INFANTILE NYSTAGMUS

This demonstrates a typical "chin-down" up-gaze eccentric null position common in patients with Type 1 OCA when asked to fixate. Courtesy of Richard W Hertle MD

The nine-year-old boy arrived at the office of Richard W Hertle MD, who specialises in paediatric ophthalmology and ocular motor disorders, with oculocutaneous albinism (OCA). He displayed decreased acuity strabismus, anomalous head posture and nystagmus.

The boy’s visual acuity (VA) tested 20/200 binocularly, with 20/300 monocularly, Dr Hertle recalled. His parents had been told 20/200 was the best VA they could expect.

It is a story Dr Hertle hears often on referral, even in the USA, where he practises at Akron Children’s Hospital in Akron, Ohio. “They say, ‘there is nothing we can do, sign your child up for school for the blind, they are never going to drive.’ And this is the baby seeing the ophthalmologist for the first time, usually in the first two months of life.”

But Dr Hertle knew better vision was not only possible but likely. Over the past three decades he has treated more than 4,500 nystagmus patients and operated on nearly 3,000. With colleagues he has developed diagnostic and treatment algorithms that improve many visual functions in all patients and letter VA in 75 per cent of nystagmus patients – particularly those related to dynamic function, such as target recognition time, gaze dependent vision, motion processing and contrast sensitivity.

Dr Hertle found the boy had iris transillumination, foveal and optic
nerve dysplasia – and an uncorrected refractive error of -5.00D sphere, +6.25D cyl x 120° right and -5.00D sphere, +6.25D cyl x 60° left.

“It’s hard to believe some of these kids aren’t even given glasses,” said Dr Hertle.

In addition, the patient had typical infantile nystagmus, with its tell-tale increasing velocity slow phase that is a positive indication of infantile nystagmus syndrome (INS). He also showed a static chin-down head posture, which is common but underdiagnosed in albinism, Dr Hertle added.

Employing a staged approach of optical, medical and surgical treatment, Dr Hertle first prescribed spectacles – immediately improving bilateral VA to 20/180. Eye muscle surgery, consisting of bilateral 5.0mm superior rectus recession with inferior oblique myectomy and lateral rectus tenotomy with reatttachment, improved corrected VA to 20/100.

Switching to peripherally tinted contact lenses to block stray light and improve correction over the full range of eye motion brought VA to 20/80, Dr Hertle reported. With the medication baclofen to reduce the associated periodic component of the nystagmus, common in patients with albinism, final binocular letter VA reached 20/70 – good enough to drive with restrictions in most American states.

The outcome was no fluke. In a series of 85 OCA nystagmus patients undergoing the same approach, mean VA improved from a group mean of 20/170 before treatment to 20/80 after, Dr Hertle reported at the 3rd World Congress of Paediatric Ophthalmology and Strabismus in Barcelona, Spain.

Other outcomes also improved significantly, including contrast sensitivity and gaze-dependent VA. Non-albino patients, who make up about two-thirds of Dr Hertle’s patients, see similar gains.

Multiple comorbidities are common with nystagmus. Among Dr Hertle’s INS patients, 69 per cent have other eye diseases, 61 per cent associated systemic diagnoses, 62 per cent anomalous head posture, 21 per cent a periodic or aperiodic component, 71 per cent strabismus, and 71 per cent refractive error. Treating all these problems generally yields the most vision improvement, Dr Hertle said.

“Medical, optical and surgical combined treatment of the visual system of patients with nystagmus will improve their visual function. All contribute in different ways in different patients but, by and large, a contact lens or glasses can be as powerful as surgery. Every little bit helps these children and makes a big difference in their visual function.”

Diagnostic challenges

Still, nystagmus is a complex disorder. It involves defects of both the afferent system, including the retina, optic nerve and lateral geniculate nucleus, and the efferent system controlling neurological image processing and ocular motor control. These include the smooth-pursuit, saccadic and vergence systems, Dr Hertle noted. He counts over 40 different types of nystagmus.

Nystagmus can result from multiple causes, some are present in infancy and others acquired later in life; some are benign and others are associated with neurological disease or injury. Its presentation can be inconsistent, with speed, amplitude and direction of the oscillation varying with a patient’s visual exertion and attention, gaze direction, target type and range, use of one or both eyes, fatigue, or even from social pressures or no identifiable reasons.

Moreover, variations in nystagmus eye movement are often subtle. Is the movement truly pendular or jerk? Is the slow phase speed constant or accelerating? Does the direction and/or intensity change at regular or irregular intervals? Such features can be impossible to determine from unaided clinical observation. Yet distinguishing them is often vital for proper nystagmus diagnosis – and by extension, effective treatment.

As a result, electronic eye movement recording, usually using infrared or high-speed video devices sampling at hundredths to thousandths of a second, is the gold standard for definitive nystagmus diagnosis, Dr Hertle said.

Much like electrocardiography (EKG) enables identification of specific heart arrhythmias by their electrophysiologic signatures, plotting the direction and amplitude of eye movement in time generates waveforms characteristic of specific nystagmus types and subtypes, and even layered coincident types, Dr Hertle noted. But unlike EKG, which is nearly universally available, most ophthalmology practices don’t have eye movement recorders.

So researchers, including Dr Hertle and long-time collaborator Louis F Dell’Osso PhD, have used eye movement technology to classify nystagmus diagnoses – and developed clinical algorithms useable without eye movement technology to diagnose and effectively treat many nystagmus patients.

Nystagmus algorithms in practice

In his book co-authored with Dr Dell’Osso, Nystagmus in Infancy and Childhood: Current Concepts in Mechanisms, Diagnoses and Management (Oxford University Press 2013 ISBN 978-0-19-985700-5), Dr Hertle provides diagnostic flowcharts that can reliably diagnose many nystagmus types, including many forms of INS, the most common form of nystagmus, based on clinical observation. Just as important, these flowcharts help identify ambiguous cases that will require eye movement studies for a definitive differential diagnosis.

The book also includes treatment algorithms, including specifying nine surgical procedures to treat INS based on clinical variables – a procedure for a chin-down (up gaze eccentric null position) is surgical procedure number two in the algorithm, which also includes procedures for nystagmus associated with strabismus.

Dr Hertle calls the algorithms a “black box” approach that simplifies INS treatment.

“It is for surgeons all over the planet who are asking, ‘how can I help these patients, how can I operate and improve aspects of the patients' ocular motor oscillation and improve many visual functions?'” said Dr Hertle, who has helped set up nystagmus services in clinics all over the world.

One surgery algorithm user is Massimiliano Serafino MD, of San Giuseppe Hospital, Milan, Italy. “Prof (Paolo) Nucci and I have been using it for five years and it is very useful,” Dr Serafino told the 3rd World Congress of Paediatric Ophthalmology and Strabismus in Barcelona, where he presented his experience with the clinical algorithm for diagnosing nystagmus without eye movement recorders.

Theory and future research

The theory underlying Dr Hertle’s surgical approach is that reducing nystagmus intensity and correcting head position improves many visual functions, largely by increasing the proportion of time the patient’s fovea spends time on an object of regard (“foveation”). Eye muscle surgery also restores peripheral visual fields (by decreasing esotropia), improves functional vision (contrast sensitivity, visual recognition time, gaze dependent VA, and also improves patients’ comfort and appearance.

Recent discoveries have elucidated that the portion of the surgery where the extraocular muscle is cut reduces nystagmus intensity regardless of whether any movement (recession) or removal (resection) is made – a phenomenon first recognised and reported by J Ringland Anderson MD, of Melbourne, Australia, in his 1959 textbook on ocularmotor surgery, Dr Hertle noted.

Dr Hertle’s working hypothesis is that INS is caused by a defect in the smooth-pursuit system, which enables the eye to track moving targets by anticipating their motion, and directing the eye to move accordingly. In INS, this system is not properly damped, resulting in the eye running away, which accounts for the observed acceleration of slow phase movement. The fast phase is corrective and employs the saccadic system to bring the eye back on target.

Dr Hertle further hypothesises that cutting the eye muscles, particularly at the point where the tendon attaches to the globe (its “enthesis”), constitutes a “rebooting” of the brain and taps into central nervous system plasticity similar to a traumatic brain injury during which the brain responds with a period of renewed plasticity. The entheseal damage stimulates the brain to recalibrate resulting in a dampening, or change in gain, of the smooth-pursuit system. The greater potential plasticity of younger brains may also help explain why nystagmus surgery is more effective in children under two and eight years old than in older patients,
he noted.

Animal models suggest that proprioceptive nerve endings in the area where the ocular muscles tendons attach to the sclera (enthesis) may be especially sensitive to disruption that promotes brain plasticity, Dr Hertle said (Dell’Osso LF, Wang ZI. Prog Brain Res. 2008;171:67-75. Fackelmann L et al. Prog Brain Res. 2008;171:17-20). This is a current subject of neuroanatomy research.

The relationship between foveation time and VA has been established across populations, and formulae such as the expanded nystagmus acuity function (NAFX) have been developed that predict VA improvement based on how much foveation can be improved with treatment. But whether the connection is causative on an individual basis is controversial, Larry Abel PhD, of The University of Melbourne, Australia, told the 3rd World Congress of Paediatric Ophthalmology and Strabismus in Barcelona.

Dr Abel noted that several clinical studies show improvements in both VA and foveation waveforms after medical and surgical treatment. However, basic research undercuts the notion that interrupting retinal images reduces VA, including one study that found no difference in perception of grating images presented under flashing illumination or steady illumination among subjects with and without nystagmus. (Dunn MJ et al. Invest. Ophthalmol. Vis. Sci.. 2015; 56(9):5094-5101)

Another study in which nystagmus patients received small shocks when they made mistakes recognising figures found that the stress actually reduced foveation time, but improved VA (Jones PH et al. Invest Ophthalmol Vis Sci. 2013 Dec 5;54(13):7943-51). “The evidence for causation is weak and there is some contrary evidence,” Dr Abel noted.

Still, the positive effects of nystagmus surgical and medical treatment demonstrated again and again in clinical series cannot be ignored, Dr Abel said. Part of the problem may be that static VA is an inadequate indicator of functional visual performance, which generally includes dynamic and temporal elements in the real world. He suggested that further research is needed to develop outcomes measures that simulate tasks such as finding items in a grocery store or navigating in traffic.

Dr Hertle agreed, and pointed out that VA is not an outcome measure routinely reported when assessing the effectiveness of strabismus surgery. Improvement in eye and head posture, binocular function, reduction of patient effort to see, and improvements in social function are considered reason enough.

Most of all, Dr Hertle wants more surgeons to recognise that treating nystagmus is not a lost cause. “I’m really hoping that ophthalmologists who see these patients will go from ‘there’s nothing I can do’, to ‘maybe there’s something I can do’, to ‘there is something I can do,’ and then do it.”

Richard W Hertle: rhertle@chmca.org

Massimiliano Serafino:
massimiliano.serafino@multimedica.it

Larry Abel: label@unimelb.edu.au