Congenital nystagmus

By Marcello Cherchi, MD PhD

For patients

Congenital nystagmus (CN) is an eye movement abnormality that usually begins in infancy. It consists of an involuntary, somewhat rhythmic, oscillation of the eyes that tends to worsen when a person tries to focus (visually) on a target. The most common symptom of CN is poor vision. Since there are numerous causes of poor vision, your doctor may consider checking for other diseases, and may refer you to an ophthalmologist or neuro-ophthalmologist. The condition is lifelong. Some patients with CN seem to benefit from oral medications (gabapentin or memantine), though these have only been studied in small numbers of patients. Sometimes patients consider treatment with surgery of the muscles around the eyes.

For clinicians

Overview

In otoneurology the phrase, “congenital nystagmus” (CN), refers to an eye movement abnormality that becomes evident around 3 months of age, consists of involuntary cyclical jerk nystagmus or pendular nystagmus that is usually conjugate and usually predominantly horizontal, which worsens on attempted fixation, and may improve when the eyes are in a certain orientation within the orbits (called a “null point”). CN is rare. CN can occur in isolation, or in conjunction with other diseases (such as albinism), including ophthalmologic disease (such as achromatopsia). The most common presenting symptom is poor vision, which results from the fact that the involuntary eye movements interfere with foveation of a target. The underlying pathophysiologic mechanism of CN is unknown. A number of genetic mutations have been reported in association with CN. CN is usually evident on face-to-face examination, though accurate characterization requires instrumented oculographic testing. Some imaging studies report increased gray matter volume in certain temporo-occipital regions and parts of the cerebellum. Patients with CN can also have vestibular disease, and it is reasonable to screen for these. CN patients can also have unrelated ophthalmic disease, so evaluation by ophthalmology or neuro-ophthalmology is appropriate. Small case series report improvement of nystagmus with gabapentin or memantine. Surgery is sometimes attempted. CN is a lifelong condition.

Introduction

The unqualified phrase “congenital nystagmus” (CN) refers broadly to any abnormal pattern of eye movements identified at or shortly after birth. However, in otoneurology, the term is often used to refer more narrowly to a set of oscillatory eye movement disorders (recognized at birth or during infancy) of variable rhythmicity that result from a deficit of the visual fixation and smooth pursuit systems. Clinically what distinguishes these abnormal eye movements is that they worsen (become more pronounced) when the patient is attempting to fixate (Abadi and Dickinson 1986; Dell’Osso and Daroff 1975). This contrasts with most forms of nystagmus arising from peripheral vestibular disease, in which fixation tends to reduce or suppress the nystagmus.

Congenital nystagmus can appear in a variety of forms, and is often difficult to characterize. Dell’Osso and Daroff (Dell’Osso and Daroff 1975) offer the following classification of congenital nystagmus. The tracings show horizontal eye movements.

Pendular nystagmus.
Pure pendular nystagmus (PP). As the name implies, the nystagmus is pendular, meaning there is an approximately sinusoidal (and therefore symmetrical) movement.
Asymmetric pendular nystagmus (AP). While still pendular, the movement in one direction is rapid enough that it is sometimes mistaken for a saccade. “This form usually occurs as the subject looks laterally, but is occasionally present in primary position.”
Pendular nystagmus with foveating saccades (Pfs). This form exhibits “small ‘braking’ saccades [that] stop the SEM [slow eye movement] after it has bypassed the target and, in addition, the saccades achieve refoveation of the target.”
Jerk nystagmus.
Unidirectional jerk nystagmus.
Saccadic foveation. “In both [forms], the saccades are of sufficient amplitude to fully refoveate the target.”
Pure jerk nystagmus (PJ). This has a “classical saw-tooth appearance.”
Jerk nystagmus with extended foveation (Jef). In this form, “There are long periods of foveation following each saccade during which eye is motionless and good vision possible.”
SEM (slow eye movement) foveation. “In the other two types of unidirectional jerk nystagmus, the saccades, although corrective in nature, are of insufficient amplitude to fully refoveate the target.”
Pseudo-cycloid nystagmus (PC). This form is, “often misidentified clinically as pendular [but actually] consists of an accelerating… drift off target which is terminated by a small… braking saccade and following by a SEM [slow eye movement] which refoveates the target.”
Pseudo-jerk nystagmus (PJ). In this form, “the actual direction of the ‘fast’ phase is opposite to the apparent direction.”
Bidirectional jerk nystagmus. These forms, “occur at gaze angles in the transition (neutral) zone in which the direction of the jerk nystagmus is reversed. As such, they are transient, quite variable, and usually not conducive to good vision.”
Pseudo-pendular nystagmus.
Pure pseudo-pendular nystagmus (PP). This form consists of, “alternating accelerating SEM [slow eye movement] and braking saccades.”
Pseudo-pendular nystagmus with foveating saccades (PPfs). In this form, “the waveform is biased (as is Pfs) such that the braking saccades that actually foveate the target are larger than those at the other peaks. They are also of variable amplitudes depending upon the actual overshoot of the target.”
Triangular nystagmus (T). “When bidirectional jerk waveforms occur at the termination of SEM [slow eye movement] that are not rapidly accelerating, a triangular waveform (T) results.”
Bidirectional jerk nystagmus (BDJ). In this form, “one of the two saccades actually foveates the target.”
Dual jerk nystagmus (DJ). This form, “consists of the simultaneous admixture of jerk and pendular nystagmus with the superimposition of a rapid small amplitude sinusoidal oscillation upon the larger amplitude jerk nystagmus.”

The classification described by Dell’Osso and Daroff (Dell’Osso and Daroff 1975) has been adopted by other investigators (Abadi and Dickinson 1986).

The nystagmus is nearly always conjugate, though monocular CN has been described (Kamel 1974). The eye movements are predominantly horizontal, though modest torsional (Abadi and Dickinson 1986; Averbuch-Heller et al. 2002) or vertical (Gresty et al. 1984) components may also be present.

Some forms of CN can be modulated by vergence (Abadi and Dickinson 1986) — typically the spontaneous nystagmus improves with convergence.

Epidemiology

Huang and colleagues (Huang et al. 2018) identified 50 patients with congenital nystagmus out of a clinic population of 32,050 patients who had presented for, “vertigo/dizziness, tinnitus, hearing loss or pathological eye movements,” amounting to 0.16% of that population, and they described this as comparable to the prevalence rate of 1 in 1000 – 1500, citing Self and Lotery (Self and Lotery 2006). In their 50 patients (27 male, 23 female), the mean age at presentation was 36 years, with a range of 3 to 76 years.

Genetics

A range of genetic defects has been reported in association with CN (Arshad et al. 2023; Du et al. 2011; Gupta et al. 2015; Gutmann et al. 1991; He et al. 2008; Hoffmann et al. 2004; Hu et al. 2011; Hu et al. 2012; Kerrison et al. 1996; Kerrison et al. 1998; Kim et al. 2016; Kohmoto et al. 2015; Li et al. 2020; Liu et al. 2007; Patton et al. 1993; Pearce 1978; Peng et al. 2009; Schorderet et al. 2007; Self and Lotery 2006, 2007; Wang et al. 2021; Xiu et al. 2018). The mechanism by which these mutations cause or contribute to CN is unknown.

Pathophysiological mechanism of disease

The underlying pathophysiological mechanism of CN is unknown, though Optican and Zee (Optican and Zee 1984) have proposed a model based on control systems analysis.

Clinical presentation

“The commonest symptom of congenital nystagmus is reduced visual acuity which can range from mild to severe” (Gresty et al. 1984), but this symptom in isolation is not a common reason for referral to otoneurology.

Common reasons for CN patients to be referred to otoneurology include observation (by a family member or another clinician) of abnormal eye movements. It is uncommon for CN patients to be referred for the symptom of disequilibrium (“dizziness,” “vertigo”), but insofar as poor vision can interfere with equilibrium, this is sometimes the basis for the referral.

CN may be apparent at birth, but typically becomes evident around the age of 3 months when infants begin visually to fixate (Huang et al. 2018), and it is a lifelong condition.

It has been well documented that CN reduces visual acuity (Simmers et al. 1999), and in fact, “For all cases of idiopathic congenital nystagmus visual acuity is reduced” (Abadi and Sandikcioglu 1975). This is because, “Normal visual acuity requires a stationary retinal image on the fovea. If fixation instabilities cause movement of the retinal image across the fovea for a few degrees, visual acuity is diminished” (Dorn et al. 2005).

Since untreated congenital nystagmus is constant and lifelong, some investigators have suggested that the chronic interference with foveation may additionally introduce a component of amblyopia, further interfering with vision (Bedell 2006).

The intrusive involuntary eye movements make it difficult to execute visual tasks requiring precise control of eye movements, such as reading (Kudo et al. 1995).

Despite the spontaneous oscillatory nature of eye movements in CN, oscillopsia is not a common complaint. Gresty and colleagues comment that, “When viewing a stationary target under normal illumination oscillopsia is generally not a symptom of congenital nystagmus regardless of eye position” (Gresty et al. 1984). However, patients whose CN manifests as periodic alternating nystagmus (PAN) may intermittently complain of oscillopsia (Abadi and Dickinson 1986).

Physical examination

In a patient with CN who is otherwise healthy, aside from the ocular motor abnormalities and possible head tilt (see below), the remainder of the physical examination should be normal.

However, note that CN is often comorbid with other pathologies (such as albinism) and other ophthalmic diseases (such as achromatopsia).

Ocular motor examination

CN can often be identified on face-to-face examination.

The Video below, from https://www.youtube.com/watch?v=MJgiptV_l3c (accessed 4/2/23), shows a face-to-face examination of a patient with CN.

CN often has a “null point,” meaning a position of the eyes within the orbits at which the nystagmus waveform is smallest. “If the null point is eccentric this leads to a head turn in the opposite direction” (Gresty et al. 1984), which is why many CN patients assume some type of head tilt or rotation when looking “straight ahead.”

Testing: oculographic

Detailed oculographic recordings are often helpful in characterizing CN and distinguishing it from alternative diagnoses.

CN patients often have impaired optokinetic responses, with decreased gain of optokinetic nystagmus and reduced or absent optokinetic afternystagmus (Yee et al. 1980). These findings are sensitive but not specific for CN.

Some studies of patients with CN report the vestibulo-ocular reflex (VOR) to be normal (Yee et al. 1981), while others report it to be consistently abnormal (Gresty et al. 1985). There have been very few studies of the high frequency end of the vestibular spectrum (Denia-Lafuente and Lombardero 2021).

Gresty and colleagues (Gresty et al. 1984) report that, “Abnormalities of responses to rotational testing occur in about 50% of asymptomatic patients with congenital nystagmus” (Gresty et al. 1984).

Curiously, CN patients have reduced motion aftereffects (Shallo-Hoffmann et al. 1998). Presumably this is because consistent foveation (which CN patients lack) is required to build the habituation that generates motion aftereffect illusions when the visual stimulus stops moving.

Imaging

Hufner and colleagues (Hufner et al. 2011) compared MRIs of 14 CN patients (7 males, mean age 28.3 ± 9.38 years) and 18 healthy controls (11 males, mean age 28.56 ± 8.58 years) using voxel-based morphometry. Compared to controls, the CN patients exhibited “significant volume increases in [the gray matter of] the human motion sensitive complex V5/MT+, the fusiform gyrus, and the middle occipital gyrus bilaterally,” and speculate that, “These volume increases may be associated with excess visual motion stimulation due to involuntary retinal slip of the visual scene.”

They further observed a “positive correlation (linear model) of nystagmus sway path with cerebellar GM [gray matter] volume… in the following areas: vermal parts VIII-X as well as hemisphere lobule II, hemisphere VI, crus I, crus II, and lobule VII-IX bilaterally,” and speculated that this, “might be related to the subjects’ attempt to maintain fixation, rather than be due to the generation of nystagmus.”

Differential diagnosis

CN is rare. It can occur in isolation, though is sometimes associated with other pathologies (such as albinism) and other ophthalmic diseases (such as achromatopsia).

It should be kept in mind that CN patients are just as vulnerable to common otovestibular diseases as the general population. Of the 50 CN patients studied by Huang and Hsu (Huang et al. 2018), they report that:

“Audiometry revealed normal mean hearing level (MHL) in 66 ears and abnormal MHL in 34 ears (34%). The caloric test showed normal responses in 75 ears, canal paresis in 6 ears and caloric areflexia in 19 ears, representing 25% (25/100) abnormality. The oVEMP test was performed in 8 patients (16 ears) and showed normal oVEMPs in 11 ears, reduced oVEMPs in 1 ear and absent oVEMP in 4 ears, accounting for 31% (5/16) abnormality. The cVEMP test was performed in 16 patients (32 ears) and identified normal, delayed and absent responses in 22, 2 and 8 ears, respectively, representing 31% (10/32) abnormality. In sum, approximately one-third of the congenital nystagmus patients (n = 17) had comorbid inner ear disorders including labyrinthine insufficiency 4, endolymphatic hydrops 4, sequela of otitis media 2, congenital deafness 2, acoustic trauma 2 and others 3. The remaining 33 patients, about two-thirds of the congenital nystagmus patient, lacked inner ear disorders” (Huang et al. 2018).

This emphasizes the point that screening for other otovestibular disorders may be worthwhile, as some may be treatable; for example, vestibular weakness may be managed with vestibular rehabilitation therapy.

Since poor vision is a common reason for referral, it should be kept in mind that the differential diagnosis of poor vision is very broad, and includes (non-otoneurological) primary ophthalmologic diseases as well. Holmstrom and colleagues (Holmstrom et al. 2014) studied 62 patients referred for “nystagmus,” and found that only 2 (3%) were ultimately diagnosed with CN; the remaining diagnoses included foveal hypoplasia, albinism, achromatopsia, rod-cone dystrophy and degenerative high myopia — all primary ophthalmological diseases. This emphasizes the point that even in a patient with CN, evaluation by ophthalmology or neuro-ophthalmology is important.

Treatment

In a retrospective review Sherry and colleagues (Shery et al. 2006) observed improvement in visual acuity and nystagmus in two patients with CN treated with gabapentin and memantine. Consequently, McLean and colleagues (McLean et al. 2007) performed a prospective randomized, double-blinded study of 48 CN patients treated with memantine (n=16), gabapentin (n=16) and placebo (n=15). They reported that at 56 days, outcomes in the treatment groups (memantine and gabapentin) were similar to each other, and were statistically significantly superior to placebo in terms of improvement in visual acuity, nystagmus intensity and foveation.

Periodic alternating nystagmus (PAN) can be acquired, in some cases appearing after cerebellar lesions, and in some such cases the nystagmus may improve with baclofen (Halmagyi et al. 1980). Case reports (Solomon et al. 2002) and case series (Comer et al. 2006) have also observed improvement in patients with congenital periodic alternating nystagmus (cPAN) treated with baclofen.

A variety of non-pharmacologic approaches have been attempted in CN, including contact lenses (Allen and Davies 1983), acupuncture (Blekher et al. 1998), biofeedback (Mezawa et al. 1990), auditory feedback (Sharma et al. 2000), extraocular muscle injection with onabotulinum toxin (Carruthers 1995) and cannabis (Pradeep et al. 2008).

A variety of surgical approaches to CN has been proposed (Bagheri et al. 2008; Dell’Osso and Flynn 1979; Erbagci et al. 2004; Flynn and Dell’Osso 1979; Nelson et al. 1985; Spielmann 2000; Taylor and Jesse 1987; Wagdy et al. 2017; Whittle 1999).

Prognosis

CN is a lifelong condition.

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