SAN DIEGO—"Despite the improved testing for multiple sclerosis, it still ultimately remains a clinical diagnosis and a diagnosis of exclusion," said Jeffrey Alan Cohen, MD. "Although our ability to make the diagnosis has improved over recent years, there still are frequent misdiagnoses—either patients with multiple sclerosis who fail to be diagnosed and conversely people who have other diseases that are misdiagnosed as multiple sclerosis. As we develop effective disease-modifying treatments and as there is increasing impetus to begin treatment at an earlier stage, these diagnostic issues become increasingly important." At the 52nd Annual Meeting of the American Academy of Neurology, Dr. Cohen and Richard A. Rudick, MD, reviewed diagnostic criteria and offered clues to recognizing alternative disorders in some atypical presentations of suspected multiple sclerosis. Drs. Cohen and Rudick are affiliated with the Mellen Center for Multiple Sclerosis Treatment and Research.

Dr. Rudick briefly reviewed the fundamental characteristics of multiple sclerosis, noting that symptoms typically emerge as a series of relapses and remissions. According to Dr. Rudick, evidence of an inflammatory component can typically be detected via magnetic resonance imaging (MRI) or, in some cases, via a cerebrospinal fluid (CSF) tap. Oligoclonal bands, elevated immunoglobulin (IgG) synthesis, free kappa chains, and normal protein and glucose levels were also listed as typical findings in the classic patient scenario.

A CALL FOR IMPROVED CRITERIA

The true dilemma in regard to multiple sclerosis, Dr. Rudick explained, is that the phenotype for the disease extends well beyond this classic course. It is this disparity among multiple sclerosis patients that has led to the development of diagnostic criteria for the disease. The most recent set of criteria was established by a panel of neurologists led by Charles M. Poser, MD, which appeared in 1983 in the Annals of Neurology. According to Dr. Rudick, the criteria focus heavily on spinal fluid and the incorporation of MRI as a diagnostic tool.

"Poser presents a problem in that it is a very complicated set of criteria," remarked Dr. Rudick. "I find it extremely difficult to apply, and I believe others share this opinion. What's more, it is definitely not useful for clinical care in my experience."

Dr. Rudick instead cited the Shumacher criteria, published in 1965, as a more approachable set of criteria for diagnosing multiple sclerosis. He warned colleagues, however, that some assumptions within the criteria have become dated and findings must be supplemented by cranial or spinal MRI.

"I think that over the next few years, based largely on therapeutic results in first-attack cases, we will see a new set of diagnostic criteria emerge for multiple sclerosis," he said. "I think there will be another committee gathered, who will focus on bringing the diagnosis earlier and utilizing the MRI scan more heavily. Whether we will have MRI-only criteria for establishing multiple sclerosis, I'm not sure."

WHAT TESTS ARE APPROPRIATE?

As for tests to verify a diagnosis of multiple sclerosis, Dr. Rudick suggested that physicians develop a course that is appropriate to a patient's specific manifestations. "I think that MRI is always necessary," stated Dr. Rudick. In his practice, he screens patients to verify that they have been tested for antinuclear antibodies (ANA), vitamin B12 deficiency, complete blood cell count (CBC), and sedimentation rate. "I'm basically looking for things that imply a systemic disorder, particularly something that is treated differently than multiple sclerosis. But, as indicated, I'll do serologies for connective tissue disease, for infections—including Lyme, syphilis, HIV, human T-lymphotrophic virus type 1 (HTLV-1)—as well as thyroid function, paraneoplastic diseases, or adrenoleukodystrophy.

"I tailor things," Dr. Rudick continued. "I don't do much on the typical case. But I think you should do what you feel you need to do. I, for example, use CSF to confirm a multiple sclerosis diagnosis and exclude tumor or infection, but there are some patients in whom a tap would add very little to the diagnosis. In some atypical cases—like a progressive case or someone whose onset involves cognitive disorders—I think that a spinal tap is in order."

In conducting a spinal tap, Dr. Rudick explained that clinicians should look for mononuclear pleocytosis, generally with less than 20 cells per µL, virtually always less than 100 µL. In typical cases, a cell count over 100 suggests something other than multiple sclerosis.

He advised colleagues to look for the following in MRIs, adding that combinations of these features strengthen the case for multiple sclerosis.

• Four or more white matter lesions (equal to or greater than 3 mm).
• Three white matter lesions, one of which is periventricular.
• Lesions over 6 mm.
• Ovoid lesions that are perpendicular to the ventricles.
• Lesions in the corpus callosum.
• Brainstem lesions.

CATEGORIZING PATIENTS FACILITATES DIAGNOSIS

Dr. Rudick noted that monophasic syndromes (eg, optic neuritis, acute transverse myelitis, and acute disseminated encephalomyelitis) should be separated from a diagnosis of multiple sclerosis. However, he added that many in the field are reconsidering optic neuritis and acute transverse myelitis as potential markers for the beginning of multiple sclerosis, particularly if brain lesions are present.

Dr. Cohen expanded on Dr. Rudick's discussion of alternative diagnoses, emphasizing that a physician does not necessarily have to consider every other possible disorder in every patient being tested for multiple sclerosis. He stated that, instead, certain inconsistencies—or red flags—that emerge in some cases will indicate the need for further investigation.

Finding alternative causes in patients with classic symptoms and no atypical features was, in Dr. Cohen's experience, "very unusual." For patients in whom multiple sclerosis has already been established, he cautioned colleagues to be vigilant to overlying pathologies that might be contributing to symptoms and to always evaluate the main source of a patient's disability.

"But then there are those patients who suffer from a disorder that is consistent with the broad range of manifestations commonly produced by multiple sclerosis but who exhibit some atypical feature," explained Dr. Cohen. "These patients pose the greatest challenge and demand further evaluation, both to better confirm a diagnosis of multiple sclerosis and to eliminate other possibilities."

WHEN IS MS REALLY NOT MS?

Drs. Rudick and Cohen illustrated the challenges of confirming a multiple sclerosis diagnosis in this third patient category by presenting various case reports. Among them were patients in whom a diagnosis of multiple sclerosis was eventually confirmed, but others were, after further investigation, found to have other diseases.

In one case, a 62-year-old man was referred for neurologic examination to confirm suspected progressive multiple sclerosis. His symptoms over the prior two to three years included urinary incontinence, poor memory, an ataxic gait, trouble swallowing, a left facial droop and slurred speech, and a burning sensation in his left foot and leg. Dr. Rudick described atypical MRI features and normal CSF results, which he deemed inconsistent with the patient's age and the advanced progression of symptoms. Brain biopsy and a cerebral angiogram eventually brought a diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

In another case, a 29-year-old woman had a history of relapsing symptoms consistent with multiple sclerosis as well as MRI scans demonstrating multiple lesions. The lesion enhancement pattern for T1 images was particularly atypical for multiple sclerosis, however, and the patient was noted to have persistent leukopenia. After undergoing a right temporal tip biopsy, the patient was shown to have a primitive T-cell lymphoma of the CNS, showing a predominantly perivascular location.

Sarcoidosis was yet another diagnosis uncovered after further investigation in the case of a 27-year-old black woman with a history of hand numbness and a persistent enhancing lesion in the cervical cord. An atypical cranial MRI was, according to Dr. Rudick, again the red flag that suggested another cause.

KEEP AN EYE OUT FOR FLAGS

To help recognize patients like those described, Dr. Cohen offered a list of features that can occur in multiple sclerosis but should be considered red flags in cases in which a multiple sclerosis diagnosis seems questionable.

• Disease onset outside of the 20- to 40-year age range.
• A very strong family history of some other disorder that could mimic multiple sclerosis.
• A progressive course at onset, especially in patients who do not fit the characteristic composite for primary progressive multiple sclerosis.
• Particularly sudden onsets (raising the possibility of a vascular process).
• Unifocal manifestations (even if manifestation is relapsing).
• Atypical symptoms (eg, headache, hearing loss).
• Prominent systemic features (eg, rheumatic features, weight loss, fever, etc).
• Long-standing neurologic disease in the absence of other typical manifestations (sensory, optic, or bladder problems).
• No MRI lesions (especially with other normal findings on examination, CSF analysis, evoked potentials, etc).
• Unusual response to treatment (no or very dramatic response to steroids).

In Dr. Rudick's opinion, atypical MRI features in combination with an otherwise consistent pattern of multiple sclerosis manifestations is a more troubling scenario than is one involving atypical clinical features in the presence of a classic multiple sclerosis MRI scan.

EXCLUDE THE "BETTER EXPLANATIONS"

"Diagnosis by a neurologist in the absence of any better explanation" was cited by Dr. Rudick as a basic but very important tenet in establishing a diagnosis of multiple sclerosis. He explained that while many patients meet the criteria for multiple sclerosis, a better explanation exists for their symptoms.

"I believe that MRI is always necessary," Dr. Rudick maintained. "There is an increasing perception [among multiple sclerosis experts] that the disease could be heavily subclinical in the early stages, even for years. So patients with subtle neurologic symptoms, like paresthesias, who have typical MRI scans, might very well have multiple sclerosis."

Dr. Cohen agreed, stating that a cranial MRI scan is a necessary component in evaluating patients for multiple sclerosis. He further recommended the administration of gadolinium for those patients whose scans show T2 lesions, noting that there is a small chance that some gray matter lesions not seen on a T2 image might enhance with gadolinium.

"More importantly, the extent of enhancement gives one a sense of how active the disease is," stated Dr. Cohen. "This may have some implications in terms of treatment decisions. Furthermore, one of the important red flags, at least in my experience, is that the pattern of enhancement [after gadolinium] might not look like multiple sclerosis, whereas lesions on a T2 scan might appear compatible."

Both doctors agreed that being vigilant for atypical manifestations and selecting an appropriate and comprehensive course of tests to exclude all "better explanations" remains a crucial to establishing an accurate diagnosis.

—Cheryl Salerno

Suggested Reading
Cohen JA, Rensel MR. The differential diagnosis and clues to misdiagnosis. In: Burks JS, Johnson KP, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York: Demos Vermande, 2000:127-140.
Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis; guidelines for research protocol. Ann Neurol. 1983;13:227-231.
Rudick RA. Disease-modifying drugs for relapsing-remitting multiple sclerosis and future directions for multiple sclerosis therapeutics. Arch Neurol. 1999; 56:1079-1084.

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