Defining multiple sclerosis

Once activated, autoimmune B and T lymphocytes cross the blood-brain barrier and enter the CNS. It is in the small veins that blood flow is slowest and that lymphocytes cling to their walls before passing inside the nerve tissue. Magnetic Resonance Imaging (MRI) can sometimes show this central vein in the middle of a plaque. The entire CNS is affected: the meninges, the neurons of the cerebral cortex and the neurons of the deep nuclei (thalamus and basal ganglia), the white matter which contains the majority of myelinated nerve fibres, the cerebellum, the brainstem, the spinal cord and the optic nerves (which are an integral part of the CNS). When the activated T cell recognises its target in the brain, it releases molecules called cytokines, which increase the inflammatory response and cause other lymphocytes and huge numbers of monocytes to enter the brain. These monocytes are transformed into activated macrophages in the same way that microglial cells are activated. The best-known cytokines are interferon gamma and interleukin 17. Other cytokines stimulate enzymes that destroy the myelin sheath. The same phenomena can occur with autoimmune B lymphocytes. This escalation process can be slowed or blocked by factors that inhibit inflammation. One of these inhibitory cytokines is interferon beta, which is an antagonist of interferon gamma and has been widely used in the treatment of MS.

Inflammation is localised mainly in the white matter of the CNS. This is made up of the extensions of the nerve cells themselves, the neurons, which make up the grey matter. An estimated 100 billion neurons and their extensions, which can be very long and are called "axons", link the nerve cells together. Electrical signals travel along the axons carrying information between the different nerve cells. The myelin sheath allows nerve impulses to be conducted very quickly, and economically in terms of energy, at speeds of up to 60 metres/second. Inflammation leads to demyelination and this demyelinated area forms a "plaque" with relatively well-defined contours. Electrical impulses travel through them at a slower rate, with the conduction velocity dropping by up to 10% of the normal rate, and this is how certain symptoms of the disease appear and persist. Three types of plaques can be distinguished: active plaques, containing numerous lymphocytic inflammatory cells and macrophages digesting myelin debris, visible on MRI after injection of contrast medium, caused by the invasion of inflammatory cells of blood origin; chronic active plaques, whose centre is devoid of inflammatory cells but whose periphery is composed of activated macrophages which continue to destroy and digest myelin debris; these plaques continue to enlarge progressively in a centrifugal manner and no longer capture the contrast medium, the inflammation being restricted to the CNS; chronic inactive plaques without inflammatory cells, purely cicatricial, "sclerosed" following the hypertrophy of astrocytes which fill the void left by the destruction of the myelin sheaths and often also, the axons.

The cerebral cortex , which is essentially composed of neurons, nevertheless also contains nerve fibres surrounded by myelin, but less compact and numerous than in the white matter. They can also be destroyed in MS, and so there are also "cortical" plaques. Some are located directly beneath the innermost meningeal layer, known as the pia mater. In the latter case, inflammatory meningeal foci are observed nearby, containing numerous lymphocytes of blood origin which have become "resident" in the CNS.

It was long thought that demyelination was the most important process in the disease and that the destruction of neurons and axons only occurred late in the course of the disease. Today, it is certain that nerve extensions can be injured ("transected")

A significant reduction in the number of neurons is at times observed in cortical plaques as well as in apparently normal grey matter. This neuronal and axonal loss is responsible for the increase of disability in the progressive phase of the disease, and is the cause of irreversible neurological sequelae. It also causes an excessive reduction in cerebral volume, of 0.5 to 1% per year, greater than the annual reduction of 0.2 to 0.4% observed in normal subjects. This cerebral atrophy is significantly correlated with atrophy of the retina, the thickness of which decreases. In ophthalmology, this thickness can be measured using Optical Coherence Tomography (OCT). It is therefore a very widespread and general phenomenon. In addition to overall brain atrophy, the disease can cause focal atrophy of certain brain structures, in particular the thalamus (an important relay for nerve bundles between the spinal cord and the cortex and an "activator" of the cerebral cortex), the corpus callosum (which contains all the nerve fibres linking the right and left hemispheres together) and the spinal cord. Atrophy of the latter is secondary to damage to the motor and sensory pathways it contains, and is strongly correlated with patients' level of disability.