Narcolepsy type 1 comorbid with myasthenia gravis: possible immunological link

Abstract

Narcolepsy type 1 (NT1) has a probable autoimmune pathophysiology. Myasthenia gravis (MG) is an auto-antibody–mediated neuromuscular junction disorder. In the case report below we describe 2 women who were diagnosed with NT1 at ages 33 and 46 years, respectively. Both have seronegative MG and, although the MG was diagnosed earlier than the NT1, the symptoms of both conditions in both women started simultaneously. We discuss the potential mechanism linking these 2 conditions and the possibility of early detection of NT1 in patients with MG.

Citation:

El Sammak S, Cipriani V, Sahni A, Attarian H. Narcolepsy type 1 comorbid with myasthenia gravis: possible immunological link. J Clin Sleep Med. 2022;18(7):1889–1890.

INTRODUCTION

Narcolepsy type 1 (NT1) is a rare sleep disorder characterized by the highly selective loss of hypocretin-producing neurons in the lateral hypothalamus.¹ The association of NT1 with infections, vaccination, and HLA DQB1*06:0224 (a genetic feature of the immune system) has led to the credible hypothesis of an autoimmune etiology.¹ Myasthenia gravis (MG) is a neuromuscular junction disorder that is a prototypical autoimmune disease.² There have been, to our knowledge, no previously reported cases of concomitant onset of NT1 and MG. This report highlights 2 such cases and explores the premise of an autoimmune proclivity for both conditions.

REPORT OF CASES

Case 1

A 33-year-old woman with seronegative ocular MG for 11 years, maintained on 180 mg of pyridostigmine, complained to her neurologist of severe daytime sleepiness that started around the same time as her diplopia and MG symptoms. She reported also disturbed sleep, sleep paralysis, and cataplexy. Her MG was diagnosed clinically via repetitive stimulation, as MG antibody panel and all other autoimmune panels were normal. Polysomnography (PSG) revealed no abnormalities and a total sleep time of 417 minutes. A Multiple Sleep Latency Test (MSLT) revealed a mean sleep latency of 4.1 minutes and 4 sleep-onset rapid eye movement sleep periods. Given the clinical presentation, and the results of the PSG and MSLT, this patient fulfilled the diagnostic criteria for narcolepsy.

Case 2

A 46-year-old woman, known to have seronegative MG on mycophenolate mofetil 1000 mg daily, was referred to the sleep clinic for excessive daytime sleepiness of 16 years around the same time as her MG symptoms started. She reported cataplexy, hypnagogic/hypnopompic hallucinations, dream-enacting behaviors, night sweats, and disturbed sleep. Her MG antibody panel was negative. Her repetitive stimulation was diagnostic of MG. PSG initially revealed no sleep apnea. She was scheduled for a PSG/MSLT a few months later; this time it revealed very mild sleep apnea with an apnea-hypopnea index of 8.9 events/h. An MSLT showed a mean sleep latency of 2 minutes with 2 sleep-onset rapid eye movement sleep periods. She was subsequently placed on continuous positive airway pressure treatment of 9 cm H₂O. A repeat PSG and MSLT on therapeutic continuous positive airway pressure treatment revealed a normal PSG. An MSLT-5 nap protocol showed a mean sleep latency of 2.5 minutes and 1 sleep-onset rapid eye movement sleep period.

DISCUSSION

Our patients presented with symptoms of NT1 and MG simultaneously, reinforcing the NT1 autoimmune hypothesis.

MG is a B-cell–mediated disease that targets the autoantigen acetylcholine receptor (AChR) at the neuromuscular junction.² Several antibodies have also been explored in NT1’s pathogenesis, such as the M2 muscarinic, nociception, and β-adrenergic receptors.³

The initiation or exacerbation of MG after application of immune-checkpoint inhibitors and infectious stimuli has suggested such immune dysregulation as mechanisms for MG. Molecular mimicry and bystander activation have been explored in the pathogenesis of MG.⁴ Molecular mimicry refers to the structural similarity between nonself and self-epitopes that trigger cross-reactivity of T and B cells.⁵ Bystander activation of non–antigen-specific lymphocytes is a heterologous activation that occurs in inflammatory environments. It is mediated by indirect signals—for example, ligands of cosignaling receptors, chemokines, extracellular vesicles with microbial particles, cytokines, and extracellular vesicles with microbial particles.⁵

Similarly, these processes have been suggested in NT1. The association between the genetic marker HLA-DQB1*06:0224 and patients with NT1 with evidence of hypocretin deficiency has established the role of T cells in its pathogenesis.¹ Also, the increased incidence of NT1 after the H1N1 infection and the Pandemrix vaccination suggested a combination of external stimuli and genetic predisposition as potential triggers.⁶ A mimic peptide was identified from the influenza nucleoprotein A that shared residues in common with the hypocretin receptor, leading to the speculation that molecular mimicry may be crucial for disease development.² NT1 has also been seen after varying infectious stimuli, suggesting bystander activation and epitope spreading as underlying etiologies.¹

While Intravenous Immunoglobulin (IVIG) therapy has been proven successful in MG, limited efficacy has been seen in NT1. Nonetheless, Knudsen et al⁷ reported mild clinical efficacy upon early initiation in a pediatric cohort of patients. There is evidence that early immunotherapy in NT1 may be helpful, which indicates the possibility of a one-time immune attack with subsequent permanent damage to the hypocretin-producing neurons.

Given the predilection for NT1 to present in individuals with potential autoimmune triggers, perhaps these 2 conditions did not manifest by chance alone but rather share a provoked autoimmune reaction through mechanisms such as bystander activation, molecular mimicry, and epitope spreading. It may be possible that the treatment of MG with immunotherapy may mitigate the risk of developing narcolepsy in individuals at an increased risk. Further studies are needed to assess the incidence and prevalence of NT1 in individuals with MG and evaluate the role of immunotherapy in NT1.

ABBREVIATIONS

MG

myasthenia gravis

MSLT

Multiple Sleep Latency Test

NT1

narcolepsy type 1

PSG

polysomnography

IVIG

intravenous immunoglobulin

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. Work was performed at University of Illinois and Northwestern University. The authors report no conflicts of interest.