Ann Natl Acad Med Sci (India), 49(3&4): 153-160, 2013

Causes of Hypersomnia – Narcolepsy

M.V. Padma Srivastava Department of Neurology All-India Institute of Medical Sciences, New Delhi

ABSTRACT

The causes of hypersomnia or excessive daytime sleepiness (EDS) besides volitional sleep deprivation and obstructive sleep apnea are principally due to primary central nervous system abnormalities. Most common amongst these is Narcolepsy, a primary disorder of the neural control of wakefulness and sleep. The recent discovery of hypocretin/orexin deficiency as the main cause of narcolepsy will lead to important therapeutic advances for patients with narcolepsy and further to understanding of the control of sleep and wakefulness in general. Importantly, the excessive daytime sleepiness is not due to psychiatric conditions, but rather is always due to sleep deprivation or an underlying diagnosable and treatable sleep disorder.

Key words : EDS, Sleep, Narcolepsy

Correspondence : Prof. M.V. Padma Srivastava, Department of Neurology, All-India Institute of Medical Sciences, Ansari Nagar, New Delhi – 110029. E-mail: [email protected] 154 M.V. Padma Srivastava

Volitional sleep deprivation and Signs and Symptoms : obstructive sleep apnea are the most common causes of hypersomnia. The Manifestations of narcolepsy are as remaining causes are primarily due to follows: (1,2) primary central nervous system 1. EDS abnormalities, the most common of which 2. Cataplexy is narcolepsy, a primary disorder of the 3. Hypnogogic hallucinations neural control of wakefulness and sleep. 4. Sleep paralysis

NARCOLEPSY : Excessive Daytime Somnolence (EDS) :

It is the prototypic example of EDS is the primary symptoms of dissociated sleep-wake phenomenon in n a r c o l e p s y w i t h u n w a n t e d a n d which components of one state, ie rapid unanticipated sleep episodes lasting eye movement (REM) sleep, appear in seconds to minutes and occurring at another (wakefulness) (1). inappropriate times, particularly during periods of reduced environmental Narcolepsy is a relatively frequent stimulation, such as reading, watching disorder with a prevalence of 0.09%. A television, riding in or driving or attending clear genetic component is indicated by a class or meeting. During periods of the fact that over 90% of individuals with excessive sleepiness, a brief (10 to 30 narcolepsy carry the HLA DR15 and HLA minute) nap is frequently very refreshing, DQ6 gene, which is found in less than if only for a short period of time. The 30% of the general population. Siblings of symptom of sleepiness is accompanied by individuals with narcolepsy have a 60- failing performance due to impairment of fold increased likelihood for developing sustained attention, at times reflected in a the disease. Narcolepsy if thought to result complaint of impaired memory. The also from abnormal neurotransmitter apparent memory disturbance is functioning and sensitivity and abnormal secondary to impaired attention (1,2,4). immune modulation (1,2,3). Ancillary symptoms of narcolepsy The male to female ratio in i n c l u d e c a t a p l e x y, h y p n o g o g i c narcolepsy is 1.64:1. The usual age of hallucinations, and sleep paralysis. onset of narcolepsy is adolescence or early adulthood, although it ranges from early Cataplexy : childhood to senescence (3 to 72 years of age), with a primary peek in the teens and Cataplexy, which occurs in 65% to a lesser peak in the early 30s. 70% of these patients, comprises of sudden loss of muscle tone, typically triggered by emotion such as laughter, Causes of Hypersomnia – Narcolepsy 155 anger, excitement, delight or surprise. The 3. Paralysis is often accompanied by muscle weakness of cataplexy may be hallucinations complete, resulting in the patients falling 4. Respiratory and extraocular or being forced to sit, much more muscles are spared commonly, the weakness is milder and 5. Paralysis occurs less frequently more focal, taking the form of facial when the person sleep in an sagging, slurred speech or localized uncomfortable position weakness of an extremity. Cataplexy 6. Paralysis can be relieved by may never occur in 30% of patients with sensory stimuli (eg. touching or narcolepsy or may precede the onset of speaking to the person) EDS (1,2,4). Hence the salient features of Hallucinations : Cataplexy are: Hypnogogic (at sleep onset) and 1. If severe and generalized, hypnopompic (upon awakening) cataplexy may cause a fall. hallucinations are noted in 12% to 50% of 2. More subtle forms exist with only cases. The hallucinations are extremely partial loss of tone (eg., head nod vivid and often frightening dreams that and knee bucking) occur during the transition between 3. Respiratory and extraocular wakefulness and sleep. They may be movements are preserved. associated with total body paralysis and 4. Cataplexy is usually triggered by sensations of oppression and dread. These emotions (especially laughter and hallucinations are more frightening than anger) conventional dreams because the dream imagery arises from the real (waking) Sleep Paralysis : environment, making differentiation Sixty percent of individuals with between reality and dreaming difficult narcolepsy experience sleep paralysis (1,2,4,5). upon awakening from REM sleep (usually from a dream). At times, this frightening The following are also common features manifestation consists of total-body of narcolepsy: paralysis, with sparing of respiration and 1. A tendency to take short and of eye movements, lasting from seconds refreshing naps during the day; to minutes (1,2,4). these may be accompanied by dreams. The salient features of Sleep paralysis are: 2. Trouble sleeping at night 1. Usually the patient is unable to 3. Nocturnal compulsive behaviours move upon awakening. (sleep related eating disorder and 2. Less commonly, the patient is nocturnal smoking) unable to move upon falling 4. Obesity asleep with consciousness intact. 156 M.V. Padma Srivastava

Features of Narcolepsy in children are : addition, the DSM-5 identifies five (6) subtypes as follows: 1. Narcolepsy without cataplexy but 1. Restlessness and motor over with hypocretin deficiency activity may predominate 2. Narcolepsy with cataplexy but 2. A c a d e m i c d e t e r i o r a t i o n , without hypocretin deficiency inattentiveness and emotional 3. Autosomal dominant cerebellar lability are common ataxia deafness and narcolepsy 3. At disease onset, children with 4. Atuosomal dominant narcolepsy, narcolepsy and cataplexy may obesity and type 2 diabetes display a wide range of motor 5. Narcolepsy secondary to another disturbances that do not meet the medical condition classic definition of cataplexy. 4. Motor disturbances may be Whenever possible, the diagnosis negative (hypotonia) or active. of narcolepsy should be confirmed by 5. Motor disturbances may resolve polysomnography (PSG) followed by a later in the course of the disorder. multiple sleep latency test (MSLT). The MSLT should show sleep latency 8 Diagnosis : minutes or less and 2 or more SOREMPs. An alternative criterion is a CSF The DSM-5 defines narcolepsy as hypocretin level of 110 pg/ml or lower. recurrent episodes of irrepressible need to The hypersomnia must not be explained as sleep, lapsing or napping occurring within another sleep, neurologic, mental or the same day. These must have been medical condition, or induced by occurring at least three times per week medicine /substance use. over the past 3 months. There must also be presence of at least one of the following Pathophysiology : (1,2,5). 1. Episodes of cataplexy occurring at Narcolepsy is thought to result least a few times per month from genetic predisposition, abnormal 2. Hypocretin deficiency neurotransmitter functioning and 3. REM sleep latency < 15 minutes sensitivity, and abnormal immune or a mean sleep latency < 8 modulation. Current data indicate certain minutes and two or more sleep- human leukocyte antigen (HLA) subtypes onset REM periods (SOREMPs). and abnormal hypocretin (orexin) neurotransmission, which leads to Narcolepsy can be categorized as abnormalities in monoamine and mild, moderate or severe based on the actylcholine synaptic transmission, frequency of cataplexy, need for naps, and particularly in the pontine reticular disturbance of nocturnal sleep. In activating system (3,7). Causes of Hypersomnia – Narcolepsy 157

U n d e r s t a n d i n g o f t h e adjuvant, narcolepsy in Finish children neurochemistry of narcolepsy began with increased 8 to 12 fold. All affected research involving narcoleptic dogs. In children who underwent HLA typing were these animal models, the disorder is found to have the HLA DQB*0602 allele transmitted in an autosomal recessive (3,7). fashion with full penetrance and is characterized mainly by cataplexy. REM Sleep : Muscarinic cholinergic stimulation increases cataplexy in these animals, and Dysfunction and inappropriate cholinergic blockade eliminates the regulation of REM sleep are thought to symptom. Nicotinic agents have no effect exist in narcolepsy. Neuroanatomic on the cataplexy (8). control of REM sleep appears to be localized to the pontine reticular Receptor subtypes such as the activating system. alpha-1-noradrenergic receptor appear to mediate cataplexy. Prazosin, an alpha-1- The brain contains REM-on cells, antagonist, worsens symptoms in canine which fire selectively during REM sleep and human subjects. The pons is not the periods, and REM-off cells, for which the only neuroanatomic site that is converse holds true. Most REM-on cells responsible for mediating cataplexy. The function through cholinergic transmission mesocorticolimbic dopaminergic system whereas REM-off cells are noradrenergic also has been implicated. This connection o r s e r o t o n e rg i c . I n n a r c o l e p s y, with the limbic system in part explains the monoamine-dependent inhibition of relationship of cataplexy to emotion. REM-on cells may be defective (5,4).

The centrality of hypocretin Symptoms can be viewed as REM transmission in the pathophysiology of sleep components intruding into wakeful narcolepsy was demonstrated when states. For example, cataplexy and sleep hypocretin knockout mice displayed paralysis represent an intrusion of REM cataplexy and sleepiness. Further sleep atonia, whereas hallucinations evidence for impaired hypocretin represent an intrusion of dreams. functioning in humans was found with the discovery of low levels of hypocretin in Hypocretin : the CSF of narcoleptic patients (9,10). Hypocretin plays an important Subsequently, abnormal immune role in the pathophysiology of human modulation was associated with the narcolepsy. Patients with narcolepsy have clinical development of narcolepsy in been found to have little or no hypocretin children in Scandinavia and Finland. After in their CSF. Postmortem pathologic vaccination against H1N1 influenza virus examination of the brains of people with with a vaccine using a potent ASO3 n a r c o l e p s y w i t h c a t a p l e x y h a s 158 M.V. Padma Srivastava

demonstrated dramatically reduced to maintain wakefulness. A deficiency of numbers of hypocretin neurons. hypocretin neurons may decrease the Hypocretin deficiency is theorized to threshold for transitioning between produce instability of sleep and wake wakefulness and sleep. This is a proposed states, thereby preventing the persons explanation for the sleepiness and REM from sustaining more continuous sleep or intrusion into wakefulness found in wakefulness. A large majority of patients narcolepsy (9,10). with narcolepsy without cataplexy have normal CSF hypocretin levels (9,10). Destruction of hypocretin- producing neurons appears to be an Investigators have also found low autoimmune process. A specific levels of histamine (that helps maintain autoantigen against Tribbles homolog 2 wakefulness) in the CSF of patients with (Trib2) have been found to be higher in hypocretin-deficient narcolepsy. They are narcolepsy patients with cataplexy than in also seen in narcolepsy patients with normal controls. The autoimmune model normal CSF hypocretin levels and in of narcolepsy inspired trials of patients with idiopathic hypersomnia. intravenous immunoglobulin therapy in Low CSF histamine levels have not been narcoleptic patients with low levels of found in patients with hypersomnia hypocretin – 1. In these trials, IVIG secondary to obstructive sleep apnea reportedly improved cataplexy and syndrome. The CSF histamine level may sleepiness in many cases, but the effects serve as a biomarker reflecting the degree did not last long (11). of hypersomnia of central origin (9,10). Genetic Factors: CNS nuclei for wakefulness and the relevant neurotransmitters generated in The genetics of Narcolepsy are those nuclei include the following: complex. The risk is as high as 40% in the first-degree relatives. 1. Locus ceruleus – Norepinephrine 2. Raphe nucleus – Serotonin There is a striking association 3. Tubomammillary nucleus – between narcolepsy and the HLA Histamine haplotype DQA1*01:02-DQB1*06:02. A 4. Ventral tegmental area – genome wide association study proposed Dopamine a protective variant DQB1*06:03. GWA 5. Basal forebrain – Acetylcholine studies in Caucasians with replication in 3 These areas also inhibit REM sleep. ethnic groups have revealed associations between SNP in the T cell receptor alpha Hypocretin neurons thought to be locus and narcoplepsy. This association autoexcitatory project from the lateral further supports the autoimmune basis of hypothalamus into these regions and serve narcolepsy (3,7). Causes of Hypersomnia – Narcolepsy 159

An SNP in the purinergic receptor M o d a fi n i l i s n o v e l w a k e - subtype P2Y11gene also appears to be promoting agent. The mechanism of associated with Narcolepsy. A GWA study action is not understood, but it does not that investigated 202 candidate genes in a appear to involve altering levels of replication study in 222 narcoleptic dopamine or norepinephrine. Unlike patients and 380 controls identified 6 traditional medications, modafinil does genes that were associated with not appear to affect total sleep time or narcolepsy: NFATC2, SCP2, CACNA1C, suppress REM sleep; the most common TCRA, POLE and FAM3D (3,7). adverse effect is headache. Its safety in children has not been established (11). Management : Armodafinil has fewer side Treatment of Narcolepsy has both effects. It is indicated for the treatment of nonpharmacologic and pharmacologic EDS associated with narcolepsy. TH most components. Sleep hygiene is important. common side effects are headache, Most patients improve if they maintain a nausea, dizziness and difficulty in regular sleep schedule, usually 7.5 to 8 sleeping (11). hours of sleep per night. Scheduled naps during the day also may help (1,2,11). Cataplexy in patients with Pharmacologic treatment of narcolepsy can be treated with the CNS narcolepsy involves the use of central depressant sodium oxybate. Other agents nervous system stimulants such as that are used off-label for cataplexy are m e t h y p h e n i d a t e , m o d a fi n i l , tricyclic antidepressants, selective d e x t r o a m p h e t a m i n e s u l p h a t e , serotonin reuptake inhibitors and methamphetamine and amphetamine. serotonin-norepinephrine reuptake These medications help reduce daytime inhibitors. The strongest evidence is for sleepiness, improving the symptom in clomipramine, fluoxetine and sodium 65% to 85% of patients. In patients for oxybate (11). whom stimulant treatment is problematic, subjective benefit from treatment with codeine has been reported (1,2,11).

M e t h y l p h e n i d a t e w a s t h e stimulant most frequently used for treatment of narcolepsy. It improves sleep tendency in a dose-related fashion. Undesirable side effects include h e a d a c h e , n e r v o u s n e s s , a n d gastrointestinal complaints. Nocturnal sleep may be impaired with a resulting decrease in total sleep time (11). 160 M.V. Padma Srivastava

REFERENCES 7. Aldrich MS (1996). The clinical spectrum of narcolepsy and 1. American Academy of Sleep i d i o p a t h i c h y p e r s o m n i a . M e d i c i n e . I n t e r n a t i o n a l Neurology 46: 393-401. Classification of Sleep Disorders., 2 nd edition. Darien, IL: American 8. Krahn LE, Black JL, Silber MH Academy of Sleep Medicine: ( 2 0 0 1 ) . N a r c o l e p s y : n e w (2005). understanding of irresistible sleep. Mayo Clin Proc 76: 185-194. 2. Plazzi G, Serra L, Ferri R (2008). Nocturnal aspects of narcolepsy 9. Lin L, Faraco J, Li R et al. ( 1999). with cataplexy. Sleep Med Rev The sleep disorder canine 12(2): 109 – 128. narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 3. Mignot E (2004). Sleep, sleep 2 gene. Cell 98: 365 – 376. d i s o r d e r s a n d H y p o c r e t i n (orexin). Sleep Med 5 10. Ripley B, Overeem S, Fujiki N et Suppl 1: S2 – S8. al. (2001). CSF hypocretin/orexin levels in narcolepsy and other 4. Sehgal A, Mignot E (2011). n e u r o l o g i c a l c o n d i t i o n s . Genetics of Sleep and sleep Neurology 57: 2253 – 2258. disorders. Cell 146(2): 194 – 207. 11. R o g e r s A E , M e e h a n J , 5. Lockrane B, Bhatia P, Gore R Guilleminault C et al. (1997). (2005). Successful treatment of H L A D R 1 5 ( D R 2 ) a n d narcolepsy and cataplexy. A DQB1*0602 typing in 188 review Can Respir J 12(4): 225 – n a r c o l e p t i c p a t i e n t s w i t h 227. cataplexy. Neurology 48: 1550 – 1556. 6. Guilleminault C, Pelayo R (1998). Narcolepsy in prepubertal children. Ann Neurol 43(1): 135 – 142.