Guidelines for Differentiating Diagnosis of Suspected Multiple Sclerosis Updated

Jeffrey A. Cohen, MD

Recently, the International Advisory Committee on Clinical Trials in Multiple Sclerosis published an update to its 2008 guidelines on diagnosing suspected multiple sclerosis (MS), providing additional clarity on the key clinical and paraclinical red flags clinicians should be aware of.

Led by senior investigator Jeffrey A. Cohen, MD, director of Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research, the updated guidelines describe approaches to the evaluation of common MS presentations, as well as clinical and paraclinical indicators of alternative diagnoses. Although the availability of aquaporin-4-immunoglobulin (AQP4-IgG) and MOG-IgG testing has improved the ability to diagnosis AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte-associated disease (MOGAD) and differentiate them from MS, comparable diagnostic biomarkers for MS remain a major unmet, the study authors noted.

In the clinical considerations for optic neuritis, a condition associated in the early stages of MS, the authors noted that several disorders frequently mistake for optic neuritis do not involve the optic nerve. Key clinical findings supportive an optic nerve lesion include unilateral central scotoma with abnormal visual acuity, relative to afferent pupillary defect, and impaired color vision. The absence of these findings and the presence of other clinical red flags may suggest an alternative localization, and the need for an ophthalmological evaluation.

Cohen et al added that severe visual loss, bilateral simultaneous or rapidly bilateral sequential visual loss, severe optic disc oedema, or severe retro orbital pain, are all infrequent with MS-associated optic neuritis and should prompt consideration of AQP4-IgG-positive NMOSD, MOGAD, infection, genetic disorder such as Leber’s hereditary optic neuropathy, or toxic or nutritional optic neuropathies. Patients older than 50 years old are more likely to present with arteritic and non-arteritic ischemic optic neuropathy than with MS. In terms of paraclinical considerations, the authors noted that using optical coherence tomography and visual evoked potentials can further guide differential diagnosis considerations.

In the paper, the authors highlighted clinical considerations for symptoms typical of MS attack localized to the brainstem or cerebellum. These included diplopia, oscillopsia, unilateral facial numbness with or without pain, incoordination, and gait instability. Internuclear ophthalmoparasesis, sixth nerve palsy, gaze-evoked nystagmus, ocular ataxia, and limb or gait ataxia, may all be found in corresponding neurological examinations.

Key findings suggestive of alternative diagnosis, noted in the piece, included complete gaze palsy, bilateral or multiple cranial nerve involvement, and intractable nausea, vomiting, or hiccups (area postrema syndrome). Hearing loss and paroxysmal dysarthria with ataxia can occur in MS but are rare presentations and should prompt consideration of other neurological disorders. MRI findings are critical for distinguishing patients who present with brainstem and cerebellar syndromes. While MS lesions most frequently are located at the surface of the brainstem or the fourth ventricle, other locations, morphologies, and enhancement patterns of MRI lesions may suggest diagnoses other than MS.

For suspected myelitis, clinical features consistent with myelopathy include numbness in extremities/trunk, weakness in extremities, hyperreflexia, spasticity, extensor platar response, bowel, bladder, or sexual dysfunction, and Lhermitte’s phenomenon. Severe acute myelitis associated with loss of ambulation and neurologic bladder require catheterization without recovery is uncommon in MS and suggests APQ4-IgG-positive NMOSD, MOGAD, or an infectious or ischemic disorder. A worsening of acute-onset myelitis beyond 4 weeks is atypical for MS and should prompt consideration of alternative inflammatory, neoplastic or paraneoplastic, metabolic, vascular, and structural diagnoses.

Although MS rarely presents with a supratentorial syndrome, an initial approach to differential diagnosis should be broad and include evaluation for additional clinical characteristics typical of MS, such as evidence of previous attacks suggestive of optic neuritis, myelitis, or common brainstem or cerebellar syndromes. "Although they indicate involvement of supratentorial regions, predominant subacute cognitive changes, encephalopathy, or seizures in isolation from other symptoms or neurological findings are atypical for multiple sclerosis and should prompt consideration of alternative diagnoses," Cohen et al wrote.

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While most patients initially present with clinically isolated syndrome and a subsequent relapsing-remitting course, there are a group of patients with progressive MS with a previous relapsing course that was not recognized. For these patients, clinical considerations stated that progression usually manifests as asymmetric myelopathy or, less commonly, as predominant ataxia or cognitive impairment, alone or in combination. A longitudinal assessment of 12 months or longer is required for a diagnosis or primary progressive MS by diagnostic criteria.

MRI findings can often aid the diagnosis of patients with progressive neurological deficits mimicking MS. The study investigators noted that, "Progressive myelopathy in the setting of T2-hyperintense spinal cord lesions that are longitudinally extensive, transverse (spanning the entire spinal cord), or central should prompt a broad consideration of diagnoses other than multiple sclerosis. Absence of T2-hyperintense MRI spinal cord lesions in patients with progressive myelopathy is exceptionally atypical for multiple sclerosis, and suggests stiff person syndrome, HIV, amyotrophic or primary lateral sclerosis, hereditary spastic paraparesis, adrenomyeloneuropathy, or functional neurological disorder."

When discussing considerations in specific patient populations, it was noted that race, ethnicity, and genetic ancestry can influence potential risk of MS. Furthermore, some racial and ethnic groups appear to be at increased risk for specific disorders than can mimic MS. For example, a higher prevalence of AQP4-IgG-positive NMOSD has been seen in east Asian and Black populations than in White populations, as well as a higher prevalence of neurosarcoidosis in Black individuals than White.

In its conclusion, Cohen et al concluded that novel MRI findings—central vein sign and paramagnetic rim lesions—have potential to improve rapid diagnosis in patients with typical MS presentations and in those with challenging clinical or radiographic presentations. "In coming years, data from large prospective multicenter cohorts of patients undergoing evaluation for suspected multiple sclerosis will be necessary to confirm the promise of putative biomarkers to complement clinical approaches to ensure that there is no better explanation other than multiple sclerosis," they wrote.

REFERENCE
1. Solomon AJ, Arrambide G, Brownlee WJ, et al. Differential diagnosis of suspected multiple sclerosis: an updated consensus approach. Lancet Neurol. 2023;22(8):750-768. doi:10.1016/S1474-4422(23)00148-5