Self Management of Fatal Familial Insomnia. Part 1: What Is FFI?

Joyce Schenkein, PhD; Pasquale Montagna, MD

Disclosures
In This Article

Sleep Deprivation in FFI

Despite its suggestive name, the insomnia of FFI may not be an early or essential symptom of the disorder. Among a series of German patients, sleep disturbances were mild and often recognized only in retrospect after detailed questioning of the family or reinvestigation of the hospital records.[5] Similar observations have been reported in other international populations.[14,39,40] We propose that the term insomnia must be used in a technical sense, meaning not just the complaint of subjective insomnia, but a disorganization of processes intrinsic to sleep. This requires lab confirmation, which is not often available. For example, Julien and colleagues[41] reported a patient who "sometimes lapsed into a short-lasting behavioral state of sleep with closed eyes, but EEG performed during these periods did not disclose any sleep pattern." Charts and retrospective reports do not clarify this issue. Moreover, FFI patients may be admitted late in the course of the disease, when insomnia is already lost as a symptom, or may receive a single polysomnography which is not sufficient to demonstrate abnormalities.

The EEG of normal sleep-deprived subjects shows a predominance of delta activity[42] and episodes of "micro-sleep," brief bursts of high-amplitude slow waves, K-complexes, and sleep spindles.[43] The absence of this response is associated with disturbed perception, lapses of consciousness, and erratic behavior.[44] In patients with FFI, sleep EEGs contain a mixture of rhythms that are neither typical of wake nor of light sleep, and may be called "subwakefulness."[3] Similarly, EEG testing of an FFI patient "without insomnia" demonstrated an absence of sleep spindles and K-complexes.[45] Total sleep time was reduced and showed only slow activity or desynchronization without rapid eye movements.

The impact of sleep deprivation upon the course of FFI is not trivial. Many of the other symptoms of FFI that contribute to dysfunction and death may be secondary to the insomnia. Chronic sleep deprivation has been associated with hypometabolism in the thalamo-limbic circuits (in a way similar to the PET markers of FFI).[17] epileptic seizures,[46] aggravation of the autonomic functions,[3,47] increased cortisol, and reductions in both thyroid-stimulating hormone and melatonin.[48] Observed deficits in memory encoding may result from degeneration in the dorsomedial thalamus[49] or the disruption of consolidation that normally occurs during sleep.[23] In addition, the secretion of GH that normally occurs during deep sleep is reduced in FFI.[47] Because GH plays a role in body growth, fat mobilization, and inhibition of glucose utilization, its disruption might underlie the rapid aging and weight loss noted in the FFI patient. Neuroimaging studies of cerebral energy metabolism during the sleep-wake cycles show a global decrease in energy consumption during SWS as opposed to REM and waking states, suggesting that, for the normal, it is a time of relative rest of brain cells.[50]

As described by Montagna,[34] sleep in FFI is characterized by an early and progressive reduction in sleep spindles and K-complexes, a reduction in total sleep time, and disruption of the cyclical organization of sleep; SWS is lost first, then REM disengages from its circadian cycle and intrudes into the waking state. Lugaresi and colleagues[47] explain that circadian rhythms involving melatonin gradually decrease and shift in phase, and finally disappear. The rhythmicity of somatotropin (GH) shows a similar reduction or total loss in tandem with the loss of deep sleep. Only prolactin rhythmicity remains unaltered.[3]

Met-Met patients demonstrate a different sleep pattern than Met-Val patients, including severe fragmentation, brief but repeated episodes of sudden-onset REM (with oneiric enactment), and an earlier loss of total sleep. Sleep loss in Met-Val patients progresses more slowly, although they, too, ultimately lose deep-sleep stages, slow-wave EEG activity, and circadian motor rhythms. Nevertheless, body temperature, heart rate, and blood pressure remain elevated (Reder, personal communication, 2005).

Circadian factors regulating sleep are primarily localized in the hypothalamic suprachiasmatic nuclei (SCN) and promote sleep in concert with other biological events, including lowering core temperature and cortisol levels.[51] An obvious mystery of FFI is the disappearance of circadian rhythms despite ostensible integrity of the hypothalamus.[7,39,52] Mignot and associates[18] attribute disruption of circadian rhythms to an interdependence between hypothalamic and thalamic nuclei. Specifically, the dorsomedial hypothalamus innervates not only the mediodorsal (MD) and paraventricular (PVT) nuclei of the thalamus, but also other hypothalamic areas involved in non-REM sleep and thermoregulation (ie, medial preoptic area), circadian rhythms (eg, SCN), and adrenocortical axis (ie, PVN), as well as other neuroendocrine secretions. In addition, hypothalamic function in FFI may still be altered despite the lack of histologic evidence. Indeed, an abnormal accumulation of PrPres is noted in the FFI hypothalamus as early as 7-8 months into the disease.[7]

Rodent studies suggest that circadian rhythms can be promoted even in the absence of neural connections between SCN and other brain structures. Transplants of fetal SCN tissue into the brains of SCN-lesioned hamsters restore circadian rhythms even when the transplanted tissue is encapsulated and has no neural connections to the recipient animal.[53] The SCN of pregnant mice synchronizes fetal SCN activity,[54] and its removal during the gestational period results in desynchronization of the unborn. The means of entrainment is probably hormonal. These findings raise the question of whether administration of missing hormones (eg, GH or melatonin) may help restore circadian rhythms or compensate in some way for their absence. Administering melatonin induces sleep sooner at night and has been used to treat jet lag.[54] Several studies have shown that circadian rhythms are influenced by external stimuli, such as light. Direct retinohypothalamic pathways exist in rodents.[55] Human subjects deprived of light stimulation follow rhythms slightly out of sync with the 24-hour diurnal solar pattern, indicating that light information finely tunes these rhythms.

Although patients with FFI share many features with those who are sleep deprived, certain differences are apparent:

  1. Experimental subjects experience constant sleep pressure and immediately lapse into sleep if permitted. The FFI patient cannot fall asleep.

  2. Selective deprivation of REM or non-REM sleep is followed by selective rebound, indicating the necessity of each. As compared with the pre-deprivation period, human adults recovering from SWS deprivation show rapidly appearing and long-lasting delta. This increase in delta waves (most notably in the frontal area), occurs in both REM and non-REM sleep.[38] In FFI, sleep loss is initially SWS, which does not show any form of rebound. Loss of nocturnal REM is replaced by brief, periodic episodes of "parasomnia," a state resembling REM but without atonia. This parasomniac REM is not experienced as refreshing. Except when the patient is distracted by others, he or she remains almost continually in this stuporous state.[34]

  3. Normal sleep-deprived subjects are most impaired during the nighttime hours because circadian rhythms depress overall functioning level. In FFI, circadian rhythms break down and the distinction between day and night is blurred.

  4. Temperature decline associated with chronic sleep deprivation does not occur in patients with FFI. On the contrary, temperature is frequently elevated.

  5. Hypocretin levels are elevated in sleep-deprived animals but not in FFI patients.[18]

  6. Rats who die of sleep deprivation do not show cortical apoptosis,[17,56] as seen in patients with FFI.

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