What is the treatment for IGLON5 antibody-associated encephalitis?

Treatment of IGLON5 Antibody-Associated Encephalitis

Initiate first-line immunotherapy with high-dose intravenous methylprednisolone (1g daily for 3-5 days) combined with IVIG immediately after excluding infection, as IGLON5 disease responds to aggressive early immunotherapy and has high mortality without treatment. 1, 2, 3

Initial Diagnostic Considerations

Before starting immunotherapy, rapidly complete the following workup:

• Perform lumbar puncture to exclude infectious causes and confirm inflammatory etiology (elevated protein, lymphocytic pleocytosis, oligoclonal bands may be present) 1, 4
• Obtain brain MRI which is typically unremarkable in IGLON5 disease, though atypical inflammatory lesions can occasionally occur 2, 4
• Test for IGLON5 antibodies in both serum and CSF, as antibodies are present in both compartments 3, 5
• Check HLA typing for DRB110:01 and DQB105:01, which show strong correlation with IGLON5 disease 5
• Screen for malignancy with CT chest/abdomen/pelvis, as paraneoplastic associations can occur 1

First-Line Immunotherapy Protocol

Start combination therapy immediately once infection is excluded:

• Methylprednisolone 1g IV daily for 5 consecutive days as the cornerstone of treatment 2, 3
• Add IVIG (0.4 g/kg/day for 5 days) concurrently rather than sequentially, given the severity and poor prognosis of untreated IGLON5 disease 1, 2
• Do not use corticosteroids alone, as monotherapy has been associated with higher mortality compared to more aggressive immunotherapy 5

The rationale for combination therapy from the outset is that IGLON5 disease has historically shown poor responsiveness to immunotherapy and high mortality, making aggressive initial treatment critical 5. Cases treated with IV corticosteroids alone had worse outcomes than those receiving more potent immunotherapy 5.

Monitoring Response to Treatment

• Expect rapid improvement within days to weeks if treatment is effective 2, 3
• Monitor clinical symptoms including sleep dysfunction, bulbar symptoms, gait instability, movement disorders, and cognitive function 3, 5
• Repeat neuropsychological testing at follow-up to assess memory and cognitive improvements 3

Second-Line Therapy for Inadequate Response

If no meaningful clinical improvement occurs after 2-4 weeks of first-line therapy:

• Add rituximab (375 mg/m² weekly for 4 weeks) as the preferred second-line agent for antibody-mediated autoimmunity 1
• Consider plasma exchange (5-10 sessions every other day) as an alternative or additional therapy, particularly if there is severe presentation or contraindications to other treatments 1
• Cyclophosphamide may be considered if there is evidence of cell-mediated inflammation, though rituximab is generally preferred 1

Maintenance and Bridging Therapy

After achieving clinical improvement:

• Initiate monthly high-dose methylprednisolone (1g IV for 5 consecutive days) to prevent relapse 3
• Alternative bridging options include gradual oral prednisone taper or monthly IVIG 1
• Continue maintenance therapy for extended periods, as IGLON5 disease often has a chronic progressive course 5

Critical Pitfalls to Avoid

• Never delay immunotherapy while awaiting antibody results if clinical suspicion is high, as early treatment improves outcomes 2, 5
• Do not use corticosteroids alone as monotherapy—always combine with IVIG or plan for escalation 5
• Avoid premature discontinuation of immunotherapy, as IGLON5 disease requires prolonged treatment given its neurodegenerative component 5
• Do not dismiss mild presentations—even patients with subtle symptoms may progress without treatment, though some mild cases have shown spontaneous improvement 6

Special Considerations

IGLON5 disease differs from typical autoimmune encephalitis in several important ways:

• It has a dual pathophysiology involving both autoimmunity and neurodegeneration with tau protein deposition 5
• Response to immunotherapy is often partial rather than complete, unlike NMDAR or LGI1 encephalitis 5
• The disease typically has an insidious onset and slow progression, making early recognition challenging 5
• Aggressive immunotherapy appears to increase survival compared to conservative approaches 5

The evidence base for IGLON5 treatment consists primarily of case reports and small case series, with no randomized controlled trials 2, 3, 5, 4. However, the consistent finding across multiple reports is that more aggressive immunotherapy correlates with better outcomes and survival 5.