Introduction: What is Kleine-Levin syndrome?

Kleine-Levin Syndrome (KLS) is a rare sleep disorder that is characterised by episodes of severe hypersomnia, when an individual experiences excessive sleep during the day, as well as cognitive impairment, apathy, derealisation, and behavioural disturbances. This disorder mainly affects adolescents, and boys are more frequently affected than girls. Over half of the patients with KLS have hypergraphia (intense desire to write or draw), become hypersexual, or show depressive emotions. This condition is episodic, so between episodes, patients return to normal with normal sleep patterns, positive mood, and cognitive brain function.¹

Medical imaging for Kliene-Levin syndrome

Brain imaging studies are pivotal for understanding the striking neuropsychiatric symptoms of KLS. Several functional neuroimaging approaches have been applied to identify the causes of KLS and to possibly diagnose it. Within the brain, there are two structures called the thalamus and the hypothalamus, and these two structures work closely together to maintain consciousness and sleep cycles. As KLS is a disorder that is mostly characterised by disordered sleep, these two brain structures are of interest during brain scans for KLS.

With any medical condition, accurate diagnosis is important to strategise an appropriate plan of action to help alleviate symptoms and to cure the condition, if that is a possibility.² In the medical imaging world, MRI and PET scans are very popular imaging methods due to their high-quality performance and accessibility within healthcare.

Diagnosis of KLS is based on the clinical symptoms, but MRI and PET imaging techniques have been instrumental when exploring brain abnormalities associated with KLS and to also eliminate other more serious, overlapping conditions.

MRI and Kliene-Levin syndrome: What is it and what has been found?

MRI stands for magnetic resonance imaging, and it is a medical imaging technique that uses strong magnetic fields and radio waves to produce detailed images of the body. It is best at imaging joints, blood vessels, bone, soft tissue, and organs, and for this reason, it is popular with brain imaging for KLS.³

The body is made up of subatomic particles called protons. They are found in the hydrogen atoms within the body, which are stored mostly as water molecules. These protons behave like magnets, and when under the influence of a magnetic field, they can be manipulated to be aligned. With the MRI, short bursts of radio waves are released, and they knock the protons out of alignment. A complex computation system monitors the degree of alignment and forms this into images.

Across many different studies, the standard MRI scans used within hospitals show no consistent structural abnormalities in the brain scans. However, functional MRI scans did show some differences. This form of MRI records metabolic activity within the brain over a certain duration of time. For example, the individual may be asked to do certain activities, such as performing different types of verbal memory tasks or visual attention tasks, and the rate of oxygenation (activity) of different brain areas is recorded. This is to study the response of different parts of the brain to different tasks. It is equally important, however, to gain an understanding of the brain in a resting state.

With the functional MRI, there was observed hyperactivity in the frontal lobe of the brain (responsible for memory and planning) and the thalamus (responsible for relaying sensory information) when performing these given tasks. Therefore, communication between different parts of the brain is altered in KLS, compared to a healthy brain. This could be a reason why those with the disorder have cognitive trouble focusing and memory issues.

Another key finding using functional MRI scans was that in a portion of KLS patients, there were decreased levels of a chemical called NAA or N-acetylaspartate, which is a metabolite found in neurons. This chemical is closely linked with healthy brain cells and is often used as a marker for neuronal health and viability, suggesting that the brain cells in KLS are not healthy.

Though MRI is a fantastic tool and has given healthcare professionals great insight into brain functioning, there are risks regarding the contrast agents used. Gadolinium-based contrast agent is used to make images clear; however, some people may experience an allergic reaction to the agent. Also, in terms of the machine's comfort, some patients may feel claustrophobic with the MRI scan as it is performed within a magnetic tube.

Another issue is that when in the tube, you must remain as still as possible. Younger patients may struggle to stay still within the tube, which can affect the quality of results, and as Kleine–Levin Syndrome typically affects younger adolescents, this may be a disadvantage with MRI scans.⁴

PET and Kliene-Levin syndrome: What is it and what has been found?

PET (positron emission tomography) is mostly used for the imaging of blood flow, metabolic activity, and radiolabelled drugs in the body. It is popular for these purposes as it enables real-time monitoring of these processes. PET utilises atomic physical behaviours to produce images. It is based on the detection of radioactivity emitted from a radiotracer, which is administered via injection. Usually, the radiotracer is composed of radioactive oxygen, fluorine, carbon, or nitrogen. When these are in the body, they eventually release a positron. When these positrons collide with electrons, they release a burst of energy, and this energy form is detected by the computational system, which formulates this into an image, somewhat similar to the MRI.⁵

According to PET scans of people with KLS, a decrease in glucose metabolism can be observed in multiple regions of the brain, including the thalamus. These findings are consistent with apathy and cognitive dysfunction, which are key symptoms of the disorder. As well as that, hypermetabolism during the episode was observed again in the thalamus and supplementary areas, which can induce these behavioural symptoms, such as hypersexuality. Another study found that this hypermetabolism was apparent both on and off episodes of an individual with KLS, which results in altered cognitive function.⁶

Scientists investigated whether or not this disorder is correlated with inflammation of the brain. To do this, PET was used along with a contrast agent to specifically target and visualise microglia cells, which are elements of the brain structure associated with the dense inflammatory mechanism of the central nervous system. They compared PET scans of people with KLS to a healthy brain, and highlighted relevant sections of the brain, including the thalamus and hypothalamus, but found little to no difference in microglia or inflammation.⁷ Therefore, this may indicate that inflammation is not associated with the disorder, or a more effective technique needs to be developed.⁸

Integration of medical techniques diagnosis and treatment:

KLS presents with no defining symptom or characteristic, so instead the diagnosis is based on the elimination of other conditions. Symptoms of KLS, such as excessive sleeping, can overlap with many conditions, ranging from depression (mental health conditions) to Parkinson’s Disease (motor function conditions). Therefore, it can be beneficial to combine imaging techniques to help rule out other neurological disorders. 

To rule out psychiatric disorders such as bipolar or schizophrenia, isolated psychiatric evaluation may be performed. More often than not, within healthcare, multiple imaging techniques are used to build a comprehensive and accurate understanding of the images. For KLS, MRI and PET are often used in conjunction with each other. MRI more so helps to rule out structural damage, whereas PET helps observe function and metabolic abnormalities.

Despite the power of mixing imaging techniques, studying KLS remains a challenge due to its rarity. There are approximately only 1–5 cases per million people with the disorder, and this makes it challenging to study and observe.⁹ Additionally, there is, unfortunately, no definitive treatment for KLS; however, there are different management techniques, which include:¹⁰

• Supportive care of patients, ensuring the patient is well hydrated and nourished during episodes
• Medications like SSRIs or antipsychotics to alleviate mood and behavioural issues- 
• Behavioral therapy and counselling for patients and their families to deal with the emotional and social impact of KLS

Summary

In summary, KLS is a rare neurological sleep disorder characterised by excessive sleep and behavioural issues. Due to its rarity, studying the condition proves difficult; however, the conjunctive use of MRI and PET has helped to build an understanding of the brain activity associated with the condition. There is no cure, but treatment includes supportive care during episodes, medications for mood and behaviour, and therapy for emotional support. Continued research and awareness are essential to improve the diagnosis and management of KLS.