Introduction

The pineal gland is an endocrine gland located in the posterior aspect of the cranial fossa in the brain. Its importance is in the circadian cycle of sleep and wakefulness. The pineal gland is also known as the epiphysis cerebri. The gland is pine cone-shaped and about 0.8 cm long. In an adult, it weighs about 0.1 g. It is an unpaired gland that resides between the thalamic bodies behind the habenular commissure. It is located near the corpora quadrigemina, which is behind the third ventricle. Cerebrospinal fluid bathes the gland through the pineal recess.

The following are the relations of the pineal gland in the brain on the coronal section:

• Superiorly: Corpus callosum (splenium aspect)
• Inferiorly: Inferior and superior colliculi
• Superolateral: Third ventricle choroid plexus

In a sagittal section, the following is seen:

• Anterosuperior: Thalamus and the habenular commissure
• Anteroinferior: Cerebral aqueduct of Sylvius, posterior commissure, and the cerebral peduncle.
• Posterosuperior: Cerebral vein of Galen
• Inferiorly: Quadrigemineal plate

The epiphysis cerebri is supplied by the adrenergic nerves. The neurons are sensitive to epinephrine. The sympathetic innervation is from the superior cervical ganglion, while the parasympathetic innervation is from the optic and pterygopalatine ganglia. The pineal stalk of the gland also has nerve fibers along with innervation from neurons from the trigeminal ganglion. The neurons from the trigeminal ganglion have nerve fibers that contain the PACAP, which is a neuropeptide. 

The blood supply of the pineal gland is derived from the posterior cerebral artery from its choroidal branches. The internal cerebral vein drains the blood from the epiphysis cerebri.

Histologically the gland consists of cells called pinealocytes and supporting cells.

Cellular Level

The epiphysis cerebri is surrounded by the pia mater. The following are the cells in the pineal gland.

The pineal gland has a structure called the corpora arenacea (brain sand) located in the gland. These bodies are prone to an increase in calcification with an increase in age. They are visible on x-ray and can be used as landmarks. Chemical analysis of the calcium deposits shows the different compositions, including calcium phosphate, magnesium phosphate, calcium carbonate, and ammonium phosphate.

Development

The development of the pineal gland occurs from the third ventricle roof, the caudal-most portion. At the seventh week of intrauterine development, the ependymal area of the roof of the third ventricle thickens. The gland structure at this point is a cavity that is connected to the third ventricle. The developing parenchyma of the gland starts to form tubules, transforming into cells that are innervated by developing nerves and separated by connective tissue. The development of the mature gland is seen in the first decade of life. Basically, the pineal gland will increase in size from birth to about 2 years in age. The pineal gland at this stage is seen to have lobules of pinealocytes that are divided from each other by connective tissue septa and blood vessels. The gland remains stable in size from age 2 to age 20.

Function

The epiphysis cerebri is the main producer of 5-methoxyindole. Two that are of importance are melatonin and 5-methoxytryptophol. Both of these hormones are shown to be antigonadotrophic; yet, it is unknown whether these hormones directly suppress other hormones that are gonadotrophic or the gonadotropin hormones of the adenohypophysis. One of the most important functions of melatonin is to help modulate the circadian rhythm of sleep. Melatonin production is upregulated by darkness and has a decrease in production when exposed to light. Light would be perceived in the retina by the nerve cells (rods and cones) that are sensitive to light. Specialized ganglia take the impulses generated by the light to the suprachiasmatic nucleus of the hypothalamus. The fibers from the hypothalamus then give fibers off to the superior cervical ganglia in the spinal cord. From the spinal cord, relays are sent back to the pineal gland via the post-ganglionic neurons.[1][2]

Functions Studied in Other Mammals

Studies in rodents have attempted to demonstrate other roles for pineal gland involvement.

• Drug Metabolism: It was demonstrated that the gland might influence the actions of some drugs, such as antidepressants and cocaine. Melatonin also protects against neurodegeneration.
• Bone Metabolism: In mice, melatonin helps regulate new bone deposition. Its action is mediated through the MT2 receptors.
• Pituitary Gland Regulation: It was suggested that there is an influence of the pineal gland on follicle-stimulating hormone (FSH) and luteinizing hormone (LH). When the pineal gland is removed in these rodents, it was found that there was an increase in concentrations of FSH and LH.

Mechanism

Light exposure establishes the pattern for melatonin secretion. Basically, serum concentrations of melatonin are low during the daylight hours and increase and peak during the dark. The duration of melatonin secretion is directly proportional to the interval of darkness. The rate-limiting step that helps this is process is controlled by the enzyme serotonin N-acetyltransferase (NAT). This enzyme, which is needed to synthesize melatonin from serotonin, is low during daylight hours. Serotonin is the precursor of melatonin. Serotonin is also derived from an amino acid called tryptophan. In the pineal gland, serotonin undergoes acetylation and then methylation to yield the end product of melatonin. Melatonin then reacts with G- protein receptors to implement the biological effects that are needed. These receptors are found in the suprachiasmatic nucleus of the hypothalamus, the retina, and the pars tuberalis in the adenohypophysis. Receptors are also scattered around various areas of the brain. Melatonin binds to albumin in the human plasma.[3]

Related Testing

The gland can be visualized with an imaging test such as an MRI or a CT scan. Usually, these methods of imaging are done to help determine whether pineal tumors or cysts are present. Tumor markers can also be checked on a blood test to help determine if a treatment plan is working. X-rays can also reveal the pineal gland if there is the presence of calcification. The pineal gland is sometimes used as a landmark (when it is calcified) when trying to identify different structures and areas of the brain via an X-ray.

Pathophysiology

Tumors and Cysts

Due to the pineal gland's location, any tumor or cyst formation would lead to the compression of the aqueduct of Sylvius. It is the aqueduct of Sylvius that allows the cerebrospinal fluid (CSF) to circulate out. When there is a blockage to this area by an abnormal pineal gland, the passage of the duct is blocked, and CSF pressure builds up, leading to hydrocephalus. This causes nausea, vomiting, visual changes, headaches, seizures, and memory changes. This increase in intracranial pressure can even be life-threatening, prompting emergency treatment. The hydrocephalus can be relieved by the placement of a VP shunt. This would lead to a pathway for CSF drainage. Another procedure that can be done is a ventriculostomy. In this procedure, a small opening is made using an endoscope to allow the CSF to drain. 

Vision changes would also occur due to the involvement of the tectal region. The tectal region helps dictate eye movements. Fault in the tectal region causes double vision, trouble focusing on objects, and impaired eye movement. The pineal gland can cause Parinaud syndrome due to the increasing size of the gland compressing the pretectal area and superior colliculi of the midbrain. Parinaud syndrome prevents a person from moving his or her eyes up and down. The thalamus can be affected, and if so, there can be disturbances on that side of the body, resulting in weakness and loss of sensation. The tumor's effect on the hypothalamus will lead to weight gain, disruption of sleep, disruption of temperature control, and water regulation. Cerebellar involvement would result in motor impairment. If the tumor of the pineal gland is present in childhood, then endocrine dysfunctions can also result, such as precocious pseudopuberty, diabetes insipidus, and a slowed growth rate.[4]

Clinical Significance

Calcification

Calcification of the pineal gland is quite common. So much so that a calcified pineal gland is commonly used as a landmark on X-rays. Calcium and phosphate deposits have a direct correlation with age. Corpora arenacea can be associated with calcification of the pineal gland. Some studies have demonstrated that the degree of calcification of the pineal gland is higher in those affected by Alzheimer disease compared to conditions demonstrating other types of dementia. There is a loose correlation between the calcification of the pineal gland and some migraine and cluster headaches.

Tumors

Several different tumors can arise from the pineal gland. Diagnosis of the type of tumor is crucial for treatment. The primary symptom of the tumor would be hydrocephalus. If the pineal gland invades the thalamus, it can cause weakness and loss of sensation in half of the body. Invasion of the hypothalamus would disrupt sleep, impede temperature and water regulation, and cause weight gain. An MRI is important when trying to see the location and size of the tumor. A biopsy is required when trying to determine the type of tumor. Usually, a biopsy is done via a stereotactic or endoscopic procedure. Sometimes biomarkers are used to detect the presence of the tumor, and if these are found in the CSF and blood, then a biopsy might not be needed. Some of these chemicals are beta-human chorionic gonadotropin, carcinoembryonic antigen, and a-fetoprotein.

Multi-Step Treatment Plan for Pineal Tumors

• Surgical removal of the tumor is quite difficult because of its location and relation to various structures that surround the gland. The surgeon always tries to opt for a minimally invasive technique before considering other options.
• Management of hydrocephalus is also undertaken. The blockage of CSF flow due to the enlarged gland makes the third ventriculostomy via endoscopic approach a consideration. If this fails, then a shunt might be necessary.
• Radiation therapy is shown to be effective as a majority of pineal gland tumor is sensitive. 
• Chemotherapy is only used when required for the type of tumor.

Dysfunction of Pineal Gland Secretions

• Pineal gland damage in children has been shown to accelerate skeletal and sexual organ development.
• Low melatonin levels in elderly persons have shown sleep pattern disturbances. There has been a modest benefit with melatonin therapy.

Jet Lag

Disturbance of the sleep-wake cycle is seen when traveling across multiple time zones. It takes several days for melatonin to adjust to a new light-dark pattern.

Retinal Degeneration

Degeneration of the retina would not allow for light appreciation. In this case, the retina would not be able to appreciate or pick up changes in light. The low levels of light would cause an increased level of melatonin secretion.[3]

Circadian Rhythm Disorders

During the daytime, light stimulates the retinohypothalamic pineal pathway. The retinal ganglion cells activate the suprachiasmatic nucleus (SCN) through the optic nerve. SCN via a complex network inhibits the superior cervical ganglion, causing sympathetic nervous system inhibition, preventing melatonin release from the pituitary into the circulation. However, at night, lack of activation of SCN causes sympathetic nervous system stimulation, causing melatonin release by the pineal gland, inducing sleepiness.[5][6] The two most common disorders due to circadian rhythm disruption include advanced sleep phase and delayed sleep phase syndromes.[7] Melatonin is effective in sleep onset insomnia and delayed sleep phase syndrome.[8]

Neuropsychiatric Disorders

Hydroxyindole-O-methyltransferase (also known as Acetylserotonin O-methyltransferase) is an enzyme involved in the final step of melatonin synthesis. It is present predominantly in the pineal gland. However, low amounts of mRNA have been detected in the retina.[9] The gene for this enzyme is located in the pseudoautosomal regions of chromosomes X, and Y. Gene mutations have been linked to decreased melatonin synthesis and neuropsychiatric disorders like autism spectrum disorder and attention deficit hyperactivity disorder.[10][11][12]

Parinaud syndrome

Pineal gland tumors (pinealoma) can cause Parinaud syndrome by compressing centers in the dorsal midbrain due to progressive gland enlargement.  Pineal gland tumor is one of the most common causes of Parinaud syndrome in young adults. Most patients present with complaints of progressive blurring of vision and diplopia. It is associated with a classic triad of upgaze palsy, convergence retraction nystagmus, and light-near dissociation.[13]