m<scp>G</scp>lur5 Encephalitis Causing Myoclonus‐Ataxia Syndrome and Psychosis: A Case Report

Metabotropic glutamate receptors (mGluRs) are involved in synaptic transmission and neuronal excitability. Encephalitis related to mGluR-1 or mGluR-2 antibodies commonly exhibit cerebellar syndrome. In 2011, mGluR-5 antibodies were found in patients with Hodgkin lymphoma and limbic encephalitis (Ophelia's syndrome).1 Since then, few cases reported have expanded the clinical spectrum, comprising prominent neuropsychiatric features, amnesia, prosopagnosia, movement disorders, and seizures. Pleocytosis in cerebrospinal fluid (CSF) and MRI abnormalities are common. Besides Hodgkin lymphoma or small-cell lung cancer, it can also occur without a tumor. Immunomodulatory therapy and tumor removal are effective, but relapses may occur.2-4 A 69-year-old right-handed man with no medical history or family history presented acutely with flu-like symptoms, headache, odynophagia, dysphagia, and hypophonia. Amoxicillin provides no benefit. Two days later, continuous semi-rhythmic jerks began on the left side of the face, throat, and right foot. In the following month, his jerking movements continued, persisting during sleep, accompanied by dysarthria, feeding difficulties, balance issues, and weight loss. After an unremarkable head CT and an unsuccessful trial with risperidone, he was admitted to hospital because of aspiration pneumonia. An extensive etiological study was inconclusive; see Table 1. Diagnosed with possible Creutzfeldt-Jackob disease, he was discharged with valproic acid 750 mg TID, levetiracetam 500 mg TID, and diazepam 5 mg daily with no benefit. Additionally, anterograde memory difficulties, prosopagnosia, visual hallucinations, hypersomnia, snoring, sleep apnea, seemingly purposeful movements during sleep (Video 1, Segment 1), and maculopapular rash on proximal arms and lower back emerged, see Figure 1. White cells 16 mm3, mononuclear 94%, Proteins 39 mg/dL, Glucose 64 mg/mL, Lactate 15.9 mmol/L. Negative Gram staining, film Array, current and fungi cultures, VDRL, India ink, adenosine deaminase. Negative oligoclonal bands. Negative cytological study. Negative for neoplasm. Subtle right pleural effusion. Prostate-specific antigen: 7.26 ng/mL Negative carcinoembryonic antigen and CA19-9. Negative Anti amphyfisin, anti CV2, PNMA2 (Ma2/Ta), Ri, Yo, Hu, Recoverin, SOX1, Titin, Zic4, GAD-65, Tr (DNER). Sample: Blood Method: Immunoblot Negative for CASPR2, AMPAR 1/ 2, LGI1, DPPX, GABAb R1/R2 antibodies Sample: Blood Method: commercial indirect immunofluorescence cell-based assay (IF-CBA) Positive for serum IgG anti- mGluR5 ab. (CSF sample was negative). Negative for: NMDAR, AMPAR1/2, CASPR2, LGI1, DPPX, GABAb R1/R2, GAD65, and IgLON5 ab. Sample: CSF and Blood Method: IF-CBA by EUROIMMUN Two months after symptoms onset, he visited our clinic. At that time, neurological examination revealed attention and delayed memory deficit, dysarthria, hypophonia, downward vertical gaze palsy, and gaze fixation impairment. He exhibited action-induced myoclonus on the left hemiface, with slight stimulus-induced myoclonus when taping his upper lip and gaze-evoked myoclonus of the forehead. He displayed prominent right lower limb action-induced myoclonus and marked stimulus-sensitive right-foot myoclonus (Video 1, Segment 2). No oculopalatal myoclonus was observed. He exhibited paratonia but no signs of motor-neuron dysfunction. He had lower limb pallhypesthesia and severe difficulties walking unassisted, walking in tandem, or performing the Romberg test. The finger-to-nose assessment revealed no dysmetria. An immune-mediated encephalitis was suspected. A new brain MRI and EEG were normal. A fluorodeoxyglucose whole-body PET scan showed a hypermetabolic prostate focus. The autoimmune encephalitis panel and onconeural antibodies panel were negative, see Table 1. A new lumbar puncture and an expanded autoimmune encephalitis panel were ordered, revealing mild hyperproteinorrachia and positive mGluR5 serum antibodies by cell-based immunofluorescence assay; the sample was titer at 1/5 and 1/10 and still positive (the technique reports a sensitivity of 75% and specificity of 99.9% for serum samples and only 45% sensitivity for CSF samples). With the diagnosis of mGluR5-encephalitis, 3 months after symptoms onset, methylprednisolone was started at 1000 mg/day for 5 days, followed a month later by Intravenous immunoglobulin (IVIg) 2 g/kg over 5 days. Psychosis, sleep problems, and memory issues disappeared, myoclonus improved, and he was able to walk without assistance again (Video 1, Segment 3). Myoclonus recurred a month after receiving IVIg. Therefore, a plasmapheresis cycle was performed, resulting in independent gait, and marked improvement of myoclonus. The patient's modified ranking score improved from 4 at the peak of the disease to 2 at the last follow-up. A prostate biopsy was positive for an acinar adenocarcinoma. The patient received 3 months of Isoniazid plus rifapentine after the interferon-γ release assay detected latent tuberculosis infection. At the time of sending this article, it has been over a year since the onset of the patient's symptoms. The patient has been on rituximab for about a month, which has resulted in the remission of myoclonus. Currently, he is waiting for oncological treatment. Our patient exhibited various red flags for autoimmune encephalitis, including flu-like symptoms, subacute-onset progressive neuropsychiatric symptoms, sleep disorders, epilepsia-partialis-continua, new onset movement disorders, and brainstem symptoms; unspecific abnormalities in the EEG and a neoplasm. Noteworthy, immune-mediated encephalitis may not always show abnormalities in brain MR-imaging, EEG testing, or identification of neuronal autoantibodies in blood or CSF.5 As recommended, in patients with subacute onset myoclonus accompanied by encephalopathy, seizures, brainstem involvement, autonomic features, and a recent major sleep disorder, CASPR2, LGI1, DPPX, GlyR, and IgLON5 antibodies should be considered.6 Likewise, myoclonus is a feature of mGluR-antibodies-related encephalitis. Our report contributes to a better clinical comprehension of mGluR5 encephalitis. Unlike insomnia or daytime sleepiness, parasomnias have rarely been reported. Status epilepticus is common; however, to the best of our knowledge, this is the first report of epilepsia-partialis-continua related to mGluR5 encephalitis. The combination of vertical gaze palsy and myoclonus-ataxia syndrome, with prominent stimulus-sensitive foot myoclonus, is a novel finding. Remarkably, ataxia is less common in mGluR5 than other mGluR encephalitis.3 Skin changes, which are not well characterized in the literature, seem less likely to be explained by other etiology. The link between prostate cancer and encephalitis is uncertain,2 and oncological treatment and a longer follow-up are required to draw conclusions. Our patient responded well to immunotherapy despite delayed treatment and early relapse.3 (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. P.A.S: 1A, 1B, 1C, 2A O.T.G., P.L.I., P.C.C.: 2B Ethical Compliance Statement: The Center for Movement Disorders CETRAM's institutional review board approved the study. Written consent was obtained from the patient and their family and documented for this publication. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.

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