# Kleine-Levin syndrome. Clinical boarderlands based on a thorough analysis of 475 case reports

Michel Billiard, Isabelle Jaussent

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## To cite this version:

Michel Billiard, Isabelle Jaussent. Kleine-Levin syndrome. Clinical boarderlands based on a thorough analysis of 475 case reports. Sleep Medicine, 2024, 121, pp.135-143. 10.1016/j.sleep.2024.06.003. hal-04965739

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# Kleine-Levin syndrome. Clinical boarderlands based on a thorough analysis of 475 case reports

Michel Billiard<sup>a, *,</sup> , Isabelle Jaussent<sup>b</sup>

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## ARTICLE INFO

**Keywords:**

Kleine-Levin syndrome

Kleine-Levin syndrome: opposite symptoms

Kleine-Levin syndrome: alternation of typical and opposite symptoms

Kleine-Levin syndrome: precipitating factors and symptoms in males and females

## ABSTRACT

**Objective/background:** Kleine-Levin syndrome (KLS) is a rare sleep disorder characterized by recurrent episodes of severe hypersomnolence in association with various degrees of cognitive impairment, perceptive abnormalities, apathy, behavioral disturbances. Some of these symptoms, hypersomnolence, compulsive eating and increased sexual drive may be replaced by their opposites or alternate with them. Remarkably enough, these « atypical symptoms » have never been enlightened nor compared in frequency with corresponding typical symptoms. Besides, KLS is more frequent in males than in females but no review has ever compared the frequency of precipitating factors and symptoms in males and females.

**Patients/methods:** To uncover these as yet uninvestigated aspects of KLS, a predesigned template was used to extract precipitating factors and symptoms, in 475 case reports of KLS, comprising 364 males and 111 females.

**Results:** Precipitating factors were more frequently recorded in males (67.31 %) than in females (49.55 %). Recurrent episodes of hypersomnolence were present in 94.32 % of cases, recurrent insomnia in 1.05 % and alternation of hypersomnolence and insomnia in 4.63 %. Cognitive impairment was present in 67.37 % of cases and absent in 6.95 %. Derealization/altered perception was present in 38.32 % of cases and absent in 1.68 %. Severe apathy was present in 44.63 % of cases. Compulsive eating was present in 59.58 % of cases, absent in 13.26 %, replaced by anorexia in 9.05 %, alternation of compulsive eating and anorexia in 5.68 % and alternation of compulsive eating and no compulsive eating in 8.42 %. Increased sexual drive was present in 33.68 % of cases, absent in 22.74 %, replaced by decreased sexual drive in 1.47 %, alternation of increased sexual drive and no increased sexual drive in 2.95 %. Odd behaviors were present in 45.05 % of cases. Psychiatric features were present in 71.58 % of cases, absent in 2.95 %. Finally, the percentages of precipitating factors and of sleep disorder, apathy, sexual disorder, irritability/agressivity, were higher in males than in females.

**Conclusions:** The frequency of the opposites of hypersomnolence, compulsive eating and increased sexual drive appears to be quite significant. In addition, a systematic comparison of precipitating factors and symptoms in males and females has shown limited differences between sexes.

## 1. Introduction

KLS is a rare relapsing-remitting sleep disorder first named by Critchley and Hoffman in 1942 [1] and first described in details by Critchley in 1962 [2]. It is characterized by recurrent episodes of hypersomnolence and, to various degrees, cognition impairment, derealization/altered perception, severe apathy while awake, behavioral disorders including compulsive eating, increased sexual drive and odd behaviors, psychiatric features, irritability/aggressiveness when prevented from sleeping, restlessness/agitation and dysautonomic

symptoms. These episodes may be immediately preceded by headache, plus or minus vomiting, and terminated by transient symptoms such as amnesia of the episode, insomnia, elation, for one or two days. Alertness, cognitive and mental functions, eating and sexual behaviors are most often normal between episodes. In 1979, KLS was first classified in the Diagnostic Classification of Sleep and Arousal Disorders [3] and, from 1990 on, in the successive editions of the International Classification of Sleep Disorders [4–7] containing the diagnostic criteria of the condition. Here are the diagnostic criteria contained in the last edition of the International Classification of Sleep Disorders referred to as ICSD-3-TR

<footnote><sup>a</sup> Department of Neurology, Gui de Chauliac Hospital, Montpellier, France</footnote>

<footnote><sup>b</sup> Institute for Neurosciences of Montpellier INM, Montpellier University, INSERM, Montpellier, France</footnote>

<footnote>* Corresponding author. Department of Neurology, Gui de Chauliac Hospital, 80 Avenue Augustin Fliche, Montpellier, 34295, France.
E-mail address: mbilliard@orange.fr (M. Billiard).</footnote>
[7].

« Diagnostic Criteria.

Criteria A-E must be met:

A. the patient experiences at least two recurrent episodes of excessive sleepiness and sleep duration, each persisting for two days to several weeks

B. Episodes usually recur more than once a year and at least once every 18 months.

C. The patient has normal sleep or near normal sleep and wakefulness, cognition, behavior and mood between episodes, at least during the first years of the syndrome.

D. The patient must demonstrate at least one of the following during episodes:

1. Cognitive dysfunction

2. Derealization

3. Major apathy

4. Disinhibited behavior (such as hypersexuality or hyperphagia)

E. The symptoms and signs are not better explained by chronic insufficient sleep, a circadian rhythm sleep-wake disorder or other current sleep disorder, medical disorder, mental disorder or medication substance use or withdrawal.

Notes: Several new studies in a large series show that sleep duration is longer, cognition is mildly altered, and some mental disorders may be evident in 15-20 % of patients during inter-episodic periods over the longitudinal course of the disorder ».

One symptom may be present during one or several episodes and absent during other episodes [8–10], an extreme example of that being the presence of compulsive eating in only 3 out of 45 hypersomnolent episodes and the presence of increased sexual drive in only 1 out of 45 hypersomnolent episodes in one patient [11], remain stable or wax and wane during all episodes [12,13], or be asynchronous with other symptoms [14]. Moreover, recurrent hypersomnolence may be replaced by its opposite, recurrent insomnia in rare cases, or alternate with it; compulsive eating may be replaced by its opposite, anorexia, alternate with it or with no compulsive eating, or be absent; and increased sexual drive may be replaced by its opposite, decreased sexual drive, alternate with no increased sexual drive, or be absent. Consequently, Smolik and Roth [15] described « atypical KLS » in which hypersomnolence, compulsive eating, increased sexual drive are replaced or alternate with their opposite, namely insomnia, anorexia or decreased sexual drive. However these features of KLS have never been reviewed in detail and are hardly referred to in the Diagnostic Classification of Sleep and Arousal Disorders [3] and in the successive editions of the International Classification of Sleep Disorders [4–7]. Another remarkable feature of KLS is the predominance of males affected by this condition. Yet, up to now, comparisons have been made between males and females in terms of age of onset [16] and duration of the condition [17], but not in terms of precipitating factors and symptoms.

Thus, the aim of this review was 1) to investigate the frequency of typical and atypical symptoms in KLS, and 2) to compare the frequency of precipitating factors and symptoms, between males and females.

Abbreviations

CNS: Central nervous system

EEG: Electroencephalography

ICSD: International classification of sleep disorders

KLS: Kleine-Levin syndrome

SAS: Institute: Statistical Analysis System Institute

## 2. Methods

### 2.1. Literature search

A Medline search using the terms KLS, recurrent hypersomnia, periodic hypersomnia and sleeping beauty syndrome was performed, from inception to December 2023. In addition, historical articles dating from William Oliver [18] to Critchley and Hoffman [1] who coined the term KLS, monographies, medical theses, medical congress abstracts (when clinically sufficiently documented) and potentially missed literature hand searched from references accompanying review articles, were also reviewed. On the contrary, insufficiently documented case reports, abstracts of case reports, case reports with a single episode, menstruation linked KLS and unpublished personal cases were excluded. All case reports met 2023 ICSD-3-TR diagnostic criteria [7], with the exception of a few case reports remarkable for the presence of recurring insomnia or alternation of hypersomnolence and insomnia.

### 2.2. Data extraction

We used the terms hypersomnolence, cognitive impairment, derealization/altered perception, apathy, disinhibited behavior (including compulsive eating, compulsive drinking, increased sexual drive and odd behaviors), irritability/aggressiveness, psychiatric features, restlessness/agitation, dysautonomic symptoms, headache at the onset of episodes and transient symptoms at the end of episodes, to designate key and accessory symptoms of KLS. To be as accurate as possible, we listed the main equivalents of these symptoms encountered in the world literature (Table 1). The predesigned template of the symptoms and of their various status, presence, opposite, alternation of positive and opposite symptoms, absence and no data, appears on the left column (variable) of Table 5. « No data », introduced for the first time in a review of KLS, correspond to case reports with no mention of the symptom. It may reflect either the lack of consideration of the symptom by the author(s) - all authors are not KLS specialists - or its absence. This is of importance for sound statistics: a symptom not referred to in a case report is not necessarily absent.

### 2.3. Statistical analysis

Categorical variables were presented as numbers and percentages, and quantitative variables as either the mean and standard deviation or the median and range, depending on the distribution of the variables (normal or not). Frequencies between males and females were compared using the Chi-square test or the Fisher's exact test, and continuous variables were compared between males and females using either the t-test or the Mann-Whitney U test, depending on the distribution of the data. All statistical analyses were performed using SAS (SAS institute, Cary, NC, USA), with statistical significance level at $p < 0.05$.

## 3. Results

### 3.1. Demographics

Overall, 475 case reports were collected, 246 from Europe (Austria, Belgium, Croatia, Cyprus, Czechoslovakia and later Czech Republic, Denmark, France, Germany, Hungary, Ireland, Italy, the Netherlands, Poland, Portugal, Rumania, Russia, Serbia, Spain, Sweden, Switzerland, Turkey, United Kingdom), 132 written in English and 114 in national languages; 115 from Asia (Ceylon, China, Hong-Kong, India, Japan, Malaysia, Pakistan, South Korea, Taïwan, Thailand), 110 in English and 5 in another language; 65 from North America (Canada, Puerto Rico, USA), 62 in English and 3 in another language; 25 from the Middle East (Dubaï, Iran, Israel, Kowait, Lebanon, Saudi Arabia), 20 in English and 5 in other languages; 15 from Latin America (Argentina, Brazil), 9 in English and 6 in other languages; 5 from Africa (Ivory Coast, Morocco,
**Table 1**

Terminology of key and accessory symptoms, and equivalents in the world literature.

**Hypersomnolence:** hypersomnia, somnolency, deep sleep, excessive daytime sleepiness, continuous inclination to sleep, irresistible need to rest, drowsiness, lethargy, dopiness, sopor

**Cognitive impairment:** apathy, confusion, desorientation, hazyness, impaired memory, impaired speech, non sense talking, slow in speaking and answering, lack of concentration, disconnected thinking, drugged, mental slowness, communication with monosyllables or short sentences.

**Derealization/alters perception:** depersonalization, experiencing life outside of their own boddies, dream-like state, being in an unreal state, in a bubble, in a fog, incapacity to judge properly the nearness or distance of objects, bizarre sensation, bitter dysgueusia, blunted hearing, sight, smell, touch, taste, hypersensitivity to light, micro or macropsy, lack of sensitivity to temperature.

**Apathy:** indifference, social withdrawal, loss of verbal communication, haggard look, trance-like state, distant behaviour, dullness, strangeness, listlessness, bewilderment, inertia, flat affect, avoidant behavior, sluggishness, languor, stupor

**Compulsive eating:** hyperphagia, megaphagia, polyphagia, overeating, increased appetite, increased desire for food, pathological hunger, gluttony, ravenous appetite, voracious appetite, eating a great deal, morbid hunger, bulimia, insatiable appetite.

**Compulsive drinking:** overdrinking, polydipsia, two helpings of soup, considerable thirst, consumption of large quantities of liquids, drinking a lot, up to 8 L of fluids, up to ten cups of water.

**Increased sexual drive:** hypersexuality, overt masturbation, abnormally frequent sexual relations, repeated orgasms, sustained erections, sexual comments, amorous towards women, touching genitalia, aggressively amorous, sexually provocative behavior, throwing kisses, provocative dress, mental fantasy related to sexual themes.

**Odd behaviors:** abnormal facial expression, bizarre posture, childish behavior, continuous or repetitive vocal pattern, imaginative action, loss of decency, pacing, running away, stereotyped behavior, violent behavior.

**Psychiatric features:** anxiety disorder, depressive disorder, suicidal ideation, bipolar disorder, schizophrenic disorder, delusions, hallucinations.

**Irritability/aggressiveness:** bad temper, belligerence, hostility, impoliteness, uncooperativeness.

**Restlessness/agitation:** useless motion, excitation periods

**Dysautonomic symptoms:** acrocyanosis, bradycardia, disorganized thermic regulation, epistaxis, hypotension, intense body odor, myosis, perspiration, puffy face, sweating, anisocoria, ptosis, flushing of the face.

**Headache at the onset of episodes:** headache, cephalgia

**Transient symptoms at the end of episodes:** anterograde amnesia, depression, elation, hyperactivity, insomnia rebound, mania.

**Neurological signs:** brisk tendon reflexes, sluggishness of tendon reflexes, transient left or right side paralysis, minimal meningism, tremor, diminished tone of muscles, paresthetic sensations, alteration in the body scheme, numbness, Chvostek's sign, Hoffman's sign, contraction of muscles, clonic jerks, flexion posture, impaired coordination, upward or downward gaze palsy, nystagmus, diplopia, vertigo, Romberg's sign, ataxic gate.

Nigeria), 4 in English and 1 in another language; and 4 from Oceania (Australia, New Zealand) all in English (Table 2). Altogether, there were 341 case reports written in English (71.7 %) and 134 in other languages (28.2 %). Of these, 364 case reports (76.6 %) were from males, 111 (23.3 %) from females, giving a 3.49/1 male-female ratio. The age of onset varied from 4 to 80 years in males and from 1 to 69 in females, with an onset below 10 years in 13 males and 10 females and an onset equal or above 40 in 11 males and 12 females. The median age of onset in age groups was higher in females than in males (Table 3). Furthermore, 12 familial cases were identified, that is 2.52 % of the whole sample, including two mothers/sons, four brothers, two siblings, one uncle/nephew, one first degree cousins and two twin pairs.

## 3.2. Precipitating factors

Table 4 displays the total number and percentage of patients with the presence, absence, and availability of data on precipitating factors, in the whole sample as well as in males and females. Additionally, it gives the number and percentage of patients with 0, 1, 2, ≥3 precipitating factors prior to the first episode of KLS. Furthermore, it details, in the descending order of frequency, the number and percentage of patients with each precipitating factor, in patients with at least one precipitating factor. Precipitating factors were documented in 63.16 % of case reports, with a higher frequency observed among males (67.31 %) than among females (49.55 %). However, there were many more case reports with no data in females (41.59 %) than in males (28.81 %). Out of the 300 case reports that documented a precipitating factor, the most frequent one

**Table 2**

Distribution of case reports by country.

<table><thead><tr><th rowspan="2">Continents or<br>subcontinents</th><th>Whole population N<br>= 475</th><th>Males N =<br>364</th><th>Females N =<br>111</th></tr><tr><th>n (%)</th><th>n (%)</th><th>n (%)</th></tr></thead><tbody><tr><td>Africa</td><td>5 (1.05)</td><td>3 (0.82)</td><td>2 (1.80)</td></tr><tr><td>Asia</td><td>115 (24.21)</td><td>90 (24.73)</td><td>25 (22.52)</td></tr><tr><td>Europe</td><td>246 (51.79)</td><td>191 (52.47)</td><td>55 (49.55)</td></tr><tr><td>Latin America</td><td>15 (3.16)</td><td>10 (2.75)</td><td>5 (4.50)</td></tr><tr><td>Middle East</td><td>25 (5.26)</td><td>19 (5.22)</td><td>6 (5.41)</td></tr><tr><td>North America</td><td>65 (13.68)</td><td>48 (13.19)</td><td>17 (15.32)</td></tr><tr><td>Oceania</td><td>4 (0.84)</td><td>3 (0.82)</td><td>1 (0.90)</td></tr></tbody></table>

**Table 3**

Distribution of age of onset in the whole sample and according to sex.

<table><thead><tr><th rowspan="2">Variable</th><th>Whole population<br>N = 475</th><th>Males N =<br>364</th><th>Females N =<br>111</th><th rowspan="2">p</th></tr><tr><th>n (%)</th><th>n (%)</th><th>n (%)</th></tr></thead><tbody><tr><td>Age of onset, in<br>years</td><td></td><td></td><td></td><td rowspan="5">&lt;0.0001</td></tr><tr><td>&lt;10</td><td>23 (4.84)</td><td>13 (3.57)</td><td>10 (9.01)</td></tr><tr><td>[10–20]</td><td>344 (72.42)</td><td>283 (77.75)</td><td>61 (54.95)</td></tr><tr><td>[20–30]</td><td>63 (13.26)</td><td>43 (11.81)</td><td>20 (18.02)</td></tr><tr><td>[30–40]</td><td>22 (4.63)</td><td>14 (3.85)</td><td>8 (7.21)</td></tr><tr><td>≥40</td><td>23 (4.84)</td><td>11 (3.02)</td><td>12 (10.81)</td><td rowspan="2">0.05</td></tr><tr><td>Age of onset, in<br>years<sup>a</sup></td><td>15.00 (1.00;<br>80.00)</td><td>15.00 (4.00;<br>80.00)</td><td>16.00 (1.00;<br>69.00)</td></tr></tbody></table>

<sup>a</sup> Continuous variable is expressed by median (minimum value-maximum value).

was an unspecified infection (41.33 %) followed by an upper airway infection (19.67 %) and an emotional shock (15.00 %). The frequencies of the various factors did not differ between males and females, except for emotional shock and anaesthesia, which were more frequent in females than in males.

## 3.3. Symptoms

### 3.3.1. Frequency of typical and atypical symptoms in the whole sample and in males and females

Table 5 displays 1) the number and percentage of patients with hypersomnolence, insomnia, hypersomnolence/insomnia in the case of sleep disorders, 2) the number and percentage of patients with compulsive eating, anorexia, compulsive eating/no compulsive eating, compulsive eating/anorexia, absence of symptoms (when indicated) and no data in the case of eating disorders, 3) the number and percentage of patients with increased sexual drive, decreased sexual drive, increased sexual drive/no increased sexual drive, absence of symptoms (when indicated) and no data in the case of sexual disorders, 4) the number and percentage of patients with presence, absence of symptoms (when indicated), and no data in the case of all other symptoms.

The most striking result of this survey was the replacement of hypersomnolence, compulsive eating, and increased sexual drive by their
<table><caption>**Table 4**
Precipitating factors in the whole sample and according to sex.</caption><thead><tr><th rowspan="2">Variable</th><th>Whole<br>sample N =<br>475</th><th>Males N<br>= 364</th><th>Females N<br>= 111</th><th rowspan="2">p</th></tr><tr><th>n (%)</th><th>n (%)</th><th>n (%)</th></tr></thead><tbody><tr><td>Precipitating factors</td><td></td><td></td><td></td><td>0.003</td></tr><tr><td>Presence</td><td>300 (63.16)</td><td>245<br>(67.31)</td><td>55 (49.55)</td><td></td></tr><tr><td>Absence</td><td>36 (7.58)</td><td>23 (6.32)</td><td>13 (11.71)</td><td></td></tr><tr><td>No data</td><td>139 (29.26)</td><td>96<br>(26.37)</td><td>43 (38.74)</td><td></td></tr><tr><td>Number of precipitating<br>factors prior to the first<br>episode of KLS</td><td></td><td></td><td></td><td>0.03</td></tr><tr><td>0</td><td>36 (10.71)</td><td>23 (8.58)</td><td>13 (19.12)</td><td></td></tr><tr><td>1</td><td>231 (68.75)</td><td>187<br>(69.78)</td><td>44 (64.71)</td><td></td></tr><tr><td>2</td><td>51 (15.18)</td><td>45<br>(16.79)</td><td>6 (8.82)</td><td></td></tr><tr><td>≥3</td><td>18 (5.36)</td><td>13 (4.85)</td><td>5 (7.35)</td><td></td></tr><tr><td>Detailed precipitating factors in the 300 patients with identifiable precipitating<br>factors<sup>a</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Unspecified infection</td><td>124 (41.33)</td><td>102<br>(41.63)</td><td>22 (40.00)</td><td>0.82</td></tr><tr><td>Upper airway infection</td><td>59 (19.67)</td><td>50<br>(20.41)</td><td>9 (16.36)</td><td>0.49</td></tr><tr><td>Emotional chok</td><td>45 (15.00)</td><td>30<br>(12.24)</td><td>15 (27.27)</td><td>0.005</td></tr><tr><td>Alcohol intake</td><td>30 (10.00)</td><td>26<br>(10.61)</td><td>4 (7.27)</td><td>0.46</td></tr><tr><td>Outing with high<br>temperature</td><td>24 (8.00)</td><td>21 (8.57)</td><td>3 (5.45)</td><td>0.59</td></tr><tr><td>Exhaustion</td><td>23 (7.67)</td><td>20 (8.16)</td><td>3 (5.45)</td><td>0.78</td></tr><tr><td>Head traumatism</td><td>19 (6.33)</td><td>17 (6.94)</td><td>2 (3.64)</td><td>0.54</td></tr><tr><td>Specified infection</td><td>11 (3.67)</td><td>10 (4.08)</td><td>1 (1.82)</td><td>0.70</td></tr><tr><td>Gastro-enteritis</td><td>11 (3.67)</td><td>9 (3.67)</td><td>2 (3.64)</td><td>0.99</td></tr><tr><td>Intoxication</td><td>9 (3.00)</td><td>7 (2.86)</td><td>2 (3.64)</td><td>0.67</td></tr><tr><td>Surgery</td><td>9 (3.00)</td><td>8 (3.27)</td><td>1 (1.82)</td><td>0.99</td></tr><tr><td>Seasickness</td><td>7 (2.33)</td><td>6 (2.45)</td><td>1 (1.82)</td><td>0.99</td></tr><tr><td>Sleep deprivation</td><td>7 (2.33)</td><td>5 (2.04)</td><td>2 (3.64)</td><td>0.62</td></tr><tr><td>Anaesthesia</td><td>7 (2.33)</td><td>3 (1.22)</td><td>4 (7.27)</td><td>0.02</td></tr><tr><td>Vaccination</td><td>6 (2.00)</td><td>5 (2.04)</td><td>1 (1.82)</td><td>0.99</td></tr></tbody></table>

opposites, insomnia, anorexia, decreased sexual drive or by the alternation of hypersomnolence and insomnia, compulsive eating and anorexia, compulsive eating and no compulsive eating, increased sexual drive and no increased sexual drive, in a number of cases. The second finding was the order of frequency of the different symptoms. A sleep disorder, either hypersomnolence or insomnia or alternation of hypersomnolence and insomnia, was present in 100 % of patients. Psychiatric features were the second most frequent symptom (71.58 %) followed in the descending order by cognitive impairment (67.37 %), compulsive eating (59.58 %), irritability/aggressiveness (53.47 %), apathy (44.63 %), derealization/altered perception (38.72 %) and increased sexual drive (33.68 %). All other symptoms were found in less than 20 % of case reports.

Finally, the percentage of symptoms with no data was generally high in symptoms not indicated in the diagnostic criteria, with the notable exception of psychiatric features, 25.47 % only. This table does not include data on neurological symptoms. Indeed, neurological symptoms were of two types: those permanently present for months or years in patients with a comorbid neurological disorder such as brain tumour, multiple sclerosis, brain infarct, Parkinson's disease present in 6.7 % of patients, and those accompanying KLS episodes, such as brisk or sluggish tendon reflexes, transient left or right side paralysis, minimal meningism, tremor, diminished tone of muscles, numbness, Chvostek's sign, clonic jerks, ataxic gate, most often discreet, questionable or even factitious, present in 6.5 % of patients.

<table><caption>**Table 5**
Symptoms in the whole sample and according to sex.</caption><thead><tr><th rowspan="2">Variable</th><th>Whole<br>sample<br>N = 475</th><th>Males<br>= 364</th><th>Females<br>= 111</th><th rowspan="2">p</th><th rowspan="2">p<sup>a</sup></th></tr><tr><th>n (%)</th><th>n (%)</th><th>n (%)</th></tr></thead><tbody><tr><td>Sleep disorder</td><td></td><td></td><td></td><td>0.03</td><td></td></tr><tr><td>Hypersomnolence</td><td>448<br>(94.32)</td><td>349<br>(95.88)</td><td>99<br>(89.19)</td><td></td><td></td></tr><tr><td>Insomnia [19,20]</td><td>5 (1.05)</td><td>3 (0.82)</td><td>2 (1.80)</td><td></td><td></td></tr><tr><td>Hypersomnolence/<br>Insomnia [21–40]</td><td>22 (4.63)</td><td>12<br>(3.30)</td><td>10 (9.01)</td><td></td><td></td></tr><tr><td>Cognitive impairment</td><td></td><td></td><td></td><td>0.51</td><td>0.76</td></tr><tr><td>Presence</td><td>320<br>(67.37)</td><td>250<br>(68.68)</td><td>70<br>(63.06)</td><td></td><td></td></tr><tr><td>Absence</td><td>33 (6.95)</td><td>25<br>(6.87)</td><td>8 (7.21)</td><td></td><td></td></tr><tr><td>No data</td><td>122<br>(25.68)</td><td>89<br>(24.45)</td><td>33<br>(29.73)</td><td></td><td></td></tr><tr><td>Derealization/Altered<br>perception</td><td></td><td></td><td></td><td>0.43</td><td>0.67</td></tr><tr><td>Presence</td><td>182<br>(38.32)</td><td>145<br>(39.84)</td><td>37<br>(33.33)</td><td></td><td></td></tr><tr><td>Absence</td><td>8 (1.68)</td><td>6 (1.65)</td><td>2 (1.80)</td><td></td><td></td></tr><tr><td>No data</td><td>285<br>(60.00)</td><td>213<br>(58.52)</td><td>72<br>(64.86)</td><td></td><td></td></tr><tr><td>Apathy</td><td></td><td></td><td></td><td>0.04</td><td>NA</td></tr><tr><td>Presence</td><td>212<br>(44.63)</td><td>172<br>(47.25)</td><td>40<br>(36.04)</td><td></td><td></td></tr><tr><td>No data</td><td>263<br>(55.37)</td><td>192<br>(52.75)</td><td>71<br>(63.96)</td><td></td><td></td></tr><tr><td>Eating disorder</td><td></td><td></td><td></td><td>NA</td><td>0.09</td></tr><tr><td>Compulsive eating</td><td>283<br>(59.58)</td><td>215<br>(59.07)</td><td>68<br>(61.26)</td><td></td><td></td></tr><tr><td>Anorexia [41–65]</td><td>43 (9.05)</td><td>35<br>(9.62)</td><td>8 (7.21)</td><td></td><td></td></tr><tr><td>Compulsive eating/no<br>compulsive eating [25,<br>65–99]</td><td>40 (8.42)</td><td>33<br>(9.07)</td><td>7 (6.31)</td><td></td><td></td></tr><tr><td>Compulsive eating/<br>anorexia [100–121]</td><td>27 (5.68)</td><td>16<br>(4.40)</td><td>11 (9.91)</td><td></td><td></td></tr><tr><td>Absence</td><td>63<br>(13.26)</td><td>53<br>(14.56)</td><td>10 (9.01)</td><td></td><td></td></tr><tr><td>No data</td><td>19 (4.00)</td><td>12<br>(3.30)</td><td>7 (6.31)</td><td></td><td></td></tr><tr><td>Drinking disorder</td><td></td><td></td><td></td><td>0.03</td><td>0.90</td></tr><tr><td>Compulsive drinking</td><td>48<br>(10.11)</td><td>30<br>(8.24)</td><td>18<br>(16.22)</td><td></td><td></td></tr><tr><td>Absence</td><td>14 (2.95)</td><td>9 (2.47)</td><td>5 (4.50)</td><td></td><td></td></tr><tr><td>No data</td><td>413<br>(86.95)</td><td>325<br>(89.29)</td><td>88<br>(79.28)</td><td></td><td></td></tr><tr><td>Sexual disorder</td><td></td><td></td><td></td><td>0.001</td><td>0.005</td></tr><tr><td>Increased sexual drive</td><td>160<br>(33.68)</td><td>139<br>(38.19)</td><td>21<br>(18.92)</td><td></td><td></td></tr><tr><td>Decreased sexual drive<br>[122–129]</td><td>7 (1.47)</td><td>6 (1.65)</td><td>1 (0.90)</td><td></td><td></td></tr><tr><td>Increased sexual drive/<br>No increased sexual<br>drive [130–141]</td><td>14 (2.95)</td><td>12<br>(3.30)</td><td>2 (1.80)</td><td></td><td></td></tr><tr><td>Absence</td><td>108<br>(22.74)</td><td>75<br>(20.60)</td><td>33<br>(29.73)</td><td></td><td></td></tr><tr><td>No Data</td><td>186<br>(39.16)</td><td>132<br>(36.26)</td><td>54<br>(48.65)</td><td></td><td></td></tr><tr><td>Odd behaviors</td><td></td><td></td><td></td><td>0.08</td><td></td></tr><tr><td>Presence</td><td>214<br>(45.05)</td><td>172<br>(47.25)</td><td>42<br>(37.84)</td><td></td><td></td></tr><tr><td>No data</td><td>261<br>(54.95)</td><td>192<br>(52.75)</td><td>69<br>(62.16)</td><td></td><td></td></tr><tr><td>Psychiatric features</td><td></td><td></td><td></td><td>0.46</td><td>0.74</td></tr><tr><td>Presence</td><td>340<br>(71.58)</td><td>264<br>(72.53)</td><td>76<br>(68.47)</td><td></td><td></td></tr><tr><td>Absence</td><td>14 (2.95)</td><td>12<br>(3.30)</td><td>2 (1.80)</td><td></td><td></td></tr><tr><td>No data</td><td>121<br>(25.47)</td><td>88<br>(24.18)</td><td>33<br>(29.73)</td><td></td><td></td></tr><tr><td>Irritability/<br>aggressiveness</td><td></td><td></td><td></td><td>0.046</td><td>0.34</td></tr></tbody></table>

(continued on next page)

<footnote>a Several precipitating factors may be reported in a single patient.</footnote>
<table><caption>**Table 5 (continued)**</caption><thead><tr><th rowspan="2">Variable</th><th>Whole<br>sample<br>N = 475</th><th>Males<br>N = 364</th><th>Females<br>N = 111</th><th rowspan="2">p</th><th rowspan="2">p<sup>a</sup></th></tr><tr><th>n (%)</th><th>n (%)</th><th>n (%)</th></tr></thead><tbody><tr><td>Presence</td><td>254<br>(53.47)</td><td>206<br>(56.59)</td><td>48<br>(43.24)</td><td></td><td></td></tr><tr><td>Absence</td><td>17 (3.58)</td><td>12<br>(3.30)</td><td>5 (4.50)</td><td></td><td></td></tr><tr><td>No data</td><td>204<br>(42.95)</td><td>146<br>(40.11)</td><td>58<br>(52.25)</td><td></td><td></td></tr><tr><td>Restlessness/agitation</td><td></td><td></td><td></td><td>0.54</td><td>NA</td></tr><tr><td>Presence</td><td>73<br>(15.37)</td><td>58<br>(15.93)</td><td>15<br>(13.51)</td><td></td><td></td></tr><tr><td>No Data</td><td>402<br>(84.63)</td><td>306<br>(84.07)</td><td>96<br>(86.49)</td><td></td><td></td></tr><tr><td>Dysautonomic symptoms</td><td></td><td></td><td></td><td>0.48</td><td>0.99</td></tr><tr><td>Presence</td><td>67<br>(14.11)</td><td>49<br>(13.46)</td><td>18<br>(16.22)</td><td></td><td></td></tr><tr><td>Absence</td><td>3 (0.63)</td><td>2 (0.55)</td><td>1 (0.90)</td><td></td><td></td></tr><tr><td>No data</td><td>405<br>(85.26)</td><td>313<br>(85.99)</td><td>92<br>(82.88)</td><td></td><td></td></tr><tr><td>Headache at the onset of<br>hypersomnolent<br>episodes</td><td></td><td></td><td></td><td>0.86</td><td>0.99</td></tr><tr><td>Presence</td><td>80<br>(16.84)</td><td>63<br>(17.31)</td><td>17<br>(15.32)</td><td></td><td></td></tr><tr><td>Absence</td><td>8 (1.68)</td><td>6 (1.65)</td><td>2 (1.80)</td><td></td><td></td></tr><tr><td>No data</td><td>387<br>(81.47)</td><td>295<br>(81.04)</td><td>92<br>(82.88)</td><td></td><td></td></tr><tr><td>Transient symptoms at<br>the end of<br>hypersomnolent<br>episodes</td><td></td><td></td><td></td><td>0.48</td><td>0.99</td></tr><tr><td>Presence</td><td>67<br>(14.11)</td><td>49<br>(13.46)</td><td>18<br>(16.22)</td><td></td><td></td></tr><tr><td>Absence</td><td>3 (0.63)</td><td>2 (0.55)</td><td>1 (0.90)</td><td></td><td></td></tr><tr><td>No data</td><td>405<br>(85.26)</td><td>313<br>(85.99)</td><td>92<br>(82.88)</td><td></td><td></td></tr></tbody></table>

NA: Test non applicable.

### 3.3.2. Comparison of the frequency of symptoms in males and females

The percentage of precipitating factors was greater in males than in females. Specifically, the percentages of hypersomnolence, apathy, increased sexual drive, irritability/aggressiveness were higher in males than in females, while the percentage of compulsive drinking was higher in females than in males.

## 4. Discussion

### 4.1. Demographics

Case reports were from seven continents and subcontinents, hence a multi-ethnic distribution, with a majority from Europe (246) and Asia (115) and a minority from Africa (5) and Oceania (4). Approximately, 28.2 % of case reports, especially among those published before the eighties, were written in non English languages, hence a multi-language picture of the condition. Clinical features were often less developed in case reports focussing on modern techniques such as EEG, polysomnography, magnetic resonance imaging, functional brain imaging, monitoring of circadian rhythms, hormonal studies, genetic analyses, biochemistry and neuropsychological tests than in purely clinical case reports.

### 4.2. Comparisons of our results with those of previous reviews

#### 4.2.1. Preliminary remarks

Comparison of our results with those of previous reviews is not straightforward. First, the number of patients in each review varies a lot: 7 in Huang et al. [142], 8 in Smolik and Roth [15], 10 in Boscher [143],

11 in Critchley [2], 18 in Shukla et al. [144], 30 in Dauvilliers et al. [145], 33 in Orlosky [146], 34 in Gadoth et al. [147], 74 in Fresco et al. [148], 108 in Arnulf et al. [16], 168 in Arnulf et al. [17], 339 cases in Billiard et al. [149], 430 in Qasrawi and BaHamman [150] and 475 in the current review. Second, reviews with a limited number of cases, Huang et al. [142], Smolik and Roth [15], Boscher [143], Critchley [2] Shukla et al. [144], Gadoth et al. [147], are based on patients coming from one center only, hence a likely homogeneous interview in comparison with reviews based on multiple case reports coming from different centers. Third, the percentage of patients with one specific symptom must be interpreted according to the referred population, whole sample including or excluding patients with menstruation related KLS, whole sample including or excluding patients with secondary KLS. Fourth, patients interviewed by use of a questionnaire designed by the authors and submitted to external sleep experts, Arnulf et al. [16] versus simple case reports. Finally, some reviews could not be used for comparisons, due to KLS patients without compulsive eating considered apart, Billiard et al. [149], or due to the absence of statistics bearing on the total population, Fresco et al. [148] and Qasrawi and BaHamman [150].

#### 4.2.2. Precipitating factors

Although a causative relationship between putative precipitating factors and occurrence of KLS cannot be ascertained, the number of possible similar precipitating factors in a number of case reports, specially infectious-like conditions such as flu, fever, cold, gastroenteritis and the proximity of these factors with the onset of KLS, are in favour of an actual relationship. Precipitating factors were identified in 63.08 % of cases, a figure intermediate to 44 % in Boscher [143], 47 % in Gadoth et al. [147], 77 % in Dauvilliers et al. [145], 61 % in Arnulf et al. [17] and 82 % in Arnulf et al. [16].

Most case reports focussed on precipitating factor(s) preceding the first episode of KLS, and neglected those preceding later episodes. However, from other case reports, subsequent episodes may not be preceded by any precipitating factor [151], may be preceded by the same precipitating factor, for example a flu-like infection [152], or by several precipitating factors such as a bronchitis, an amygdala infection, mumps [153]. It is worth pointing out that apart from a few case reports preceded by a severe precipitating factor such as a terrific beating while boxing, a lethargic encephalitis, an Epstein-Barr virus infection, a monoxyde carbon intoxication, a large majority of precipitating factors were relatively benign, a brief or mild flu-like illness; a common cold, a pharyngitis, a sore throat; a school examination, an unpleasant remark from a teacher, a conflict with a friend, a missed penalty shoot out; a first ever exposure to alcohol, a single glass of beer; a scout outing, a school trip in summer, a sunstroke; a slight head injury; a physical effort; a febrile diarrhea, an increased bowel activity, a summer gastro-enteritis; an aesthetic surgery, a septoplasty, a tonsillectomy; a sea-sickness during ocean travel; a sleep deprivation; a tooth filled under anaesthesia; an anti-typhoid inoculation.

#### 4.2.3. Symptoms

Hypersomnolence alone, replaced by insomnia or alternation of hypersomnolence and insomnia in a few case reports, was found in 100 % of patients in all reviews, enforcing the priority of this symptom in KLS.

Compulsive eating and alternation of compulsive eating and no compulsive eating were present in a rather similar percentage of patients in the different series, 59.70 % of patients in our review, 63 % in Critchley [2], 50 % in Smolik and Roth 44 % in Boscher [143], 65.6 % in Gadoth et al. [147], 57 % in Dauvilliers et al. [145], 78 % in Arnulf et al. [17], 66 % in Arnulf et al. [16]. On the contrary, anorexia and alternation of compulsive eating and anorexia varied from one review to the other, 15,61 % of patients in our review, 25 % in Smolik and Roth [15], 44 % in Boscher [143], 5 % in Arnulf et al. [17] and 34 % in Arnulf et al. [16]. It is worth mentioning the very low percentage of no data for eating disorders, 4 % only, indicating the striking visibility of these

<footnote>a Statistical test without the « no data » category.</footnote>
disorders. In regard of compulsive eating, compulsive drinking was very rare (10.11 %). Increased sexual drive and alternation of increased sexual drive and no increased sexual drive were present in 35 % of patients in our review, a figure intermediate to 18 % in Orlosky [146], 12.5 % in Smolik and Roth [15], 44 % in Boscher [143], 47 % in Dauvilliers et al. [145], 43 % in Arnulf et al. [17], 53 % in Arnulf et al. [16]. Decreased sexual drive was alluded to in a limited number of reviews, 3 % in Orlosky [146], 6 % in Arnulf et al. [16] and 2.7 % in our own review. Altogether, The major difference in the percentage of patients with compulsive eating (59.70 %) and increased sexual drive (34.39 %) could partly depend on the high percentage of no data (39.16 %) in the case of sexual disorders, likely explained by the discretion of physicians and the reluctance of patients to dwell on this issue. Odd behaviors were present in 45.05 % of patients in the current review, 44 % in Boscher [143], and compulsions to sing, write, pace in 17 out of 59 patients (29 %) in Arnulf et al. [17]. Cognitive impairment was present in a high proportion of patients whatever the review, 90 % in Critchley [2], 87 % in Smolik and Roth [15], 77 % in Boscher [143], 96 % in Arnulf et al. [17], 100 % in Arnulf et al. [16] and 67 % in our own review, while derealization/altered perception was present in a variable proportion of patients in previous reviews, 90 % in Critchley [2], 15 % in Orlosky [146], 33 % in Boscher [143], 24 % in Arnulf et al. [17], 57 % in Huang et al. [142], 100 % in Arnulf et al. [16], and in our own review 38.40 %, likely in relation with the heterogenous terminology used for derealization/altered perception » in the different reviews.

An impressive result of this survey was the high frequency of psychiatric features (72.15 %), concordant with 90 % in Critchley [2], 75 % in Smolik and Roth [15], 85 % in Huang et al. [142], 87 % in Arnulf et al. [16], even if it is sometimes difficult to disentangle temporary psychiatric features specific to KLS and manifestations of a long time psychiatric condition such as bipolar disorder. Consequently, psychiatric disturbances should appear in the future diagnostic criteria of KLS. Irritability, sometimes culminating into aggressiveness, mainly when prevented from sleeping or eating, was reported in 52.53 % of patients, against 63 % in Critchley [2], 58 % in Orlosky [146], 50 % in Smolik and Roth [15], 44 % in Boscher [143], 92 % in Arnulf et al. [17], 100 % in Huang et al. [142], 65 % in Arnulf et al. [16].

Lastly, comparisons between the percentages of dysautonomic features, cephalgias at the onset of episodes and transient symptoms at the end of episodes could not be made, given the extremely elevated percentage of no data, in our review, more than 80 %, without any possibility to ascribe this paucity of data to the absence of these symptoms or to the absence of consideration of the author(s) towards these symptoms.

### 4.3. Pathophysiology and precipitating factors

Connecting the pathophysiology of KLS with precipitating factors is appealing. Indeed, the high frequency of infectious triggers (unspecified infections, upper airway infections, specified infections, gastro-enteritis) 38.1 % of 168 primary and 18 secondary cases of KLS [17] and in 43.1 % of our 475 own cases, together with an increased frequency of HLA DQB1* 0201, are in favour of an autoimmune mechanism. However, KLS may occur after non infectious precipitating factors or without any precipitating factors.

### 4.4. Functional brain imaging studies and symptoms

Functional brain imaging studies have demonstrated hypoperfusion in the thalamus, hypothalamus and variable cortical areas including temporal lobes, orbitofrontal and parasagittal frontal lobes in patients with KLS [154-156]. Correlations between these locations, namely decreased thalamic activity and sleep disorders, decreased hypothalamic activity and eating and sexual disorders, widespread and variable cortical changes and abnormal preception and cognition, should be based on brain imaging studies performed in homogenous phenotypic

groups.

### 4.5. Limitations

A first limitation of this review, as well as of previous reviews, is the unequal description of precipitating factors and symptoms in the different case reports, hence the indication of presence, absence (when indicated by the authors) and no data for precipitating factors (Table 4) and for each symptom (Table 5). A second limitation is the strict focus of the review on the precipitating factors and clinical symptoms at the expense of mean number and duration of the episodes, mean intervals between the episodes, mean duration of the disease, which may interfere with the occurrence of opposite symptoms and alternation of positive and opposite symptoms.

### 4.6. Strengths

This is by far the largest review of case reports of the Kleine-Levin syndrome ever delivered in the world literature. A second strength of the study is the systematic review of opposite symptoms of hypersomnolence, compulsive eating and increased sexual drive, i.e. insomnia, anorexia and decreased sexual drive, and of the alternation of symptoms with their opposite or no symptom, hardly considered in previous reviews. Third, this is the first review comparing the frequency of precipitating factors and symptoms in males and females.

## 5. Conclusions

In this review we have shown that some symptoms of KLS, hypersomnolence, compulsive eating and increased sexual drive could be replaced by their opposites, insomnia, anorexia and decreased sexual drive systematically or intermittently. Besides, a systematic comparison of precipitating factors and symptoms between males and females has been performed for the first time and has shown relatively minor differences between sexes.

The next edition of the ICSD should take into account the results of the present review to rewrite the essential features of KLS, in particular, the non exceptional presence of opposite symptoms of hypersomnolence, compulsive eating and increased sexual drive. Moreover, the presence of recurrent psychiatric features in a number of case reports should appear in the diagnostic criteria.

Lastly, interpretation of technical investigations such as polysomnography, magnetic resonance imaging, functional brain imaging, monitoring of circadian rhythms, hormonal studies, genetic analyses, biochemistry and neuropsychological tests, should take into consideration the presence of opposite symptoms and alternation of key symptoms and opposite symptoms in a number of patients.

## Funding

This review did not receive any specific grant from funding agencies.

## CRediT authorship contribution statement

**Michel Billiard:** Writing – original draft, Validation, Supervision, Methodology, Data curation. **Isabelle Jaussent:** Writing – review & editing, Methodology, Formal analysis.

## Declaration of competing interest

The authors declare no conflict of interest in relation to this work.

## Acknowledgments

None.
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