- Last edited on April 30, 2020
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sleep:4-narcolepsy [on May 20, 2019] |
sleep:4-narcolepsy [on July 7, 2022] (current) psychdb [Narcolepsy Type 2] |
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| == Prevalence == | == Prevalence == | ||
| - | Narcolepsy-cataplexy affects 0.02%-0.04% of the general population in most countries. Narcolepsy affects both genders, with possibly a slight male dominance. | + | * Narcolepsy-cataplexy affects 0.02% to 0.04% of the general population. |
| + | * Narcolepsy type 1 (with cataplexy) has a prevalence between 0.025 to 0.05% | ||
| + | * Narcolepsy type 2 (without cataplexy) has a prevalence between 0.02 to 0.034% | ||
| + | * Narcolepsy affects both genders, with possibly a slight male dominance. | ||
| + | * There is a bimodal age of onset, at ages 15 to 25, and ages 30 to 35.[(American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.)] | ||
| - | ===== Diagnostic Criteria ===== | + | ===== DSM-5 Diagnostic Criteria ===== |
| == Criterion A == | == Criterion A == | ||
| Recurrent periods of an irrepressible need to sleep, lapsing into sleep, or napping occurring within the same day. These must have been occurring at least ''3'' times per week over the past ''3'' months. | Recurrent periods of an irrepressible need to sleep, lapsing into sleep, or napping occurring within the same day. These must have been occurring at least ''3'' times per week over the past ''3'' months. | ||
| Line 13: | Line 17: | ||
| == Criterion B == | == Criterion B == | ||
| The presence of at least ''1'' of the following: | The presence of at least ''1'' of the following: | ||
| - | - Episodes of cataplexy, defined as either (A) or (B), occurring at least a few times per month: (A) In individuals with long-standing disease, brief (seconds to minutes) episodes of sudden bilateral loss of muscle tone with maintained consciousness that are precipitated by laughter or joking, OR (B) In children or in individuals within 6 months of onset, spontaneous grimaces or jaw-opening episodes with tongue thrusting or a global hypotonia, without any obvious emotional triggers. | + | - Episodes of cataplexy, defined as either (A) or (B), occurring at least a few times per month: |
| - | - Hypocretin deficiency, as measured using cerebrospinal fluid (CSF) hypocretin-1 immunoreactivity values (less than or equal to one-third of values obtained in healthy subjects tested using the same assay, or less than or equal to 110 pg/mL). Low CSF levels of hypocretin-1 must not be observed in the context of acute brain injury, inflammation, or infection. | + | * **(A)** In individuals with long-standing disease, brief (seconds to minutes) episodes of sudden bilateral loss of muscle tone with maintained consciousness that are precipitated by laughter or joking, //OR// |
| - | - Nocturnal sleep polysomnography showing rapid eye movement (REM) sleep latency less than or equal to 15 minutes, or a multiple sleep latency test showing a mean sleep latency less than or equal to 8 minutes and two or more sleep-onset REM periods. | + | * **(B)** In children or in individuals within ''6'' months of onset, spontaneous grimaces or jaw-opening episodes with tongue thrusting or a global hypotonia, without any obvious emotional triggers. |
| + | - Hypocretin deficiency, as measured using [[neurology:lumbar-puncture-lp|cerebrospinal fluid (CSF)]] hypocretin-1 immunoreactivity values (less than or equal to one-third of values obtained in healthy subjects tested using the same assay, or less than or equal to ''110'' pg/mL). Low CSF levels of hypocretin-1 must not be observed in the context of acute brain injury, inflammation, or infection. | ||
| + | - Nocturnal sleep [[neurology:polysomnography|polysomnography]] showing rapid eye movement (REM) sleep latency less than or equal to ''15'' minutes, or a multiple sleep latency test (MSLT) showing a mean sleep latency less than or equal to ''8'' minutes and ''two'' or more sleep-onset REM periods. | ||
| <callout type="info" icon="true" title="Narcolepsy Tetrad"> | <callout type="info" icon="true" title="Narcolepsy Tetrad"> | ||
| - | The classic symptoms of narcolepsy, often referred to as the "tetrad of narcolepsy" are: cataplexy (pathognomonic), sleep paralysis (essential), hypnagogic hallucinations, and excessive daytime sleepiness. | + | The classic symptoms of narcolepsy, often referred to as the "tetrad of narcolepsy" are: cataplexy (pathognomonic), [[sleep:2-benign-sleep-phenomena#sleep-paralysis|sleep paralysis (essential)]], hypnagogic hallucinations, and excessive daytime sleepiness. |
| </callout> | </callout> | ||
| == Specifiers == | == Specifiers == | ||
| - | <accordion collapsed="true"> | + | <WRAP group> |
| + | <WRAP half column> | ||
| <panel icon="fa fa-search-plus" size="xs" title="Specifiers"> | <panel icon="fa fa-search-plus" size="xs" title="Specifiers"> | ||
| **Specify if:** | **Specify if:** | ||
| - | * **Narcolepsy without cataplexy but with hypocretin deficiency**: Criterion B requirements of low CSF hypocretin-1 levels and positive polysomnography/ multiple sleep latency test are met, but no cataplexy is present (Criterion B1 not met). | + | * **Narcolepsy without cataplexy but with hypocretin deficiency**: Criterion B requirements of low CSF hypocretin-1 levels and positive polysomnography/multiple sleep latency test are met, but no cataplexy is present (Criterion B1 not met). |
| * **Narcolepsy with cataplexy but without hypocretin deficiency**: In this rare subtype (less than 5% of narcolepsy cases), Criterion B requirements of cataplexy and positive polysomnography/multiple sleep latency test are met, but CSF hypocretin-1 levels are normal (Criterion B2 not met). | * **Narcolepsy with cataplexy but without hypocretin deficiency**: In this rare subtype (less than 5% of narcolepsy cases), Criterion B requirements of cataplexy and positive polysomnography/multiple sleep latency test are met, but CSF hypocretin-1 levels are normal (Criterion B2 not met). | ||
| * **Autosomal dominant cerebellar ataxia, deafness, and narcolepsy**: This subtype is caused by exon 21 DNA (cytosine-5)-methyltransferase-1 mutations and is characterized by late-onset (age 30-40 years) narcolepsy (with low or intermediate CSF hypocretin-1 levels), deafness, cerebellar ataxia, and eventually dementia. | * **Autosomal dominant cerebellar ataxia, deafness, and narcolepsy**: This subtype is caused by exon 21 DNA (cytosine-5)-methyltransferase-1 mutations and is characterized by late-onset (age 30-40 years) narcolepsy (with low or intermediate CSF hypocretin-1 levels), deafness, cerebellar ataxia, and eventually dementia. | ||
| - | * **Autosomal dominant narcolepsy, obesity, and type 2 diabetes**: Narcolepsy, obesity, and type 2 diabetes and low CSF hypocretin-1 levels have been described in rare cases and are associated with a mutation in the myelin oligodendro cyte glycoprotein gene. | + | * **Autosomal dominant narcolepsy, obesity, and type 2 diabetes**: Narcolepsy, obesity, and type 2 diabetes and low CSF hypocretin-1 levels have been described in rare cases and are associated with a mutation in the myelin oligodendrocyte glycoprotein gene. |
| * **Narcolepsy secondary to another medical condition**: This sub type is for narcolepsy that develops secondary to medical conditions that cause infectious (e.g., Whipple’s disease, sarcoidosis), traumatic, or tumoral destruction of hypocretin neurons. | * **Narcolepsy secondary to another medical condition**: This sub type is for narcolepsy that develops secondary to medical conditions that cause infectious (e.g., Whipple’s disease, sarcoidosis), traumatic, or tumoral destruction of hypocretin neurons. | ||
| </panel> | </panel> | ||
| + | </WRAP> | ||
| + | <WRAP half column> | ||
| <panel icon="fa fa-signal" size="xs" title="Severity Specifier"> | <panel icon="fa fa-signal" size="xs" title="Severity Specifier"> | ||
| **Specify if:** | **Specify if:** | ||
| Line 37: | Line 46: | ||
| * **Severe**: Drug-resistant cataplexy with multiple attacks daily, nearly constant sleepiness, and disturbed nocturnal sleep (i.e., movements, insomnia, and vivid dreaming). | * **Severe**: Drug-resistant cataplexy with multiple attacks daily, nearly constant sleepiness, and disturbed nocturnal sleep (i.e., movements, insomnia, and vivid dreaming). | ||
| </panel> | </panel> | ||
| - | </accordion> | + | </WRAP> |
| + | </WRAP> | ||
| - | ===== Pathophysiology ===== | + | ==== Signs and Symptoms ==== |
| - | Narcolepsy-cataplexy nearly always results from the loss of hypothalamic hypocretin (orexin)-producing cells, causing hypocretin deficiency. The loss is likely due to autoimmune causes. | + | * [[sleep:2-benign-sleep-phenomena|Hypnagogic and hypnopompic hallucinations]] can occur in up to 30% of individuals with narcolepsy.[([[https://www.ncbi.nlm.nih.gov/pubmed/8894197|Ohayon, M. M., Priest, R. G., Caulet, M., & Guilleminault, C. (1996). Hypnagogic and hypnopompic hallucinations: pathological phenomena?. The British Journal of Psychiatry, 169(4), 459-467.]])]. |
| + | * These are usually visual and involve elements of the individual's environment. | ||
| + | * Individuals with narcolepsy may also experience sleep paralysis. | ||
| - | ===== Investigations ===== | + | ===== ICSD-3 Diagnostic Criteria ===== |
| + | The International Classification of Sleep Disorders, third edition (ICSD-3) criteria for narcolepsy is as follows: | ||
| + | ==== Narcolepsy Type 1 ==== | ||
| + | For Narcolepsy Type 1 (also known as: Hypocretin deficiency syndrome, narcolepsy-cataplexy, narcolepsy with cataplexy), ''Criteria A'' and ''B'' must be met: | ||
| - | ==== Hypocretin (Orexin) ==== | + | == Criterion A == |
| - | Cerebrospinal Fluid (CSF) hypocretin-1 measurement is the gold standard. A lumbar puncture is performed to obtain CSF. Hypocretin deficiency is diagnosed when there is less than or equal to one-third of control values, or 110 pg/mL in most laboratories). Very rarely, low CSF levels of hypocretin-1 can occur without cataplexy, mostly in youths who may develop cataplexy later. It is important to remember that associated severe conditions (neurological, inflammatory, infectious, trauma) that can interfere with the assay. | + | The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least ''3'' months. |
| - | ==== Genotyping (DQB1*06:02) ==== | + | == Criterion B == |
| - | Approximately 99% of affected individuals carry HLA-DQBl*06:02. Genotyping for the presence of DQB1*06:02 prior to a lumbar puncture for evaluation of CSF hypocretin-1 immunoreactivity may be useful. | + | The presence of ''one or both'' of the following: |
| + | - Cataplexy (as defined under Essential Features) //and// a mean sleep latency of ≤ ''8'' minutes //and// ''2'' or more sleep onset REM periods (SOREMPs) on an MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal polysomnogram may replace one of the SOREMPs on the MSLT. | ||
| + | - CSF hypocretin-1 concentration, measured by immunoreactivity, is either ≤ 110 pg/mL or <1/3 of mean values obtained in normal subjects with the same standardized assay. | ||
| - | ==== Polysomnography ==== | + | <callout title="Notes"> |
| - | Nocturnal polysomnography (PSG) followed by an MSLT is also used to confirm the diagnosis, prior to treatment or if there is no measured hypocretin deficiency. The test should be performed in the absence of psychotropic drugs and after regular sleep-wake patterns have been documented. | + | * In young children, narcolepsy may sometimes present as excessively long night sleep or as resumption of previously discontinued daytime napping. |
| + | * If narcolepsy type 1 is strongly suspected clinically but the MSLT criteria of B1 are not met, a possible strategy is to repeat the MSLT. | ||
| + | </callout> | ||
| - | ===== Treatment ===== | + | ==== Narcolepsy Type 2 ==== |
| - | Treatment is usually with a stimulants, including amphetamines such as [[meds:stimulants:amphetamine:dextroamphetamine|dextroamphetamine]] and [[meds:stimulants:2-methylphenidate:home|[[meds:stimulants:2-methylphenidate|methylphenidate]]]] are common. Wakefulness promoting agents like modafinil may also be used. | + | For Narcolepsy Type 2 (also known as: narcolepsy without cataplexy), ''Criteria A'' to ''E'' must be met: |
| + | |||
| + | == Criterion A == | ||
| + | The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months. | ||
| + | |||
| + | == Criterion B == | ||
| + | A mean sleep latency of ≤ 8 minutes and 2 or more sleep onset REM periods (SOREMPs) are found on a MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal polysomnogram may replace one of the SOREMPs on the MSLT. | ||
| + | |||
| + | == Criterion C == | ||
| + | Cataplexy is absent. | ||
| + | |||
| + | == Criterion D == | ||
| + | Either CSF hypocretin-1 concentration has not been measured or CSF hypocretin-1 concentration measured by immunoreactivity is either > 110 pg/mL or > 1/3 of mean values obtained in normal subjects with the same standardized assay. | ||
| + | |||
| + | == Criterion E == | ||
| + | The hypersomnolence and/or MSLT findings are not better explained by other causes such as insufficient sleep, obstructive sleep apnea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal. | ||
| + | |||
| + | <callout title="Notes"> | ||
| + | * If cataplexy develops later, then the disorder should be reclassified as narcolepsy type 1. | ||
| + | * If the CSF Hcrt-1 concentration is tested at a later stage and found to be either ≤ 110 pg/mL or < 1/3 of mean values obtained in normal subjects with the same assay, then the disorder should be reclassified as narcolepsy type 1. | ||
| + | </callout> | ||
| + | |||
| + | ===== Narcolepsy Type 1 vs. Type 2 ===== | ||
| + | <panel type="info" title="Narcolepsy Type 1 vs. Type 2" subtitle="" no-body="true" footer="* = Sleep onset REM periods (SOREMPs) are REM sleep periods that occur within 15 minutes of sleep onset."> | ||
| + | <mobiletable 1> | ||
| + | ^ Type ^ Narcolepsy Type 1 ^ Narcolepsy Type 2 ^ | ||
| + | ^ Formerly called | Narcolepsy with cataplexy | Narcolepsy without cataplexy | | ||
| + | ^ Description | People diagnosed with type 1 narcolepsy have an 85% to 95% reduction in the number of neurons that produce orexins. HLA haplotype DQB1*0602 is present in 95% of narcolepsy type 1 patients, but this is also present in about 20% of the general population without narcolepsy. | The pathophysiology of narcolepsy type 2 is not well understood. | | ||
| + | ^ Polysomnogram | Sleep onset REM periods (SOREMPs) may be present.* | Sleep onset REM periods (SOREMPs) may be present.* | | ||
| + | ^ Multiple Sleep Latency Test (MSLT) | Sleep onset latency (SOL) must be <8 minutes and 2 SOREMPs are required (one may be substituted from previous night PSG) | Sleep onset latency (SOL) must be <8 minutes and 2 SOREMPs are required (one may be substituted from previous night PSG) | | ||
| + | ^ Cataplexy | Yes | No | | ||
| + | ^ CSF Orexin-1 | <110pg/mL or <1/3 of mean values | >110pg/mL or >1/3 of mean values | | ||
| + | </mobiletable> | ||
| + | </panel> | ||
| + | |||
| + | ===== Cataplexy ===== | ||
| + | * Cataplexy is a sudden, brief loss of voluntary muscle tone, and often can be triggered by strong emotions such as laughing. Importantly, the individual retains full awareness and alertness during the episode, and there is no confusion before or after the event (i.e. - not a [[neurology:approach-seizures|seizure]]). Cataplexy is thought to result from //intrusion// of REM sleep paralysis into a state of wakefulness | ||
| + | * Cataplexy is defined by the ICSD-3 as more than 1 episode of generally brief (<2 minutes) and usually bilaterally symmetrical sudden loss of muscle tone with retained consciousness. | ||
| + | * Cataplexy typically develops several years after onset of sleepiness symptoms and occurs in about 70% of individuals with narcolepsy | ||
| + | * The episodes are precipitated by strong emotions, usually positive, with almost all patients reporting some episodes being precipitated by emotions associated with laughter | ||
| + | * During an episode, if observed, transient reversible loss of deep tendon reflexes is a strong diagnostic finding. | ||
| + | * In children (and rarely in adults), cataplexy may present close to disease onset as facial (or generalized) hypotonia with droopy eyelids, mouth opening, and protruded tongue, or gait unsteadiness, which clearly are not related to emotion. | ||
| + | ==== "Sleep Attacks" ==== | ||
| + | * Sleep attacks are different from episodes of cataplexy, and not the same thing! | ||
| + | * These attacks involve irresistible urges to sleep that last usually for 10 to 20 minutes | ||
| + | * However, can last as long as an hour | ||
| + | * An individual will have between 2 to 6 episodes of these sleep attacks each day (whether intentional or unintentional) | ||
| + | * The sleep episodes are restorative, but sleepiness usually returns within several hours | ||
| + | |||
| + | ===== Pathophysiology ===== | ||
| + | * Narcolepsy-cataplexy nearly always is due to the loss of hypothalamic hypocretin (also known as orexin)-producing cells, causing a orexin (hypocretin) deficiency. | ||
| + | * Orexin is a neuropeptide, and is made in the lateral hypothalamus and promotes wakefulness (associated with the locus coeruleus, raphe nuclei and tuberomamillary nucleus) | ||
| + | * The loss of orexin signalling can be due to multiple causes including autoimmune causes, traumatic brain injuries, viral infections, or streptococcal infection. | ||
| - | Symptoms of cataplexy, sleep paralysis, and hypnagogic phenomena may be treated with tricyclic antidepressants such as [[meds:antidepressants:tca:imipramine|imipramine]], [[meds:antidepressants:tca:desipramine|desipramine]]) or [[meds:antidepressants:ssri:home|selective serotonin reuptake inhibitors]]. Cataplexy may also be treated with sodium oxybate, but because of potential abuse, this medication is highly regulated. | ||
| ===== Differential Diagnosis ===== | ===== Differential Diagnosis ===== | ||
| * Other hypersomnias | * Other hypersomnias | ||
| Line 67: | Line 137: | ||
| * Chorea and movement disorders | * Chorea and movement disorders | ||
| * Schizophrenia | * Schizophrenia | ||
| + | |||
| + | ===== Investigations ===== | ||
| + | |||
| + | ==== Hypocretin (Orexin) ==== | ||
| + | Cerebrospinal Fluid (CSF) hypocretin-1 measurement is the gold standard. A lumbar puncture is performed to obtain CSF. Hypocretin deficiency is diagnosed when there is less than or equal to one-third of control values, or 110 pg/mL in most laboratories). Very rarely, low CSF levels of hypocretin-1 can occur without cataplexy, mostly in youths who may develop cataplexy later. It is important to remember that associated severe conditions (neurological, inflammatory, infectious, trauma) that can interfere with the assay. | ||
| + | |||
| + | ==== Genotyping (DQB1*06:02) ==== | ||
| + | * Approximately 99% of affected individuals with narcolepsy plus cataplexy will carry the HLA-DQBl*06:02. | ||
| + | * However, it is only present in about 40% of those with narcolepsy without cataplexy (and 20 to 25% in the general population) | ||
| + | * Genotyping for the presence of DQB1*06:02 prior to a lumbar puncture for evaluation of CSF hypocretin-1 immunoreactivity may be useful. | ||
| + | |||
| + | ==== Polysomnography ==== | ||
| + | * Nocturnal polysomnography (PSG) followed by an MSLT is also used to confirm the diagnosis, prior to treatment or if there is no measured hypocretin deficiency. The test should be performed in the absence of psychotropic drugs and after regular sleep-wake patterns have been documented. | ||
| + | |||
| + | ===== Treatment ===== | ||
| + | ==== Non-pharmacological ==== | ||
| + | * Good sleep hygiene (scheduled naps, regular sleep schedule) | ||
| + | ==== Pharmacological ==== | ||
| + | * Treatment for excessive daytime sleepiness alone is usually managed with a stimulant, including: | ||
| + | * [[meds:stimulants:amphetamine:dextroamphetamine|Dextroamphetamine]] 5 to 30 mg BID | ||
| + | * [[meds:stimulants:2-methylphenidate:home|methylphenidate]] 10 mg to 30 mg BID | ||
| + | * Modafinil (wakefulness promoting agent) 100 to 400 mg PO daily or divided doses may also be used for daytime sleepiness, but it is not first line for cataplexy. | ||
| + | * In cataplexy with REM intrusions, sleep paralysis, and/or [[sleep:2-benign-sleep-phenomena|hypnagogic hallucinations]] this can be treated with: | ||
| + | * [[meds:antidepressants:tca:home|Tricyclic antidepressants]] such as [[meds:antidepressants:tca:imipramine|imipramine]], [[meds:antidepressants:tca:desipramine|desipramine]] | ||
| + | * [[meds:antidepressants:ssri:home|Selective serotonin reuptake inhibitors (SSRIs)]] | ||
| + | * [[meds:antidepressants:snri:home|Selective noepinephrine reuptake inhibitors (SNRIs)]], such as venlafaxine | ||
| + | * In those with cataplexy with combined daytime sleepiness, they may be treated with sodium oxybate (the sodium salt of γ-hydroxybutyric acid, or GHB), but because of the potential for abuse, this medication is highly regulated. | ||
| ===== Resources ===== | ===== Resources ===== | ||
| Line 72: | Line 169: | ||
| <WRAP group> | <WRAP group> | ||
| <WRAP quarter column> | <WRAP quarter column> | ||
| - | ==== For Patients ==== | + | == For Patients == |
| * [[https://med.stanford.edu/narcolepsy/faq1.html|Stanford Medicine: Narcolepsy Research - FAQs]] | * [[https://med.stanford.edu/narcolepsy/faq1.html|Stanford Medicine: Narcolepsy Research - FAQs]] | ||
| + | * [[http://healthysleep.med.harvard.edu/narcolepsy/|Harvard Medical School: Narcolepsy]] | ||
| </WRAP> | </WRAP> | ||
| <WRAP quarter column> | <WRAP quarter column> | ||
| - | ==== For Providers ==== | + | == For Providers == |
| + | * **[[https://www.nature.com/articles/s41582-019-0226-9?proof=t|Bassetti, C. L. et al. (2019). Narcolepsy—clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nature Reviews Neurology, 15(9), 519-539.]]** | ||
| + | * **[[https://www.nature.com/articles/nrdp2016100|Kornum, B. R. et al. (2017). Narcolepsy. Nature reviews Disease primers, 3(1), 1-19.]]** | ||
| * [[https://med.stanford.edu/narcolepsy/faq1.html|Stanford Medicine: Narcolepsy Research - FAQs]] | * [[https://med.stanford.edu/narcolepsy/faq1.html|Stanford Medicine: Narcolepsy Research - FAQs]] | ||