Nystagmus and Saccadic Intrusions.

PURPOSE OF REVIEW: This article provides an overview of nystagmus and saccadic intrusions with the goal of facilitating recognition and differentiation of abnormal eye movements to assist with accurate diagnosis of neurologic disease and evidence-based specific treatment of oscillopsia. Myriad advances have been made in the understanding of several types of nystagmus and saccadic intrusions, even in the past 5 to 10 years, especially regarding underlying pathophysiology, leading to pharmacologic advances rooted in physiologic principles. RECENT FINDINGS: Specific recent advances in the study of nystagmus and saccadic intrusions include (1) improved understanding of the underlying etiologies and mechanisms of nystagmus enhanced or unmasked by provocative maneuvers such as supine position or head shaking; (2) recognition of the differences in behavior and treatment responsivity of acquired pendular nystagmus in demyelinating disease versus oculopalatal myoclonus; (3) recognition that oculopalatal myoclonus results from a dual mechanism of abnormal inferior olivary gap junction connection formation and maladaptive cerebellar learning; and (4) well-controlled clinical trials to evaluate the efficacy of pharmacologic interventions, such as memantine for acquired pendular nystagmus and 4-aminopyridine for downbeat nystagmus. SUMMARY: Accurate recognition of nystagmus and saccadic intrusions, including familiarity with the subtleties of examination techniques that allow such eye movements to be unmasked, is critical to proper diagnosis and ultimate alleviation of the visual impairment these patients experience.

Familial congenital cataract, coloboma, and nystagmus phenotype with variable expression caused by mutation in PAX6 in a South African family.

Purpose: To report on a clinical and genetic investigation of a large, multigenerational South African family of mixed ancestry with autosomal dominant congenital cataracts, coloboma, and nystagmus. Methods: Ophthalmic examination was performed in 27 individuals from the same admixed South African family. DNA was sampled from either peripheral blood or buccal swabs in all 27 individuals, and whole genome sequencing was performed in six individuals. Sanger sequencing was used to validate the probable mutation in the remaining family members. Results: Twenty-seven family members with 19 affected individuals were included in the study. The predominant phenotype, with highly variable expression, was congenital cataract (14 individuals), posterior segment coloboma (17 individuals), and nystagmus (18 individuals). Other features present included high myopia, microcornea, and strabismus. An R208W mutation in PAX6 (dbSNP rs757259413; HGMD CM930572; NM_000280.3:c.622G>A; NP_000271.1:p.Arg208Trp) was identified as being the most probable pathogenic mutation. Cosegregation of the mutation with the phenotype was confirmed in all 27 family members. Conclusions: PAX6 is a highly conserved gene crucial for normal oculogenesis, and although mutations within the gene may cause an array of ocular developmental abnormalities, most are associated with aniridia and aniridia-related ocular defects. The observation that PAX6 aniridia phenotypes are largely associated with nonsense mutations and milder non-aniridia phenotypes with missense mutations suggested that there may be specific genotype-phenotype correlations for the gene. The R208W mutation in PAX6 identified in this family challenges this theory as it has previously been reported in three unrelated families and is associated with aniridia and non-aniridia phenotypes across the four families. PAX6 with its wide phenotypic associations and highly variable expression should be considered a candidate gene in the diagnostic screen for any ocular developmental abnormality.

Treatment of Nystagmus.

Acquired and congenital forms of nystagmus are commonly encountered in the course of clinical practice. Although some patients are asymptomatic, many others describe disabling oscillopsia that impairs visual function, social function, and quality of life. Such patients may present to the neurologist to request treatment. Numerous treatment approaches for nystagmus have been proposed, including medical, surgical, and optical treatments. Some of the treatments aim to reduce nystagmus slow-phase speed, whereas others aim to negate the visual consequences of the nystagmus. The approach must be tailored depending on the type of nystagmus, its characteristics, and in some cases, its cause. In this review, the treatment approach for acquired and congenital forms of nystagmus is summarized with an emphasis on treatments that have been evaluated in well-designed clinical trials. Novel approaches that have not yet been evaluated in clinical trials are also discussed.

Quick phases of infantile nystagmus show the saccadic inhibition effect.

PURPOSE: Infantile nystagmus (IN) is a pathological, involuntary oscillation of the eyes consisting of slow, drifting eye movements interspersed with rapid reorienting quick phases. The extent to which quick phases of IN are programmed similarly to saccadic eye movements remains unknown. We investigated whether IN quick phases exhibit 'saccadic inhibition,' a phenomenon typically related to normal targeting saccades, in which the initiation of the eye movement is systematically delayed by task-irrelevant visual distractors. METHODS: We recorded eye position from 10 observers with early-onset idiopathic nystagmus while task-irrelevant distractor stimuli were flashed along the top and bottom of a large screen at ±10° eccentricity. The latency distributions of quick phases were measured with respect to these distractor flashes. Two additional participants, one with possible albinism and one with fusion maldevelopment nystagmus syndrome, were also tested. RESULTS: All observers showed that a distractor flash delayed the execution of quick phases that would otherwise have occurred approximately 100 ms later, exactly as in the standard saccadic inhibition effect. The delay did not appear to differ between the two main nystagmus types under investigation (idiopathic IN with unidirectional and bidirectional jerk). CONCLUSIONS: The presence of the saccadic inhibition effect in IN quick phases is consistent with the idea that quick phases and saccades share a common programming pathway. This could allow quick phases to take on flexible, goal-directed behavior, at odds with the view that IN quick phases are stereotyped, involuntary eye movements.

A novel PAX6 mutation in Chinese patients with severe congenital aniridia.

PURPOSE: We identified a novel mutation in Paired Box gene 6 (PAX6) and characterized its associated clinical features of severe ocular malformation in a Chinese family with congenital aniridia. METHODS: We studied two patients with aniridia from a Chinese family. All patients and noncarriers in this family underwent full ophthalmologic, general and urinary examinations. Total genomic DNA was isolated from peripheral blood of two aniridia patients. PAX6 levels were determined by PCR and its mutational status was determined by sequencing. Direct sequencing detected variations in PAX6. RESULTS: Patients had bilateral congenital nystagmus, anterior polar cataract, absence of iris tissue, and foveal hypoplasia with severely reduced visual acuity. A novel heterozygous PAX6 mutation in exon 6 c.662G>A (p.W100X) was identified which created a premature termination codon. This observed sequence alteration was not found in 100 normal controls and has not been previously reported. CONCLUSIONS: We identified a novel PAX6 mutation in a family with severe ocular malformation. Our study expands the mutational spectrum of PAX6 and enriches our knowledge of the relationship between genotype and phenotype due to these mutations.

Design and efficacy of surgery for horizontal idiopathic nystagmus with abnormal head posture and strabismus.

The design and efficacy of surgery for horizontal idiopathic nystagmus (HIN) with abnormal head posture and strabismus were investigated. Different surgical procedures were selected according to the angle of head turn in 44 cases of HIN with abnormal head posture and strabismus. For patients with a head turn of 15° or less, the Anderson procedure was used; the yoke muscles were recessed upon slow-phase. For patients with a head turn between 15° and 25°, the surgery was designed as a Kestenbaum 5-4-4-5 procedure. For patients with a head turn of 25° or more, the surgery was designed as a Parks 5-8-6-7 procedure. The surgery to correct the abnormal head posture was performed on the fixating eye while that to correct the deviation was then performed on the non-fixating eye at the same time. The amount of surgery of the horizontal rectus muscles on the non-fixating eye was sum of the angle of head turn and the degree of deviation, which was calculated as follows: recession/resection amount of medial and lateral rectis / 2×5 =angle of head turn ± degree of deviation. The results showed as follows: (1) Visual acuity: the visual acuity in the primary ocular position increased two lines or more in 35 patients, accounting for 79.55%. Nine patients had no or only one-line improvement, accounting for 20.45% of the entire study population; (2) The degree of deviation in the primary ocular position: 37 cases had a normal primary ocular position or the degree of deviation ≤ 8(δ) after surgery, accounting for 84.09%. Six patients had a residual degree of deviation of 8(δ)-15(δ), accounting for 13.64%. One patient had a residual degree of deviation >20(δ), accounting for 2.27% of the patients examined; (3) Abnormal head posture: 34 patients had a normal head posture or a head turn of less than 5°, accounting for 72.27%. Eight patients had a residual head turn of 5°-15°, accounting for 18.18%. Two patients had a head turn of 15°-25°, accounting for 4.55%. It was concluded that different surgical procedures based on the angle of head turn and the relationship between deviation and null zone can eliminate anomalous head posture, correct deviation, and improve vision acuity in the primary ocular position.

[Hereditary glaucoma associated with oculodentodigital dysplasia]. / Glaucoma hereditario asociado a displasia oculodentodigital.

CASE REPORT: A newborn evaluated at 20 days old due to occasional nystagmus. Her mother had presented with oculodentodigital dysplasia (ODDD) and glaucoma. The physical examination revealed opaque micro-corneas, and horizontal nystagmus. The tonometry showed 35 mm Hg in OD and 40 mm Hg in OS and the fundus examination was normal. She had a narrow nasal bridge with narrow nostrils, and fourth and fifth finger syndactylyl in both hands. A bilateral trabeculectomy was performed with a good response. DISCUSSION: ODDD is a rare autosomal dominant disease with heterogeneous phenotype manifestations. The most frequent cause of loss of visual acuity is the glaucoma, requiring long-term follow up with periodical control of the intraocular pressure (IOP).

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.

Influence of motion smear on visual acuity in simulated infantile nystagmus.

PURPOSE: In persons with infantile nystagmus (IN), visual acuity correlates with the duration of the foveation period of the nystagmus waveform, i.e., when the retinal image is on or near the fovea and moves with low velocity. In this study, we asked how acuity is affected by the non-foveating phases of the nystagmus waveform, when the velocity of retinal image motion is substantially higher. METHODS: Visual acuity was measured in three normal observers for high contrast, four-orientation single T-stimuli, presented during image motion that simulated either the whole jerk-IN waveform (whole-waveform) or only the foveation periods of the IN waveform (foveation-only). Simulated foveation durations ranged from 20 to 120 ms. For both motion waveforms, we displayed the acuity target for different number of cycles to examine whether acuity benefits from multiple presentations of the stimulus. RESULTS: As expected, visual acuity improves with longer simulated foveation durations in both the whole-waveform and foveation-only conditions. Acuity is consistently better (by ∼0.1 logarithm of the minimum angle of resolution) in the foveation-only than the whole-waveform condition, indicating that the high-velocity image motion during the simulated IN waveform has a detrimental effect. This difference in acuity between the two waveform conditions increases with the number of cycles, apparently because summation occurs across cycles in the foveation-only condition but not in the whole-waveform condition. CONCLUSIONS: In normal observers, visual acuity in the presence of a simulated nystagmus waveform is limited not only by the duration of the foveation periods, but also by the non-foveating phases of the waveform. However, because persons with IN report little or no motion smear in association with their nystagmus, it remains unclear whether the rapid retinal image motion during the non-foveating phases of the nystagmus waveform generates a similar degradation of visual acuity in IN.

Absent optic chiasm presenting with horizontal nystagmus.

A female infant with horizontal nystagmus and normal ophthalmic examination had isolated absence of the optic chiasm on magnetic resonance imaging. Eye movements were recorded on video and reviewed. Horizontal nystagmus without see-saw nystagmus was observed. Visual evoked potential showed inter-hemispheric asymmetry compatible with the absence of crossing chiasmal fibers. Systemic abnormalities in this patient included cleft lip, preauricular skin tags, broad thumbs, and an anteriorly positioned anus, suggestive of Townes-Brock syndrome.

A new autosomal dominant Peters' anomaly phenotype expanding the anterior segment dysgenesis spectrum.

PURPOSE: To test the association of genes involved in anterior segment development in a family with autosomal dominantly inherited Peters' anomaly (PA) with a unique ocular phenotype. METHODS: Six members of a five-generation family with PA were extensively phenotyped and linkage analysis of candidate genes, namely, PAX6, PITX2, FOXC1, CYP1B1 and MAF, was performed. RESULTS: The complete pedigree consisted of 38 members, 19 of whom were affected. The six probands examined had bilateral microcornea, corneal opacity, iridocorneal adhesions, nystagmus and strabismus, but cataract, keratolenticular adhesions, glaucoma and posterior embryotoxon were absent. PAX6 gene mutations had been previously excluded in one of the affected members. DNA markers for candidate genes CYP1B1 on 2p22, PITX2 on 4q25, PAX6 on 11p13, MAF on 16q23 and FOXC1 on 6p25 were genotyped. Highly negative lod scores were obtained for all markers. CONCLUSIONS: The exclusion of these genes as likely candidates supports the hypothesis that the ocular phenotype associated with PA segregating in this family is a distinct, new, autosomal dominant entity in the anterior segment dysgenesis spectrum.

Lumpers or splitters? The role of molecular diagnosis in Leber congenital amaurosis.

Clarification and classification of the congenital form of blindness known as Leber congenital amaurosis (LCA) continues to provide its challenges and dilemmas. Until recently, seven genes have been identified that cause LCA. Clarifying the relation between LCA and associated neurological abnormalities such as autism, seizures, and hypotony, and unraveling the relationship between the ocular LCA phenotype and that associated with distinct systemic entities such as Joubert syndrome, Senior-Loken syndrome and Saldino-Mainzer syndrome has taken on new importance with the discovery that a substantial proportion of patients with LCA have mutations in the CEP290 gene that causes Joubert syndrome. This commentary explores the implications of this recent discovery and revisits the classification of LCA.

Oculomotor instabilities in zebrafish mutant belladonna: a behavioral model for congenital nystagmus caused by axonal misrouting.

A large fraction of homozygous zebrafish mutant belladonna (bel) larvae display a reversed optokinetic response (OKR) that correlates with failure of the retinal ganglion cells to cross the midline and form the optic chiasm. Some of these achiasmatic mutants display strong spontaneous eye oscillations (SOs) in the absence of motion in the surround. The presentation of a stationary grating was necessary and sufficient to evoke SO. Both OKR reversal and SO depend on vision and are contrast sensitive. We built a quantitative model derived from bel fwd (forward) eye behaviors. To mimic the achiasmatic condition, we reversed the sign of the retinal slip velocity in the model, thereby successfully reproducing both reversed OKR and SO. On the basis of the OKR data, and with the support of the quantitative model, we hypothesize that the reversed OKR and the SO can be completely attributed to RGC misrouting. The strong resemblance between the SO and congenital nystagmus (CN) seen in humans with defective retinotectal projections implies that CN, of so far unknown etiology, may be directly caused by a projection defect.

X-linked infantile periodic alternating nystagmus.

OBJECTIVE: To describe the clinical and electrophysiological characterization of four family members from three generations who have X-linked infantile periodic alternating nystagmus (XIPAN). METHODS: Complete clinical ophthalmological evaluation, pedigree analysis, electroretinograms (ERG), eye movement recordings (EMR), color vision, and fundus photography were performed on all subjects. RESULTS: Three males in two generations and one female were examined. Clinical examinations showed a jerk/pendular nystagmus with a latent component, strabismus, and a significant refractive error in the three affected males, while the female had only myopic astigmatism. ERG, color contrast, and fundus examinations were normal in all four family members. All four family members showed EMR abnormalities with infantile jerk/dual jerk and pendular nystagmus waveforms. The female had nystagmus present on EMR only and all patients showed (a)periodicity to their nystagmus. CONCLUSIONS: In this family with no other congenital visual sensory system disease, affected males had obvious periodic alternating nystagmus, strabismus, and refractive errors, while the female had clinically "silent" periodic nystagmus that is probably a marker for the carrier state.

Relationships between visual acuity and anomalous head posture in patients with congenital nystagmus.

PURPOSE: To determine whether patients with congenital nystagmus and an anomalous head posture have better binocular visual acuity than such patients without an anomalous head posture. PATIENTS AND METHODS: This was an observational case series of prospectively collected data for 125 patients with clinical and oculographically confirmed congenital nystagmus. Clinical data were tabulated using computer software. Statistical analyses compared binocular visual acuity with and without the presence of a clinically evident anomalous head posture and visual acuity with and without associated sensory disease. RESULTS: The mean visual acuity was 20/42 (log of the minimal angle of resolution [MAR], 0.32) in patients with an anomalous head posture and 20/83 (logMAR, 0.62) in patients with no anomalous head posture (P < .001). Among patients with disease of the sensory system, those with an anomalous head posture had a mean visual acuity of 20/55 (logMAR, 0.44) and those without an anomalous head posture had a mean visual acuity of 20/108 (logMAR, 0.73; P < .001). CONCLUSIONS: Visual acuity was found to be significantly better in patients with congenital nystagmus who had an anomalous head posture versus those without such a head posture. Our findings indicate that the presence of an anomalous head posture in a patient with congenital nystagmus correlates with good vision and thus may be considered a positive prognostic sign in a preverbal child.

Nystagmus.

Advances in understanding the organization of the ocular motor system, including its anatomy and pharmacology, have provided new insights into the pathogenesis of various forms of nystagmus. The discoveries of fibromuscular pulleys that govern the pulling directions of the extraocular muscles has provided a new conceptual framework to account for the different axes of rotation of vestibular and other types of movements that may contribute to nystagmus. Theoretical and experimental evidence has suggested that acquired pendular nystagmus, which is commonly due to multiple sclerosis, arises from the neural network that normally guarantees steady gaze by integrating premotor signals. Pharmacologic inactivation studies have implicated both gamma-aminobutyric acid (GABA) and glutamate as important transmitters in the neural integrator and suggested new drug therapies. New electro-optic devices may eventually prove to be effective treatment for the visual symptoms cause by acquired nystagmus. The demonstration of proprioceptive mechanisms in the distal extraocular muscles has provided a rationale for new operative treatments for congenital nystagmus.

[Treatment of congenital jerky nystagmus with opposite bidirectional neutral zone].

OBJECTIVE: To explore a method for the treatment of congenital jerky nystagmus with opposite bidirectional neutral zones. METHOD: The relatively used side between the two neutral zone was found by neutralizing bilateral head torsion angle with prisms. The surgical intervention was indicated for those patients whose head position would not turn to another side. RESULT: There were 14 cases treated by this method, none of these cases whose head position turned to another side. Ten cases underwent once operation, 2 cases, twice operations and another 2 cases undertook once operation with additional prism correction. The compensatory head posture was corrected and the vision in the primary position of gaze was improved in all the cases. CONCLUSION: This therapy for congenital jerky nystagmus with opposite bidirectional neutral zone shows significant therapeutic effects and can be available for clinical application.

Modelling of congenital nystagmus waveforms produced by saccadic system abnormalities.

Models of the mechanisms of normal eye movements are typically described in terms of the block diagrams which are used in control theory. An alternative approach to understanding the mechanisms of normal eye movements involves describing the eye movement behaviour in terms of smooth changes in state variables. The latter approach captures the burst cell firing against motor error (difference between target gaze angle and current gaze angle) phase plane behaviour which is found experimentally and facilitates the modelling of variations in burst cell behaviour. A novel explanation of several types of congenital nystagmus waveforms is given in terms of a saccadic termination abnormality.