The Case for Including Optic Nerve Lesions in MS Dx Criteria The Case for Including Optic Nerve Lesions in MS Dx Criteria

The McDonald criteria for diagnosing multiple sclerosis (MS) has been around since 2001, with revisions in 2005, 2010, and 2017. They focus on lesions disseminated in space (DIS) and disseminated in time (DIT). As with any diagnostic, new science and methods inform changes. Although optic nerve lesions (ONL) have been considered in past revisions, they have yet to be adopted as a key diagnostic measure of MS.

At the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), several speakers made the case for the addition of ONL to the next McDonald revision. Arguments ranged from the inherent injustice that patients with a diagnosis of optic lesions should have to meet three symptoms of MS to get a diagnosis, while other patients require only two, to the possibility that early presentation with ocular symptoms could be an indicator of a more severe prognosis.

Still, many conditions can mimic the symptoms of ONL, so it is critical to be sure of the diagnosis before considering it a symptom of MS. For example, central serious maculopathy in young to middle-aged patients is often painless and could lead to an inadvertent MS diagnosis if it were added to the criteria. However, treatment with steroids can make it worse, according to Laura Balcer, MD, who spoke at the session. Balcer is a neuro-ophthalmologist at NYU Langone Health.

Adding ONL to McDonald

In the first talk of the session, Frederik Barkhof, MD, PhD, discussed some of the history of the McDonald criteria and laid a groundwork for why it should be updated. He began by pointing out that the latest criteria require either symptomatic or asymptomatic MRI lesions to determine DIS or DIT.

Barkhof has led the Magnetic Imaging in Multiple Sclerosis (MAGNIMS) group, which had some doubts about the 2017 revision to the McDonald criteria. “We discussed this and said, ‘Well, that is interesting. So you can have a brainstem lesion, which can be the symptomatic lesion and then you need one further region, so you have two regions, and then you have MS. But now if you have an optic nerve presentation, and you can find the optic nerve, it doesn’t count, and then you need two more regions. So there’s a bit of an imbalance. Why would you need three regions if you have an optic nerve, and only two if you have a spinal cord or a brainstem presentation?” recalled Barkhof, professor of radiology and neuroscience at Vrije Universiteit Amsterdam.

Identifying optic nerve lesions requires a good MRI that should use fat-saturation techniques.

Barkhof pointed out that the ONLs are a common presentation among MS patients. “We’re now preparing for the next revisions of the McDonnell criteria, and I’m confident and hopeful that we’ll make it this time,” said Barkhof.

Confirm the MS Diagnosis

In the second talk, Angela Vidal-Jordana, MD, PhD, discussed ways to implement ONLs in the clinic. She emphasized the importance of ruling out other causes. “Even when a patient comes to us with a diagnosis of optic neuritis, we should question that. Different studies have shown that the optic neuritis overdiagnosis rate at referral might be as high as 60% of the cases,” said Vidal-Jordana, a neurologist at Centre d’Esclerosi Multiple de Catalunya in Barcelona. Studies show that about half of those are due to misinterpretation of the clinical history and examination, she said.

“So when presenting new visual symptoms, we should ask whether this is suggestive of an inflammatory etiology or not, and whether they are typical for MS or not. If both answers to these questions are yes, then we should apply the diagnostic criteria,” said Vidal-Jordana.

She presented results from a longitudinal, prospective study conducted within the MAGNIMS network supporting the inclusion of ONL into DIS criteria for MS. It included use of optic nerve MRI, OCT, and VEP [visual evoked potential]. “All of the modified DIS criteria, that is including one of the tests at each time, or a combination of them, led to a higher sensitivity of the diagnostic criteria (when optic nerve involvement was included), albeit with a small decrease in specificity which mainly was due to the fact that we only had 3 years of follow-up. The same held true when analyzing the secondary outcome of new T2 lesions or second relapse during the follow up,” said Vidal-Jordana.

“As a summary, I would say for sure we will need first of all an MRI, and we need to know if we can evaluate the optic nerve by MRI or not. If not, and we still do not have a diagnosis of a MS, maybe we can order VEP or OCT and then the test selection should be based on the time elapsed since first CIS [clinically isolated syndrome]. If it’s less than 3 months, I would go for a VEP. If it’s more than 3 months, then I probably want to go for OCT,” said Vidal-Jordana.

An Aid to Earlier Diagnosis

In the last talk, Balcer discussed non-MRI methods for assessing ONLs. She noted that in about 25% of MS patients, ONLs are the first clinical demyelinating event. “Adding the optic nerve to the MS diagnostic criteria will allow us to diagnose our patients even earlier, [it] may help their vision and could also help us to reduce the overall burden of MS disability over a lifetime. Importantly, entry into MS diagnosis can be delayed among patients for whom optic neuritis or even asymptomatic optic nerve lesions are noted at presentation, and there has been an enormous amount of data that have emerged over the past 5 years demonstrating the importance of the optic nerve in the MS diagnosis with implications for early therapy,” said Balcer.

She discussed optical coherence tomography (OCT), which is a key technique for diagnosing optic neuropathy. It measures the thickness of the retinal nerve fiber and ganglion cell layers, which have been associated with vision impairment and can reveal asymptomatic involvement of optic nerves in MS.

Beware of Misdiagnosis

In the Q&A period following the talks, much of the discussion turned to reliability of ONL diagnoses.

“Misdiagnosis is a huge problem. That’s my experience: People who are referred to me with optic neuritis often don’t have optic neuritis,” said comoderator Wallace Brownlee, MBChB, PhD, a consultant neurologist at Cleveland Clinic London. Misha Pless, MD, spoke up from the audience to second that. “I’m delighted that the optic nerve will finally get a place at the table. I’ve been practicing neuro-ophthalmology and I have also [been] an MS doctor for about 25 years. What I see here in this fantastic discussion is that a lot of neurologists are going to be — I hate to use the word ‘misled’ — into relying on technology like OCT, VEP, and MRI to make the diagnosis. I will submit to this panel that that will lead to a number of MS misdiagnoses because I have been doing this for 25 years and the number of patients that I’ve received with rule-out optic neuritis that had macular disease, optical changes, or corneal abrasions are too numerous to count. If you’re going to add optic neuritis in the list of criteria [for MS], you definitely have to have a little asterisk in my opinion and say, ‘with prior blessing from an ophthalmologist to rule out ocular disease,’ because I don’t know any neurologist that knows how to look in the back of the eye, and I don’t know any neurologist that has an OCT in their office,” said Pless, professor of ophthalmology and a neurologist at Mayo Clinic in Jacksonville, Fla.

The panelists generally agreed with his point, although the hot mic picked up when one panelist whispered to another, ‘I have one,’ referring to an office OCT. “Using OCT in that regard, but also collaborating with your neuro-ophthalmologist and ophthalmologist is critical,” said Balcer.

Barkhof has financial relationships with Biogen, Merck, Roche, EISAI, Prothena, IXICO, Jansen, Combinostics, Novartis, GE, Queen Square, and Analytics. Vidal-Jordana has financial relationships with Roche, Novartis, Merck, and Sanofi. Balcer has no relevant financial disclosures. Brownlee has financial relationships with Biogen, Celgene, Merck, Mylan, Novartis, Roche, and Sanofi.

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