The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability.

The relationship of relapses to long-term disability in multiple sclerosis is uncertain. Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation. We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort. Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing-remitting phase. Survival was compared among groups stratified by (i) early relapses--number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing-remitting phase. Early clinical features can predict hard disability outcomes. Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints. Attack frequencies, in the first 2 years, of 1 versus >or=3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively. Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10. In contrast, neither total number of relapsing-remitting phase attacks nor of relapses experienced during the relapsing-remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints. The failure of a regulatory mechanism tied to neurodegeneration is suggested. Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome. These appear to be separated by a watershed within the relapsing-remitting phase, just a few years after clinical onset. Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression. They increase the probability of its occurrence, its latency and influence--to a lesser degree--its slope. The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing-remitting patients.

Clinical prognostic factors in multiple sclerosis: a natural history review.

This Review summarizes the natural history studies on multiple sclerosis (MS) that have evaluated prognostic factors. Reassessment of prognostic factors is warranted, as our ability to offer patients a reliable prognosis is limited, yet we rely on this knowledge to appropriately design clinical trials and interpret their results. The selection criteria for studies to review included a geographical referral base, duration of at least 9 years, prospective design, and populations of at least 100 patients with MS. For all forms of MS combined, negative prognostic factors included progressive disease, and disability at 2 and 5 years. In relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) combined, negative prognostic factors were the onset of progression, a higher relapse rate, greater disability in the first 5 years, a shorter interval to the second relapse, and the involvement of more systems. Additional negative factors include a shorter time to progression in SPMS and a faster rate of disability in the first 2 and 5 years in primary progressive MS (PPMS). Onset of progression, relapse rate and disability in the initial 5 years could be fruitful therapeutic targets; however, longer-term clinical trials will be required to justify these end points.

Mutations in the hemochromatosis gene and the clinical outcome of multiple sclerosis.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. Given a possible role for dysregulation of iron metabolism in MS disease pathogenesis, we investigated whether or not mutations in the HFE gene influence the prognosis of the disease. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of HFE on MS disease severity. This approach increases the effective sample size by some 40-fold. Genotyping the two sets of MS patients (112 benign and 51 malignant) provided no evidence to suggest that mutations in HFE have any outcome modifying activity, although small effects cannot be ruled out. The frequency of HFE mutations was not different in MS compared to the general population.

The genetics of clinical outcome in multiple sclerosis.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS), the clinical course of which varies considerably between patients. Genetic complexity and interactions with as yet unknown environmental factors have hindered researchers from fully elucidating the aetiology of the disease. In addition to influencing disease susceptibility, epidemiological evidence suggests that genetic factors may affect phenotypic expression of the disease. Genes that affect clinical outcome may be more effective therapeutic targets than those which determine susceptibility. We present in this review a comprehensive survey of the genes (both MHC- and non-MHC-related) that have been investigated for their role in disease outcome in MS. Recent studies implicating the role of the genotype and epistatic interactions in the MHC in determining outcome are highlighted.

Analysis of 45 candidate genes for disease modifying activity in multiple sclerosis.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. As little is conclusively known about MS disease mechanisms, we have selected a variety of candidate genes that may influence the prognosis of the disease based on their function. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of on MS disease severity. The MS cases selected represent the prognostic best 5 % (benign MS) and worst 5 % (malignant MS) of cases in terms of clinical outcome assessed by the EDSS. Genotyping the two sets of MS patients (112 benign and 51 malignant) and a replication cohort from Sardinia provided no evidence to suggest that the genes selected have any outcome modifying activity, although small effects of these genes cannot be ruled out.

High-resolution anatomic, diffusion tensor, and magnetization transfer magnetic resonance imaging of the optic chiasm at 3T.

PURPOSE: To evaluate techniques for anatomical and physiological imaging of the intracranial optic nerve (ON), optic chiasm (OC), and optic tract (OT) at 3T with the aim of visualizing axonal damage in multiple sclerosis (MS). MATERIALS AND METHODS: Imaging was performed on a 3T scanner employing a custom-designed head coil that consisted of a coil array with four coils (30 x 30 cm(2)). Oblique fast spin echo (FSE) images, magnetization transfer (MT)-enhanced 3D gradient-echo (GRE) time-of-flight (TOF) images, and line scan diffusion images (LSDI) were obtained. Full diffusion tensor (DT) analysis was performed, and apparent diffusion coefficient (ADC), fractional anisotropy (FA), and fiber direction maps were obtained. RESULTS: FSE anatomic images were obtained with an in-plane resolution of 0.39 x 0.52 mm(2). The in-plane resolution of the MT and LSDI images was 0.78 x 0.78 mm(2). The OC, intracranial ON, and OT can be seen on these images. The dominant fiber orientations in the OC, ON, and OT, as derived from the DT images, are displayed. CONCLUSION: This study shows that by using 3T and a custom-designed, four-channel head coil, it is possible to acquire high-resolution anatomical and physiological images of the OC, ON, and OT. The pilot results presented here pave the way for imaging the anterior visual pathway in patients with MS.

Anti-tumor necrosis factor alpha-associated multiple sclerosis.

A case of multiple sclerosis presenting during anti-tumor necrosis factor treatment for rheumatoid arthritis is discussed. This association has been reported in the nonradiological literature, but is an important association for radiologists to be aware of, as they may be in a position to first suggest the diagnosis.