To diagnose or not to diagnose? Timing is the question: balancing early diagnosis of multiple sclerosis with misdiagnosis

KEYWORDS:

• Multiple sclerosis
• misdiagnosis
• early diagnosis
• demyelinating disease
• 2017 McDonald criteria

1. Introduction

Multiple sclerosis (MS) is a neurodegenerative central nervous system (CNS) demyelinating disease with clinical and radiologic heterogeneity in which a pathognomonic biomarker has yet to be uncovered. Consequently, atypical presentations of MS can present a diagnostic challenge, especially in those patients who do not initially fit the classic picture of clinically isolated syndrome (CIS) and/or those who do not fulfill the 2010 McDonald criteria for MS [1,2].

Misdiagnosis can have both negative clinical and financial impacts on the patient and healthcare system [3]. Yet, there is increased pressure to make an earlier accurate diagnosis of MS due to the possibility for early initiation of disease-modifying therapies (DMT) to have improved clinical outcomes, including long-term disability reduction [4]. Finding the balance between making an early accurate diagnosis where timely intervention can commence, while avoiding the potential for misdiagnosis, remains an important topic for continual review.

2. The challenge: reasons for the misdiagnosis of MS

MS remains a clinical diagnosis based on the integration of a history and physical examination that suggests CNS demyelinating disease (i.e. unilateral optic neuritis (ON), internuclear ophthalmoplegia/brain stem syndrome, partial myelitis), in the context of supporting radiologic and cerebrospinal fluid (CSF) analysis when clinically indicated. Diagnosis also requires cautious assessment for red flags that may suggest a mimicking diagnosis [5], many of which require alternative treatments that would be essential for the patient’s overall well-being. This is especially true in scenarios where certain MS medications have proven to worsen disease, such as neuromyelitis optica spectrum disorder (NMOSD) [1,6,7]. Even though imaging techniques continue to improve over time and validated diagnostic criteria for MS exist, misdiagnosis remains problematic [3].

It is important to recall that the McDonald criteria were developed to validate and identify patients with MS or a high likelihood of MS, more specifically in patients who present with a typical CIS. The criteria were not initially designed to differentiate MS from other mimicking conditions and were not thoroughly studied in those with atypical presentations [1,8]. A study by Solomon and colleagues in 2016 reviewed patients diagnosed with MS at four academic institutions and uncovered 110 misdiagnosed patients. The most common misdiagnosis or syndromes mistaken for MS were migraine, fibromyalgia, nonspecific or nonlocalizing neurological symptoms with abnormal magnetic resonance imaging (MRI), conversion/psychogenic disorder, NMOSD, and CIS [3,4]. Seventy percent of theses misdiagnosed patients were treated with a DMT [3], which underlines the potential harmful effects of misdiagnosis.

Thompson and colleagues noted that aside from NMOSD, they found the most frequent reason for misdiagnosis was misinterpretation of nonspecific symptoms, neurological signs, and MRI findings in patients with other common disorders such as migraine [1]. When reviewed, these misdiagnosed patients did not actually meet the 2010 McDonald criteria [1]. Supplementary authors have also reiterated the most common potential pitfalls leading to misdiagnosis include overreliance on the diagnostic criteria or MRI imaging in patients who have atypical presentations [1,8,9].

3. The discussion: the benefits of early diagnosis and considerations to help avoid misdiagnosis

3.1. The benefits of early diagnosis

It is well documented that MS more commonly affects a younger subset of patients (i.e. 20–40 years of age). Moreover, a study by Tremlett and colleagues followed over 2000 patients with relapsing-remitting MS (RRMS) over 2 years to monitor for indicators of relapse. Results showed that relapses were age and time dependent, meaning that relapses were more common in patients with younger age of onset and earlier in the course of their disease [10]. MS relapses are characterized by periods of acute CNS inflammatory activity, in which the accumulating effects often result in clinical disability over time. Hence, the drive for early initiation of DMT in patients diagnosed with MS is valid, given the notions that irreversible CNS damage occurs early on, the early course influences long-term evolution and recovery mechanisms may become less effective later in the disease course.

However, a gray area still exists in patients with CIS who do not yet meet the McDonald criteria for MS. One vantage point argues that CIS patients warrant early initiation of treatment to decrease the onset of clinically definite MS and reduce the potential for disability accumulation over time. This is supported by clinical studies such as PreCISe, which showed that early treatment with glatiramer acetate was efficacious in delaying conversion to clinically definite MS in patients presenting with CIS and brain lesions detected by MRI [11]. The CHAMPIONS and BENFITS CIS studies also support the value of treatment in CIS [12,13]. A different viewpoint is that not all patients with CIS go on to develop clinically definite MS [14,15]. Therefore, subjecting all patients with CIS to DMT could place patients at undue risk given the potential adverse medication effects, in addition to the financial burden to both the patient and the healthcare system that results from these expensive medications [16].

3.2. Considerations to help avoid misdiagnosis

While earlier diagnosis can be beneficial, the push to make an earlier diagnosis can also increase the potential for misdiagnosis. We suggest that considering the following notions can decrease the incidence of misdiagnosis [1]:

• Though it is important to confirm dissemination in space (DIS) and dissemination in time (DIT) by criteria, it is equally important to meticulously assess the supporting clinical data and test results in patients that lack typical CIS. Attentiveness to confounding comorbidities and potential alternative diagnosis is essential.

• In nonconforming cases, there should be a low threshold for supportive data such as CSF examination and/or MRI of the spinal axis. This is supported by numerous studies which confirm that CSF oligoclonal bands (OCBs) and typical MRI changes serve as independent prognostic factors for developing further attacks and disability accumulation in CIS patients [1,17,18]. Consider postponing the diagnosis and initiation of DMT until you accrue additional supporting evidence.

• Exhibit caution in accepting historical events that lack objective evidence to validate the claims.

• Consider NMOSD in all patients being evaluated for MS and include testing for aquaporin-4 antibody and myelin oligodendrocyte glycoprotein antibody when signs and symptoms are suggestive of this diagnosis.

• Diagnosis should be confirmed by additional clinical and radiological follow-up.

Current follow-up brain MRI protocol for patients with CIS and/or suspected MS to look for evidence of DIT include the following [19]:

1. MRI every 6–12 months for high-risk CIS (e.g. ≥2 ovoid lesions on first MRI)

2. MRI every 12–24 months for low-risk CIS (i.e. normal brain MRI findings) and/or uncertain clinical syndrome with suspicion MRI features (e.g. radiographically isolated syndrome)

4. Current developments: the efforts to improve earlier and more accurate diagnosis

In our opinion, the most applicable effort to aid in the diagnostic quandary is the newly published 2017 revisions to the 2010 revised McDonald criteria, by Thompson and colleagues [1]. The 2017 McDonald criteria revisions help to facilitate earlier diagnosis of MS in cases where patients do not meet the 2010 McDonald criteria but MS is felt to be likely, to maintain specificity of the 2010 criteria and to clarify components of the 2010 criteria [1]. Additionally, the revised criteria also offer guidance to help reduce the risk of misdiagnosing MS [1].

The main evidence-based modifications included in the 2017 McDonald criteria for RRMS include the following [1,20]:

• In a patient with typical CIS and fulfillment of clinical or MRI criteria for DIS and no better explanation for the clinical presentation, demonstration of CSF-specific OCBs allows a MS diagnosis to be made.

• Both symptomatic and asymptomatic MRI lesions can be considered in determination of DIS or DIT in patients with supratentorial, infratentorial, or spinal cord syndrome, but not ON. Note that in the 2010 McDonald criteria, the symptomatic lesion in a patient presenting with a brain stem or spinal cord CIS could not be included as MRI evidence of DIS or DIT.

• In addition to juxtacortical lesions, cortical lesions can now be utilized in fulfilling MRI criteria of DIS.

There were not many modifications to McDonald criteria for primary progressive MS, except the removal of the distinction between symptomatic and asymptomatic lesions, and that cortical lesions can be used [1].

Other modifications were considered, but after thorough review were not felt to have sufficient evidence-based support to be added to the criteria. These considerations included the following [1]:

• Should the McDonald criteria include more than one periventricular lesion in the anatomical locations used to assess for DIS?

• Should involvement of the anterior visual system/ON be incorporated into the McDonald criteria?

• What additional concepts can assist in further defining nonclassical presentation such as radiologically isolated syndrome, solitary sclerosis, and possible MS?

These revisions are very beneficial for improving the diagnosis of MS, though further validation of the 2017 McDonald criteria in clinical practice as well as in diverse populations (i.e. regions of Asia, Latin America, the Middle East, and Africa, those with pediatric and late onset disease course, and patients with other comorbidities, etc.) is still warranted. Ultimately, research efforts to uncover distinct serum and imaging biomarkers remain the key to unlocking the enigmatic MS diagnosis. However, it is essential that the clinical aspects of the MS diagnostic criteria remain its foundation.

Declaration of interest

C Dixon has been a consultant for Sanofi Genzyme. D Robertson has been a consultant for Biogen, EMD Serono, Genentech, Genzyme, Novartis, and Teva; has received honoraria or speaker’s fees from Acorda, Biogen, EMD Serono, Genentech, Genzyme, Mallinckrodt, Novaris, and Teva Pharmaceuticals; and has received research grant support from Actelion, Biogen, EMD Serono, Genetech, Genzyme, Mallinckrodt, MedImmune, Novartis, Parexel, Sun Pharma, and TG Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. One peer reviewer was the lead author of the paper which is the subject of the editorial but have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.