Multiple Sclerosis (MS)

Multiple sclerosis (MS) is the most common demyelinating disease of the brain and spinal cord.1 It is characterized by an immune system attack on the myelin-forming oligodendrocytes, leading to inflammation and nerve cell damage.

Symptoms of MS

MS can cause a wide range of symptoms affecting many organs and systems in the body. The most common symptoms of the disease include vision problems, numbness and tingling, muscle spasms, stiffness, weakness, fatigue, bowel and bladder problems, sexual dysfunction, cognitive issues, and mental health conditions such as anxiety and depression. The severity and types of symptoms can vary widely from patient to patient and may overlap with those of other diseases.

Diseases That Can Mimic MS

The differential diagnosis of multiple sclerosis includes a number of other diseases.2,3 These include other idiopathic inflammatory diseases that can either be demyelinating or nondemyelinating.

Idiopathic inflammatory demyelinating disorders that could mimic MS include acute disseminated encephalomyelitis (ADEM), Balo’s concentric sclerosis, Marburg variant of MS, neuromyelitis optica spectrum disorder (NMOSD), and Schilder’s disease.

Idiopathic inflammatory nondemyelinating diseases that can mimic MS include Behçet’s disease, granulomatous polyangiitis, paraneoplastic neurological syndromes, sarcoidosis, Sjogren’s syndrome, and systemic lupus erythematosus (SLE).

MS differential diagnosis can also include central nervous system (CNS) infections such as human immunodeficiency virus (HIV) associated central nervous system involvement, human T lymphotropic virus (HTLV) associated myelitis, Lyme disease, neurosyphilis, and progressive multifocal leukoencephalopathy (PML).

Metabolic conditions that can mimic MS include copper deficiency, Fabry disease, leukodystrophies, Leber’s hereditary optic neuropathy (LHON), and subacute combined degeneration.

Certain vascular conditions can also mimic MS. These include antiphospholipid antibody syndrome (APLAS), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), small vessel disease, stroke, and Susac’s syndrome.

Other differential diagnoses of MS include central nervous system lymphoma, cysticercosis, metastatic tumors, migraine attacks with aura, multifocal gliomas, toxoplasmosis, and tuberculosis.

MS Disease Courses

The symptoms of MS can also vary greatly according to the disease course. There are 4 disease courses in MS. These include clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS).

Read more about multiple sclerosis types.

Differential diagnoses in CIS and RRMS include bacterial infections such as brucellosis and borrelia, meningococci, mycobacteria, salmonella, and streptococci infections, acute necrotizing myelitis after rabies vaccination, acute lymphoblastic leukemia, lymphoma, carcinomas, tuberculosis, HIV, and HTLV-1, chronic recurrent inflammatory optic neuropathy (CRION), idiopathic transverse myelitis, LHON, sarcoidosis, and systemic vasculitides.3

Differential diagnoses in the case of multifocal involvement and relapsing disease course include idiopathic inflammatory disorders such as acute disseminated encephalomyelitis, antiphospholipid syndrome, Behçet’s disease, isolated central nervous system vasculitis, neurosarcoidosis, Sjogren’s syndrome, SLE, and Susac’s syndrome.

MS Diagnostic Tests

In patients presenting with an attack, the most important test to confirm the diagnosis is magnetic resonance imaging (MRI) with intravenous gadolinium.4

Primary tests for MS diagnosis include blood tests, cranial, cervical, and thoracic MRI, and cerebrospinal fluid (CSF) analysis.5

Secondary tests to reach an MS diagnosis include evoked potentials, optic coherence tomography, urodynamic testing, and cognitive testing.

Read more about multiple sclerosis testing.

Other Tests for Differential Diagnosis

Additional blood tests for differential diagnosis include a wider autoantibody panel, 24-hour urine analysis, and glomerular filtration rate evaluation for vasculitis. If rheumatological disorders are suspected, anti-CCP levels and serum complement levels should be assessed.3 For a diagnosis of lymphoma, serum anti-beta 2 microglobulins should be checked. For sarcoidosis, ACE levels should be checked. For adrenoleukodystrophy, levels of adrenal hormone and long/very long-chain fatty acids should be analyzed. For mitochondrial diseases, serum pyruvate and lactate levels should be assessed. Finally, for NMOSD, anti-aquaporin 4 and anti-MOG tests should be performed.

Specific tests for infectious etiologies include antibodies for Lyme disease and brucellosis, and the PPD skin test and QuantiFERON test for tuberculosis.

Other differential diagnosis tests include retina evaluation for metabolic disorders, uvea evaluation for sarcoidosis and Behçet’s disease, hearing tests for Susac’s disease, chest X-rays for chronic latent/sequel infectious lung disorders and hilar adenopathy, echocardiogram for SLE and mitochondriopathies, Schirmer test and salivary gland scintigraphy for Sjögren’s disease, and tomography for malignancies and metabolic disorders.

Importance of MS Differential Diagnosis

Due to the similarities in symptoms between MS and other diseases, it can be difficult to reach a definite diagnosis in a short time. MRI remains the gold standard of differential diagnosis in MS.5 However, it should not be the only approach used to reach a diagnosis as this could lead to diagnostic errors and the adoption of the wrong therapeutic approach.


  1. Demyelinating disease: what can you do about it? Mayo Clinic. May 5, 2020. Accessed June 11, 2021.
  2. Differential diagnosis. National Multiple Sclerosis Society. Accessed June 11, 2021.
  3. Ömerhoca S, Yazici Akkaş S, Kale İçen N. Multiple sclerosis: diagnosis and differential diagnosis. Noro Psikiyatr Ars. 2018;55(Suppl 1):S1-S9. doi:10.29399/npa.23418
  4. Hemond CC, Bakshi R. Magnetic resonance imaging in multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8(5):a028969. doi:10.1101/cshperspect.a028969
  5. Multiple sclerosis. Mayo Clinic. June 12, 2020. Accessed June 11, 2021.
  6. Wildner P, Stasiołek M, Matysiak M. Differential diagnosis of multiple sclerosis and other inflammatory CNS diseases. Mult Scler Relat Disord. 2020;37:101452. doi:10.1016/j.msard.2019.101452

Reviewed by Michael Sapko, MD, on 7/1/2021.