What is the diagnosis and treatment approach for a patient suspected of having limbic encephalitis, potentially associated with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) or paraneoplastic syndromes?

Limbic Encephalitis: Diagnosis and Treatment

Immediate Diagnostic Approach

When limbic encephalitis is suspected, immediately order brain MRI with contrast, CSF analysis including viral PCR and neuronal antibody panel (both serum and CSF), and screen for underlying malignancy—do not wait for antibody results before initiating treatment if clinical suspicion is high. 1, 2

Key Clinical Features to Recognize

• Subacute onset (typically <12 weeks) of short-term memory deficits, confusion, disorientation, and seizures 1
• Hyponatremia occurs in approximately 60% of cases, particularly with LGI1-antibody encephalitis, and may be the presenting feature 1, 2
• Psychiatric symptoms including depression, behavioral changes, and psychosis are common 1
• Movement disorders such as faciobrachial dystonic seizures (pathognomonic for LGI1-antibody encephalitis), orofacial dyskinesia, or choreoathetosis suggest specific antibody subtypes 1
• Absence of fever is typical in autoimmune limbic encephalitis, distinguishing it from infectious encephalitis 1

Essential Investigations

Brain MRI:

• Bilateral hippocampal T2/FLAIR hyperintensity with or without swelling is seen in ~60% of cases and is sufficient for definite diagnosis when viral studies are negative 1
• MRI may be normal in up to 40% of cases, so normal imaging does not exclude the diagnosis 1

CSF Analysis:

• Lymphocytic pleocytosis (≥5 WBC/mm³), elevated protein, oligoclonal bands, or elevated IgG index support the diagnosis 1
• Critical: CSF may be completely normal in autoimmune encephalitis—do not exclude the diagnosis based on normal CSF alone 1, 2
• HSV-1/2 and VZV PCR must be performed to exclude infectious causes 2

Antibody Testing:

• Test both serum and CSF for neuronal antibodies, as sensitivity varies by antibody type 2
• Priority antibodies: NMDAR, LGI1, CASPR2, VGKC-complex, AMPAR, GABA-B receptor 1, 2
• Collect samples before administering immunotherapy, IVIg, or plasmapheresis to avoid false results 2
• Do not delay testing if CSF is acellular 2

Malignancy Screening:

• All patients require comprehensive tumor screening, as 10-60% have underlying malignancy depending on antibody type 1
• VGKC-complex antibodies: screen for thymoma and small cell lung cancer 1
• NMDAR antibodies: screen for ovarian teratoma (especially in young women) 1
• FDG-PET/CT may reveal occult malignancy 3

Distinguishing SIADH from Limbic Encephalitis

Critical distinction: Hyponatremia with memory impairment and seizures may represent either limbic encephalitis with associated SIADH or paraneoplastic SIADH mimicking limbic encephalitis 4

• If MRI, EEG, and CSF are all normal despite classic symptoms, consider ectopic ADH secretion from occult neuroendocrine tumor (particularly Merkel cell carcinoma) rather than true limbic encephalitis 4
• True limbic encephalitis typically shows at least one abnormality on MRI, EEG, or CSF 1

Treatment Algorithm

First-Line Immunotherapy (Start Immediately):

High-dose corticosteroids are the cornerstone of initial treatment: methylprednisolone 1g IV daily for 3-5 days, followed by oral prednisone 0.5-1 mg/kg/day. 1, 2

• IVIg (0.4 g/kg/day for 5 days) can be added for severe or rapidly progressive cases 1, 2
• Plasma exchange (5-7 sessions) is an alternative to IVIg or can be used in combination 1
• When using plasma exchange, perform it before IVIg to avoid removing infused immunoglobulins 1

Second-Line Immunotherapy (for non-responders after 2-4 weeks):

• Rituximab (375 mg/m² weekly for 4 weeks) or cyclophosphamide (750 mg/m² monthly) 1
• Consider second-line therapy earlier in NMDAR-antibody encephalitis, as responses can be slow 1

Tumor Treatment:

• Tumor removal is essential when identified and significantly improves outcomes 1
• Continue immunotherapy alongside oncologic treatment 1

Treatment Duration and Monitoring

• Continue oral steroids for 3-6 months until antibody levels normalize, then taper over 12 months 1
• Pitfall: IVIg alone without steroids is less effective at reducing antibody levels and associates with poorer outcomes 1
• Monitor serum antibody levels every 3-6 months to guide treatment duration 2
• Repeat brain MRI at 3-6 months to assess response 2

Prognosis and Expected Recovery

Antibodies to surface antigens (NMDAR, LGI1, CASPR2) have significantly better outcomes than antibodies to intracellular antigens (Hu, Ma2, CV2/CRMP5). 1, 5, 6

• Confusion and seizures typically improve within weeks of immunotherapy 1, 2
• Hyponatremia normalizes rapidly with treatment 1
• Memory recovery is slower, often requiring months to years 1, 2
• Most cases are monophasic; relapse is uncommon once antibodies become undetectable 1

Common Pitfalls to Avoid

• Do not wait for antibody results before starting treatment—clinical diagnosis is sufficient to initiate therapy 1
• Do not exclude limbic encephalitis based on normal MRI, normal CSF, or absence of fever 1, 2
• Do not use steroids alone long-term without monitoring antibody levels—inadequate treatment increases relapse risk 1
• Do not discharge patients without definitive tumor screening, as occult malignancy may not be apparent initially 1
• Do not assume all hyponatremia with encephalopathy is limbic encephalitis—consider paraneoplastic SIADH if all neurodiagnostic tests are normal 4