1. INTRODUCTIONNarcolepsy is a chronic neurological disorder primarily characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis1. Globally, its prevalence ranges from 25 to 50 per 100,000 individuals2. The disease’s core mechanism involves the selective loss of hypothalamic hypocretin neurons, a process closely linked to abnormal immune system activities. Diagnosing and treating narcolepsy present numerous clinical challenges, especially in pediatric and adolescent patients whose complex and varied symptoms often lead to misdiagnoses. Therefore, early and accurate diagnosis, along with personalized treatment plans, are essential for enhancing patients’ quality of life.In this paper, we review a case of narcolepsy treated in our department in 2024, providing a detailed account of the patient’s clinical manifestations and the diagnostic and therapeutic processes. Through this case analysis, we aim to offer clinical practitioners valuable insights for the diagnosis and treatment of narcolepsy.Case PresentationPatient: Female, 11 years old, first-year middle school student.Chief Complaints: Excessive daytime sleepiness and hallucinations for 4 years, memory decline for 2 years.Present Illness: Four years ago, the patient developed a fever with a maximum body temperature of 38°C following a cold. Laboratory tests at a local hospital revealed an elevated anti-streptolysin O (ASO) titer of 311 IU/mL, suggesting a streptococcal infection. The patient received anti-inflammatory treatment at a local clinic and showed improvement after one week. However, two weeks later, the patient gradually began experiencing excessive daytime sleepiness, characterized by uncontrollable episodes of drowsiness, including sudden sleep attacks even during meals. At night, she frequently experienced hypnagogic hallucinations, such as out-of-body experiences and seeing grotesque figures, often accompanied by screaming. During sleep, she exhibited involuntary leg movements and loud vocalizations. For a period of six months, the patient remained undiagnosed and did not receive systematic treatment at local medical facilities, with no improvement in symptoms. Subsequently, the patient was referred to Shanghai Children’s Hospital for further evaluation. Laboratory tests, including complete blood count, C-reactive protein (CRP), biochemistry, electrolytes, myocardial enzyme profile, cellular and humoral immunity, complement, autoantibodies, and neuron-specific enolase (NSE), revealed no significant abnormalities. However, the ASO titer was elevated at 1328 IU/ml. Cerebrospinal fluid (CSF) analysis showed normal levels of white blood cells (WBC), red blood cells (RBC), aspartate aminotransferase (AST), creatine kinase (CK), lactate dehydrogenase (LDH), glucose, chloride (Cl), adenosine deaminase (ADA), protein, and lactate. No pathogens, including Cryptococcus, hyphae, spores, bacteria, or acid-fast bacilli, were detected in the CSF. EEG findings were abnormal, showing moderate to low amplitude 9-10c/s α waves, low amplitude 14-17 c/s β waves, and low amplitude 5-7c/s δ waves, along with 2-4c/s δ waves. The multiple sleep latency test (MSLT) indicated PSG patterns consistent with narcolepsy. MRI of the brain revealed slight abnormal signals in the posterior horns of both lateral ventricles and the centrum semiovale, suggesting possible localized myelination abnormalities in the white matter. The patient was diagnosed with narcolepsy and streptococcal infection. Following treatment with long-acting penicillin, her anti-streptolysin O levels gradually returned to normal. However, after starting methylphenidate, the patient experienced difficulty initiating sleep at night and worsening hypnagogic hallucinations, leading to self-discontinuation of the medication. There was no significant improvement in her daytime sleepiness or hypnagogic hallucinations. Over time, she developed auditory hallucinations, engaging in imaginary conversations, and spontaneous laughter. There were no symptoms of depression, hyperactivity, or paranoid delusions. Three years ago, she was diagnosed with a ”psychiatric disorder” at the Shanghai Mental Health Center and was treated with risperidone (up to 4.5 mg/day), after which she gradually developed involuntary mouth movements, tongue licking, and body tilting. Two years ago, her daytime sleepiness symptoms gradually resolved, but she began experiencing significant memory impairment, frequent episodes of staring blankly, slowed reactions, difficulty with academic performance, and poor personal hygiene, often going days without washing her face or brushing her teeth. She is currently on medical leave and staying at home. Recently, she continues to exhibit involuntary mouth opening, tongue and lip licking, and body tilting, with occasional auditory hallucinations. She requires assistance with daily activities but does not exhibit symptoms of depression or spontaneous laughter. Her parents have brought her to our hospital for further treatment.Her past medical, personal, and family history were unremarkable.Physical Examination on Admission: Internal medicine and neurological examinations were unremarkable.Psychiatric Examination: The patient is alert and oriented but presents with a disheveled appearance. She engages passively in interactions but provides appropriate responses to questions. Auditory hallucinations are present; she occasionally hears voices of several people talking about live-streaming sales, which she perceives as unrelated to herself. There were no illusions or complex perceptual disturbances. No delusions of reference or persecution were detected. The patient denied feelings of depression and anxiety, and her emotional responses were appropriate. However, she showed decreased attention, memory, and calculation abilities, with partial insight.Auxiliary Examinations: Wechsler Intelligence Test: Total score 88 (General Knowledge 8, Classification 10, Picture Completion 3, Block Design 12), below the normal level. Memory Test: Memory quotient of 71, indicating borderline memory function. Social Dysfunction Screening Scale (SDSS): Mild dysfunction, with a decline in daily living or working abilities. Activities of Daily Living Scale (ADL): Total score 17, indicating varying degrees of functional decline in daily activities. Attention Span Test: Total score 8, indicating ”poor concentration.”Admission Diagnosis: 1. Mental disorders caused by brain organic diseases. 2. Tardive Dyskinesia.Treatment Course:The patient was advised to undergo further evaluation in the Department of Neurology to rule out the possibility of organic brain disease. The dosage of risperidone was gradually reduced to 1 mg/day to minimize extrapyramidal side effects associated with antipsychotic medications. Following treatment, the patient’s auditory hallucinations resolved, and symptoms such as body tilting and mouth opening significantly improved. After discharge, the patient was encouraged to maintain a regular sleep schedule and participate in rehabilitation exercises.DiscussionIn this case, the patient exhibited clear symptoms of daytime sleepiness and vivid hypnagogic hallucinations following a streptococcal infection, which met the diagnostic criteria for narcolepsy. As the disease progressed, the patient developed psychotic symptoms, primarily characterized by hallucinations and apathy, which were also attributed to organic brain changes induced by the streptococcal infection. Unfortunately, the patient did not receive an early diagnosis or timely treatment. During the use of wake-promoting agents, the patient’s psychotic symptoms worsened. Additionally, the patient was misdiagnosed with ”psychiatric disorder” for an extended period and received long-term, high-dose antipsychotic treatment, leading to extrapyramidal side effects. As the psychotic symptoms improved, the dosage of antipsychotic medications was gradually reduced, resulting in alleviation of the extrapyramidal side effects.Narcolepsy is commonly regarded as a central nervous system disorder arising from the interplay of genetic predisposition, environmental factors, and immune responses. Its pathophysiology is complex, centered around the selective loss or dysfunction of hypocretin neurons in the hypothalamus, closely linked to aberrant immune activity3. For instance, certain infections (bacterial or viral) or vaccinations may trigger an immune response that leads to the damage of these neurons4. Research indicates that prior to the onset of narcolepsy, children are over five times more likely to have experienced streptococcal infection compared to the general pediatric population5. Streptococcal infection may serve as an environmental trigger by increasing blood-brain barrier permeability through T-cell activation during inflammatory and febrile responses, thereby facilitating an autoimmune attack on hypocretin neurons in the hypothalamus.Genetic factors also play a critical role in the pathogenesis of narcolepsy. The HLA-DQB1*06:02 allele has been strongly associated with the disease, significantly raising the risk of its development in carriers. This allele may alter immune system function, making it more susceptible to initiating an autoimmune response against hypocretin neurons. Additionally, specific amino acid variations, such as Serine182 and Threonine185 located on the DQβ1 chain receptor epitope, have been identified as increasing susceptibility to narcolepsy6.The coexistence of narcolepsy and psychotic-like symptoms presents significant clinical complexity and demands careful attention. A systematic review by Haninet et al.7, which analyzed 100 full-text articles on narcolepsy and psychotic symptoms, identified two categories of psychotic-like symptoms in narcolepsy patients. The first category involves typical narcolepsy patients who predominantly experience visual hallucinations during the sleep-wake transition (e.g., when falling asleep or waking up), which patients usually recognize as unreal. The second category includes atypical narcolepsy patients who may encounter more severe, vivid REM-related hallucinations or a blurring of the line between dreams and reality, sometimes rationalized as delusions. The early-stage psychotic symptoms observed in the patient described in this case likely correspond to the first type, characterized by frequent visual hallucinations before sleep without significant delusional symptoms.Although there have been case reports of narcolepsy coexisting with schizophrenia, this comorbidity is relatively rare. In this case, following the narcoleptic-like symptoms, the patient developed hallucinations and disorganized behavior, which were considered to result from functional changes due to organic brain disease rather than from comorbid schizophrenia. Additionally, her psychotic symptoms were not associated with sleep disturbances. For instance, two cases of narcolepsy comorbid with schizophrenia have been reported in China, with both showing symptom improvement following antipsychotic therapy8,9. It is important to note that hallucinations in narcolepsy typically occur during the sleep-wake transition, while in schizophrenia, hallucinations are more frequently observed during periods of wakefulness 7. This distinction may be attributed to the loss of hypocretin neurons in narcolepsy, which allows REM sleep phenomena (such as dreaming) to intrude into wakefulness, thereby causing hallucinations during the transition between sleep and wakefulness. In contrast, schizophrenia is associated with an imbalance in dopamine and other neurotransmitters in the brain, leading to hallucinations and delusions in the absence of external stimuli10.Cognitive impairment associated with narcolepsy is a significant concern that requires careful attention. In this case, the patient exhibited a gradual decline in cognitive functions, including intelligence, attention, and memory, as well as in social functioning. These observations are consistent with findings from several studies. A systematic review analyzing cognitive function in patients with central hypersomnia disorders revealed that type 1 narcolepsy patients show pronounced deficits in attention. Although their memory function generally remains intact, they display a complex pattern of impairment in higher cognitive functions, such as poor decision-making and difficulties in emotional processing11. The mechanisms by which narcolepsy contributes to cognitive decline are not yet fully understood. In this case, the cognitive impairment that manifested later in the course of the illness is more likely associated with post-infectious organic brain changes. Some researchers have observed that type 1 narcolepsy patients exhibit reduced whole-brain network efficiency during the N2 sleep stage12. Further studies by Ni et al., using diffusion tensor imaging (DTI), identified topological abnormalities in the brain’s white matter network in NT1 patients, linking these structural changes to cognitive decline. The decreased efficiency of the whole-brain white matter network may underlie the observed deterioration in both cognitive and social functioning in these patients13.This case report describes a patient who developed narcolepsy following a streptococcal infection. Unfortunately, the patient did not receive an early diagnosis or timely treatment. During the use of wake-promoting agents, the patient’s psychotic symptoms worsened, and long-term high-dose antipsychotic treatment led to the development of extrapyramidal side effects. This case highlights the need for clinicians to enhance their understanding of streptococcal infection-related narcolepsy and to emphasize early diagnosis and individualized treatment strategies.