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  5. FP1519 : Treating Refractory Glaucoma with High-Intensity Focused Ultrasound: A safety study

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Dr. Neha Midha, M16171, Dr. Srikanta Kumar Padhy, Dr. Dada Tanuj

ABSTRACT

Purpose :To establish safety of high intensity focused ultrasound (HIFU) in Indian population for treating refractory glaucoma.

Methods: 30 patients with refractory glaucoma and no visual potential were recruited. Patients underwent HIFU treatment using EyeOP1 device, 6 sectors were treated for 8 seconds each. Primary outcome measure was to determine the incidence of device or procedure related adverse events and post procedure complications. Secondary outcome was to report the reduction in IOP and number of ocular hypotensive drugs being used.

Results: The mean IOP before treatment was 33.56 ± 7.96 mm Hg. The mean IOP (mm Hg) at day 1, 7, 1month and 3 months was 15.76 ± 7.75, 17.59 ± 10.66, 15.18 ± 3.56 and 18.32 ± 3.37.The no. of topical medications reduced from 2.9±0.99 before treatment to 2.1±1.1 at 3 months. No complication or major adverse effect linked with the procedure or with the device were observed except mild subconjunctival haemorrhage in 15 cases.

Conclusion: HIFU appears to be a safe procedure and has shown significant IOP reduction in treatment of refractory glaucomas.

Keywords: cycloablation, high intensity focused ultrasound, refractory glaucoma.

INTRODUCTION

Glaucoma is a progressive neuropathy localized in the optic nerve that may lead to blindness, which progresses by the accelerated degeneration of the retinal ganglion cells, resulting, anatomically, in the excavation of the optical papilla and functionally, in a decrease of the visual field.

Numerous techniques using various physical agents have been used to reduce the production of aqueous humour by destroying the ciliary processes. The first difficulty is to determine the quantity of ciliary tissue to be destroyed, in order to efficiently reduce the IOP without inducing excess destruction which could then cause hypotony. The second difficulty is to selectively reach the ciliary processes without damaging the adjacent tissues. Trans-scleral cyclo-destruction with diode laser is the most used method in the world. This technique does not require ‘opening’ the eyeball. The laser beam is transported via an optical fiber to a probe superimposed on the sclera surface approximately 1.2 mm posterior to the limbus. More recently, the endoscopic cyclo-photo-coagulation technique has been described. Visually controlled, this technique allows effective tissue coagulation to be achieved by using much less energy, thereby inducing less inflammatory reactions than laser diode. But this technique is a real “open eyeball” surgery.

The EyeOP1 is a device using high frequency ultrasound to coagulate part of the ciliary body in a reproducible, non-operator-dependent manner, by creating lesions in a curve-shaped pattern distributed over the whole circumference of the ciliary body without manipulation and eliminating the need for repeated and successive imprecise interventions. The device enables to perform a very accurate treatment via its centration and suction system, which secures the device on the eyeball and the high frequency ultrasound energy delivered. Indeed, the 21 MHz frequency enables to focus on targeted tissue (ciliary body) whereas crossed and surrounding tissue are preserved. The device also enables to perform a treatment without opening the eyeball (non-invasive treatment) and in a very short period of time, i.e. less than 5 min. Lastly, the user-friendly device enables to significantly reduce the learning period and the risks habitually associated with the acquisition of a new skill.

MATERIALS AND METHODS

It was a prospective interventional safety study. Patients with end-stage glaucoma and no potential vision(No perception of light or perception of light present with projection of rays inaccurate in atleast one quadrant) presenting to the Glaucoma Clinic/ OPDshall be screened. Out of them, thirty patients meeting the following inclusion criteria were included in the study-

  • IOP >= 21 mmHg without upper limit.
  • Patient with no vision potential or blind eye
    • Open Angle Glaucoma patients (Primary Open Angle Glaucoma (POAG) including Pigmentary Glaucoma (PG), Pseudoexfoliative Glaucoma (PXF), steroid responders and Neovascular Glaucoma (NVG),Angle Closure Glaucoma (ACG)
    • Glaucoma patients whose IOP is not well controlled with 2 or more glaucoma medication
    • Any patients with previous conventional glaucoma surgery failure (such as Trabeculectomy and/or Deep Sclerectomy), or end stage glaucoma patient indicated or contraindicated for conventional filtering surgery (e.g. Trabeculectomy).
    • No previous intraocular surgery or laser treatment during the 90 days before HIFU Day
    • Age > 18 years and < 90 years
    • Able and willing to sign the informed consent form and complete postoperative follow-up requirements.

Exclusion criteria were as follows:

  • History of cyclo-destructive procedures (cryotherapy, diode laser cyclo-destruction, and endo-photocoagulation)
  • History of ciliary body surgery
  • History of ocular or retrobulbar tumor
  • Ocular infection within 14 days prior to the procedure of Ultrasound CiliaryPlasty
  • Eyes with implantation of glaucoma drainage device
  • Congenital glaucoma
  • Neovascular glaucoma with hyphema and/or vitreous hemorrhage
  • Structure abnormalities in anterior segment which lead to excessive scleral expansion or change of ciliary body location
  • Ocular disease other than glaucoma that may affect assessment of IOP (choroidal hemorrhage or detachment, lens subluxation, thyroid ophthalmopathy, and retinal detachment)
  • Any other systemic illness as per investigator’s discretion which will jeopardize patient’s participation in the study.
  • Any patient participating in another drug or device study

Patients scheduled to have glaucoma treatment with EyeOP1 were asked to give voluntary consent by signing the consent form for participation in the study and collection of data for this study.

Procedure: After peribulbar anaesthesia, the positioning cone is placed in direct contact with the eye, which allows for proper positioning of the transducers in terms of centering and distance. At the base of the cone, a suction ring allows a low level vacuum to be applied and enables one to maintain the cone in contact with the eye. The probe containing six active piezoelectric elements is inserted in the upper part of the positioning cone. The cavity created between the eye, the cone and the probe (4 ml) is filled with room temperature saline solution. The six transducers are placed at regular intervals on the upper and lower circumference of the ring, avoiding the nasal and temporal meridians, and oriented to create a focal zone consisting of 6 regularly distributed elliptical cylinder-shaped volumes.

Device models with different ring diameters, equipped with the 6 transducers, are available. In each patient, the probe model whose focal zones actually matched the ciliary body is determined via ultrasound biomicrosopy (UBM) imaging or Anterior Segment OCT (Optical Coherence tomography) performed before the treatment, or using biometric anatomic parameters such as white-to-white and axial length measurements.

The probe is connected to the control unit which allows each of the 6 sectors to be sequentially activated according to the program. We treated 6 sectors for 8 seconds each with an interval of 20 secs between each sector.

After ultrasound treatment, appropriate anti-inflammatory (steroids eye-drops for duration of 3-4 weeks) were prescribed. Other medications, such as antibiotic eye-drops or pain killers were prescribed as necessary. All anti glaucoma medications were continued as before.

Patients were followed on day 1, 1 week, 1 month and 3 month. At each follow up complete ocular examination and IOP measurement was done and documented. All IOP measurements were done at same time of the day. On follow up the topical drugs were reduced if IOP was believed to have fallen below the target level.

Safety and Efficacy/ Outcome assessment

  1. Primary outcome: Safety – Incidence of all device and or procedure related adverse events during the study (Intraoperative and Postoperative)
  2. Secondary outcome: Efficacy – Reduction of IOP
  • Mean IOP (mmHg) at each follow-up visits compared to the baseline IOP.
  • Number and mean number of ocular hypotensive medications used at each follow-up visits

RESULTS

Total 30 patients meeting the inclusion criteria were recruited in the study. Seven patients were lost to follow up. A total 23 patients who completed the follow-up protocol were enrolled for statistical analysis. 21 out of 23 patients responded to the treatment i.e. a success rate of 91.3% was noted in our study. The distribution of cases was as follows- Post vitreoretinal surgery(n=6, 26.08%), Post traumatic(n=5, 21.7%), Primary angle closure glaucoma(n=4, 17.39%), Steroid induced glaucoma(n=3, 13.04%), Combined mechanism glaucoma(n=1, 4.34%),Aphakic glaucoma(n=1, 4.34%), Pseudophakic glaucoma (n=1, 4.34%), Post Penetrating Keratoplasty (n=1, 4.34%) and  Primary congenital glaucoma (n=1, 4.34%). The mean IOP before treatment was 33.56 ± 7.96 mm Hg. The mean IOP (mm Hg) at day 1, 7, 1month and 3 months was 15.76 ± 7.75, 17.59 ± 10.66, 15.18 ± 3.56 and 18.32 ± 3.37 respectively. Anti-glaucoma medication was gradually tapered over 1 month. 9 patients were on oral acetazolamide before treatment. At 1 and 3 months, none of the patients required oral therapy. The number of topical medications reduced from 2.9±0.99 before treatment to 2.1±1.1 at 3 months. 14 out of 23 patients had mild subconjunctival hemorrhage due to placement of suction cone. No serious complication or major adverse effect linked with the procedure or with the device (severe hypotony, phthisis of the eyeball, scleral perforation) were observed.

DISCUSSION

Glaucoma treatment, be it medical, surgical or via physical agent, mainly aims at reducing the intraocular pressure (IOP) and slowing down the progress of the disease. Two main strategies that are presently implemented are:  first, to restore sufficient drainage of the aqueous humour and second, to reduce the production of aqueous humor. Reduction of aqueous production is by administration of eye drops (medical treatment) or by destruction of part of the ciliary body, by using physical agents (laser, cold, ultrasound, etc.). The technique being used in this study pertains to the second strategy for the treatment of glaucoma: to reduce the production of aqueous humour via well-controlled thermal coagulation of part of the ciliary body, in a single step, using High Intensity Focused Ultrasound.

Many clinical studies have shown that the current laser methods of cyclo-destruction are usually effective, but poorly tolerated (pain, significant ocular inflammation, risk of over-dosing the treatment that may lead to hypotony and phthisis) and associated with a high risk of vision-threatening complications [1-6]. These methods are therefore usually reserved for advanced glaucoma refractory to conventional treatments.

Ultrasonic ablation of the ciliary body for treating glaucoma has been extensively studied in the 1980’s and early 1990’s. Several animal studies and then clinical series have reported that high-intensity focused ultrasound (HIFU) is an effective method with favorable results in terms of IOP reduction [7-13]. Maskin et al achieved a 38.4 % IOP reduction 8 months after HIFU cyclo-destruction in 158 eyes having refractory glaucoma using a commercially available device (Sonocare Therapeutic Ultrasound System Model, Sonocare Inc., Ridgewood, NJ) [12]..With the same device, Sterk et al obtained a 42.2 % IOP reduction 3 to 4 months after HIFU cyclo-destruction in 44 eyes with refractory glaucoma [13].

The specific advantage of HIFU is that the energy can be focused through non-optically transparent media without uncontrolled energy absorption, thus reducing the effects on the adjacent tissues. Similarly, energy deposition and tissue heating at the focus site do not depend on tissue pigmentation, which may vary greatly, particularly in the ciliary body. HIFU allows for a defined and adjustable tissue volume to be heated and treated at any depth or location within the eye.

In a previous model named Sonocare, the transducer was a bulky and heavy – piezo ceramic of 80 mm in diameter – and attached to an articulated arm which had to be positioned manually using an imaging probe. The procedure was long (more than 1 hour) and complex, the use of HIFU for cyclo-destruction with Sonocare was gradually abandoned in the mid 1990’s. Moreover, scleral thinning or perforation had been reported, probably due to improper positioning of the transducer. More than 20 years later, the HIFU technology has considerably progressed and reached a maturity which has enabled the creation of the EyeOP1 device. The objective was to reduce the production of aqueous humor via well-controlled thermal coagulation of part of the ciliary body, in a single step, using High Intensity Focused Ultrasound. This miniaturized device has an ergonomic feature that makes the treatment of the eyeball much more accurate, simple and fast. Furthermore, this miniaturization has allowed  usto securely position the device onto the eyeball via a centering and suction system ensuring accurate and reproducible operating procedure. Lastly, with this technology, the procedure can be automated with an increased level of safety for the patient.

Functional in vivo studies have demonstrated the efficacy of coagulation of part of the ciliary body with HIFU. Histological and macroscopic results published in 2010 by Aptel et al [14] have demonstrated the very good local tolerance of the treatment and the accurate and targeted destruction of the ciliary body.

In accordance with results of our study, various clinical studies have confirmed the tolerance and efficacy of the coagulation of part of the ciliary body with focused ultrasound. No complication or major adverse effect linked with the procedure or with the device (severe hypotony, phthisis of the eyeball, scleral perforation) was observed, with a 40% average reduction of the IOP in responder patients. This ultrasound treatment allows for the IOP to be very significantly reduced in patients suffering from glaucoma, without complications or major adverse effects.[13-22].

A prospective multicenter study conducted in 5 University hospitals on thirty eyes of open angle glaucoma patients naïve of filtering surgery demonstrated that the ultrasound glaucoma treatment is an effective and a well-tolerated procedure to reduce IOP.[20]. Intraocular pressure was significantly reduced from a mean preoperative value of 28.2 ± 7.2 mmHg (n=3.6 hypotensive medications) to 19.6 ± 7.9 mmHg at 12 months (n=3.1 hypotensive medications) (mean IOP reduction of 30%. No major intra or post-operative complications occurred during 1-year follow-up period.[20].

Clinical studies in Europe and India conducted with the second generation of probes confirmed the results published since 2011.

A multicenter study conducted in 4 academic glaucoma centers in Europe on 52 eyes of 50 patients demonstrated that the intraocular pressure was significantly reduced from a mean preoperative value of 24.7 ± 7.1 mmHg (n=3.0 hypotensive medications) to 17.1 ± 7.4 mmHg (n=2.7 hypotensive medications) at 6 months, with a mean IOP reduction of 47% in responding patients.[21].

A dose study has been conducted on 75 patients (comparison of two ultrasound doses – 8 seconds vs 10 seconds ultrasound activation per transducer) on open angle glaucoma patients. Intraocular pressure was reduced from a mean preoperative value of 23.3 ± 2.3 mmHg (n=0.5 hypotensive medications) to 15.4 ± 3.5 mmHg (n=1.0 hypotensive medications) at 6 months, with a mean IOP reduction of 33.6% in responding patients for dose “8 seconds”, and from a mean preoperative value of 23.7 ± 3.4 mmHg (n=0.8 hypotensive medications) to 16.1 ± 3.5 mmHg (n=0.8 hypotensive medications) at 6 months, with a mean IOP reduction of 32.2% in responding patients for dose “10 seconds”.[22].

Graber M et al suggested HIFU cyclocoagulation to be a safe and reliable alternative to filtering surgery in the management of chronic angle closure glaucoma among patients with a high risk of malignant glaucoma..[23]

Giannaccare G et al [24] in their multicenter study recruited 30 patients and showed at days 1 and 180, the mean IOP was significantly reduced (18.4 ± 7.2 and 20.2 ± 6.2 mmHg, respectively; all p < 0.0001). Group 3 patients (8-s ultrasound exposure time) showed a greater IOP reduction than the other two groups-4s and 6s (-16.2 ± 8.3 for group 3 vs. -8.8 ± 6.6 for group 2 and -3.7 ± 6.5 for group 1; p = 0.02 and p < 0.001, respectively). Qualified and complete success was achieved in 23.3% and 46.7% of patients, respectively; treatment failure was recorded in 6.6%.

To conclude HIFU appears to be a safe and effective procedure with no serious vision threatening complications. There are various limitations to our study most important being the short duration of follow up, no data on the effect of HIFU on visual acuity and no control group. A long term follow up study is needed before this modality can be used in treatment naïve eyes with good visual potential.

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