Longitudinal Studies and Eye-Movement-Based Treatments of Infantile Nystagmus Syndrome: Estimated and Measured Therapeutic Improvements in Three Complex Cases.

INTRODUCTION AND PURPOSE: To demonstrate the utility of using eye-movement data to reveal the diagnostic characteristics of infantile nystagmus syndrome (INS), determine treatment, and both estimate and document therapeutic improvements in three patients with well-developed foveation periods, fairly broad, lateral gaze "nulls," head turns, strabismus, and complex, multiplanar nystagmus. PATIENTS AND METHODS: Infrared reflection, magnetic search coil, and high-speed digital video systems were used to record the eye movements of INS patients, pre- and post-Kestenbaum null-point correction surgery (horizontal or vertical). Data were analyzed and estimations made, using the eXpanded Nystagmus Acuity Function (NAFX) that is part of the OMtools toolbox for MATLAB. RESULTS: In all three subjects (S1-S3), both peak NAFX and longest foveation domain (LFD) improved from their pre-Kestenbaum values. S1: 0.700-0.745 (6.4%) and 25-34° (36%), respectively. S2: 0.445-0.633 (42.4%) and >40° to >50° (10%), respectively. S3: 0.250-0.300 (20%) and 13° to ≫18° (see text), respectively. CONCLUSIONS: S1: Even at the high ends of the pre-therapy NAFX and LFD spectra, INS foveation (and therefore, visual-function) improvements may be adequate to justify nystagmus surgery and provide clinical improvements beneficial to the patient. S2: INS foveation improvements in the vertical plane are equal to those originally estimated using the horizontal data in prior patients. S3: Two apparent NAFX peaks can be converted into a very broad peak by surgery based on the preferred lower peak.

Clinical and ocular motor complications of extraocular muscle extirpation for infantile nystagmus syndrome.

PURPOSE: To describe the effects of extraocular muscle extirpation performed after previous eye muscle surgery in a 20-year-old woman with infantile nystagmus syndrome (INS) for whom we have 19 years of follow-up data. METHODS: Clinical examinations were performed. Eye movement data analysis was carried out using the eXpanded Nystagmus Acuity Function (NAFX) and longest foveation domain (LFD). RESULTS: The patient re-presented to the authors at age 20, 2 years after bilateral anterior myectomy of the horizontal rectus muscles, bilateral anterior nasal transposition of the inferior oblique muscle, and bilateral superior oblique recessions. Evaluation revealed deterioration in nystagmus at lateral gaze angles, new incomitant strabismus with severe loss of convergence, limited ductions, saccadic hypometria, slow saccades, and hypo-accommodation. Also, there was a pre- to post-extirpation minimal change of 21% in her peak NAFX, a 50% decrease in LFD, plus a predominant, asymmetric, multiplanar oscillation. CONCLUSIONS: It appears that in this patient, horizontal extirpation failed to abolish the nystagmus and caused significant, new, symptomatic deficits interfering with many of the patient's visual functions.

Effects of augmented tenotomy and reattachment in the infantile nystagmus syndrome.

PURPOSE: To test the hypothesis that augmented tenotomy and reattachment surgery (AT-R), which involves placing an additional suture in each distal tendon during the 4-muscle tenotomy and reattachment (T-R) or other infantile nystagmus syndrome (INS) procedures, could increase the beneficial effects of many types of extraocular muscle (EOM) surgery to treat INS. METHODS: Both infrared reflection and high-speed digital video systems were used to record the eye movements in 4 patients with INS before and after AT-R surgery. Data were analyzed using the eXpanded Nystagmus Acuity Function (NAFX) that is part of the OMtools software. RESULTS: Placement of the augmentation suture did not interfere with Kestenbaum, Anderson, bilateral medial rectus muscle recession, or T-R surgeries. The therapeutic effects of AT-R were similar to but not equal to those from the traditional single-suture surgeries (ie, broadening longest foveation domain [LFD] but no improvement of NAFX peak). The average of the NAFX percent improvements after AT-R was within 31% of those estimated from NAFX values before T-R; the average of the percent broadenings of the LFD values after AT-R was within 16%. CONCLUSIONS: The AT-R does not improve the foveation quality in INS above the traditional T-R surgery. It is not improved by an additional suture; indeed, some improvements may be diminished by the added suture. The hypothesized augmented-tendon suture technique (sans tenotomy) has been modified and remains to be tested.

Fusion maldevelopment (latent/manifest latent) nystagmus syndrome: effects of four-muscle tenotomy and reattachment.

PURPOSE: To examine the waveform and clinical effects of the four-muscle tenotomy and reattachment procedure in fusion maldevelopment nystagmus syndrome (FMNS) and to compare them to those documented in infantile nystagmus syndrome (INS) and acquired nystagmus. METHODS: Both infrared reflection and high-speed digital video systems were used to record the eye movements in a patient with FMNS (before and after tenotomy and reattachment). Data were analyzed using the eXpanded Nystagmus Acuity Function (NAFX) that is part of the OMtools software. Model simulations and predictions were performed using the authors' behavioral ocular motor system model in MATLAB Simulink (The MathWorks, Inc., Natick, MA). RESULTS: The model predicted, and the patient's data confirmed, that the tenotomy and reattachment procedure produces improvements in FMN waveforms across a broader field of gaze and decreases the Alexander's law variation. The patient's tenotomy and reattachment plots of NAFX after surgery versus gaze angle were higher and had lower slope than before surgery. Clinically, despite moderate improvements in both peak measured acuity and stereoacuity, dramatic improvements in the patient's abilities and lifestyle resulted. CONCLUSIONS: The four-muscle tenotomy and reattachment nystagmus surgery produced beneficial therapeutic effects on FMN waveforms that are similar to those demonstrated in INS and acquired nystagmus. These results support the authors' prior recommendation that tenotomy and reattachment nystagmus should be added to required strabismus procedures in patients who also have FMNS (ie, perform tenotomy and reattachment on all unoperated muscles in the plane of the nystagmus). Furthermore, when strabismus surgery is not required, four-muscle tenotomy and reattachment may be used to improve FMN waveforms and visual function.

Effects of topical brinzolamide on infantile nystagmus syndrome waveforms: eyedrops for nystagmus.

BACKGROUND: Recent advances in infantile nystagmus syndrome (INS) surgery have uncovered the therapeutic importance of proprioception. In this report, we test the hypothesis that the topical carbonic anhydrase inhibitor (CAI) brinzolamide (Azopt) has beneficial effects on measures of nystagmus foveation quality in a subject with INS. METHODS: Eye movement data were taken, using a high-speed digital video recording system, before and after 3 days of the application of topical brinzolamide 3 times daily in each eye. Nystagmus waveforms were analyzed by applying the eXpanded Nystagmus Acuity Function (NAFX) at different gaze angles and determining the longest foveation domain (LFD) and compared to previously published data from the same subject after the use of a systemic CAI, contact lenses, and convergence and to other subjects before and after eye muscle surgery for INS. RESULTS: Topical brinzolamide improved foveation by both a 51.9% increase in the peak value of the NAFX function (from 0.395 to 0.600) and a 50% broadening of the NAFX vs Gaze Angle curve (the LFD increased from 20° to 30°). The improvements in NAFX after topical brinzolamide were equivalent to systemic acetazolamide or eye muscle surgery and were intermediate between those of soft contact lenses or convergence. Topical brinzolamide and contact lenses had equivalent LFD improvements and were less effective than convergence. CONCLUSIONS: In this subject with INS, topical brinzolamide resulted in improved-foveation INS waveforms over a broadened range of gaze angles. Its therapeutic effects were equivalent to systemic CAI. Although a prospective clinical trial is needed to prove efficacy or effectiveness in other subjects, an eyedrops-based therapy for INS may emerge as a viable addition to optical, surgical, behavioral, and systemic drug therapies.

Using the NAFX to measure the effectiveness over time of gene therapy in canine LCA.

PURPOSE: To use ocular motility recordings to determine the changes over time of infantile nystagmus syndrome (INS) in RPE65-deficient canines with Leber Congenital Amaurosis (LCA) and assess the time course of the recalibration of the ocular motor system (OMS). METHODS: Nine dogs were treated bilaterally with AAV-RPE65. A second cohort of four dogs was treated with AAV2.RPE65, an optimized vector. Their fixation eye movements were recorded before treatment and at 4-week intervals for 3 months, by using high-speed (500 Hz) digital videography. The dogs were suspended in a sling and encouraged to fixate on distant (57 inches) targets at gaze angles varying between +/-15 degrees horizontally and +/-10 degrees vertically. The records for each eye were examined for qualitative changes in waveform and for quantitative changes in centralisation with the expanded nystagmus acuity function (NAFX) and compared with ERG results for restoration of receptor function. RESULTS: First group: Before treatment, five of the dogs had clinically apparent INS with jerk, pendular, or both waveforms and with peak-to-peak amplitudes as great as 15 degrees . One dog had intermittent nystagmus. At the 1- and 2-month examinations, no change in nystagmus waveform or NAFX was observed in any of the initial dogs, while at 10 weeks, one dog treated bilaterally with the standard dosage showed reduced nystagmus in only one eye. The other eye did not respond to treatment, as confirmed by ERG. This result was unexpected since it was previously documented that unilateral treatment leads to bilateral reduction of INS. The other dog treated with the standard dosage showed no reduction of its small-amplitude, high-frequency pendular nystagmus despite positive ERG responses. Second group: Only one dog of the four had clinically detectable INS, similar in characteristics to that seen in the affected dogs of the first group. Unlike any previous dog studied, this one showed a damping of the nystagmus within the first 4 weeks after treatment. CONCLUSIONS: In all but one of the cases in which OMS recalibration occurred, as measured by the clinical appearance of nystagmus and by quantitative measurement using the NAFX, the improvement was apparent no sooner than 10 weeks after treatment. Longer term, dose-related studies are needed to determine the minimum necessary degree of restored receptor functionality, the duration after rescue for recalibration of the OMS, and the conditions under which recalibration information can successfully affect the contralateral eye.

Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer.

We evaluated the safety and efficacy of an optimized adeno-associated virus (AAV; AAV2.RPE65) in animal models of the RPE65 form of Leber congenital amaurosis (LCA). Protein expression was optimized by addition of a modified Kozak sequence at the translational start site of hRPE65. Modifications in AAV production and delivery included use of a long stuffer sequence to prevent reverse packaging from the AAV inverted-terminal repeats, and co-injection with a surfactant. The latter allows consistent and predictable delivery of a given dose of vector. We observed improved electroretinograms (ERGs) and visual acuity in Rpe65 mutant mice. This has not been reported previously using AAV2 vectors. Subretinal delivery of 8.25 x 10(10) vector genomes in affected dogs was well tolerated both locally and systemically, and treated animals showed improved visual behavior and pupillary responses, and reduced nystagmus within 2 weeks of injection. ERG responses confirmed the reversal of visual deficit. Immunohistochemistry confirmed transduction of retinal pigment epithelium cells and there was minimal toxicity to the retina as judged by histopathologic analysis. The data demonstrate that AAV2.RPE65 delivers the RPE65 transgene efficiently and quickly to the appropriate target cells in vivo in animal models. This vector holds great promise for treatment of LCA due to RPE65 mutations.

Combined gaze-angle and vergence variation in infantile nystagmus: two therapies that improve the high-visual-acuity field and methods to measure it.

PURPOSE: To investigate the convergence-induced waveform and high-acuity-field improvements resulting from different therapies in two subjects with infantile nystagmus (IN) that was damped by convergence and to report a new finding in one of the subjects. METHODS: Infrared reflection was used to measure eye movements during fixation of targets at different gaze and convergence angles and the expanded nystagmus acuity function (NAFX) to evaluate the IN waveform's foveation quality at all fixation points. RESULTS: Recordings demonstrated that, at far, both subjects exhibited classic nulls (high NAFX values) with NAFX reduction at gaze angles lateral to the null. S1 was treated with prisms and S2 with surgery. When converged at near or at far with base-out prisms (S1) or after bimedial recession and bilateral tenotomy surgery (S2), NAFX was higher at both the null and lateral gaze angles; the null region was broadened. The longest foveation domain (gaze angles where the NAFX is within 10% of its peak) at near was three times wider than at far for S1 and two times wider after than before surgery for S2. The therapeutic improvement domain (gaze angles where the posttherapy NAFX is higher than pretherapy) was even broader. At fixed gaze angles in the central 20 degrees of gaze, S1's NAFX variation with vergence exhibited hysteresis, higher during divergence than convergence; S2 exhibited no hysteresis after surgery. CONCLUSIONS: Damping IN by means of convergence, induced either surgically or with prisms, broadened the range of gaze angles with higher foveation quality, mimicking the null-broadening effects of tenotomy. The discovery of vergence hysteresis may reflect pulley movement and might allow higher acuity, if a near point is transiently fixated just before a far target. The acuity domains provide new and more comprehensive evaluations of both pre- and posttherapy visual function than do primary-position acuity measurements, suggesting that high-visual-acuity fields should be included in clinical measures of visual function in nystagmus.