Sunday, October 20, 2019

PRIMARY CONGENITAL GLAUCOMA


Guest author

SABEEH

Ajmal Khan Tibbiya Colege
Aligarh, India



Introduction

Primary Congenital Glaucoma (PCG) is a potentially blinding disease of children, which if untreated, would result in a lifetime of blindness. It occurs due to obstruction of the drainage of the aqueous humor caused by a primary developmental anomaly at the angle of anterior chamber. Although PCG is the most common glaucoma seen in infancy, it is still an uncommon disease. The variable incidence in various ethnic groups points towards a genetic basis for the disease.



Epidemiology


  • The disease varies sustainability in different ethnic groups from 1:1250 births in Slovakian Roms to 1:20,000 in Scandinavian regions.
  • In the West, the average incidence is about 1:10,000 births, but appears to be higher in Asians.
  • In Saudi Arabia, it is reported to be 1:2500, while Indian's have incidence of 1:3300.
  • The disease was responsible for 4.2% of blindness in the pediatric population.


Inheritance


  • Most cases of PCG are sporadic in occurrence.
  • Recessive inheritance of some cases of PCG is proved by:
  1. A high frequency of parental consanguinity.
  2. The presence of disease in about 25% of sibs of probands.
  3. The presence of the disease in all children of a marriage between 2 affected persons.
  4. The occurrence of Glaucoma in collaterals of both parents some families.


Genetic defects


  • According to Human Genome Organization (HUGO) Nomenclature Committee, loci for congenital glaucoma are designated by GLC3 and letters are added to distinguish specific loci in order of their discovery.
  • Till date, 3 genetic loci have been linked to PCG:
  • GLC3A at chromosome locus 2p21.
  • GLC3B at chromosome locus 1p36.
  • GLC3C at chromosome locus 14g24.3
  • Of these only the GLC3A locus has been linked to a specific gene. This gene is called CYP1B1 and is the largest known enzyme of the human cytochrome p450 pathway.
  • There are several known missense mutations within the CYP1B1 gene.
  • Among these, the mutations identified are:
  • G61E, Ter223, P193L, E229K, R390C, R368H.
  • A study on the genotype-phenotype correlation of these patients identified the frame shift mutation and R390C homozygous mutation as being associated with very severe disease and poor prognosis regardless of any treatment.


Structural defects and clinical features


  • The glaucomas are a heterogeneous group of insidious diseases associated with elevated IOP and optic nerve atrophy.
  • Primary Congenital Glaucoma is a specific, inherited developmental defect in the trabecular meshwork and anterior chamber angle.
  • The developmental anomalies of the anterior chamber angle prevent drainage of aqueous humor, thereby elevating IOP.
  • Elevation of IOP in children younger than 3 years of age causes rapid enlargement of the globe, occurs primarily at the corneo-scleral junction.
  • As the cornea and limbus enlarge, the endothelium of the cornea and Descemets membrane are stretched. This stretching can result in a linear rupture of Descemet's membrane known as Haab's striae.
  • The Descemet's membrane ruptures may occur acutely causing an influx of aqueous into the stroma and epithelium resulting in sudden corneal edema.


Haab's striae

Clinical features of PCG typically include:

  1. Tearing
  2. Photophobia
  3. Buphthalmos (enlargement of the globe)
  4. Clouding of the cornea


More serious consequence of elevated IOP is that it can rapidly lead to axonal loss and permanent visual impairment in untreated children.

Buphthalmos


Management

The management of Congenital Glaucoma starts with parental counseling, which includes discussion for: need for surgery and possibilities of multiple surgeries; the need for lifelong follow up and the combination of problems to be tackled (IOP, amblyopia management, refractive correction, possible keratoplasty).

Panicker and associates have graded the severity of glaucoma depending upon the clinical features as given below in table.

SEVERITY INDEX FOR GRADING PCG

Clinical parameters used for grading
Normal
Mild
Moderate
Severe/Very severe
Corneal diameter
Upto 10.5mm
>10.5-12mm
>12-13mm
>13mm
IOP
Upto 16 mmHg
>16-20 mmHg
>2030 mmHg
>30mmHg
C/D ratio
0.3-0.4
>0.4-0.6
>0.6-0.8
>0.8
Last recorded VA
20/20


<20/400-NPL
Corneal opacity
No edema
Mild edema
Severe edema
Severe edema+Haab’s striae

Examination under anesthesia is an essential part of PCG management. It includes the following examinations:

EUA

Tonometry
General anesthesia usually lowers the IOP, except for ketamine.
The Tono-pen is convenient and easy to use.
The normal IOP in infants under anesthesia is usually in the low teens.
A pressure of 20 mmHg or more should be considered abnormal.

Corneal diameter
Using calipers the corneal diameter measurement should be taken from limbus to a similar point 180-degree away at the opposite limbus.
The 95% ranges of normal corneal diameters are: 9.4 mm to 11 mm at age 1 month, 10.5 mm to 11.7 mm at age 6 months, and 10.8 mm to 12 mm at age 12 months.
In PCG, the diameter of cornea may enlarge to as much as 17 mm.
Changes in the corneal diameter less than 0.5 mm in the follow up examination should be interpreted cautiously.

Gonioscopy
A 14 mm Koeppe lens provides a clear view of the angle of the eye and a hand held microscope with a Barkan light or any type of illuminator is necessary for gonioscopy during anesthesia.
In Congenital Glaucoma the Iris usually is inserted anterior to scleral spur and the angle recess is poorly formed.

Fundoscopy
Dilated fundus examination and disc evaluation are essential in diagnosing congenital glaucoma.
Optic nerve cupping larger than 30% of the disc diameter, especially if asymmetric between two eyes, is strong evidence that the disc is under pressure and may be glaucomatous.
Glaucomatous cupping in infants, unlike adults is usually reversible after normalization of IOP.
The younger the child, the faster is the reversibility.

Surgical treatment

The surgical options include:
Goniotomy
Trabeculectomy
Trabeculectomy with anti-fibrotic agents

Goniotomy

 
Trabeculotomy
A trabeculotomy-trabeculectomy combined surgery has been found to result in more favorable outcomes and many surgeons prefer that approach.
In case of refractory cases not responding to surgery, a repeat surgery is needed.


Thursday, October 17, 2019

SYSTEMIC ANTI-GLAUCOMA THERAPY



Guest author

LOVELY SINGH

Ajmal Khan Tibbiya College
Aligarh, India


HYPEROSMOTIC AGENTS

Administered systemically to lower intra-ocular pressure (IOP) acutely.

MECHANISM OF ACTION


  • Reduce vitreous volume and thus IOP, by creating an osmotic gradient between blood and vitreous.
  • Larger the dose and more rapid the administration, greater the reduction in IOP.
  • Limited effectiveness and duration of action when blood-aqueous barrier is disrupted.
  • Serum osmolality rises by the hyperosmotic agents, causing a net movement of intra-ocular water, primarily from the vitreous, into the retinal and uveal vessels.
  • Gradually, when the osmolality gradient between the serum and vitreous decreases, the flow of water out of the eye diminishes. Once the hyperosmotic agent is cleared from systemic circulation, there is relative reversal of osmotic gradient due to the dehydrated vitreous and a subsequent rebound rise in IOP.
  • An alternative theory suggests hyperosmotic agents may act through receptors in the central nervous system. Hyperosmotic agents were found to be active only in eyes with intact optic nerves.
  • The induced blood-ocular osmotic gradient is influenced by the following factors:

  1. Size: Smaller molecules increase osmolality greater than larger molecules per unit of weight.
  2. Rate of administration: A larger osmotic gradient can be achieved with rapid administration of the hyperosmotic agents.
  3. Rate of ocular penetrance: The lesser the ocular penetrance the larger the blood ocular gradient is allowed to persist. This increases the IOP-lowering effect.
  4. Drugs and inflammation: May alter the blood-ocular barrier and affect the hyperosmotic agents’ action.
  5. Systemic clearance: A drug with faster metabolism and clearance allows shorter duration of IOP control.
  6. Oral ingestion of fluids: Concomitant ingestion of fluids decreases serum osmolality, causing decreased IOP control.
  7. Distribution of drug in body fluids: A drug contained primarily in extracellular space (e.g. mannitol) allow a greater osmotic effect than a substance which passes intracellularly and distributed in total body water (e.g. urea).
INDICATIONS

Short-term or emergency treatment of elevate IOP.
Useful in acute conditions of elevated IOP (e.g. acute angle closure).
Effective when elevated IOP renders iris non-reactive to agents which combat pupillary block such as parasympathomimetic agents (e.g. pilocarpine).
Used to lower IOP or reduce vitreous volume prior to initiation of surgical procedures.

CONTRAINDICATIONS


  • Should not be used for long-term therapy.
  • May cause rebound elevation in IOP if the agent penetrates the eye and reverses osmotic gradient.
  • Diabetes mellitus.
  • Congestive heart failure.
  • Renal failure.
ORAL AGENTS

AGENT
DOSE
ONSET OF ACTION
PEAK EFFECT
DURATION OF ACTION
NOTES
GLYCEROL (50% or 75%) solution
1-1.5gm/Kg BW (2-3cc/Kg BW)
10 min. after ingestion.
30-60 minutes
5 hours
100% solution also available.
ISOSORBIDE (45% solution)
1-1.5gm/Kg BW

1-3 hours
3-5 hours
Fewer side-effects than glycerol
ETHYL ALCOHOL (40-50% solution)



Brief action, since alcohol rapidly enters the eye.
Can cause nausea, vomiting.



INTRAVENOUS AGENTS


(1) Mannitol
10-20% solution is given in a dose of 1-1.5g/kg BW, at a delivery rate of 3-5 ml/minute.
Onset of action: 10-30 minutes
Peak effect: 40-60 minutes
Duration of action: 2-6 hours
It is excreted in urine.
Mannitol penetrates the eye poorly and so it is especially effective in the presence of ocular inflammation.
Mannitol does not cause tissue necrosis if it extravasates during administration.


(2) Urea
30% solution is used in the dose of 2-7 ml/kg BW.
Onset of action: 15-30 minutes.
Maximum effect in: 60 minutes
Duration of action: 4-6 hours

Urea diffuses throughout the body fluids and has relatively greater ocular penetrance so it's less effective than mannitol.
Ocular inflammation may make Urea ineffective and cause a rebound rise in IOP.
It is excreted in urine.
It does not have a long shelf-life and decomposes to ammonia.
May cause local thrombophlebitis and skin necrosis.

ORAL CARBONIC ANHYDRASE INHIBITORS





(1) Acetazolamide
Synthetic sulfonamide.
Decreases IOP by reducing aqueous production.
It acts locally at the ciliary processes to inhibit isozyme II of carbonic anhydrase.
Concomitant administration of bicarbonates does not affect the IOP lowering efficacy of Acetazolamide.
There is complete absorption following oral administration of Acetazolamide.
Peak plasma levels are attained 1 hour after ingestion.
Maximum IOP reduction occurs 2-6 hours after an oral dose and persists beyond 7 hours.
Sustained release capsule produces peak levels in 3-4 hours and the effect is seen upto 6-18 hours.
Principle route of excretion is via active secretion of the unaltered drug by the renal tubules.

Pharmaceutics:
Acetazolamide is available in following forms=
(1) 125mg and 250mg tablets.
(2) 500mg sustained release capsules.
(3) Intravenous (each vial has equivalent to 500mg Acetazolamide).

Indications:
It is reserved for patients in whom topical drugs are ineffective or the patient is intolerant to them.

Contraindications:
It produces metabolic acidosis. Therefore, may potentiate acid-base imbalance in patients with pre-existing acidosis.
Urinary citrate excretion is reduced leading to renal stone formation.
Renal potassium excretion is increased.
High dose aspirin increases the risk of salicylate toxicity.
Sulpha-type allergic reactions may also occur.
The induced acidosis and hemoconcentration may predispose patients with hemoglobinopathies to sickling of red blood cells.

Adverse reactions:
Life-threatening reactions= marrow suppression, aplastic anemia.
Sulpha-type reactions= including anaphylactic shock
Potassium depletion
Renal stones
Metabolic acidosis
Malaise
Weight loss
Depression
Anorexia
Paresthesia
Transient myopia due to ciliary body swelling.

Dose: 250-1000mg/day in four divided doses.
Pediatric dose: 5-10mg/kg BW 4-6 times per day.
Known to produce forelimb abnormalities in rodent offspring and so should be avoided in pregnancy or lactation.
Elderly individuals have higher incidence of side effects and tolerate carbonic anhydrase inhibitors poorly. Therefore, the initial dose should be reduced.

(2) Dichlorphenamide (Daranide)
The concentration of drug required to inhibit 50% of carbonic anhydrase activity is 30 times higher for Acetazolamide than for Dichlorphenamide.
It has been reported to be more efficacious than Acetazolamide.
IOP reduction starts in 30 minutes after a 200mg dose.
Maximum pressure reduction occurs in 2 hours and persists for 6 hours.
An initial priming dose of 100-200mg is followed with 25-50mg, one to four times a day.
Confusion and anorexia are more common with Dichlorphenamide.

(3) Methazolamide
Better tolerated and carbonic anhydrase inhibitors.
Produces less metabolic disturbance.
Well tolerated in elderly and young patients.
Available in 25 and 50mg tablets; for twice or thrice daily dosage.
Severe hematologic reactions including aplastic anemia have been reported.

Complications of hyperosmotic agents

  1. Headache
  2. Backache
  3. Nausea and vomiting
  4. Increased Urination frequency and retention
  5. Cardiac complications (chest pain, pulmonary edema and congestive heart failure).
  6. Renal impairment
  7. Neurologic status (lethargy, seizures and obtundation.
  8. Subdural and subarachnoid hemorrhage
  9. Hypersensitivity reactions
  10. Hyperkalemia or ketoacidosis (especially on glycerol administration to diabetic patients).