LGI1 & CASPR2 Encephalitis
Leucine-rich glioma inactivated protein 1 (LGI1) and contactin-associated proteinlike 2 (CASPR2) antibodies were historically classified under “voltage-gated potassium channel (VGKC) antibodies” but are now recognized as distinct entities targeting specific synaptic and paranodal proteins. LGI1 encephalitis is the most common autoimmune encephalitis in adults overall, while CASPR2 antibody disease encompasses a broader spectrum including limbic encephalitis, peripheral nerve hyperexcitability, and the distinctive Morvan syndrome. Both are predominantly IgG4-mediated disorders with strong HLA associations, reflecting a fundamentally different immunopathologic mechanism from the IgG1-mediated receptor-internalizing antibodies (e.g., NMDA receptor).
Bottom Line
- LGI1: Most common adult autoimmune encephalitis; median age ~65; M:F 2:1; faciobrachial dystonic seizures are pathognomonic; hyponatremia in ~50%; low cancer association (<10%)
- CASPR2: Affects males far more (9:1); median age ~66; presents as limbic encephalitis, peripheral nerve hyperexcitability, or Morvan syndrome; thymoma in ~20–25%
- Both are IgG4-dominant: Pathogenic mechanism is disruption of protein-protein interactions rather than receptor internalization or complement activation
- Faciobrachial dystonic seizures (FBDS): Brief (<2 seconds) dystonic posturing of arm ± face, occurring tens to hundreds of times daily; respond to immunotherapy, not antiepileptic drugs
- Both respond well to immunotherapy: 80% reach mRS 0–2 at 2 years; however, almost all show incomplete recovery with residual cognitive deficits
- Relapses: ~40% in LGI1; ~30% in CASPR2
LGI1 Encephalitis
Epidemiology
- Incidence: approximately 1–2 per million per year (most common adult autoimmune encephalitis)
- Median age: ~65 years; few patients present before age 50; some present in their 90s
- M:F ratio: 2:1
- HLA association: HLA-DRB1*07:01 (~90% of patients)
- Cancer association: rare (<10%), mostly thymoma or SCLC; routine repeat cancer screening generally not indicated
Pathophysiology
LGI1 is a secreted synaptic protein that bridges presynaptic ADAM23 and postsynaptic ADAM22 receptors, forming a trans-synaptic complex critical for synaptic transmission. LGI1 antibodies are predominantly IgG4, which is functionally monovalent (unable to cross-link or activate complement). The pathogenic mechanism is disruption of the LGI1-ADAM22 protein-protein interaction, interfering with synaptic function rather than causing neuronal death. This mechanism may partly explain the capacity for recovery with immunotherapy.
Clinical Features
Seizures
The hallmark of LGI1 encephalitis is the nature of the seizures, which are among the most frequent in neurology (up to hundreds per day):
Seizure Semiologies in LGI1 Encephalitis
- Faciobrachial dystonic seizures (FBDS): Brief (<2 seconds) dystonic posturing of the arm (~100%) and face (~90%), sometimes leg (~40%); tens to hundreds per day; highly specific for LGI1 — only rarely reported with other antibodies
- Piloerection attacks: Frequently associated with an antibody, often LGI1
- Paroxysmal dizzy spells: Brief, intense episodes of dizziness without physical signs
- Temporal lobe seizures: Automatisms, epigastric rising, déjà vu
- FBDS phenomenology is slower and more dystonic than cortical myoclonus, without the pain of tonic spasms
- Critical: FBDS respond to immunotherapy, NOT to antiepileptic drugs
Cognitive and Behavioral Features
- Limbic encephalitis: Amnesia (primarily anterograde), confusion, disorientation
- Behavioral and personality changes
- Sleep disturbances, including REM sleep behavior disorder
- Progressive cognitive decline if untreated — can lead to hippocampal atrophy
Associated Features
- Hyponatremia: Present in approximately 50% of patients; attributed to SIADH; an important clinical clue
- Neuropathic pain (less common than CASPR2 but reported)
- Thermal sensations (feeling hot or cold)
Investigations
| Test | Findings in LGI1 Encephalitis |
|---|---|
| Brain MRI | ~40% show increased T2/FLAIR signal with swelling in mesial temporal lobes (unilateral > bilateral); may progress to hippocampal atrophy |
| CSF | Only ~25% abnormal (mild pleocytosis with elevated protein); CSF is often normal |
| EEG | ~50% abnormal; ~30% epileptiform; often normal during FBDS; ~20% focal slowing |
| Serum sodium | Hyponatremia in ~50% |
| Antibody testing | LGI1 IgG in serum (higher sensitivity) and/or CSF; CSF-only positivity can be missed |
Diagnostic Pitfalls
- FBDS are often misdiagnosed as epilepsy and treated ineffectively with AEDs; immunotherapy is the correct treatment
- Normal CSF and EEG during FBDS can lead to delayed diagnosis
- Patients often do NOT fulfill criteria for “possible autoimmune encephalitis” (TABLE 2-2) due to normal CSF and MRI; direct clinical recognition and antibody testing are essential
- VGKC-complex antibodies that are not LGI1 or CASPR2 specific are of uncertain clinical significance and should not be used for diagnosis
CASPR2 Encephalitis
Epidemiology
- Median age: ~66 years
- M:F ratio: 9:1 (marked male predominance)
- HLA association: HLA-DRB1*11:01
- Cancer association: thymoma in ~20–25% (especially Morvan syndrome); lower in isolated limbic encephalitis
Clinical Phenotypes
| Phenotype | Key Features | Tumor Association |
|---|---|---|
| Limbic encephalitis | Disorientation, amnesia, seizures; usually no coexistent LGI1 antibodies; low neoplasm rates | Low |
| Peripheral nerve hyperexcitability (neuromyotonia) | Muscle cramps, fasciculations, myokymia; detected on EMG as continuous motor unit activity, fasciculation potentials, myokymic discharges | Variable |
| Morvan syndrome | Combination of encephalopathy (insomnia, hallucinations, agitation, confusion) + peripheral nerve hyperexcitability + dysautonomia (hyperhidrosis); coexistent LGI1 antibodies common | ~25% thymoma (common cause of death) |
Additional Clinical Features
- Neuropathic pain: Common, especially in Morvan syndrome; may relate to small fiber neuropathy with reduced intraepidermal nerve fiber density
- Movement disorders: Ataxia, myoclonus, tremor, paroxysmal ataxia, orthostatic leg myoclonus
- Psychiatric features: Hallucinations, agitation, delusions (more prominent in Morvan syndrome)
- Pain can be troublesome and may be unresponsive to further immunosuppression or neuropathic pain agents
Investigations
| Test | Findings in CASPR2 Disease |
|---|---|
| Brain MRI | ~30% show increased T2/FLAIR signal in mesial temporal lobes; often normal |
| CSF | ~30% abnormal (pleocytosis, elevated protein ± OCBs) |
| EEG | ~70% abnormal (40% epileptiform) |
| EMG | Peripheral nerve hyperexcitability in ~60%: continuous motor unit activity, fasciculation potentials, myokymic discharges, neuromyotonia |
| Antibody testing | CASPR2 IgG in serum and CSF; higher serum titers and CSF positivity increase specificity (commercially available kits have higher false-positive rates in serum) |
Comparison of LGI1 and CASPR2 Encephalitis
| Feature | LGI1 | CASPR2 |
|---|---|---|
| IgG subclass | IgG4 | IgG4 |
| Sex predominance | Male (2:1) | Male (9:1) |
| Median age | ~65 years | ~66 years |
| Hallmark feature | Faciobrachial dystonic seizures | Peripheral nerve hyperexcitability/Morvan |
| CSF | Often normal (25% abnormal) | Often normal (30% abnormal) |
| MRI temporal lobe | 40% abnormal | 30% abnormal |
| Hyponatremia | ~50% | Uncommon |
| Neuropathic pain | Less common | Common |
| EMG hyperexcitability | Rare | 60% |
| Cancer | <10% | ~20–25% (thymoma) |
| HLA association | DRB1*07:01 | DRB1*11:01 |
| 2-year outcome (mRS 0–2) | 80% | ~50% with good sustained response |
| Relapse rate | ~40% | ~30% |
Treatment
First-Line Immunotherapy
- IV methylprednisolone 1 g/day for 3–5 days, followed by oral prednisolone taper
- Plasma exchange: Particularly effective in IgG4-mediated syndromes
- IVIg: 0.4 g/kg/day for 5 days
- FBDS respond rapidly to immunotherapy (often within days), providing diagnostic confirmation
Second-Line and Maintenance
- Rituximab: For non-responders or to sustain response and prevent relapse
- Given the ~40% relapse rate in LGI1, long-term immunosuppression is often warranted
- Oral immunosuppressants (mycophenolate, azathioprine) as steroid-sparing alternatives
Tumor Removal
- Thymectomy for CASPR2/Morvan patients with thymoma
- May improve outcomes and reduce relapse risk
Symptomatic Management
- AEDs are generally ineffective for FBDS (immunotherapy is required)
- Standard AEDs may be used for other seizure types
- Neuropathic pain management (gabapentin, pregabalin, duloxetine) — often treatment-resistant in CASPR2
- Sodium monitoring and management for SIADH-related hyponatremia
Long-Term Outcomes
Key Prognostic Points
- LGI1: 80% reach mRS 0–2 at 2 years, but almost all show incomplete recovery with residual cognitive deficits (particularly memory)
- CASPR2: Good response in survivors; neuropathic pain may be a persistent and disabling residual symptom
- Morvan syndrome: ~25% mortality, primarily from thymoma-related complications
- Hippocampal atrophy on follow-up MRI is associated with persistent memory deficits
- Early treatment initiation is associated with better long-term outcomes
- Relapse surveillance: both LGI1 and CASPR2 have significant relapse rates, warranting ongoing monitoring
References
- Irani SR. Autoimmune encephalitis. Continuum (Minneap Minn). 2024;30(4):995-1020.
- Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain. 2010;133(9):2734-2748.
- Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain. 2018;141(2):348-356.
- van Sonderen A, Thijs RD, Coenders EC, et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology. 2016;87(14):1449-1456.