The outcome of multiple sclerosis (MS), assessed according to the Kurtzke Disability Status Scale (DSS), was reviewed in 1,099 consecutive patients followed in London, Canada, between 1972 and 1984. A geographically based subgroup of 196 patients representing 90% of Middlesex County MS patients as well as a group of 197 patients seen from onset of disease were separately analysed. The clinical course was progressive from onset in 33% of the total population and in 28% of the Middlesex County subgroup. Of those with duration of 6-10 yrs, 30-40% with initially remitting disease developed progressive MS. The cross-sectional distribution of disability was bimodal with peaks at DSS 1 (no disability) and DSS 6 (assistance required for walking). Actuarial analysis showed that the median time to reach DSS 6 from onset of MS was 14.97 +/- 0.31 yrs in the total population and 9.42 +/- 0.44 yrs in the "seen from onset' subgroup. Survival was minimally altered; 87% of patients followed up to 40 yrs were still alive, although ascertainment of cases with this duration of MS was incomplete. Data describing the rate at which disability develops after the onset of a progressive phase of MS are also presented. The implications of these data in planning and interpretation of clinical therapeutic trials are discussed.

In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

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 ≥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.

Controversy exists regarding the predictive value of the early clinical course of multiple sclerosis (MS). Three parameters often considered are the attack rate, the first interattack interval and the rate at which disability develops in the early years of the disease. We have recorded the time to reach successive levels of disability defined by the Kurtzke Disability Status Scale (DSS) in 1,099 MS patients followed at University Hospital, London, Canada between 1972 and 1984. Our population is particularly suitable because of its size, the high degree of ascertainment of cases in the community, and the regular follow-up provided. Life table analysis was used to compare survival in patients stratified according to the above three parameters using DSS 6 as end point. Significant differences were evident in the survival distributions. Despite the extensive interindividual variation in the rate at which disability developed, the early course of MS may be useful in determining the relative risk of rapid progression.

The clinical features of relapses and progression largely define multiple sclerosis phenotypes. A relapsing course is followed by chronic progression in some 80% of cases within 2 decades. The relationship between these phases and long-term outcome remains uncertain. We have analysed these clinical features within a well-studied natural history cohort with mean follow-up of 25 years. For the entire cohort, median times to reach Disability Status Scale (DSS) 6, 8 and 10 were 12.7, 20.6 and 43.9 years, respectively. Among 824 attack-onset patients, the great majority entered a progressive phase with a mean time to progression of 10.4 years. The effects of relapses often cloud the clinical onset of progression. However, there are circumstances where onset of progression is early, relatively discrete and identifiable at DSS of 2 or less. Three subgroups allow for clarity of outcome comparison and they are (i) cases of primary progressive (PP) disease, (ii) attack-onset disease where only a single attack has occurred before onset of progression (SAP) and (iii) secondary progressive (SP) disease where recovery from relapses allows recognition of the earliest clinical stages when progression begins. Here we compare survival curves in these three groups. Among cohorts of SAP (n = 140), PP (n = 219) and SP (n = 146) where progression was stratified by DSS at its onset, there was no difference in time to DSS 6, 8 and 10. These findings demonstrate that the progressive course is independent of relapses either preceding the onset of relapse-free progression or subsequent to it. Among SAP patients, the degree of recovery from the single defining exacerbation had no significant effect on outcome. The site of the original attack was not usually where progression began. The relatively stereotyped nature of the progressive phase seen in all progressive phenotypes suggests regional and/or functional differential susceptibility to a process that appears degenerative in nature. The highly prevalent distal corticospinal tract dysfunction in progressive disease and the pathologically demonstrated selective axonal loss seen in this tract raises the possibility of a dying back central axonopathy, at least in part independent of plaque location or burden. Despite considerable individual variation, the progressive course of disability seen in groups of PP, SAP and SP-DSS2 is similarly stereotyped in quality and pace and may entail mechanisms common to all forms of progressive multiple sclerosis. The possibility that this is the primary process in some cases must be considered.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

In this investigation, we studied the ability of human cytomegalovirus to infect peripheral blood mononuclear cells. With monoclonal antibody technology, we demonstrated that cytomegalovirus could infect human lymphocytes of T-and B-cell (PBM). Infectious CMV has occasionally been found in buffy-coat preparations (4-6) obtained from patients with clinical CMV infection; only rarely has the virus been isolated from healthy donors (7). Neither the exact cell involved in the leukocyte fraction nor the state of the virus in such cells has been established. When transformed lymphoblastoid and erythroleukemia cell lines were studied for the ability to support CMV replication, some researchers found evidence of short-term virus replication (8, 9), but rarely was infectious virus produced (10, 11). There have been occasional reports of expression of CMV antigens on B-lymphoblastoid cell lines (12). Attempts to infect normal PBM from healthy donors with laboratory-adapted strains of CMV have failed (11, 13).In the cascade regulation of the CMV genome (14), immediate-early protein synthesis precedes early polypeptide synthesis, both of which set the regulatory state for late polypeptide synthesis and production of mature virions. The early class polypeptides appear to have predominantly regulatory functions; the late polypeptides have mainly structural functions. We reasoned that if lymphocytes were abortively infected, techniques such as cocultivation assays and probes for late CMV gene products would be negative. Hence, we looked for CMV expression in peripheral blood lymphocytes (PBL) with monoclonal antibodies specifically produced to detect polypeptides relevant to major epochs in the cascade regulation of the viral genome. Prompted by observations of biological differences between strains of virus recently derived from infected patients and the fibroblastadapted strains of virus (15), we also studied both forms of this virus. MATERIALS AND METHODSLymphocyte Infection. PBM were removed from the blood of healthy human donors by density gradient centrifugation on Ficoll-Paque and infected at a multiplicity of 0.01-1.0 with CMV recently isolated from patients with various CMV syndromes (Table 1), or with stocks of plaque-purified laboratory-strain AD-169. The recent isolates were propagated in human foreskin fibroblasts (Flow Laboratories) for <12 passages. Because low-passage isolates of human virus are associated predominantly with the cell matrix (15), infected or mock-infected fibroblasts were sonicated, and this material was cultured with PBM for up to 6 days. Thereafter, the PBM were washed 3 times and prepared for immunofluorescence studies by air-drying and fixing the cells with acetone on glass slides. In some experiments, T-lymphocytes were positively selected from the PBM cultures by erythrocyterosetting techniques (17) or by sorting on a fluorescence-activated cell sorter (16).Immunofluorescence Techniques. Monoclonal antibodies were raised against CMV-infected fibroblasts with standard techniques...

Oral teriflunomide was effective in reducing MRI lesions and was well tolerated in patients with relapsing multiple sclerosis.