Radiotherapy for Uveal Melanoma

Biology, Neurophysiology and Treatment of Circadian Rhythm Sleep-Wake Disorders

Yonah ZiembaWhen the Brains Clock Tells the Wrong TimeThird year medical studentDept. of PsychiatryThomas Jefferson University Hospital

Patient PresentationAL is a 18F, cant fall asleep before 2am and has difficulty waking up before 10am.Recurrent episodes of falling asleep during her morning college classes.During her previous semester, her classes were all in the afternoon. She slept from 2-10am without any trouble.Her friends tease that she thinks she is in California, but she never lived in a different time zone and has no desire to move.

Every animal has cicadian rhythm without outside input, even in cave or outer space

Biomarkers such as salivary dim light melatonin onset should be obtained only when the diagnosis is unclear.

EntrainmentThe humans natural body clock is approx. 25 hours. In order to function, our brain uses external light to adjust the circadian rhythm to external day/night cycles.This adjustment is called Entrainment.

How

Question: Is entrainment via rods & cones, or are there a separate set of photosensitive ganglion cells dedicated to circadian rhythm? Study Design: Develop knockout mice without rods & cones, and see whether they are capable of entrainment. Results: Entrainment can be done without rods & cones. Entrainment can not be done without eyes.

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Studies published in the early 1970s established the suprachiasmatic nucleus of the hypothalamus as the central circadian pacemaker in mammals (15). This pacemaker is comprised of individual cells which, when isolated, can oscillate independently with a near-24- hour period (5;6). The SCN receives direct input from the retina (79), providing a mechanism by which entrainment to light-dark cycles occurs. Recently, a subset of retinal ganglion cells has been described that serve as photoreceptors for circadian and other non-image-forming responses (1012). These specialized retinal ganglion cells are distributed throughout the retina, project to the SCN, are photosensitive, and contain melanopsin as their photopigment (13;14). While the photosensitive retinal ganglion cells can mediate circadian responses to light, there is also evidence that rod and cone photoreceptors can play a role in circadian responses to light (15;16). The relative contribution of different photoreceptors to circadian responses is not yet well understood, and this is an area of intense research currently. It is likely that the intensity, spectral distribution, and temporal pattern of light can all affect the relative contribution of different photoreceptors to circadian responses. The same neuroanatomical features of the circadian system described in mammals are also present in humans (1724). Sleep Med Clin. Author manuscript; available in PMC 2010 June 1.

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Circadian Rhythm Sleep-Wake Disorders Diagnostic Criteria Persistent pattern of sleep disruption that is due to a misalignment between the endogenous circadian rhythm and the sleep-wake schedule required by an individuals environment.

The sleep disruption leads to excessive sleepiness or insomnia, causing impairment.

Confirmation of the diagnosis includes a complete history and use of a sleep diary or actigraphy (i.e., a wrist-wom motion detector that monitors motor activity for prolonged periods and can be used as a proxy for sleep-wake patterns for at least 7 days).

The period covered should include weekends, when social and occupational obligations are less strict, to ensure that the individual exhibits a consistently delayed sleep-wake pattern.

Biomarkers such as salivary dim light melatonin onset should be obtained only when the diagnosis is unclear.

CRSWD- Delayed Sleep Phase TypeDelay in the timing of the major sleep period in relation to the desired sleep and wake- up time When allowed to set their own schedule, patients will exhibit normal sleep quality and duration.Symptoms of sleep-onset insomnia, difficulty waking in the morning, and excessive early day sleepiness are prominent.

When allowed to make own sched: NOT excessive sleep inertia

Excerpt of DSM

Excerpt of DSM

Alterations in response to light Hypersensitivity to nocturnal light exposure has been proposed in DSWPD, although the evidence is mixed. In one study, 2000 lux-hours of nocturnal light exposure was associated with a greater degree of melatonin suppression in adults with DSWPD compared with controls, suggestive of excessive circadian sensitivity to light [35].Other studies have failed to find similar effects but may not have controlled for differences in daytime light exposure, which can alter the melatonin response [12,22,36]. Alternatively, a blunted phase-advance response to morning light has also been proposed in DSWPD [37-39].Changes in light exposure Increased evening light exposure or decreased morning light exposure could theoretically contribute to the DSWPD phenotype, independent of issues regarding sensitivity to light [40,41]. However, a prospective cohort study of light exposure patterns among adolescents found comparatively less pre-sleep light intensity (lux) exposure in those with DSWPD compared with controls, and no differences in the amount of post-sleep light exposure [36].

Psychoactive medications have occasionally been implicated in circadian rhythm disturbances. In a study of seven adults with schizophrenia, receipt of typical antipsychotics (haloperidoland flupenthixol) was associated with circadian dyssynchrony, including delayed and free-running patterns, but no such association was found withclozapine

Excerpt of DSM

Developmental changes in sleep-wake timing A delay in preferred bedtimes and wake times during the adolescent period has been demonstrated across varying societies worldwide [12-21]. This coincides with a variety of pubertal changes, both physiologic and social [22].

A systematic assessment of circadian preference in >20,000 individuals demonstrated a crescendo pattern of increasing "eveningness" until the age of approximately 20 years, followed by a gradual decline [23]. Adolescent DSWPD may represent an extreme expression of this scheduling preference [5,24-29].

American and Norwegian adolescents: 7 percent [7,8], Japanese young people estimated a prevalence