Cataplexy is defined as a sudden involuntary muscle weakness or paralysis during wakefulness, typically triggered by strong emotions, and is the pathognomonic symptom of narcolepsy with cataplexy ( a sleep disorder that affects 0,06% of the adult population). In addition to cataplexy, narcolepsy is characterized by sleep paralysis, sleep-onset REM periods, hypnagogic hallucinations and fragmented night-time sleep. Cataplexy is the optimal behavioural biomarker of this disease.
The age of oneset of narcolepsy ranges from early childhood to the fifth decade (with a peak at 15 years and 35 years of age). Patients with narcolepsy have difficulty in executing daily activities, socializing and maintaining personal relationships mainly due to cataplexy and EDS, and are estimated to experience a quality of life that is comparable or inferior to that of patients with epilepsy or sleep apnoea.
Cataplexy is still an under-recognized symptom of narcolepsy- a disease that is currently underdiagnosed. In Europe, the delay between the onset of symptoms and a correct diagnosis is about 10 years, and many patients are affected during the most important period in their education and/or career. To overcome these consequences early diagnosis and treatment are essential to best improve patient quality of life.
Narcolepsy with cataplexy, 2008
Cataplexy associated with narcolepsy: epidemiology, pathophysiology and management, 2006
SYMPTOMS OF CATAPLEXY
Cataplexy can be difficult to diagnose, as the symptoms vary not only between patients but also within individuals.
Cataplectic attacks range from partial muscle weakness to complete paralysis, but are always bilateral, even if one side of the body is more affected than the other. These attacks are debilitating for patients because they leave the affected individual awake but either fully or partially paralyzed. Cataplexy affects all skeletal muscles apart from the diaphragm and extraocular muscles, but its greatest effect is on facial and neck muscles. Typically the result is dysarthria, twitching of the facial muscles, jaw tremor. Extreme muscle weakness in the knees, arms and shoulder is also common. 50% of patients with cataplexy experiece both partial muscle weakness and complete paralysis, whereas 30% experience only partial paralysis. During a cataplectic attack, patients remain conscious and are able to remember what happened to them before, during and after the cataplectic episode. Some patients with narcolepsy report hypnagogic hallucinations during attack, and some patients enter into REM sleep, but this is rare. Skeletal muscke tone is reduced or absent during a cataplectic episode. Most episodes are accompained by reduced heart rate and EEG desynchronization. The duration of an attack varies from several seconds to several minutes (rare hours)-status cataplectitus. The frequency of attacks in patients varies from fewer than one episode per year to several episodes per day. Cataplexy persists throughout life, altought the frequency of attacks might decrease with age. Men often experience a higher number of cataplectic attacks than do women.
TRIGGER FACTORS
More than 90% of patients with narcolepsy and cataplexy present with low levels of orexin (<110 pg/ml) in CSF, which undoubtedly stem from the loss of approximately 90% of orexin-expressing neuron. Importantly, a postmortem study of a patient who exhibited narcolepsy without cataplexy indicated loss of 33% of orexin-positive cells, largerly in the posterior hypothalamus. This finding suggests that narcolepsy with cataplexy only enuses when a patient loses almost all their orexin-positive cells.
OREXIN
Orexin, also called hypocretin, is a neurotransmitter that regulates arousal, wakefulness, and appetite.
There are two types of orexin: orexin -A and -B (hypocretin-1 and -2). They are excitatory neuropeptide hormones with approximately 50% sequence identity, produced by cleavage of a single precursor protein. Orexin-A is 33 amino acid residues long and has two intrachain disulfide bonds; orexin-B is a linear 28 amino acid residue peptide. Studies suggest that orexin-A may be of greater biological importance than orexin-B. In 1996, a set of neuropeptides related to the hormone secretin were isolated from the rat lateral hypothalamus by the process of directional tag PCR subtraction cloning. The cloning of the gene for these peptides from rat and mouse, the localization of the peptide-producing cell bodies and a description of some of their efferent projections were first presented in 1977.
The receptors for these neuropeptides (Hcrtr1 [Orxr1] and Hcrtr2 [Orxr2]) have been identified as G-protein coupled receptors and shown in the rat brain, by analysis of their mRNA, to display a striking distribution. The Hcrtr1 receptor has a much higher (100 to 1000-fold) affinity for Hcrt-1 than for Hcrt-2. The Hcrtr2 receptor seems to have equal affinities for both neuropeptides. The distinctive distribution of the receptors has led some authors to hypothesize a sleep-specific role for the Hcrtr1 receptor and a more general role for Hcrtr2 receptor. The receptors have been mapped on human chromosome 1p33 and 6cen, respectively.
The hypocretin-producing cell bodies are specific to the hypothalamus and have widespread anatomical projections within the central nervous system of the rat with the densest extra-hypothalamic projection to the noradrenergic locus coeruleus and lesser projections to the basal ganglia, thalamic regions, the medullary reticular formation, and the nucleus of the solitary tract. There are minor projections to the cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. In humans, the localization of hypocretin-producing cell bodies is restricted to the dorso-lateral hypothalamus with extensive dense projections to the locus coeruleus (LC), dorsal raphe nuclei, amygdala, suprachiasmatic nucleus, basal forebrain, cholinergic brainstem and spinal cords.
The hypocretins are thought to act primarily as excitatory neurotransmitters. Systemic and intracerebroventricular administration of hypocretins directly stimulates cells on the LC noradrenergic system in rats and monkeys, suggesting a role for the hypocretins in various central nervous functions related to noradrenergic innervation, including vigilance, attention, learning, and memory. Their actions on serotonin, histamine, acetylcholine and dopamine neurotransmission is also thought to be excitatory and a facilitatory role on gamma-aminobutyric acid (GABA) and glutamate -mediated neurotransmission is suggested.
Apart from their primary role in the control of sleep and arousal, the hypocretins have been implicated in multiple functions including feeding and energy regulation, neuroendocrine regulation, gastrointestinal and cardiovascular system control, the regulation of water balance, and the modulation of pain. A role in behaviour is also postulated.
The hypocretin/orexin system, 2002
CATAPLEXY AND EMOTIONS
A Cataplectic attack is generally triggered by strong positive emotions such as excited laughter, elation, or surprise. Infrequently they are associated with negative emotios such as frustation or anger, stress, fear.
Orexin neurons are active in the response to strong emotions; therefore, loss of orexin-positive neurons in patiens who have narcolepsy with cataplexy hypothetically destabilizes the motor control system within brainstem such that positive emotions trigger sever muscle weakness or total motor paralysis. Evidence exists that patients with cataplexy have altered neuronal responses to positive emotions. Neuroimagining studies show that patients with narcolepsy have a reduced threshold for neuronal activation in the amygdala ( a brain region that has a key role in the regulation of emotional activity) in response to both humorous and reward stimuli compared with controls. In addition functional neuroimaging studies describe changes in brain perfusion and glucose metabolism during cataplexy in humans. A PET study revealed increased metabolic activity during cataplexy in the bilateral precentral and postcentral gyri and primary somatosensory cortex, and a marked decrease in activity in the hypotalamus.
Abnormal functioning of the amygdala during cataplexy might stem from orexin deficiency, because the release of orexin from neurons is maximal when healthy individuals are experiencing positive emotions.(Amygdala lesions reduce cataplexy in orexin knock-out mice). Animal studies also indicates that cataplexy is associated with abnormal function of amygdala. Postmortem data show marked axonal degeneration in the amygdala of narcoleptic dogs.
ANIMAL MODELS
Genetic studies in narcoleptic dogs and mice have provided valuable insights into the pathophysiology of cataplexy. In mice, genetics deletion of Hcrt, which encodes orexin, and the consequent degeneration of orexin-expressing neurons induces a behavioural phenotype that includes cataplexy, sleepiness and distrurbed REM sleep. In dogs, introduction of exon skipping into the Hcrt-R2 gene causes a narcoleptic phenotype. These findings suggest that the orexin system is important in promoting arousal, controlling Rem sleep, and regulating postural muscle tone. Catapletctic attacks in mice seem similar to those in human cataplexy. Mice seem to be awake during attacks, because they respond to visul stimuli, and their EEG activity is similar to the spectrum of waking EEG activity seen during cataplectic episodes in children. Most cataplectic attacks in mice range from 15s to 2 min, and as in humen narcolepsy, these attacks can be trigged by positive emotional stimuli (palatable foods, play, sex, social reunion).
PATHOPHYSIOLOGY
A longstanding hypothesis in sleep medicine is that cataplexy results from intrusion of REM sleep paralysis into wakefulness. This idea stem from the observation that cataplexy and REM sleep paralysis have a common neural mechanism. For exemple deep tendon and monosynaptic Hoffmann reflex activity are absent during both cataplexy and REM sleep. The underlying cause of clinical cataplexy is a reduction in skeletal motor neuron activity, which results from increased inhibitory and reduced excitatory signalling in the brain. Inhibitory signals are produced by GABAergic and glycinergic neurons in the medial medulla, which are intensly activated during cataplexy and REM sleep, but not during normal weaking. Simultaneously pontine grey neurons, which are responsible for atonia both in cataplexy and REM sleep activate GABAergic neurons, which in turn inhibit noradrenergic neurons in the locus coeruleus. The cessation of firing of noradrenergic neurons stops the release of noradrenaline to motor neurons and results in their disfacilitation. The two processes cause reduced motor neuron activity and decrease in, or elimination of, tone in the postural muscles.
The close association between the occurrence of cataplexy and orexin deficiency in patients with narcolepsy suggests that orexin has a key role in the pathophysiology of cataplexy. The strength of excitatory projections from orexin neurons to noradrenergic neurons in the locus coeruleus is thought to prevent cataplexy in healthy individuals. In patients with narcolepsy orexin deficiency reduces normal levels of noradrenergic neuronal activity, which closely correlates with cataplectic attacks. Drugs that increase noradrenaline levels in CNS are effective in alleviating cataplexy in human, dogs and mice.
Orexin A and orexin B are two different peptides produced by 70/80.000 neurons in the healthy hypoyhalamus in humans. Orexin neurons not only strongly innervate and directly excite noradrenergic, dopaminergic, serotoninergic, histaminergic and cholinergic neurons, but also modulate the release of glutammate and other amino acid transmitters. Behavioural studies revealed that orexin is released at high level during active waking, at intermediate or low levels in quiet but alert waking periods and during REM sleep, and at minimal levels in non-REM sleep.
Electrophysiological recording of neuronal unit activity in narcoplectic dogs shows that most of the brain regions involved in the generation of REM sleep atonia are also involved in episodes of cataplexy. These findings support the concept of cataplexy as an intrusion of REM sleep paralysis into weakfulness. They are not identical, the main difference being the maintenance of consciousness. Preservation of activity of histaminergic neurons during cataplexy but not in REM sleep suggest a function for histamine in maintaining wakefulness during cataplectic episodes.
About amygdala another study indicates that bilateral lesion o amygdala significantly reduce the frequency of cataplectic attacks in Hcrt mice. A population of GABAergic neurons in the amygdala innervates the locus coeruleus, lateral pontine tegmentum and ventrolateral periacqueductal grey, the functions of which are to support muscle tone during wakefulness.
In patients experiencing positive emotions, therefore, GABAergic neurons in the amygdala might become active and in turn inhibit the activity of cells in the locus coeruleus,LPT,vlPAG that would normally maintain waking postural tone.
The medial prefrontal cortex(mPFC) also has a role in triggering cataplexy. Ingesting of palatable foods (for exemple chocolate), which trigger cataplexy in Hcrt+ mice, also activates neurons in the mPFC, and inhibition of mPFC neurons markedly reduces cataplectic attacks associated with positive emotional stimuli. In addition neurons of the mPFC innervate the amygdala and lateral hypothalamus which contain neurons that are active during cataplexy and might innervate brainstem regions incolved in the regulation of muscle tone.
Amygdala Lesions Reduce Cataplexy in Orexin Knock-Out Mice,The Journal of Neuroscience, 5 June 2013
Role of the Medial Prefrontal Cortex in Cataplexy,The Journal of Neuroscience, 5 June 2013
TREATMENT
The inhibitory effect of various antidepressants on the adrenergic system is supported by in vivo and in vitro studies. The effectivness of drugs used to treat cataplexy is difficult to evaluate, as the methods employed to assess the frequency and severity of cataplectic attacks vary from one study to another.
Antidepressants (tricyclic agents and SSRIs (selective serotonin reuptake inhibitors)) are reportedly the most effective drugs to treat cataplexy, decreasing the frequency of cataplectic attacks.
γ -hydroxybutyrate functions as a neurotransmettitor at the GHB receptor at physiological concentrations and as a GABA receptor agonist at pharmacological concentrations, and also modulates dopaminergic signalling.
GHB is effective at reducing both the frequency and intensity of cataplectic attacks, as well as restoring nocturnal sleep continuity and reducing EDS in patients with narcolepsy (with cataplexy). Despite a half-life of only 40-60 min, its clinical benefit persists wll beyond this period, and, unlike antidepressants, interruption of treatment with GHB does not result in a rebound of cataplexy.
Drugs that increase adrenergic and dopaminergic signalling, such as amphetamines, methylphenidate hydrochloride and mazindol also decrease the frequency of cataplectic attacks. A careful cardiological follow-up is required with mazindol and amphetamines.
If we think about the future, orexin replacement therapy could be an effective strategy.
CONCLUSION
To overcome the consequences of narcolepsy and cataplexy, early diagnosis and treatment of patients are essential. Despite a major advance in our understanding of the neurobiology and narcolepsy-cataplexy, there is no cure. Current therapeutic management is only symptomatic, with widespread use if antidepressants and GHB to reduce frequency of cataplectic attacks. The discover of orexin deficiency in humans has led to a new diagnostic test for narcolepsy and might lead, in the future, to orexin replacement therapy. Future therapeutic targets must be focused on immunotherapies at early stages in the disease to prevent the loss of orexin neurons and disease progression.
Bibliography:
Nature reviws neurology, volume 10 July 2014
