Lupine Publishers | Demography and Population Aging

 Lupine Publishers | Trends in Ophthalmology Open Access Journal 

Abstract

Demographes and economistes warn about a phenomenon which is currently observed in developed nations: The population aging. The analysis of the causes of this disappointing verdict lets think that time could be a misleading demographic parameter.

Introduction

Time is not a phenomenon; instead it’s a concept. Therefore time is not the cause of aging of an individual nor is it the cause of aging of a population [1]. We are wondering why the average age is higher in developed nations and why it is lower in underdeveloped nations. What are the causes of this Strange contrast. The increase of the average age is an expected syndrome of the development of a nation. Therefore, time appears as a deceptive demographic indicator.

Chronological Age and Biological Age

Chronological age is commonly called age; it’s a concept of time which is expressed with some numbers (years, months and days since the beginning); the information are very poor. Medicine has introduced the concept of biological age which takes into account physical and mental health of the individual , the quality of life, the cultural level. Unfortunately the collection of these data is difficult; but the information is very rich, and it is paramount in economics and in sociology to smartly evaluate a situation and take appropriate political decisions. For example, quality of life is now taken into account by some OECD statistics.

Etiology of Aging

The word etiology comes from the Greek, aitia, which means cause, aitiologia means study of causes. Aging affects all living and hardware systems; it results from three main factors: endogenous factors, exogenous factors, and frequent potentiation of both. Jonathan Hutchinson and Hastings Gilford have identified a genetic anomaly of which results an accelerated biological aging at the infant age, with no action on chronological age.

Let’s mention two examples in construction engineering.The Tower of Pisa (12th century), is an example of change not from time, but from insufficient foundations (Figure 1). It’s a famous example of the syndrome of Hutchinson-Gilford. The collapse of the bridge of Genova in August 2018 is another illustration of the syndrome of Hutchinson-Gilford, not from time but from low quality of materials, errors in structures calculations or improper maintenance. It’s interesting to compare with Roman and Egyptian architecture.

 

Causes of Aging of Bacteria

The innocuity of time on aging of bacteria is demonstrated in combining observations with a mathematical model [1]. At each generation, the population doubles.

1 --> 2 --> 4 --> 8 --> 16 --> 32 - - - - 2exp(n)

If we start with « N₀ » bacteria, at the « nth » generation the population of bacteria will be

N = N0 2exp (n)

In an homogenous medium, the generations reproduce at approximmately the same rate « μ » (Greek letter mu), and the number « n » of generation is

n = μ t

The number of bacteria finally reads

N = N0 2exp (μ t)

Time « t » is not involved in the experiment ; it is what the clock of the laboratory indicates. The proliferation rate « μ » has various causes such as temperature, humidity, gravity, presence of sugar, specific genotype, and possible potentiation of these factors, one making the other more effective in some way. « μ » contains all these componants. Sugar increases the speed of duplication of bacteria; therefore it reduces the lifetime of a population of bacteria, because the rate of scissiparity is approximately limited to 60. Prof. Valter Longo has observed that bacteria could triple their lifetime when they are deprived of sugar [2].

Causes of Aging of an Individual

For Horace, during their course, the years strip us all our advantages [3]. Horace thought that time was the main cause of aging. In the early twentieth centutry, someone 60 years old was an old person; at same age, nowadays he is in a much better health status. In January 2017, the French Robert Martin 105 years old, broke his bike record by traveling 22 km in one hour. The aging of an individual does not result from time; instead, it results from numerous causes including junk food, lack of hygiene, lack of medicalization, exposure to ionizing factors which produce free radicals, genetic inheritance. According to Prof. Longo there are three aging genes. [2].

Demography and Age

During classical period, lifetime was about 25 years, mainly in reason of infant mortality [4]. Demographers take into account the chronological age rather than the biological age; the chronological age distribution of a population is easy to measure, but unfortunately, it does not contain much information. In underdeveloped countries, the average age is low because infant mortality between 0 and 6 years is about 50%. Adults die young, in reason of the deficit or the absence of the factors of progress. Marveling about the youthfulness of a population and about the demographic dynamics in coutries with low average age, is a error of analysis, which is driven by ignorance of the nature of time; this youthfulness and this pretended demographic dynamics are paid at price of a high birth rate and of an important premature deaths rate, which lower statistical averages.

The expressions population old age and population aging, which describe demography of developped countries, are misleading. The median chronological age (poorly informative) and the biological age (physical and mental health) are widely diverging.

Conclusion

The combination of a statistical modeling based on temporal parameters, distorts the evaluation of reality by conveying a falsified information; age, that is to say time, is a faulty indicator in this specific case.The increase of average age of a population, is a normal result of health progress, caused by feeding, by hygiene, by medicalization, by education and by mastering of demography. It leads to the theorem: a low average age is a syndrome of underdevelopment.

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Lupine Publishers | Pupil Functions in Diabetes Mellitus

 Lupine Publishers | Trends in Ophthalmology Open Access Journal 

Abstract

Pupil is innervated by autonomic nerve system. As a result, its dimension or actions well reflects the autonomic nervous system function. Pupillary autonomic neuropathy is considered an early symptom of the development of systemic autonomic neuropathy. Pupil tests present suitable and easy methods for evaluation of autonomic nervous system function. Most patients with autonomic nervous system disorders show data of sympathetic or parasympathetic deficits in the pupil, and these findings can be detected using a combination of clinical signs, pupillometric and pharmacological tests.

Introduction

As a circular aperture in the middle of iris, along with leading aqueus humor from posterior chamber to anterior chamber, pupil has functions like regulating the amount of light entering the orbit, increasing the focusing depth, decreasing the spheric and chromatic aberrations. Under normal circumstances pupil has a diameter between 2-6mm with an average diameter of 3 mm. In neonatal period/babyhood pupilla has a smaller diameter that reachs its normal size at around 7-8 ages. On the other hand it is observed smaller in size in the old age, related on atrophy of iris stroma (1).

 

The muscles in the iris stroma are responsible miosis and mydriasis of pupil. These muscles are examined in two groups. The encircling muscle fibers all around the pupil are settled in the iris and they are named as circular and sphincter muscles innervated by parasympathetic system. When they contract miosis of pupil happens. The parasympathetic nerve fibers leading to miosis start from Edinger-Westphal nucleus and end in ciliary ganglion and nerve fibers that start from ciliary ganglion end in circular muscles (Figure 1).The other muscle fibers located perpendicular to the pupil are radial (dilatator) fibers. These fibers are sympathetically innervated and lead to mydriasis. The start point of the fibers that bring sympathetic impulses to the radial muscles is posterior hypothalamus. Nerve fibers originating from this region descend from mesensephalon and pons and end in the Budge ciliospinal center which is located in between 8th cervical and 2nd thoracic spinal segments of the medulla. 2nd nerve fibers for pupil which start from this region leave the medulla especially from 1st thoracic spinal segment. After being neighbor on apex of lung while ascending, these fibers join sympathetic chain at the level of inferior cervical ganglion. Fibers passing directly through the inferior and middle cervical ganglions end in upper cervical ganglion. 3rd nerve fibers starting from the upper cervical ganglion enter the cranium with internal carotid artery and communicates with ophthalmic branch of trigeminal nerve in the cavernous sinus. Sympathetic fibers reach the radial muscles, responsible for mydriasis, through the ciliary ganglion by the nasociliary nerve and the long ciliary nerves (Figures 1-2).

 

The tract of pupillary light reaction is composed of an afferent way that takes light impulse to the central nervous system, and an efferent way that takes the response to the iris muscles. This tract is composed of an arc containing four neurons. First neuron is in between retina and pretectal nucleus which is in the middle brain at the level of superior colliculus. Ganglion cells that start from retina end in this center. Light reaction starts with the excitation of retinal photoreseptors by light. Impulses, coming from temporal half of the retina by nerve fibers not crossing at the optic chiasma, reach the pretectal nucleus by passing through the optic tractus on the same side. However impulses coming from nasal half of the retina crosses in the chiasma and reach the pretectal nucleus by passing through the contralateral optic tractus. Nerve fibers responsible for light reaction leave the optic tractus and reach out the pretectal nucleus without a stop by lateral geniculate nucleus. The second neuron is the neuron that connects the pretectal nucleus, on one side, to both Edinger-Westphal nuclei. This neural tract is the reason of symmetric constriction of pupils at the same time when a light impulse is given. The third neuron starts with Edinger-Westphal nucleus. These parasympathetic nerve fibers interfere with the motor fibers that come from other nuclei of nervus occulomatorius and they reach the ciliary ganglion in orbita. The course of these fibers in the nervous occulomatorius is important. These superficial fibers that course between the brain stem and cavernous sinus are sensitive to pressure in this region. A lesion that presses on nervus occulomatorius in this region leads to 3rd cranial nerve palsy that also affects the pupil. The fibers related to pupil take part in the center of the nerve after the cavernous sinus. For this reason, even there are lesions in this area that cause external ophthalmoplegia, pupil fibers are preserved even. After the enterance of nervous occulomatorius into the orbita, the nerve fibers related to pupil leave the nerve and reach the ciliary ganglion within the inferior branch that goes to the inferior oblique muscle, while the fourth neuron starts from ciliary ganglion and ends in the circular muscles of iris. In orbita the ciliary ganglion is located in the extraocular muscle conus, just behind the eye ball. Only the nerve fibers that bring pupil’s light reaction form synapses in the ciliary ganglion, while the others don’t form any synapses while ending in their related places. Figure 1 Neural pathways related to accomodation start from retina like the fibers responsible for light reaction. Unlike the fibers related to light reaction, they reach the visual cortex by the route of chiasma, optic tractus and optic radiation. The source of the impulses that lead to accomodation is the peristriat cortex that is located in the 19th area on the superior end of calcarin fissure. The impulses that excite from here somehow activates the Edinger-Westphal nucleus. Fibers that start from Edinger-Westphal nucleus and come in orbita with nervus occulomatorus, reach the ciliary ganglion. A group of postganglionic nerve fibers that leave from here, goes to ciliary muscle for accomodation, another group goes to medial rectus muscle for convergence and another group goes to circular muscle of iris for miosis (1).

The examination of pupil reactions provides information about autonomic nerve system of the eye. In order to set out the functions of ocular autonomic nerve system, either pharmacological tests that show the denervation hypersensivity, or measurement methods like time of pupillary cycles that show the integrity of pupillary reflex arc can be used. In diabetes, there are some changes occur in pupil, as there are in all structures of the eye. In diabetic people, pupil is smaller than normal values, and its response to mydriatics is lower. The reason of pupil being smaller in diabetes is because of impairment of the balance between sympathetic and parasympathetic innervation. Being longer than the nerve trace of parasympathetic innervation makes the sympathetic innervation more vulnerable to development of sympathetic neuropathy. A neuropathy in sympathetic innervation causes the parasympathetic system become effective resulting in the pupil smaller in size. Failure in accomodation, can be seen in diabetes. Factors like infiltration of glycogen in the ciliary muscle, diabetic neuropathy or changes in lens structure can lead to failure in accomodation.

One of the methods that give some information about pupillary reflex arc is the measurement of pupillary cycle time. It practically gives information about the afferent and efferent ways of pupillary light reaction and the integrity of iris. This test is done by biomicroscope. The examination room is provided to be dark and the patient is waited at least two minutes to adapt to the darkness. The light of biomicroscope is set to be in horizontal position and 6x0.5 mm in size. The patient places his head on biomicroscope and he is looked at a small red light which is at least 5 metres away to avoid accomodation. Then the light of biomicroscope is slowly brought on the edge of the pupil to drop it on the retina. The pupil constricts by the effect of light. For this reason retina is exposed to darkness again and pupil tends to dilate again. Meanwhile again by the effect of light that is brought before, the pupil constricts and enlarges in a rhythmic process. When the rhythmic process starts, the time of 100 processes of constriction dilatation is determined by keeping a chronometer in milisecond (ms) type. The duration of this process can be determined both by a single time or by summing up 50+50 or 30+30+40 processes in order to get a total time of 100 constriction dilatation processes. While normal duration is between 850 ms and 950 ms, for applications done in specific clinics, it is better to determine the normal values of people in the same conditions who are in similar age groups (Figure 3).

 

It is shown that depending on the poor glisemic control of patients with diabetes melliltus, autonomic neuropathy can develop frequently and by affecting especially cardiovascular system vital complications can occur. At the same time it is found that symptoms of ocular autonomic neuropathy are the precursors of symptoms of systemic autonomic neuropathy. Pupil changes in diabetes can be grouped as below.

Pupil Changes in Diabetes

Myopathic causes: The storage of glycogen in iris muscles of people with diabetes has been shown in studies. There are two main muscle groups in iris as known. Being one of these muscle groups as mentioned before, circular muscle fibers that sorround the pupil are innervated by occulomotor nerve and responsible for miosis. The other muscle group is located perpendicularly to the pupil that is innervated by sypmpathetic nerve system and responsible for mydriasis. Accumulation of glycogen in iris muscles lead to contraction disfunctions. Histologically apart from accumulation of glycogen in iris muscles, vacuoles ares seen in the iris epithelium. These vacuoles are accepted as a sign of acute diabetes and thought of originating from abnormal storage of glycogen (2).

Neuropathic causes: Pupil changes developed by neuropathic causes, can be examined under three major headings.

Optic Neuropathy: Ischemic optic neuropathy are more seen in patients with diabetes. The form of pupil change in optic neuropathy is afferent pupillary defect. The direct pupillary light reaction is weaken or lost in the eye where optic neuropathy has developed. In the other eye it is the same subject for the indirect pupillary light reflex (3-5).

Cranial Neuropathy: Pupil changes can come out depending on affected occulomotor nerve that is one of the cranial nerves. In such a case there are findings like efferent pupillary defect. There are also findings added to the table which develop depending on affected motor fibers. Parasympathetic nerve fibers taking part in the third neuron start from Edinger-Westphal nucleus and extend to the ciliary ganglion that is located in the orbita. Because of the course of nerve fibers in the occulomotor nerve, any lesion located in a region between the brain stem and cavernous sinus and presses on occulomotor nerve, leads to 3rd nerve pasly which also affects pupil. On the other hand in the lesions locating after the cavernous sinus, pupillary fibers can be preserved. After the occulomotor nerve enters the orbita, the fibers that bring the pupillary light reflex reach the ciliary ganglion within the inferior branch that goes to inferior oblique muscle. In the occulomotor nerve palsy, superior, medial and inferior recti with inferior oblique muscles are affected. However usually because of ptosis developed by affected levator palpebralis superior muscle, patients don’t complain about diplopia. Usually pupil is not affected in diabetic occulomotor nerve palsy. Nevertheless it should be kept in mind that there are also diabetic palsies in which the pupil is affected.

Autonomic Neuropathy:

a) Sympathetic

b) Parasympathetic

In long lasting diabetes, a decrease in physiological hippus and a smaller pupil in size are detected. These effects are thought to result from selective diabetic autonomic neuropathy that rather shows itself significantly more in sympathetic system than parasympathetic system. Diabetic autonomic neuropathy which is a complication of diabetes, manifests itself as pupillary disfunction in the eye. Autonomic neuropathy is asymptomatic in the early stage and it can be reversible by glisemic control in the early stages of diabetes. In order to aviod permanent pathologies, scanning of autonomic disfunction is substantial. Pupil tests would be a method for the diagnosis of such a case at the earliest time. Pfeifer et al have shown that autonomic pupil disfunction has shown itself as miosis, and they has stated that this situation was due to impairment of balance between sympathetic and parasympathetic innervation, in favor of parasympathetic system (6).

Clark has determined that there are parasympathetic denervation supersensivity with %2,5 metacolin and sympathetic denervation supersensivity with %0,5 phenylephrin in patients with diabetic retinopathy. They had also determined a significant relationship between proliferative diabetic retinopathy and autonomic neuropathy. They had found that in proliferative cases, the incidence of rate of the parasympathetic retinopathy was %36, sympathetic neuropathy was %38; where as in nonproliferative cases they were %6 and %5 respectively (7).

Cahill et al have argued that the pupil responses to the %4 cocaine were same both in diabetics and control group, and for this reason they had argued that in both groups the sympathetic tract was intact (8). In the same study they had suggested that the changes in the superior cervikal ganglion were causing denervation hypersensivity in sympathetic tracts and this was the reason for the pupillary changes in diabetics. On the other side, (9) have studied the denervation sensivity of aproclonidin. They have shown the denervation sensivity in diabetic cases and found it to be proportionate to the duration and severity of the disease (5).

Söylev et al. (10) have studied the response to diluted pilocarpine in groups of diabetic patients with or without retinopathy and in control group. They have found a response to diluted pilocarpine more in diabetic group with retinopathy, according to diabetic group without retinopathy and control group (10). At the same time they have detected that marked mydriasis developed with diluted phenylephrine in diabetic group with retinopathy, which was found significantly different comparing to the other groups.

Clark et al. (11) have detected the rate of the defect in pupillary reflex arc as %88,5 in patients with proliferative diabetic retinopathy. They have also mentioned that this result was the earliest sign of autonomic nerve disfunction (11). Pena et al. (12) emphasized that the pupillary symptoms were the earliest evidence of autonomic nerve disfunction.

In our study the pupil cycle time was found longer in diabetic cases. At the same time the rate of inability of measuring pupil cycle time was found more in the diabetic group. Pupil cycle time was found related both with the existence of diabetic retinopathy and the level of periferic retinopathy (13). As seen in all structures of eye, there are some changes in diabetes that can be seen in the pupil, too. These changes can be basicly myogenic or neurogenic. As a complication of diabetes, diabetic autonomic neuropathy can show itself as pupillary disfunction in the eye, so early diagnosis is significant. Pupil findings usually come out in direct proportion to the length and severity of diabetes (14). Rarely they can be seen in the early stages of diabetes; even sometimes before the somatic neuropathy. The findings of cardiovascular system among the systemic autonomic neuropathy findings are vitally important. By determining the abnormalities of pupillary function earlier, growth of autonomic function abnormalities of cardiovascular system may be prevented and measures for diabetic regulation may be taken. Autonomic neuropathy is asymptomatic in early phase and it can be reversible by glisemic control in early stages. From this point, scanning for autonomic disfunction is important to prevent permanent pathologies. Pupil tests can be methods for diagnosis of this situation in the earliest time

 

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Lupine Publishers | Guide Lines for Wet AMD Treatment

 Lupine Publishers | Trends in Ophthalmology Open Access Journal 

Abstract

Purpose: To give practical guide lines for the management of neovascular AMD

Methods: To evaluate the above-mentioned item based on recently published data.

Results: Although many therapeutic modalities have been employed for neovascular AMD treatment, yet anti-VEGFs are still the best line of treatment.

Conclusion: Although anti-VEGFs are up till now the best line of treatment for nAMD yet a knowledge of how to use them with or without other modalities is very important to get the best therapeutic results.

Keywords: nAMD; Anti-VEGFs

Introduction

Many therapeutic modalities have been employed for neovascular AMD which includes:

I. Macular laser photocoagulation [Macular Photocoagulation Study (MPS) can result in preventing severe loss of vision in about 50 percent of treated patients with extra/ juxta foveal CNV, with about 50 percent of patients developing recurrent choroidal neovascular membrane (CNVM).

II. Photodynamic therapy (PDT) with verteporfin acts via activating a photosensitizing dye within the pathologic vessels by infrared laser leading to occlusion of choroidal new vessels with minimal damage to the retina. PDT can prevent 3-line vision loss in about 49 to 77 percent of treated patients but seldom improves vision [1].

III. With the establishment of VEGF as the main cause for the development and progression of neovascularization, novel agents to block them and thereby preventing further progression was sought for. With the advent of anti-VEGF agents, the treatment for neovascular AMD has completely changed, with dramatic outcomes.

Anti-VEGFs

The inclusion of ranibizumab, a nonspecific VEGF inhibitor further refined the results of anti-VEGF therapy for neovascular AMD [2]. The MARINA study evaluated the effect of ranibizumab injection in patients with minimally classic or occult CNV. The conclusion of Marina study was that monthly IVL injection for 2 years prevented vision loss and improved mean VA in patients with minimally classic / occult CNV secondary to AMD. The conclusion of the ANCHOR trial was that Lucentis was superior to PDT as treatment of predominantly classic NAMD [3- 9]. The Comparison of AMD Treatments Trial Study (CATT study) trial was primarily designed to determine if bevacizumab works as well as ranibizumab in terms of visual outcomes (a difference of <5 letters), and also to identify any safety differences between the two drugs.

Visual outcome results:

When comparing ranibizumab monthly to bevacizumab monthly, the CATT study demonstrated no difference between the two drugs, with patients in both groups gaining more than 8 letters on the eye chart on average over the course of a year and the results were maintained over 2 years.

Safety Outcomes

The rate of ocular infection following injection of medication was similar with the two drugs [10].

A similar head to head comparison trial between the two drugs was the alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularization [IVAN]: 1year results concluded similar efficacy of both drugs [11].

Treatment Protocols: Primarily Designed for AMD

Ranibizumab: As-needed Regimen The Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab [PrONTO] Study: In this study patients received 3 consecutive monthly injections of 0.5 mg ranibizumab and were then followed monthly and retreated if there was an increase in OCT central retinal thickness [CRT] of at least 100 microns or a loss of best-corrected ETDRS VA of 5 letters or more. In the PrONTO study, VA outcomes were comparable with those reported in ranibizumab phase III clinical studies, but with fewer intravitreal injections [12]. The Sailor [13], Sustain [14] and Horizon [15] trials are other as needed regime studies. Overall, these studies support frequent follow-up and individualized retreatment to achieve the best visual acuity gains with the as-needed treatment regimen.

Ranibizumab: Treat-and-Extend Regimen:

Treat-and-extend dosing regimen involves increasing intervals between treatment up to 10 weeks as long as no fluid is present on OCT. If fluid is present, the interval between treatments is shortened. Oubraham found that at one-year, mean gain in VA was greater in the treat and-extend group than in the as-needed group [+10.8 versus+2.3 letters, resp.]. Eyes in the treat-and-extend group received significantly more mean injections [7.8 versus 5.2] [16]. Similar trials were also done with Bevcizumab with similar results [17-25].

Aflibercept as Compared to Other Anti-VEGFs

A. Aflibercept is a soluble decoy receptor produced by fusing all-human DNA sequences of the second immunoglobulin domain of human VEGFR1 and the third immunoglobulin domain of human VEGFR2, which then fused to the Fc region of human IgG1.2. The intravitreal half-life of aflibercept is 4.7 days in rabbit eyes, which is longer than ranibizumab [2.9 days] and comparable with bevacizumab [4.3 days].

B. The combined high affinity and longer half-life has led to a calculated duration of effect of a single intravitreal injection of 2 mg aflibercept of 48-83 days. Monthly treatment with aflibercept has been shown to improve the vision in exudative AMD in 2 clinical trials. VIEW [VEGF Trap-Eye: Investigation of Efficacy and Safety in wet AMD] 1 and View 2 showed that, at 1 year, aflibercept treatment [0.5, 2 mg monthly, or 2 mg every 2 months after three initial monthly doses] was non-inferior and clinically equivalent to ranibizumab [0.5 mg] given monthly [26].

C. Aflibercept therapy appears to be beneficial in a subset of patients with neovascular age-related macular degeneration who exhibit recurrent or resistant intra-retinal or subretinal fluid following multiple injections with either bevacizumab or ranibizumab [27].

Anatomical Measures as Predictors of Visual Outcomes in Ranibizumab-Treated Eyes with Neovascular Age- Related Macular Degeneration:

a) First and foremost, an initial anatomical [according to FFA and/or OCT analyses] or visual improvement after three monthly ranibizumab injections does not guarantee longterm success. For eyes with FFA lesion activity at Month 3, CFT>/=200mm at Month 3, and qualitative OCT activity at Months 2 and Month 3 the average BCVA gain from 3 monthly loading doses of ranibizumab was lost after switching to quarterly dosing [every 3 months], and eyes lost vision compared with baseline at Months 12 and 24.

b) Second, it appears that the longer anatomical improvements were maintained [according to FFA or OCT], the more likely it was that the BCVA benefits of ranibizumab persisted on a quarterly dosing regimen. Eyes with inactive FFA lesions at Month 5 or inactive OCT lesions at Month 5 or Month 8 were much more likely to maintain their BCVA gains.

c) While a surprisingly low number of eyes demonstrated inactive FFA lesions after 3 loading doses of ranibizumab (i.e., 10% at Month 3), eyes with a dry FFA showed the strongest association with BCVA outcomes at Months 12 and 24. At the same 3-month time point, 60% of evaluated eyes were dry on qualitative OCT grading. This disparity may result from the sampling error introduced by having only two scans available for grading (rather than all 6 radial line scans available from a Stratus macular thickness map or the greatly increased sample size of currently available spectral-domain OCT devices). It is also known that an effective RPE pump sometimes keeps the retina dry and gives a “dry” OCT reading, despite active CNV leakage [28].

Comparison of Spectral-Domain and Time-Domain Optical Coherence Tomography in the Detection of Neovascular Age- Related Macular Degeneration Activity:

a. With high-resolution volumetric SD-OCT imaging, physicians are capable of detecting signs of exudative AMD activity more precisely. Time domain platforms are less likely to identify active exudative disease activity; this could potentially lead to undertreatment of active neovascular AMD.

b. Both volumetric and raster scans collect data in the same way, via parallel B-scans. The important difference being that volumetric scanning includes more parallel B-scans, in a denser array, providing higher resolution and the ability to render a three-dimensional image. For example, with the Cirrus platform, the 5-line raster algorithm uses only 5 B-scans compared with 128 B-scans used with the volumetric scan [29-30] (Figure 1).

c. Some areas of exudative activity that oriented more vertically were better visualized with radially oriented SD imaging compared with the more traditional horizontal raster scanning patterns [30] (Figure 2).

 If after 3 loading doses of Ranibizumab the CNV activity disappeared but the visual acuity did not improve as expected, this might be either due to a disrupted IS/OS line or a thick CNV membrane. In conclusion Visual acuity was most improved when the disrupted IS/OS line was better restored, and CNV thickness was more decreased [31] (Figure 3).

Correlation of Spectral Domain Optical Coherence Tomography Characteristics with Visual Acuity in Eyes with Sub-foveal Scarring After Treatment for Wet Age-Related Macular Degeneration

In a case series, visual acuity in cases of sub foveal scarring was affected mainly by the integrity of the IS/OS and external limiting membrane lines [32] (Figure 4).

Spectral domain OCT scans of patients with sub foveal scarring:

A. Thin fovea with subfoveal scarring, VA: Counting fingers.

B. Intact IS/OS junction (arrowhead) and ELM (arrow) in fovea, VA: 20/32.

C. Normal foveal thickness with no IS/OS or ELM seen, VA: Counting fingers.

D. Intact ELM at fovea, with intact IS/OS near fovea, VA: 20/40.

E. Foveal cystoid degeneration, VA: 20/800.

F. Cystoid degeneration with disrupted IS/OS within central 1,000 mm, but intact near fovea, VA: 20/80 [32].

Response 0f Pigment Epithelial Detachments to Intravitreal Aflibercept among Patients with Treatment-Resistant Neovascular Age-Related Macular Degeneration

Three PED types were identified on OCT; hollow, solid and mixed. The hollow type showed the best response to aflibercept treatment while the solid type was the worst in response (Figure 5).

a) Hollow: are hypo reflective and contain fluid exudate

b) Solid: hyper reflective and represents fibrinous leakage or fibrovascular proliferation, suggesting active neovascularization.

c) Mixed:

i) Vision loss associated with PEDs seems to be largely nonreversible , even with structural reduction of the lesion.

ii) Retinal pigment epithelium tears may complicate treatment of PEDs during treatment with intravitreal anti-VEGF therapy. Larger vascularized PEDs that have a higher intraluminal pressure are at a significantly greater risk of producing RPE tears after anti- VEGF therapy (especially in the early stages of ttt), with acute vision loss [33].

Unfavorable Anatomical Response to Anti VEGFs

I. Some patients, however, have a good initial response to Avastin & Lucentis with resolution of fluid, but then later become resistant to further treatment and develop recurrent exudation with vision loss. The mechanism of this resistance to treatment with these drugs is not known, but one possibility is tolerance or tachyphylaxis, manifested by a decreased response over time to repeated treatment with a medication. Tachyphylaxis sometimes can be reversed by increasing the dose or halting therapy for a period of time before reinstating the same treatment.

II. Aflibercept therapy as mentioned above, appears to be beneficial in a subset of patients with neovascular age-related macular degeneration who exhibit recurrent or resistant intraretinal or subretinal fluid following multiple injections with either bevacizumab or ranibizumab [27].

Response of Type 3 Neovascularization to Anti-VEGF Treatment

a) The CME and sub-RPE fluid associated with Type 3 neovascularization resolve briskly with intravitreal anti-VEGF therapy, typically after only one or two injections.

b) A recent, longitudinal prospective study examining the response of Type 3 lesions to anti-VEGF therapy demonstrated that all eyes had stable or improved vision at 3 years of follow-up after a mean of 9.4 injections during that time. The visual prognosis was excellent [34].

Combination Therapies for Wet AMD

Role of Additional Dexamethasone for the Management of Persistent or Recurrent Neovascular Age Related Macular Degeneration Under Ranibizumab Treatment

a) The efficacy of a combination therapy of intravitreal ranibizumab together with a dexamethasone implant in comparison with ranibizumab monotherapy in persistent or recurrent neovascular age-related macular degeneration was studied and it was found that combined therapy delays retreatment in patients with persistent/recurrent neovascular age-related macular degeneration and an overall reduction in required ranibizumab retreatments compared with ranibizumab monotherapy with consistent functional outcomes. [35].

b) The expectations on the improved effect of a combination therapy lie on the multifactorial pathogenesis of nAMD involving angiogenesis and inflammation. As CNV persist under monotherapy, a combined approach seems to be reasonable to decelerate disease progression. Corticosteroids act because of their anti-inflammatory, antiangiogenic, and antiedematous effects [36-38]. Hence, additional corticosteroids seem to have the ability to target chronic inflammation when combined with anti-VEGF. In addition, a decrease in effect during an anti- VEGF monotherapy has been reported, and desensitization of tachyphylaxis by adding corticosteroids in chronic CNV was suggested [39].

Anti- VEGF Combined with Photodynamic Therapy

The combination has an additive or synergistic effect; PDT targets the vascular component Anti-VEGF targets the mediators of the angiogenic cascade and counteracts up-regulation of angiogenic factors that occur after PDT treatment. The combination causes reduction of re-treatment rate BUT may not achieve equivalent visual acuity outcomes [40-42].

Avastin Triple Therapy

a. The aim of this treatment is to combine Avastin with PDT and Dexamethasone. First PDT Light dose 42j/cm is delivered in 70 sec then after 16h. Intravitreal injection of 800mcg dexamethasone plus 1.5mg Avastin are given.

b. Triple therapy in one study was found to result in a good VA outcome with lower cost compared to repeated injections. Other studies, however, failed to show any benefit of the triple therapy as compared to anti-VEGF monotherapy [43-44].

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