Introduction
Nystagmus is defined as a rhythmic oscillation of the eyes. The term “nystagmus” is a transliteration of a Greek word for “drowsy head-nodding movements,” since the jerky eye movements seen in many types of nystagmus resemble the slow downward drift and upward-jerking head movements observed when sleepy. Nystagmus caused by pathology is essentially involuntary, although individuals may be able to modulate certain features of their nystagmus voluntarily. The appearance of the eye movements in nystagmus is extremely diverse. They can be described using a number of characteristics which can also assist in the diagnosis ( Figure 45.1A ):
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Intensity: the overall speed or intensity of the eye movements can be estimated by multiplying the amplitude (degrees) with the frequency (hertz) of the eye movements.
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Plane: nystagmus most commonly occurs along the horizontal axis, although nystagmus can also be vertical, torsional, or any combination of these, such as seesaw nystagmus (vertical with torsional) or cyclorotatory nystagmus (horizontal with vertical).
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Waveform: historically, nystagmus has been divided into jerk nystagmus, which exhibits a quick and slow phase, and pendular nystagmus, which is a sinusoidal-like oscillation without any obvious quick phase. Many nystagmus waveforms, however, are more complex, often consisting of an underlying pendular oscillation interrupted by regularly occurring quick phases.
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Conjugacy: with most nystagmus the eyes move in tandem and are described as conjugate or associated. Disconjugate or dissociated nystagmus occurs when the eye movements differ in amplitude, frequency, waveform, or when the oscillations of the two eyes are out of phase with each other.
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Foveation: many forms of congenital nystagmus show periods where the eyes move at a lower velocity allowing high-acuity vision at the fovea to function. The dynamics of these foveation periods can be related to visual acuity.
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Dependence on other parameters: certain types of nystagmus waveform are not constant but vary with time (e.g., can be intermittent or reverse direction), monocular or binocular viewing, convergence or eccentricity of gaze ( Figure 45.1B ). Nystagmus may also be associated with head movements.
Nystagmus can be grouped into infantile nystagmus, which usually appears within the first few months of life, and acquired nystagmus. Acquired nystagmus is typically associated with oscillopsia, the perception that the world is in motion. This can be extremely disabling, leading to worse visual function than is caused by low vision or age-related macular degeneration. Nystagmus leads to deterioration in visual acuity mainly because of deterioration in foveal vision when images move across the retina rapidly. The constant motion can also lead to reduced motion sensitivity. Nystagmus can also have a significant psychological and social impact.
A classification scheme for pathological nystagmus has been proposed by the National Eye Institute, USA, under the Classification of Eye Movement Abnormalities and Strabismus (CEMAS). Nystagmus has been subdivided into: (1) infantile nystagmus syndrome; (2) fusion maldevelopment nystagmus syndrome; (3) spasmus nutans syndrome; (4) vestibular nystagmus; (5) gaze-holding deficiency nystagmus; (6) vision loss nystagmus; (7) other pendular nystagmus and nystagmus associated with disease of central myelin; (8) ocular bobbing (typical and atypical); and (9) lid nystagmus. Although the CEMAS classification is comprehensive and includes all forms of nystagmus it is mainly based on the nystagmus waveform observed using eye movement recordings which can be difficult to determine in routine clinical practice. It also pools together many forms of infantile nystagmus such as idiopathic infantile nystagmus (IIN), nystagmus associated with albinism, and achromatopsia.
The prevalence of nystagmus is 2.4 per 1000. The main types of childhood nystagmus are IIN, associated with albinism, nystagmus secondary to retinal disease and low vision, manifest latent nystagmus (MLN), spasmus nutans, and nystagmus due to neurological syndromes ( Figure 45.2 ). Acquired nystagmus can result from a range of neurological disorders, of which the most common are multiple sclerosis, disease of the vestibular apparatus and innervations, insult to the nervous system caused by stroke, tumours, or trauma, and as a result of drug toxicity.
Infantile nystagmus
Manifest latent nystagmus
Clinical background
MLN (classified as “fusion maldevelopment nystagmus syndrome” by CEMAS) is a predominantly horizontal, jerk nystagmus that becomes more apparent when one eye is covered ( Box 45.1 ). It is caused by a slow drift towards the covered eye with corrective quick phases towards the open fixing eye. In almost all patients, nystagmus is present with both eyes open: it is smaller in intensity and may be subclinical in size. The manifest component describes the nystagmus observed when both eyes are open and the latent component when one eye is covered ( Figure 45.3A ). MLN is associated with congenital squint syndrome which leads to disrupted binocular vision. The manifest component of MLN is due to suppression of the image from one eye. In patients who show an alternating esotropia, the direction of drift and beating can change spontaneously depending on which eye is fixing.
Characteristics
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Predominantly a horizontal, jerk nystagmus with decelerating slow phases
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The manifest component of the nystagmus is evident when both eyes are open
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The latent component (increase in nystagmus amplitude) is revealed when one eye is occluded
Underlying cause
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Interruption of binocular visual development, through strabismus and amblyopia, leading to a nasalward bias of the eyes
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This leads to a drift towards the nonfixing (or covered) eye with the fast phases being corrective
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Due to reduced input from the visual cortical binocular motion areas leading to the domination of the direct retinal pathway which has a nasalward motion bias
Treatment
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Surgical correction of strabismus
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May also be combined with correction of a head posture used by some patients to suppress the nystagmus
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Treatment of amblyopia using occlusion therapy
Eye movements of MLN typically have “decreasing velocity” or “decelerating” slow phases and increasing intensity in abduction ( Figure 45.3A ). Patients with MLN can show a head turn to keep the fixating eye in adduction in order to reduce the nystagmus intensity ( Figure 45.3B ). Patients may also show a head tilt which could be part of the congenital squint syndrome unrelated to MLN or may be to compensate for the cyclovertical (i.e., torsional and vertical) component often seen in MLN. MLN can be treated by correcting the esotropia: this can be combined with correction of the head posture using eye muscle surgery. Treating the underlying amblyopia using patching therapy can also reduce the nystagmus caused by MLN.
Pathology
The underlying mechanism behind MLN is the disruption of binocular vision during visual development. Specifically, MLN appears to result when the motion-sensitive areas of the middle temporal and medial superior temporal (MT/MST) cortex do not develop binocular function.
Etiology
Most commonly MLN is associated with congenital esotropia or congenital squint syndrome. A genetic component of concomitant strabismus is supported by twin studies. Inheritance does not follow mendelian patterns, however, but is more complex, with environmental risk factors contributing. MLN can also result from conditions that cause unilateral loss of vision during visual development such as cataract and optic nerve hyoplasia. MLN is often associated with Down syndrome.
Pathophysiology
Insights into the cause of MLN come from neurophysiological investigations in monkey models with strabismus induced using visual deprivation. The nucleus of the optic tract (NOT), a subcortical structure, appears to have a pivotal role in the generation of MLN ( Figure 45.3C ). This structure receives two types of inputs (indicated by right and left sides of Figure 45.3C ). The NOT receives ascending projections directly from the contralateral retina and responds primarily to nasalward motion from that eye. Through this pathway a simple optokinetic response to global motion of the visual field is generated but demonstrates a monocular nasalward preference. This pathway is complementary to the rotational vestibulo-ocular reflex driven by the semicircular canals. A second projection descending from motion-sensitive MT/MST cortex causes the NOT to be driven by moving images that have no disparity between the eyes. This is a more refined level of global motion processing generating optokinetic responses to moving stimuli at a particular depth and requires normal binocular alignment. It drives more symmetrical horizontal optokinetic nystagmus (OKN) responses. It is complementary to the translational vestibulo-ocular reflex (horizontal), mediated by the otoliths, which has a gain dependent on viewing distance.
During early visual development, infants demonstrate a monocular nasalward preference to optokinetic stimulation due to the later development of pathways from the visual cortex causing the optokinetic response to be dominated by the retinal pathway to the NOT. With development of binocular vision OKN usually becomes symmetrical. If development of binocular function is interrupted in MT/MST then asymmetry persists and can become exaggerated, leading to a nasalward drift under monocular conditions, i.e., MLN. Since the NOT projects to the vestibular nuclei which integrate visual and vestibular inputs, MLN can be considered as an imbalance between visual and vestibular inputs caused by deficient binocular input from MT/MST cortex.
Idiopathic infantile nystagmus
Clinical background
IIN is an often hereditary condition that usually appears in the first few months of life. The oscillations are usually horizontal and conjugate but may also rarely appear as primarily vertical or even torsional nystagmus. The term “idiopathic infantile nystagmus” is used in preference to “congenital idiopathic nystagmus” as the nystagmus is not always present at birth. The waveform is typically a large slow pendular or triangular oscillation when the nystagmus first appears in infancy and develops into a smaller jerk waveform with age ( Box 45.2 ). This has led to the view that individuals with IIN develop a “foveation strategy” during visual development to improve vision. The jerk nystagmus develops with age as individuals learn how to use “foveating saccades” to maximize the time periods when the eyes are moving slowly. Individuals use these slow periods (called foveation periods) to line up the fovea with targets of interest.
Characteristics
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Mainly horizontal conjugate nystagmus, often consisting of accelerating slow phases or an underlying pendular oscillation interrupted by regularly occurring fast phases
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Usually associated with a null region where the nystagmus has a lower intensity
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The nystagmus appears before 6 months of age and changes during childhood, possibly due to the development of a foveation strategy to improve vision
Underlying cause
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Recent developments have been made in establishing the genetic basis of IIN in locating the FRMD7 gene (on chromosome Xq26.2) which is associated with a common form of X-linked nystagmus
Treatment
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Surgery can be used to correct head postures due to eccentrically placed null regions
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Treatment of the underlying IIN is empirical
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Future treatments with surgical and drug interventions look promising
The intensity of the nystagmus will usually change with the direction of gaze, with the region of lowest nystagmus intensity and longest foveation periods being described as the “null region.” The patient will often prefer to take up fixation at the null region to improve vision and this may result in an anomalous head posture if the null region is eccentric. Although IIN is often described in the literature as being a jerk nystagmus with accelerating slow phase, IIN may show different waveforms that usually vary with eccentricity. Often IIN consists of an underlying pendular oscillation interrupted by regularly occurring foveating saccades (quick phases). Typically, the oscillation drifts towards the null region with the drift becoming accentuated further away from the null region. This results in the quick phases usually beating away from the null region. At the null region the quick phases may beat in either direction or the nystagmus may be pendular. Twelve types of waveform have been described by Del’Osso and Daroff. The majority of these are variations in the timing, amplitude, and direction of foveating saccades with respect to the underlying pendular oscillation.
Apart from the correction of head posture using eye muscle surgery the treatment of IIN has mainly been empirical with most previous research lacking placebo-controlled comparisons. Since IIN dampens on convergence, artificial divergence introduced with eye muscle surgery or prisms has been used to treat patients with IIN and binocular vision. Recession of all four horizontal muscles and, more recently, tenotomy (disinsertion and reattachment on the original insertion) of the four horizontal muscles have been reported to improve visual function and eye movements in nystagmus. Gabapentin and memantine, drugs which may both have an antiglutaminergic action, have also been recently shown to improve vision in IIN patients in a randomized-controlled trial. The mechanism behind how these interventions improve nystagmus is unclear. Several treatments are now becoming available, although they are still at trial stage.
Pathology
The mechanisms underlying IIN are still unknown; however, the genetic basis of the most common form of inherited IIN is just beginning to emerge.
Etiology
IIN can be sporadic or inherited. The most common mode of inheritance is due to X-linked mutations.
Pathophysiology
The cause of IIN is still unknown, with suggested mechanisms remaining in the realm of speculation. In many respects the visual system of IIN patients has been found to be normal. IIN patients can make smooth pursuit eye movements and vestibular responses if foveation is considered. They show normal saccadic oculomotor dynamics, although latencies are delayed. IIN patients also perceive a stable world and can localize targets in space accurately, even outside foveation periods.
Because disorders of the optic chiasm such as seen in albinism lead to nystagmus with many similarities to IIN it has been suggested that the anatomical cause of IIN could be developmental miswiring of the visual system. Physiologically, the sinusoidal-like oscillations commonly lying behind IIN suggest an unstable feedback loop of some sort. Various models have been proposed based around current knowledge of oculomotor circuitry. However, there is no consensus concerning the dysfunctional neuronal structure(s) in IIN, with suggestions including the fixational eye movement system, the pursuit system, and the saccadic system. Recently, it has also been suggested that IIN is a developmental response to poor high-contrast foveal vision where contrast sensitivity to low spatial frequencies is enhanced by moving images across the retina.
Tangible developments in understanding the pathophysiology of IIN have been made with respect to the genetic basis of IIN. Recently, we described IIN associated with a frequently occurring X-linked recessive inheritance localized to various mutations on a single gene called FRMD7 (Xq 26.2) (NYS1) ( Figure 45.4A ). Although the exact function of this gene is still unknown, it is expressed in the retina, cerebellum, and lateral ventricles during development. The FRMD7 protein shows a close homology to the amino acid sequence seen in FARP1 and FARP2 proteins. These appear to modulate the length and degree of neurite outgrowth in the developing rat cortex.
Individuals with mutations in the FRMD7 gene have relatively good visual acuity and typically possess stereopsis. Waveforms associated with a single type of mutation on the FRMD7 gene (as found in family members) can show a wide phenotypic variability ( Figure 45.4 ). However, individuals with FRMD7 mutations show a less anomalous head posture compared to individuals with IIN not caused by FRMD7 mutations ( Figure 45.4B ). This appears to be caused by an increased likelihood of a central null region in individuals possessing mutations in the FRMD7 gene.
Albinism
Clinical background
Oculocutaneous albinism (OCA) is characterized by a lack of pigmentation in the eyes, skin and hair ( Figure 45.5A and Box 45.3 ) and is caused by disruption in the production of melanin due to a number of genetic mutations. In certain forms of albinism there is no apparent lack of pigmentation in hair or skin ( Figure 45.5B ) and only disorders in the visual system are evident (listed below). This is described as ocular albinism (OA) and has a different genetic basis.
