Autoimmune encephalitis with coexistent LGI1 and GABA_BR1 antibodies: case report

Abstract

Background

Autoimmune encephalitis (AE) with multiple auto-antibodies is of great clinical significance because its complex clinical manifestations and atypical imaging increase the difficulty of diagnosis, differential diagnosis and treatment, which may aggravate the disease, increase the recurrence rate and mortality. The coexistence of anti-Leucinie-rich Glioma Inactivated 1 (LGI1) and anti-γ-aminobutyric acid-beta-receptor 1 (GABA_BR1) has not been published before.

Case presentation

We herein present the case of a 60-year-old man with slow response, behavioral changes, psychosis and sleep disorders. Laboratory test included serum hyponatremia, positive serum LGI1 and GABA_BR1 antibodies using transfected cell-based assays. Electroencephalogram exhibited moderate diffusion abnormality. The patient responded well to steroid impulse treatment and sodium supplement therapy, and did not recur during the follow-up.

Conclusions

Here we report the first AE characterized by positive LGI1 and GABA_BR1 antibodies, as well as summarizing AE with multiple auto-antibodies reported so far, hopefully to provide experience for clinical practice.

Background

There are basically two kinds of auto-antibodies related to autoimmune encephalitis (AE). One is against neuron surface receptor, among which anti- N-methyl-D-aspartic acid receptor (anti-NMDAR) is the most common, others also including anti-γ-aminobutyric acid-beta-receptor (anti-GABA_BR), anti-contactin associated protein-like 2 (anti-CASPR2), anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (anti-AMPAR), anti-Leucinie-rich Glioma Inactivated 1 (anti-LGI1), etc. The other kind is against neuronal intracellular antigen, mainly referring to classic paraneoplastic neuropathy antibody, such as anti-Hu, etc. [1, 2]. The majority of AE patients have only one of the above auto-antibodies, and very few have multiple auto-antibodies.

Different types of auto-antibodies correspond to specific neurological syndrome, which has strong specificity or directivity for etiological diagnosis. Both LGI1 and GABA_BR1 are autoantigens of treatment-response limbic encephalitis, whose clinical manifestations include the rapid development of mood changes, depression, anxiety and dramatic loss of short-term memory [3]. LGI1-AE is characterized by confusion, cognitive impairment, sleep disorder, refractory hyponatremia, fascio-brachial dystonic seizures and high signal in medial temporal lobe and hippocampus [4]. The symptoms of GABA_BR1-AE include cognitive dysfunction, seizures and abnormal behavior [5]. The simultaneous occurrence of both antibodies has not been reported before. Herein we report a case of a 60-year-old man with positive anti-LGI1 and anti-GABA_BR who improved greatly after steroid therapy. We aim to remind physicians of this rare AE case with multiple auto-antibodies in potential clinical context.

Case presentation

A 60-year-old Chinese male has developed slow response, abnormal behavior and sleep disorder for 1 month. At first, after admitted to the hospital in his hometown and given only sodium supplement and support treatment, his symptoms disappeared but quickly reoccurred. After that, his symptoms became more and more serious and he gradually developed seizures and irritability. He demonstrated confusion, memory loss, insomnia and abnormal behavior when transferred to our hospital in April 2020.

He had no particular previous medical history except for typhia 40 years ago and recovered with no sequel. Neurological exam revealed poor mental state, slow response and damaged memory, attention, calculation and orientation. Cranial nerves, cerebellar function, motor system, sensory system, deep tendon reflexes and pathological reflexes remained normal.

Serum sodium was 119 mmol/L (reference range: 135 ~ 153 mmol/mL) and chlorine was 81 mmol/L (reference range: 90 ~ 110 mmol/L) at first admission. Serum procalcitonin was 0.048 ng/mL (reference range: < 0.046 ng/mL), C reaction protein was 8.05 mg/L (reference range: < 5 mg/L). Cerebrospinal fluid (CSF) electrophoresis IgG index was 0.71 (reference range: 0.3 ~ 0.7). Intracranial pressure was 150mmH₂O. CSF routine biochemistry for protein content and glucose were normal and infectious test for virus, including herpes simplex virus, tuberculosis, fungal and Cryptococcus were negative. CSF cytology and cytometry were negative for malignant cells. Serum AE antibody spectrum demonstrated positive anti-LGI1 IgG and anti-GABA_BR1 IgG using cell-based assays, while other AE-related auto-antibody, such as anti-NMDAR, anti-AMPAR1, anti-AMPAR2, anti-CASPR2 were negative (Fig. 1). Mini mental state examination score was 15. Electroencephalogram (EEG) indicated moderate diffusion abnormality (Fig. 2A and B). Brain enhanced MRI scan was normal. Tests for screening malignancy, including tumor markers and an ultrasound of the liver, gallbladder, spleen, pancreas, kidney, testicle were normal. Chest enhanced CT scan revealed mild inflammation in left lower lobe.

Fig. 1

AE-related auto-antibodies in serum measured by cell-based assays. A NMDA; B AMPA1; C AMPA2; D CASPR2; E LGI1; F GABA R1. Anti-LGI1 and Anti-GABA_BR1 were positive

Fig. 2

A EEG of the patient before treatment (2020-04-21): moderate diffusion abnormality, Wide range of slow waves occur in medium-high waves. B EEG of the patient after treatment (2020-04-29): normal

For treatment of AE with coexistent anti-LGI1 and anti-GABA_BR1, he received 1 g and 0.5 g intravenous methylprednisolone separately, 3 days for each dosage, and then remained on an oral steroid taper for half year. After intravenous and oral sodium supplement, blood sodium and chlorine gradually increased to normal (Table 1). His symptoms improved greatly and EEG recovered to normal.

Table 1 Blood test for sodium and chlorine

Discussion and conclusion

Here we report the first case of AE with coexistent serum anti-LGI1 and anti- GABA_BR1. The 60-year-old male, with subacute onset, mainly manifested cognitive decline, behavioral abnormality, insomnia, refractory hyponatremia, abnormal EEG, and positive anti-LGI1 and anti-GABA_BR1 in serum. According to research and clinical guidelines [6], the cognitive decline, behavioral abnormality and seizures of the patient are the common clinical manifestations of LGI1-AE and GABABR1-AE, but sleep disorder is more common in LGI1-AE, and hyponatremia is unique to LGI1-AE. So, the clinical characteristics of this case were more inclined to anti-LGI1 encephalitis. The patient responded well to glucocorticoid treatment, and we will continue to follow up the prognosis.

LGI1 is a secretory protein mainly expressed in the hippocampus and neocortex, that connects presynaptic epilepsy-related ADAM23 to postsynaptic ADAM22. Anti-LGI1 interrupts the inhibitory signal transmission from the presynaptic potassium channel to the postsynaptic AMPA receptors, thus increasing the excitability of nerve tissue and resulting epilepsy or encephalitis. LGI1-AE, mostly found in elderly men with subacute onset, can demonstrate cognitive impairment, behavioral change, personality abnormality, hyponatremia and frequent seizures, characterized by facio-brachial dystonic seizures, while the majority of patients does not present with generalized tonic-clonic seizures. Most patients have no related tumors, only about 10% had thymoma, while other tumors were rare. Up to 75% of cases have normal CSF routine analysis. EEG can show mild diffuse slow wave, and about half may have swelled medial temporal lobe with high T2/flair signal. The good news is the relatively low recurrence rate [7, 8]. GABA_BR regulates voltage-sensitive calcium channel and inward compensatory potassium channels through G protein. GABA_BR is widely spread in brain and spine and particularly abundant in the hippocampus, thalamus and cerebellum. Anti-GABA_BR is related to seizures, memory loss, anxiety and mood disorder. GABA_BR1-AE mostly presents limbic encephalitis symptoms, with temporal lobe epilepsy as the core symptomatology, and most of them are accompanied by cognitive function decline, personality change and mental behavior abnormality. About 50% of patients have small cell lung cancer or neuroendocrine tumor. It is suggested that anti-GABA_BR encephalitis should further take chest CT or PET examination [9].

The overlying of neuronal auto-antibodies may cause the superposition of clinical syndrome, but not a simple complete superposition, which needs to be analyzed according to the specific antibody type and clinical manifestation. According to Professor Guan Hongzhi’s newly published review, it is necessary to distinguish whether the antibodies in patients belong to pathogenic markers or concomitant antibodies [10]. The main manifestations of this case are psychobehavioral abnormality and hyponatremia, more similar to clinical manifestations of anti-LGI1 AE.

The co-existence of multiple auto-antibody is rare (summarized in Table 2). Ren Haitao reported 531 cases of AE with auto-antibodies, and only 10 cases detected multiple anti-neuronal antibodies, among whom 5 cases were anti-GABA_BR/anti-Hu, 1 anti-NMDAR/APQ-4, 1 anti-LGI1/anti-CASPR2, 1 anti-LGI1/anti-Yo, 1 anti-AMPAR/anti-CV2 and 1 anti-AMPAR/anti-Hu [10]. In the 20 anti-GABA_BR-AE cases reported by Hoftberger, 7 detected multiple auto-antibodies, among whom 3 cases with anti-Sox1, 1 with anti-Ri, 1 with anti-amphiphysin, 1 with anti-GAD65 and 1 with anti-NMDAR [11]. Liu XY recently reported one case characterized by double positive of anti-LGI1 and anti-NMDAR [12]. Boronat reported a case of anti-GABA_BR combined with anti-GAD65, manifesting cerebellar ataxia and thyroid carcinoid [13]. Qi Hengchang reported two cases of AE with multiple auto-antibodies against neuron (one was anti-NMDAR/anti-GABA_BR, and the other anti-LGI1/anti CASPR2. Both patients were adult women with acute onset. Their first symptom was epilepsy, and the treatment effect was good [14]. Wang XJ retrospectively analyzed 255 AE patients from our hospital and found 7 cases with multiple autoantibodies [15]. Also, Qiu ZD reported 6 AE with coexistent autoantibodies out of 134 cases [16]. Chung recently described a patient with antibodies to GABAB and IgLON5, who presented with sleep disorders like our case [17].

Table 2 Clinical data of AE cases with multiple auto-antibodies

The clinical significance of multiple auto-antibody has already raised attention of many neurologists and needs to be interpreted in combination with clinical practice. For example, anti-GABA_BR can be combined with anti-Hu. When anti-GABA_BR is positive, it is recommended to screen anti-Hu and carry out tumor screening at the same time, such as chest CT, tumor markers, etc., excluding the possibility of tumor as much as possible. In this case chest enhanced CT scan didn’t find tumor, but the patient was advised to take regular examination during follow-up. However, since it’s a single case report, it might be a coincidence despite its great significance.

Here we first report an AE case with co-existing anti-LGI1 and anti-GABA_BR1. The existence of concomitant autoantibodies should be considered when the patients exhibit atypical and overlapping symptoms. Caution should be given because it’s a single-case report. With the discovery of more multiple auto-antibody positive cases of AE, it will provide evidence for further revealing the clinical characteristics, treatment and prognosis.