Multiple Sclerosis Research: What the eye doesn't see?

I saw someone with possible MS earlier this week and he had been told that he couldn't have MS because he only had one detectable lesion on his MRI. Is this correct?

The problem: 'MS has become an MRIscopic disease'.

The diagnosis of MS remains clinical and is underpinned by the need to show (1) dissemination in time (typically new activity 4 weeks apart or the presence of locally produced oligoclonal IgG bands in the spinal fluid) and (2) dissemination is space (symptoms and/or signs affecting two different pathways in the CNS) and (3) the exclusion of other possible diagnoses. It is clear that based on these criteria you don't necessarily need to have visible, or specific, MRI lesions to make a diagnosis of MS. However, neurologists feel uncomfortable making a diagnosis of MS or CIS if there are no visible lesions on MRI. In other words from a practical and clinical perspective, MS has become a macroscopic or MRIscopic disease. Therein lies the rub.

MS is a biological disease that is characterised pathologically by multifocal inflammatory lesions that cause demyelination and variable degrees of axonal loss. Please note I have dropped using the term white matter. MS is clearly both a white and grey matter disease with more than half the lesion burden in the largely MRI-lesion-invisible grey matter component (see study below). Even in the white matter where it is easier to see lesions the resolution of an MRI scan is down to about 3-4 mm. Many more lesions are found pathologically than what is seen on MRI or the naked eye. Therefore, particularly early on in the course of the disease, there will be a small number of people with MS with one or no lesions who have MS.

A very small lesion in a strategic pathway can cause typical symptoms and signs, but when you investigate many of these patients with an MRI scan you see no obvious lesion in the expected area. This happens more often than not with a so-called internuclear ophthalmoplegia (INO); a very specific eye movement problem that presents with double-vision on looking to the left or right. This is an example of a microscopic lesion causing an MS attack. This is why we shouldn't be using MRI to confirm, or make, a diagnosis of relapse in pwMS.

The study below that is rapidly becoming a citation classic in the field of MS, shows you with elegant infographics how large the lesion burden is in areas that are MRI invisible using our standard clinical sequences.

Kutzelnigg et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005 Nov;128(Pt 11):2705-12.

Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.