Clinical study of primary progressive multiple sclerosis in Northern Ireland, UK

Abstract

Objective-To investigate the clinical and demographic characteristics of primary progressive multiple sclerosis (PPMS) in Northern Ireland and to establish a database of such patients for genetic and immunological studies and future therapeutic trials. Methods-Diagnosis and categorisation were performed by two neurologists, potential cases being identified from the following sources: neurology outpatient clinics; neurology inpatients; a review of hospital discharges; and an ongoing epidemiological study of multiple sclerosis in Northern Ireland. Only those with a progressive course from onset and a clear history of no prior relapses were accepted. Potential cases were invited for interview and assessment, the minimal record of disability (MRD) being established. Results-One hundred and eleven cases of PPMS have been identified, 63 women and 48 men (ratio 1.3:1), with a mean age at onset of 39.5 (SD 11.0) (range 17-66)years, and mean disease duration of 13.6 (SD 9.3)years. The mean interval between onset and diagnosis was 4.7 (SD 4.2) years. Nineteen patients (17.1%) did not satisfy the requirements for any category in the Poser criteria. Motor disturbance was the commonest mode of onset (67.6%) with visual loss occurring only rarely at onset (3.6%). Kurtzke EDSS scores were concentrated at the upper end of the scale with a median of 6.0 and levels of unemployment and financial dependence were high. Conclusions-PPMS in Northern Ireland has a generally later age at onset, lower female preponderance, and predominantly motor onset compared with other subgroups of multiple sclerosis. The delay to diagnosis reflects the often insidious onset and the nature of the clinical course makes application of the Poser criteria diYcult. Levels of neurological impairment, disability, and handicap as measured by the MRD are high. (J Neurol Neurosurg Psychiatry 1998;64:451-454)

The pathogenesis of primary progressive multiple sclerosis: antibody-mediated attack and no repair?

“…Primary progressive MS tends to have a later age of clinical onset (mean ~39 years), typically about 10 years later, than relapsing-remitting MS. 1,2 Interestingly, a recent case report of the clinical presentation of primary progressive MS 10 years after the incidental finding of typical magnetic resonance imaging (MRI) brain lesions raises the possibility that the CNS lesions may actually have a similar age of onset as in relapsing-remitting MS. 3 The female to male ratio in primary progressive MS (1.3:1.0) is lower than in relapsing-remitting MS.…”

“…2,5,6 Irreversible disability occurs sooner after clinical onset in primary progressive MS than in patients with an initial relapsing-remitting course. 7 In contrast, once irreversible disability occurs, the time course of progressive disability is similar in primary progressive and secondary progressive MS. 7 Primary progressive MS is more difficult to diagnose than relapsing-remitting MS for the following reasons: (1) in contrast to the relapsing-remitting pattern which occurs in few neurological diseases other than MS, the progressive neurological deterioration over months and years that occurs in primary progressive MS is also typical of many other neurological diseases; (2) the variety of neurological symptoms and signs occurring in primary progressive MS tends to be more limited than in relapsingremitting MS, and this also reduces the distinctiveness of the clinical features; (3) there are fewer MRI focal brain lesions 8,9 and less frequent gadolinium-enhancing brain lesions 10 in primary progressive MS than in relapsing-remitting / secondary progressive MS; and (4) oligoclonal immunoglobulin (Ig) bands restricted to the cerebrospinal fluid (CSF) occur less frequently in male patients with a later onset and progressive myelopathy, 11 that is the type of patient likely to have primary progressive MS. New diagnostic criteria have recently been proposed for definite primary progressive MS; 12,13 however, the absolute requirement for evidence of intrathecal IgG synthesis will significantly reduce the diagnostic sensitivity.…”

Disease-modifying agents in progressive multiple sclerosis: Management of 100 patients at Louis Stokes Cleveland VAMC, Spinal Cord Injury Division

“…Multiple reports describing the natural history of PPMS suggest a worse prognosis and more significant disability levels compared with patients with RRMS. SPMS is known to follow a similar course, with advancing levels of disability [7,13]. The progressive disease course is defined by the absence or near absence of clinically identifiable relapses, making this diagnosis intuitively less responsive to FDA-approved medications that decrease relapse rates in patients with MS. With these considerations in mind, we reviewed a cohort of patients whom the LSCVAMC SCI Division manages and most have progressive disease.…”

Multiple sclerosis genetics: leaving no stone unturned

“…The association was most apparent among patients with signal abnormalities on the baseline brain MRI 135 A number of small studies failed to show any association between PPMS and DR2, although a larger study from Northern Ireland appeared to show the association. Others suggested an association between PPMS and the HLA-DR4 haplotype although a post hoc analysis is consistent with an effect decreasing the risk for RRMS in HLA-DR4+ individuals, rather than increasing the risk for PPMS 22,77,88,136,137 Glutamic acid at position 71 or 74 in pocket 4 of DRb1 is associated with PPMS 138 CD24 6q21 ORF A/V 50% of CD24 V/V patients with expanded disability status scale 6.0 reached the milestone in 5 years, whereas the CD24 A/V and CD24 A/A patients did so in 16 and 13 years, respectively 60 ESR1 6q21.5 PvuII and XbaI RFLP The P allele-positive patients had a significantly higher progression of disability and a worse ranked MS severity score. The study also suggests an interaction between the ESR1 genotype and DR2 in women with MS. Esr1 and -2 appear to regulate the severity of clinical EAE 139,140 PvuII RFLP The study suggests an interaction between the ESR1 genotype and DR2 in women with MS.…”

“…A number of small studies failed to show any association between PPMS and DRB1*1501, although a larger study from Northern Ireland appeared to show the association. 77 We recently studied HLA class II alleles in an MS data set carefully ascertained in Sicily, an island 3 km apart from continental Italy, with a population of just over 5 100 000, but unique demographic history and high MS prevalence and incidence. 78 Evidence for excess transmission to affected individuals was observed for HLA-DRB1*1501, DRB1*04, DQB1*02 and DQB1*0302 alleles but not for DQB1*0602.…”