Scott E. Olitsky

Effects of dilution and prolonged storage with preservative in a polyethylene container on Bevacizumab (Avastin™) for topical delivery as a nasal spray in anti-hereditary hemorrhagic telangiectasia and related therapies

BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia and severe, recurrent epistaxis is a common clinical phenotype associated with HHT. An intranasal treatment regime of diluted Avastin™ (Bevacizumab; recombinant humanized anti-vascular epithelial growth factor immunoglobin G1) using apulsatile nasal irrigator has proven efficacious in clinical practice. However, concerns regarding the stability of Avastin™ following dilution and prolonged storage in standard containers used for drug delivery, such as polyethylene bottles, have so far prevented a more widespread clinical use. Compatibility with the preservative benzalkonium chloride was also unknown. OBJECTIVE This study aimed at determining, whether dilution, prolonged refrigerated storage and the presence of the preservative benzalkonium chloride - as required for novel Avastin™ formulations - affected the biochemical and electrochemical properties of the drug. METHODS We performed a detailed biochemical and electrochemical analysis of Avastin™, including native and sodium dodecyl sulfate polyacrylamide gel electrophoresis, enzyme-linked immunosorbent assay and isoelectric focusing. RESULTS We did not detect any evidence of degeneration or aggregation following dilution and prolonged, refrigerated storage or from the presence of benzalkonium chloride. All biochemical and electrochemical properties of Avastin™ after dilution and prolonged, refrigerated storage were undistinguishable from control. CONCLUSIONS Our data provide important insight into the stability of Avastin™ and allow the consideration of novel Avastin™ formulations, including its use in a metered-dose nasal spray for the treatment of HHT and other applications.

Topical timolol for the treatment of epistaxis in hereditary hemorrhagic telangiectasia

Epistaxis is the most common problem affecting patients with hereditary hemorrhagic telangiectasia (HHT). Approximately 90% of patients with HHT experience epistaxis that can range in severity from a social nuisance to lifethreatening hemorrhages. Until recently, the treatment of significant epistaxis in these patients consisted of surgery. Surgical options have included laser photocoagulation, septal dermoplasty, and modified Youngs procedure [1]. Recently, the vascular endothelial growth factor (VEGF) inhibitor bevacizumab has shown promise as a medical treatment for HHT-related epistaxis [2]. Propranolol is a nonselective β-blocker that has been shown to be useful for the treatment of infantile hemangiomas [3]. Timolol is also a nonselective β-blocker and is commonly used in the treatment of glaucoma. It has been used topically for the treatment of superficial hemangiomas [4]. Because of its potential mechanism of action, it is possible that timolol could also be useful for the treatment of epistaxis related to HHT. This report describes a case of epistaxis in a patient with HHT that was improved with the use of topical timolol drops. A 48-year-old man with a known diagnosis of HHT presented with frequent epistaxis. His past treatment had included nasal cauterization with silver nitrate as a child and topical bevacizumab. His epistaxis had improved after topical bevacizumab on several occasions. The effect would last for several months with retreatment needed when the nosebleeds became more frequent. Six months after his last treatment, he was experiencing 3 to 4 nosebleeds a day. Some would last for more than 30 minutes. It was decided to try topical timolol at that time. He began using timolol 0.5% ophthalmic solution and placed 1 drop in each nostril 3 times a day. Within 3 to 4 days, he noticed a significant reduction in the frequency and severity of his epistaxis. A month after the initiation of treatment, his nosebleeds had decreased to an average of 1 to 2 per week, and they lasted less than 5 minutes when they occurred. There was no change in blood pressure or heart rate during the treatment. Topical timolol has been used to treat superficial hemangiomas in infants. The mechanism of action of βblockers in the treatment of hemangiomas is currently unknown but may be related to vasoconstriction, endothelial cell apoptosis, and decreased VEGF expression [5]. Vascular endothelial growth factor levels have been shown to be elevated in patients with HHT and may play a role in the development of nasal telangiectasia [6]. Therefore, it was theorized that timolol could be a viable option in the treatment of epistaxis in patients with HHT. The patient described in this report had both a rapid and persistent response to treatment as is seen in infants with hemangiomas that are treated with β-blockers. The initial response may be secondary to the vasoconstrictive properties of timolol. The longer term effect may be due to endothelial cell apoptosis as well as decreased VEGF expression. The potential advantage of topical timolol compared with bevacizumab includes greater availability of the medication without the need for compounding, ease of application, and decreased cost. Although this is a single case report, the results are encouraging, and further study will allow a greater understanding of the potential use of topical β-blockers in this patient population.

Disorders of the Conjunctiva

The conjunctiva is a transparent mucous membrane lining the inner surface of the eyelids and the surface of the globe as far as the limbus. It is richly vascular, supplied by the anterior ciliary and palpebral arteries. There is a dense lymphatic network, with drainage to the preauricular and submandibular nodes corresponding to that of the eyelids. It has a key protective role, mediating both passive and active immunity. Clinically, it is subdivided into the following:

Utility of MR imaging in cat-scratch neuroretinitis

About 80% of cat-scratch disease (CSD) infections occur in children, and CSD neuroretinitis (optic neuropathy with retinal exudates in a “macular star” pattern) mostly occurs in children and young adults. A recent study suggested that CSD optic neuropathy has specific features on MR imaging. However, MR imaging findings in CSD neuroretinitis are not well described in the pediatric literature. We present a patient with CSD neuroretinitis in whom these specific MR imaging features preceded the macular star, a funduscopic finding strongly suggestive of neuroretinitis. This case demonstrates how knowledge of these features is important in the appropriate diagnostic work-up of optic neuropathy. MR imaging also incidentally revealed neuritis of another cranial nerve in the auditory canal—a rare manifestation of CSD.

Complications of Strabismus Surgery.

All surgeries carry risks of complications, and there is no way to avoid ever having a complication. Strabismus surgery is no different in this regard. There are methods to reduce the risk of a complication during or after surgery, and these steps should always be taken. When a complication occurs, it is important to first recognize it and then manage it appropriately to allow for the best outcome possible. This article will discuss some of the more common and/or most devastating complications that can occur during or after strabismus surgery as well as thoughts on how to avoid them and manage them should they happen.

Sixth Nerve Palsy in Children

Sixth nerve palsy is a cause of incomitant esotropia that increases in the field of action of the paralytic lateral rectus muscle. Acquired palsies are much more common than congenital, and etiologies include trauma, neoplasm, elevated intracranial pressure, infection, and inflammation, as well as other miscellaneous and idiopathic causes. Due to the high association of sixth nerve palsy with brain tumors in children, neuroimaging is generally indicated. Sixth nerve palsies must be distinguished from entities such as Duane retraction syndrome and Mobius syndrome, both of which possess distinct clinical features that are not present in isolated sixth nerve palsy. Partial or complete recovery of acquired sixth nerve palsies are common, compelling observation until at least 6 months of stable misalignment prior to surgical intervention. Conservative management seeks to avoid amblyopia if the palsy occurs during the period of visual development or to relieve diplopia if it occurs after visual maturation. The goal of surgical management, often utilizing muscle transposition procedures, is to restore binocularity in primary gaze and provide the greatest field of single binocular vision.