Narcolepsy with cataplexy (NT1) is a rare hypothalamic disorder that presents with a dysregulation of the sleep-wake cycle (i.e., excessive daytime sleepiness and sleep and cataplectic attacks) and other motor, cognitive, psychiatric, metabolic, and autonomic disturbances, with putative autoimmune pathogenesis. Pediatric acute-onset neuropsychiatric syndrome (PANS) is a clinically heterogeneous disorder that presents with acute-onset obsessive-compulsive symptoms and/or a severe eating restriction, with concomitant cognitive, behavioral, or affective symptoms caused by infections and other environmental triggers provoking an inflammatory brain response, which evolves into a chronic or progressive neuroimmune disorder. In this study, we present the case of a 13-year-old boy with vocal tics and syncopal-like episodes, eventually diagnosed as NT1 and PANS, and from this we discuss the hypothesis that both NT1 and PANS might belong to the same immunological spectrum, resulting in comparable imbalances in key neurotransmitter axes (i.e., orexinergic and dopaminergic), with conceptual and operational implications, especially with regards to the pharmacological tretament.

UNASSIGNED: This case suggests using dual orexin receptor antagonists to treat alcohol use disorder and comorbid sleep disorders may be effective, commencing treatment in withdrawal and continuing it to prevent relapse.
UNASSIGNED: Effective medications for the treatment of alcohol use disorder are limited. This is partially due to the heterogenous nature of the symptomatology associated with alcohol use disorder and the abundance of presenting comorbidities. One common, and often overlooked, symptom that occurs during withdrawal of alcohol use is sleep disruption. Here, we report a case study of a participant with comorbid alcohol use disorder and insomnia. This participant was treated with a dual orexin receptor antagonist, suvorexant (Belsomra®), currently approved to treat insomnia. We demonstrate improvements in alcohol cravings, physical and psychological health, and sleep outcomes with treatment. These data support abundant preclinical and emerging clinical data in this space. The findings from this case report highlight the potential for suvorexant to treat comorbid alcohol use disorder and insomnia with fully powered, randomized controlled trials moving forward.

Cataplexy is the sudden loss of muscle tone often provoked by emotion such as laughter or excitement. Cataplexy is one of the essential diagnostic features of Narcolepsy type 1 (NT1). We describe two cases of isolated cataplexy with different outcomes, highlighting the diagnostic and prognostic challenges. There is conflicting literature as to whether it is a legitimate standalone diagnosis or an early warning sign of narcolepsy. Our cases do not fit with current diagnostic criteria for narcolepsy, yet still share some clinical or laboratory features. These ambiguous cases question what the mechanistic relationship between narcolepsy and cataplexy may be.

Lemborexant is a dual orexin antagonist and is considered a safe and effective hypnotic. Dual orexin antagonists induce physiological sleep by blocking orexin receptors. Although the blockade of orexin signaling has triggered narcolepsy-like symptoms in rodents, there is currently no evidence of lemborexant inducing narcolepsy-like symptoms in humans. We describe the case of a 79-year-old Japanese woman with bipolar depression who experienced lemborexant-induced cataplexy and sleep attack. Her previous results on the Multiple Sleep Latency Test excluded the diagnosis of narcolepsy. She experienced narcolepsy-like symptoms on 2 occasions after she was administered lemborexant, in the context of hyperactive delirium, but not in a relaxed state. Her case suggests that lemborexant could trigger narcolepsy-like symptoms in patients with hyperactive delirium, even those with no history of narcolepsy. This case also emphasizes that clinicians must be very careful when they prescribe lemborexant to patients who experience hyperactive delirium.
Shibata S, Oda Y, Ohki N, et al. Narcolepsy-like symptoms triggered by lemborexant in the context of hyperactive delirium in a patient with bipolar depression: a case report. J Clin Sleep Med. 2022;18(5):1459-1462.

Sepsis is a potentially lethal condition characterized by systemic inflammation and multiple organ failure, and sepsis-associated encephalopathy (SAE) is an independent risk factor for mortality in patients with sepsis. We previously reported that orexin improved survival in an animal model of sepsis by acting in the brain. Peripherally administered orexin entered the brain under the conditions of systemic inflammation because of BBB dysfunction and produced survival-related effects. As a therapeutic concept, we hypothesized that orexin treatment enhances recovery from sepsis by restoring reduced orexin levels in cerebrospinal fluid (CSF). Here, we report that CSF orexin levels were reduced in a 63-year-old woman with sepsis. The patient presented with coma, fever, headache, vomiting, and seizures upon arrival at the emergency room. She had a history of subarachnoid hemorrhage which led to the development of hydrocephalus, and as a consequence, a ventriculoperitoneal shunt (VP shunt) tube had been installed to ameliorate the complication. Physical examinations showed dehydration and abnormality of circulation, arterial blood gas analysis showed insufficient oxygenation, blood tests showed an inflammatory response, liver injury, kidney injury, hyperkalemia, and hyperglycemia, and radio graphical examinations showed mild hydrocephalus and several old microinfarctions. She was diagnosed with sepsis because her Sequential Organ Failure Assessment (SOFA) score was 13 and Enterococcus faecalis was isolated form her blood and CSF. Status epilepticus, hyperglycemia, and sepsis-associated encephalopathy were considered possible causes of coma. Her CSF could be safely sampled because she had a VP shunt, although it is ethically difficult to sample CSF routinely from patients with sepsis. Reduced CSF orexin levels gradually recovered as she recovered from sepsis. Unexpectedly, orexin was detected in the blood, which is unusual in healthy humans. Blood orexin was not detected after recovery from sepsis. This result may imply that orexin leaks into the blood because of BBB dysfunction. To the best of our knowledge, this is the first report investigating orexin levels in the CSF and blood of a patient with sepsis, and the data obtained from this case may provide a new understanding of the pathophysiology of SAE.

We describe the case of a male patient who was diagnosed with narcolepsy type 1 on the basis of sleep and wake symptoms, and the results of investigations including video-polysomnography, multiple sleep latency test, human leukocyte antigen status and orexin level in cerebrospinal fluid. During the first years after disease onset, the patient did not show any significant improvement despite treatment with a variety of stimulant and anti-cataplectic drugs. However, spontaneous remission of disease occurred after 15 years.

Conditions such as Alzheimer\'s (AD) and Parkinson\'s diseases (PD) are less prevalent in cancer survivors and, overall, cancer is less prevalent in subjects with these neurodegenerative disorders. This seems to suggest that a propensity towards one type of disease may decrease the risk of the other. In addition to epidemiologic data, there is also evidence of a complex biological interconnection, with genes, proteins, and pathways often showing opposite dysregulation in cancer and neurodegenerative diseases. In this narrative review, we focus on the possible role played by orexin signaling, which is altered in patients with narcolepsy type 1 and in those with AD and PD, and which has been linked to β-amyloid brain levels and inflammation in mouse models and to cancer in cell lines. Taken together, these lines of evidence depict a possible case of inverse comorbidity between cancer and neurodegenerative disorders, with a role played by orexins. These considerations suggest a therapeutic potential of orexin modulation in diverse pathologies such as narcolepsy, neurodegenerative disorders, and cancer.

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Narcolepsy is a neurological disease characterized by excessive daytime sleepiness, cataplexy, and/or a sudden loss of muscle tone due to malfunction of the orexinergic system, which may cause delayed emergence from general anesthesia. We report a successful anesthetic management of 24-year-old female narcoleptic patient undergoing left anterior cruciate ligament reconstruction. Anesthesia was induced and maintained with total intravenous anesthesia (TIVA) using propofol and remifentanil. Ultrasound-guided left femoral nerve block was also performed with 0.375% ropivacaine 20 ml. Acetaminophen 1000 mg was intravenously administered as part of a multimodal analgesia. After the surgery, the trachea was extubated 9 min after termination of TIVA, and then, the patient correctly responded to verbal commands. The postoperative course was uneventful without any narcoleptic symptoms.

OBJECTIVE: To describe a second case of treatment refractory chronic cluster headache responsive to clomiphene citrate and with long-term follow-up.
METHODS: Case report with 7-year evaluation.
METHODS: A 63-year-old man with a 17-year history of chronic cluster headache preceded to have significant adverse events or was nonresponsive to multiple cluster headache preventive medications including verapamil, lithium, valproic acid, topiramate, baclofen as well as greater occipital nerve blocks and inpatient hospitalization. The patient experienced 3-5 headaches per day. On clomiphene citrate 100 mg/day he became 100% pain-free and remained so for 3.5 years with only mild fatigue as a side effect. He then had cluster headache recurrence and did well on gabapentin for another 3 years with repeat headache recurrence. Clomiphene was restarted, and he became pain-free once again.
CONCLUSIONS: This is the second reported case of the effective use of clomiphene citrate for the preventive treatment of medicinal refractory chronic cluster headache. This is the first case to report long-term follow-up of this neurohormonal treatment. Clomiphene citrate appears to be safe for extended use in chronic cluster headache even in an elderly sufferer and has a minimal side effect profile. The mechanism of action of how clomiphene prevents cluster headache may involve both its ability to enhance testosterone production and its ability to bind to hypothalamic estrogen receptors. Clomiphene citrate should join the list of alternative cluster headache prophylactic treatments to be considered by headache specialists when conventional cluster headache preventives are ineffective.