Juniper Publishers- JOJ Ophthalmology

 Translational Research on BDNF may Lead to New Research Therapy in Glaucoma

Introduction

Glaucoma is a group of eye disorders, currently recognized to be multi factorial, progressive, leading to reduction in vision and eventual blindness. Glaucoma is characterized by progressive degeneration of the retinal ganglion cells (RGCs) and optic nerve (ON) fibers it is one of the leading causes of vision loss. Usually glaucoma affects the older population. Over 60 million people worldwide were estimated to be affected by glaucoma in 2010, and bilateral blindness from the disease was estimated to be present in 4.5 million people with glaucoma [1] . A generally accepted theory suggests an initial insult to the axons of RGCs in the ON head region, where they exit the eye [2] . Glaucoma is characterized by anomalies such as the RGC degeneration and cell death, loss of RGC axons as well as ON atrophy, impairment of visual function with visual field defects and finally loss of neurons in the lateral geniculate nucleus and visual cortex. Several types of glaucoma are known; these can be divided in primary and secondary. Primary open-glaucoma (POAG) is considered the most common subtype of glaucoma. In POAG, ocular hypertension represents the major risk factor for glaucoma onset and progression. Ocular hypertension is a condition in which intraocular pressure (IOP) is consistently greater than normal. In the presence of ocular hypertension, there is no obvious damage to the ON as detected by an eye examination, ON imaging, or evidence of visual field changes. However, retinal responses to patterned visual stimuli (pattern electro retinogram, P-ERG) together with a transcription factor (Brn3) expressed in RGCs are altered during ocular hypertension in a murine model of glaucoma [3]. It is reasonable to think that ocular hypertension applies some stress to RGCs and their circuitry during a phase preceding the degeneration of RGCs and ON atrophy. In addition, it has been reported that the rate of untreated ocular hypertension patients in developing glaucoma was 9.5 percent in 5 years and 22 percent at 13 years [4].

There are limitations to treating IOP exclusively, including:

1. Several glaucoma patients do not show an elevated pressure (normotensive glaucoma).
2. There are patients who continue to progress with controlled low IOP.

Indeed, IOP lowering by means of anti-glaucoma drugs, laser or incisional surgery is unable to arrest the progression of glaucoma till blindness.

These observations suggest that IOP-independent mechanisms contribute to disease progression, and require a new therapeutic approach independent of IOP lowering to prevent vision impairment, RGC death and ON degeneration. Neuro protection by neurotrophic factors was initially investigated for neurodegenerative diseases such as the Alzheimer's disease; evidence suggests that treatments with neurotrophic factors such as the brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-4 (NT-4) increase the survival of neurons in rodent models of injury and disease [5]. BDNF appears to provide the highest level of protection by supporting both protective and regenerative functions. The notion of a neuro protective role for BDNF in retinal degenerations derives from the observation that death of photoreceptors is prevented by intravitreal BDNF administration [6]. BDNF has been shown to protect retinal cells, in particular RGCs, in various models of ON injury and disease [7,8], interestingly, BDNF is effective in a rat glaucoma model as shown by Martin and coworkers [9] using AAV-BDNF transfection. BDNF is a high molecular weight protein locally produced by cells in the ganglion cell and inner nuclear layers [10], its TrkB receptor is expressed in RGCs, amacrine and Müller cells [10,11] that represent the cellular target of BDNF trophic action. RGC take up BDNF and transports it along axons towards target neurons and back to the cell body in the retina [12], BDNF is one of the molecules delivered to the retina by way of retrograde axonal transport [13]. These studies suggest a role for BDNF in retinal injury and diseases. A strong rational supports BDNF treatment in glaucoma. Previous work showed that BDNF delivery to the retina is reduced in glaucoma models [13,14] and BDNF level is reduced in ocular tears [15] and blood [16]. BDNF, but not its receptor TrkB, is reduced in murine models of glaucoma [17,18]. Altogether, these studies suggest that BDNF is expressed in the retina, to help protect neurons maintaining their survival and connections when damaged by injury and diseases. Thus, neuro protection by BDNF in glaucoma can be pursued to protect RGCs. However, the therapeutic approach based on BDNF is promising if the restrictions imposed by complex pharmacokinetic of high molecular weight proteins (for example BDNF low propensity to pass blood- brain barrier following systemic treatment) can be overcome. So far BDNF, as well as other growth factors, has been typically administered to the internal ocular tissues by intravitreous or retrobulbar injection, these methods of treatment are associated with the risk of various complications such as the ocular bulb perforation and infections [19]. Given that glaucoma is a chronic condition, developing over several years, the prospect of chronic, intravitreous administration of BDNF is not realistic. To overcome these obstacles we recently settled a simple method of treatment with BDNF in the form of collyrium. We showed that treatment for a short period with BDNF eye drops was able to increase the retinal level of BDNF in the mouse and rat retina [3]. Remarkably, BDNF topical eye treatment was able to rescue retinal responses to visual stimuli in a murine model of glaucoma during an early phase of degeneration characterized by ocular hypertension, visual impairment and RGC alterations [3] . Thus, the specific anatomical construction of the eye and, possibly, the presence of BDNF carriers offer the possibility for local drug delivery that can avoid the barriers. However, in view of therapeutic approach based on BDNF in glaucoma there are fundamental questions to be answered.

The first question is whether neuro protection by BDNF in glaucoma depends on the stage of retinal degeneration. In our previous work we showed that a short period of treatment with BDNF eye drops was able to restore vision and protect RGCs during an early phase of retinal degeneration in a murine model of glaucoma [3]. However, whether BDNF protects retinal cells at advanced stages of neuro degeneration in glaucoma is still an open question. The second question concerns the durability of BDNF neuro protective effect. Indeed, for glaucoma like other progressive neurodegenerative diseases, it is challenging to identify clinical outcome measures for use in short term proof-of-concept studies. A related question is whether BDNF treatment results in long-term neuro protective effects [20]. Previous results on this issue were contradictory. Interestingly, recent results showed that over expression of BDNF delayed progressive RGC and axon loss in hypertensive eyes [21].

The third question concerns the dose/concentration of BDNF to be used when supplied in the form of eye drops. In other words, does the topical eye application of BDNF represent a safe method of neuroprotection in glaucoma? In a previous work we used high BDNF doses to restore vision in a murine model of glaucoma [3]. This raises concerns over promotion of tumor growth resulting from BDNF taken up from non-retinal tissues; indeed, BDNF, as well as other neurotrophic factors, has been associated with neovascularization and tumor promotion [22]. To reduce the dose/concentration of BDNF we recently formulated BDNF in tamarind seed polysaccharide (TSP) [23], the TSP-BDNF combination appeared to confer a relatively higher bioavailability to BDNF.

Future Directions

Proven neurotrophic factors such as the BDNF should be safe, effective and characterized by long-lasting protection, thus these agents can be taken to clinical trials in glaucoma and other retinal degenerations such as the Retinitis Pigmentosa and age- related macular degeneration (AMD). Drug delivery systems suchas eye drops and, possibly, encapsulated cell technology, AAV-BDNF transfection should be considered for use.

Acknowledgment

Supported by the Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L'Aquila, and? the scientific consortium IN-BDNF. We thank Ms. S. Wilson for revising the English style.  

Juniper Publishers- JOJ Ophthalmology

 Nasolacrimal Duct Obstruction Review-JOJ Ophthalmology

Introduction

The lacrimal system comprises two components the main and accessory lacrimal glands and their secretions and the lacrimal excretory system [1]. The lacrimal excretory system is divided into the proximal and distal sections. The proximal section includes the punctum, canaliculus, and the common canaliculus [2,3]. The distal lacrimal drainage system consists of the lacrimal sac and the nasolacrimal duct that finally ends under the inferior turbinate and empties into the inferior meatus [2].

The precorneal tear film is composed of aqueous, mucinous and oily components and is necessary for the maintenance of the cornea as well as the maintenance of the ocular surface epithelium. More than 90% of the lacrimal fluid is removed by the excretory system, whereas less than 10% evaporates between blinks. Outflow is mainly regulated by the pumping effect of the orbicularis oculi muscle (Horner muscle) [3,4]. Tears are thus drawn into the lacrimal excretory system after each blink. The passage of tears down the nasolacrimal duct is influenced by gravity, evaporation in the nose, and inspiration and expiration.

Diagnosis

A detailed history of any systemic or topical medication, surgery, trauma or scarring, and infection must be obtained. It is valuable to grade the severity of epiphora using a uniform grading system such as the Munk scale [5]. Slit lamp examination starts with recognizing the papilla, presence of a membrane or fibrosis over the punctum, punctum size, tear meniscus height, eyelid margin, conjunctiva around the punctum, eyelid malposition, position of the punctum in the tear lake, and any sign of previous surgery. The Schirmer test [6], tear break up time [7], ocular surface staining, and tear meniscus height will rule out any associated ocular surface abnormalities. Abnormal dye disappearance test is a very maneuver to assess abnormal tear drainage system and is especially helpful in pediatric patients [7].

Congenital Nasolacrimal Duct Obstruction

Congenital nasolacrimal duct obstruction is the first cause of pediatric epiphora. Other causes include congenital punctum and canaliculus stenosis and/or atresia, nasal malformations and craneofacial abnormalities. It is frequently seen at birth due to lack of perforation of the valve of Hasner or an inferior and distal nasolacrimal duct opening failure. At birth, half of the nasolacrimal new born pathways are not permeable. A spontaneous apoptosis mechanism takes place between 3^rd- 4^th weeks after birth. Nevertheless, the obstruction persists in approximately 20% of the patients. Symptoms of congenital nasolacrimal duct obstruction consist of epiphora and dacryocystitis. The diagnosis is easily made in the office by observing epiphora and mattering of the eyelashes (Figure 1). It can be confirmed by compression over the nasolacrimal sac, which results in regurgitation of mucopurulent material in those patients who have developed chronic dacryocystitis. Instillation of 2% fluorescein dye and observation of abnormally delayed passage from de cul-de-sac is helpful in confirming the diagnosis.

This is a rare entity presented at birth or within the fourth week after birth. The blockage Rosenmüller valve. An edematous, tender and red mass below the medial canthal tendon will be clinically found (Figure 2). Conservative management (medical treatment). If dacryocele is initially sterile, all patients must be treated with warm compresses, local massage and topical antibiotics [8]. Those infected will be treated with broad spectrum intravenous antibiotic therapy [9]. Local massage by pushing down the lacrimal sac is useful and accelerates the lumen duct perforation process (Figure 3). Controversy exists whether conservative management or early probing for decompression are preferable.

Surgical Management of Congenital Nasolacrimal Obstruction

Probing consist by introducing a thin metal probe into the lacrimal punctum trough the nasolacrimal pathway, producing a mechanical opening in the obstruction site. It is an operating room procedure under general anesthesia. The ideal time is controversial, most of the time the procedure is performed around the first year of life for those patients that did not show spontaneous improvement or despite conservative treatment [10].

Close dacryointubation is performed by placement of silicone stents through the superior and inferior canaliculus and down to the nasolacrimal duct. This dilates the inferior meatus. The duration of the stent employment ranges from 6 weeks to 6 months [10]. Dacryocystorhinostomy surgical procedure involves the removal of bone adjacent to the lacrimal sac draining directly into the nasal cavity and it is performed when siliconte intubation have failed.

Differential Diagnosis

Dermoid cyst, dongenital glaucoma, acute conjunctivitis, corneal abrasion, trichiasis, ocular foreign body sensation and meningoencephalocele must be discarded.

Acquired Nasolacrimal Duct Obstruction

The primary acquired nasolacrimal duct obstruction is caused by inflammation or fibrosis without any precipitating cause. Appears in middle age and elderly females in 3:1 ratio. The obstruction site is located in the lower nasolacrimal fossa and middle nasolacrimal duct. The secondary acquired obstruction is caused by inflammation or fibrosis with precipitating causes as infectious, inflammatory, neoplastic, traumatic or mechanical factors [11,12].

Clinical presentation Patients with primary acquired nasolacrimal duct obstruction most commonly present with a history of epiphora. A chronic dacryocystitis owing to tear stasis can show a mucopurulent discharge at the punctum, or pus can be expressed from the punctum by massage of the lacrimal sac. Two stages can be distinguished [13].

Acute Dacryocystitis

Is an acute inflammation of the lacrimal sac due mostly to the obstruction of nasolacrimal duct. In most cases is a clinical diagnosis. Lacrimal sac bacterial overgrowth and inflammation? occludes the superior and the natural drainage creating a true abscess. Symptoms and signs include a no compressible painful and erythematous mass below the medial canthal tendon. Medical treatment must be initiated because of the risk of extension to the periocular tissues and the orbit (Figure 4 ) including topical and systemic antibiotics, analgesics and antiinflammatory measures. Local heat and massages helps drainage and the opening of the obstruction siteLacrimal sac abscess requires sometimes manual percutaneous drainage, material can be collected and cultivated (Figure 5). Avoid irrigation during the acute phase because the risk of dissemination of the infectious process. Definitive treatment is a dacryocystorhinostomy procedure which can be performed as an external or internal endoscopic. It is preferable to postpone two or three weeks after the acute phase resolution.

Chronic Dacryocystitis

Symptoms and signs include recurrent epiphora, swelling and redness at medial canthus and a painless and compressible mass below the medial canthal tendon. The patient usually refers history of previous acute dacryocistitis or chronic unilateral conjunctivitis.

The lacrimal sac is filled with mucoid or purulent discharge that can be expressed frequently with local massage (Figure 6). Medical treatment includes topic and systemic antibiotics and a dacryocystorhinostomy as the surgical first choice. Differential Diagnosis: Preseptal cellulitis, sinusitis, canaliculitis, sebaceous cyst and neoplastic tumours.

Conclusion

For most tearing patients a diagnosis can be arrived at after a thorough history and a few relatively simple office procedures. A small number of cases will require more sophisticated studies to confirm the site of anatomic block. With the various test available, appropriate medical or surgical management can be determined in the vast majority of patient with tear production and drainage imbalance. Nasolacrimal duct obstruction is a common finding and the ophthalmologist must be prepared to recognize signs and symptoms to perform an accurate diagnosis and offer a correct management.

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Posterior Astigmatism: Improving Refractive Outcomes with Toric IOL Implantation-Juniper Publishers

Abstract

Cataract surgery is not only a rehabilitative surgery, but also a refractive procedure, largely because of the intraocular lens (IOL) improves in latest years. However, recent studies showed a significant residual astigmatism after phacoemulsification with toric IOL implantation. There are several factors that can cause astigmatism refractive errors, such as IOL misalignment, factors related to the incision, incorrect calculation of toric IOL and corneal measurement errors. We believe that overlooking posterior corneal power is one of the most relevant reasons for refractive errors after cataract surgery with toric IOL.

Mini Review

Cataract is one of the leading causes of blindness worldwide, and its extraction is one of the most performed surgical procedures nowadays. The improvement of phacoemulsification techniques contributes for an increasingly less invasive procedure. Advances in IOL (intraocular lens) calculation, as well as the evolution of IOL technology increase patient's expectations for better results and postoperative spectacle independence [1}. Astigmatism is responsible for 13% of refractive errors [2]. Approximately 20 to 30% of patients submitted to cataract surgery had corneal astigmatism of 1.25 diopters (D) or higher, and around 10% of the patients have 2,00D or higher [3]. Recent studies demonstrate that residual astigmatism after toric IOL implantation is frequent [1,4]. Therefore, the correct astigmatism measurement is crucial for better post-operative results and, consequently, the patient's satisfaction. Furthermore, in present days, the 'gold standard’ in IOL power calculation is optical coherence biometry associated with keratometry. However, the capacity of this technique to determine the true corneal power is limited [5] because it assumes a fixed posterior-anterior curvature ratio, to estimate the posterior corneal curvature influence in the total corneal power [2]. Ignoring the posterior corneal power was recently highlighted as an important factor that leads to errors in toric IOL [5,6]. Posterior corneal refractive power is low when compared to the anterior surface, but when we take the astigmatic power into account, the posterior cornea surface can represent more than 20% of the total astigmatism power of the cornea [5].

Devices for an accurate measurement of posterior corneal surface have a shorter story when compared to the methods to evaluate the anterior surface. Nevertheless, this data can currently be obtained by several methods such as Scheimplug imaging and optical coherence tomography. This way, total corneal power can be calculated by using ray tracing or Gaussian optics thick-lens formula [2]. Posterior astigmatism has its own clinical importance demonstrated since 1890 by Javal, and recent studies show that posterior astigmatism is usually against the rule and the mean power is around 0.3D (Table 1) [7-10]. When the anterior corneal surface shows with the rule astigmatism, the posterior astigmatism compensates the anterior surface, and consequently reduces the total astigmatism. However, if the anterior surface astigmatism is against the rule, the total astigmatism will increase [9]. Ho et al showed that neglecting posterior astigmatism can cause absolute errors of 0.2±0.16D in astigmatism magnitude and 7.4±10.3 degrees in astigmatism angle [11]. The surgical prognosis related to the reduction of postoperative residual refractive cylinder is influenced by the correct calculation of the total corneal astigmatism and its axis. In conclusion, the efficacy of toric IOL implantation can be enhanced with the measurement of both anterior and posterior astigmatism.

Competing Interest

The authors declare that they have no conflict of interests regarding the publication of this paper.

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