Despite the voluminous evidence showing the adverse effects of impaired sleep across all major systems, several studies have demonstrated that clinicians fail to obtain a thorough sleep/wake history from their patients. Why does sleep receive inadequate attention in the clinic?
I find sleepiness to be the most underrecognized, misdiagnosed, and undertreated symptom in medicine. The sensation of sleepiness is a universal experience. For many individuals, and certainly all of those having done medical residencies, even severe sleepiness has been experienced. Hence, many clinicians dismiss it as a normal variant. Also, many patients with pathological sleepiness present with symptoms including fatigue, lack of energy, tiredness, and lack of motivation, which is often mistaken for depression. Thus, most clinicians trivialize sleepiness or fail to recognize it. It must be remembered that pathological sleepiness has a clear cause that may lead to significant morbidity if left untreated. Examples of disease-specific morbidities include hypertension in obstructive sleep apnea (OSA), and increased risk of cancer in shift work sleep disorder. The morbidities associated with pathological sleepiness are more imminent and include cognitive impairment, decreased productivity, mood disturbances, and increased risk of accidents. Clinicians must appreciate that pathological sleepiness is common and associated with specific medical, psychiatric, and sleep disorders. Thus, the clinician should be able to properly assess and diagnose sleepiness in their patients.
A 2006 study published by your team and and a separate study done independently by Emmanuel Mignot, MD, PhD, demonstrated a greater prevalence of multiple sleep onset rapid eye movement periods (SOREMPs) (Mignot E, et al. Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults. Brain. 2006;129(Pt 6):1609-1623; Singh M, et al. The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep. 2006;29(7):890-895.) in the general population than previously thought. What are SOREMPs and what are the practical implications of this finding?
Individuals normally transition into and cycle through sleep in discrete stages. About 80 to 90 minutes after sleep onset an individual will go into rapid eye movement (REM) sleep. In the 1960s, Rechtschaffen et al reported that narcolepsy patients would occasionally exhibit REM sleep immediately or within 10 minutes of falling asleep (Rechtschaffen A, et al. Nocturnal sleep of narcoleptics. Electroencephalogr Clin Neurophysiol. 1963;15:599-609.). The presence of these so-called SOREMPs had appeal as the auxillary symptoms of narcolepsy-cataplexy, hypnagogic hallucinations, and sleep onset paralysis-were judged to be manifestations of REM sleep. So both the symptoms and the SOREMPs were suggestive of increased (or abnormal) REM pressure. Unfortunately, SOREMPs did not occur every night. To better assay this diagnostic characteristic for narcolepsy, the Multiple Sleep Latency Test (MSLT) was employed. The MSLT measures sleep onset during a series of nap opportunities throughout the day. It became clear that patients with narcolepsy virtually always had at least 2 SOREMPs out of 5 nap opportunities while controls did not. This became the gold standard for polysomographic evidence of narcolepsy. It was felt that cataplexy was the pathognomonic symptom of narcolepsy and multiple SOREMPs were the pathognomonic sign of narcolepsy. Subsequently, papers appeared reporting multiple SOREMPs in patients with sleep apnea syndrome as well as scattered reports of SOREMPs in other conditions including in normal control subjects. The important thing in the paper from our laboratory as well as from that of Mignot et al was that the subjects were not clinical samples, but were rather from a population-based sample. It is also very important to note that the subjects with multiple SOREMPs were significantly more sleepy than the general population; most of these subjects exhibited pathological levels of sleepiness on the MSLT. Taken together these data support the hypothesis that these represent a variant of narcolepsy. These are people who are asymptomatic but exhibit all the signs of narcolepsy. It is not very different from other disorders as once we start to study a condition we see variants of the syndrome. For example, in the case of OSAwe became aware of variants like upper airway syndrome and other sleep-related respiratory disorders. To that end, they are now referred to as sleep-related breathing disorders.
What follow-up studies are you conducting to further elucidate these data?
We have to determine two things about the phenotype of multiple SOREMPs—whether they are reliable , and if so, is there familial aggregation. To that end, we must evaluate individuals with and without SOREMPs and see if they reliably reproduce the presence or absence of SOREMPs, respectively. If the pattern of SOREMPs is reproducible, it will be important to evaluate family members and determine whether there is a familial aggregation of this phenotype. Ideally this would be done with classical narcoleptic patients, asymptomatic narcoleptic patients, and controls.
Finally there have been several studies over the years demonstrating an HLA marker in narcolepsy as well as the finding of decreased or absence of orexin in patients with narcolepsy. Thus, the final study needs to evaluate these biological markers in asymptomatic patients with multiple SOREMPs. If they are abnormal, these subjects would represent a narcolepsy variant.
Evidence now strongly supports the idea that chronic insomnia is a disorder that demands independent assessment and treatment and should no longer be regarded merely as a symptom of an underlying disorder. What were some of the major insights supporting this paradigm shift in insomnia management?
There is convincing data that insomnia is a disorder. In fact, one of the major conclusions of the 2005 NIH State of the Science Conference (NIH State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults statement. J Clin Sleep Med. 2005;1(4):412-421.)was that insomnia should not be thought of as secondary to another medical or psychiatric disorder, rather comorbid with them. It is estimated that insomnia is a stand-alone condition about 10% of the time (primary insomnia) and exists in the context of other medical, psychiatric, and sleep disorders about 90% of the time (comorbid insomnia). Three facts lead to this conceptualization. First, often the insomnia precedes the onset of the comorbid condition. Second, insomnia is refractory to the successful treatment of the comorbid condition. Third, improving insomnia improves the comorbid condition. This third fact is the most important and has been demonstrated in multiple psychiatric conditions, a variety of pain conditions, and with vasomotor symptoms.
The definition of a disorder, as opposed to a symptom, is that it is characterized by morbidity not mediated by normal physiology, rather by pathophysiology. In the case of insomnia, a variety of morbidities may also be associated. These include increased risk of depression, falls in the elderly, and hypertension, among others. Additionally, this has been paralleled in the literature with reports on the pathophysiology of insomnia. Insomnia is generally viewed as a disorder of arousal. Insomnia does not so much represent an impairment of the sleep systems, rather an overactivation of arousal systems which override the normal sleep systems. There are data from a variety of sources demonstrating an increase in arousal systems, and changes in cortisol and norepinehrine levels. Also, this increased arousal is associated with core body temperature, EEG fast activity, and brain imaging (PET). The MSLT affords us a great opportunity to better understand the pathophysiology of insomnia. Sleep fragmentation leads to decreases in sleep latency (more sleepiness). In insomniacs there is an increase in sleep latency. Despite the fact that insomniacs have disturbed sleep, daytime fatigue, and tiredness, they take longer to fall asleep than matched controls. All of the morbidity and pathophysiology data support insomnia as being a primary disorder which merits treatment in its own right. This must be put in the context of the fact that in the majority of cases, the patient with insomnia will have a comorbid condition where there is, generally, a bidirectional relation between insomnia and the comorbidity. Thus treating the comorbid condition improves the insomnia and treating the insomnia improves the comorbid condition.
What do you feel was the most clinically important study published last year in sleep/wake medicine?
It is difficult to pick a single study as science does not move forward with quantum leaps as much as with a body of evidence using different approaches to gain an understanding. In addition, the field of sleep and associated disorders is so broad that there are many new findings which have important clinical impacts. For the purpose of this column, I will select a basic science paper which supports much of what was discussed about the pathophysiology of insomnia by Cano et al (Cano G, et al. Neural circuitry of stress-induced insomnia in rats. J Neurosci. 2008;28(40):167-184.). The authors describe a rat model of insomnia which produces a sleep disruption similar to that seen in humans suffering from stress-induced insomnia. In this model, the group looked at Fos expression as a measure of activated brain circuitry. They found an activation of the cerebral cortex, the limbic system, and parts of the arousal and autonomic systems. Of most interest, they found simultaneous activation of sleep promoting areas. This paper supports the view of insomnia as a disorder and points to the need to develop therapies which will blunt arousal systems rather than simply activate sleep systems.
Professor Jim Horne is interested in sleep, sleep loss, sleep function, qualification and quantification of sleepiness, circadian rhythms. Driver sleepiness, accidents; neuropsychology of the frontal lobes; sleep need.
The following slide presentations were presented on Monday, Jun 8, 2009 as part of the clinical workshop titled, “Sleep, Wake and Traumatic Brain Injury.”
CK is a 43 year old male without significant past medical history who presents to his primary care physician with an 8 week history of generalized fatigue and malaise.