Rare diseases in Neuropediatrics: KLS Spotlight

Authored By: Amy Li and Lindsey Li

Art By: Amber Briscoe

Have you ever heard of the “Sleeping Beauty” Syndrome?

While the name may sound idyllic, it actually refers to Kleine-Levin Syndrome, a rare neurological disorder characterized by recurrent episodes of excessive sleep, first defined in the 1920s by German neurologist Max Kleine and French neurologist Jean-Pierre Levin. [1]

Epidemiology

The estimated prevalence of this condition is around 1/500,000 individuals. Mainly reported in western countries, the majority of cases occur during adolescence—with 81% of patients developing this disorder in their second decade of life—and men are twice as likely to be affected as women. It is suspected that around 70% of people living with KLS are male. [2] Overall, the disorder remains something of a mystery, due to its uncommon nature.

Clinical presentation

The first presentation of Kleine-Levin Syndrome is usually recurrent hypersomnia, where patients often need to sleep for 12 to 24 hours a day. [3] In between episodes, patients are usually asymptomatic and may display normal sleep patterns. [4] Also common symptoms that KLS patients may experience include cognitive challenges such as confusion, difficulty concentrating, disorientation, and amnesia. One interesting thing to note is that patients can experience alterations in their eating habits. Most patients experience what is called megaphagia, causing them to overeat and require 6 to 8 meals a day. Patients with Kleine-Levin syndrome may also exhibit compulsory behaviors, such as compulsive singing or rocking. [5] Patients may also experience hallucinations and paranoia, sometimes describing feeling as if they are in a dream while actually being awake. [6]

Causes and Theories

While the etiology is not absolute (i.e.. there is no certain cause), some research shows that the Kleine-Levin Syndrome is inherited. Thus, certain individuals may be more genetically predisposed if they have family members with the disorder. [7] Other studies suggest that KLS may have an autoimmune link. This is particularly because an episode of KLS may be triggered by infection [8], and the episodic nature of KLS, with periods of intense symptoms followed by remission, could be reminiscent of autoimmune disorders. [9]

Diagnosis

A healthcare provider will usually take a detailed medical history from the patient and family. By assessing duration, frequency, and symptoms of KLS, particularly hypersomnia. In differential diagnoses, polysomnography, or a comprehensive sleep study, may help rule out other sleep disorders like narcolepsy (sudden induced sleep during the daytime). [10] Brain imaging could also be used to rule out structural brain abnormalities. In most cases of KLS, brain scans should show a healthy brain structure. There are no specific blood or laboratory tests to diagnose KLS, so the diagnosis is primarily based on symptom evaluation and the exclusion of other causes. [11]

Kleine-Levin syndrome is often misdiagnosed as psychiatric conditions, such as depression, bipolar disorder, narcolepsy, mitochondrial disease, Lyme disease, and temporal lobe epilepsy. In one example of a man whose episodes of hypersomnia reached as high as 36 to 60 hrs, high commonalities of symptoms between bipolar disorder and Kleine-Levin syndrome interfered with the proper diagnosis of KLS. [12]

Treatment and management

Although there is no cure for Kleine-Levin Syndrome (KLS), the condition can be managed through symptom treatment and lifestyle adjustments. For example, modafinil (a wakefulness drug) can help reduce excessive sleepiness. [13] Lifestyle adjustments may include having to create a safe environment in case of spontaneous sleeping episodes, postponing or rescheduling activities, and avoiding possible triggers such as alcohol and stress. However, for many people with KLS, it is still difficult to pinpoint specific triggers, and it may be best to consult with a somnologist (a medical doctor who specializes in sleep disorders).

Long-term effects, Prognosis, and Resolution

The Kleine-Levin Syndrome may resolve spontaneously over time, usually in the form of decreasing occurrences of abnormal sleeping episodes. It is important to note that most cases resolve within 10 to 20 years, with a median time of resolution of 14 years. Healthcare providers consider the condition to be cured if an individual does not experience episodes for six years. [14] However, with KLS, cognitive impairment may occur over time. In one study, a third of the patients monitored showed long-term cognitive deficits, including slower retrieval and processing speed [15].

Future research directions

There is also emerging data demonstrating that the amplitudes of circadian active/rest cycles significantly decreased when patients with Kleine-Levin syndrome experienced severe rounds of hypersomnia. However, the amplitudes of the circadian active/rest cycles of Kleine-Levin syndrome did not differ significantly from those of the control group when the patients were experiencing an asymptomatic period. [16] There have also been findings in the form of dysregulated proteomic patterns that have the potential to be used in the diagnosis of Kleine-Levin syndrome. [17]

Conclusion

For those living with KLS, the condition can feel like life is put on pause for days, weeks, or even months at a time. While there is still much we don’t know about the causes of KLS, or the reasons behind the gradual decrease of symptoms over time, continued research and awareness are key. Although KLS is very rare, with an occurence rate of 1 in 500,000, it is still a very interesting condition that can help us better understand the principles linking physiology and sleep.

References:

1. Afolabi-Brown O, Mason TBA. Kleine-Levin Syndrome. Paediatric Respiratory Reviews. 2018;25:9-13. doi:https://doi.org/10.1016/j.prrv.2016.12.004

2. Orphanet: Kleine-Levin syndrome. www.orpha.net.https://www.orpha.net/en/disease/detail/33543

3. Shah F, Gupta V. Kleine-Levin Syndrome (KLS). https://mdsearchlight.com/child-health/kleine-levin-syndrome-kls/.

4. Lavie P, Gadoth N, Gordon CR, Goldhammer G, Bechar M. Sleep patterns in Kleine-Levin syndrome. Electroencephalography and Clinical Neurophysiology. 2003;47(3):369-371. doi:https://doi.org/10.1016/0013-4694(79)90287-6

5. Heywood AL. Do People with Kleine-Levin Syndrome Eat? Healthline. Published November 19, 2024. Accessed April 26, 2025. https://www.healthline.com/health/kleine-levin-syndrome-how-do-they-eat#Kleine-Levin-syndrome-with-reduced-appetite

6. Kleine-Levin Syndrome. NORD (National Organization for Rare Disorders). Published April 6, 2007. https://rarediseases.org/rare-diseases/kleine-levin-syndrome/

7. Al Shareef SM, Basit S, Li S, et al. Kleine-Levin syndrome is associated with LMOD3 variants. Journal of Sleep Research. 2019;28(3):e12718. doi:https://doi.org/10.1111/jsr.12718

8. AlShareef SM, Smith RM, BaHammam AS. Kleine-Levin syndrome: clues to aetiology. Sleep and Breathing. 2018;22(3):613-623. doi:https://doi.org/10.1007/s11325-017-1617-z

9. Dauvilliers Y, Mayer G, Lecendreux M, et al. Kleine-Levin syndrome: An autoimmune hypothesis based on clinical and genetic analyses. Neurology. 2002;59(11):1739-1745. doi:https://doi.org/10.1212/01.wnl.0000036605.89977.d0

10. Kleine-Levin Syndrome: Symptoms, Causes & Outlook. Cleveland Clinic. Published July 13, 2022. https://my.clevelandclinic.org/health/diseases/23484-kleine-levin-syndrome

11. Stanford Health Care. Stanfordhealthcare.org. Published September 2017. https://stanfordhealthcare.org/medical-conditions/sleep/recurrent-hypersomnia/diagnosis.html

12. Reddy MSS, Sinha S, Thippeswamy H, Ganjekar S, Chaturvedi SK. Klein-Levin syndrome versus bipolar disorder not otherwise specified- diagnostic challenges. Asian Journal of Psychiatry. 2017;28:186-187. doi:https://doi.org/10.1016/j.ajp.2017.06.001

13. Aggarwal A, Garg A, Jiloha R. Kleine-Levin Syndrome and Response to Modafinil in a Young Woman. The Journal of Neuropsychiatry and Clinical Neurosciences. 2011;23(1):E33-E34. doi:https://doi.org/10.1176/jnp.23.1.jnpe33

14. Summer J, Rehman A. Kleine-Levin Syndrome: Symptoms, Diagnosis, and Treatment. Sleep Foundation. Published July 2, 2021. https://www.sleepfoundation.org/kleine-levin-syndrome

15. Uguccioni G, Lavault S, Chaumereuil C, Golmard JL, Gagnon JF, Arnulf I. Long-Term Cognitive Impairment in Kleine-Levin Syndrome. Sleep. 2016;39(2):429-438. doi:https://doi.org/10.5665/sleep.5458

16. Qasrawi SO, BaHammam AS. An Update on Kleine–Levin Syndrome. Current Sleep Medicine Reports. 2022;9(1):35-44. doi:https://doi.org/10.1007/s40675-022-00246-1

17. Hédou J, Cederberg KL, Ambati A, et al. Proteomic biomarkers of Kleine–Levin syndrome. Sleep. 2022;45(9). doi:https://doi.org/10.1093/sleep/zsac097