Overview Of Kleine-Levin Syndrome

It is a rare neurological condition that mostly affects teenage men. It is a sleep disorder which is characterised by hyperphagia, hypersomnia, hypersexuality, and behavioural/cognitive disturbances¹ and compulsive eating.² It is known to affect only one in a million people, as it is considered a very rare disease.¹ In girls, it is seen as being in a depressed mood.⁴

This condition has been named after Max Levin and Willi Kleine, who showed symptoms of hypersomnia and hyperphagia in 1930 and 1925. The syndrome was defined in 1942 by Critchley and Hoffman based on a scientific paper which was published on the morbid hunger and periodic somnolence seen in patients with this disorder.² The first case of Kleine-Levin syndrome (KLS) was reported by Brierre de Boismont.¹

Emotional Symptoms In Kleine-Levin Syndrome And The Hypotheses Related To Mood Dysregulation

Some of the emotional symptoms in Kleine-Levin syndrome are:

• Irritation and aggressive behaviour³
• Lack of energy to do things (feeling lethargic)³
• Apathy, i.e., lacking emotional expression and motivation³
• Confusion (disoriented) and hallucinations, which impact mood and emotional regulation³
• Depressive mood⁴
• Other cognitive issues, such as derealization⁴
• Exhibiting behaviour which is uncharacteristic⁴

The disease is associated with the hypothalamus not functioning well, which is a crucial part of the brain that is required for mood regulation and sleep patterns.

The mechanisms associated with the impact of sleep deprivation on emotional symptoms seen in people with this disorder are an increase in amygdala (part of the brain) reactivity and a decrease in medial prefrontal cortex-amygdala connectivity. Sleep loss in an individual due to this syndrome leads to an increase in the activity in the peripheral sympathetic nervous system.⁵

Treatments (Mood Stabilisers) for KLS

Several medications have been tried to treat the different symptoms in people with Kleine-Levin syndrome; however, most of them have not shown much success.⁶ 

Lithium as a mood stabiliser

Lithium has been known for its use in the treatment of bipolar disorder for its periodicity, which is similar to people suffering from Kleine-Levin syndrome.⁶ 

Mechanism of action of Lithium for KLS

The exact way by which lithium acts on the body is still unknown to this day, despite being used for treating other disorders, such as bipolar disorder, for over 40 years. There are several different hypothetical mechanisms behind the action of lithium in the human body. It is known to deplete the levels of inositol in the brain, which further causes a deficiency of substrate for the synthesis of phosphatidylinositol again. This theory might help give some clarification on the effect of lithium in the body. Another possibility could be due to a decrease in the availability of glutamate in the synapses.⁶ 

Research studies

There was an open-labelled controlled study conducted to study the effects of lithium therapy in Kleine-Levin syndrome. 130 KLS participants took part in this clinical research study to help researchers understand the benefits of using lithium for KLS. Some of the disease characteristics, such as the mean, frequency and duration of the episodes and time debilitated before as well as after lithium usage, were studied in the participants. The results of this study showed that the frequency of episodes was higher before being treated with lithium, and it decreased significantly in patients treated with lithium. Besides frequency, even the duration of episodes decreases in people with KLS who are treated with lithium.⁷

Another single case report study, which was performed on an adolescent male with KLS, showed a response to lithium after exhibiting symptoms for two years. The person was a 19-year-old male who was healthy previously but showed KLS episodes, which were 1-2 weeks in duration and kept recurring every 4 to 5 weeks. Different treatments were tried on this person, as stated by the study, but lithium showed a promising response in the patient despite KLS remaining a treatment-resistant condition. This study concluded that lithium should be used in KLS patients who do not respond to other therapies, and there should be appropriate monitoring.⁸

A study was done on a 16-year-old female who showed KLS symptoms of episodes which lasted from 2 to 15 days. During her episodes, she became dull and withdrawn at school, slept for nearly 20 hours a day and experienced reassurance-seeking behaviour. Several medications such as risperidone, olanzapine, valproate and carbamazepine were tried without any signs of improvement in the girl. The girl was then initiated on treatment with lithium and administered at a dose of 750mg/day. On starting her treatment with lithium, she did not show any further episodes for the next 6 months, which led to her going back to school and resuming normal life.⁹

A literature review conducted on 186 cases of KLS included 68% male participants with an age of 15 years and above. Some of the core symptoms they showed were hypersomnia, hyperphagia, hypersexuality and a depressed mood. In the medication trials, 313 different treatment attempts were made. Stimulants, neuroleptics and antidepressants showed poor results; however, lithium was the only agent with a high success rate, showing its effectiveness in 41% of the cases. The study concluded that KLS that lithium is the most effective and promising medication option for reducing relapses of episodes despite being only partially effective.¹⁰ 

Lithium dosage

Lithium dosing started at 750 mg per day and was increased to up to 1500 mg/day over time as days passed. The ‘standard dose’ for lithium was established at 1650mg per day.

Pros and Cons of using lithium for emotional symptoms in Kleine-Levin syndrome

The benefits of using lithium for KLS include:

• Reduced frequency and duration of episodes⁷
• May help with some behavioural and emotional symptoms, such as irritation, aggressive behaviour and confusion⁹

The potential drawbacks of using lithium for KLS are:

• Requires continuous long-term monitoring if a patient is on lithium⁸
• More research is needed to determine its underlying mechanism of action for patients with KLS, as it is unknown⁶

Other mood stabilisers for KLS

Carbamazepine

It is a mood stabiliser and an anticonvulsant which can be used for managing Kleine-levin syndrome.¹¹

The mechanism of action of this drug is not fully understood for KLS. However, it might be involved in the stabilisation of the limbic system, which is a part of the brain that is involved with a person’s behaviour and emotions.¹² 

A single patient report on a child who got misdiagnosed with epilepsy showed KLS when treated with carbamazepine. Upon changing the dosing of carbamazepine, it was confirmed that the child had KLS, and the symptoms associated with that disorder were further resolved after restarting and continuing to use this drug.¹¹ 

This drug was selected over lithium because of its better safety profile and being better tolerated by the patient. This showed that this medication is a better option for treatment in some KLS patients based on individual needs and side effects.¹¹

Valproic acid

Valproic acid is a mood stabiliser and anticonvulsant that can be used for KLS patients, especially for epileptic episodes.

There are several different mechanisms of action of this medication, and it is not yet fully understood. Mainly, the medication acts by inhibiting the voltage-gated sodium channels, which stops the entry of sodium ions into the neurons and leads to decreased excitability of the neurons.¹⁴ 

There was a 17-year-old male Indian student who was showing symptoms of hypersomnia, low mood and appetite, inappropriate social acts such as singing obscene songs, etc. The person was initially treated with SSRIs but had a relapse. Lithium showed partial benefits for only 6 months and led to relapse again. The treatment intervention was then switched to valproate at 750 mg/day when seizures emerged. This led to symptom-free status in the patient for the next 4 years and an absence of seizures. This study concluded the long-term effectiveness of valproate in this patient with KLS. It also showed the dual nature of valproate in reducing episodes as well as seizure activity in KLS patients.¹³ 

Future Directions and Research Gaps

Some of the research gaps and areas of future research in the study of Kleine-Levin syndrome include:

• No research studies on randomised clinical trials exist on KLS¹⁵
• There is a need for functional imaging and understanding immunopathogenesis and genetics. A centralised registry and biorepository can be used to facilitate understanding of those areas¹⁶
• More mechanistic exploration is required to understand the circadian involvement during episodes in KLS¹⁶

Summary

KLS is a rare condition which affects males and females, but mostly males in their teenage years. The main emotional symptoms associated with this disorder include irritation, lack of energy to do things, depressed mood and many more.

Among different mood stabilisers, lithium has been known to be the most extensively used for its potential to decrease the duration and frequency of episodes in people with KLS. Evidence from different research studies has shown that lithium is helpful for some patients, although there is a need for long-term monitoring due to certain side effects. Other alternative mood stabilisers used for the treatment of KLS include valproic acid and carbamazepine.

Despite existing research studies showing promising results regarding the use of lithium for KLS, there are no randomised clinical trials, and there is a need for future research in other areas of genetics as well as immunology.