Mark R. Pressman

Potential novel predictors of mortality in end-stage renal disease patients with sleep disorders.

Patients with end-stage renal disease (ESRD) have an annual mortality rate exceeding 20%, although some survive many years. The ESRD population has a high incidence of sleep disorders, including sleep apnea and periodic limb movements in sleep (PLMS). Sleep disorders result in sleep deprivation, which can negatively affect immune function and cardiovascular-related outcomes, common causes of death in patients with ESRD. This study examined predictors of mortality in patients with ESRD with sleep problems. Twenty-nine consecutive patients with ESRD reporting disrupted sleep or daytime sleepiness were studied by all-night polysomnography. All patients were followed up until death, transplantation, or study termination. Among the variables studied, including such previously reported predictors as serum albumin level, urea reduction ratio, and hematocrit, only the PLMS index (PLMSI), arousing PLMSI (APLMSI), and total number of arousals per hour of sleep significantly predicted mortality. The 20-month survival rate with a PLMSI less than 20 was greater than 90% versus 50% for a PLMSI of 20 or greater (exact log-rank, P = 0.007). For the deceased versus survivor groups, mean PLMSI was 119.1 versus 19.8 (P = 0.01) and APLMSI was 48.1 versus 7.8 (P = 0.00006), with a mean survival of 10.3 versus greater than 25.5 months, respectively (P = 0.001). Median survival of patients with a PLMSI greater than 80 was only 6 months. PLMSI, APLMSI, and total arousals per hour of sleep were strongly associated with mortality in patients with ESRD with sleep disorders independent of other factors and may be novel predictors of near-term mortality.

A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study)

End-stage renal disease (ESRD) is commonly associated with complaints of disturbed sleep and sleep disorders, frequently related to periodic limb movements in sleep (PLMS) or sleep apnea that may result in daytime sleepiness and other sequelae. Improvements in quality of life, including subjective sleep quality, have been reported in ESRD patients treated with recombinant human erythropoietin (rHuEPO). We investigated the objective effects of normalizing hematocrit on sleep disorders, sleep patterns, and daytime ability to remain awake in ESRD patients. Ten hemodialysis patients with sleep complaints while on rHuEPO therapy were studied by polysomnography while moderately anemic (mean hematocrit, 32.3%) and again when hematocrit was normalized (mean hematocrit, 42.3%) by increased rHuEPO dosing. Sleep patterns and associated parameters were monitored. Delivered dialysis dose and iron storage factors were monitored. Maintenance of Wakefulness Testing (MWT) was performed to assess daytime alertness/sleepiness. All 10 subjects experienced highly statistically significant reductions in the total number of arousing PLMS (P = 0.002). Nine of 10 subjects showed reductions in both the Arousing PLMS Index (P < 0.01) and the PLMS Index (P = 0.03) when hematocrit was normalized. Measures of sleep quality showed trends to improved quality of sleep. MWT demonstrated significant improvement in the length of time patients were able to remain awake (9.7 versus 17.1 minutes; P = 0.04). RHuEPO therapy with full correction of anemia reduces PLMS, arousals from sleep, and sleep fragmentation while allowing for more restorative sleep and improved daytime alertness. These findings may explain one mechanism for the improved quality-of-life parameters reported in ESRD patients treated with rHuEPO.

Alcohol-induced sleepwalking or confusional arousal as a defense to criminal behavior: a review of scientific evidence, methods and forensic considerations

An increasing number of criminal cases have claimed the defendant to be in a state of sleepwalking or related disorders induced by high quantities of alcohol. Sleepwalkers who commit violent acts, sexual assaults and other criminal acts are thought to be in a state of automatism, lacking conscious awareness and criminal intent. They may be acquitted in criminal trials. On the other hand, criminal acts performed as the result of voluntary alcohol intoxication alone cannot be used as a complete defense. The alcohol‐induced sleepwalking criminal defense is most often based on past clinical or legal reports that ingestion of alcohol directly ‘triggers’ sleepwalking or increased the risk of sleepwalking by increasing the quantity of slow wave sleep (SWS). A review of the sleep medicine literature found no sleep laboratory studies of the effects of alcohol on the sleep of clinically diagnosed sleepwalkers. However, 19 sleep laboratory studies of the effects of alcohol on the sleep of healthy non‐drinkers or social drinkers were identified with none reporting a change in SWS as a percentage of total sleep time. However, in six of 19 studies, a modest but statistically significant increase in SWS was found in the first 2–4 h. Among studies of sleep in alcohol abusers and abstinent abusers, the quantity and percentage of SWS was most often reduced and sometimes absent. Claims that direct alcohol provocation tests can assist in the forensic assessment of these cases found no support of any kind in the medical literature with not a single report of testing in normative or patient groups and no reports of validation testing of any sort. There is no direct experimental evidence that alcohol predisposes or triggers sleepwalking or related disorders. A legal defense of sleepwalking resulting from voluntarily ingested alcohol should be consistent with the current state of art sleep science and meet generally accepted requirements for the diagnosis of sleepwalking and other parasomnias.

Sleep Disorders Associated with Chronic Kidney Disease

Twenty-six million American adults have Chronic Kidney Disease (CKD). Chronic Kidney Disease is defined as kidney damage for 3 or more months with or without decreased GFR. Chronic Kidney Disease is divided into five stages, from Stage 1 to Stage 5. End-Stage renal disease is the 5th stage of CKD when dialysis is needed to sustain life. Sleep disorders are common and under recognized in advanced stages of Chronic Kidney Disease. Sleep disorders affect the quality of life and may also increase cardiovascular morbidity and mortality.

Spectral EEG analysis and sleepwalking defense: unreliable scientific evidence.

I a recent publication in JCSM,1 Drs. Cartwright and Guilleminault suggest that spectral analysis of the sleep EEG can be used to support a defense of sleepwalking in criminal cases. In particular the authors point to 3 publications that concluded that the sleep of sleepwalkers is defi ned by frequent arousals during SWS (slow wave sleep) as well as—or as a result of—lower % of SWA (slow wave activity).2-4 However, the authors of the study most often referred to have themselves concluded that spectral analysis of the sleep EEG in sleepwalkers is not suitable for forensic use. Gadreau and colleagues2 write: “ Given the likelihood that results of our study could be used in medico-legal settings, it is worth noting that the presence or absence of a decrease of SWA early in the night and of awakenings from SWS in a given individual does not conclusively establish or refute a tendency toward sleepwalking” (pages 4-5). The issue of frequent arousals and changes in SWS% in sleepwalkers as forensic evidence has also been previously reviewed in detail5 and was the subject of a series of letters to the editor of Sleep Medicine Reviews between Drs. Cartwright and Pressman in 2007-8 that readers might fi nd of interest.6-9 As noted by Drs. Cartwright and Guilleminault, establishing a current diagnosis of sleepwalking for a defendant is not the same as establishing that the defendant was sleepwalking during the commission of a crime. Nevertheless, this article suggests that spectral analysis of sleep recorded months or years after the incident offense can be used to support such a sleepwalking defense. There are 3 scientifi c publications currently available that conclude that arousals from SWS sleep and hypersynchronous delta waves are not diagnostic for sleepwalking.10-12 These published scientifi c studies analyzed arousals and SWS using standard visual methods and have reported a lack of statistical sensitivity and especially specifi city as diagnostic markers. Further, there are now more than 7 published studies that report arousals indexes for patients with sleepwalking (see Table 1 in ref. 10). While they are often elevated compared to normal controls there is signifi cant interstudy variability and there is no specifi c cutoff statistically or otherwise to assist in making the diagnosis. Additionally, the Spectral EEG Analysis and Sleepwalking Defense: Unreliable Scientifi c Evidence Mark R. Pressman, Ph.D., F.A.A.S.M.1; Mark Mahowald, M.D., F.A.A.S.M.2; Carlos Schenck, M.D.2; Michel Cramer Bornemann, M.D., F.A.A.S.M.3; Dev Banerjee, M.D.4; Michael Howell, M.D.2; Peter Buchanan, M.D.4; Alon Avidan, M.D., M.P.H., F.A.A.S.M.5 1Lankenau Medical Center and Lankenau Institute for Medical Research, Jefferson Medical School, Villanova School of Law, Villanova, PA; 2University of Minnesota, Minneapolis, MN; 3Sleep Medicine Services, HealthEast Care Systems of Minnesota, Minneapolis, MN; 4NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, Sydney, Australia; 5UCLA Sleep Disorders Center, Department of Neurology David Geffen School of Medicine at UCLA, UCLA, Los Angeles, CA

Alcohol, sleepwalking and violence: lack of reliable scientific evidence.

Sir, The recent Letter to the Editor by Drs Ebrahim and Fenwick (2012) challenges one sentence in a 2010 article published in Brain (Siclari et al. , 2010) stating that, because of the lack of reliable evidence, alcohol-induced sleepwalking should not be allowed as a defence to criminal acts. This, in turn, refers to an article published 22 years ago (Mahowald et al. , 1990). Drs Ebrahim and Fenwick express concern that defendants who have allegedly committed criminal acts while severely intoxicated with alcohol are potentially being denied a valid defence. In our opinion, claims of alcohol-induced sleepwalking violence or sleep sex …

Alcohol and Sleep Review: Flawed Design, Methods, and Statistics Cannot Support Conclusions

N A RECENT publication, Ebrahim and colleagues state in their abstract that they have provided an assessment of “all known scientific studies of the effects of alcohol on the nocturnal sleep of healthy volunteers” (Ebrahim et al., 2013, p. 539). Our review of this article found it to be seriously flawed by research design and statistical problems. Ebrahim and colleagues (2013) selected 20 published articles concerned with the effects of alcohol on sleep in humans. Numerous articles were excluded from consideration. Within these articles are 38 groups of subjects based on other criteria such as sex or dose of alcohol administered. Although all sleep stages were addressed, Ebrahim and colleagues (2013) focus on the effects of alcohol on slow-wave sleep (SWS); variously known as or abbreviated as SWS, deep sleep, Stages 3 + 4. Current nomenclature combines stages 3 and 4 sleep and renames them “N3”(Iber et al., 2007). As noted in their conclusion, One area of debate and sometimes controversy has been the issue of the impact of alcohol on SWS. For the first time, all the available data are presented here and based on the findings from all available studies, and in the majority, alcohol clearly increases SWS in the first part of sleep at all doses, across gender and ages. Data for the impact of alcohol on total night SWS display a dose dependent effect with low doses showing no clear trend, moderate doses show a trend toward an increase in SWS and with high doses there is a significant and clear effect of increasing total SWS. This effect is consistent across gender and age groups. (Ebrahim et al., 2013, pp. 547–548)

No scientific evidence that alcohol causes sleepwalking

Thank you for the opportunity to respond to Drs. Ebrahim and Fenwick s letter. We are somewhat confused by the content of their letter. We note that in 2000+ words they failed to address, raise, contradict or even comment on even a single point regarding the main conclusions of our review article (Pressman et al., 2007b). Specifically, they do not comment on or criticize our conclusions that: 1. There is no scientific evidence that alcohol predisposes, primes or precipitates sleepwalking. 2. There is extremely limited evidence that alcohol in social drinkers increases slow wave sleep (SWS). 3. There is no evidence that SWS is increased in alcohol abusers of any description or diagnosis. 4. The Alcohol (Challenge) Provocation Test is a completely unvalidated test. 5. In the severely alcohol intoxicated individual there is no scientific reason to attribute violence or sexual abuse to sleepwalking. Instead, Drs. Ebrahim and Fenwick spend almost all their time discussing tangential matters that do not bear on our main conclusions and in some cases don t appear related to this article at all. Most of the content appears very similar to another letter to editor they sent to Sleep Medicine Reviews (SMR) regarding a completely different article and editorial published in that journal (Ebrahim and Fenwick, 2007; Pressman 2007a; Mahowald et al., 2007). Readers may also want to look at our response to that letter (Pressman et al., 2007a). Among the various tangential topics addressed by Drs. Ebrahim and Fenwick, we were most mystified by their claim we were unacceptably biased towards the role of increased SWS in the occurrence of sleepwalking compared to some other unspecified theory. They state that they apparently arrived at this peculiar conclusion because we did not cite what appears to be a random assortment of journal articles that they list in their letter. We strongly suggest that Drs Ebrahim and Fenwick read the articles they cited if they have not done so already, as we find nothing in them to support an alternate theory of sleepwalking. Ebrahim and Fenwick apparently are referring to a completely different article published in a completely different journal. They appear to be paraphrasing – out-of-context – two letters to the editor of SMR by Dr. Rosalind Cartwright concerning another previously published article by one of us (MRP) (Pressman, 2007a; Cartwright 2007a,b). Their comments suggest they are unfamiliar with the extensive research that supports the role of increased SWS in sleepwalking. The role of increased SWS in sleepwalking is very well established and supported by numerous published empirical studies in the sleep laboratory that address this question directly and have highly significant statistical results (Pressman, 2007a; Zadra et al., 2008; Joncas et al., 2002; Pilon et al., 2006). On the other hand, there is no generally accepted alternate theory of sleepwalking. However, interested readers might want to look at the exchange of letters to editor between Dr. Cartwright and Dr. Pressman in SMR (Cartwright 2007a,b; Pressman, 2007b, 2008) for further information. Thus, yes, we freely admit that we are biased towards theories that are supported by extensive empirical scientific research and biased against theories that have little or no empirical support. Drs. Ebrahim and Fenwick also continue to defend their use of the Alcohol Challenge or Alcohol Provocation Test. We feel obligated to state for at least the fifth time in print that this test should not be permitted for clinical or forensic purposes (Pressman, 2007a; Pressman et al., 2007b,c,d). It is a completely unvalidated test with no published data regarding its sensitivity, specificity or reliability. It has never been replicated independently. No normative data for this test regarding any patient group including sleepwalkers exists. We again call upon Dr. Ebrahim to stop using this test until such time as the published scientific data supports its use. In summary, nothing in Drs. Ebrahim and Fenwick s letter addresses or contradicts the main points of our article. There is no scientific evidence that alcohol is involved in the occurrence of sleepwalking in any way.

Effects of Low-Dose Naloxone on Subjective Alertness and Pupil Diameter in Normal and Narcoleptic Subjects

Recent evidence suggests that endogenous opiates may be involved in the pathophysiology of narcolepsy. To test this theory, the effect of 0.8 mg naloxone hydrochloride on pupil size and subjective alertness was measured in normal and narcoleptic subjects. Naloxone resulted in significant pupillary constriction in the normal but not in the narcoleptic subjects. The extent of contraction of the pupil light reflex was reduced significantly in the narcoleptic but not in the normal subjects. There was no effect on subjective ratings of alertness on the Stanford Sleepiness Scale or the visual analogue scale in either group. The naloxone-related miosis in the normal group confirms that naloxone is not a pure opiate antagonist. The lack of naloxone-related miosis in the narcoleptics suggests that narcoleptic individuals do not respond to naloxone as do normal individuals. However, this difference can not be definitely attributed to the antagonism of endogenous opiates. The reduction of the extent of contraction of the light reflex suggests that naloxone caused an increase in supranuclear inhibition of parasympathetic pupil reflex activity. However, this finding may have resulted from mechanical limitations of a small pupil or technical limitations of the recording equipment. This study does not support previous reports that naloxone causes an increase in subjective alertness in narcoleptics.

Sleepwalking into a paradigm shift

The article by Perrault et al. [1] in this issue of Sleep Medicine may appear to be a technical report of interest to parasomnia specialists only. However, this article is just the latest in a series of research publications by the group led by Drs. Montplaisir and Zadra at the University of Montreal and Hopital du Sacre-Coeur de Montreal [2–5]. Taken along with brain imaging research [6] and other recent neurophysiological studies [7], these reports suggest sleepwalking research, and perhaps sleep science itself, has undergone a definite shift in methodology and theory in the last 10 years. In 1962 Thomas Kuhn published his famous volume on history and science asserting that scientific change does not occur slowly and incrementally, but rather follows sudden shifts in paradigm [8]. It is not certain if the current momentum in sleepwalking research would meet all the requirements of a Kuhnian paradigm shift, but the history of sleepwalking, which dates back to the ancient Greeks, has certainly changed with the prevailing religious, medical, and scientific beliefs. In the current era of digital computing, brain imaging, and evidence-based medicine, the Montreal group has clearly led the charge toward an improved understanding of sleepwalking that breaks considerable new ground. Historical reports of “sleepwalking” no doubt included many types of nocturnal wandering. Only in recent years has sleepwalking been separated from epilepsy, alcohol intoxication, psychiatric disorders, drug effects, and many other disorders and states. In eras dominated by religious beliefs and superstition, sleepwalking was often attributed to demon possession or to the devil [9]. This changed in the 17th and 18th centuries when sleepwalking was understood and confused with so-called Mesmerism – a state of consciousness related to hypnotism – sometimes called waking somnambulism [10]. In the late 19th century and first half of 20th century sleepwalking was seen through the lens of Freud and psychodynamic theories [11]. Around this period when the first descriptions of rapid eye movement (REM) sleep were developed, researchers most often hypothesized that sleepwalkers were enacting dreams during which traumatic memories were relived. In a classic case of good article, bad timing, Sours and colleagues in 1963 published an article on somnambulism in the military that relied heavily on psychodynamic theory and dreaming [12]. In the same year, the first sleep laboratory studies noted that sleepwalking and confusional arousals were not related to REM sleep or dreaming [13]. Rather, they occurred out of deep nonREM (NREM) sleep following a partial arousal. This resulted in the landmark description of NREM parasomnias as “Disorders of Arousal” that persists to this day [14]. Conducting an objective study of sleepwalking has always been difficult because sleepwalking infrequently occurs in the sleep laboratory. Nonetheless, the modern sleep laboratory has been used to test theories of certain electroencephalography (EEG) markers described in earlier sleep laboratory studies – hypersynchronous delta waves and sudden arousals from deep sleep as biological markers for sleepwalking. However, recent sleep laboratory studies show that these markers lack sensitivity and specificity [15,16]. Sleepwalking in the diagnostic sleep laboratory occurs so infrequently that a sleep study is not required by the International Classification of Sleep Disorders – Third Edition (ICSD-3) for the diagnosis of sleepwalking. This may yet change with further research. Zadra, Montplaisir, and colleagues have developed and operationalized a method to study sleepwalking objectively in the sleep laboratory with a combination of sleep deprivation and acoustic stimulation. They have shown that this method can provoke complex behaviors in slow-wave sleep (SWS) in 100% of clinically diagnosed sleepwalkers tested. Thus, when questions arise, it may now be possible to objectively test them. Opinions or theories need not persist for years without a basis in reliable sleep science. Imaging studies have demonstrated that the brain of the sleepwalker during NREM parasomnias shows functional dissociations [6,17]. Other studies have shown that sleep stages and wakefulness are not homogenous states of consciousness [7]. “Local sleep” research shows that certain parts of the brain may be active or “awake” at the same time other parts are inactive, deactivated or “asleep.” Thus, the basis of dissociated states in which complex movements may be present during sleep in the absence of higher cognitive function has been shown to have a foundation in measureable neurophysiology. Has a paradigm shift in sleepwalking research occurred? This may be unknown at present, but there certainly have been significant changes in methodology and understanding of the functional neurophysiology of sleepwalking.