How is Multiple Sclerosis (MS) diagnosed?

Diagnosis of Multiple Sclerosis

The diagnosis of multiple sclerosis (MS) requires objective demonstration of lesions disseminated in both time and space, along with exclusion of alternative explanations for the clinical presentation. 1 This diagnostic approach integrates clinical findings with paraclinical testing, particularly magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and visual evoked potentials (VEP).

Diagnostic Criteria Framework

The International Panel on MS Diagnosis has established criteria that focus on:

1. Dissemination in space (DIS): Evidence of lesions in multiple areas of the central nervous system
2. Dissemination in time (DIT): Evidence that lesions have occurred at different time points
3. No better explanation for the clinical presentation

Clinical Presentations and Required Evidence

Clinical Presentation	Additional Data Needed for MS Diagnosis
Two or more attacks; objective clinical evidence of 2+ lesions	No additional tests required*
Two or more attacks; objective clinical evidence of 1 lesion	DIS by MRI or 2+ MRI lesions consistent with MS plus positive CSF
One attack; objective clinical evidence of 2+ lesions	DIT by MRI or second clinical attack
One attack; objective clinical evidence of 1 lesion	DIS by MRI or 2+ MRI lesions plus positive CSF AND DIT by MRI or second attack
Insidious neurological progression suggestive of MS	DIS by specific MRI criteria AND DIT by MRI or continued progression for 1 year

*While no additional tests are technically required in this scenario, if MRI or CSF tests are performed and negative, extreme caution should be taken before making an MS diagnosis 1

MRI Criteria

For Dissemination in Space (DIS)

MRI evidence must show at least three of the following:

• One or more gadolinium-enhancing lesions or nine T2 hyperintense lesions
• One or more infratentorial lesions
• One or more juxtacortical lesions
• Three or more periventricular lesions

For Dissemination in Time (DIT)

• If first scan occurs 3+ months after clinical onset: presence of gadolinium-enhancing lesion (not at the site of original clinical event) is sufficient
• If first scan is within 3 months of clinical onset: a follow-up scan showing new T2 or gadolinium-enhancing lesion is required 1

Laboratory Testing

Cerebrospinal Fluid Analysis

• Positive CSF is determined by oligoclonal bands detected by established methods (preferably isoelectric focusing) that differ from any bands in serum, or by a raised IgG index 1, 2
• CSF analysis is particularly important when clinical and MRI evidence is insufficient or atypical

Visual Evoked Potentials

• Abnormal VEP of the type seen in MS (delay with well-preserved wave form) can support diagnosis, especially in cases with fewer brain lesions but evidence of spinal cord involvement 1

Diagnostic Pitfalls and Differential Diagnosis

Several conditions can mimic MS and must be ruled out:

• Neuromyelitis optica spectrum disorders (NMOSDs)
• Acute disseminated encephalomyelitis (ADEM)
• Vascular disorders (e.g., small vessel disease)
• Infectious diseases
• Neoplastic conditions
• Metabolic disorders
• Other idiopathic inflammatory demyelinating disorders 3

Important caveat: The McDonald criteria should be applied with caution in atypical presentations and special populations. Misdiagnosis remains a significant issue even at MS specialty centers 4.

Diagnostic Algorithm

1. Evaluate clinical presentation:

   • Typical MS symptoms: unilateral optic neuritis, partial myelitis, sensory disturbances, brainstem syndromes
   • Typical age: 20-30 years (mean age of onset)
   • More common in women (3:1 female to male ratio) 2

2. Perform MRI of brain and spinal cord:

   • Look for characteristic lesions (periventricular, juxtacortical, infratentorial, spinal cord)
   • Assess for gadolinium enhancement (indicates active inflammation)

3. Consider CSF analysis if:

   • Clinical presentation is atypical
   • MRI findings are insufficient or equivocal
   • Alternative diagnoses are strongly considered

4. Perform VEP if:

   • Clinical history suggests optic nerve involvement
   • Need to demonstrate additional evidence of dissemination

5. Apply McDonald criteria to determine if diagnosis is:

   • MS (criteria fully met)
   • Possible MS (criteria not completely met)
   • Not MS (criteria fully explored and not met) 1

6. Follow up patients with "possible MS" with repeat clinical and MRI evaluations to monitor for development of definitive MS

Final Diagnostic Considerations

The diagnosis of MS remains partly subjective and partly objective. It is best made by a neurologist with expertise in MS who is familiar with the disease, its differential diagnoses, and the interpretation of paraclinical assessments 1.

Remember that there must be no better explanation for the clinical picture and investigative findings. Biopsy is rarely needed but can confirm inflammatory demyelination when diagnosis remains uncertain despite thorough evaluation 1.