Early Treatment
Dr. Xavier Montalban presented a lecture entitled “Early Treatment” at ECTRIMS 2005 that discussed the rationale for treating patients with MS early in the disease process.
Key reasons for early treatment include:
• Preventing irreversible axonal injury that occurs early in MS
• Delaying the natural progression of MS
• Minimizing cumulative axonal loss, which is associated with disability.
Neural Damage Occurs Early in MS
Several lines of investigation suggest that important axonal damage occurs in patients with early MS before the diagnostic criteria for clinically definite MS (CDMS) are satisfied. In one study, brain biopsies obtained during diagnostic work-up of patients who had experienced clinical events suggestive of MS1 were compared with biopsies or autopsy specimens obtained from patients with longer histories of MS. Subsequently, 19 of these patients were diagnosed with CDMS. Both infiltration of inflammatory cells and acute axonal damage were greater in the lesions of patients studied during the first year after an isolated clinical event than in subsequent years.
Patients with early MS also had significantly reduced total brain volume (1164±119 mL vs 1263±106 mL; P=0.01), and ventricular enlargement indicative of brain atrophy. Patients with syndromes suggestive of MS also demonstrated reduced concentrations of whole brain Nacetylaspartate (a neuronal metabolite) compared with normal subjects.
Furthermore, functional MRI revealed that patients with early MS use different parts of the cortex to perform a specific motor task than normal subjects, suggesting that adaptive cortical reorganization occurs to compensate for neural damage.
One study presented at ECTRIMS emphasized that patients with early MS and minimum disability (eg, EDSS <2.5) may experience significant cognitive deficits. Twenty-six percent (N=106) of patients with early MS had cognitive deficits with a major effect on quality of life. This finding is consistent with the hypothesis that important damage occurs early in MS.
Neural Damage Can Be Progressive
The general course of MS involves several distinct stages, although symptoms and recurrence rates of RRMS vary. Patients who experience two or more symptomatic attacks of MS may continue in the relapsing remitting phase, experiencing relatively frequent attacks associated with inflammation. Over time, the frequency of attacks decreases, but axonal loss and disability gradually increase. Eventually, he or she may enter the secondary progressive phase (SPMS), in which attacks occur infrequently, but significant brain tissue has been lost and disability may be chronic and severe. While the path of MS progression is generally accepted, the association between early inflammation and later disability is controversial. Some experts hypothesize that early inflammation and later progression are separate processes.
Others propose that inflammation causes initial neural damage that results in secondary damage to the remaining neurons and axons because they lack necessary trophic support from myelin, oligodendrocytes, and glia.
Treatment Reducing Early Inflammation May Reduce Disability
Treatment to reduce inflammation may reduce disability if given prior to the onset of progressive MS. The investigational drug Campath-1H was used to reduce inflammation in patients with MS by causing rapid and sustained depletion of lymphocytes. While significant adverse events were noted in 24 of 58 patients (8 cases of infectious diseases and 15 cases of Graves disease), marked improvements in disability were observed in patients with RRMS. In contrast, progressive disability continued in patients with SPMS. Patients with more rapid progression of disability after treatment exhibited the greatest evidence of inflammation prior to treatment. The authors suggested that early rescue of neurons and axons from an inflammatory environment and prevention of demyelination may prevent long-term axonal degeneration. Laplaud et al presented data from an epidemiological database suggesting that treatment with oral immunosuppressants before patients reach an EDSS of 3 significantly reduces disability 20 years later. Fifty-two percent of patients treated early in the disease process had an EDSS <6 (N=71), whereas only 37% of patients treated later in the disease process (after an EDSS of 3) had an EDSS <6 (N=375).