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Kleine-Levin Syndrome-A Systematic Study of 108 Patients
Kleine-Levin Syndrome-A Systematic Study of 108 Patients
of 108 Patients
Isabelle Arnulf, MD, PhD,1,2 Ling Lin, MD, PhD,1 Nathan Gadoth, MD,3 Jennifer File, DO,1
Michel Lecendreux, MD,2 Patricia Franco, MD, PhD,2 Jamie Zeitzer, PhD,1 Betty Lo, PhD,1
Juliette H. Faraco, PhD,1 and Emmanuel Mignot, MD, PhD1
Objective: Kleine–Levin syndrome is a rare disorder characterized by relapsing-remitting episodes of hypersomnia, cognitive
disturbances, and behavioral disturbances, such as hyperphagia and hypersexuality.
Methods: We collected detailed clinical data and blood samples on 108 patients, 79 parent pairs, and 108 matched control
subjects. We measured biological markers and typed human leukocyte antigen genes DR and DQ.
Results: Novel predisposing factors were identified including increased birth and developmental problems (odds ratio, 6.5).
Jewish heritage was overrepresented, and five multiplex families were identified. Human leukocyte antigen typing was unre-
markable. Patients were 78% male (mean age at onset, 15.7 ⫾ 6.0 years), averaged 19 episodes of 13 days, and were incapac-
itated 8 months over 14 years. The disease course was longer in men, in patients with hypersexuality, and when onset was after
age 20. During episodes, all patients had hypersomnia, cognitive impairment, and derealization; 66% had megaphagia; 53%
reported hypersexuality (principally men); and 53% reported a depressed mood (predominantly women). Patients were remark-
ably similar to control subjects between episodes regarding sleep, mood, and eating attitude, but had increased body mass index.
We found marginal efficacy for amantadine and mood stabilizers, but found no increased family history for neuropsychiatric
disorders.
Interpretation: The similarity of the clinical and demographic features across studies strongly suggests that Kleine–Levin syn-
drome is a genuine disease entity. Familial clustering and increased prevalence in the Jewish population support a role for a
major genetic susceptibility factor. Considering the inefficacy of available treatments, we propose that disease management
should primarily be supportive and educational.
Ann Neurol 2008;63:482– 492
Kleine–Levin syndrome (KLS) was first described more is notable in most cases during episodes, without epi-
than 80 years ago.1–3 The disorder is characterized by leptic activity. Diffuse brain hypoperfusion, mostly fo-
recurrent episodes of hypersomnia associated with cog- cused on the thalamic and frontotemporal areas, has
nitive and behavioral abnormalities, such as megapha- been reported.6 Viral and autoimmune causative fac-
gia (eating increased amounts of food) and hypersexu- tors have been suggested, based on the frequent report
ality. Episodes are separated by weeks or months of of flu-like symptoms at onset and a significant associ-
normal sleep and behavior.4 KLS primarily affects ad- ation with DQB1*02.7
olescent boys and has an unpredictable course of recur- KLS poses diagnostic and therapeutic challenges.
rence and remission that lasts for years and most often The identity of KLS as a disorder is often questioned,
mysteriously disappears in young adults.5 and cases are frequently misdiagnosed. Therapies are
An underlying hypothalamic pathology is suggested marginally helpful and have not been systematically
by the critical role of this structure in regulating sleep, evaluated. Stimulants are partially effective on sleepi-
appetite, and sexual behaviors; however, no consistent ness but not on cognitive and behavioral abnormalities.
hypothalamic abnormalities have been identified. Lithium showed positive effects on preventing or de-
Structural brain imaging and evaluation of the cerebro- laying recurrences in a few reported cases.8
spinal fluid and serological inflammatory markers are Published work on KLS primarily consists of single-
unremarkable. Electroencephalographic (EEG) slowing case reports and retrospective, uncontrolled series that
From the 1Stanford Center for Narcolepsy and Howard Hughes This article includes supplementary materials available via the Inter-
Medical Institute, Stanford University, Palo Alto, CA; 2National net at http://www.interscience.wiley.com/jpages/0364-5134/supp-
Center for Rare Diseases-Narcolepsy, Hypersomnia and Kleine- mat
Levin Syndrome and Assistance Publique-Hôpitaux de Paris, Paris,
France; and 3Department of Neurology, Meier General Hospital, Published online in Wiley InterScience (www.interscience.wiley.com).
Kfar Saba and the Sackler Faculty of Medicine, Tel Aviv University, DOI: 10.1002/ana.21333
Tel Aviv, Israel.
Address correspondence to Dr Arnulf, Fédération des Pathologies du
Received Jul 18, 2007, and in revised form Oct 24. Accepted for Sommeil, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital,
publication Dec 10, 2007. 75651 Paris Cedex 13, France. E-mail: isabelle.arnulf@psl.aphp.fr
All whites 71 (98.6%) 54 (75.1%) p ⬍ 0.00003 321 (85%) 283 (75.1%) p ⬍ 0.0001
(24) (1.9)
Jewish Americans 10 (13.9%) 2 (2.2%) p ⬍ 0.033 5 (1.3%) 8 (2.2%) NS
(5.1)
Hispanic Americans 1 (1.4%) 9 (12.5%) p ⬍ 0.017 14 (3.7%) 47 (12.5%) p ⬍ 0.00001
(0.1) (0.27)
Native Americans 0 (0%) 1 (0.9%) NS 6 (1.6%) 3 (.9%) NS
Blacks 0 (0%) 9 (12.3%) p ⬍ 0.003 15 (4.2%) 46 (12.3%) p ⬍ 0.00004
(0) (0.30)
Asian Americans 0 (0%) 3 (3.6%) NS 19 (5.0%) 14 (3.6%) NS
Pacific Islanders 0 (0%) 0 (0.1%) NS 2 (0.53%) 0 (0.1%) NS
Ethnicity was self-declared. Samples include Kleine–Levin syndrome (KLS) and patients recruited at Stanford from across the United
States (US). Of note, hypersomnia referrals were not necessarily subsequently confirmed with a hypersomnia diagnosis. These were
compared with the frequency expected from US census data (http://censtats.census.gov/data/US/01000.pdf). Note that Hispanic and
black subjects were systematically underrepresented in all Stanford referrals. In contrast, increased Jewish heritage was observed only in
KLS patients. OR ⫽ odds ratio; NS ⫽ nonsignificant difference.
Continuous variables were analyzed by t test and analysis of more frequently than expected, based on the US pop-
variance. HLA association was examined using the transmis- ulation census (Table 1).15 Strikingly, six times more
sion disequilibrium test,14 (trio study) or 2 and Fisher’s ex- Jewish patients than expected were identified ( p ⬍
act tests (case–control). Median disease course was calculated 0.033), all Ashkenazi (not different in age, sex ratio, or
using a Kaplan–Meier survival curve analysis using both age of onset). In US patients referred to our center for
“noncensured data” (in “cured” patients with terminated
hypersomnia or narcolepsy, Hispanic and black pa-
KLS) and “censured data” (others). A patient was considered
“cured” when he/she had not had episodes for at least twice
tients were also underrepresented versus US census, but
the longest interepisode duration before disease termination. the frequency of Jewish subjects was as expected (see
To verify the adequacy of this criterion, we analyzed a subset Table 1).
of patients who had not had episodes for 5 years or more
and are thus definitively cured (n ⫽ 26). We found that the Events Surrounding Kleine–Levin Syndrome Onset
use of this criterion would have been appropriate in all these
The first episode of KLS occurred most often in au-
cases. Comparison of disease course between groups was per-
formed by the log-rank test. tumn (31.1%) or winter (31.1%), peaking in Decem-
ber (14.8%). Eighty-nine percent of patients remem-
Results bered an event closely associated with onset, most often
infections (72%; 25% with a coldlike syndrome with
Demographics and Ethnicity
fever), alcohol use (23%), sleep deprivation (22%), un-
Our sample was worldwide (Americas, Europe, Asia,
usual stress (20%), physical exertion (19%), traveling
Australia) and mostly composed of adolescent boys
(10%), head trauma (9%), marijuana use (6%).
(75.9%; sex ratio, 3:1). Mean age of onset was 15.7 ⫾
6.0 years (range, 6 –59 years) with 81.7% onset during
their second decade. Girls were older (18.5 ⫾ 9.5 Symptoms Experienced during Episodes
years) at onset than boys (15.0 ⫾ 4.2 years; p ⬍ 0.01), Although “positive” symptoms such as irritability, ag-
although they were pubescent earlier (11.8 ⫾ 1.0 vs gressiveness, abnormal perception, increased eating,
13.2 ⫾ 1.5 years; p ⬍ 0.0001). At KLS onset, 89% of and sexuality were common, the overall impression was
US patients were located in eastern states, reflecting lo- that of apathy, exhaustion, and dramatically increased
cal regions of high population density (see Supplemen- sleep (Table 2). Only hypersexuality and depression
tary Fig A). Of 108 cases, only 7 (6.5%) had been differed by sex. There was no evidence for disease het-
described in previous case reports. erogeneity, as patients with full-blown KLS (hypersom-
Of 108 international cases, 88 were non-Jewish nia, cognitive impairment, megaphagia, and hypersex-
whites, 18 Jewish, 1 Latino, and 1 Asian. In the uality) had similar demographic and clinical
United States, KLS presented in whites three times characteristics as those with “incomplete” disease (eg,
without megaphagia or hypersexuality) (data not ficult, and perceived abnormally (astereognosia); clum-
shown). Disease presentation and demographics in 18 siness led to broken limbs in three patients. Temporal
Jewish patients also did not differ from other subjects. disorientation was twice as frequent as spatial disorien-
Sleep was enormously increased during episodes, av- tation. Altered perception was always present and could
eraging 17.9 ⫾ 3.6 hours per 24 hours (range, 14.7 ⫾ affect all senses, with feelings that things were unreal,
4.8 to 21.35 ⫾ 2.5). Most patients were difficult to dreamlike: “Things seemed hazy, foggy”; “I would
awaken and reported intense dreaming and hypnagogic break a cup to see if it would break to reassure me
hallucinations, whereas sleep paralysis was uncommon. things were normal.”
A brief overshoot of insomnia was often seen at episode Nearly all patients reported eating abnormalities dur-
termination, sometimes associated with euphoria: “All I ing at least one episode. Patients ate large amounts of
want to do is stay awake and get things done that I was food with a preference for sweets and atypical food
unable to while in the episode. Plus, it is as if I have choices. Patients tended to eat any and all food that
been reenergized.” was presented, reminiscent of frontal lobe syndrome.
All patients reported cognitive impairment, and al- Hyperphagia was observed in 66% of patients leading
most all had difficulty reading and speaking: “I have to striking weight gain (4.6 ⫾ 3.1kg/episode): “I
trouble forming thoughts into words. I respond mostly would not eat for 10 to 14 hours then would eat 4 or
with grunts and groans.” Memory disturbances were 5 peanut butter and jellies–without even chewing–very
common; only 13% had complete recollection of epi- fast, then would start to fall sleep again with food still
sodes: “It seems like a movie that is cut up so scenes in my mouth.” Notably, however, one third of the pa-
are missing.” Eye–hand coordination and simple ges- tients reported decreased appetite.
tures (such as finding one’s key in a pocket) were dif- Half of the patients reported increased sexual drive
n 108 108
Age, yr 27 ⫾ 11 26 ⫾ 10 NS
pamine reuptake inhibitory stimulant and antiviral mained “absent” or “awake but still in bed, eyes open,
properties, had the most significant effect (Table 6). feeling bad.” Stimulant use occasionally showed more
It helped terminate episodes or “gave clear moments” positive, disabling symptomatology (eg, exacerbated
in 41% of patients. This effect was typically obtained aggression). Antidepressants were frequently used,
only in the first trial, often lost in subsequent epi- with no effect on most KLS symptoms and a limited,
sodes. Modafinil, methylphenidate, and amphetamine occasional effect on depressive mood (bupropion and
occasionally improved alertness, but most patients re- fluoxetine only). Among neuroleptics, only risperi-
Discussion
Our sample of more than 100 new cases recruited se-
quentially within a single year is the largest ever re-
ported. It is comparable in size with the bulk of all
previously published cases. This suggests that KLS, al-
though rare, is more prevalent than generally assumed.
In such studies, there is a theoretical small risk for
overdiagnosing KLS. We are, however, confident this
was not the case here, as we selected participants after
a consistent, long medical interview of patients (diag-
nosed by colleagues and never self-diagnosed) or their
parents by phone, using the International Classification
of Sleep Disorders criteria, and followed by a long
are intact, whereas sleep and higher associative brain brain dysfunction rather than an incidental factor con-
functions are altered. Together with the diverse symp- ferring future liability.
tomatology reported, these results suggest that KLS is Our most intriguing findings are the familial clus-
associated with widespread brain abnormalities involv- tering and a potential increased risk in the Jewish
ing primarily the thalamus, hypothalamus, and fronto- population, supporting a role for genetic susceptibility
temporal areas.6,18 A striking fourfold increase in self- factors. HLA-DQ2 has been suggested to be associat-
reported birth difficulties was found in KLS patients ed,7 but we could not replicate this finding in our
versus control subjects. This finding is reminiscent of much larger independent sample. Although familial
autism,19,20 epilepsy,21 and schizophrenia.22 Birth dif- risk was low (1% per first-degree relative), we readily
ficulties could cause perinatal brain injury and subse- identified multiplex families and estimate an 800- to
quent symptomatology, as established in developmental 4,000-fold increased risk in first-degree relatives (esti-
disorders and epilepsy.21 Alternatively, increased prev- mating KLS prevalence at 2–10 per million, and 5
alence of obstetric complications could reflect an un- first-degree relatives per proband). Increased familial
derlying fetal KLS pathology. Birth difficulties are clustering is consistent with multiple prior reports of
prevalent in children with hypothalamic defects, indi- multiplex families in the literature. Shared environ-
cating a role for the fetal hypothalamus in the timing mental effects cannot be excluded, but delayed onset
and process of birth.23 In light of this, increased ob- among siblings17 argues against the sole effect of an
stetric complications in KLS could signal an underlying infectious agent. One sixth of KLS patients reported
Stimulants
Modafinil 43 79% 21% 0%
Methylphenidate 27 89% 11% 0%
Amantadine 24 58% 29% 12%
Amphetamine 14 87% 13% 0%
Bupropion 4 50% 50% 0%
Antidepressant drugs
Sertraline 17 100% 0% 0%
Fluoxetine 16 81% 19% 0%
a
Others 23 87% 13% 0%
Melatonin 15 87% 13% 0%
Phototherapy 6 94% 6% 0%
Neuroleptics
Risperidone 8 63% 37% 0%
b
Others 15 100% 0% 0%
Antiepileptic drugs
Carbamazepine 22 91% 9% 0%
Valproate 17 75% 19% 6%
c
Benzodiazepines 26 96% 4% 0%
Othersd 13 100% 0% 0%
Lithium 30 77% 17% 7%
Others
Immunoglobulins 3 66% 33% 0%
Acyclovir 2 100% 0% 0%
Corticosteroid 2 100% 0% 0%
Nonmedical therapies
Vitamin supplements 24 100% 0% 0%
Phototherapy 6 83% 17% 0%
Otherse 4 100% 0% 0%
Medication reports were tabulated based on reports and response per episode codified into no change or worse, partial benefit, or
important benefit. Benefit was subjectively defined by the patients as helping to terminate/shorten episodes, reducing episode intensity,
or preventing episode recurrence.
a
Amitryptilin, clomipramine, fluvoxamine, trazodone, moclobemide, venlafaxine, nortryptilin, imipramine, phenelzine, amineptine,
mirtazapine, citalopram.
b
Amisulpride, levomepromazine, thioridazine, quietapine.
c
Clonazepam, lorazepam, diazepam, alprazolam, temazepam, zolpidem.
d
Gabapentine, phenytoine, lamotrigine, tiagabide.
e
Acupuncture, hypnotherapy, psychotherapy.
between 1962 and 2004 were from Israel,5 potentially finding is exciting in light of recent identification of
a reflection of a long-standing interest in KLS. In our strong genetic effects in infectious disease manifesta-
series, Jewish ancestry was also significantly overrep- tions,24,25 including the development of herpes sim-
resented in patients from the United States but not in plex virus encephalitis.26 The parallels with herpes
hypersomnia referrals. The predominance of Ash- simplex virus encephalitis and the interplay between
kenazi descent also suggests a role for Jewish-specific pathogen and inherent genetic risk (in the later case a
or enriched polymorphisms in this population. This Toll-like receptor mutation affecting immune re-