LGI1 Antibody Encephalitis Presenting as Focal Cortical Encephalitis

Leucine-rich, glioma-inactivated protein 1 (LGI1), which is functionally related to voltage-gated potassium channels, is expressed in the temporal cortex and hippocampus, is secreted into the synaptic space, and has a role in linking presynaptic voltage-gated potassium channels and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Genetic disruption of the LGI1 protein causes autosomal dominant temporal lobe epilepsy.¹

Anti-LGI1 antibodies were discovered in 2010. Anti-LGI1 and anti-AMPAR encephalitis produce a clinical picture of limbic encephalitis, including subacute memory and behavioral disturbances with seizures of mesial temporal origin. Brain MRI scans show unilateral or bilateral hippocampal T2 hyperintensities.² The association of focal cortical encephalitis with anti-LGI1 antibodies has not been reported in the literature. We present a case report of an individual who presented with seizures and behavioral disturbances in the setting of left frontal focal cortical encephalitis.

Case Presentation

HB, age mid-50s, who had preexisting diabetes and hypertension, had a progressive neurologic illness of 1 month’s duration that started with a low-grade fever. A few days after fever onset, HB had multiple seizure episodes, involving tonic-clonic movements of the right upper and lower limbs and impaired consciousness, followed by multiple episodes of tonic posturing as well as clonic movements of the right upper and lower limbs. This was followed by seizures of multiple semiologies, initially involving the right upper and lower limb and progressing to status epilepticus, and HB was admitted to the hospital.

During the hospitalization, HB had focal seizures with impaired awareness and head turning to the right. The semiologies pointed to a left mesial temporal onset of seizure eventually evolving to focal motor status epilepticus. Over time, HB’s seizure semiology evolved, leading to focal seizures with impaired awareness involving head turn to the left with associated facial clonic movements and posturing of the left upper limb. This semiology pointed to a right mesial frontal localization, also involving the right frontal operculum. HB’s caregivers also noted episodes of behavioral arrest followed by postictal nose wiping with the left upper limb, which also localizes to the left mesial temporal lobe. The varying seizure semiologies suggested multiple areas of seizure onset: mesial frontal, frontal opercular, and left mesial temporal. HB also had 15 to 20 episodes a day of transient brief stereotyped posturing of upper limbs, with episodes lasting a few seconds. These episodes were associated with impaired awareness and considered likely to be faciobrachial dystonic seizures, which are characteristic of LGI1 antibody encephalitis. HB also had behavioral disturbances, with episodes of anger outbursts, use of profane language, and undressing in public areas of the hospital. HB’s relatives also reported that HB frequently misplaced objects of daily use, repeatedly asked for food, and had decreased sleep.

Executive dysfunction was indicated by abnormal results on Trail Making Test A (a measure of processing speed), Trail Making Test B (a measure of executive function), and a go–no go test (a measure of response inhibition). HB had decreased lexical fluency with preserved semantic fluency and impaired working memory. Clock drawing performance was also impaired, and HB had perseveration while drawing double loops. Recent memory was impaired for both verbal and visual cues, as evidenced by impaired recall (visual and verbal). Paired-association test results revealed impairment. Remote memory was intact. The test results suggested dysfunction of the orbitofrontal cortex, dorsolateral prefrontal cortex, medial prefrontal cortex, and mesial temporal lobe, with relatively preserved parietal lobe and occipital lobe function. No motor sensory deficit or incoordination was noted during examinations.

MRI brain scan (Figure 1) showed left focal frontal T2 hyperintensity with focal leptomeningeal enhancement. A T2 hyperintense lesion was present at the junction of the left insular region and the left medial temporal lobe. The latter lesion did not demonstrate any contrast enhancement. Figure 2 presents a timeline of the illness course.

Diagnostic Process and Treatment

Based on the symptoms and imaging findings, a workup for focal encephalitis was performed, with possible etiologies including metabolic causes, viral encephalitis, and tubercular and autoimmune encephalitis. Considering HB’s age, metabolic causes were considered, but the only abnormality of significance was an elevated blood glucose level. Renal and liver measures were normal. Mild hyponatremia (128 mEq/L) was present, which did not necessitate correction. HB continued to experience symptoms despite glucose control.

A cerebrospinal fluid (CSF) study showed a mildly elevated protein level (50 mg/dL) and 2 lymphocytes. A viral panel and cartridge-based nucleic acid amplification test for Mycobacterium tuberculosis were negative. Autoimmune and paraneoplastic panels produced positive results for serum and CSF anti-LGI1 antibodies. Other autoantibodies associated with status epilepticus (GABA-A, GABA-B, anti-NMDAR) were negative in both serum and CSF. Because myelin oligodendrocyte glycoprotein (MOG) antibodies are known to cause focal cortical encephalitis and their co-occurrence with LGI1 has been reported in the literature,³ testing for serum anti-MOG antibodies was pursued but did not show evidence of antibodies. Whole-body positron emission tomography (PET)–CT scanning did not show any evidence of malignancy. Brain PET showed no hypermetabolism of the brain lesion.

HB was treated with 1 g/day intravenous (IV) methylprednisolone for 5 days and scheduled to receive 1 g IV methylprednisolone weekly for 6 weeks. However, after 1 week, HB had worsening behavioral symptoms and an increase in seizure frequency. IV immunoglobulin (IVIg), 25 g/day for 5 days, was initiated and resulted in disease response. HB was discharged with prescriptions for mycophenolate mofetil (500 mg BD) and oral prednisolone (50 mg [1 mg/kg]).

HB had no further seizure episodes and experienced substantial improvement in function and behavior. An episode of urinary tract infection and impaired glycemic control were ameliorated with appropriate antibiotics and supportive care, and the dose of mycophenolate mofetil was reduced transiently until the infection resolved. On continued follow-up, HB is independent in activities of daily living and exhibits appropriate behavior.

Discussion

LGI1 antibody encephalitis is the second most common autoimmune encephalitis after anti-NMDAR encephalitis.⁴ Clinical data on LGI1 antibody encephalitis have been obtained from 2 large-scale studies: one by Van Sonderen et al,2 which included 38 individuals; and the second by Li et al,4 which included 44 individuals. LGI1 antibody encephalitis usually occurs in men older than 60 years.⁵ The initial presenting symptom is usually a faciobrachial dystonic seizure, which consists of sudden, brief, lateralized tonic contractions, mainly involving the upper limb and the ipsilateral face (or, less frequently, the leg), often associated with hand dystonia.⁶ The typical duration is less than 15 seconds. LGI1 antibody encephalitis has characteristics of both a movement disorder and a seizure disorder. The absence of EEG correlate, alternating pattern with involvement of either limb, poor response to antiseizure medication, and hypermetabolism of basal ganglia on PET are features of a movement disorder; the stereotyped nature and impairment of awareness during episodes are characteristic of a seizure disorder.⁶ Episodes are usually followed by behavioral and memory disturbances and later by generalized tonic-clonic seizures. Hyponatremia is seen in 65% of cases.2 MRI scan shows unilateral or bilateral T2 hippocampal hyperintensities in 74% of the cases, and normal results in the rest.

Focal cortical T2 hyperintensities in individuals with LGI1 antibody encephalitis have not been reported previously in the literature. HB had left focal frontal cortical T2 hyperintensities with focal leptomeningeal enhancement (Figure 1). The differential diagnosis for focal cortical encephalitis includes viral encephalitis, MOG antibody–associated disease (MOGAD),⁷ Rasmussen encephalitis,⁸ and postictal MRI change. In HB, viral etiology was ruled out by CSF analysis, the age at presentation made Rasmussen encephalitis highly unlikely, and the persistence of signal changes on serial MRI made postictal MRI abnormality unlikely, because these changes usually resolve on serial imaging.⁹ Because co-occurrence of LGI1 and MOG antibodies has been reported, and the presence of fluid-attenuated inversion recovery–hyperintense lesions in anti–MOG-associated encephalitis with seizures (FLAMES) is a known presentation of MOGAD, we performed serum MOG antibody testing for HB; results were negative, ruling out MOGAD.⁷

A total of 5% to 15% of individuals with LGI1 antibody encephalitis may have an underlying malignancy, commonly a thymoma.⁵ LGI1 antibody encephalitis responds well to tier 1 treatment options, which include IV steroids, IVIg, and plasma exchange. About 90% of individuals have a favorable response to first-line treatment, and IVIg can be used as a steroid-sparing agent.2 Spatial disorientation may persist, as long-term depression is necessary for spatial orientation. Long-term potentiation and long-term depression are forms of synaptic plasticity that play a role in memory encoding. The relapse rate is widely variable (ranging from 0 to approximately 18%).

Conclusions

The spectrum of autoimmune encephalitis is constantly evolving. Individuals may have atypical symptoms, which may lead to delay in diagnosis. We report a case of LGI1 antibody encephalitis presenting as focal cortical encephalitis with focal meningeal enhancement, which has not been reported previously.