Anti-Ma2 Encephalitis as a Treatable Cause of Narcolepsy Type 1: A Case Report

Introduction

Autoimmune encephalitis (AIE) is a group of neuroinflammatory disorders mediated by anti-neuronal antibodies, characterized by diverse clinical manifestations involving structures such as the limbic system, brainstem, cerebellum, and diencephalon [1]. With advances in neuroimmunology and the widespread application of antibody testing, numerous AIE subtypes have been identified. Anti-Ma2 encephalitis is an important paraneoplastic autoimmune encephalitis, predominantly affecting male patients with testicular germ cell tumors. Typical manifestations include limbic encephalitis, ocular motility disturbances (particularly vertical gaze palsy), excessive daytime sleepiness, and widespread brainstem-diencephalic dysfunction [2].

Sleep-wake disturbances are among the common yet frequently overlooked core symptoms of AIE. Studies indicate that approximately two-thirds of AIE patients exhibit significant sleep architecture abnormalities or impaired wakefulness [3,4]. In anti-Ma2 encephalitis, central hypersomnia occurs in 20% to 40% of cases [2,5]. The mechanism is closely linked to autoimmune attack on hypocretin/orexin-producing neurons in the hypothalamus, leading to decreased cerebrospinal fluid (CSF) hypocretin-1 levels and resulting in a clinical phenotype very similar to idiopathic narcolepsy type 1, including cataplexy and sleep paralysis [5,6].

Although the association between anti-Ma2 encephalitis and hypocretin-deficient central hypersomnia is increasingly recognized, well-documented cases fulfilling strict diagnostic criteria – namely, the presence of excessive daytime sleepiness, cataplexy, abnormal Multiple Sleep Latency Test (MSLT) findings, and reduced CSF hypocretin-1 levels – remain rare, with only a handful of cases described in detail over the past decade [7,8]. The complex and often subacute clinical presentation of such cases, particularly in older adults, frequently leads to diagnostic delay or misclassification as idiopathic NT1, underscoring the urgent need for systematic antibody screening and neurophysiological evaluation in atypical presentations. Furthermore, the optimal therapeutic strategies and long-term prognosis for these patients remain poorly defined, representing a significant clinical challenge [4,7].

This article reports a compelling case of an older man who presented with a rapid progression of severe daytime sleepiness, cataplexy, and cognitive decline, ultimately diagnosed as anti-Ma2 encephalitis secondary to NT1. This case is noteworthy for its exemplification of the diagnostic dilemmas posed by overlapping symptomatology and its comprehensive multimodal workup, which serves as a model for clinical practice. By detailing the diagnostic workup, polysomnography (PSG) and MSLT characteristics, treatment response, and follow-up outcomes, we aim to bridge the gap between emerging immunological knowledge and clinical application. We seek to enhance clinicians’ recognition of this syndrome, provide insights into overcoming diagnostic challenges, and emphasize the importance of early intervention and multidisciplinary management based on multimodal evaluation.

Case Report

HISTORY OF PRESENT ILLNESS:

The patient developed excessive daytime sleepiness (EDS) 6 months earlier without an obvious trigger. He experienced irresistible sleep attacks during daily activities, occurring 5 to 6 times per day, each lasting approximately 10 min. He would awaken spontaneously, and brief naps temporarily improved his alertness. Nocturnal sleep quality was poor, with frequent awakenings, vivid dreaming, and hypnagogic hallucinations; recall of dream content was vague upon waking. Four months after onset, he began experiencing cataplexy attacks in relaxed emotional states, manifesting as ptosis, a sensation of heavy-headedness, and weakness of the limbs without loss of consciousness, convulsions, or incontinence. By the fifth month, involuntary twitching of the mouth corner and limbs occurred during sleep episodes. Prior evaluation at another hospital was inconclusive, leading to his transfer to our institution. The subacute progression of severe EDS with cataplexy in an older man prompted a broad differential diagnosis, including autoimmune/paraneoplastic encephalitis (eg, anti-Ma2, LGI1), idiopathic narcolepsy type 1 (despite the atypical age), and other central nervous system disorders. The presence of additional neurological symptoms (cognitive decline, limb weakness) heightened the suspicion for an autoimmune etiology.

PAST MEDICAL AND PERSONAL HISTORY:

Our patient was previously healthy, with a history of smoking and alcohol consumption. His family history was notable for mental illness in his mother.

PHYSICAL EXAMINATION ON ADMISSION:

The patient was conscious and fully oriented. His Mini-Mental State Examination (MMSE) score was 25. Neurological examination revealed limited rightward gaze to the left (reportedly present since childhood); left eye movements were full, with no nystagmus or diplopia. Facial sensation was symmetric bilaterally, and the tongue protruded midline. Muscle strength was grade 5 in all limbs, with normal tone, symmetric tendon reflexes, steady coordination, and intact symmetric sensation. Pathological signs and meningeal signs were negative.

TREATMENT AND CLINICAL COURSE:

The patient was diagnosed with narcolepsy type 1 secondary to anti-Ma2-associated encephalitis. He was treated with intravenous methylprednisolone pulse therapy (1000 mg/day for 3 days, followed by 500 mg/day for 3 days, and then 250 mg/day for 3 days, subsequently tapered orally) combined with intravenous immunoglobulin (IVIG, 0.4 g/kg/day for 5 days). Following this regimen, the patient’s daytime sleepiness, cataplexy, and limb weakness significantly improved. Adjunctive symptomatic therapy was initiated with venlafaxine as a wake-promoting agent, along with zopiclone, estazolam, and GABAergic drugs to regulate sleep architecture and improve refractory hypersomnolence and nighttime sleep quality. At 1-month follow-up after discharge, his symptoms remained stable with good control of excessive daytime sleepiness.

DIAGNOSTIC CLARITY:

The diagnosis of anti-Ma2 encephalitis was confirmed by highly specific serological and CSF testing, which effectively excluded alternative etiologies such as idiopathic NT1 (clinically inconsistent with the patient’s age and additional neurological deficits) and other autoimmune or paraneoplastic syndromes (comprehensive antibody panel negative for NMDAR, LGI1, and CASPR2).

This case, with its atypical age of onset and full narcolepsy phenotype, underscores that anti-Ma2 encephalitis can closely mimic idiopathic NT1. A high index of suspicion, coupled with the systematic diagnostic approach outlined herein, is critical for identifying this treatable condition.

Discussion

This report presents a case of an older man with severe daytime sleepiness, cataplexy, and cognitive decline, who was ultimately diagnosed with anti-Ma2 encephalitis secondary to narcolepsy type 1 through comprehensive neuroimmunological testing, CSF hypocretin-1 analysis, and neurophysiological evaluation [2,6]. This case report not only reinforces the established association between anti-Ma2 encephalitis and sleep-wake disturbances but also offers practical insights for diagnosing and managing this rare disorder. Notably, the patient’s advanced age (60 years) at onset is atypical for both idiopathic NT1 (which typically presents in adolescence) and classic anti-Ma2 encephalitis (which often affects younger males with tumors), highlighting the diagnostic challenge and expanding the known clinical spectrum of this paraneoplastic syndrome.

Recent studies have further elucidated the pathophysiological link between anti-Ma2 encephalitis and narcolepsy. The core mechanism involves an immune-mediated attack on hypothalamic and brainstem structures [6], particularly the selective damage to hypocretin/orexin-producing neurons, leading to significantly reduced or absent CSF hypocretin-1 levels. In our patient, the CSF hypocretin-1 level was markedly decreased to 22.836 pg/mL (reference range >200 pg/mL), biochemically supporting this mechanism and aligning with previously reported cases [10]. This degree of deficiency is comparable to that seen in severe idiopathic NT1 and is more profound than that reported in some other autoimmune hypersomnias, strengthening the specific link to the narcolepsy phenotype in this context.

Differential diagnosis should carefully distinguish this condition from idiopathic narcolepsy type 1. Although both disorders share core symptoms such as excessive daytime sleepiness, cataplexy, sleep-related hallucinations, and low cerebrospinal fluid (CSF) hypocretin-1 levels, they differ significantly in clinical context and disease course. Idiopathic narcolepsy type 1 typically manifests during adolescence, is rarely accompanied by other neurological signs or structural abnormalities on neuroimaging, and is strongly associated with the HLA-DQB1*06: 02 allele [11,12]. In contrast, the present case featured a subacute onset in an older patient, accompanied by cognitive impairment, ataxia, and ocular movement abnormalities in addition to sleep symptoms. Brain MRI revealed white-matter abnormalities, and both serum and CSF were positive for anti-Ma2 antibodies, supporting a diagnosis of secondary narcolepsy in the context of paraneoplastic/autoimmune encephalitis. Furthermore, the patient’s neurological symptoms partially resolved, with marked improvement in daytime sleepiness, following treatment with corticosteroids and intravenous immunoglobulin. Therefore, new-onset hypersomnia-cataplexy syndrome in adults, particularly when accompanied by multifocal neurological deficits, should raise a strong suspicion for an autoimmune etiology and warrants comprehensive antibody testing and neuroimaging evaluation.

The diagnostic process in this case underscores the critical role of polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). Initial evaluation identified comorbid sleep apnea; however, the MSLT objectively revealed the underlying central hypersomnia-significantly shortened mean sleep latency and multiple sleep-onset REM periods (SOREMPs), thus fulfilling the electrophysiological diagnostic criteria for narcolepsy. This highlights the importance of actively addressing comorbid and treatable factors in patients with suspected autoimmune central hypersomnia and performing repeat assessments when feasible to avoid underdiagnosis. The presence of SOREMPs in 60% of naps is a striking feature, aligning closely with the classic narcoleptic profile and providing objective evidence distinct from other causes of hypersomnia [13].

Therapeutic management in this case illustrates a dual treatment strategy. The choice of high-dose corticosteroid pulse therapy combined with IVIG was based on established protocols for severe autoimmune encephalitis, aiming for rapid immune suppression. This was prioritized due to the subacute progression and the presence of multiple neurological deficits (cognitive decline, limb weakness). For symptomatic management of hypersomnia, venlafaxine was selected for its dual benefit in managing both cataplexy and daytime sleepiness, while zopiclone and estazolam were introduced to address poor nocturnal sleep quality, a factor exacerbating daytime symptoms. GABAergic drugs were added as an adjunctive neuromodulator. This combination was chosen over first-line narcolepsy drugs like modafinil or sodium oxybate due to the primary need to address the autoimmune process and the patient’s complex symptom profile. The sequential improvement – first in limb weakness and then in sleepiness – supports the rationale of this dual-track approach. Immunotherapy (corticosteroids combined with IVIG) effectively suppressed neuroinflammation and improved certain neurological symptoms (eg, limb weakness); however, its effect on hypersomnia resulting from irreversible hypocretin neuron loss was limited and delayed. Thus, early initiation of symptomatic treatments, including wake-promoting (such as venlafaxine in this case) and sedative-hypnotic agents (such as zopiclone, estazolam, and GABAergic drugs in this case), in conjunction with immunotherapy is essential for alleviating symptoms and improving quality of life [11].

It is noteworthy that although PET-CT in this case showed no evidence of malignancy, anti-Ma2 encephalitis is a well-defined paraneoplastic syndrome, most associated with testicular germ cell tumors [14]. Therefore, comprehensive and ongoing tumor screening – including high-frequency ultrasonography, repeated PET scans, and serum tumor marker surveillance – is recommended in all diagnosed patients. The absence of an identified tumor at presentation, while not uncommon (reported in up to 30% of cases), mandates vigilant long-term monitoring, as tumor discovery can occur years after neurological onset.

This study has several limitations. First, the follow-up assessments, although indicating clinical stability, lacked standardized quantitative metrics such as serial Epworth Sleepiness Scale (ESS) scores or comprehensive neuropsychological testing beyond the MMSE to objectively quantify the improvement in hypersomnolence and cognitive function. Second, HLA genotyping and extended paraneoplastic antibody testing were not performed due to financial constraints, making it difficult to entirely exclude other coexisting immune factors. Furthermore, the follow-up period remains relatively short, and longer observation is needed to evaluate long-term prognosis, evolution of sleep symptoms, and potential tumor development. In conclusion, this case demonstrates that anti-Ma2 encephalitis is an important and treatable cause of secondary narcolepsy. Clinicians should maintain a high index of suspicion for autoimmune etiologies in cases of acute or subacute central hypersomnia, and pursue early antibody screening, CSF hypocretin testing, and formal sleep studies to enable timely diagnosis and integrated management. This case, with its atypical age of onset and full narcolepsy phenotype, underscores that anti-Ma2 encephalitis can mimic idiopathic NT1 with high fidelity. A high index of suspicion, coupled with the systematic diagnostic approach outlined herein, is critical for identifying this treatable condition.

Conclusions

This case definitively establishes anti-Ma2 encephalitis as a treatable cause of secondary narcolepsy type 1. The diagnosis was solidified by a characteristic triad – markedly low CSF hypocretin-1, specific MSLT findings (short latency with SOREMPs), and positive anti-Ma2 antibodies – which together tightly link the autoimmune etiology to the NT1 phenotype.

For clinical practice, we propose a standardized approach integrating antibody/hypocretin testing with PSG/MSLT for atypical hypersomnia cases. A “dual-track” therapeutic strategy combining prompt immunotherapy with symptomatic management proved effectively.

Future priorities should include systematic long-term follow-up to refine prognosis and exploration of targeted therapies. Sustained tumor surveillance is imperative. Enhanced disease recognition is crucial for timely intervention.