Whole exome sequencing detects homozygosity for ABCA4 p.Arg602Trp missense mutation in a pediatric patient with rapidly progressive retinal dystrophy.

BACKGROUND: A pediatric patient presented with rapidly progressive vision loss, nyctalopia and retinal dystrophy. This is the first report of homozygosity for the p.Arg602Trp mutation in the ABCA4 gene. The child became legally blind within a period of 2 years. CASE PRESENTATION: An eight year-old Hispanic female presented with bilateral decreased vision following a febrile gastrointestinal illness with nausea and vomiting. Extensive workup involved pediatric infectious disease and rheumatology consultations.Initial visual acuity was 20/60 at distance and 20/30 at near in both eyes. Rapidly progressive vision loss occurred during a 2-year period resulting in visual acuities of 20/200 at distance in both eyes. Fundus exam disclosed attenuated vessels and multiple subretinal blister-like elevations. Optical coherence tomography showed far more lesions than were clinically evident with different levels of elevation. Autofluorescence imagery showed dramatic and widespread geographic areas of atrophy. The deposits that appeared drusen-like on clinical exam were hyperfluorescent, consistent with lipofuscin deposits containing A2e (N-retinylidene-N-retinylethanolamine) indicative of RPE cell dysfunction. Electroretinography was consistent with cone dystrophy, with relative preservation of rod function. Blood analysis and rheumatology evaluation found no evidence of a diffuse post-infectious/inflammatory process. The unique and rapid progression of her subretinal blister-like lesions was documented by fluorescein angiography, optical coherence tomography, autofluorescence imagery, and fundus photography. Family pedigree history disclosed consanguinity, her parents being first cousins. DNA analysis by whole exomic sequencing revealed homozygosity of p.Arg602Trp in the ABCA4 gene. CONCLUSION: The pediatric patient presented with a striking clinical appearance and dramatic rate of progression that was clinically more characteristic of an infectious or inflammatory process. This case expands the diverse range of phenotypes attributed to ABCA4 mutations and further supports the role of whole exome sequencing as a powerful new tool available to aid clinicians in establishing diagnosis for challenging cases.

Comparative regional pupillography as a noninvasive biosensor screening method for diabetic retinopathy.

PURPOSE: We describe infrared regional pupillometry as an objective comparative assessment of midperipheral to central retinal sensitivity and to correlate with midperipheral retinal ischemia in diabetic subjects. METHODS: We tested 12 normal and 17 diabetic subjects using bilateral infrared pupillometry. The diabetic cohort included seven subjects without, five with mild, three with moderate, and two with severe non-proliferative diabetic retinopathy (NPDR). Central and annular stimuli of varying intensity were presented to one eye, and pupillary amplitude and constriction velocity were measured from both eyes. Light stimulus of increasing intensity was presented as 20 consecutive trials (stimulus duration of 300 ms with 3000 ms intervals). The ratio of central to peripheral responses (Q values) was calculated for each stimulus configuration. Average responses with respect to the stimulus strength were regressed with Gompertz sigmoid function. RESULTS: Control and moderate/severe NPDR cases comparison showed statistically significant differences in amplitude (Q(A)) and constriction velocity (Q(CV)) (Wilcoxon rank sum test P = 0.002, respectively). Age difference for these groups was not statistically significant (Wilcoxon rank sum test P = 0.15). The comparison of control and diabetic subjects without NPDR/mild NPDR was statistically significant for Q(A) and Q(CV) (Wilcoxon rank sum test P = 0.0002 and P = 0.001, respectively). Q(A) and Q(CV) differences were statistically significant between moderate/severe NPDR cases and subjects without or mild NPDR cases (Wilcoxon rank sum test P = 0.013). CONCLUSIONS: Q(A) and Q(CV) values correlated highly with the severity of diabetic retinopathy, but not with the duration of diabetes.

Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype.

BACKGROUND: Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking. METHODS: To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry. RESULTS: In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies. CONCLUSION: The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.

Sustained elevated intraocular pressures after intravitreal injection of bevacizumab, ranibizumab, and pegaptanib.

PURPOSE: To investigate elevated intraocular pressures (IOP) (defined by a measurement >25 mmHg at a follow-up visit) after an intravitreal injection of anti-vascular endothelial growth factor agents for age-related macular degeneration. METHODS: Retrospective review of medical records. RESULTS: A total of 127 patients (155 eyes) received an intravitreal injection of anti-vascular endothelial growth factor agents (bevacizumab, ranibizumab, or pegaptanib) ranging from 1 to 39 injections for more than a period of 30 to 1759 days. Among this population, 12 patients (14 eyes; 9.4%) developed elevated IOP >25 mmHg. Of these, 7 patients (5.5%) developed sustained elevated IOP (IOP >25 mmHg on 2 separate visits requiring glaucoma medication or surgery), of which 8 eyes required topical medications and 1 eye underwent glaucoma surgery. Mean IOP of injected eyes receiving intravitreal injection was 15.2 ± 2.4 mmHg, and the mean IOP was 14.9 ± 2.6 mmHg for noninjected eyes. Among eyes that had elevated IOPs, there was no association with injection frequency, number of injections, or anti-vascular endothelial growth factor agent used. CONCLUSION: Elevated IOP, sustained or unsustained, after intravitreal injection is not uncommon. No association with patient demographics or injection history was identified in the authors' study population.

Orbital ectopic brain tissue in Aicardi syndrome.

BACKGROUND: Aicardi syndrome is a cerebroretinal disorder originally described in 1965. Its salient clinical features are infantile spasms, agenesis of corpus callosum, hypsarrhythmia, and a pathognomonic optic disc appearance consisting of multiple depigmented chorioretinal lacunae clustered around the disc. METHODS: Clinical report with cranial computed tomography and biopsy results. RESULTS: A 3-year-old female patient presented with Aicardi syndrome and progressive proptosis of the left eye since birth. Visual acuity was light perception only in the right eye. Ocular motility examination showed large angle of left exotropia. Direct funduscopy showed a large optic nerve head and chorioretinal lacunae in the right eye; the left eye was not visible. Magnetic resonance imaging detected a large retrobulbar cyst and left microphthalmia. The patient underwent neurosurgery. Intraoperative microscopic dissection of the dural membrane led to exposure of an underlying cyst, which was 80% resected. Biopsies of walls of the orbital cyst showed fragments of neuroglial and meningothelial tissues with some calcification and mild chronic inflammation. Psammoma bodies were identified. The diagnosis was heterotopic brain tissue. CONCLUSIONS: Heterotopia of brain tissue within the orbits is a very rare finding. Two previous reports have described an orbital cyst in association with Aicardi syndrome, both attributed to encephaloceles. We report a very rare case of heterotopia of brain tissue in Aicardi syndrome. The patient did not have an encephalocele.

Ocular manifestations of oblique facial clefts.

INTRODUCTION: In the Tessier classification, craniofacial clefts are numbered from 0 to 14 and extend along constant axes through the eyebrows, eyelids, maxilla, nostrils, and the lips. We studied a patient with bilateral cleft 10 associated with ocular abnormalities. METHOD: Clinical report with orbital and cranial computed tomography. RESULTS: After pregnancy complicated by oligohydramnios, digoxin, and lisinopril exposure, a boy was born with facial and ocular dysmorphism. Examination at age 26 months showed bilateral epibulbar dermoids, covering half the corneal surface, and unilateral morning glory anomaly of the optic nerve. Ductions of the right eye were normal, but the left eye had severely impaired ductions in all directions, left hypotropia, and esotropia. Under anesthesia, the left eye could not be rotated freely in any direction. Bilateral Tessier cleft number 10 was implicated by the presence of colobomata of the middle third of the upper eyelids and eyebrows. As the cleft continued into the hairline, there was marked anterior scalp alopecia. Computed x-ray tomography showed a left middle cranial fossa arachnoid cyst and calcification of the reflected tendon of the superior oblique muscle, trochlea, and underlying sclera, with downward and lateral globe displacement. DISCUSSION: Tessier 10 clefts are very rare and usually associated with encephalocele. Bilateral 10 clefts have not been reported previously. In this case, there was coexisting unilateral morning glory anomaly and arachnoid cyst of the left middle cranial fossa but no encephalocele. CONCLUSIONS: Bilateral Tessier facial cleft 10 may be associated with alopecia, morning glory anomaly, epibulbar dermoids, arachnoid cyst, and restrictive strabismus.

Orbital magnetic resonance imaging of extraocular muscles in chronic progressive external ophthalmoplegia: specific diagnostic findings.

INTRODUCTION: Chronic progressive external ophthalmoplegia (CPEO) is characterized by slowly progressive bilateral ophthalmoplegia and blepharoptosis. Molecular diagnosis is problematic because sporadic mitochondrial DNA deletions can be causative. We sought findings using magnetic resonance imaging (MRI) that might support the diagnosis of CPEO. METHODS: Two men (ages 31 and 47 years) and 3 women (ages 40-49 years) with CPEO and symptom durations of 8 months to 28 years underwent high-resolution (2-mm slice thickness, 312 micron pixels), surface coil, T1-weighted orbital MRI in coronal planes. Images were analyzed quantitatively to determine extraocular muscle (EOM) sizes and were compared with 10 age- and gender-matched normal volunteers, one subject with myasthenia gravis, and with 30 subjects having EOM paralysis caused by oculomotor, trochlear,0 and abducens neuropathies. RESULTS: EOM function was clinically diminished in CPEO, most markedly for the superior rectus (SR) and levator muscles. All EOMs in CPEO exhibited unusual qualitative T1 MRI signal abnormalities. Unlike the profound EOM atrophy typical of neurogenic paralysis, anterior volumes of medial rectus, lateral rectus, and inferior rectus muscles in CPEO were not smaller than normal (p>0.003). Anterior volumes of the SR muscle-levator complex and superior oblique were significantly reduced (p<0.003). Denervated EOMs exhibited statistically significant volume reduction when compared with normal and CPEO groups. Volume of the SR muscle-levator complex was the same in subjects with CPEO and oculomotor palsies. CONCLUSIONS: CPEO is associated with minimal EOM volume reduction despite clinically severe weakness. This combination of findings may be specific for CPEO and could resolve the diagnostic dilemma in difficult cases.

High-resolution magnetic resonance imaging demonstrates abnormalities of motor nerves and extraocular muscles in patients with neuropathic strabismus.

INTRODUCTION: Although the ocular motility examination has been used traditionally in the diagnosis of strabismus that is a result of cranial nerve (CN) abnormalities, magnetic resonance imaging (MRI) now permits the direct imaging of lesions in CN palsies. METHODS: Prospectively, nerves to extraocular muscles (EOMs) were imaged with T1 weighting in orbits of 83 orthotropic volunteers and 96 strabismic patients in quasicoronal planes using surface coils. Intraorbital resolution was 234-312 microns within 1.5- to 2.0-mm thick planes. CNs were imaged at the brainstem using head coils and T2 weighting, yielding 195 micron resolution in planes 1.0-mm thick in 6 normal volunteers and 22 patients who had oculomotor (CN3), trochlear (CN4), or abducens (CN6) palsies and Duane syndrome. RESULTS: Oculomotor (CN3) and abducens (CN6) but not trochlear (CN4) nerves were demonstrable in the orbit and skull base in all normal subjects. Patients with congenital CN3 palsies had hypoplastic CN3s both in orbit and skull base, with hypoplasia of involved EOMs. Patients with chronic CN6 and CN4 palsies exhibited atrophy of involved EOMs. Patients with Duane syndrome exhibited absence or hypoplasia of CN6 in both orbit and brainstem regions, often with mild hypoplasia and apparent misdirection of CN3 to the lateral rectus muscle. Unlike CN6 palsy, patients with Duane syndrome exhibited no EOM hypoplasia. Patients with congenital fibrosis exhibited severe hypoplasia of CN3, moderate hypoplasia of CN6, and EOM hypoplasia, particularly severe for the superior rectus and levator muscles. CONCLUSION: High-resolution MRI can directly demonstrate pathology of CN3 and CN6 and affected EOM atrophy in strabismus caused by CN palsies. Direct imaging of CNs and EOMs by MRI is feasible and useful in differential diagnosis of complex strabismus.

Orbital imaging demonstrates occult blow out fracture in complex strabismus.

BACKGROUND: While strabismologists are familiar with diagnostic evaluation of suspected blow out fractures, unsuspected blow out fractures may further complicate difficult cases of strabismus not clinically supposed to be related to orbital trauma. METHODS: According to a prospective protocol, we studied five adults presenting with diplopia, and one with convergence-related asthenopia. No patient recalled or had any clinical suspicion of orbital fracture at initial evaluation. Surface coil magnetic resonance imaging of the orbits was performed at 312 microm resolution, slice thickness 2 mm. Quasicoronal images in central gaze were supplemented with eccentric gaze positions, and sagittal and axial images as indicated. RESULTS: Five patients had incomitant hypertropia, and one had abducens paralysis. Magnetic resonance imaging disclosed previously unsuspected blow out fractures in all six patients. Three patients had medial wall fracture, one bilaterally. Two patients had inferior wall fractures, and one inferomedial. Although only one patient had an extraocular muscle displaced into a sinus, all had evidence of orbital connective tissue distortion in the region of the rectus extraocular muscle pulleys influencing muscle paths. These effects altered the presentations of more familiar pathologies such as superior oblique palsy. After learning of the MRI findings, most patients then recalled orbital trauma from as early as childhood. CONCLUSION: Unsuspected blow out fractures occur and may confound the usual findings in complex strabismus. High-resolution orbital imaging can detect blow out fractures and clarify the pathophysiology, enabling appropriate surgical management.