What are the key considerations in the differential diagnosis of multiple sclerosis, particularly in patients presenting with ascending sensory disturbance or weakness?

Differential Diagnosis of Multiple Sclerosis with Ascending Sensory Disturbance or Weakness

Critical Distinction: Ascending Symptoms Suggest Alternative Diagnoses

When a patient presents with ascending sensory disturbance or weakness, this pattern is atypical for MS and should immediately raise suspicion for alternative diagnoses, particularly acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome), transverse myelitis, or neuromyelitis optica spectrum disorder (NMOSD). 1, 2

Typical MS Presentations vs. Ascending Patterns

Classic MS Clinical Syndromes

MS typically presents with subacute neurological symptoms developing over hours to days, not ascending patterns: 3, 4, 5

• Unilateral optic neuritis with painful vision loss and color vision impairment 4, 5
• Partial (incomplete) transverse myelitis with sensory level, weakness, or bladder dysfunction—but not ascending 4, 5
• Brainstem syndromes including diplopia and internuclear ophthalmoplegia 3, 4
• Sensory disturbances that are focal and non-ascending 3, 5

Red Flags Against MS Diagnosis

Ascending sensory or motor symptoms constitute a major red flag that should prompt immediate reconsideration of the differential diagnosis. 1, 6

Additional red flags include: 1, 2

• Bilateral sudden hearing loss 2
• Sudden onset of focal symptoms (suggests stroke rather than MS) 2
• Symmetric bilateral symptoms at onset 6
• Progressive symptoms from onset without relapses in patients under 40 years 6

Key Differential Diagnoses for Ascending Symptoms

Neuromyelitis Optica Spectrum Disorder (NMOSD)

NMOSD is the most critical MS mimic requiring immediate differentiation because MS treatments can worsen NMOSD outcomes. 1, 2

NMOSD characteristics: 1

• Longitudinally extensive transverse myelitis (LETM): MRI lesion extending over ≥3 contiguous spinal cord segments
• AQP4-IgG antibody positivity (aquaporin-4 immunoglobulin G)
• Optic nerve lesions extending over half the optic nerve length or involving optic chiasm
• Area postrema syndrome with dorsal medulla lesions
• Brain MRI often normal or showing only nonspecific white matter lesions (up to 70% have brain lesions, but different pattern than MS)

Acute Transverse Myelitis

Complete or near-complete transverse myelitis with ascending symptoms suggests: 4, 6

• Monophasic inflammatory myelitis (not MS)
• Requires whole spinal cord imaging to rule out compression, tumor, or NMOSD 4
• Bilateral symptoms and sensory level more common than in MS 6

Guillain-Barré Syndrome (GBS)

Classic ascending paralysis with: 6

• Areflexia or hyporeflexia
• Symmetric motor weakness progressing over days to weeks
• CSF showing albuminocytologic dissociation (elevated protein, normal cell count)
• Peripheral nerve involvement, not CNS demyelination

Other Critical Differentials

When evaluating ascending or atypical presentations: 2, 7, 6

• Cerebrovascular disease: Multifocal cerebral ischemia in young adults 2
• Infectious diseases: HTLV-1, Lyme disease, HIV-associated myelopathy 2, 7
• Paraneoplastic disorders 2
• Genetic disorders of myelin 2
• Acute disseminated encephalomyelitis (ADEM): Monophasic, often post-infectious 8, 7

Diagnostic Workup for Suspected MS vs. Mimics

Essential MRI Characteristics

MS diagnosis requires characteristic lesion patterns—not just any white matter lesions. 1, 3

MS-typical "green flag" lesions: 1, 3, 4

• Periventricular location with sharp edges
• Ovoid/flame-shaped orientation perpendicular to ventricles (Dawson's fingers)
• Juxtacortical location (touching cortex)
• Infratentorial location (brainstem, cerebellum)
• Short spinal cord lesions (<3 segments, typically <2 vertebral segments)
• Gadolinium-enhancing lesions indicating active inflammation

NMOSD-typical patterns (red flags against MS): 1

• LETM (≥3 contiguous segments)
• Peri-ependymal brainstem lesions
• Dorsal medulla/area postrema lesions
• Normal brain MRI or only nonspecific lesions

McDonald Criteria Requirements

Diagnosis requires dissemination in space (DIS) and time (DIT): 2, 3, 4

DIS requires ≥1 lesion in ≥2 of these locations: 4

• Periventricular
• Juxtacortical
• Infratentorial
• Spinal cord

DIT requires: 4

• Simultaneous gadolinium-enhancing and non-enhancing lesions, OR
• New T2 or gadolinium-enhancing lesion on follow-up MRI

Critical Laboratory Tests

CSF analysis is essential when presentation is atypical or diagnosis uncertain: 2, 3, 4

• Oligoclonal bands specific to CSF (not in serum) support MS diagnosis 3, 4
• AQP4-IgG antibody testing mandatory to exclude NMOSD 1
• MOG-IgG antibody for anti-MOG disease 1
• Cell count and protein (elevated protein with normal cells suggests GBS) 6

Visual evoked potentials may show delayed conduction in optic nerve involvement 3, 4

Age-Specific Considerations

Diagnostic criteria apply best to ages 10-59 years: 2, 3, 4

• Pediatric cases (<11 years): Require ≥1 black hole (T1 hypointense lesion) and ≥1 periventricular lesion to distinguish MS from monophasic demyelination 2, 4
• Patients >50 years or with vascular risk factors: Apply more stringent criteria (higher number of periventricular lesions required) 2

Diagnostic Algorithm for Ascending Symptoms

Step 1: Recognize the atypical pattern 1, 6

• Ascending sensory/motor symptoms are NOT typical MS
• Immediately expand differential diagnosis

Step 2: Obtain comprehensive spinal cord imaging 4

• Whole spine MRI (cervical, thoracic, lumbar)
• Look for LETM (≥3 segments = NMOSD until proven otherwise)
• Rule out compressive lesions, tumors

Step 3: Obtain brain MRI with contrast 3, 4

• Assess for MS-typical vs. atypical patterns
• Normal or minimal brain involvement suggests NMOSD or isolated myelitis

Step 4: Perform targeted serological testing 1

• AQP4-IgG antibody (mandatory for any myelitis presentation)
• MOG-IgG antibody
• Consider infectious workup (Lyme, HTLV-1, HIV)

Step 5: CSF analysis 3, 6

• Oligoclonal bands
• Cell count and differential
• Protein level
• Consider infectious studies

Step 6: Neurophysiology if indicated 6

• Nerve conduction studies and EMG if GBS suspected
• Visual evoked potentials if optic nerve involvement

Critical Diagnostic Pitfalls

Never diagnose MS on MRI findings alone—at least one clinical event consistent with acute demyelination is mandatory. 1, 2, 3

Applying MS criteria to atypical presentations (like ascending symptoms) without additional supportive evidence dramatically increases misdiagnosis risk. 1, 4

Misdiagnosing NMOSD as MS leads to treatment with MS therapies that can worsen NMOSD outcomes. 1, 2

The clinical syndrome must be typical of demyelination before applying McDonald criteria. 1, 3

When to Refer

Diagnosis should be made by a specialist familiar with MS, its differential diagnoses, and interpretation of paraclinical assessments. 2

Any patient with ascending symptoms requires urgent neurological evaluation to distinguish between MS mimics that require different treatments. 6