Multiple Sclerosis

1-When to diagnose MS relapse?

Acute MS relapses should be diagnosed when the patient develops symptoms that occur over a minimum of 24 hours and separated from a previous attack by at least 30 days, in the absence of fever or infection. In the radiological domain, the criteria for relapses are defined as an increase in lesion load/size on T2 imaging or gadolinium enhancement of lesions on magnetic resonance imaging (MRI) in the brain or spinal cord (strong recommendation) (high quality evidence)(1) .

2- How to treat MS relapses?

It is recommended to treat initially acute MS relapses with a 3–5 day course of intravenous methylprednisolone  (strong recommendation) (high quality evidence)(2).

Statement 2.2: It is recommended to consider plasma exchange in the treatment of patients with severe disability who fail to respond to intravenous methylprednisolone (refer to a tertiary center if not available)(strong recommendation) (high quality evidence) (2) .

3-When to diagnose Relapsing Remittent Multiple Sclerosis?

The diagnosis of relapsing remittent multiple sclerosis (RRMS) should be promptly considered after the patient experiences the first symptoms that may be suggestive of MS relapse, what is termed as clinical isolated syndrome (CIS)  (strong recommendation) (high quality evidence)(3).

3.1 What are the criteria needed to diagnose relapsing remittent multiple sclerosis in patients presenting with typical clinical isolated syndrome?

Statement 3.1.1: According to the 2024 revisions of McDonald criteria, MS is conventionally diagnosed based on the presence of symptoms typical of demyelinating disease, objective evidence of CNS white matter lesions typical of multiple sclerosis, and no better explanation  (strong recommendation) (high quality evidence)(3).

Statement 3.1.2: Dissemination in space (DIS) is fulfilled when two of the five regions (optic nerve, cortical or juxtacortical, periventricular, infratentorial, and spinal cord) show typical lesions, regardless of whether these lesions are symptomatic  (strong recommendation) (high quality evidence) (3).

Statement 3.1.3: Dissemination in time (DIT) is proved if there is simultaneous presence of gadolinium enhancing and non-enhancing lesions at any time, or if a new T2 lesion on follow up MRI irrespective of timing of baseline scan, or positive cerebrospinal fluid  for oligoclonal bands or kappa free light chain index  (strong recommendation) (high quality evidence)(3).

Statement 3.1.4: Fulfillment of DIS and DIT are sufficient to diagnose RRMS  (strong recommendation) (high quality evidence)(3).

Statement 3.1.5: In patients with typical clinical presentations, the presence of typical lesions in at least four anatomical locations is sufficient to diagnose RRMS(strong recommendation) (high quality evidence) (3) .

Statement 3.1.6: In patients with typical clinical presentations and typical lesions in one region, a positive select 6 central vein sign or presence of one or more paramagnetic rim lesions plus DIT or CSF positivity is sufficient to diagnose RRMS (strong recommendation) (high quality evidence)(3) .

3.2 What is the role of MRI in diagnosis of MS?

Brain MRI should be obtained in all patients being considered for an MS diagnosis. Spinal MRI is recommended when the presentation suggests a spinal cord localization, when there is a primary progressive course, or when additional data are needed to increase diagnostic confidence. In general, MRI shows excellent diagnostic performance using sequences, such as susceptibility-weighted imaging that can demonstrate lesions with central vein sign or paramagnetic rim lesions (strong recommendation) (high quality evidence)(3) .

3.3 What is the role of CSF in diagnosis of MS?

In patients with typical CIS, fulfillment of MRI criteria for DIS, and no better explanation for the clinical presentation, demonstration of CSF oligoclonal bands (OCBs) or kappa free light chain (KFLC) index allows a diagnosis of MS to be made, even if the MRI findings on the baseline scan do not meet the criteria for DIT and in advance of either a second attack or MRI evidence of a new or active lesion on serial imaging. This recommendation allows the presence of CSF OCBs to substitute for the requirement for fulfilling DIT in this situation(strong recommendation) (high quality evidence)(3).

4-When to diagnose Secondary Progressive Multiple Sclerosis?

We suggest that secondary progressive MS (SPMS) is diagnosed if there is a history of confirmed gradual progression for 3 months at least without preceding relapse, with a minimum Expanded Disability Status Scale (EDSS) score of 4, after an initial RRMS course  (conditional recommendation) (moderate quality evidence)(4) .

5-When to diagnose Primary Progressive Multiple Sclerosis?

According to the 2017 McDonald criteria, primary progressive MS (PPMS) should be diagnosed in patients who experience worsening disability for at least one year (based on previous symptoms or ongoing observation), and who exhibit at least two of the following criteria: at least one MS-like lesion in the brain, at least two lesions in the spinal cord, or positive test for oligoclonal bands in the CSF  (strong recommendation) (high quality evidence)(3).

6- How to manage patients with Relapsing Remittent Multiple Sclerosis?

Neurologists should offer early treatment with disease modifying therapies (DMTs) in patients with relapsing remitting MS as defined by clinical relapses and/or MRI activity (strong recommendation) (high quality evidence). Please check the annexes for the list of the available DMTs in RRMS (5).

6.1 Starting DMT: Recommendations

Statement 6.1.1: Neurologists should counsel patients with MS that DMTs are prescribed to reduce relapses and new MRI lesion activity, and should counsel on the importance of adherence to DMT  (strong recommendation) (high quality evidence)(6).

Statement 6.1.2: Neurologists must ascertain and share with the patient the terms of safety, route of administration (according to patient’s preference),incorporate/review preferences in terms of safety, route of administration, accessibility of the drug, efficacy, common adverse effects, and tolerability in the choice of DMT in MS patients  (strong recommendation) (high quality evidence)(6).

Statement 6.1.3: Neurologists should monitor the reproductive plans of women with MS and counsel regarding reproductive risks and use of birth control during DMT use in women of childbearing potential who have MS  (strong recommendation) (high quality evidence)(6).

Statement 6.1.4: Neurologists could prescribe highly effective DMTs (such as fingolimod, cladribine, natalizumab, or ocrelizumab) from the beginning for highly active MS patients and aggressive MS patients. The choice depends on the patient’s characteristics and comorbidities, drug safety profile, pregnancy issue and accessibility of the drug (conditional recommendation) (moderate quality evidence)(7) .

The following clinical and radiological features should determine if a patient has highly active MS:

- Relapse frequency in the previous year (≥2 relapses).

- Relapse severity (pyramidal/cerebellar systems involvement).

- Incomplete recovery from relapses.

- High T2 lesion load on MRI (≥10 lesions), especially with spinal or infratentorial lesions.

- Multiple Gadolinium enhancing lesions (7).

The following clinical and radiological features should determine if a patient has aggressive MS:

- Patients reaching an EDSS score of 6.0 within 5 years of disease onset or by 40 years of age.

- Treatment naïve patients who had 2 or more relapses with incomplete recovery in the past year.

- Two or more disabling relapses in 1 year with ≥1 Gadolinium enhancing lesion or significant high T2 lesion load on MRI (≥10 lesions) (7).

6.2 Switching DMT: Recommendations

Statement 6.2.1: Neurologists should monitor MRI disease activity from the clinical onset of disease to detect the accumulation of new lesions in order to inform treatment decisions in people with MS using DMTs (strong recommendation) (high quality evidence)(6) .

Statement 6.2.2: Neurologists should discuss switching from one DMT to another in MS patients who have been using a DMT long enough for the treatment to take full effect and are adherent to their therapy when they experience 1 or more relapses, 2 or more unequivocally new MRI-detected lesions, or increased disability on examination, over a 1-year period of using a DMT(strong recommendation) (high quality evidence) (6) .

Statement 6.2.3: Neurologists should discuss a medication switch with people with MS for whom these adverse effects negatively influence adherence (strong recommendation) (high quality evidence)(6) .

6.3 Monitoring treatment response: Recommendations

Statement 6.3.1: Neurologists should combine MRI with clinical measures when evaluating disease progression in patients treated with DMTs  (strong recommendation) (high quality evidence)(5).

Statement 6.3.2: When monitoring the treatment response, a standardized reference brain MRI should be performed within 6 months of treatment onset and then compared with a further brain MRI performed typically 12 months after starting treatment. Adjust the timing of both MRIs, taking into account the drug’s mechanism of action (particularly the speed of action) and disease activity (including clinical and MRI measures)  (strong recommendation) (high quality evidence)(5).

7- How to treat patients with Secondary Progressive Multiple Sclerosis?

Neurologists should offer siponimod for active SPMS patients evidenced by relapses or imaging-features of inflammatory activity  (strong recommendation) (high quality evidence)(8).

8- How to treat patients with Primary Progressive Multiple Sclerosis?

Neurologists should offer ocrelizumab for PPMS patients (strong recommendation) (high quality evidence) (9).