Davide Nasuelli

A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis

OBJECTIVE (a) To establish whether the cognitive decline of the early phase of relapsing-remitting multiple sclerosis depends on the progression of the burden of disease, or on the loss of brain parenchyma, or is influenced by both; (b) to monitor the loss of brain parenchyma in the early phase of the disease; and (c) to examine its possible relation with the progression of physical disability. METHODS For 2 years 53 patients with clinically definite relapsing-remitting multiple sclerosis with disease duration 1–5 years and expanded disability status scale⩽5.0 at baseline were monitored. The neuropsychological performances, the psychological functioning, the neurological impairment, and the disability have been assessed at baseline and after 2 years. Patients also underwent PD/T2 and T1 weighted brain MRI. T2 and T1 lesion volumes were measured by a semiautomatic technique. Quantification of brain parenchymal volumes was obtained using a highly reproducible computerised interactive program. The relation between cognitive impairment and MRI findings has been investigated by partial correlation and stepwise multiple regression analyses excluding the effects of age, education, anxiety, depression, and total days of steroid use. RESULTS In the 2 years of the study the mean change for T2 and T1 lesion volumes and brain parenchymal volumes were +1.7 ml (95% confidence interval (95% CI) 1.3–2.2, p=0.005, (29.8%); +0.2 ml, 95% CI 0.15–0.26, p=0.004, (25%); and –32.3 ml, 95% CI 24.2–42.3, p<0.0001, (2.7%), respectively. Overall, 14 patients (26.4%) were judged to be cognitively impaired at baseline and 28 (52.8%) at the end of the follow up. Of the 18 neuropsychological tests and subtests employed in the study, patients with multiple sclerosis failed 5.8 (SD 2.3) tests at the baseline and 8.4 (SD 2.9) (p<0.0001) tests at the end of the study. When the cognitive changes were examined in individual patients, five (9.4%) of them were considered cognitively improved, 33 (62.3%) remained stable, and 15 (28.3%) worsened over 2 years. T2 and T1 volume changes in improved, stable, and worsened patients did not show any significant difference, whereas brain parenchymal volume decrease in cognitively worsened patients was significantly greater (−66 ml (5.4%), 95% CI 37–108.9, p=0.0031). The cognitive impairment was independently predicted over 2 years only by the change of brain parenchymal volumes (R=0.51, p=0.0003). Ten patients (18.9%), who worsened by one or more points in the EDSS during the follow up period had significant decreases in brain parenchymal volumes (−99 ml (8%), 95% CI 47.6–182.3, p=0.005). At the end of the study the loss of brain parenchyma correlated significantly with change in EDSS (r= 0.59, p<0.0001). CONCLUSIONS In the early phase of relapsing-remitting multiple sclerosis the cognitive deterioration relies more on the development of brain parenchymal volume atrophy than on the extent of burden of disease in the brain. The loss of brain parenchymal volume underlies the progressive accumulation of physical disability from the initial phase of the disease, which becomes more demonstrable only if studied with longer observation periods. Probably, the main pathological substrate of brain atrophy in the early stage of the disease is early axonal loss, which causes the progression of neurological deficits and the development of cognitive impairment. These data support the debated opinion that disease modifying therapy should be initiated as early as possible.

Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS

Background: IV methylprednisolone (IVMP) has been used to treat relapses in patients with relapsing-remitting (RR) MS, but its effect on disease progression is not known. Furthermore, there are no data on the impact of IVMP on T1 black holes or whole-brain atrophy. Objective: To determine the effect of IVMP on MRI measures of the destructive pathology in patients with RR-MS and secondarily to determine the effect of IVMP on disability progression in patients with RR-MS. Methods: The authors conducted a randomized, controlled, single-blind, phase II clinical trial of IVMP in patients with RR-MS. Eighty-eight patients with RR-MS with baseline Expanded Disability Status Scale (EDSS) scores of ≤5.5 were randomly assigned to regular pulses of IVMP (1 g/day for 5 days with an oral prednisone taper) or IVMP at the same dose schedule only for relapses (IVMP for relapses) and followed without other disease-modifying drug therapy for 5 years. Pulsed IVMP was given every 4 months for 3 years and then every 6 months for the subsequent 2 years. Patients had quantitative cranial MRI scans at study entry and after 5 years and standardized clinical assessments every 4 to 6 months. Results: Eighty-one of 88 patients completed the trial as planned, and treatment was well tolerated. Baseline demographic, clinical, and MRI measures were well matched in the two study arms. Patients on the pulsed IVMP arm received more MP than patients on the control arm of the study (p < 0.0001). Mean change in T1 black hole volume favored pulsed IVMP therapy (+1.3 vs +5.2 mL; p < 0.0001), as did mean change in brain parenchymal volume (+2.6 vs −74.5 mL; p = 0.003). There was no significant difference between treatment arms in the change in T2 volume or annual relapse rate during the study. However, there was significantly more EDSS score worsening in the control group, receiving IVMP only for relapses. There was a 32.2% reduction (p ≤ 0.0001) in the probability of sustained EDSS score worsening in the pulsed MP arm compared with the relapse treatment arm. At the end of the study, EDSS was better in the pulsed MP group (1.7 vs 3.4; p < 0.0001). Prolonged treatment with pulsed IVMP was safe and well tolerated; only two patients dropped out for toxic side effects over 5 years. Conclusions: In patients with RR-MS, treatment with pulses of IVMP slows development of T1 black holes, prevents or delays whole-brain atrophy, and prevents or delays disability progression. A phase III study of IVMP pulses is warranted.

Depression and anxiety in multiple sclerosis. A clinical and MRI study in 95 subjects

Abstract The aim of the present study was to investigate the relationship between involvement of specific areas of the brain and the occurrence of depression and anxiety in patients with multiple sclerosis. We studied 95 patients (62 women and 33 men, mean age 39.5 years, SD 11.2) with definite MS, 97 patients (65 women and 32 men, mean age 40.7, SD 11.9) suffering from chronic rheumatoid diseases and 110 healthy subjects (71 women and 39 men, mean age 40.1, SD 12.7). The disability, the independence, the cognitive performances, the depressive and anxiety symptoms were assessed. The diagnosis of major depression was made according to the DSM-IV. The patients with multiple sclerosis underwent a 1.5 Tesla magnetic resonance examination including T1 and T2 weighted images. Calculation of regional and total lesion loads and brain volumes were performed. The number (%) of subjects with a diagnosis of major depression was 18 (18.9) among MS cases, 16 (16.5) among controls with chronic disease (p=NS), and 4 (3.6) among healthy volunteers (p < 0.0001). The Hamilton Depression and Anxiety rating scales median scores were 5 and 18, respectively in the MS patients, 5 (p= NS) and 14 (p= NS) in the chronic rheumatoid diseases controls, and 3 (p= < 0.0001) and 6 (p= < 0.0001) in the healthy controls. Both severity of depressive symptoms and diagnosis of major depression correlated, albeit weakly, with right frontal lesion load (r=0.22, p=0.035, and r=0.23, p=0.026, respectively) and right temporal brain volume (r=0.22, p=0.005 and r=0.22, p=0.036, respectively). The severity of depression was related significantly also with total temporal brain volume (r=0.26, p=0.012), right hemisphere brain volume (r=0.25, p=0.015), disability (r=0.30, p=0.003) and independence of MS cases (r=−0.26, p=0.01). The anxiety did not correlate significantly with any of the measures of regional and total lesion loads and brain volume or with any of the considered clinical variables. The similar frequency of depression and severity of depressive symptoms in MS patients and in chronic disease patients, the significant difference in this respect with the normal controls, and the significant correlation between depression and the disability measures would suggest a psychological reaction to the impact of the disease but the relationship between depression and the alterations in the frontal and temporal lobes of the right hemisphere supports, on the contrary, the causative role of organic brain damage. The lack of any significant association between symptoms of anxiety and either MRI abnormalities or clinical variables led us to the opinion that anxiety is a reactive response to the psychosocial pressure put on the patients.

MRI techniques and cognitive impairment in the early phase of relapsing-remitting multiple sclerosis.

Abstract Correlation studies between various conventional and non-conventional MRI parameters and cognitive impairment in the early stages of multiple sclerosis (MS) are lacking, although it is known that a number of patients with early MS have mild cognitive impairment. Our aim was to explore whether this cognitive impairment is dependent on the extent and severity of the burden of disease, diffuse microscopic brain damage or both. We studied 63 patients with clinically definite relapsing-remitting (RR) MS, duration of disease 1–10 years and Expanded disability status scale scores ≤ 5.0. Mean age was 35.4 years, mean duration of disease 5.8 years and median EDSS score 1.5. Neuropsychological performance, psychological function, neurological impairment and disability were assessed. The patients also underwent MRI, including magnetisation-transfer (MT) studies. We quantified the lesion load on T2- and T1-weighted images, the magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT) and the brain parenchymal fraction (BPF). No significant difference was found between lesion loads in patients with and without cognitive impairment. In 15 patients (23.8 %) with overall cognitive impairment, median BPF and average NABT MTR were significantly lower than those in patients without cognitive impairment (0.868 vs 0.892, P = 0.02 and 28.3 vs 29.7 P = 0.046, respectively). Multiple regression analysis models demonstrated that the only variables independently correlated with cognitive impairment were: BPF (R = 0.89, P = 0.001) and average NABT MTR (R = 0.76, P = 0.012). Our findings support the hypothesis that, cognitive decline in patients with MS, a low disability score and short duration of disease is directly associated with the extent and severity of diffuse brain damage. The loss of brain parenchyma did not correlate with the severity of microscopic damage in the NABT, indicating that the two processes could be distinct in the early stages of the disease.

Risk factors of multiple sclerosis: a case-control study.

Abstract.We assessed the risk of multiple sclerosis (MS) associated with a series of putative risk factors. We studied 140 patients (90 women) with MS (mean age, 42.1 years; SD=10.2 years; disease duration, 10.9 years, SD=7.5 years) and 131 sexand age-matched controls. Using a structured questionnaire, we collected information related to demographic data, socio-economic status, education, ethnicity, changes of domiciles, migration, occupation, environmental, nutritional and hormonal factors, exposure to various bacterial and viral agents, vaccinations, and family history of diseases. In multiple logistic regression analysis, we found independent risk factors of MS to be: familiarity for MS (OR=12.1; 95% CI, 1.3–110.7), autoimmune diseases (OR=3.8; 95% CI, 2.0–7.1) and migraine (OR=8.7; 95% CI, 1.0–75.4); comorbidity with autoimmune disease (OR=6.8; 95% CI, 1.4–32.0) and migraine (OR=13.5; 95% CI, 1.5–116.6); and vaccination against measles (OR=92.2; 95%, 12.1–700.2). Familial susceptibility to MS, autoimmune diseases and migraine, and vaccination to measles are associated with an increased risk of MS. The data collected in this study are confirmatory and support the hypothesis that etiology of MS constitutes the effect of interplay between genetic and environmental risk factors. However, the relatively small number of cases and controls prevents firm conclusions.

Sexual dysfunction in multiple sclerosis: a 2-year follow-up study

BACKGROUND AND OBJECTIVE Sexual dysfunction severely affects the quality of life of patients, but longitudinal studies of sexual function in multiple sclerosis are lacking. We performed a study on a group of patients with multiple sclerosis to evaluate the change in sexual function and to examine the relationship between sexual dysfunction and other clinical variables over time. METHODS A 2-year follow-up study on 99 patients with definite multiple sclerosis. Information on sexual and sphincteric disturbances have been collected through face-to-face structured interviews. Disability, independence, cognitive performances and psychological functioning have also been assessed. Spearman rank correlation analysis corrected for multiple comparisons, and linear regression analysis have been performed to test variables relationship and remove the effect of potential confounding covariates. RESULTS The proportion of patients with sexual dysfunction remained over 70% and did not change during the 2-year follow-up, but the extent and number of symptoms increased significantly The number of symptoms of sexual dysfunction did not change significantly after an exacerbation. Significantly, more patients than before the study resorted to counseling and discussed with doctors of sexual matters. In the univariate analysis, changes in sexual function over time correlated with changes in bladder function (r=0.47, p<0.0001) and EDSS score (r=0.41, p<0.0001), but the multivariate analysis demonstrated that only bladder dysfunction was independently related to sexual dysfunction (R=0.36, p=0.003) when the effect of psychological factors were removed. CONCLUSIONS Symptoms of sexual dysfunction increase in significance and number over time in patients with multiple sclerosis. Relapses did not influence the number of symptoms of sexual dysfunction, but a worsening of pre-existing symptoms cannot be excluded. The change of sexual function appears to be independently associated to bladder dysfunction.

A longitudinal study of quality of life and side effects in patients with multiple sclerosis treated with interferon beta-1a

In a 12-month follow-up study, we evaluated 27 patients (18 F and 9 M) with relapsing-remitting (RR) multiple sclerosis (MS), who had started treatment with interferon beta-1a (IFNbeta-1a) (Avonex), 30 microg i.m. once weekly, 6-18 months (median 10 months) before study entry. Quality of life (QOL), disability, independence, cognitive performances, symptoms of depression and anxiety, and fatigue were assessed at baseline, 6 months and 12 months. The frequency and severity of the side effects of treatment, at hours 0-12, 13-48 and 49-168 after the injection, were self-reported weekly in a structured questionnaire. QOL did not change significantly during the follow-up. The percentage of patients who reported side effects after the injection of IFNbeta-1a remained constant during the 52 weeks. The mean number of side effects increased significantly from the 6th to the 12th month. The general linear model analysis of variance disclosed significant changes over time for almost all side effects, but we did not find any correlation between QOL and number of side effects. In conclusion, 1-year treatment with IFNbeta-1a did not significantly change patients QOL. Disability progression correlated with patients QOL. Side effects, which were mild, did not diminish over time, did not induce treatment discontinuation and did not interfere with QOL.

Long-term effects of intravenous high dose methylprednisolone pulses on bone mineral density in patients with multiple sclerosis

To determine the effects of high dose methylprednisolone (HDMP) pulses on bone mineral density (BMD) in patients with multiple sclerosis (MS), we studied 25 MS patients who received regular pulses of HDMP as well as pulses of HDMP for relapses, 18 MS patients who received HDMP at the same dose schedule only for relapses, and 61 healthy controls. We measured BMDs at lumbar spine and femoral neck and we assessed biochemical markers of bone metabolism and turnover. The average lifetime dosage of MP was 75.4 (SD 11.9) g in the pulsed HDMP group and 28.6 (SD 18.3) g in the HDMP for relapses group (P < 0.0001). Two MS patients (4.7%) and four controls (6.6%) had osteoporosis (P = NS), whereas 25 patients with MS (58.1%) and 21 controls (34.4%) had osteopenia (P = 0.016). BMDs measured at lumbar spine and femoral neck and biochemical indices of bone metabolism did not differ in MS patients and controls. BMD measures were not associated with lifetime methylprednisolone dosage. In partial correlation analysis, controlling for age, gender and menopausal status there was a significant inverse correlation between BMD at femoral neck and Expanded Disability Status Scale (EDSS) score (r = −0.31, P =0.05). In conclusion, treatment with repeated HDMP pulses was not associated with osteoporosis in patients with MS who participated in a trial of methylprednisolone. However, osteopenia was observed more frequently in MS patients than healthy controls. Our data are reassuring, as them suggest that repeated pulses of methylprednisolone do not result in substantially increased risk of osteoporosis in MS patients. Moreover, osteopenia was found only in patients treated for relapses, who had a significantly higher EDSS score than patients in the HDMP group, suggesting that decreased mobility may contribute to bone loss more than corticosteroid use. BMD should be monitored in patients with MS, regardless of the use of methylprednisolone.

Sexual dysfunction in multiple sclerosis: a MRI, neurophysiological and urodynamic study

We studied 31 patients with relapsing-remitting (RR) multiple sclerosis (MS) in which we performed an urodynamic study, the pudendal cortical evoked potentials, the tibial cortical evoked potentials and the cranial and cervical spinal cord magnetic resonance imaging (MRI). We calculated the T(1) and T(2) lesion load (LL) and brain parenchymal fraction (BPF) of whole brain, frontal lobes, pons and cervical spinal cord. We also estimated the cross-sectional area at C(2) level. Spearmans rank correlation analysis showed a relationship between symptoms of sexual dysfunction and age (r=0.73, p<0.0001), cognitive performances (r=-0.63, p<0.0001), level of independence (r=-0.63, p<0.0001), disability (r=0.56, p<0.001), symptoms of anxiety (r=0.55, p<0.001) and depression (r=0.50, p<0.005), disease duration (r=0.42, p<0.02) and parenchymal atrophy in the pons (r=-0.38, p=0.031). Sexual dysfunction was not correlated with any other MRI measure, urodynamic patterns or cortical evoked potentials. In multiple regression analysis, sexual dysfunction was predicted only by T(1) lesion load of the pons. In conclusion, we confirmed previous correlations of sexual dysfunction with various clinical variables and demonstrated an association between sexual dysfunction and destructive lesions in the pons, as detected by MRI, in patients with relapsing-remitting multiple sclerosis.

Depressive symptoms and MRI changes in multiple sclerosis.

To determine whether changes in specific regions of the brain can contribute to the development of depression in patients with multiple sclerosis (MS). We prospectively studied 90 patients with clinically definite MS. Disability, independence, cognitive performances, and depressive and anxiety symptoms have been assessed at baseline and 2 years later. At these two time‐points, patients underwent a 1.5‐T magnetic resonance examination of the brain including T1‐ and T2‐weighted images. Calculation of regional and total lesion loads (LL) have been performed by a semiautomatic technique; total and regional brain volumes have been calculated by a fully automatic highly reproducible computerized interactive program. Measurements of LL did not show any significant difference between depressed and non‐depressed patients. Brain atrophy was significantly more conspicuous in the left frontal lobe (P=0.039), in both frontal lobes (P=0.046) and showed a trend towards a difference in the right frontal lobe (P=0.056), in the right temporal lobe (P=0.057) and in both temporal lobes (P=0.072) of depressed patients. Disability, independence and cognitive performances were similar in depressed and non‐depressed patients (P=NS). Spearman correlation analysis and multiple‐regression analysis demonstrated that the severity of the depressive symptoms score was associated both with the disability score and the right temporal brain volume. Destructive lesions in the right temporal lobe can contribute to the severity of depression in patients with MS but the influence of the severity of neurological impairment should be taken into account.