Monte D. Mills, MD, MS
A 12-week-old infant boy presented to his pediatrician after his parents saw abnormal eye movements and cloudiness. He was born at 33 weeks GA by cesarean section, triplet birth, at 4 lb, 8 oz. At 6 weeks his parents noticed he did not visually follow as well as his siblings, and at 10 weeks they noticed bilateral haziness of the corneas, as well as “jumping” eye movements which had become worse over the past 2 weeks. He also seemed more sensitive to bright lights than his siblings.
Figure 1: Infant with aniridia and glaucoma; note hazy corneas. The red reflex, cataract, and iris are obscured by corneal haze.On examination, his head circumference is at the 50th percentile, weight 75th percentile for adjusted age, with normal appearing facial features and eyelids. The conjunctivae are white, but the corneas of both eyes appear to be hazy with “ground glass” appearance and normal in size. The pupils appear to be widely dilated or absent, and the pupillary red reflex appears dim with a central shadow (See Figure 1). There is pendular nystagmus symmetrically, but the patient is able to briefly follow his mother’s face.
Observation of the triplet siblings demonstrates normal ocular appearance and visual fixation behavior in both. There is no family history of infantile or childhood eye or vision abnormality in the parents. There are no older siblings.
Discussion: The diagnosis of aniridia is made on careful clinical evaluation. The complete absence of iris, or small iris stump, gives the appearance of a widely dilated pupil. The condition is bilateral and symmetrical, present at birth, and may be associated with early onset of glaucoma with corneal edema and haze. Nystagmus is usually not present at birth, but develops within the first 2 months of life, with other frequently associated clinical ophthalmic features including anterior polar cataract (seen in this case as a shadow within the pupillary red reflex), progressive vascularization of the cornea (usually not present at birth but progressive during childhood), and frequent corneal surface abnormalities and recurrent spontaneous corneal erosion.
However, our diagnosis is not complete with the ophthalmic diagnosis of aniridia. Aniridia may occur in an autosomal dominant, heritable form and may also be associated with WAGR syndrome. (WAGR is an acronym for Wilms’ tumor, aniridia, genitourinary malformations, and growth retardation.) In infants with aniridia in whom there is a family history consistent with autosomal dominant transmission, the WAGR association can be excluded. Both WAGR and simple isolated aniridia can occur sporadically, but only isolated aniridia is seen in the familial, autosomal dominant pattern.
In our case, with no family history, we are obliged to evaluate for possible WAGR associations with chromosomal analysis (WAGR is associated with 11p13 deletion) as well as abdominal ultrasound for renal abnormalities and Wilms’ tumor. Up to half of sporadic cases of aniridia will have the WAGR deletion and develop Wilms’ tumor. Isolated aniridia is associated with mutations of the PAX6 gene, contiguous to the Wilms’ tumor gene on 11p.
The initial renal ultrasound was normal, but subsequent genetic testing demonstrated chromosomal deletion at 11p13, and repeat renal ultrasound at 1 year of age showed new bilateral renal masses. The patient was referred to the Cancer Center at CHOP. Surgical excision followed by systemic chemotherapy was curative.
The eyes were initially treated with topical aqueous suppressants (timolol and dorzolamide). Bilateral glaucoma surgery and bilateral cataract surgery were performed during the first 3 years of life (See Figure 2). Nystagmus and residual visual impairment persisted, and our patient also had global developmental delays requiring early intervention referral. His growth remains below the 25th percentile.
2A: Eye with aniridia, showing central cataract (white solid arrow), corneal haze, and peripheral “red reflex” (blue arrow). Only a small remnant of iris is visible (white dotted arrow). 2B: Eye with aniridia, after placement of glaucoma tube shunt device (arrow). Notice the clearing of the corneal haze compared with Figure 1 and 2A.
The permanent visual impairment expected with aniridia varies in individual cases, from moderate impairment (acuity of 20/100) to severe (acuity less than 20/200, legal blindness) and will require individualized adaptations for school and other activities. Most patients will also benefit from corrective glasses and usually use dark sunglasses outdoors due to the associated sensation of glare and light sensitivity. Surgical treatment for cataracts and for glaucoma is frequently required. Progressive ocular surface abnormalities may lead to corneal scarring and vision loss during the first and second decades, and other ocular treatments may also be needed.
In our case, the ocular diagnosis led to a significant syndromic diagnosis. Pre-symptomatic testing with ultrasound for renal abnormalities, and the early diagnosis and treatment of the bilateral Wilms’ tumor and anticipation of associated growth and developmental issues allowed our patient’s pediatrician and parents to comprehensively address his visual, medical, and developmental issues.
Fischbach B, Trout KL, Lewis J, Luis CA, Sika M. WAGR syndrome: a clinical review of 54 cases. Pediatrics. 2005;116(4):984-988.
Lee H, Khan R, O’Keefe M. Aniridia: current pathology and management. Acta Ophthalmol. 2008;86(7):708-715.
James R. Treat, MD, and William R. Katowitz, MD
A 9-week-old boy presents with a bluish mass of the right eyelid and orbit. His parents noted only a small flat red-blue spot at birth. They indicated this mass had increased in size for the 5 weeks prior to presentation. The patient was afebrile and otherwise healthy.
Figure 3: Before treatment (3A): 9-week-old boy with an eyelid/orbirtal lesion. After treatment (3B): The same child at age 4 months, after 6 weeks of oral propranolol.On examination he had a soft blue mass with overlying telangiectasias in the right upper eyelid with an inferiorly displaced right eye (see Figure 3A) and severe right upper eyelid drooping (ptosis). He had no other skin lesions and no palpable abdominal masses.
An MRI of the orbits was performed, which showed a large orbital lesion that was likely vascular in origin. An empirical diagnosis of infantile hemangioma was made with imaging alone and no tissue biopsy. The patient underwent an echocardiogram at CHOP to screen for cardiac abnormalities. He was treated over the next 13 months with the beta-blocker propranolol. Figure 3B shows this same patient at age 4 months, just 6 weeks after initiating therapy.
Discussion: Other vascular entities such as venous or venolymphatic malformations could have this appearance but should not be rapidly growing. Orbital malignancies such as neuroblastoma, rhabdomyosarcoma, or orbital retinoblastoma are always a concern and need to be ruled out via imaging or sometimes biopsy.
Infantile hemangiomas are the most common acquired benign tumors in infants, occurring in approximately 5% of children. They typically are not present at birth, but instead appear in the first few days to weeks of life. They tend to grow rapidly in the first few months of life but larger lesions can continue to grow up to 10 to 12 months of age (proliferative stage). Hemangiomas then slowly shrink over the next 1 to 9 years (involutional stage). Patients with a larger than 5cm segmental (growing in a pattern, not oval or round) facial hemangioma are at risk for PHACES syndrome. The acronym of PHACES stands for posterior fossa abnormalities, hemangiomas, arterial abnormalities, cardiac defects including coarctation of the aorta, eye malformations, and sternal abnormalities. Patients at risk for PHACES should have a workup including an echocardiogram, MRI, and MRA of the brain and neck, as well as ophthalmology evaluation.
The treatment for infantile capillary hemangiomas can be observation alone if dysfunction or disfigurement is not of concern. In our patient, his hemangioma could induce deprivation amblyopia and thus warranted treatment. In the past, corticosteroids either taken orally or injected directly into the hemangioma were the mainstay of treatment. Surgery was, and remains, a last resort after a patient has failed medical therapy and still needs debulking.
In 2008, a group of French authors reported on the use of propranolol for infantile hemangiomas. Since then, beta-blockers have become the mainstay and first-line intervention for large capillary hemangiomas, and recently a formulation of propranolol was approved by the Federal Drug Administration for treatment of infantile hemangiomas. Smaller and more superficial lesions can be treated with a topical beta-blocker preparation (timolol gel-forming solution), though this therapy will not treat deeper lesions. Patients at risk for PHACES should have a workup prior to initiation of propranolol so any cardiac or neurologic contraindications to beta-blocker therapy can be identified.
Once a patient has been diagnosed by Ophthalmology with a hemangioma warranting therapy, the child is promptly referred to the Division of Dermatology at CHOP. If a child with a periocular hemangioma presents to Dermatology, Ophthalmology is consulted. If there are no contraindications such as hypoglycemia, bradycardia, hypotension, PHACES syndrome, or concurrent respiratory illness, the patient is started on a loading dose of propranolol. Children older than 3 months can be treated as outpatients, and those under 3 months adjusted for prematurity are admitted for a 48-hour dose escalation. Parents administering oral propranolol to their children are consented to the main side effects of propranolol, which include (but are not limited to) hypoglycemia (secondary to impairment of gluconeogenesis), bradycardia, hypotension, bronchoconstriction, and lack of optimal response to therapy.
Patients are then seen monthly for heart rate and blood pressure monitoring, as well as weight-dependent dose adjustment. A patient usually needs to receive oral beta-blocker therapy 4 to 6 months beyond the end of the proliferative phase of their hemangioma. Therefore they are usually on medication until 12 to 18 months of age. Early tapering or cessation of propranolol can lead to tumor recurrence necessitating restarting therapy.
Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131(1):128-140.
Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358(24):2649-2651.
Stefanie Davidson, MD
A 3-year-old girl presents for evaluation of red and irritated left eye of 5 days duration. Past medical history is noteworthy for eczema. She denies any sick contacts or recent upper respiratory infection. Her mother also notes the presence of a rash around her daughter’s left eye. The rash worsened with use of topical steroids medication.
Figure 4: Herpectic dendrites.On examination, there were multiple, discrete, and coalescing vesicles on an erythematous base along the left lower lid. The bulbar and palpebral conjunctiva appear inflamed. Fluorescein staining revealed positive corneal staining in a dendritic pattern. (See Figure 4.)
Discussion: The patient is especially at risk for herpes simplex virus-1 (HSV-1) with ocular involvement because of her history of eczema. The worsening of a rash with topical steroid use is suspicious for herpetic dermatitis as well. Dendritic lesions of the cornea can be seen with fluoroscein stain and a cobalt blue light of direct ophthalmoscope. HSV can also cause blepharoconjunctivitis and stromal keratitis.
HSV-1 should be suspected in any pediatric patient with recurrent unilateral keratoconjunctivitis. Children tend to have poorer visual outcomes as compared with adults with HSV because they can be difficult to examine, resistant to topical medications, and are susceptible to amblyopia. Furthermore, children with ocular HSV have a higher rate of misdiagnosis, increasing the risk of corneal scarring and vision loss.
Recurrence of HSV keratitis is more likely to occur in children, with a rate above 50% and a mean time to recurrence of 13 months.
Liu et al. found that in children with herpetic blepharoconjunctivitis (HBC), there appears to be an increased rate of asthma, atopy, and systemic disease. The sensitivity of atopic patients to HSV infection may in part result from depression of Th1-cell activity, which is the primary effective immune response against ocular HSV. Instead, atopic individuals display a predominant Th2-cell response, which suppresses Th1 activity and hinders effective immunity against HSV.
Children with HSV keratitis tend to have poor visual outcomes. Liu et al. most recently reported final vision of 20/40 or worse in 10 of 39 eyes (26%) of their pediatric patients with HSV keratitis. Corneal scars may develop in up to 80% of these patients, with as many as half being centrally located. In addition, patients are at risk for refractive amblyopia caused by keratitis-induced astigmatism. Liu et al. reported more than two diopters of astigmatism in 11 of 39 eyes with herpes simplex keratitis (HSK).
Confirming Diagnosis in the Lab: Whereas most cases of HSV keratitis are diagnosed based on clinical exam, atypical presentations benefit from laboratory confirmation to more rapidly and definitively confirm a diagnosis. The gold standard for detection of HSV-1 is through live viral culture, but this process is time-consuming and carries with it a low sensitivity. Available modalities for detection of HSV include immunofluorescence assay (IFA) and polymerase chain reaction (PCR). However, both require expensive equipment, special training, and are difficult to perform in the clinical setting. Furthermore, PCR is very sensitive and often detects physiologic HSV shedding in normal individuals. Nonetheless, if a laboratory is readily accessible, PCR remains the gold standard for molecular diagnosis.
A recently developed alternative for fast and efficient detection of HSV is the immunochromatographic assay (ICGA) kit (Checkmate Herpes Eye, Wakamoto Pharmaceutical Co., Tokyo, Japan). It utilizes a monoclonal antibody against HSV glycoprotein D which is present on the HSV virion and required for infectivity. The kit can be performed as an “in the office” diagnostic test within 15 minutes. Inoue et al. recently explored its efficacy (see References). An ICGA kit will likely not be useful as a general screening tool, but given the high rate of misdiagnosis and atypical presentation of ocular HSV in children, it may be valuable in the pediatric office.
Medical Management: Oral acyclovir (ACV) is an effective treatment of herpetic keratitis. Various groups have shown that oral acyclovir is well tolerated in the pediatric population. As children tend to have difficulty with eyedrop regimens, oral therapy is a desirable treatment option. Furthermore, there are local toxicity issues with topical agents that can be avoided using oral regimens. (See Table 1 below).
|Current recommendations for treatment dosing:|
|Younger than 18 months||100 mg||3 times/day|
|18 months to 3 years||200 mg||3 times/day|
|3 to 5 years||300 mg||3 times/day|
|Older than 6 years||400 mg||3 times/day|
Given the higher rate of recurrence of herpetic keratitis in children, long-term prophylactic oral ACV is frequently employed, especially in stromal disease. Although its use in children is currently off-label, ACV has a wide safety margin, with maximal tolerated daily doses of 40mg to 80mg/kg/day. For prophylactic dosing, follow the same regimen as for treatment, but give 2 times per day instead of 3 times per day administration. Prophylaxis should be extended for at least 1 year after the last episode of recurrence, with periodic kidney and liver function monitoring.
Liu S, Pavan-Langston D, Colby K. Pediatric herpes simplex of the anterior segment: characteristics, treatment, and outcomes. Ophthalmology. 2012;119:2003–2008.
Inoue Y, Shimomura Y, Fukuda M, et al. Multicentre clinical study of the herpes simplex virus immunochromatographic assay kit for the diagnosis of herpetic epithelial keratitis. Br J Ophthalmol. 2012;00:1–5.
Inoue T, Kawashima R, Suzuki T, Ohashi Y. Real-time polymerase chain reaction for diagnosing acyclovir-resistant herpetic keratitis based on changes in viral DNA copy number before and after treatment. Arch Ophthalmol. 2012;130:1462–1464. [This paper details clever use of RT-PCR in management of HSK not responding to therapy.]
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