Diagnosis of MS and differential diagnosis

Neurologists pay particular attention to the criteria used to diagnose MS, and these are regularly reviewed in the light of the new technologies available to us. Schumacher's 1965 criteria were modified by Charles Poser in 1983 and then by Ian McDonald in 2001, with revisions in 2005, 2011 and 2017. However, all these criteria are based on the same principle, namely that in order to diagnose MS, the symptoms and/or lesions characteristic of the disease must result from a dissemination in space (of the central nervous system) and in time. All these criteria also emphasise the need to exclude any other neurological disease that might better explain the patient's symptoms, the MRI abnormalities and the CSF disturbances.

In the presence of a clinically isolated syndrome, to demonstrate spatial dissemination, at least one lesion in two distinct territories of the CNS must be shown: 1° in the periventricular region, or 2° in the cortical or juxta cortical area, or 3° in the posterior fossa (brainstem and cerebellum), or 4° in the spinal cord. A lesion in the optic nerve is not currently taken into consideration, as other diseases can attack the optic nerve. However, technical improvements in MRI make it possible to define MS lesions in the optic nerve more specifically and many experts believe that the optic nerve should be included as a 5th specific territory especially as around 20% of patients start their disease with optic neuritis. Similarly, in the presence of a clinically isolated syndrome, to demonstrate dissemination in time, the MRI must show one (or more) lesion(s) taking up the contrast medium, i.e. at least one active inflammatory lesion, as well as older lesions that do not take up the contrast medium (a new lesion takes up contrast for an average of 4 to 6 weeks and then, contrast enhancement disappears even in the absence of any treatment). If the MRI shows no lesions that pick up the contrast medium, the presence of an inflammatory reaction in the CSF in the form of IgG oligoclonal bands replaces this criterion and is also considered as evidence of dissemination in time. On the other hand, if the CSF contains too many inflammatory cells (> 50/µL) or too many proteins, the diagnosis of MS is unlikely and another disease should be sought.

To diagnose a primary progressive form of MS, the progression of disability must be determined retrospectively or prospectively over a period of at least one year. Two of the following 3 additional criteria must also be met: 1° at least one lesion detectable by MRI in the periventricular or cortical/juxta cortical region, or the cerebellum or brainstem; 2° at least two lesions in the spinal cord; 3° the presence of specific oligoclonal bands in the CSF.

The rule is also to exclude other diseases that could "mimic" MS. We should be wary of relying excessively on brain imaging and avoid at all costs a false diagnosis of MS. The differential diagnosis must therefore consider other pathologies:

• Migraines with aura or ophthalmic migraines: these are characterised by visual disturbances, sometimes in the absence of headaches, which may suggest optic neuritis, and may be accompanied by sensory disturbances (paraesthesia) which may last longer than the headache. In addition, migraine sufferers regularly present small hyperintense foci on MRI which could be interpreted as MS lesions. Given the high frequency of migraines in the general population, people can obviously suffer from both migraines and MS. Headache is NOT a symptom of an MS relapse.
• Neuromyelitis optica is an inflammatory disease of the CNS, preferentially affecting the spinal cord and optic nerves, and more rarely the brain itself. It can occur at any age in flare-ups. It is now well differentiated from MS and more easily diagnosed by the detection in the blood of specific antibodies, either anti-aquaporin 4 or anti-MOG (Myelin Oligodendrocyte Glycoprotein).
• Nervous Lyme disease or neuroborreliosis, in which the CSF is severely disturbed and specific anti-Borrelia antibodies are detectable in the blood and CSF.
• Systemic inflammatory diseases which sometimes manifest themselves mainly in the CNS: neurolupus, neurosarcoidosis, etc.
• Susac syndrome, which affects the retina, inner ear and periventricular white matter, is an inflammation of the arteriolar walls in these three areas which can be clearly seen in the retina using fluoangiography. IgG oligoclonal bands are never seen in this syndrome. The main after-effect is deafness, which is never seen in MS.
•  Abnormal signals are also seen on MRI in people over 55, especially if they have vascular risk factors (high blood pressure, diabetes, smoking, high cholesterol). In this case, brain imaging is less specific, but MS lesions have characteristics that are increasingly recognised by experienced radiologists and neurologists. 
• Amyotrophic Lateral Sclerosis (ALS) is, in principle, not a problem of differential diagnosis with MS. In France (and only in France...), it is known as Charcot's disease, but Charcot, a brilliant founder of neurology, described many neurological diseases, including ALS and MS. ALS is not an inflammatory disease, unlike MS, and never causes sensory disorders (optic nerves are intact). It is a neurodegenerative disease that selectively causes the death of motor nerve cells in both the brain and the spinal cord. The result is progressive paralysis of the 4 limbs, the respiratory muscles, swallowing and phonation. It is fatal within a few years and there is currently no cure.

This list, which is not exhaustive, explains why the initial diagnosis can sometimes remain in abeyance and can only be definitively retained or excluded on the basis of the clinical (new attack) and radiological (new lesions on MRI) evolution in the months and years that follow.