Congenital Nystagmus (Infantile Nystagmus)

Congenital nystagmus, (more correctly termed infantile nystagmus) is a clinical sign that may take many different forms. Involuntary, rhythmic eye movements are characteristic, as they are in acquired nystagmus. Waveform, amplitude, and frequency can vary with changes in focal distance, direction of gaze, and under monocular or binocular viewing conditions.[1]

Oscillations are usually horizontal in direction but may be primarily vertical, torsional, or any combination of these three. Infantile nystagmus often is associated with other ocular conditions (eg, bilateral congenital cataracts) that impair visual acuity and occasionally can herald life-threatening conditions.[2] Some other associated conditions include achromatopsia, Leber congenital amaurosis, anorexia, and ocular albinism.

Few patients are noted to have nystagmus onset at birth. The term infantile probably is more accurate than congenital and includes nystagmus that presents within the first 6 months of life. This disorder classically has been divided into afferent (sensory deficit) nystagmus, which is due to visual impairment, and efferent (idiopathic infantile) nystagmus, which is due to oculomotor abnormality, with most cases being sensory in origin. It is believed that the nystagmus may reflect a failure of early sensorimotor integration. Although visual sensory defects are common in individuals with infantile nystagmus, a sensory defect is not a prerequisite for the development of nystagmus.

Data from eye movement recordings have conclusively shown that waveform alone is not a reliable method of distinguishing between these 2 entities. Therefore, it is essential that all infants with nystagmus be evaluated thoroughly for a primary sensory cause. In addition, it recently has been suggested that the following 3 additional subtypes of infantile nystagmus exist: (1) nystagmus associated with albinism, (2) latent and manifest latent nystagmus, and (3) spasmus nutans.

Frequency

United States

In one US study, the annual incidence of pediatric nystagmus was estimated to be 6.72 per 100,000 persons younger than 19 years, with infantile nystagmus comprising 87% of the study patients.[3]

Mortality/Morbidity

Visual morbidity associated with nystagmus relates most closely to the underlying disorder affecting the visual or ocular motor system, which is responsible for the fixation instability. Infantile nystagmus rarely is associated with a life-threatening disorder.

Race

No reported racial predilection exists among patients with infantile nystagmus.

Sex

Infantile nystagmus may be more common in males.[4]

Age

Most patients with infantile nystagmus present within the first several months of life.

Nystagmus present at birth or prior to age 2 months is more likely to be idiopathic in nature or due to neurologic dysfunction. Sensory deficit nystagmus most commonly presents at age 2-3 months. Further investigation of the visual system is warranted in these cases. Nystagmus associated with albinism has characteristics similar to idiopathic nystagmus but usually is absent until after age 2 months.

Nystagmus that presents after age 6 months is considered late infantile or childhood nystagmus and carries a graver prognosis. The exception is spasmus nutans, with onset in children aged 4 months to 3 years. Resolution of this condition usually occurs within a year of onset. Chiasmal glioma can present in an identical manner to spasmus nutans.

Latent or manifest latent nystagmus often is discovered after the first few months of life, but it most often is associated with infantile strabismus and can be identified by its unique characteristics.

Nystagmus intensity (frequency x amplitude) often improves spontaneously with increasing age but depends on etiology.

There often is a known family history of this disorder. The pattern of heredity usually is sex-linked, with dominant being more common.

Establishing the precise age of onset is helpful in differentiating between sensory deficit and idiopathic infantile forms. Spasmus nutans rarely is seen prior to age 4 months. Onset prior to age 2 months, particularly in the setting of gaze-associated variable intensity and torticollis, strongly suggests idiopathic infantile nystagmus.

Patients with infantile nystagmus due to albinism may have a positive family history and often appear photosensitive. A history of infantile strabismus increases the likelihood of latent or manifest latent nystagmus.

A history of abnormal head movements (bobbing or nodding) or torticollis raises the possibility of spasmus nutans.

CNS disease can produce many other forms of nystagmus and always must be considered. A history of failure to thrive or other evidence of neurologic dysfunction should prompt immediate investigation.

Older children and adults with a history of infantile nystagmus typically deny oscillopsia but frequently may have signs and symptoms of accommodative dysfunction. These signs and symptoms include asthenopia, headaches, avoidance of near tasks, tearing, and blurry vision.

Both idiopathic infantile nystagmus and many forms of sensory deficit nystagmus have a familial pattern. X-linked, autosomal dominant, and autosomal recessive modes of inheritance have been reported.

Both sensory deficit nystagmus and idiopathic infantile nystagmus almost always are bilateral, symmetric, and conjugate.[5]

Eye movements usually are horizontal and remain so during vertical gaze (horizontal uniplanar) rather than changing to a gaze-evoked vertical nystagmus. The nystagmus disappears during sleep.

The nystagmus movements may be pendular or jerk in nature. The nystagmus may be intermittent or continuous. The patient with congenital nystagmus may have good vision or poor vision. There is no oscillopsia. There may be an inversion of the optokinetic reflex.

Nystagmus intensity (a product of the frequency and amplitude) often increases with fixation effort, attention, or anxiety, and diminishes with convergence.

Various waveforms have been described. Both pendular and jerk types have been documented to occur in idiopathic infantile and sensory deficit nystagmus. Nystagmus associated with albinism has characteristics similar to idiopathic infantile nystagmus. Latent and manifest latent nystagmus always are jerk-type with the fast phase in the direction of the fixing eye and decreasing velocity of the slow phase; the nystagmus is larger in the amblyopic or nonfixing eye, and amplitude decreases in adduction. Spasmus nutans classically is a triad of nystagmus, head nodding, and torticollis. The nystagmus is disconjugate, high frequency, small amplitude, pendular, and intermittent. It is suppressed with head nodding. A head tilt often is present. Spasmus nutans often disappears after a few years.

The hallmark of idiopathic infantile nystagmus is a gaze-dependent, variable intensity resulting in a "null zone" where nystagmus is least marked and visual acuity is maximized. This often corresponds to adoption of an anomalous head posture and frequently is the stated reason for referral.

In patients with nystagmus, visual acuity should be measured by fogging the contralateral eye with a +4 to +10 hyperopic lens over the patient's normal refractive error.

Slit-lamp examination should be performed to exclude iris transillumination defect. Funduscopy should be used to document the presence or absence of foveal hypoplasia, optic disc morphology, and any lack of fundus pigmentation.

Idiopathic infantile nystagmus is believed to be due to a primary abnormality in oculomotor control. Increasing evidence suggests a genetic mechanism with one gene mapped to the X chromosome and another gene mapped to band 6p12. Hackett et al have found evidence that mutations in the calcium/calmodulin-dependent serine protein kinase (CASK) gene are frequently associated with congenital nystagmus and X-linked mental retardation.[6]

Many ocular disorders have been associated with sensory deficit nystagmus. This is not meant to be an exhaustive listing. The variety of sensory causes suggests that the underlying cause is a failure of sensorimotor integration due to reduced vision and/or contrast sensitivity. See the following:

• Early (usually bilateral) visual deprivation (eg), congenital cataracts, severe glaucoma, Peters anomaly[7]

• Foveal hypoplasia (eg, aniridia, albinism [nystagmus associated with albinism has characteristics similar to idiopathic infantile nystagmus])

• Retinal disease (eg, Leber congenital amaurosis, achromatopsia, macular toxoplasmosis [especially if bilateral])

• Retinal detachment (eg, severe retinopathy of prematurity, posterior persistent hyperplastic primary vitreous, familial exudative vitreoretinopathy)

• Optic nerve abnormalities (eg, hypoplasia, coloboma, atrophy)

• Cortical visual impairment from perinatal insult or structural CNS abnormality

Nystagmus associated with albinism is the result of multifactorial visual impairment. Anatomical findings include abnormal ocular pigmentation, foveal hypoplasia, abnormally increased chiasmal decussation, and high cylindrical refractive errors. Several subtypes have been described. Most are autosomal recessive, but all modes of inheritance have been described.

Latent nystagmus is a conjugate, jerk nystagmus with the fast phase toward the side of the fixing eye. It is often seen in patients with congenital esotropia and following surgery for infantile esotropia, probably resulting from subnormal binocular interaction. Latent nystagmus can coexist with manifest nystagmus (in which case the nystagmus amplitude increases with occlusion). Latent nystagmus is a jerk nystagmus with the fast phase toward the side of the fixing eye. It often is seen following surgery for infantile esotropia and probably results from subnormal binocular interaction. Visual acuity measurement should be performed using the polarized vectograph or blurring one eye with a high plus lens to avoid iatrogenic reduction of acuity with occlusion. So-called manifest latent nystagmus can occur if monocular visual loss occurs in this setting.

The cause of spasmus nutans is unknown. Some studies have found an association with children from lower socioeconomic status, as well as coexisting strabismus and refractive error. Chiasmal glioma can present with an identical appearing nystagmus prior to affecting the anterior visual pathway. It may be more common in African Americans and in Latinos.

Laboratory investigation usually is not required for infantile nystagmus.

Exceptions include workup for metabolic or infectious etiology in congenital cataracts, serology in suspected toxoplasmosis, toxicology in optic atrophy, endocrine assay for pituitary dysfunction in optic nerve hypoplasia, and others.

Children with opsoclonus who otherwise are well should undergo measurement of urine vanillylmandelic acid (and abdominal CT scan) to rule out neuroblastoma.

Infantile nystagmus may indicate underlying neurologic disease. Neuroimaging is indicated when a space-occupying lesion or brain malformation is suspected, as in cortical visual impairment or ocular motor disturbance.

Patients presenting with spasmus nutans should undergo MRI to rule out glioma if evidence suggests an anterior visual pathway or hypothalamic disease.

Patients with sporadic (as opposed to familial) aniridia are at risk of developing Wilms tumor and should undergo periodic renal ultrasound. The need for this may be modified with increasing availability of genetic testing.

Patients with optic nerve hypoplasia are at increased risk for other midline CNS abnormalities, such as absence of the corpus callosum or pituitary ectopia; MRI may be indicated to assess the need for endocrine evaluation.

Ocular ultrasonography is indicated in nystagmus patients with persistent hyperplastic primary vitreous (PHPV), cataract, Peters anomaly, and other disorders in which the ocular fundus cannot be visualized. It also is useful to assess the status of the retina in advanced retinopathy of prematurity, familial exudative vitreoretinopathy, and perinatal trauma.

Electroretinography is an essential component of evaluation if intrinsic retinal diseases such as Leber congenital amaurosis, achromatopsia, congenital stationary night blindness, or other disorders are suspected.

Visual-evoked response (VER) has limited use in the evaluation of infantile nystagmus due to the inability of infants to perform pattern VER. Flash VER provides little insight into visual pathway dysfunction but may be of some value in documenting abnormal chiasmal crossing in albinism.

Genetic testing is poised to provide increasing diagnostic insight for patients with nystagmus and many other ocular disorders. However, because of its low diagnostic yield, routine FRMD7 gene mutation screening is not recommended in isolated cases of idiopathic infantile nystagmus syndrome. Nonetheless, it may be considered in patients with a pedigree that indicates X-linked inheritance.[4]

Eye movement recordings can be done to measure the amplitude and frequency of nystagmus, but they mainly are used for research purposes. Pendular waveforms are often punctuated by brief foveation periods on such recordings. Jerk waveforms have highly characteristic increasing velocity slow phases.[4]

Examination under anesthesia may be required to adequately evaluate ocular structures in the workup of infantile nystagmus.

Sedation may be required to perform ocular ultrasonography, electroretinography, VER, and neuroimaging.

The treatment of these patients should begin with correction of any refractive error. Amblyopia should be addressed as well.

Contact lens wear has been noted to diminish infantile nystagmus, presumably by a trigeminal efferent pathway. This may also increase foveation time by avoiding induced spectacle distortion with ocular movement in patients with high degrees of ametropia.

Refractive errors, even low plus, should be prescribed, as this has been shown to improve visual acuity. An optical system with high plus spectacles and high minus contact lenses has also been shown to improve visual acuity in some patients.

Base-out prisms (eg,7 prism diopters) may be combined with -1.00 D myopic overcorrection for convergence damping in patients with binocular vision.[4]

Pharmacologically useful agents for patients with nystagmus are primarily GABA agonists or inhibitors of the excitatory neurotransmitter system. The only drug found to be of benefit in adult patients with a history of idiopathic infantile nystagmus is baclofen. This drug has not been approved for use in children. Baclofen has been effective in treating the periodic alternating nystagmus (PAN) subtype.

Recent case reports have shown gabapentin to be beneficial in congenital nystagmus, with an improvement in foveation time and vision and a decrease in amplitude and frequency of the nystagmus.

McLean et al investigated treatment of congenital nystagmus with memantine or gabapentin in a randomized, double-blind, placebo-controlled trial of 48 patients.[8] Improvement in mean visual acuity was noted in both treatment groups (F=6.2; p=0.004, analysis of variance). Patients with afferent visual defects showed poorer improvements in visual acuity to medication than those with apparently normal visual systems. However, nystagmus intensity (F=7.7; p=0.001) and foveation (F=8.7; p=0.0007) improved in both nystagmus forms as shown on eye movement recordings. Patients in both treatment groups reported vision improvement more often than patients in the placebo group (p=0.03). McLean et al concluded that memantine and gabapentin can improve visual acuity, reduce nystagmus intensity, and improve foveation in congenital nystagmus.

More study is needed to determine the role of oral and topical carbonic anhydrase inhibitors.[4]

Treatment for aquired nystagmus may be useful in cases of congential nystagmus as well. Low force magnets may be one such option. Pankhurst et al implanted paired magnets in the orbital floor and extraocular muscles of subjects with acquired nystagmus. The force applied in voluntary eye movements is much greater than the force involved in nystagmus. This allowed the magnets to dampen the oscillation at the point of fixation, with out hindering gaze shifts at other times.[9]

Alternative measures, such as biofeedback, acupuncture, or cutaneous head and neck stimulation, have been reported to decrease nystagmus in select (adult) patients with a history of infantile nystagmus.

Retrobulbar or intramuscular injection of botulinum toxin

Retrobulbar or intramuscular injection of botulinum toxin (BOTOX®) has been demonstrated to abolish nystagmus temporarily, but patient satisfaction has been poor due to adverse effects, such as ptosis or diplopia, and the need for reinjection.

Strabismus surgery

Strabismus surgery is used in patients with certain forms of nystagmus with varying degrees of success.

Anderson or Kestenbaum procedures are used to move the eyes into the null zone to diminish an anomalous head position in the setting of idiopathic infantile nystagmus.

Recession or simple tenotomy of all 4 horizontal rectus muscles has been advocated; however, preliminary results have been mixed. A pilot study has been completed that showed some improvement, but the definitive study is still pending.[10]

Surgery occasionally is used in the treatment of superior oblique myokymia.

Hertle et al conducted a prospective interventional case study to determine the effects of early eye muscle surgery on 19 patients younger than 24 months who had infantile nystagmus syndrome.[11] Outcome measures included acuity, head position, strabismic deviation, and eye movement recordings, including waveform types and a nystagmus optimal foveation fraction (NOFF). Improvements were noted in all outcomes measured. Hertle et al concluded that early eye muscle surgery in patients with oculographically infantile nystagmus syndrome improves the oscillation and visual functions. Increases in foveation periods and the NOFF were measureable.

Pediatric neurology consultation can be helpful in patients suspected of harboring CNS disease and in evaluating nystagmus for localizing a CNS lesion.

Pediatric endocrinology consultation may be useful in patients with optic nerve hypoplasia to assist in evaluation of pituitary function.

Pediatric metabolic disease specialists can offer assistance in patients with congenital cataracts or optic atrophy who are thought to have an underlying metabolic abnormality.

Pediatric geneticists play an increasing role in the diagnosis and management of patients with nystagmus whose diagnosis is uncertain or who have dysmorphic features.

Pediatric neuroradiologists are of considerable value in evaluating the infant brain for abnormalities uncovered with neuroimaging.

Strabismus surgery carries anesthesia risks, as well as the risk for vision loss. This consideration becomes more important when potential benefits are less certain.

Alternative therapy probably is harmless at worst but should not delay diagnosis or treatment of an underlying disorder.

The only drugs used in the management of nystagmus are not useful in infants but are useful in adults with persistent nystagmus in which the motility disturbance itself is believed to cause visual impairment or other undesirable symptoms.

Class Summary

Agents acting through gabapentin binding sites that may activate voltage-gated calcium channels may be useful in treating nystagmus.

Gabapentin (Neurontin)

Has been shown to be useful in some adults with congenital nystagmus in improving symptoms. No studies have been done in children to date. Exact mechanism of action is unknown but thought to be due to its antiglutamatergic activity. Has been used successfully to treat adult acquired nystagmus in multiple sclerosis.

Class Summary

Agents used to treat reversible or intractable spasticity are helpful.

Baclofen (Lioresal)

May be effective in reducing nystagmus in adult patients with a history of idiopathic infantile nystagmus. Exact therapeutic mechanism unknown but may relate to inhibition of glutamate release rather than augmentation of GABA-ergic pathways as originally believed. It has been used to treat several types of nystagmus, most commonly PAN.

Improvements in nystagmus intensity appear within minutes and regress after several hours. Medication should not be taken at bedtime or other times when use of eyes is not anticipated.

Class Summary

Agents that produce a state of muscle denervation are helpful.

OnabotulinumtoxinA (BOTOX®)

Used in treatment of nystagmus by injection into specific extraocular muscles and retrobulbar placement within the muscle cone.