Kavya Liyanage

Phototherapy

Objectives

1 Introduction2 History of phototherapy3 Phototherapy in Neonatal Jaundice

3.1 Bilirubin Metabolism3.2 Jaundice3.3 Phototherapy as a Treatment of Choice3.4 Mechanism of Action3.5 Best Indications

4 Applications in the Field of Dermatology4.1 Mechanism of Action

4.1.1 Vitiligo4.1.2 Psoriasis4.1.3 Eczema Cont.

Cont.

5 Applications in the Field of Psychiatry5.1 Mechanism of Action5.2 Best Indications

5.2.1 Wavelength5.2.2 Irradiance and Duration

5.3 Jet Lag5.4 Shift Work Sleep Disorder5.5 Delayed Sleep Phase Syndrome5.6 Advanced Sleep Phase Syndrome5.7 Adverse Effects5.8 Light Sources

6Photodynamic Therapy

Introduction

Phototherapy, also known as light therapy is a therapeutic method that is done with the non-ionizing portions of the electromagnetic spectrum.

The objective of phototherapy is to heal a clinical condition, minimizing the adverse effects.

Light contains energy in the form of photons. Light absorbing molecules or chromophores

can utilize the light energy can make a certain change.

Cont.

Sunlight is known to have a healing power from the ancient times.

With this concept, by the development of modern science, the power of artificial light has been using in treating certain clinical conditions such as given as in dermatitis, psoriasis, common acne, eczema, seasonal affective disorders, vitiligo, neonatal jaundice, circardian rhythm disorders etc.

Modern phototherapy light sources include sunlight, fluorescent light, halogen spotlight, fibre-optic system, light emitting diodes (LEDs) and etc.

History of phototherapy

Early Egyptians and Indians had used sunlight for treating several skin disorders.

The very first use of the light as a medical treatment in the history was as a treatment for the skin disease vitilgo, by ancient Indians.

This particular disease causes loss of pigmentation of the skin, whereas it was treated with exposure to sunlight, after applying seeds of photosensitizing Psoralea.

So, when applied it on the non-pigmented areas of the skin and made them expose to the sun, the re-pigmentation occurs.

The ancient people had done this therapy with natural sunlight.

Cont.

It was in the 19th century that the use of artificial light sources for phototherapy happened.

Prof. Niels Ryberg Finsen is known as the father of phototherapy.

He turned a new page in the field of medicine, by his work on treating for lupus vulgaris, a skin infection caused by Mycobacterium tuberculosis, with concentrated light rays.

This therapy was done with natural sunlight and ultraviolet radiation from a carbon arc.

Hence, he was the Nobel Prize winner in Physiology and Medicine in 1903, for his remarkable work. Since then, many works in the pathway of phototherapy have been done.

Phototherapy in Neonatal Jaundice

Jaundice, hyperbilirubinaemia or icterus is a condition that results from elevated serum bilirubin levels.

This condition manifests as a yellowish discolouration of skin and mucous membranes.

Bilirubin Metabolism

Bilirubin pigment is a product of haeme degradation pathway.

Bilirubin is in two forms, unconjuated and conjugated forms, depending on its solubility in plasma.

The unconjugated bilirubin, produced in the reticulo-endothelial system, is lipid soluble and is transported to the liver by binding with albumin.

Cont.

In the liver hepatocytes, the unconjugated form of bilirubin conjugates with glucuronic acids and known as the conjugated form.

It is the soluble form in plasma. The conjugated bilirubin is secreted into bile

and the later is released to the gut. Some of the conjugated bilirubin is

reabsorbed into the circulation as unconjugated bilirubin, the process of recycling biirubin, known as enterohepatic circulation.

Jaundice

In the newborns, foetal haemoglobin is replaced by adult haemoglobin.

Hence, the red blood cell haemolysis occurs more and billirubin formation occurs in high rates in them.

This results in both unconjugated and conjugated forms of bilirubin.

Indeed, the immaturity of the hepatic metabolic pathway too leads to increased levels of bilrubin.

As such, neonates are more prone to get hyperbilirubinaemic conditions.

Cont.

Neonatal jaundice can be either physiological or pathological.

The physiological jaundice occurs in the first week of life, usually within the 2-5 days after delivery.

Also, this returns back to normal in 10-14 days after birth.

If the signs of jaundice appear within the 48 hours after birth, it is due to a pathological reason and is the pathological jaundice

Cont.

One severe complication of neonatal jaundice is kernicterus.

When the unconjugated biilirubin is elevated in the blood, those bilirubin molecules can cross the immature neonatal blood brain barrier and get deposited in the basal ganglia.

This causes irreversible damage to the brain tissue, resulting in kernicterus.

Therefore, it is important to treat this neonatal hyperbilirubinaemia before the complications take place.

Phototherapy as a Treatment Of Choice

Phototherapy is the treatment of choice of most of the clinicians. It is detected as jaundice in neonates when the serum bilirubin level is more than 5 mg/dl.

When this level israised above the required level according to the days of life, the neonate is prescribe for a phototherapy treatment along with breast feeding.

Exchange blood transfusion is the other treatment option if the phototherapy is ineffective in severe jaundice conditions.

Mechanism of Action

Some bilirubin, are present in the interstitial spaces and superficial capillaries of the skin, subcutaneous tissues.

During the phototherapy, these molecules are exposed to light.

The photons of energy are absorbed by the pigment, bilirubin.

This leads to a sequence of photochemical reactions; configurational isomerisation, structural isomerisation and photo-oxidation.

Cont.

This energy converts bilirubin into its nontoxic isomers such as photobilirubin (4Z, 15E biliirubin), lumilirubin which are more polar and thus water soluble.

These photo-isomers can be eliminated from the body more easily without undergoing the process of conjugation in the liver.

Indeed, since they are water soluble, transporter proteins are not required.

But the photobilirubin is reversible to naive bilirubin while the lumirubin is irreversible.

Cont.

Hence, the former isomer can enter the entero-hepatic circulation and less amount is excreted.

As formation of lumirubin is the rate limiting step, less amount of lumirubin is formed.

But it is cleared from the body more effectively. Excretion of bilirubin isomers from the body, especially lumirubin, declines the elevated serum bilirubin and thus reduces the risk of kernicterus.

Best Indications

When administrating the therapy, the dose depends on the wavelength of the light source, irradiance of the light and the distance between the light source and the infant.

Higher the irradiance of the light is, higher the efficiency of the therapy.

Relatively a narrow wavelength range (400-520 nm) is very effective with a peak wavelength of 460±10 nm for the photoisomerization of bilirubin.

This is range that belongs to the blue light.

Cont.

When the light source is near the neonate, the intensity of it is more.

But some sources like halogen phototherapy lamps, it may give burns if the source is closer to the skin than the recommended distance.

For a faster decline in the serum bilirubin level, large body area can be exposed to light.

When giving the therapy, the eyes and genitalia of the baby must not be exposed to the light.

Commercially Available Light Sources

Fibreoptic blanketsFluorescent tubesHalogen spot lights Gallium nitride light emitting diodes (LEDs)

Applications in the Field of Dermatology

Ultraviolet (UV) part of the light spectrum consists of light of long, medium and short wavelength.

These waves are known as UVA (wavelength more than 320 nm) UVB (wavelength between 290-320 nm) UVC (wavelength less than 290 nm)

Cont.

Though most of the UVC is absorbed by the ozone layer, the UVA and UVB penetrate the atmosphere and reach the skin.

This particular light is harmful for the normal skin.

In comparison, UVA is more harmful than UVB. It may cause mutations, skin malignancy,

premature skin aging and also cause cataract in eye lens.

White skinned people are more vulnerable for these effects.

Cont.

Even though both UVA and UVB are potentially harmful, they have ability to suppress cutaneous inflammation.

This scientific phenomenon has used in phototherapy in treating dermatological problems.

Indeed, these are capable of suppressing the immunoreactivity of the whole system.

So that, non affected areas and high risk areas like eyes and scrotum are not exposed to this light.

Cont.

Several types of light treatment are used in the field.

Narrow band UVB in the range of 310-315 nm, with a peak at 311 nm is usually chosen as the therapeutic spectrum.

As UVA is less effective, it is used along with Psoralen, a photo-sensitizing chemical, in the method known as photo chemotherapy (PUVA).

Sometimes, a combination of UVA and UVB is given.

Cont.

In some dermatological problems such as vitiligo, psoriasis, common acne and eczema, phototherapy is a choice of treatment.

Mechanism of Action

Narrow-band UVB, to which the skin is exposed, is absorbed by the DNA and urocanic acid. It alters the antigen presenting cell activity.

This narrow-band radiation is less potent than the broad-band UVB. But the former has relatively more suppressive effect than the latter on systemic immune responses.

Mechanism of Action In Vitiligo

A common autoimmune disorder, vitiligo causes depigmentation of the skin due to the loss of melanocytes.

In this condition, PUVA or narrow-band UVB is used for the phototherapy treatment.

In both cases, the UV light stimulates the amelanotic melanocytes in the skin.

Then they get activated and proliferation occurs, leading to the production of melanin.

This melanin migrates outward to adjacent depigmented areas and causes perifolliclar repigmentation.

Mechanism of Action In Psoriasis

Psoriasis is a common paplo-squamous disorder that is characterised by well demarcated red scary plaques.

In this condition, the skin becomes inflamed and hyperproliferation of the skin occurs.

In psoriasis like conditions, the narrow-band decreases lymphocyte proliferation natural killer cell activity cytokine production (IL-2, IL-10)

suppressing the immune activity of the body.

Mechanism of Action In Eczema

Eczema is a kind of dermatitis which can be seen over a large proportion of the skin.

This condition is also treated with narrow-band UVB phototherapy similarly as in psoriasis.

Applications in the Field of Psychiatry

According to the records of the history, bright light was used to treat patients with the winter seasonal affective disorder, for the first time in 1984, in the field of psychiatry.

Cont.

Circadian rhythm cycle is an endogenously generated biological clock. This cycle is roughly of 24 hours.

By the influence of biological and environmental cues or zeitgebers, physiological and behavioural aspects of the circadian cycles of animals and humans are modulated.

The most important zeitgebers regulating the circadian and seasonal rhythm of mammals is the light-dark cycle.

Cont.

An “oscillator” in the suprachiasmatic nucleus of the anterior hypothalamus senses the environmental light via its special neuronal pathway with the retina of the eye, the retino-hypothalamic pathway.

Studies have shown that a sufficient light intensity indeed influences the human circadian rhythm cycle.

This rhythmicity is sometimes melatonin dependent. Melatonin is a hormone secreted by the pineal gland

which involves in timing signals to coordinate events with light-dark cycle.

However, the bright light is a stronger exogenous factor that effects on the endogenous biological rhythm.

Cont.

Light therapy is an effective treatment option for the disorders with disturbances in the circadian rhythm. Jet lag, shift work sleep disorder, delayed sleep phase syndrome and advanced phase sleeping syndrome are some of the examples for such disorders.

Cont.

These sleeping disorders are due to the changes in the circadian cycle. As a treatment option, the 24 hours clock of the body can be “re-set” by the aid of bright light therapy. In this case, the patient’s sleeping patterns are synchronized as he or she desires to match with the daily routine of the particular person.

Mechanism of Action

The activation of ocular photoreceptors exclusively mediates the light treatment of circadian rhythm cycle.

The blue light sensitive photo-pigment melanopsin.

It is in specialised ganglionic cells of the retina, directly projects to the circadian clock in the suprachiasmatic nucleus.

The treatment efficiency depends on the wavelength and the dose of the light, indeed the time of the day that the light is administered.

Wavelength

Human eye uses three cone types in order to sense light in three colour bands.

The photo-pigments of the cones have maximum absorption at certain wavelengths.

This absorption occurs with maximum efficacy at a wavelength of 555 nm in the green light area.

With regarding the primary mediating effect of the melanopsin, exposure to bright monochromic blue light (460 nm) is more effective than green light (555 nm).

Cont.

But the peak sensitivity of the three cone photo-optic visual system is in the green area.

This process is for the phase resetting of the circadian cycle and for the suppression of night time release of melatonine hormone by the pineal gland.

Therefore, the blue enriched light is effective in treating the circadian sleeping disorders as compared to longer wavelength light.

Irradiance and Duration

The irradiance and the duration of the light stimulus are the facts that are important in considering the dose of the light therapy.

In studies regarding this matter, only the exposure to bright artificial light (2,500- 10,000 lux) has been shown to improve the circadian cycle and the behavioural aspect.

In comparison of the intensity of the light administrated, bright light shows more effective changes in re-synchronizing the rhythm if preceded with dim light.

Cont.

The magnitude and direction of phase synchronising rely upon the circadian phase at which the stimulus of light is applied.

Generally, this cycle is most sensitive during the actual night time.

So that, the light therapy is more appropriate to be given shortly after awakening and shortly before bedtime.

Jet Lag

Jet lag or Rapid time zone change syndrome is seen in the people who travel across time zones.

They present with excessive sleepiness and lack of daytime alertness.

In this case, the eastward travellers show difficulty in waking in the morning, while the westward ones are having early morning awakenings.

Cont.

The desired outcome of the phototherapy in the eastward travellers is to phase advance shift the cycle while that of the westward travellers is to phase delay shift the cycle.

Therefore, in treating the eastward travellers, morning bright light therapy after waking time (home time zone) and dim light prior to bedtime is administered.

Evening bright light therapy prior to bedtime (home time zone) and dim light after wake time is treatment method suitable for the westward travellers.

Shift Work Sleep Disorder

This particular disorder results in people who frequently rotates work shifts and work at night.

They are having excessive sleepiness during the wake time, and desire to have a large phase delay shift.

They should be administered bright light therapy in the evening and dim light after work.

Delayed Sleep Phase Syndrome

Patients with this condition may fall asleep lately and they have difficulty to wake up in the morning in order to involve in day-today routine.

Their goals of the therapy would be earlier sleep-wake times and to have a phase advance shift.

Therefore, morning bright light after wake time and dim light prior to bedtime should be administrated.

Advanced Sleep Phase Syndrome

This advanced sleep phase syndrome is commonly seen among adults.

These people go to sleep early (6.00- 9.00 p.m.) and they wake up earlier than desired, around 2.00- 5.00 a.m. .

So that, required effect is to have a phase delay shift, following a later sleep-wake times.

Phototherapy treatment is given as evening bright light therapy prior to bedtime and dim light after wake time.

Adverse Effects

Retinopathy is absolutely inadvisable for bright light therapy.

Therefore, in order to avoid ocular damage, prior to the therapy, eye examination of the patient should be done.

Light Sources

White light boxes, light visors, dawn stimulators coloured light boxes

are some commercially available devices used in this therapy.

Anyhow, the light source should provide adequate filtering of ultraviolet and infra-red light, to avoid ocular damages.

The illuminance of the phototherapy light source can be kept constant, unlike the variable natural light sources.

Photodynamic Therapy

Photodynamic therapy is also a form of phototherapy, where light is administrated after giving a photosensitising drug to the patient. Though this drug is non toxic to the normal cells, it is toxic to the malignant and diseased cells.

Cont.

By absorbing the energy of the light, photosensitizing agent reaches to its excited state.

Then the excited molecule reacts with oxygen and forms reactive oxygen species.

The latter causes damage to the malignant and diseased cells.

So it is important to not to expose the unaffected areas of the body.

Hence, target phototherapy or photodynamic therapy is used as a treatment option for breast cancers, oesophageal carcinoma, bronchial lung carcinoma etc.

References

1] Grossweiner, Leonard I., Linda Ramball. Jones, James B. Grossweiner, and B. H. Gerald. Rogers. The Science of Phototherapy: An Introduction. Dordrecht: Springer, 2005. Print.

2] The Nobel Prize in Physiology or Medicine 1903." The Nobel Prize in Physiology or Medicine 1903.N.p., n.d. Web. 25 Jan. 2016

3] Robert Murray, Victor Rodwell, David Bender, Kathleen M. Botham, P. Anthony Weil, Peter J. Kennelly. Harper's Illustrated Biochemistry. 28th Edition ed. N.p.: Mcgraw-hill, Jun 2, 2009. Print.

4] Stokowski, Laura A. "Fundamentals of Phototherapy for Neonatal Jaundice." Advances in Neonatal Care 11 (2011): n. pag. Web.

5] "Phototherapy of Neonatal Jaundice." The Science of Phototherapy: An Introduction (n.d.): 329-35. Web.

6] Kumar, Parveen J., and Michael L. Clark. Kumar & Clark's Clinical Medicine. 9th ed. Edinburgh: Saunders Elsevier, 2009. Print.

7] Dogra S, Kanwar AJ. Narrow band UVB phototherapy in dermatology. Indian J Dermatol Venereol Leprol 2004;70:205-9

8] Gelder, Michael G., Lopez Ibor Juan Jose, and Nancy C. Andreasen. New Oxford Textbook of Psychiatry. Oxford: Oxford UP, 2000. Print.

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