Relapsing–remitting and primary progressive MS have the same cause(s)- the neuropathologist’s view: 2

Abstract

Multiple sclerosis (MS) is a heterogeneous disease with respect to clinical symptoms, neuroradiological findings and treatment responses. The obvious differences in disease courses between patients led to the classification of MS as either relapsing–remitting (RRMS), secondary progressive (SPMS) or primary progressive MS (PPMS). The majority of patients starts with a relapsing–remitting disease course characterized by acute exacerbation followed by partial or total recovery; whereas PPMS is associated with a continuous worsening of symptoms and is only observed in about 10–15% of the patients. However, even the clinical presentation does not always allow clear separation between RRMS or PPMS, since some MS patients start with a progressive disease course after a single or few relapses or suffer from a progressive disease from the beginning superimposed by few relapses. The subsequent rate of disease progression is comparable in SPMS and PPMS and is not affected by relapses as soon as a certain Expanded Disability Status Scale (EDSS) score is reached. 1 Only about 50% of siblings with MS show an identical disease course. The recently identified susceptibility genes, each of which each contributes less than 1% of disease risk, are comparably distributed in RRMS and PPMS. 2 These epidemiological findings suggest that the different disease courses represent different ends of a disease spectrum rather than different diseases or disease etiologies. This point of view is supported by histopathological and imaging studies that describe quantitative rather than qualitative differences between different clinical courses. Although no fundamental differences have been identified between patients with either RRMS/SPMS or PPMS, this does not mean that the same pathomechansims are responsible for clinical symptoms in all MS patients. The histopathological hallmarks of MS change with disease duration. Whereas the development of new focal inflammatory demyelinating lesions in grey and white matter dominate the pathology at the beginning of the disease, the progressive disease phase is characterized by diffuse white matter abnormalities, accumulation of axonal loss in demyelinated as well as normal-appearing white matter and limited remyelination. The relapses are believed to be the consequences of focal inflammatory lesions whereas recovery may be induced by resolution of inflammation and edema, increased plasticity and endogenous repair mechanisms such as remyelination. RRMS patients develop numerous contrastenhancing lesions which presumably represent actively demyelinating lesions and the number of newly developing lesions decrease with disease duration. 3 This point of view is supported by histological studies which demonstrate a higher number of actively demyelinating lesions in RRMS than in SPMS. Patients with PPMS also develop contrastenhancing lesions and this is associated with a more rapid progression of disease. 4 Not surprisingly, actively demyelinating lesions can also be found in patients with PPMS. 3 These highly inflammatory lesions, observed in the early disease stages, are heterogeneous with respect to composition of inflammation and extent of initial oligodendroglial cell death, suggesting that different pathomechanisms may lead to demyelination. However, these different histological patterns described by Lucchinetti et al. are not predictive for the clinical disease course. 5 Due to the accumulation of new lesions, the extent of demyelination increases with disease duration: histopathological and imaging studies show that patients with PPMS tend to have comparable lesion loads to RRMS or SPMS patients but that the lesions