Chutithep   Teekaput

CASE REPORT:
We report a patient who presented with progressive ophthalmoplegia, ptosis, oropharyngeal dysphagia, gait instability, and sleep disorders. The paraneoplastic antibody screening tested double- positive for IgLON5-IgG and SOX1-IgG. However, there was no clinical sign of LEMS in this patient. After extensive cancer screening, only lung nodules with hilar adenopathy were noted.

DISCUSSION:
We reported the case with chronic and severely progressive ophthalmoplegia, dysarthria, ptosis, gait disturbance, dysphagia, insomnia, and severe obstructive sleep apnea. All these features were compatible with brainstem dysfunction. IgLON5-IgG and SOX1-IgG were detected. Extensive malignancy screening showed pulmonary nodule with hilar adenopathy unchanged at the time of follow-up. This patient’s clinical symptoms were compatible with “classic” IgLON5-IgG autoimmunity disorder. Age-related brain atrophy with another prominent lesion, no CSF pleocytosis, and no increased CSF protein was compatible with the previous case series. Azathioprine and steroids were given to this patient with little response. The coexistence of IgLON5-IgG and SOX1-IgG is very rare. No case report was identified of a double- positive case. IgLON5-IgG spectrum disease mostly presents with central nervous system symptoms especially brainstem dysfunction while SOX1-IgG patients are likely to have peripheral nervous system symptoms (mostly were LEMS) which was not found in this patient. However, the presence of onconeuronal antibodies would predict cancer rather than a specific neurological syndrome. This case could not prove the malignancy by pathological tissue except for the pulmonary nodules by imaging. But the limited form of lung cancer could not be ruled out even though the lung nodules and mediastinal nodes had not changed eighteen months later. The tumor suppression ability of the cytotoxic T cell which also caused the paraneoplastic neurological disease may explain this finding. In pathologically established CJD cases, autoantibodies against the N-methyl-D-aspartate (NMDA) receptor or the voltage-gated potassium channel (VGKC) complex have been identified in serum but not in CSF(5). In another study, anti-NMDAR was found to be co-existing with anti-aquaporin 4 (AQP4) or anti- myelin oligodendrocyte glycoprotein (MOG)(6,7). The release of antigens by neuronal cell death as a result of the degenerative process could explain secondary autoimmunity from neurodegeneration. These antigens may activate the immune system production of antibodies that target cell surface antigens. Contrarily, SOX1-IgG targets the antigen at the nucleus, not the cell surface epitope. We considered that the positive findings of coexisting IgLON5-IgG with SOX1-IgG would suggest the paraneoplastic process which may support the underlying immune-mediated process of primary autoimmunity rather than the secondary immunity due to neurodegeneration. Until now, there was a scarcity of information on prognosis and management in individuals with double- positive antibodies. In a published study, patients with positive NMDA receptor-IgG with anti-AQP4 or anti- MOG antibodies may have atypical and overlapping symptoms for both disorders, making diagnosis difficult.6 Compared to our case, positive IgLON5-IgG and SOX1- IgG may share both classic symptoms of IgLON5-IgG and SOX1-IgG-related diseases. Double-positive cases might carry poorer outcomes. However, further studies are required to explain the association. From our autoimmune screening laboratory database 2010-2017 comprising approximately 13,000 samples, there were five positive samples for SOX1-IgG or anti- glail nuclear antibody (AGNA). The first case is a 77-year- old man who presented necrotizing myopathy. The second case was a 66-year-old man who presented with polyneuropathy. The third case involved a 52-year-old lady who had sensory ataxia. The fourth case is a 79-year- old man suffering from encephalopathy. The fifth case is a 67-year-old woman who had cerebellar ataxia. Only one of five cases (the third case) had concomitant tissue- confirmed SCLC. In contrast to earlier published studies, the symptoms of individuals in our registry were not limited to LEMS. However, the data on underlying tumors in each case was limited because our institute is a referral center for mainly laboratory investigations. Tissue-proven investigation, on the other hand, is invasive and not commonly available. The presence of the SOX1-IgG in our case could be a subsequent autoantibody following glial cell death, or it could be co-existing, as patients with autoimmune disease frequently have several antibodies. Coexisting paraneoplastic antibodies are not uncommonly encountered and help to predict cancer(8). Even though the presence of co-existing antibodies may not be clinically significant, it is suggested that tumor-negative individuals with onconeuronal antibodies undergo serial tumor surveillance for at least two to five years(9). However, further studies and case series were needed to evaluate this association.