Natural History And Clinical Variability

Epidemiological study must also encompass the natural history and the phenotypic variations of diseases to ensure that the entities studied are indeed unique and that the emerging data can be applied specifically to each.

Prognosis

The short-term prognosis in early RRMS is worsened by factors such as later age of onset; multiple (especially pyramidal or cerebellar) onset symptoms; positive MRI findings at onset; a short interval between the first and second attacks; the attack frequency in the first two years; a progressive disease course; incomplete recovery from the initial attack; and higher baseline expanded disability status scale (EDSS) scores—the more of these factors, the worse the prognosis (175-179). However, the total number of relapses in the first two years of the disease has no prognostic value. It was reported that 58% of patients with a diagnosis of probable MS, who have positive MRI findings, will progress rapidly to clinically definite MS (178). Later age, the number of neurological functional systems involved, sphincter, or motor, or motor-sensory symptoms and the presence of sequelae after onset are all valid predictors of the time to progression (180).

In the longer term, data on 248 patients in a prevalence study in Northern Ireland (181) indicated that 29% were fully independent in all basic activities of daily living (ADLs) of bathing, dressing, grooming, and feeding; 23% were unable to climb a flight of stairs; and 42% acknowledged problems with sexual function. Sixty-one (25%) were working essentially full-time, but 53 (21%) had no external financial support. Twelve (5%) were institutionalized and 86 (35%) required assistance with activities of daily living (ADLs) for at least 1 hr/day. Eighty-one (33%) were unable to drive a car or use public transport. Forty-two (17%) were accessing community services for at least 1 hr/day on average.

A prospective study (182) of 54 subjects (36 female) with CDMS and with disease onset at 15 years or earlier gave a female-to-male ratio of 4.7 in subjects with age >12 years, suggesting a role of hormonal changes in triggering MS onset. Over a mean follow-up duration of 10.9 ± 5.6 years, it was found that the onset was mono-symptomatic in 57%. The functional systems more frequently involved at onset were the pyramidal and brainstem (28% each); and the course was relapsing-remitting in 72% and relapsing-progressive in 28%. Disability after eight years was highly predicted by disability in the first year (P = 0.008) but this outcome was not influenced by the characteristics of symptoms at onset, age, or gender.

In a five-year study of 83 patients with clinical onset of MS aged < 16 years and of 710 with onset between 16 and 65 years adult-onset multiple sclerosis (AOMS). Simone et al. (183) showed that the EDSS evaluated at the last clinical examination was lower in those with earlier onset multiple sclerosis (EOMS), despite a longer disease duration. Median times to reach EDSS score of 4 and secondary progression were longer in EOMS than in AOMS, but the age at both endpoints was significantly lower in EOMS. In both EOMS and AOMS, irreversible disability was related to a secondary progressive course, sphincter involvement at onset, and an older age at onset. In adult onset cases, other unfavorable factors were pyramidal involvement at onset and a high relapse frequency in the first two years. The risk of developing secondary progressive MS (SPMS) was increased by a high number of relapses in early, and by a higher age at onset, and a short inter-attack interval in adult onset disease. Both these studies are in agreement with the findings of Hawkins and McDonnell (179) (see below).

Such findings are hardly surprising because MS is likely to be an axonopathy and the cumulative damage to axons with minimal ability for repair must lead to earlier and faster clinical deterioration, although the gender difference remains unexplained.

Clinical disability in MS is influenced by the patient's age (P < 0.01) rather than by the age at onset (184). EDSS scores increase in parallel with age and duration of disease (P = 0.007) (187). Median times to reach EDSS scores of 4 and 6 are significantly longer among patients aged 20 to 35 years compared with those aged 36 to 50 years and 51 to 65 years (P < 0.0001). Significant associations were observed between mean EDSS scores and age at disease onset, current age, and the interaction of age at disease onset and current age (P < 0.001). An age-adjusted progression index may be a more relevant criterion for defining differences between MS groups.

Moris et al. (185) evaluated 55 MS patients [46 CDMS, 9 CPMS; 33 RRMS, 11 SPMS, and 11 primary progressive MS (PPMS)] longitudinally from onset of the disease over a mean duration of seven years. The mean age of onset was 31.1 years, pyramidal weakness and sensory symptoms being the most common initial problems. The median times to reach EDSS-3 and EDSS-6 from onset were 4.5 and 7.5 years, respectively. The average time from onset of MS to secondary-progressive was 6.1 years. There were no significant differences between treatment and nontreatment patients.

In a retrospective review of the clinical protocols of 17 patients with young onset MS (first symptoms before 21 years) (186), the mean age at onset was 16.9 ± 4.4 and median time to diagnosis was four weeks. The clinical course was relapsing-remitting in 76.5% and secondary progressive in 23.5%. The mean annual exacerbation rate was 1.5 ± 0.9 and median time to second exacerbation was 12 months. The actual EDSS score was 2.6 ± 2 after a mean disease duration of 11.4 ± 8.0 years. The only statistically significant result was a correlation between the EDSS and the mean disease duration. Age at onset did not correlate with final neurological disability.

Among 640 patients with the first presentation of clinical symptoms of MS (Poser criteria and brain MRI), 30 (4.6%) were diagnosed as suffering from late-onset MS. In half of them the initial disease course was relapsing-remitting. Motor symptoms were the most common neurological presentation. Major depressive episode was diagnosed in 6 out of 30 patients (20%) in the two years prior to the diagnosis of MS. Late-MS onset may present as major depression, progression to disability is more rapid, and a primary progressive course is more prevalent (187).

Benign MS

Although this form of the disease is usually considered to occur in 10% of subjects, among 23 patients followed up for 10 or more years, 11 (48%) were so diagnosed

(188). It seems that the longer the duration of stable MS to date and the less the initial disability, the more likely a patient is to remain stable without progression, especially for the patients who have ''benign MS'' by virtue of their EDSS scores of <2 for >10 years. These subjects have a > 90% chance of remaining stable

(189) and are most often relatively young females who experienced ON or sensory rather than motor symptoms at onset (179). However, further follow-up more than 10 years after the initial ascription of the ''benign'' status indicates that this is not necessarily permanent.

Optic Neuritis

Reviewing nearly 100 cases of isolated ON, Ghezzi et al. (190) found that about a third developed CDMS after a mean of 2.3 years. The risk was 13% after two years, 30% after four years, 37% after six years, and 42% after 8 and 10 years. These figures were not affected by gender, age, or season of onset. The 10-year risk of MS following an initial episode of acute ON is significantly higher in the presence of a single brain MRI lesion, but larger numbers of lesions do not appreciably increase that risk (191), and in those that progress to CDMS, disability remains relatively mild for at least the first 10 years (192). Most patients with a diagnosis of probable MS and positive brain MRI will progress rapidly to clinically definite MS (178).

In Pokroy's study of 10 black South African patients with ON (193), only two had truly unilateral ON, the others had either bilaterally simultaneous or consecutive disease. After at least three months follow-up, only six eyes recovered visual acuity of 6/12 or better, and only three eyes recovered color vision of 10/13 or better. No patient had clinical MS on presentation, nor developed it on follow-up. The higher the prevalence of bilateral cases and optic disc swelling, the weaker the association with MS, and the extremely poor visual outcome distinguishes ON in black South Africans. In a large U.S. study (194) the five-year conversion rate from ON to neuromyelitis optica (NMO) was 12.5% and 14.4% to MS. Patients with a rapid succession of severe ON events were found to be more likely to develop a generalized demyelinating disease.

Predictors of a relapsing course after an episode of NMO were longer inter-attack interval between the first two clinical events [rate ratio (RR) = 2.16 per month increase], older age at onset (RR = 1.08/yr increase), female sex (RR = 10.0, female vs. male), and less severe motor impairment with the sentinel myelitis event (RR = 0.48/severity scale point increase). A history of other autoimmune disease (RR = 4.15 for presence vs. absence), higher attack frequency during the first two years of disease (RR = 1.21/attack), and better motor recovery following the index myelitis event (RR = 1.84/point increase) were associated with mortality due to relapsing NMO (195).

Primary Progressive Multiple Sclerosis

MS has been clinically classified by an international survey of MS experts (196) as relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS) disease. PPMS has been defined as that form showing disease progression from onset, though occasional plateaus and temporary minor improvements are allowed (196). Between 10% and 15% of MS, patients follow a primary progressive course with a distinct clinical and paraclinical phenotype (197). However, the male-to-female ratio is lower than RRMS (1:1.5-2) (198) and patients with PPMS are more likely to present with progressive myelopathy and at a later age (37 years for PPMS vs. 31 years for RRMS) (87,198). The rate of deterioration from disease onset is substantially more rapid than for RRMS, with a median time to disability status score (DSS) 6 and 8 of 8 and 18 years, respectively. Life expectancy, cause of mortality, and familial history profile are similar in PPMS and non-PPMS. The mean time to death is decreased when more neurological systems are involved at the onset of disease but age, gender, and neurological system involved at onset appear to have little influence on prognosis (199).

Even though their clinical courses are different, PPMS and RRMS may have similar HLA haplotype associations (200) but in comparison with RRMS, there are fewer lesions on MRI (201), higher in vitro migration, differences in immune cell products (202), and less inflammation on necropsy (201).

New evidence suggests that the spectrum of disease may also be delineated along pathophysiological boundaries, which may or may not correlate with the clinical/genetic boundaries suggested above (203). It has been suggested that one form of MS may be characterized by inflammation directed against myelin while another form is due to progressive axonal degeneration (204,205). Whether the final pathophysiological categorization of MS correlates with the clinical/genetic categorization of MS remains to be established.

Psychiatric Features

Suicidal intent (a potential harbinger of suicide) is common in MS and is strongly associated with major depression, alcohol abuse, and social isolation (206). Anxiety is a frequent accompaniment to depression in MS (207). A major depressive episode was diagnosed in 20% of cases in the two years prior to the diagnosis of (late-onset) MS, which may therefore be considered as able to present as major depression (187).

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