2014 Round-up
Sleep: what the day owes the night
www.thelancet.com/neurology Vol 14 January 2015
and alertness similar to those reported after one night of total sleep deprivation, chronically disturbed sleep might promote the accumulation of Aβ. These findings suggest the beneficial effects of allowing for more sleep time in chronically sleep-deprived modern lifestyles. Obstructive sleep apnoea syndrome is a common disorder, leading to daytime sleepiness and increased risk of cardiovascular disease. During obstructive sleep apnoea, the tongue, which is insufficiently stimulated by the brainstem during sleep, is sucked backwards, obstructing and sometimes blocking the upper airways. Treatments such as surgery, continuous positive airway pressure, or the use of a dental appliance that pulls the tongue forwards can keep the upper airways open during sleep. Unfortunately, such measures are not always effective or well tolerated. Electrical stimulation of the hypoglossus nerve is a major therapeutic advance.4 At the beginning of inspiration, the hypoglossus nerve is stimulated by a pacemaker that is synchronised with chest effort, causing one half of the tongue to be pulled forwards. This stimulation of the hypoglossus nerve can reduce the number of apnoea and hypoapnoea episodes from 29 per h to 9 per h after 12 months. Blood oxygenation, daytime sleepiness, and quality of life can also be improved. However, hypoglossal stimulation shows no lasting effect, and sleep apnoea resumes after 5 nights without stimulation. Hypoglossal stimulation is currently an expensive treatment, but it has potential for wider application.
Mauro Fermariello/Science Photo Library
Sleep is crucial for memory consolidation, emotion processing, daytime alertness, and metabolic and immune function. Several studies published in the past 12 months have shed light on new functions of sleep in babies and elderly people and uncovered mechanisms of sleep that will help in the treatment of sleep disorders. The muscle twitches seen in sleeping puppies, as if they are actively dreaming, also occur during rapid eye movement (REM) sleep in human babies. The twitches are thought to be triggered in the brainstem; a peduncular section that isolates the pons and medulla from any descending influences from the mesencephalon, diencephalon, and cortex does not abolish them. The function of these twitches was, however, unknown until recent work1 on newborn rats showed that muscle twitches serve a developmental purpose in shaping the sensory–motor cortex. During wakefulness, the nervous system simultaneously drives movements and generates a copy of the motor command (the corollary discharge) to inform the sensory cortex of expected changes. This process helps to distinguish sensations that are selfgenerated from those that are external. Alexandre Tiriac and colleagues1 show that during REM sleep, the twitches might not be accompanied by corollary discharges. These twitches are processed in the sensory cortex and trigger strong activity in the primary motor cortex, which is not seen in response to passive movements of the tail when the animals are awake. Applications of this new concept in brain development of sensorimotor control are under investigation in robotics. The accumulation of β-amyloid (Aβ) protein within the brain is thought to be one of the mechanisms leading to Alzheimer’s disease. Increasing evidence suggests that Aβ is produced during wakefulness and removed during sleep. Indeed, the concentration of Aβ in the CSF of both humans and rodents decreases substantially during sleep.2 As expected, results of a study3 in healthy middle-aged men showed that the concentration of Aβ in CSF increased with extended wakefulness. A night of unrestricted sleep led to a significant 6% decrease in pre-sleep compared with post-sleep concentration of Aβ1–42 in CSF (the longest sleep correlated with the highest decrease in Aβ1–42), whereas no decrease in Aβ1–42 concentration was seen after total sleep deprivation. Because chronic sleep deprivation has effects on cognition
19
2014 Round-up
The mechanisms underlying excessive daytime sleepiness in people with Parkinson’s disease are multifactorial and include sedative effects of drugs, poor sleep quality, and neurodegeneration of arousal systems. Aleksander Videnovic and colleagues5 investigated circadian rhythms in the absence of external clocks and light and showed that patients with Parkinson’s disease have a lower secretion of melatonin during the night than healthy controls, and melatonin secretion is further decreased in patients with excessive daytime sleepiness. Low melatonin might explain difficulties in night-time sleep and daytime alertness, as shown by the common combination of night insomnia and recurrent daytime naps in these patients and in a primate model of parkinsonism.6 In clinical practice, oral melatonin is frequently used at bedtime to improve insomnia and reduce REM sleep behaviour disorder. It will be interesting to establish whether melatonin can also improve nextday alertness in patients with Parkinson’s disease. Kleine-Levin syndrome is a rare neurological disorder that affects adolescents.7 It is characterised by relapsingremitting episodes of major hypersomnia, confusion, derealisation (the feeling of being in a dream or disconnected from reality), and apathy, although patients are apparently normal between episodes. The cause of Kleine-Levin syndrome is unknown, but the mechanism of derealisation was identified in a recent functional imaging study8 of 41 patients. Several diencephalic and associative cortical areas remained hypoperfused between episodes, whereas the additional
hypoperfusion seen in the right parietotemporal junction (including the angular gyrus) during episodes correlated with the intensity of derealisation and the duration of episodes. These results suggest that patients feel unreal because the temporoparietal junction does not fully integrate temperature, pain, and superficial skin sensations with auditory and visual information. These findings provide potential mechanism for derealisation, a symptom common to several neurological and mental disorders, which can lead to depersonalisation and an out-of-body experience. Isabelle Arnulf Sleep Disorder Unit, Pitié Salpêtrière Hospital, Pierre and Marie Curie University, Paris, 75651 cedex 13, France [email protected] IA has been a consultant and an invited speaker for UCB Pharma. 1 2 3
4 5 6
7 8
Tiriac A, Del Rio-Bermudez C, Blumberg MS. Self-generated movements with “unexpected” sensory consequences. Curr Biol 2014; 24: 2136–41. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science 2013; 342: 373–77. Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JA. Effect of 1 night of total sleep deprivation on cerebrospinal fluid beta-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol 2014; 71: 971–77. Strollo PJ Jr, Soose RJ, Maurer JT, et al. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med 2014; 370: 139–49. Videnovic A, Noble C, Reid KJ, et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol 2014; 71: 463–69. Belaid H, Adrien J, Laffrat E, et al. Sleep disorders in Parkinsonian macaques: effects of L-dopa treatment and pedunculopontine nucleus lesion. J Neurosci 2014; 34: 9124–33. Arnulf I, Rico T, Mignot E. Diagnosis, disease course, and management of patients with Kleine-Levin syndrome. Lancet Neurol 2012; 11: 918–28. Kas A, Lavault S, Habert MO, Arnulf I. Feeling unreal: a functional imaging study in 41 patients with Kleine-Levin syndrome. Brain 2014; 137: 2077–87.
CNS infections in 2014: guns, germs, and will Important advances in neurological infections during 2014 spanned antimicrobial treatments (guns), pathogenesis and detection of germs, including viruses and prions, and the will to develop and implement prevention programmes in resource-limited settings. One study addressed the complex issue of appropriate timing of initiation of combined antiretroviral therapy (CART) in patients with AIDS-associated opportunistic infections. Clinical decision making must weigh the potential risk of delaying treatment in patients with profound immunosuppression against the risks associated with co-administration of treatments for opportunistic infections with CART, including potential drug 20
interactions and risk of immune reconstitution syndrome. Although previous studies have shown a potential benefit of early initiation of antiretroviral drugs in patients with non-CNS opportunistic infections, available data suggests that there might be separate considerations for individuals with CNS opportunistic infections. In the COAT trial, done in Uganda and South Africa, David Boulware and colleagues1 provide evidence that helps to clarify when to start CART in patients with cryptococccal meningitis. After 7–11 days of antifungal treatment, 177 CART-naive individuals were randomly assigned to receive early (started ≤48 h after randomisation) or deferred (started 4 weeks after randomisation) CART. www.thelancet.com/neurology Vol 14 January 2015
Sleep: what the day owes the night
www.thelancet.com/neurology Vol 14 January 2015
and alertness similar to those reported after one night of total sleep deprivation, chronically disturbed sleep might promote the accumulation of Aβ. These findings suggest the beneficial effects of allowing for more sleep time in chronically sleep-deprived modern lifestyles. Obstructive sleep apnoea syndrome is a common disorder, leading to daytime sleepiness and increased risk of cardiovascular disease. During obstructive sleep apnoea, the tongue, which is insufficiently stimulated by the brainstem during sleep, is sucked backwards, obstructing and sometimes blocking the upper airways. Treatments such as surgery, continuous positive airway pressure, or the use of a dental appliance that pulls the tongue forwards can keep the upper airways open during sleep. Unfortunately, such measures are not always effective or well tolerated. Electrical stimulation of the hypoglossus nerve is a major therapeutic advance.4 At the beginning of inspiration, the hypoglossus nerve is stimulated by a pacemaker that is synchronised with chest effort, causing one half of the tongue to be pulled forwards. This stimulation of the hypoglossus nerve can reduce the number of apnoea and hypoapnoea episodes from 29 per h to 9 per h after 12 months. Blood oxygenation, daytime sleepiness, and quality of life can also be improved. However, hypoglossal stimulation shows no lasting effect, and sleep apnoea resumes after 5 nights without stimulation. Hypoglossal stimulation is currently an expensive treatment, but it has potential for wider application.
Mauro Fermariello/Science Photo Library
Sleep is crucial for memory consolidation, emotion processing, daytime alertness, and metabolic and immune function. Several studies published in the past 12 months have shed light on new functions of sleep in babies and elderly people and uncovered mechanisms of sleep that will help in the treatment of sleep disorders. The muscle twitches seen in sleeping puppies, as if they are actively dreaming, also occur during rapid eye movement (REM) sleep in human babies. The twitches are thought to be triggered in the brainstem; a peduncular section that isolates the pons and medulla from any descending influences from the mesencephalon, diencephalon, and cortex does not abolish them. The function of these twitches was, however, unknown until recent work1 on newborn rats showed that muscle twitches serve a developmental purpose in shaping the sensory–motor cortex. During wakefulness, the nervous system simultaneously drives movements and generates a copy of the motor command (the corollary discharge) to inform the sensory cortex of expected changes. This process helps to distinguish sensations that are selfgenerated from those that are external. Alexandre Tiriac and colleagues1 show that during REM sleep, the twitches might not be accompanied by corollary discharges. These twitches are processed in the sensory cortex and trigger strong activity in the primary motor cortex, which is not seen in response to passive movements of the tail when the animals are awake. Applications of this new concept in brain development of sensorimotor control are under investigation in robotics. The accumulation of β-amyloid (Aβ) protein within the brain is thought to be one of the mechanisms leading to Alzheimer’s disease. Increasing evidence suggests that Aβ is produced during wakefulness and removed during sleep. Indeed, the concentration of Aβ in the CSF of both humans and rodents decreases substantially during sleep.2 As expected, results of a study3 in healthy middle-aged men showed that the concentration of Aβ in CSF increased with extended wakefulness. A night of unrestricted sleep led to a significant 6% decrease in pre-sleep compared with post-sleep concentration of Aβ1–42 in CSF (the longest sleep correlated with the highest decrease in Aβ1–42), whereas no decrease in Aβ1–42 concentration was seen after total sleep deprivation. Because chronic sleep deprivation has effects on cognition
19
2014 Round-up
The mechanisms underlying excessive daytime sleepiness in people with Parkinson’s disease are multifactorial and include sedative effects of drugs, poor sleep quality, and neurodegeneration of arousal systems. Aleksander Videnovic and colleagues5 investigated circadian rhythms in the absence of external clocks and light and showed that patients with Parkinson’s disease have a lower secretion of melatonin during the night than healthy controls, and melatonin secretion is further decreased in patients with excessive daytime sleepiness. Low melatonin might explain difficulties in night-time sleep and daytime alertness, as shown by the common combination of night insomnia and recurrent daytime naps in these patients and in a primate model of parkinsonism.6 In clinical practice, oral melatonin is frequently used at bedtime to improve insomnia and reduce REM sleep behaviour disorder. It will be interesting to establish whether melatonin can also improve nextday alertness in patients with Parkinson’s disease. Kleine-Levin syndrome is a rare neurological disorder that affects adolescents.7 It is characterised by relapsingremitting episodes of major hypersomnia, confusion, derealisation (the feeling of being in a dream or disconnected from reality), and apathy, although patients are apparently normal between episodes. The cause of Kleine-Levin syndrome is unknown, but the mechanism of derealisation was identified in a recent functional imaging study8 of 41 patients. Several diencephalic and associative cortical areas remained hypoperfused between episodes, whereas the additional
hypoperfusion seen in the right parietotemporal junction (including the angular gyrus) during episodes correlated with the intensity of derealisation and the duration of episodes. These results suggest that patients feel unreal because the temporoparietal junction does not fully integrate temperature, pain, and superficial skin sensations with auditory and visual information. These findings provide potential mechanism for derealisation, a symptom common to several neurological and mental disorders, which can lead to depersonalisation and an out-of-body experience. Isabelle Arnulf Sleep Disorder Unit, Pitié Salpêtrière Hospital, Pierre and Marie Curie University, Paris, 75651 cedex 13, France [email protected] IA has been a consultant and an invited speaker for UCB Pharma. 1 2 3
4 5 6
7 8
Tiriac A, Del Rio-Bermudez C, Blumberg MS. Self-generated movements with “unexpected” sensory consequences. Curr Biol 2014; 24: 2136–41. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science 2013; 342: 373–77. Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JA. Effect of 1 night of total sleep deprivation on cerebrospinal fluid beta-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol 2014; 71: 971–77. Strollo PJ Jr, Soose RJ, Maurer JT, et al. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med 2014; 370: 139–49. Videnovic A, Noble C, Reid KJ, et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol 2014; 71: 463–69. Belaid H, Adrien J, Laffrat E, et al. Sleep disorders in Parkinsonian macaques: effects of L-dopa treatment and pedunculopontine nucleus lesion. J Neurosci 2014; 34: 9124–33. Arnulf I, Rico T, Mignot E. Diagnosis, disease course, and management of patients with Kleine-Levin syndrome. Lancet Neurol 2012; 11: 918–28. Kas A, Lavault S, Habert MO, Arnulf I. Feeling unreal: a functional imaging study in 41 patients with Kleine-Levin syndrome. Brain 2014; 137: 2077–87.
CNS infections in 2014: guns, germs, and will Important advances in neurological infections during 2014 spanned antimicrobial treatments (guns), pathogenesis and detection of germs, including viruses and prions, and the will to develop and implement prevention programmes in resource-limited settings. One study addressed the complex issue of appropriate timing of initiation of combined antiretroviral therapy (CART) in patients with AIDS-associated opportunistic infections. Clinical decision making must weigh the potential risk of delaying treatment in patients with profound immunosuppression against the risks associated with co-administration of treatments for opportunistic infections with CART, including potential drug 20
interactions and risk of immune reconstitution syndrome. Although previous studies have shown a potential benefit of early initiation of antiretroviral drugs in patients with non-CNS opportunistic infections, available data suggests that there might be separate considerations for individuals with CNS opportunistic infections. In the COAT trial, done in Uganda and South Africa, David Boulware and colleagues1 provide evidence that helps to clarify when to start CART in patients with cryptococccal meningitis. After 7–11 days of antifungal treatment, 177 CART-naive individuals were randomly assigned to receive early (started ≤48 h after randomisation) or deferred (started 4 weeks after randomisation) CART. www.thelancet.com/neurology Vol 14 January 2015
