What is the differential diagnosis for a patient with Systemic Lupus Erythematosus (SLE) presenting with progressive leg weakness?

Differential Diagnosis for SLE with Progressive Leg Weakness

The differential diagnosis for an SLE patient presenting with progressive leg weakness must prioritize SLE myelopathy (transverse myelitis) as the most critical diagnosis, followed by Guillain-Barré syndrome, peripheral neuropathy variants, and neuromyelitis optica spectrum disorder. 1

Primary Neuropsychiatric SLE Manifestations

SLE Myelopathy (Transverse Myelitis)

• This is the most important diagnosis to exclude immediately as it presents with rapidly evolving leg weakness and requires urgent immunosuppressive therapy within hours to prevent permanent neurological deficit 1
• Patients present with either lower motor neuron signs (flaccidity, hyporeflexia) indicating grey matter involvement or upper motor neuron signs (spasticity, hyperreflexia) suggesting white matter dysfunction 1
• Associated features include sphincter dysfunction (bladder/bowel), sensory level deficits, and severe back pain 1, 2
• Occurs in only 1.2% of SLE patients but carries significant morbidity and mortality (21% mortality in one cohort) 3
• Can occur as the first manifestation of SLE (28% of cases) and independently of systemic disease activity 3
• Contrast-enhanced spinal MRI shows T2 hyperintense lesions in 70-93% of cases, with longitudinal involvement (>3 segments) being characteristic 1, 3

SLE Peripheral Neuropathy

• Polyneuropathy occurs in 2-3% of SLE patients, presenting with distal sensory loss, pain, and progressive weakness 1
• Mononeuropathy multiplex can be the initial presentation of SLE, characterized by asymmetric weakness and sensory deficits in multiple nerve distributions 4
• Nerve conduction studies differentiate axonal from demyelinating patterns and distinguish mononeuropathy from polyneuropathy 1, 4
• Look for asymmetric involvement, muscle atrophy, and absent reflexes in affected limbs 4

Inflammatory Demyelinating Disorders

Guillain-Barré Syndrome (GBS)

• GBS presents with rapidly progressive bilateral leg weakness ascending to arms over days to 2 weeks, with areflexia as a cardinal feature 1
• Key distinguishing features: symmetric weakness, distal paresthesias preceding weakness, and progression to maximum disability within 2 weeks (typically) or up to 4 weeks 1
• Dysautonomia (blood pressure/heart rate instability, bladder dysfunction) is common 1
• CSF shows albuminocytologic dissociation (elevated protein with normal cell count) 1
• Critical distinction from SLE myelopathy: GBS has areflexia throughout, while SLE myelopathy often shows hyperreflexia with upper motor neuron signs 1

Neuromyelitis Optica (NMO) Spectrum Disorder

• Consider when longitudinal myelopathy (>3 spinal segments) is present on MRI 1
• Associated optic neuritis occurs in 21-48% of SLE myelopathy cases 1
• Test serum NMO IgG (aquaporin-4) antibodies to diagnose co-existing NMO, which changes treatment approach 1
• NMO-positive patients may have more white matter involvement and association with antiphospholipid antibodies 1

Vascular/Thrombotic Etiologies

Antiphospholipid Antibody-Related Myelopathy

• Ischemic/thrombotic myelopathy presents with acute onset weakness, often with upper motor neuron signs 1
• Check anticardiolipin, anti-β2-glycoprotein I, and lupus anticoagulant as these are present in 45% of SLE myelopathy cases 3
• Requires anticoagulation rather than immunosuppression alone if thrombotic mechanism is confirmed 1
• Associated with worse prognosis and severe neurological deficit 1

Critical Diagnostic Workup Algorithm

Immediate Imaging (Within Hours)

• Contrast-enhanced spinal MRI is mandatory to identify cord lesions, exclude compression, and assess extent of involvement 1
• Brain MRI should be performed when other neuropsychiatric symptoms coexist or to differentiate demyelinating disorders 1
• MRI abnormalities present in 70-93% of SLE myelopathy but only 50-70% of other NPSLE manifestations 1

Electrodiagnostic Studies

• Nerve conduction studies and EMG differentiate peripheral neuropathy from myelopathy and identify specific patterns (axonal vs demyelinating, mononeuropathy vs polyneuropathy) 1, 4
• Normal studies suggest small-fiber neuropathy, requiring skin biopsy showing loss of intraepidermal nerve fibers 1

Laboratory Evaluation

• CSF analysis shows mild-to-moderate abnormalities (pleocytosis in 50-70%) in SLE myelopathy but is non-specific 1, 3
• Microbiological studies are critical to exclude infectious myelitis (bacterial, HSV, CMV) before starting immunosuppression 1
• Antiphospholipid antibodies (persistently positive in moderate-to-high titers) predict thrombotic mechanism 1, 3
• Disease activity markers (anti-dsDNA, C3, C4) may be normal as myelopathy occurs independently of systemic activity 3

Other Considerations

Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP)

• A GBS variant that can occur in SLE patients 1
• CSF shows elevated protein with minimal pleocytosis 1
• Responds to IVIG or plasma exchange rather than immunosuppression 1

Myasthenia Gravis

• Presents with fatigable weakness rather than progressive fixed weakness 1
• Proximal muscle weakness with preserved reflexes 1
• Requires acetylcholine receptor antibody testing and repetitive nerve stimulation studies 1

Critical Pitfalls to Avoid

• Never delay spinal MRI and treatment initiation beyond 2 weeks as this is associated with severe permanent neurological deficit in SLE myelopathy 1
• Do not assume normal systemic disease activity excludes SLE myelopathy—64% occur without concurrent systemic activity 3
• Always exclude infection before starting high-dose immunosuppression, as sepsis causes 21% mortality in SLE myelopathy patients 3
• Check for antiphospholipid antibodies as their presence changes management from pure immunosuppression to include anticoagulation 1
• Distinguish upper motor neuron signs (hyperreflexia, spasticity) from lower motor neuron signs (hyporeflexia, flaccidity) as this guides differential diagnosis between myelopathy and peripheral neuropathy 1