What are the differential diagnoses for a patient presenting with autoimmune hemiplegia?

Differential Diagnoses for Autoimmune Hemiplegia

The differential diagnosis for a patient presenting with hemiplegia in the context of suspected autoimmune etiology should prioritize autoimmune encephalitis syndromes, demyelinating disorders (particularly MS, NMOSD, and MOG-EM), systemic autoimmune diseases with CNS involvement (especially SLE and neurosarcoidosis), and acute inflammatory conditions like ADEM. 1

Primary Autoimmune/Inflammatory Considerations

Autoimmune Encephalitis Syndromes

• Cortical/subcortical encephalitis is a key consideration when hemiplegia presents with altered mental status, seizures, or focal neurological deficits 1
• Look for rapid onset over days to weeks, preceding viral infection, fever ≥38°C, new-onset seizures, and CSF pleocytosis (≥5 cells/mm³) 2
• Brain MRI may show cortical/subcortical white matter lesions; EEG often demonstrates focal slowing, lateralized periodic discharges, or extreme delta brush (in NMDAR encephalitis) 1
• GAD65 antibody-associated encephalitis can present with hemiplegia when high titers (>1:50) are present, often with CSF inflammation and polyendocrine autoimmunity 3
• Anti-glutamate receptor antibodies may be detected in CSF and symptoms are typically highly steroid-responsive 4

Demyelinating Disorders

Multiple Sclerosis (MS)

• Hemiplegia occurs with acute inflammatory episodes affecting motor pathways, typically in patients aged 10-59 years 5
• MRI shows focal periventricular lesions (≥3 required), ovoid/flame-shaped, perpendicular to ventricles ("Dawson's fingers"), with sharp edges 5
• Lesions must demonstrate dissemination in space (periventricular, juxtacortical, infratentorial, or spinal cord) and time 1, 5
• CSF oligoclonal bands specific to CSF (not serum) support diagnosis 5
• Red flags against MS: subacute onset over weeks, progressive course without stabilization, dementia, epilepsy, or aphasia as presenting features 5

Neuromyelitis Optica Spectrum Disorder (NMOSD)

• Can present with acute hemiplegia mimicking stroke, particularly in patients ≥50 years old 6
• Look for longitudinally extensive transverse myelitis (≥3 spinal segments), area postrema lesions, or bilateral optic neuritis 1, 6
• AQP4-IgG seropositivity confirms diagnosis; testing should not be delayed by requiring dissemination in space 1
• Brain lesions may not follow typical MS patterns; can involve brainstem, diencephalon, or periventricular regions 1
• Steady progression and/or recurrence of symptoms distinguishes from stroke 6

MOG Antibody-Associated Encephalomyelitis (MOG-EM)

• Presents with ADEM-like features: large white matter lesions, disturbance of consciousness, brainstem involvement 1
• Can manifest as simultaneous unilateral optic neuritis and longitudinally extensive transverse myelitis extending into brainstem 1
• CSF shows pleocytosis (often with neutrophils 5-10%) but typically negative oligoclonal bands 1
• Symptoms often flare after steroid tapering; good response to plasma exchange 1
• MOG-IgG testing by cell-based assay is diagnostic gold standard 1

Systemic Autoimmune Diseases with CNS Involvement

Systemic Lupus Erythematosus (SLE)

• Lupus cerebritis presents with acute hemiplegia, seizures, and psychiatric symptoms 1
• Brain MRI has modest sensitivity (50-70%) and specificity (40-67%); SPECT identifies perfusion deficits in 80-100% of severe cases 1
• CSF may show mild-to-moderate abnormalities (50-70%); check ANA/ENA, anti-ribosomal-P antibodies 1
• SLE myelopathy can present with rapidly evolving transverse myelitis; contrast-enhanced spinal MRI shows T2 hyperintense lesions in 70-93% 1
• Antiphospholipid antibodies suggest thrombotic rather than inflammatory mechanism 1

Neurosarcoidosis

• Causes diencephalic, brainstem, or meningoencephalitis patterns with hemiplegia 1
• Check serum ACE levels and CT chest to rule out systemic sarcoidosis 1
• Brain MRI may show leptomeningeal enhancement; CSF shows elevated protein and lymphocytic pleocytosis 1

Behçet's Disease

• Presents with brainstem or diencephalic involvement causing hemiplegia 1
• Check HLA-B51 status; look for oral/genital ulcers, uveitis, skin lesions 1

Sjögren's Syndrome

• Can cause myelitis with hemiplegia; often coexists with NMOSD 7, 8
• Check anti-SSA/SSB antibodies; consider lip biopsy if clinical suspicion high 7

Acute Inflammatory Demyelinating Conditions

Acute Disseminated Encephalomyelitis (ADEM)

• Monophasic demyelinating disease with large cortical/subcortical white matter lesions 1
• Onset often 3 weeks after vaccination or viral infection 1
• Diagnosis requires no new symptoms/signs or imaging abnormalities for >3 months after clinical onset 1
• Brain MRI shows large, poorly demarcated lesions; may involve deep gray matter 1

Acute Hemorrhagic Leukoencephalitis (AHL)

• Severe, fulminant variant of ADEM with hemorrhagic component 1
• Brain MRI shows hemorrhagic white matter lesions with mass effect 1

Vascular and Infectious Mimics

Cerebrovascular Disorders

• Multifocal cerebral ischemia/infarction in young adults from phospholipid antibody syndrome, acute disseminated lupus, CADASIL, Takayasu's disease, meningovascular syphilis, or carotid dissection 1
• Distinguish by vascular territory distribution, absence of CSF inflammation, and vascular imaging findings 1

Infectious Etiologies

• Viral encephalitis (HSV, VZV, HHV6, West Nile virus) can cause hemiplegia with cortical/subcortical involvement 1, 9
• CSF viral PCR (HSV, VZV, enterovirus) and viral serology are essential 1, 9
• Rhombencephalitis (Listeria) causes brainstem involvement with hemiplegia 1
• Neurosyphilis and Lyme disease can mimic MS with multifocal CNS lesions 1
• Mycoplasma myelitis may occur with concurrent pneumonia 9

Other Important Considerations

Neoplastic/Paraneoplastic

• Lymphoma (primary CNS or systemic) can cause focal lesions mimicking inflammatory disease 1
• Paraneoplastic cerebellar degeneration may present with ataxia and hemiparesis 1
• Leptomeningeal carcinomatosis causes meningoencephalitis pattern 1

Metabolic/Toxic

• Toxic encephalopathy affecting striatum or cortex 1
• Hyperglycemic injury or uraemia causing striatal changes 1
• Central pontine myelinolysis in brainstem encephalitis pattern 1
• Wernicke encephalopathy causing diencephalic syndrome 1

Other Inflammatory Conditions

• CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) shows punctate brainstem/cerebellar enhancement 1
• Autoimmune GFAP astrocytopathy demonstrates radial perivascular enhancement 1
• Granulomatosis with polyangiitis (GPA) and IgG4-related disease cause meningoencephalitis 1

Critical Diagnostic Algorithm

1. Obtain brain MRI with and without contrast to identify lesion pattern (cortical/subcortical, periventricular, brainstem, or multifocal) 1, 5
2. Perform lumbar puncture with CSF cell count, protein, glucose, oligoclonal bands, IgG index, and viral PCR panel (HSV, VZV, enterovirus) 1, 2
3. Order EEG to exclude subclinical status epilepticus and identify focal abnormalities supporting encephalitis over metabolic causes 1
4. Obtain comprehensive autoantibody panel: AQP4-IgG, MOG-IgG (by cell-based assay), ANA/ENA, anti-dsDNA, antiphospholipid antibodies, GAD65 antibodies 1, 3
5. If MRI negative but high clinical suspicion, obtain brain FDG-PET to confirm focal/multifocal abnormality 1
6. Check serum ACE, HLA-B51, and CT chest if neurosarcoidosis or Behçet's suspected 1
7. Obtain spinal MRI with contrast if myelopathy suspected (look for longitudinally extensive lesions suggesting NMOSD/MOG-EM) 1

Common Pitfalls to Avoid

• Do not assume stroke in older patients (≥50 years) without considering NMOSD, which can present with stroke-like symptoms and later onset 6
• Do not diagnose MS in patients with negative oligoclonal bands and longitudinally extensive spinal lesions; test for AQP4-IgG and MOG-IgG first 1
• Do not delay immunotherapy while awaiting antibody results if clinical presentation strongly suggests autoimmune encephalitis with altered mental status, seizures, and CSF pleocytosis 2
• Do not use anti-TNF biologics in patients with suspected MS, as these can induce inflammatory CNS disease 7
• Do not diagnose monophasic ADEM unless patient remains symptom-free for >3 months; earlier relapses suggest MS or MOG-EM 1
• Do not overlook coexisting systemic autoimmune disease, particularly in NMOSD patients who may have concurrent SLE or Sjögren's syndrome 7