ULTRASOUND CYCLOPLASTY IN EYES WITH GLAUCOMA

Guest author

Malik Nuzhat

Ajmal Khan Tibbiya College

Aligarh, India

INTRODUCTION

Over the last few years a new device named "Ultrasound Cycloplasty" (UCP) has been developed. This device uses high-intensity focused ultrasound (HIFU).

The main purpose of this device is to overcome the limitations of traditional cyclodestructive technique by achieving a more selective coagulation of the ciliary body and avoiding possible damage to the adjacent Ocular structures.

In addition the stimulation of supra-choroidal and trans-scleral portions of the uveoscleral outflow pathway has recently been proposed as possible adjunctive mechanisms in reducing intra-ocular pressure (IOP).

PREOPERATIVE PROCEDURE AND OPHTHALMOLOGICAL EXAMINATION

A.

1. Test distance and near best corrected visual acuity.

2. Evaluate the Anterior segment of the eye using a slit-lamp biomicroscope.

3. Examine the anterior chamber angle using a goniolens.

4. Evaluate the fundus by slit-lamp indirect ophthalmoscopy with the use of a non-contact fundus lens.

5. Measure the IOP using Goldmann applanation tonometry.

Measure the ocular anatomical parameters by means of a non-contact optical biometer.

B. Pre-surgical procedures

1. Place the patient in a supine position on the surgical bed.

2. Administer local anesthesia by performing one peri-bulbar infiltration with 10 ml of local anesthetic (mepivacaine plus ropivacaine), 30 minutes prior to surgery.

3. Perform the injection infero-temporally at the junction of outer 1/3rd and inner 2/3rd of the lower orbital rim or supero-nasally beneath the superior orbital notch using a 27- gauge needle.

C. Preparation of the treatment device

1. Enter data about the surgeon and patient using the control unit touch screen, and then select the eye to treat.

2. Open the sterile single-use device pack containing the coupling cone and the treatment probe and connect their cables to the control unit.

D. UCP procedure

1. Disinfect the palpebral and periorbital skin with 10% povidone iodine 3 times.

2. Wipe the disinfected skin with sterile guaze.

3. Put a sterile surgical drape over the face of the patient with a central hole centered over the eye.

4. Place the patients head lying slightly backwards in order to put the ocular surface horizontal. This allows easy placement of the cone (of the device).

5. Open the eye without using the speculum.

6. Put the coupling cone over the ocular surface with tubing on the temporal side and gently move to correctly position and center it.

7. Push the aspiration button on the foot switch to start a low-level suction from the peripheral ring of the coupling cone until the vertical bar on the screen becomes green. This allows the maintenance of the coupling cone in direct contact with the patients eye throughout the entire procedure.

8. Insert the treatment probe inside the coupling cone, with the cable in nasal position.

9. Fill the empty space delimited by the eye, cone and probe with sterile balanced salt solution (BSS) at room temperature.

10. Ask the patient to hold the position and keep the head perfectly still.

11. Push the start button on the foot switch to start the treatment and hold the pressure during the procedure.

12. Maintain firmly in the optimal position the probe and the coupling cone during the entire procedure. Avoid moving, rotating or pushing the probe.

13. At the end of the procedure deactivate the suction system by pushing the aspiration button on the foot switch.

14. Tilt the cone slightly until BSS is removed through the tube.

E. Post-surgical procedure

1. Instill antibiotic-steroid eyedrops in the treated eye and patch the eye for 24 hours.

2. Remove the eye patch next day and measure the IOP.

3. Prescribe the patient antibiotic-steroid eyedrops, 4 times per day for a month.

4. Examine the treated eye and measure the IOP at day 1, 7 and 14; 1,3 and 6 months; and  after 1 year.

F. Results

In a study 8 patients successfully underwent follow-up for 1 year without need for oral hypotensive agents. 2 patients required incisional surgery for better IOP control.

No major complications were reported in the study, except for 1 case of fixed and dilated pupil with accommodation deficit, which spontaneously resolved 3 months after the UCP procedure.

G. Discussion

1. UCP is a new non-incisional cyclodestructive technique that can lower IOP, acting in 2 different ways.

2. It reduces aqueous humor inflow determining the selective necrosis of secretory epithelium of the ciliary body.

3. It increases aqueous humor outflow through the uveoscleral tract, stimulating the trans-scleral and supra-choroidal pathways.

4. The technique is fast, easy, safe and surgeon friendly.

5. Several technical improvements have been made in UCP technology compared to the previous techniques, providing more precise focusing on the target zone.

6. In particular the probe is placed in direct contact with the eye and the treatment is conducted using the same setting throughout the entire procedure.

7. The higher operating frequency (21 MHz) compared to previous systems (5 MHz) allows centring the target zone while sparing the adjacent tissues.

8. The UCP device is composed of a sterile single-use treatment pack, which comprises a polymer made coupling cone and a treatment probe.

9. The coupling cone and the probe cone are connected by cables to a portable control unit (36x32x26 cm).

10. It permits setting of the treatment parameters and controls the procedure by means of a touch screen.

11. The probe is a ring of 30 mm diameter and 15 mm height. It contains 6 piezoelectric transducers.

12. Each transducer is approximately a cylinder segment of 7.0 mm length, 4.5 mm width and 10.2 mm radius. The total surface area is 35 mm2. 

13. Depending upon the diameter the 6 piezoelectric elements are centred on 11 mm, 12 mm or 13 mm diameter circle over the circumference of the eye. The ultrasound beams are focused 2 mm deep to the sclera.

14. The 6 transducers deliver Ultrasound operating at a frequency of 21 MHz with an acoustic power of 2 W, determining the rapid increase of local temperature of the ciliary body upto 90'C.

NORMAL TENSION GLAUCOMA

Guest author

SHARBEEN 

Ajmal Khan Tibbiya College 

Aligarh, India

INTRODUCTION

Glaucoma is a multifactorial neurodegenerative disorder. The fundamental nature of this disease is a pathology of the optic nerve. The single most important factor determining it's rate and severity is intra-ocular pressure (IOP).

The level of IOP appears to determine whether the etiological factor will lead to development of progressive glaucomatous damage or not.

Around half of all individuals having IOP of 35 mmHg develop glaucomatous cupping and visual field damage. With IOP between 21-30 a smaller percentage of patients develop Glaucoma. Individuals having statistically normal range of IOP less often develop Glaucoma but their numbers are significantly high (around 50%) among all Glaucoma groups.

There is no fundamental difference between Normal tension glaucoma (NTG) and primary open angle Glaucoma (POAG) except that the etiological triggers or pathologic process is accelerated at a lower level of IOP in NTG.

A normal IOP does not necessarily guarantee against developing glaucoma. 

Patients with NTG often have IOP between 15-20 mmHg.

CLINICAL FEATURES

(1) Patients with NTG often have parapapillary atrophy (PPA) of the optic nerve with cupping. There is absence of retinal pigment epithelium in the region of PPA and visual field (VF) loss is most conspicuous in the corresponding region.

(2) Feature of cupping: Some patients have a notch in the optic cup (a highly localized region of thin or absent neuro-retinal rim which is sometimes called “focal ischemic” type of cupping).

It is associated with a highly localized dense arcuate field defect or even a dense upper hemifield defect.

Other discs have diffuse shallow cupping and a pale color of the disc and surrounding tissue. This is called “senile sclerotic” disc. There is apparently some association of focal ischemic type to vascular dysregulation and of senile sclerotic type to systemic atherosclerosis.

(3) Splinter hemorrhages are most frequently seen in NTG.

(4) There can be intermingling of POAG and NTG in the same family.

(5) Patients with NTG often have features of Flammer’s Syndrome.

(6) Some eyes with signs of glaucoma maybe related to an acute ischemic episode (“shock induced neuropathy”) or chronic obstructive arterial disease. Often glaucomatous changes in these patients are non-progressive.

DIAGNOSIS 

NTG is usually discovered due to an abnormal disc appearance. Mild cupping may be overlooked unless VF shows scotomas near or below fixation, prompting a more careful examination of the disc.

Certain features which point towards diagnosis of NTG include:

Family history of glaucoma, prominent crescent or halo of absent RPE adjacent to the disc, splinter hemorrhages, tendency towards cold hands and feet, low blood pressure (BP), wearing socks at night while sleeping and migraine headaches.

DIFFERENTIAL DIAGNOSIS 

(1) Large physiologic cup

(2) Congenital anomaly of disc

(3) Anterior ischemic optic neuropathy

(4) Branch retinal vein occlusion

(5) “Giant” drusen of optic nerve

(6) Orbital or intra-cranial tumor

(7) Inaccurate tonometry

(8) Variable IOP

(9) Previously elevated IOP (related to previous steroid use or resolved uveitis)

(10) POAG, where IOP has been lowered by systemic medications (e.g. systemic beta-blockers for systemic hypertension)

(11) Special form of NTG: Shock-induced neuropathy. It is related to a previous cardiovascular episode or atherosclerosis.

It is hypothesized that NTG could be a primary form of glaucoma unrelated to IOP. These patients may continue to progress despite significant lowering of IOP (upto 8-10 mmHg).

RHO KINASE INHIBITORS IN GLAUCOMA

Guest author

RAMSHA ANWAR

Ajmal Khan Tibbiya College, Aligarh, India

INTRODUCTION:

Rho Kinase is a serine/threonine protein kinase involved in the regulation and modulation of cell shape and size via its action on the cytoskeleton.

FUNCTIONS OF RHO KINASE:

As downstream effectors of Rho GTPase, Rho Kinases are involved in calcium independent regulation of smooth muscle contraction.

(A small GTP-binding protein, called Rho, acts on ROCKs downstream, to produce certain changes in the tissues)

Rho Kinases are also linked with: 

(1) the control of cytoskeleton dynamics 
(2) actinomyosin contractile forces 
(3) cell adhesion 
(4) cell stiffening 
(5) extracellular matrix and re-organization 
(6) cell morphology.

The above mentioned factors regulate aqueous humor outflow via the trabecular pathway resulting in lowered intra-ocular pressure (IOP).

Rho Kinases (ROCK) exist in 2 isoforms: ROCK 1 and ROCK 2.

ROCK 1 is located on chromosome 18 and contains 1354 aminoacids. 
ROCK 2 is located on chromosome 12 and encodes a 1388 aminoacid product.

In humans ROCKs are expressed in majority of tissues, including trabecular meshwork and ciliary muscle cells.

Structurally, ROCKs are composed of 3 major domains:

1. An N-terminal kinase domain (which phosphorylates protein targets).
2. A C-terminal kinase domain (which limits kinase activity via intramolecular interactions)
3. A coiled-coil Rho-binding domain (which facilitates the switch from the inactive to active conformation).

On binding to Rho, the catalytic activity of ROCKs is moderately enhanced.

ROCKs inhibit myosin light chain phosphatase thereby mediating actin cytoskeletal changes. These directly affect the contractile properties of trabecular meshwork outflow tissue.

ROCK promotes the assembly of actin stress fibers and focal adhesions.

ROCK also regulates cell contraction and motility.

Inhibition of ROCK improves aqueous outflow through the trabecular meshwork resulting in lowered IOP.

RHO KINASE SIGNALING PATHWAY:

1.  Rho Kinase is a downstream effector of the RhoA protein, a small GTPase.
2. GTPase interchange between two conformations (a) A Guanosine triphosphate (GTP)-bound ACTIVE conformation and a Guanosine Diphosphate (GDP)-bound INACTIVE conformation.
3. A number of factors control GTPase activation. These regulators include:

·         Guanine nucleotide Exchange Factors (GEFs)

·         GTPase Activating Proteins (GAP)

·         Guanine nucleotide Dissociation Inhibitors (GDIs)

·         Myosin Light Chain

·         LIM kinase

The above mentioned substrates interact to control actinomyosin contractility, membrane permeability, cellular adhesion, cell stiffening, cell morphological changes, extracellular matrix organization and DNA synthesis.

EFFECTS OF RHO KINASE INHIBITORS AS IOP LOWERING AGENTS

No new class of anti-glaucoma drugs has been introduced since 1996, when FDA approved latanoprost.

Therefore, this group of Rho Kinase inhibitors are an exciting new class of drugs available to lower IOP.

Two drugs are commonly available commercially. These include: Ripasudil (K-115) and Netarsudil (AR-13503).

DRUGS	RIPASUDIL	NETARSUDIL
COMMERCIAL NAME	Glanatec (Derivative of Fasudil)	Rhopressa
CHEMICAL FORMULA	C15H18FN3O2S	C28H27N3O3
IUPAC NAME	4-fluoro-5-(((2S)-2-methyl-1,4-diazepan-1-yl)sulfonyl)isoquinoline	(4-((1S)-1-(Aminomethyl)-2-(isoquinolin-6-ylamino)-2-oxoethyl)pheny)methyl2,4-dimethylbenzoate
DURATION IT TAKES TO LOWER IOP AFTER INSTILLATION	2 hours	2 hours
DOSAGE	0.4% drug instilled twice daily	0.02% solution used once daily
SIDE EFFECTS	Conjunctival hyperemia Conjunctival haemorrhage (Hyperemia usually resolves spontaneously over few hours) ROCK inhibitors usually lower BP and vascular resistance. ROCK inhibition reduced the intraocular penetration of concurrent timolol instillation (presumably by increasing the elimination through the dilated conjunctival vasculature).	Conjunctival hyperemia Cornea verticillatae (Usually asymptomatic and did not reduce visual function) Pain at instillation site Conjunctival haemorrhage

MECHANISM:

ROCK inhibition lowers IOP by:

1. Increasing aqueous humor outflow.
2. Reducing aqueous humor production.
3. Decreasing episcleral venous pressure (EVP). This can be understood by the following equation=

IOP= EVP + 1/ C(F-U)

Here, C= Facility of outflow.

F= Formation of aqueous humor.

U= Resorption rate of aqueous humor.

IOP= Intra-ocular pressure.

As the metabolic pathway of Rho Kinase controls many aspects of cell morphology, when it is inhibited following changes occur:

1. Change of cell shape in the trabecular meshwork.
2. Change in actin cytoskeletal structure
3. Rounding of cell bodies
4. Disruption of actin production.

All these changes allow greater outflow of aqueous humor through the trabecular meshwork which ultimately results in decreased IOP.

NOR-EPINEPHRINE TRANSPORT INHIBITION:

Many ROCK inhibiting drugs chemically include a nor-epinephrine transport (NET) inhibition component.

This nor-epinephrine inhibitor helps to reduce aqueous production and decreases EVP.

Nor-epinephrine transport inhibition lowers aqueous humor production by (i) vasoconstriction (ii) reducing blood flow to the ciliary processes.

Aqueous humor production may be reduced by 20-23% by nor-epinephrine transport inhibition.

NEUROPROTECTION:

ROCK inhibitors increase blood flow in the optic nerve head by relaxation of the vascular endothelial smooth muscle. Nitric oxide synthase inhibitor induced impairement of optic nerve blood flow was also prevented by ROCK inhibition.

ROCK inhibitors influence neuron survival and axon regeneration. Fasudil protected against glutamate-related excitotoxicity in the retina and better preserved cells of the ganglion cell layer on exposure to N-methyl-D-aspartate.

CLINICAL TRIALS:

Phase 1,2,3 clinical trials of netarsudil were conducted in more than 2000 patients. 0.02% once daily in the evening was found to be the most efficacious and well tolerated dosing regimen. The phase 2 clinical trial included comparison with latanoprost and four phase 3 trials comparing netarsudil with timolol.

When netarsudil and latanoprost were compared, IOP reductions were similar [-5.8 mmHg in Netarsudil group vs -5.9 mmHG in the latanoprost group]. Among all patients netarsudil was 1 mmHg less effective than latanoprost and did not meet the statistical analysis for non-inferiority of netarsudil to latanoprost criteria.

Rocket 1,2,4 phase 3 trials compared netarsudil to timolol. All studies showed comparable IOP reduction with both drugs.

A fixed-dose combination of netarsudil and latanoprost (Roclatan) has been tested with individual components in two clinical studies (Mercury 1 and Mercury 2). Mercury 3 is an ongoing trial comparing Roclatan and Ganfort.

Mercury 1 & 2 have shown 1-3 mmHg greater IOP lowering with Roclatan compared to the individual components. IOP reductions of atleast 30% were achieved in 65% of patients treated with Roclatan, compared to 40% when individual components were used.

Roclatan treated patients achieved 16 mmHg or less IOP in 61% cases, while ≤ 14 mmHg was achieved in 33% cases. This was comparable to those treated with individual components who achieved similar results in 40% or less and 15% or less patients respectively.

CONCLUSION:

Use of Rho Kinase inhibitors in treating glaucoma has been proven to be of benefit. Although there is evidence showing that Rho Kinase inhibitors are related to increased conjunctival hyperemia.

AHMED CLEARPATH DEVICE

Guest author

SUMERA SAGHEER

Ajmal Khan Tibbiya College

Aligarh- India

INTRODUCTION:

Minimally Invasive Glaucoma Surgery (MIGS) devices such as the ExPress Mini Shunt and Glaukos iStent provide ease of use for the surgeon. However, they allow only modest reductions in intra-ocular pressure (IOP). Therefore, MIGS devices are typically reserved for mild-to-moderate glaucoma cases.

New World Medical, USA, a company famous for its iconic Ahmed Glaucoma Valve has developed the Ahmed ClearPath device which offers patients another treatment option and surgeons more convenient and efficient tube surgery. This device targets patients with severe or moderate glaucoma.

The ClearPath is the culmination of the efforts of a group of glaucoma surgeons to develop a non-valved glaucoma drainage device to shunt aqueous out of the eye.

FEATURES:

The device is available in two sizes, viz, 350 mm² and 250 mm².

The ClearPath consists of a flexible plate with contour closely conforming to the curvature of the eye.

The suture fixation points for the device are conveniently positioned much anteriorly compared to other devices, enabling ease of fixation.

CLEARANCE FROM FDA:

The device received clearance from FDA earlier this year and the company had a limited launch of the technology.

The limited launch to a small group of surgeons was to receive input and feedback from the surgeons and clinicians on their unmet needs; to assess the device’s safety and efficacy and to know if it makes the surgical procedure much more efficient.

New World Medical has CE mark for the device, but is evaluating commercialization strategies outside the USA.

SURGICAL PROCEDURE:

https://www.newworldmedical.com/Clients/NewWorldMedical/Content/NWMCorp/media/pdf/ClearPath_Surgical_Steps.pdf

Once a conjunctival peritomy and sub-tenon’s pocket are created, the ClearPath is secured to the sclera using the surgeon’s preferred suture material. If the Model 350 is selected, the extraocular muscles will need to be isolated. The body of the plate is placed 8 to 10 mm from the limbus in the superior quadrants, resulting in the anterior edge of the suture arms being placed 6 to 8 mm from the limbus. An anterior bevel is cut on the distal end of the silicone tube, and the tube is then inserted into the anterior chamber using forceps to feed the tube through a scleral tunnel created by a 23-gauge needle. If the tube is inserted into the sulcus, a posterior facing bevel may be used to prevent occlusion by the posterior iris. 

NEW WORLD MEDICAL:

https://www.newworldmedical.com/ClearPath

New World Medical was founded in the early 90s by Dr Abdul Mateen Ahmed and has a humanitarian segment.

The mission is to benefit humanity and stems not only from providing innovative high quality products but also supporting surgeons in medical missions, particularly medical missions outside of US, where the glaucoma treatment or procedures are limited.

The organization helps a lot of non-profit organizations to go out to some of these undeveloped markets.