Multiple Sclerosis Diagnostic Criteria

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Multiple Sclerosis Diagnostic Criteria

Therapeutics Initiative logoMS Therapeutic Review

Date: January 16th 2020

Report 1: Poser criteria and McDonald criteria 2001, 2005, 2010 and 2017

The Drug Assessment Working Group of the Therapeutics Initiative undertook a review of diagnostic criteria for multiple sclerosis (MS). The McDonald (2017) criteria for MS diagnosis offers a more refined diagnostic tool, especially in cases where individuals experience their first MS-like symptoms, with higher predictive power and the ability to detect MS at earlier stages in the disease compared to more dated tools MS diagnostic tools. However, some limitations of the McDonald (2017) criteria include a possibility for overdiagnosis, delayed diagnosis, ethical issues of retrospective diagnosis, and issues arising in realms of medico-legal implications and socioeconomic impacts. Overall, a collaborative effort amongst medical experts to understand the benefits and challenges of these criteria are required prior to its implementation.

Key takeaways:

  1. Enhanced Diagnosis: The McDonald (2017) criteria offer refined methods for detecting MS, particularly in patients experiencing their first MS-like episode (clinically isolated syndrome or CIS).
  2. Predictive Power: Studies showed that these new criteria better predicted MS development compared to the older 2010 criteria. Symptoms involving balance or coordination, along with specific brain scan findings, held greater predictive value.
  3. Early Detection: Application of the new criteria enabled quicker MS diagnosis, aiding in timely intervention and management.
  4. Balancing Act: While the McDonald (2017) criteria improved case identification, they also increased the likelihood of diagnosing MS in cases that didn’t warrant it, prompting concerns about overdiagnosis.
  5. Lumbar Puncture Role: Experts leaned towards using lumbar punctures and spinal fluid analysis for MS diagnosis. However, there were ethical dilemmas about retrospectively informing patients of new MS diagnoses based on these tests.
  6. Complex Implications: These criteria raised ethical, legal, and social questions about retrospective diagnosis shifts and potential socioeconomic impacts.
  7. Holistic Consideration: A comprehensive dialogue among medical experts is crucial to address the broader implications, including patient oriented aspects, and medico-legal aspects.

Overall, the McDonald (2017) criteria facilitate early MS detection, especially in initial MS-like episodes. However, the challenge lies in balancing accurate diagnosis with potential consequences and implications, necessitating ongoing discussions and guidance within the medical community

Executive summary

Multiple sclerosis (MS) is an incurable autoimmune, chronic inflammatory and degenerative disorder of the central nervous system (CNS) affecting more than 2 million people worldwide. It is approximately three times more common in women than in men. Onset is typically between the ages of 20 and 40 years. The Multiple Sclerosis Society of Canada estimates that there are currently 100,000 patients with MS in Canada, which is one of the highest prevalence rates in the world. Because onset of MS occurs at a relatively early age, it affects individuals during their most productive years, and they face challenges in the workforce including underemployment, unemployment and long-term disability.

MS is classified into four clinical subtypes: relapsing-remitting multiple sclerosis (RRMS); primary-progressive multiple sclerosis (PPMS), secondary-progressive multiple sclerosis (SPMS) and progressive-relapsing multiple sclerosis (PRMS). The RRMS subtype comprises 85% to 90% of MS patients at first presentation, and is characterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery; with lack of progression of disability during the periods between relapses. The relapsing forms of MS are associated with better prognosis than progressive forms of disease.

MS is a notoriously variable disease and natural history studies using comparable survival techniques report longer time to disability milestones. The natural history of MS evolves over 30 to 40 years. The median times to requiring a cane ranged from 15 to 32 years. A secondary progressive phase (SPMS) supervenes in more than 80% of relapsing-remitting patients. Although the probability of survival has increased in MS, life expectancy remains approximately 10 years shorter than the age matched general population.

As there is currently no cure for MS, the goal of therapy is to decrease the number and severity of relapses, reduce MRI burden of disease, limit disability progression, and maintain patient quality of life through the use of disease-modifying therapies.

MS has heterogeneous imaging and clinical manifestations, which differ between patients and change within individual patients over time. There is no single pathognomonic clinical feature or diagnostic test. Diagnosis of MS relies on the integration of clinical, imaging, and laboratory findings. Currently, no laboratory test in isolation confirms the diagnosis of MS. MRI abnormalities associated with other diseases and non-specific MRI findings, which are common in the general population, can be mistaken for MS. The increasingly strong focus on timely diagnosis to alleviate uncertainty for patients and allow initiation of disease-modifying therapy also may increase the risk of misdiagnosis. It will be increasingly important to determine which patients with an initial presentation suggestive of demyelination, referred to as Clinically Isolated Syndrome (CIS), are unlikely to develop MS or to justify the risks of more aggressive disease-modifying therapies.

Interpretation and integration of the history, physical examination, and results of imaging and laboratory testing by a clinician with expertise in MS remain fundamental in making a reliable diagnosis of MS or an alternative diagnosis. To reach a diagnosis of MS a physician must be sure that two criteria are met: there is 1) dissemination in space characterized by inflammation in different regions of CNS, and 2) dissemination in time characterized by recurring inflammation. Both criteria have to be fulfilled either by clinical disease course with relapses and different neurological symptoms or by magnetic resonance imaging (MRI) demonstrating inflammatory lesions in different regions and different activity stages.

The Poser criteria established the framework for diagnosing MS in 1983 (definite or probable or laboratory supported). It disregarded subclinical disease activity and required at least 2 clinical events to diagnose MS. However, since the introduction of McDonald 2001 criteria “asymptomatic attack”, defined as new lesion formation but no new symptoms, also qualifies as a precursor to diagnose MS. MRI has become a powerful tool to bridge the gap between clinical symptoms and silent demyelinating lesions, and has been used for the diagnosis of multiple sclerosis since 2001.Sets of diagnostic criteria that establish dissemination in space as well as in time by MRI are included in the McDonald criteria 2001, which was revised in 2005, 2010 and 2017. Therefore, the new diagnostic criteria have enabled diagnosis of MS earlier and in more patients compared to earlier criteria. The original McDonald 2001 criteria led to a 2-fold to 4-fold increase in diagnosis of definite MS in the first 12 months. The 2001 and 2005 criteria required 2 MRI time points to meet dissemination in time criteria. However, since 2010 modification of the criteria, a single MRI may be sufficient to meet both DIT and DIS criteria.

According to the 2017 McDonald criteria, dissemination in space can be demonstrated by one or more T2-hyperintense lesions (no distinction between symptomatic and asymptomatic MRI lesions is required) that are characteristic of MS in two or more of four areas of the CNS: periventricular, cortical or juxtacortical, and infra-tentorial brain regions, and the spinal cord. Dissemination in time can be demonstrated by the simultaneous presence of gadolinium-enhancing and non-enhancing lesions (no distinction between symptomatic and asymptomatic MRI lesions is required) at any time or by a new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI.

The 2017 McDonald criteria identified a significant number of patients with CIS with MRI evidence of dissemination of time and space in the absence of further clinical events, and the numbers have increased as the criteria have been revised (Table 9).  The incorporation of CSF-specific oligoclonal bands is the major reason explaining improvement of criteria performance.

The revisions in McDonald criteria have also significantly decreased time to diagnosis as shown by Brownlee 2018 in a CIS cohort of 157 patients. The mean time to clinically definite MS using Poser criteria was 23.1 months compared with 12.0, 10.5 and 6.2 months using the 2001, 2005 and 2010 McDonald, respectively. The mean time to diagnosis of MS halved from 12 months with the 2001 criteria to 6.2 months with the 2010 criteria, a time gain of 16.9 months compared with mean time to CDMS.  McNicholas 2019’s retrospective analysis of a cohort of 267 patients with relapsing remitting MS using the 2010 McDonald criteria and with a follow up of 4.6 years, showed the median time to diagnosis with 2010 criteria was 7.4 months as compared to 2.3 months using the 2017 criteria.

Several studies have shown that in a cohort of patients with CIS (N = 1065), retrospective diagnosis of MS using 2017 McDonald criteria compared to 2010 criteria increased diagnosis of MS by 24% to 44% (Table 9). As compared to 2010 criteria, the 2017 McDonald criteria increased sensitivity, decreased specificity, had similar accuracy, decreased positive predictive value, and increased negative predictive value (Table 10). Significantly lower specificity in various cohorts of CIS patients leads to a higher number of MS diagnoses with less active disease course, at least in the first years after onset. As a result, immunotherapy options (disease modifying therapies) that are licensed for MS, but not yet approved for CIS, could be initiated earlier.

It is also important to note that the McDonald criteria were not developed for differential diagnostic purposes but rather to reliably and sensitively identify MS, or a high likelihood of this disease, in a patient with CIS. Discussions need to continue as to whether the benefits of early MS diagnosis outweigh the potential harm resulting from more frequent misdiagnoses. The impact of early exposure to DMT in patients who will be diagnosed with MS using the 2017 McDonald criteria needs to be carefully investigated in prospective studies.

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