Albinism: particular attention to the ocular motor system.

The purpose of this report is to summarize an understanding of the ocular motor system in patients with albinism. Other than the association of vertical eccentric gaze null positions and asymmetric, (a) periodic alternating nystagmus in a large percentage of patients, the ocular motor system in human albinism does not contain unique pathology, rather has "typical" types of infantile ocular oscillations and binocular disorders. Both the ocular motor and afferent visual system are affected to varying degrees in patients with albinism, thus, combined treatment of both systems will maximize visual function.

INTRODUCTION

Albinism is a genetic condition of hypopigmentation caused by an abnormality in melanin pigment production. The absence or reduction of melanin has a severe impact on the development of the eye and visual system, such that persons with albinism display a variety of ophthalmic deficits, including foveal hypoplasia, translucency of the iris, nystagmus, reduced visual acuity and an abnormal decussation pattern at the optic chiasm.12 The characteristic, which is thought to distinguish albinism from other visual disorders resulting in foveal hypoplasia and other disorders of hypopigmentation is the abnormal routing of visual pathways from the eye to the brain.13 Clinically, it is this abnormality in conjunction with phenotypic evaluation and ophthalmic examination that has been used to diagnose albinism.

Albinism is not a single entity; it encompasses a heterogeneous group of congenital hypomelanotic disorders. Using one system of classification oculo-cutaneous albinism (OCA1A), being the most severe type, is characterized by a complete lack of melanin production throughout life, while the milder forms OCA1B, OCA2, OCA3 and OCA4 show some pigment accumulation over time. These disorders can also be classified into three general categories of regional hypopigmentation involving neuroectoderm (ocular albinism [OA]), neural crest (albinoidism), or both (oculocutaneous albinism). In OA, there is hypopigmentation of ocular neuroectoderm (iris and retinal pigment epithelium) that manifests clinically with iris transillumination, macular hypoplasia, chorioretinal hypopigmentation, photophobia, and nystagmus. The term albinoidism is applied to a condition in which hypopigmentation is limited to tissues of neural crest origin (skin, hair, and iris stroma). Unlike patients with OA, those with albinoidism do not manifest macular hypoplasia, nystagmus, photophobia, or decreased vision.24

EPIDEMIOLOGY

Albinism can affect people of all ethnic backgrounds. Approximately one in 17,000 people have one of the types of albinism.35 Prevalence of the different forms of albinism varies considerably worldwide. OCA1 has a prevalence of approximately 1 per 40,000 in most populations but is very uncommon among African-Americans.35 In contrast, OCA2 is the most common type of albinism in African OCA patients.35 The overall prevalence of OCA2 is estimated to be 1:36,000 in the USA, but is about 1:10,000 among African Americans.35 It affects 1 in 3,900 of the population in some parts of the Southern part of Africa.35 OCA3 or Rufous oculocutaneous albinism has been reported to affect 1:8,500 individuals in Africa, whereas it is very rare in Caucasians and Asiatic populations.35 Recently, mutations in a fourth gene were shown to be the cause of albinism, OCA4, and were reported to explain the disease in approximately 5-8% of German patients with albinism but 18% of Japanese patients.6

Clinical description

All types of OCA and OA have similar ocular findings, including various degrees of early onset nystagmus, hypopigmentation of iris and retinal pigment epithelium, foveal dysplasia, ametropia, strabismus and reduced best-corrected visual acuity [Figure 1]. Photophobia and light interference may be prominent. The abnormal crossing of chiasmatic, post-chiasmatic fibers can be demonstrated by monocular visual evoked potentials.

Figure 1

Typical appearance of skin, hair, lashes and eyes of patient with oculo-cutaneous albinism 1. Complete iris transillumination is also illustrated

Because albinism is often associated with decreased vision, nystagmus, and refractive errors, recognition visual acuity may vary depending on an eccentrically induced head position, accuracy of glasses prescription, and experience of the visual acuity tester. Reliance on fixation preference testing, such as Teller acuity cards, to assess vision has been required for patients younger than 2 years.7 Sweep visual evoked potential (VEP) testing is a novel technique that can be used to assess visual acuity in pre-verbal patients with albinism.8 Reports have demonstrated a correlation between binocular grating acuity and future letter recognition acuity in patients with ocular and oculocutaneous albinism.9 Studies demonstrates that sweep VEP testing can be used as a predictive tool for recognition acuity in patients with albinism.3810 It has been reported that Teller acuity over-estimates recognition acuity in children with albinism. Because albinism is a rare diagnosis, most published studies that compare grating with recognition acuity involve small patient numbers.3810

A number of inherited diseases with nystagmus show a combination of immunological and pigmentation defects.11121314151617181920 Chediak-Higashi, Hermansky-Pudlak, Griscelli, and paroxysmal autonomic instability with Dystonia syndromes are all autosomal diseases with these characteristics. The molecular links between immunodeficiencies and albinism reflect the fact that both melanosomes and secretory lysosomes are not secreted normally. Chediak-Higashi syndrome, a disease characterized by repeated infections and albinism, shows the presence of abnormally large lysosomes and melanosomes, suggesting that melanosomes are not secreted normally, and supporting a functional link with the secretory lysosomes of hematopoietic cells.21

Diagnostic methods

The diagnosis of OCA is usually based on clinical findings of hypopigmentation of the skin and hair, in addition to the characteristic ocular symptoms.1322232425 However, due to the clinical overlap between the OCA subtypes, other testing such as molecular, electrophysiological or radiological may be necessary.1322232425 Molecular genetic testing of tyrosinase (TYR) and OCA2 are available on a clinical basis, while at present, analysis of tryparedoxin peroxidase gene (TYRP1) and Ter macrodomain organizer matS-binding protein gene (MATP) is on research basis only.1322232425

Increased crossing of optic nerve fibers in the chiasm is one of the most consistent findings in albinism in all species.2627 In humans, it has been found to be highly specific and asymmetries in visual evoked potentials are very helpful as a diagnostic tool for albinism. While the great majority of children with albinism show crossed hemispheric asymmetry on visual evoked potentials, occasional all otherwise classic albinism show no evidence of hemispheric asymmetry.2627

Individuals with mild ocular or oculocutaneous albinism are often misdiagnosed as having idiopathic Infantile Nystagmus Syndrome (INS). The finding of subtle signs of ocular hypopigmentation in some infantile nystagmus and anomalous head postures (AHPs) [Figure 2] syndrome patients with good vision has led to speculation that patients with idiopathic INS may actually be heterozygous for albinism. Simon et al. have demonstrated that when patients with INS are carefully examined, many show iris transillumination, blunting of the macular reflex, and chorioretinal hypopigmentation consistent with albinism.28 In evaluating the INS patient, it is critical to perform a careful slit lamp examination with the room lights turned off, the door closed, and a retro-illumination through a thin, axial light beam to detect basal iris transillumination. Varying degrees of macular hypoplasia (absence of the foveal pit, absence of macula lutea pigment, absence of normal macular pigment epithelial hyperpigmentation, and passage of retinal vessels through the fovea), together with other signs of ocular hypopigmentation, suggest the diagnosis of albinism. However, isolated foveal hypoplasia may also occur as a hereditary condition in children with normal pigmentation. Other valuable clinical signs of albinism are often overlooked. For example, patients with albinism have a positive angle kappa that is usually absent in patients with idiopathic INS. Studies have suggested a characteristic optic disc appearance in albinos consisting of a small, cupless disc, with temporal entrance and situs inversus of the vessels, an oblique long axis of the disc26 [Figure 3].

Figure 2

A composite illustration of the typical differences in the photographic appearance of a normal optic in disc (top) and patient with albinism (bottom)

Figure 3

Illustration of typical anomalous head posturing in patients with albinism. Many patients have a chin-down posture associated with a vertical eccentric gaze nystagmus null position, although horizontal head/face turns dominate

Other ocular and systemic hypopigmentation disorders should be considered in the differential diagnosis of albinism. Creel et al. have reported asymmetrical hemispheric VEPs in patients with Prader-Willi syndrome (a condition characterized by hypotonia, hypomentia, hypogonadism, and hyperphagia).29 Aland Island eye disease (Forsius-Eriksson syndrome) is a form of ocular hypopigmentation associated with electroretinographic findings of congenital stationary night blindness.15 Other ocular and systemic hypopigmentation disorders such as Waardenburg syndrome and phenylketonuria also lack the hemispheric VEP asymmetry seen in albinism.

THE OCULAR MOTOR SYSTEM

Eye movements bring visual stimuli to the fovea, maintain foveal fixation of stationary and moving targets during head movements, assist with body orientation in space and during motion. These movements are performed by the ocular motor system that consists of ocular motor nerves and nuclei in the brainstem originating in the cerebral cortex, cerebellum, vestibular structures, and the extraocular muscles. Anatomically, the ocular motor system may be divided according to location into infranuclear, nuclear, internuclear, and supranuclear components. It is important to distinguish between supranuclear, internuclear, nuclear and infranuclear (orbital, cranial nerves) disorders because the disturbances have highly varied causes and present different clinical pictures. Eye-movement abnormalities of supranuclear origin are characterized by gaze palsies, tonic gaze deviation, saccadic and smooth pursuit disorders, vergence abnormalities, nystagmus, and saccadic oscillations. Supranuclear disorders such as nystagmus in infancy and childhood result from brain dysfunction above the level of the ocular motor nerve nuclei.

In 1985 Collewijn suggested a subdivision of albinos into three classes of oculomotor behavior. Class I was characterized by vigorous spontaneous nystagmus (of the pendular unidirectional jerk or bidirectional jerk type), the absence of true horizontal optokinetic nystagmus (OKN) but the presence of the ability to control the direction of gaze in an imprecise way. In Class II there is a vigorous unidirectional jerk nystagmus that reverses in direction spontaneously or as a result of visual stimulation. Moving stimuli typically elicited inverted pursuit, the smooth eye movements having a direction opposite to that of the stimulus movement. Class III is characterized by very little or no spontaneous nystagmus and virtually normal oculomotor responses.30

There are several types of nystagmus usually seen in infancy. The most common are those in the INS (INS, aka “congenital” nystagmus). Others are the nystagmus called Fusion Maldevelopment Nystagmus syndrome (FMNS, aka latent/manifest latent nystagmus [LMLN]) and the pendular nystagmus of the Spasmus Nutans syndrome. The nomenclature recommended by the Classification of Eye Movement Abnormalities and Strabismus Working Group is referred in this report as it eliminates the confusing and misleading terminology of the classical names found in the literature.31 The nystagmus comprised in the INS is usually present at birth or noted in early infancy during the various sensitive periods defining the development of visual fixation and it persists throughout life. The syndrome consists of one or more types of characteristic waveforms, head turns, tilts, or oscillations.32333435

The nystagmus waveform in idiopathic INS (in which there is no afferent visual pathway rerouting) is identical to the ones present in albinism, suggesting that anomalous afferent pathway of the albino visual system interferes with ocular motor calibration in the same way as other congenital or early infantile sensory system deficits and it is that similar anomalous ocular motor calibration that is primarily responsible for INS in albinism.73436373839 In addition to retinogeniculate, cortical, and intracortical neural misrouting, albino animals have also been found to have misrouting of their subcortical visual pathways, which are intimately involved in optokinetic responses.40 Although numerous studies have described INS pathophysiology and its effect on the visual system, its etiology remains elusive. Defects involving the saccadic, optokinetic, smooth pursuit, and fixation systems as well as the neural integrator for conjugate horizontal gaze have been proposed.73436373839 Biomedical control system models have reproduced this oscillation and it has been attributed it to a “high gain instability” in the ocular motor system. This loosely translates as an error in “calibration” of the eye movement system during attempted fixation. Including genetic predisposition, many clinical conditions are associated with the INS oscillation.4142

Regardless of its clinical associations, nearly all patients with INS have infantile onset in common; we can deduce that this oscillation is most likely to occur in an immature ocular motor system. The etiology is probably multifactorial but the final common pathway may be interference with neural “cross talk” between the developing sensory and motor systems during a period of developmental sensitivity.

Two of the more particular associations of the INS and albinism include the predominant and underappreciated presence of an eccentric vertical gaze null (chin-up or chin-down head posture), and the presence of spontaneous changing direction/intensity of the oscillation43 [Figures 2, 4 and 5].

Figure 4

Eye movement recording from patient with albinism and typical periodic alternating nystagmus performed under binocular conditions using velocity data trace from the preferred right eye over 200 s illustrating a typical periodic, symmetric, oscillation with approximately 90 s of jerk right followed by 10-20 s of slowing and direction change followed by 90 s of jerk left. Up is right (R), down is left (L), upper trace is position and lower trace is velocity in both upper and lower portions of the figure

Figure 5

Eye movement recording data of OS from patient with oculo-cutaneous albinism performed under binocular conditions using data from the left eye illustrating a typical asymmetry during a periodic type of rhythmic cycle with changes in the waveforms evident when the fast phase is to the left (pure jerk left wave form) and to the right (jerk right with extended foveation). It is easy to see that this patient will have better vision and visual function during the jerk right phase of the cycle. OS = left eye, up is right (R), down is left (L), upper trace is position and lower trace is velocity

Most clinicians are familiar with the dynamic oscillation of 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 min, followed by a quiet period, and then reappearance of the nystagmus in the opposite direction for a similar length of time36444546 [Figure 4]. It is usually seen in association with vestibulo-cerebellar disease, neurodegenerative conditions such as Friedreich's ataxia, or vision loss.36444546 The dynamic neutral zone in INS varies spontaneously with time in up to 1/3 of patients with albinism while fixating a static target. Many of these albino patients with INS, exhibit an asymmetric, (a) periodic alternating nystagmus (APAN).34353638474849 Unlike acquired PAN, APAN is usually asymmetric, with unequal time periods of jerk nystagmus in each direction. APAN has all the characteristics of INS except that the null point shifts position in either a regular (periodic) or irregular (aperiodic) pattern and is usually also asymmetric (unequal intervals of jerk nystagmus in each direction) [Figure 5]. This results in changes in the intensity and/or direction of the nystagmus from seconds to minutes. APAN encompasses all idiosyncratic variations in intra- and inter-cycle timing and amplitudes; more specific nomenclature can be applied when these characteristics are known. The occurrence of APAN in INS was thought to be rare but many authors have reported otherwise.34353638474849 There is also switching between accelerating and linear slow phases in the two directions and asymmetries, even in those patients who's APAN was essentially periodic. The recognition of both PAN and APAN is essential when surgery is being considered for either acquired nystagmus or INS. Abadi and Pascal studied 25 subjects with oculocutaneous albinism (16 tyrosinase negative and 9 tyrosinase positive) and seven with OA (five x-linked and two autosomal recessive) and found that 12 exhibited APAN.36 The nystagmus waveforms encountered during the APAN active phases were either jerk-with-extended-foveation or pseudocycloid, whereas a variety of oscillations (including triangular and bidirectional) were evident during the quiet phases. Gradstein et al. diagnosed APAN in 18 (9%) of their 200 patients with infantile nystagmus, although most had not been diagnosed49 with APAN before referral, despite changing nystagmus reported by referring clinicians. In those 18 patients, they found five to have ocular or oculocutaneous albinism and 16 had an alternating AHP. The APAN cycle was of variable duration, often with asymmetric right- and left-beating components. Half of the patients showed a combination jerk and pendular waveforms in both phases. In another report, the same authors found ocular oscillations consistent with INS evident in 24 of 27 patients with oculocutaneous albinism and Hermansky-Pudlak syndrome (HPS) and half showed PAN. They concluded that most patients with HPS have INS, and many have PAN. Hosokawa et al. found periodicity in the time-frequency distribution in 3 of 13 patients (23%) with albinism and INS.50

Hertle, et al. reported 78 patients with APAN and found that 46% had an associated diagnosis of oculocutaneous or OA34. Most of their patients had strabismus (72%) and an AHP (87%) with one-third having a visually preferred eye. The clinical head/face position was evenly split between those patients with a static head posture and a dynamic (alternating) posture. Interestingly, those patients with strabismus were more likely to have a static head posture, even with a periodic rhythm detected on eye-movement recordings.

Although, INS may result from a primary genetic defect directly affecting ocular motor calibration, it may also result from abnormal cross-talk from a defective sensory system to the developing motor system at any time during the motor system's sensitive period [Figures 6 and 7]. This can occur from conception due to a sensory defect (e.g., foveal, retinal dystrophy), during embryogenesis due a developmental abnormality (e.g., optic nerve hypoplasia), or after birth during infancy (e.g., congenital cataracts). This theory of the genesis of INS incorporates a pathophysiologic role for the sensory system in its genesis and modification. While the set of physiologic circumstances may differ, the final common pathway is abnormal calibration of the ocular motor system during its sensitive period. The primary ocular motor instability underlying INS is the same but its clinical and oculographic expression are modified by both initial and final developmental integrity of all parallel afferent visual system processes.

Figure 6

Eye-movement video and recording from an 86 year-old patient with albinism and Infantile Nystagmus syndrome. The recording illustrates conjugate, jerk with extended foveation waveforms. Notice that after the 2 s mark the nystagmus improves due to a null position in immediate left gaze. On the figure, up is right, down is left

Figure 7

Patient with albinism and unidirectional direction jerk Infantile Nystagmus syndrome (INS) waveforms with change in direction with changing eye fixation (INS with “latent component”). Note the accelerating slow phases; R-right; L-left. Figures, by convention, eye motion to the right up and to the left down, OD = right eye, OS = left eye, Sec = seconds

The other childhood form of nystagmus reported in patients with albinism is FMNS (FMNS, aka LMLN) which exhibits : A jerk nystagmus with either a linear or decreasing-velocity exponential slow phase identical to that of gaze-paretic nystagmus; strabismus; alternating hyperphoria/dissociated vertical deviation; and pendular torsional nystagmus in primary position5152535455 [Figure 8]. The constantly present, conjugate, horizontal, jerk nystagmus increases in intensity by monocular occlusion, blurring, or reducing image brightness. A jerk nystagmus with a linear slow phase may be present when both eyes are closed. Rarely, the nystagmus is only evoked by the “pure” or “true” latent condition and occurs only with uniocular viewing (i.e., the other eye being occluded). That is, there is no nystagmus when both eyes are viewing, but when one eye is occluded, jerk nystagmus develops in both eyes, with the fast phases toward the uncovered eye, The term, “manifest latent nystagmus” was first defined by Kestenbaum as being present with both eyes open but only one being used for fixation. Using eye movement recordings mild fusion maldevlopment nystagmus (FMNS) with both eyes viewing can usually be detected in those patients who may appear to have “pure” latent nystagmus clinically. True/pure FMNS “latent nystagmus vera” is uncommon.5152535455 The intensity of FMNS decreases when visual attention declines and increases during attempted fixation. FMNS may clinically resemble other types of nystagmus (e.g., INS with a latent component) and require eye-movement recordings to differentiate it.

Figure 8

Eye movements (position and velocity) of albino patient with Fusion Maldevelopment Nystagmus syndrome (FMNS) and changing Nystagmus jerk direction to the direction of the fixing eye (note linear and decreasing velocity slow phases typical of FMNS)

The prevalence of strabismus averages 53% in patients with albinism but varies depending on the phenotype or genetic diagnosis, with a prevalence of almost 100% in patients OCA1. The most common forms are basic comitant esotropia or exotropia, although all motor components of the Infantile Esotropia syndrome have been reported, i.e., dissociated deviations, apparent over- or under-action of the obliques, alphabet patterns. There are also reports of frequent saccadic intrusions in patients with albinism, the sizes of which were correlated with velocities of steady drifts in fixations.56

TREATMENT

Other aspects of visual functions have been reported affected in patients with OCA and INS, both with and without diagnosed sensory system deficits.35758596061 These include contrast sensitivity, color vision, motion perception, temporal luminance, contour interaction, smooth pursuit and OKN.35758596061 Despite foveal hypoplasia, spectacle correction should be encouraged in children with albinism, since improved visual acuity and ocular alignment and reduction of abnormal head positions are among the recognized benefits. Children with albinism may similarly appreciate improved vision from INS surgery and from eye muscle surgery which improves the ocular oscillation and secondary torticollis.34394362

Numerous treatments have been described for INS. These include dietary manipulation, drugs, contact lenses, prisms, biofeedback, intermittent photic stimulation, acupuncture, transcutaneous vibratory or electronic stimulation of the face and neck, injection of botulinum toxin, and a variety of surgical procedures. Excepting those treatments that directly improve visual acuity (spectacle and contact lens correction of refractive errors), all these treatments have in common a desired effect of reducing the nystagmus intensity directly or indirectly, allowing for an increase in visual acuity. In a review of a total of 361 patients undergoing surgical repositioning of the eyes for INS from 21 reports in which vision was measured both pre-operatively and post-operatively, 273 (76%) had improved vision after the surgery.3438636465666768697071 There are specific reports showing an improvement in 1 or greater LogMar in OCA patients after extraocular muscle (EOM) surgery72 [Figure 9].

Figure 9

Eye movement recordings from the null position before (left panels) and after (right panel) eye muscle surgery in a patient with albinism showing significant favorable changes in foveation without a significant change in frequency

CONCLUSIONS

Other than the association of vertical eccentric gaze null positions and APAN in a large percentage of patients, the ocular motor system in human albinism does not contain unique pathology, rather has “typical” types of infantile ocular oscillations and binocular disorders. This summary emphasizes that both the ocular motor and afferent visual system are affected to varying degrees in patients with albinism, thus combined treatment of both systems will maximize visual function.