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Fatal familial insomnia
Sleep Medicine Reviews (2005) 9, 337–338
www.elsevier.com/locate/smrv
GUEST EDITORIAL
Fatal familial insomnia It is certainly not an insult to state that fatal familial insomnia is to the thalamus what epidemic encephalitis has previously been to the hypothalamus. The initial description of fatal familial insomnia was based on the observation that patients who progressively lose sleep become fatigued and experience increasing autonomic hyperactivity in the form of sweating, increased heart rate and blood pressure, and eventually die after 7–25 months. A follow-up pathological evaluation showed a degeneration of the dorso-medial and ventral anterior nuclei of the thalamus. Very comparable indeed to the observation, 90 years ago, of patients with somnolence and ophthalmoplegia, associated with inflammatory lesions of the posterior hypothalamus on the one hand and patients with insomnia and chorea associated with inflammatory lesions of the anterior hypothalamus on the other hand. The neurology of sleep is rich, with such examples from complete sleep loss, oneirism and autonomic hyperactivity, characterising Morvan’s chorea, an autoimmune encephalitis involving the limbic areas, to excessive daytime sleepiness characteristic of patients with paramedian thalamic stroke. Other examples include rapid-eye movement (REM) sleep behaviour disorder, indicative of synucleinopathy; altered timing of sleep and wakefulness consecutive to degeneration of the suprachiasmatic nuclei; hypersomnia in myotonic dystrophy; obstructive sleep apnea/hypopnea syndrome; and dysrythmic breathing and laryngeal stridor due to laryngeal abductor paralysis in multiple system atrophy. These, and many other examples, should definitely be an incentive for neurologists to interview patients with central nervous system sleep disorders, and their families, about the continuity and quality of their sleep, and at the slightest doubt to have them closely watched at night or
polysomnographically recorded. Unfortunately, this is not yet the case, and several neurological conditions are misdiagnosed owing to lack of interest in sleep manifestations. Let us return to fatal familial insomnia, ‘the third most frequent genetic prion disease in the world’ and its masterly description by one of its discoverers, Doctor Pasquale Montagna, Professor of Neurology at the Institute of Clinical Neurology, University of Bologna. Dr Montagna proposes that fatal familial insomnia could be a model disease for sleep regulation and raises several issues: there is ample clinical, pathological and functional imaging evidence for an essential role of medial thalamic structures in the genesis of slow-wave sleep, and it is likely that the disappearance of sleep spindles in the prefrontal cortex of people with fatal familial insomnia is due to the atrophy of the dorso-medial nucleus. Indeed, the dorso-medial nucleus represents an intermediate station in a network interconnecting the cortical limbic region to the hypothalamus. Might I be allowed, in this context, to ask whether fatal familial insomnia might shed some light on the pathophysiology of more common forms of insomnia, such as psychophysiological insomnia or insomnia due to mental disorder? Unfortunately, the answer is definitely no; as polysomnographic studies carried out in these types of insomnia have never disclosed dramatic decrease or disappearance of slow-wave sleep, sleep spindles or K-complexes. On the other hand, progressive supranuclear palsy, possibly the neurodegenerative disease with the most severe insomnia, which is associated with the loss of sleep spindles and K-complexes, includes functional alteration of the thalamus as one of its pathologic features. On the basis of the similarities in delirium tremens, Morvan’s chorea and fatal familial
1087-0792/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2005.07.001
338 insomnia, the author proposes the new concept of ‘agrypnia excitata’ as a clinical condition, characterised by loss of sleep, especially slow-wave sleep, oneirism, motor and autonomic sympathergic activation, due to dysfunction of the thalamo-limbic system. This is definitely a clinical breakthrough that should help clinicians treating people with extreme agitation. Are there other candidates for such an agrypnia excitata? Paraneoplastic limbic encephalitis can result in delirium, agitation and sleeplessness, and encephalitis lethargica can present itself as severe insomnia, hyperkinesia, tics, myoclonias and chorea. In this context, polysomnography would certainly be beneficial to achieve a better description of these latter conditions. Fatal familial insomnia is remarkable for loss of slow-wave sleep, sleep spindles and K-complexes while stage 1 non-rapid eye movement (NREM) sleep is conserved. Thus, the proposal that ‘light sleep, until the appearance of sleep spindles, should probably more meaningfully be conjoint with relaxed wakefulness under the concept of sleep onset’, and that its mechanisms are probably different from those of other sleep stages, is certainly appealing. However, the decision is still pending. If it is true that electrical brain activity of stage 1 does not include any of the electrical patterns of stages 2, 3 and 4, the relatively lowvoltage, mixed-frequency pattern of stage 1 is clearly different from the rhythmic alpha (8–13 Hz) activity of wakefulness. By introspection, the onset of stage 1 EEG pattern, may or may not coincide with perceived sleep onset, and it has been shown that even the stage 2 pattern (K-complex or sleep spindle) is not unequivocally associated with perceived sleep. Hypnagogic hallucinations and vivid perceptual experiences, occurring at sleep onset, clearly differ from logically progressive thoughts of wakefulness and cognitivre activity of NREM sleep, characterised by imagery, thinking, reflecting, bodily feelings, and vague and fragmentary impressions.
Guest editorial Is there room for prions in sleep regulation? This possibility is tempting. It has been shown that the main differences in sleep between prion protein null mice and wild-type mice was a larger degree of sleep fragmentation and a larger increase of slow-wave activity after sleep deprivation in the null mice, hence the suggestion that prion protein may play a role in maintaining sleep continuity. Subsequent evidence has shown that null mice have a lower peak frequency within the theta band in REM sleep and waking, and not in REM sleep, hence the proposal that the prion protein may be affecting the theta-generating mechanisms during waking and REM sleep. However, controversial results have been provided, and Dr Montagna comes to the wise conclusion that the role of the prion protein in sleep regulation must still be considered unsubstantiated. To conclude: is the term fatal familial insomnia still appropriate? Indeed, one may question the link between fatal and insomnia, given the importance of autonomic impairments, including hyperhidrosis, pyrexia, tachycardia, hypertension and irregular breathing just before patients die. Obviously, the ultimate cause of death in the first four reported cases of fatal familial insomnia was not insomnia but respiratory impairment: in the first patient, breathing was quick, irregular in frequency and depth, and associated with prolonged apnea; in the second, breathing became so difficult that admission to an intensive-care unit was necessary, where the patient died; the third patient died from respiratory arrest and, in the fourth, apnea became more and more frequent. Consequently, ‘fatal familial autonomic hyperactivation with loss of sleep’ would certainly be less attractive but closer to reality. Michel Billiard School of Medicine, Gui de Chauliac Hospital, F-34295, Montpellier, Cedex 5, France E-mail address: [email protected]
www.elsevier.com/locate/smrv
GUEST EDITORIAL
Fatal familial insomnia It is certainly not an insult to state that fatal familial insomnia is to the thalamus what epidemic encephalitis has previously been to the hypothalamus. The initial description of fatal familial insomnia was based on the observation that patients who progressively lose sleep become fatigued and experience increasing autonomic hyperactivity in the form of sweating, increased heart rate and blood pressure, and eventually die after 7–25 months. A follow-up pathological evaluation showed a degeneration of the dorso-medial and ventral anterior nuclei of the thalamus. Very comparable indeed to the observation, 90 years ago, of patients with somnolence and ophthalmoplegia, associated with inflammatory lesions of the posterior hypothalamus on the one hand and patients with insomnia and chorea associated with inflammatory lesions of the anterior hypothalamus on the other hand. The neurology of sleep is rich, with such examples from complete sleep loss, oneirism and autonomic hyperactivity, characterising Morvan’s chorea, an autoimmune encephalitis involving the limbic areas, to excessive daytime sleepiness characteristic of patients with paramedian thalamic stroke. Other examples include rapid-eye movement (REM) sleep behaviour disorder, indicative of synucleinopathy; altered timing of sleep and wakefulness consecutive to degeneration of the suprachiasmatic nuclei; hypersomnia in myotonic dystrophy; obstructive sleep apnea/hypopnea syndrome; and dysrythmic breathing and laryngeal stridor due to laryngeal abductor paralysis in multiple system atrophy. These, and many other examples, should definitely be an incentive for neurologists to interview patients with central nervous system sleep disorders, and their families, about the continuity and quality of their sleep, and at the slightest doubt to have them closely watched at night or
polysomnographically recorded. Unfortunately, this is not yet the case, and several neurological conditions are misdiagnosed owing to lack of interest in sleep manifestations. Let us return to fatal familial insomnia, ‘the third most frequent genetic prion disease in the world’ and its masterly description by one of its discoverers, Doctor Pasquale Montagna, Professor of Neurology at the Institute of Clinical Neurology, University of Bologna. Dr Montagna proposes that fatal familial insomnia could be a model disease for sleep regulation and raises several issues: there is ample clinical, pathological and functional imaging evidence for an essential role of medial thalamic structures in the genesis of slow-wave sleep, and it is likely that the disappearance of sleep spindles in the prefrontal cortex of people with fatal familial insomnia is due to the atrophy of the dorso-medial nucleus. Indeed, the dorso-medial nucleus represents an intermediate station in a network interconnecting the cortical limbic region to the hypothalamus. Might I be allowed, in this context, to ask whether fatal familial insomnia might shed some light on the pathophysiology of more common forms of insomnia, such as psychophysiological insomnia or insomnia due to mental disorder? Unfortunately, the answer is definitely no; as polysomnographic studies carried out in these types of insomnia have never disclosed dramatic decrease or disappearance of slow-wave sleep, sleep spindles or K-complexes. On the other hand, progressive supranuclear palsy, possibly the neurodegenerative disease with the most severe insomnia, which is associated with the loss of sleep spindles and K-complexes, includes functional alteration of the thalamus as one of its pathologic features. On the basis of the similarities in delirium tremens, Morvan’s chorea and fatal familial
1087-0792/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2005.07.001
338 insomnia, the author proposes the new concept of ‘agrypnia excitata’ as a clinical condition, characterised by loss of sleep, especially slow-wave sleep, oneirism, motor and autonomic sympathergic activation, due to dysfunction of the thalamo-limbic system. This is definitely a clinical breakthrough that should help clinicians treating people with extreme agitation. Are there other candidates for such an agrypnia excitata? Paraneoplastic limbic encephalitis can result in delirium, agitation and sleeplessness, and encephalitis lethargica can present itself as severe insomnia, hyperkinesia, tics, myoclonias and chorea. In this context, polysomnography would certainly be beneficial to achieve a better description of these latter conditions. Fatal familial insomnia is remarkable for loss of slow-wave sleep, sleep spindles and K-complexes while stage 1 non-rapid eye movement (NREM) sleep is conserved. Thus, the proposal that ‘light sleep, until the appearance of sleep spindles, should probably more meaningfully be conjoint with relaxed wakefulness under the concept of sleep onset’, and that its mechanisms are probably different from those of other sleep stages, is certainly appealing. However, the decision is still pending. If it is true that electrical brain activity of stage 1 does not include any of the electrical patterns of stages 2, 3 and 4, the relatively lowvoltage, mixed-frequency pattern of stage 1 is clearly different from the rhythmic alpha (8–13 Hz) activity of wakefulness. By introspection, the onset of stage 1 EEG pattern, may or may not coincide with perceived sleep onset, and it has been shown that even the stage 2 pattern (K-complex or sleep spindle) is not unequivocally associated with perceived sleep. Hypnagogic hallucinations and vivid perceptual experiences, occurring at sleep onset, clearly differ from logically progressive thoughts of wakefulness and cognitivre activity of NREM sleep, characterised by imagery, thinking, reflecting, bodily feelings, and vague and fragmentary impressions.
Guest editorial Is there room for prions in sleep regulation? This possibility is tempting. It has been shown that the main differences in sleep between prion protein null mice and wild-type mice was a larger degree of sleep fragmentation and a larger increase of slow-wave activity after sleep deprivation in the null mice, hence the suggestion that prion protein may play a role in maintaining sleep continuity. Subsequent evidence has shown that null mice have a lower peak frequency within the theta band in REM sleep and waking, and not in REM sleep, hence the proposal that the prion protein may be affecting the theta-generating mechanisms during waking and REM sleep. However, controversial results have been provided, and Dr Montagna comes to the wise conclusion that the role of the prion protein in sleep regulation must still be considered unsubstantiated. To conclude: is the term fatal familial insomnia still appropriate? Indeed, one may question the link between fatal and insomnia, given the importance of autonomic impairments, including hyperhidrosis, pyrexia, tachycardia, hypertension and irregular breathing just before patients die. Obviously, the ultimate cause of death in the first four reported cases of fatal familial insomnia was not insomnia but respiratory impairment: in the first patient, breathing was quick, irregular in frequency and depth, and associated with prolonged apnea; in the second, breathing became so difficult that admission to an intensive-care unit was necessary, where the patient died; the third patient died from respiratory arrest and, in the fourth, apnea became more and more frequent. Consequently, ‘fatal familial autonomic hyperactivation with loss of sleep’ would certainly be less attractive but closer to reality. Michel Billiard School of Medicine, Gui de Chauliac Hospital, F-34295, Montpellier, Cedex 5, France E-mail address: [email protected]