Kleine-Levin Syndrome (KLS)

Etiology

No specific and definitive cause of Kleine–Levin syndrome has been determined.[4] Possible etiologies include a psychologic disturbance, trauma, toxins, infection, serotonergic or dopaminergic neurotransmitter abnormalities, and autoimmunity.[5] It has also been thought that an underlying hypothalamic pathology plays a role behind Kleine–Levin syndrome, given its function in regulating sleep, appetite, and sexual behaviors. However, a definitive association has not been completely determined.[4] 

It has been documented that increased frequency of the human leukocyte antigen DQB1 * 0201 allele is associated with Kleine–Levin syndrome.[6] Psychological theories regarding the origin of Kleine–Levin syndrome were considered throughout the 1970s but later were disregarded in favor of more tangible causes.[5] However, psychodynamic theories could help explain behavioral disturbances with the hypersomnolence seen in Kleine–Levin syndrome. Infectious agents that may lead to a viral infection precipitating Kleine–Levin syndrome include EBV, VZV, Asian influenza virus, entero-virus, typhoid vaccine, and Streptococcus. There has been a significant correlation between an upper respiratory infection and a Kleine–Levin syndrome symptomatic episode.[7]

Epidemiology

Due to its extreme rarity, the exact prevalence of Kleine–Levin syndrome is unknown, while according to a systematic review, between 1962 and 2004 found 186 worldwide cases.[4] The estimated prevalence of Kleine–Levin syndrome is 1 to 5 cases per million population.[8] While most cases are reported in western countries, one-sixth of patients were noted to be found in Israel.[9] Men are affected more than women, with a ratio of 2 to 1.[4] It mostly affects adolescent males with the median age of the disease onset is 15 years, and 81% of the cases have been noted to begin during the second decade of life.[1] 

It is considered rare for patients over the age of 30 to have their first episode of Kleine–Levin syndrome. Events that have been documented to be closely associated with the onset of Kleine–Levin syndrome include infections such as a cold-like syndrome with a fever, alcohol use, sleep deprivation, head trauma, physical exertion, unusual stress, traveling, and marijuana use.[4]

Pathophysiology

The pathogenesis of Kleine–Levin syndrome is not wholly understood. Viral and autoimmune processes may also be involved in the pathophysiology of Kleine–Levin syndrome since flu-like symptoms are noted at disease onset.[10] Diffuse brain hypoperfusion, mainly in the thalamic and frontotemporal areas, has been found on SPECT.[11] Functional neuroimaging during the symptomatic period of Kleine–Levin syndrome revealed frequent transient hypoactivity in the thalamic region, with lesser degrees of hypoactivity noted in the hypothalamus, frontal and temporal regions.[2] While the thalamic hypoperfusion demonstrated during acute disease episodes resolved completely during the asymptomatic periods.[4] 

Possible autoimmune-induced inflammation may cause the hypoperfusion observed on SPECT. However, no changes in serum cytokine levels during Kleine–Levin syndrome episodes were observed compared to between episodes.[12] Inflammation in the thalamus, diencephalon, and mid-brain, and other abnormalities of the hypothalamus, amygdala, and temporal lobe grey matter have been described as well.[4] 

Functional neuroimaging has also shown decreased striatal dopamine transporter binding potential in asymptomatic patients with Kleine–Levin syndrome when compared to control patients. Hypermetabolism of cerebral glucose was found within the thalamus and putamen during symptomatic Kleine–Levin syndrome episodes. While, in contrast, relatively lower glucose metabolism was found during symptomatic Kleine–Levin syndrome episodes bilaterally in occipital gyri, in left lingual gyrus, and right angular and middle and superior temporal gyri.[13] Similarities between the clinical presentation of Kleine–Levin syndrome and that seen in patients with hypothalamic or third ventricle tumors lend support to the notion of an underlying thalamic pathology playing a role in Kleine–Levin syndrome.[4] 

Since derealization often appears in the presentation of Kleine–Levin syndrome, this may suggest underlying parieto-temporal dysfunction. The parieto-temporal junction is involved in the cross-modal association between somatosensory (body knowledge), auditory and visual information. Thus dysfunction and/or hypoperfusion in the junction could possibly lead to derealization.[14] Apathy, as seen in Kleine–Levin syndrome, may be caused by the right medial prefrontal cortex and orbitofrontal cortex hypoperfusion, and lesions of the orbitofrontal cortex may also result in abnormal eating behaviors.[4] Abnormalities in serotonin and dopamine neurotransmitter metabolism have also been reported.[1] 

Hypocretin has been studied closely in regard to Kleine–Levin syndrome since greater than 90% of patients with narcolepsy have reduced cerebrospinal fluid (CSF) hypocretin concentrations. However, hypocretin levels in the CSF of Kleine–Levin syndrome patients have sometimes been found to be normal, while other times found to be decreased. Hence, analysis of CSF hypocretin levels in Kleine–Levin syndrome needs to be carefully evaluated while recognizing that episodic reductions in Kleine–Levin syndrome may not be as drastic as seen in narcolepsy-cataplexy.[4] Electroencephalographic (EEG) slowing is noted in most cases during acute episodes of KLS.[4]

History and Physical

Patients with Kleine–Levin syndrome will present with recurrent hypersomnia that is sudden in onset. Sleep duration during these episodes can range from 12 to 24 hours a day. Prodrome can include a sudden overwhelming sense of lethargy.[15] The urge to sleep can be very intense and can be associated with irritability and aggression when there is interference with the patient's sleep. Afterward, the patient can appear to regret their outbursts and may even have partial amnesia of the episode.[2] During intense hypersomnia, the patients can remain arousable and can wake up spontaneously to void and eat.[2] 

Frank hypersomnia is noted in the first episodes, while heavy fatigue characterizes later episodes.[2] The majority of Kleine–Levin syndrome patients have endorsed cognitive abnormalities such as confusion, concentration, attention, and memory defects.[4] Abnormal speech pathology, including mutism and slurred speech, amnesia, temporal disorientation, and altered perception, is associated with Kleine–Levin syndrome.[2] 

Seventy-five percent of patients had an alteration in their eating behaviors during episodes of KLS, with the majority experiencing megaphagia, preferring sweets. The increased food intake can include 6 to 8 meals a day and result in a  7 to 30 lb (3.2 to 13.6 kg) weight gain.[16] Fifty percent of Kleine–Levin syndrome patients had a depressive mood during episodes, more frequently found to occur in women, while approximately 15% reported suicidal ideations.[4] Fifty percent of Kleine–Levin syndrome patients experienced hypersexuality, found to be significantly more frequent in men than in women. In males, this behavior included making unwanted sexual advances, increased/overt masturbation, exposing oneself, fondling genitalia, and obscene language.

Compulsive behaviors and actions can also occur and have included inappropriate and compulsive singing, rocking one's body, chewing one's lips, and compulsive writing on the walls. Afflicted patients can endorse a sensation of derealization with feelings of detachment and strangeness.[17] This can be coupled with sensations like being in a dream or disconnected from one's environment.  Also, visual or auditory hallucinations and paranoia can occur.[2]

Evaluation

Diagnosis of Kleine–Levin syndrome can be challenging. It is a clinical diagnosis of exclusion, requiring the clinician to rule out other disease processes that can mimic the symptoms of Kleine–Levin syndrome.[2] It is diagnosed based on the clinical features, especially the classic triad of hypersomnolence, hyperphagia, and hypersexuality, and after ruling out metabolic, neurological, and psychiatric causes. CT and MRI of the brain generally show normal cerebral morphologies.[2] EEG revealed either a slowdown in the alpha, delta, or theta rhythms in the majority of cases.[4] Polysomnography indicated an extension of the total duration of sleepiness.[18] 

Decreased slow wave sleep early in Kleine–Levin syndrome attacks with a subsequent return to baseline despite continuing symptoms and, paradoxically, normal rapid eye movement (REM) sleep early in an attack but decreased REM sleep as the attack progresses has been reported.[18] To evaluate the deficits of the working memory of KLS patients, the Wechsler Memory Scale can be utilized, in which Kleine–Levin syndrome patients typically perform poorly.[18]

Treatment / Management

There is no definitive treatment for Kleine–Levin syndrome during either the acute episode or interepisodic period.[2] Non-pharmacological treatment of Kleine–Levin syndrome can include psychoeducation and related support. No single drug therapy has been efficacious, but several psychotropic agents, including lithium, anticonvulsants, and antidepressants, have been tried.[19] (B3)

Antidepressants did not prevent relapse, except in a single case, in which a monoamine oxidase inhibitor (moclobemide) was utilized. Carbamazepine improved abnormal behavior. Lithium was found to significantly improve abnormal behavior, reduce the duration of episodes, and decrease relapses, improving recovery of symptoms.[20] Risperidone may improve psychotic symptoms and normalize sleep cycles, while dopamine agonists and gabapentin can also be effective.[18] (A1)

Modafinil was shown to decrease the duration of the symptomatic periods but did affect the recidivism rate.[19] Different stimulants such as methylphenidate, ephedrine, methamphetamine, and amphetamine can treat sleepiness but do not affect the impaired cognition and mentation.[21](A1)

Differential Diagnosis

Kleine–Levin syndrome can often be mistaken for psychiatric conditions. Differentials can include atypical depression, severe depression, bipolar disorder, narcolepsy, Klüver-Bucy syndrome, menstruation-related hypersomnia, mass brain lesions, mitochondrial disease, urea cycle defects, Lyme disease, acute intermittent porphyria, and temporal lobe epilepsy.[2] Pronounced and similar bipolar disorder symptomatology coupled with major depression and suicidality can impede the diagnosis of Kleine–Levin syndrome.[22]

Prognosis

Kleine–Levin syndrome has a fair prognosis and typically has a benign clinical course, ultimately leading to spontaneous resolution of symptoms.[2] Patients typically experience an average duration of 6 months between episodes, and episodes tend to decrease in intensity and frequency over time. Patients are considered cured if there are no further episodes for at least six years. The median disease duration is 10 years in Kleine–Levin syndrome patients without hypersexuality and 21 years in KLS patients with hypersexuality.[4]

Complications

There are no known long-term complications of untreated Kleine–Levin syndrome, as the disease spontaneously resolves on its own.