Is It MS? New Guidance to Dx Atypical Populations Explained

An international expert panel has developed consensus guidelines to help clinicians navigate multiple sclerosis (MS) diagnosis in atypical populations — specifically children and older adults. Here’s what these new expert recommendations are and what they mean for clinicians.

MS typically develops between the ages of 20 and 40, but 2%-10% of cases appear before age 18, and about 5% after age 50. Diagnosing MS in these atypical age groups can be difficult, as it often mimics other neurologic disorders.

Why Now?

The original guidance on the differential diagnosis of MS was published in 2008. “Since then, our understanding of MS, in particular the underlying biological factors that drive disease processes, has greatly expanded,” first author Le Hua, MD, director of the Neuroimmunology and MS Division, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, told Medscape Medical News.

“We now have better understanding of how biological differences in children under 18 and adults over age 50 influence the clinical presentation of MS. With that, the challenges of making a correct diagnosis have also increased.”

“Thus, it was imperative to update guidance in how to approach the diagnosis of MS and what other disorders need to be considered in these two age populations,” Hua said.

The consensus document was published online on September 16 in JAMA Neurology.

The panel consisted of experts in pediatric and adult neuroimmunology and MS and represented a diverse group in terms of gender, academic rank, geographic region of practice, and clinical focus.

The panel reached consensus through online meetings, a systematic review of relevant studies, and expert opinions.

The scope of work included identifying common clinical presentations, biologic differences, and key diagnostic “red flags” in pediatric-onset MS (POMS), defined as clinical MS onset prior to age 18 years, and late-onset MS (LOMS), defined as onset at or after age 50 years.

“We provide practical approaches to distinguish disorders that most commonly require consideration in the differential diagnosis of MS based on clinical presentation at both ends of the age spectrum,” they noted.

Key Takeaways for POMS

In POMS, “diagnostic dilemmas” may include differentiating MS from monophasic acute disseminated encephalomyelitis and myelin oligodendrocyte glycoprotein antibody-associated disease. These conditions share some clinical and imaging features of MS and most commonly occur in children, the panel noted.

It’s also important to know that POMS is associated with higher inflammatory activity than typical adult-onset MS (AOMS).

“Children have larger and higher proportions of naive T cells and higher B-cell functional capacities, resulting in more robust immune responses to antigens than adults, which may amplify the inflammatory pathology of MS and explain why most POMS cases (> 98%) present with a relapsing-remitting course,” the panel noted.

Patients with POMS tend to experience more active disease, distinguished by frequent relapses followed by good recovery, than those with AOMS.

Progressive MS is “exceedingly rare” in children, said Hua. Therefore, progressive onset in children should lead to careful consideration of alternate diagnoses, including leukodystrophies or mitochondrial disorders, among other metabolic diseases.

Given higher relapse rates and inflammatory disease activity in POMS vs AOMS, timely and accurate diagnosis is important to facilitate early initiation of disease-modifying therapy and to provide appropriate pediatric-specific support, the panel said.

Also, despite the fact that progressive-onset MS is rarely seen in childhood and the transition to the secondary progressive phenotype occurs after a longer interval, patients with POMS still reach ambulatory disability milestones at younger chronological ages than AOMS owing to the earlier onset, they noted.

Key Insights on LOMS

LOMS can include both patients who experience a first inflammatory demyelinating event as well as those who have progressive onset of neurologic symptoms after age 50, the panel noted.

“In adults over age 50, common conditions such as vascular disease, spinal stenosis/compressive myelopathy, and arthritis can present with similar symptoms such as worsening gait and balance or numbness and tingling, and inappropriate diagnoses will lead to delays in care and potentially inappropriate treatment,” said Hua.

“Vascular diseases are also associated with white matter changes on MRI that will increase with age and is a common reason for misdiagnosis in older adults,” Hua cautioned.

Making an accurate diagnosis of LOMS is “extremely important,” as the decision to start disease-modifying therapy in LOMS is complicated by evidence suggesting disease-modifying therapies may be less effective or unnecessary with older age while the risk for adverse effects increases, the panel said.

The consensus document includes four comprehensive tables that highlight potential clinical and paraclinical “red flags” for differential diagnosis of non-MS conditions when POMS and LOMS are suspected.

A Valuable Initiative to Prevent Misdiagnosis

Vito Arena, MD, clinical assistant professor of neurology at New York University (NYU) Langone Multiple Sclerosis Comprehensive Care Center, New York City, said these tables are especially helpful.

“By highlighting both clinical and radiological red flags, clinicians will have these more readily in their thought process and be able to identify them in patients, thus helping prevent misdiagnosis of MS,” said Arena, who was not involved in the consensus initiative.

“It can be easy to mistakenly attribute symptoms or white matter changes on a brain MRI to MS, but being aware of these other factors will help clinicians pause and be more considerate of alternative diagnoses or consider additional testing to refine or clarify the diagnosis,” Arena noted.

Arena said the diagnostic process for suspected MS at NYU starts with taking a thorough history, including presenting symptoms, any previous neurologic symptoms, and other systemic (non-neurologic) symptoms, as well as past medical history, family history, medications, and other exposures.

“All these details help identify historical factors that may contribute to current presentation or imaging findings and identify features that are both typical and atypical,” Arena said.

The neurologic exam, Arena noted, is “critical, and we do a thorough exam to help us localize symptoms to the appropriate part of the nervous system as well as identify other abnormalities that can clue us in. We review labs and imaging including MRIs personally, and we often order additional imaging, blood, or spinal taps to help clarify a diagnosis or evaluate for mimics.”

Arena said suspected MS cases are often presented at neuroradiology conferences, where MS providers and neuroradiologists review cases together.

“Our center has a strong working relationship with colleagues in other specialties such as rheumatology, hematology, neurosurgery, other neurological subspecialties, etc. This allows us to evaluate cases in a multidisciplinary way, especially when we identify a red flag,” Arena said.

This research had no commercial funding. Hua reported personal fees from Genentech, Novartis, EMD Serono, TG Therapeutics, Horizon, Alexion, and Genzyme and grants from Biogen outside the submitted work. Arena had no relevant disclosures.