Maintenance Lithium Therapy in Kleine–Levin syndrome

A. B. Biswas1*, V. Kumar2, S. P. Singh3
1*Consultant in Psychiatry of Learning Disability, Frith Hospital, Groby Road, Leicester, LE3 9QF. e-mail:
2Consultant in Child and Adolescent Psychiatry, Central Notts. Healthcare NHS Trust, Mansfield, Notts. NG18 1QJ.
3Consultant Psychiatrist, B floor, South Block, Queen’s Medical Centre, Nottingham, NG7 2UH.

A case is described of a 19 year old man with Kleine-Levin syndrome intially presenting with episodes of hypersomnolence, behaviour disturbance and polydipsia which was replaced by megaphagia during later episodes. He showed a remarkable response with treatment using lithium carbonate at therapeutic levels (for bipolar mood disorder), but the episodes recurred on its discontinuation. The decision to continue lithium carbonate due to the recurrent nature of the episodes has resulted in sustained benefit to the patient.

Kleine-Levin syndrome, lithium carbonate, maintenance therapy, hypersomnolence, megaphagia, behaviour disturbance, polydipsia.

The symptom triad consisting of periodic hypersomnia, megaphagia and mental disturbances, is recognised as the ‘Kleine-Levin syndrome’.1 The German psychiatrist Willi Kleine was the first to describe five cases with somnolence, two of whom had associated hyperphagia, confirming to the syndrome.2 It is now recognised that megaphagia or compulsive eating, rather than morbid hunger, is a cardinal manifestation of the syndrome. The urge to sleep is reported to be profound and patients may sleep for days or weeks at a stretch, awakening only to eat or to evacuate the bowel or bladder. The sleep episodes which may have associated prodromes, tend to recur. The period between episodes varies from days to months.3
Psychiatric disturbances in behaviour, mood and thinking have been reported to occur during episodes. Behavioural symptoms recognised to occur include lethargy, sexual disinhibition, apathy, withdrawal, truculence, agitation, social disinhibition, inappropriate singing, slurred speech, screaming, poor hygiene, muteness, bizarre movements, decreased sex drive, wandering and fire setting. Mood disturbances described are irritability, depression, euphoria and lability. Confusion, amnesia, delusions, thought blocking, vivid dreams, auditory and visual hallucinations have been described during the episodes. The onset of the illness is usually spontaneous and appears to have a male preponderance.4 The duration of the episodes may range, from a few days to several weeks with normal inter-episodic periods lasting a few days to several months. The mean frequency of episodes may be two per year and may vary from one to twelve per year.4 The syndrome seems to ‘burn itself out’ spontaneously in due course without any therapeutic intervention.3 However they may recur in adulthood and eventually cease altogether but no associated mortality is reported.3 The true prevalence of this syndrome in those with learning disability or for that matter in the general population is unknown due to lack of epidemiological data. Outcomes of treatment for this syndrome are yet to be fully evaluated.

JB, aged twelve years at the time, presented at the local child psychiatry clinic in August 1992, with a history of self-remitting episodes of behavioural disturbance and sleepiness since May 1992. He was living with his parents who are physically healthy and caring and supportive towards him. There is no family history of any psychiatric or neurological illness. JB is the youngest of a sibship of three, born at full-term with a birth weight of seven pounds four ounces. His mother had an episode of ante-partum haemorrhage, six months into the pregnancy but was otherwise well. Developmental milestones were normal, but for speech difficulties for which he received speech therapy between the ages of three and four.

JB had initial difficulties with speech and arithmetic at school but eventually caught up with his peers. His parents described him to be pleasant as a child and during adolescence. He has a few close friends and is affectionate towards family members. He had a history of otitis media with diminished hearing in his right ear for which he had a grommet fitted in childhood followed by myringoplasty at the age of fourteen years.
JB had experienced episodes of sudden onset of abnormal behaviour each month, between May and August 1992, as reported by parents. A typical episode consisted of excessive sleepiness or lethargy, clinginess, restlessness and demanding behaviour. He was unable to explain the cause of his apparent distress. No perceptual disturbances were described during the episodes. These episodes were of sudden onset and occurred usually after a period of normal sleep.

There were no precipitating factors identified. The duration of each episode had gradually increased from five days in May to eleven days in August 1992. Each episode culminated gradually and JB had no recollection for most events during the episode. There was no history of increased appetite during these episodes. However he would drink enormous amounts of fluid, and would compulsively drink any fluid in sight. There was some suggestion of disorientation during the very first episode, when the patient tried to urinate at an inappropriate place. Nonetheless cognitive testing during the episodes did not reveal any impairment.

In periods between the episodes his functioning and behaviour was observed to be normal. JB was hospitalised during two subsequent episodes and complete psychiatric and neurological assessments were carried out. Psychometric assessment revealed mild learning disability. Haematological and biochemical parameters were within normal limits. HLA haplotype for narcolepsy was not detected. Electroencephalography, computerized tomography and magnetic resonance imaging of the brain did not reveal any brain abnormality. Positron emission tomography between attacks showed no abnormalities but one performed during an attack showed a possible area of metabolic activity in the lateral region of the right temporal lobe. This was however interpreted as inconclusive due to the technical quality of the scan.
Lithium carbonate was started at the dose of 400 mgs. nocte, in late August 1992 after the fourth episode. A few days later JB had another episode consisting of the same symptom cluster in September 1992 that lasted seven days. He was more arousable and less clingy than during previous episodes. Between September 1992 and June 1993 he had no further episodes and his serum lithium levels were stable at 0.6 mmol/l..

There were no reports of disturbances in sleep, appetite or behaviour during this period. In June-July 1993 he had another episode with similar symptoms as before including polydipsia. He was reported to be ‘greedy’ asking for items of food and generously helping himself. Lithium carbonate was increased to a dose of 1000 mgs. nocte with trough levels of 0.9 mmol/l.

This episode lasted for over a month with gradual recovery and lithium was discontinued. Four days after an abandoned dental procedure due to bradycardia and hypotension JB had another episode of similar symptoms as before, lasting for a month. He responded favourably to lithium carbonate. This was reduced and subsequently stopped in September 1994 in consideration of the risks of general anaesthesia during a planned dental surgical procedure. Lithium carbonate was re-introduced in February 1995 at the dose of 800 mgs. nocte, increased to 1000mgs. nocte due to low serum lithium levels.

He had no further episodes and once again it was stopped in August 1995. He suffered another episode with hypersomnolence and excessive appetite during July-August 1996 for seven days responding to lithium carbonate 1000 mgs. nocte on its introduction. The medication was discontinued in September 1996. He had two further episodes one each in March 1997 lasting nine days and in April 1997 lasting five days with hypersomnolence, megaphagia and stubborn behaviour. Lithium carbonate was re-started in March 1997 and increased to 1200 mgs. nocte in April 1997 with trough serum lithium levels of 0.7 mmol/l. No subsequent episodes have been reported on follow-up until August 1999, with ongoing treatment with lithium carbonate 1200mgs. nocte.

JB experienced episodic hypersomnia and behavioural disturbance that are characteristic features of Kleine-Levin syndrome. Polydipsia was a presenting feature while megaphagia was conspicuously absent during the initial episodes. This is a variation from the Kleine-Levin syndrome triad of periodic hypersomnia, hyperphagia and mental disturbances. However during the latter episodes ‘Megaphagia’ was reported which conforms to classical descriptions of this syndrome. Polydipsia was an important presenting feature in this patient but has not been reported previously as a feature of Kleine-Levin syndrome. 2,4. Hypersomnolence is the most prominent symptom reported during each of the episodes in this patient. Incontinence did not occur. Behavioural and mental disturbances were seen when JB was aroused from sleep or when he woke up spontaneously and this included irritability and aggression. The mental symptoms gradually subsided at the end of the period of somnolence. Depression or insomnia, suicidal tendencies, motor retardation, pathological guilt. vivid imagery, visual and auditory hallucinations, features reported elsewhere, were not reported during or between attacks of hypersomnolence in the patient described.

Precipitating factors that have received consideration are hot weather, stress, head trauma, post flu and encephalitis among others but none were clearly recognised in JB’s case, apart from when he had bradycardia and hypotension during a dental extraction procedure in March 1994..

Patients with Kleine-Levin syndrome have been reported to benefit from Lithium carbonate therapy, as can be ascertained from case reports. 5-8. Valproic acid 9 and Carbamazepine10 have been claimed to be of therapeutic benefit in Kleine-Levin syndrome. Early diagnosis and treatment, are vital for alleviating suffering, loss of schooling or work and allaying anxieties of family members, teachers and school or work colleagues. Hence a therapeutic trial with a mood stabiliser such as lithium carbonate would be appropriate, unless otherwise contraindicated in a patient with Kleine-Levin syndrome and a need to consider it for maintenance against further episodes may be necessary, carefully weighing the risks against potential benefits.

Key Points
• Kleine-Levin syndrome is definitive syndrome that can present with variations
• Mood stabilisers such as Lithium Carbonate need to be considered early in treatment for maximising benefit
• A mood stabiliser may need to be considered for maintenance therapy to prevent recurrenceAcknowledgements
We wish to express our gratitude to Ms. Ann Saxton for secretarial assistance and Ms. Reshma Davda for providing IT support.

1. Critchley M and Hoffman HL (1942) Syndrome of periodic somnolence and morbid hunger. British Medical Journal 2: 326.
2. Kleine W (1925) Periodische Schlafsucht. Mschr Psychiatr Neuro. 57: 285-320.
3. Critchley M (1962) Periodic hypersomnia and megaphagia in adolescent males. Brain 85: 41-657.
4. Orlosky MJ (1982) Kleine-Levin syndrome. Psychosomatics 23: 609-621.
5. Abe K (1977) Lithium prophylaxis of periodic hypersomnia (letter). British Journal of Psychiatry 130: 312-313.
6. Goldberg MA (1983) The treatment of Kleine-Levin syndrome with lithium. Canadian Journal of Psychiatry 28: 491-493.
7. Malhotra S, Das MK, Gupta N, Muralidharan R (1997) A clinical study of Kleine-Levin syndrome with evidence for hypothalamic-pituitary axis dysfunction. Biological Psychiatry 42: 299-301.
8. Ogura C, Okuma T, Nakazawa K, Kishomoto A (1976) Treatment of periodic hypersomnolence with lithium carbonate. Archives of Neurology 33: 143.
9. Crumley FE (1997) Valproic acid for Kleine-Levin syndrome. Journal of the American Academy of Child & Adolescent Therapy 36: 868-869.
10. Mukkaddes NM, Kora ME, Bilge S (1999) Carbamazepine for Kleine-Levin syndrome (letter). Journal of the American Academy of Child and Adolescent Psychiatry 38: 791-2.

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