Diagnosis and Misdiagnosis of Narcolepsy

According to the International Classification of Sleep Disorders, a tetrad of symptoms are required for the diagnosis of narcolepsy[1]. These include Excessive Day-Time Sleepiness (EDS), sleep paralysis, cataplexy and hallucinations[1]. Diagnostic tests are carried out in the sleep clinic in order to measure each of these symptoms, thereby confirming presence of narcolepsy in patients. The standard test used to measure sleep drive it the Multiple Latency Test (MSLT), which is preceded by the Polysomnography used to differentiate narcolepsy from other sleep disorders[2]. Furthermore, current research has shown a direct relationship between the hypocretin-1 levels in the cerebrospinal fluid of narcolepsy which has a major impact on diagnostic accuracy[2]. Although no gold standard test has been agreed upon, evidence suggests that pairing the polysomnography with the MSLT is a reliable and valid method in diagnosing narcolepsy, with or without cataplexy.

3.1 Diagnosis

3.1a Polysomnography

Polysomnography
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Example of a Polysomnograph Reading Showing N3 Stage Sleep.
Retrieved from http://en.wikipedia.org/wiki/File:Sleep_Stage_N3.png

Diagnosis of narcolepsy with or without cataplexy is based on persistent excessive day-time sleepiness, that occurs almost daily for a period of 3 months[3]. In order to test excessive day-time sleepiness, the nocturnal or night-time polysomnography is used in the diagnosis method is used. The polysomnography effectively rules out causes other than narcolepsy for excessive day-time sleepiness, such as sleep apnoea or periodic leg movement disorder[2]. Patients are brought into the sleep clinic in order to perform the polysomnography the night prior to the MSLT, after ruling out alternative sleep disorders.

In the sleep laboratory, the patient is monitored throughout the night, observing physiological measures such as heart rate, body movement, breathing, heart rate while they are asleep[1]. An EEG is also recorded to measure the time the patient spends asleep, the stages of sleep they go through and the duration of those sleep stages[1],[4]. The preferred method is to two 3 electrodes to asses the frontal, central and occipital EEG activity[4]. Two EOG electrodes are placed on the scalp in such a way as to be able to track eye movement whilst the patient is asleep, thus making it possible to distinguish the sleep stages such as REM sleep[4]. Moreover, a video recording and sound recording is also made in order to assess any abnormal behaviour such as sleep walking or snoring during sleep[1].

The sleeping position of the body, and any movement that occurs during sleep can also be recorded. Limb movements, for example, are measured by placing two ECG electrodes 5cm on the lower leg, for each leg[4]. Movement of the limbs can then be recorded. This enables doctors to make a final diagnosis; ruling out periodic limb movement as cause of excessive day-time sleepiness, instead of, or co-morbid with narcolepsy. The polysomnography is a crucial method in diagnosing sleep disorders, because it allows medical professionals to observe the patient first-hand, enabling them to pinpoint the etiology of their excessive sleepiness and abnormal behaviours that cause pathology.
Polysomnography is also used to ensure that the patient had had at least 6 hours of sleep prior to the MSLT the following day[1]. A limitation of the polysomnography is the potential sleep disturbance it may cause. Because the sleep laboratory is an unfamiliar and uncomfortable environment for some, it could lead to sleep disturbances which may effects results of the MSLT the following day[1]. It is crucial that the patient is not sleep deprived the day before the MSLT, the American Academy of Sleep Medicine advises to ensure that the patient has had at least 6 hours of sleep the night before, which can reliably only be observed in the sleep laboratory during the nocturnal polysomnography[5].

3.1b Multiple Sleep Latency Test

The MSLT
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Diagnostic Tests
Dr. Scammell discussing the MSLT and Polysomnography. Retrieved from
http://healthysleep.med.harvard.edu/narcolepsy/diagnosing-narcolepsy/narcolepsy-testing

The multiple sleep latency test, (MSLT) is performed after the nocturnal polysomnography. It is used to objectively measure sleep drive in the patient, but does not explain cause for the observed excessive sleepiness[1]. A regular MSLT tests consists of 5 naps, that take place throughout the day at 2 hour intervals. Each nap lasts for a duration of 15 minutes, or is terminated after 20 minutes if the patient has not fallen asleep[2]. The MSLT usually begins 1.5 hours after awakening from sleep, around 9-10 am[2]. The environment is kept as warm and comfortable as possible to allow for sleep, and data is collected[1]. The MSLT focuses on the time it takes for the patient to fall asleep on average over the 5 naps, and the presence or absence of REM sleep in these instances[1].

Diagnosis of narcolepsy requires that a sleep latency onset of 8 minutes or less be observed, and periods of two or more SOREM be present during the MSLT[5]. The sleep-onset rapid eye movement (SOREM) is the occurrence of REM sleep that occurs within 15 minutes of the onset of sleep[4]. It is common in people with narcolepsy, but rarely seen in healthy individuals, and so is an effective measure of narcolepsy[1]. However, there are some patients with narcolepsy, young children and elderly people, sometimes do not undergo SOREM. Therefore it is suggested that a mean sleep-onset latency of 8 minutes across the 5 naps should also confirm diagnosis[3].

The MSLT is not without its limitations. What was once considered a gold standard for narcolepsy diagnosis, its reliability has not come under question[6]. Around 15% of patients with cataplexy do not meet the diagnostic criteria during a single MSLT. They do not have short sleep latency or the occurrence of at least 2 SOREM periods[2]. Moreover, in cases of narcolepsy that present without cataplexy, it is difficult to conclude with a definitive diagnosis[5]. Although in such cases, hypocretin-1 levels from the cerebrospinal fluid are measured to confirm diagnosis, it is an invasive method[5]. A recent study has shown that repeat MSLT in cases where narcolepsy is suspected, especially after an inconclusive first MSLT, is a reliable alternative[5]. Results from this study found that 20% of those with an ambiguous result from a first-time MSLT met the diagnostic criteria during the repeat MSLT[5]. Moreover, 90% of those who were suspected of narcolepsy met the sleepiness criteria for the repeat test, where as only 50% did so in the first-test[5]. This study suggests that mild cases of narcolepsy, especially without cataplexy can be hugely under diagnosed[5]. Though repeat MSLT may be tedious and expensive, as it usually requires a whole day of testing, analysis for hypocretin-1 levels in the cerebrospinal fluid is not a readily available procedure in most places[5]. The repeat MSLT is a valid and beneficial alternative to the traditional single MSLT.

3.1c Neurobiological Marker

Neurobiological markers, such as the hypocretin-1 levels in the cerebrospinal fluid can significantly aid in the diagnosis of narcolepsy. For narcolepsy with cataplexy, low CSF hypocretin-1 levels lower than 110 pg/ml, is a reliable positive diagnostic tool[3]. However, in cases of narcolepsy without cataplexy, low CSF hypocretin-1 levels have only been associated with 20% of cases presented[1].

Genetic testing, such as human leucocyte antigen HLA typing for HLA DQB1*0602 haplotype can support diagnosis as well[1],[2],[5]. Although most cases of narcolepsy with cataplexy that show deficient hypocretin levels are also positive for HLA DQB1*0602 haplotype, it can not lead to a conclusive diagnosis; but is simply a supportive finding[3]. Caution must be taken when taking into account genotype, as the HLA DQB1*0602 haplotype is also seen in those with multiple sclerosis (MS)[1]. The plaques formed in the hypothalamus due to MS can cause the development of secondary narcolepsy[1].

3.2 Misdiagnosis

Because of the idiosyncratic nature of the disorder, narcolepsy often misdiagnosed [1],[7]. It is particularly mistaken for various psychological disorders. Due to overlapping symptoms, narcolepsy has been misdiagnosed as bipolar disorder, major depressive disorder and even some psychotic disorders[7].

3.2a Psychological Disorders

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Cases of misdiagnosis of narcolepsy are abundant in literature. Due to the non-specific nature of the early symptoms of narcolepsy, and limited awareness narcolepsy can be misinterpreted as a psychological disorder[7]. Compounding this is the fact that early onset of narcolepsy is often rooted by an emotionally stressing episode, leading many medical practitioners to attribute excessive sleepiness to mood disorders[7]. Furthermore, the overlapping symptoms of narcolepsy and a wide range of psychological disorders which are more frequently seen complicates matters[1],[7]. A hallmark of major depression is hypersomnia or insomnia, fatigue and excessive day-time sleepiness. Polysomnographic results of mood disorder patients indicate a reduce REM latency, especially when not medicating with antidepressant medication[1].

Symptoms of narcolepsy such as hypnagogic (hallucinations when falling asleep) and hypnopompic (hallucinations when waking up from sleep) hallucinations, as well as sleep paralysis can often lead to the misdiagnosis of schizophrenia[1],[7],[8]. Although auditory hallucinations commonly occur in both disorders, only 23% of patients with schizophrenia experience visual hallucinations compared to 83% of narcolepsy patients[1]. Narcoleptic patients experience vivid, dream-like hallucinations which can be disturbing to young children, and often dismissed as night terrors by parents[7],[8]. Misdiagnosis of narcolepsy for psychological illness, like psychotic disorders is understandably devastating to the patient but also majorly impacts treatment. Due to the sedative side effects of most antipsychotic medication, treating for narcoleptic patients for schizophrenia can exacerbate their symptoms of day-time sleepiness [1],[9]. In cases where patients diagnosed with schizophrenia do not respond to their treatment, it has been found that testing and treating for narcolepsy had significantly improved their symptoms and behaviour[9].

Bibliography
1. Peacock, J., & Benca, R. (2010). Narcolepsy: Clinical features, co-morbidities & treatment. Indian J Med Res, 131, 338-349.
2. Nishino, S. (2007). Clinical and neurobiological aspects of narcolepsy. Sleep Medicine, 8, 373-399.
3. Dauvilliers, Y., Arnulf, I., & Mignot, E. (2007). Narcolepsy with cataplexy. Lancet, 369, 499-511.
4. Penzel, T., & Canisius, S. (2006). Polysomnography.Prog Respir Res. Basel, 35, 51-60.
5. Coelho, F., Georgsson, H., & Murray, B. (2011). Benefit of repeat multiple sleep latency testing in confirming a possible narcolepsy diagnosis. Journal of Clinical Neurophysiology, 28, 412-414.
6. Johns, M. (2000). Sensitivity and specificity of the multiple sleep latency test (mslt), the maintenance of wakefulness test and the epworth sleepiness scale: Failure of the mslt as a gold standard . J. Sleep Res., 9, 5-11.
7. Stores, G. (1999). Recognition and management. Arch Dis Child, 81, 519-524.
8. Stores, G. (2007). Clinical diagnosis and misdiagnosis of sleep disorders. J Neural Neurosurg Psychiatry,78, 1293-1297.
9. Talih, F. (2011). Narcolepsy presenting as schizophrenia: a literature review and two case reports. Innov Clin Neurosci, 8(4), 30-34.

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