cerebral inflammation in the pretreatment phase. These data support the formulation that inflammation and demyelination are responsible for relapses of multiple sclerosis; that inflammatory mediators, but not tumor necrosis factor-alpha, cause symptomatic reactivation of previously demyelinated lesions; and that axonal degeneration, conditioned by prior inflammation but proceeding despite its suppression, contributes to the progressive phase of disability. These results provide evidence supporting the emerging view that treatment in multiple sclerosis must be given early in the course, before the consequences of inflammation are irretrievably established.

Adult↗

PubMed1984

Characteristics of patients found not to have multiple sclerosis.

Of 400 consecutive patients referred to Dalhousie University's multiple sclerosis research unit 52 (13%) were found not to have multiple sclerosis. Forty-one (79%) of the patients were female and 11 (21%) were male. About half of the patients had raised the suspicion of multiple sclerosis, and about half had either a medical background or a close association with a patient with the disease. Although in many cases a diagnosis was made at the initial visit, in difficult cases the most effective diagnostic technique was repeated assessment of the patient over a long period. It is important to keep an open mind when assessing patients suspected of having multiple sclerosis and to apply the recognized criteria for diagnosis of the disease.

Adult↗

PubMed1991

Hemifacial spasm. Occurrence in multiple sclerosis.

We present six patients with hemifacial spasm and multiple sclerosis. To our knowledge, this association has not been described previously in the North American literature. Magnetic resonance imaging was obtained in all the patients and plaques consistent with multiple sclerosis were identified. In two patients the plaques were seen in the area of the facial nucleus on the involved side. We suggest that hemifacial spasm can be a manifestation of multiple sclerosis. These cases illustrate the utility of magnetic resonance imaging in the investigation of hemifacial spasm. Our findings also support a central (nuclear) origin in multiple sclerosis associated with hemifacial spasm.

Adrenocorticotropic Hormone↗

PubMed2005

Suicide among Danes with multiple sclerosis.

OBJECTIVE: To compare the suicide risk among Danish citizens with multiple sclerosis with that of the general population, and to evaluate changes over 45 years. METHODS: The study was based on linkage of the Danish Multiple Sclerosis Registry to the Cause of Death Registry. It comprised all 10,174 persons in whom multiple sclerosis was diagnosed in the period 1953 to 1996. The end of follow up was 1 January 1999. Standardised mortality ratios (SMRs) were calculated for various times after diagnosis and for age and calendar period of diagnosis. RESULTS: In all, 115 persons (63 men, 52 women) had taken their own lives, whereas the expected number of suicides was 54.2 (29.1 men, 25.1 women). Thus the suicide risk among persons with multiple sclerosis was more than twice that of the general population (SMR = 2.12). The increased risk was particularly high during the first year after diagnosis (SMR = 3.15). CONCLUSIONS: The risk of suicide in multiple sclerosis was almost twice as high as expected more than 20 years after diagnosis. The excess suicide risk has not declined since 1953.

Adult↗

PubMed1989

Colonic and anorectal dysfunction associated with multiple sclerosis.

Gastrointestinal symptoms are common in patients with multiple sclerosis. In a recent survey of 280 unselected patients with multiple sclerosis, 68% reported constipation and/or fecal incontinence. In contrast to bladder dysfunction which has been extensively studied, bowel dysfunction in this disease has received relatively little attention. This review outlines the clinical features and pathophysiology of constipation and fecal incontinence in multiple sclerosis and presents treatment options and suggestions for investigation of colonic and anorectal dysfunction in this population.

Colon↗

PubMed1997

Increased immunoreactivity to two overlapping peptides of myelin proteolipid protein in multiple sclerosis.

We tested the proliferative responses of peripheral blood mononuclear cells from 61 patients with multiple sclerosis, 56 healthy control subjects and 52 patients with other neurological diseases to seven synthetic peptides of myelin proteolipid protein (PLP) and 19 synthetic peptides of myelin basic protein (MBP). Increased proliferative responses to two overlapping PLP peptides, PLP184-199 and PLP190-209 were found significantly more frequently in blood from patients with relapsing-remitting or secondary progressive multiple sclerosis (52.3%), but not from those with primary progressive multiple sclerosis (18.2%), than in that from healthy control subjects (8.9%) and patients with other neurological diseases (20.8%). Reactivity to these PLP peptides was most frequently seen in blood from patients with multiple sclerosis of 6-15 years duration and with moderate to severe disability (Kurtzke's Expanded Disability Status Scale > 4.0); the blood from 15 of 19 patients in this group reacted to one or both of the peptides. Both peptides could be recognized by short-term T-cell lines specific for whole PLP, and lines specific for one or other of the two overlapping peptides were able to recognize whole PLP, indicating that these peptides can be processed naturally from the intact molecule. This region of PLP is encephalitogenic in a number of strains of mice. Samples from multiple sclerosis patients did not react more frequently to any of the MBP peptides than those from healthy control subjects. The proportions of patients with other neurological diseases whose blood responded to the MBP peptides that most frequently elicited responses in blood from multiple sclerosis patients were significantly lower than the proportions of multiple sclerosis patients and healthy control subjects whose blood responded to these peptides.

Adolescent↗

PubMed2005

Tau, phospho-tau, and S-100B in the cerebrospinal fluid of children with multiple sclerosis.

Axonal injury and glial activation are an early neuropathologic event in adults with multiple sclerosis. To investigate whether markers of axonal injury and glial activation are already elevated in the cerebrospinal fluid of children with multiple sclerosis, we studied the cerebrospinal fluid of 25 children with multiple sclerosis and 67 controls for the presence of tau, phospho-tau, and S-100B proteins using specific enzyme-linked immunoabsorbent assays. In general, tau, phospho-tau, and S-100B protein levels did not differ significantly between groups. However, in a subgroup of nine children with multiple sclerosis, all of whom had prominent clinical symptoms at the time of lumbar puncture and radiologic disease activity, tau protein levels were significantly elevated when compared with other controls. These data indicate that axonal injury is not restricted to adult multiple sclerosis but can already occur in children with multiple sclerosis.

Adolescent↗

PubMed1990

Epilepsia partialis continua in multiple sclerosis.

Epilepsia partialis continua (EPC) in multiple sclerosis is extremely rare. We report a case of a patient with clinically definite multiple sclerosis who developed EPC. Magnetic resonance imaging (MRI) depicted high signal in subcortical white matter and basal ganglia. A combination of lesions may be important in the generation of EPC.

Adrenocorticotropic Hormone↗

PubMed2002

Age-related disability in multiple sclerosis.

There is evidence that the clinical course of multiple sclerosis is age related. The present study evaluated the relationship between age and rate of disability progression in a large hospital-based cohort of definite cases of multiple sclerosis (n= 1,463). Patients were followed every 6 to 12 months for a total period of observation of 11,387.8 person-years. Expanded Disability Status Scale scores increased significantly with increasing current age and longer duration of disease (p=0.007). Median times to reach Expanded Disability Status Scale scores of 4.0 and 6.0, assessed using an extended Kaplan-Meier method with age as a categorical time-varying covariate, were significantly longer among patients aged 20 to 35 years compared with patients aged 36 to 50 and 51 to 65 years (p < 0.0001). Significant associations were observed between mean Expanded Disability Status Scale scores and age at disease onset, current age, and the interaction of age at disease onset and current age (p < 0.001). Current age had a greater effect (59% of variability in the model) on disease severity than did age at disease onset. Furthermore, a multiplicative effect on Expanded Disability Status Scale score was observed for age at disease onset and current age combined, indicating a faster rate of disease progression in older patients. In conclusion, the results of the current study demonstrate the impact of age on rate of disability progression in multiple sclerosis and suggest that an age-adjusted progression index may be a more relevant criterion for defining differences between multiple sclerosis groups.

Adult↗

PubMed1988

[Comparative study of visual evoked potentials and magnetic resonance imaging in multiple sclerosis].

19 patients with clinically definite, probable or possible multiple sclerosis were examined by means of visual evoked potentials and magnetic resonance imaging. The patients were classified in three groups according to the criteria of Mac Alpine. 11 patients had definite multiple sclerosis: 8 of these patients, who had visual disorders evoking an optic neuropathy, had abnormal visual evoked potentials and 7 of these 8 patients had a pathological magnetic resonance imaging. In the other 3 patients of this group without optic neuropathy. 2 of them had abnormal visual evoked potentials and the 3 had a pathological magnetic resonance imaging. Two patients had probable multiple sclerosis, one of them had abnormal visual evoked potentials and a pathological magnetic resonance imaging. Finally, 6 patients had possible multiple sclerosis, one had a optical neuropathy, with abnormal visual evoked potentials but with a normal magnetic resonance imaging. Among the 5 other patients, 2 had abnormal visual evoked potentials and a pathological magnetic resonance imaging. The results obtained in comparison with the other reported in the literature show that magnetic resonance imaging brings a certain number of criteria which when associated with visual evoked potentials seem to be a further development in the diagnosis of the affection. However, despite of the existence of correlations, the lack of specificity of the lesions found with magnetic resonance imaging should lead the clinicians to a cautions optimism.

Adolescent↗

PubMed2001

Optokinetic reflex dysfunction in multiple sclerosis.

The aim of this study was to further investigate optokinetic reflex function in multiple sclerosis. Gaze-holding in darkness, optokinetic nystagmus, optokinetic afternystagmus and latency to circularvection were measured using electro-oculography and a rotating optokinetic drum. Gaze-holding was not significantly different between the multiple sclerosis and control groups; however, four of 23 multiple sclerosis patients exhibited eccentric gaze-evoked nystagmus. There were no significant differences in either optokinetic nystagmus frequency or latency to circularvection. However, optokinetic nystagmus slow phase velocity during rise time and amplitude during beat time were significantly reduced in the multiple sclerosis group (p < 0.05 and p < 0.0001, respectively). The time constant of optokinetic afternystagmus was also significantly reduced in the multiple sclerosis group (p < 0.005). These results indicate that optokinetic nystagmus and optokinetic afternystagmus are significantly impaired multiple sclerosis.

Adult↗

PubMed2003

Expression of beta2 adrenoreceptors on peripheral blood mononuclear cells in patients with primary and secondary progressive multiple sclerosis: a longitudinal six month study.

BACKGROUND: Beta(2) adrenoreceptor expression on peripheral blood mononuclear cells is increased in progressive multiple sclerosis. This increase has been correlated with disease activity in relapsing-remitting multiple sclerosis. OBJECTIVE: To determine the beta(2) adrenoreceptor expression in primary and secondary progressive multiple sclerosis in relation to findings on magnetic resonance imaging (MRI) and clinical disease activity. METHODS: 10 patients with multiple sclerosis were studied (five with primary progressive and five with secondary progressive forms of the disease) over a period of six months. Monthly clinical and MRI assessments of the brain and spinal cord were carried out. Beta(2) adrenoreceptor expression was assessed monthly using a ligand binding assay with [(125)I]iodocyanopindolol. Expression of beta(2) adrenoceptors on peripheral blood mononuclear cells was also assessed in five normal controls over a similar period. RESULTS: The mean (SEM) value of beta(2) adrenoreceptor density for the five normal controls was 1346 (183) sites/cell, with affinity Kd of 120 (40) pM. MRI disease activity in primary progressive multiple sclerosis was reported on two occasions and on those occasions the expression of beta(2) adrenoreceptors was increased in excess of 1900 sites/cell; in the remaining 28 observations beta(2) adrenoreceptor expression was within the normal range (800 to 1900 sites/cell). In patients with secondary progressive disease, MRI disease activity was observed on 16 occasions. In these patients expression of beta(2) adrenoreceptors was increased in excess of 2000 sites/cell in all measurements except in one subject who did not show MRI activity throughout the six months period of study. The affinity of the receptors was within the normal range in all cases. CONCLUSIONS: Increased expression of beta(2) adrenoreceptors was correlated with MRI disease activity in two patients with primary progressive multiple sclerosis. In secondary progressive multiple sclerosis, increased expression of beta(2) adrenoreceptors tended not to correlate with MRI disease activity. This may reflect a persistent Th1 immune reaction in the secondary progressive form of the disease.

Adult↗

PubMed1989

The contribution of mortality statistics to the study of multiple sclerosis in Australia.

Mortality statistics provided a valuable source of support for data obtained from prevalence surveys of multiple sclerosis in Australia. Firstly, multiple sclerosis mortality data for the decade 1971-80 in the States of Australia confirmed the relationship between increasing disease frequency and increasing south latitude shown by State and regional point prevalence surveys based on the national census day 30 June 1981. Secondly, a comparison with mortality data from the decade 1950-59 showed that in most States there had been a substantial fall in multiple sclerosis mortality in the more recent decade and this was clearly an important contributing factor to the rise in prevalence noted between the morbidity surveys of 1961 and 1981. Thirdly, multiple sclerosis mortality in the UK-born migrant population dying in Australia was found to be similar to that of the Australian-born population and very much lower than that found in the UK. This observation corroborated evidence from the 1981 morbidity surveys and suggested that migration from the UK to Australia may lower the risk of developing multiple sclerosis either through a reduction in disease incidence or the operation of environmental factors curbing disease expression.

Australia↗

PubMedDate not supplied

[Diabetes and multiple sclerosis].

We report four patients who had multiple sclerosis associated with diabetes mellitus. Multiple sclerosis and diabetes mellitus share clinical, epidemiological and immunological features. The association between these two putative autoimmune diseases may suggest a similar pathogenic mechanism.

Adult↗

PubMed1999

[Multiple sclerosis: one or several diseases?].

The various clinical courses of multiple sclerosis (relapsing-remitting, primary progressive, secondary progressive, progressive-relapsing) are likely related to different severity or distribution of the main lesions that constitute the plaques (inflammation, demyelination, axonal injury and loss, necrosis). They might lead to different therapeutic approaches. Some cases of the other clinico-radiological or clinico-pathological variants (pseudo-tumoral, concentric sclerosis of Baló, acute disseminate encephalomyelitis, Devic's neuromyelitis optica) obviously share similar mechanisms with multiple sclerosis. Other cases are, on the contrary, linked to different diseases. Do the variants of multiple sclerosis could be the consequence of different diseases? This is, today, a highly speculative conjecture. The prevalent hypothesis suggests that the clinico-pathological heterogeneity of multiple sclerosis is linked to the variability of the reaction of the nervous tissue to an initial injury. This different vulnerability, that depends on unknown factors, would explain the variants of the disease.

Diagnosis, Differential↗

PubMed1999

Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. A longitudinal clinical and MRI study.

Metalloproteinases have been implicated in the pathogenesis of multiple sclerosis. We report longitudinal serum levels of gelatinase B and of the tissue inhibitors of matrix metalloproteinases (TIMP), TIMP-1 and TIMP-2, in 21 patients with relapsing multiple sclerosis. Patients had monthly clinical and gadolinium-enhanced MRI follow-up for 10 months. Longitudinal samples in nine healthy controls and cross-sectional samples from 12 patients with inflammatory CNS disease and 15 patients with other neurological diseases were used for comparison. Average serum gelatinase B, TIMP-1 and TIMP-2 levels were significantly higher in multiple sclerosis patients and those with other neurological diseases than in healthy controls. In the patients with multiple sclerosis, gelatinase B levels were significantly higher during clinical relapse compared with periods of clinical stability. Multiple sclerosis patients with high mean serum gelatinase B levels had significantly more T1-weighted gadolinium-enhancing MRI lesions than those with mean levels within the control range. TIMP-1 levels were not different during relapse and between relapses. There was a trend for TIMP-2 levels to be lower during relapse compared with non-relapse periods. For similar levels of serum gelatinase B, associated TIMP-1 levels were significantly lower and TIMP-2 levels significantly higher in multiple sclerosis patients compared with the inflammatory CNS control group. We propose that an abnormality in the inhibitory response to metalloproteinases may play an aetiological role in the chronicity of multiple sclerosis.

Adult↗

PubMed1997

1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis.

OBJECTIVES: To test the hypothesis that irrecoverable neurological deficit in multiple sclerosis is associated with axonal loss. METHODS: 1H magnetic resonance spectroscopy (MRS) was carried out in a group of patients with clinically definite multiple sclerosis (n=31). Using this technique, the apparent concentration of NA ([NA] the sum of N-acetyl aspartate (NAA), a neuronal marker, and N-acetylaspartylglutamate has been compared in four groups of patients with multiple sclerosis classified as relapsing-remitting, secondary progressive, primary progressive, benign, and a control group. RESULTS: In the patients with relapsing-remitting disease (n=9) there was a highly significant reduction of apparent NA (median 8.73 mM, range 6.86 mM-10.74 mM, P=0.0008) from an area of high signal compared with the control group (median 11.97 mM, range 10.55 mM-14.5 mM). In the patients with secondary progressive disease (n=10), there was again a highly significant reduction of apparent NA (median 7.82 mM, range 3.5 mM-10.3 mM, P=0.0003) from an area of high signal compared with the control group. In the patients with primary progressive disease (n=6) there was once again a highly significant reduction of apparent NA (median 8.83 mM, range 6.95 mM-9.89 mM, P<0.002) from an area of high signal compared with the control group. In the patients with benign disease, however, there was no significant difference in the apparent NA (median 10.5 mM, range 8.53 mM-12.8 mM, P>0.05) from an area of high signal compared with the control group. In the patients with benign disease (n=5) there was also no significant difference in the apparent NA (median 10.74 mM, range 8.58 mM-13.4 mM, P>0.3) from an area of normal appearing white matter compared with the control group. In the patients with primary progressive disease, however, there was a significant reduction of apparent NA from an area of normal appearing white matter (median 8.78 mM, range 8.7 mM-12.38 mM, P< 0.025) compared with the control group. There was a significant inverse correlation between [NA] from lesions in the patients with multiple sclerosis and disability as measured on the Kurtzke expanded disability scale score (r= -0.364, 0.05>P>0.02). CONCLUSION: These findings support the hypothesis that axonal loss is important in the development of disability in multiple sclerosis. They also provide evidence for axonal loss in normal appearing white matter in patients with primary progressive disease.

Adolescent↗