Juvenile open angle glaucoma

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 by Shu Feng on June 5, 2018.


Juvenile open-angle glaucoma (JOAG) is a rare subset of glaucoma diagnosed in individuals greater than 3 years old and less than 40 years of age. It is characterized by autosomal dominant inheritance and early age of onset. Compared to adult onset primary open-angle glaucoma (POAG), the juvenile form tends to be rapidly progressive with more severely elevated and fluctuating intraocular pressures (IOPs). In addition, JOAG is less responsive to medications and often requires surgical therapy. Surgical treatment most commonly consists of trabeculectomy although IOP control can be achieved with glaucoma drainage implants and angle surgery as well.

Disease Entity

Juvenile open-angle glaucoma (JOAG)

Disease

Juvenile open-angle glaucoma (JOAG) is an uncommon subset of primary open-angle glaucoma (POAG) characterized by autosomal dominant inheritance and early age of onset. Like other forms of glaucoma, JOAG is a condition of optic nerve degeneration manifested by optic nerve head changes and corresponding visual field defects. JOAG is most commonly diagnosed in individuals between 5 and 35 years old and rarely after 40, but age at diagnosis is variable due to the insidious disease course.[1] [2] In a study of 70 JOAG patients, the mean age at diagnosis was 26 ± 9.8 years.[3] JOAG should be distinguished from infantile glaucoma, which develops before the age of 3 and is a clinically distinct disease entity.[4] The estimated prevalence of JOAG ranges from 0.38 to 2 in 100,000 in individuals between 4 and 20 years of age.[1][5] A study from the Dallas Glaucoma Registry estimates that JOAG comprises 4% of childhood glaucomas.6[6]

Etiology

As with primary open angle glaucoma, JOAG is associated with elevations in IOP. It is hypothesized that the increased IOP is due to an abnormal trabecular meshwork causing reduced aqueous outflow.[1] Evidence for this mechanism includes ultra-structural findings of thick compact tissue and extraceullular deposits in the trabecular meshwork of individuals with JOAG.[7]

Genetics

JOAG is inherited in an autosomal dominant pattern with high penetrance.[2] Of particular importance in the pathogenesis of JOAG is a gene called myocilin (MYOC). Genetic linkage analysis in pedigrees with JOAG identified a locus on chromosome 1q21-31 called GLC1A that was further refined to 1q23-25.[8][9] From this GLC1A locus, the TIGR (trabecular meshwork inducible glucocorticoid response) gene, later renamed myocilin, was isolated.[1] Mutations in myocilin are strongly linked with JOAG, occurring in up to 36% of affected individuals. Disease-causing myocilin mutations are also present in adult onset POAG but at a lesser prevalence of 4%.[10] The lifetime risk of developing glaucoma in MYOC mutation carriers is 60-100%.[11] In addition, patients with strong family histories of glaucoma have an increased likelihood of harboring a disease-causing myocilin mutation.[12]

Myocilin is so named because of its homology to myosin and localization to the ciliary rootlet.[1] Disease-causing mutations in myocilin are thought to increase aqueous outflow resistance as the protein product is expressed on the trabecular meshwork (including trabecular beams and juxtacanalicular connective tissue).[13][14] Myocilin mutations also may have prognostic value as phenotype has been found to correlate with severity of disease.[15] [16] For example, the Gln368Stop mutation is associated with a mild phenotype with later age at diagnosis and lower mean IOP compared to the Tyr437His and Ile477Asn mutations.[1] Another important genetic variation is CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1), which may be a modifier gene that predisposes to JOAG.[7] CYP1B1 has also been linked to congenital glaucoma.[4]

Risk Factors

  1. Male gender: In a study of 125 eyes, there was a male preponderance of 64%.[17]
  2. Myopia: 87% of JOAG individuals are myopic. In families with JOAG, myopia occurs more frequently in affected individuals.[18]
  3. Severe elevation of IOP: A characteristic feature of JOAG, IOPs generally range over 40 mmHg and even over 50mmHg.[15][16]
  4. African ancestry: There is a higher prevalence of JOAG in this population but not a corresponding higher frequency of MYOC mutations.[11]
  5. Prominent iris processes: This feature may be unrelated to JOAG as it is noted in both affected and unaffected family members in families with JOAG.[18]
  6. MYOC mutation: see Genetics.

Risk factors for visual field (VF) progression:

The projected lifetime risk of perimetric blindness in JOAG is similar to POAG despite the longer duration of disease in JOAG patients.[19]

  1. Long-term IOP fluctuation is associated with faster rates of VF progression.[20]
  2. Higher IOP at the last visit[17]
  3. Family history of glaucoma is weakly associated with VF progression despite similar baseline and last IOPs, number of surgeries, medications, and baseline VF defect.[17]

General Pathology

Ultrastructural findings on electron microscopy showed similar findings to steroid-induced glaucoma, including abnormal extracellular material in a fingerprint-like pattern, resembling basement membrane-like material. A study of 11 trabeculectomy specimens found this material present in the outer corneoscleral and inner cribiform regions of the trabecular meshwork, which thickened the cribiform region to a greater degree compared to eyes with late onset POAG. There is also a significant amount of sheath-derived plaque material in the endothelial layer adjacent to Schlemm’s canal, which is a feature also seen in late onset POAG.[7]

Diagnosis

History

As in POAG a significant proportion of individuals with JOAG are diagnosed when asymptomatic. If symptoms are present, these may include blurred vision, ocular pain from IOP elevation, or decreased visual acuity at later stages.[17] Patients should be asked about family history of glaucoma as well as other history that may indicate a secondary glaucoma.

Physical examination

Physical examination and findings of JOAG are similar to POAG. Exam should include measurement of IOP and central corneal thickness as well as assessment of the anterior chamber angle, optic disc, and visual fields.

  1. IOP: Goldmann Applanation Tonometry (gold standard) or handheld devices such as the Tono-pen may be used. Young individuals may have a larger difference in measurement of IOP between these two methods.[21] See Intraocular Pressure and Tonometry.
  2. Pachymetry: The role of pachymetry in evaluation or management of JOAG has not been formally studied but is currently recommended as part of the work-up for and pre-operative evaluation of JOAG.[4][22]
  3. Anterior chamber angle: In JOAG the anterior segment generally appears normal on gonioscopy. However, with severely elevated pressures, dysgenesis of the angle may be present.[23] High iris insertion or prominent iris processes may also be seen.
  4. Optic disc: Dilated eye exam often reveals bilateral cupping of the optic nerve head at the time of diagnosis.[4] A recent analysis of optic discs using scanning laser ophthalmoscopy concluded that optic discs of JOAG tended to be larger in size compared to adult onset POAG discs including parameters of cup depth, volume, and cup to disc area ratio.[24] This is also true of treated JOAG discs compared to treated primary congenital glaucoma discs. There are no major structural or morphologic differences of the optic nerve head in myocilin mutations versus nonmyocilin glaucoma.[25]
  5. Visual field: Humphrey visual field (HVF) analysis via automated static threshold perimetry is the gold standard. For younger children for whom HVF is not possible, Goldmann visual fields may be used.[4]

Diagnostic procedures

While not necessary for diagnosis, optical coherence tomography (OCT) is helpful for objectively monitoring disease progression in children, especially with the normal increase in axial length that accompanies growth.[26] Humphrey or Goldmann visual field tests may be used to detect early peripheral loss and to monitor progression.

Laboratory test

No laboratory testing is recommended for diagnosis of JOAG.

Differential diagnosis

The differential for JOAG includes other types of open angle glaucoma, late congenital glaucoma, and secondary glaucomas including steroid-induced, traumatic, and inflammatory glaucoma.

The differential for pediatric glaucoma also includes neovascularization of the iris (associated with retinoblastoma presenting with glaucoma), neovascular glaucoma, phakomatoses, juvenile xanthogranuloma, and medulloepithelioma.

JOAG can be distinguished from late congenital glaucoma by the absence of the classic triad of symptoms: buphthalmos, tearing, and photophobia.[4] Exam findings of megalocornea, Descemet’s breaks (Haab’s striae), and anterior segment digenesis seen in congenital glaucoma are also absent in JOAG.[18]

Management

General treatment

Goals of treatment in JOAG include lowering IOP to prevent further degeneration of the optic nerve with serial imaging of the optic nerve head and perimetry to assess disease progression. IOP in JOAG tends to be refractory to maximally tolerated medical therapy and often requires surgical therapy for IOP control.[27]

Medical therapy

In contrast to congenital glaucoma, JOAG is first treated medically followed by adjunctive surgery. It should be noted, however, that medical therapy is often used as a bridge to surgery due to persistently elevated IOPs. In a study of multiple pedigrees genetically linked to the juvenile glaucoma locus on chromosome 1q21-q31, glaucoma filtration surgery was required in 83% of these patients.[18]

Medical therapy is similar to mangagement of POAG and includes carbonic anhydrase inhibitors, prostaglandin analogues (including latanoprost, which is ineffective in congenital glaucoma), beta blockers, and adrenergic agonists. Miotics such as pilocarpine are poorly tolerated due to ciliary spasm and induced myopia. In addition, alpha-agonists should be used with caution in small children due to adverse side effects such as central nervous system depression; for this reason, apraclonidine may be preferable to brimonidine in young children with JOAG.[28]

Surgery

Options for surgical therapy of JOAG include filtration procedures (trabeculectomy), drainage implants, angle procedures (goniotomy, trabeculotomy), and cycloablative procedures.[29]

Trabeculectomy has been the mainstay of surgical therapy for JOAG. Three years postoperatively, IOP control without medications has been reported to occur at rates of 50-87%.[30][31][32] However, filtering surgery in JOAG is generally less successful compared to adult POAG because of a more robust healing response in young eyes. Intraoperative antifibrotics such as mitomycin C (MMC) have been used in an attempt to prevent fibrosis.[32] Although addition of MMC compared to trabeculectomy alone has resulted in lower IOPs, there is an increased risk of adverse effects including hypotony maculopathy and bleb-related infection. This led the authors of a retrospective analysis of 44 eyes to caution against using MMC with an initial trabeculectomy for JOAG.[32]

Glaucoma drainage implants (GDIs) such as the Ahmed glaucoma valve, Molteno implant, and Baerveldt implant are an alternative surgical therapy for JOAG. A GDI may be preferable when significant conjunctival scarring precludes filtration surgery.[33] In a retrospective study of the Ahmed glaucoma valve used for pediatric glaucoma, there was a 100% success rate at 1 year defined as a final IOP between 6-18 mmHg without loss of light perception or reoperation for glaucoma.[34] In a study of 52 eyes with juvenile glaucoma, the Molteno implant resulted in IOP control < 21 with a probability of 0.89 at 1 year.[35] Angle procedures are more commonly used in surgical management of congenital glaucoma and less often for JOAG. However, there are reports of successful angle surgery in JOAG.[22] For example, 360-degree trabeculotomy facilitated by illuminated microcatheter has also been used. In a study of 10 eyes using this technique, there was a 50% reduction in mean IOP

References

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