A New Clinical Method for Visual Function Evaluation Including Estimation and Measurement of Therapeutic Effectiveness: Lessons From Infantile Nystagmus Research.

PURPOSE: To translate infantile nystagmus system (INS) research into easily understood, clinically relevant terminology and suggest modifications to research and clinical testing, data and clinical interpretation, and therapeutic choices and evaluation. METHODS: A clinical method is presented using only three best-corrected visual acuity measurements of patients with INS, whereby (1) a measure of the quality of visual acuity across the visual field is possible; (2) pre-therapy estimates of post-therapy improvements in peak acuity and the high-acuity range of gaze angles are possible; and (3) more realistic visual function outcome measures of therapy are available to the practitioner. RESULTS: The application of the high-acuity field quality spreadsheet to the analyses of patients with INS (before and after therapy) results in a quantitative measure of visual function based on three visual acuity measurements. CONCLUSIONS: The clinician can now duplicate adequate functional visual acuity descriptions in patients with INS along with their pre-therapy estimates and outcome measures. Previously, these have only been available to researchers or the rare clinicians who have access to both eye movement data and the expanded nystagmus acuity function analysis of INS waveforms. [J Pediatr Ophthalmol Strabismus. 2021;58(3):188-195.].

Two Electrical Engineers, One Problem, and Evolution Produced the Same Solution: A Historical Note.

This note adds historical context into solving the problem of improving the speed of the step response of a low-order plant in two different types of control systems, a chemical mixing system and the human saccadic system. Two electrical engineers studied the above problem: one to understand and model how nature and evolution solved it and the other to design a control system to solve it in a man-made commercial system. David A. Robinson discovered that fast and accurate saccades were produced by a pulse-step of neural innervation applied to the extraocular plant. Leonidas M. Mantgiaris invented a method to achieve rapid and accurate chemical mixing by applying a large stimulus for a short period of time and then replacing it with the desired steady-state value (i.e., a "pulse-step" input). Thus, two humans used their brains to: 1) determine how the human brain produced human saccades; and 2) invent a control-system method to produce fast and accurate chemical mixing. That the second person came up with the same method by which his own brain was making saccades may shed light on the question of whether the human brain can fully understand itself.

Topical lambda-cyhalothrin in reducing eye oscillations in a canine model of infantile nystagmus syndrome.

PURPOSE: To determine the ocular and systemic safety of using topical Lambda-Cyhalothrin (LCL) in a canine model of infantile nystagmus syndrome (INS). The rationale for this proposal is based on a case study of a patient whose INS improved after inadvertent ocular exposure to a pyrethroid pesticide containing LCL. METHODS: After in-vitro safety testing and IUCAC approval, we studied increasing concentrations of topical LCL drops (0.002% to 0.07%) in canines with a purposely bred defect in the RPE65 gene resulting in both retinal degeneration and INS. We collected data on ocular and systemic effects and performed eye-movement recordings (EMR). RESULTS: At the 0.07% concentration dose of LCL, there was minimal, reversible, conjunctival hyperemia. There was no other ocular or systemic toxicity. At the 0.06% dose, there was a visible decrease in the INS and EMR showed a 153%-240% increase in the nystagmus acuity function and a 30%-70% decrease in amplitude across gaze. There was also a 40%-60% decrease in intraocular pressure while on the drop in both eyes. CONCLUSION: This animal study suggests this new pharmacological agent has potential for topical treatment of both INS and diseases with raised intraocular pressure. Further, this new treatment approach confirms the importance of extraocular muscle proprioception in ocular motor diseases and their treatment.

Foveation dynamics in congenital nystagmus IV: vergence.

PURPOSE: To evaluate foveation dynamics and characteristics of vergence eye movements during fixation of static targets at different distances and while tracking a target moving in depth in a subject with congenital nystagmus (CN). METHOD: Eye movements of a well-studied subject with CN were recorded using the magnetic search coil technique and analyzed using the OMtools software, including the eXpanded Nystagmus Acuity Function (NAFX). RESULTS: Both the phase planes and NAFX values during fixation of targets at various near distances were equivalent to those during fixation of a far target. When applied to vergence data, the NAFX values ("binocular" NAFX) were higher than for the individual eye data. Vergence tracking of targets moving in depth was demonstrated and was accurate for targets moving at speeds up to ~ 35°/sec. CONCLUSIONS: Target foveation qualities during fixation of targets at various near distances were equivalent to that during fixation of a far target. Stereo discrimination was limited by the foveation quality of the eye with the higher NAFX waveform. Foveation period slopes during vergence tracking demonstrated vergence movements despite the ongoing CN oscillation. Similar to what we found with fixation, pursuit, and the vestibulo-ocular systems, these findings establish that vergence in both static and dynamic viewing conditions functions normally in the presence of the CN oscillation.

Ocular Motor System Control Models and the Cerebellum: Hypothetical Mechanisms.

To review our studies and "top-down" models of saccadic intrusions and infantile nystagmus syndrome with the aim of hypothesizing areas of cerebellar connections controlling parts of the ocular motor subsystems involved in both types of function and dysfunction. The methods of eye-movement recording and modeling are described in detail in the cited references. Saccadic intrusions, such as square-wave jerks and square-wave oscillations, can be simulated by a single malfunction, whereas staircase saccadic intrusions required two independent malfunctions. The major infantile nystagmus syndrome waveforms are traceable to a failure to calibrate the damping ratio of the smooth pursuit system. The use of a behavioral ocular motor system model demonstrated how putative cerebellar dysfunctions could accurately simulate both the oscillations and the ocular motor responses seen in patients with both saccadic and pursuit disorders.

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.

Development and surgical removal of an epiretinal membrane in infantile nystagmus syndrome: a new type of oscillopsia.

PURPOSE: To report and discuss a focal oscillopsia in a small area of the visual field produced by, and after the removal of, an epiretinal membrane (ERM) in an individual with infantile nystagmus syndrome (INS) since birth with no associated afferent visual deficits. STUDY DESIGN: A retrospective case report. METHODS: A chart review, including clinical and electrophysiological data. A 74 y/o man with INS and an epiretinal membrane was studied. Detailed studies of the retina post-removal of an epiretinal membrane, with consequent changes in best-corrected visual acuity (BCVA), and subjective oscillopsia compared to INS waveforms. OCT measurements and eye-movement data from digital video and scleral search-coil systems were used. RESULTS: The monocular ERM produced an unexpected focal area of torsional/vertical oscillopsia (noted 1 year prior to the ERM surgery) in the portion of the visual field that corresponded with distortions from the ERM. The remainder of the visual field, corresponding with normal healthy retina was unaffected and stable in all planes. Post-removal, BCVA improved with redevelopment of the foveal pit and focal oscillopsia became less noticeable but remained due to the retinal distortion. CONCLUSIONS: In patients with INS, complete oscillopsia suppression across the visual field requires undistorted vision. If a retinal area of visual distortion develops or results from retinal surgery, a symptomatic island of oscillopsia in one or more planes may result.

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.

A unifying neurologic mechanism for infantile nystagmus.

Lateral-eyed afoveate animals use the subcortical accessory optic system to generate accurate responses to full-field optokinetic input. When humans rotate their eyes to pursue a moving target, the visual world sweeps across their retinas, creating a contraversive optokinetic stimulus. Humans have developed a cortical foveal pursuit system that suppresses the perception of this full-field optokinetic motion during active pursuit. When foveal vision is slow to develop in infancy, this phylogenetically old optokinetic system, which is normally operative in the first 2 months of human life, continues to be ontogenetically expressed. Hypothetically, the incursion on cortical pursuit of the antagonistic motion stimulus from this subcortical optokinetic system facilitates development of the unstable oscillatory activity of the eyes that characterizes infantile nystagmus.

Smooth-pursuit changes after the tenotomy and reattachment procedure for infantile nystagmus syndrome: model predictions and patient data.

PURPOSE: Patients with infantile nystagmus syndrome (INS) often cannot quickly locate new visual targets or track moving objects. Dynamic demands on visual function are not measured by static measures (eg, visual acuity); they require time-sensitive measures. The authors investigated how dynamic properties of INS (pursuit-target acquisition times) were affected by the tenotomy and reattachment (T&R) procedure in both patients with INS and behavioral ocular motor system model predictions. METHODS: Responses of 3 patients with different INS waveforms were compared before and after T&R to test the model's predictions. A high-speed digital video system was used to take eye-movement data. Human responses to target-ramp stimuli were analyzed. RESULTS: T&R did not improve the smooth-pursuit responses of patients with INS; pursuit-target acquisition times did not show marked improvements. However, in one case, T&R allowed the patient to pursue targets "faster" in a specific direction. CONCLUSION: T&R can improve peak visual acuity, broaden the high-acuity gaze-angle range, and reduce target acquisition times to static targets but not moving targets. When the target moves simultaneously with an ongoing saccade in the nystagmus cycle, the steady-state errors and elongated target acquisition times observed might be part of the intrinsic characteristics of normal pursuit responses.

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.

Two hypothetical nystagmus procedures: augmented tenotomy and reattachment and augmented tendon suture (Sans tenotomy).

PURPOSE: To review the hypothetical mechanism and therapeutic benefits of the four-muscle tenotomy and reattachment (T&R) procedure using knowledge accrued over the 10 years since its proposal; to describe an augmented tendon suture (ATS) technique to improve the procedure based on one of the originally suggested alternative methods (mechanical); and to hypothesize a new ATS procedure to achieve the same therapeutic benefits without extraocular muscle tenotomy or reattachment to the globe. METHODS: Standard surgical methods were used. RESULTS: The T&R procedure damps and improves infantile nystagmus syndrome (INS) waveforms, improves eXtended Nystagmus Acuity Function (NAFX) values, broadens the NAFX peak versus gaze angle, and damps slow eye movements but not saccades. The T&R procedure also damps acquired pendular and downbeat nystagmus, decreasing the patients' oscillopsia, and lowers the target acquisition time in INS. CONCLUSION: The T&R procedure directly affects only the enthesis of the tendon; there is idiosyncratic variation in the distribution of afferent fibers in the tendons. The ATS technique consists of placing several additional sutures in the tendon proximal to the tenotomy. Based on the hypothetical proprioceptive mechanism for the beneficial effects of the T&R procedure, the authors hypothesize that the ATS technique will maximize the therapeutic benefits and that an ATS procedure, using only tendon sutures without tenotomy, will duplicate the therapeutic effects of T&R. Eliminating the tenotomy component results in a simpler procedure more suitable for single-session, multi-muscle surgery that may be required for improving the waveforms of multiplanar nystagmus and less prone to cause complications.

Eye-movement-based assessment of visual function in patients with infantile nystagmus syndrome.

PURPOSE: Infantile Nystagmus Syndrome (INS) is an ocular motor system dysfunction characterized by the rhythmic to-and-fro oscillations of the eyes. Traditionally, the assessment of INS visual function solely focused on null- or primary-position visual acuity. Our purpose is to use the past four decades of INS research to introduce a more complete assessment of visual function in patients with INS. METHODS: All eye-movement data were obtained using high-speed digital video, infrared reflection, or scleral search coil systems. RESULTS: We have introduced four important aspects of a more complete INS visual function assessment: the eXpanded Nystagmus Acuity Function and visual acuity measurements in primary position; broadness of the eXpanded Nystagmus Acuity Function peak and high-acuity field; target acquisition time; and gaze-maintenance capability. CONCLUSIONS: Visual function in patients with INS is multifactorial and the simple assessment of primary position visual acuity is both inadequate and may not be the most important characteristic in overall visual function. A more complete visual function assessment should also include primary and lateral gaze eye-movement and visual acuity examinations, target acquisition time and gaze holding.