Introduction

What happens in Kleine-Levin syndrome (KLS)?

KLS is mainly a group of multiple problems having recurrent episodes of excessive sleepiness, cognition deficits, mood swings, compulsive eating of food items, incessant sexual drives, and behavioural abnormalities.^1,2,3

Some writers may call it a sleeping syndrome coupled with uncontrolled mental problems.^1,2

Prevalence of KLS

KLS is very rare, occurring in 1 in a million people during adolescence. Males are more vulnerable than females, with a gender ratio of 2:1³

How is KLS related to cognitive dysfunction?

Cognitive dysfunction is the loss of all mental abilities in which a person is unable to learn, recall, memorise, judge, retain memory, make decisions, and control emotions.

Kleine-Levin syndrome falls in between neurology and psychiatry.⁴ It mostly damages the parts of the brain that process mental capabilities, which results in anxiety, trouble focusing, anger, psychiatric issues, and confusion. These kinds of anomalies relapse after a short period of normal attitude or activity.^4,5

Pathogenesis of cognitive dysfunction in KLS

Normal physiological patterns:

The hippocampus, amygdala, and hypothalamus make up the limbic system. Normally, these regions, along with the prefrontal cortex (PFC), are pivotal in the consolidation, retrieval, and acquisition of memory. Hypothalamic nuclei are crucial in rage, placidity, and sleep patterns.

The cerebral cortex (lobes) is involved in cognition, learning, concentration, awareness, thoughts, reasoning, and decision-making processes.

Pathology behind cognitive dysfunction:

It is still difficult to highlight the precise cause of KLS.^3,5 Numerous reasons have been documented in the literature. 

As far as cognitive and psychiatric problems in KLS are concerned, the following regions of the brain are disrupted:⁵ 

• Lobes of the brain, like occipital, parietal, and frontal 
• PFC
• Limbic system
• Thalamic regions

Lesions in the amygdala and hypothalamus, as well as neuroinflammation in the thalamus, lead to cognitive problems.^2,4

• Other possible reasons are abnormal levels of brain chemicals (neurotransmitters).^6,7 For example:
  • Gamma-aminobutyric acid (GABA)
  • Acetylcholine (Ach)
  • Glutamate
  • Dopamine
  • Serotonin

These affect memory formation:

• Less serotonin and more GABA concentrations lead to aggression, an impulsive attitude, confusion, anxiety, changes in mood, tremors, and memory impairment⁷
• Likewise, both non-verbal and verbal memory are influenced by GABA, glutamate, and Ach
• Dopamine, as reported by Patrick in 2008, is crucial in behavioural patterns, reward processing, and motivation⁷

Types of neuroimaging techniques: how these are related to KLS

The following are used for the screening of KLS :

• Functional magnetic resonance imaging (fMRI):  neuronal hyperactivity or hypoactivity
• Positron emission tomography (PET): metabolism in neurons
• SPECT (single photon emission computed tomography): cerebral blood flow

Phases of KLS

Symptomatic phase: 

In this period, coordination between the brainstem and thalamic region is disturbed, ultimately leading to hypersomnolence (excessive sleepiness), confusion, and memory impairment. Lesions in thalamic nuclei are present. Dopamine levels are also dropped in it. Hypoperfusion or metabolic activity occurs in the thalamus and PFC as per SPECT and PET. This is compensated by hypermetabolism in the striatum, leading to hyperphagia (excessive hunger) and more sexual drive. Hippocampal activity is also reduced.^4,8,9,10

Additionally, microglia are activated, leading to cytokine release as a result of neuroinflammation from stress and viral infections.^.8

Asymptomatic phase:

fMRI showed that the thalamus and hypothalamus are overactivated to restore normal working. N-acetyl aspartate levels are decreased in neurons. This highlights the neuronal deficit in the brain.^4,8

KLS and memory impairment

It is a type of cognitive deficit and is of two types:

• Short-term memory impairment (STM): also called working memory, in which a person is unable to recall immediate events⁹
• Long-term memory loss (LTM): retrieval difficulty from stored data⁹

How short-term memory loss leads to long-term memory impairment in KLS

Hypoperfusion and hypoactivity in the hippocampus, thalamus, and PFC impair encoding of memory during the symptomatic period of KLS.⁸ This causes working memory loss. 

Furthermore, this disruption is maintained during the asymptomatic phase by compensatory thalamic overactivation and chronic hypoperfusion, which prevents the brain from returning to normal functioning.¹⁰ Relapses in the condition and recurrence ultimately lead to residual deficits in brain regions between episodes – asymptomatic phases – leading to LTM. During LTM, a person can retain pre-existing information but is unable to form new memories.^8,11

Risk factors: which individuals are more prone to KLS

These may include:³

• Injury in the head region
• Alcohol 
• Flu
• Stress

Differential diagnosis

The clinical manifestations of KLS are much more similar to other diseases.^2,4,6,10 For example,

• Cognitive impairment, as in brain tumor
• Metabolism dysfunction – thyroid problems and diabetes
• Hallucinations and delusions – psychosis 
• Prolonged sadness – depression

How it is investigated: which medical tests can examine KLS patients

In addition to brain imaging, multiple screening tests are available:^3,4,6,10

Cerebrospinal fluid (CSF) analysis

Fewer hypocretin peptides and high serotonin levels in KLS patients.⁶

Neuropsychological testing

To find out the working memory deficit.⁴

Electroencephalogram (EEG)

High frequency alpha waves in the temporal lobes indicate more neuronal activity.^4,6

Polysomnography

For recording sleep patterns before and during episodes of sleep^.4,6

How to avoid KLS and related cognitive problems

• Proper hygienic measures to avoid triggers like allergens¹
• Adequate sleep¹
• Refrain from alcoholism¹

Solution for KLS: how to get rid of it

Non-pharmacological treatment 

This is as follows:^1,2,4

• Patients should consult clinicians and keep communication open in case of abnormality
• During episodes, stay at home
• Between the episodes, regularly make them check in at clinics
• Check neuroimaging tests (yearly)
• Obtain past history from the affected
• Keep an eye on the patients’ cognitive and behavioural abnormalities (suicidal attempts)
• Guide KLS patients and get them ready for appropriate treatment
• Refrain patients from aggression
• Ensure professional coordination (psychologists, physicians, pharmacists, and psychiatrists) for prompt treatment

Pharmacological interventions

There is no specific treatment for KLS. Only symptomatic treatment is encouraged to control the progression of Kleine-Levin syndrome:^2,4,10

• Amantadine (600–2000 mg, one time)  at the onset of the episode prophylactically⁴
• Lithium is administered—reduce the severity and number of episodes in KLS⁶
• Mood stabilisers like valproic acid (500–2000 mg)—between the episodes⁶
• Stimulants like modafinil (100–200 mg twice in a day)—wakefulness and lessen the duration of episodes
• Sodium oxybate—for insomnia
• Melatonin—good quality of sleep
• Risperidone, olanzapine and quetiapine -to mitigate abnormal behavior and psychosis
• Diazepams – for anxiety
• Fluoxetine – antidepressant

Complications

Kleine-Levin syndrome disturbs everyday life, and it leads to:¹

• Anxiety, frustration, and depression
• Neurodegenerative diseases (Alzheimer's disease)
• Drugs treating KLS cause severe side effects like tachycardia, elevation of blood pressure, and atrial flutters

­FAQs

What clinical symptoms are manifested by KLS patients?

Clinical signs range from memory problems like confusion, disorientation, difficulty focusing, and memory retrieval incapacity to psychiatric issues like epileptic attacks, and delirium, as well as other symptoms like uncontrolled thirst, unnecessary hunger pains, and hypersexual drives.^2,4

How does memory loss and forgetfulness occur in KLS?

Any factor that injures neurones causes perfusion problems and ultimately impairs the underlying neurotransmission. For example:²

• Ethanol impairs cholinergic transmission—important in memory formation and retention
• Accidental head injury
• Tumor in the brain 
• Administration of medicines like fentanyl

Is KLS a permanent disability?

With time, the frequency and severity of episodes in KLS may decrease. When the inter-episodic duration is more than 5–6 years, then it is considered cured as per clinicians. 

One typical episode of symptoms goes from hours to days and even persists for months in the case of longer episodic events.¹² Patients may return to normal behaviour for some time and then revert to the same cognitive disabilities.⁴

Summary

Kleine-Levin syndrome is rare and may relapse. Normally, one episode lasts from weeks to months, and the patient’s condition will determine the duration of the episode. The exact aetiology is unknown, but factors causing neuronal damage become the reason for KLS cognitive dysfunction. Similarly, there is no specific treatment to mitigate KLS. The best approach is to go for symptomatic therapy, and so, KLS will recur less frequently. Imaging techniques and several diagnostic tests can assist the professional team to find out the precipitating factor for this syndrome. For future directions, more research can be carried out at the molecular level in order to target the exact inflammatory pathway for better outcomes for KLS patients.