Multimodal diagnostic approach for limbic encephalitis associated with antivoltage‐gated potassium channel complex antibodies

Limbic encephalitis associated with voltage-gated potassium channel complex antibodies (VGKC-LE) is characterized by subacute onset of memory impairment, confusion and disorientation, behavioral changes, psychotic symptoms, faciobrachial dystonic seizures, and low sodium secondary to syndrome of inappropriate secretion of antidiuretic hormone. Most patients are aged older than 40 years, and men predominate. The disease is responsive to immunotherapies, such as steroids, plasmapheresis and intravenous immunoglobulins. Recent studies have shown that autoantibodies previously thought to be directed towards the VGKC complex are, in fact, binding to other proteins, such as leucine-rich glioma inactivated 1 (LGI-1) and contactin-associated protein-2, which are components of VGKC complexes. Antibodies to LGI-1 have been detected predominantly in patients with non-paraneoplastic limbic encephalitis. A formerly healthy 61-year-old man visited a community hospital 2 days after his wife noted his memory impairment. She complained that he was suddenly unable to carry out his job, because he could not remember recent events. On his first visit, the neurological examination was normal except for retrograde and severe anterograde amnesia. Cerebral magnetic resonance imaging (MRI), electroencephalography (EEG) and cerebrospinal fluid analysis showed entirely normal results. He was suspected of limbic encephalitis as a result of subacute onset amnesia and was subsequently hospitalized at the community hospital on day 3. A second EEG detected a subclinical seizure, which showed generalized rhythmic theta evolved and lasted 20 s. He began antiepileptic therapy with levetiracetam (1500 mg/day). Because his amnesia did not improve, he was referred to Kyushu University Hospital on day 12. His Mini-Mental State Examination was 24 out of 30, and his orientation to time was completely impaired and he was able to recall only one word. He had neither psychotic episodes nor clinical seizures. Routine laboratory examination showed entirely normal results. Serum analyses were negative for antiviral antibodies (herpes simplex virus, human herpes virus-6 and human immunodeficiency virus), antinuclear antibodies and thyroid antibodies. Cerebrospinal fluid showed mildly elevated protein levels (56 mg/dL), but neither pleocytosis nor immunoglobulin G elevation was detected. Oligoclonal immunoglobulin G bands were negative. Fluoro-D-glucose positron emission tomography (FDG-PET) at day 24 showed hyperglucose metabolism at bilateral medial temporal lobes (Fig. 1c). MRI (day 33) detected hyperintensity in the same lesions on T2 and fluid-attenuated inversion recovery imaging (Fig. 1a). Long-term video EEG monitoring (days 25–26) showed frequent subclinical seizures arising from the left temporal area, which lasted 32 s (Fig. 1e). We thought autoimmune-mediated limbic encephalitis remained active and started treatment with methylprednisolone pulse therapy (1000 mg/day for 3 days), followed by plasma exchange (three times) and intravenous immunoglobulins (400 mg/kg/day for 5 days). Subsequently, serum VGKC complex antibodies were strongly positive (1154 pmol/L; normal <100) with positive anti-LGI-1 antibodies. Amnesia and FDG-PET showed minimal improvement on day 45. Therefore, additional immunotherapy with plasma exchange and dexamethasone was carried out, and levetiracetam was increased to 3000 mg/day to target suspected non-convulsive status epilepticus. His clinical symptoms gradually improved, followed by MRI and PET improvement (Fig. 1b,d). Long-term EEG monitoring (day 73) detected no subclinical seizure pattern. His serum VGKC complex antibodies were negative (40.2 pmol/L) on day 80. This case was rare, in that VGKC-LE presented only amnesia; the patient showed no other symptoms except for memory impairment, which typically co-occurs with psychosis or seizure. Butler et al. reported a case series of 19 patients with VGKC-LE, in which only one patient presented amnesia alone. A multimodal diagnostic approach has led to the diagnosis of VGKC-LE in the present case. Although MRI results from the community hospital were unremarkable, a second EEG showed ictal patterns that led to further evaluation at a tertiary referral center. MRI is a diagnostic tool,