Despite the remarkable improvement in our knowledge and understanding of multiple sclerosis (MS), the principles of MS diagnosis have not changed since the 19th century. To make a diagnosis of MS, a patient should have signs and symptoms compatible with those of MS with dissemination in time (more than one clinical episode of disease) and dissemination in space (more than one area of CNS involved). In addition, all possible alternative explanations of a patient’s signs and symptoms (other diseases) should be excluded. While the principles of diagnosis have remained relatively unchanged, the specific diagnostic criteria have been improved over time, especially with the introduction of new diagnostic tools1.

The majority of MS patients present with signs and symptoms of visual, sensory, motor, cerebellum, or autonomic system involvement. Because MS lesions can affect any part of the brain, spinal cord, and optic nerves, a wide variety of signs and symptoms might be observed in patients. However, some clinical problems are more common than others, and some neurological manifestations are rare. Different patients with MS can present different signs and symptoms. In addition, clinical manifestation of the disease may change in one individual over the course of his/her disease2,3.

Visual symptoms, paresis, and paresthesias are the three most common clinical manifestations of MS at the time of first presentation. A great majority of MS patients experience these symptoms at some point during the course of their disease. In addition to these common symptoms, patients may present a long list of neurological signs and symptoms including but not limited to limb incoordination, tremor, vertigo, dysarthria, impaired speech, spasticity, cognitive impairment, bladder dysfunction, constipation, and impotence. General fatigue and pain are also common. None of these features are MS-specific. Lhermitte’s symptom (an electrical sensation that runs down a patient’s back into the limbs on neck flexion) and Uhthoff phenomenon (a temporary worsening of MS symptoms when body temperature rises, for example after exercise or a hot bath) are particularly considered standard clinical features of MS; however, they may also be seen in conditions other than MS. Some signs and symptoms like seizures (except in pediatric MS) and focal cortical deficits are rarely seen in MS. These rare symptoms should raise a red flag for clinicians, and a very careful exclusion of other causes will be required2,3.

Because MS shares its clinical manifestations with many other diseases, a patient’s diagnosis may pose a challenge to clinicians, especially in the earlier stages of the disease when enough clinical history does not exist. The differential diagnosis of MS includes a long list of infectious, autoimmune, metabolic, and neoplastic diseases and syndromes such as Lyme disease, syphilis, progressive multifocal leukoencephalopathy (PML), human T-cell leukemia virus 1 (HTLV1) infection, Devic’s disease (also known as neuromyelitis optica or NMO), Behcet’s syndrome, sarcoidosis, systemic lupus erythematosus, central pontine myelinolysis, vitamin B12 deficiency, vitamin B6 deficiency, CNS lymphoma, glioma, and metastatic cord compression4,5. As mentioned earlier, exclusion of all diseases that can alternatively explain a patient’s signs and symptoms is an integral part of MS diagnosis1.

Magnetic resonance imaging (MRI) has become a useful tool for MS diagnosis as well as for monitoring the disease in an individual. MRI is a highly sensitive technique in MS diagnosis and typically shows several hyper-intense T2 lesions. Several guidelines have been published to describe suggestive or typical MRI features of MS on both dual-echo (T2- and proton density) and contrast-enhanced T1-weighted imaging that are mostly based on lesion size, site, and shape6,7. It has been argued that the introduction of MRI has also led to a significant increase in the number of false positive diagnoses. Patients without MS with white matter lesions similar to those seen in MS may be misdiagnosed8,9. Nevertheless, MRI plays an important role in MS diagnosis and follow-up6,7.

A qualitative CSF assessment for IgG oligoclonal bands has shown an acceptable sensitivity and specificity in MS diagnosis. When combined with MRI, the two tests show an enhanced sensitivity greater than each test alone. In some individuals, studies of evoked potentials may help with the diagnosis. Other lab tests may be used mainly to exclude other conditions that mimic MS. Specific circumstances in which a clinician should order these tests remain to a great extent controversial10.

In essence, MS is a clinical diagnosis based on patient’s clinical history and examination. The diagnosis can further be supported or confirmed by paraclinical techniques. Today, McDonald diagnostics criteria for multiple sclerosis (2010 revision) is widely accepted as a tool to facilitate an earlier diagnosis of MS with a reasonable sensitivity and specificity. McDonald diagnostic criteria takes into consideration a combination of the number of observed MS attacks, objective clinical evidence of lesions, and MRI and CSF findings in order to make the diagnosis. In principle, the stronger the clinical evidence, the lower the need to be supported by MRI or other tests11.

Miller et al. published an article with detailed recommendations on clinical, laboratory, and imaging assessments in people with possible MS, including those with clinically isolated syndrome (CIS) via an international consensus-based approach. The guideline follows the principles of MS diagnosis as previously described and has references to the McDonald criteria. It provides both a definition and categorization of CIS and describes how to exclude some of the most important differential diagnoses of the disease. Nevertheless, as authors themselves indicate, not every recommendation in the article could be backed up by evidence-based medicine, as evidence in many cases is not sufficient. Thus, authors decided to pick a consensus-based approach in order to come up with the guidelines12. In practice, there remains a great deal of variation in clinicians’ preferred diagnostic workup for MS.