Ординатура / Офтальмология / Английские материалы / Advances in Understanding Mechanisms and Treatment of Infantile Forms of Nystagmus_Leigh, Devereaux_2008

and, if possible, a predictive measure of the medical goals of improved primary-position acuity and improved visual function. As Figure 11.2 shows, the electroretinogram, pupillary light reflex, and visual evoked potential are the most direct measures for afferent therapies. Each is predictive of visual acuity, which is determined slightly upstream, albeit requiring higher cortical function. In animal studies, where visual acuity is not easily measured, the NAFX provides an easily obtainable, in vivo measure of gene therapy’s effectiveness by measuring nystagmus waveform improvements. Although an indirect measure of afferent therapy, the NAFX predicts potential acuity. For central and peripheral therapies, the best and least invasive direct measure is the NAFX; the electromyogram is both invasive and not easily related to visual acuity. Because the NAFX both predicts acuity improvements and measures increases in the range of gaze angles over which those improvements are present, it was chosen as the primary outcome measure of the effectiveness of tenotomy36,37 and in two masked clinical trials of tenotomy for INS in adults38 and children.39 In many patients with INS, increasing the effective high-acuity visual field does more to improve visual function than increasing Snellen acuity in one small region of the visual field—unfortunately, this is neither appreciated nor measured in the physician’s office. It does explain why a given therapy may result in a patient reporting that he can “see better” even when the preand post-therapeutic primary-position Snellen acuities are essentially equal.

As Figure 11.2 illustrates, peripheral surgical therapy acts at the muscle to damp the resulting nystagmus; it does not change the brainstem nystagmus signal itself. Also, it is equally effective in damping both infantile and acquired nystagmus (the muscle cannot determine the origin of the nystagmus signal). Central pharmacological therapy is administered to damp the brainstem nystagmus signal. Because of their independence, if both central and peripheral therapies are applied together (in either order), the result will be the multiplicative damping from both therapies. This type of “dual-mode” therapy has been shown to maximally damp the nystagmus and maximally improve visual function.43

We have shown, for the first time and with the use of eye movement data and the NAFX analyses, that we can accurately determine a priori whether the patient has INS or some other form of nystagmus, whether surgery will improve visual function enough to justify it, what surgery is best for each patient, how much visual acuity will improve, and how much the highacuity range of gaze angles will broaden. None of these diagnostic or therapeutic assessments is possible from only a clinical examination and visual acuity measurement.

Finally, we have recently uncovered a “dynamic” source of visual function deficit in INS that causes patients to complain that they are “slow to see.” They have an elevated target acquisition time (far longer than their slightly elevated saccadic reaction time).44 This raises the question, “Does nystagmus surgery (specifically, four-muscle tenotomy) also improve visual function by reducing target acquisition time?” Preliminary data suggest that it does.

Eye movement recordings and NAFX analysis used in the diagnostic workup and therapeutic decision processes should produce accurate and repeatable diagnoses and reduce repeat (i.e., corrective) nystagmus surgeries. Complex cases combining INS, strabismus, latent components, and even FMNS require eye movement recordings and analyses.

ACKNOWLEDGMENTS The author acknowledges the following colleagues, whose collaboration during the past 40 years of INS research formed the foundation for this data-based approach to diagnosis, therapy, and evaluation of visual function improvement (listed chronologically): L. Stark, G. Gauthier, R. B. Daroff, J. T. Flynn, L. A. Abel, D. Schmidt, S. Traccis, C. Ellenberger, R. J. Leigh, A. Tabuchi, R. M. Steinman, H. Collewijn, J. Van der Steen, B. M. Weissman, R. W. Hertle, N. V. Sheth, J. Shallo-Hoffmann, R. W. Williams, L. Averbuch-Heller, J. B. Jacobs, B. F. Remler, D. W. Hogan, D. M. Erchul, R. L. Tomsak, G. M. Acland, J. Bennett, R. A. Burnstine, A. Serra, and Z. I. Wang.

This work was supported in part by the Office of Research and Development, Medical Research Service, U.S. Department of Veterans Affairs.

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ABSTRACT

This chapter reports the effect of extraocular muscle surgery on the clinical and ocular motility characteristics of infantile periodic and aperiodic alternating nystagmus. Of 1423 recordings performed between the years 1998 and 2006 in 506 patients with infantile nystagmus syndrome (INS), 78 had ocular oscillations consistent with infantile periodic alternating nystagmus. Fifty-three patients had virgin eye muscles operated on for strabismus alone, nystagmus alone, a static head posture alone, or a static head posture plus strabismus. Outcome variables were vision, strabismus, head position, periodic cycle and null period duration, foveation time, and waveforms. Age range was 1 to 67 years; 57% had pure periodic and 43% the aperiodic form of nystagmus, 42% had albinism, 42% had strabismus, 40% had amblyopia, and 32% had other eye disease. Asymmetry was present in 65%, while 35% were symmetric about the null period. Head posture and strabimsus improved in all patients. Average LogMAR acuity increased from 0.55 preoperatively to 0.42 postoperatively (p < 0.01). The average, pure periodic alternating nystagmus (PAN) cycle duration increased from 221 seconds to 266 seconds after surgery (p < 0.01), the average pure PAN null period duration increased from 11.2 to 20.0 seconds after surgery (p < 0.05), and the average best duration foveation increased from 132 to 178 milliseconds after surgery (p < 0.05); post-surgery waveform changes during the null period were those associated with improved visual function. Fifteen percent of our total INS

population had either the periodic or aperiodic form of alternating nystagmus. This report adds to the evidence that surgery on the extraocular muscles in patients with INS has independent neurological and visual results from simply repositioning the head, eye(s), or visual axis.

Distinguishing neurologically serious forms of nystagmus in infancy and childhood are important because of the implications for diagnosis, prognosis, and treatment of the neurological disease or the nystagmus directly. Any pattern of nystagmus with onset in the first two months of life could be considered congenital nystagmus. The term congenital nystagmus is only appropriate when the nystagmus is present at birth (and presumably also in utero). This term, however, has become synonymous with the most common form of neonatal nystagmus, which is characterized electrophysiologically by an accelerating slow phase on eye movement recordings and is termed infantile nystagmus syndrome (INS).1 The recently sponsored National Eye Institute Workshop on Classification of Eye Movement Abnormalities and Strabismus (CEMAS) has attempted to resolve some of these issues. This report utilizes the CEMAS working group definition of INS.2 Other clinical characteristics, with variable association, include increased intensity with fixation and decreased intensity with sleep or inattention; variable intensity in different positions of horizontal, vertical, or torsional gaze (about a null position); with monocular cover, a changing direction in different positions of gaze (about a neutral position) and decreased intensity (damping) with convergence or induced esotropia (“blockage”); and anomalous head

posturing, strabismus, and the increased incidence of significant refractive errors. INS can occur in association with congenital or acquired defects in the visual sensory system (i.e., optic nerve hypoplasia, achromatopsia, foveal hypoplasia, congenital cataracts).3-5

In addition to the above characteristics, 9% to 33% of patients with INS will have an inherent, rhythmic, periodic, or aperiodically changing nystagmus intensity and/or direction over time.6-9 Most clinicians are familiar with this oscillation as acquired periodic alternating nystagmus (PAN). Acquired PAN has a specific pattern identified by the presence of spontaneous nystagmus in the primary position, which beats horizontally in one direction for 1 or 2 minutes, followed by a quiet period, and then reappearance of the nystagmus in the opposite direction for a similar length of time. It is usually seen in association with disease affecting the cerebellar nodulus and uvula, such as Friedreich’s ataxia, but also with vision loss.10-13 Infantile periodic alternating nystagmus (IPAN) has all the characteristics of INS, except that the null point shifts position in a regular (periodic) or irregular (aperiodic) pattern. This results in changes in the intensity and/or direction of the nystagmus from seconds to minutes. Although neuroimaging is obtained in almost all cases of clinically evident PAN, the definitive diagnosis of the ocular oscillation is made using eye movement recordings. IPAN is more common in patients with oculocutaneous albinism and is usually not associated with serious central nervous system pathology.6-8,14 There are clinical and scientific data that show that if the slow foveation periods occurring during each beat of nystagmus can be lengthened or increased by the patient (adaptation) or by therapeutic interventions (e.g., medicines, surgery, contact lenses, biofeedback), some of a patient’s visual function may be increased.15-17 The purpose of this chapter is to describe the effect of extraocular muscle surgery on the electrophysiological and clinical characteristics of 53 patients with IPAN.

METHODS

surgery prior to one performed by the author (RWH),

(b) follow-up for at least 6 months after surgery, (c) eye movement recordings with waveforms characteristic of INS, and (d) periods of changing oscillation direction and/or intensity. The periodic changing eye intensity and/or direction is independent of a changing eye fixation and is present during continuous, binocular eye movement recordings over a 10to 15-minute period. All patient data were obtained from a prospectively collected computerized database.

Ophthalmologic Examination

All patients underwent several routine clinical evaluations. Visual acuity testing was performed with refraction in place both binocularly and monocularly, using behavioral methods in infants and the “early treatment for diabetic retinopathy” chart or the amblyopia treatment study single and surrounded, HOTV optotype protocol in those able to cooperate with subjective testing.18 Binocular function was assessed using the Worth 4-Dot test near and at distance and the Randot preschool stereoacuity test at near. Ocular motor examination also included a determination of heterophoria/tropia at distance (3 to 6 m) and near (33 cm) in all diagnostic positions of gaze using the simultaneous prism cover test and alternate prism cover test. Versions and ductions were examined and color vision was tested in those able to cooperate for subjective testing, using D-15 color plates. The ocular examination also included cycloplegic refraction, tonometry in older children, slit-lamp and ophthalmoscopic examination of the anterior and posterior segments, and fundus photographs if an abnormality was detected during the examination. Clinical evaluation of the ocular motor oscillations included examination and measurement of any anomalous head posture using a previously described technique.19 Changes in the oscillation were examined in primary position, at near, and in all positions of gaze under monocular and binocular conditions.

All testing was approved by the Institutional Review Boards of the National Eye Institute, National Institutes of Health, Bethesda, Maryland; The Columbus Children’s Hospital, Columbus, Ohio; and The Children’s Hospital of Pittsburgh, in Pennsylvania. All procedures observed the declaration of Helsinki, and informed consent/assent was obtained from all family members.

Inclusion Criteria

In order to be eligible for this study, nystagmus patients had to meet the following criteria: (a) no eye muscle

Electroretinography and Visual

Evoked Potential Testing

Electroretinographic (ERG) and/or visual evoked potential (VEP) testing was performed in patients with suspected retinal and/or optic nerve disease to exclude the possibility of a retinal or optic nerve dystrophy/ degeneration associated with the nystagmus. A commercially available electrodiagnostic testing unit (LKC Technologies, Gaithersburg, MD) was used for both ERG and VEP testing. ERG testing included lightand dark-adapted recordings using a corneal contact lens electrode technique and the International Society of

Clinical Electrophysiology in Vision protocol.20 VEP testing was performed in a darkened room using the commercially available LKC sweep and flash programs in each eye.

Eye Movement Recording

All subjects had eye movement recordings. The presentation of stimuli and the acquisition, display, and storage of data were controlled by a series of computers using standard Microsoft and MATLAB software, as well as specially designed software such as Visual and Experimentation and Real-time EXperimentation packages (distributed by the Laboratory of Sensorimotor Research NEI/NIH, Bethesda, MD).

The horizontal and vertical eye movement recordings of the subjects were made using an infrared (IR) reflection method (IOTA Eye Movement Recording, Applied Science Laboratories, Bedford, MA); the system bandwidth was 0–500 Hz. In older children and adults, signals were calibrated (using the end of the fast phase during the nystagmus cycle) at the beginning of the recording session by having the patient fixate on small target lights located on a screen at a distance of 1 meter. Data were sampled at 500 Hz. These patients were seated with their head stabilized by means of a chin cup and headrest and instructed to look at targets at ±15° or ±20° horizontally and ±10° vertically. After calibration, all recording sessions followed the same protocol. The patient was required to fixate between 0°, ±5°, ±10°, ±15°, and ±20° with the right eye, the left eye, and both eyes. The patient was then asked to make binocular step vergence responses from distance to near. Finally, fixation at 0° with both eyes was accomplished for 10 to 15 minutes. Infants were seated in a comfortable position in a parent or caretaker’s lap. The goggles rested comfortably on the infant’s face in front of the visual axis, and the head was held steady by the examiner. After 7.5 to 10.0 minutes of continuous binocular recordings, the left and then the right eye was occluded with an opaque trial lens placed in a holder attached to the front of the goggles. At all times during recording, attempts were made to pacify the child and obtain his or her attention to the fixation screen at 1 m. When possible, attempts were made to have young children look to the right and left as well as near while recording the oscillation’s response to gaze and vergence changes. This method, in use for more than two decades, produces clear, arti- fact-free records of INS waveforms in infants and young children. Although the amplitude of the INS in either was not always accurately determined (i.e., all the data are not calibrated), all phase and timing information (e.g., periodicity, foveation time, symmetry, waveforms) could be accurately measured. All eye

movement data were analyzed offline. Mathematical and statistical analysis was done on a computer spreadsheet.

OUTCOME VARIABLES

Clinical Data

Clinical variables included age in years; follow-up from initial diagnosis in months; other eye diagnoses (determined through clinical and electrophysiological examinations); systemic diagnoses (determined through history); best-corrected binocular acuity using the methods listed; anomalous head position; and presence and type of heterotopia defined as esotropia, exotropia, and hypertropia.

Eye Movement Recording Data

The PAN cycle duration was defined, in seconds, as the period of time from the beginning of one lowintensity or quiet period to the beginning of the next low-intensity or quiet period, and was calculated from at least 12 continuous cycles, sometimes over many recording sessions, for each patient (Fig. 12.1).

Null period duration was defined, for the purposes of this report, as the time in seconds during the quiet period where continuous, individual nystagmus beats had foveation periods 80% to 100% as long as the patients single best (longest duration) foveation period. (Fig. 12.2).

Foveation duration was determined by averaging the foveation time from at least 100 beats of nystagmus during the null period (Fig. 12.3).4,5

Patients were defined as having a periodic (regular) rhythm if there were regular cycles of leftand rightbeating nystagmus separated by an almost quiet phase, or regular periods of high intensity followed by low intensity and again by high intensity without a clear change in direction. Patients were defined as having an aperiodic (irregular) rhythm if there were irregular cycles of leftand right-beating nystagmus separated by an almost quiet phase, or irregular periods of high intensity followed by low intensity and again by high intensity without a clear change in direction. These cyclic changes were present under binocular viewing in the absence of a change in eye fixation, thus eliminating the possibility that the change in nystagmus direction was due to a “latent component” in those patients with strabismus.

The types of waveforms present were classified according to the previously described 13 waveforms associated with horizontal INS.1 Symmetry was defined as similar nystagmus beat-to-beat characteristics

(waveforms, intensity) in both directions prior to and after the low-intensity or quiet period.

RESULTS

Clinical Data

Of 1423 eye movement recordings performed from 1998 to 2006 in 506 patients with INS, 78 had IPAN (15.4%). Fifty-three who had previously had eye muscle surgery are the subjects of this report. Ages ranged from 1 to 67 years (average 15.5 years, SD 14.1), and 49 (63%) were male. Follow-up has, to the point of this writing, ranged from 7 to 60 months (average 20.5 months). Twenty-three patients (42%) had strabismus,

21 patients (40%) had unilateral amblyopia, 23 patients

(42%) had ocular or oculocutaneous albinism, and

1 patient had a systemic disease diagnosis.21 Eight patients (15%) had surgery for strabismus alone, 19 patients (36%) had surgery for an anomalous posture or tenotomy alone, and 7 patients (13%) had surgery for strabismus and an anomalous head posture (Table 12.1). Best binocular acuity did not change in 14%, and it improved 0.10 LogMAR in 33%, 0.20 LogMAR in 37%, 0.30 LogMAR in 14%, and > 0.32 LogMAR in 2% (Table 12.2, Fig. 12.4). The postoperative primary position deviation was less than 10 prsim diopters in each of the 15 patients with strabismus (Fig. 12.5). In the 19 patients with a static head posture, all but 2 had less than a 5º posture after surgery (Fig. 12.6).

Eye Movement Recording Variables

A periodic (regular) cycle was present in 30 patients (57%), and an aperiodic (irregular) cycle in 23 (43%). The PAN cycle duration averaged 221 seconds (SD 31 seconds) in the 57% with periodicity, and changed postoperatively to 266 seconds (SD 70) (p < 0.01) (Fig. 12.1). The aperiodic cycle varied from as little as 2 seconds to as long as 300 seconds in the 43% with aperiodicity, and did not change after surgery. The duration of the null period in those patients with periodic

cycles, preoperatively, averaged 11.2 seconds (SD 3.9), and this increased to an average of 20.0 seconds (SD 5.1) (p < 0.001) after surgery (Fig. 12.2). The duration of the null period in those patients with aperiodicity was as short as 2 seconds to as long as 366 seconds. Best foveation duration averaged 132 milliseconds (SD 36.5) preoperatively and increased to 178 milliseconds (SD 40.9) postoperatively in all patients (p < 0.05) (Figs. 12.3 and 12.7). The most common waveforms during the null period were jerk with extended

foveation in 27 (51%), pure jerk in 17 (32%), and asymmetrical pendular in 5 (10%); other variants of jerk waveforms were seen in 4 patients (7%). After surgery, this hanged to jerk with extended foveation in 45 (85%), pure jerk in 5 (10%), asymmetrical pendular in 1 (2%), and other variants of jerk waveforms in 2 (3%) (Fig. 12.8).21

DISCUSSION

Acquired PAN is associated with disorders involving the cerebellum, especially the nodulus and ventral uvula. These conditions include trauma, Chiari malformations, cerebellar mass lesions (cyst, tumor), ischemia,

hereditary cerebellar degenerations, infections (syphilis, encephalitis), and multiple sclerosis.10,11,22,23 Acquired PAN can also occur as an adverse effect of medication such as lithium and anticonvulsants, or it may result from loss of vision (cataracts), vitreous hemorrhage, or syphilitic optic atrophy. Although the mechanism of PAN is not fully understood, lesions of the uvula and nodulus, as well as structures located in the posterior vermis of the cerebellum, can result in PAN.24-27 The nodulus and uvula are also known to control velocity storage, and removal of these structures causes an increase in the duration of the time constant of velocity storage. At the molecular level, it has been demonstrated that control of the velocity storage by the nodulus and uvula is achieved, at least in part, by inhibitory

Patient number

VA-PRE VA-PO