Modulating brain function with microbiota.

Microbial metabolites identified in animal models and human neurological diseases could be therapeutic targets.

Dealing with Nystagmus.

Nystagmus has a profound impact on patients visual function and social life. Infantile nystagmus (IN) is much more common than neurological nystagmus, and establishing the correct diagnosis is key in guiding the appropriate treatment paradigm. This paper attempts to demonstrate a stepwise approach in investigation and clinical evaluation, that is (often) sufficient in differentiating IN from nystagmus of neurological origin, and to uncover underlying sensory etiologies of IN. Targeted and rational uses of paraclinical exams are emphasized when they deemed necessary to complement the clinical assessment. The author's preferred surgical and non-surgical strategies to optimize vision, and improve the head posture and strabismus that can accompany nystagmus, are discussed (although without the goal of writing a complete revision on the topic).

Soft Contact Lenses to Optimize Vision in Adults with Idiopathic Infantile Nystagmus: A Pilot Parallel Randomized Controlled Trial.

PURPOSE: The optimal management of infantile nystagmus syndrome (INS) is still unclear. Contact lenses (CL) may be superior to glasses in improving visual function in INS but it is not known whether their beneficial effects are due to optical correction alone, or to an additional proprioceptive effect, and whether soft CLs would be as effective as rigid CLs. There is little data on feasibility and and the present study aimed to provide this information. METHODS: We completed a pilot Randomized Control Trial (RCT) at a single tertiary referral centre in London, UK. We enrolled 38 adults with idiopathic INS and randomised them to either plano CL (with corrective spectacles if required) or to corrective CL. CL wear was required for a minimum of 2 weeks. Primary outcome measures were feasibility and safety of CL wear in INS; secondary outcome measures were visual acuity and nystagmus waveform parameters. RESULTS: 27 completed the study (27/38,71%). 4 partcipants withdrew due to difficulty with CL insertion/removal and 7 were lost to follow up. CL tolerability was high (24/27,89%) - 2 found the CLs irritant, and 1 had an exacerbation of allergic eye disease. At two weeks, mean improvement in binocular visual acuity from baseline with plano CLs was 0.07 logMAR (95% confidence interval (CI: 0.03-0.11) and 0.06 logMAR with fully corrective CLs (95% CI:0.02-0.1). Mean improvement in the eXpanded Nystagmus Acuity Function (NAFX, a nystagmus acuity function based on eye movement recording) with plano CLs was -0.04(95% CI: -0.08-0.005) and -0.05 with fully corrective CLs(95% CI: -0.09-0.003). CONCLUSIONS: CLs are well tolerated, with a low risk profile. Whilst our study was not powered to detect significant changes in BCVA and waveform parameters between treatment arms, we observed a trend towards an improvement in visual function at two weeks from baseline with CLs.

Infantile nystagmus syndrome: clinical characteristics, current theories of pathogenesis, diagnosis, and management.

Infantile nystagmus syndrome (INS) is an important clinical diagnosis because it is a common presenting sign of many ocular, neurologic, and systemic diseases. Although INS has been studied for more than a century, its diagnosis and treatment remains a challenge to clinicians because of its varied manifestations and multiple associations, and its pathogenesis continues to rouse considerable scientific debate. Fueled by these challenges, recent basic research and clinical investigations have provided new insights into INS. New genetic discoveries and technological advances in ocular imaging have refined our understanding of INS subtypes and offer new diagnostic possibilities. Unexpected surgical outcomes have led to new understanding of its pathogenesis based on novel hypothesized pathways of ocular motor control. Comparative studies on nonhuman visual systems have also informed models of the neural substrate of INS in humans. This review brings together the classic profile of this disorder with recent research to provide an update on the clinical features of INS, an overview of the current theories on how and why INS develops, and a practical approach to the diagnosis and management of INS.

A randomized controlled trial comparing soft contact lens and rigid gas-permeable lens wearing in infantile nystagmus.

OBJECTIVE: To perform the first randomized controlled trial comparing soft contact lens (SCL) with rigid gas-permeable lens (RGPL) wearing in infantile nystagmus (IN), using spectacle wear as a baseline. DESIGN: Randomized, controlled cross-over trial with an intention-to-treat design. PARTICIPANTS AND CONTROLS: A total of 24 participants with IN (12 idiopathic, 12 with albinism). METHODS: Participants were randomized into 1 of 2 treatment arms receiving the following sequence of treatments (2-3 weeks for each treatment): (A) spectacles, SCL, RGPL, and spectacle wear; or (B) spectacles, RGPL, SCL, and spectacle wear. MAIN OUTCOME MEASURES: The main outcome measure was mean intensity of nystagmus at the null region viewing at 1.2 m. Secondary outcome measures included the same measure at 0.4 m viewing and across the horizontal meridian (measured over a ±30° range at 3° intervals) for distance and near. The nystagmus foveation characteristics were similarly assessed over ±30° and at the null region at 1.2 m and 0.4 m viewing. Visual outcome measures included best-corrected visual acuity (BCVA) at 4 m and 0.4 m, gaze-dependent visual acuity (GDVA) (i.e., visual acuity when maintaining gaze angles over a ±30° range at 10° intervals) at 4 m, and reading performance at 0.4 m derived from the Radner reading chart. RESULTS: There were no significant differences between SCL and RGPL wearing for any nystagmus characteristics or compared with spectacle wearing. The BCVA, reading acuity, and critical print size were significantly worse for SCL wearing compared with RGPL and baseline spectacle wear (P<0.05), although mean differences were less than 1 logarithm of the minimum angle of resolution (logMAR) line. CONCLUSIONS: Nystagmus was not significantly different during SCL and RGPL wearing in IN, and contact lens wearing does not significantly reduce nystagmus compared with baseline spectacle wearing. The wearing of SCL leads to a small but statistically significant deterioration in visual function compared with both RGPL and spectacle wearing at baseline, although mean effect sizes were not clinically relevant.

[Clinical research progress in infantile nystagmus syndrome].

Infantile nystagmus syndrome (INS) is an ocular motor disorder that presents at birth or early infancy. It is clinically characterized by involuntary and conjugated oscillation of the eyes, which often causes several complications such as amblyopia, lateral view, strabismus and torticollis. The etiology of INS is not fully understood, and this disease cannot be cured completely. This paper reviews the progress of research on the concept, etiology and pathogenesis, clinical manifestations, common examination methods, diagnosis and treatment of INS.

Infantile and acquired nystagmus in childhood.

Nystagmus is an involuntary, periodic eye movement caused by a slow drift of fixation which is followed by a fast refixation saccade (jerk nystagmus) or a slow movement back to fixation (pendular nystagmus). In childhood most cases are benign forms of nystagmus: idiopathic infantile, ocular or latent nystagmus. They arise at the age of 3 months, without oscillopsia and show the absence of the physiologic opto-kinetic nystagmus. A full ophthalmologic evaluation is all that is needed in most cases: albinism, macular or optic nerve hypoplasia and congenital retinal dystrophies are the most common forms of ocular nystagmus. Idiopathic infantile nystagmus can be hereditary, the most common and best analyzed form being a mutation of the FRMD7 gene on chromosome Xq26.2. The mutation shows a mild genotype-phenotype correlation. In all female carriers the opto-kinetic nystagmus is absent and half had mild nystagmus. Latent nystagmus is part of the infantile esotropia syndrome and shows the unique feature of change of direction when the fixing eye changes: it is always beating to the side of the fixing eye. There is no cure for infantile nystagmus but therapeutic options include magnifying visual aids or eye muscle surgery at the age of 6-8 y in patients with head turn. Less than 20% of childhood nystagmus are acquired and need further neurological and imaging work-up. Alarming signs and symptoms are: onset after the age of 4 months, oscillopsia, dissociated (asymmetric) nystagmus, preserved opto-kinetic nystagmus, afferent pupillary defect, papilloedema and neurological symptoms like vertigo and nausea. The most common cause is due to pathology of the anterior optic pathway (e.g. optic nerve gliomas). It shows the same clinical feature of dissociated nystagmus as spasmus nutans but has a higher frequency as in INO. Other forms of acquired nystagmus are due to brainstem, cerebellar or metabolic diseases.

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.

The diagnosis and treatment of infantile nystagmus syndrome (INS).

The successful treatment of infantile nystagmus syndrome (INS) depends primarily on accurate and repeatable diagnosis of the type(s) of nystagmus present as well as their variation with gaze and convergence angles or fixating eye. Research over the past 40 years has demonstrated that the only way to achieve both is by making and analyzing ocular motility recordings. Determination of the direct effects of peripheral and central INS therapies can only be made by pre- and post-therapy comparisons of the nystagmus characteristics, specifically of the quality of the foveation periods within each cycle. If one is only interested in cosmetic improvements, diminution of the nystagmus amplitude is all that need be measured. However, if improvement of visual function is the primary goal of therapy, then measurement of the pre- and post-therapy foveation quality must be made, both in primary position and over a broad range of gaze angles. The use of the eXpanded Nystagmus Acuity Function (NAFX) on nystagmus data yields both an accurate measure of foveation quality and a prediction of maximum potential acuity for the patient's waveform. When used with the patient's measured, pre-therapy visual acuity, the NAFX demonstrates the amount of visual acuity loss that is due to sensory abnormalities, demonstrates the amount due to the nystagmus waveform, and estimates the measured post-therapy acuity for all values of improved NAFX and gaze angles measured. The ability to predict visual acuity improvement was not possible before the use of the NAFX. The failure to incorporate accurate measures of nystagmus waveform and foveation quality into their diagnostic evaluation continues to deprive patients of the best possible standard of care and results in mistaken diagnoses as well as inappropriate and, in some cases, unneeded multiple surgeries.

Eye movement recordings as an effectiveness indicator of gene therapy in RPE65-deficient canines: implications for the ocular motor system.

PURPOSE: To perform ocular motility recordings of infantile nystagmus (IN) in RPE65-deficient canines and determine whether they can be used as a motor indicator of restored retinal function to investigate the effects of gene therapy. METHODS: Treated and untreated canines were comfortably suspended in a custom-built sling and encouraged to fixate on distant targets at gaze angles varying between +/-15 degrees horizontally and +/-10 degrees vertically. Ocular motility recordings were made, using two distinct methods-infrared reflection and high-speed video. The resultant recordings from three untreated, four treated, and three pre- and post-treatment dogs were analyzed for using the eXpanded Nystagmus Acuity Function (NAFX), which yields an objective assessment of best potential visual acuity, based on the duration and repeatable accuracy of foveation and centralisation. RESULTS: During fixation, the untreated dogs exhibited large-amplitude, classic IN waveforms, including pendular and jerk in both the horizontal and vertical planes, which prevented them from keeping the targets within the area centralis (the region of highest receptor density, spanning +/-3 degrees horizontally by +/-1.5 degrees vertically, analogous to the fovea). Some untreated dogs also had small-amplitude (0.5-1 degrees), high-frequency (6-9 Hz) oscillations. Under the same conditions, successfully treated canines no longer exhibited clinically detectable IN. Their IN was converted to waveforms with very low amplitudes that yielded higher NAFX values and allowed target images to remain well within the area centralis. Of note, uniocular treatment appeared to damp the IN in both eyes. Behaviorally, the treated dogs were able to successfully navigate through obstacles more easily without inadvertent contact, a task beyond the untreated dogs' ability. CONCLUSIONS: Gene therapy that successfully restored retinal function also reduced the accompanying IN to such a great extent that it was not clinically detectable approximately 90% of the time in many of the dogs. IN improvement, as quantified by the NAFX, is an objective motor indicator of visual improvement due to gene therapy.

Interventions for infantile nystagmus syndrome: towards a randomized controlled trial?

A PubMed search for papers in the last 10 years on interventions for Infantile Nystagmus Syndrome (INS) reveals 18 papers on surgical or pharmacological interventions and 6 papers describing other interventions. There is only one randomized controlled trial (RCT), with all the other studies being uncontrolled trials/case series. To investigate the importance of RCTs, the data from the one RCT is re-analyzed as if it had been a case series. If only the group receiving the experimental treatment are considered, then the visual acuity was significantly better after than before treatment (paired t-test, p = 0.04). However, the control group who received a placebo treatment improved to a similar degree (p = 0.90). The literature on the placebo effect shows that it can influence objective variables and the outcome of surgical interventions. It is suggested that previous studies on interventions for nystagmus have laid an important foundation for future work in this field, which should involve RCTs.

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.

Infantile nystagmus: current concepts in diagnosis and management.

This review examines current approaches to the diagnosis and management of congenital forms of nystagmus. Emphasis is placed on diagnostic features that are amenable to clinical identification but those issues that can be addressed only with more detailed investigations, such as eye movement recording, are indicated. Non-surgical management, including prism spectacles, contact lenses and vision therapy, is discussed, as are surgical approaches. Because many aspects of congenital forms of nystagmus, particularly as experienced by patients with the condition in their normal lives, are poorly addressed in both the clinical and research literature, these limitations are also highlighted.

The use of contact lenses to treat visually symptomatic congenital nystagmus.

It has been suggested that contact lens wear improves the visual function of patients with visual loss from congenital nystagmus. In this study, four patients with congenital nystagmus had two evaluations separated by at least one week (one with spectacles, one with contact lenses) including visual acuity, contrast sensitivity, oscillopsia scale, quality of life questionnaire (NEI VFQ-25), and eye movement recording with an infrared tracking system. All patients subjectively preferred contact lenses to spectacles. Their contrast sensitivity and VFQ-25 scores were improved with contact lenses compared with spectacles alone. Several parameters of nystagmus showed no change in two patients, worsening in one patient and improvement in one patient. This suggests that much of the clinical improvement observed in our patients may result from a better optical correction of their refractive error with contact lenses than with spectacles, rather than from a true damping effect of the nystagmus by contact lenses.

Development of new treatments for congenital nystagmus.

The use of ocular motor data as the basis for the development of both nonsurgical and surgical therapies for congenital nystagmus (CN) has been underway since the mid-1960s. This paper presents three nonsurgical therapies (composite prisms, soft contact lenses, and afferent stimulation) and a new surgical therapy (four-muscle tenotomy) hypothesized from analysis of ocular motor data. The expanded nystagmus acuity function test was developed to both predict and measure the effectiveness of CN therapies and for intersubject comparisons. Base-out prisms may be used to damp CN during distance fixation in patients whose CN damps during near fixation and who are binocular (i.e., they have no strabismus). Soft contact lenses may be used in those whose CN damps with afferent stimulation of the ophthalmic division of the trigeminal nerve. Cutaneous afferent stimulation (rubbing, vibration, or electricity) of the forehead or neck damps CN in some individuals. Finally, as first demonstrated in an achiasmic Belgian sheepdog and later in humans, tenotomy of the four horizontal rectus muscles and reattachment at their original sites may also damp CN. Taken together, these findings suggest the existence of one or more proprioceptive feedback loops acting to change the small-signal gain of the extraocular plant. Four-muscle tenotomy provides a needed therapeutic option for the many individuals with CN for whom other surgical therapies are contraindicated. Tenotomy may also prove useful in see-saw nystagmus (it abolished it in the aforementioned canine) or other types of nystagmus; further studies of the latter are required.

Reduction of congenital nystagmus amplitude with auditory biofeedback.

PURPOSE: Treatment options for congenital nystagmus without null position are limited. The purpose of this study was to evaluate the role of auditory biofeedback in controlling congenital nystagmus. METHODS: Ten patients with congenital nystagmus without null position underwent 6 sessions (twice a week for 3 weeks) of auditory biofeedback. Each half-hour session had simultaneous electronystagmographic recording done during the session. RESULTS: The patients could reduce the nystagmus during the treatment sessions. Mean amplitude (degrees) of nystagmus was reduced from 6. 28 +/- 4.94 to 3.05 +/- 2.48 (P =.028) and mean intensity (amplitude x frequency) was reduced from 33.37 +/- 22.84 to 13.35 +/- 7.99 (P =. 0174), but the mean frequency change was not significant, from 5.8 +/- 1.05 to 4.98 +/- 1.35 (P =.148). The mean amplitude and mean intensity decreased by 51% and 60%, respectively. After completion of the session, although a subjective improvement was reported, the patient's binocular visual acuity on Snellen's charts and contrast sensitivity did not show any significant change. Also no sustained benefit was noted because the electronystagmographic recordings reverted to baseline after the auditory stimulus for biofeedback was discontinued. CONCLUSION: Simultaneous electronystagmographic recording shows significant reduction of nystagmus amplitude and intensity because of auditory biofeedback only during the treatment session. The beneficial effect does not persist after the auditory stimulus is discontinued. No objective effect on visual acuity and contrast sensitivity was noted after the therapy.

Prospects for treating acquired pendular nystagmus with servo-controlled optics.

PURPOSE: To determine whether a device featuring electronically controlled motor-driven prisms can reduce oscillopsia and improve acuity in patients with acquired pendular nystagmus (APN). METHODS: A device was developed that senses eye movements and, by the use of motor-driven prisms, oscillates the image of the world in lockstep with the pathologic nystagmus, to negate its deleterious visual effects. Unlike existing optical and surgical treatments for nystagmus, the device negates only the pathologic movements. Voluntary and normal reflex eye movements required for normal vision are unaffected. The benefits of the device were assessed by its impact on acuity in five patients with medication-refractory APN. RESULTS: All patients reported decreases in oscillopsia when the device was in operation. Averaged across patients, the device increased the percentage of time in which retinal image velocity was within +/-4 degrees/sec from 12.8% to 33.3%. Acuities improved in four of five patients, by an average of 0.21 logMAR units. CONCLUSIONS: The symptoms of pendular nystagmus can be treated with a servomechanical device. Further refinements in the device should result in greater improvements in acuity, and a portable, wearable version is feasible using existing technologies.