Clinical Aspects Of Narcolepsy

Narcolepsy remains an under- and misdiagnosed condition, in part due to the misperception that it is an extremely rare disorder. However, the prevalence of narcolepsy-cataplexy approximates that of Multiple Sclerosis (MS) and Parkinson's Disease (PD)23 and may be as high as 20-60 per 100,000 people in the Western countries.24 Furthermore, as symptoms often emerge during adolescence, the development of social skills and self-esteem, as well as academic achievement may be adversely affected. Moreover, individuals may be reluctant to disclose symptoms fully, given their often bizarre nature and, as such, life-long morbidity may prove significant. The population prevalence of narcolepsy without cataplexy is unknown.

Severe daytime sleepiness, often combined with nocturnal sleep fragmentation, leads to a feeling of constant tiredness in narcoleptics. This chronic sleep pressure coupled with poor sleep/wake state boundary control may underlie the commonly observed sudden, uncontrollable bouts of sleepiness or "sleep attacks" during the day. Cataplexy (Gk., "to strike down"), another cardinal symptom of narcolepsy, was first used by Loewenfeld (1902) to describe the sudden, bilateral loss of muscle tone without loss of consciousness. Triggered by any situation that requires sudden action or strong emotion (laughing and mirth are the most commonly reported triggers), these attacks may be partial (isolated muscle groups) or complete (causing complete collapse), but rarely involve all muscles simultaneously. The knees (buckling) and head/neck muscles (head bobbing, jaw sagging and slurred speech) are most commonly affected, with such episodes lasting for seconds to (rarely) minutes. Muscle weakness escalates progressively over several seconds and significant bodily injury typically does not occur. Cataplexy is pathognomonic for narcolepsy. Another common symptom of narcolepsy is hypnagogic hallucinations, which are dream-like episodes that occur as one is falling asleep and may be particularly terrifying when associated with sleep paralysis. Both hypnagogic hallucinations and sleep paralysis, however, are not specific to narcolepsy, and are commonly reported in the general population, especially in association with severe, chronic sleep deprivation. Other symptoms of narcolepsy may include automatic behavior and sleep-talking, which also reflect abnormal vigilance state boundary control. In addition, other sleep disorders such as periodic limb movement disorder (PLMD), REM-Behavior Disorder (RBD), the sleep-related breathing disorders (SRBD) and rarely, sleep-walking, are seen in the context of narcolepsy.25,26

Until recently, the diagnosis of narcolepsy has been primarily based on clinical symptomatology, with cataplexy being the most specific symptom and diagnostic predictor for the disorder.27 Cataplexy is, however, sometimes difficult to distinguish clinically from normal experiences; these may include feelings of weakness when laughing hysterically, in the context of exciting athletic activities, during sex or when extremely angry. Atonic seizures or other forms of hypotonia may also be difficult to differentiate from cataplexy.26 The MSLT is therefore commonly used to objectively quantify sleepiness and the occurrence of soREMPs, which are both consistent with the diagnosis of narcolepsy. In the MSLT, narcoleptics typically exhibit a short mean sleep latency (< 8 minutes) and more than two transitions into REM sleep (or soREMPs). The MSLT is typically performed after a night in the sleep laboratory, where nocturnal sleep is studied to exclude other causes of EDS or nocturnal sleep disruption, including sleep-related breathing disorders (SRBDs). Subjects undergoing an MSLT also must be free from psychotropic drug use, such as antidepressants and stimulants, as these will confound interpretation of the MSLT.

In most international classifications, narcolepsy is defined by the presence of sleepiness and cataplexy or by the polysomnographic documentation of REM sleep abnormalities. The diagnosis of narcolepsy has been complicated by the realization that not all people described as having narcolepsy manifest all of the aforementioned classical symptoms. Additionally, the association with HLA and hypocretin deficiency is very tight only in idiopathic ("primary") narcolepsy with typical cataplexy. Other cases, such as those associated with atypical cataplexy or without any cataplexy, constitute a grey area, which has been called the "narcolepsy clinical borderland".28

Table 2 Proposed Icd2 (International Statistical Classification Of Diseases And Related Health Problems) For Hypersomnia Not Due To Sleep Related Breathing Disorders

Diagnosis

Diagnostic Criteria

Pathophysiology and Clinical/Pathological Subtypes

Narcolepsy with Typical Cataplexy

► EDS occurring almost daily for at least 3 months.

► Definite history of cataplexy

► No other medical or mental disorder which accounts for symptoms.

► Confirmation by:

1. Nocturnal PSG followed by MSLT (SL <8 min, >2 soREMPs)

2. CSF Hcrt-1 level (<110 pg/mL)

= 95% with Hcrt deficiency and DQB1*0602

1. Hypocretin gene mutations: Only one case of a pre- pro-hypocretin mutation causing narcolepsy has been reported, in an individual who was HLA negative and in whom symptoms began unusually early (atypical case).

2. Narcolepsy-cataplexy with normal CSF hcrt levels: up to 10% of cases with typical cataplexy in reported cases

3. Multiplex/familial subtypes

4. HLA DQB1*0602 negative cases: These individuals generally have normal CSF Hcrt-1 levels and may occur more frequently in multiplex families

5. Late onset narcolepsy-cataplexy: It is rare but possible for symptoms of narcolepsy to appear after 40 years of age

6. Isolated cataplexy: Very rare cases of familial isolated cataplexy with very early onset have been reported and may represent a distinct clinical entity. Isolated cata plexy is also occasionally observed in children at time of disease onset; sleepiness usually develops within one year of the onset of cataplexy.

Narcolepsy without Typical Cataplexy

► EDS occurring almost daily for at least 3 months

► No or doubtful cataplexy

► No other medical or mental disorder which accounts for symptoms

► MSLT: SL < 8 min, > 2 soREMPs

= Unknown, heterogeneous 16% Hcrt-1 deficiency, 40% HLA-DQB1*0602

Narcolepsy associated with a known Physiologic Condition

► EDS occurring almost daily for at least 3 months

► History of definite cataplexy, atypical cataplexy, or no cataplexy Concurrent medical/neurological disorder

► MSLT : SL < 8 min, > 2 soREMPs

= With or without Hcrt-1 deficiency; caused by various disorders

Idiopathic Hypersomnia

► EDS occurring almost daily for at least 3 months

► MSLT: No soREMPs

= Unknown, likely heterogeneous etiology

The symptoms of narcolepsy may also bee seen in association with, or caused by other medical and neurologic conditions, which has been referred to as "secondary" or "symptomatic" narcolepsy. In his classic studies of the encephalitis lethargica pandemic (1917-1923), Von Economo (1931) described individuals with hypothalamic and upper brainstem lesions in whom sleepiness was a primary symptom.

He went on to hypothesize that the posterior hypothalamus was critical to the promotion of wakefulness, a premise consistent with various reports of hypersomnia secondary to structural lesions in that region.25 These recent advances have led to a reclassification of narcolepsy into more distinct subcategories as described in Table 2.

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