Overview

Sleep is fundamental for everyone to complete day-to-day activities effectively and smoothly. It maintains healthy brain function by forming long-term memories and supporting learning, as well as our physical health by regulating hormones and blood pressure and boosting the immune system. Notably for babies, sleep is a vital building block for them to advance and grow and for their wellbeing.¹ For adults, it is recommended that they should have at least 7 to 9 hours of sleep, as sleeping less than 7 hours regularly has been linked to an increased risk of health complications such as increased blood pressure, weight gain, type 2 diabetes and depression.² The circadian rhythm, which is the 24-hour internal clock in our brain, is responsible for maintaining a healthy sleeping pattern. However, when this becomes disrupted, it can lead to sleeping disorders such as Kleine-Levin syndrome and narcolepsy.³

Kleine-levin syndrome

Kleine-Levin syndrome (KLS) (also called “Sleeping Beauty syndrome”) is a rare sleeping disorder that can affect 1 to 5 people per million in the population. The condition involves repetitive sleeping episodes (hypersomnia) where those affected can sleep up to 20 hours per day in an episode, with episodes lasting for a few days to a few weeks. Patients with KLS also have changes to their behaviour and reasoning and may suffer from impulse control disorders such as binge eating and hypersexuality. There is a greater degree of males affected with this condition compared to females; however, females can also acquire the condition. The median value (the midpoint value in the population) of the duration of the condition can be up to 8 years for some patients, with females experiencing the condition for longer.^4,5

Pathophysiology

The exact pathophysiology of the condition remains uncertain. Theories suggest that the disease can derive from trauma, toxins, infection and a change in activity to the chemicals in the brain (neurotransmitters like serotonin, noradrenaline (norepinephrine) and dopamine). From a study that analysed numerous journals, it was discovered that patients were more at risk of developing the condition after infection, head trauma, or alcohol intake.

From analysing the brain, patients with KLS are shown to have reduced blood flow throughout the brain, especially in the thalamus and frontotemporal areas. Low brain activity has also been observed in the hypothalamus, thalamus and the frontal and temporal lobes. In addition, inflammation in these areas can also potentially cause KLS.^4,6

Symptoms

• Hypersomnia
• Changes to cognition (confusion, concentration, attention and memory loss)
• Weight gain (from eating excessively)
• Hypersexuality
• Compulsive disorder
• Low mood and suicidal ideation
• Feeling disengaged, a lack of interest and motivation
• Hallucinations and paranoia^4,5

Risk factors

Risk factors that can potentially predispose KLS  are age, in which symptoms can start from childhood to adulthood, with the median age of onset of the disease being 15 years old. Infections such as an upper airway infection can increase the probability of KLS. In addition, genetics may also play a role, with the Jewish population possibly having a higher risk. Moreover, patients who have had birth and developmental problems may be more prone to getting the condition.^6,7

Diagnosis

For a diagnosis to be made, all the criteria listed below need to be met according to the American Academy of Sleep Medicine.

1. The patient endures at least 2 repeated occurrences of excessive sleepiness and sleep duration, each continuing for 2 days to 5 weeks
2. Episodes return more than once a year, with patients having episodes at least once every 18 months
3. The patient experiences normal watchfulness, cognitive function, behaviour and mood between episodes
4. The patient must meet at least 1 of the symptoms below during an episode:
   1. Eating disorder (anorexia or overeating)
   2. Cognitive dysfunction
   3. A change in perception
   4. Impulse control disorder (hypersexuality)
5. Symptoms exclude other differential diagnoses, drugs or medicines taken⁸

Treatment

Currently, there is no formal treatment to treat KLS; however, some medicines have been trialled for patients, such as stimulants, antiepileptics and antipsychotic medicines, antidepressants, lithium, aciclovir, hydrocortisone, melatonin, benzodiazepines and levodopa/benserazide (co-beneldopa). Stimulants (mostly amphetamines) have been shown to reduce drowsiness for some patients. For most patients, antipsychotics and antidepressants provided no benefit. Lithium was shown to provide some benefit to prevent relapses, and modafinil (a stimulant drug used to treat narcolepsy) helped minimise symptom duration.⁹

Narcolepsy

Narcolepsy is a rare sleep disorder that affects the brain long-term. In the UK, it is predicted to affect 1 in 2,500 people, which means that roughly 30,000 people have the condition.¹⁰ The condition causes excessive daytime sleepiness and fragmented sleeping patterns due to disruption to the sleep and waking cycle. Patients with narcolepsy experience rapid eye movement (REM) sleep faster (within 15 minutes of falling asleep) compared to normal people (60 to 90 minutes). There are 2 types of narcolepsy: type 1 narcolepsy, which is less common, involves an abrupt and momentary weakness or loss in muscle tone (cataplexy), whereas type 2 narcolepsy does not.^11,12 Men and women seem to be equally impacted by narcolepsy; however, women are usually diagnosed later compared to men.¹³

Pathophysiology

In type 1 narcolepsy, there is a great loss in orexins (hypocretin), which are neuropeptides (protein molecules made and released by neurons that send chemical messages) in the brain that regulate the sleep/wakefulness cycle of the circadian rhythm. The gene HLA-DQB1*06:02 may also play a role in causing type 1 narcolepsy. For type 2 narcolepsy, the pathophysiology is undefined. Theories suggest reduced breakdown in orexin cells and decreased orexin receptor signalling. Some patients diagnosed with type 2 narcolepsy have also developed cataplexy, which suggests that there is a potential link between the 2 types in disease progression.¹¹

Symptoms

• Hypersomnia
• Sleep attacks (abrupt episodes of sleeping without warning)
• Cataplexy (slurred speech, legs collapsing, jaw dropping, slumped head)
• Fragmented sleep and insomnia
• Sleep paralysis
• Hallucinations
• Low mood
• Headaches
• Impaired memory^12,14

Risk factors

Age can also be a risk factor in narcolepsy, as there is a higher degree of patients having the condition during their late teens to early twenties. Other risk factors that may be involved include genetics, hormonal imbalances, significant psychological stress, sudden alterations in sleeping patterns and infections.¹⁵

Diagnosis

For a diagnosis to be made, patients need to experience symptoms at least 3 times a week over the past 3 months, and at least one criterion needs to be met according to The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5):

1. Low levels of orexin
2. Cataplexy occurrences that take place at least several times a month
3. REM sleep latency to be less than 15 minutes, or an average sleep latency of less than 8 minutes and 2 or more sleep-onset REM periods (SOREMPs)¹¹

A sleep analysis test can also be conducted to view sleeping patterns. Examples include the Epworth sleepiness scale questionnaire, polysomnography (sleep study) and the multiple sleep latency test, which helps health providers diagnose narcolepsy.¹⁶

Treatment

First-line treatment in those with hypersomnia is modafinil 100 mg twice a day, with amphetamines being second-line. In patients where cataplexy is a problem, sodium oxybate is considered first line. Antidepressants are also treatment options, in particular, tricyclic antidepressants (clomipramine) and serotonin and noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) (venlafaxine). Solriamfetol and pitolisant are also available options.^11,17

Additional differences

To differentiate between the 2 disorders, an orexin test can be conducted. In the majority of patients with narcolepsy, it is identified that they have lower (≤110 pg/mL) cerebrospinal fluid orexin concentrations. However, this is usually within the normal range (>200 pg/mL) for patients with KLS.^8,18 

Summary

Kleine-Levin syndrome and narcolepsy are both conditions that cause patients to suffer from extreme sleepiness. However, there are major differences between the 2 conditions. The incidence of narcolepsy is greater than KLS, with KLS being a rarer illness. There is a higher percentage of men having KLS, whereas in narcolepsy, men and women can equally have the disease. The pathophysiology of KLS is inconclusive, with trauma and infection being potential causes, compared to narcolepsy, where orexin concentration levels and the HLA-DQB1*06:02 gene play a major role in its predisposition. Symptoms also differ: patients with KLS are more prone to having impulse control disorders like overeating and hypersexuality, whereas narcolepsy does not show these symptoms. In addition, in narcolepsy, cataplexy is common, though this is not seen in patients with KLS. Both conditions also have different diagnostic criteria. In terms of treatment, narcolepsy has approved medicines that are effective to treat the condition, in comparison to KLS, which does not have a definitive treatment, and medicines are trialled in patients.