How to start investigating multiple sclerosis (MS)?

Diagnostic Approach for Multiple Sclerosis

The diagnosis of multiple sclerosis (MS) requires evidence of inflammatory-demyelinating injury within the central nervous system that is disseminated in both time and space, with no better explanation for the clinical presentation. 1

Initial Diagnostic Steps

• Obtain objective clinical evidence of neurological lesions separated in time and space, as historical accounts of symptoms alone are insufficient for diagnosis 2
• Perform brain and spinal cord MRI, which is considered the most sensitive and specific test for MS diagnosis 2, 1
• Conduct cerebrospinal fluid (CSF) analysis to detect oligoclonal IgG bands or elevated IgG index, particularly when imaging criteria fall short or clinical presentation is atypical 1
• Consider visual evoked potentials (VEP) to provide additional support, especially when MRI abnormalities are few or have lesser specificity 2, 1

MRI Criteria for MS Diagnosis

• Dissemination in space requires three of four of the following: 1

  • One gadolinium-enhancing lesion or nine T2-hyperintense lesions if no gadolinium enhancement
  • At least one infratentorial lesion
  • At least one juxtacortical lesion
  • At least three periventricular lesions

• Dissemination in time can be demonstrated by: 1

  • Presence of gadolinium-enhancing lesion (not at site of original event)
  • New T2 lesion on follow-up scan

CSF Analysis

• Look for oligoclonal IgG bands detected by isoelectric focusing that are different from any bands in serum 1
• Check for elevated IgG index 1
• Ensure lymphocytic pleocytosis is less than 50/mm³ 1
• CSF analysis is particularly valuable when imaging criteria are not fully met or in atypical presentations 1

Diagnostic Scenarios

1. Two or more attacks with objective clinical evidence of two or more lesions:

   • No additional tests required for MS diagnosis, though MRI and CSF would typically be abnormal if performed 1

2. Two or more attacks with objective evidence of one lesion:

   • Requires demonstration of dissemination in space through MRI or CSF analysis 1

3. One attack with objective evidence of two or more lesions:

   • Requires demonstration of dissemination in time through MRI or a second clinical attack 1

4. One attack with objective evidence of one lesion:

   • Requires demonstration of both dissemination in space and time 1

5. Insidious neurological progression suggestive of MS:

   • Requires demonstration of dissemination in space and time or continued progression for one year 1

Important Considerations and Pitfalls

• Always consider alternative diagnoses, particularly when tests are negative or atypical 2, 1
• Take special care in patients younger than 10 or older than 59 years, those with progressive onset, or unusual presentations 2, 1
• Be aware that persistent neurological symptoms without objective clinical evidence do not typically lead to MS development 3
• Ensure high-quality paraclinical analyses (MRI, CSF, evoked potentials) as poor quality can lead to misdiagnosis 2
• Early diagnosis is crucial as axonal loss occurs early in the disease process, and early treatment significantly benefits patients 4

Differential Diagnosis to Consider

• Cerebral ischemia/infarction in young adults (phospholipid antibody syndrome, lupus, CADASIL) 2
• Infections such as HTLV1 and Lyme disease 2
• Paraneoplastic disorders 2
• Monophasic demyelinating diseases (acute disseminated encephalomyelitis, Devic's syndrome) 2
• Genetic disorders of myelin (leukodystrophies) in children and teenagers 2

Diagnostic Outcomes

• If criteria are fulfilled: diagnosis is MS 1
• If criteria are not completely met: diagnosis is "possible MS" 1
• If criteria are fully explored and not met: diagnosis is "not MS" 1