Anti‐IgLON5 Disease Responsive to Immunotherapy: A Case Report with an Abnormal MRI

Case Report

A 65‐year‐old man presented with a 3‐month history of gait disturbance, generalized chorea, and painful intermittent cervical dystonia. He also reported sleep disruption, mood changes, and irritability. He had a medical history of hypertension and polymyalgia rheumatica. There was no family history. Neurological examination evidenced moderate generalized chorea, dystonia of the neck, mild unsteady gait, and subtle dysarthria. There were no signs of parkinsonism or limitation of eye movements. Also, no Kayser‐Fleischer ring, xanthomas, or signs of neuropathy were observed. A neuropsychiatric assessment evidenced emotional lability with no neurocognitive impairment. A blood test showed normal iron profile, cholestanol, phytanic acid levels, vitamin E, copper, ceruloplasmin, creatine kinase, chitotriosidase activity, hypercoagulability, systemic autoimmunity assays, and peripheral blood smear examination. HIV and bacterial serologies were negative. Genetic testing excluded both Huntington's disease and the main Huntington's disease‐like spinocerebellar ataxia 17. A brain MRI showed paramagnetic deposits in the basal ganglia, substantia nigra, and red nucleus (Fig. 1A,D). A normal CT of the brain (Fig. 1C,F) ruled out calcification. A video‐polysomnography showed fragmented sleep, motor restlessness, vocalizations, the absence of REM‐sleep, and an apnea‐hypopnea index of 57 (severe sleep apnea). Symptomatic treatment with tetrabenazine, quetiapine, trazodone, and CPAP was started.

Figure 1.

Magnetic Resonance Imaging (MRI) of the brain (T2 sequences) showing a notable hipointensity of substantia nigra and red nucleus (up: A, B) and the basal ganglia (down: D, F), congruent with metal deposits. A normal computed tomography (CT) scan of the brain (C, F) ruled out calcification of the basal ganglia. There is an increase of paramagnetic deposits: first MRI (left: A, D), second MRI, performed 9 months later, (right: B, F).

Nine months later, the patient's clinical state was suddenly impaired by an exacerbation with bulbar dysfunction (severe dysarthria, dysphagia, and aspiration pneumonia) and severe gait instability. Due to this impairment, the patient was admitted to our hospital. A lumbar puncture showed CSF pleocytosis (9 cells per mm³, 100% lymphocytes). Oligoclonal bands were negative. An autoimmune etiology of the disorder was suspected. After intravenous methylprednisolone pulses (250 mg per day for three days), the patient improved to his baseline. A total body CT was normal. At this time, a control MRI revealed an increase of paramagnetic deposits (Fig. 1B,E). AntiGAD, antiIA2, and a panel of antibodies against neuronal cell‐surface antigens (NMDAR, AMPAR, CASPR2, LGI1, DPPX, and GABAB) were negative in serum and CSF. Anti‐IgLON5 antibodies were specifically assessed, obtaining a positive result in serum and CSF (Fig. 2). HLA‐DQB1*0501 and HLA‐DRB1*10:01 alleles were present. Anti‐IgLON5 encephalopathy was diagnosed. In addition to symptomatic treatment, rituximab was started as maintenance immunosuppressive therapy. At present, four years after disease onset, the patient remains stable (slight dysarthria and mild chorea persist) with no new exacerbation.

Figure 2.

Immunoreactivity of patient's CSF, first screened by immunohistochemistry on frozen sections of rat brain (IHQ): (A) diffuse staining of the neuropil; (B) negative CSF control, and subsequently confirmed by cell‐based assay (CBA) using human epithelial kidney (HEK‐293) cells transfected with plasmids containing green fluorescent protein (GFP)‐tagged IgLON5: (C) staining (in red) of the cell surface of the transfected cells with (GFP)‐tagged IgLON5 by patient's CSF, but not by control CSF (D).

Discussion

Anti‐IgLON5 disease has recently been described as a progressive antibody‐associated encephalopathy, characterized by prominent sleep and movement abnormalities.1, 2, 3 Postmortem findings, consistent with a neuronal tauopathy involving the hypothalamus and tegmentum of the brainstem,1, 4 have placed anti‐IgLON5 disease at the convergence of neurodegenerative and autoimmune disorders.3 Parasomnias, obstructive sleep apnea, and stridor were first described as the hallmark of anti‐IgLON5 disease,1 but other symptoms have not been described nor reported in detail yet.3

We report a case of anti‐IgLON5 disease with subacute exacerbations and concomitant pleocytosis in CSF analysis. The patient improved to his baseline after immunosuppressive treatment. A temporary improvement was also reported in four other cases, but soon after the patients worsened and three died suddenly.1, 2, 3 The current case had not only temporary improvement, but also a long‐term maintained response, remaining stable with no new exacerbations. Previously, only a few cases had a maintained response.2, 5, 6 The pathogenic role of anti‐IgLON5 antibodies is supported by sudden exacerbations, CSF pleocytosis, association with anti‐IgLON5 antibody, HLA‐DQB1*05:01, HLA‐DRB1*10:01, and improvement after immunosuppression.

Moreover, in this case, an increasingly altered paramagnetic deposition on brain MRI is reported for the first time in anti‐IgLON5 encephalopathy. Increased accumulation of metals has been linked to other neurodegenerative diseases, such as Alzheimer's disease7 and to other neuroinflammatory diseases.8 Hyperphosphorylated tau accumulation is a common pathological finding in both anti‐IgLON5 encephalopathy and Alzheimer's disease. There is evidence that iron binds to hyperphosphorylated tau and induces its aggregation.9, 10 Whether there is a relation between the metal deposits of our patient and tau deposits is unknown. Additionally, excess iron can promote inflammatory states and could be a consequence of inflammatory activity.8 Even if no conclusion can be drawn from just one case, the progression of metal deposits in MRI during disease impairment makes it unlikely that metal deposits would be merely coincidental. Whether or not neurologists should acknowledge anti‐IgLON5 encephalopathy in patients with metal deposits in the brain MRI will be elucidated if our finding is reproduced in additional cases. Nevertheless, the lack of genetic testing for diseases associated with iron accumulation should be noted as a limitation of this case report.

To conclude, as a novel entity, the pathogenicity of anti‐IgLON5 antibodies, the role of neuroimaging, and the clinical features of a potentially treatable early stage of the disease, remain unknown. Although the majority of previously reported cases had poor responsiveness to immunotherapy, the favorable outcome of this case supports that, in clinical practice, immunotherapy must be tried in all anti‐IgLON5 encephalopathies.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

A.M‐E.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B.

K.B.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B.

M.G‐O.: 2A, 2B, 2C, 3A, 3B.

B.T.: 3A, 3B.

T.F‐V.: 3A, 3B.

J.C.G‐E.: 3A, 3B.

Disclosures

Ethical Compliance Statement: 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. To ensure confidentiality and anonymity of our patient, we presented only images and clinical data. The patient allowed authors to use those clinical data for scientific research and publication purposes, giving written informed consent, according to the requirement of the Clinical Research Ethics Committee (CREC) of Cruces University Hospital.

Funding Sources and Conflict 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 for the previous 12 months.