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Kleine-Levin syndrome/Lithium

Posted by @davidwhitehurstbrown, Aug 6, 2016

According to a 2015 KLS review by Arnulf (presenting evidence published by Laval, Ann Neurology, 2015):
“Lithium therapy
• Complete responders: 36.6% 
 • Partial responders: 51% 
 • Non responders: 12.4% 
 • 9.8% had « mini-episodes » (1 day) on lithium 
 • 13 patients had an episode after stopping lithium 2 consecutive nights 
 • Level IV evidence of benefit in KLS 
 • Lithium : 1 month less in episode per year 
 • The level should be high and monitored”

According to a 2014 KLS review by Miglis and Guilleminault:
“… Although an autoimmune mechanism has been suggested, there are likely heterogeneous factors at play in certain susceptible individuals. When combined with a precipitating event such as a minor infection, a transient multifocal encephalopathy ensues. It has been proposed that such a precipitating event may lead to transient permeability of the blood–brain barrier, thus predisposing these individuals to recurrent events. An animal model would add much to the understanding of the underlying pathophysiology. This is yet to be developed and should be considered in future research. …”

In Table 4 on page 2771 there is a list of attempted treatments for KLS: I. Arnulf, J. M. Zeitzer, et al. “Kleine–Levin syndrome: a systematic review of 186 cases in the literature.” Brain 128, no. 12 (2005): 2763-2776.

According to Tondo, et al. (2001) in a review of lithium carbonate therapy:
“… The majority of patients showed substantial reductions in episode frequency and the proportion of time ill; 28.9% had no new episodes of mania or depression during lithium maintenance treatment, and about a quarter of patients showed no improvement (Table 3).
… It is important to emphasise that only about a quarter of the patients in this study (29%) experienced complete remission from all recurrences of affective illness during maintenance treatment (see Table 3). This level of protection is in keeping with past reports suggesting that full protection is not commonly achieved with lithium or with alternative treatments (Rybakowsky et al, 1980; Prien et al, 1988; Gelenberg et al, 1989; Goodwin & Jamison, 1990; Tohen et al, 1990; Keller et al, 1993; Koukopoulos et al, 1995a; Baldessarini et al, 1996; Greil et al, 1997; Maj et al, 1998; Baldessarini & Tondo, 2000). Although perfect prophylaxis was uncommon, at least 60% of patients experienced reductions in episode frequency and in the proportion of time ill by at least one-half (see Table 3). These considerations strongly suggest that requiring complete protection against all recurrences of mania or bipolar depression as a test of effectiveness of a mood-stabilising agent is unrealistic and, specifically, would tend to lead to underestimates of the substantial, long-term, overall beneficial effects of lithium. …” TONDO, L., BALDESSARINI, R. J., & FLORIS, G. (2001). Long-term clinical effectiveness of lithium maintenance treatment in types I and II bipolar disorders. The British Journal of Psychiatry, 178(41), s184-s190.

According to the empirical evidence cited in this posting, lithium carbonate has roughly the same efficacy for Kleine-Levin syndrome as for bipolar disorder.


If a KLS patient tries lithium carbonate and it doesn’t work — then what?
Thoughts on KLS:
I. Fundraising
According to an August 2nd 2016 email that I received from Christian Guilleminault, MD:
“… the people who have been the most helpful to raise funds in KLS have been the board members of the KLS foundation.”
“… The disorder strikes adolescents primarily but can occur in younger children and adults. …”
Because KLS strikes adolescents primarily, KLS fundraisers might attempt to raise money for a children’s hospital with specialists in KLS.

II. Crowdsourcing
It might be possible to gather a group of KLS medical experts and/or KLS families and then pool ideas on various aspects of KLS. A crowdsourcing contest (with or without monetary prizes) might be considered.

III. Experimental therapies
There are many different medical therapies that might be worth considering for KLS. Wikipedia outlines some different approaches to medical therapy in general.

In Table 4 on page 2771 there is a list of attempted treatments for KLS: I. Arnulf, J. M. Zeitzer, et al. “Kleine–Levin syndrome: a systematic review of 186 cases in the literature.” Brain 128, no. 12 (2005): 2763-2776.

If some cases of KLS are caused by an autoimmune disorder and the specific problem can be identified, then plasmapheresis might be a highly effective therapy. Dauvilliers, Y., G. Mayer, M. Lecendreux, E. Neidhart, R. Peraita-Adrados, K. Sonka, M. Billiard, and M. Tafti. “Kleine-Levin syndrome An autoimmune hypothesis based on clinical and genetic analyses.” Neurology 59, no. 11 (2002): 1739-1745.

Crowdsourcing might help to identify plausible experimental therapies for KLS.

IV. Coping strategies

“… Family burden refers to “all the difficulties and challenges experienced by families as a consequence of someone’s illness. …” Ennis, Edel, and Brendan P. Bunting. “Family burden, fEnnis, Edel, and Brendan P. Bunting. “Family burden, family health and personal mental health.” BMC Public Health 13, no. 1 (2013): 1.amily health and personal mental health.” BMC Public Health 13, no. 1 (2013): 1.

KLS families with severe family burden issues might want to contact someone at the KLS foundation.

According to a 2015 KLS review by Arnulf (in the section “Treatment in KLS”), there are at least 2 points to remember in coping with KLS episodes:
“•During episodes
• Leave at home, quiet and safe, do not disturb
 • No benefit of amantadine”

Speculations on Prader-Willi syndrome and KLS

Hyperphagia is a fundamental characteristic feature of Prader-Willi syndrome (PWS) and is also found in about 75% of KLS patients.
According to Wikipedia, “… Characteristic of PWS is “low muscle tone, short stature, incomplete sexual development, cognitive disabilities, behavior problems, and a chronic feeling of hunger that can lead to excessive eating and life-threatening obesity.” …”–Willi_syndrome Ramdurg, S. (2010). Kleine-Levin syndrome: Etiology, diagnosis, and treatment. Annals of Indian Academy of Neurology, 13(4), 241.
“… The relationship between the two syndromes, the Prader-Willi syndrome and the Kleine-syndrome, deserves further study. …” S.-F. Gau, W.-T. Soong, et al. “Kleine-Levin syndrome in a boy with Prader-Willi syndrome.” Sleep 19, no. 1 (1996): 13-17.

It seems to me that most of the KLS experts now believe that most KLS cases are sporadic with a minority of KLS cases genetically determined. On the sporadic versus genetic issue in KLS, it seems to me that the situation is unclear.
Consider two hypothetical genes, one gene with alleles AA, Aa, with aa fatal in embryo and the other gene with alleles BB, Bb, with bb fatal in embryo.
Assume that AA, BB has a normal phenotype, AA, Bb has a normal phenotype, and Aa, BB has a normal phenotype. Assume that Aa, Bb has a disease phenotype (QS – Questionable Syndrome). Assume that the prevalence of AA is 7/9 and that of Aa is 2/9. Assume that the prevalence of BB is 99/100 and that of Bb is 1/100. Then, with random mating, the prevalence of QLS would be (2/9)^2 * (1/100)^2 = (1/4.5)^2 * (1/10000) = roughly (1/20) * (1/10000)  = 1/200000) = 5 per million.
Consider two parents F & M with the father F having genotype AA, Bb and the mother M having genotype Aa, BB. If the first-born sibling has genotype Aa, Ba then the likelihood of the second-born sibling having Aa, Bb would be (1/4) * (1/4) = 1/16 = roughly 6%. Note that the numbers in this hypothetical situation very crudely approximate the empirical KLS situation.
Empirical facts on KLS can be found at the following website;

The genes involved in chromosome 15q11.2 microdeletion syndrome and chromosome 15q13.3 microdeletion syndrome merit thorough investigation in connection with KLS. Cox, D. M., & Butler, M. G. (2015). The 15q11. 2 BP1–BP2 microdeletion syndrome: a review. International journal of molecular sciences, 16(2), 4068-4082. Sveinsson, Olafur. “A striking response to lithium in Kleine–Levin syndrome.” Frontiers in neurology 5 (2014): 33.

Why should lithium therapy for KLS work in some cases and fail in other cases? The lack of a KLS animal model makes the preceding question extremely difficult to answer. How might KLS researches discover or develop animal models for KLS? Why am I personally interested in the preceding question?
Consider the following hypothetical table:
********************Prolonged high level****Prolonged low level
Acetylcholine:****catalepsy*****************Kleine-Levin episode Brown, D. W. “Abnormal fluctuations of acetylcholine and serotonin.” Medical hypotheses 40, no. 5 (1993): 309-310.

Do prolonged abnormal levels of serotonin and/or acetylcholine occur in PANDAS? Gerardi, D. M., Casadonte, J., Patel, P., & Murphy, T. K. (2015). PANDAS and Comorbid Kleine–Levin Syndrome. Journal of child and adolescent psychopharmacology, 25(1), 93-98.

Investigations of animal models of PANDAS might lead to insights concerning Tourette syndrome and, possibly, KLS.

Consider the following experiment: Over a 10-day period inject a group of mice with acetylcholinesterase and compare the injected group to a control group of non-injected mice. Repeat the experiment with an acetylcholinesterase-injected group of PANDAS-model mice and a control group of non-injected PANDAS-model mice.

“… A prospective cohort study was conducted with a sample of 77 non-consecutive patients observed between May 2009 and September 2010. … Results In the present study, 38 (49.6%) patients developed delirium during their intensive care unit stays. Neither serum acetylcholinesterase activity nor serotonin level was independently associated with delirium. No significant correlations of acetylcholinesterase activity or serotonin level with delirium/coma-free days were observed, but in the patients who developed delirium, there was a strong negative correlation between the acetylcholinesterase level and the number of delirium/coma-free days, indicating that higher acetylcholinesterase levels are associated with fewer days alive without delirium or coma. …”
Tomasi, C.D., Salluh, J., Soares, M., Vuolo, F., Zanatta, F., Constantino, L.D.S., Zugno, A.I., Ritter, C. and Dal-Pizzol, F., 2015. Baseline acetylcholinesterase activity and serotonin plasma levels are not associated with delirium in critically ill patients. Revista Brasileira de terapia intensiva, 27(2), pp.170-177.

Very interesting post! Im not educated on rare diseases however I do know of as they are very helpful when it comes to these disorders.

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