Klein-Levin syndrome

Historical Perspective: KLS was first introduced by Willi Kleine in 1925 as a " periodic sleep disorder," focusing on the recurrent hypersomnia and hyperphagia. In 1936, Max Levin expanded the description by including the excessive hunger characteristic of the syndrome. The name "Kleine-Levin Syndrome" was proposed by Critchley and Hoffman in 1942, based on their observations, which included cases among naval personnel serving during World War II. Critchley provided a more precise definition of the syndrome, refining the diagnosis with his observations and contributing to a clearer understanding of the condition and proposed Kleine-Levin Syndrome as an official name of the disease.

Pathophysiology: In KLS, active symptoms are linked to decreased activity in the thalamus of the brain, which contributes to excessive sleep. This decrease in thalamic activity is also linked to other symptoms such as emotional blunting, increased sexual behavior, and a sense of detachment from reality. Patients who experience the disease onset more recently or have had more episodes in the past year often show reduced brain metabolism in the hippocampus and posterior brain regions. However, about half of the patients exhibit increased metabolic activity in the frontal areas of the brain. These changes in brain function not only explain the hypersomnia but also account for the behavioral and cognitive symptoms associated with the condition. Symptoms: The main feature of the disease is recurrent extreme sleepiness and during the episodes, they also experience, confusion, change in mood, behavior alteration, and feeling like things aren't real overeating symptoms vary from person to person. Causes: The cause of the diseases is still unknown but some factors are still considered as the potential causes of the diseases such as genetic factors, infectious or immune-mediated causes, neuropathological Causes and other factors. Genetic factor: The specific gene causing the KLS has not been identified yet but some literature suggests that genetics might be involved in the development of the diseases. There are many cases of KLS among Ashkenazi Jews and it often runs in families including (identical twins), the family members of Patients with KLS have a higher chance of developing conditions themselves. Indicating a possible

genetic link. Reported literature suggested the TRANK1 gene which controls the body's internal clock and is also associated with bipolar and schizophrenia Infectious or immune-mediated cause: Some studies suggest that KLS might be triggered by the infection or immune system. This is based on observation that many patients had such as fever, or cold before their KLS symptoms started and Inflammation has also seen in certain area of the brain such as thalamus, diencephalon, and midbrain. Additionally a specific type of HLA antigen called DQB1*02 might be related to KLS. Neuropathological Causes: Few researches suggest that this problem affect multiple parts of the brain for example a study found that the diencephalic-hypothalamic malfunction which is caused by the tumor has the similar symptoms as KLS. This suggests that the problem of the hypothalamus and as well as other area of the brain such as temporal and frontal lobe might be involved. Other Factors: Seasonal change, mild infection, Alcohol use, head injury, physical strain, stress and lack of sleep, vaccination, and SARS-CoV2 Vaccine are also considered as risk factors. Epidemiology and Demographics: It is the rare problem and the prevalence of the diseases is 1-5 people per million people. Age: These diseases affect teenagers mostly and adults are also affected. Gender: This disease is observed in male more than females approximately 70-90% patients are male. Race: KLS found in various races and location around the world and it is most of the cases are reported in Ashkenazi Jews then other groups. Diagnosis: Kleine–Levin Syndrome (KLS) is uncommon and its symptoms can overlap with other problems, patients being evaluated for KLS should also be investigated for other possible causes. Evaluation should include a detailed medical history of the patient and their family, physical examination, and close observation of any fluctuations in cognitive and behavioral patterns. If any unusual findings are present, they may indicate a different diagnosis. Diagnostic Criteria: It is diagnosed on the basis of pattern of excessive sleep, behavior and thinking International Classification of Sleep Disorders (Third Edition; ICSD-3) present the diagnostic criteria for KLS that includes. Episode of Excessive Sleep: Individual with disorder has at least two episodes of sleep and the duration of the sleep is more than the normal days, the duration for each episode fall from two days to five weeks. Frequent episodes: Episodes usually happen more than once a year and at least once every 18 months. Normal between Episodes: After each episodes patient have a normal mood behavior and thinking. Symptoms between Episodes: during the episodes patients must show at least one of following symptoms such as Thinking or memory problem Change in perspective Change in diet pattern (East a lot or not enough) Unusual behavior (such as hypersexuality) Exclusion Of other causes: Doctor have to make sure that the excessive sleepiness is not caused by the other sleep problems, medical conditions, brain issue, mental health problem or due to medication or drug. Laboratory Findings: Test should be done on the basis of symptoms and other possible diagnosis. There are no specific finding in urine sample while autoimmune cause are considered, CSF and blood test does not show sign of inflammation however a recent study identified some biomarkers that are helpful for the diagnosis of KLS. In CSF 28 protein was found to be different from healthy individual some proteins were higher (such as IL-34 and IGF-1), and others were lower (such as DKK4). In blood sample protein 141 was different changes in brain protein, especially in areas like pons and mid brain were observed and protein levels varied during and between the episodes. Neuroimaging Ususlly MRI and CT do not show KLS related findings and functional imaging techniques (like fMRI) is considered useful for the evaluation process it shows abnormal results in KLS patient during and between the episodes the findings include abnormal blood flow at the thalamus and hypothalamus and freontal region of the brain PET /CT is also used to find out the metabolic activity which is usually lower in patients with KLS. Treatment: As the etiology of the diseases is still unknown therefore the definitive treatment is not available however supportive treatment is given to delay the duration of episodes and relieve the symptoms. Pharmacotherapy: Numerous medications are used for symptomatic treatment including stimulants, amantadine, antiepileptics, antidepressants, antipsychotics, steroids, and clarithromycin some of these sows benefit but their long-term effectiveness is ot known due to their rarity according to the American Academy of Sleep (AASM) lithium is the conditional recombination because it can reduce the symptoms.