Morvan Syndrome Associated With Anti-LGI1 Antibodies and Thymoma

Dear Editor,

Morvan syndrome (MoS) is a rare neurological syndrome with the characteristic triad of peripheral nerve hyperexcitability, autonomic dysfunction, and encephalopathy. MoS is known to be associated with autoantibodies against voltage-gated potassium-channel complexes or proteins, such as contactin-associated protein-like 2 (CASPR2) and leucine-rich glioma inactivated-1 (LGI1).¹ While anti-CASPR2 antibodies are predominantly seen in MoS,¹ anti-LGI1-antibody-related MoS cases have rarely been reported due to the spatial characteristics of these synaptic proteins.² Here we report the first case of anti-LGI1-antibody-related MoS associated with thymoma in South Korea.

A 62-year-old male presented with progressive paresthesia in both legs originating from the soles and extending to the thighs in a nondermatomal pattern. Muscle twitching was observed in both calves, along with subjective weakness and gait disturbance. Four months later he first experienced syncope and started to present with memory impairment and disorientation. He also reported experiencing insomnia, along with talking, screaming, and flailing of the extremities as dream-enactment behaviors. The muscle twitching and gait disturbance had worsened over 6 months, resulting in the patient not being able to walk without assistance (modified Rankin Scale [mRS] score=4). He finally visited the emergency room after a generalized tonic seizure. His only medical history was diabetes mellitus (HbA1c=6.0% on admission). He had a 20-year history of heavy alcohol consumption, averaging 1,200 g per week.

A neurological examination revealed no remarkable weakness in the extremities. Mildly decreased position sensation was detected, but neither limb dysmetria nor dysdiadochokinesia was found. Continuous fasciculation on both legs was observed. He could not stand or walk more than one step without assistance, with knee buckling observed when he tried to walk. His initial score on the Mini Mental State Examination (MMSE) was 19. Laboratory tests demonstrated hyponatremia (126 mmol/L). Brain MRI and EEG showed no definite abnormalities, and the CSF profile was also unremarkable with a normal protein level (34 mg/dL). A nerve conduction study and EMG showed cervical and lumbosacral radiculopathy, and sensorimotor polyneuropathy with myokymic discharge in the extremities (Fig. 1). The findings of a repetitive nerve stimulation test were normal. An autonomic function test revealed severe cardiovagal, adrenergic, and sudomotor dysfunction with orthostatic hypotension. Chest CT for a hidden-malignancy workup revealed thymoma (Fig. 1). He was seropositive for anti-LGI1 antibodies, while negative for anti-Titin, -CASPR2, -AMPA, -DPPX, -GABA-B, and -NMDA antibodies based on cell-based immunoassays.³ Anti-GAD-II antibodies was within the normal range.

Fig. 1. Laboratory and imaging findings of the patient. A and B: Myokymic discharges in EMG. EMG was performed on the patient’s left peroneus longus, gastrocnemius, first dorsal interosseous muscles. Involuntary motor-unit discharges were observed with single, doublet, triplet, and multiplet forms (arrowheads). C: Chest CT findings. A mildly enhanced 48-mm encapsulated mass was observed at the anterior mediastinum, which was initially assumed as probable benign thymic epithelial tumor (arrow). The tumor was revealed to be thymoma (WHO type B3) after video-assisted thoracoscopic surgery thymectomy.

We made a diagnosis of anti-LGI1-related MoS and administered intravenous methylprednisolone (1 g) for 5 days, followed by intravenous immunoglobulin (IVIG). While receiving IVIG, the patient underwent thymectomy. As soon as he received methylprednisolone, his sleep-talking and movements disappeared, and memory impairment recovered. Although he still had paresthesia and occasional muscle twitching in his legs, the gait disturbance was markedly improved. The patient was able to walk and stand up independently when he was discharged and at the 3-month follow-up (mRS score=2, MMSE score=30).

This patient represented a rare case of MoS with anti-LGI1 antibodies as the only detected autoantibody. It was particularly interesting that this patient had thymoma, and that 2 cases of MoS out of 85 patients with thymoma-related autoimmune diseases carried anti-CASPR2 antibodies.⁴ Two most-common MoS-associated antibodies (anti-LGI1 and anti-CASPR2 antibodies) are known to show different clinical phenotypes. Patients with anti-CASPR2 antibodies experience symptoms involving both the central nervous system (CNS) and the peripheral nervous system (PNS), while patients with anti-LGI1 antibodies mainly experience CNS symptoms such as limbic encephalitis. Nevertheless, there have been reports of LGI1 expression in the PNS⁵,⁶ and rare cases showing peripheral nerve hyperexcitability with only anti-LGI1 antibodies.²,⁷ While further research is needed to fully explain this rare phenomenon, there are several hypotheses. The severity of PNS involvement could be influenced by individual genetic susceptibility. Alternatively, anti-LGI1 antibodies might share specific domains with other LGI proteins, such as LGI4, which has a stronger association with PNS,⁶,⁸ or false-negative anti-CASPR2 antibodies results might occur due to low antibody levels.

Anti-LGI1 antibody positive patients reportedly show good response rates to first-line immunotherapies, ranging from 83% to 100%,⁹,¹⁰ although long-term follow-ups have demonstrated that 33% of patients relapse within 2 years.¹⁰ On the other hand, the prognosis of MoS is known to be worse when thymoma is present, regardless of its degree of malignancy.¹ Although the present patient responded well to first-line immunotherapy, further follow-up is required to understand the long-term prognosis of MoS with isolated LGI1 antibodies.

Availability of Data and Material

The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.