Surgical Management of Iris Bombe in Muscle-Eye-Brain Disease

Abstract

A 2-year-old girl with severe muscular dystrophy presented with unilateral eye pain and corneal clouding. She was found to have absent red reflex, hypotonia, cerebral hypoplasia, and iris bombe on ultrasound biomicroscopy, a feature not previously reported in this syndrome. She responded favorably to surgical management. Iris bombe can be a cause of glaucoma in muscle-eye-brain disease. This highlights the importance of incorporating ultrasound biomicroscopy into the diagnostic algorithm of muscle-eye-brain disease and other types of congenital syndromic glaucoma.

INTRODUCTION

Muscle-eye-brain disease is a severe autosomal recessive inherited congenital muscular dystrophy, specifically caused by variants within a group of genes linked to reduced alpha-dystroglycan function or expression. Clinically, muscle-eye-brain disease presents as severe weakness and motor impairment with brain malformations and eye disease. Patients present with retinal malformations seen as a spectrum of retinal detachment or dysplasia and optic nerve atrophy.¹ Cessation of anterior chamber angle development after the fourth gestational month manifests as anterior chamber malformation in approximately 76% of cases and microphthalmia in 38% to 62%.² Life expectancy is highly variable depending on the diagnosis of muscle-eye-brain disease versus a more severe form known as Walker-Warburg syndrome. The average for children with muscle-eye-brain disease is 10 to 30 years, whereas it is 1 to 3 years for Walker-Warburg syndrome.¹ Variants in the ISPD/CRPPA gene on chromosome 7p21 contribute to approximately 10% of cases of severe dystroglycanopathy³ and are associated with defective alpha-dystroglycan (DAG1) glycosylation. Without glycosylation, alpha-dystroglycan is unable to bind to extracellular matrix proteins, causing a severe neuromuscular and neurological phenotype.^4,5 Patients frequently present with hypotonia and global developmental delay, and they commonly experience a spectrum of eye anomalies.^1–2,5,6

This case is the first report of iris bombe in muscular dystrophy cases and the first utilization of ultrasound biomicroscopy (UBM) for diagnosis and disease monitoring.

CASE REPORT

A 2-year-old girl with muscle-eye-brain disease presented with right eye redness, pain, corneal clouding, and enlargement. She had previously been diagnosed as having bilateral congenital cataracts in the setting of remnants of tunica vasculosa lentis.

Birth history was significant for full-term birth with hypotonia and absent red reflex, and evaluation in the neonatal intensive care unit identified elevated creatine kinase level (4,289 unit/L) and abnormal brain magnetic resonance imaging with cerebral malformations (polymicrogyria, pachygyria, and cobblestone lissencephaly), thin corpus callosum posteriorly, cerebellar dysplasia, and brainstem hypoplasia and dysplasia (Figures 1A–1B). Findings were suggestive of a diagnosis of muscle-eye-brain disease, a severe subtype of congenital muscular dystrophy. By age 1 year, the patient achieved brief head control when held upright but she was unable to sit, crawl, stand, or reach up for objects and required gastrostomy tube feedings.

Figure 1.

(A) Brain magnetic resonance imaging scan (SSFSE, T2 axial) at 6 days of life shows typical pachygyria/cobblestoning lissencephaly anteriorly in the cerebrum involving the frontal lobes, temporal lobes, and insula, as well as polymicrogyria observed posteriorly. (B) Sagittal T1 brain magnetic resonance imaging scan showing hypoplastic pons, enlarged fourth ventricle, and cerebellar hypoplasia. (C) Ultrasound biomicroscopy of the right eye demonstrating a deep anterior chamber and angle closure secondary to anteriorly bowed iris. (D) Gonioscopy demonstrating iris bombe. (E) Immunofluorescence staining of the muscle with dystrophin c-terminus, alpha-dystroglycan (IIH6), beta-dystroglycan, and merosin (80 kd) showing the patient’s severe dystroglycanopathy.

On ophthalmological examination at age 2 years, she was found to have no light perception visual acuity in both eyes, elevated intraocular pressure (IOP) of 40 mm Hg in the right eye, and normal IOP (10 mm Hg) in the left eye. Her corneal diameters were 13 and 10 mm, respectively. UBM found bilateral dense homogenous fibrovascular tissue behind the clear lenses. On B-scan ultrasound, vitreous was clear extending to the optic nerves with no stalk, masses, detachment, or calcifications. The right eye had a deep anterior chamber with dome-shaped anterior bowing of the iris in iris bombe configuration (Figures 1C–1D).

Genetic testing revealed only a single maternally inherited variant (c.1120-1 G>T) in the ISPD gene (which is linked to a recessively inherited form of congenital muscular dystrophy). The diagnosis of presumed alpha-dystroglycanopathy (clinically demonstrating muscle-eye-brain disease rather than Walker-Warburg syndrome) was confirmed by muscle biopsy, which showed nearly negative staining for alpha-dystroglycan (IIH6) and relative preservation of dystrophin and beta-dystroglycan (Figure 1E), thus further supporting the suspected clinical diagnosis of muscle-eye-brain disease.

A surgical iridectomy was performed on the right eye. Cataract removal was considered for IOP control and vision, but this was not consistent with the family’s conservative goals of care and preference for comfort measures only. After iridectomy, IOP improved (from 12 to 15 mm Hg) and bombe configuration on UBM was resolved at postoperative weeks 1 and 4. At postoperative week 5, IOP elevation recurred (35 mm Hg) with increased corneal diameter and clouding. UBM showed no recurrence of bombe. A trial of topical timolol was initiated with excellent response. Pain, redness, corneal enlargement, and clouding reversed. Visual acuity was light perception (after more than 10 visits with confirmed no light perception visual acuity). The IOP elevation was attributed to steroid response. The patient continued topical IOP-lowering monotherapy (timolol) for 1 year, after which the family self-discontinued. She continues to have normal IOP (maximum of 16 mm Hg while taking timolol, and after discontinuing timolol) and is pain free at age 4 years. Her visual acuity continues to fluctuate between light perception and no light perception, perhaps due to light responses limited by neurologic status. The patient’s parents provided informed consent for use of their child’s ocular imaging in research.

DISCUSSION

Muscle-eye-brain disease is an inherited syndrome presenting with ophthalmic, muscular, and cerebral symptoms. The cataracts, glaucoma, and anterior chamber dysgenesis seen in our patient have been documented in previous literature.^1,2,5,6 The tunica vasculosa lentis due to persistent fetal vasculature has not been previously reported. The subsequent diagnosis of iris bombe is another novel finding in this spectrum of diseases and demonstrates the utility of UBM in tracking the development of prognostically relevant anterior chamber sequelae in this spectrum of diseases.^2,5,7

Prior uses of UBM in dystroglycanopathies found anterior segment dysgenesis including angle and ciliary body dysgenesis, anterior and posterior lens capsule malformation, posterior adhesions, severe agenesis of the lens capsule, and iridocorneal touch.⁷ To our knowledge, this is the first report where UBM was performed longitudinally to diagnose and follow the glaucoma subtype, and to observe the surgical response. The progression of anterior segment changes, including the novel finding of iris bombe and the corresponding response to treatment, contribute significant value to the published literature on this rare condition.

This report demonstrates the clinical potential of UBM in the diagnosis of glaucoma associated with severe congenital muscular dystrophy due to muscle-eye-brain disease, given the necessity for detailed anatomic visualization in a pediatric patient with corneal clouding. The novel finding of iris bombe in this case of muscle-eye-brain disease, with successful surgical treatment, demonstrates an opportunity to provide treatment despite the dire prognosis of these rare congenital disorders.