Stephen H. Sheldon

Introduction

Kleine-Levin syndrome is an unusual disorder of recurrent episodes of excessive sleepiness and prolonged total sleep time. It is a rare syndrome with an onset typically in late adolescence, but younger and older cases have been reported. It has been suggested that a predisposing event occurs prior to onset of symptoms.¹ This may occur in nearly half of the reported cases. Most commonly, a flu-like syndrome precedes the onset of symptoms.

Clinical Characteristics

Hypersomnia is the characteristic symptom of the Kleine–Levin syndrome. Sleepiness is profound and, during spells, patients may sleep continuously for more than 20 hours. This excessive sleepiness and true hypersomnia can develop suddenly. However, symptoms typically have a more gradual onset of 1–7 days. During spells of hypersomnia, patients rarely leave their beds and sleep continuously. Sleep may be calm, but at times agitated, restless sleep occurs and vivid dreams are occasionally reported.

In addition to excessively long sleep episodes, abnormal behaviors, including but not limited to compulsive and excessive overeating and sexually acting-out behaviors occur. Other mental disturbances may be present. Compulsive overeating and hypersexuality may not be present with each episode. Excessive caloric intake during spells frequently results in weight gain by the end of the spell.

Overt expression of hypersexuality may include indiscriminate sexual advances, masturbation, and/or public display of sexual fantasy. Sexually acting-out is reported in approximately one-third of males with Kleine–Levin syndrome. Hypersexuality is less often reported in females. The presence of excessive eating and/or hypersexuality is not required for the diagnosis of Kleine–Levin syndrome. In many cases, hypersomnia and its recurrence may be the only symptom.² Psychological symptoms vary considerably. Irritability is common. Confusion, visual hallucinations, or auditory hallucinations frequently occur.

Recurrent episodes of hypersomnia may be brief and last less than 1 week or may be prolonged and last up to 30 days. Characteristic of the Kleine–Levin syndrome is recurrence of episodes of hypersomnia and behavioral abnormalities. Patients are normal between episodes. Nevertheless, neuropsychological sequelae, changes in personality, and decrease in school performance have been reported after a second hypersomnolent episode. Physical examination is generally normal.

Although Kleine–Levin syndrome is characterized by the triad of recurrent spells of hypersomnolence, hyperphagia, and hypersexuality, it is likely that incomplete manifestation is more common than the complete triad. Isolated abnormal sleepiness and recurrent periods of hypersomnia without associated symptoms may be a more common manifestation.

Periods of hypersomnia gradually decrease in frequency as the youngster ages. Spells gradually become less severe and eventually resolve.³ Nonetheless, patients have been reported with recurrent episodes of hypersomnia occurring 20 years after the initial onset of symptoms.^4,5

Menstruation-associated hypersomnia has been reported in female patients. Recurrent periods of hypersomnolence occur and are coupled to menses. Occasionally, mental disturbances also occur, and also occur with the menstrual cycle.⁶ (Several female patients with recurrent hypersomnia had notable absence of symptoms.¹) Prognosis of menstrual-related hypersomnia is similar to that of the Kleine–Levin syndrome.

Etiology

The cause of recurrent hypersomnia is unknown. A possible viral etiology may be present in some cases. In other cases, there may be a suggestion of a local encephalitis in the region of the diencephalon.7–9 Recurrent transient episodes of unresponsiveness and clearly identified stage 2 sleep pattern with the presence of sleep spindles has also been reported due to bilateral paramedian thalamic infarctions.¹⁰ Although the exact cause of recurrent hypersomnia and other manifestations is still unclear, the symptoms of hypersomnolence, excessive and compulsive eating, hypersexuality, recurrence, and absence of any identifiable abnormalities between spells is suggestive of a functional abnormality at the level of the diencephalon. The hypothalamus may also be involved. Indeed, identical symptoms have been reported in patients with tumors of the hypothalamus or third ventricle and in patients with epidemic encephalitis. Most literature and case reports suggest that this recurrent hypersomnia is caused by dysfunction of the hypothalamus and midbrain limbic system. There is also evidence that brainstem dysfunction may also be involved. Recurrent hypersomnia associated with decreased blood flow in the thalamus on single photon emission computed tomography has also been reported.¹¹ During the remission period, there were no abnormal data in these tests.

Social and professional consequences are not negligible. Students miss classes and young workers may be fired because of repeated absences.

Neuroendocrine function in patients with Kleine–Levin syndrome has been assessed; however, only a limited number of subjects have been investigated and most literature consists of case reports. Investigation is complicated by the inability to predict timing of episodes, lack of a prodromal period, and relatively rapid recovery once symptoms begin.

Nonetheless, some abnormal laboratory data reported to date include a paradoxical growth hormone response to thyroid-releasing hormone stimulation,¹² a blunted cortisol response to insulin-induced hypoglycemia,^13,14 and an absent thyroid-stimulating hormone response to thyroid-releasing hormone.¹³ These findings suggest a possible dysfunction within the hypothalamic–pituitary axis. However, other basal and post-stimulation values of hormones are usually normal and laboratory values are normal during the asymptomatic periods between spells.

Studies of nocturnal or 24-hour secretory patterns of pituitary hormones have been conducted in a limited number of patients. Normal secretory pattern of growth hormone was reported in one patient, but the sampling at 4-hour intervals was sparse.¹⁵ On the other hand, an elevated growth hormone secretory pattern was reported in two patients.¹⁶ A normal secretory pattern of cortisol and somewhat abnormal patterns of growth hormone have been identified in four other patients.¹⁷ Normal 24-hour patterns of melatonin, prolactin, and cortisol secretion have been reported.¹⁸ Gadoth and colleagues found an increased nocturnal prolactin secretory pattern and an abnormally flat nocturnal luteinizing hormone secretory pattern, whereas follicle-stimulating hormone and thyroid-stimulating hormone secretory patterns were normal.¹² Chesson and Levine compared 24-hour secretions in the symptomatic and the asymptomatic period and found that values obtained during nocturnal sleep showed a significantly decreased growth hormone, but increased prolactin and thyroid-stimulating hormone, in a direction that supports the hypothesis that dopamine tone is reduced during the symptomatic period in Kleine–Levin syndrome.¹⁹ However, Mayer and colleagues found only minor hormonal changes in five patients.²⁰ Altogether, these data suggest some functional disturbance in the hypothalamic–pituitary axis in Kleine–Levin syndrome, but the disturbance may be in response to the sleep-related and behavioral changes rather than a cause. An observation supporting a diencephalic dysfunction is the occurrence of dysautonomic features in some patients.²¹ Differentiating Kleine–Levin syndrome from organic etiologies is often difficult. Diagnosis is often based on clinical presentation of recurrence of symptoms with asymptomatic intervals and progressive improvement to resolution. In addition, it is often a diagnosis of exclusion. Recurrent hypersomnia may occur with space-occupying lesions of the central nervous system, idiopathic recurring stupor, and certain psychological/psychiatric conditions.

Tumors in the region of the third ventricle, such as cysts, astrocytomas, and/or craniopharyngiomas, may be responsible for intermittent obstruction of the third ventricle leading to headache, vomiting, sensory disturbances, and intermittent impairment of alertness. Less frequently, tumors in other CNS locations may result in hypersomnia. Tumors in the middle fossa may disrupt the suprachiasmatic nucleus and an irregular sleep–wake pattern or a free-running state might occur. If a free running state occurs, hypersomnia may alternate with sleeplessness at a regular interval as the pacemaker cycles at its inherent rhythm. Recurrent hypersomnia may also develop after encephalitis or head trauma. Periodic hypersomnia has also been reported in a patient with a Rathke’s cleft cyst.²²

Major recurrent depression and bipolar affective disorder can be associated with excessive sleepiness.²³ Patients with psychogenic recurrent hypersomnia complain of extreme sleepiness and fatigue, and may spend many hours in bed. Continuous night-and-day polygraphic recording often fails to demonstrate increased total sleep time despite the complaint of sleepiness.²⁴