Early Treatment Of Multiple Sclerosis Research Articles

Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial

In patients who present with clinically isolated syndromes suggestive of multiple sclerosis, interferon beta-1a is effective in delaying evolution to clinically definite disease and in reducing MRI-measured disease activity. We aimed to assess whether this drug can also reduce the rate of brain volume decrease in such patients enrolled in the ETOMS (early treatment of multiple sclerosis) trial. MRI data for brain volume measurements at baseline, month 12, and month 24 were available from 131, 111, and 112 patients assigned treatment (22 microg interferon beta-1a), and 132, 98, and 99 patients assigned placebo respectively. Normalised brain parenchymal volume (NBV) at baseline and percentage brain volume changes (PBVC) were measured with a fully-automated segmentation technique. The primary endpoint was conversion to clinically definite multiple sclerosis due to clinical relapse. Analysis was by intention to treat. 41 (31%) of 131 patients on interferon beta-1a and 62 (47%) of 132 on placebo converted to clinically definite multiple sclerosis (odds ratio 0.52 [95% CI 0.31-0.86], p=0.0115). Mean PBVC for patients on placebo was -0.83% during the first year, -0.67% during the second year, and -1.68% during the entire study period. Respective values for treated patients were -0.62%, -0.61%, and -1.18%. The changes in brain volume were significant in both groups at all timepoints. A significant treatment effect was detected for month 24 versus baseline values (p=0.0031). The number of new T2 lesions formed during the first year correlated weakly with PBVC during the second year. Early treatment with interferon beta-1a is effective in reducing conversion to clinically definite multiple sclerosis and in slowing progressive loss of brain tissue in patients with clinically isolated syndromes. The modest correlation between new lesion formation and brain volume decrease suggests that inflammatory and neurodegenerative processes are, at least partly, dissociated from the earliest clinical stage of multiple sclerosis onwards.

The pros and cons of early treatment of relapsing forms of multiple sclerosis.

Cerebral axonal damage and brain atrophy begin at the earliest stages of multiple sclerosis (MS). Progressive neuronal degeneration contributes to irreversible neurological deficit, and ultimately disability. Axonal loss, which seems to be related to the inflammatory process, occurs much more rapidly in the early than later phases of disease, providing additional impetus for early intervention. The CHAMPS (Controlled High risk Avonex MultiPle Sclerosis) and ETOMS (Early Treatment Of MS) studies show that fewer patients with a first demyelinating event and abnormal magnetic resonance imaging (MRI) had a second clinical attack within 2 years if once-weekly treatment with interferon beta-1a was started at the time of the first episode. However, these studies provide no information on long-term outcomes. The BENEFIT study (BEtaferon/betaseron in Newly Emerging multiple sclerosis For Initial Treatment) will evaluate the efficacy and tolerability of 250 micro g (8 MIU) interferon beta-1b administered every other day to patients with a first demyelinating event suggestive of MS. This study should add some information about some of the outstanding questions relating to the long-term effects of early treatment on disease course, although it is likely that further investigation will be needed before a definite picture can be obtained.

Imaging neuronal and axonal degeneration in multiple sclerosis.

Neuronal and axonal damage has become an important issue in multiple sclerosis. This has been emphasised by recent magnetic resonance imaging (MRI) studies that have shown evidence of axonal damage in both lesional and non-lesional white matter and in grey matter. In this respect, proton MR spectroscopy (by monitoring levels of Nacetylaspartate, a putative marker of axonal integrity) and computed measurements of cerebral volumes have been particularly illuminating. Recent studies using these MRI measures have demonstrated that cerebral neuro-axonal damage begins and contributes to disability from the earliest stages of the disease. This implies that the apparently primary role of neuronal pathology in the pathogenesis of the disease should be given due importance and argues for the early treatment of multiple sclerosis with agents directed not only against inflammation, but also towards neuronal protection.

Cognitive impairments in multiple sclerosis: a review.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Cognitive impairment (CI) may develop at any time during the course of the disease in the presence or absence of neurological disability. On the basis of comprehensive neuropsychological studies, there is now a consensus among investigators that 45 percent to 65 percent of MS patients suffer from some degree and form of cognitive difficulty. Features of CI include bradyphrenia; impaired attention, concentration and abstract reasoning; reduced manual speed and dexterity; deficits in memory retrieval; and language deficits in both the relapsing-remitting and progressive forms of MS. Impairments in all cognitive domains may result from the diffuse spread of microscopic pathology, although a preferential lobar distribution of plaques can present with a predominant deficit in the corresponding cognitive function. Nevertheless, the severity of CI best correlates with total microscopic and macroscopic disease burden of the brain as defined by recently developed magnetic resonance imaging (MRI) sequences. A disruption of connecting intercortical and subcortical pathways is likely to be the main cause of metabolic and functional abnormalities in neurons. However a direct toxic effect of soluble inflammatory products may also compromise neuronal function and survival. Early treatment of MS with interferons and copaxone can prevent or delay the onset of both neurological and cognitive disabilities by reducing the inflammatory activity and damage in the CNS. Until more powerful neuroprotective agents become available, simple neuropsychological screening and cognitive rehabilitation for memory and language impairments will remain important components in the care of MS patients.

Imaging axonal damage in multiple sclerosis by means of MR spectroscopy.

Axonal damage in multiple sclerosis has become an important issue. This has been emphasized by recent in vivo proton magnetic resonance (MR) spectroscopy and in vitro pathology studies that have found axonal damage in both lesions and the surrounding normal-appearing white matter. In particular, proton MR spectroscopy, by monitoring levels of N-acetylaspartate (a putative marker of axonal integrity), has been particularly illuminating, as the extent of axonal injury associated with white matter inflammation and demyelination had not been well appreciated from classical pathology studies. Recent MR data demonstrate that cerebral axonal damage begins and contributes to disability from the earliest stages of the disease. This implies that the apparently primary role of axonal damage and loss in the pathogenesis of the disease should be given due importance, and argues for the early treatment of multiple sclerosis with agents directed not only against inflammation, but also towards axonal protection.

Fundamento racional para el tratamiento precoz de la esclerosis múltiple

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) of unknown etiology. Its pathological hallmark is the presence within the CNS of inflammatory infiltrates containing few autoreactive T cells and a multitude of pathogenic nonspecific lymphocytes. Based on that, various non-specific immunosuppressive agents have been tested with marginal benefits on the natural evolution of the disease and frequent short- and long-term adverse effects. Moreover, due to their unfavourable profile, these therapies have been usually limited to patients with progressive courses or high clinical activity. The recent approval of IFN beta and Copolymer 1, as therapies able to modify the disease course in relapsing-remitting and secondary progressive, as well as the available immunopathological and clinical data suggesting that the early treatment of MS with safe profile immunomodulatory drugs could be advantageous compared to late treatments, supports the 'putative' relevance of these new drugs in the early treatment of MS patients. However we must wait for the results of ongoing clinical trials to define if such an early treatment has substantial advantages compared to late treatment.