Cataplexy

Etiology

Type 1 narcolepsy (historically known as narcolepsy with cataplexy) is due to a deficiency of orexin-A, a wakefulness-promoting peptide neurotransmitter.[1] There is a near-perfect association of type 1 narcolepsy with HLA-DQB1*06:02, leading to the auto-immune hypothesis, which posits a selective, self-destruction of orexin-A producing neurons as the driving force behind the disorder.[4][5] The onset of narcolepsy is seasonal, most often surfacing in the spring, following upper respiratory tract infections that had occurred in the preceding months.[6] Moreover, there was an increased incidence of narcolepsy following the use of the 2009 European Pandemrix vaccination, suggesting the involvement of molecular mimicry in the development of this disorder.[7]

Secondary narcolepsy, on the other hand, is due to the development of lateral hypothalamic lesions. Although rare, lesions secondary to arteriovenous malformations, cerebrovascular accidents, inflammatory processes, and neoplasms result in the destruction of orexin-A-producing neurons.[8][9] It is worth noting that other neurological deficits are often evident in individuals who develop secondary narcolepsy, as lesions are not typically confined to the lateral hypothalamus.

Epidemiology

In the U.S., narcolepsy affects 1 in 2000 individuals with an equal distribution amongst the sexes.[1] Symptom onset most frequently occurs during adolescence; however, diagnosis often gets delayed on average by 15 years.[10] Two forms of narcolepsy exist: type 1 is associated with cataplexy while this feature is absent in type 2. In the U.S., Type 1 narcolepsy affects 1 to 2 in 4000 individuals.[11]

Pathophysiology

In addition to the physical feature of cataplexy, type 1 narcolepsy further distinguishes from type 2 narcolepsy on the molecular level. In patients with type 1 narcolepsy, the examination of cerebrospinal fluid demonstrates decreased levels of orexin-A, a wakefulness-promoting peptide neurotransmitter.[1] Neurons located in the lateral hypothalamus produce orexin-A; it potentiates the production of the following neurotransmitters: dopamine, histamine, norepinephrine, and serotonin, leading to the suppression of rapid eye movement (REM) sleep.[12] Intense emotions transmitted from the medial prefrontal cortex to the amygdala, in conjunction with the loss of orexin-A, decrease inhibitory signals of REM sleep, ultimately inhibiting motor neurons in the pons, leading to muscle paralysis and cataplexy.[1]

History and Physical

Obtaining an accurate and detailed history is imperative in the diagnosis of narcolepsy. The clinician should perform an investigation of behavioral (i.e., caffeine use, insufficient sleep, poor sleep hygiene, tobacco use, etc.) and alternative diagnoses (i.e., anemia, hypothyroidism, obstructive sleep apnea, etc.) of excessive daytime sleepiness. It is essential to realize that patients with narcolepsy are well-rested following a brief nap or sufficient nights' sleep; however, the symptoms of excessive daytime sleepiness occur within hours of awakening.[1] In addition to excessive daytime sleepiness, patients with type 1 narcolepsy experience symptoms of disordered regulation of REM sleep (i.e., cataplexy, hypnagogic hallucinations, and sleep paralysis).

The sudden onset of muscle weakness characterizes cataplexy.[1] Such episodes are transient, lasting seconds to minutes, and get precipitated by intense emotions.[1] Cataplectic attacks are more frequently incited by positive emotions (i.e., laughter, excitement, etc.) than negative emotions (i.e., anger, fear, frustration, etc.), with laughter being the most common precipitant.[13] It is the complete or partial paralysis of voluntary muscles that is responsible for the weakness associated with cataplexy; however, it bears noting that the muscles of eye movement and respiration get spared during these attacks.[1] The suppression of serotonergic and noradrenergic neuronal circuits permits the complete or partial paralysis of voluntary muscles.[14] Consciousness, however, is uncompromised during cataplectic attacks as wake-promoting histaminergic signaling is preserved.[14] Cataplectic attacks typically follow a crescendo pattern, first involving the muscles of the face and neck with progression to the muscles of the trunk and limbs.[1] Physical findings depend on the severity of each episode, ranging from facial drooping and slurring of speech (partial attacks) to collapse (complete attacks).[13][15] Episodes of cataplexy often resolve within two minutes, and those afflicted are without lingering effects.

Evaluation

The diagnosis of type 1 narcolepsy requires the subjective complaint of excessive daytime sleepiness (occurring daily for a minimum of 3 months) in addition to either decreased cerebrospinal fluid (CSF) concentrations of orexin-A or cataplexy in conjunction with the following findings on a multiple sleep latency testing: Mean sleep latency less than or equal to 8 minutes and greater than or equal to 2 sleep-onset REM sleep periods.[16]

Treatment / Management

While behavior modifications (i.e., planned naps, a sufficient night's sleep) play a role in the management of the excessive daytime sleepiness associated with type 1 narcolepsy, treatment of cataplexy is purely pharmacological. The duration of therapy is indefinite, as type 1 narcolepsy is incurable. It bears mentioning that treatment options include various combinations of medications, often creating an individualized treatment. Clinicians can use the Epworth Sleepiness Scale to follow the response to treatment. For completeness, the pharmacologic treatment of type 1 narcolepsy, as a whole, is presented below:

Successful management of excessive daytime sleepiness often requires the use of wakefulness-promoting agents, as behavioral modifications fail to provide complete relief.[14] Modafinil (100 to 400 mg by mouth once daily every morning) and its isolated R-enantiomer, armodafinil (150 to 250 mg by mouth once daily every morning), are considered first-line pharmacologic agents in the management of excessive daytimes sleepiness. While the mechanism of action of these agents is not entirely understood, the thinking is that their effects are due to an increase in dopaminergic signaling via the inhibition of dopamine reuptake.[17] Two medications received FDA approval in 2019: pitolisant and solriamfetol. Pitolisant (8.9 to 35.6 mg by mouth once daily every morning) is a histamine-3 receptor inverse agonist, while solriamfetol (75 to 300 mg by mouth once daily every morning) is a selective dopamine/norepinephrine reuptake inhibitor.[18] For breakthrough excessive daytime sleepiness, the following agents are options on an as-needed basis: dextroamphetamine-amphetamine (5 to 60 mg by mouth daily in one to three divided doses) and methylphenidate (5 to 60 mg by mouth daily in two to three divided doses).[19](B3)

Successful management of cataplexy requires the use of REM sleep-suppressing drugs. Such agents increase the concentration of norepinephrine and serotonin. The following pharmacologic agents are considered first-line in the management of cataplexy: Selective serotonin reuptake inhibitors (fluoxetine 10 to 80 mg by mouth daily every morning), norepinephrine reuptake inhibitors (atomoxetine 40 to 80 mg by mouth daily every morning), serotonin/norepinephrine reuptake inhibitors (venlafaxine extended-release 37.5 to 150 mg by mouth once daily every morning), and tricyclic antidepressants (clomipramine 10 to 150 mg by mouth daily every morning). Prescribers of the medications, as mentioned earlier, should keep in mind the following considerations:

• Tricyclic antidepressants (TCAs) have fallen out of favor for the treatment of cataplexy due to their anticholinergic side effects (i.e., delirium, dry mucous membranes, hyperthermia, ileus, mydriasis, tachycardia, and urinary retention). Moreover, TCA overdose can result in a toxidrome: anticholinergic symptoms, cardiac toxicity, and CNS toxicity. Cardiac toxicity includes interventricular conduction delay (QRS prolongation), right-axis deviation, and tachycardia (anticholinergic effect).[20]
• Serotonin syndrome is diagnosed clinically using the Hunter criteria: administration of a serotonergic agent in the setting of inducible clonus with either agitation or diaphoresis. It can occur with the use of a single serotonergic agent as prescribed/taken in excess or with the co-ingestion of multiple serotonergic agents simultaneously. Its manifestations are due to an increase of serotonin in the central nervous system. Typical presentation includes altered mental status, increased autonomic activity, and neuromuscular changes. Great care is necessary to avoid the prescription of multiple serotonergic agents in a single patient.[21]

Currently, only one medication has FDA approval for the treatment of both cataplexy and the excessive daytime sleepiness associated with narcolepsy: Sodium oxybate, the sodium salt of gamma-hydroxybutyrate. The mechanism of action of this medication is unknown; however, it is a known metabolite of gamma-aminobutyric acid (GABA). It is therefore thought to work via the GABA-B receptor. This medication is dosed initially at bedtime with subsequent dosing 2.5 to 4 hours later and has a significant salt content of 1100 mg to 1640 mg when dosed in the effective range (6 g to 9 g per night in two divided doses).

The management of type 1 narcolepsy in children differs slightly from management in adults. In children, the first-line pharmacologic agents for the treatment of symptoms of excessive daytime sleepiness are stimulants such as dextroamphetamine-amphetamine (10 to 40 mg by mouth daily in one to two divided doses) or methylphenidate (10 to 60 mg by mouth daily in two to three divided doses) rather than wakefulness-promoting agents such as armodafinil (50 to 250 mg by mouth once daily every morning) and modafinil (50 to 200 mg by mouth once daily every morning). Moreover, the first-line pharmacologic agent for the treatment of cataplexy is sodium oxybate (1 to 2 g per night in two divided doses), rather than REM sleep-suppressing drugs, in children over the age of seven. In children under seven with cataplexy requiring treatment, the following REM sleep-suppressing drugs are possible therapies: clomipramine 25 mg by mouth once daily at bedtime, fluoxetine 5 to 10 mg by mouth once daily, or venlafaxine extended-release 25 mg by mouth once daily.

Differential Diagnosis

Cataplexy is all but unique to type 1 narcolepsy; therefore, the differential diagnosis of this feature is sparse. Pseudocataplexy, a feature of conversion disorder, is characterized by cataplexy-like attacks; however, the other defining characteristics of narcolepsy are often absent.

Although rare, cataplexy can occur in the presence of lateral hypothalamic lesions implicated in the development of secondary narcolepsy. Such lesions may arise in the setting of arteriovenous malformations, cerebrovascular accidents, inflammatory processes, and neoplasms.[8][9] Again, if cataplexy were to occur in such situations, other neurological deficits will likely be evident, as neuronal destruction does not typically remain confined to the hypothalamus.

Prognosis

Patients must be capable self-advocates, accurately describing their symptoms to the clinician, to facilitate the diagnosis of type 1 narcolepsy. While type 1 narcolepsy is an incurable neurological disorder, there are treatment options directed towards symptom management. In patients with narcolepsy with cataplexy, multiple individual pharmacological agents exist for symptomatic management of cataplexy and excessive daytime sleepiness alone, except sodium oxybate, which targets all features of type 1 narcolepsy.

Complications

Severe episodes of cataplexy resulting in complete collapse can result in musculoskeletal injury and intracranial hemorrhage.[22] Factors determining the severity of sequela following a cataplectic fall include age, ground-surface composition, height, preexisting metabolic bone disease, and surrounding objects.