Multiple Sclerosis (MS)

Clinically isolated syndrome (CIS) is one of the disease courses in multiple sclerosis (MS).1 It refers to the first episode of neurologic symptoms resembling a typical MS relapse in a patient not known to have MS. It lasts at least 24 hours and occurs without fever or infection and with no clinical features of encephalopathy.2 

CIS can be focal or multifocal. Focal CIS is characterized by a single neurologic sign or symptom caused by a single lesion, while in multifocal CIS, lesions in more than 1 place lead to more than 1 sign or symptom.1

Clinically Isolated Syndrome Causes

MS is characterized by immune-mediated demyelination and axonal damage in the central nervous system, typically involving the optic nerve, brainstem, cerebellum, spinal cord, and/or cerebral hemispheres. 

Like other MS courses, the cause of CIS is not known. However, some factors could increase the risk of developing the condition, including Epstein-Barr virus infections, vitamin D deficiency, smoking, living in a temperate climate, genetic factors such as the HLA-DRB1*1501 allele, and immunological abnormalities.3

Clinically Isolated Syndrome Symptoms

Symptoms of CIS include vision problems (such as double vision), dizziness, numbness or tingling, spasticity, muscle stiffness or weakness, paralysis, coordination and ambulatory issues, urinary or fecal incontinence, and sexual dysfunction.4 These symptoms overlap with those of MS, but in CIS they occur only once. If they occur again, patients are diagnosed with MS.

The likelihood of CIS progressing to MS is linked with the presence of brain lesions detected by magnetic resonance imaging (MRI). Patients with lesions detected by MRI have a 60% to 80% chance of experiencing a second neurological episode and being diagnosed with MS. In patients with no MRI-detectable brain lesions, this risk is 20%.1

Clinically Isolated Syndrome Diagnosis

Clinically isolated syndrome diagnosis begins with a medical history of the patient including birthplace, environmental exposures, and places traveled, as well as symptom review.5 This is usually followed by a neurological exam, which includes tests assessing vision, hearing, swallowing, sensation, strength, reflexes, coordination, walking, and balance.

An MRI scan of the central nervous system and blood tests to rule out other inflammatory or infectious disorders of the nervous system, such as systemic lupus erythematosus and neuroborreliosis, can also be conducted.2 

The revised McDonald Criteria that the International Panel on the Diagnosis of Multiple Sclerosis published in 2017 include specific guidelines for the use of MRI and cerebrospinal fluid (CSF).6 MRI findings can help determine the risk of CIS progressing into MS. It can also be used to look for a second lesion and confirm whether damage has occurred at 2 different points in time. In some circumstances, the presence of oligoclonal bands in the CSF can be used to confirm the MS diagnosis.

If a patient is diagnosed with CIS, they should be routinely checked to determine whether their condition is progressing to MS. Research has shown that a third of patients with CIS have a benign disease course with minimal or no disability after 15-20 years, and half will have developed secondary progressive MS with increasing disability.2

Clinically Isolated Syndrome Treatments

There is currently no cure for CIS or MS. However, patients with CIS and a high risk of developing MS, ie, those in whom the disease is accompanied by MRI-detected brain lesions, are typically treated with disease-modifying therapies, as these can prevent or delay the onset of MS. 

The US Food and Drug Administration approved several medications for the treatment of CIS. These include interferon beta-1a (Avonex®), interferon beta-1b (Betaseron® and Extavia.), and siponimod (Mayzent®).1

Interferon Beta-1a and Beta-1b for CIS

Interferon beta-1a is an immunomodulator that reduces inflammation and may prevent nerve damage in patients with MS and CIS.7 A clinical trial called the CHAMPS study found that treatment with intramuscular interferon beta-1a in patients with CIS delayed the transition to MS by about 55%.8

Side effects of interferon beta-1a include dizziness, numbness, burning, tingling, or pain in the hands or feet, muscle tightness, joint pain, eye problems, toothache, and hair loss.7

The exact mechanism of action of interferon beta-1b in treating MS is not known, but it is also an immunomodulator like interferon beta-1a that reduces inflammation and immune attack against myelin.9

Interferon beta-1b can have side effects including flu-like symptoms, injection site reactions, blood cell abnormalities, diarrhea, nausea and vomiting, and muscle or joint pain. The treatments can also increase the risk of infections.

Siponimod for CIS

Siponimod is an immunomodulator that acts on the sphingosine 1-phosphate receptor (S1P).10 It specifically binds to S1P subtypes 1 and 5, and it induces receptor internalization and degradation in T and B cells, ultimately preventing lymphocytes from exiting the lymphoid tissue and entering the central nervous system. 

The side effects of siponimod are slow or irregular heartbeat, vision problems, headache, confusion, seizures, cold sores, skin changes, shortness of breath, and nausea.11


  1. Clinically isolated syndrome (CIS). National Multiple Sclerosis Society. Accessed June 11, 2021.
  2. Efendi H. Clinically isolated syndromes: clinical characteristics, differential diagnosis, and management. Noro Psikiyatr Ars. 2015;52(Suppl 1):S1-S11. doi:10.5152/npa.2015.12608
  3. Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol. 2012;11(2):157-169. doi:10.1016/S1474-4422(11)70274-5
  4. Clinically isolated syndrome. Cedars Sinai. Accessed June 11, 2021.
  5. Diagnosing MS. National Multiple Sclerosis Society. Accessed June 11, 2021.
  6. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173. doi:10.1016/S1474-4422(17)30470-2
  7. Interferon beta-1a intramuscular injection. Medline Plus. Updated June 8, 2021. Accessed June 11, 2021.
  8. Galetta SL. The controlled high risk Avonex multiple sclerosis trial (CHAMPS Study). J Neuroophthalmol. 2001;21(4):292-295. doi:10.1097/00041327-200112000-00013
  9. Interferon beta-1b injection. Medline Plus. Updated June 8, 2021. Accessed June 11, 2021.
  10. Siponimod. Cleveland Clinic. Accessed June 11, 2021.
  11. Multum C. Siponimod. Updated April 5, 2021. Accessed June 11, 2021.

Reviewed by Kyle Habet, MD on 7/1/2021

Reviewed by Kyle Habet, MD, on 7/1/2021.