PRECISE IDENTIFICATION OF MULTIPLE SCLEROSIS (MS) demands a meticulous examination of its differential diagnosis because numerous conditions can imitate both the clinical symptoms and paraclinical observations of this ailment. In recent decades, our comprehension of neuroimmunology has experienced significant growth, leading to the recognition of various novel disorders that were once misclassified as MS. An effective diagnostic strategy entails a thorough evaluation of the potential alternative diagnoses, particularly in cases involving common location-specific clinical presentations including optic neuritis, myelitis, infratentorial and supratentorial syndromes.1 In this brief review, we discuss the conditions that can resemble MS based on these presentations.
Optic Neuritis
Optic neuritis may be associated with various conditions and is not limited to MS. When suspecting optic neuritis, it is crucial to differentiate it from retinal, ocular, and functional visual issues. Symptoms such as flashing lights could indicate retinal disease, whereas subconjunctival and corneal injection suggest uveitis. Migraines often present with stereotyped visual disturbances, and functional visual loss may manifest as severe vision loss with a tubular field defect and an absence of an afferent pupillary defect.2,3 Optic neuritis related to MS typically occurs in individuals aged 20 to 40 years and presents with subacute onset, painful vision loss exacerbated by eye movement, central scotoma, mildly swollen optic discs, abnormal visual acuity, color vision impairment, and a relative afferent pupillary defect. It responds well to corticosteroid management, with a good recovery.4 MRI of the orbits typically reveals short-segment optic nerve abnormalities.5
Different clinical features may suggest alternative diagnoses. Painless hyperacute visual loss in older individuals may indicate ischemic optic neuropathy, whereas progressive visual loss over an extended period is more common in hereditary or neoplastic optic neuropathies. Aquaporin-4 seropositive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte antibody-associated disease (MOGAD) may lead to bilateral severe visual loss with extensive optic nerve involvement.6
Paraclinical assessments, such as optical coherence tomography (OCT) and visual evoked potentials (VEPs), can aid in differential diagnosis. Severe thinning of the peripapillary retinal nerve fiber layer or ganglion cell–inner plexiform layer on OCT is more indicative of NMOSD or MOGAD than MS.6,7 In ischemic optic neuropathy, superior and inferior involvement or altitudinal thinning is more common, contrasting with the typical temporal quadrant thinning seen in MS. Prolonged VEP P100 latency with preserved amplitude is characteristic of MS, whereas severe amplitude reduction without latency prolongation may suggest NMOSD or noninflammatory optic neuropathies.8
Supratentorial Syndromes
Clinical presentations of MS in supratentorial regions can vary from homonymous visual field impairments to hemisensory motor deficits.9 When these symptoms occur suddenly, it is crucial to consider the possibility of cerebral ischemia rather than demyelination.
Isolated seizures and encephalopathy are atypical for MS and should raise concerns. In such cases, potential diagnoses to consider include vasculitis, cerebral venous sinus thrombosis, autoimmune or infectious encephalitis, MOGAD, primary central nervous system (CNS) neoplasms, cerebral metastases, lymphoma, gliomatosis cerebri, mitochondrial disorder, and posterior reversible encephalopathy syndrome.1 Although MS can lead to cognitive issues,10 it is essential to explore other causes of gradual cognitive decline, such as neurodegenerative disorders (eg, Alzheimer and Parkinson diseases), infections (eg, HIV and progressive multifocal leukoencephalopathy [PML]), vitamin B12 deficiency, and leukodystrophies.1 Persistent headaches or meningismus should also be taken seriously and prompt consideration of alternative diagnoses such as neurosarcoidosis, lupus, vasculitis, migraine, central venous sinus thrombosis, cerebral autosomal dominant arteriopathy with subcortical infarcts, and leukoencephalopathy.1,11
Paraclinically, supratentorial lesions in MS are usually found in the occipital cortex and perirolandic area, and may involve the internal capsule at times.1 Although tumefactive lesions can mimic CNS infections, neoplasms, or metastases, certain MRI features (incomplete rim enhancement, absence of mass effect) can help differentiate them from MS.1,11 Restricted diffusion with an apparent diffusion coefficient pattern in the supratentorial lesions may suggest ischemia, although acute MS lesions can have this feature.12
Infratentorial Syndromes
Infratentorial symptoms of MS encompass hemifacial paresthesias, vision abnormalities (eg, blurred vision, diplopia, and oscillopsia), and coordination issues leading to gait instability. Clinical examinations may reveal internuclear ophthalmoplegia, trigeminal neuralgia, abducens palsy with gaze-evoked nystagmus, and gait or limb ataxia.13
Symptoms atypical for MS may include symptom onset after the age of 50 years, worsening of symptoms over more than 4 weeks, ptosis with fatigable and fluctuating bulbar weakness, gaze palsies (neuromuscular junction disorders), isolated trigeminal neuralgia, intractable hiccups with nausea and vomiting (NMOSD),14 hyper-acute symptom onset (ischemia), severe positional vertigo (otolith displacement), encephalopathy, and fever with meningismus (CNS infections such as meningitis, encephalitis, neurosyphilis, listeriosis, Lyme disease, and Whipple disease). Other differentials to consider include neurosarcoidosis, neuro-Beçhet disease, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, acute disseminated encephalomyelitis, lupus, nutritional deficiencies (eg, vitamin B12 and B1 deficiency), alcoholism, metabolic disorders (eg, central pontine myelinolysis), and malignant tumors, including paraneoplastic rapidly progressive cerebellar syndrome.1
Radiologically, MS lesions affecting the brainstem and cerebellum typically appear as round or ovoid T2 hyperintensities, often observed in the paramedian medulla, cerebellar peduncles, hemispheres, and periventricular area (fourth ventricle). These lesions usually exhibit open ring-like or nodular enhancement on MRI. Any patterns different from this should lead to consideration of alternative diagnoses for MS. For example, lesions in the area postrema are a distinctive feature of NMOSD.14 Large, poorly defined T2-hyperintense brainstem lesions should raise the possibility of MOGAD, PML, and NMOSD,1 whereas symmetric T2 hyperintensities in the pons are commonly associated with metabolic disorders and microvascular ischemic disease.15-17 If contrast enhancement persists for more than 3 months in the cerebellum and brainstem, it could indicate conditions other than MS, such as inflammation, infection, or tumors.15,16,18,19
Myelitis
Acute myelitis associated with MS typically manifests as moderate sensory or motor symptoms, occasionally accompanied by bladder problems, progressing over 4 hours to 3 weeks.20,21 The severity and progression of symptoms are critical in distinguishing between inflammatory and noninflammatory causes. Hyperacute myelopathy occurring within hours may indicate ischemia or trauma, but functional disorders can mimic these symptoms.22,23 The absence of reflexes and flaccid muscle tones suggest peripheral nervous system disorders or infectious acute flaccid myelitis.24
Severe myelitis leading to loss of mobility and neurogenic bladder without recovery is rare in MS and may suggest NMOSD, MOGAD, or infectious or ischemic conditions.21,25 Prolonged worsening beyond 4 weeks raises the possibility of alternative diagnoses such as neoplastic, paraneoplastic, and metabolic causes.20
MRI findings such as lesion length, location, and enhancement patterns can assist in diagnosis. In MS-associated myelitis, lesions are typically short, are located peripherally, and exhibit nodular or ring-like enhancement.
Long lesions or extensive involvement should trigger consideration of other potential diagnoses. On the other hand, the merging of several T2-hyperintense lesions in individuals with MS might give the impression of a longitudinally extensive lesion on sagittal imaging.26 Even though NMOSD and MOGAD are typically linked to long lesions, they can also initially manifest as short lesions, potentially leading to confusion with MS.27,28 Radiographic changes can be informative, with MS lesions persisting and MOGAD lesions tending to resolve.29 Short segments of spinal cord atrophy and severe disability are suggestive of longstanding MS, whereas longer segments may indicate other disorders.30 Conus medullaris involve- ment indicates MOGAD.31
Key Takeaways
Optic Neuritis Evaluation: MS-related optic neuritis demands careful identification through age-specific symptoms, clinical features, and advanced imaging, considering alternatives for accurate diagnosis.
Supratentorial Syndrome Recognition: Rapid-onset supratentorial symptoms require differentiation from cerebral ischemia, emphasizing the need for discernment in distinguishing from typical MS presentations.
Complex Myelitis Assessment: Assessing myelitis severity, progression, and MRI patterns aids in distinguishing MS from alternatives, especially considering prolonged symptoms or unique lesions prompting alternative diagnostic considerations.
Although contrast enhancement on MRI often indicates inflammatory myelitis, it can also occur in other conditions. Particular enhancement patterns, such as dorsal-subpial or persistent enhancements, may suggest neurosarcoidosis.32 If MRI results are inconclusive, evoked potentials can confirm spinal cord issues, and normal evoked potentials in the presence of normal spinal cord imaging should prompt consideration of alternative diagnoses such as functional disorders of the peripheral nervous system.1
Conclusion
Despite advances in the understanding of MS differential diagnosis in recent decades, the precise identification of MS continues to rely significantly on clinical expertise. The process of exploring potential alternative diagnoses for MS demands a careful and comprehensive approach, considering the clinical presentation and remaining vigilant for any concerning indicators, both in clinical and paraclinical evaluations, that might suggest other conditions. In this brief overview, we have touched upon the typical features of MS, red flag signs, and alternative diagnostic considerations. We encourage further reading for in-depth information, which can be found in the recently published article by the Multiple Sclerosis Differential Diagnosis Consortium organized by the Americas Committee for Treatment and Research in Multiple Sclerosis.1
Authors’ note: For figures, we suggest readers see Figures 1, 2, and 3 from reference 1.
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