خدار

(تم التحويل من Numbness)
هذا المقال هو عن the medical condition. إذا كنت تريد الاستخدامات الأخرى، انظر خدار (توضيح).
خدار
The concentration of orexin-A neuropeptides in the cerebrospinal fluid of individuals with narcolepsy type 1 is usually very low
التحضير لإجراء رسم نوم متعدد polisomnografía لمريض طفل.
النطق
التخصصSleep medicine, neurology
الأعراضExcessive daytime sleepiness, involuntary sleep episodes, sudden loss of muscle strength, hallucinations[1]
المضاعفاتMotor vehicle collisions, falls[1]
البداية المعتادةAdolescence[1]
المدةLifelong[1]
الأنواعType 1 (NT1), Type 2 (NT2), Secondary Narcolepsy[1]
المسبباتOrexin deficiency[1]
عوامل الخطرNT1: Family history Secondary Narcolepsy: brain injury[1]
الطريقة التشخيصيةBased on the symptoms, sleep studies(PSG + MSLT) NT1: genetic testing and/or lumbar puncture [1]
التشخيص المفاضلSleep apnea, major depressive disorder, anemia, heart failure, drinking alcohol, idiopathic hypersomnia, sleep deprivation,[1] Kleine-Levin syndrome
العلاجMedication, regular short naps, sleep hygiene[1]
الدواءStimulants (modafinil, pitolisant, solriamfetol, methylphenidate, amphetamine), sodium oxybate, mixed oxybate salts, serotonin reuptake inhibitors[1]
التردد0.2 to 600 per 100,000[2]

الخُدَار أو التغفيق Narcolepsy حالة مرضية تُسبب نومًا مفرطًا. تنتاب المصابين بالخدار نوبات نوم عدة مرات في النهار حتى وإن ناموا في الليل. وسبب هذا المرض غير معروف، ولكن هناك دلائل كثيرة تبين أنه حالة وراثية. ويستعين الأطباء على تخفيفه بالأدوية إلا أنه لا علاج له.

وللخدار أعراض شتى، إضافة إلى النوم المفرط. فمثلا، قد يعاني المصابون بالخدار عوارض (نوبات) يكونون فيها مستيقظين ولكنهم لايستطيعون التحرك. وتُسمَّى هذه الحالة الإغماء التخشُّبي. وتحدث معظم العوارض نتيجة لانفعالات شديدة، خصوصا الغضب أو الضحك، وتستمر لدقيقتين أو أقل. كما قد يعاني المصاب بالخدار شلل النوم والهلوسة النعاسية. ففي شلل النوم، لايستطيع المصاب التحرك مباشرة بعد النوم. أما الهلوسة النعاسية، فهي أحلام مفعمة بالحيوية والواقعية تحدث عند بداية النوم.

ويعتقد العلماء أن أعراض الخدار مرتبطة بنوم حركة العين السريعة، وهي مرحلة من مراحل النوم التي يحلم الناس خلالها. تدور العيون بسرعة في هذه المرحلة ويُشلُّ الجسم أثناء الحلم. ويعاني المصابون بالخدار هذا النوع من الشلل نفسه وهم مستيقظون أثناء حالة الإغماء التخشبي. وإضافة إلى ذلك، فإنهم ينزعون إلى نوم حركة العين السريعة في أوقات غير عادية، خصوصا عند بداية النوم. وفي هذه الحالات، قد تبدو أحلام حركة العين السريعة كأنها هلوسة نعاسية.

ليس جميع من يصيبهم نعاس غير مألوف مصابين بالخدار، لكن إذا عانوا الإغماء التخشبي فهم تقريبا مصابون بالخدار.

أسباب الخدار

البنية البلورية ل HLA-DQ 0602 (جزيء مرمز DQA1*0102/DQB1*0602) في اتحاد مع كايپوكرتين پپتيد (orexina). HLA-DQ 0602 يجعل الشخص أكثر عرض بدرجة كبيرة للخدار، بينما يقي من مرض السكري من النوع الأول.[3][4]

إن العوامل الفسيولوجية ، والتغيرات العصبية الكيميائية ، والعوامل الوراثية ، والعوامل البيئية كلها قد تلعب دورًا في النشأة المرضية للخدار . إن الاضطراب في حالة النوم واليقظة هو أصل الخلل الفسيولوجي الذي يحدث في زملة الخدار ، وإن علامة الاختبار الفسيولوجي هي وجود نوم الحركة السريعة للعينين عند بداية النوم ، ويتسم الفقدان المفاجئ للنبض العضلي باليقظة في رسام المخ الكهربائي الذي يرتبط بالارتخاء العضلي لنوم الحركة السريعة للعينين دون أي سمات أخرى ، وعندما تطول تلك الأحداث يحدث نوم كامل في نوم الحركة السريعة للعينين .

الاضطراب العصبي الكيميائي يعد هو الأساس في الخدار غير معلوم المنشأ ، ومن ناحية أخرى فإن هناك دلائل تشير إلى حدوث عدم توازن في التنظيم الكيميائي بين الكولينرجيك cholinergic والكيت كولا مينيرجيك catecholaminergic مما يؤدي إلى تداخل آليات تنظيم نوم الحركة السريعة للعينين rapid eye movement sleep في جذع المخ ، إن الجرعات الصغيرة من عقار الكولينرجيك لحالات الخدار تزيد من التوقف المفاجئ للنبض العضلي ، في حين أن ذلك لم يحدث لدى الكلاب التي لم يتم حقنها بعقار الاتروبين atropine وأسكوبولامين scopolamine فيؤدي إلى خفض التوقف المفاجئ للنبض العضلي.

التشخيص

The third edition of the International Classification of Sleep Disorders (ICSD-3) differentiates between narcolepsy with cataplexy (type 1) and narcolepsy without cataplexy (type 2), while the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the diagnosis of narcolepsy to refer to type 1 narcolepsy only. The DSM-5 refers to narcolepsy without cataplexy as hypersomnolence disorder.[5] The most recent edition of the International Classification of Diseases, ICD-11, currently identifies three types of narcolepsy: type 1 narcolepsy, type 2 narcolepsy, and unspecified narcolepsy.[6]

ICSD-3 diagnostic criteria posit that the individual must experience "daily periods of irrepressible need to sleep or daytime lapses into sleep" for both subtypes of narcolepsy.[5] This symptom must last for at least three months. For a diagnosis of type 1 narcolepsy, the person must present with either cataplexy, a mean sleep latency of less than 8 minutes, and two or more sleep-onset REM periods (SOREMPs), or they must present with a hypocretin-1 concentration of less than 110 pg/mL.[5] A diagnosis of type 2 narcolepsy requires a mean sleep latency of less than 8 minutes, two or more SOREMPs, and a hypocretin-1 concentration of more than 110 pg/mL. In addition, the hypersomnolence and sleep latency findings cannot be better explained by other causes.[5]

DSM-5 narcolepsy criteria requires that the person to display recurrent periods of "an irrepressible need to sleep, lapsing into sleep, or napping" for at least three times a week over three months.[5] The individual must also display one of the following: cataplexy, hypocretin-1 concentration of less than 110 pg/mL, REM sleep latency of less than 15 minutes, or a multiple sleep latency test (MSLT) showing sleep latency of less than 8 minutes and two or more SOREMPs.[5] For a diagnosis of hypersomnolence disorder, the individual must present with excessive sleepiness despite at least 7 hours of sleep as well as either recurrent lapses into daytime sleep, nonrestorative sleep episodes of 9 or more hours, or difficulty staying awake after awakening. In addition, the hypersomnolence must occur at least three times a week for three months, and must be accompanied by significant distress or impairment. It also cannot be explained by another sleep disorder, coexisting mental or medical disorders, or medication.[7]

الاختبارات

Diagnosis is relatively easy when all the symptoms of narcolepsy are present, but if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult. Three tests that are commonly used in diagnosing narcolepsy are polysomnography (PSG), the multiple sleep latency test (MSLT), and the Epworth Sleepiness Scale (ESS). These tests are usually performed by a sleep specialist.[8] Polysomnography involves the continuous recording of sleep brain waves and a number of nerve and muscle functions during nighttime sleep. When tested, people with narcolepsy fall asleep rapidly, enter REM sleep early, and may often awaken during the night. The polysomnogram also helps to detect other possible sleep disorders that could cause daytime sleepiness.[citation needed]

The Epworth Sleepiness Scale is a brief questionnaire that is administered to determine the likelihood of the presence of a sleep disorder, including narcolepsy.[9] The multiple sleep latency test (MSLT) is performed after the person undergoes an overnight sleep study. The test consists of four to five scheduled nap opportunities at two-hour intervals in a sleep laboratory, during which sleep is not permitted between naps. Sleep latency (the time it takes to fall asleep) is measured during each nap trial. Individuals with narcolepsy typically exhibit shorter sleep latencies and enter REM sleep earlier than average, which is considered a key diagnostic feature of the disorder. [10] Measuring orexin levels in a person's cerebrospinal fluid sampled in a spinal tap may help in diagnosing narcolepsy, with abnormally low levels serving as an indicator of the disorder.[11] This test can be useful when MSLT results are inconclusive or difficult to interpret.[12]

علاج المرض

استبدال أوركسين

People with narcolepsy can be substantially helped but not cured; however, the technology exists in early form such as experiments in using the prepro-orexin transgene via gene editing restored normal function in mice models by making other neurons produce orexin after the original set have been destroyed, or replacing the missing orexinergic neurons with hypocretin stem cell transplantation, are both steps in that direction for fixing the biology effectively permanently once applied in humans.[13][14] Additionally effective ideal non-gene editing and chemical-drug methods involve hypocretin treatments methods such as future drugs like hypocretin agonists (such as danavorexton)[15] or hypocretin replacement, in the form of hypocretin 1 given intravenous (injected into the veins), intracisternal (direct injection into the brain), and intranasal (sprayed through the nose), the latter being low in efficacy, at the low amount used in current experiments but may be effective at very high doses in the future.[16][17]

السلوكي

General strategies like people and family education, sleep hygiene, medication adherence, and discussion of safety issues, for example driving license, can be useful. Potential side effects of medication can also be addressed.[18] Regular follow-up is useful to be able to monitor the response to treatment, to assess the presence of other sleep disorders like obstructive sleep apnea, and to discuss psychosocial issues.[18] In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS, but only improve symptoms for a short duration. A 120-minute nap provided benefit for 3 hours in the person's alertness whereas a 15-minute nap provided no benefit.[19] Daytime naps are not a replacement for night time sleep. Ongoing communication between the health care provider, the person, and their family members is important for optimal management of narcolepsy.

الأدوية

بالرغم من أنه لا يوجد علاج يشفي من هذا المرض إلا أنه يمكن السيطرة على أكثر الأعراض في أغلب الحالات. إذ تسهم المنبهات والمثيرات بدور فعال في علاج هجمات نوم الخدار ، إذ وجد أن حوالي 65 – 85 % من المرضى تتحسن لديهم حالة الرغبة المفرطة في النوم من خلال تلك المنبهات ، وتشتمل العقاقير المنبهة على عقار ديكسترو- أمفيتامين dextroamphetamin ، وميثيل فينيدات أو ريتالين methylphenidate ، و بيمولين Pemoline وظهر حالياً عقار جديد يعرف بـ مودافينيل Modeafinil . ويشجع أيضًا استخدام عقار ميثيل فينيدات methylphenidat ، ونجد أن عقار پمولين Pemoline يستخدم مع ذوي الرغبة البسيطة في النوم بجرعات تبدأ تتراوح ما بين 18.75 -37.50 مجم في الصباح.

العثور على نمط يمثل رسم نوم متعدد لموجات المخ أثناء نوم حركة العين السريعة.

أما عقار ميثيل فينيدات أو ريتالين فيعطي بجرعة تصل لـ 5 مجم يتم تقسيمها على مرتين أو ثلاث مرات في اليوم الواحد ، ولتجنب الأرق لا يتم تناول الجرعة الأخيرة بعد الساعة الرابعة مساءاً ، أما المرضي الذين لا يستجيبون لتلك العقاقير فيحل محلها عقار ديكسترو- أمفيتامين بجرعات تبدأ من 5 -10مجم مرة أو مرتين يومياً ، أما الحد الأقصى المقبول من عقار بيمولين فهو 150مجم يومياً ، و 50 مجم من عقار ميثيل فينيدات ، و50 مجم لكلاً من ديكسترو -أمفيتامين وعقار ميثيل فينيدات وأكثر التأثيرات الجانبية لتلك العقاقير هي العصبية ، والأرق ، والهياج ، القلق ، والصداع ، والأعراض المعدي معوية وسرعة نبضات القلب والارتجاف ، ويلاحظ أن مدى التحمل Tolerance يعد مشكلة أخرى تظهر لدى 30 % من المرضى خصوصاً الذين يتعاطون جرعات زائدة.

ويعد عقار مودافينيل modafinil المثير لليقظة علاج فعال للرغبة المفرطة في النوم المرتبطة بالخدار وجرعة هذا العقار هي 200مجم في الصباح قبل الإفطار أو بعده بساعة وتشتمل تأثيراته الجانبية على الصداع ، والإغماء ، والأرق ، والقلق ، والعصبية . إن هذا العقار قد يتفاعل مع العقاقير التي تعوق أو تؤدي إلى ظهور بعض الأنزيمات مثل diphenylhydantioin diazepam & propranolol 101 إن علاج الخدار أو الأعراض المساعدة لم يشتمل على أداء ثلاثية مضادات الاكتئاب مثل Protriptyline الذي تبدأ جرعته بـ 5 مجم يومياً ، أما عقار imipramine ، فتبدأ جرعته من 25، وحتي200 مجم ، وعقار clomipramine 10-200 مجم يومياً ، ويتم بنجاح استخدام بعض معوقات امتصاص السيروتونين serotonin مثل فلوكستين fluoxetine وتبدأ جرعته بـ 20 مجم في الصباح.

كما أن العلاجات اللادوائية للخدار تشتمل على الانتظام الكامل في مواعيد النوم والاستيقاظ وفي نظام الحياة بصورة عامة ، والقيلولة لفترة بسيطة نهاراً، أو أخذ غفوات قصيرة (10-15 دقيقة) عند الشعور بالنعاس الشديد إذا سمحت الظروف.

الأطفال

انظر أيضاً: النوم القهري في الأطفال

Common behavioral treatments for childhood narcolepsy include improved sleep hygiene, scheduled naps, and physical exercise.[20] Many medications are used to treat adults and may be used to treat children. These medications include central nervous system stimulants such as methylphenidate, modafinil, amphetamine, and dextroamphetamine.[21] Other medications, such as sodium oxybate[22] or atomoxetine, may also be used to counteract sleepiness. Medications such as sodium oxybate, venlafaxine, fluoxetine, and clomipramine may be prescribed if the child presents with cataplexy.[23]

الوبائيات

Estimates of frequency range from 0.2 per 100,000 in Israel to 600 per 100,000 in Japan.[2] These differences may be due to how the studies were conducted or the populations themselves.[2] In the United States, narcolepsy is estimated to affect as many as 200,000 Americans, but fewer than 50,000 are diagnosed. The prevalence of narcolepsy is about 1 per 2,000 persons.[24] Narcolepsy is often mistaken for depression, epilepsy, the side effects of medications, poor sleeping habits or recreational drug use, making misdiagnosis likely.[citation needed] While narcolepsy symptoms are often confused with depression, there is a link between the two disorders. Research studies have mixed results on co-occurrence of depression in people with narcolepsy, as the numbers quoted by different studies are anywhere between 6% and 50%.[25]

Narcolepsy can occur in both men and women at any age, although typical symptom onset occurs in adolescence and young adulthood. There is about a ten-year delay in diagnosing narcolepsy in adults.[26] Cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented. For these to occur in the crucial teen years, when education, development of self-image, and development of occupational choice are taking place, is especially devastating. While cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence.[27]

المجتمع والثقافة

انظر أيضاً: List of people with narcolepsy

In 2015, it was reported that the British Department of Health was paying for sodium oxybate medication at a cost of £12,000 a year for 80 people who are taking legal action over problems linked to the use of the Pandemrix swine flu vaccine. Sodium oxybate is not available to people with narcolepsy through the National Health Service.[28]

الاسم

The term "narcolepsy" is from the French narcolepsie.[29] The French term was first used in 1880 by Jean-Baptiste-Édouard Gélineau, who used the Greek νάρκη (narkē), meaning "numbness", and λῆψις (lepsis) meaning "attack".[29]

الأبحاث

انظر أيضاً: List of investigational narcolepsy and hypersomnia drugs

GABA-directed medications

Given the possible role of hyperactive GABAA receptors in the primary hypersomnias (narcolepsy and idiopathic hypersomnia), medications that could counteract this activity are being studied to test their potential to improve sleepiness. These currently include clarithromycin and flumazenil.[30][31]

Flumazenil

Flumazenil is the only GABAA receptor antagonist on the market as of January 2013, and it is currently manufactured only as an intravenous formulation. Given its pharmacology, researchers consider it a promising medication in the treatment of primary hypersomnias. Results of a small, double-blind, randomized, controlled clinical trial were published in November 2012. This research showed that flumazenil provides relief for most people whose CSF contains the unknown "somnogen" that enhances the function of GABAA receptors, making them more susceptible to the sleep-inducing effect of GABA. For one person, daily administration of flumazenil by sublingual lozenge and topical cream has proven effective for several years.[30][32] A 2014 case report also showed improvement in primary hypersomnia symptoms after treatment with a continuous subcutaneous flumazenil infusion.[33] The supply of generic flumazenil was initially thought to be too low to meet the potential demand for treatment of primary hypersomnias.[34] However, this scarcity has eased, and dozens of people are now being treated with flumazenil off-label.[35]

Clarithromycin

In a test tube model, clarithromycin (an antibiotic approved by the FDA for the treatment of infections) was found to return the function of the GABA system to normal in people with primary hypersomnias. Investigators, therefore, treated a few people with narcolepsy with off-label clarithromycin, and most felt their symptoms improved with this treatment. To help further determine whether clarithromycin is truly beneficial for the treatment of narcolepsy and idiopathic hypersomnia, a small, double-blind, randomized, controlled clinical trial was completed in 2012.[31] "In this pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia. Larger trials of longer duration are warranted."[36] In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of people with GABA-related hypersomnia.[37] "It is important to note that the positive effect of clarithromycin is secondary to a benzodiazepine antagonist-like effect, not its antibiotic effects, and treatment must be maintained."[38]

Orexin receptor agonists

انظر أيضاً: Orexin receptor

Orexin-A (a.k.a. hypocretin-1) is strongly wake-promoting in animal models, but it does not cross the blood–brain barrier. The first-line treatment for narcolepsy, modafinil, has been found to interact indirectly with the orexin system. It is also likely that an orexin receptor agonist will be found and developed for the treatment of hypersomnia.[38] One such agent which is currently in clinical trials is danavorexton.[39][40]

L-carnitine

Abnormally low levels of acylcarnitine have been observed in people with narcolepsy.[41] These same low levels have been associated with primary hypersomnia in general in mouse studies. "Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity." Administration of acetyl-L-carnitine was shown to improve these symptoms in mice.[42] A subsequent human trial found that people with narcolepsy given L-carnitine spent less total time in daytime sleep than people who were given a placebo.[43]

النماذج الحيوانية

Animal studies try to mimic the disorder in humans by either modifying the Hypocretin/Orexin receptors or by eliminating this peptide.[44] An orexin deficit caused by the degeneration of hypothalamic neurons is suggested to be one of the causes of narcolepsy.[45] More recent clinical studies on both animals and humans have also revealed that hypocretin is involved in other functions beside regulation of wakefulness and sleep. These functions include autonomic regulation, emotional processing, reward learning behaviour and energy homeostasis. In studies where the concentration of the hypocretin was measured under different circumstances, it was observed that the hypocretin levels increased with positive emotion, anger, or social interaction, but stayed low during sleep or pain experience.[46] The most reliable and valid animal models are the canine (narcoleptic dogs) and the rodent (orexin-deficient mice), which set the focus on the role of orexin.[45]

نماذج الكلاب

Dogs (and other species including cats and horses) can exhibit spontaneous narcolepsy with symptoms similar to those in humans, and can involve partial or full collapse.[45] Narcolepsy with cataplexy was identified in breeds including Labrador retrievers and Doberman pinschers, where the possibility of inheriting the disorder in an autosomal recessive mode was investigated.[47] A reliable canine model for narcolepsy would be one in which the symptoms result from a mutation in the gene HCRT 2. The animals affected exhibited excessive daytime sleepiness with a reduced state of vigilance, and severe cataplexy in response to food and interactions with humans or other animals.[44]

نماذج القوارض

Mice that are genetically engineered to lack orexin genes demonstrate many similarities to human narcolepsy. During nocturnal hours, when mice are normally present, those lacking orexin demonstrated murine cataplexy and displayed brain and muscle electrical activity similar to the activity present during REM and NREM sleep. This cataplexy can be triggered through social interaction, wheel running, and ultrasonic vocalizations. Upon awakening, the mice also display behavior consistent with excessive daytime sleepiness.[45] Mouse models have also been used to test whether the lack of orexin neurons is correlated with narcolepsy. Mice whose orexin neurons have been ablated have shown sleep fragmentation, SOREMPs, and obesity.[45] Rat models have been used to demonstrate the association between orexin deficiency and narcoleptic symptoms. Rats that lost the majority of their orexinergic neurons exhibited multiple SOREMPs as well as less wakefulness during nocturnal hours, shortened REM latency, and brief periods of cataplexy.[45]

انظر أيضاً

الهامش

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