Continuing Education

In the second of our series in association with the Academy of Life Sciences, Aston, Dr Miriam Conway describes retinitis pigmentosa in its various forms and the latest research findings in investigating the condition (C3517, one standard CET point)

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Retinitis pigmentosa (RP) is the collective term for a group of retinal dystrophies leading to progressive degeneration of the photoreceptor cells. The prevalence of RP is thought to be approximately one in 4,000 people,1,2 making the disease one of the leading causes of blindness in the younger population in the western world.

Types of RP
Retinitis pigmentosa may be subdivided according to the inheritance patterns of the disease. Sex-linked (X chromosome) RP has a prevalence of approximately 8 per cent of all RP.2

A father diagnosed with X-linked RP will produce sons who do not develop the disease, all of his daughters will become carriers of RP and will have a 50 per cent probability of having an RP-afflicted son and a 50 per cent chance of having an RP carrier daughter.

Problems arise when attempting to identify the true inheritance pattern of a family where there have been no sons for several generations, as the faulty gene may have passed down a long line of female carriers. Autosomal dominant RP affects both genders equally and the prevalence is estimated as 19 per cent.2

The probability of RP being passed from one affected parent to child is exactly 50 per cent. In autosomal recessive RP, two parent carriers have a 25 per cent chance of having a child affected by the disease. Both genders are equally affected and the frequency is estimated as 19 per cent.2
Clinical experience shows that individuals diagnosed with X-linked and autosomal recessive RP tend to have an earlier, more aggressive form of the disease.3,4 The remaining 46 per cent of RP cases may not be solely explained by the laws of inheritance and are referred to as primary isolated retinitis pigmentosa or retinitis pigmentosa simplex.2 Eight per cent of RP cases remain undetermined.2

The condition may also be subdivided according to the relationship between rod and cone degeneration. Patients diagnosed with Type one RP usually report night blindness near the beginning of their childhood, a finding which is probably explained by the early preferential loss of rod sensitivity which is later followed by a progressive localised loss of their visual field. Patients diagnosed with Type two RP do not usually complain of night blindness until they become adults, where it is characterised by localised progressive loss of both rod and cone sensitivity.

Symptoms
The disease is devastating to the individual as vision progressively deteriorates over a period of many years.

Symptoms usually start with night blindness and mobility problems such as bumping into obstacles, particularly in environments with reduced levels of illumination. At the end stages of the disease, patients may also complain of difficulties with their central visual acuity and colour vision abnormalities.

Individuals sometimes have difficulty in receiving a formal diagnosis of the condition, particularly in the isolated form when there are no family members affected by the disease. Patients occasionally attend their ophthalmologist and/or optometrist for many years complaining of night blindness before any obvious fundus abnormalities become evident.

Clinical findings
Visual field loss begins as an irregular-shaped scotoma lying in the mid-peripheral visual field.5, 6 The defect enlarges and eventually merges to form a ring scotoma.

Over a period of many years, the peripheral edge of the ring scotoma progressively expands to destroy the entire peripheral visual field. During the end stages of the disease, the central edge of the scotoma also increases to engulf the central visual field. The rate of visual field loss is controversial and has led to significant debate in recent years. Berson et al7 has reported that individuals diagnosed with RP lose on average 4.6 per cent of their remaining visual field per year and between 14-16 per cent of their remaining electroretinographic (ERG) amplitude per year.

Massof et al4 has suggested that retinal denegration is a secondary phenomenon and that individuals diagnosed with the condition only start to lose their visual field after a certain critical age has passed. After this event has occurred, individuals will on average lose 16-18 per cent of their remaining visual field per year.

Patients rarely lose their entire central vision and become totally blind. The majority of patients retain a small area of severely reduced central vision and are diagnosed as legally blind. Central visual acuity was initially reported as unaffected, in patients diagnosed with RP, despite extensive peripheral visual field loss. Recent evidence suggests that visual acuity declines between 1.2 per cent8 to 6 per cent a year.3
The disparity shown in these figures is unsurprising and probably caused by the different age ranges and genetic composition in each research population. A similar variation of 6/12 to 6/60 has been quoted for the estimated final visual acuity outcome (Baumgartner 1999).

Kiser et al9 have reported that individuals with severe visual impairment produce significantly more inter-test variation in their visual acuity and contrast sensitivity measurement when compared with a group of normal healthy individuals. Patients with severely reduced visual acuity may experience diplopia or suppression depending on the age where retinal degeneration occurred.10

Patients may present with a normal fundus during the earliest stages of the disease.5 The first clinical signs detected via ophthalmoscopy are mild pigment epithelial atrophy in the mid-peripheral visual field, giving rise to the appearance of small white dots at the level of the retinal pigmented epithelium.11 Pigmentation is later found in the equatorial region of the retina along with arteriolar narrowing and optic nerve head pallor.5

During the end stages of the disease, pigment epithelial atrophy consisting of black 'bone spicules' are evident (Figure 1).11 Other ophthalmoscopic signs include posterior subcapsular cataract which has a prevalence of approximately 53 per cent in the RP population.12 Macular oedema was documented in 12 eyes of six patients (13 per cent) diagnosed with RP using optical coherence tomography.13

Pathogenesis
To date, the mechanism behind retinal pathology is not fully understood. All individuals diagnosed with RP are born with photoreceptors expressing the same mutant gene across their entire retina.

The critical age where photoreceptor degeneration begins and sight loss occurs is known to vary significantly across the affected population. Massof et al4 reports the average critical age for retinal degeneration as 28 years old 13.9 years.

This finding has led many scientists to believe that individuals simply inherit a genetic susceptibility to retinal degeneration and environmental factors such as ischaemia, toxicity or inflammation initiate or act as a catalyst in photoreceptor degeneration.

Abnormal haemodynamics associated with RP
Circulatory changes such as narrowing and/or attenuation of the retinal vessels, choroidal sclerosis and optic nerve atrophy are regularly documented in the retina of individuals diagnosed with RP.5, 6

Investigations using fluorescein angiography confirm abnormal circulation via delays in the appearance of dye in the retinal arterioles and prolonged transit of the dye through the retinal circulation.14, 15

For the majority of individuals, visual loss begins as an irregular-shaped scotoma in the equatorial region of the retina.6 This area is the same location where vision is lost in normal eyes when blood flow is reduced by raising intraocular pressure.16

The last stages of vision loss have been documented in the macula, which is the area next to a dense network of retinal capillaries fed by arterial blood at maximal perfusion pressure from short posterior cillary arteries.17 Colour Doppler Imaging (CDI) consistently reveals reduced peak systolic and diastolic blood flow velocity in the ophthalmic artery,18 central retinal artery18, 19 and posterior ciliary arteries18 in those individuals diagnosed with RP.

Taner et al20 documented reduced mean peak systolic and diastolic flow velocity in the central retinal artery, after a period of dark adaptation during the early stages of RP. An investigation using pulsatile ocular blood revealed reduced mean pulsatile ocular blood flow in 13 patients diagnosed with RP when compared against 10 age-matched normal controls.16 The authors concluded that the ciliary choroidal vessels were predominantly affected in RP patients as the reduction in pulsatile blood flow far exceeded the total retinal blood flow.

Abnormal retinal circulation ultimately results in retinal hypoxia. The correct balance between oxygen supply and oxygen consumption is essential for retinal homeostasis. Research collected from two different species of rats has shown significant changes in the intraretinal oxygen distribution during the degenerative period of photoreceptor degeneration.21, 22

Hyperoxia was shown to slow the rate of photoreceptor degeneration in the early stages of retinal degeneration in the Royal College of Surgeons' rats.23 Hyperoxia has also been used in humans as a therapeutic agent to treat patients diagnosed with RP.24

The authors concluded that patients receiving regular hyperbaric oxygen delivered over a three-year testing period produced significant (p<0.001) increases in their ERG b-wave amplitude. In contrast, the RP patients receiving no treatment (controls) demonstrated a significant decrease in their ERG b-wave amplitude amplitudes (p<0.02).

Management
Neurotrophic factors are currently being investigated for their potential to work as regenerators or anti-apoptotic (preventing programmed cell death) agents of damaged nerve cells.

Brain-derived neurotrophic growth factor has been documented as significantly reducing photoreceptor degeneration in a population of rats exposed to constant light.25 Basic fibroblast growth factor resulted in a prolonged photoreceptor life, in the Royal College of Surgeons' rats.26

However, a serious drawback of such therapeutic agents is the fact that these factors do not solely affect one particular cell type and may potentially cause problems elsewhere in the retina.

In addition, the long-term treatment would necessitate developing a strategy to regularly administer the substance in a controlled, sustained, non-invasive way which is currently unavailable.

Research to date indicates that transplanted retinas are not capable of developing ganglion cells after transplantation.27 Scientists are consequently investigating the prospect of transplanting sheets of photoreceptor cells28 or individual photoreceptor cells29 to areas of damaged retinas in a population of rats.

Berger et al28 investigated the therapeutic efficacy of transplanted harvested cadaver photoreceptor sheets into eight patients with advanced RP. No significant improvement in visual acuity, contrast sensitivity or visual fields was evident in the treated eyes postoperatively.

A wide variety of nutritional supplement regimens have been designed to protect retinal cells against oxidative damage and ischaemia. Toxic supplements, such as monosodium glutamate, aspartame, ibuprofen, vitamin supplements containing iron, calcium supplements, alcohol, excessive stress and extensive light (particularly blue light) should all be avoided.30

To date, the only research to have undergone double-masked placebo-controlled clinical trials, reported that a dose 15,000 IU of vitamin A per day slowed the course of retinal degeneration when measured via electroretinogram.31

In a later study, the same authors reported that the addition of 1,200mg docosahexaenoic acid (an omega-3 fatty acid) slowed the course of the disease further, however only in those patients beginning vitamin A therapy.32

Other treatments for RP are aimed at minimising the effects of an individual's functional disability. Multidisciplinary management should ensure
that each patient receives a management regimen to suit their work, home and recreational lifestyle. Help may include visual rehabilitation through refraction, optical aids, light illumination, filters to reduce the glare, scanning training, orientation and mobility training, activities of daily living training, financial support, and assistance in their education, home or work environment via therapists. It is important to remember that clinical investigations such as visual acuity assessment, contrast sensitivity measurement and visual field examinations do not reveal the entire functional disability. This fact is reflected in the government's recent change from the old Registration of Blindness form (DB8) to the new Certificate of Vision Impairment form which includes factors such as daily living information, psychosocial and quality of life. In order to provide satisfactory care throughout the entire course of the retinal disease, optometrists need to be aware of the initial symptoms, the natural progression and how this affects visual performance and the range of treatments and support available.

Summary
RP continues to have devastating consequences for both the individual affected by the disease and their families. Despite extensive research into numerous medical interventions, there remains no cure for the disease or agents capable of arresting its development. The majority of treatments currently available target slowing the advancement of the disease in order to improve visual prognosis.

References
A list of references is available from the clinical editor: william.harvey@rbi.co.uk

Dr Miriam Conway is an optometrist undertaking post-doctoral research

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