The Strabismus Research Foundation (SRF) is a 501(c)(3) non-profit operating foundation dedicated to translational research in ocular motility.
||Taliva D Martin, MD
Pediatric ophthalmologist at California Pacific Medical Center.
||Iara Debert, MD, PhD
Clinical Fellow at SRF.
Research Fellow at Eidactics.
Attending Ophthalmologist at Hospital das Clinicas, Univ of São Paulo (2012-present).
Recent Journal Club Presentations
- Akhtar N, Cunha TM (2017). Bupivacaine Injection:Histological changes in Extraocular muscles. SRF (PDF).
- Miller JM (2017). Explanatory & pragmatic research. Eidactics (PDF).
- Miller JM (2017). Non-inferiority testing. Eidactics (PDF).
Presentations at the USP Ophthalmology Congress
- Miller JM (2016). The Orbit™ Gaze Mechanics Simulation. Eidactics (PDF).
- Miller JM, Debert I (2016). History of Botulinum Toxin Therapy. SRF (PDF).
- Miller JM, Scott AB, Debert I (2016). Bupivacaine Injection Treatment Of Strabismus. SRF (PDF).
Pharmacologic Treatment of Strabismus
Strabismus is mostly treated surgically by compensatory impairment of healthy muscles, rather than by correcting the underlying disorder. We have therefore long been interested in pharmacologic injection treatments to supplement or provide alternatives to surgery. Oculinum® (now called Botox®) was originally developed in our lab to relax and lengthen short eye muscles (Scott 1980). We’ve now turned our attention to the opposite problem: in a recently completed NIH project, we treated 45 volunteer patients with bupivacaine (BPX), demonstrating the first practical method for strengthening weak eye muscles, causing them to shorten and correct eye misalignments (eg, Miller, Scott, et al 2013). BPX is a selective myotoxin with effects similar to mechanical overloading – myofiber damage or destruction followed by rapid repair or regeneration – which we are learning to harness. We have demonstrated the clinical effectiveness of BPX injection in comitant adult strabismus, and are now developing injection techniques suitable for children. BPX injection may also have clinical applications in other small muscles.
Here are two concise introductions to this work, originally created for Wikipedia®. In the first, we discuss the relationships of pharmacologic to surgical treatments, drugs that weaken and strengthen muscles, injection techniques for cooperative adults and for children, and clinical indications. In the second, we review the history surrounding the first medical application of botulinum toxin, which was strabismus, for which it was also the first pharmacologic treatment. So dauntingly counterintuitive was the notion of injecting this most toxic substance without visual guidance alongside the healthy eye of an alert patient that its safe and efficacious development, and the many subsequent applications it led to, make a fascinating story.
Bupivacaine dissociates sarcomeres (a muscle's contractile elements), triggering satellite cells (a kind of natural adult stem cell) to rebuild the destroyed fibers, stronger, stiffer, and at reduced length, particularly if its antagonist is temporarily weakened with a small dose of botulinum toxin. In our most recent study, more than 100 volunteer strabismus patients received BPX injection treatments, optionally with epinephrine to increase exposure to the drug. Most also received botulinum toxin in the antagonist muscle to prevent stretching while the BPX-injected muscle rebuilt. Fifty-five of these patients satisfied criteria for inclusion in a study of comitant horizontal strabismus. Clinical alignment was measured at 6 mo, 1 yr, 2 yrs, 3 yrs, 4 yrs, and 5 yrs after treatment, as possible, with mean followup of 29 mo.
- Debert I, Miller JM (2015). Pharmacologic Treatment of Strabismus. Eidactics (PDF).
- Debert I, Miller JM (2015). History of Botulinum Toxin Therapy. Eidactics (PDF).
Results support and extend findings previously reported (Scott, Alexander et al. 2007, Scott, Miller et al. 2009, Miller, Scott et al. 2013). On average, initial misalignments of 23.8∆ (13.4°) were reduced at 29 mo by 15.3∆ (8.7°) with residual deviations ≤10∆ in 60% of patients. For patients with initial misalignment larger than 25∆, pharmacological treatment correction averaged 21.1∆ (11.9°). Alignment corrections were stable over followups as long as 5 yrs.
Each curve in the graph shows alignment data for a cohort of patients who all returned for the same followup measurements, so individual lines are unaffected by patients leaving the study. 74% of initial misalignments were corrected at 6 mo after treatment. It can be seen that alignment regressed slightly over the next 1.5 years, and were stable at clinically significant levels thereafter. Most patients enjoyed successful treatment by the conventional criterion of residual deviation ≤10∆. Dosage guidelines are shown in the table. In summary, injection treatments effect stable, clinically significant corrections in comitant horizontal strabismus, providing a safe, low-cost alternative to conventional strabismus surgery, particularly where it is desirable to minimize surgical anesthesia and avoid extraocular scarring.
Thus far, all BPX injections have been given to alert, cooperative adults using EMG guidance. However, because most strabismus patients are children in whom injection would require brief anesthesia, we are investigating targeting by electrical stimulation. Preliminary studies have shown that low-current square-wave pulses at 150-200 Hz elicit eye movements suitable to indicate correct placement of an injection needle.
- Debert I, Miller JM, Danh KK, Scott AB (2015). Pharmacologic Injection Treatment of Comitant Strabismus. Journal of AAPOS, vol 20, pgs 106-111. (Authors' Cut PDF; Publisher's site).
- Scott AB, Miller JM (2014). Extraocular Muscle (EOM) Responses to Bupivacaine (BPX) Injection, Grant 1R01EY018633, Final Progress Report 1 Sep 2009 – 31 Aug 2014. (Report PDF)
|| Accurate Injection of Eye Muscles in Children (Knights Templar Eye Foundation • Taliva D Martin, MD & Alan B Scott, MD)
Early treatment of infantile strabismus facilitates normal development of stereopsis (depth perception from binocular vision), prevents amblyopia (suppression of vision in one eye), and improves cosmesis. But surgical correction in young children is problematic:  additional surgery is often necessary, and is made more difficult by scarring from the initial surgery; it would be better if non-surgical treatment were used, at least initially, and  strabismus surgery requires prolonged general anesthesia, which may cause cognitive deficits in a developing brain (eg, Rappaport et al 2015).
Botulinum toxin A (BTXA) injection treatment of extraocular muscles (EOMs) is an effective and widely-accepted alternative to conventional surgical treatment of esotropia. Because EOMs lie deep in the orbit, a technique is needed to accurately place the injection needle within the target muscle. In awake, cooperative adults, electromyography (EMG) signals are recorded from the tip of the injection needle, which is advanced until the relationship of the EMG signal to the patient’s voluntary eye movement indicates desired placement. But most strabismus patients are children, who must be briefly anesthetized to accept injection treatment, and anesthetized muscles show little or no movement-related electrical activity. Injection treatment in children is therefore currently performed without EMG guidance, and so, cannot target the deeper neuromuscular junctions, resulting in reduced treatment effect and increased unwanted effects on adjacent muscles. Although no useful EMG signal can be recorded, an anesthetized muscle can be readily stimulated. We have determined from animal studies (funded by The Pacific Vision Foundation) that brief trains of negative, 0.5-5.0 mA, 1 ms square-wave pulses at 150-200 Hz produce eye movements characteristic of optimal needle placement. We now propose to develop a suitable stimulating device, and evaluate its effectiveness on young strabismus patients in improving efficacy and reducing side effects of EOM injection treatment. Stimulation-guided injection is expected to be similarly useful in extending to children other pharmacologic injection treatments now under development.
We thank the Knights Templar Eye Foundation for supporting this clinically significant work in its early stages. In the photo, Bud Ramsey, Past Grand Commander, tours SRF's labs and presents the check to Drs Martin & Scott.
||Reanimating Paralyzed Eye Muscles
Blepharospasm sufferers may be functionally blind despite having normal eyes, because of spasms in surrounding facial muscles and inability raise their eyelids. The cause is unknown, and may be present from birth or develop later. Botox injection can relieve the spasms but leave patients unable to open their eyes or keep them open. Functional electrical stimulation (FES) of the muscle that raises the eyelid (the levator palpebrae superioris or LPS), could provide these patients with useful vision. Surgical lid elevation is the current treatment, but static repositioning makes normal eye blinking and lid closure problematic. Programmable, coordinated, binocular elevation by FES would be far superior, both functionally and cosmetically.
Similarly, patients suffering from paretic strabismus (misaligned eyes or gaze limitations caused by weak or paralyzed muscles) could be rehabilitated with FES of the extraocular muscles (EOMs). The signal for controlling stimulation of a paretic EOM could be derived from the intact innervation of its antagonist (the opposing muscle in the same eye), with which it normally has a reciprocal relationship. Implantable pulse generators (IPGs), already approved for other applications, are suitable to connect directly to electrodes we have developed for implantation on EOM and LPS.
Our aim is to reduce FES of eye muscles to clinical practice. The focus of our work is development of electrodes that are both safe and effective, tested in animals with realistic stimulation regimens. As we develop stimulation parameters, we will refine simultaneity of binocular stimulation and coordination of reciprocal stimulation, and will evaluate tissue tolerance and electrode durability. With these results in hand, we will be in a position to design clinical trials. We’ve already produced useful lid elevation in rabbits as long as a year following implantation, with no evidence of tissue damage. We’ve designed a new electrode for improved reliability, and will also test capacitive electrodes, which may provide even gentler stimulation.
In Jan 2013 we relocated our labs to San Francisco's landmark Medical Arts Building. These new facilities are configured for micro-device development and fabrication, histological and MRI image analysis, and project management.
Our clinical studies are now conducted in collaboration with Eidactics, at California Pacific Medical Center under supervision of their IRB, and our physiological studies are conducted with Eidactics at Bay Area CROs under supervision of their IACUCs.