Interrater reliability in pupillary measurement

STUDY OBJECTIVE: A previous report documented ranges of normal pupil size on the basis of measurements by the principal investigator. In this report, we examine interrater reliability of pupillary measurement. METHODS: According to a randomized double-blind assignment, healthy volunteers received phenylephrine in one eye and sterile water in the other. After a wait period, the principal investigator and then other observers, using a gauge with a modified Haab scale, took measurements of each pupil, both in fluorescent light (2,700 to 5,400 lux) and bright light (>54,000 lux), whereas the contralateral pupil was concealed. For the first pupil observed in each session, each observer also provided a gestalt judgment of whether the pupil was dilated. In the study's main comparison, paired differences between principal investigator and nonprincipal investigator measurements were summarized by using the median and interquartile range for measurements taken in both light intensities. Interrater agreement in diagnosing pupillary dilation was also calculated for gestalt judgment and for simple measurement. RESULTS: Among 149 principal investigator/nonprincipal investigator pairs taken from 102 participants, principal investigator room-light measurements were 0.2 mm (median 0.2 mm; interquartile range -0.4 to 0.7 mm) greater than those from other observers, but there was no difference in bright-light measurements (median 0 mm; interquartile range -0.5 to 0.4 mm). Nevertheless, principal investigator/nonprincipal investigator percentage agreement in judging dilation by means of measurement was high in both light intensities (85% to 86%). In pupils with gestalt judgment of the presence or absence of pupillary dilation, percentage agreement between nonprincipal investigator observers was higher for measurement (75% to 82%) than for gestalt judgment (61%). CONCLUSION: There was no systematic difference between principal investigator and nonprincipal investigator bright-light measurements, supporting the range of normal values published previously. Interrater agreement in diagnosing pupillary dilation by means of measurement was high.     

Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work

Decreases in melatonin production in human and animals are known to be caused by environmental lighting, especially short-wavelength lighting (between 470 and 525 nm). We investigated the novel hypothesis that the use of goggles with selective exclusion of all wavelengths less than 530 nm could prevent the suppression of melatonin in bright-light conditions during a simulated shift-work experiment. Salivary melatonin levels were measured under dim (<5 lux), bright (800 lux), and filtered (800 lux) light at hourly intervals between 2000 and 0800 h in 11 healthy young males and eight females (mean age, 24.7 +/- 4.6 yr). The measurements were performed during three nonconsecutive nights over a 2-wk period. Subjective sleepiness was measured by self-report scales, whereas objective performance was assessed with the Continuous Performance Test. All subjects demonstrated preserved melatonin levels in filtered light similar to their dim-light secretion profile. Unfiltered bright light drastically suppressed melatonin production. Normalization of endogenous melatonin production while wearing goggles did not impair measures of performance, subjective sleepiness, or alertness.     

Valid parameters for investigation of the pupillary light reflex in normal and diabetic subjects shown by factor analysis and partial correlation

Summary Pupillary test data of 103 normal and 119 diabetic subjects (47 IDDM, 72 NIDDM) were evaluated by factor analysis. From a total of nine pupillary parameters three factors were extracted in the analysis. Factor 1 represents maximal pupillary area, contraction velocity at 1 s, dilation velocity at 6 s and minimal pupillary area — static and simple dynamic parameters; factor 2 amplitude of pupillary unrest, area under the detrended curve of pupillary unrest and period of pupillary unrest — parameters of pupillary unrest; factor 3 fusion frequency of pupillary response following flicker stimuli and latency time of pupillary light reflex — second order dynamic parameters. Factor analysis was then applied to investigate diabetic patients with a high percentage of autonomic neuropathic participants (about 39 % had pupillary and about 35 % had cardio-respiratory function disorders), which revealed the same three factors as those identified in normal subjects. Furthermore, an age-related database of parameters of pupillary unrest is given. It demonstrates that normal subjects and diabetic patients did not differ in the period of pupillary unrest (normal vs diabetic (mean±SEM): 1550±29 vs 1536±27 ms; 2p>0.5). The difference in amplitude (47.8±2.8 vs 41.0±2.6 % percentile; 2p=0.071) and area under the detrended curve of pupillary unrest (47.9±2.8 vs 40.8±2.6 % percentile, 2p=0.062) seems to show a trend but was not significant. In conclusion, factor analysis revealed three different pupillary test factors. From the comparison of normal and diabetic subjects factor 1 which accounts for the highest percentage of variance (43 %) and factor 3(12 %) appear to be useful for investigating the pupillary light reflex. Factor 2 is not useful because of the insignificant differences between the normal and diabetic group. From factor analysis and partial correlation we believe that pupillary autonomic function in diabetic patients can be best assessed by using only two parameters, maximal pupillary area and latency time.Abbreviations IDDM Insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - lx lux - lm lumen     

Peripheral vision suppression of melatonin.

The suppression of melatonin by bright light is probably mediated by the suprachiasmatic nucleus (SCN) in humans. In animals, SCN cells have broad visual receptive fields, suggesting that peripheral bright light could be effective for melatonin suppression. Twelve healthy subjects were subjected to 1000 lux illumination for 2 hr from 0100 to 0300 on two occasions: once lighting the central visual field 5 degrees from the center of gaze and once lighting the peripheral visual field 60 degrees lateral to the direction of gaze. Six subjects were observed on a third occasion in dim light. The three conditions differed significantly, with less melatonin secreted in 1000 lux, but melatonin levels with central and peripheral illumination did not differ. This suggests that phototherapy using bright light in the visual periphery may be effective.     

Peripheral vision suppression of melatonin

Abstract: The suppression of melatonin by bright light is probably mediated by the suprachiasmatic nucleus (SCN) in humans. In animals, SCN cells have broad visual receptive fields, suggesting that peripheral bright light could be effective for melatonin suppression. Twelve healthy subjects were subjected to 1000 lux illumination for 2 hr from 0100 to 0300 on two occasions: once lighting the central visual field 5° from the center of gaze and once lighting the peripheral visual field 60° lateral to the direction of gaze. Six subjects were observed on a third occasion in dim light. The three conditions differed significantly, with less melatonin secreted in 1000 lux, but melatonin levels with central and peripheral illumination did not differ. This suggests that phototherapy using bright light in the visual periphery may be effective.     

Entrainment of the human circadian pacemaker to longer-than-24-h days

Entrainment of the circadian pacemaker to the light:dark cycle is necessary for rhythmic physiological functions to be appropriately timed over the 24-h day. Nonentrainment results in sleep, endocrine, and neurobehavioral impairments. Exposures to intermittent bright light pulses have been reported to phase shift the circadian pacemaker with great efficacy. Therefore, we tested the hypothesis that a modulated light exposure (MLE) with bright light pulses in the evening would entrain subjects to a light:dark cycle 1 h longer than their own circadian period (tau). Twelve subjects underwent a 65-day inpatient study. Individual subject's circadian period was determined in a forced desynchrony protocol. Subsequently, subjects were released into 30 longer-than-24-h days (daylength of tau + 1 h) in one of three light:dark conditions: (i) approximately 25 lux; (ii) approximately 100 lux; and (iii) MLE: approximately 25 lux followed by approximately 100 lux, plus two 45-min bright light pulses of approximately 9,500 lux near the end of scheduled wakefulness. We found that lighting levels of approximately 25 lux were insufficient to entrain all subjects tested. Exposure to approximately 100 lux was sufficient to entrain subjects, although at a significantly wider phase angle compared with baseline. Exposure to MLE was able to entrain the subjects to the imposed sleep-wake cycles but at a phase angle comparable to baseline. These results suggest that MLE can be used to entrain the circadian pacemaker to non-24-h days. The implications of these findings are important because they could be used to treat circadian misalignment associated with space flight and circadian rhythm sleep disorders such as shift-work disorder.     

Origin and size of the coronary arteries in the north-west Indians

The origin of the coronary arteries and sizes of their ostia were studied in 500 adult hearts (385 male and 115 female), obtained from medico-legal autopsies performed by one of the authors on subjects varying in age from 18 to 75 years and residents of Chandigarh zone. Third coronary artery was present in 34.8% male and 27.8% female hearts (p greater than 0.05). Whereas the incidence of the origin of right coronary artery above the supravalvular ridge was 3.4% in the males and 1.7% in females (p greater than 0.05), that of the left coronary artery was 7% in both sexes. The mean diameter of the origin of the right coronary artery in the males was 3.2 +/- 0.5 mm, and that of the females was 2.8 +/- 0.4 mm (p less than .001). The mean diameter of the left coronary artery in the males was 3.7 +/- .7 mm, and in famels 3.2 +/- .6 mm (p less than .001). The size of the left coronary artery in unsexed hearts of north-west Indian population was calculated as 3.6 mm while that of the right as 3.1 mm. The former is definitely smaller than that given in Western literature, while the size of the right artery is only marginally so. The sizes of both coronary arteries had significant correlationship with body weight, body weight, body surface area, heart weight and age. This investigation showed that the size of the coronary arteries increased with an increase in age.     

Systemic atropine administration during cardiac arrest does not cause fixed and dilated pupils

OBJECTIVES: Systemic administration of atropine during CPR may postpone brain death determination because of its reputed ability to produce fixed and dilated pupils. We studied the effect of atropine administered in the usual doses as an adjunct to endotracheal intubation and for cardiac arrest to determine if it would interfere with neurological assessment. DESIGN: Two groups of children were studied. Group 1 consisted of 28 patients who received atropine (0.03 +/- 0.003 mg/kg) prior to endotracheal intubation. Group 2 consisted of 21 patients previously without evidence of brainstem disease who suffered a witnessed arrest and had prompt return of spontaneous circulation and received an atropine dose of 0.03 +/- 0.01 mg/kg. RESULTS: In group 1, pupillary size averaged 4.02 +/- 0.78 mm before and 4.75 mm +/- .84 mm after atropine (P less than .001). In group 2, the pupillary examination was conducted 30 minutes after return of spontaneous circulation. The pupillary diameter was 4.80 +/- 0.91 mm. All pupils were reactive to light in both groups. CONCLUSION: Atropine administration in conventional dose causes slight pupillary dilation but does not abolish pupillary light reactivity.     

Evening melatonin and bright light administration induce additive phase shifts in dim light melatonin onset

In healthy young men, administration of a single light pulse (5000 lux for 3 hr) or a single melatonin pill (5 mg) at 20:40 hr under controlled constant routine conditions of <10 lux, yielded a phase delay and a phase advance, respectively, in the circadian marker of dim light melatonin onset 24 hr later. Phase shifts after combining the two interventions were additive. Melatonin suppression is not necessary for a phase shift by light, and melatonin is not a 'weak' Zeitgeber relative to bright light when ambient lighting is strictly controlled.     

Effects of a two-hour early awakening and of bright light exposure on plasma patterns of cortisol, melatonin, prolactin and testosterone in man.

Bright light is a synchronizing agent that entrains human circadian rhythms and modifies various endocrine and neuroendocrine functions. The aim of the present study was to determine whether and how the exposure to a bright light stimulus during the 2 h following a 2 h earlier awakening could modify the disturbance induced by the the sleep deprivation on the plasma patterns of hormones whose secretion is sensitive to light and/or sleep, namely melatonin, prolactin, cortisol and testosterone. Six healthy and synchronized (lights on: 07.00-23.00) male students (22.5 +/- 1.1 years) with normal psychological profiles volunteered for the study in winter. The protocol consisted of a baseline control night (customary sleep schedule) followed by three shortened nights with a rising at 05.00 and a 2 h exposure to either dim light (50 lux; one week) or bright light (2000 lux; other week). Our study showed a phase advance of the circadian rhythm of plasma cortisol without significant modifications of the hormone mean or peak concentration. Plasma melatonin concentration decreased following bright light exposure, whereas no obvious modifications of plasma testosterone or prolactin patterns could be observed in this protocol.     

Newborn primate infants are entrained by low intensity lighting

At the present time we do not know when the circadian timing system of human infants becomes responsive to light. Because of human study limitations, it is not currently possible to address this issue in clinical studies. Therefore, to provide insights into when the circadian system of humans becomes responsive to light, baboons were studied. We first assessed if the biological clock located in suprachiasmatic nuclei (SCN) is responsive to light at birth. When term newborn infants were exposed to bright light at night (5000 lux), SCN metabolic activity and c-fos mRNA expression increased, indicating the presence of photic responsiveness. When photic entrainment of developing rhythmicity was examined in infants, low intensity (200 lux) cycled lighting was sufficient to entrain circadian phase. However, low intensity lighting was not sufficient to induce changes in SCN metabolic activity or c-fos mRNA expression. Phase–response studies indicated that light exposure (200 lux) before the onset of activity most effectively shifted circadian phase. These data provide direct evidence that the SCN are responsive to visually mediated light information in a primate at birth. Further consideration of lighting conditions that infants are exposed to is therefore warranted.     

The biological clock of very premature primate infants is responsive to light

Each year more than 250,000 infants in the United States are exposed to artificial lighting in hospital nurseries with little consideration given to environmental lighting cycles. Essential in determining whether environmental lighting cycles need to be considered in hospital nurseries is identifying when the infant's endogenous circadian clock becomes responsive to light. Using a non-human primate model of the developing human, we examined when the circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), becomes responsive to light. Preterm infant baboons of different ages were exposed to light (5,000 lux) at night, and then changes in SCN metabolic activity and gene expression were assessed. After exposure to bright light at night, robust increases in SCN metabolic activity and gene expression were seen at ages that were equivalent to human infants at 24 weeks after conception. These data provide direct evidence that the biological clock of very premature primate infants is responsive to light.     

Case Report: Explantation of A Binkhorst Iridocapsular Lens >30 Years After Implantation in an Eye With Pseudoexfoliation Syndrome

An 86-year-old man with a Binkhorst 2-loop intraocular lens (IOL) that was implanted in the pupillary sphincter 33 years earlier was examined. The pupil of the implanted eye with the Binkhorst IOL was irregular and the eye had pseudoexfoliation (PEX) syndrome. Pupillary erosion resulted from rubbing of the IOL edge against the pupillary sphincter with PEX material. The IOL was removed because of visual distortion and intense pseudophakodonesis. Gross and light microscopic analyses showed no irido-fibro-lenticular adhesions over the lens or fragments of iris tissue attached to the lens. Scanning electron microscopy showed several pores of different sizes. No inflammatory cells were present, suggesting that the IOL was well tolerated.The case suggested that the pupillary ruff was not a good location for implantation of an IOL in an eye with PEX. Caution is recommended before implanting or suturing an IOL close to the pupillary border in eyes with PEX during cataract surgery.     

High-intensity environmental light in dementia: effect on sleep and activity

OBJECTIVES: To determine whether high-intensity ambient light in public areas of long-term care facilities will improve sleeping patterns and circadian rhythms of persons with dementia. DESIGN: A cluster-unit crossover intervention trial involving four conditions: morning bright light, evening bright light, all-day bright light, and minimum standard light. SETTING: The common areas of two geriatric units in a psychiatric hospital and a dementia-specific residential care facility. PARTICIPANTS: Sixty-six older adults with dementia. INTERVENTION: Ambient bright light of approximately 2,500 lux, delivered through a low-glare lighting system installed in the dining and activity areas. Participant exposure averaged 2.5 to 3.0 hours for the morning and evening interventions and 8.4 hours for the all-day intervention. MEASUREMENTS: Nighttime sleep using wrist actigraphy and daytime activity using nonobtrusive daytime observations. RESULTS: Night-time sleep increased significantly in participants exposed to morning and all-day light, with the increase most prominent in participants with severe or very severe dementia (mean increase 16 minutes (P=.008) for morning, and 14 minutes (P=.01) for all-day). Morning light produced a mean phase advance of 29 minutes (P=.02) and evening light a mean phase delay of 15 minutes (P=.06). Effects on daytime sleepiness were inconsistent, and the number of sleep bouts, mesor, amplitude, intradaily variability, and interdaily stability were not significantly different, indicating that the overall strength of day and night activity rhythms did not change significantly under any treatment condition. CONCLUSION: Bright light appears to have a modest but measurable effect on sleep in this population, and ambient light may be preferable to stationary devices such as light boxes.     

Pupillary size in children and adolescents with type 1 diabetes

Pupillary adaptation to darkness was studied in 63 children and adolescents with Type 1 diabetes using a simple portable pupillometer. Results were compared with those in a group of age-related non-diabetic children and expressed as the ratio of the pupil diameter to the iris diameter (pupil diameter %). In the diabetic patients the pupil diameter % was 61.1 +/- 5.8 (44.4-71.9) % compared with 64.2 +/- 4.1 (53.2-72.6) % in the control subjects (p less than 0.001). Abnormal pupillary adaptation to darkness was found more commonly than abnormal heart rate variation in response to a variety of stimuli in the diabetic patients. Pupillary adaptation to darkness may be useful as an indicator of subclinical autonomic neuropathy in diabetic children.     

Scheduled Bright Light for Treatment of Insomnia in Older Adults

OBJECTIVES: To determine whether bright light can improve sleep in older individuals with insomnia.
DESIGN: Single-blind, placebo-controlled, 12-week, parallel-group randomized design comparing four treatment groups representing a factorial combination of two lighting conditions and two times of light administration.
SETTING: At-home light treatment; eight office therapy sessions.
PARTICIPANTS: Thirty-six women and fifteen men (aged 63.6±7.1) meeting primary insomnia criteria recruited from the community.
INTERVENTION: A 12-week program of sleep hygiene and exposure to bright (∼4,000 lux) or dim light (∼65 lux) scheduled daily in the morning or evening for 45 minutes.
MEASUREMENTS: Within-group changes were observed for subjective (sleep logs, questionnaires) and objective (actigraphy, polysomnography) sleep measures after morning or evening bright light.
RESULTS: Within-group changes for subjective sleep measures after morning or evening bright light were not significantly different from those observed after exposure to scheduled dim light. Objective sleep changes (actigraphy, polysomnography) after treatment were not significantly different between the bright and dim light groups. Scheduled light exposure was able to shift the circadian phase predictably but was unrelated to changes in objective or subjective sleep measures. A polymorphism in CLOCK predicted morningness but did not moderate the effects of light on sleep. The phase angle between the circadian system (melatonin midpoint) and sleep (darkness) predicted the magnitude of phase delays, but not phase advances, engendered by bright light.
CONCLUSION: Except for one subjective measure, scheduled morning or evening bright light effects were not different from those of scheduled dim light. Thus, support was not found for bright light treatment of older individuals with primary insomnia.     

Sensitivity of Goats to a Light Pulse During the Night as Assessed by Suppression of Melatonin Concentrations in the Plasma

This study investigates the ability of a 1 h light pulse of different intensities at night to suppress plasma melatonin in goats. Six female Saanen dairy goats, about 2 yr old, were housed in a light-tight shed. The goats were habituated for 1 wk to an 8L:16D photoperiod (40.70 +/- 4.16 microW/cm2; 137 +/- 14 lux), lights on 0800 h. A 1 h light pulse, of different intensity on each occasion, was given from 1900 to 2000 h. Light intensity was measured by using a lux meter (mean of 36 measurements at goat's eye level). Five different light intensities were given during December in the order 4.22 +/- 0.62 microW/cm2 (14.2 +/- 2.1 lux), 0.68 +/- 0.09 microW/cm2 (2.3 +/- 0.3 lux), 0.26 +/- 0.004 microW/cm2 (0.87 +/- 0.14 lux), darkness, 40.70 +/- 4.16 microW/cm2 (137 +/- 14 lux), with 1-3 d between treatments. The goats were bled hourly from 1500 to 1900 h and every 15 min from 1900 to 2100 h, and a last bleed occurred at 2200 h. Dark-phase samples were taken in dim red light (less than 0.03 microW/cm2; 0.1 lux). Plasma was assayed for melatonin by radioimmunoassay. Suppression of melatonin concentrations increased as light intensity increased as follows: Darkness, 0%; 0.26 +/- 0.004 microW/cm2; 0%; 0.68 +/- 0.09 microW/cm2; 43.1%; 4.22 +/- 0.62 microW/cm2, 71.1%; 40.70 +/- 4.16 microW/cm2, 81.2%. Suppression was significant (P less than 0.05) at light intensities greater than 0.68 microW/cm2, 2.3 lux. A hyperbolic relationship existed between percent suppression and light intensities.     

Senile miosis: the possible contribution of disordered sleep and daytime sleepiness

The contribution of disordered sleep and daytime sleepiness to senile miosis was investigated in 23 participants aged 60 to 80 years and 12 participants aged 21 to 40 years. All participants filled out questionnaires and were interviewed about their health, sleep, and daytime alertness. On this basis the older group was subdivided into a group of 13 participants with sleep disorders or daytime sleepiness and 10 participants without. All participants were studied with a computerized infrared television pupillometry system for 15 s in ambient lighting, 15 s after 5 min dark adaptation and with 5 light flashes. Pupil diameter after dark adaptation was significantly larger in the older group without sleep disorders than in the older group with sleep disorders (5.94 +/- .73 mm vs. 4.49 +/- .62 mm, M +/- SD, p less than .001). Significant partial correlation coefficients controlled for age were found between pupillary diameter and a variety of sleep variables. The data suggest that occult sleep disorders and daytime sleepiness may contribute to senile miosis.     

Carotid artery wall hypertrophy in children with metabolic syndrome

Preclinical vascular changes (increased stiffness and/or wall thickness) have been observed in children with known metabolic risk factors. Aim of the present study was to evaluate different carotid parameters, representative of vascular health, in children with and without metabolic syndrome (MS). We studied 38 children with MS (mean age 9.6+/-2.6 years; range 6-14 years) and 45 healthy age-matched subjects. Children who met three or more of the following criteria qualified as having the MS: fasting glucose >110 mg dl(-1), fasting triglyceride concentration >100 mg dl(-1), fasting high-density lipoprotein cholesterol concentration <50 mg dl(-1) for females or <45 mg dl(-1) for the males, waist circumference >75th percentile for age and gender and systolic or diastolic blood pressure >90th percentile for age, gender and height. Carotid B-mode ultrasound examinations were performed and intima-media thickness and diameters were measured in all subjects. Arterial geometry was further characterized by calculation of carotid cross-sectional area. Carotid intima-media thickness and lumen diameters were increased in children with MS as compared to children without MS. Moreover, carotid cross-sectional area was significantly higher in the group of children with MS 9.83+/-1.86 mm(2) [mean+/-s.d.] compared with the control group: 7.77+/-1.72 mm(2), P<0.001, even after adjustment for age, gender and height. Carotid hypertrophy is already detectable in children with MS. High-resolution B-mode ultrasound could provide a valuable tool for the cardiovascular risk stratification of children.     

The effects of prior light history on the suppression of melatonin by light in humans

We investigated the impact of light exposure history on light sensitivity in humans, as assessed by the magnitude of the suppression of melatonin secretion by nocturnal light. The hypothesis was that following a week of increased daytime bright-light exposure, subjects would become less sensitive to light, and that after a week of restriction to dimmer light they would become more sensitive. During the bright week, subjects (n = 12) obtained 4.3 +/- 0.4 hr of bright light per day (by going outside and using light boxes indoors). During the dim week, they wore dark goggles (about 2% light transmission) when outside during daylight and spent 1.4 +/- 0.9 hr per day outside. Saliva samples were obtained every 30 min for 7 hr in dim light (<15 lux) on two consecutive nights (baseline and test night) at the end of each week. On the test night, 500 lux was presented for 3 hr in the middle of the collection period to suppress melatonin. There was significantly more suppression after the dim week compared with after the bright week (to 53 versus 41% of the baseline night values, P < 0.05). However, there were large individual differences, and the difference between the bright and dim weeks was most pronounced in seven of the 12 subjects. Possible reasons for these individual differences are discussed, including the possibility that 1 wk was not long enough to change light sensitivity in some subjects. In conclusion, this study suggests that the circadian system's sensitivity to light can be affected by a recent change in light history.