Apparent resolution of hypersomnia episodes in two patients with Kleine–Levin syndrome following treatment with the melatonin receptor agonist ramelteon

Abstract

Kleine–Levin syndrome (KLS) is a rare disorder characterized by episodic bouts of severe hypersomnia associated with cognitive and behavioral abnormalities and normal alertness and functioning in between episodes. The pathophysiology is unclear but may involve neurotransmitter abnormalities, hypothalamic/thalamic dysfunction, viral/autoimmune etiology, or circadian abnormalities. No single treatment has been shown to be reliably efficacious; lithium has demonstrated the most consistent efficacy, although many do not respond and its use is limited by side effects. Due to the evidence of circadian involvement, we hypothesized that strengthening circadian signals may ameliorate symptoms. Ramelteon is a potent melatonin receptor agonist. In this report, two patients with KLS are described with apparent resolution of hypersomnia episodes following ramelteon initiation.

Citation:

Dominguez D, Rudock R, Tomko S, Pathak S, Mignot E, Licis A. Apparent resolution of hypersomnia episodes in two patients with Kleine–Levin syndrome following treatment with the melatonin receptor agonist ramelteon. J Clin Sleep Med. 2024;20(4):657–662.

INTRODUCTION

Kleine–Levin syndrome (KLS) is a rare and debilitating disorder that manifests as recurrent episodes of hypersomnia associated with cognitive dysfunction, anorexia, or hyperphagia and disinhibited behavior, typically lasting from 2 days to 4 weeks. These episodes alternate with periods of normal functioning.

According to diagnostic criteria of the International Classification of Sleep Disorders manual, third edition, to meet diagnostic criteria episodes should recur at least once per year and include the presence of cognitive abnormalities, abnormal behavior, hyper- or hypophagia, or hypersexuality and alertness, cognitive function, and behavior should be normal in between episodes.¹ Although traditionally the symptom triad of hypersomnia, hyperphagia, and hypersexuality have been considered classic for the disorder, all 3 symptoms are only present in 45% of patients and instead symptoms of hypersomnia, confusion, apathy, and derealization are the most common.² The prevalence of KLS is estimated at 1.5 per million, although it could be underdiagnosed.² KLS occurs most commonly in males, and symptom onset is most frequently observed in adolescence, although the syndrome can start in younger children, females, or adults.² Interestingly, KLS usually resolves spontaneously, with 50% of cases showing resolution 8–10 years after onset.² Resolution is typically preceded by reduced episode intensity and frequency.²

Although the pathophysiology remains undetermined, various causes have been proposed including neurotransmitter abnormalities, hypothalamic/thalamic dysfunction, or a viral/autoimmune etiology.^2–4 Functional imaging studies have shown decreased activity in temporal, frontal, hypothalamic, and thalamic areas during episodes, with decreased activity in cortical areas perhaps contributing to cognitive and derealization symptoms and decreased activity in thalamic and hypothalamic areas perhaps contributing to hypersomnia.^2,5 Sleep architecture abnormalities have been described, with reduced slow-wave sleep percentage in the first half and reduced rapid eye movement percentage during the second half of hypersomnia episodes.²

Genetic causes also contribute, and approximately 5% of KLS cases occur in family members of individuals with KLS.² Recently, a KLS genome-wide association study in a worldwide multiethnic cohort found a significant signal in the TRANK1 region and a strongly repeatable polygenic risk score, suggesting genetic predisposition.⁵ The TRANK1 marker may confer increased risk of KLS, especially in the presence of a past history of pregnancy or birth complications (such as a history of preterm or postterm birth, prolonged labor, hypoxemia, maternal pre-eclampisa, or maternal gestational diabetes).⁵ Interestingly, the same TRANK1 genetic marker is associated with bipolar disorder and schizophrenia, a possible overlap also suggested by the response to lithium in some cases.⁵ Pathway analysis of the genetic architecture associated with KLS also suggests involvement of circadian abnormalities.⁵

Based on these genetic findings, we hypothesized that circadian factors are a causative or perpetuating factor in KLS, because reduced circadian entrainment associated with low light exposure during hypersomnia episodes may prolong hypersomnia episodes.⁵ Circadian abnormalities are suggested by single cases in which activity monitoring suggests a free running pattern or other abnormalities during actigraphy (Rosa Hasan, personal communication).⁶ Other abnormal circadian activity that has been shown in patients with KLS with actigraphy includes decreased amplitude of day-to-night activity differences and decreased interdaily stability in activity patterns compared to asymptomatic periods or control patients.⁶ Also, in the later phase of the hypersomnia attacks, an increase in circadian activity levels was detected on actigraphy prior to any noted improvement in self-reported sleepiness, indicating that normalization of sleep–wake activity patterns may underlie episode resolution.⁶ The fact that KLS often improves with adulthood could also relate to changes in circadian physiology that are well-documented during the transition from adolescence to adulthood.

No single treatment has shown to be reliably efficacious in KLS syndrome. Medications have been used both to improve symptoms during hypersomnia episodes and to reduce the frequency of hypersomnia episodes, with only a portion of patients experiencing a benefit. Lithium has demonstrated the most consistent efficacy, with 25–62% of patients experiencing reduction in hypersomnia episode frequency, but its use is limited by side effects such as kidney insufficiency or thyroid dysfunction.² Other medications showed less reduction in episode frequency than lithium, including risperidone, valproic acid, carbamazepine, amantadine, antipsychotics, antivirals (acyclovir), hydrocortisone, melatonin, and levodopa.^2,3 In one study, 20% of patients with KLS reported that wakefulness-promoting medications such as modafinil, methylphenidate, and amphetamine improved alertness during hypersomnia episodes, but cognitive abnormalities remained; thus, they are generally contraindicated except toward the end of the disease evolution, when episodes become less severe.² Other medications given for symptoms associated with hypersomnia episodes include risperidone for psychotic symptoms and benzodiazepines for anxiety.² Based on the theory of a possible autoimmune involvement, treatment with intravenous steroids has been studied in patients with prolonged episodes and appeared to shorten the episode length in a portion of patients.⁷

Medication options with greater response rates are needed. Due to the evidence of circadian involvement noted above, we hypothesized that strengthening circadian signals may ameliorate KLS symptoms. Ramelteon is a potent melatonin receptor agonist. In this report, its usage in two patients with KLS is described with positive effects.

REPORT OF CASES

Case 1

Patient 1 is a 17-year-old boy with a history of type 1 diabetes mellitus, intermittent alopecia, and an unremarkable birth history who presented to the sleep clinic with recurrent hypersomnia episodes. At the age of 5 years, the patient started to experience recurrent fevers of unclear etiology that later resolved, and at the age of 6 years he was diagnosed with type 1 diabetes mellitus. The periods of hypersomnia also began at the age of 6 years and would last for 1–2 weeks. During the hypersomnia episodes, he woke mainly to eat or use the restroom, sleeping for 16–18 hours per 24-hour period and exhibited irritability, hypophagia, and sparse speech. The hypersomnia episodes were followed by several months of normal wake periods. Waking him during episodes to manage blood glucose levels became difficult, such that he had a gastrostomy insertion to improve blood glucose management. There seemed to be no clear association between his blood glucose level and the onset of his hypersomnia episodes, because blood glucose levels could be low, high, or normal at the onset of the hypersomnia episodes. He presented to the sleep clinic at the age of 10 years and was diagnosed with KLS.

The hypersomnia patterns varied over the next several years, sometimes lasting 3 days and occurring about every other week. At other times, episodes were more frequent, occurring 2–5 times weekly with a duration of 16–20 hours, and sometimes occurring most days of the week. He also had a couple of prolonged hypersomnia episodes lasting for several weeks. Premonitory symptoms of irritability, eating more than normal, headaches, and abdominal pain were sometimes reported. He was able to maintain good grades at grade level when hypersomnia episodes were less frequent but switched to homebound schooling during periods of high episode frequency.

He had no history of cataplexy, hypnagogic hallucinations, hypnopompic hallucinations, or sleep paralysis. An overnight polysomnogram showed mild obstructive sleep apnea (apnea-hypopnea index of 1.4 events/h). Intranasal steroids and elevation of the head of the bed were recommended. His family history includes anxiety disorder and depression in his brother and autoimmune disease and migraines in his mother.

An electroencephalogram obtained at the age of 10 years was read by a pediatric epileptologist as being abnormal due to the presence of generalized spike–wave discharges during sleep. In retrospect his family reported a history of staring spells, usually brief and usually resolving with loud voices or clapping. One prolonged staring spell lasted 30 minutes; however, his family had not touched him to try to interrupt the episode because they thought he was sleepy at the time. He was initially trialed on levetiracetam with no symptomatic improvement in episodes of sleepiness and developed a side effect of abdominal discomfort, so he was transitioned to zonisamide. Zonisamide was increased to 125 mg twice daily (8 mg/kg/d). Initially zonisamide seemed to be associated with fewer hypersomnia episodes, but the improvement was not sustained. Also, on further review, interpretations by 2 additional pediatric epileptologists differed from the initial reading of generalized spike–wave discharges and instead favored hypnogogic hypersynchrony. Zonisamide was eventually stopped and 2 additional electroencephalograms were normal.

A multiple sleep latency test performed in between hypersomnia episodes showed an average sleep latency of 9.8 minutes and 1 sleep-onset rapid eye movement period, and the overnight polysomnogram was normal the preceding night. Brain CSF was normal. A serum and cerebrospinal fluid (CSF) encephalopathy autoimmune panel was negative, serum and CSF N-methyl-d-aspartate receptor antibody was negative, and CSF showed no pleocytosis (78 total cells with 0 nucleated cells; glucose was 20 mg/dl, and protein was 13.5 mg/dl). Serum lactate was 1.5 mM, pyruvate 0.11 mM, and thyroglobulin peroxidase and thyroglobulin antibodies were negative. Also, a urine amino acids panel showed multiple amino acids with abnormal excretion, although the pattern did not correlate with any specific disease. Urine organic acids were normal, and Hgb A1C was 9.1%, Epstein–Barr virus, cytomegalovirus, rheumatoid factor, antinuclear antibody, and extractable nuclear antigens were negative, but group A strep was positive. An echocardiogram showed borderline dilation of the proximal right coronary artery without focal dilation or aneurysm.

Therapies attempted to treat KLS included 150 mg of lithium 3 times daily, which was not effective, and higher doses were not tolerated due to nausea. At the age of 15 years, he received a course of intravenous immunoglobulin but experienced side effects of headache and fever; arousability during hypersomnia episodes improved temporarily following administration of intravenous immunoglobulin but the frequency and duration of hypersomnia episodes were unchanged. Insurance authorization was not received for multiple courses of intravenous immunoglobulin, despite appeals. He tried taking modafinil but reported feeling “like a zombie.”

In an attempt to strengthen circadian signaling, melatonin was initiated when he was 13 years old and morning light therapy was recommended. Melatonin did not improve the frequency of hypersomnia episodes, and he continued to sleep 16–18 hours 4 days per week. His family noted a benefit of greater arousability during the melatonin trial at immediate-release doses of 3 mg and 5 mg nightly but also noted a side effect of sleepiness even on days without hypersomnia episodes. Immediate-release melatonin at a dosage of 1 mg nightly was then administered for several months without any side effect of sleepiness but also without any clear effect on hypersomnia episode frequency or arousability. Melatonin was stopped after a > 6-month total trial period. Following the completion of the melatonin trial, 20 mg of tasimelteon nightly was started when he was 14 years old to assess the theory that a melatonin receptor agonist could strengthen circadian signaling more effectively than melatonin supplements. Tasimelteon appeared to increase arousability but had no further benefit in preventing or reducing hypersomnia episodes after 3 months of administration. When taking tasimelteon, he continued to have hypersomnia episodes lasting 16–20 hours occurring 2–6 days per week. Tasimelteon was stopped due to incomplete insurance coverage, high cost, and insufficient benefit.

He started taking 8 mg of ramelteon nightly at the age of 16 years, 10 years after the onset of hypersomnia episodes. In the several weeks prior to ramelteon initiation, he had hypersomnia episodes occurring 5–6 times per week in which he slept for 17–18 hours per day. After starting ramelteon he had 2 hypersomnia episodes lasting about 14 hours that occurred within the first month after initiation but has had no further episodes to date, for over 1 year following ramelteon initiation. He noted improvement about 3 weeks after starting ramelteon. In addition, when he missed 2 doses of ramelteon because the pharmacy was out of stock for 2 days he did not have a hypersomnia episode but had more irregular sleep. He also reports a sense of general improved alertness since starting ramelteon.

He continues to take 8 mg of ramelteon nightly without any subsequent hypersomnia episodes and with no reported side effects. On all days he feels alert and receives all As at grade level in an in-person school, to which he returned after ramelteon initiation from his prior homebound program. He has also taken 20 mg of extended-release methylphenidate daily for the past several years with some improvement in alertness, although no clear improvement in the frequency or duration of hypersomnia episodes was attributed to methylphenidate. On weekdays his bedtime is 11:30 pm, and his rise time is 6:00 am, and he reports a sleep onset of 30 minutes and no awakenings. During weekends, his bedtime is 2–3 am and rise time 8-11 am, and he occasionally naps.

Case 2

The patient is a 19-year-old woman with a history of mannose-binding lectin deficiency, migraines, asthma, anxiety, depression, postterm birth at 43 weeks, and cesarean section birth due to breech presentation who presented to the sleep clinic with recurrent hypersomnia episodes. At the age of 15 years she fell down a flight of stairs but did not have a known concussion. One month later she had a prolonged upper-respiratory infection. After its resolution, she started having recurrent hypersomnia episodes. During an episode, she would typically sleep continually for about 20 hours per day at least 1 day per week, often 5–6 days per week, arising only to eat or use the restroom. She also exhibited hypophagia and difficulty waking up, including to vigorous tactile stimuli such as pinching or sternal rub. Each episode would start either as a severe migraine or with a general sense of not feeling well that she would be unable to clarify further. She would then lie down, recognizing that a hypersomnia spell was starting. Following the onset, she would either stare and not respond to speech or speak a nonsensical phrase with limited verbiage and prolonged speech latency. She would answer “I don’t know” to almost any question her family asked, including “how are you feeling?” She ate little during these episodes. Also, she seemed “snippier” and “moodier.” She didn’t remember the episodes and when she woke up she did not sense the passage of time. Due to her hypersomnia episodes, she stopped attending her local public school and entered a homeschooling program. An awake and asleep 23-hour electroencephalogram, brain magnetic resonance imaging, and brain magnetic resonance venography were performed and results were found to be normal. A switch from topiramate to amitriptyline and an increase in amitriptyline to 75 mg nightly improved her headaches but not hypersomnia episodes. She presented to the sleep clinic at the age of 16 years and was diagnosed with KLS. She took 3 mg of immediate-release melatonin nightly at the age of 16 years for 1 month without any clear benefit.

After the melatonin trial was stopped she began taking 8 mg of ramelteon nightly when she was 16 years old, 17 months after the onset of hypersomnia episodes. Since starting ramelteon, she reports no further episodes except 3 instances related to missed or late doses: once when she missed a dose because the pharmacy was out of stock, once when she did not take ramelteon for 1 night while attending her prom, and once after she took ramelteon several hours late following eastward travel across several time zones. During her trip, she took ramelteon at 8:15 pm Hawaii Standard Time (equivalent to 1:15 am Central Standard Time in her home state of Illinois) during the 5 days in Hawaii. The night she returned to Illinois before the hypersomnia episode started, she took ramelteon late, around 4:30 am Central Standard Time. Following the missed doses and the late administration associated with her travel she had typical hypersomnia episodes, but otherwise has had no other episodes in the 2 years since ramelteon initiation. In addition, she reports improved daytime alertness and focus on ramelteon.

She continues taking 8 mg of ramelteon nightly without side effects and morning bright light therapy. In addition, she takes 75 mg of amitriptyline nightly for headaches, with significant improvement in headaches. She keeps a regular sleep schedule with bedtime at 10:30 pm and rise time around 7:30–8:00 am, within initial sleep onset estimated as within 5 minutes, and a return to sleep estimated as within 5 minutes after waking once at night. After starting ramelteon, she was able to enter a General Educational Diploma program.³

DISCUSSION

The two patients with KLS described in our case series appeared to have experienced resolution of hypersomnia episodes following ramelteon administration. Ramelteon is a potent melatonin receptor agonist that acts on MT1 and MT2 melatonin receptors without any known significant affinity for other receptors.⁸ Its soporific effects are likely exerted by its action on the MT1 receptors and its chronobiotic effects by its actions on MT2 receptors.⁹ It has a longer half-life than melatonin supplements, estimated at 5 hours vs 30 minutes for regular-release melatonin, with greater lipophilicity and tissue penetration than melatonin and greater affinity for the MT1 receptors vs melatonin.^8,9 Ramelteon’s active metabolite, M‐II, has a half-life of 2.27 hours and likely contributes to the circadian response.⁹ Ramelteon has not been shown to alter sleep architecture and has a low likelihood of side effects. Because it is primarily metabolized by CYP1A2 and CYP2C19, inhibitors of those enzymes can considerably increase ramelteon’s concentrations, especially fluvoxamine.^8,9 Based on our patients’ experiences, ramelteon may require 1 month or more of consistent administration to achieve full effects.

When studied in a group of patients with insomnia and bipolar disorder, ramelteon was shown to improve mood; bipolar disorder has been associated with disrupted circadian rhythms.⁸

Interestingly, our patients had undergone trials of melatonin therapy of 1-month and > 6-month durations, respectively, without clear improvement. In addition, one patient tried tasimelteon without much success before improving with ramelteon. Because ramelteon has a 10-fold greater affinity for MT1 than for MT2 receptors and tasimelteon a 4-fold greater affinity for MT2 vs MT1 receptors, MT1 may be important in the mediation of the effect of ramelteon.⁹ Data suggest that MT2 receptor activation enacts phase‐shifting of the clock, whereas MT1 activation, as with agonists such as ramelteon, inhibits suprachiasmatic nucleus activity and likely causes downstream effects on sleep circuits, perhaps mediating inhibition of hypersomnia episodes in these cases.⁹

The anti-inflammatory effects of ramelteon may also account for the positive effects. Ramelteon has been shown to reduce C-reactive protein by 26.8%, perhaps through an antioxidant effect caused by MT receptor stimulation.¹⁰ Also, melatonin has been observed to cause a reduction in elevated levels of nuclear factor-kappa B and proinflammatory cytokines interleukin 6 or tumor necrosis factor alpha in a model of diabetic neuropathy and to decrease peripheral and central T helper 1 and T helper 17 cell responses in an experimental model of autoimmune encephalomyelitis.^11,12 Of note, there is mixed evidence for a possible neuroinflammatory component of KLS. In cases in which pathology is available, there have been reports of inflammatory infiltrates in the diencephalon and midbrain.¹³ Clinically, in many patients the first episode follows an infection.² Although this association is often seen in inflammatory conditions it is not specific regarding etiology. More generally, there is a proposed link between human leukocyte antigen type and other sleep disorders, such as narcolepsy, and a similar link has been suggested for KLS, although this link was not confirmed in subsequent bigger samples.^4,14 High-throughput proteomic studies of magnetic resonance imaging and serum in patients with KLS, including samples taken both during and separately from hypersomnia episodes, showed dysregulated proteomic signatures with pathways involved in inflammation, microglial alterations, and disrupted blood–brain barrier permeability compared with controls.¹⁵ Changes in proteins enriched in the pons, medulla, and midbrain were also noted, potentially associating immune abnormalities to brainstem and possible forebrain dysfunction.¹⁵ Specifically in our series, additional features supporting an immune etiology in our patients are the onset after recurrent fevers, concurrent development of type 1 diabetes, and the strong family history of autoimmunity in one patient and the onset after an infection plus mannose-binding lectin deficiency in the other.

In one patient, whereas the improvement in hypersomnia seemed most closely linked to ramelteon initiation, headache treatment may have also lessened the symptomatology. In addition to hypersomnia episodes, she exhibited severe recurrent headaches associated with photophobia, phonophobia, and nausea that typically occurred at hypersomnia onset but also at other times and improved with sleep. Headaches have been described in 48–60% of patients with KLS in 2 overlapping case series, with an additional 59–70% of patients also reporting photophobia.^14,16,17 Hypothalamic modulation may be a common pathophysiologic mechanism in migraines and KLS; activation of the hypothalamus has been shown in functional imaging studies of migraine patients, and core features of KLS, including hypersomnolence, hyperphagia, and disinhibition, could be explained by hypothalamic dysfunction leading to downstream malfunctioning of similar neurotransmitter systems.^4,16 Also, the cortical spreading depression described in migraines may affect brainstem arousal networks, as demonstrated by hypometabolic deficits in brainstem areas in a rat model, and may contribute to the hypersomnia noted in patients with KLS with headaches.¹⁶ In her case, headaches decreased in frequency and intensity after treatment with amitriptyline, a tricyclic antidepressant with proposed antimigraine activity involving inhibition of noradrenaline reuptake, direct effects on the histamine and serotonergic systems ultimately leading to suppression of cortical spreading depression and perhaps contributing to the improvement in hypersomnia.¹⁸ Melatonin agonists may also confer migraine improvement; melatonin has been reported to cause analgesic effects through multiple mechanisms and has been shown to improve migraine frequency and severity.^19,20 In addition, there is case-report-level evidence that ramelteon may improve migraines.²¹

An additional, although less likely, pathophysiologic contributor to the improvement in hypersomnia episodes noted with ramelteon may be its antiepileptic effect. Melatonin has been reported to improve seizures in clinical studies, and ramelteon has shown antiepileptic potential in animal models.^22,23 Although postictal sleepiness tends to be relatively short in duration (ie, minutes to hours), compared to that which is typically described in KLS (ie, days to weeks), sleepiness associated with unrecognized status epilepticus can sometimes present similarly to KLS. Unlike in many patients with seizures, the electroencephalograms of patients with KLS is rarely epileptiform but demonstrates diffuse slowing in approximately 70% of patients with KLS during hypersomnia episodes.² Although one patient had been noted to have epileptic discharges, pediatric epileptologists disagreed about whether the discharges were truly epileptiform or represented hypnogogic hypersynchrony. Additionally, there were no clinical indicators to suggest that a direct antiepileptic effect caused the improvement in hypersomnia episodes. Hypnogogic hypersynchrony is a normal variant that consists of bursts of diffuse 4- to 5-Hz slowing activity that typically occur while falling asleep, although most commonly in children 4–9 years of age or up to 13 years of age. It can sometimes take on a notched appearance, falsely appearing epileptiform, mimicking a spike and slow wave.²⁴

Frequent episodes are described in some patients with KLS, as in one of the patients with KLS in the series. The other patient with KLS had variation in episode frequency and duration, with both periods of discrete episodes separated by long periods of normality and also periods of more frequent episodes. These are typical patients with KLS who represent the variability within the KLS phenotype. The ramelteon response time seemed to vary between the two patients, potentially related to phenotypic or pathophysiologic variation.

In summary, although only tried in 2 cases, ramelteon may be a promising therapeutic option in KLS. Although the improvement in hypersomnia episodes appeared to be time-associated with the initiation of ramelteon, uncertainty remains about whether the improvement was coincidental or causal. Indeed, a majority of affected individuals eventually recover and a natural history of recovery cannot be excluded.² However, the time-linked association in improvement and recurrence with the missed doses or late administration suggest that the ramelteon effect was causative of improvement.

Next steps should include the assessment of efficacy in a larger sample or a research study. The information available through a small clinical case series is limited and not as robust as the information available through a trial. Future N-of-1 trials with a meta-analysis and pooled effect size could generate the high-quality evidence required to better assert the effectiveness of ramelteon. Because there are no consistently effective therapies besides lithium, it would be helpful to have additional therapeutic options such as ramelteon. Further study is needed to better understand the applicability of these findings and the mechanisms of the benefits.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. E.M. is funded by the Kleine–Levin Syndrome Foundation for work on this disease. The authors report no conflicts of interest. The authors report the off-label/investigational use of ramelteon for the treatment of Kleine–Levin syndrome.

ABBREVIATIONS

KLS

Kleine–Levin syndrome