Novel clinical features of glycine receptor antibody syndrome

Discussion

This series adds to the growing phenotypic spectrum of glycine receptor autoimmunity. GlyR antibodies have recently been described as strongly associated with spinal and brainstem disorders and SPS-spectrum phenotype. The clinical features of GlyR-associated SPSD continue to evolve. Martinez-Hernandez et al.¹ described a cohort of 121 patients with SPS in which those with GlyR antibodies were found to develop SPS-plus phenotypes (defined by all or partial elements of PERM with brainstem dysfunction, myoclonus, upper or lower motor neuron symptoms, sensory and/or autonomic dysfunction, seizures, and cognitive changes) compared with those isolated GAD65-seropositive or GAD65-seronegative patients. In this series, all patients had a positive GlyR autoantibody in the serum. One limitation of the study, due to the lack of CSF availability, was that most patients did not have testing for CSF antibodies (table e-1, links.lww.com/NXI/A127). Documentation of CSF GlyR antibody positivity has been well described in PERM phenotypes⁴; however, GlyR antibodies in the sera have been reported in patients with a more diverse neurologic phenotype including oculomotor disturbance,⁴ encephalopathy,⁴ SPSD,^4,12 and epilepsy in the absence of CSF positivity.¹³ The presence of sera positivity in these more diverse neurologic phenotypes and in other immune-mediated neurologic diseases (e.g., seen concurrently with other autoantibody syndromes including aquaporin-4 or myelin oligodendrocyte glycoprotein antibody syndromes and MS controls)^1,14,15 and in control samples found to have underlying cancer,^15,16 suggests that the specificity of serum GlyR is likely not as strong compared with CSF testing. Previous literature suggests that CSF testing might improve specificity,¹² whereas another study has supported the use of serum antibody testing as sufficient to support diagnosis in the proper clinical context.⁴ Here, we expand on the SPS-plus phenotypes to include novel visual symptoms, autoimmune epilepsy, a cerebellar syndrome, and atypical SPS phenotypes with parkinsonian features including a presentation of MSA in patients with antiglycine receptor antibody disease.

Although previous studies have described GlyR antibody patients with optic neuropathy and progressive vision loss³ and ocular dysmotility,⁴ positive visual phenomena or palinopsia have not been previously described. Patients 1 and 2 presented with several years of visual symptoms before the onset of progressive lower extremity stiffness and cramping. Patient 3 had evidence of retinal dysfunction with an abnormal full-field ERG. Therefore, visual disturbances may be an early hint to the GlyR autoimmunity in the appropriate clinical setting. Because GlyRα1 is a major inhibitory neurotransmitter of the human retina,¹⁰ dysregulated signaling may result in positive visual phenomena and unformed visual hallucinations. Further neuro-ophthalmologic investigations are needed to clarify potential retinal and cortical contributions.

GlyRs have been identified in various regions of the basal ganglia, including lower concentrations in the striatum and globus pallidus and higher concentration in the substantia nigra.⁸ Given the presence of these GlyRs in the basal ganglia, it is hypothesized that GlyRs may form another inhibitory mechanism modulating basal ganglia function. This is relevant, as it may suggest that parkinsonism present in a subset of patients could be related to GlyR autoimmunity. Glycine stimulates striational and mesolimbic dopamine release.¹⁷ Notably, 42% of patients in this series had evidence of parkinsonian features on their neurologic examination, and 2 patients had a positive DaT scan.

GlyRα1-IgG, like other cell surface antibodies, targets membrane neuronal surface receptors and alters synaptic transmission. The mechanism for hereditary hyperekplexia inspired the discovery of mutated GlyR resulting in muscle stiffness and an exaggerated hyperstartle response. GlyR antibodies have been described to activate complement and cause receptor internalization via lysosomal pathways,⁴ which would be compatible with the clinical signs of decreased glycinergic neurotransmission and the loss of brainstem and spinal inhibition seen in hyperekplexia.¹⁸ The GlyR antibody–mediated pathology could be similar in the basal ganglia and retina, and direct study may provide novel insights into GlyR antibody immunopathophysiology.

GlyR antibodies can coexist with variable titers of GAD65 antibodies. In this study, 53% of patients were identified to have coexisting GAD65 antibodies, most of which were considered low titer (41% of the total cohort). Other prior published reports have seen a similar coexistence of these antibodies.^3,4,12 The coexistence of GAD65 and GlyR is unlikely explained on the basis of cross-reaction alone, given the difference in testing methods—specifically cell-based assay for GlyR and radioimmunoassay for GAD65 testing. Prior published studies have suggested that coexpression of GAD65 and GlyR antibodies portent a good clinical response to immunosuppression.^4,12 Our experience with immunotherapy in this series, however, was not as promising. Although patients may have experienced an initial response to immunosuppression, many developed a relapsing or progressive course. These differences could be due to the longer follow-up time in our study (range 2 months to 17 years) or small sample size.

Clinicians should consider testing for GlyR antibodies in negative or low-positive GAD65 autoantibody patients with SPS-like presentations, especially in the setting of atypical features such as visual disturbances or parkinsonism. Our observation broadens the spectrum of clinical presentations associated with GlyR antibodies and emphasizes clinical presentations outside of the classic SPS and PERM phenotypes. Furthermore, although some patients responded quite well to immunomodulation initially, many had a more progressive, immunotherapy-refractory course, especially when followed over time.