When Multiple Sclerosis Is Suspected in Patients Under 18 or Over 50

Approximately 85% of cases of multiple sclerosis (MS) initially present in patients between 18 and 50 years old. Guidelines for diagnosis and management have been designed primarily for this typical age range, and little has been published specifically on patients who fall outside it.

To address this gap, the Americas Committee for Treatment and Research in MS (ACTRIMS) spearheaded a group to provide guidance on diagnosing suspected MS in pediatric patients (about 2%-10% of cases, mostly in those older than 10) and in individuals older than 50 (about 5% of cases at time of presentation).

The international committee — consisting of 19 members from North America, Europe and South America — was led by Le Hua, MD, Director of the MS Program at Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. A comprehensive review of the committee’s findings was recently published in JAMA Neurology.

In the following Q&A, Dr. Hua discusses the importance of this topic and highlights takeaways from the committee’s findings.

Q: Why is specific guidance needed for diagnosing MS in pediatric and older populations?

Dr. Hua: Until now, we have approached these patients as typical adults. But neither end of the age spectrum fits that model well. Differences in underlying immunologic and hormonal physiology are prominent, and comorbidities must be taken into account, particularly in the late-onset group. There is still much to understand about how these populations are different, and this is an important focus of research.

It’s critical to diagnose MS accurately for individuals of all ages, but this is especially true for these groups. For children, delaying an MS diagnosis can lead to missing the chance to address the disease early with disease-modifying therapies (DMTs) to help postpone disability progression from overt inflammatory activity. For older patients, adverse side effects of MS drugs may tip the balance over benefits even if the diagnosis is accurate, so it’s particularly important not to prescribe them inappropriately, especially as DMTs have not been shown to be efficacious in nonrelapsing progression.

Helping clinicians in the community establish an accurate diagnosis drove the efforts of our committee. The article and its accompanying supplemental materials provide detailed figures and tables on frequently encountered MS mimics in the pediatric and late-onset populations, as well as on clinical and imaging features that are red flags suggesting an alternative diagnosis.

Q: What are some key points specific to the pediatric population?

Dr. Hua: Children tend to have high immunological reactivity. This manifests in how MS presents and by the fact that other rare immunological conditions arise in childhood that can mimic MS. There is increasing recognition of, and improved testing for, other acquired demyelinating syndromes that present in the pediatric population, such as acute disseminated encephalomyelitis (ADEM), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), neuromyelitis optica spectrum disorder (NMOSD) and hemophagocytic lymphohistiocytosis.

Clinical features of MS in childhood often differ from those in adults. I tell my colleagues that if a child presents with what appears to be a progressive MS course, look hard for an alternative diagnosis. Childhood tends to be a time of high inflammation in MS, not disease progression.

Because inflammatory activity is so high in children, it’s important to establish a diagnosis of MS promptly if it is present so that immunomodulatory therapies can be started. While children with MS tend to have a longer time before reaching disability compared to their counterparts with adult-onset MS, they are still likely to reach disability milestones at earlier ages, and we’d like to prevent that. That said, it is daunting to start children on potent DMTs, knowing that they may potentially face four decades or more of their use. The advisability of staying on these drugs for so long is an important area in need of more research.

Q: What should clinicians know about suspected MS in older people?

Dr. Hua: For a late-onset presentation, it’s critical not to miss conditions that are more prevalent in older populations that can mimic MS. Vascular disease, spinal stenosis/compressive myelopathy and arthritis can cause progressive cognitive or mobility issues that resemble MS. For acute presentations, timing of symptom onset can be a helpful guide; for instance, manifestations of stroke tend to come on suddenly, while those of late-onset MS typically develop over hours to days. Polypharmacy is another consideration, as certain medications may cause fatigue, cognitive impairment, dizziness and falls.

Unlike in the pediatric population, older age is a time of reduced inflammatory activity, especially in women after estrogen levels drop with menopause. MS relapses triggered by inflammation are fewer, but disability progression tends to accelerate. Because DMTs primarily target inflammation, their benefits in older people are less clear.

MRI provides important clues to the correct diagnosis. Because inflammatory activity is usually low, white matter changes are more likely due to vascular disease or migraines. The appearance and anatomical location of lesions can help discriminate demyelination from chronic vascular abnormalities.

For all age groups, MS lesions on MRI tend to be periventricular, ovoid and often have a central vein sign, a specific biomarker for MS. Another biomarker, identifiable on susceptibility-based MRI sequences, is the paramagnetic rim lesion.

Q: What should we be looking for next in the area of MS diagnosis?

Dr. Hua: We’re all awaiting the new revision of the McDonald diagnostic criteria, to be unveiled at the ECTRIMS meeting in September, shortly after the publication of our review in JAMA Neurology. In the near future, watch for reports from other ACTRIMS committees focused on geographic and racial/ethnic considerations in MS differential diagnosis.

On the horizon, we can expect to see validation of biomarkers in imaging, cerebrospinal fluid and even blood. These promise to be of enormous help for diagnosis and treatment monitoring.