With input from Dr Monica Vasudev

1304: Possible explanations of post COVID symptoms

Misalignment of the circadian timekeeping system with the desired sleep schedule or impairment of the circadian modulation of sleep and wakefulness often leads to clinically significant symptoms of insomnia and excessive daytime sleepiness, besides impaired physical, neurocognitive, emotional, and social functioning.

Types

A: Disrupted sleep-wake pattern: Characterized by abnormalities in the sleep-wake pattern compared with those of most healthy adults under similar environmental conditions.

1. Delayed sleep-wake phase disorder: The circadian system aids wakefulness until late in the evening, giving way to delayed sleep onset, typically occurring at midnight or later. If sleep is attempted at an earlier desired bedtime, sleep onset insomnia will occur. In the morning, the circadian system actively drives sleep later than conventional or desired wake-up times. If left undisturbed, such as on weekends or vacation, patients sleep well into the morning, sometimes until noon or later. When conventional rise times are required depending on school or work, patients with delayed sleep-wake phase disorder find it very difficult to wake up and feel alert.
2. Advanced sleep-wake phase disorder: Patients become sleepy earlier in the evening compared to conventional or desired bedtimes, and wake up earlier in the morning and cannot go back to sleep. This pattern of phase advancement is seen physiologically with aging but is more marked in patients with pathologic phase advance. When patients force themselves to stay awake in the evening, they wake up early and thus accumulate sleep debt.
3. Non-24-hour sleep-wake rhythm disorder:Patients have a free-running circadian system, which is often longer than 24 hours. There are periods when the circadian system actively drives wake during the night- time, causing insomnia, and actively drives sleep during the daytime, causing excessive daytime sleepiness. As the clock continues to free run, there are periods of proper alignment, with temporary resolution of the sleep-wake disturbances. Alternatively, patients may simply go to bed later and later on every subsequent night.
4. Irregular sleep-wake rhythm disorder:The circadian system fails to consolidate periods of wakefulness and periods of sleep. This leads to multiple short sleep episodes spread across the 24-hour day, interspersed with multiple periods of wakefulness.
5. Jet lag disorder:People find it difficult to fall asleep or maintain sleep at night after air travel across two or more time zones. Excessive daytime sleepiness may also occurs on account of reduced total sleep time as well as circadian misalignment. The disturbances continue until the circadian system adjusts to the new light-dark cycle at the destination.
6. Shift work disorder: It manifests as difficulty with sleep or wakefulness at times that are imposed by shifts running counter to the light-dark cycle. Patients accumulate sleep debt and have increased risk for accidents, errors, and other adverse health outcomes.

B: Functional impairment: As seen in any sleep disorder resulting in inadequate duration or quality of sleep, patients tend to experience impaired functioning in the workplace, at home, or in school, which appears to occur as a result of suboptimal neurobehavioral functioning in domains of concentration, memory, and processing speed. Physical fatigue may also contribute to impairment. Mood disturbances may also accompany circadian disorders. Comorbid depression is well recognized in association with delayed sleep-wake phase disorder. (https://new.uptomed.ir/)

The suprachiasmatic nucleus in the hypothalamus is often referred to as the master biological clock or pacemaker. This generates and synchronizes (entrains) internal circadian rhythms with external time cues such as light, and helps control multiple circadian rhythms, such as daily fluctuations in core body temperature, as well as melatonin secretion by the pineal gland. Bright light can shift the timing of circadian rhythms.

Light just before the temperature minimum will typically shift the temperature minimum clockwise to a later time (phase delay). Light soon after the temperature minimum will shift the temperature minimum counter-clockwise to an earlier time (phase advance). The timing of the light relative to the temperature minimum will determine how much the circadian rhythms shift.

Darkness generally has the opposite effect of light upon circadian rhythms. Darkness in the morning will cause a phase delay in the rhythms; darkness in the evening will cause a phase advance in the rhythms.  

A case for melatonin

1. Melatonin secretion manifests a similar circadian rhythm, with plasma and urine concentrations low during daylight, rising after the onset of darkness, peaks in the middle of the night between 11 PM and 3 AM, and falling sharply before the time of light onset.
2. While this rhythm normally is tightly entrained to the environmental light cycle, it does persist when people are placed for a few days in a dark room. It does not immediately phase shift when the light schedule is altered, thus suggesting that it is not simply generated by the light-dark cycle but also by cyclic endogenous signals, probably arising in the SCN. Signals that originate in the retina or the SCN reach the pineal gland through a retino-hypothalamic tract, the superior cervical ganglia, and postganglionic sympathetic fibers that re-enter the cranial cavity. Light has no known direct effects on pineal melatonin synthesis in humans and other mammals.
3. The potential of exogenous melatonin to synchronize and to shift the phases of various human circadian rhythms is generally accepted.
4. In studies with healthy volunteers, 0.5 mg of pure melatoninor 0.05 mg of melatonin in corn oil (which leads to earlier peaks in, and the more rapid disappearance of, elevated plasma melatonin concentrations) could advance the onset of nocturnal melatonin secretion when administered at 5 PM, and larger doses led to greater phase advances. [uptodate.com]

Furthermore, melatonin was able to shift the core body temperature rhythm. But a statistically significant effect was found only with doses ≥0.5 mg. These doses raised plasma melatonin concentrations well above the upper limits of normal (>1327 pg/mL [5712 pmol/L]), suggesting that this may not be a physiologic effect. [Brain Res. 1995;688(1-2):77. ]

Caution: Don’t take melatonin right before bed because it takes several hours for it to become effective.

If you normally stays up past midnight, but would like to nod off around 11 p.m., take melatonin at 6 p.m.

Conversely, if you go to bed at 8 p.m. and rise at 4 a.m., it’s better to take melatonin in the late morning or early afternoon.

Comments: Biological clock is disturbed in COVID; thermo dysregulation is seen; melatonin may be the answer, given at 5PM.

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA