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The Role of Differential Diagnosis in Multiple Sclerosis

diagnosis of MS requires a diligent look at its differential diagnosis as many conditions can mimic the clinical presentation and paraclinical findings of this disease.

Updated Differential Diagnosis Recommendations

An international consortium led by the Americas Committee for Treatment and Research in MS (ACTRIMS) has published detailed updated recommendations for how to distinguish suspected MS from other look-alike disorders. This critical guidance aims to reduce the time spent to confirm an accurate diagnosis of MS by reviewing specific clinical, MRI and laboratory findings that are typically associated with MS versus atypical features for MS-associated presentation and, therefore, suggestive of a look-alike disorder.The paper also provides new guidance for how to consider race, ethnicity and genetic ancestry in the differential diagnosis of MS." c-nmssatomrichtext_nmssatomrichtext-host="">

Accurately diagnosing multiple sclerosis can be a challenge. Misdiagnosis can be costly to the patient — medically, psychologically and financially. For people living with MS, an accurate, early diagnosis can lead to appropriate treatment early in the disease course, which can ultimately influence a person’s journey. An accurate diagnosis of MS requires a diligent look at its differential diagnosis as many conditions can mimic the clinical presentation and paraclinical findings of this disease.

Updated Differential Diagnosis Recommendations

diagnosis of MS requires a diligent look at its differential diagnosis as many conditions can mimic the clinical presentation and paraclinical findings of this disease.

Updated Differential Diagnosis Recommendations

Findings That Are Typical Features of MS

Overview of inflammatory optic neuritis
Painful loss of vision, worse with eye movements
Subacute onset developing over hours or days
Abnormal visual acuity
Dyschromatopsia
Relative afferent pupillary defect
Typical features of optic neuritis associated with MSClinical features:
Unilateral
Mild to moderate visual loss
Central scotoma
Normal or mildly swollen optic disc
Responsive to corticosteroids with good recovery
MRI:
Short-segment optic nerve T2 hyperintensity with or without gadolinium enhancement
Asymptomatic T2-hyperintense ovoid well demarcated brain or spinal cord lesions typical of multiple sclerosis
Visual evoked potential:
Prolonged P100 latency with only mild to moderate amplitude reduction
Optical coherence tomography:
Optic nerve head elevation and pRNFL thickening acutely
Subacute ganglion cell-inner plexiform layer thinning and temporal quadrant predominant pRNFL thinning
CSF:
Positive oligoclonal bands
Elevated IgG index (>0·7)
Leukocytes (0–50/μL)
Protein concentrations normal or <100 mg/dL
Typical features for MS-associated presentationClinical:
Young adult
Internuclear ophthalmoplegia
Sixth nerve palsy
Gaze-evoked nystagmus
Hypometric or hypermetric saccades
Unilateral facial numbness
Trigeminal neuralgia
Gait or limb ataxia
MRI:
Round or ovoid T2-hyperintense lesions in the brainstem, involving the subpial surface or proximal to fourth ventricle
Round or ovoid T2-hyperintense lesions in cerebellar peduncles or cerebellar hemispheres
Involvement of trigeminal tract or nerve (with or without enhancement)
Asymptomatic T2-hyperintense brain or spinal cord ovoid or short segment lesions
Contrast enhancement: nodular or open-ring (peripheral, abutting ventricles or grey matter), with corresponding abnormality on T2 or T2-FLAIR images
CSF:
Positive oligoclonal bands
Elevated IgG index (>0·7)
Leukocytes (0–50/μL)
Protein concentrations normal or <100 mg/dL
Overview of suspected myelitis: Consistent features associated with myelopathy
Numbness in extremities, trunk (sensory level)
Weakness in extremities
Hyperreflexia, spasticity, extensor plantar response
Bowel, bladder, or sexual dysfunction
Lhermitte’s phenomenon
Time from symptom onset to nadir: between approximately 4-5 hours and 2-3 weeks
Typical features for MS-associated myelitisClinical:
Young adult
Sensory predominant
Mild motor deficit, asymmetric
Urinary urgency or incomplete emptying
Spinal MRI:
Single or multiple short segment T2- hyperintense lesions reaching the spinal core surface: asymmetric dorsal or lateral column
More frequent involvement of cervical segments than thoracic segments
Enhancement: focal with or without ring; transient (<3 months)
Head MRI:
Typical multiple sclerosis T2 lesions in infratentorial, juxtacortical, periventricular locations
Well demarcated
CSF:
Positive oligoclonal bands
Elevated IgG index (>0·7)
Leukocytes (0–50/μL)
Protein concentrations normal or <100 mg/dL
Progressive neurological disorders of >1 Year: Typical features for MSClinical:Myelopathy
Asymmetric weakness
Motor and sensor involvement
Autonomic symptoms (e.g., bladder dysfunction)
Ataxia
Asymmetric involvement
Cerebellar dysmetria or dysdiadochokinesis
Sensory predominant ataxia
Accompanying sensory and motor deficits
Accompanying oculomotor impairment or dysarthria
Cognitive impairment
Impairment in processing speed, sustained attention, working memory, episodic memory, executive function, verbal fluency, and visuospatial function
Accompanying myelopathy or ataxia
MRI:
Short segment, partial and lateral or dorsal column MRI spinal cord lesions
Focal spinal cord atrophy corresponding to T2-hyperintense lesions
T2 hyperintense cerebellar and cerebral peduncle lesions
Brain lesions fulfilling McDonald criteria MRI dissemination in space
CSF:
Positive oligoclonal bands
Elevated IgG index (>0·7)
Leukocytes (0–50/μL)
Protein concentrations normal or <100 mg/dL

“Differential diagnosis of suspected multiple sclerosis: an updated consensus approach” by Andrew J Solomon, Georgina Arrambide, Wallace J Brownlee, Eoin P Flanagan, Maria Pia Amato, Lilyana Amezcua, Brenda L Banwell, Frederik Barkhof, John R Corboy, Jorge Correale, Kazuo Fujihara, Jennifer Graves, Mary Pat Harnegie, Bernhard Hemmer, Jeannette Lechner-Scott, Ruth Ann Marrie, Scott D Newsome, Maria A Rocca, Walter Royal III, Emmanuelle L Waubant, Bassem Yamout, and Jeffrey A Cohen is published in Lancet Neurology (2023;22:750-68). This paper is available free of charge with registration on the journal website.For information on the more common look-alike disorders, see Neuroinflammatory Disorders.

Further Research on Biomarkers To Help Diagnose MS

Ultimately, having biomarkers that can better distinguish MS from other disorders would be ideal. This would speed up diagnosis and allow those with MS to receive treatment as early as possible. Investigators around the world are working to find these biomarkers." c-nmssatomrichtext_nmssatomrichtext-host="">

For a comprehensive list of alternative diagnoses to consider based on presenting features suggestive of a look-alike disorder, please reference the tables and charts in this paper:“Differential diagnosis of suspected multiple sclerosis: an updated consensus approach” by Andrew J Solomon, Georgina Arrambide, Wallace J Brownlee, Eoin P Flanagan, Maria Pia Amato, Lilyana Amezcua, Brenda L Banwell, Frederik Barkhof, John R Corboy, Jorge Correale, Kazuo Fujihara, Jennifer Graves, Mary Pat Harnegie, Bernhard Hemmer, Jeannette Lechner-Scott, Ruth Ann Marrie, Scott D Newsome, Maria A Rocca, Walter Royal III, Emmanuelle L Waubant, Bassem Yamout, and Jeffrey A Cohen is published in Lancet Neurology (2023;22:750-68). This paper is available free of charge with registration on the journal website.For information on the more common look-alike disorders, see Neuroinflammatory Disorders.

Differential Diagnosis of Multiple Sclerosis

The Role of Differential Diagnosis in Multiple Sclerosis

Findings That Are Typical Features of MS

Findings of optic neuritis

Findings of suspected inflammatory brainstem or cerebellar syndrome

Findings of suspected myelitis

Findings of progressive neurological disorder

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