Late-onset narcolepsy type 1 comorbid with anti-IgLON5 disease in an older male patient

INTRODUCTION

A 66-year-old man was referred to our hospital with a 2-year history of excessive daytime sleepiness. The irresistible sleepiness could occur at any time of day, even while eating food and chatting with friends. He also experienced a 1-year history of cataplexy triggered by strong emotions, particularly of a positive nature (laughing), and occasionally negative emotions (anger). These cataplexy episodes leading to a fall with retained consciousness were generally brief and lasted around 1 minute. Polysomnography revealed a short sleep latency of 0.5 minutes, as well as poor sleep architecture with longer wakefulness after sleep and four instances of rapid eye movement sleep at onset. Multiple Sleep Latency Test examinations showed lower mean sleep latency of 4 minutes and five instances of rapid eye movement sleep at onset (Figure 1). Polysomnography revealed severe sleep apnea with an apnea-hypopnea index of 52.4 events/h; the minimum oxygen saturation associated with apnea was 87.0%. The patient’s bedpartner reported snoring and other unusual respiratory sounds (sleep apnea) at home since he was young. There were no abnormal behaviors reported during sleep. However, the patient refused to undergo a lumbar puncture for the cerebrospinal fluid (CSF) analysis. Narcolepsy with sleep apnea was diagnosed at his first visit. He started on duloxetine. A single morning dose of duloxetine 60 mg led to cataplexy decrease and excessive daytime sleepiness improvement.

Figure 1. PSG and MSLT tests showed disorganized sleep architecture with lower mean sleep latency of 4 minutes and instances of REM sleep at onset (arrows).

MSLT = Multiple Sleep Latency Test, PSG = polysomnography, REM = rapid eye movement.

One year later, the patient reported experiencing breathing difficulties while awake during the second admission. Additionally, the patient began to develop gait instability, dysarthria, dysphagia, and ataxia. Alongside these symptoms, significant cognitive impairment was also observed. The second video polysomnography showed poor sleep architecture, with a total sleep time of 203 minutes and increased frequency and duration of wakefulness throughout the entire night. Interestingly, the apnea-hypopnea index during the second polysomnography was only 5.02, indicating rare occurrences of hypopnea during sleep. However, multiple central apnea and hypopnea events were observed during wakefulness (Figure 2). Brain magnetic resonance imaging showed atrophy and white matter demyelination. The patient agreed to undergo a lumbar puncture to be evaluated for autoimmune disease. The CSF level of orexin-A (hypocretin-1) was very low at 35.26 pg/mL (> 200 pg/mL). Human leukocyte antigen (HLA) typing was performed and the patient presented with HLA-DRB1*07:01 and *15:01 allele, HLA-DQB1*02:02 and *06:02 allele. The analysis of antibodies by cell-based assay revealed the presence of positive anti-IgLON5 antibodies in the patient’s serum at a titer of 1:30. However, these antibodies were not detected in the patient’s CSF. To further confirm these findings, immunoprecipitation assays were conducted. The results of the immunoprecipitation assays confirmed that the patient was indeed positive for the anti-IgLON5 antibody in the serum but not in CSF. The diagnosis of anti-IgLON5 disease was confirmed.

Figure 2. PSG revealed disorganized sleep architecture with central sleep apnea mainly occurred during wakefulness (red rectangle).

PSG = polysomnography.

The patient was treated with immunotherapy including single courses of intravenous methylprednisolone during hospitalization and long-term oral low-dose corticosteroids after discharge. After 3 months of immunotherapy, gait instability, dysarthria, dysphagia, and ataxia had mild improvement. Although there was an initial improvement in neurodegeneration symptoms with immunotherapy, after a few months he reported symptoms had continued to progress. At the last follow-up with telephone, he was unable to walk by himself.

QUESTION: Why have the patient’s symptoms not been significantly improved after immunotherapy?

ANSWER: The neuropathological mechanisms underlying the dysfunction of IgLON5 disease involve the accumulation of hyperphosphorylated tau protein in neurons, leading to neuronal dysfunction.

DISCUSSION

It is reported that up to 68% of patients with the anti-IgLON5 disease describe sleep problems at the initial visit,¹ but cataplexy has not been reported as far as we know. A very low hypocretin-1 level in CSF revealed the impairment of the hypocretin-producing neurons in the hypothalamus. The patient’s HLA-DQB1*06:02 allele, which is the most impactful risk factor in narcolepsy type 1,² suggests that there may be an autoimmune mechanism at play, with a higher prevalence of autoimmune diseases.^3,4 Since the causality for hypocretin cell destruction through autoimmune mechanisms was not yet been proven, it is reasonable to consider alternative explanations. One possibility is that the patient coincidentally developed late-onset narcolepsy type 1 and anti-IgLON5 disease, which have distinct pathophysiological mechanisms. Alternatively, narcolepsy with cataplexy could be a secondary manifestation of anti-IgLON5 disease, caused by autoimmune attack on the hypothalamus by anti-IgLON5 disease antibodies.⁵

The precise neuropathological mechanisms underlying the dysfunction of IgLON5 caused by antibodies are still not fully understood. It is yet to be determined whether the underlying pathophysiology of anti-IgLON5 disease is neurodegenerative or autoimmune. One potential mechanism involves the accumulation of hyperphosphorylated tau protein in neurons, leading to neuronal dysfunction. This process primarily affects the hypothalamus and, to a greater extent, the tegmental nuclei of the brainstem, with a gradually increasing severity along the cranio-caudal axis until the upper cervical cord.⁶ Furthermore, a strong association has been observed between the disease and the presence of the microtubule-associated protein tau H1 haplotype, suggesting a potential involvement of neurodegenerative processes in anti-IgLON5 disease.⁷ Additionally, a recent study using patient-derived anti-IgLON5 antibodies demonstrated their ability to induce disease symptoms in animal models, indicating an irreversible impact on neuronal function and abnormal behaviors.⁸ Although clinical and basic research studies have provided insights into the characteristics of anti-IgLON5 disease, it is evident that it exhibits features of both autoimmunity and neurodegeneration due to the distinctive activity of anti-IgLON5 antibodies.⁹

Overall, this report highlights the need for testing for autoantibodies in older patients with late-onset sleep manifestations and for clinicians to consider the potential relationship between narcolepsy and autoimmune diseases.^10,11 Further studies are necessary to better understand the pathophysiology and treatment options for autoimmune diseases.

SLEEP MEDICINE PEARLS

1. Patients with IgLON5 antibodies could develop a characteristic sleep disorder at the initial stage of the disease.

2. Patients with HLA-DQB1*06:02 allele, which is the most impactful risk factor in narcolepsy type 1, are usually associated with a higher prevalence of autoimmune diseases.

3. The potential neuropathological mechanisms of anti-IgLON5 disease involve neurodegenerative and autoimmune processes.

4. Testing for autoantibodies should be considered in older patients with late-onset sleep manifestations, and clinicians should consider the potential relationship between narcolepsy and autoimmune diseases.

DISCLOSURE STATEMENT

Study funding was received from the National Key R&D Program of China (Grant No.2022YFC2503806). The authors report no conflicts of interest.