Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

Figure 19: Fundus photograph R/E showing a cyst of cysticercus in vitreous with a dense white scolex

Figure 20: Fundus photograph of a 64-year-old woman suffering from carcinoma breast; with mild vitritis and fundus shows a choroidal metastatic lesion along the supero-temporal vessel (arrows)

MASQUERADE

Masquerade syndrome should always be ruled out in an elderly patient presenting with uveitis (Figure 20).

RETINAL VASCULITIS

Retinal vasculitis is seen as yellowish exudation along the retinal vessels (Figure 21).

OCCLUSIVE VASCULITIS

The occluded vessels are seen as thread like sheathed vessels (Figure 22).

Figure 21: Fundus photograph (panorama) L/E showing retinal vasculitis in sarcoidosis

Figure 22: Fundus photograph R/E showing pale disc with occluded vessels in a patient with Behçet’s disease

KEY POINTS

1.Fundus photographs provide accurate visual records of the retinochoroidal lesions.

2.A digital fundus camera offers the advantages of instantaneous results and facilities for data storage and retrieval; image modification.

3.Red-free photographs document nerve fibre and retinal vasculature better.

REFERENCES

1.Parnell JR, Jampol LM, Yannuzzi LA, et al. Differentiation between presumed ocular histoplasmosis syndrome and multifocal choroiditis with panuveitis based on morpho-

logy of photographed fundus lesion and fluorescein angiography. Arch ophthalmol 2001;119:208-12.

2.Stanford MR, Gras L, Wade A, et al. Reliability of experts interpretation of retinal photographs for the diagnosis of toxoplasma retinochoroiditis. Br J Ophthalmol 2002; 86:636-9.

3.Amirika A, Szwartz IC, Reichel E. Digital imaging of the posterior segment. Ophthalmology Clinic of North America 1999;11(3):445-64.

4.Hansell P, Beeson EJ. Retinal photography in color. Br J Ophthalmol 1953;37:65-9.

5.Novotny HR, Alvis DL. A method of photographing fluorescence in circulating blood in the human retina. Circulation 1961;24:82-6.

6.Destro M, Puliafito CA. Indocyanine green videoangiography of choroidal neovascularization. Ophthalmology 1989;96:846-53.

INTRODUCTION

Fluorescein angiography has established its role in the clinical arena of uveitis diagnosis as well as management. It helps in differentiating active from inactive, healed uveitis, monitoring response to therapy, diagnosing coexistent exudative retinal detachment, cystoid macular oedema, choroidal or retinal neovascularisation, capillary non-perfusion, as well as optic disc hyperfluorescence.

HISTORICAL PERSPECTIVE

Fischer, in 1929, was the first one to observe the flow of dye in the iris vessels of rabbits.1 Between 1937 and 1939, Sorsby and coworkers observed the dye circulation in the human retina.2 In 1959, Flocks et al3 studied the retinal circulation in cats with a variety of injectables. The use of sodium fluorescein to evaluate ocular circulation and chorioretinal disorders dates back to the 1950s. In 1960 Maclean and Maumenee described intravenous fluorescein injection in patients with choroidal tumors.4 Novotny and Alvis were the first ones to record the transit of fluorescein through the human retina on a photographic film, a method that has since changed the face of ophthalmology.5 Novotony and Alvis, in 1960, upgraded the existing fundus camera with an electronic flash light source and motorised it to allow the rapid and sequential photography that was needed for fluorescein angiography.5,6 By the late 1980s retinal fundus camera had peaked in their advancement.

PRINCIPLE

Luminescence is a phenomenon of light emission due to causes other than intense heat, suc as caused by chemical reaction and electrical energy etc. Incandescence on the other hand is a phenomenon when the objects are made visible due to the light emission from a heated source like sun. Fluorescence is a type of luminescence, and optical phenomenon in cold bodies in which in absorption of a photon triggers in emission of another photon mimic longer wavelength. Usually in absorbed photon is in the ultraviolet rays and the limited photon is in the visible rays. The glow stops immediately after the exciting light is removed. During fluorescein angiography, intravenous fluorescein dye that reaches the retinal vessels will glow with stimulation by blue light at a wavelength varying between 465 and 490 nm and emits a yellowish green light between 520 and 530 nm. The photographic capture of this phenomenon is fluorescein angiography (Figure 1).6-8

HARDWARE

The hardware is essentially the same as for fundus imaging (see Chapter 4) with the addition of appropriate filters (exciter and barrier) and a flash of sufficient intensity to excite the fluorescein dye (Figure 2). The exciter filter is placed in the path of light that allows only blue light of a particular wavelength to stimulate the fluorescein dye. The fluorescein dye present in the retinal blood vessels emits yellow-green

Figure 1: Schematic diagram depicting principle of photographic capture in fluorescein angiography (Courtesy Prashant Desai, Carl Zeiss Meditec)

light. In order to accentuate the fluorescence of yellowgreen light, the blue light must be eliminated before it reaches the photographic film. A yellow barrier filter placed in front of the film absorbs the unwanted reflected blue light. The images can be captured in both analog and digital systems. For analog recording, a fast black and white film needs to be used that can record the small amount of fluorescence emitted from the eye. For digital recording, the camera must be sensitive to

pick up the very dim light available during angiography.

ANALOG VERSUS DIGITAL

Traditionally images have been recorded on a photographic film. These images are in analog. They are created when light from a camera is focused on film sensitising silver halide embedded on the surfaces of the film.

Digital images, on the other hand, are composed of pixels or images elements. Each image is made of an array of pixels. The greater the number of pixels, the greater the spatial resolution and accuracy with which the images represent the original. Depending on whether the images are in colour or black and white, pixel may be assigned a variety of colours or shades of grey, black and white. A computer at the discretion of the photographer who fires fundus camera’s flash lamp captures digital images individually. The intensity of light detected by each pixel while the fundus is illuminated with a flash lamp, is transmitted to the computer where images are stored in a digital format for immediate viewing, manipulation or storage. These digitalised images are then stored into a hard disc.

Images are then sent to a high-resolution monitor for editing and storage. Single frame or multiple images may be viewed in a proof sheet form. Single images filling the entire screen provide the highest resolution. A resolution of 1024 × 1024 pixel per images is the standard in most of fundus camera systems. Images can be modified (sharpness, magnification and contrast) for better analysis. Images can also be transmitted to another monitor or centres via a network connection or modem.

The ideal camera should have the following characteristics:

1.A compact and integrated electronic power-pack system, capable of recharging between 0.3 and 0.6 seconds, mounted on an adjustable table. The table should have space for wheelchair adjustment in front.

2.Both vertical and horizontal swing to photograph wider areas of fundus without having to move the eye.

3.Ability to view and photograph variable fundus fields between 20° and 60 degree. These fundus fields are usually provided in steps of 20°, 35°, 50° and 60°. Wider the field, lesser the magnification.

4.An iris diaphragm to control the aperture. A wider aperture gives less depth of field for focusing and need for full mydriasis.

5.Two camera back attachment ports—one for the colour and the other for black and white. One of the ports can be used for polaroid or video if necessary.

6.Separate lens to correct patient’s refractive error and lenses to correct astigmatism particularly when photographing the peripheral retina.

7.Focusing knob that can be operated by either hand.

8.Both an integral and external fixation devices.

9.Integrated trigger switch and height adjustment knob.

10.Clock–timer to record the time lapse.

11.Cross-matched excitation and barrier filter and red free filter along with some empty slots for future applications.

THE DYE

Sodium fluorescein is an orange–red crystalline hydrocarbon with a low molecular weight of 376

Dalton. The colour of its aqueous form varies from dark red to yellow green depending upon its concentration. The colour can be detected at dilutions as low as 1:1000000 by using ultraviolet light. The intensity of fluorescence is maximum at pH 7.5, the optimum excitation point is at 485 nm and emission is 530 nm.The dose used in man for fundus fluorescein angiography is usually 5 ml in 10-20% concentration corresponding roughly to 15 mg/kg body weight. The dye is excreted in urine and may give false positive testing for sugar in urine. The skin stains yellow for 4-6 hours following dye injection. The patients should be warned not to expose to strong sunlight while the skin remains yellow as the dye is photosensitive and may cause skin burns.9 Up to 70-80% of the injected dye is bound to albumin and other large protein molecules and 20% remains unbound and produces most of the fluorescence. Both the protein bound and the unbound portion can diffuse through the choriocapillaris but neither one diffuses through normal retinal vascular endothelium nor the normal retinal pigment epithelium. The fluorescein dye is metabolised and excreted by liver and kidney respectively.

TECHNIQUE OF FLUORESCEIN ANGIOGRAPHY

PRECAUTIONS

Fluorescein angiography is an invasive procedure. The dye is prone to having several adverse effects, some of which may be serious. It is essential that a selection of emergency drugs is kept readily available for use. The list can be drawn up in consultation with accidental and emergency department. It is also necessary for the user to be familiar with emergency resuscitation methods before undertaking such procedure. As it is an invasive procedure and carries risk (though minimal) an informed consent should be taken and procedure should be explained in detail to every patient.

PATIENT SELECTION

A full medical history including enquiry for any allergy in particular to iodine or any radiopaque substance should be made before considering fluorescein angiography. It should, however, be made clear to the patient that fluorescein contains no iodine.

Absolute Contraindication

FFA should not be carried out during first trimester of pregnancy. Though the animal studies have not shown any evidence of teratogenicity, there are no controlled trials available in pregnant women and thus, angiography during pregnancy should be avoided as much as possible.

Relative Contraindications

Patients with hepatic failure, renal failure, recent myocardial infarction and congestive cardiac failure. In these patients FFA should be carried out with caution and in consultation with treating physician. Nursing mothers should be warned that dye will be secreted in the milk and it is best to store breast milk for one or two feedings before injecting fluorescein and to discard the newly secreted milk.9

High-risk Patients

Respiratory illness such as chronic bronchitis, asthma, hay fever, atopy and patient who has mild reaction to the dye during their previous exposure. These individuals may need a test dose before undergoing angiography.

Those on regular renal dialysis should be warned to discard all tubes and other items as they may become discoloured on contamination. In diabetics where repeated urine and blood glucose estimation are required the patients must be warned about the false positive nature of the result for the next 24 hours.

PATIENT PREPARATION

Acquisition of a good quality fluorescein angiogram needs patient’s cooperation. Patient can be trained during colour fundus photography session if done before the angiography. The common concerns like not seeing the fixation light, closing the eyes or opening the mouth can be best addressed prior to the dye injection.

The procedure must be explained to the patient in detail so that a trouble free session can be achieved and good quality photographs obtained. It is a good practice to explain to the patient that test will be carried out in the dark. He/She will hear series of clicking sounds and see flashlights. Patients should be advised not to move during the session and to follow

the instruction regarding the eye movement necessary for imaging the peripheral fundus.

In case of a history of undetermined allergic background or previous nausea or reaction, some doctors prefer to give preventively an anti-histaminic agent blocking H1 receptors. In case of anxious patients or young patients impressed by the procedure, some doctors also resort to a low potency benzodiazepine drug such as lorazepam.

Combination with beta-blockers could rarely cause severe anaphylactic reactions. Therefore, the procedure in such patients should be done under medical supervision and the patients should be told to discontinue beta-blockers on the day of angiography. It is important to know that in the event these patients need resuscitation, they may fail to respond to adrenaline and volume therapy.

MYDRIASIS

The pupil should be fully dilated and should be checked before seating the patient in front of camera. Patients with glaucoma and diabetes may take little extra time to dilate. Some doctors prefer to dilate the pupil only with parasympathetic blockers such as tropicamide and prefer not to use sympathomimetics to avoid cardiovascular effects, as the investigation itself already represents stress for the patient.

POSITIONING

The patient is seated in front of the camera. The height of the seat should be adjusted so that the chin rests comfortably on the chin rest, the forehead presses firmly against the forehead bar and the eye line is adjusted.

DYE INJECTION

5 ml of 10-20% fluorescein is drawn into a 5 ml syringe. Usually an antecubital vein is selected from either arm. A number 23-gauge butterfly cannula with a luer-lock system is inserted into the antecubital vein and is held securely by adhesive tape. If the blood flow is not free or it is suspected that the cannula may not be in position it should be repositioned. It is very important to have the cannula in vein as extravasation of the dye can result in discolouration of skin and pain. Once the cannula is in position, the dye is injected. Some

investigators use a two-way cannula with a second syringe filled with normal saline to flush the fluorescein dye that is believed to give a better contrasting picture. The cannula should remain in place till the angiography is over as this can be of help during any emergency condition that might arise during the session.

TEST DOSE

If any patient is suspected of having an allergy, a test dose of injection is vital. Normally 0.1 ml of 20% fluorescein diluted with 2 ml of normal saline is injected into the inserted cannula. The patient is monitored over next 5 minutes for any untoward reaction. If there are any signs of adverse reaction the fluorescein angiography must be abandoned.

ADVERSE REACTIONS

Fluorescein is a relatively safe injectable drug.

Mild Adverse Reaction

Mild adverse reaction has a rapid and complete resolution without any sequelae. Nausea, vomiting, extravasations of dye, sneezing and pruritis have been classified as mild adverse reactions. A mild reaction is transient and usually does not require treatment. The most common reaction is nausea, which occurs with nearly 3-5% of patients undergoing FFA and probably occurs because of a fast bolus injection of fluorescein dye.

Moderate Adverse Reaction

It is also transient but may require some treatment. The reaction has a complete but gradual recovery. Urticaria, syncope, other skin eruption, thrombophlebitis, pyrexia, local tissue necrosis, and nerve palsy have been categorised as moderate adverse reactions. The overall frequency is 1:63.10

Severe Adverse Reaction

It affects respiratory, cardiac or neurological system. Respiratory adverse reactions are laryngeal oedema, bronchospasm and anaphylaxis. Cardiac adverse reaction includes circulatory shock, myocardial infarction and arrest. A tonic clonic seizure is a neurological reaction. Overall frequency of severe reaction is 1:1900.

These reactions require intensive treatment and leave permanent deficiency in the system affected.

Death is a rare complication of FFA with a frequency of 1:222,000.10

STEPS IN FILMING

Identification

It is important to label the film with the patient’s identification. Most cameras have ready-made slot for this purpose but it is good to write all necessary information on a piece of paper and then photograph it on the film prior to starting angiography. It is also good practice to take patients photograph prior to fundus photograph. In the digital fundus camera there is personal record card in which all necessary information is filled in the diagnosis. Diagnosis can be revised from time to time if necessary.

FUNDUS PHOTOGRAPHY

The patient with dilated pupils sits down with his/ her chin on the chin rest and forehead against forehead rest. The knurled handle is turned to bring the patient’s eye level with the eye level marks on the head rest.

Use the external or internal fixation as required. Move the whole camera towards the eye while looking from the side to focus. Now, looking through the eyepiece or an additional monitor, tune the fine focusing knob to sharpen the retinal image. Centration of image can be achieved by moving the whole camera up or down. Be sure not to have any peripheral fringing. Finally trigger the flash switch to take the picture. Repeat the same procedure as many times as necessary.

PERFORMING THE FLUORESCEIN

ANGIOGRAPHY

Following colour photography switch to take red free photographs. Then ask the assistant to inject the dye and run the clock timer from the end of injection. Insert both exciter and barrier filter. At first you will not see any thing but very soon a bright glow will appear in the choroidal circulation. Now start taking photographs, initially at 0.5 second intervals for the first 6 seconds, then increase the time to one every 4-10 seconds for the next few minutes. This marks the end of transit period. The patient is then asked to wait for

10-12 minutes when the late phase photographs should be taken. Do not forget to warn the patients about skin and urine discoloration and to avoid direct exposure to sunlight for the next 24 hours. The dye reaches the eye in 12 to 15 seconds and depends upon the ‘aim- to-retina’ circulation time and is affected by cardiac output, viscosity of blood and caliber of nerves in blood vessels.6

OCULAR TISSUE RESPONSE TO FLUORESCEIN

The anatomical and physiological differences between the ocular tissues lead to different response to the circulating fluorescein. It will be helpful to learn the behaviour of different ocular tissue response to fluorescein dye before studying the normal pattern.

CHOROID

Larger choroidal vessels are impermeable to both bound and unbound fluorescein. However, choriocapillaris vessels are leaky due to multiple fenestrations and allow egress of both forms of fluorescein. The extra vascular fluorescein stains the choroidal stroma which can however not be seen when the retinal pigment epithelium is intact. Because fluorescein is a small molecule, especially the fluorescence producing free portion, it is washed out of the choroid quickly and choroidal fluorescence returns to an insignificant levels several minutes after injection.

BRUCH’S MEMBRANE

Extracellular fluorescein dye from the choriocapillaris permeates through the Bruch’s membrane, binding to the collagen tissue and to any colloid bodies on it.

RETINAL PIGMENT EPITHELIUM (RPE)

The tight junction provided by the zonula occludens of healthy retinal pigment epithelium prevents fluorescein dye passing beyond the RPE. However, in pathological conditions the barrier can be broken.

RETINA

Like the retinal pigment epithelium, the endothelial cells of the retinal vessels possess special qualities preventing permeability of fluorescein. However even slight inflammation allows the egress of the smallunbound fluorescein molecule making FFA a very distinctive method for retinal vasculitis.

CILIARY BODY

Blood vessels of the ciliary body are freely permeable and allow free movement of fluorescein dye in the ciliary body stroma. Diffusion to the posterior and anterior chambers is however limited by the tight junctions of the ciliary body epithelium.

VITREOUS BODY

It takes several days for the fluorescein dye to clear from the vitreous. The anterior vitreous loses fluorescein through forward diffusion into the aqueous. The posterior vitreous clears through the retinal vessels and by the process of active transport via the retinal pigment epithelium.

OPTIC NERVE

Retinal capillaries on the superficial layers of the disc are derived from the retinal vessels and are impermeable to fluorescein. However, the peripapillary choroidal plexus leaks, which accounts for the staining of the optic disc seen during the late phase of angiography.

SCLERA

The inner surface of the sclera stains with fluorescein, which leaks through the choriocapillaris. In case of choroidal atrophy, the sclera appears hypofluorescent in late frames due to staining from fluorescein that has diffused from adjacent areas.

MACULA

The xanthophyll pigment present in the macula lutea masks the background choroidal fluorescence hence a small area of hypofluorescence persists in this region throughout the period of angiography.

The centre of the fovea is completely devoid of the blood vessels. The perifoveal arcade is seen during the venous phase. There is free anastomosis of retinal capillaries around the perifoveal arcade that results in the development of macular oedema in disease affecting the peripheral part of the retina even if they are involving one sector only.9

INTERPRETING THE FLUORESCEIN ANGIOGRAM

An angiogram consists of five phases.

Figure 3: FFA right eye in the prearterial phase showing filling of the choroid and choriocapillaris with fluorescein dye. Note the simultaneous perfusion of cilioretinal artery

Figure 4: FFA right eye in the arterial phase showing filling of retinal arteries

Choroidal Phase (Prearterial)

During the first phase the prearterial phase, the choroid and choriocapillaris fill with dye. Fluorescein usually appears in the choroidal circulation approximately one second before it appears in the retinal circulation (Figure 3).

This can be clearly demonstrated in patients who have a pale pigment epithelium or in patients with albinism. Even in normal patients the filling pattern of the choriocapillaris is patchy and variable (Shimizu’s sign or Shimizu’s islands). In most angiograms the details of the choriocapillaris are not visible and only choroidal flush will appear on the angiogram

Arterial Phase

Shortly (1-3 sec after choroidal fluorescence) after filling of the choriocapillaris, the first appearance of fluorescein dye in the arteries signifies the beginning of the arterial phase, which extends till the arteries are completely filled (Figure 4).

Arteriovenous Phase

Complete filling of the arteries and capillaries and the first evidence of laminar flow in the veins characterise the arteriovenous phase (Figure 5).

The laminar flow is the result of two factors; fluorescein dye entering veins from smaller venules and second, the vascular flow being faster in the centre of the vessel as compared to the vessel wall.

Figure 5: FFA right eye in the arteriovenous phase showing complete filling of the arteries and capillaries and laminar filling of retinal veins

Venous Phase

The venous phase begins as the arteries are emptying and the veins are filling with dye (Figure 6).

Transit Phase

The aggregate of the arterial, arteriovenous and venous phase is commonly referred to as the transit phase of the angiogram. The transit phase represent the first complete passage of fluorescein-containing blood through the retina and choroid. At the end of the transit phase fluorescein dye remains in the choroid and sclera due to leakage from choriocapillaris vessels. A small amount of fluorescein also remains in

Figure 6: FFA right eye in the venous phase showing maximum dye concentration in the retinal veins

Figure 7: FFA left eye lower temporal quadrant in the recirculation phase showing leakage of dye from vessels in a patient with vasculitis

Figure 8: Fundus photograph right eye of a patient with intermediate uveitis showing media haze due to overlying vitritis

Figure 9: FFA same eye as in Figure 8 showing diffuse leakage in the posterior pole with disc hyperfluorescence

the optic nerve head and retinal vessels, but there is no leakage. Any additional fluorescein dye remaining in the eye should be regarded as pathologic.

Recirculation Phase

Recirculation phase of the angiogram follows the transit phase and represents the first return of blood containing fluorescein (a small amount) to the eye. This occurs after the blood has passed through the kidney. The fluorescein dye in the recirculation is very dim in contrast to the transit phase in which the dye in the blood is in much higher concentration. The

recirculation phase is useful for looking at leaking pathology (Figure 7).

Abnormal vessels that may be supplied by choroidal system, such as neovascularisation of the disc and subretinal neovascularisation often fills before normal retinal vessels.

In certain inflammatory conditions like diffuse vasculitis, intermediate uveitis or extensive neovascularisation, there is greater than normal accumulation of the fluorescein dye in the vitreous resulting in vitreous haze and poor visibility of the retinal structures (Figures 8 and 9).