Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting
the central nervous system (CNS) characterized by a relapsing-remitting course in
the majority of the patients. In the last two decades, an increasing number of approved
drugs for MS showed efficacy on clinical relapses and magnetic resonance imaging (MRI)
lesions related to inflammatory activity in the CNS. Although, MS treatments have
limited effect in the progressive disease course[1], which is probably not just related to the damage caused by accumulation of disease
relapses over time[2]. Axonal loss can be already observed in the early stages of the disease[3], suggesting that neurodegenerative mechanisms may play a role in the long-term disability.
Brain atrophy measured by MRI scans may be a non-invasive tool to quantify neuronal
and axonal loss.[4] Interestingly, the loss of cerebral volume can be already seen on patients with
the first clinical event and radiologically isolated syndrome cases highly suggestive
of MS[5]. Brain atrophy also correlates with cognitive decline and disability progression[3] and might predict conversion from clinically isolated syndrome to definite MS[6].
In this issue of Arquivos de Neuropsiquiatria, Rojas et al.[7] review the impact of brain atrophy in the clinical practice. The neuroimaging techniques
that have been proposed to measure brain atrophy include automated and semi-automated
methods (transversal and longitudinal) with a certain level of reproducibility. Amongst
several MRI techniques used to estimate brain volume loss, there are several available
cross-sectional and longitudinal methods (e.g. brain parenchymal fraction - BPF, structural
image evaluation using normalization of atrophy - SIENA, Freesurfer, voxel-based morphometry and Brain Boundary Shift Integral). The
BPF and SIENA were the most frequently used.[3] However, these methods could yield some technical difficulties when applied in daily
practice. Some years ago, Figueira et al.[8] proposed the corpus callosum index, a morphometric parameter that correlates with
BPF and could potentially distinguish relapsing-remitting and progressive forms of
MS. However, given the possible confounding factors that could cause loss of brain
volume, like pseudoatrophy phenomenon, concomitant diseases that might also lead to
brain atrophy (e.g. cardiovascular risk factors, stroke) and the lack of standard
parameters that take into account other factors commonly seen in the clinical practice[3], the reproducibility of the proposed methods and their application should be validated
in large MS populations. Nevertheless, it might be only a question of time and allocation
of resources to translate some of this research into the clinical practice.
Rojas et al.[7] also discuss about the disability progression and cognitive impairment associated
with global or segmental brain volume loss. The global gray matter volume loss correlates
with the progression of motor disability and both gray and white matter losses are
associated with cognitive impairment[3]. Moreover, Steenwijk et al.[9] recently found that brain atrophy in MS occurs in a non-random manner and described
different anatomical patterns associated with cognitive dysfunction. Physical dysfunction
as measured with Expanded Disability Status Scale (EDSS) score correlated with changes
in the cortical thickness of the bilateral sensorimotor cortex and bilateral insula,
while cognition correlated with cortical atrophy of the bilateral posterior cingulate
cortex and bilateral temporal pole. In another study, Damasceno et al.[10] evaluated functional tests, cognition and brain atrophy in 42 relapsing-remitting
MS patients receiving treatments who achieved no evidence of disease activity (NEDA)[9] status, defined as a composite outcome measure that includes absence of clinical
relapses, no progression in the EDSS and the lack of new or enlarging T2 and gadolinium-enhancing
MRI lesions. In the group of MS patients remaining with NEDA status after 2 years
of follow-up, there was a slower atrophy rate of the subcortical gray matter volume,
but 58.3% of them had deterioration in ≥2 cognitive domains. Taken together, these
studies suggest that the progressive clinical and cognitive worsening are associated
to neurodegenerative processes that may occur more aggressively in specific areas
of the brain and they cannot be totally explained by the presence of actual inflammatory
activity in the CNS. Therefore, it is expected that current MS treatments that mainly
control the inflammatory process may have a limited therapeutic impact on these outcomes.
In the near future, we expect a ‘new drug development era’ in MS, tackling the current
lack of treatment options to undoubtedly control specific neurodegenerative processes
seen in MS. The development of advanced neuroimaging techniques to measure brain atrophy
allows us now to incorporate MRI parameters beyond inflammation and blood-brain barrier
disruption commonly used by neurologists. The evidence of progression on clinical
disability scores and/or cognitive tests associated with brain atrophy and other potential
biomarkers may be used as endpoints in clinical trials. If a single drug cannot control
effectively both inflammation and neurodegeneration, a combination therapy with currently
approved drugs for MS and pro-remyelinating inducers[11] or other restorative therapies might be an alternative to reduce the cognitive dysfunction
and long-term disability.
