Anti‐metabotropic glutamate receptor 5 encephalitis: Five case reports and literature review

Abstract Objective To describe the clinical and radiological characteristics of anti‐metabotropic glutamate receptor 5 (mGluR5) encephalitis. Methods We reviewed the clinical data of five patients with anti‐mGluR5 encephalitis, and performed a literature review. Results The five cases included a 52‐year‐old man who developed a biphasic course of anti‐mGluR5 encephalitis after herpes simplex encephalitis, a 22‐year‐old woman who showed bilateral basal ganglia lesions on brain magnetic resonance imaging (MRI), and a 36‐year‐old man with mixed aphasia and generalized tonic‐clonic seizures, a 51‐year‐old man presented with personality changes, hallucinations, delusions, sleeping disorders and a 58‐year‐old man with short‐term memory deficits and absence seizures.. There are 16 reported cases of anti‐mGluR5 encephalitis worldwide. Of all 21 patients, with a median onset age of 35 years old, the main neurological symptoms were cognitive impairment (85.7%, 18/21), psychiatric or behavior problems (76.2%, 16/21), seizures (57.1%, 12/21), sleeping disorders (52.4%, 11/21), different degrees of decreased consciousness (42.9%, 9/21), and movement disorders (23.8%, 5/21). Brain MRI was normal in 11 of 21 patients. Lesions of the limbic lobes were presented in 5 patients, while involvement of other extralimbic regions was also reported. Seven of 21 (33.3%) cases were combined with tumors. Elevated white blood cell counts or specific oligoclonal IgG bands in the cerebrospinal fluid were found in 18 of 21 patients, with marked improvements observed after immunotherapy. Discussion Patients with anti‐mGluR5 encephalitis typically present with diffuse, rather than purely limbic, encephalitis. Anti‐mGluR5 encephalitis can be triggered by herpes simplex encephalitis. The risk of a combined tumor may be reduced in anti‐mGluR5 encephalitis patients.


INTRODUCTION
Anti-metabotropic glutamate receptor 5 (mGluR5) encephalitis is a rare neurological autoimmunity disease, which was first identified in two patients with limbic encephalitis (Ophelia syndrome) (Lancaster et al., 2011). With the increasing numbers of nonparaneoplastic cases, anti-mGluR5 antibodies are now classified into intermediate-risk antibodies using the latest diagnostic criteria for paraneoplastic neurologic syndromes (Graus et al., 2021).
To our knowledge, only 16 cases of anti-mGluR5 encephalitis have been reported since the discovery of anti-mGluR5 autoantibodies in 2011. In the present study, we report five additional patients with anti-mGluR5 encephalitis from the Encephalitis Collaborative Group, including a case with post-herpes simplex virus encephalitis (HSE) anti-mGluR5 encephalitis, and a case with bilateral basal ganglia lesions on brain MRI. We also summarize the phenotype of this rare autoimmune encephalitis by reviewing peer-reviewed cases reported in the English and Chinese literature.

Literature review
Previous cases reported in English and Chinese peer-reviewed journals between 1 January 1990 and 1 August 2022 were identified with the "PubMed/Medline," "Web of Science," "Embase," and "China National Knowledge Infrastructure" databases, using the search strings "anti-mGluR5 encephalitis" or "metabotropic glutamate receptor 5 AND encephalitis."

Standard protocol approvals, registrations, and patient consents
This study was approved by the Ethics Committee of PUMCH (JS-891).
All patients or their representatives signed a written informed consent form.

Case 1
A 52-year-old man was admitted to a hospital with fever, vomiting, diarrhea, generalized tonic-clonic seizures, sensory aphasia. His Glasgow Coma Scale score at admission was E4V2M5.

Case 2
A previously healthy 22-year-old woman was hospitalized with insomnia and short-term memory deficits for 1 month. At admission, she

F I G U R E 2
Examples of anti-metabotropic glutamate receptor 5 antibodies in tissue-based and cell-based assays. The detection of autoimmune encephalitis autoantibodies in rat hippocampus sections was carried out using immunofluorescence and the results were then confirmed using a cell-based assay that involved human embryonic kidney (HEK) 293 cells that over-expressed the mGluR5 after they were transfected with the cognate cDNA. (a) Immunoreactivity of CSF from Case 1 in a tissue-based assay, with neuropil (arrowed) staining of the hippocampus of rat brain sections (×100). (b) Reactivity of CSF from Case 1 in a cell-based assay of HEK293 cells expressing mGluR5 (×200).

Case 3
A 36-year-old man was admitted because of mixed aphasia for 3 months and generalized tonic-clonic seizures. Brain MRI showed no encephalitis-related lesions. Spikes were noticed in bilateral frontal regions. CSF showed 2×106/L leukocytes, while specific OCB was positive. Anti-mGluR5 antibody testing was positive in the serum (1:10) and negative in the CSF. Tumor screening was negative. Diagnosed with anti-mGluR5 encephalitis, he was treated with glucocorticoids and IVIg. At 6 months of follow-up, he was seizure free with significant improvement in his mixed aphasia.
F I G U R E 3 Brain magnetic resonance imaging of Case 2. Patchy fluid-attenuated inversion recovery lesions were observed in the bilateral medial temporal lobes (a) and basal ganglia, and the bilateral insula lobes (b).

Case 4
A 51-year-old man was admitted to the hospital with personality changes for 1 year, hallucinations, delusions and sleeping disorders for 3 months. Physical examination showed MoCA score was 7/30 (delayed memory 0/5). Abnormal signals were noticed in bilateral medial temporal lobes in brain MRI. CSF showed 16×106/L leukocytes. Anti-mGluR5 antibody testing was negative in the CSF but positive in the serum (1:10). He was administered intravenous methylprednisolone (500 mg/d) for 5 days and tapered to oral prednisone (60 mg/d). At discharge, the score reached 13/30 and after 4 months of follow-up, his mental state gradually became stable and he could even go out to buy food.

Case 5
A 58-year-old man presented with short-term memory deficits and

DISCUSSION
Although some early studies reported anti-mGluR5 encephalitis as lim-   , these patients require screening for tumors at long-term follow-up.
A marked improvement was observed after immunotherapy in most reported anti-mGluR5 encephalitis patients. However, in the present study, Case 1 had a poor outcome after IVIg and steroids, which may be due to the residual parenchymal damage after HSE. It was previously reported that the outcomes of post-HSE autoimmune encephalitis patients were markedly worse than those of classical ones (Armangue et al., 2018), and that rituximab treatment could improve the residual symptoms in post-HSE anti-NMDAR encephalitis (Dorcet et al., 2020). Further studies examining the efficacy of rituximab in post-viral autoimmune encephalitis are required.
In summary, we found that anti-mGluR5 encephalitis is often associated with a wide range clinical symptoms and radiological extralimbic lesions and HSE is a potential trigger of anti-mGluR5 encephalitis. Further reports of nonparaneoplastic patients indicate the lower risk of combined tumors in anti-mGluR5 encephalitis.

CONFLICT OF INTEREST STATEMENT
The author declares that there is no conflict of interest.

DATA AVAILABILITY STATEMENT
Anonymized data are available from the corresponding author for replicating the procedures.