A case of unusual presentation with anti-glycine receptor (GlyR) and myelin oligodentrocyte glycoprotein (MOG) antibody

Abstract

Movement disorders can be a prominent feature in autoimmune encephalitis. Here we present a rare case of a 73-year-old woman, who presented with a complex phenotype with encephalopathy, parkinsonism, cervical dystonia, left-sided hemidystonia and hemifacial spasm of subacute onset and was found to have breast cancer and positive anti-Glycine Receptor (GlyR) and Myelin Oligodentrocyte Glycoprotein (MOG) antibodies.

Dear Editor,

Autoimmune encephalitis is a rapidly expanding group of diseases, characterized by an immune response against neuronal antigens with production of specific autoantibodies [1]. Movement disorders are a prominent feature in many cases of autoimmune encephalitis with or without other neurological manifestations [2]. The type of movement disorder varies usually according to the associated autoantibodies, albeit there is a significant phenotypical overlap between the different syndromes [2].

A 73-year-old woman with a past medical history of hypertension and osteoporosis was admitted at the neurological department with altered mental status, hyperkinesias, dystonic posture of the neck and left hand, and gait disturbance since one month. Neurological examination revealed a combination of hypophonia and dystonic speech, dysphagia, cervical dystonia (laterocaput to the left and torticollis to the right), dystonic posture of the hands (more prominent on the left) (video,https://www.youtube.com/watch?v=dRtdc9VWvIY&ab_channel=StefaniaKalampokini) and occasionally of the left foot with inversion, mild extrapyramidal rigidity, rest tremor of the hands and wrist and patella clonus on the left. The patient had constant myoclonic jerks of the left half of the face, which persisted during sleep. There was no hyperekplexia. The patient was disorientated, irritable and at times uncooperative, she was unable to sit and stand unassisted. A nasogastric tube had to be placed for feeding. Trihexyphenidyl (2 mg OD) was initiated for dystonia, however had to be discontinued due to hallucinations. Levodopa (400 mg/d) did not have any effect on parkinsonism and was discontinued. The myoclonic jerks did not respond to treatment with clonazepam or levetiracetam.

Brain magnetic resonance imaging (MRI) revealed small vessel disease without evidence of lesion in the basal ganglia (Fig. 1). Cerebrospinal fluid (CSF) examination showed normal cells, glucose and lactate, protein was slightly elevated. Cytologic examination of CSF revealed reactive lymphocytes without suggestion for B- or malignant cells. Electroencephalograph showed periodic delta activity in the frontotemporal areas without any signs of sharp-wave discharges. Computer tomography of thorax and abdomen revealed slightly enlarged axillary lymph nodes. Breast ultrasound revealed a hypoechoic 11 mm mass in the left breast. Biopsy revealed a mucinous carcinoma Nottingham histologic score grade III. anti-MOG antibodies were positive in serum (>1/320) and weak positive in CSF. anti-GlyR antibodies were positive in serum (1:100) and ambiguous in the CSF. anti-GABAb Receptor antibodies were ambiguous in serum. anti-Caspr2, LGI1, NMDAR, mGluR5 in both serum and CSF were negative. Amphiphysin, anti-CV2, Hu, Ri, SOX1, Yo, Zic4, Tr, Titin, GAD were negative in serum. All the above antibodies were tested using cell based assays with the exception of GAD antibodies, which were tested using ELISA.

Fig. 1.

MRI brain sequences on the level of the basal ganglia a) T1 b) T1 with contrast c) T2 and d) Diffusion-weighted imaging (DWI).

The patient received intravenous steroids (1 gr/d) for 5 days and underwent plasmapheresis (5 sessions) without significant improvement. She then received intravenous immunoglobulin (0.4 mg/Kg bodyweight/day) for 5 days with partial remission of her symptoms after completion. The patient became orientated, her speech, voice, neck dystonia and myoclonus improved. The nasogastric tube could be removed and she could walk with assistance. Steroids were given orally (1 mg/kg) and tapered within two months. The patient received letrozole and underwent surgical removal of carcinoma as well as adjuvant radiotherapy. The patient continued to receive intravenous immunoglobulin (1 gr/ Kg bodyweight) every-two months. Anti-MOG antibodies after three months and one year were found to be positive in serum (>1/320 on both occasions) and anti-GlyR antibodies weakly positive (<1/100 and 1/50 respectively). At six-month and one year follow-up, she had only mild rest and postural hand tremor, mild left-sided hemidystonia and rigidity, swallowing and speech were normal. She also remained in complete remission with regard to malignancy. Follow-up brain MRI of the brain and cervical spine on both occasions showed no significant changes.

Our patient fulfilled the criteria for autoimmune encephalitis [1]. Double positivity for GlyR and MOG antibodies as well as clinical response to immunotherapy and breast cancer treatment further supported this diagnosis. anti-MOG antibodies have been reported as a marker of autoimmune/paraneoplastic encephalitis mostly in children and rarer in adults[3]. They have also been reported in association with LGI1-[3] or NMDA-receptor antibodies [4]. In this context, we hypothesize that GlyR antibodies, which have been previously associated with paraneoplastic conditions [5], and breast cancer as well[6] could be peripherally triggered by cancer cells and subsequently gained access into the CNS to exert their blocking effects on glycine receptors in the basal ganglia [7]. MOG antibodies may well represent a bystander effect of tumor-related immune response.

GlyR antibodies are commonly associated with stiff-person spectrum disorders, which comprise variants ranging from isolated stiff-limb symptoms to progressive encephalitis with rigidity and myoclonus (PERM) [5]. The commonest movement disorders associated with anti-GlyR antibodies are axial and limb rigidity, myoclonus, gait disorder [5], cerebellar ataxia and parkinsonism[4] while there were rare cases of laryngeal dystonia and hyperkinesias (hemiballism/tics) described[5]. ‘’Lockjaw’’ dystonia, has been reported in stiff person spectrum disorders[4] but it is the first time cervical or limb dystonia is described in that context.

This case adds to the growing phenotypic spectrum of GlyR-related autoimmune syndromes. A movement disorder of subacute onset should be a red flag for a treatable immune-mediated condition. Tumor screening should be considered in cases of MOG positivity along with other antibodies positivity. Lastly, not only novel antibodies are steadily discovered, but various phenotypes are associated with known antibodies. This redefines our thinking of movement disorders and immunological neurological diseases.

1. Study Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

2. Ethical standard

The patient gave written consent for the anonymous publication of her case with video without personally identifiable information.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.