Cause
The underlying mechanisms of KLS are not known. However, there are hypotheses. The first is genetics. Gene association studies have shown a link to changes in the gene called TRANK1. This gene is also associated with bipolar disorder, in which bipolar disorder is associated with birth defects. The suspicion is that changes in the TRANK1 region may increase the risk of developing KLS in patients who have had obstetric/birth difficulties [1]. In addition, other studies have found changed in the gene called LMOD3 [2].
Figure 1: Schematic of TRANK-1 Gene Location
Schematic illustrating the location of the TRANK1 gene locus on chromosome 3, with a size of 118,846 bases and a specific position of chr3:36,826,816-36,945,662 [3].
Another hypothesis is that there are underlying autoimmune mechanisms that lead to the development of KLS, or at least, contribute to the symptoms. This hypothesis began following the clinical observation that a majority of patients exhibit KLS symptoms soon after experiencing a bacterial or viral-like illness [4,5]. Although studies are inconsistent, some patients have an increase in the frequencies of something called HLA alleles [6,7]. Furthermore, a small cohort of patients with KLS had significantly higher levels of a cytokine (an inflammatory molecule) called sVCAM1, within and in-between episodes compared to normal controls, which may be indicative of a low level inflammatory response [8]. Given the primary characteristic of hypersomnolence (excessive sleep), it is suggested that KLS results from a dysfunction in the hypothalamus, excluding abnormal findings of brain structure as patients typically have normal CT and MRI studies [9]. The most consistent finding is hypoperfusion (decrease is blood flow) and hypometabolism (decrease in metabolism of oxygen and glucose) found via functional MRI and SPECT studies [9]. The major characteristic of derealization in KLS may be as a result of this hypoperfusion and hypometabolism in the portions of the brain called the thalamus, hypothalamus, and right and left parieto-temporal junctions [9].
Diagnostics
The lack of a known and definite underlying mechanism of KLS poses a challenge for diagnosis.
The most current diagnostic criteria from the ICSD-3 are:
A. The patient experiences at least 2 recurrent episodes of excessive sleepiness and sleep duration, each persisting for 2 days to 5 weeks
B. Episodes recur usually more than once a year and at least once every 18 months
C. The patient has normal alertness, cognitive function, behavior, and mood between episodes
D. The patient must demonstrate at least one of the following during episodes:
1. Cognitive dysfunction
2. Altered perception
3. Eating disorder (anorexia or hyperphagia)
4. Disinhibited behavior (such as, hypersexuality)
E. The hypersomnolence and related symptoms are not better explained by another sleep disorder, other medical, neurologic, or psychiatric disorder (especially bipolar disorder), or use of drugs, or medications
According to the ICSD-3, criteria A-E must be met for the diagnosis of KLS.
It is important to note that not all KLS patients have hypersexuality and/or hyperphagia; the profound characteristics of KLS are idiopathic episodes of recurrent hypersomnia, behavioral changes, and cognitive abnormalities.
Recurrent Hypersomnia
• Recurrent episodes of sleep lasting for more than 2 days.
• Episodes have a frequency of at least one per year.
• Cognitive functioning and behavior tend to be normal during the inter-episodic periods.
• Hypersomnia is not caused from another medical or psychological disorder, medication use, or substance abuse.
Kleine-Levin Syndrome
In addition to the Recurrent Hypersomnia criteria:
• Cognitive abnormalities, e.g., derealization, confusion, memory loss.
• Behavioral changes, e.g., uncharacteristic for the “normal” state of the patient.
• Hyperphagia
• Hypersexuality
Unfortunately, there is no biomarker for the diagnosis of KLS. Diagnosis is currently a matter of exclusion based on the patients’ symptoms and ruling out other diseases. Cases of KLS may look like another disorder and disease, and provide the necessity to exclude differential diagnoses. For example, if arriving at the emergency room, patients may undergo a workup with suspicion for acute confusion and substance abuse, and imaging to rule out a stroke or status epilepticus. Laboratory tests should include ammonia, folate, pyruvate, and lactate, evaluation for endocrinopathies and current viral or bacterial infections. Spinal taps (also known as lumbar puncture) and imaging studies should be completed as well. Encephalitis, head trauma, and other encephalopathies may mimic the symptoms of KLS. Relatedly, psychiatric disorders, such as depression, dipolar disorder, and conversion disorder need to be ruled out.
TREATMENTS
Treatment of KLS has previously been addressed symptomatically. Stimulants are typically attempted to address hypersomnia [11]. However, this method fails to address cognitive and behavioral abnormalities and may result in irritability from treatment. A small cohort of patients have experienced benefit from an antibiotic, called clarithromycin, which appears to oppose GABA-a receptors, as it is believed that some hypersomnolence disorders are associated with GABA-a receptors [12]. Patients administered with the antibiotic showed that measures of sleepiness improved during treatment [13]. However, this method has failed to address other characteristics of KLS and may not outweigh long-term administration of an antibiotic. Lithium has shown great promise in patients treated with the medication; this may relate to the association with bipolar disorder [14]. Anticonvulsants (seizure medications), particularly one called Valproate, have been attempted with the suspicion of thalamic dysfunction and may be used as an alternative to lithium [15]. Some patients treated with steroids, specifically one called methylprednisolone, resulted in a beneficial response of shorter episode duration, which may be related to the potential autoimmune mechanisms involved [18]. Given this result, it may be worth attempting other immune modulatory methods, such as increased amounts of Vitamin D3 and CellCept. Ultimately, the treatment of KLS is trial-and-error as one method may be beneficial to one patient, while it may not be beneficial for another.
REFERENCES
Ambati, A., Hillary, R., Leu-Semenescu, S., Ollila, H. M., Lin, L., During, E. H., Farber, N., Rico, T. J., Faraco, J., Leary, E., Goldstein-Piekarski, A. N., Huang, Y. S., Han, F., Sivan, Y., Lecendreux, M., Dodet, P., Honda, M., Gadoth, N., Nevsimalova, S., Pizza, F., … Mignot, E. J. (2021). Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci. Proceedings of the National Academy of Sciences of the United States of America, 118(12), e2005753118. https://doi.org/10.1073/pnas.2005753118
“TRANK1 Gene (Protein Coding).” GeneCards, www.genecards.org/cgi-bin/carddisp.pl?gene=TRANK1.
Fenzi, F., Simonati, A., Crosato, F., Ghersini, L., & Rizzuto, N. (1993). Clinical features of Kleine-Levin syndrome with localized encephalitis. Neuropediatrics, 24(5), 292–295. https://doi.org/10.1055/s-2008-1071559
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; DOI: 10.1212/01.WNL.0000036605.89977.D0
BaHammama, A., GadElRabb, M., Owaisa, S., Alswata, K., Hamamb, K. (2006). Clinical characteristics and HLA typing of a family with Kleine–Levin syndrome. Sleep Medicine, 9(5): 575-8. Epub 2007 Aug 29.
Kornum, B.R., Rico, T., Lin, L., Huang, Y.S., Arnulf, I., Jennum, P., Mignot, E. (2015) Serum cytokine levels in Kleine-Levin syndrome. Sleep Medicine 16(8):961-5. doi:10.1016/j.sleep.2015.02.540. Epub 2015 May 15.
Kas, A., Lavault, S., Habert, M. O., & Arnulf, I. (2014). Feeling unreal: a functional imaging study in patients with Kleine-Levin syndrome. Brain : a journal of neurology, 137(Pt 7), 2077–2087. https://doi.org/10.1093/brain/awu112
American Academy of Sleep Medicine, The International Classification of Sleep Disorders, third edition (ICSD-3) (2014), American Academy of Sleep Medicine, Chicago, IL.
de Oliveira, M. M., Conti, C., & Prado, G. F. (2016). Pharmacological treatment for Kleine-Levin syndrome. The Cochrane database of systematic reviews, 2016(5), CD006685.
Rye, D. B., Bliwise, D. L., Parker, K., Trotti, L. M., Saini, P., Fairley, J., Freeman, A., Garcia, P. S., Owens, M. J., Ritchie, J. C., & Jenkins, A. (2012). Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors. Science translational medicine, 4(161), 161ra151. https://doi.org/10.1126/scitranslmed.3004685
Trotti, L. M., Saini, P., Bliwise, D. L., Freeman, A. A., Jenkins, A., & Rye, D. B. (2015). Clarithromycin in γ-aminobutyric acid-Related hypersomnolence: A randomized, crossover trial. Annals of neurology, 78(3), 454–465. https://doi.org/10.1002/ana.24459
Leu-Semenescu, S., Le Corvec, T., Groos, E., Lavault, S., Golmard, J. L., & Arnulf, I. (2015). Lithium therapy in Kleine-Levin syndrome: An open-label, controlled study in 130 patients. Neurology, 85(19), 1655–1662. https://doi.org/10.1212/WNL.0000000000002104
Nebhinani, N., Avasthi, A., & Modi, M. (2015). Successful Use of Valproate in Kleine-Levin Syndrome: A Case Report and Review of Cases Reported from India. Indian journal of psychological medicine, 37(3), 352–354. https://doi.org/10.4103/0253-7176.162931 