Primary Congenital Glaucoma: An Update

Primary congenital glaucoma is a rare maldevelopment of the eye that affects children in the first few years of their lives. Blindness invariably occurs in untreated individuals. Early diagnosis by detailed examination under anaesthesia followed by prompt treatment is necessary for favourable visual outcomes. Surgery is the primary treatment modality due to limited role of medical management. Visual rehabilitation with management of refractive errors and amblyopia is key for long term visual success. This article gives an overview of the epidemiology, genetics, diagnosis and treatment of this devastating disease.


Introduction
Primary congenital glaucoma occurs due to abnormal development of trabecular meshwork and anterior chamber angle leading to impaired aqueous outflow. The terminology has replaced the older term Buphthalmos (Greek: bous = ox; ophthalmos = eye) which is now restricted to primary congenital glaucoma occurring before 3 years of age with resultant increased growth in eye ball. 1 The dismal disease consequences emphasised by Anderson's comment "Future of hydrophthalmia patients is dark and one seeks in vain for a best operation in treatment 2 have changed over the last few decades to more promising outcomes. This review traces the improved understanding and treatment evolution of this condition.

Historical Trail
Although abnormal large eyeballs in children were recognized by Hippocrates (4th century BC) and Celsus (1st century AD) 3 , it was only in late nineteenth century that von Hippel and Parsons linked disease pathology to malformation of anterior chamber angle.
The first successful surgery 'goniotomy' by Otto Barkan, in 1938 4 was modification of de Vincentis goniotomy, name derived from Greek gonio (angle), tomein (cut) by designing a glass contact lens to visualize and knife to cut trabecular tissue. Two decades later 'ab externo trabeculectomy' was simultaneously and independently performed by Burian with metal probe and Redmond Smith with nylon filament, which ushered in the era of Schlemm's canal surgery. 3

Epidemiology
Prevalence has racial connects varying from 1 in 10,000/ 68,254 live births. (Caucasians) 8,9 to 1 in 2,500 (high rate of consanguinity eg. Slovakian Gypsies and Middle East) 2,10 to 1 in 3,300 (India). 11 Consanguinity promotes founder effect or frequent mutations of a key mutation in an ancestor with reported 45-80% consanguinity in PCG cohorts. 12,13 Age of presentation is also linked to race, with early disease at 3-6 months in Asians /Arabians to 11 -12 months in Caucasians. 14,15 British Infantile glaucoma study (BIG) reports earlier age of presentation in children with Asian background (50% present before 3 months) compared to Caucasian peers (52% by 6 months) 16 Disease phenotype is more severe in developing countries, with almost 2/3rd PCG children in India presenting with blindness and most reporting late, after 6 months. 11,17 Slight male predominance (65%) has sometimes been noted for both Western and Asian cohorts. 3,15 Bilateral disease is the rule (70-85 %). 14 Since asymmetric presentation occurs and fellow "apparently normal, currently disease free" eye develops subclinical disease, it is imperative that children of unilateral PCG have lifetime screening. 15

Genetics
Occurrence is sporadic with familial inheritance in 10-40% cases (autosomal recessive with incomplete or variable penetrance). 3,19 Genetic loci identified are GLC3A, 3B, 3C and 3D. 19 • GLC3A loci (chromosome 2p21): Around 120 mutations have been described with mutations in CYP1B1 gene, encoding cytochrome P450 enzyme being commonest at 42%. [20][21][22][23][24] Gene effect has been traced to monooxygenase enzyme in endogenous steroid metabolism 25  Genetic unravelling introduces molecular screening as the preferred prevention tool in asymptomatic individuals with a high risk of disease, and for prenatal diagnosis. It is already being done for Slovak gypsies.

Clinical Manifestations
Classical triad remains blepharospasm, epiphora and photophobia with large eyeball with hazy corneas emerging to be more common in Indian subcontinent. 3,17 Corneal: Corneal enlargement implies disease onset prior to 3 years. Corneal diameter of >11 mm (newborn), > 12 mm (infant) and >13 mm (any age) is suspicious (Table 1).
Haab's striae due to breaks in Descemet's membrane are hallmark of disease. Typically horizontal and linear in central cornea or parallel /curvilinear to limbus in peripheral cornea, they need to be differentiated from post forceps assisted birth trauma Descemet tears, the latter being aligned vertically.
Corneal edema progress is from epithelial to stromal edema and scarring in case of persistently raised pressures.

Intra-Ocular Pressure And Its Measurement
Intraocular pressure (IOP) measurement depends on anaesthesia stage/agent, corneal thickness, corneal edema and corneal biomechanics. Scleral / corneal stretch with reduced corneal hysteresis may mask the IOP rise. Effect of corneal hysteresis (CH) and corneal resistance factor (CRF) on IOP is significant, with both indices being reduced in PCG. 28

Optic Disc Dimensions
Disc excavation of > 0.1 C: D ratio in children younger than 1 yr should be regarded with caution and > 0.3 most certainly investigated for glaucoma. 39,40 Elasticity of scleral canal sometimes partly reverse this cupping. 41

Examination Under Anaesthesia (Eua)
Ophthalmic examination under sedation (intravenous or mask anesthesia) suffices for diagnosis, followed by general anaesthesia for definitive surgery.

Treatment
Surgical treatment is the mainstay of therapy. Medical therapy serves as a stop gap, an adjunct post-surgery or in interval between repeat surgery to allow time for visual maturation.
Beta-blockers are first line drugs, resulting in 30% reduction in IOP. 45 Systemic side effects are minimized by using 0.25% dose or punctal occlusion. Both systemic and topical carbonic anhydrase inhibitors (CAIs) are effective, with topical Dorzolamide being the 2nd option. 46 Oral acetazolamide is used with caution due to its side effects of growth suppression, renal impairment and metabolic acidosis, the latter may precipitate an occlusive episode in sickle cell anaemia. The drug is given in 10 mg/ kg/day in three divided doses.
Alpha-2 agonists are not recommended children younger than 6-9 years for risk of central nervous system mediated respiratory depression and fatigue 47,48 Prostaglandin analogues are the last resort, majority of children being non-responders. 49 Irreversible iris pigmentation and eyelash elongation side effects require counselling, especially in unilateral PCG. Sustained release implants have been developed. 50

Surgical Treatment
Surgery is the mainstay with options dictated by corneal clarity and disease severity. Surgical interventions are of two types: • Ab-interno surgeries: Goniotomy, circumferential Schlemm's canal surgery • Ab-externo surgeries: Trabeculectomy with or without Mitomycin C, trabeculotomy, combined trabeculectomy with trabeculotomy (CTT) or use of Glaucoma drainage devices. CTT is the surgery preferred for severe disease and in eyes presenting with cloudy cornea. 51 Due to this aspect it remains the most often performed surgery for PCG in Indian subcontinent at 80%. 14 However the recent Cochrane meta-analysis suggests that there may be little to no difference between CTT and routine conventional trabeculotomy, or between viscotrabeculotomy and routine conventional trabeculotomy. 52 It stated that 360-degree circumferential trabeculotomy may show greater surgical success than conventional trabeculotomy. 52

Goniotomy
The procedure requires a clear cornea for proper visualization of angle structures. Tissue obstructing trabecular meshwork is incised by Barraquer knife/ Worst knife/ long 25 or 30 gauge needle, under direct visualization of Swan-Jacob gonioscopic lens in a viscoelastic formed chamber. Entry is from temporal clear cornea and nasal 3-4 clock hours are treated. 53 Globe rotation manoeuvre permit excision of 5-6 clock-hours of meshwork 54,55 Trabecular meshwork is incised circumferentially laying bare a white line, followed by falling back of iris. A single goniotomy is effective in controlling pressures in almost 75% cases 56 , multiple goniotomies increase the success rate to 93%. 57,58 Modifications of the procedure are: twin site approach for wider coverage, Kahook dual blade use for more controlled incision and endoscopic goniotomy. [59][60][61][62] Goniotomy has the advantage of short operating time, conjunctiva-sparing nature, with low incidence of complications. 53,57 Hyphema is a common complication, but it resolves with time. Ab externo Circumferential 360° trabeculotomy First performed by Beck and Lynch in 1995, using a 6/0 polypropylene suture passed in a purse string manner to create a 360 degree incision in inner wall of Schlemm's canal. 67 Sustained IOP control with a single session, with success rates of 87-93% over long term follow-up are reported. [68][69][70] Few unacceptable complications being creation of false passage due to suture misdirection, subretinal and suprachoroidal damage iris tear and prolonged hypotony. DJO μm sans lumen). Both devices incorporate an optical fibre illuminating the tip, permitting continuous visualization. After 360 degree catheterization, catheter is retrieved from other cut end of Schlemm's canal and two ends of catheter are pulled like a purse string, resulting in 360 0 rupture of inner wall of Schlemm's canal. Success rates range from 80-87%. 72,73 Complications reported are hyphema in 100%, canal malformation restricting catheterization in 7-20% and cataract. 72,74,75 Trabeculectomy With Mitomycin-C A tested surgery with long term success rates ranging from 60 -90 %. 76,77 adjunctive anti-metabolites improve success 78,79 Mitomycin-C is used in doses ranging from 0.2 -0.4 mg/ml for durations of 2 -3 minutes. 80 Postoperative complications like prolonged hypotony, scleral and conjunctival fragility and endophthalmitis are known consequences of MMC use. 81 The most problematic aspect of creation of bleb for life with subsequent tear film abnormalities, corneal astigmatism and bleb related infections. Propensity to eye rubbing and trauma often results in high rates of bleb related endophthalmitis in children (7-14%). [78][79][80]82

Combined trabeculotomy with trabeculectomy (CTT)
This surgery combines conventional trabeculectomy with Schlemm's canal exploration and rupture of its inner walls by Harm's trabeculotome. This is followed by excision of deeper trabecular block and suturing of superficial scleral flap and conjunctival flap.
Combined trabeculotomy and trabeculectomy with or without MMC is the most commonly procedure for PCG eyes in Asia, with figures as high as 80% in Indian scenario. 14,83 Success of the procedure ranges from 85 % at 1 year declining to 75 -77 % over a 2-3 year follow up. 51,84 A large series of 624 eyes with a 3 year follow up and 299 with over 8 year follow up report success rates of 77 and 63% respectively. 84,85 The longest reported follow up till date of 21 years from India has documented 6% compete success with 63% qualified success. 86

Glaucoma Drainage Devices (GDD)
Glaucoma drainage implants (GDD) come to rescue in situations of multiple failed angle and or limbal surgeries. 87 Bleb of GDD being posterior to limbus makes it less susceptible to endophthalmitis. Tube implants currently used in pediatric glaucoma are Baerveldt and Ahmed tube shunts. For smaller sized eyes, smaller area models of FP 8 Ahmed valve (96 mm 2 ) compared to FP7 (184 mm 2 ) and 250 mm2 size Baerveldt compared to 350 mm2 (adult) version are recommended. 88 Keeping in mind anticipated growth of child's eye with high incidence of tube retraction, some recommend adult size implants if it can fit the paediatric eye. 19 Efficacy of tube shunts in PCG has been reported to be high from 87-90% at 1year 87-92 however survival declines over time, from 80-97% during first year to 58-66 % by 2-4 years and 20-40% by 5 -10 years. 87,89,93 Comparative studies score GDD to perform better than trabeculectomy with success of 87 to 53% (at 1 and 6 year) compared to 36 and 19% with trabeculectomy. 90 The same group reported more postoperative complications with GDD use in children, especially tube repositioning.
Long term complications are otherwise high with reported pupil abnormalities (16%), cataract (20% of phakic eyes), corneal touch, corneal decompensation (10%). 89 Hypertensive phase post tube shunts is less frequently seen in children 87,93 and is controlled by prophylactic use of aqueous suppressants. 88 Conditions peculiar to the child's eye like eye rubbing, growth and elasticity result in specific complications namely corneal decompensation, tube erosion /extrusion and tube retraction. 82,88 Elastic recoil of sclera after normalization of IOP can cause tube rotation leading to corneal contact. Growth of eyeball carries the potential risk of tube retraction. Treatment of latter is done with tube extenders or by tube-in-tube technique (threading new tube within existing tube lumen) 94

Deep Sclerectomy
Utility of non-penetrating deep sclerectomy is doubtful given that obstruction to aqueous humour flow is internal, with only few studies supporting its success in PCG eyes. 95,96 Cyclophotocoagulation Cyclophotocoagulation by transscleral Nd:YAG , transscleral diode, endoscopic diode, or micropulse trans-scleral diode are reserved for eyes with guarded visual prognosis , has a success rate ranging from 28 -79% [97][98][99] Transscleral cyclophotocoagulation diode (TSCPC) is safe and effective, however efficacy is often transient and several sessions are required. Lens opacification requiring cataract surgery is common in phakic eyes (40%) 100

Prognosis And Complications
Visual gain in children depends on the degree of corneal scarring, astigmatism, anisometropic amblyopia, extent of glaucomatous damage and sequel like cataract or strabismus. Timely surgery with amblyopia therapy can result in good vision and a large series of 624 eyes from India reports 42% children gaining near normal vision. 84 Functional gain of vision occurs in 50-80% patients when IOP, refractive error and amblyopia are managed adequately. 58 Axial myopia is common (50 % and more), with younger age of surgery related to worse retinal parameters. 100 Cataract and strabismus often occur after successful PCG surgery. Cataract surgery requirement is reported for 22% within 8 years and strabismus for 38% over 5 years increasing to 50% over 10 years. [102][103][104] Risk factor for occurrence of cataract are number of anti-glaucomatous surgeries and tube shunts. Performing strabismus or cataract surgery in filtered eyes can have an adverse effect on bleb longevity, due to liberation Delhi Journal of Ophthalmology Vol. 32, No. 2, October-December 2021 DJO of inflammatory cytokines. Performing cataract surgery can also result in refractive surprise primarily due to greater myopic shift, subsequent to increased responsiveness to IOP fluctuation. 105 Visual acuity improvement post-surgery is gratifying, however these children need to be monitored for lens subluxation, capsular phimosis and endophthalmitis. Visual sequel to PCG surgery have clinical implications in visual prognosis and counselling of parents. Consent for probable need of strabismus surgery, cataract surgery, amblyopia therapy and low visual aids should be taken from the parents prior to performing surgery. Management of residual vision with and lifelong follow-up and low vision aids is integral to enable these children to retain functionality.

Conclusion
Early diagnosis, appropriate surgical management before irreversible damage ensues can result in functional visual gain to most of the children of primary congenital glaucoma. Choice of surgery depends on the severity of glaucomagoniotomy being preferred in milder disease and clearer corneas, CTT or assisted goniotomy in severe PCG. We reserve use of drainage implants or cyclodestruction for cases with surgical failure. Medication can help pre-and post-operatively for IOP spikes. Genetic counselling, molecular diagnosis, possibly antenatal and reversing the trend of consanguineous marriage in certain populations are the means to reduce this devastating childhood blindness.