Hypocretin Cell Loss In Pwn W/o Cataplexy

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Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy.

THANNICKAL TC, NIENHUIS R, SIEGEL JM. Sleep 2009;32(8):993-8.

Veterans Administration Greater Los Angeles Healthcare System, Neurobiology Research, North Hills, CA 91343, USA Abstract:

STUDY OBJECTIVES: Narcolepsy with cataplexy is characterized by a loss of approximately 90% of hypocretin (Hcrt) neurons. However, more than a quarter of narcoleptics do not have cataplexy and have normal levels of hypocretin in their cerebrospinal fluid, raising the possibility that their disease is caused by unrelated abnormalities. In this study we examined hypocretin pathology in narcolepsy without cataplexy.

DESIGN: We examined postmortem brain samples, including the hypothalamus of 5 narcolepsy with cataplexy patients; one narcolepsy without cataplexy patient whose complete hypothalamus was available (patient 1); one narcolepsy without cataplexy patient with anterior hypothalamus available (patient 2); and 6 normal brains. The hypothalamic tissue was immunostained for Hcrt-1, melanin-concentrating hormone (MCH), and glial fibrillary acidic protein (GFAP).

MEASUREMENTS AND RESULTS: Neither of the narcolepsy without cataplexy patients had a loss of Hcrt axons in the anterior hypothalamus. The narcolepsy without cataplexy patient whose entire brain was available for study had an overall loss of 33% of hypocretin cells compared to normals, with maximal cell loss in the posterior hypothalamus. We found elevated levels of gliosis with GFAP staining, with levels increased in the posterior hypothalamic nucleus by (295%), paraventricular (211%), periventricular (123%), arcuate (126%), and lateral (72%) hypothalamic nuclei, but not in the anterior, dorsomedial, or dorsal hypothalamus. There was no reduction in the number of MCH neurons in either patient.

CONCLUSIONS: Narcolepsy without cataplexy can be caused by a partial loss of hypocretin cells.

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Thanks, Bafflegab! That's really fascinating. Even though it feels really weird, I sent an email to Stanford asking that they send two sets of the paperwork necessary for brain donation after death - one for me, and one for my husband, who is willing to donate his as a "healthy control." I guess because I really identify my brain as the organ that determines who I am, as opposed to the way I feel about already being an organ donor for the rest of the organs in my body - my heart, my kidneys... - it feels weird to sign papers saying yeah, sure! Take my brain when I'm done with it! But man, if I can do anything with my life to help other people with narcolepsy either right now or in the future, I'm in!!

I've been looking at my 94 year old grandmother lately, who's extremely disabled in part because her sleep cycles have become completely unregulated, and wondering if it's possible that she has a very late onset narcolepsy. She has lots of classic symptoms - frequent inability to fall asleep all night long for a day or two, followed by a day when she can't wake up sufficiently to get out of bed; and on most days when she can get up and around, she now falls asleep constantly, even when she's in the middle of speaking to me. So it makes me wonder - could that be narcolepsy? And if it is, then it's likely that I'm one of the 8 - 12% of PWN who has narcolepsy in part due to a genetic vulnerability to the disease. And if THAT's true, then it's highly likely that some of my own ancestors will also have the disease. When I look at the question of donating my own brain as a matter of advancing understanding of the causes and treatment of narcolepsy so that perhaps even my own grandchild or great-grandchild with narcolepsy has access to better medication, or earlier diagnosis, or perhaps even a cure! That biological drive towards altruism for the purpose of propogation of one's own genetic code handily kicks right in there.

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Thanks for posting this, Bafflegab, I'll definitely check it out.

Saraiah - That's very generous of you to donate your brain! As for your grandmother, if she's just now manifesting these symptoms for the first time, and (reliably) doesn't recall difficulty staying awake during the day in the past, I would think that the cause is probably not a genetic predisposition or basis for narcolepsy. I remember hearing that the circadian rythym of the elderly is skewed, but that means they start sleeping earlier and earlier. I found a nice overview of some of the causes of insomnia in the elderly:

Sleep and aging: 1. Sleep disorders commonly found in older people

Norman Wolkove, Osama Elkholy, Marc Baltzan, and Mark Palayew

From the Sleep Clinic, Mount Sinai Hospital Center, and the Department of Medicine, McGill University, Montréal, Que.

CMAJ. 2007 April 24; 176(9): 1299–1304.


Insomnia, defined as difficulty falling or staying asleep, is frequent in older people.1,2 In some patients, insomnia can be caused by an underlying medical condition or a medication side effect (secondary insomnia). In the absence of a causative factor, it is referred to as primary insomnia. Monane3 has estimated that insomnia affects nearly half of all those over the age of 65 years. Elderly women tend to report sleep disturbances more frequently than elderly men.4 The sleep changes noted among older women may be partly related to changes in the postmenopausal profile of sex hormones. Estrogen deficiency in particular has been postulated to contribute to the sleep difficulties that women often begin to experience in their perimenopausal period, and then increasingly with age.5

Frequent awakenings are particularly common among elderly people and may be related to their more frequent incidences of concurrent medical conditions. Among the most common causes of secondary insomnia are a variety of musculoskeletal disorders, nocturia related to benign prostatic hypertrophy in men and bladder instability with decreased urethral resistance in women, congestive heart disease, and chronic obstructive lung disease.

Depression and anxiety disorders, common among people over 65 years of age, frequently contribute to insomnia.6 Risk factors for depression in older people include loss of a spouse, retirement, social isolation, comorbid disease and onset of dementia.

Sleep disturbance or disruption is common among patients experiencing dementia, particularly those with Alzheimer's disease.7 Such patients often have difficulty not only falling asleep but also with repeated nighttime awakenings. In general, as the dementia progresses, these symptoms become increasingly severe and patients become noticeably and progressively sleepier during the daytime. They may also exhibit recurrent agitated behaviour, known as “sundowning,” during which these patients are more confused, disoriented, suspicious and restless. They may yell or exhibit violent behaviour, and are prone to wandering. Although episodes may occur at any hour, they are most common in late afternoon or evening — hence its descriptive term. For caregivers, this behaviour is extremely disruptive, and often becomes the ultimate reason for admission of a patient with dementia to an institution. Interestingly, McKibbon and colleagues8 also showed that elderly caregivers of patients with Alzheimer's disease reported more sleep problems and functional impairment from sleepiness than noncaregivers.

Insomnia is also common in people who have Parkinson's disease,9 who may experience frequent awakenings with difficulty returning to sleep. They also frequently complain of vivid dreams, nightmares and leg jerks. Restless legs syndrome and rapid eye movement (REM)-sleep behaviour disorder, described following, may also affect these patients.

Use of medication increases with age. Older, community-dwelling people commonly undergo polypharmacy and receive inappropriate prescriptions from physicians,10 which unfortunately increases the possibility of insomnia related to medication use. A careful drug history is therefore imperative when an older patient with insomnia is assessed. Many drugs and other ingested substances have been shown to cause or contribute to insomnia; examples are presented in Table 2. This is particularly important in elderly patients who may, for physiologic reasons, be more susceptible to the stimulatory effects of these agents. The stimulant effect of caffeine, for example, which can last 8–14 hours, may be more pronounced in older people, especially when decreased liver function impairs caffeine clearance. Many older people use alcohol as a sleep aid, but even moderate consumption near bedtime can cause intense dreaming and nocturnal awakenings. These arousals appear to result from sympathetic stimulation and catecholamine release associated with the eventual fall of blood alcohol levels. Older people seem to be more sensitive to these effects.

As for narcolepsy presenting in the elderly:


A chronic neurologic disorder of unclear origin, narcolepsy results in excessive daytime somnolence and fatigue.16 The main symptoms of this condition are “sleep attacks,” during which patients experience an irresistible urge to sleep (for a few minutes or up to an hour); hypnogogic hallucinations (extremely vivid auditory or visual hallucinations experienced while falling asleep or when waking up); sleep paralysis (a temporary inability to move upon wakening or before falling asleep); and cataplexy (a sudden, temporary, often unpredictable loss of muscle tone, which leads frequently to complete collapse).

Cataplexy can occur in the absence of other features of narcolepsy. Some attacks last up to half an hour, during which the patient is awake but unable to move or, in milder cases, experiences focal muscle weakness. Cataplexic episodes are sometimes triggered by intense emotion, including crying or laughing.

Although narcolepsy usually begins during the teen years or early twenties, symptoms tend to be lifelong.16 It may therefore be seen in older patients who have had the condition for many years.16 In others, mild disease severity, misdiagnosis or long delays in cataplexy expression may prevent proper diagnosis and treatment.17,18 Chakravete and Rye18 estimated that it first comes to medical attention after the age of 40 years in nearly half of affected patients. Rye and associates19 stressed that, during differential diagnosis, narcolepsy should always be considered by physicians faced with an older patient experiencing sleepiness or with transient loss of muscle tone.

Once suspected, narcolepsy is usually evaluated by documenting the presence and severity of daytime sleepiness by means of a multiple sleep-latency test.20 Polysomnography is essential to rule out other sleep disorders.

There is no doubt more out there, but there's some info from a quick search. Hope it helps!

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Nyx, you're a treasure! Yeah, my grandmother has dementia, so I guess maybe that's it. Sigh. I have this fantasy that it could be narcolepsy, and we might figure that out and treat it, and she might sleep at night, and...maybe my grandmother would come back to me. I miss her. She still always recognizes me, and I see flashes of her sharp wit and intelligence and wry sense of humor. And of her strength. Sometimes, if I stay all day and just sit quietly with her as she is in and out of napping in her chair, sometimes there will be this brief and sudden moment when I realize that she is really right there with me. Sometimes, we'll get to talk in those few minutes before she gets lost again. It is worth it to me to wait all day for those few minutes.

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