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What is Kleine-Levin Syndrome?

Kleine-Levin-SCOFA-1

 
Medically reviewed by
Dacelin St Martin, MD
Triple board-certified in Sleep Medicine,
Internal Medicine, and Pediatrics.

 
 
Epidemiology | Etiology | Infectious and immune-mediated theories | Clinical Features | Diagnosis | Treatment

 

Overview

Sleep is an essential biological function, playing a significant role in the recovery, energy conservation, and survival of an individual. 

It plays a vital role in normal neural development, learning, memory, emotional regulation, cardiovascular and metabolic function, and cellular toxin removal.[1]

Sleep has been classified by the American Academy of Sleep Medicine (AASM) to differentiate disorders and facilitate the understanding of symptoms, etiology, and pathophysiology that allows for effective treatment.[2]

The ICSD-2 lists the 81 disorders major sleep disorders in 8 major categories:

When talking about hypersomnia, which is explained as daytime sleepiness or the inability to stay alert and awake during the significant waking occurrences of the day, the cause of its symptoms lies elsewhere than in disturbed sleep or a misaligned circadian rhythm. 

Kleine–Levin syndrome (KLS) is one of several disorders of hypersomnia that fall into the category of central disorders of hypersomnia, with others including narcolepsy types 1 and 2 and idiopathic hypersomnia.

The term “Kleine-Levin syndrome” was first described by Kleine in 1925 and later elaborated by Levin in 1936, but Critchley and Hoffman further elaborated its definition in 1942. 

In their work “The Syndrome of Periodic Somnolence and Morbid Hunger,” they described the case of two men who developed hypersomnia and hyperphagia (extreme hunger), with one of the two patients developing symptoms six months after vaccination. 

Furthermore, the authors stated that potential mechanisms could involve a form of mild inflammation of the brain, known as encephalitis, affecting the hypothalamus and the frontal lobes.[3]

The American Academy of Sleep Medicine described KLS as a rare disease characterized by recurrent episodes of hypersomnia and behavioral or cognitive disturbances, compulsive eating behavior, and hypersexuality to various degrees.[2] 

In addition to hypersomnia, at least one of the following symptoms must be present: 

  • Cognitive or mood disturbances
  • Excessive hunger with compulsive eating
  • Hypersexuality
  • Abnormal behavior, such as irritability, aggression, or personality changes

SCOFA Kleinen-Levin Syndrome

Epidemiology

  • Since it is a rare disease, its estimated prevalence is between one to five cases per million population
  • The disease predominantly affects adolescent males 
  • Worldwide, there are patients with primary KLS, but the disorder is more prevalent among Ashkenazi Jews
  • The disease predominantly affects adolescent males 
  • Studies show that the median age of onset of KLS is 16 years 
  • Approximately 80 percent of cases reported belonged to the second decade of life within a range of 4 to 82 years.
  • Patients with typical symptoms were of the age group >35 years
  • Whereas the patient with childhood onset, i.e., <12 years, was associated with more frequent episodes.

Milder cases of KLS experience one or three episodes a year, but moderate cases can have episodes every month that last from seven to ten days. [3–8]

 

Etiology 

Currently, the etiology of KLS is unknown. Although theories were explained, they were primarily focused on genetic and immune-mediated causes.

Genetic factors – the preponderance of cases in the Ashkenazi Jewish population was the basis of the genetic hypothesis, although, to date, no specific genes have been identified. There’s an estimated 1% chance of getting KLS from a first-degree relative of a patient with KLS. 

 

Infectious & Immune-Mediated Theories 

According to studies conducted by Billiard M et al., it was stated that “Focal viral encephalitis or postinfectious autoimmune encephalitis affecting specific areas of the brain (i.e., thalamus-hypothalamus, frontal and temporal lobes) would be consistent with the nature of the disease.”

KLS-like symptoms are also associated with tumors of the hypothalamus, frontal lobe, and temporal lobe, which control sleep, perception, mood, and impulse control. 

Infections reported in association with KLS include:

  • Epstein-Barr virus 
  • Varicella-zoster 
  • Herpes zoster 
  • Influenza A and B 
  • Adenovirus, enterovirus 
  • H1N1
  • Salmonella typhi
  • Streptococcus 

Precipitating factors – apart from genetic and immune factors include:

  • Infection 
  • Alcohol ingestion 
  • Sleep deprivation 
  • Unusual stress 
  • Physical exertion 

The onset of KLS has also been reported after vaccinations, including: 

  • Typhoid and Tetanus  
  • Tuberculosis 
  • Human papilloma virus 
  • H1N1 influenza [9–15]

 

Clinical Features

The key share of clinical presentation of KLS includes recurrent hypersomnia, which means recurrent episodes of excessive daytime sleepiness lasting for 2 days to 4 weeks. The reoccurrence of these episodes is at least once per year. 

Apart from the recurrent hypersomnia, the clinical features of Kleine Levin syndrome also include:

– Cognitive abnormalities such as:

  • Confusion 
  • Derealisation: sensations of unreality
  • Hallucinations
  • Apathy 

– Abnormal behavior such as:

  • Irritability
  • Aggression
  • Change in eating orders

– Hyperphagia

– Hypersexuality [16–18]

 

Diagnosis

The diagnostic procedures for KLS include:

1) Electroencephalography (EEG): the EEG in KLS shows a generalized slowing in up to 70% of cases during episodes

2) Polysomnography (PSG): 

  • When done at the beginning of an episode, a decrease in slow-wave sleep is observed
  • Whereas when performed towards the end of an episode, a decrease in rapid eye movement (REM) sleep may be observed

3) Single-Photon Emission Computed Tomography (SPECT): 

  • SPECT is a diagnostic tool used to show blood flow through organs and tissues
  • During SPECT, a positive finding may include inadequate delivery of oxygen, known as hypoperfusion, to the brain, namely the thalamus, hypothalamus, temporal lobes, orbitofrontal and parasagittal frontal lobes, and, less commonly, the basal ganglia and occipital regions
  • Hypoperfusion may persist in the mesial temporal lobe, frontal lobe, and basal ganglia during asymptomatic periods

4) Neuropsychological Testing: 

  • This test can help identify the impairment in working memory during episodes 
  • Persistent deficits in immediate and delayed verbal and visual recall in some individuals

5) Cerebrospinal Fluid Hypocretin may be lower during episodes but still within the normal range. [19,7,8,17]

 

Treatment

According to a review, the treatment procedure of KLS primarily comprises 2 phases:[19]

Supportive/ Education Phase 

  1. Resting
  2. Postponing or adjusting school and work activities
  3. Not allowing the patient to wander unattended or to operate a car or heavy machinery
  4. Monitoring the symptoms of depression or anxiety
  5. Maintaining consistent sleep-wake schedules, avoiding alcohol and sick contacts 

Medication

  1. Consider amantadine if a patient presents in the early stages of an episode
  2. Consider modafinil for excessive daytime sleepiness in the early symptomatic period
  3. Consider the short-term course of an antidepressant, mood stabilizer, anxiolytic or antipsychotic for psychiatric symptoms[19]

 

Conclusion

Consistent restorative sleep is critical for good health and overall quality of life. So for maintaining physical and mental well-being, it is vital to address the etiology of the sleep disorders and have adequate knowledge regarding the same.

 

References:

  1. Mukherjee, S., Patel, S. R., Kales, S. N., Ayas, N. T., Strohl, K. P., Gozal, D., Malhotra, A., & American Thoracic Society ad hoc Committee on Healthy Sleep (2015). An Official American Thoracic Society Statement: The Importance of Healthy Sleep. Recommendations and Future Priorities. American journal of respiratory and critical care medicine, 191(12), 1450–1458. https://doi.org/10.1164/rccm.201504-0767ST
  2. Thorpy, M. J. (2012). Classification of sleep disorders. Neurotherapeutics, 9(4), 687-701.
  3. Arnulf, I., Zeitzer, J. M., File, J., Farber, N., & Mignot, E. (2005). Kleine-Levin syndrome: a systematic review of 186 cases in the literature. Brain : a journal of neurology, 128(Pt 12), 2763–2776. https://doi.org/10.1093/brain/awh620
  4. Gadoth, N., Kesler, A., Vainstein, G., Peled, R., & Lavie, P. (2001). Clinical and polysomnographic characteristics of 34 patients with Kleine-Levin syndrome. Journal of sleep research, 10(4), 337–341. https://doi.org/10.1046/j.1365-2869.2001.00272.x
  5. Dauvilliers, Y., Mayer, G., Lecendreux, M., Neidhart, E., Peraita-Adrados, R., Sonka, K., Billiard, M., & Tafti, M. (2002). Kleine-Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses. Neurology, 59(11), 1739–1745. https://doi.org/10.1212/01.wnl.0000036605.89977.d0
  6. Arnulf, I., Lin, L., Gadoth, N., File, J., Lecendreux, M., Franco, P., Zeitzer, J., Lo, B., Faraco, J. H., & Mignot, E. (2008). Kleine-Levin syndrome: a systematic study of 108 patients. Annals of neurology, 63(4), 482–493. https://doi.org/10.1002/ana.21333
  7. Billiard, M., Jaussent, I., Dauvilliers, Y., & Besset, A. (2011). Recurrent hypersomnia: a review of 339 cases. Sleep medicine reviews, 15(4), 247–257. https://doi.org/10.1016/j.smrv.2010.08.001
  8. Huang, Y. S., Guilleminault, C., Lin, K. L., Hwang, F. M., Liu, F. Y., & Kung, Y. P. (2012). Relationship between Kleine-Levin syndrome and upper respiratory infection in Taiwan. Sleep, 35(1), 123–129. https://doi.org/10.5665/sleep.1600
  9. Haugh, R. M., & Markesbery, W. R. (1983). Hypothalamic astrocytoma. Syndrome of hyperphagia, obesity, and disturbances of behavior and endocrine and autonomic function. Archives of neurology, 40(9), 560–563. https://doi.org/10.1001/archneur.1983.04050080060011
  10. Mendez, G., Ozpinar, A., Raskin, J., Gultekin, S. H., & Ross, D. A. (2014). Case comparison and literature review of glioblastoma: A tale of two tumors. Surgical neurology international, 5, 121. https://doi.org/10.4103/2152-7806.138034
  11. Itokawa, K., Fukui, M., Ninomiya, M., Yamamoto, T., Imabayashi, E., Tamura, N., Matsuda, H., & Araki, N. (2009). Gabapentin for Kleine-Levin syndrome. Internal medicine (Tokyo, Japan), 48(13), 1183–1185. https://doi.org/10.2169/internalmedicine.48.2204
  12. Das, A., & Radhakrishnan, A. (2012). A case of PANDAS with Kleine-Levin type periodic hypersomnia. Sleep medicine, 13(3), 319–320. https://doi.org/10.1016/j.sleep.2011.11.003
  13. Kodaira, M., & Yamamoto, K. (2012). First attack of Kleine-Levin syndrome triggered by influenza B mimicking influenza-associated encephalopathy. Internal medicine (Tokyo, Japan), 51(12), 1605–1608. https://doi.org/10.2169/internalmedicine.51.7051
  14. Shukla, G. D., Bajpai, H. S., & Mishra, D. N. (1982). Kleine-levin syndrome: a case report from India. The British journal of psychiatry : the journal of mental science, 141, 97–98. https://doi.org/10.1192/bjp.141.1.97
  15. Gallinek A. (1967). The Kleine-Levin syndrome. Diseases of the nervous system, 28(7 Pt 1), 448–451.
  16. Billiard, M., & Podesta, C. (2013). Recurrent hypersomnia following traumatic brain injury. Sleep medicine, 14(5), 462–465. https://doi.org/10.1016/j.sleep.2013.01.009
  17. Pike, M., & Stores, G. (1994). Kleine-Levin syndrome: a cause of diagnostic confusion. Archives of disease in childhood, 71(4), 355–357. https://doi.org/10.1136/adc.71.4.355
  18. Ferguson B. G. (1986). Kleine-Levin syndrome: a case report. Journal of child psychology and psychiatry, and allied disciplines, 27(2), 275–278. https://doi.org/10.1111/j.1469-7610.1986.tb02336.x
  19. Miglis, M. G., & Guilleminault, C. (2014). Kleine-Levin syndrome: a review. Nature and science of sleep, 6, 19–26. https://doi.org/10.2147/NSS.S44750