What is the treatment for clinically isolated syndrome (CIS)?

Treatment of Clinically Isolated Syndrome (CIS)

Disease-modifying therapies (DMTs) should be initiated promptly in patients with clinically isolated syndrome to prevent conversion to clinically definite multiple sclerosis and reduce long-term disability. 1, 2

Definition and Diagnosis

Clinically isolated syndrome (CIS) is defined as a first clinical episode with features suggestive of multiple sclerosis (MS), typically affecting the optic nerves, brainstem, or spinal cord 3. According to the 2010 McDonald criteria, CIS can be diagnosed as MS if there is evidence of:

• Dissemination in space (DIS): One or more T2 lesions in at least two of four characteristic MS locations (periventricular, juxtacortical, infratentorial, or spinal cord)
• Dissemination in time (DIT): New T2 and/or gadolinium-enhancing lesions on follow-up MRI or simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions 4

Risk Stratification

The risk of conversion from CIS to MS varies from 20-75% 5. Key predictors of conversion include:

• High-risk factors:
  • Multiple baseline MRI T2-hyperintense lesions (>10 lesions) (OR 3.107) 6
  • Positive cerebrospinal fluid oligoclonal bands (OR 5.958) 6
  • Subclinical evoked potential abnormalities (OR 14.400) 6
  • Presence of asymptomatic gadolinium-enhancing lesions 4

Treatment Approach

First-line Treatment Options

1. Interferon beta-1a (IM): FDA-approved for CIS, administered intramuscularly once weekly 2

   • Demonstrated reduction in conversion rates to clinically definite MS
   • Benefits persist even when treatment is delayed by 2-3 years 7

2. Natalizumab: FDA-approved for relapsing forms of MS, including CIS 1

   • Administered as 300 mg intravenous infusion every four weeks
   • Consider carefully due to risk of progressive multifocal leukoencephalopathy (PML)
   • Should be used as monotherapy (not combined with other immunosuppressants)

3. Other DMTs with evidence in CIS:

   • Glatiramer acetate: Shown to decrease conversion rates to clinically definite MS 7
   • Teriflunomide and cladribine: Evaluated in randomized controlled trials with beneficial effects 8

Treatment Selection Considerations

When selecting therapy, consider:

1. MRI lesion burden (higher burden suggests more aggressive treatment)
2. Presence of oligoclonal bands (positive bands suggest higher risk)
3. Patient factors (age, comorbidities, pregnancy plans)
4. Side effect profiles of medications
5. Monitoring requirements

Monitoring and Follow-up

• MRI follow-up at 6-12 months after treatment initiation, then annually
• Clinical assessment every 3-6 months to evaluate for new neurological symptoms
• Monitor for medication-specific adverse effects
• Assess treatment efficacy based on:
  • Prevention of new clinical relapses
  • Prevention of new MRI lesions
  • Absence of disability progression

Special Considerations

• Differential diagnosis: Consider other conditions that may mimic CIS, including acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), and small vessel ischemic disease in older adults 7
• Pregnancy planning: Some DMTs require washout periods before conception
• Risk of PML with natalizumab: Consider JC virus antibody status, prior immunosuppressant use, and duration of therapy 1

Treatment Algorithm

1. Confirm CIS diagnosis using 2010 McDonald criteria
2. Assess risk of conversion to MS based on MRI findings and CSF results
3. For high-risk CIS (multiple MRI lesions, positive oligoclonal bands):
   • Initiate DMT promptly
   • Consider interferon beta-1a as first-line therapy for most patients
   • Consider natalizumab for more aggressive presentation with high lesion load
4. For low-risk CIS (few MRI lesions, negative oligoclonal bands):
   • Consider close monitoring with repeat MRI in 3-6 months
   • Discuss risks/benefits of early DMT initiation

Early treatment of CIS with appropriate DMTs has been shown to delay conversion to MS and potentially reduce long-term disability, making prompt intervention the standard of care for patients at high risk of developing MS 5, 7.