Therapeutic ultrasound for glaucoma: clinical use of a low-frequency low-powerultrasound device for lowering intraocular pressure
© Schwartz et al.; licensee BioMed Central Ltd. 2014
Received: 1 March 2014
Accepted: 20 August 2014
Published: 26 September 2014
This is a first-in-human study to determine the efficacy and tolerability ofa new method of treating glaucoma using a low-power, low-frequency, focusedtherapeutic ultrasound for glaucoma (TUG) device designed to trigger aninflammatory reaction in the anterior chamber angle and trabecular meshworkto enhance outflow. The use of the device is anticipated for mild ormoderate open-angle glaucoma as an enhancement to outflow.
In a two-branch clinical trial, a total of 26 primary open-angle glaucomapatients underwent a procedure consisting of the external application of theTUG device. In branch 1, nine of these patients were naïve topharmaceutical treatment or had been off of medication for over6 months. In branch 2, 17 patients were treated after a medicationwashout period. All patients in the study were followed for12 months.
In branch 1, there was a decrease in intraocular pressure averaging over 20%lasting at least a year in 74% of the eyes with non-normotensive open-angleglaucoma. In branch 2, an average of two visits while on medication providedthe comparison intraocular pressure (IOP) to the effect of the TUG treatmentafter washout. It was seen that the intraocular pressure over the yearpost-treatment was equal to or better than the pharmaceutical control inclose to 80% of measurements.
A novel device for lowering intraocular pressure is described with apotential for adding to our armamentarium for treating glaucoma. This is asmall cohort study which indicates beneficial trends.
Trial registration number
The study was a registered clinical trial, #ISRCTN50904302.
KeywordsUltrasound Glaucoma Trabecular meshwork
Open-angle glaucoma is a worldwide problem for which newer, portable, low-cost, andeffective treatments are needed. Glaucoma affects approximately 3 million people inthe United States (source: preventblindness.org—Prevent Blindness America) and70 million worldwide (source: glaucoma.org—Glaucoma Research Foundation). Itis expected that the increasing age of our population will significantly increasethe number of people with this blinding disease. The present methods used to treatglaucoma have significant drawbacks. Pharmaceutical agents must depend oncompliance, often have side effects, and may interfere with other medicationsrequired by the patient. The use of lasers such as argon or selective lasertrabeculoplasty offers a useful alternative to many of the problems inherent withpharmaceutical agents. However, these instruments require a slit lamp biomicroscopeapparatus for viewing the trabecular meshwork and a contact lens system forapplication of the energy for such treatment.
Cataract surgery lowers intraocular pressure in patients with coexisting glaucoma [1–6]. The basis for this effect may be due to both anatomic and biochemicalchanges in the area of the trabecular meshwork since observations have suggestedthat the use of ultrasound in the eye may result in a decrease in pressure . The association of the decrease in pressure with cataract surgery becamemore evident when the use of phacoemulsification (ultrasound) became prevalent. Thefinding that there is a decrease in the intraocular pressure (IOP) afterphacoemulsification has often been attributed to an increase in the opening of theangle. This is certainly true with narrow-angle glaucoma, but recent studies haverevealed no correlation between the change in chamber depth and the IOP decreasewith open-angle glaucoma whereas the decrease is correlated with the pre-treatmentIOP [8–11]. In addition, reports of cataract surgery performed with an intracapsularlens extraction did not indicate a decrease in IOP. Intracapsular cataract surgerydid not involve the use of ultrasound. Radius et al. reported that after theintracapsular cataract surgery, there was a slight increase in the IOP .
The author confirms that (1) the research followed the tenets of the Declaration ofHelsinki, (2) informed consent was obtained, (3) the research was approved by theinstitutional review board to allow clinical studies (on the basis of previousanimal studies supporting a non-significant risk classification), and (4) poweranalysis was performed to justify the number of patients enrolled in the study.
Prior to the use of the instrument, a power determination was performed within vitro and in vivo animal studies based on a temperatureelevation of approximately 6°C. This temperature elevation was just belowthat which causes pain and cell necrosis [15–17]. It was found that with external application of the TUG device ofapproximately 3 W of power/cm2 to the hand piece, thetemperature increased and then stabilized at approximately 43°C, whenmeasured by a “K type” microthermocouple positioned 0.5 mmbelow the surface of a pig eye at the limbus using an Omega HH508 digitalthermometer. The instrument was developed and tested with this microthermocoupleto determine the power required to raise the temperature by 7° frombaseline. Testing was then repeated with pig eyes raised to a basal temperatureof 36.5°C by water bath to determine the power to raise the temperature to43°C to 44°C and maintain this steady-state increased temperature.
In vivo work on the animal model at power settings above4 W/cm2 resulted in a large corneal inflammatory reaction.Further in vivo studies therefore used only power settings below thislevel. A point was then chosen on the sclera side with 0.5 mm of clearancefrom the limbus for this study.
In early clinical work, the first two series TUG.1 and TUG.2 (not published) wereconducted to determine the tolerability (TUG.1) and to refine the parameters(TUG.2) for treatment. The presently reported study (TUG.3) was a prospectivecontrolled study using the ultrasound instrument in the manner which optimizedthe intraocular pressure-lowering effect.
This study was funded by EyeSonix Incorporated and followed a protocol approvedby Western Institutional Review Board (WIRB). The study was conducted at onesite in the Long Beach Eye Care Associates offices. Health Insurance Portabilityand Accountability Act (HIPPA)-compliant informed consent was approved by WIRB.Each patient who participated in the study (or a designated family member) gavewritten consent. The study was a registered clinical trial, #ISRCTN50904302.
Recruitment was conducted among glaucoma patients seen at the study site.
Patients with open-angle glaucoma and without medical or laser treatment for at least 6 months, or
Patients presently on pharmaceutical treatment for glaucoma.
The exclusion criteria included both previous invasive glaucoma surgery and aninability to comply with follow-up visits. Treatment-naïve patients wereoffered the option of pharmaceutical agents or laser (always in this order) andalso the option of being part of the study.
Randomization and treatment protocol
Patients with symmetric IOP were randomized by a coin flip as to the eye selectedfor the TUG treatment. If there was a significantly higher IOP in one eye, thiseye was selected for the TUG treatment.
If patients were presently on pharmaceutical agents, a bilateral washout periodwas performed. Prostaglandin analog medications were washed out for1 month. Other agents were washed out for 1 week.
A tip cover was then put over the hand piece. Next, the tip was placedsequentially at the treatment sites. The application was at a point 0.5 mmon the scleral side of the limbus. Applications were 45 s in duration ateach clock hour position for 12 clock hours. The four previously placed marksallowed for an equal positioning of the spots of three per quadrant. Throughoutthe procedure, the power output was monitored and adjusted to maintain thecorrect delivery of energy to the hand piece. The intraocular pressure wasmeasured 1 h after the treatment as a safety precaution, since after lasertrabeculoplasty there is a small chance of a pressure spike after the treatment.No significant post-treatment pressure elevations were seen. Post-treatment, thepatients received Nevanac (nepafenac ophthalmic suspension) 0.1% three times aday for 1 day. This non-steroidal medication was used if there weresymptoms of inflammatory response: soreness, photophobia, or signs ofinflammation; the treatment continued until the symptoms and signs resolved.Steroids, although more powerful, were avoided as the post-inflammatory responsewas desired. The patients were seen 14 times post-surgically: on the followingday, 1 week later, and after that once a month for 12 months. Themeasurements of IOP were not taken in 17 patients for a total of 47 missedfollow-up visits to the investigator’s office. Two patients were lost tothe follow-up visits after the 6-month appointment, and two dropped out afterbeing in the study for 10 months.
Results of the treatment were tabulated at each follow-up visit into two generalcategories. The first category was that of the intraocular pressure. Thepre-treatment (or baseline) IOP reading was an average of the two most recentreadings prior to the washout. These were Goldmann applanation measurements.Post-treatment readings of both eyes were obtained by the technician before theinvestigator entered the room. Post-treatment tonometry was performed in twodifferent methods. “Tonopen” (Tono-Pen XL Medtronic) measurementswere taken by well-trained technicians with at least four separate readings.These readings were then averaged. After the tonopen measurements were recorded,the technician performed Goldmann applanation tonometry. A second Goldmannapplanation tonometry was performed by the investigator. The two Goldmanreadings were then averaged with the average of the tonopen readings; therefore,the Goldman readings were weighted at 66% of the average for the single overallreported average. The Goldmann tonometer was calibrated at least once aweek.
The second category was of an analysis of the inflammatory reaction from thetreatment. This evaluation included the subjective symptoms of irritation,discomfort, and pain and an objective slit lamp evaluation for signs ofconjunctival injection and signs of anterior chamber cells and flare. Each ofthe parameters was graded on a 0 to 4 scale (minimal to maximal presence). Thesubjective symptoms were elicited by staff technicians and verified by theinvestigator and were always asked in the same manner. The slit lamp evaluationwas performed by the investigator. Each of the markers was characterized on ascale of 0 to 4 with 0 being minimally present and 4 the worst possible. Thesesubjective responses were obtained by assistants and verified by theinvestigator. The signs were observed at the same slit lamp at each visit. Theconjunctival injection was observed under low magnification in a low-light roomcondition whereas cell and flare were evaluated with high power in a darkroom.
The IOP was analyzed separately in medication-free patients, in medication-freenon-normotensive glaucoma patients, and in those who were previously onmedication.
For the nine patients, the mean age was73.3 ± 9.0 years (min = 62 years,max = 89 years). Eight patients were Caucasian and one wasAfrican-American. One patient was female and eight patients were male. Twopatients had primary open-angle glaucoma, four had normotensive glaucoma,and one had pigmentary glaucoma. In Figure 3, thegraph of an average IOP decrease from the baseline for the treatment andcontrol groups is presented. In both groups, there is an overall downwardtrend in average IOP, with the control group profile remaining above butshadowing that of the treatment group.
Medication-free non-normotensive glaucoma patients
When reviewing the findings, it became apparent that the decrease inintraocular pressure was less evident with those whose pre-treatmentpressure was below 19.5 mmHg. Thus, the analysis was redone without thefour normotensive glaucoma patients in order to obtain further perspectivein considering the treatment on patients with intraocular pressures of 20 orgreater.
For the remaining five patients, the mean age was71.8 ± 11.8 years (min = 62 years,max = 89 years). All patients were Caucasian males. Fourpatients had primary open-angle glaucoma and one had pigmentary glaucoma. Ofthese five patients, one missed two follow-up visits, and thus, the datawere unavailable in the two cases.
Example of a medication-free non-normotensive glaucoma patient
Note that the control eye exhibits a similar behavior in terms of the IOPmeasurements to the treated eye. Noteworthy is the length of this effect inboth eyes after only one treatment in one eye for this patient.
Medication washout patients
The mean age of the 17 patients was 73.1 ± 13.2 years(min = 51 years, max = 92 years). Fourteenpatients were Caucasian, one African-American, and one Hispanic. Six femalesand 11 males were treated. Eight patients had primary open-angle glaucoma,seven had normotensive glaucoma, and two had pigmentary glaucoma. Twelvepatients missed a follow-up, but came back for subsequent visits. Twopatients dropped out after being in the study for 6 months, and twodropped out after 10 months.
In this group of 17 medication washout patients, three patients had a secondTUG treatment within 1 year. Such retreatments were performed if theintraocular pressure approached the washout pressure. These retreatmentsoccurred at either the fifth or the sixth month post-initial TUG treatment.Also in this group of patients, four of the 17 had a reintroduction ofmedication. It should be noted that the washout of the medication was forboth eyes. One of the patients had a resumption of medication in the controleye, but not in the treated eye. Of the group that went back on medication,one patient used the medication for only 1 month and found themedication again led to unacceptable irritation. She then was one of thefour who had a second TUG treatment.
The baseline IOP value for these patients was an average of the IOPmeasurements for two visits prior to the medication washout period. Theeffect of the TUG treatment in the IOP reduction was compared to the IOP onthe pharmaceutical regimen.
Figure 8 shows theaverage change in IOP from the baseline after the initial TUG treatment.Where the graph is above zero, the post-TUG treatment IOP was higher, belowzero—the medication IOP was higher. Note that the two IOP measurementsdeviate very little from each other always remaining within±2 mmHg.
Figure 9 represents thesame results as in Figure 8 but in terms of theaverage percent of change in IOP from the patient’s pharmaceuticalregimen. The positive values on the graph indicate that the post-TUGtreatment IOP exceeds that of the pharmaceutical regimen.
Examples of medication washout patients
Figure 11 demonstrates an historical perspectiveof IOP measurements in both eyes across the visits for a patient in themedication washout group. This patient was among the 13 (74%) patients whoneeded only a single TUG treatment to last 1 year. In the past, he hadbeen on latanoprost which controlled his IOP to approximately 16. He had awashout of this medication. At the end of the 1-year period, he was offmedication in both eyes with an IOP around 16 mmHg. Even longerfollow-up shows his IOP to be maintained at a significant decrease frombaseline and even from pharmaceutical control.
The next graph(Figure 12) illustrates an IOP historicalperspective for a patient who was compelled to return to medication withadditive effect and later chose to have a TUG retreatment which showed anenhanced effect from the second treatment over the original. This patientwas on latanoprost and then changed to Combigan as a result of side effectsof the latanoprost. Her IOP on medication was 21 mmHg. She had a 1-weekwashout of the Combigan with a resultant IOP of 23 mmHg. Her TUGtreatment led to a decrease in IOP to 17 mmHg, but it graduallyincreased to 23 mmHg over a 5-month period of time. She was offered theoption of returning to medication. She was reintroduced to medication with asubstantial decrease to 12.5 mmHg. But she again was bothered by theside effects of Combigan and elected to have a second TUG treatment afterwashout. The second TUG treatment was performed, and after 7 monthspost-TUG #2 (1 year after TUG#1), the IOP was 15 mmHg withoutmedication.
Tolerability of the procedure
The intraocular pressure was measured at a time approximately 2 h after thetreatment to look for any possible pressure spikes. No pressure spikes werefound in the patients treated.
The tolerability of the treatment with the TUG device was evaluated at eachvisit. Patients were queried about three markers of patient symptoms:irritation, discomfort, and pain. Similarly, there were three findings which weassociated with signs of inflammatory response: conjunctival injection, anteriorchamber cells, and flare.
Irritation scores ranged between 1 and 2.5 in three patients at the 1-day visit. One week after the treatment, irritation was gone.
Discomfort was present in four patients at the 1-day visit. One had a score of 2, and three were at 1. At 1 week post-treatment, one patient was at 1, one at 1.5, and the rest were at 0. Afterwards, this symptom has disappeared.
Pain was experienced by one patient at the level of 2 at the 1-day visit. Besides this instance, pain was absent for each and every patient at each and every visit.
Injection of the conjunctiva was a frequent but short-lived finding. At the first visit, 1 day after the treatment, it was found in 24 of the 26 patients. One had a score of 3, one had a score of 2.5, and seven were at 2. There were five at 1.5, seven at 1, and the other three scored 0.5. By the 1-week visit, only eight had any such finding: two at 0.5 and six at 1. This sign was not apparent afterwards.
Cells in the aqueous humor were not observed in any of the patients at any visit.
Flare was observed in the treated eye of nine patients on the first day. In five patients, the score was 0.5, and the other four had a score of 1. At the 1-week visit, a flare score of 0.5 was measured in a single patient. In the other patients, this sign was absent.
In summary, there is a frequent finding of conjunctival injection with asubjective feeling of irritation that fades over several days. No symptom orsign reached the level of 3 at any time. The more serious symptom of pain andsign of cells in the aqueous humor were remarkable for their absence at each andevery visit including the first day (with one exception of pain on day 1).
From the graphs, the patients tolerated the procedure quite comfortably with theonly common comment of mild irritation which was consistent with a mild tomoderate conjunctival injection. These typically resolved in a few days inalmost all cases without treatment. If the patient had these findings, Nevanac(nepafenac ophthalmic suspension) was offered. Most patients declined to use themedication and stated that the discomfort did not warrant any pharmaceuticaltreatment.
The armamentarium of treatment modalities for glaucoma is increasing. At the presenttime, pharmaceutical agents are typically the first line of treatment with the useof laser seen as an adjunct method. A new method of decreasing intraocular pressureis described. This is the initial study to be reported using a low-frequency,low-power, focused ultrasound for the treatment of glaucoma.
The mechanism of action has yet to be described fully, but the design of theultrasound was with the purpose of creating a focal area of hyperthermia within theanterior chamber angle. It was felt that such an effect could trigger inflammatorycytokines analogous to the effect of SLT laser. The finding of a concurrent decreasein the intraocular pressure in the contralateral eye may support this mechanism ofaction.
We hypothesized that ultrasound energy applied externally near the limbus may have atleast three modes of action all of which could trigger a decrease in the intraocularpressure. None of these potential modes of action are mutually exclusive, and othermodes are certainly possible.
Firstly, there may be a sonomechanical, or vibratory, effect transmitted to thetrabecular meshwork, loosening debris and flushing out blockages [18–24]. Work in Sweden by Björn Svedbergh resulted in a patented devicewith the expressed concept of shaking debris to loosen trabecular meshwork blockage(Ultrasound Probe—US Patent 6162193, filing date Sep 15, 1997, issue date Dec19, 2000). This device utilized a fluid-filled chamber with a membrane for applyingnon-focused ultrasound transmission to the external eye.
A second mechanism, that of a localized hyperthermia, may trigger heat shock proteinsand potentially beneficial cytokines. This would hypothetically be similar to acytokine response evoked by laser trabeculoplasty [25–33]. Specific cytokines have been demonstrated to lower the IOP after bothargon and selective laser trabeculoplasty and have also been found to be triggeredby ultrasound of a frequency similar to that used in phacoemulsification .
A third mode of effect may be an induction of cytokines through integrins [35, 36]. These receptors absorb ultrasound energy and in turn induce cytokineactivity which may be beneficial in lowering the IOP.
Ultrasound energy applied externally to the eye has a significant advantage comparedwith many other treatment modalities in that it can be applied in a non-invasivemanner. Previous treatments to use ultrasound to treat glaucoma have been directedmore posteriorly [37–42]. Coleman et al. revealed that high-intensity focused ultrasound (HIFU)led to an ablation of the ciliary body and a subsequent thinning of the sclera. Theenergy was directed from the outside of the eye towards the ciliary body with anattempt to ablate the tissue and thereby decrease aqueous production. Thishigh-powered ultrasound had an additional effect in leading to a thinning of thesclera overlying the ciliary body. The use of this ultrasound model was forintransigent glaucoma, and its use fell from favor with the advent of other superiortreatment methods. Recently, another group (EyeTechCare of Lyon, France) hasreported an ultrasound device, “EyeOP1”, used to coagulate the ciliaryepithelium. This device uses a single-treatment strategy with a circular tip with amultiple port array. These ports focus high-intensity ultrasound into the ciliarybody to decrease aqueous inflow in patients with refractory glaucoma .
In a single-center pilot study of a novel glaucoma treatment technique (TUG), wefound a significant decrease in intraocular pressure. The effect on intraocularpressure in the “naïve” group was significant with an averagedecrease in the total group of almost 20% and almost 25% when not including thenormotensive glaucoma patients. The effect of the treatment appeared to be moresignificant in the higher baseline intraocular pressures. In over 74%, the effectlasted for 1 year. A second treatment was offered if the IOP rose to baseline.Subsequent TUG treatments typically lasted far longer than the first treatment(beyond the 1 year reported in this study).
In those subjects washed out of their pharmaceutical glaucoma medication, theintraocular pressure measurements after the TUG treatment were equal (within 10%) toor even better (70% of the visits) than their pharmaceutical control for the year ofthe study.
The subjects tolerated the procedure well with only minimal discomfort noted on thefirst day post-treatment. There was typically a symptom of only a mild feeling ofirritation and a slit lamp finding of mild to moderate conjunctival hyperemia.
A method to treat glaucoma which reduces the issues of pharmaceutical compliance,allergy, and side effects and has the potential for portability could be asignificant contribution. It has even more potential for areas of the third worldwhere glaucoma is more prevalent and treatment with medication and/or surgery isunavailable. An updated prototype weighing less than 5 lbs with the samecharacteristics as that used for this study has now been produced and is in earlymulticenter clinical trials.
This is a report of a first-in-human trial of a low-power, low-frequency ultrasoundinstrument to treat open-angle glaucoma. The findings are supportive of awell-tolerated procedure with a significant decrease in intraocular pressure.Further studies are needed for validation.
laser selective lasertherapy
therapeutic ultrasound for glaucoma.
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