insightVol. XXI No. 3 NOVEMBER 2003

Scientific Journal of

MEDICAL & VISION RESEARCH FOUNDATIONS18, COLLEGE ROAD, CHENNAI - 600 006, INDIA

Editorial

Perspective — Amblyopia : diagnosis and management— S. Meenakshi and T. S. Surendran

Purtscher's retinopathy following childbirth — Vikas Khetan and Lingam Gopal

Unilateral frosted branch angiitis in a patient with abdominal tuberculosis— Mamta Agarwal and Jyotirmay Biswas

Conjunctival Siderosis — Geetha K Iyer and Rajesh Fogla

Comparison of Conventional Refractive Technique and Automated Refractor (TopconRm-A 7000) in Pseudophakic Eyes — Ramesh S Ve, Deepa B M S, Manish J Shelat,Kumari B, Ramya S, Pradeep G Paul, Sripriya Krishnamoorthy and Smita Praveen

" MUCH ADO ABOUT NOTHING?"— Anaesthesiologist's Insistence on Preoperative Fasting — Ian Sundararaj

Development genes and eye— Sarangapani Sripriya and Govindaswamy Kumaramanickavel

Last Page - I-125 Brachytherapy — Mahesh P Shanmugam

Fundus picture of both eyes showing multiple white patches of soft exudates in the posterior pole.

48

Amblyopia is a very important cause of monocular blindness in childrenand young adults. Accurate diagnosis of amblyopia is possible with a fewsimple and easy to practice clinical methods. Timely management of thesepatients is critical in ensuring good recovery of vision. Our perspective articlein this issue deals with this topic, which is of great importance to the practicingophthalmologist.

Several unusual, interesting clinical cases seen at our tertiary centrehave been reported, which include purtscher's retinopathy, frosted branchangiitis, and conjunctival siderosis.

Preoperative fasting is essential to prevent life threatening complicationsduring anesthesia, especially general anesthesia.We look at ananesthesiologist's view on current trends of preoperative fasting.

Vital genes regulate the development of the human eye. This issue carriesan article that provides some basic information regarding the same, and thevarious developmental eye diseases that occur as a result of mutation ofthese regulatory genes.

Brachytherapy is the process of delivering precise radiation to anintraocular tumor, with limited exposure of normal surrounding tissue toradiation, thus avoiding unnecessary radiation to the periocular structures.This treatment is used for treating intraocular tumors such as retinoblastomaand malignant melanoma. This treatment facility has recently started atSankara Nethralaya. Our last page article provides detailed informationregarding this modality of treatment of intraocular tumours.

Dr Rajesh Fogla

Dr Mahesh P Shanmugam

Editors

EDITORIAL

CME PROGRAMMES FOR THE SILVER JUBILEE YEAR 2003

This Academic Year being the “Silver Jubilee Year” of Sankara Nethralaya attracts specialsignificance and importance. Apart from the continuous efforts directed towardsimprovement of Patient’s Care and Patient’s Education on prevention and cure, thefoundation has also lined up various CME Programmes for Ophthalmologists andOptometrists for updating their skill and knowledge.

Sl.No. Topics Date

1. Glaucoma 6th & 7th December 2003

The programmes are aimed to provide continuing medical education to the practisingOphthalmologists, Residents in Ophthalmology and to the Optometrists.

FOR MORE DETAILS, PLEASE CONTACTMr. N. Sivakumar

The Academic Officer — SANKARA NETHRALAYA18, College Road, CHENNAI – 600 006

Fax: 91-44-8254180 Email: academic@sankaranethralaya.org

49

Perspective:

Amblyopia : diagnosis and managementS. Meenakshi and T. S. Surendran

acuity testing in children is not without itschallenges. Children will often memorize lines,peek around the occluders and guess freely.Their intent is not to falsify but to performand please.

Traditional testing methods such asSnellen acuity do not work in preverbal andilliterate children. Children are often shy orwary of the examiner and sometimes franklyuncooperative. This calls for creativity andinnovation. So let us look into what methodsare easily available to the generalophthalmologist without resorting to expensivecharts and equipment.

Monocular and Binocular fixation pattern:

This is useful in very young infants andchildren. It is better to use one's thumb, whichis gently lowered in front of one eye, whilethe child is made to fixate on somethinginteresting, which the parent or the examinerholds up. A note is made if the fixation iscentral or eccentric. The latter implies visionless than 6/60.

The next step is to make note, if thefixation is steady or unsteady. Nystagmus inbilaterally vision-deprived infants tends to behorizontal, with a symmetrical pendularquality in primary gaze and jerky in lateralgaze. Especially in strabismic patientsbilateral motor nystagmus may coexist withunilateral amblyopia. Many children with verypoor vision may have manifest latentnystagmus on occlusion of one eye, whichreduces the acuity further. In these kids itmay be better to use a plus lens or translucentoccluder while testing fixation.

Most amblyopic eyes with better than 6/60 acuity, have fixation that is grossly centraland steady. So this does not rule outamblyopia. In such cases when acuity cannotbe measured directly, it is possible to

Amblyopia, one of the most importantcauses of childhood blindness, is a treatablecondition in most children, using simple timetested methods. Let us first very briefly reviewthe definition and pathogenesis of amblyopia,to enable us to diagnose and treat it better.

How do we define amblyopia?

Amblyopia is an acquired defect inmonocular vision that is due to abnormalvisual experience early in life. It is usuallyunilateral but may be bilateral.

Why does amblyopia occur?

Abnormal early visual experience canaffect monocular vision through either or bothof two amblyogenic mechanisms:

In the first, lack of exposure to thesharply focused images necessary for normaldevelopment disturbs and limits thematuration of form vision.

In the second, marked disparity in thequality and directionality of inputs from thetwo eyes prevents binocular fusion and resultsin abnormal competitive binocular interaction.This leads to exclusion or interference withone eye's input to higher visual centers, whichpersists during monocular viewing

What are the known causes?

Classically these are due to the following:

1. Strabismus

2. Anisometropia

3. Ametropia (usually in hyperopiamore than myopia)

4. Form deprivation (secondary tocataracts, lid tumors, ptosis etc.)

How does one test vision in children?

Since the diagnosis depends on visualacuity level, this is the single most importantstep in the clinical exam. However, visual

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exam. Remember the old adage "One toy, onelook".

There are a few charts that are usefuleven in preverbal but cooperative children.We have found the Lea symbols more easilycomprehensible than the Allen, which ispopularly used in the West. The Lea symbolsuses four objects, a house, an apple, a squareand a circle, which are recognizable by mostchildren. Whereas some of the objects depictedon the Allen e.g. a cake, may not be familiarto all children. Some others like the man onthe horse are abstract and difficult sometimeseven for adults to comprehend.

A hand held photocopy card of thereduced original chart can be made and theshy child can be taught to match theoptotypes. The shy but verbal child can alsowhisper the answer to the parent. It also helpsfor the other parent or helper to point theletters out on the screen or the chartindividually, but taking care not to cover theothers. Covering the other letters willartificially improve the vision by eliminatingthe crowding phenomenon seen in amblyopia.

We often will send the parents home withthe Lea symbols drawn on a piece of paper.This makes the child more compliant withvision testing in the follow up visits.

Snellen acuity is quite adequate in olderchildren. The Tumbling E and Landolt C areagain useful in illiterate children who arecooperative.

Other tests such as neutral densityfilters, Teller acuity may not be available tothe general ophthalmologist and actually couldbe later added if a large number of childrenwith amblyopia are seen and managed in thepractice.

What else is needed to complete the exam?

A good cycloplegic refraction is the nextimportant step, which helps uncover refractiveerrors including anisometropia as the cause.This is the time to look for media opacitieslike cataract. A good look at the posterior poleto rule out organic causes like optic nerve

document amblyopia by finding a significantunilateral fixation preference. This is done withthe help of fixation devices described belowand occluding each eye with a thumb, oroccluder. This works well in strabismicpatients.

Fixation pattern Visual acuity

Eccentric fixation 6/240 or lessUnsteady fixation 6/240-6/90Central fixation

but will not hold 6/60-6/30Central fixation-will hold OU

but prefers one eye 6/21-6/9Alternates spontaneously 6/6 OU

(These are conversions from the originalnumbers in feet)

16∆∆∆∆∆ or 10∆∆∆∆∆ Base down test:

This test is useful if the child has nomanifest strabismus. A 16 or 10 loose prismis held in front of one eye and any upwardrefixation movement is noted. If the eye withthe prism spontaneously shifts upwards topick up fixation then it is maintained. If itdoes not then the eye without the prism iscovered to force the prism covered eye tofixate. Then the cover is removed. If the eyewith the prism maintains fixation through ablink it is termed maintained. If the eye withthe prism does not maintain fixation througha blink then it is termed unmaintained. If thechild holds briefly, then a significantamblyopia is present. If the child holds uptobut not through a blink, then mild amblyopiaof atleast two lines are present. This isrepeated with the prism in front of the othereye.

The visual acuity testing described above,is ideally done at both distance and near,with interesting fixation targets. The distancefixation targets could be in the form ofmotorized toys which light up and move withthe flip of a switch or foot pedal. These aremounted at six metres. It could also be acartoon played on a video.

As far as the near toys, sky is the limit.But the more you have the better will be your

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astigmatism (also known as meridionalamblyopia when oblique axis are involved), isone such situation.

In anisometropic amblyopia, when thereis no manifest squint, you could give onlyglasses as a trial before deciding on furthertherapy.

For all other amblyopes some form offorcing the amblyopic eye to work has to beadopted. The gold standard treatment isocclusion of the "good eye" or the eye withthe better vision. The next question is HOWand HOW MUCH.

First decide how severe is the amblyopia.Occlusion with a patch applied to the skinfor ten or twelve hours a day is consideredfull time occlusion. Full time occlusion is thebest treatment for large differences in vision.But these patients need to be followed veryclosely due to the risk of inducing occlusionamblyopia. The patch can be a precut onewith adhesive, available by the brand nameof Opticlude. Some patients find theseexpensive, especially if the therapy involvesmany months. An inexpensive option is asterile eye pad like the ones used inpostoperative patients. This is secured withsome micropore tape. Other occluders like theslip on ones for wearing over the glasses aremore popular nowadays. But a word of cautionabout these and any form of patching. Thewhole point of the patching therapy is thatno light should enter the "good eye". A lot ofeffort is needed on the parents' part to ensureno peeking around the patch is going on. Wehave on several occasions sent letters toteachers requesting their cooperation in thismatter. We have also found it useful todemonstrate to the parent exactly how thepatch is applied and on which eye. This leavesno room for confusion.

Occluding the amblyopic eye for six daysand the normal eye for one day may have arole to prevent occlusion amblyopia especiallyin situations where follow-up is difficult.

For uncooperative children who tend torip the patches off, some type of arm restraint

hypoplasia that may explain the decreasedvision will conclude the exam. Usually by thispoint you should have a good idea as to thedensity of the amblyopia and its cause, inmost cases.

How do you manage amblyopia?

Just like many things in medicine, thereis nothing carved in stone. But here are someguidelines. If you are not sure as to thepresence of amblyopia, then re-examine thechild and only when sure, initiate amblyopiatherapy. At the outset we recommend a sounddiscussion with the parents. They need tounderstand that amblyopia treatment is a longand arduous task. It needs to be impressedon them that compliance with treatment isthe single most important factor affectingoutcome. They also need to know that theprognosis for vision recovery is fairly goodbefore nine years of age.

The two important components ofamblyopia treatment are

First, optical correction of the amblyopiceye to provide the best possible vision

Second, patching or penalization of the"good eye". Or in other words, by some methodforce the amblyopic eye to work

Optical correction of the amblyopic eyeis usually in the form of spectacles. Theprescription depends on other factors suchas presence of strabismus. But usuallywhatever provides the best vision in theamblyopic eye is given as the prescription.

Sometimes in anisometropic amblyopiawhen there is a very high degree ofanisometropia or when glasses have been triedin high hyperopia or high myopia and thevision does not improve, contact lenses maybe an alternative worth trying. Many otherconsiderations such as the ability of theparents to afford and maintain them may playa role in that decision.

There are a few situations in amblyopiatreatment when simply giving glasses alonemay usually suffice. Ametropic amblyopia, i.e.high myopia, high hyperopia or high

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What is the endpoint for full time occlusion?

1. Less then two lines difference in visionbetween the two eyes

2. No improvement after three consecutiveepisodes with good compliance.

Several important points to rememberduring these follow-ups are

1. The amblyopic eye is always checked first.

2. If memorization is suspected then thevision is double checked with another chartsuch as the E chart.

3. Near vision is always checked to make surethe child glasses are not too hyperopic.

4. Also if the glasses were broken and remadein the interim it is better to verify them, asit is not too uncommon for prescriptionsto be reversed.

5. If the child's vision should improve giventhe clinical situation and has not, then itis better to repeat a cycloplegic refractionand look again for organic causes such assubtle posterior lenticonus, optic nervehypoplasia etc., which may have beenmissed on an earlier exam especially in adifficult child.

6. It also is often helpful in repeating thecycloplegic refraction especially in cases ofhigh astigmatic errors to make sure thatthe axis of the cylinder has beenappropriately detected and prescribed.

What about part-time occlusion?

As the Amblyopia Treatment Study'spreliminary results have recently revealed,when the amblyopia is of mild to moderatelevel i.e. 20/40 to 20/80 then one can usejust two hours of patching and this may allthat is necessary. This should be combinedwith one hour of near activity.

Part-time occlusion is also used tomaintain the gain after the end point of fulltime occlusion has been reached. This isusually done about four to six hours a daytill the child is eight to nine years old. Part

(one can use one's imagination, but a rolledup old x ray slipped around the elbow andtied with strings works like a charm!), mayalso help reinforce compliance.

Is there any role for frosted glasses?

The use of frosted glasses is part ofmethods known as optical penalization. Someothers do not prescribe the hyperopiccorrection for the better eye, leaving it blurred,which works like a frosted glass. These areuseful in mild to moderate amblyopia. It hasthe advantage of preserving binocularity. Butthe children are prone to peek on top of theglasses, which is its drawback. But with poorfollow-ups it may be a safer alternative to fulltime occlusion provided there is parentalsupervision.

What about Atropine?

Otherwise known as pharmacologicalpenalization, is useful in a limited number ofpatients. Again it can be used in mild tomoderate amblyopia. It is useful only inhyperopia. The results of one of the arms ofthe Amblyopia Treatment Study revealed, inmoderate amblyopia (20/40 to 20/100) in theage group of 3 to 7 years, 10 hours or moreof patching seems to cause a more rapidimprovement in vision than atropine or parttime patching initially, but at six months therewas no difference. The problem of atropineside-effects has to be kept in mind. Also in asun drenched country like ours long term useof agents that dilate a pupil raises questionsof safety for the lens and the retina. We useit selectively for those who are completely noncompliant with patching or opticalpenalization.

How does you follow these patients?

Patients following full-time occlusionneed close careful follow-ups to avoidocclusion amblyopia. A general guideline is,one week for every one year of the child's age,e.g. a one year old is followed every one week,a two year old every two weeks and so on toa maximum of four weeks. Each such periodis described as an episode.

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Reference:

1. Keech RV. Practical management ofamblyopia. In: Focal points 2000. AmericanAcademy of Ophthalmology; 2000. vol XVIII(2).

2. Greenwald MJ, Parks MM. Amblyopia. In:Tasman W, Jaeger EA. Duane's clinicalophthalmology vol 1(10). Philadelphia.Lippincott William Wilkins. 1998.

3. Repka MX, Beck RW, Holmes JM, BirchEE, Chandler DL, Cotter SA, Hertle RW,Kraker RT, Moke PS, Quinn GE, ScheimanMM; Pediatric Eye Disease InvestigatorGroup. A randomized trial of patchingregimens for treatment of moderateamblyopia in children. Arch Ophthalmol.2003 May;121(5):603-11.

4. A comparison of atropine and patchingtreatments for moderate amblyopia bypatient age, cause of amblyopia, depth ofamblyopia, and other factors. Pediatric EyeDisease Investigator Group. Ophthalmology.2003 Aug;110(8):1632-7; discussion 1637-8.

time occlusion is also helpful when there areamblyogenic factors like a large anisometropia,or ptosis and can be used to prevent thedevelopment of amblyopia. Part time occlusionalso has a role when the child is very youngand follow-up is very difficult. After institutingpart time occlusion, the child will still needclose observation to make sure he or she doesnot slip. The younger the child and moresevere the anisometropia and more differentthe acuities the closer the follow up needs tobe.

Are there any drugs that can be used?

Levodopa has been tried and found to beeffective in even older amblyopes, but theeffect does not seem long lasting. It is likelythat after a randomized clinical trial provesits benefit, it may gain widespread acceptance.

In conclusion, amblyopia and itstreatment can be easily mastered with amixture of patience and diligence. You canprovide the child with lifelong good vision ifyou catch them in that window of opportunitybefore time passes by.

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Purtscher's retinopathy was firstdescribed by Omar Purtscher in 1912 in fivepatients with visual loss following headinjury1. Classically they were seen to behaving superficial white retinal patches andretinal haemorrhages. The fluoresceinangiography is known to reveal patches ofcapillary nonperfusion and variable degree ofleakage from involved retinal vessels1.

Case report:

A 22 yr old lady came to us withcomplaints of sudden diminution of vision inboth eyes a day following caesarean sectionat 8 months of pregnancy. There was a historyof moderate blood loss during the surgery.There was no history of altered sensorium.There was no preceding history of eclampsiaor diabetes mellitus during the pregnancy.

On examination the best-corrected visualacuity was counting fingers ant 1 meter inboth eyes. The anterior segment examinationdid not reveal any abnormality and theapplanation tonometry revealed an intraocular pressure of 7mm/Hg in both eyes.Fundus examination revealed normal discsand blood vessels in both eyes. There weremultiple white retinal patches in the

Purtscher's retinopathy following childbirthVikas Khetan and Lingam Gopal

peripapillary area and the posterior pole (Fig1). Fundus fluorescein angiography showedfocal areas of hypo fluorescence in thecorresponding areas (Fig 2). The patient wason tab. Prednisolone 60mgs per day when shepresented to us. The same was tapered off inthe course of next few days. No other specifictreatment was administered. 10 days later thevision improved to 6/200. At this stage thefundus picture was unaltered. Flash VEPshowed delayed latency for P1 while patternVEP showed extinguished response for allcheck sizes. Two months later the visionimproved to 20/40 in the right eye and to20/80 in the left eye. At one-year follow-upthe right eye vision improved further to 20/30. Fundus at this stage revealed nerve fibrelayer atrophy in the peripapillary region.Visual fields with Humphrey field analyserusing the 30-2 programme did not identifyany field defects.

Discussion:

Purtscher's retinopathy has beenclassically described after trauma. Thepresent-day understanding of thepathogenesis is one of complement activationleading to leukoemboli that cause the retinal

Fig 1. Fundus picture of both eyes showing multiple white patches of soft exudates in theposterior pole.

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arteriolar infarction. Reports of the occurrenceof Purtcher's retinopathy following childbirthare very rare. Table 1 lists the 4 cases ofPurtscher's like retinopathy after childbirthreported by Blodi et al. One of them also hadpancreatitis, which is also known to producethis fundus appearance. The others also hadsome additional problem such as uncontrolledhypertension. In two cases evidence of intracranial micro embolism in the form of seizureor cerebral infarction were present. Similarfundus picture has been described afteramniotic fluid embolism, but this case hadseveral other systemic features of amnioticfluid embolism. Our case had no other

attributable cause for the Purtscher'sretinopathy except child delivery. Thepathogenesis in this regard is hard to explain.The clinical appearance in our case and othersreported, clearly point to the occlusion ofarterioles of the retina. The nature of theoccluding material is however conjectural.Micro embolism of amniotic fluid has beensuggested but can never be proved. The visualimprovement in the four cases reported byBlodi et al was variable with one patientsuffering permanent damage. Our patientrecovered good visual acuity but consistentlycomplained of poor quality of vision and poorcontrast sensitivity. In the absence of a better

Fig 2. Fundus fluorescein angiography showing focal areas of hypofluorescence.

Table. List of reported cases of Purtscher's retinopathy following childbirthS. Author and Obstetrical Weeks Type of Additional Onset Initial Final

Year of Age of HTN of VisualNo. Publication history gestation delivery features loss V.A VA

1. Blodi et al 29 G3P2 32 Vaginal Pancreatitis + 8 hrs OD-20/30 OD-20/20(1990) OS-CF OS-20/60Case-1

2. Blodi et al 24 G1P0 32 Caesarian Pre eclampsia + 12 hrs OD-20/400 OD-20/40(1990) OS-20/400 OS-20/30Case-2

3. Blodi et al 16 G1P0 40 Vaginal Post - 18 hrs OD-HM OD-20/40(1990) With patum OS-20/200 OS-20/20Case 3 Pitocin seizure

4. Blodi et al 22 G1P0 37 Caesarian Eclampsia, + 6-12 hrs OU-CF OD-20/30(1990) Cerebral 1mtr OS-20/80Case 4 infarct

5. Present case 22 G1P0 42 Caesarian Uneventful - 24 hrs OU-CF OD-20/301mtr OS-20/80

G- Gravida; P- Para; HTN- Hypertension; V.A- Visual acuity: mtr- meter; CF- Counting fingers; HM- Hand motions

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AN APPEALA lot of things in this world depend on money - security, shelter, education and evenhealth. But at Nethralaya, money has ceased to be a pre-requisite for sight.

Day after day, year after year, Nethralaya treats hundreds of patients absolutely freeof cost and gives them back their sight. Treatment is provided free of cost to allpatients with a monthly income below Rs.1,750/-.

Yet there is no discrimination between the free patient and the one who pays. Apartfrom the treatment, food, medicines and travel expenses are absolutely free.

Those free patients depend on Nethralaya, and Nethralaya depends on you.

So, come and join the OPHTHALMIC MISSION TRUST.

For questions about tax exempt status and contributions, please contact:

Mr S V Acharya, TreasurerOphthalmic Mission Trust Inc. (OM Trust)

14613, Pommel Drive, Rockville,MD 20850, U.S.A.

Phone: (301)251 0378INTERNET e-mail : omtrustusa@hotmail.com

www.omtrust.org

For those of you in India and elsewhere, please contact:

Dr S S Badrinath,President & ChairmanSankara Nethralaya

(UNIT OF MEDICAL RESEARCH FOUNDATION)18 College Road, Chennai 600 006

Phone: 826 1265, 827 1616Fax: (044) 825 4180, 821 0117

INTERNET e-mail : chairman@sankaranethralaya.orgLOOK US UP ON THE WEB at http://www.sankaranethralaya.org

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understanding of the pathogenesis of thisdisease, a scientific approach to the treatmentor prophylaxis does not seem to be possiblein the context of women developing Purtscher'sretinopathy after childbirth.

REFRENCES:1. Barbara A. Blodi, Mark W. Johnson, J.

Donald M. Gass, Stuart L. Fine, LeonardM. Joffe. Purtscher's -like retinopathy afterchildbirth: Ophthalmology; 1990: l97:12:1654-1659.

2. William G. Marr Ernest G. Marr: Some

observations on Purtscher's disease:traumatic retinal angiopathy. Am JOphthalmology 1962:54; 693-705.

3. Snady J L, Morse P H . Retinopathyassociated with acute pancreatitis. Am JOphthalmology 1985; 100; 246-251

4. Meimei Chang, William N.P.Herbert. RetinalArteriolar Occlusions following Amnioticfluid embolism Ophthalmology 1984, 91:1634-1637

5. F.I. Fischbein. Ischaemic retinopathyfollowing amniotic fluid embolization. AmJ Ophthalmology 1969: 67:3:351-355

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Unilateral frosted branch angiitis in a patientwith abdominal tuberculosisMamta Agarwal and Jyotirmay Biswas

Tuberculosis is one of the most commonsystemic disease in India. Intraoculartuberculosis is however rare.1 Various ocularlesions caused by tuberculosis includesscleritis, iritis, iridocyclitis, choroiditis,chorioretinitis, retinal vasculitis, choroidaltuberculoma, subretinal abscess andpanophthalmitis. Choroiditis is the mostcommon ocular manifestation. Retinalvasculitis is relatively rare.2 Frosted branchangiitis is a rare vasculitis where severesheathing of retinal vessels are seen. It hasbeen reported in cytomegalovirus retinitis inAIDS and various other infectious entities. Thediagnosis of intraocular tuberculosis is made1) by demonstrating Mycobacterium tuber-culosis from ocular fluids or tissue specimensby microbiological or histopathological study,2) presumed ocular tuberculosis with provenactive systemic disease 3) presumed oculartuberculosis without any active systemicdisease. We report a case of unilateral frostedbranch angiitis in one eye and healedchoroiditis in other eye in a patient withabdominal tuberculosis.

Case report

A 17 yr old girl came to emergency withcomplaints of sudden diminution of vision inboth the eyes since morning. There were noother ocular complaints. She gave a historyof chronic abdominal pain since 5 months.She also had loss of appetite associated withweight loss, since past 2 months. She wasalso suffering from chronic cough since 3months. Gynaecological history revealedamenorrhoea in the last 3 months. The patientwas extensively investigated elsewhere.Ultrasound abdomen showed free fluid in thecul de sac and retroperitoneum. Chest X rayand barium meal study were normal. Mantouxtest was 13 mm x13mm positive. Haemoglobin

was 7.7mg/dl and peripheral blood smearshowed microcytic hypochromic red bloodcells. Stool test for occult blood was negative.ESR was found to be 45 mm at 1st hour. Thepatient underwent duodenal biopsy, whichshowed features consistent with granulo-matous colitis with areas of necrosissuggestive of tuberculosis. On examination,her vision in both eyes was counting fingersat 2 meters. Extraocular movements were full.Anterior segment evaluation with slit lampbiomicroscope was normal. There were fewanterior vitreous cells in the right eye. Fundusexamination in the right eye showed discodema, dilated tortuous vessels withperivascular sheathing and macular odema.There were scattered areas of superficial anddeep retinal hemorrhages. (Fig 1) The left eyeshowed areas of healed choroiditis in theposterior pole and along the superior temporalarcade. (Fig 2) The patient underwentgastrointestinal endoscopy which showedulcers in the ascending colon and wasdiagnosed as tubercular colitis. Laboratoryinvestigations revealed RA and antinuclearantibody to be negative. But C reactive proteinand serum angiotensin converting enzyme wasraised i.e 24 mg/l and 37.0 units.Hematological work up was with in normallimits. A diagnosis of retinal vasculitissecondary to tuberculosis was made and shewas started with antitubercular therapy (Tab.isoniazid 300mg, tab rifampicin 600mg, tabethambutol 800mg and tab pyrazinamide1000mg) along with low dose oral steroids inthe tapering doses. She was monitored everymonth and after 6 months of treatment,fundus examination in the right eye showedresolution of retinal vasculitis.(Fig 3) At thelast follow up, her best corrected visual acuityin both the eyes was 6/36.

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Discussion

Frosted branch angiitis is described whenretinal vascular sheathing is so extensive thatthe underlying vessels are obscured. Thecondition has been described incytomegalovirus retinitis, herpes simplex virusinfection, rubella3 and even neoplasticdiseases. There are several reports of retinalvasculitis due to tuberculosis. Gupta and coworkers described 13 patients of retinalvasculitis.4 In all patients, polymerase chainreaction of intraocular fluid (aqueous andvitreous) was positive for Mycobacteriumtuberculosis. Rosen and coworkers describedin a series of twelve patients with intraoculartuberculosis, 9 of them had florid ischaemicretinal vasculitis.5 Hoh et al reported a caseof bilateral retinal periphlebitis whichresponded promptly to 2 months ofantitubercular treatment.6 Eales disease isanother form of retinal vasculitispredominantly affecting the peripheral retinaof young and otherwise healthy adults between15 - 40 years. Recently in a study by us,Mycobacterium tuberculosis DNA has beendemonstrated by nested polymerase chainreaction supporting the association ofMycobacterium tuberculosis in this disease.7

Our case is the first report of frostedbranch angiitis due to tuberculosis. Theevidence favouring tubercular aetiology in thiscase is associated abdominal tuberculosis andpositive Mantoux test. In addition the patienthad healed choroiditis in other eye suggestiveof tuberculosis. The vasculitis in this patientresponded to a course of antituberculartreatment with low dose of systemic steroids.Differential diagnosis in our case was collagenvascular disease, sarcoidosis andhematological disorder. Rheumatoid arthritisfactor and antinuclear antibody were negative.Although serum angiotensin convertingenzyme was elevated (37.0 units), there wasno other evidence suggestive of sarcoidosis.Hematological work up was with in normallimits. Anti tubercular therapy in a patient ofsuspected tubercular retinal vasculitis shouldbe four drug regimen which includes isoniazid5mg/kg/day, rifampicin 450 mg daily if body

Fig 1.Montage fundus photograph of the righteye showing frosted branch angiitis, disc odemaand scattered retinal hemorrhages.

Fig 2. Fundus photograph of the left eyeshowing areas of healed choroiditis

Fig 3. Montage fundus photograph of the righteye showing resolution of vasculitis after 6months of antitubercular treatment

59

weight is less than 50 kg and 600 mg /day ifbody weight is more than 50 kg, ethambutol15mg/kg/day for first 4 months followed byrifampicin and isoniazid for 9-14 months. Ourreport indicates that frosted branch angiitiscan be a rare manifestation of intraoculartuberculosis. Prompt treatment withantitubercular therapy can preserve vision insuch cases.

References

1. Biswas J, Madhavan HN, Gopal L,Badrinath SS: Intraocular tuberculosis.Clinicopathologic study of five cases.Retina 1995; 15(6):461-8.

2. Shah S, Howard RS, Sarkies NJ et al:Tuberculosis presenting as retinalvasculitis. J R Soc Med 1988; 81:232-233.

3. Biswas J, Fogla R, Madhavan HN: Bilateralfrosted branch angiitis in an 8 yr oldIndian girl. Retina 1996; 16:444-445.

4. Gupta A, Gupta V, Arora S, Dogra MR,Bambery P: PCR positive tubercular retinalvasculitis: clinical characteristics andmanagement. Retina. 2001;21:435-44.

5. Rosen P, Spalton D, Graham E:Intraoculartuberculosis.Eye 1990;4:486-492.

6. Hoh HB, Kong VY, Jaais F: Tubercularretinal vasculitis. Med J Malaysia.1998;53:288-9.

7. Madhvan HN, Therese L, Gunisha P,Jayanthi U, Biswas J: Polymerase chainreaction for detection of Mycobacteriumtuberculosis in epiretinal membrane inEales' disease. Invest Ophthalmol Vis Sci2000;41:822-825.

SANKARA NETHRALAYACHENNAI

SIR RATAN TATA TRUST COMMUNITYOPHTHALMOLOGY FELLOWSHIP PROGRAMME

December 2003 / February 2004 / April 2004June 2004 / August 2004 / October 2004

CATARACT MICROSURGERY FELLOWSHIP (Basic & Advanced) - 2 months duration.A registered Medical Practitioner with Post Graduate Diploma or Degree in Ophthalmologycan apply.

Bio DataProvide all useful information about yourself in plain paper and send it to theundersigned.

InterviewCandidates called for interview need to appear for MCQ / personal interview at theirown cost. Rush application indicating the batch required. For details write to :

Academic Officer, MEDICAL RESEARCH FOUNDATION, 18, College Road,Chennai - 600 006. Fax : 044-28254180 e-mail : academic@sankaranethralaya.org

Bio Data & Application can be faxed or e-mailed or sent by speed post.

60

A variety of foreign bodies both metallicand non-metallic can be retained on the ocularsurface. The tissue response to these foreignbodies depends mainly on their chemicalcomposition. Metal and stone fragments aremore common in the industrial setting,whereas seeds, thorns, and insect fragmentsare more common in agriculturalsurroundings.1 Conjunctival granulomas havebeen reported to occur with retained syntheticand non-synthetic fibers in the fornices.2,3

Conjunctival siderosis is a rare condition thatoccurs secondary to retained iron particles orpreparations.1,4

We report the occurrence of conjunctivalsiderosis with pyogenic granuloma formationfollowing accidental instillation of an ironcontaining preparation into the conjunctivalfornix.

Case report

A 5-year-old male child presented to theoutpatient department with complaints of areddish mass lesion in the left eye since lasttwo months. His parents informed that anaccidental instillation of an iron and folic acidcombination medication (Fesovit, SmithKline- ferrous sulphate 150mg, folic acid 1mg,

Conjunctival SiderosisGeetha K Iyer and Rajesh Fogla

nicotinamide 50mg, vitamin B-6 2mg, andvitamin B-12 15mg) into the left eye hadoccurred four months back. This happenedwhen the parents were away and the childrenwere playing doctor patient game at home.The older sister acted as the doctor andinstilled the iron tablet into the left eye ofthis patient. This was retained in the upperfornix for almost three hours till the parentsreturned back home. The medication wasfinally removed from the eye by the localophthalmologist under general anaesthesia. Atreview two months later, he was noted to havedeveloped symblepharon involving the superiorfornix medially in the left eye. Surgical releaseof the symblepharon was performed by thelocal ophthalmologist. Subsequent to this hepresented to us two months later with aprogressively increasing reddish mass lesionin the left eye. On examination his bestcorrected visual acuity was 6/6 in the righteye and 6/9 in the left eye. A fleshy,pendunculated, reddish-brown mass lesionmeasuring 6 - 7mm in diameter was noted atthe 9'o clock nasal limbus. (Fig 1) The lesionwas also associated with loss of limbalpalisades of Vogt, besides symblepharonextending into the superior and inferiorfornices. The adjacent conjunctiva revealedpresence of brownish pigmentation. Rest ofthe ocular examination was normal and didnot reveal any features suggestive intraocularsiderosis. The right eye did not reveal anyabnormality. Extra ocular motility testingrevealed restricted abduction in the affectedeye. A clinical diagnosis of conjunctivalpyogenic granuloma was made. Surgicalexcision of the conjunctival mass wasperformed along with release of symblepharon,followed by conjunctival autografting from theunaffected fellow eye. The conjunctival graftmeasured 10mm x 8 mm.

Histopathological examination of theexcised mass revealed features consistent with

Fig 1. Slit lamp photograph of the left eyeshowing the reddish brown mass lesion at thelimbus in the left eye.

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diagnosis of pyogenic granuloma along withsecondary dilatation of blood vessels. Specialstaining for iron (Perls' stain) was positive,indicating possibly conjunctival siderosis. (Fig2)

Four months later he was asymptomatic,and examination of the left eye revealed ahealthy conjunctival graft with diffusebrownish pigmentation and no restriction ofocular movements. (Fig 3)

Discussion

Conjunctival siderosis was first describedby Reich in 1881, in a soldier who suffered aself inflicted injury with iron sulphate.1

Salmien et al reported epibular siderosis in a5-year-old boy, induced by iron containingtablets.4 Our case also had findings similarto their patient. Foreign bodies are often sweptup by the upper lid in the violent movementsof blinking, excited by its impact on the ocularsurface. These then progressively moveupward and reside in the recesses of the upperfornix.1 The bivalent iron (ferrous) is moretoxic to the ocular tissues than the trivalentiron (ferric).5 Siderosis is the deposition ofiron ion as ferritin or cytoplasmic siderosomesin many tissues throughout the eye. Toxicityis mainly caused by interference of excessintracellular free iron with some essentialenzyme process leading to various changesthroughout the eye.

In the earlier report on epibulbarsiderosis4, the initial reaction to the iron tabletwas characterized by inflammation andnecrosis of the involved conjunctiva, andcorneal de-epithelialization with dark browndiscoloration of the stromal layers. It ispossible that our patient also had similarclinical features initially following the injury.This represents a form of chemical injurywhich leads to tissue destruction and mayinvolve the limbal stem cell population ifsituated close to the limbus. Due to diffusionof the iron ions, continued tissue damage mayoccur especially if the foreign body is retainedfor a longer duration. The pyogenic granulomain our case could have been the result ofinitial surgical intervention. Positive stain foriron in the excised conjunctival tissue, andpost operative brownish discoloration of theconjunctival graft harvested from theunaffected fellow eye, both support the clinicaldiagnosis of conjunctival siderosis.

Due the presence of extensivesymblepharon, restricted ocular movements,and associated conjunctival damage, aconjunctival autograft was performed from theunaffected fellow eye to restore the ocularsurface in our case.

In conclusion, iron containingpreparations commonly used for treatment ofanemia, if accidentally instilled into the eyecan result in tissue damage and conjunctival

Fig 3. Slit lamp photograph of the left eyeshowing a healthy conjunctival graft withdiffuse brownish pigmentation

Fig 2. Histopathology of the mass lesionshowing positive stain for iron (Perls' stain,original magnification x 100)

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siderosis. These preparations should be keptout of reach of children at home. Conjunctivalautografting may be required if there isextensive conjunctival damage andsymblepharon formation.

References

1. Duke-Elder S. Retained foreign bodies. InSystem of Ophthalmology. Henry Kimpton,London, 1972; Vol XIV (Part 1): 451 - 467

2. Ainbinder DJ, O'Neill KP, Yagci A,Karcioglu ZA. Conjunctival mass formationwith unexpected foreign body. J PediatrOphthalmol Strabismus. 1991 ;28:176-7.

3. Resnick SC, Schainker BA, Ortiz JM.Conjunctival synthetic and nonsyntheticfiber granulomas. Cornea 1991 ;10:59-62

4. Salminen L, Passio P, Ekfors T. Epibulbarsiderosis induced by iron tablets. Am JOphthalomol 1982; 93: 660 - 661

5. Yanoff M, Fine BS. Eds Ocular pathology.Fourth edition, Mosby-Wolfe, London.1996; Chapter 5: 144 - 145

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Autorefractors have become commonplace in ophthalmic examination in the recenttimes. The popularity stems from, that theycan be operated by relatively less trainedtechnicians, leaving the professional cliniciantime to deal with more specialized examinationtechniques. The main draw back of theseautorefractor machines is that they are lessable to detect patient reliability as comparedto refraction done by a clinician.

Theoretically an individual who hadintraocular lens implantation followingcataract extraction should be an ideal patientwhen it comes to comparing Autorefractors1,2

,since pseudophakic eyes have very less or noaccommodation. In normal patients, withactive human lens, proximal accommodationto the targets projected inside aautorefratometer can produce erroneousreadings3, thus in pseudophakic eyes thereadings that are obtained can be trusted tobe the actual refractive error of the patient.But in reality, the noise caused by theintraocular lens interferes with the reading ofthe autorefractor. Most manufacturerscompensate for this by providing an“intraocular lens setting” algorithmn in theirmachines. These machines are advertised tobe as accurate as conventional refraction whenit comes to pseudophakic individuals and apossible alternative to the conventionalrefracting techniques in phakic and aphakicindividuals too4,5. So to determine Topcon RM-A 70007 (Topcon Co-corporation, Tokyo,Japan) autorefractor’s efficiency and accuracyin a clinical situation, comparison was madebetween conventional refractive technique andautomated refractor.

Previous studies have shown that theCanon Model RK – 1 autorefractor providesreasonably accurate postoperative refractionfor patients who have undergone posterior andanterior chamber intra-ocular lensimplantation following extra-capsularextraction1,2. While the Nikon autorefractorNR1000F tended to overestimate myopia (orunder estimate hyperopia) in younger patients,it gave reasonably accurate reading in patientsabove the age of 40 as well as aphakicindividuals and individuals with mixedastigmatism. Cylinder axis was found to beaccurate in all cases3. The refraction readingobtained by using model 6600 showed a highdegree of accuracy in determining therefractive error, but the errors were sufficientenough to perform subjective refinementbefore prescribing4.

Previous studies have indicated that theIOL setting algorithm holds true for somedevices1,3,4. As different machines use differentalgorithm, we were interested to ascertain thelevel of agreement between the Topcon ModelRM-A 7000 and conventional refraction in aneffort to simplify the Outpatient procedureregarding the refraction of pseudophakicpatients in a tertiary eye care center.

MATERIALS AND METHODS

Objective retinoscopy was performedusing streak retinoscope (Beta 200, Heine,Germany), Retinoscopy is based on Foucault’sprinciple, where the patient’s refractive erroris obtained by coinciding the subject’s farpointwith the examiners nodal point. The TopconRM-A 70007 (Topcon Co-corporation, Tokyo,Japan) uses infra red light to obtain patients

Comparison of Conventional RefractiveTechnique and Automated Refractor(Topcon Rm-A 7000) in Pseudophakic EyesRamesh S Ve, Deepa B M S, Manish J Shelat, Kumari B, Ramya S, Pradeep G Paul,Sripriya Krishnamoorthy and Smita Praveen

64

refractive error. It measures sphericalrefractive errors from –25.00diopter to +22.0diopter in 0.25 diopter steps. For cylindricalpower it is capable of measuring refractiveerrors from –7.00 diopter to +7.00 diopter in0.25 diopter steps and axis from 1º to 180ºin one-degree steps.

The study was carried out at a tertiaryeye care center from November 2002 toJanuary 2003. All subjects enrolled for thestudy had undergone extra-capsular cataractextraction with posterior chamber intraocularlens implantation. Criteria for inclusion werebest-corrected visual acuity of 6/12 and noposterior capsular opacification. Post sutureremoval subjects were excluded. All subjectswho fulfilled the inclusion criteria underwentrefraction in the 6th postoperative week, whichfollowed conventional techniques like objectiveretinoscopy following by subjective refinement.Retinoscopy was conducted at a workingdistance of 66 cm using streak retinoscope(Beta 200, Heine, Germany). This was followedby full subjective refraction- spherical foggingand refinement of cylinder using a Jackson’sCross Cylinder.

All these procedures were conducted inthe same room, with a constant illuminationto reduce any bias. The conventional refractiontechnique was conducted by only one of theauthors. Subsequently every subjectunderwent automated refraction using theTopcon Model RM-A 7000. These readingswere taken by one of the authors. Threereadings were taken using the autorefractor,the final reading being the average of thethree. Only the magnitude of cylindrical errorwas taken for analysis and the axis was notincluded in analysis. All measurements weregrouped into three groups for separateanalysis.

Group A: Measurements of Objectiverefraction (OR) and the readings from theAutorefractors (AR) were compared.

Group B: Measurement of Objectiverefraction and Subjective acceptance (SA) werecompared.

Group C: Measurements of subjectiveRefraction and the readings from theAutorefractors were compared.

Analysis of the data was carried outusing the Altman-Bland method6 to ascertainthe limits of agreement, correlation coefficientand coefficient of variation.

RESULTS AND ANALYSIS

A total of 161 subjects (216 eyes), withmean age of 58.54 + 9.3 years passed ourinclusion criteria.

GROUP A

Sphere: the mean difference between ORand AR was –0.01 +0.42 diopter. The 95%limits of agreement were 0.66 diopter and -0.68 diopter. There was significant positivecorrelation between OR and AR (r=0.92,p=0.01) and the 95 % CI was 0.04 diopterand –0.07 diopter. The coefficient of variationof OR and AR were 337.7 and 336.2respectively. (Graph 1)

GRAPH 1

AGREEMENT Spherical errors (in diopter)

Autorefraction (AR) - Objective refraction (OR)

Average

531-1-3-5

Diff

eren

ce (

AR

-OR

)

2.0

1.5

1.0

.5

0.0

-.5

-1.0

-1.5

Cylindrical correction: The meandifference between OR and AR was -0.26 +0.54diopter. The 95% limits of agreement were0.8 diopter and -1.32 diopter. There wassignificant positive correlation of thecylindrical errors between OR and AR (r=0.79,p=0.01) and the 95 % CI was 0.19 diopterand 0.34 diopter. The coefficient of variationof OR and AR were 47.63 and 47 respectively.(Graph 2)

65

GRAPH 1

AGREEMENT Cylindrical errors (in diopter)

Autorefraction (AR) - Objective refraction (OR)

Average

0-1-2-3-4

Diff

eren

ce (

AR

- O

R)

2

1

0

-1

-2

-3

GROUP B

Sphere: the mean difference between ORand SA was 0.08 +0.24 diopter. The 95% limitsof agreement could were 0.55 diopter and –0.39 diopter. There was significant positivecorrelation of the cylindrical errors betweenOR and SA (r=0.97, p=0.01) and the 95 % CIwas 0.05 diopter and 0.11 diopter. Thecoefficient of variation of OR and SA were337.7 and 444.43 respectively.

Cylindrical correction: The meandifference between OR and SA was –0.15+0.30diopter. The 95% limits of agreement were0.44 diopter and -0.74 diopter. There wassignificant positive correlation of thecylindrical errors between OR and SA(r=0.92,0.01) and the 95 % CI was –0.19diopter and -0.11 diopter. The coefficient ofvariation of OR and SA were 47.63 and 52.73respectively.

GROUP C

Sphere: the mean difference between ARand SA was –0.09+ 0.44 diopter. The 95%limits of agreement were 0.77 diopter and –0.95 diopter. There was significant positivecorrelation of the cylindrical errors betweenAR and SA (r=0.91, p=0.01) and the 95 % CIwas -0.15 diopter and -0.04 diopter. Thecoefficient of variation of AR and SA were336.28 and 444.43 respectively.

Cylindrical correction: The meandifference between AR and SA was 0.42+0.55diopter. The 95% limits of agreement were

1.5D diopter and -0.65 diopter. There wassignificant positive correlation of thecylindrical errors between AR and SA (r=0.78,p=0.01) and the 95 % CI was 0.34 diopterand 0.49 diopter. The coefficient of variationof AR and SA were 47 and 52.73 respectively.

DISCUSSION

All three groups showed correlationbetween the two techniques. However, as onewould expect good correlation betweentechniques that measure the same parameter,the Altman and Bland technique of assessingagreement is more appropriate. Using thistechnique there was a clinically acceptablelevel of agreement between the autorefractorreadings as well as conventional refractionwhen it comes to spherical errors. Themagnitude of difference in sphericalmeasurement could range between 0.55diopter to -0.39 diopter in Group B to 0.77diopter to -0.95 diopter in Group C.

But when it comes to cylindrical error,the large limits of agreements for Groups A(0.8 diopter to -1.32 diopter) and C (1.5diopter to -0.65 diopter) is probably notclinically acceptable and has moderatecorrelation in Group A(r=0.79) and C(r=0.78).Group B (0.44 diopter to -0.74 diopter) onthe other hand shows a strong correlation(r=0.92) with an acceptable level of agreement.Thus the conventional technique of OR andSA shows good agreement but the cylindricalmeasurements obtained with AR did not showgood agreement when compared with OR andSA. Both the spherical and cylindrical errorsin Group B show good agreement as expectedbecause objective refraction was the startingpoint for subjective acceptance.

Depending on the clinical situation, theclinician could consider replacing conventionalretinoscopy with the Topcon Model RM-A 7000Autorefractor, thus enjoying the speed thatcomes with use of an autorefractor, keepingin mind that in case of cylindrical error it isadvisable to follow the current philosophy ofconducting retinoscopy followed by subjectiverefraction, as these two readings (Group B)show an acceptable agreement.

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The decision on prescribing spectacle lenswould depend on the clinical situation. In thisstudy the auto refraction data inpseudophakes were all acceptably accurateespecially as far as objective refraction wasconsidered. If this level of agreement isacceptable and the clinician conducts a fullsubjective refinement following autorefractionit is possible to achieve the optimumcorrection as required by the patient as wellas saving time by conducting autorefractioninstead of manual objective retinoscopy.

Overall, the Topcon Model RM-A 7000autorefractor is capable of replacing manualretinoscopy as long a proper subjectiverefraction is conducted as well. In conclusionthis autorefractor is capable of providing areasonably accurate starting point forsubjective refraction.

CONCLUSION

There was good agreement in thespherical correction between both theconventional refractive techniques (objectiverefraction and subjective acceptance) andautorefraction. The spherical correctionbetween objective refraction and subjectiveacceptance shows good agreement. But onlya reasonable agreement was seen in thecylindrical correction between both theconventional refractive techniques and AR.The Topcon Model RM-A 7000 autorefractorcan replace manual retinoscopy as long as aproper subjective refraction is conducted aswell.

REFERENCE

1. Sunder Raj P, Akingbehin T, Levy AM.Objective autorefraction in posteriorchamber pseudophakia. Br JOphthalmology, 1990, 74, 731-33.

2. Sunder Raj P, Villada JR, Myint K, LewisAE, Akingbehin T. Clinical evaluation ofautomated refraction in anterior chamberpseudophakia. Br J Ophthalmology, 1991,75, 42-44.

3. SupriyoG, Nayak BK, Singh JP. CriticalEvaluation of NR-1000F auto refracto-meter. Br J Ophthalmology, 1986, 70, 221-6.

4. Pappas C, Anderson DR, Briese F. Clinicalevaluation of the 6600 autorefractor. ArchOphthalmology, 1978, 96, 993-6.

5. Pappas C, Anderson DR, Briese F. Is theautorefractor reading closest to manifestrefraction- A comparison of the patient’sprevious spectacles and the 6600autorefractor. Arch Ophthalmology, 1978,96, 997-8.

6. Bland JM, Altman DG. Statistical methodsfor assessing agreement between twomethods of clinical measurement. Lancet,1986, I, 307-310.

7. Manual of Topcon new autorefractometers,Topcon Co-orporation, Tokyo, Japan.

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or a chemical pneumonitis can occur if gastricpH is 2.5 or less. This can sometimes provefatal.1

To prevent pulmonary aspiration duringgeneral anaesthesia the traditional practiceof NPO ( nulla per os ) or nothing by mouthafter midnight, prior to elective surgery wasfollowed by anaesthesiologists and surgeonsthroughout the world.

In recent years several studies have beenconducted regarding gastric volume and pHof gastric secretions and the consequences ofpulmonary aspiration in order to formulateacceptable fasting guidelines. As a result ofthese studies fasting guidelines have been re-formulated in many centers throughout theworld.

NPO after midnight is applied only tosolids. Clear fluids are now allowed until 3hours before the scheduled time of surgery or2 hours before the actual time of surgery.This allows for any change in surgery timingand still allows for the 2 hour fasting regime..

Clear fluids include apple juice, water,carbonated water, tea or coffee without milk.Milk is considered as a solid which takes 3-4 hours to empty from the stomach.

Children may be allowed to have clearfluids upto 2 hours before surgery to avoidhypoglycaemia and dehydration. This isespecially important in children with

Starvation, refusing to eat, hunger strikesare not new to us. Each one is observed witha specific motive, be it to save our environmentor press demands for better workingconditions!

At home the sulking grandchild orgrandfather refusing to eat is not uncommon!

Fasting for religious purposes is observedby many.

But when fasting is advised beforeanesthesia and surgery why is the “nil peroral”schedule not strictly observed? This isthe plaint of the anaesthesiologist!!

A crying baby or an adamant boy mayeat during the recommended fasting periodinspite of parent’s objection. An elderly patientwhose surgery is postponed, waitinganxiously, hungry, may be irritable and maywant to eat or drink.

So why so much fuss about preoperativestarvation?

General anaesthesia produces loss ofconsciousness, muscle relaxation andanalgesia. The physiology of bodily functionsare altered. Any ingested food or drinkpartially digested may be regurgitated, vomitedor aspirated at the time of induction ofanaesthesia, at the conclusion or when thepatient recovers. Aspirated particulate mattercan block the respiratory passages resultingin respiratory distress. Aspiration pneumonia

“MUCH ADO ABOUT NOTHING?”ANAESTHESIOLOGIST’S INSISTENCE ON PREOPERATIVE FASTING

Ian Sundararaj

American Society of Anaesthesiologists Fasting Guidelines ( 1999)

Ingested material Minimum fasting (hrs)

Clear fluids (water, fruit juice without pulp, tea, coffee without milk) 2

Breast milk 4

Infant formula 6

Non human milk 6

Light meal (dry toast & clear fluid) 6

Solid food (fried & fatty food) 8

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homocysteinuria when thrombosis can occurif dehydration is present.

When a patient does eat solid food, thequantity and time of ingestion should be noted.

An early breakfast with clear liquids ispermissible for cases scheduled in theafternoon.

In 1999, the American Society ofAnaesthesiologists formulated certain guide-lines for preoperative fasting.2

Anaesthesiologists insist on strictadherence to fasting guidelines to enhancethe quality and efficiency of anaesthetic careand to reduce the morbidity and mortalityassociated with anaesthetic complicationssuch as vomiting and pulmonary aspirationof gastric contents, should they occur.

The change from the traditional NPO frommidnight for both solids and liquids to NPO

from midnight for solids only, allowing liquidsuntil two hours before the actual time ofsurgery has increased patient satisfaction,decreased incidence of complications of unduestarvation such as dehydration orhypoglycaemia and minimized preoperativemorbidity.

References:

1. Warner MA, Epstein BS, Gibbs C, et al:Practice guidelines for preoperative fastingand the use of pharmacological agents toreduce the risk of pulmonary aspiration:application to healthy patients undergoingelective procedures. Anaesthesiology 1999;900:896-905

2. Warner MA, Warner ME, Weber JG:Clinical significance of pulmonaryaspiration during the perioperative period.Anaesthesiology 1993; 78: 56-62

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Development genes and eyeSarangapani Sripriya and Govindaswamy Kumaramanickavel

The development process of eye iscontrolled through a network of regulatorygenes that are conserved throughoutevolution. Studies on drosophila models andmouse models have led to the identificationof vertebrate homologue for the developmentalgenes. The vertebrate eye comprises tissuesfrom different embryonic origins. Most of theregulatory genes are expressed throughout theeye compartments during the early stage ofeye development.1 Later, the expression of thegenes are regulated according to tissuespecification. The identification of differentdevelopmental genes of the eye is based onthe drosophila and mouse models. In the fruitfly, cluster of genes with similar domain (helixloop helix domain) that are required for thedevelopment of the different organs areidentified. These genes encoding homeodomainproteins are also found to interact during theeye development process. Based on this,vertebrate homologue to these proteins arethen identified to understand the molecularregulation during eye development. The vitalregulatory genes that are identified in the fruitfly and the vertebrate homologue to the sameare discussed.

Pax genes: Pax-6 is a member of thepaired box gene class and encodes atranscription factor containing a paireddomain and a homeodomain and act as themaster controller of eye morphogenesis.1 Pax6 regulates eye development process byactivating/repression of downstream targets.The gene is expressed in head ectoderm andin optic vesicle during the early stages ofmorphogenesis and later restricted to the lensplacode, vesicle and optic vesicle. In retina,Pax-6 regulates the proliferation of retinalprogenitor cells. 2 Homologue for thevertebrate Pax 6 genes are the eyeless (ey) ,twin of eyeless (toy) in Drosophila and smalleye (sey) gene in mouse.1 In human, Pax6

gene mutations have been found to result inmany developmental eye diseases.Haploinsufficeincy of Pax6 gene results inaniridia, foveal hyperplasia, accompanied bycataract, corneal opacificaiton and progressiveglaucoma while homozygous mutations resultin anophthalmos, nasal hypoplasia andcentral nervous system defects.3 In mousemutation in the sey gene results in small eyewith characteristics similar to that inaniridia.4 This similarity suggests that humanand mouse Pax6 genes function in a similarway to regulate eye development. In Xenopus,ectopic induction of the Pax6 gene results information of ectopic retinal and lentoidstructures.1 This suggests that Pax6 gene alsoplays an important role in the development ofboth retina and the lens. Loss of functionalmutation seen in the Pax6 gene in associationwith the disease explains the function of thedisease. Pax2 gene is another member of thePax family that is involved in patterning theoptic stalk during development. Mutations inPax2 gene in human and mouse are found toresult in kidney and ear defects.5

Six family genes: Six family of genesare homologue to the sine oculis (so)homeobox gene of drosophila. This generegulates the initial events of eye discformation and also the optic lobe and is alsoexpressed in the anterior neural plate. Thegene is expressed even in the non-oculartissues.1 In drosophila three genes are presentin the six family: so, Optix and Dsix4. In mousesix homologues are identified. Many of theseare expressed in the retina. Another memberof the six family called the Optx2 gene (six6and six9 ) identified in mouse is found toexpress the lens placode and optic vesicle. Inhuman being, 6 six genes, are identified : (1).SIX3 and SIX6 gene orthologous to Optix, (2)SIX1 and SIX2 genes orthologous to sine oculisand SIX4 and SIX5 gene closely related to

70

DSix4.6 In human mutations in the Six3 geneleads to holoprosencephaly andmicrophthalmia.7 Human chromosomaldeletions of the Optx2 containing region isfound to result in bilateral anophthalmia.1 Themisexpression of this gene in Xenopus eyesinduces expression of neural retina-specificmarkers and increases the proliferation of theretinal cells.1

Eya (Eye absent genes): Eye absentgenes (eya) encodes a member of a network ofnuclear transcription factors that promoteseye development in both vertebrates andinvertebrates. The mouse homologue of theeya gene are expressed in lens placode.1 Theeya protein is found to regulate transcriptionby binding to other DNA binding proteins..Even though the role of eya gene is unclear,human mutations in eya genes results incataracts and anterior segment defects. Recentstudies have demonstrated that eya genetriggers programmed cell death atinappropriate levels.8

Daschand (Dach1 and 2): In drosophila,misexpression of the Dach 1 and 2 genesinduces ectopic eye formation. Twohomologues to fly Dach1 and 2 genes areidentified in mouse which are related to theski and Sno genes that negatively regulatethe TGFb signal transduction. In mammals,these genes are suggested to have a possiblefunction in retinal development.1

BMP (Bone morphogenetic protein):These are a large family of proteins with morethan 20 proteins of the TGFb superfamily.The functions of these proteins are regulatedaccording to the gene dosage. Bmp2 and Bmp4genes of this family are closely related to theDrosophila dcapentaplegic. . The Bmp4 geneis expressed in multiple tissues duringembryonic development including the heart,lung, kidney, brain and eye. Decreasedfunctional dosage of the Bmp4 genes are foundto contribute to anterior segment dysgenesisand elevated intra ocular pressure.9,10 Bmp7,another member of this family is found toregulate the lens palcode formation along withPAX6 gene.

Otx and Crx gene genes: These familyof genes in vertebrates share homology withthe drosophila orthodenticle gene.1 Thesegenes are members of transcription factor thatare necessary for head and photoreceptordevelopment in the fly. Recent studies havesuggested that Otx genes are required fortissue specification. The gene is expressed indifferent stages of eye development.Heterozygous and homozygous mutant for Otxgene are found to have ocular malformationsincluding, lens, pigment epithelium, neuralretina and optic stalk defects.11 Mutations inthe human Otx1/2 genes are not yet reportedbut mutations in CRX genes are shown to beassociated with cone-rod dystrophy12 andretinitis pigmentosa and Lebers congenitalamaurosis.13

REIG/PITX family: PITX2 and PITX3 arethe two human homologues to the mousePITX/REIG family. The members of this familyare found to be mutated in developmentaldisorders of the eye. PITX2 is transcriptionfactor located in the human chromosomal loci10q25. This gene encodes for transcriptionfactor, which is expressed throughout eyeontogeny and also left-right axisdetermination. In human, this gene is mutatedin Rieger syndrome, a haploinsufficiencydisorder affecting eyes and teeth. Pitx2 alsohas a postulated role in left-right axisdetermination. Heterozygotes for either allelehave eye abnormalities consistent with Riegersyndrome. Analysis of mutations in this geneare associated with distortion in right leftsymmetry of the abdominal organs.14

Homozygotes are found to exhibit septal andvalve defects, and null homozygotes are foundto have a single atrium proving that athreshold level of Pitx2 is required for normalheart development. Null homozygotes exhibitarrest of pituitary gland development at thecommitted Rathke pouch stage and eye defectsincluding optic nerve coloboma and absenceof ocular muscles. Another gene of this PITXfamily, the PITX3 is also found to be expressedin lens. The rat homologue to this gene isPtx3. Mutations in this gene is recentlyreported in Rieger syndrome, Axenfeld-Rieger

71

anomaly, glaucoma, various anterior chamberanomalies, anterior segment mesenchymaldysgenesis (ASMD) and congenital cataracts.15

Foxc1and 2 (Mf1 and Mf2): These arethe forkhead transcription factor genes thatare expressed in the mesenchyme from wherethe ocular drainage system is derived.. Thehuman homolgoue for Foxc genes are theFKHL7 (Foxc1 ) and FKHL14 (Foxc2) genes.16

Mutant mouse model for Foxc genes are foundto have anterior segment abnormalities.Similar abnormalities are found associatedwith FKHL7 mutations in patients withanterior segment abnormalities as in Axenfeld-Reiger syndrome.16 Mouse embryoshomozygous for null mutations in Mf1 showseverely abnormal development of the anteriorsegment. The cornea fails to separate fromthe lens, resulting in the complete absence ofthe anterior chamber.

Other homologues to the Drosophila eyegenes: Several other developmental genes indroshophila are identified for which thevertebrate homologues are also identified.These are the Prox1 gene which is responsiblefor lens fiber elongation. The humanhomologue to the Drosophila crumbs gene arefound to be mutated in retinitis pigmentosa.1

The Rx/Rax homeobox gene (retina and neural

fold homeobox) required for the optic vesicleand neural patterning in mice is expressed inthe eye primordia regulates the proliferationof the cells that forms the retina.17 Overexpression of this gene is found to induceectopic retinal tissue formation.

Regulation of eye development is througha complex cascade of the above mentioneddevelopmental homeobox genes. In drosophila, the epistatic interaction of the ey , toy withthe so, eya and dac genes controls the eyedevelopment process. Pax6 mediated geneticcascade act as the master regulator of eyedevelopment.1 Six3 expression is found to bespecifically reduced in lenses of Pax6heterozygous mouse embryos. Both thetranscription factors (Six3 and Pax6)18 bindregulatory sequences from the counterpartgene and mutually activate their expression.SOX 2 is yet another protein with which thePax6 transition factor binds to form a complex.This complex binds to the enhancer elementof crystalline during the lens development.19

Thus it is demonstrated that Pax6 is themaster regulator of the eye development.

To summarize, the developmental genesof the eye determines the fate of the embryonictissues during eye development by forming acomplex network system. Table 1 summarizes

Table1:Vital development genes of eye, their site of expression and associated diseases

Developmental genes Expression in the eye Disease in human

CRB1 Retina Retinitis pigmentosa (RP)

Crx Neural Retina Cone-rod dystrophy, RP,Lebers congenital amaurosis

Pax6 Lens placode, optic vesicle Aniridia

Pax2 Optic stalk Optic nerve coloboma

Bmp4 Optic vesicle Anterior segment dysgenesis

Bmp7 Optic vesicle

Eya1 Perioptic mesenchyme Cataract, anterior defects

Six3 Lens palcode, optic vesicle Holoprosencephaly,microphthalmia

Pitx/REIG family Lens, anterior segment Reigers’ syndrome

FKHL-7 Mesenchyme (drainage system ) Anterior segment dysgenesis

Optx2 Optic vesicle Anoptholmos

72

11. Martinez-Morales JR, Signore M, AcamporaD et al. Otx genes are required for tissuespecification in the developing eye.Development, 2001:128:2019-30.

12. Freund CL, Gregory-Evans CY, FurukawaT, etal Cone-rod dystrophy due tomutations in a novel photoreceptor-specifichomeobox gene (CRX) essential formaintenance of the photoreceptor.Cell.1997; 91: 543-53.

13. Freund CL, Wang QL, Chen S, etal. Denovo mutations in the CRX homeobox geneassociated with Leber congenitalamaurosis. Nat Genet. 1998: 18:311-2.

14. Kozlowski K, Walter MA. Variation inresidual PITX2 activity underlies thephenotypic spectrum of anterior segmentdevelopmental disorders. Hum Mol Genet.2000 ; 9:2131-9.

15. Semina EV, Ferrell RE, Mintz-Hittner HA,etal. A novel homeobox gene PITX3 ismutated in families with autosomal-dominant cataracts and ASMD. Nat Genet.1998 19(2):167-70..

16. Smith SR, Zabaleta A, Kume T, et al.Haploinsufficiency of the transcriptionfactors FOXC1 and FOXC2 results inaberrant ocular development. Hum MolGen, 2000, 9;1021-1032.

17. Mathers PH, Jamrich M. Regulation of eyeformation by the Rx and pax6 homeoboxgenes, Cell Mol Life Sci 2000 ,57:186-94.

18. Goudreau G, Petrou P, Reneker LW,et al.Mutually regulated expression of Pax6 andSix3 and its implications for the Pax6haploinsufficient lens phenotype. Proc NatlAcad Sci U S A 2002: 99:8719-24.

19. Kamachi Y, Uchikawa M, Tanouchi Aet al. Pax6 and SOX2 form a co-DNA-binding partner complex that regulatesinitiation of lens development Genes &dev, 2001,15:1272-1286.

the different genes involved in eye developmentand the disease associated with them.Understanding the roles of these genes willthus help to probe in the different ocularabnormalities which will further help tomanage the disease effectively.

References

1. Wawersik S, Maas RL. Vertebrate eyedevelopment as modeled in Drosophila.Hum Mol Genet. 200 ;9:917-25.

2. Ashery-Padan R, Gruss P. Pax6 lights-upthe way for eye development Curr OpinCell Biol 2001; 13:706-14.

3. Grindley JC, Davidson DR, Hill RE. Therole of Pax-6 in eye and nasaldevelopment, Development, 1995;121:1433-1442.

4. Hill RE, Favor J, Hogan BL et al. Mousesmall eye results from mutations in apaired like homeobox containing gene.Nature, 1991: 324:522-525.

5. Sanyanusin P, Schimmenti LA, McNoe LA,etal. Mutations of the PAX2 gene in afamily with optic nerve colobomas, renalanomalies and vesicourectal reflux. NatureGenet, 1995,9:358-364.

6. www.genetics.med.ed.ac.uk.

7. Wallis DE, Roessler E, Hehr U etal.Mutations in the homeodomain of thehuman SIX3 gene cause holopro-sencephaly. Nat Genet. 1999 (2):196-8.

8. Clark SW, Fee BE, Cleveland JL.Misexpression of the eyes absent familytriggers the apoptotic program. J Biol Chem2002 ;277(5):3560-7.

9. Chang B, Smith RS, Peters M, et al.Haploinsuficient Bmp4 ocular phenotypesinclude anterior segment dysgenesis withelevated intraocular pressure. BMCGenetics 2001; 2:18.

10. Wordinger RJ, Agarwal R, Talati M, etal.Expression of bone morphogenetic proteins(BMP), BMP receptors, and BMP associatedproteins in human trabecular meshworkand optic nerve head cells and tissues.Mol Vis 2002 ; 8:241-50.

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(contd. from page 74)

chemotherapy is currently the preferredprimary modality of treatment inretinoblastoma, brachytherapy would still bea viable option in unilateral solitaryretinoblastomas, tumors that do not showadequate response to chemoreduction andthose resistant tumors which have notresponded to chemoreduction or externalbeam radiotherapy.

The limitation to I-125 brachytherapy inIndia was the short half life of the isotopewhich until recently had to be imported.Currently, BRIT (Board of Radiation IsotopeTechnology), isotope arm of BARC, Bombay,has been able to manufacture the seedsindigenously which has made I-125brachytherapy possible in India. We haverecently begun the clinical trial of these seedsat Sankara Nethralaya.

Tumors that can be treated withI-125 Brachytherapy

1. Malignant melanoma of the choroid 2.5 -10 mm thick / <16 mm in diameter

2. Retinoblastoma

a. Post chemoreduction residue that istoo large for local resection

b. Post chemoreduction / EBRTpersistent, recurrent tumor that istoo large for local treatment

c. Primary brachytherapy in unilateralunifocal retinoblastoma in an eyewith visual potential

3. Solitary choroidal Hemangioma withsecondary retinal detachment precludinglaser photocoagulation

4. Selected solitary or one quadrant vonHippel Lindau retinal angiomatosis

74

(contd. on page 73)

Last Page

I-125 BrachytherapyMahesh P Shanmugam

Iodine-125 has the advantage of gooddepth penetration, which makes it suitable totreat tumors up to 10 mm in height. Thisisotope can be easily shielded with a thin plateof gold, unlike the cobalt plaque whichenhances its safety. The low radioactivity alsolimits its depth penetration thereby avoidsdamage to the periocular structures. Iodine -125 is available in the form of seeds. Theseeds are glued on to a gold carrier, which isthen sutured on to the sclera for a specifiedperiod of time to deliver the required dose ofradiation. The gold carrier can be fabricatedin various sizes to suit the particular tumor.The number of seeds per plaque and thedesign of the plaque can be custom designedto suit a given patient. This flexibility isanother advantage of I-125 brachytherapy.Custom made plaques to treat ciliary bodytumors or pars plana seeding inretinoblastoma have been achieved with I-125seeds. Similarly, I-125 seeds have also beenused to treat select orbital malignancies suchas orbital recurrence of retinoblastoma,residual orbital tumor after resection etc.,

Results with brachytherapy have beengratifying. COMS found that the mortality ratein medium sized choroidal melanomas to besimilar to enucleation, the advantage ofbrachytherapy being that most patients mayretain the eye with some vision as well. Curerate of >90% has been reported in treatingretinoblastomas with brachytherapy. Though

Brachytherapy is the process of deliveringradiation as precisely as possible to the tumor,the main advantage being the limited exposureof normal surrounding tissue to radiation.This form of treatment is particularlyattractive for treating intraocular tumors suchas retinoblastoma and malignant melanoma.Growing children with retinoblastoma areparticularly susceptible to the adverse effectsof external beam radiation therapy such asimpaired growth of the orbital bones, delayeddentition etc., By limiting the area ofirradiation by taking the radioactive sourceclose to the eye as in brachytherapy,unnecessary radiation to the periocularstructures can be avoided. Melanomas are notparticularly radio sensitive and need largedose of radiation to achieve regression.Delivering large doses precisely to the tumorby external beam radiation machines is notpossible without delivering inadvertentradiation to the adjacent structures. This ishowever possible with particle beam therapymachines which are available in very fewcenters in the world. Brachytherapy hence hasbecome the widely used treatment option forintraocular melanoma.

Various radioisotopes such as Cobalt 60,Iridium, Ruthenium105 and Iodine 125 / 131have all been used to treat intraocular tumors,but Iodine 125 is most widely used isotopeand has come to be accepted as safe andeffective.

This issue of Insight is sponsored by:Rampion Eyetech Pvt. Ltd., Kalash, New Sharda Mandir Road, Paldi, Ahmedabad - 380 007Apex Laboratories Pvt. Ltd., 44, Gandhi Mandapam Road, Kotturpuram, Chennai - 600 085Pharmacia & Upjohn India Pvt. Ltd., SCO 27, Sector 14, Gurgaon 122 001, HaryanaWarren Pharmaceuticals Ltd., 2/10, Joti Wire House, Veera Desai Road, Andheri (W), Mumbai - 400 053

Medical & Vision Research Foundations thank the above sponsors for their generosity.

Editors : Dr Rajesh Fogla & Dr Mahesh P Shanmugam Private Circulation Only