Updated Diagnostic Criteria for MS an 'Enormous Jump' Forward

Updated diagnostic criteria for multiple sclerosis (MS) in patients with clinically isolated syndrome (CIS) may lead to more, and earlier, MS diagnoses, new research suggests.

Investigators found the updated 2017 McDonald criteria provide higher sensitivity, lower specificity, and about the same degree of diagnostic accuracy as the 2010 iteration.

In addition, researchers note, the new criteria are easier to apply, add cerebrospinal fluid evidence, and expand imaging findings to include asymptomatic and symptomatic lesions.

A clear and early diagnosis helps patients understand the origin of their symptoms, and in that respect, "these criteria are an enormous jump," study author Rogier Q. Hintzen, MD, PhD, a neurologist at the MS Center ErasMS at the Erasmus Medical Center in the Netherlands, told Medscape Medical News.

The study was published online August 6 in JAMA Neurology.

False-Positive Concerns

In 85% of patients, MS starts with CIS, a first clinical episode of central nervous system (CNS) demyelination. A CIS can remain a single event but can also be followed by relapsing disease.

MS is diagnosed based on clinical or MRI evidence of "dissemination in space (DIS) and time (DIT)" — meaning symptoms or lesions need to be seen in different locations and at different times.

Up to now an MS diagnosis can occur when a typical CIS is followed by a new clinical event, or when there are new lesions on T2-weighted images on a follow-up MRI scan.

The investigators note that disease-modifying therapies, which have the potential to delay a second attack and prevent future disability, can be administered early in the disease course. However, they point out, these therapies have adverse effects.

"To select patients for early treatment, it is important to predict accurately who will develop a relapsing disease course and who will not. Accurate diagnostic criteria are therefore essential," the investigators write.

In 2017, new diagnostic criteria were proposed for MS in patients with a typical CIS. The investigators note that the most important addition to these new criteria is they allow an MS diagnosis when the MRI scan meets criteria for DIS and unique oligoclonal bands (OCBs) are present in cerebrospinal fluid (CSF), even in the absence of DIT on MRI.

The other major difference is that not only asymptomatic but also symptomatic lesions can be used to demonstrate DIS and DIT on MRI. Furthermore, cortical lesions can be used to demonstrate DIS.

These revisions, the researchers note, will likely lead to more MS diagnoses at the time of CIS. However, there is a concern that the revised criteria may be accompanied by a higher rate of false-positive diagnosis.

"Therefore," they write, "it is of great importance to apply these criteria to available cohorts of patient s with CIS and validate their accuracy in clinical practice."

In a head-to-head comparison, the investigators examined the new vs old criteria to evaluate the sensitivity, specificity, accuracy, and positive and negative predictive values at 1, 3, and 5 years.

They analyzed data from 229 patients from a prospective CIS cohort study known as Predicting the Outcome of Demyelinating Event (PROUD).

Participants were 18 to 50 years old and were enrolled in the cohort between March 2006 and August 2016.

Patients underwent baseline MRI within 3 months of symptom onset and, if clinically required, underwent a lumbar puncture.

Investigators assessed patients with CIS at baseline and annually thereafter. Follow-up was at least 1 year.

Neurologic examinations confirmed any disease exacerbations. Clinically definitive MS diagnoses were made by using the criteria of Poser et al criteria.

Potential Trade-off

The investigators found the 2017 criteria had 68% sensitivity vs 36% for the 2010 criteria. In addition, specificity was lower with the 2017 criteria, at 61% vs 85%.

Accuracy did not significantly differ between the 2017 and 2010 versions, at 64% and 61%, respectively.

Hintzen cautioned against erroneous interpretation of the lower specificity associated with the 2017 criteria.

"There is a chronic misunderstanding here on specificity. Low specificity does not imply a high number of misdiagnoses in these patient groups," he said. The rates of MS misdiagnosis in other published cohorts of people with CIS are "quite low," he added.

When asked if the trade-off in terms of lower specificity with the 2017 criteria is worthwhile given the greater number of at-risk patients identified, Hintzen said it was "a clear yes."

A total 46 of 180 patients with CIS, or 26%, would be diagnosed with MS at baseline using the 2010 criteria. In contrast, 51 more patients would be diagnosed using the updated criteria, for a total of 97 people or 54%. This difference was statistically significant (P < .001).

A total 113 patients (49%) developed clinically definitive MS during the mean 5.4 years of follow-up. The median time to such a diagnosis was 23.4 months (interquartile range, 10.2 - 45.3 months).

During follow-up, the number of patients fulfilling the criteria but with no second attack was higher for the 2017 version at 46%, compared with 36% using the 2010 criteria (46% vs 36%).

However, the researchers note that more participants were diagnosed with clinically definitive MS after the 5 years of follow-up. This group included six patients who fulfilled the 2017 criteria at baseline and three who fulfilled the 2010 criteria.

"This shows that a longer follow-up will probably lead to a higher PPV [positive predictive value]" for the 2017 criteria, the investigators note.

Survival curve analysis demonstrated that MS diagnoses would be made significantly earlier by using the 2017 criteria compared with the 2010 criteria (P < .001).

The investigators did not exclude the 31% of patients who used a disease-modifying therapy before their clinically definitive MS diagnosis because of the possibility that doing so may introduce selection bias.

They also did not exclude patients who did not have CSF or MRI data available.

"In this way, our findings are more applicable to the general clinical practice," the researchers note. They assessed participants without these measures in subanalyses, and the resulting specificity and sensitivity did not differ from those of the entire cohort.

Need for Real Biomarkers

A potential limitation of the study is that not all patients had spinal cord MRI performed, even though presence of spinal cord lesions is included as a parameter in both the 2010 and 2017 McDonald criteria.

However, they point out that although this procedure is known to increase sensitivity, "it is not common clinical practice to include spinal cord MRI in the routine diagnostic workup when there are no spinal cord symptoms."

In addition, cortical lesions were added as a new parameter to the 2017 criteria for demonstrating disease DIS. However, the researchers did not study any contribution from this factor because "these techniques are hardly available in clinical practice."

The "most important addition" to the 2017 McDonald criteria, the researchers note, is they allow an MS diagnosis when an MRI scan meets the DIS requirement and analysis of the cerebral spinal fluid reveals unique OCBs.

This is the first time these criteria have included CSF evidence of MS. Hintzen said this reflects US physicians acknowledging a practice that is already commonplace in many parts of Europe.

"In Europe we have always appreciated the information obtained by CSF. It has been a mistake not to include CSF information in the criteria during previous rounds," he said.

Reluctance to perform lumbar punctures, combined with research guided by neurologists from research centers focused on imaging studies, could have contributed to absence of CSF indicators in previous McDonald criteria, he added.

"In centers that very much rely on MRI, patients with a first attack may be treated sooner because positive CSF now counts," Hintzen said.

Even though MS still can be diagnosed without CSF findings, based on a definitive MRI and first clinical attack, he recommends that when neurologists do order a lumbar puncture, the CSF sample should be sent to a "good lab" to detect OCBs.

He added that neurologists not shy away from CSF analysis when there is any doubt based on other criteria.

In terms of research implications, the 2017 criteria may increase the number of participants with less active disease in studies. This potential shift in disease severity may lessen the difference between treatment and placebo effects, Hintzen said.

Although MRI has a clear value in MS diagnosis, the technique is not predictive enough. This is despite 30 years of MRI research in MS, he said.

"We need real biomarkers measuring cells and/or molecules within the body, and we need to sort out which patients really need rapid and riskier treatments," he said. Hintzen added that many researchers are in hot pursuit of such a distinction.

The investigators are also validating the new criteria in children with a first attack of suspected demyelination.

"Concerning Limitations"

Commenting on the findings for Medscape Medical News, Ellen M. Mowry, MD, MCR, associate professor of neurology and epidemiology, Johns Hopkins University in Baltimore, Maryland, applauded the investigators for evaluating the "performance of the new diagnostic criteria outside of the population in which they were initially tested."

However, she said, the study had some "concerning limitations."

She noted the cohort size was relatively small and from a single European country, raising concerns about the generalizability of the findings.

She also noted data that are critical to correctly classify patients, including spinal cord imaging, imaging after the administration of gadolinium contrast, and oligoclonal banding, were missing for many patients. These omissions, she said, could potentially lead to misclassification of patients and greatly affect the performance of the criteria.

Mowry said she would like to see the findings replicated in a larger study in which the entire cohort has data available for all 2017 McDonald criteria items.

Evaluating how the criteria perform in other populations, such as those with Asian or African backgrounds, who may be at higher risk for neuroinflammatory disorders that are not MS, is also critical, she said.

The Dutch Multiple Sclerosis Research Foundation supported the study. Hintzen receives honoraria for serving on the advisory boards for Biogenldec, Roche, and Sanofi. He also participated in trials outside the current work for Biogenldec, Merck, Roche, Sanofi, Genzyme, and Novartis. Mowry disclosed that she is a site principal investigator for studies by Biogen and Sun Pharma; is a researcher for investigator-initiated studies funded by Genzyme and Biogen; and receives free medication for a clinical trial from TEVA Pharmaceuticals.

JAMA Neurol. Published online August 6, 2018. Abstract

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