Retinitis pigmentosa and ocular blood flow
Is the concept of integrative, preventive and personalised medicine applicable to the relationship between retinitis pigmentosa (RP) and ocular blood flow (OBF)? RP encompasses a group of hereditary diseases of the posterior segment of the eye characterised by degeneration, atrophy and finally loss of photoreceptors and retinal pigment epithelium, leading to progressive visual loss. Many different mutations affecting different genes can lead to the clinical picture of RP. Even though the disease has a clear genetic background, there are obviously other factors influencing the manifestation and progression of RP. In this review, we focus on the role of OBF. There is evidence that, in PR patients, OBF is more reduced than one would expect secondary to the retinal atrophy. The main cause of this additional component seems to be primary vascular dysregulation (PVD) syndrome. As PVD syndrome is partly treatable, a vascular evaluation of RP patients is meaningful. Based on the outcome, a targeted individualised, preventive or supportive treatment might be introduced in selected RP patients.
KeywordsRetinitis pigmentosa Primary vascular dysregulation syndrome Ocular blood flow Endothelin Integrative medicine Predictive, preventive and personalised medicine
Calcium channel blocker
Ocular blood flow
Primary vascular dysregulation
Retinal pigment epithelium.
The fact that a number of different mutations affecting different genes  lead to the clinical picture described phenomenologically as RP explains the heterogeneity of the phenotypes, including age of onset, rate of progression and severity of the disease. Even though the disease has a genetic background, we assume that additional factors influence the manifestation of the disease. One potential modifying factor is disturbed ocular blood flow (OBF). Indeed, reduced OBF in RP patients has been described [2, 3, 4]. Blood flow is more or less always reduced in atrophic tissue, secondary to a decreased demand for supply. However, in this review, we summarise and focus on findings indicating an additional primary component of OBF reduction and explore the potential causes of such a primary component. Finally, we discuss the potential benefit of a vascular evaluation of RP patients with regard to prophylactic and supportive treatment in selected patients.
Phenomenology of RP
It should be noted that both the types and the severity of clinical symptoms and signs, as well as age of onset and rate of progression, vary markedly among patients (reviewed in ). Symptoms may already start in childhood; however, they more often begin in early adulthood and sometimes in mid-adulthood. Although the progression of the disease is variable, typically, severe visual impairment occurs most often by the age of about 40–50 years .
This large clinical heterogeneity is at least partly explained by the genetic heterogeneity. However, after a short summary of the genetics of RP, we will focus our discussion here mainly on the question of whether disturbed blood flow may also contribute.
Genetics of RP
The condition can be inherited in an autosomal-dominant, autosomal-recessive or X-linked fashion. Non-Mendelian inheritance patterns, such as digenic  and maternal (mitochondrial)  inheritance, have also been reported. For the genetics of RP, we refer to a recently published review .
The exact mechanism of cell death in RP is not yet known. There are indications, however, that oxidative stress is also involved . Any condition that increases or decreases oxidative stress in the retina is therefore of interest.
RP and ocular blood flow
It is meanwhile well established that OBF in RP patients is reduced not only in the retina  and choroid , but also in the retroocular vessels . The question arises whether this is only secondary to the retinal atrophy or whether there is a primary component of OBF dysfunction (such as an atrophy-independent reduction of OBF) potentially contributing to the damage. In this context, two questions are important: (1) At what stage of the disease does the onset of OBF reduction occur? (2) Is blood flow reduction confined to the eye?
The impact of primary vascular dysregulation syndrome in RP
PVD is a predisposition to react differently to a number of stimuli like coldness [24, 25] and physical or emotional stress. The most prominent sign of PVD is the dysregulation of vessels, hence the name of the syndrome . The most notable sign in the vessels are vasospasms. This explains why for PVD the term vasospastic syndrome  was used in the past.
Furthermore, they respond very sensitively to certain drugs—most probably due to altered expression of ABC-transport proteins . PVD subjects also require a longer time to fall asleep, especially when they are cold  (as warm feet are generally a prerequisite for falling asleep). They also suffer more often from headaches and migraines  and have increased pain sensation  (ET level influences the threshold of pain sensation). PVD occurs more often in females  and in thin subjects [37, 38, 39].
The high prevalence of PVD in RP patients might explain the primary component of OBF dysfunction in RP patients.
Dealing with a severe disease, any treatment ameliorating this condition would be welcome. On the other hand, it would be wise to avoid encouraging false hope. We know from clinical experience that the symptoms of PVD can be reduced to some extent. If blood pressure is very low, increased salt intake increases blood pressure slightly but improves vascular regulation markedly. The same observation has been made with fludrocortisone . The other symptoms of dysregulation can be mitigated either by magnesium  or by a low dose of calcium channel blockers (CCBs)  or even omega-3 fatty acids [46, 47].
Interestingly, it has been shown that central visual field defects progress slower in RP patients treated with the CCB nilvadipine . Furthermore, in a patient with the clinical picture of RP, without a genetic history but with chronic hypomagnesaemia, the visual field progression was stopped after magnesium (a physiological CCB) substitution . Magnesium and CCBs both have some neuroprotective effect and improve blood flow regulation. They reduce the vasoconstrictive effect of ET-1 [50, 51].
Interestingly, diet rich in omega-3 fatty acids—which we often use to treat PVD—can also slow mean annual rates of decline of visual acuity in RP patients receiving vitamin A . Furthermore, antioxidants (used to treat PVD subjects) may also be helpful for RP patients. Indeed, oxidative damage is under investigation as a possible therapeutic target in RP disease [15, 53].
As OBF dysfunction, potentially due to PVD syndrome, occurs often in RP patients, we consider the vascular evaluation of such patients meaningful. If reduced OBF in the context of PVD syndrome is diagnosed, a supportive treatment with a diet rich in both omega-3 fatty acids and antioxidants and with magnesium (or, in selected patients, even with low-dose CCBs) might be helpful. If blood pressure is very low, increased salt intake or, in extreme cases, even low-dose fludrocortisone might be worthwhile. We would like to emphasise, however, that such recommendations are mainly based on clinical experience. Scientific studies are unfortunately, at present, still sparse.
RP is a disease with a clear genetic background. However, OBF is more reduced in RP than one would expect secondary to the retinal atrophy. The main cause of this OBF reduction seems to be PVD syndrome. As PVD syndrome is partly treatable, an individualised treatment [54, 55] might be introduced in selected RP patients based on the outcome of a vascular evaluation.
Further studies are recommended to establish the relationship between reduced OBF and the different stages of the RP disease and to confirm our hypothesis that the main cause of this blood flow reduction is the PVD syndrome. Furthermore, a more detailed relationship between the vascular dysfunction and other involved factors such as ET or nitric oxide should be established. Controlled studies evaluating the effect of vascular treatment on visual function will be crucial. While waiting for the outcomes of such studies, we recommend simple, not expensive treatments such as magnesium or omega-3 fatty acids in targeted selective patients [54, 55].
We would like to acknowledge the great support of Mrs. C. Fasser and Mr. S. Huesler-Lichtsteiner from Swiss RP Association, Zurich, Switzerland. Mrs. Daniela Hauenstein is also acknowledged for preparing the figures.
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