Protracted Presentation of Anti‐LGI 1 Encephalitis Associated with Prostate Cancer: A Case Report

Autoimmune encephalitis mediated by leucine-rich glioma-inactivated 1 antibody (anti-LGI1) classically presents over weeks to months with faciobrachial dystonic seizures (FBDS) in older men, involving the face, arm, and occasionally the leg.1, 2 These seizures are usually preceded by a frontal electrodecremental pattern and infra-slow activity on electroencephalography (EEG).3 Early immunotherapy after diagnosis is recommended to prevent irreversible cognitive impairment.4 The anti-LGI1 is a low-risk paraneoplastic antibody, with a tumor detected in less than 10% of the cases, typically thymoma or neuroendocrine neoplasms.5-7 We present a case of anti-LGI1 encephalitis with FBDS and lower-limb involvement that is unique due to its protracted (>2 year) course, association with prostate cancer, and substantial improvement with cancer treatment in the absence of immunotherapy. A 62-year-old man presented with a 2-year history of paroxysmal movements in his right hemibody. Initially, his right fifth finger started to extend for 3 to 5 s involuntarily, and the episodes occurred twice or thrice daily. Two months after onset, the movements spread to his mouth, causing lip deviation to the right and tongue protrusion. After 7 months, right leg extension was added to the episodic movements (Video 1). The episodes gradually increased in frequency, occurring every 10 min, including during sleep. There were no associated sensory symptoms or specific triggers. Cognitive assessment was not performed, although the patient reported no cognitive symptoms. Anti-LG1 was measured using the fixed cell-based assay (CBA). Serum was reported as weak positive for anti-LGI1 after 1 year of symptoms (London Health Sciences Centre Clinical Immunology laboratory) and as high positive for anti-LGI1 after 2 years of symptoms (Mitogen Diagnostics Laboratory). Serum testing was performed at 1:10 dilution. Further dilutions to determine endpoint serum titer by fixed CBA were not performed. Cerebrospinal fluid was analyzed, and anti-LGI1 was negative after 2 years of symptoms (Mitogen Diagnostics Laboratory). He had low serum sodium (124–133 mmol/L). Brain magnetic resonance imaging showed nonspecific small T2-FLAIR (fluid attenuated inversion recovery) hyperintense lesions in the subcortical white matter. Surface electromyography (EMG) of the FBDS showed burst durations of 2.5 s, beginning in the quadriceps and spreading to the upper-limb and facial muscles (Fig. 1). The jerk-locked EMG–EEG analysis showed frontal electrodecremental activity (Fz, F3) at 1.9 s and central infra-slow activity (Cz and C3) at 0.4 s preceding the movement (Fig. 1). Brain fluorodeoxyglucose positron emission tomography showed asymmetric increased metabolic activity within the left caudate nucleus. Treatment with clonazepam and lorazepam was ineffective. The patient had a previous diagnosis of acinar adenocarcinoma of the prostate and underwent prostatectomy 4 years earlier. For 2 years, he had low levels of prostate-specific antigen (PSA) until the FBDS started, when PSA levels increased from 0.014 to 0.22 μg/L (Fig. 2). The cancer was classified as biochemically recurrent, and he was treated with radiotherapy. After radiotherapy, FBDS significantly improved; 5 months after completing a course of 6-month androgen deprivation therapy and a 2-month course of salvage radiotherapy to the prostate bed and pelvis, the PSA titers decreased to <0.008 μg/L and FBDS reduced in amplitude and frequency, occurring approximately thrice weekly. Immunotherapy with the aim of completely preventing seizures was discussed. However, because his symptoms were not disruptive to his daily life, his preference was to monitor and revisit immunotherapy if they worsened. Eleven months after cancer-specific therapy, he reported no more FBDS episodes in the previous 30 days and denied cognitive symptoms (Montreal Cognitive Assessment 26/30, with 3 points lost on delayed recall). This patient is unique in several respects. He had a protracted disease course, yet he did not develop progressive cognitive impairment, which frequently follows FBDS in patients with anti-LGI1 encephalitis.4, 8 Although more definitive confirmation of a link between anti-LGI1 and prostate cancer would involve testing neoplastic tissue for LGI1 expression, the temporal correlation between the onset of anti-LGI1 encephalitis symptoms and the increase in PSA levels, along with the significant symptom reduction after cancer treatment, strongly suggests that anti-LGI1 encephalitis was secondary to prostate cancer in this case. Cancer has rarely been associated with anti-LGI1,6, 9 with prostate cancer being one of the previously recognized types of cancers associated with this antibody.10 Our patient emphasizes the importance of considering a paraneoplastic etiology even in patients with autoimmune encephalitis who harbor low-risk antibodies. Although it is well established that immunotherapy is the best treatment for FBDS and has been shown to prevent cognitive impairment,4 our patient deferred immunotherapy. Therefore, it is unknown whether this could have led to further symptom improvement. However, his dramatic improvement with prostate cancer treatment emphasizes the importance of cancer treatment in suspected paraneoplastic neurologic syndromes. In a previous series, lower-limb involvement was described in 34% of the patients with FBDS.2 Typically, muscle activation during an FBDS event initiates in the face or upper limb and then spreads to the other body parts. However, in the case described, the muscle activation during an FBDS episode began in the lower limb and subsequently spread to the arm and face, which is uncommon.2, 8 The shift of the preceding infra-slow EEG activity from the previously described frontal region3 to the central region might be related to the prominence of the movements in the lower limb. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the first draft, B. Review and critique. T.G.: 1B, 1C, 2A P.T.: 1C, 2B A.B.: 1C, 2B R.C.: 1A, 2B A.E.L.: 1A, 1B, 2B We thank the patient for consenting to the publication of his videos and Paul Saha for his assistance with the electrophysiological recordings and analysis. Ethical Compliance Statement: Written consent to be videotaped and have case published was obtained and documented from the patient. We confirm that the approval of an institutional review board was not required for this work. 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: T.G. reports unrelated disclosures, including a grant from Canadian DMRF. P.T. reports no disclosures. A.B. reports unrelated disclosures, including that he holds the London Health Sciences Centre and London Health Sciences Foundation Chair in Neural Antibody Testing for Neuro-Inflammatory Diseases and is supported by the Opportunities Fund of the Academic Health Sciences Centre Alternative Funding Plan of the Academic Medical Organization of Southwestern Ontario (AMOSO). R.C. reports unrelated disclosures, including consultancy for AbbVie, Ipsen, and Merz and research grant from CIHR. And A.E.L. reports unrelated disclosures, including that he has served as advisor for AbbVie, Amylyx, Aprinoia, Biogen, BioAdvance, Biohaven, BioVie, BlueRock, BMS, Denali, Janssen, Lilly, Pharma 2B, Sun Pharma, and UCB; received honoraria from Sun Pharma, AbbVie, and Sunovion; received grants from Brain Canada, Canadian Institutes of Health Research, Edmond J. Safra Philanthropic Foundation, the Michael J. Fox Foundation, the Ontario Brain Institute, the Parkinson Foundation, Parkinson Canada, and the W. Garfield Weston Foundation; is serving as an expert witness in litigation related to paraquat and Parkinson's disease; and received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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