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 < or =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.

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

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 < or = 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.

Olfactory dysfunction and extent of white matter abnormalities in multiple sclerosis: a clinical and MR study.

BACKGROUND: The relative contribution to the olfactory dysfunction of the lesions in the specific brain regions involved in olfaction compared with the lesions scattered all over the rest of the brain has not been fully clarified yet in patients with multiple sclerosis (MS). The concurrent use of Magnetic Resonance Imaging (MRI) and a standardized test of odor identification ability now permits to study the relation between smell loss and the extent of white matter abnormalities. METHODS: We tested the olfactory function of 40 patients with definite MS and of 40 age-sex- and smoking-habit-matched healthy controls by using the Cross Cultural Smell Identification Test. We measured also the lesion load on T2-weighted images in the inferior-frontal and temporal lobes and in the rest of the brain in MS patients. Therefore, we tried to correlate measures of lesion load and smell test scores. RESULTS: A robust correlation was demonstrated between MR measures of lesion load in the white matter of the olfactory brain region and smell loss (r=-0. 739, P<0.0001). A significant relationship has been found even after taking potential confounding factors, such as sex, age, disease duration, disability, anxiety and depression, into account (r=-0.90, P<0.0001). CONCLUSIONS: Our findings show, in MS patients with stable neurological impairment and no recent disease exacerbation, a correlation between smell loss and the lesion load in the regions of the brain involved in olfaction and support the theory that the extent and severity of MRI abnormalities in specific brain regions are related to the presence of selective neurologic and neuropsychologic impairment.

[Treatment of multiple sclerosis. The present and the future. Study Group on Diagnosis and Therapy of Multiple Sclerosis]. / Il trattamento della sclerosi multipla. Il presente ed il futuro. Gruppo di Studio per la Diagnosi e Terapia della Polisclerosi.

The last years have produced a plethora of new information including extensive studies, retrospective analysis and new perspectives on data interpretation on multiple sclerosis (MS) treatment. Considering how difficult it is to study a disease such MS with its variability, unpredictability and duration, it seems hard to resemble definite results from this experience. However, corticosteroids have been the mainstay of treatment for the management of acute relapses, showing the capacity to shorten the duration of relapses, accelerate the recovery. At present, interferon beta is generally considered to be the treatment of choice for patients with relapsing remitting disease. Glatiramer acetate is still not available in many parts of Europe, but its results demonstrate a reduction of relapses in 30% of cases. Most European experts only consider as alternative treatment the immunosuppressive drugs, chosen if patients demonstrate unacceptable side effects of interferon or clearly do not respond. Very different and even more confusing data still come from experimental trial in secondary progressive MS, where the target of treatment is to slow the progression of disability. Different drugs (methotrexate, mitoxantrone, linomide, steroids and even interferons) are employed, but the results are still debated. Future therapies are being derived from constantly changing and evolving concept of MS immunopathogenesis: therefore many experimental and clinical trials use anti-integrin antibodies or insulin growth factors, metallo-proteinase inhibitors or T-cell vaccination. Some of the above treatment may have a chance of producing the gaining control of the disease without much inner toxicity.

Sexual dysfunction in multiple sclerosis: a case-control study. I. Frequency and comparison of groups.

Sexual dysfunction is a very important but often overlooked symptom of multiple sclerosis. To investigate the type and frequency of symptoms of sexual dysfunction in patients suffering from multiple sclerosis, we performed a case-control study comparing 108 unselected patients with definite multiple sclerosis, 97 patients with chronic disease and 110 healthy individuals with regard to sexual function, sphincteric function, physical disorders impeding sexual activity and the impact of sexual dysfunction on social life. Information has been collected from a face-to-face structured interview performed by a doctor of the same gender as the patient. The disability, the cognitive performances, the psychiatric conditions and the psychological profile of patients and controls have been assessed. Sexual dysfunction was present in 73.1% of cases, in 39.2% of chronic disease controls and in 12.7% of healthy controls (P<0.0001). Male cases reported symptoms of sexual dysfunction more frequently than female cases (P<0.002). Symptoms of sexual dysfunction more commonly reported in patients with multiple sclerosis were anorgasmia or hyporgasmia (37.1%), decreased vaginal lubrication (35.7%) and reduced libido (31.4%) in women, and impotence or erectile dysfunction (63.2%), ejaculatory dysfunction and/or orgasmic dysfunction (50%) and reduced libido (39.5%) in men. Seventy-five per cent of cases, 51.5% of chronic disease controls and 28.2% of healthy controls (P<0.0001) experienced symptoms of sphincteric dysfunction. In conclusion, a substantial part of our sample of patients with multiple sclerosis reported symptoms of sexual and sphincteric dysfunction. Both sexual and sphincteric dysfunction were significantly more common in patients with multiple sclerosis than in either control group. Our findings suggest that a peculiar damage of the structures involved in sexual function is responsible for the dysfunction in patients with multiple sclerosis, but the highly significant lower frequency of symptoms of depression and anxiety in healthy controls may also imply a possible causative role of psychological factors.

Sexual dysfunction in multiple sclerosis: II. Correlation analysis.

Sexual dysfunction affects a large part of patients suffering from multiple sclerosis, but some aspects of its clinical presentation and aetiology are not clearly defined yet. In an unselected sample of 108 patients with definite multiple sclerosis we investigated the relationship between symptoms of sexual dysfunctioning and sphincteric dysfunction, patients' and disease characteristics, disability and neurological impairment, psychological and cognitive functioning. Sexual dysfunction directly correlated with presence of physical disorders (r=0.37, P=0.0004), low educational level (r=0.32, P<0.002), disability (r=0.31, P<0.003), age at onset of symptoms (r=0.30, P<0.003), sphincteric dysfunction (r=0.30, P<0.003), age (r=0.30, P<0.004), depression (r=0.29, P<0.005), fatigue (r=0.29, P=0.005), cognitive deterioration (r=0.26, P<0.01), primary-progressive course of disease (r=0.25, P<0.02), neurological impairment (r=0.25, P<0.02), marriage (r=0.24, P<0.02), anxiety (r=0. 23, P<0.03), male gender (r=0.22, P=0.03) bladder dysfunction (r=0. 29, P<0.04), and unemployment (r=0.21, P<0.04). Sexual dysfunction correlated inversely with relapsing - remitting course of disease (r=-0.31, P<0.002). No correlation was found between sexual dysfunction and bowel dysfunction, duration of disease, secondary-progressive course of disease, number and frequency of sexual intercourses in the last year, number of partners, number of exacerbations in the last year, number of months since last exacerbation, masturbation, and fertility. In conclusion, the association between sexual dysfunction and sphincteric dysfunction indicates a common aetiology corresponding to the frequent involvement of the spinal cord in multiple sclerosis, but the concomitant correlation between sexual dysfunction and other variables suggests the possible aetiological role of physical, psychological and sociological factors as well.