Cataplexy--clinical aspects, pathophysiology and management strategy

Abstract

Cataplexy is the pathognomonic symptom of narcolepsy, and is the sudden uncontrollable onset of skeletal muscle paralysis or weakness during wakefulness. Cataplexy is incapacitating because it leaves the individual awake but temporarily either fully or partially paralyzed. Occurring spontaneously, cataplexy is typically triggered by strong positive emotions such as laughter and is often underdiagnosed owing to a variable disease course in terms of age of onset, presenting symptoms, triggers, frequency and intensity of attacks. This disorder occurs almost exclusively in patients with depletion of hypothalamic orexin neurons. One pathogenetic mechanism that has been hypothesized for cataplexy is the activation, during wakefulness, of brainstem circuitry that normally induces muscle tone suppression in rapid eye movement sleep. Muscle weakness during cataplexy is caused by decreased excitation of noradrenergic neurons and increased inhibition of skeletal motor neurons by γ-aminobutyric acid-releasing or glycinergic neurons. The amygdala and medial prefrontal cortex contain neural pathways through which positive emotions probably trigger cataplectic attacks. Despite major advances in understanding disease mechanisms in cataplexy, therapeutic management is largely symptomatic, with antidepressants and γ-hydroxybutyrate being the most effective treatments. This Review describes the clinical and pathophysiological aspects of cataplexy, and outlines optimal therapeutic management strategies.

Figure 1 |

Video-polysomnographic recording of a patient during a cataplectic attack with loss of muscle tone. Video clips were taken sequentially over a period of a | 2 min and b | 30 s. The patient presents with sustained loss of muscle tone that alternates with brief enhanced EMG activity leading to a flapping up-and-down motion of the body segments. These movements were reported as voluntary by the patient, who was trying to fight against the repetitive postural losses. The patient was fully conscious during the entire episode. Note that the EEG is characterized by low voltage frequencies (alpha and theta) and a decrease in heart rate during the brief suppressions of EMG activity. Abbreviations: ECG, electrocardiogram; EMG, electromyogram; EOGD, right electrooculogram; EOGG, left electrooculogram. Written consent for publication was obtained from the patient.

Figure 2 |

Hypothetical circuits and pathways controlling cataplexy in the rodent brain. Activation during wakefulness of neural circuits involved in REM sleep paralysis is thought to underlie cataplexy, and is probably triggered by a two-part brainstem circuit—the SubC and MM connection. Glutamatergic neurons in the SubC trigger REM paralysis by activating GABAergic or glycinergic cells in the MM, which in turn project to and inhibit skeletal motor neurons. When a positive emotion is experienced, GABAergic neurons in the CeA switch on and inhibit cells in the LC, vlPAG and LPT. The LC–vlPAG–LPT circuit normally prevents muscle paralysis during wakefulness by suppressing the activity of SubC neurons. GABAergic CeA neurons inhibit neurons in the LC–vlPAG–LPT circuit, which in turn disinhibits the SubC to motor neuron circuit, triggering muscle paralysis and cataplexy. Muscle paralysis in cataplexy is also enabled by loss of noradrenergic input from LC neurons, which are inhibited during cataplexy. In healthy individuals, orexin-expressing neuronal activity cancels out the inhibitory effect of amygdalar neurons. Abbreviations: CeA, central amygdala; GABA, γ-aminobutyric acid; LC, locus coeruleus; LH, lateral hypothalamus; LPT, lateral pontine tegmentum; MM, medial medulla; mPFC, medial prefrontal cortex; REM, rapid eye movement; SubC, subcoereulus; vlPAG, ventrolateral periaqueductal grey.