Challenging Cases: Diagnosis of Multiple Sclerosis

In this video, Joseph Berger, MD, FACP, FAAN, FANA, Professor of Neurology, University of Pennsylvania; Associate Director, Multiple Sclerosis Division at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, discusses his recent virtual Neurology Week presentation on Multiple Sclerosis, “Challenging Cases.” Dr. Berger addresses MS mimics and other challenges in the diagnosis of MS.

Read the Transcript:

Dr Berger: I'm Joseph Berger. I'm a Professor of Neurology and Associate Chief of the MS Division at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

With respect to MS mimics and establishing a diagnosis of MS correctly, the most important things to remember are there are a variety of common and uncommon diseases that can masquerade as MS.

It's important to be aware of them, and also, to not be afraid to question yours and other diagnoses when things don't seem to fit together. The importance of detecting these MS mimics early in several-fold. Number one, treating an MS mimic appropriately avoids the morbidity and mortality that occurs in the absence of treatment.

Some of these MS mimics actually have specific treatments addressed to them that are not the treatments we administer for multiple sclerosis. Furthermore, minimizing the overdiagnosis of MS decreases or eliminates the impact, the pernicious impact, on the patient's psyche, their social situation, their employment, their finances, when told that they have multiple sclerosis.

It's also important in avoiding the side effects that occur with the therapies that we administer, avoiding any serious morbidity or mortality associated with some of the disease-modifying therapies we administer, and also avoiding the costs that are incurred by administering these medications, which can cost between $60,000 to $100,000 annually.

Now, why do we make the wrong diagnoses? This has actually been looked at, and there was a Nobel Prize winner, Daniel Kahneman, who with his colleague -- who would have won the Nobel Prize as well, but died in advance of its award -- they were psychologists that were looking at why people do the things they do.

They were really centered as much on economic psychology as anything else, but they've come up with a number of different terms. These have been recapitulated to various extents in a number of publications. There are two publications that I strongly recommend.

One is a book by Jerry Groopman entitled "How Doctors Think," written in 2007. The other is an Annals of Neurology paper on misdiagnosis in neurology, authored by Barbara Vickrey, Allan Ropper, and Marty Samuels, based on a series of cases that they would present at an ANA meeting every year.

One of the things is diagnosis momentum, where you make a diagnosis, even though you have insufficient evidence, and it becomes fixed in your mind. Another is the framing effect, where you're swayed by either subtle wording or subtle findings, and you give it more emphasis than anything else.

That often happens in association with MRIs that look MS-like. You go, "Oh, that looks like MS," and you become imbued with that idea, and you take it forward. There's a confirmation bias, where you dismiss the material that doesn't fit with your diagnostic impression, or a satisfaction search, where you go, "Oh, this is MS." You're satisfied with it, and you don't look any further.

There are others as well, things like blind obedience. I will tell you that blind obedience is where somebody who you respect, somebody who is an authority, is said to have made the diagnosis of MS.

Then you had heard the patient, and you just keep that diagnosis without questioning. I will tell you that I've had, on occasion, seen individuals seen by very, very competent neurologists where the diagnosis of MS was mistaken.

MS remains a clinical diagnosis. Unfortunately, we do not have any single test that would provide us the diagnosis. We now have McDonald criteria that have been revised in 2017 that are enormously helpful in establishing the diagnosis.

These are predicted on clinical attacks, what one finds objectively, the abnormalities seen on MRI. As well as, as of 2017, the use of CSF-specific oligoclonal bands for dissemination in time. Mind you, to feel comfortable with a diagnosis of MS, one would want to see both a dissemination in time and a dissemination in space.

The differential diagnosis of multiple sclerosis is quite broad. You have large categories of disease, inflammatory and autoimmune disease, that may look like it. These include things like neuromyelitis optica, at one time thought to be a form of MS, now known to be totally different.

Acute disseminated encephalomyelitis, a variety of connective tissue diseases, like lupus and Susac's, sarcoidosis, etc. There are a large number of inflammatory and autoimmune disease. There are vascular diseases like a CADASIL and Moyamoya, among others, that can be mistaken, migraine variants.

There are neoplastic disorders that may look, at least at initial presentation, very much like MS. There are infectious diseases. Some, we test for quite routinely in certain areas of the country, such as Lyme disease, which may look like MS.

Mitochondrial disorders, metabolic disorders, mechanical problems, I've seen individuals with cervical spondylotic myelopathy who've been misdiagnosis with MS, or sometimes, the two coexist, and you have to make a distinction.

A variety of miscellaneous disorders that one sees, including drugs and toxins, posterior reversible encephalopathy syndrome, etc. Then psychiatric disorders, conversion disorders, somatization, and malingering, that may be mistaken.

If one looks at the changes in the time to ascertaining MS from first presentation, one finds that there has been a significant decrease in the time it takes to comfortably establish the diagnosis between 1980 and 2004.

That was described in a paper published in Neurology in 2005, where they looked at five-year time intervals and looked at the delay from symptom onset to diagnosis. In individuals in 1980 to 1984, it could take years before one could comfortably feel confident with the diagnosis of MS.

For every five-year interval thereafter, the speed with which the diagnosis is established has improved considerably. Now, at least as of the early 2000s, over 80 percent of the individuals are diagnosed shortly after their initial presentation, within a month or two of their initial presentation.

Misdiagnosis is common, and the current estimates for misdiagnosis of MS are 5 to 10 percent. That is true, even in centers where the individuals seeing the individuals with presumed MS are highly trained, even MS authorities.

If one looks at some of these series, one finds that the rates vary from as low as 8 percent to as high as 35 percent. Alternative diagnoses, the common alternative diagnoses, include such things as psychiatric disease, migraine headaches, ischemic cerebrovascular disease, rheumatologic diseases, and even chronic fatigue.

In pathologic series -- now, this is a bit older, so the pathologic series I'm referring to was done between 1965 and 1986 -- in 518 autopsies done on individuals with presumed clinically definite multiple sclerosis, it turned out that one-third were incorrect. Even at autopsy, the diagnosis may be wrong.

The most common diagnostic error is really an overdiagnosis of MS, and the most common reason for an overdiagnosis of MS is an uncritical reliance on the MRI findings and a hasty workup. I would say, also, not thinking about the potential mimics that may look like it.

I'm very fond of a Dutch proverb that addresses this, which says, "A handful of patients is worth more than a barrelful of brains."

What I mean by that is sometimes, despite your best efforts, despite doing all the studies you need to do, the MRIs, the spinal tap looking for the mimics with the various laboratory tests, etc., at the end of the day, you're uncertain as to whether this is truly MS or not.

Sometimes, you just have to tell the patient about that uncertainty and say, "You know what? We'll repeat your MRIs in six months or a year. Call me if something comes up."

Rather than commit them to a course of therapy that is costly and labeling them with a diagnosis that may be inaccurate, it's sometimes more prudent simply to exercise patience.

John Whitaker, now deceased -- a very famous MS specialist from Alabama -- said, "It takes a good doctor to make the diagnosis of MS. It takes a great doctor to not make the diagnosis of MS."

Trust me, it is an extremely difficult task undiagnosing somebody who has previously been labeled with MS.

I will conclude with a few remarks. There are red flags for appropriately diagnosing MS. There are certain clinical features that may clue you in that it may not be MS. Onset of the disease after the age of 50 or prior to adolescence, particularly relapsing remitting disease in the older patient, should raise a red flag.

That's not to say it doesn't occur, but it should raise a red flag. A family history of a similar disease, although it's not that uncommon for family members to have MS as well. A monophasic course, continual progression, a lack of dissemination in space, so focal symptomatology, gray matter disease, so people with aphasia, dementia, seizures, particularly early in the course of the disease.

Then peripheral complaints, such as multiple neuropathies, or systemic complaints, should raise concern that you're dealing with perhaps something other than MS.

On the MRI, if you see symmetric lesions, if you see peripheral white matter lesions, but no periventricular lesions, if you have very large white matter lesions, or you have gray matter involvement, or you have a normal MRI of brain and spinal cord, or a persistent enhancement or microscopic hemorrhage, these are all some of the features, and there are others, that make it perhaps less likely that it be MS. Not to say that it isn't, but less likely.

Then in terms of laboratory testing, spinal fluid pleocytosis greater than 50, a spinal fluid protein greater than a gram, the absence of oligoclonal bands or elevated IgG, and a significantly elevated segmentation rate or C-reactive protein should raise concerns.

Then there are a variety of dictums. These are my dictums. They come from a paper that I published with a former resident, now on the faculty at the University of Oklahoma and soon to move to Texas.

Uncommon manifestations of common disorders far more common than common manifestations of uncommon conditions. MS is a common disease, so you will see uncommon manifestations of this common disorder. It may be confusing.

Recall that a recent study suggests that 1 in 750 people in the United States has multiple sclerosis. It's important to remain open-minded and question one's diagnosis when there are atypical features of the disease.

I will tell you that there are not-infrequent occurrences where, years after I've seen a patient, I say to myself, "Wait a minute. Did I make this diagnosis correctly?" I'll go back and take a look at everything once again.

Now, sometimes, the answer is in the chart, but sometimes, I may want to do another test or two. Multiple sclerosis can manifest in a wide variety of fashions, but so do its mimickers. MS remains a clinical diagnosis, and therefore, a careful history, an exquisite physical examination, and ancillary studies are fundamental to diagnosis it.

A careful and comprehensive review of systems and a general physical examination are often quite helpful in establishing whether or not mimics exist. Looking for things like fever, skin rash, arthrosis, headache, etc. And, avoid an overreliance on MRI.