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Neural Network for Multiple Sclerosis

Multiple Sclerosis

Critical Diagnostic Criteria

Pavan Bhargava, MD 
Reviewed on July 15, 2024
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Diagnosing Multiple Sclerosis

The diagnosis of multiple sclerosis (MS) relies on a combination of clinical signs and symptoms, radiographic findings and laboratory results in the context of the revised 2017 McDonald diagnostic criteria (Table 2-2). These criteria offer enhanced diagnostic accuracy compared to the previous version from 2010, enabling earlier MS diagnosis and therefore earlier initiation of the right treatment. New diagnostic criteria are set to be released next year. The diagnosis of MS is based on the demonstration of dissemination of disease characteristics in space and time. Dissemination in space (DIS) refers to the presence of lesions in different anatomical locations within the central nervous system (CNS), while dissemination in time (DIT) refers to the presence of lesions that show both active and inactive stages at the same time, or by the appearance of new lesions over time.

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Diagnostic Tests and Procedures

Diagnostic Testing: MRI Scans

Imaging is a…

Diagnosing Multiple Sclerosis

The diagnosis of multiple sclerosis (MS) relies on a combination of clinical signs and symptoms, radiographic findings and laboratory results in the context of the revised 2017 McDonald diagnostic criteria (Table 2-2). These criteria offer enhanced diagnostic accuracy compared to the previous version from 2010, enabling earlier MS diagnosis and therefore earlier initiation of the right treatment. New diagnostic criteria are set to be released next year. The diagnosis of MS is based on the demonstration of dissemination of disease characteristics in space and time. Dissemination in space (DIS) refers to the presence of lesions in different anatomical locations within the central nervous system (CNS), while dissemination in time (DIT) refers to the presence of lesions that show both active and inactive stages at the same time, or by the appearance of new lesions over time.

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Diagnostic Tests and Procedures

Diagnostic Testing: MRI Scans

Imaging is a crucial tool in the diagnosis of MS. Magnetic resonance imaging (MRI) reveals multiple demyelinated lesions scattered throughout the CNS, marked by inflammation, edema, glial reaction and scarring. During the initial stages of the disease, these lesions frequently occur alongside episodes of intermittent neurological dysfunction. Lesions typically develop in four CNS regions: periventricular, cortical/juxtacortical, infratentorial and spinal cord (Figure 2-1).

Enlarge  Figure 2-1: Regions of Lesion Formation. A (coronal) and B (axial): MRI T1-post contrast images show enhancement in the intraorbital segment of the optic nerve consistent with right optic neuritis (arrows). C: Right posterior periventricular lesion on axial T2-FLAIR (arrow). D: Ventral medullary demyelinating lesion on T2-FLAIR (arrow). E: MR cervical cord sagittal STIR demonstrating C2-3, C4 and C7 demyelinating lesions (arrows). F: Axial T2-FLAIR with demyelinating lesion in left brachium pontis (arrow). G (sagittal) and H (axial): T2-FLAIR images demonstrate left frontal juxtacortical demyelinating lesion (arrows). Source: Adapted from: Baskaran AB, et al. J Clin Neurol. 2023;19(3):217
Figure 2-1: Regions of Lesion Formation. A (coronal) and B (axial): MRI T1-post contrast images show enhancement in the intraorbital segment of the optic nerve consistent with right optic neuritis (arrows). C: Right posterior periventricular lesion on axial T2-FLAIR (arrow). D: Ventral medullary demyelinating lesion on T2-FLAIR (arrow). E: MR cervical cord sagittal STIR demonstrating C2-3, C4 and C7 demyelinating lesions (arrows). F: Axial T2-FLAIR with demyelinating lesion in left brachium pontis (arrow). G (sagittal) and H (axial): T2-FLAIR images demonstrate left frontal juxtacortical demyelinating lesion (arrows). Source: Adapted from: Baskaran AB, et al. J Clin Neurol. 2023;19(3):217

The classification of MS lesions is determined by their appearance on different types of MRI scans. They are categorized into three groups: T2 hyperintense, chronic T1 hypointense ("black holes"), and gadolinium-enhancing lesions. Dissemination in space shows characteristic T2 hyperintense lesions in at least two of the four affected CNS areas, and dissemination in time describes the presence of gadolinium-enhancing and non-enhancing lesions concurrently or by new lesions on follow-up MRI compared to a baseline scan. The 2021 MAGNIMS-CMS-NAIMS guidelines for the use of MRI in patients with MS provide evidence-based unified recommendations from European and North American experts, useful for diagnosing and monitoring MS. They feature simplified MRI protocols for clinical use and address limitations of newer diagnostic sequences and quantitative monitoring measures. The messages from the guidelines are summarized in Table 2-3.

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Diagnostic Testing: Lumbar Puncture

Lumbar puncture for cerebrospinal fluid (CSF) analysis is performed in only about 10% of suspected MS cases, typically when clinical and MRI results are inconclusive. Non-specific CSF findings include moderate pleocytosis (10-20 cells/mm³) and a modest increase in total protein (50-70 mg/dL), while more specific findings include the presence of oligoclonal bands and increased CSF immunoglobulin G (IgG) index or synthesis rate. Oligoclonal bands and an elevated IgG index indicate an ongoing autoimmune process in the CNS, and are present in 40-50% of patients with early stages of MS and 85-95% over the entire course of the disease. Moreover, oligoclonal bands have a potential to predict the progression of the disease to clinically definite MS. While a characteristic CSF pattern can provide valuable support for an MS diagnosis, its absence does not necessarily exclude MS. Given that oligoclonal bands and increased IgG levels can also be indicative of other inflammatory and non-inflammatory CNS conditions, careful interpretation is essential in clinical practice.

Diagnostic Testing: Evoked Potentials

Evoked potentials are classified into sensory (visual, somatosensory and brainstem auditory) and motor evoked potentials, with both having the ability to detect clinically silent lesions in the CNS that might be overlooked during standard clinical examination. Additionally, visual evoked potentials (VEPs) can be used to evaluate the presence of optic neuritis. Data from 2021 suggests that detecting optic nerve lesions using VEPs could enhance the sensitivity and accuracy of current diagnostic criteria. Recently, these test have been utilized to form exploratory endpoints in studies of remyeliation and progressive MS, such as the ReBUILD trial. This double-blind, randomized, placebo-controlled trial demonstrated a statistically significant reduction in visual evoked potentials latency with clemastine fumarate, potentially indicating repair and remyelination.

Diagnostic Testing: Optical Coherence Tomography

Optical coherence tomography (OCT) offers a non-invasive, quick and reliable method to produce high-resolution retinal images, with the two most frequently studied retinal layers including the ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fibre layer (RNFL). In the context of MS, OCT can detect silent optic nerve issues in patients with Clinically Isolated Syndrome (CIS) and may even predict disease prognosis. Notably, a correlation has been observed between the thickness of the GCIPL and RNFL layers measured by OCT, and brain atrophy and disease progression. Similar to VEPs, OCT can be also used to diagnose optic neuritis as it can confirm its history. However, the ability of OCT to identify retinal abnormalities in the pediatric population with MS is limited in the absence of prior optic nerve involvement.

Diagnostic Testing: Blood Tests

Blood tests are typically not used to diagnose MS directly. However, they play a crucial role in ruling out other conditions that can mimic MS symptoms, such as infections, inflammatory diseases, or metabolic disorders. Tests often check for specific antibodies, inflammatory markers and overall immune function, while researchers are actively investigating specific biomarkers for future diagnostic and monitoring purposes.

Diagnostic Testing: Differential Diagnosis

The diagnosis of MS relies on recognizing clinical symptoms and distinguishing them from those of similar conditions, often referred to as MS mimics. Imaging and laboratory testing are crucial tools for appropriate diagnosis. However, misdiagnosis can occur due to inappropriate application of the McDonald diagnostic criteria, atypical MS symptoms and excessive reliance on MRI results. One of the most common difficulties in diagnosing MS is inaccurate interpretation of MRI lesions, where typical MS lesions may be mistaken for nonspecific ones that are associated with common conditions such as headache or vertigo. Classic MS lesions are small and ovoid, and typically positioned around small vessels in the white matter of the brain. Interestingly, detection of a central vein within three lesions enhances the specificity, sensitivity and reliability for the differential diagnosis of MS. While MS shares many of its symptoms with other diseases and syndromes, some (like fatigue or overactive bladder) are so frequently reported that their absence may suggest an alternative diagnosis. Table 2-4 lists the most common MS mimics.

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Importance of Timely and Accurate Diagnosis

Timely and accurate diagnosis of MS is crucial for several reasons. Early diagnosis allows for prompt initiation of disease-modifying treatments, which can slow the progression of the disease, reduce the frequency and severity of relapses and ultimately improve long-term outcomes and quality of life for patients. Accurate diagnosis is essential to ensure that patients receive appropriate and effective therapies, thereby minimizing unnecessary treatments and associated side effects. For instance, rare diseases such as metabolic defects of B12 metabolism, Sjogren’s syndrome, or Hashimoto encephalopathy can mimic MS and misdiagnosis leads to a 100% probability of mistreatment if these conditions are not considered. Advances in diagnostic criteria, harmonized MRI guidelines, and globalized treatment recommendations have significantly improved diagnostic accuracy and enabled earlier initiation of effective immunomodulatory treatments. Revisions to the MS diagnostic criteria, such as the McDonald criteria updates in 2017, have facilitated earlier diagnoses by reducing the need to wait for a second clinical event. This accelerated diagnosis is associated with better clinical outcomes and can help alleviate the global impact of MS by reducing disability and healthcare costs.

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