Introduction

Kleine-Levin Syndrome (KLS) is a rare sleep disorder characterised by the need for excessive amounts of sleep (hypersomnia), in some cases up to 20 hours a day. KLS can also result in excessive food intake and other behavioural changes, such as increased sex drive and memory problems. Compulsive eating can lead to associated weight gain. KLS primarily affects adolescent males, usually around the age of 16 years, but there are cases of women and older men affected. While males are three times more likely to experience KLS, women tend to experience a longer disease course than males. Affected individuals may experience irritability, tiredness, apathy (a lack of emotion), confusion and may have slurred speech. Some individuals experience hallucinations or feel detached from reality or have disconnected thinking. Symptoms are experienced intermittently; individuals may experience no symptoms for several weeks or months, but then experience persistent symptoms that last days to weeks, leading to recurrent symptomatic episodes that vary in duration. Episodes occur approximately two to twelve times annually. In some cases, symptoms of KLS disappear with age, with episodes becoming less frequent with ageing and eventually stopping. However, symptomatic episodes may recur later in life, with reports of symptoms occurring in individuals into their 40s and 50s.^4,5

Currently, the exact cause of KLS is still unknown, although it is theorised that symptoms arise due to malfunction or damage to the area of the brain called the hypothalamus that regulates sleep, appetite and body temperature. Possible proposed causes include a head injury or infection which damages the hypothalamus. In some rare cases, KLS does run in families, indicating a possible involvement of genetic factors, leading to a higher risk of developing the disease.⁴

In some cases, KLS arises following an infection with a flu-like illness; this post-infection onset suggests that KLS may be triggered by an autoimmune process.^3,4 In this article, we will focus on the possible autoimmune processes that may lead to KLS development. 

Overview of Autoimmune Mechanisms

Definition of Autoimmunity

 An autoimmune disease occurs when the body’s immune system mistakenly attacks its own healthy tissues. Normally, the immune system protects the body by targeting foreign invaders, such as bacteria and viruses. In autoimmune conditions, this defence system fails to tell the difference between the body’s own cells and harmful outsiders, leading it to attack itself.^7,8 Examples of autoimmune neurological disorders include narcolepsy, multiple sclerosis, and autoimmune encephalitis. 

Common Mechanisms by which Autoimmunity Arises

Molecular mimicry is one of the primary mechanisms by which infections can induce autoimmunity. It arises when structural similarities between foreign and self-markers lead to the activation of autoreactive T or B cells (immune cells that can successfully bind to and react against your body's own cells).¹ The production of autoantibodies can lead to autoimmune reactions when immune processes are driven to attack the body’s healthy tissue. Autoantibodies are antibodies that can bind to self-markers known as antigens on cells. T-cell-mediated inflammation leading to chronic inflammation following infection can lead to non-specific activation of multiple immune cells (activation of a lot of different types of immune cells, not specifically those that would only target the foreign infection), which can activate autoreactive immune cells, leading to autoimmunity. This is sometimes known as ‘bystander inflammation’.⁶ Failure of self-tolerance occurs when the system that usually prevents the maturation of autoreactive immune cells fails. Alternatively, some self-markers are hidden from immune cells; events that damage cells or lead to immune cells being found in sites where immune cells are not normally found (such events include infection or injury) can provoke an autoimmune response to these normally hidden markers.⁸ Other factors that underline autoimmunity include genetic predisposition (such as variations in immune cell markers) that increase the chance of autoimmune reactions and environmental triggers (such as exposure to infections).^4,1,7,8

Evidence Supporting Autoimmune Involvement in KLS

While the exact cause of KLS remains unknown, harmful changes include hypothalamic dysfunction. 

Several features of KLS suggest it may be an autoimmune disease, including an early age at onset, possible links to certain immune-related genes (HLA), a wide range of symptoms, repeated episodes, and the fact that symptoms often begin after infections.  Furthermore, an underlying autoimmune process is involved in the development of KLS.^3,4 

Some studies have highlighted HLA (human leukocyte antigen) associations in patients with KLS compared to the general population. HLA is a group of proteins found on the surface of cells that are used by the immune system to help distinguish between self and non-self.² Certain HLA antigens are associated with a higher risk of developing autoimmune disorders than others. An individual's HLA phenotype is based on which HLA genes they possess. A person's HLA phenotype determines what markers (peptides) are ‘selected’ and presented to T cells, with some HLA molecules being more likely to bind, and therefore present, self-peptides to autoreactive T cells, which can precede and predispose autoimmunity.^2,4

For example, in type 1 diabetes mellitus, the ‘DR3-DQ2’ HLA type is observed in a higher proportion of those with type 1 diabetes than in the general population.² Similarly, there is a strong association of HLA-DR2 with narcolepsy.^3,4

A study found the specific HLA gene form ‘(HLA)-DQB1*0201’ had a significantly higher frequency in patients with KLS compared to the general population. Three patients in the study were homozygous for DQB1*0201, all of whom had KLS. Homozygous means they have the same gene version on both of their gene copies, so they inherited the same version of the gene from both parents.³ Reported Jewish predisposition and occasional familial cases may also support an inherited component that may predispose individuals to KLS, such as the inheritance of a specific HLA gene conferring a predisposition to autoimmunity.⁴

Further studies have also highlighted other HLA types with increased frequency in KLS patients. However, other studies have shown inconsistent HLA associations, suggesting further research is required to prove a significant association.⁴ While defining a HLA association would provide key evidence of autoimmunity, the current absence of this information does not exclude an autoimmune cause of KLS. As the development of autoimmunity is complex and HLA susceptibility is not the only factor, as certain HLA forms only predispose individuals to autoimmunity, multiple other factors influence disease development. With many autoimmune diseases, multiple different HLA peptide combinations exist, additional susceptibility genes influence risk, and a suitable trigger is required for disease development.⁴ Meaning a clear HLA disease correlation is not easily identifiable, hence, the inability thus far to define a clear HLA disease association does not exclude autoimmunity as a cause of KLS.

Frequent infectious precipitating factors at onset or before each symptomatic episode may suggest KLS is an autoimmune disease. Evidence supporting the post-infectious onset of KLS is reports of KLS episodes following viral or bacterial infections.^3,4 In one study, 16 of the 23 patients sampled had an infectious illness before disease onset.³ Some have suggested KLS stems from focal encephalitis, but inflammatory cytokines remain normal in both symptomatic and non-symptomatic episodes, and C-reactive protein levels are normal in KLS. Suggesting CNS infection is an unlikely cause of KLS, but infection may trigger autoimmune disease either through cross-reactivity or by providing an inflammatory trigger for autoreactive T cell activation.⁴ Possible methods by which infection leads to KLS include the infectious agent causing an immune response that can cross-react with a self-marker (antigen), such as in molecular mimicry. Infection may also release self-antigens not usually exposed to the immune system. Or due to the ‘danger hypothesis’ in which infection leads to an inflammatory signal that lowers the threshold for T cell activation, leading to the activation of autoreactive T cells. This inflammation may also be triggered by tissue damage, so it may be relevant to cases where a head injury precedes KLS onset.⁴

Notably, a range of sleep disorders have now been associated with auto-antibodies (antibodies that bind and drive immune attack against self), leading to focal limbic encephalitis or hypothalamic dysfunction (inflammation in the brain/hypothalamus). A similar cause is possible for KLS.⁴ Autoimmune activity in the hypothalamic regions regulating sleep and behaviour may underlie KLS development and episodes. The episodic nature of symptoms may be linked to possible cyclical immune activity or transient inflammation in the hypothalamus. The relapsing-remitting pattern of KLS is characteristic of many autoimmune diseases and suggests that episodes may be triggered by immune system stress, such as following an infection. 

Limitations of Current Research

Limitations in identifying the cause of KLS are that KLS is a rare disease, so studies usually have small sample sizes, and research is reliant on a small handful of case-based studies rather than more reliable large sample studies. There has been a lack of consistent immune findings across studies, which may be attributed to the small sample sizes or due to the complexity of immune system dysfunction, such as the interplay of multiple autoimmune susceptibility genes influencing the probability of developing an autoimmune disease. There is also still uncertainty whether the immune changes seen in KLS are causative or a consequence of the disease. There is a particular lack of research identifying consistently elevated inflammatory markers or specific disease-defining autoantibodies, unlike what has been found for other autoimmune conditions. There have so far been inconclusive genetic links, with other studies not supporting the link found between HLA DQB1*0201 and KLS.⁴ 

Summary 

The cause of KLS remains unknown, but several lines of evidence strongly indicate that KLS may be an autoimmune condition. Firstly, a possible HLA association indicates that autoimmune susceptibility genes influence KLS disease frequency. Furthermore, most cases of KLS are preceded by infection, which may act to trigger an autoimmune condition. Analysis of inflammatory markers indicates that CNS infection itself is an unlikely cause of KLS, implicating infection as a trigger of an autoimmune cause. Other factors that support an autoimmune cause of KLS are its episodic nature, young age of onset and similarity to other sleep disorders, which are linked to auto-antibodies in areas important for sleep regulation. However, more research is still required to confirm that an autoimmune process causes KLS, as some research still opposes this theory and no definitive evidence such a specific autoantibody has been found.