JOURNAL OF CRITICAL REVIEWS

ISSN- 2394-5125 VOL 7, ISSUE 11, 2020

KLEINE-LEVIN SYNDROME OR PERIODIC AND MEGAPHAGIA SYNDROME —A REVIEW

PALLAVI SARAH ALEXANDER1, GAYATHRI S G2, ROSHNI P R3

1,2 Student, Pharm D PB, Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita VishwaVidyapeetham, Kochi, Kerala, India 3Assistant Professor, Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita VishwaVidyapeetham, Kochi, Kerala, India [email protected], [email protected], [email protected] Received: 14 March 2020 Revised and Accepted: 8 July 2020

ABSTRACT: Kleine-Levin Syndrome is a which is sporadic and it is characterized by periodic episodes of hypersomnia, cognitive impairment, utmost food craving and increased sexual desire. The definite cause has not been identified and no effective treatments are available even though a well-defined clinical feature is observed. Around 1–5 per million individuals were consistently overwhelmed, and it is noticed that most of the teenagers are the victims of this disorder. In Ashkenazi Jewish population, the prevalence is considerably greater. This article reviews about the clinical symptoms, medical investigations and examinations, differential diagnosis, management and limitations. Mostly supportive treatment preferred, though a few medications that are stimulants which include MODAFINIL can help to subside the clinical manifestations. KEYWORDS: Kleine-Levin Syndrome, intermittent hypersomnia, binge eating, increased libido

I. INTRODUCTION Kleine-Levin Syndrome (KLS) or sleeping beauty syndrome is a sporadic disease. The symptoms which are embodied with Kleine-Levin Syndrome are emotional disturbances, binge eating, lascivious, intermittent hypersomnia, irascibility, hallucinations, belligerent, experiences a loss of recognition and sense of context, extreme hunger and increased libido. Approximately around 1-5 cases per million populations are reported globally1.In 1925 Kleine primarily introduced the condition naming Kleine-Levin Syndrome and in 1936 Levin elaborated it. In 1942 Critchley and Hoffman delineated further about the syndrome2. The diagnostic standards for Kleine-Levin Syndrome were revised by International Classification of Sleep Disorders (ISCD) in 1990. Kleine-Levin Syndrome was found to be differentiated into primary and secondary based on the intrinsic effect of neuropsychiatric manifestations and excessive daytime sleepiness3.Kleine-Levin Syndrome is a sporadic disease which is usually affected among 1-5 per million individuals. This syndrome is mostly seen within the age group of 13 and 19 years. Males are at a greater risk of acquiring this disease when compared to females4.The incidence of this disease was reported in western countries and most of the cases were reported from Israel, which concluded a genetic link of KLS with Jewish population. Literature studies suggest that in 5% of cases reported it revealed a family history thereby concluding a genetic inclination with the disease5. II. ETIOLOGY The aetiology of Kleine Levin syndrome is not known. However, no scientific hypothalamic dysfunction has been reported6. The examination of the cerebrospinal fluid (CSF), imaging of the structural brain and the serum inflammatory markers were not remarkable7. Recently in Taiwanese patients it was found that there is an important correlation between Kleine-Levin events and prior upper respiratory tract infection (URI)8. Few cases were reported regarding the abnormalities in dopamine and serotonin levels, which indicated an imbalance in either serotogenic or dopinergic pathway9. III. CLINICAL PRESENTATION The signs and symptoms were described by the frequency of occurrence of the disease.  HYPERSOMNIA Hypersomnia is a condition in which patient may experience excessive day time sleep from 12 to 21 hours. This symptom is very important for the diagnosis of Kleine Levin syndrome. The patients with Kleine Levin Syndrome know when an episode starts and ends because of the change in their symptoms. After the episode, patient may suffer from insomnia and then leads a normal life until the next episode begins. Kleine Levin Syndrome symptoms may be different in males and females but the idiopathic hypersomnia will be same for both sexes. Duration of 3453

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symptoms ranges from few days to a year10. In Kleine Levin Syndrome patients dissimilar results are obtained in and out of the episode. An exceptional form of recurrent hypersomnia was observed with Menstruation related hypersomnia. This can be an alternative of Kleine Levin Syndrome. Menstruation related hypersomnia patients experience a lesser degree of cognitive impairment when compared with Kleine Levin Syndrome patients11.  EATING BEHAVIOR DISORDER Excessive food cravings and polyphagia are the classic elements seen in Kleine Levin Syndrome cases. During the episodes most of patients had altered eating habits. Patients usually consume large amount of food, around 7-8 meals per day and have significant weight gain. Increased fluid intake was also reported in some cases12.  MOOD DISORDERS AND INSTABILITY The patients with suicidal thoughts were about 15% and two suicidal cases were also reported. The depressed mood of the patients usually resolves at end of each episode and rarely does it persist for longer duration13. Around 8% of cases were disclosed to be hypomania for a span of two days at the end of Kleine Levin Syndrome episodes. Almost all the patients were presented with irritability peculiarly when sleep, sex or food drive was restricted. All these aberrancies were short lived and irreversible after each episode14.  COGNITIVE DISTURBANCES Relatively all the cases with Kleine Levin Syndrome exhibited problems with communication, reasoning ability and working memory. Most of patients have partial or retrograde during episodes.Long term cognitive deficits which affect their speed of processing and verbal retrieving are also noted in some patients. Around 37% of patients have immediate episodic verbal memory15.In two third of the cases, abnormal speech was reported. The speech is usually short sentences, mute and slow in nature. Temporal disorientation occurs more frequent than spatial disorientation16.  OTHER COMPULSIVE BEHAVIORS AND HYPERSEXUALITY During these episodes, closely half of the patients’ exhibit symptoms expressed with hyper sexuality which is significantly seen moreover in males than females. The symptoms seen in males such as exposing oneself, fonding gentitalia, increased or overt , making unwanted sexual advances and usage of pornographic language. Unwanted sexual advances may include molesting of female nursing staff, patient’s sister, female visitors, daughter or other female relatives17. Other compulsive behaviours were found to be common. One third of the patients will tend to repeat stride, sing, tap their fingers, listen to the same music or watch the same video. Inappropriate and irresistible singing, chewing lips, compulsive writing on walls, compulsion to set fire, body rocking, and stripping down wallpaper were the other compulsions which occurs during the episodes18.  DEREALIZATION, HALLUCINATION AND DELUSION. Majority of patients experience a distorted or unreal altered perception during episodes. Patients are always in a dreamy state, totally or partially detached from environment. Some patients may show symptoms like both visual and auditory hallucinations. Some people visualize distorted faces, dead bodies of parents19. IV. MEDICAL INVESTIGATIONS AND EXAMINATIONS  Neurophysiological and neurochemical abnormalities In Kleine Levin Syndrome examination of biochemical abnormalities has been unrewarding. There is a decreased production of hypocretin (orexin) in patients with Klein Levin Syndrome. Analysis of Cerebrospinal fluid orexin levels should be studied with care in Kleine Levin Syndrome patients, inorder to recognise the modest episodic reductions, which may not be evident in narcolepsy-cataplexy20. Recent research studies reported that there are significant changes in the catecholamine levels. Occasionally Klein Levin Syndrome patients showed an abnormal serotonin, serotonin metabolite, dopamine or nor epinephrine activity. Thus, the biochemical and neurophysiological studies excluding epileptiform activity and low orexin production may be observed as a cause of Kleine Levin Syndrome21.  Polysomnography and A normal EEG has been observed during episodes on one fourth of the patients. Mostly around 70% of cases have a background of vague diffuse that slowdown the EEG activity, such as alpha frequency band being gradual towards 7-8 HZ. In Klein Levin Syndrome patient brain Computerized Tomography and Magnetic Resonance Imaging is normal22. 3454

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 Cerebrospinal Fluid Analysis Usually, in Kleine Levin Syndrome patients the serological inflammatory markers were found to be within the normal range. Serum and cerebrospinal fluid analysis shows no abnormalities in Kleine Levin Syndrome patients. In four patients, the cerebrospinal fluid analysis reveal that the cerebrospinal fluid levels of hypocretin-1 a hypothalamic peptide were found to be deficient in narcolepsy, where as in Kleine Levin Syndrome patients it was found to be normal23. Till date, there is no scientific evidence of cerebrospinal fluid hypocretin, to prove its significance for the diagnosis of Kleine Levin Syndrome. Rarely alterations within the pituitary hormone levels are reported in Kleine Levin Syndrome patients. Pituitary, blood sugar, thyroid profile and adrenal profile, were completed in order to rule out feasible endocrinological causes for intermittent hypersomnia24. V. PATHOPHYSIOLOGY AND NEUROIMAGING The hypothalamic dysfunction can be explained on the basis of appetite disturbance, constellation of hyper somnolence and abnormal sexual behaviour. In Kleine Levin Syndrome patients the hypothalamic functions seems to be intact. The functional imaging studies are performed in order to study the brain function as well as it helps to locate brain dysfunction in Kleine Levin Syndrome patients. In patients with Kleine Levin Syndrome, functional MRI (FMRI), single photon emission tomography (SPECT) and fluoro-deoxy glucose positron-emission tomography (FDG-PET) were used to highlight the abnormal changes in the blood flow in certain areas of brain. The thalamic hypo perfusion is examined through SPECT studies which are more prominent during the disease episodes. A working memory test by FMRI demonstrated a thalamic hyper activation in Kleine Levin Syndrome patients. A decrease in the glucose metabolism was also observed in symptomatic patients.During the symptomatic periods the derealisation/depersonalization inventory score reveals about the relation with bilateral hyperfusion of the parieto-temporal junction. In Kleine Levin Syndrome, patient apathy is seen due to the hypo-perfusion of right medial prefrontal cortex and orbitofrontal cortex. The lesion that arises from the orbitofrontal cortex may results in the weird eating behaviour. Psychometric tests have reported that lack in memory can be observed among the diseases episodes associated with continued left temporal lobe hypoperfusion25.  Kleine Levin Syndrome and infection During the episodes of Kleine Levin Syndrome the serum inflammatory cytokinines did not cause any changes when compared to between episodes. Some studies suggest Kleine Levin Syndrome is caused due to focal encephalitis where as some suggests acute viral hepatitis may be a risk factor for Kleine Levin Syndrome. The episodes of depression, dementia and other neuropsychiatric manifestations are rarely seen in central nervous system infection26.  Human Leukocyte Antigen association in Kleine Levin Syndrome An autoimmune aetiology can be clearly defined by focussing on Human Leukocyte Antigen association. In Kleine Levin Syndrome patients, the Human Leukocyte Antigen association with this disease is unclear, but it does not exclude the possibility of auto immunological aetiology for Kleine Levin Syndrome. Cases reported in 16 out of 23 cases carry an infection illness prior Kleine Levin Syndrome Onset. 28.3% of Kleine Levin Syndrome and 12.5% of controls express DQB1*0201 allele. There are reports suggesting increased frequencies of HLA-DR1, DQ1, HLA-DQB1*0201, HLA-DQB1*02, HLA DQB1*0501, HLA-DQB1, DQB1/0602, HLA-DR1 and DQ127. VI. DIAGNOSIS The diagnosis of Kleine Levin Syndrome is usually challenging for physicians since there is no specific symptoms for Kleine Levin Syndrome. The physician should first rule out other disease conditions before making final diagnosis of Kleine Levin Syndrome. The sole symptoms which are initially diagnosed in Kleine Levin Syndrome patients are Depression. The depression occurs during the onset of symptoms and disappears soon after the episode. Other psychiatric symptoms like delusion and hallucinations also disappear after the symptoms has resolved. If the patient has sleep apnoea with hypersomnia episodes, necessary evaluation should be done to rule out if there is an airway obstruction, a polysomnogram should be performed. The different patterns of hypersomnia are also considered. Hallucinations and eloquent dreaming are present among Kleine Levin Syndrome patients. Cataplexy, Rapid Eye Movement disorder, sleep paralysis should be ruled out before making the conclusion of Kleine Levin Syndrome. Menstruation related hypersomnia may also be considered about the differential diagnosis of Kleine Levin Syndrome. Symptoms of cognitive impairment and disinhibition are not commonly seen in the patients with menstruation associated hypersomnia. In patients with Kleine Levin Syndrome, hypersomnia episode occur only 2-3 times per year, but in cases with menstruation associated hypersomnia they undergo multiple events. Temporal lobe , kluver bucy syndrome secondary to temporal lobe lesions, encephalopathies like urea cycle defects, lyme defect and acute intermittent porphyria must be ruled

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out. Brain imaging studies like Magnetic Resonance Imaging are carried out to eliminate vascular lesions and EEG is done to eliminate the complex partial seizures. If pyrexia is present, lumbar puncture is practised to treat meningitis. There is certain workup which includes urine and serum, screen, folate and B12 levels urine porphobilinogen should be considered. Urine and serum assays must be done to rule out inborn errors of metabolism28. VII. TREATMENT The best treatment for Kleine Levin Syndrome is the supportive measures and educating the parents regarding the syndrome.  NON PHARMACOLOGICAL TREATMENT Non pharmacological management primary includes educational and supportive measures. The patient is advised to be safe by staying at home with family and also to maintain a healthy and pleasant environment. The patient should be kept free from all the other work until or unless the symptoms get subsided. The operation of heavy machinery or to driving a car by the patient should not be granted. Maintenance of simple hygiene routine is essential for the patients with Kleine Levin Syndrome. If any medical and psychiatric complications are present that should be observed closely and must provide the required therapy. The patients are advised to maintain good hand hygiene, to avoid intake and also to avoid direct contact with individuals having infectious conditions and to sleep at regular schedules.  PHARMACOLOGICAL MANAGEMENT A stimulant plays a major role in the early symptomatic cycle, which helps to diminish the span of the symptoms. The rate of recurrence cannot be weakened by using stimulants. Antipsychotic play a major role in cognitive and behavioural disturbances. Modafinil, Methylphenidate or Armodafinil can be used for the management of hypersomnia during the episodes. These stimulants have no effect on apathy and derealisation. Only 20% of patients reported some benefit from stimulant used during an episode. The patients should be monitored for potential toxicities and unintended adverse effects such as aggression, exacerbation of hyper sexuality or hallucination during the administration of stimulants. For the sustained and prominent psychotic symptoms during the episode, an atypical antipsychotic such as Risperidone were used for the management which provides the symptomatic benefit. or a Hydroxyzine can be used for the management of . Amantidine is a drug with dopinamergic, stimulant and antiviral properties were used as prophylactic agents which help to cease the events in 42% of cases when administered during the initial days of onset of symptoms29. Lithium can be used as a precaution, however the authentication is inadequate. Around 22% reported a mild improvement in the episode frequency and 24% reported about the benefit of therapy. 50% of patients were reported with some side effects of lithium but it was mild and led to treatment discontinuation in 7% of patients. Tremor, increased drinking, diarrhoea and subclinical hypothyroidism were the most common side effects of lithium. In some series it was reported that the effective dose range of lithium is 600mg to 200mg at bed time (to achieve serum levels of 0.8 to 1.2mmol/L). Carbamazepine, Gabapentin, Valproic acid, Phenytoin and Lamotrigine are the other mood stabilizers and antiepileptic used for the management of Kleine Levin Syndrome episodes. A case with unmanageable symptoms has been disclosed that shows a favourable feedback to Sodium Oxybate30. VIII. CONCLUSION Kleine Levin Syndrome is a sporadic, severe, homogenous disorder which is familiar for more than a century with certain clinical manifestation. The actual aetiology or treatments are not known. There are only limited studies done regarding the comparison of well defined Kleine Levin Syndrome with healthy group in particular with cause, investigations and its treatment. The altering symptomatology in Kleine Levin Syndrome is dependable with the recent records of Human Leukocyte Antigen association in Kleine Levin Syndrome and the possibility of an autoimmune mediation of the disorder. It is difficult to identify the underlying biological cause, due to the rarity of disorder. The durability of the follow up studies is essential with insistence on residual neuropsychological deterioration and there are exposures involved in patients with Kleine Levin Syndrome. In future, further investigation about the genetic aetiology, investigations or further managing of disorder should be organized. IX. REFERENCES [1]. Arnulf I, Zeitzer JM, File J, Farber N, Mignot E. Kleine-Levin syndrome: a systematic review of 186 cases in the literature. Brain. 2005;128:2763–76. [2]. Mitchel G Miglis and Christian Gilleminault,Kleine-levin syndrome: a review, Nat Sci Sleep.2014; 6:19–26.

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