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Kleine–Levin syndrome (KLS) is a rare neurological disorder characterized by persistent episodic
hypersomnia Hypersomnia is a neurological disorder of excessive time spent sleeping or excessive sleepiness. It can have many possible causes (such as seasonal affective disorder) and can cause distress and problems with functioning. In the fifth edition ...
accompanied by cognitive and behavioral changes. These changes may include
disinhibition Disinhibition, also referred to as behavioral disinhibition, is medically recognized as an orientation towards immediate gratification, leading to impulsive behaviour driven by current thoughts, feelings, and external stimuli, without regard for ...
(failure to inhibit actions or words), sometimes manifested through
hypersexuality Hypersexuality is a proposed medical condition said to cause unwanted or excessive sexual arousal, causing people to engage in or think about sexual activity to a point of distress or impairment., according to the website of ''Psychology Toda ...
, hyperphagia or
emotional lability In medicine and psychology, emotional lability is a Medical sign, sign or symptom typified by exaggerated changes in mood or affect (psychology), affect in quick succession. Sometimes the emotions expressed outwardly are very different from how th ...
, and other symptoms, such as
derealization Derealization is an alteration in the perception of the external world, causing those with the condition to perceive it as unreal, distant, distorted, or in other ways falsified. Other symptoms include feeling as if one's environment lacks spontan ...
. Patients generally experience recurrent episodes of the condition for more than a decade, which may return at a later age. Individual episodes generally last more than a week, sometimes lasting for months. The condition greatly affects the personal, professional, and social lives of those with KLS. The severity of symptoms and the course of the syndrome vary between those with KLS. Patients commonly have about 20 episodes over about a decade. Several months may elapse between episodes. The onset of the condition usually follows a viral infection (72% of patients); several different viruses have been observed to trigger KLS. It is generally only diagnosed after similar conditions have been excluded;
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
,
CT scan A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
s, lumbar puncture, and
toxicology Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating ex ...
tests are used to rule out other possibilities. The syndrome's mechanism is not known, but the
thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...
is thought to possibly play a role.
SPECT Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera (that is, ...
has shown thalamic hypoperfusion in patients during episodes. KLS is very rare, occurring at a rate of 1 in 500,000, which limits research into genetic factors. The condition primarily affects teenagers (81% of reported patients), with a bias towards males (68-72% of cases), though females can also be affected, and the age of onset varies. There is no known cure and little evidence supporting drug treatment.
Lithium Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...
has been reported to have limited effects in case reports, decreasing the length of episodes and duration between them in some patients. Stimulants have been shown to promote wakefulness during episodes, but they do not counteract cognitive symptoms or decrease the duration of episodes. The condition is named after Willi Kleine and Max Levin, who described cases of the disease in the early 20th century. It was added to the International Classification of Sleep Disorders in 1990.


Symptoms

Patients with Kleine–Levin syndrome (KLS) experience recurring episodes of prolonged sleep (
hypersomnia Hypersomnia is a neurological disorder of excessive time spent sleeping or excessive sleepiness. It can have many possible causes (such as seasonal affective disorder) and can cause distress and problems with functioning. In the fifth edition ...
). In most cases, patients sleep 15 to 21 hours a day during episodes. Excessive appetite ( hyperphagia) and unusual cravings are present in half to two-thirds of cases. About half of patients, mainly male patients, experience dramatically increased sexual urges (
hypersexuality Hypersexuality is a proposed medical condition said to cause unwanted or excessive sexual arousal, causing people to engage in or think about sexual activity to a point of distress or impairment., according to the website of ''Psychology Toda ...
). Several other symptoms usually accompany the syndrome, including marked changes in mood and cognitive ability.
Derealization Derealization is an alteration in the perception of the external world, causing those with the condition to perceive it as unreal, distant, distorted, or in other ways falsified. Other symptoms include feeling as if one's environment lacks spontan ...
and severe apathy are present in at least 80 percent of cases. About one third of patients experience hallucinations or delusions. Depression and anxiety occur less commonly; one study found them in about 25 percent of patients. Individuals usually cannot remember what happened during episodes. Repetitive behaviors and headaches are commonly reported. Some patients act very childlike during episodes, and communication skills and coordination sometimes worsen. Sleep studies of KLS show varying results based on the period the patient is observed. Slow wave sleep is often reduced at the beginning of episodes, and
REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
is reduced near the end. Conversely, REM sleep is often normal at the beginning; slow wave sleep is often normal by the conclusion. Stage two non-rapid eye movement sleep is often interrupted during KLS. Studies also show that stage one and three non-rapid eye movement sleep becomes more efficient when the episodes end. The Multiple Sleep Latency Test has yielded inconsistent results when given to KLS patients. In many cases, hours are spent in a withdrawn sleep-like state while awake during episodes. Most sleep studies have been performed while the subject is near the end of their episodes. Some patients experience brief
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
and become very happy and talkative after the episode ends. The first time a patient experiences KLS, it usually occurs along with symptoms similar to those of the flu or encephalitis. In at least 75 percent of cases, symptoms occur after an airway infection or a fever. Viruses observed before the development of the condition include
Epstein–Barr virus The Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the nine known Herpesviridae#Human herpesvirus types, human herpesvirus types in the Herpesviridae, herpes family, and is one of the most common viruses in ...
,
varicella zoster virus Varicella zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting children and young adults, and shingles (herpes zos ...
, herpes zoster virus,
influenza A virus ''Influenza A virus'' (''Alphainfluenzavirus influenzae'') or IAV is the only species of the genus ''Alphainfluenzavirus'' of the virus family '' Orthomyxoviridae''. It is a pathogen with strains that infect birds and some mammals, as well as c ...
subtypes, and
adenovirus Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from t ...
. Several days after symptoms first occur, patients become very tired. In cases after an infection, KLS usually starts within three to five days for teenagers and fewer for children. In other cases, alcohol consumption, head injury, or international travel precede symptoms. Lifestyle habits such as alcohol abuse, lack of sleep and stress have also been proposed as possible triggers. First episodes of KLS are preceded by a clear event in about 90 percent of cases. Recurrences generally do not have clear triggers; only about 15 percent have a precipitating event. The condition generally disrupts the social lives and academic or professional obligations of those with KLS. Some patients also gain weight during episodes. The most severe cases cause a long-term impact on mood and cognitive attention. In rare cases, patients experience long-term memory problems. In patients with KLS,
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
and
CT scan A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
s show normal brain morphology. When
SPECT Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera (that is, ...
is performed,
hypoperfusion Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion may also refer to fixation via perfusion, used in ...
can often be observed in the brain, particularly in the thalamic and frontotemporal areas. The hypoperfusion is significantly diminished between episodes. Serum biology,
c-reactive protein C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin ...
s and
leptin Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long ...
s, the hormonal pituitary axis, and protein in the
cerebral spinal fluid Cerebrospinal fluid (CSF) is a clear, colorless transcellular body fluid found within the meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricles of the brain. CSF is mostly produced by specialized ependym ...
(CSF) are normal in KLS patients.


Cause

It is not known what causes KLS, but several mechanisms have been proposed. One possible explanation is hypothalamic or circadian dysfunction. The thalamus probably plays a role in the out-of-control sleeping, and patients with diencephalic–hypothalamic dysfunction caused by tumors experience symptoms similar to those of KLS patients. Specifically, the medial temporal regions of the thalamus may be involved, although examinations of KLS patients have not consistently found abnormalities in this area. The
temporal lobe The temporal lobe is one of the four major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe is involved in pr ...
also appears to play a role in the condition, possibly causing cognitive difficulties. The apathy and disinhibition found in some with KLS suggest that the condition may include
frontal lobe The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a Sulcus (neur ...
dysfunction as well. The involvement of the brain's thalamus, temporal lobe, and frontal lobe suggests a multifocal, localized
encephalopathy Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...
. There are also persistent subclinical abnormalities in some with KLS. Another possible explanation concerns the metabolism of
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
and
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
. An imbalance in the neurotransmitter pathways of these chemicals could play a role. Viral infections have also been suggested as a possible cause. Evidence for their role includes lesions found in autopsies. CSF samples from KLS patients indicate that the condition has a different cause than influenza-associated encephalopathy. Triggers of KLS may also affect the blood-brain barrier, which could play a role in the condition. There is limited evidence of what role hypocretin may play, although it often influences hypersomnia. Androgen might (indirectly) block melatonin receptors, possibly through vasodilation, and cause cholinergic abnormalities in some cases of Kleine–Levin syndrome. Because KLS occurs at a much higher rate in Jews and some families, there is likely some genetic component in addition to environmental factors. Genetic studies hold promise for understanding the disease, but they have yielded inconsistent results and few patients are available for testing. Epilepsy and depression do not appear to cause KLS. The condition's rapid onset after infections indicates that the immune system is not to blame. One study has suggested a link to the gene LMOD3 on
chromosome 3 Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans more than 201 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA ...
.Al Shareef SM, Basit S, Pfister C, Pradervand S, Lecendreux M, Mayer G, Dauvilliers Y, Salpietro V, Houlden H, BaHammam AS, Tafti M (2018) Kleine-Levin syndrome is associated with LMOD3 variants. J Sleep Res e12718


Diagnosis

KLS can be diagnosed when there is confusion, apathy, derealization, and frequent bouts of extreme tiredness and prolonged sleep. The earliest it can be diagnosed is the second episode, but this is not common. The condition is generally treated as a
diagnosis of exclusion A diagnosis of exclusion or by exclusion (''per exclusionem'') is a diagnosis of a medical condition reached by a process of elimination, which may be necessary if presence cannot be established with complete confidence from history, examination o ...
. Because KLS is rare, other conditions with similar symptoms are usually considered first. MRIs can determine if the symptoms are caused by certain brain disorders,
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
, and
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
. Lumbar puncture can determine if encephalitis is the cause. KLS must be differentiated from substance abuse by toxicology tests. The use of
electroencephalography Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignal, bio signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in ...
(EEG) can exclude temporal status epilepticus from consideration. EEGs are normal in about 70% of KLS patients, but background slowing may sometimes be detected. In addition, low-frequency high-amplitude waves can be observed during waking hours. Initially, KLS appears similar to bipolar depression. Patients with frontal-lobe syndromes and Klüver–Bucy syndrome also display similar symptoms, but these conditions can be differentiated by the presence of brain lesions. KLS should also be distinguished from very rare cases of menstruation-caused hypersomnia.


Prevention

Lithium Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...
is the only drug that appears to have a preventive effect. In two studies of more than 100 patients, lithium helped prevent the recurrence of symptoms in 20% to 40% of cases. The recommended blood level of lithium for KLS patients is 0.8–1.2 mEq/ml. It is not known if other mood stabilizers affect the condition.
Anti-depressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include dry mouth, weight gain, dizziness, headaches, akathisia, sexua ...
s do not prevent recurrence.


Treatment

Several drug therapies have been used on patients with KLS, but none of them have been subject to
randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...
s. A 2016
Cochrane Review Cochrane is a British international charitable organisation formed to synthesize medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. It includes ...
concluded that "No evidence indicates that pharmacological treatment for Kleine–Levin syndrome is effective and safe". In several cases, stimulants, including
modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant and wakefulness-promoting agent, eugeroic (wakefulness promoter) medication used primarily to treat narcolepsy, a sleep disorder characteri ...
, have been reported to have a limited effect on patients, often alleviating sleepiness. They can cause behavioral problems, but they may pose fewer issues if used in older patients with mild symptoms. In some case reports, lithium has been reported to decrease the length of episodes and the severity of their symptoms and to increase the time between episodes. It has been reported to be effective in about 25 to 60 percent of cases. Its use carries the risk of side effects in the
thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...
or
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s.
Antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
s and
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
s can help alleviate psychotic and anxiety-related symptoms, respectively.
Carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...
has been reported to be less effective than lithium but more effective than some drugs in its class.
Electroconvulsive therapy Electroconvulsive therapy (ECT) is a psychiatry, psychiatric treatment that causes a generalized seizure by passing electrical current through the brain. ECT is often used as an intervention for mental disorders when other treatments are inadequ ...
is not effective and worsens symptoms. KLS patients generally do not need to be admitted to hospitals. It is recommended that caregivers reassure them and encourage them to maintain sleep hygiene. It may also be necessary for patients to be prevented from putting themselves in dangerous situations, such as driving.


Prognosis

The frequency of KLS episodes can vary from attacks one week in length occurring twice a year to dozens of episodes that follow each other in close succession. The median duration of KLS episodes is about ten days, but some last several weeks or months. A study of 108 patients found an average of 19 episodes over the duration of the disease. Another study found a median of 3.5 months between episodes. Outside of episodes, there is no disturbance in patients' sleep patterns, and they are generally asymptomatic. Patients do not experience the same symptoms in each episode. About 80 percent of patients are adolescents when they first experience KLS. On some occasions, though, its first occurrence comes in childhood or adulthood. In most adolescent-onset patients, symptoms cease by the time they are 30 years old. A French study of 108 patients found a median duration of 13 years, but a review of 186 cases found a median duration of 8 years. Unusually young or old patients and those who experience hypersexuality tend to have a more severe course. Patients who initially have frequent attacks generally see the disease cease earlier than others. The condition spontaneously resolves, and the patient is considered to be cured if there have been no symptoms for six years.


Epidemiology

Population-based studies of KLS have not been performed. Its prevalence is about 1 to 2 cases per million people, although recent studies conducted by a French research team point to a higher number of 3 per million people. It occurs most frequently among Jews in the US and Israel. First-degree relatives of people who have the syndrome are much more likely than the general population to have it, although only in about one percent of cases do family members contract it. About 68 to 72 percent of patients are male. Patients with the syndrome are more likely than the general population to have genetic disorders, and about a third of people with the syndrome encounter some form of birth difficulty. In a study of 186 older patients, about ten percent had preexisting psychiatric issues. One study found that about ten percent of patients had a neurological condition before KLS developed. The condition does not appear to occur most frequently in one season.


History

In 1815, there was a report of a young man who showed excessive appetite and prolonged sleep after experiencing a fever; this may have been an early description of the condition. Another case with similar symptoms was described by Brierre de Boismont in 1862. Five patients with symptoms of persistent sleepiness were described in detail in 1925 by Willi Kleine, a neurologist from Frankfurt. This report was followed four years later by details of a similar case by New York-based psychiatrist Max Levin. In 1935, Levin published information about several more cases, including one described by Kleine. Levin noted that some patients displayed an intense appetite and persistent tiredness. MacDonald Critchley, who first wrote about the condition in 1942, described 11 cases he had examined and reviewed 15 other published cases in a 1962 publication. In the report, which included patients he had examined in the
Royal Navy The Royal Navy (RN) is the naval warfare force of the United Kingdom. It is a component of His Majesty's Naval Service, and its officers hold their commissions from the King of the United Kingdom, King. Although warships were used by Kingdom ...
during
World War II World War II or the Second World War (1 September 1939 – 2 September 1945) was a World war, global conflict between two coalitions: the Allies of World War II, Allies and the Axis powers. World War II by country, Nearly all of the wo ...
, he observed that irritability and depersonalization often occurred while patients were awake. He named the condition Kleine–Levin syndrome and noted four common traits: hypersexuality, adolescent onset, spontaneous resolution, and compulsive eating. He believed the condition only affected males, but later studies showed some female patients. In the 1970s, several
psychoanalytic PsychoanalysisFrom Greek: and is a set of theories and techniques of research to discover unconscious processes and their influence on conscious thought, emotion and behaviour. Based on dream interpretation, psychoanalysis is also a talk the ...
and
psychodynamic Psychodynamics, also known as psychodynamic psychology, in its broadest sense, is an approach to psychology that emphasizes systematic study of the psychological forces underlying human behavior, feelings, and emotions and how they might relate t ...
explanations for the condition were proposed. In 1980, a Hawaiian–Caucasian family was found in which nine family members had the condition. Diagnostic criteria for KLS were established by Schmidt in 1990, and the International Classification of Sleep Disorders further refined them. KLS is classified as a sleep disorder, specifically one of recurrent hypersomnia. Before 2005, hyperphagia and
hypersexuality Hypersexuality is a proposed medical condition said to cause unwanted or excessive sexual arousal, causing people to engage in or think about sexual activity to a point of distress or impairment., according to the website of ''Psychology Toda ...
were thought to occur in all cases. That was changed with the guidelines published that year, which noted that they did not always occur.


References


Bibliography

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External links

*
Story of young man with Kleine–Levin syndrome
at The New York Times {{DEFAULTSORT:Kleine-Levin syndrome Sleep disorders Rare syndromes Syndromes of unknown causes Hypersomnolence disorders