Effectiveness of Piracetam in Retinitis Pigmentosa: A Case Report

Retinitis pigmentosa (RP) is a group of hereditary retinal diseases caused by a collection of different gene mutations, which involve the gradual loss of photoreceptor cells, including rod and cone cells, and loss of pigment epithelial function.

The disease usually occurs in both eyes, relatively symmetrical, having many different clinical manifestations and is divided into two groups: (1) with systemic diseases and (2) without systemic disease, in which simple retinitis pigmentosa accounts for the large number of cases. The fundus has three typical signs: bone-shaped black pigments, constricted blood vessels and optic disc pallor. These bone-shaped black pigments clustered in clumps of cells along or surrounding blood vessels originating from the retina behind the equator, then spreading to the peripheral and central retinal. When Bruch's membrane is broken, the retina gradually thins and blood vessels constrict, especially capillaries and arteries. In the late stage, the optic disc is pale and atrophic. Some paraclinical tests include visual field test, colour vision test, electroretinography, OCT, and fundus fluorescein angiography. Electroretinography is an important test, which is used to assess hereditary retinal diseases, performed early even when the disease does not present any symptoms.

Currently, there is no specific treatment for retinitis pigmentosa. In the 20th century, some countries, including Vietnam, used placenta extracts (Placentil) to treat this disease, but were not successful ⁽²⁾. After that, many trials were conducted with the aim of successfully treating retinitis pigmentosa, mainly gene therapy and stem cell therapy. Currently, there are 131 drugs all over the world being researched, not including Piracetam, which have been reported at all stages of clinical development in the treatment of retinitis pigmentosa.

There are two FDA-approved methods in 2022, include: (1) gene therapy Voretigene neparvovec (Luxturna, USA) and (2) Electronic retinal implant therapy Argus II (Canada). Luxturna is used for patients with RPE65 gene mutations with an extremely expensive price at 850 thousand USD for both eyes; patients need to undergo vitrectomy and subretinal injections, which require skillful surgeons. Studies reported that Luxturna improves visual field and light sensitivity threshold; however, the BCVA does not change ^{(2, 3)}, and the most common complication that can occur is retinal atrophy. Meanwhile, Argus II is used for patients who can only see light, including a chip system on the retina and a camera on the glasses frame.

Other treatments include stem cells, retinal photocoagulation laser, some drugs and herbs ^(1,3-5). Current studies show that high dose vitamin A 15,000 units and DHA are not effective in treating RP because they do not change the visual field, electroretinography; in contrast, excess vitamin A affects liver function, causes birth defects, increases lipofuscin accumulation in the retina, which worsen RP. Otherwise, Chen Ou (China) tested on mice, using extracts from Fructus Lycii and Salvia Miltiorrhiza Bunge with the aim of improving retinal morphology and function, by regulating the Nrf2/HO-1 pathway to inhibit oxidative reactions ⁽⁴⁾. However, the effectiveness of these therapies is still very low, or unsuccessful. The main goal is restoring vision at the level of incomplete blindness, the patient can walk and live independently.

Regarding the pathogenesis of retinitis pigmentosa, previous studies noted that oxidative stress is related to the death of photoreceptor cells in the retina. Rod cells are the most numerous in the retina, accounting for 95% of the outer nuclear layer, containing many mitochondria, having the strongest metabolic activity, as well as consuming the most oxygen. When rod cells die due to genetic mutations, oxygen consumption in the outer retina significantly decreases. Meanwhile, the oxygen supply is not reduced, leading to increased oxygen levels in the outer retina; retinal vasoconstriction shows that oxygen flows from the outer retina to the inner retina ⁽⁸⁾. Studies conducted on animals showed that an increase in oxygen levels leads to progressive oxidative damage in cone cells. The density of cone cells in the mid-periphery of the retina is low; when rod cells die, cone cells in this area are exposed to a particularly high amount of tissue oxygen levels, leading to the start of cone cell degeneration. When the cone cells in this area die, the clinical feature shows a ring scotoma. The remaining cone cells at the inner and outer edges of the scotoma are exposed to the highest amount of oxygen in the tissue, which can be predicted that the scotoma will spread to the periphery and centre. The process of cone cell death is slow and continuous. Because the density of cone cells in the fovea is the highest, the cone cells here survive the longest. When the cone cells in this area die, it leads to loss of central vision, and the patient becomes completely blind ⁽⁸⁾.

Piracetam, which is a derivative of the neurotransmitter GABA (Gamma Amino-Butyric Acid), is a substance that improves the metabolism of nerve cells such as Acetylcholine, Noradrenaline, Dopamine, helping these cells function better. Studies conducted on Alzheimer's and Parkinson's patients showed that oxidative stress and loss of mitochondrial function are one of the main causes of nerve cell death. Mitochondria are one of the main sources of oxidative stress due to the use of oxygen for energy, related to caspase protein-dependent and -independent pathways. Oxidative stress can cause neuronal death through a caspase-independent pathway. Researchers showed that Piracetam produces anti-inflammatory, antioxidant effects and prevents cell death. Oxidative stress increases the concentration of reactive oxygen species (ROS), which is inhibited by treatment with Piracetam. Piracetam improves mitochondrial function by increasing the fluidity of the mitochondrial membrane (6). Currently, the treatment of neurological and ophthalmic diseases with Piracetam has not been approved by the FDA because of some side effects such as increased movement, weight gain, anxiety, drowsiness, depression, weakness, decreased platelet aggregation as well as fibrinogen concentration, and is contraindicated in patients with cerebral haemorrhage and renal failure ⁽⁷⁾.

In our study, treatment of RP with Piracetam was effective in improving central vision,  peripheral vision and colour perception. This recovery is largely due to the antioxidant effect of Piracetam on the oxidative stress process in the retina. When exposed to high oxygen levels in the retina for a long time, cone cells gradually die; this is improved by the inhibitory effect of Piracetam on oxidative stress, which prolongs the life of cone cells. Because the patient came to the clinic late, with a significant decrease in his vision, we thought that a large number of rod cells and cone cells died. Therefore, treatment with Piracetam is only effective in preventing the oxidative stress process occurring in the remaining cone cells, mainly in the macula. On the other hand, because oxidative stress in the retinal tissue is continuous; thus, when treatment with Piracetam is stopped, the cone cells continue to be exposed to high oxygen levels. This requires constant treatment with Piracetam. After 4 courses of treatment with Piracetam, the patient currently has no side effects and liver and kidney function tests are within normal limits. However, because long-term treatment is required, it is necessary to closely monitor the side effects of Piracetam on patients. Our study was conducted as an off label trial, so the diagnosis and monitoring are mainly based on clinical practice. Therefore, monitoring of structural and functional changes after treatment with Piracetam based on paraclinical studies is still lacking. Our study provides initial assessments of the effectiveness of Piracetam in the treatment of retinitis pigmentosa, creating the premise for following studies that will perform in different clinical conditions, with sufficient paraclinical tests taken during and after treatment, to demonstrate the effectiveness of Piracetam.