VANCOUVER (FRONTLINE MEDICAL NEWS) – More than two-thirds of patients with definite or probable misdiagnosis of multiple sclerosis took unnecessary disease-modifying therapy and nearly one-third experienced unnecessary morbidity in a prospective pilot study.

The findings highlight a problem that has been noted before in the medical literature, but since many instances are case reports of unusual cases or were published about 20 or more years ago, they may not reflect the current spectrum of misdiagnosis, Dr. Andrew J. Solomon said at the annual meeting of the American Academy of Neurology.

During a 13-month period, neurologists at four U.S. academic multiple sclerosis centers reported that 51 (46%) of 110 misdiagnosed patients had “definite” misdiagnosis because an alternate diagnosis was identified after assessing clinical, laboratory, and neuroimaging data, while 59 had “probable” misdiagnoses.

Participating neurologists felt that the misdiagnoses were based in part on inappropriately attributing symptoms to demyelinating disease in 65% of cases. MS diagnostic criteria were not rigorously validated for use in patients with atypical presentations, suggesting that the misuse of the criteria could represent a misunderstanding of what constitutes a typical demyelinating attack, said Dr. Solomon of the department of neurological sciences at the University of Vermont, Burlington.

In 48% of cases, the participating neurologists said that objective evidence of a lesion was not used to corroborate historical symptoms.

Many instances also were seen in which the neurologists felt magnetic resonance imaging criteria were misinterpreted or misapplied. In 60%, the MS misdiagnosis relied too heavily on MRI abnormalities to meet the MS diagnostic criteria for dissemination in space when the patient had nonspecific neurologic symptoms, and in another 33% there was an incorrect determination of juxtacortical or periventricular lesion location to fulfill the diagnostic criteria for dissemination in space. Dr. Solomon said that the MRI criteria for MS were not developed to differentiate MS from other conditions, but instead to identify patients at high risk for MS after initial typical presentations of demyelination.

“Overreliance on MRI abnormalities in the setting of atypical symptoms and unverified prior symptoms may be a major cause of misdiagnosis,” he said.

Many earlier patient visits contained red flags that could have led to a correct diagnosis, according to the neurologists who participated in the study. There was evidence for this opportunity being missed in 79 (72%) patients.

“We don’t know how frequent this problem is in practice. I think it’s pretty frequent just based on my own clinical experience, but no one’s done a population-based study, as you can imagine that would be kind of difficult to do,” said Dr. Jonathan Carter, an MS specialist at the Mayo Clinic in Scottsdale, Ariz., who was part of the study.

Study patients were previously diagnosed with MS; none were allowed to have MS as one of several potential diagnoses. Patients were mostly female (85%) and had a mean age of 49 years. They were referred to the Mayo Clinic (55%), the University of Vermont (25%), Washington University (11%), and Oregon Health and Science University (9%). The high highest percentage of misdiagnoses were from physicians with an unknown level of specific training in neurology or (42%), followed by neurologists without MS fellowship training (34%), neurologists with MS fellowship training or a practice focus on MS (24%), and nonneurologists (3%).

It was no surprise to see MS fellowship–trained neurologists among those making misdiagnoses, Dr. Carter said in an interview. “The criteria are somewhat subjective and interpretation of test results are somewhat subjective, then it’s quite possible to have another MS specialist diagnose somebody and then have them come to a different center and have that diagnosis questioned. I think it happens probably less frequently with MS fellowship–trained physicians than with general neurologists, but it still happens.”

All but three patients were informed that their MS diagnosis was incorrect: one who had died and was determined on autopsy to have neuromyelitis optica spectrum disorder, one who had been informed already of a possible alternate diagnosis, and one who had an upcoming follow-up visit.

Many of the patients had a longstanding MS misdiagnosis. A total of 29% had been misdiagnosed for 3-9 years, and 33% for 10 or more years.

The patients received a variety of primary diagnoses following reevaluation at the centers. The most common, accounting for two-thirds of all diagnoses, were migraine alone or in combination with other diagnoses in 24 (22%), fibromyalgia in 16 (15%), nonspecific or nonlocalizing neurological symptoms with abnormal MRI in 13 (12%), conversion or psychogenic disorder in 12 (11%), and neuromyelitis optica spectrum disorder in 7 (6%). Twenty six additional diagnoses were made.

The most common primary diagnoses, except for neuromyelitis spectrum disorder, all share the lack a specific biomarker, Dr. Solomon noted. Most of them require clinical skills and critical thinking to make the diagnosis, he said.

Most (70%) patients had received immunomodulatory treatment for MS, including 36% with more than one disease-modifying therapy. The treatments included natalizumab (Tysabri) in 13%, dimethyl fumarate (Tecfidera) in 6%, and fingolimod (Gilenya) in 5% – all of which have known risk for progressive multifocal leukoencephalopathy – as well as mitoxantrone in two patients and cyclophosphamide in one. Overall, 29% of those who received immunomodulatory therapy used it for 3-9 years, and another 29% used it for 10 or more years.

Dr. Solomon acknowledged selection and referral bias as limitations to the study, as well as possibly incorrect alternate diagnoses. The disease duration and hindshight bias also may have allowed a correct diagnosis to come to light. The study could not provide information on the frequency of misdiagnosis but “provides rationale for such data in the future,” he said.


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