Kleine-Levin Syndrome and Narcolepsy

Written by Stine Knudsen MD, PhD

Dr. Stine Knudsen is a Neurologist at the Norwegian Centre of Expertise for Neurodevelopmental disorders and Hypersomnias at Oslo University Hospital. She is from Denmark where she did her training and doctoral thesis.

This article was originally titled:
Kleine-Levin Syndrome and Narcolepsy - two sides of the same coin/illness?

Introduction

The sleep disorders Kleine-Levin Syndrome (KLS) and Narcolepsy have several similarities. First and foremost, both typically first impact young people in the form of hypersomnia, that is, overwhelming sleepiness with sleep attacks. There has been speculation about whether the illnesses ought to be counted as variants of each other – an acutely current dilemma due to the swine influenza and vaccinations situation. As explained below, there certainly are a number of similarities but also important differences.

Symptoms

Prior infection:
The onset. Some cases of narcolepsy, and the absolute majority of cases of KLS are described as "beginning with an ordinary infection where the tiredness just goes on".

Hypersomnia:
KLS is a rare but probably an under-diagnosed sleep disorder with the characteristic of periodic hypersomnia. Patients and those affected report that for days or weeks they sleep a large part of every 24 hours. These periods can occur between one and 12 times annually, but in the periods between [these abnormal sleeping bouts] they are completely free of symptoms. KLS affects between approximately 1 to 5 young people per 100,000, where males comprise 68 to 87 percent of cases. Usually the hypersomnia periods gradually reduce up to the age of 30 but can become chronic irrespective of whether the illness begins in childhood or in adulthood.

Narcolepsy is a chronic hypersomnia that affects approx. 1 in 2,000 (50 per 100,000) initially young people with an average age of 15 at onset. No gender is affected more frequently. Patients tell of pronounced sleepiness with frequent sleep attacks every day, but as night sleep is not typically disturbed the accumulated sleep debt over 24 hours is either normal or slightly increased. Even though the degree of sleepiness with narcolepsy can vary, and good and bad days can normalise, patients never do. The occurrence of the symptom cataplexy (loss of muscle control triggered by emotions) exclusively points to narcolepsy, as it is never reported in KLS.

Other Symptoms:
Automatic behavior and personality changes.
Especially in KLS, but to some degree in narcolepsy, the patient's personality can be affected taking the forms of apathy and zombie like behavior, and possibly heightened and aggressive behavior during attempts at waking. With narcolepsy, it is most often automatic behavior and reactions with extreme sleepiness, but with KLS there is probably a degree of actual mental alteration with some patients displaying disinhibitions, for example masturbation* in public or childlike behavior/ regression such as baby speech.

Hallucinations and feelings of unreality/ dream states can also be experienced by both groups of patients. Narcolepsy patients experience so-called hypnagogic or hypnopompic hallucinations on going to sleep or at waking, which are assumed to represent the onset of the REM sleep phenomenon when half awake. Especially with narcolepsy patients this phenomenon can be so frequent that it feels like living constantly in a dream. Nightmare-like hallucinations are also experienced by approx. 30 percent of patients with KLS but, in contrast to narcolepsy, patients can become actually psychotic or paranoid. For example they can believe they can guess who is going to telephone or they can ‘monitor’ or ‘participate in’ TV programs (which they are watching).

Overeating and binge eating are found with both syndromes. 20 to 30 kilograms in weight gain associated with the onset of narcolepsy is not unusual, and it is found that later on, 25 percent of patients overeat, especially late in the evening or at night. In KLS overeating is seen frequently but can have a more secretive character, where patients can be found stealing food or eating amounts the person would not normally consume.

Diagnosis

Even though hypersomnia is the dominant feature in both KLS and narcolepsy, in KLS the diagnosis is often delayed or initially fails, both because the symptoms are relatively rare, so can remain unrecog- nized by all doctors, and because the symptoms can resemble those of other more prevalent illnesses. Further, only a few KLS patients in the total group have the ‘whole package’ of the symptoms ment- ioned above. This means that even experienced sleep specialists can have difficulties clinically making a correct diagnosis. This holds for example if the KLS patient in their first hypersomnia period only has subtle mental alteration, as in narcolepsy without cataplexy, suggesting varying degrees of hypersom- nia. Furthermore, if KLS hypersomnia is associated with severe pronounced mental alterations this typical patient will definitely not be referred to a sleep specialist but instead will be suspected of hav- ing a brain infection (such as meningitis or encephalitis), of being affected by narcotics, or of having a psychiatric illness. In the same way that individual narcolepsy patients would first get investigated for epilepsy, fainting and psychogenic or hysterical disorders, if they presented with very dominant cata- plexy with falls.

The difficulties in these diagnoses are complicated by the results of all the normally available hospital tests, such as neurological assessments, blood tests, cerebro-spinal fluid (CSF) analysis, and brain scans (MRI, CT) being normal. With KLS however, EEG non specific long activity can be divergent at 70 percent, but this cannot be used diagnostically. The diagnosis is eventually established primarily on the basis of the clinical sleep pattern – with KLS, in the main, always initially when the periodic hyper- somnia characteristic is significant – together with the help of sleep analysis polysomnography (PSG) and the multiple sleep latency test (MSLT.) PSG is used primarily to exclude rare causes of sleepiness and is usually normal in both illnesses. However very interrupted sleep, possibly accompanied by early REM sleep, can be seen in narcolepsy, while the unusually long periods of sleep can be registered with KLS.

MSLT however is used diagnostically for narcolepsy when in the form of short sleep latency (sleep time) with an increased tendency for REM sleep. Even though MSLT can be normal for KLS, some patients when in the hypersomnia period can have exactly the same abnormal sleep pattern as for narcolepsy.

Analysis of hypocretin–1 in cerebrospinal fluid CSF can have diagnostic value, as values under 110 pg/ml are exclusively found in narcolepsy, and frequently in patients with cataplexy. Less significant variations in hypocretin-1 levels within the normal range are found in individual KLS patients.

Causes

As the majority of narcolepsy patients have the same HLA type (DQB1*0602), and their brain biopsies have shown deficiencies in hypocretin cells in the hypothalamus, so called autoimmune disease is strongly indicated; in which a patient’s own immune defence erroneously attacks hypocretin cells. What triggers the attack is unknown, but it is thought it is due to a cross reaction from an earlier infection (virus or bacteria) or from an immunisation (vaccination).

Increased prevalence of streptococcal antibodies are found at the onset of narcolepsy but more currently the H1N1 influenza virus is the 'chief suspect'. Despite KLS also having a clear connection with earlier infections, for example with streptococcus, the cause of the illness is still unclear, because there has been no confirmation of specific HLA types, hypocretin deficiencies or other specific bio-marker alterations.

H1N1/Pandemrix: The abnormally increased incidence of narcolepsy after Pandemrix vaccinations and the H1N1 swine flu epidemic in 2009-10 suggest a virus or viral constituents could be the causal fact- or. This is supported by the H1N1 Spanish Flu epidemic in 1918 being followed by the “encephalitis epidemica” which included narcolepsy, amongst other illnesses. Until now, only single cases of KLS have been noted after H1N1 epidemics, and none after H1N1 vaccinations.

Narcolepsy however is known in two people with possible KLS, where the symptoms arose in close combination with Pandemrix vaccination, though it can be difficult purely statistically to establish any possible increase with such a rare illness.

Future of KLS

It is clear from the writings above, that in the years to come, awareness of narcolepsy and other hypersomnia cases must increase in order to gather new information on the number of cases and the course of the illness, and to increase knowledge of the connection between onset of narcolepsy and H1N1 vaccinations and infections.

With ACKNOWLEDGEMENTS to Dr Knudsen, "INNSIKT" and "SOMNUS".
INNSIKT, journal of the National Centre of Excellence for ADHD, Tourette's Syndrome and Narcolepsy;
SOMNUS, Sleep Disorders Journal, Norway, wherein this article appeared: the issue of SOMNUS was sent to NODSS by Dr Hesla.

This article was originally published in Issue No. 97 of The Reveille, November 2014.

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