What are the causes, recommended diagnostic tests, and treatment options for hippocampal (limbic) encephalitis?

Hippocampal (Limbic) Encephalitis: Causes, Testing, and Treatment

Causes

Limbic encephalitis is primarily an autoimmune disorder that can be idiopathic, paraneoplastic, postinfectious, or iatrogenic. 1

The immune-mediated inflammation targets the limbic system through two distinct pathophysiologic mechanisms:

• Antibodies against cell surface antigens (NMDAR, LGI1, CASPR2, AMPAR, GABA-B receptor, DPPX) - these are antibody-mediated and treatment-responsive 1
• Antibodies against intracellular antigens (classical onconeuronal antibodies like Hu, Ma2, GAD65) - these are T-cell mediated and poorly treatment-responsive 1, 2

Specific triggers include:

• Underlying malignancy (paraneoplastic) - particularly ovarian teratomas in NMDAR encephalitis, small cell lung cancer, testicular tumors 2
• Preceding viral infections, especially HSV encephalitis 1
• Immune checkpoint inhibitors causing accelerated paraneoplastic encephalitis 1
• TNFα inhibitors 1
• Idiopathic autoimmune mechanisms in patients with personal/family history of autoimmune disorders 1

Diagnostic Testing

Brain MRI with contrast is the first-line imaging study, with bilateral limbic encephalitis on MRI being sufficient for definite diagnosis when infection is excluded. 1

Imaging Protocol:

• MRI findings: T2/FLAIR hyperintensity in medial temporal lobes, hippocampal swelling acutely, followed by atrophy chronically 1, 3
• FDG-PET: Consider when MRI/EEG are uninformative but clinical suspicion remains high - shows hypermetabolism in affected regions 1

CSF Analysis (Critical - Second Step):

Perform lumbar puncture on all suspected cases unless herniation risk exists 1

Test the following:

• Cell count/differential (expect 20-200 lymphocytes, can reach 900) 1
• Protein, glucose, CSF/serum glucose ratio
• Oligoclonal bands, IgG index, IgG synthesis rate 1
• HSV1/2 PCR, VZV PCR and IgG/IgM (to exclude infection) 1
• Bacterial/fungal cultures
• Cytology and flow cytometry
• Neuronal autoantibody panel in CSF AND serum 1

Critical caveat: Normal CSF does not exclude limbic encephalitis - still test autoantibody panels if clinical suspicion is high 1

Serum Testing:

• Neuronal autoantibody panel (some antibodies like LGI1 are more sensitive in serum; NMDAR and GFAP more sensitive in CSF) 1
• Antithyroid antibodies, toxicology screen, ammonia, B1/B12 levels 1
• HIV, inflammatory markers, ANA, ENA, antiphospholipid antibodies 1
• Sodium level monitoring (hyponatremia common with LGI1 antibody) 1

EEG:

• Look for focal/multifocal abnormalities, slow wave or epileptiform activity 1

Cancer Screening (Mandatory in Adults):

Perform CT chest/abdomen/pelvis with contrast in all adult cases 1

• If negative, add mammogram/breast MRI, pelvic ultrasound, whole-body FDG-PET based on antibody type and cancer risk factors 1

Treatment

Once infection is ruled out by basic CSF results, immediately start high-dose corticosteroids (or IVIG/PLEX if steroids contraindicated). 1

First-Line Acute Immunotherapy:

Start with intravenous methylprednisolone 1

Specific steroid-responsive conditions include:

• Faciobrachial dystonic seizures (LGI1-antibody) 1
• Immune checkpoint inhibitor-associated encephalitis 1
• GFAP astrocytopathy 1

Escalation Algorithm:

If no improvement by end of initial treatment cycle, add IVIG or PLEX: 1

• Choose IVIG first in agitated patients and bleeding disorders 1
• Choose PLEX first (5-10 sessions every other day) in severe hyponatremia, high thromboembolic/cancer risk, or associated demyelination 1

For severe presentations (severe NMDAR encephalitis, new-onset refractory status epilepticus, severe dysautonomia), start combination therapy (steroids + IVIG or steroids + PLEX) from the beginning rather than sequentially. 1

Second-Line Therapy (if no improvement 2-4 weeks after combined acute therapy):

Choose based on antibody type: 1

• Rituximab for antibody-mediated autoimmunity (NMDAR, LGI1, surface antigens) 1
• Cyclophosphamide for cell-mediated autoimmunity (classical paraneoplastic syndromes with intracellular antibodies) 1

Novel Therapies:

If conventional second-line therapies fail, consider tocilizumab or bortezomib, though evidence is minimal 1

Maintenance/Bridging Therapy:

Start gradual oral prednisone taper OR monthly IVIG OR monthly IV methylprednisolone 1

Prognosis Distinction:

Encephalitis with surface antigen antibodies has significantly better treatment response and outcomes compared to intracellular antigen antibodies 4, 2. The latter are predominantly T-cell mediated and poorly responsive to immunotherapy 2.

Common pitfall: Delaying immunotherapy while waiting for antibody results - start treatment empirically once infection is excluded, as CSF inflammation alone justifies treatment 1.