G Ramsaransing

Benign course in multiple sclerosis: a review

Since the 1950s, it has been recognized that a subgroup of multiple sclerosis (MS) patients exists that shows little or no progression in the severity of the disease over time. This group is referred to as ‘benign’ MS. Although a substantial amount of research in MS indicates a multifactorial background in disease severity, to date it is still difficult to predict whether the course will be benign at onset and it is difficult to find factors that influence the course of the disease over time. Maintaining or restoring neural conduction inside a central nervous system lesion seems to be the essence of staying ‘benign’.

Early prediction of a benign course of multiple sclerosis on clinical grounds: a systematic review

Background: There is growing consensus that neurologists should consider disease-modifying therapies early in multiple sclerosis (MS). However, there is a subgroup with a natural benign course, in which treatment could be postponed. We sought to determine the frequency of benign MS and early clinical factors that may predict a benign course. Methods: We performed a systematic review of the existing literature on benign MS, which was defined as minimal or no disability equivalent to a score on the Expanded Disability Status Scale (EDSS) 43.0 at least 10 years after disease onset. Results: Only a small number of studies of adequate quality was available. In total there were nine published studies representing 2204 patients. The estimated frequency of benign MS was 26.7%. Onset with optic neuritis, onset before the age of 40 years, absence of pyramidal signs at presentation, duration of first remission more than 1 year, and only one exacerbation in the first 5 years after onset of MS, were associated with a benign course. Conclusions: From the existing literature a set of unrelated clinical characteristics emerged that was associated with a benign course of MS. However, there is a need for prospective studies to define more precisely clinical and paraclinical predictors of benign MS.

Plasma homocysteine levels in multiple sclerosis

Background: There is evidence that homocysteine contributes to various neurodegenerative disorders, and elevated plasma homocysteine levels have been observed in patients with multiple sclerosis (MS). Objective: To investigate if and why plasma homocysteine levels are increased in MS, and whether they play a role in the disease course. Methods: We compared plasma levels of homocysteine in 88 patients with MS and 57 healthy controls. In the MS group, 28 had a benign course, 37 were secondary progressive, and 23 primary progressive. To explore the underlying mechanisms, we measured serum levels of vitamins B6 and B12, folate, interleukin (IL)-12, tumour necrosis factor (TNF)-α, leukocyte nitric oxide production, and plasma diene conjugate levels (measure of oxidative stress). Results: Mean (SD) plasma homocysteine concentration was higher in patients (13.8 (4.9) µmol/l) than in controls (10.1 (2.5) µmol/l; p<0.0001). However, there were no significant differences in homocysteine levels between the three clinical subgroups of MS. Serum concentrations of vitamin B6, vitamin B12, and folate were not different between patients with MS and controls. In the MS group, there were no correlations between plasma homocysteine levels and the serum concentrations of IL-12 or TNF-α, leukocyte nitric oxide production, or plasma diene conjugate levels. Conclusions: Elevated plasma homocysteine occurs in both benign and progressive disease courses of MS, and seems unrelated to immune activation, oxidative stress, or a deficiency in vitamin B6, vitamin B12, or folate.

Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis

BackgroundThe role of oxidative stress in patients with multiple sclerosis (MS) is poorly understood.ObjectiveTo investigate oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of MS.MethodsDiene conjugate (DC) levels (a measure of lipid peroxidation), total antioxidative activity (AOA) and total antiradical activity (ARA) were measured in serum and peripheral blood leukocytes from 30 patients with benign relapsing remitting MS (BMS), 27 with secondary progressive MS (SPMS), 29 with primary progressive MS (PPMS), and 30 healthy controls. All MS patients were in a clinically stable phase.ResultsSerum DC levels were elevated in patients with BMS (p <0.05), SPMS (p <0.01) and PPMS (p <0.001). Serum total AOA and ARA were not different between MS patients and controls. Compared to controls, leukocyte DC levels were not different in each MS subgroup, but total ARA was elevated. There was a strong correlation, both in controls and MS patients, between leukocyte DC levels and leukocyte total ARA (p <0.0001) and leukocyte total AOA (p <0.0001).ConclusionOxidative stress occurs in progressive as well as benign MS. The finding that cells withstand oxidative stress, due to upregulated cellular antioxidant defence mechanisms, suggests that reactive oxygen species (ROS) formation in MS is not necessarily deleterious.

Predictive value of clinical characteristics for 'benign' multiple sclerosis.

We studied a cohort of 496 patients who had multiple sclerosis (MS) for at least 10 years. Ten years after disease onset, 151 had benign MS defined as an Extended Disability Status Scale (EDSS) ≤3. Between benign and non‐benign patients we compared gender, age at clinical onset, relapsing–remitting or primary progressive, symptoms at onset, recovery from first relapse, time between first and second relapse, number of relapses in the first 5 years, use of immunomodulatory drugs, and EDSS scores at 2, 5 and 10 years. A multivariate regression analysis showed that a relapsing–remitting course, a low EDSS score at 5 years, and a low number of relapses in the first 5 years were predictive for benign MS at 10 years. Other factors had no additional value. Thirty‐five of the 51 patients (69%) with benign MS at 10 years were still benign at 20 years. A low 10‐year EDSS score was the only clinical variable associated with a benign course at 20 years. Our results suggest that within the first 5 years from onset it is not possible to predict a benign course. Disease course, EDSS score and relapse rate at 5 years are predictors for benign MS at 10 years.

Serum levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in relapsing and primary progressive multiple sclerosis

Using radioimmunoassay we measured serum levels of insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 in patients with relapsing multiple sclerosis (MS) and a benign course (Expanded Disability Status Scale (EDSS)≤ 3 despite > 10 years disease duration), relapsing MS with cumulative disability leading to an EDSS score > 4 within 10 years of disease duration, primary progressive MS and healthy controls. We found no differences in IGF-1 and IGFBP-3 serum levels, and the IGF-1/IGFBP-3 ratio between the four groups. However, there was a significant correlation (P=0.005) between IGFBP-3 serum levels and both the progression index of disability and the Multiple Sclerosis Severity Score in patients with primary progressive MS.

Serum uric acid, dehydroepiandrosterone sulphate, and apolipoprotein E genotype in benign vs. progressive multiple sclerosis

The majority of patients with multiple sclerosis (MS) experience gradual progression of disability, either as secondary progressive MS (SPMS) or primary progressive MS (PPMS). A subgroup with relapsing–remitting MS shows a benign course with little or no disease progression and minimal disability decades after the first manifestations, so called benign MS (BMS). In our search to identify factors that are associated with progression of MS, we investigated serum levels of uric acid and dehydroepiandrostenedione sulphate (DHEAS), and apolipoprotein (apo)E genotype in 28 patients with BMS, 33 with SPMS, 21 with PPMS, and 29 healthy individuals. We found no significant changes in uric acid levels and apoE genotype between the four groups. Mean DHEAS levels were lower in MS patients compared with healthy controls (P = 0.049), but there were no significant differences between the clinical subgroups of MS. In patients with SPMS and PPMS there was no correlation between progression rate and serum levels of either uric acid or DHEAS. Our results suggest that serum levels of uric acid and DHEAS, and apoE genotype do not differ between patients with a benign and progressive course of MS.

Low leucocyte myeloperoxidase activity in patients with multiple sclerosis

The gene for myeloperoxidase (MPO) has been implicated in multiple sclerosis (MS). By measuring H2O2 dependent oxidation of 3,3′5,5′-tetramethylbenzidine with spectrophotometry the authors investigated MPO activity in peripheral blood leucocytes from 42 patients with MS (12 with secondary progressive MS, 17 with primary progressive MS, and 13 with relapsing remitting benign MS) and 32 healthy controls. Leucocyte MPO activity was significantly lower in patients with benign MS (mean (SEM) 0.086 (0.029) U/mg protein; p<0.01), secondary progressive MS (0.038 (0.009) U/mg protein; p<0.001), and primary progressive MS (0.057 (0.016) U/mg protein; p<0.001) compared with healthy controls (0.322 (0.053) U/mg protein). These data suggest that low MPO, which may be genetically determined, plays a part in MS pathogenesis.

Relationship between the extent of T2 lesions and the onset of secondary progression in multiple sclerosis

Patients with relapsing–remitting multiple sclerosis (MS) are at risk of converting to a secondary progressive disease course. To assess the relationship between brain magnetic resonance imaging (MRI) findings and onset of secondary progression, we reanalysed the initial brain MRI scans of 90 relapsing–remitting MS patients, who were clinically followed up for at least 10 years (median 14 years) after their scan, for the number and volume of T2 lesions, and for two measures of brain atrophy (bicaudate ratio and third ventricle width). The relationship to development of secondary progression was studied with Cox regression models and Kaplan–Meier survival analyses. At the end of follow‐up, 36 patients had become progressive. The presence of more than 10 T2 lesions more than doubled the risk of becoming secondary progressive (hazards ratio 2.36; 95% CI 1.19–4.66). When at least one of the 10 lesions was confluent the risk increased to 3.51 (1.64–7.50). The hazards ratio for an estimated T2 lesion load of more than 800 mm3 was 2.11 (1.07–4.16). Linear brain atrophy measures were not predictive. Our data show a relationship between the extent of brain T2 lesions and the onset of secondary progression in MS.

Peripheral blood leukocyte NO production in MS patients with a benign vs progressive course

Background: Nitric oxide (NO) may play a role in tissue destruction and axonal degeneration in multiple sclerosis (MS). Objective: To investigate NO production by peripheral blood leukocytes (PBL) in patients with a benign and progressive course of MS. Methods: PBL were isolated from 25 patients with a benign course of MS (BMS), 33 with secondary progressive MS (SPMS), 21 with primary progressive MS (PPMS), and 29 healthy individuals. Leukocyte supernatants were assayed for nitrite concentration, which is an index of NO generation, using the Griess reaction. Serum levels of tumor necrosis factor (TNF)α and interleukin (IL)-12 were measured using ELISA. Results: Compared to healthy controls, nitrite concentrations were higher in patients with BMS (p < 0.001), SPMS (p < 0.001), and PPMS (p < 0.05). There were no significant differences among the three clinical subgroups of MS. There was a correlation between nitrite concentrations and serum levels of IL-12 (p = 0.04), but not of TNFα. Conclusion: Increased NO production by PBL in patients with MS is independent of the disease course.