• Nystagmus

    Definition

    Nystagmus represents uncontrolled, repetitive movements of the eyes. Nystagmus can be congenital (ie, noted in the first 6 months of life) or acquired at any age. This chapter is dedicated to the workup of nystagmus with onset in childhood.

    Nystagmus is clinically described based on amplitude, frequency, and direction of oscillations. It can be broadly classified as physiologic nystagmus or pathologic nystagmus. Except for physiologic nystagmus, all nystagmus forms should be considered a symptom of a condition rather than a diagnosis in itself.1

    Physiologic nystagmus includes optokinetic nystagmus, vestibular ocular reflex, caloric nystagmus, and postrotatory nystagmus. The slow phases of physiologic nystagmus are protective for visual stability and meant to minimize retinal image slip.

    Pathologic nystagmus of childhood includes

    • infantile nystagmus syndrome (INS)
    • fusion maldevelopment nystagmus syndrome (FMNS) or latent nystagmus
    • spasmus nutans syndrome (SNS)
    • vestibular nystagmus
    • eccentric gaze nystagmus
    • nystagmus associated with disease of central myelin (eg, multiple sclerosis)
    • Pelizaeus-Merzbacher disease
    • Cockayne syndrome
    • peroxisomal disorders
    • toluene abuse
    • pendular nystagmus associated with tremor of the palate
    • pendular vergence nystagmus associated with Whipple disease
    • ocular bobbing
    • saccadic intrusions and oscillations

    INS, also called congenital nystagmus, is a broad term that describes manifest nystagmus (nystagmus present at all times) with onset in the first 6 months of life. To avoid confusion, in this paper it will only be called INS.

    Classification of eye movement abnormalities and strabismus (CEMAS) is one system used for description of nystagmus.2 In this system, the nystagmus is characterized based on the oscillation type, direction, and amplitude. Despite extensive work done to classify nystagmus and create a common language, in the clinical practice, a single disease state can result in multiple types of nystagmus, and this method of classification has low specificity in diagnosing the underlying cause of nystagmus. In order to achieve a correct diagnosis for the underlying cause of the nystagmus, workup that is inclusive and targeted at the same time is required.

    Prevalence and Risk factors

    Commonly seen in ophthalmology practice, nystagmus has a prevalence of approximately 24 per 10,000 in the general population and 17 for 10,000 in pediatric populations.3 Acquired nystagmus is estimated to comprise 17% of nystagmus in children and 40% in adults.4

    The prevalence of INS in the US is estimated to be 12 children per 10,000 live births with a male predominance of 2- to 3-fold.5 INS represents 87% of all pediatric patients with nystagmus.5

    INS’s etiology generally falls into 1 of 3 large groups of conditions: 1) primarily an ocular pathology and cause various degrees of visual deprivation, 2) primarily neurological abnormalities that may or may not be associated with ocular pathology, or 3) isolated, inherited or idiopathic, oculomotor disorder.

    The only study to determine the prevalence of nystagmus in general population (at all ages) and its causes, found that the most common forms were neurologic nystagmus (6.8 per 10,000 population), followed by nystagmus associated with low vision from early deprivation such as congenital cataracts (4.2 per 10,000), and nystagmus associated with retinal diseases (3.4 per 10,000 population).3 Combining the last 2 groups in this study, as visually/ocular driven nystagmus, approximately two-thirds of nystagmus is caused by afferent visual system abnormalities including obstructing the visual axes (eg, congenital cataracts, corneal dystrophies or edema, etc.), retinal dystrophies, and optic nerve abnormalities.3

    INS associated with neurological abnormalities overlaps to some extent with visual deprivation nystagmus when optic nerve pathology is involved. However, it occurs in absence of an ocular pathology associated with intracranial processes or malformations, hydrocephalus, or neurodegenerative or mitochondrial disorders. It is common (up to 30%) in children with Down syndrome with or without ocular pathology.6

    X-linked infantile nystagmus, related to FRMD7 mutations, or on short FRMD7 infantile nystagmus (FIN) previously called “oculomotor nystagmus” has an unknown prevalence in general population. Small studies suggest an incidence up to 50% of X-linked pedigrees and approximately 5% of sporadic cases.7 Unless confirmed with genetic testing, FIN should be a diagnosis of exclusion.

    Acquired nystagmus is almost exclusively associated with a neurological abnormality (eg, intracranial mass, hydrocephalus, trauma, neurodegeneration, etc.), trauma, medication or exposure, or treatment modalities (eg, radiation).8

    Due to long-term implications of the underlying disorders that can manifest with nystagmus, a correct, complete, and timely diagnosis is important.

    Natural History

    Nystagmus can have a variable course, depending on the underlying disorder. It might improve over time or even resolve in inherited diseases including congenital stationary night blindness (CSNB)9 or achromatopsia. Spontaneous resolution of nystagmus has been described with spasmus nutans syndrome.10

    Nystagmus can resolve after treatment, where treatment is possible. It has been reported after treatment in inherited eye disorders including Leber congenital amaurosis (LCA) due to mutations in the RPE65 gene11 or in acquired, treatable conditions (eg, hydrocephalus, medication, or alcohol and drug exposure). For most cases of nystagmus, however, the oscillatory eye movements persist long term. Some patients will adopt an anomalous head posture to diminish the amplitude of nystagmus and to improve vision.

    In physiologic nystagmus, the slow phase is meant to maintain foveal fixation, while the slow phases of pathologic nystagmus cause the retinal image to slip away from the fovea. If the displacement of the image is greater than 5 degrees per second, it results in a decline in visual acuity and oscillopsia, which is the perception of visual motion.12 A specific head posture (ie, a null position) may alleviate oscillopsia.

    Saccadic intrusions and oscillations move the eye off target so that the image no longer falls on the fovea; this affects quality of vision and causes visual symptoms, such as reading difficulty.12

    Treatment and outcome are based on the underlying condition. Extraocular muscle surgery,13 botulinum toxin type A (Botox) injections,14 various drugs,15,16 acupuncture,17 and contact lenses18 have been tried with variable success in different forms of nystagmus.

    Diagnosis and Workup

    All forms of nystagmus affect vision to a degree, and large-amplitude nystagmus may inhibit eye contact with others. All cases of pathologic nystagmus require a thorough workup to determine the etiology. Most commonly, the workup is performed by a pediatric ophthalmologist, a neuro-ophthalmologist, and/or a pediatric neurologist. There is not a single best test for the nystagmus workup, but the most important first step for diagnosis is the clinical examination.1

    Infantile Nystagmus Syndrome 

    When evaluating an infant or young child with nystagmus, the differential diagnosis should remain broad and include ocular, neurologic, and syndromic states. The examination and ancillary testing available are somewhat limited, and examination under anesthesia may be necessary.

    1. Clinical examination, history, and review of systems

    Clinical examination is the most important first step in diagnosis and must include the following for each patient:

      1. Detailed evaluation and description of nystagmus, including age of onset, direction, frequency, amplitude, conjugation, and eye movement recordings, when possible.
      2. Age-appropriate visual acuity testing with each eye separately at both distance and near. The examination includes vision assessment with proper optical correction. Glasses prescription must be based on cycloplegic retinoscopy. Appropriate testing method for each age group is critical, and Teller (or grating) visual acuity can be used in very young children. For children able to perform optotype testing, full lines of optotypes or crowding bars around single letters are recommended. The eyes must be tested one at a time. In patients with nystagmus, latent nystagmus will be increased with complete occlusion of one eye, degrading monocular visual acuities. In these children, vision should be tested using a fogging lens or translucent occluder over one eye, then the other. If the child has a null point, acuity should be tested with the head in the preferred position for the null point. Visual acuity should be interpreted in the context of age and development. Improvement of vision with age is possible in almost all diseases; however, acuity that is consistently subnormal for age suggests an ocular pathology. Progressively worsening visual acuity is common in retinal dystrophies and some optic nerve pathology (eg, dominant optic atrophy) but not expected in optic nerve hypoplasia. Continued improvement in vision, although still decreased for age, is observed in conditions such as CSNB19 and OCA.20
      3. Pupil evaluation with attention to presence of a relative afferent pupillary defect (RAPD), anisocoria, or paradoxical pupillary responses. Afferent pupillary defects may suggest an optic nerve pathology. Paradoxical responses are suggestive of a retinal abnormality, and anisocoria indicates a possible Horner syndrome.
      4. Detailed slit-lamp examination of the anterior segment, including presence or absence of iris transillumination defects (TIDs), Lisch nodules, and/or media opacities. Slit-lamp examination, although difficult in children, is critical for evaluation for cornea abnormalities (eg, edema, opacities, Haab striae, etc.), iris abnormalities (eg, hypoplasia, coloboma, aniridia, iris TIDs, etc.), lens abnormalities (eg, cataract, ectopia, phacodonesis), inflammation, and presence of vitreous cells. Anterior segment dysgenesis, pigmentation disorders, congenital cataract, congenital glaucoma, and collagen disorders can be diagnosed clinically.
      5. Intraocular pressure (IOP) measurements interpreted in context of age, central corneal thickness, and axial eye length.
      6. Color vision testing with age appropriate plates has value when possible. Usually it cannot be reliably tested in children younger than 3 years of age. Using standard tests like the D-15, HRR, or Ishihara test may not be possible for your children. Matsubara color charts may be an easier alternative. Color vision is abnormal in conditions like achromatopsia, blue cone monochromacy, and dominant optic atrophy. Results have to be interpreted in the context of visual acuity.
      7. Cycloplegic refraction. Refractive errors need to be adequately corrected for age when evaluating visual acuity. They also aid in the workup and final diagnosis. Hyperopia is commonly associated with LCA, X-linked retinoschisis, and oculocutaneous albinism (OCA). High myopia is common in CSNB and collagen disorders. These are not hard rules but rather considerations.
      8. Detailed fundus examination. The fundus examination can be diagnostic when abnormal. Macular pathology, although subtle, is diagnostic for X-linked retinoschisis, enhanced S-cone syndrome, pigmentary retinopathy, familial exudative vitreoretinopathy (FEVR) and Best disease. Some congenital infections have specific fundus appearance and associated systemic findings. Congenital cytomegalovirus (CMV) can present with central macular scarring and hearing loss; congenital infections with lymphocytic choriomeningitis virus (LCMV) and Zika virus can present with maculopathy, optic nerve edema, and hydrocephalus or microcephaly; and toxoplasma can present with macular lesions and intracranial classifications.21 Serology and imaging are necessary for complete diagnosis. Chorioretinal and/or optic nerve colobomas, optic nerve hypoplasia, optic nerve pallor, and other anomalous appearances can be diagnostic or indicate that additional work up is needed. The presence of optic nerve pallor or hypoplasia as well as RAPD or anisocoria are considered neurological abnormalities and should include magnetic resonance imaging (MRI) in the workup to rule out compression, septo-optic dysplasia, or congenital abnormalities. Some of these findings are subtle and require examination under anesthesia for details. Normal fundus examination, in a patient with INS, does not exclude retinal pathology and requires additional workup.

    History of present illness (HPI) and review of systems (ROS) are part of the initial evaluation and essential elements in the workup. They should include:

      1. Disease history, including age of onset (or when nystagmus was first noted), progression, and/or improvement.
      2. Birth history (eg, prematurity, ROP, IHE), prenatal course and exposure (infections, diseases, medication, smoking, alcohol, and recreational drugs) metabolic newborn screening history, and growth and development history, such as milestones, growth charts, regressions, current medication, and exposure.
      3. General physical examination including pigmentation of skin and adnexa (considered in report with ancestry); presence of café-au-lait spots and/or axillary freckling; hearing and speech; head circumference; fontanelle appearance; height, weight and head circumference for age; facies; body habitus; polydactyly and cleft (still present or repaired); known kidney problems or polydipsia/polyuria; presence of photophobia, nyctalopia, abnormal head posture, gum bleeding, and/or petechiae.
      4. Extended family history and complete pedigree.

    There is an overlap of certain clinical findings among different diseases. For example, optic nerve anomalies (eg, drusen, hypoplasia, elevation) are pathologic when found in isolation, but when associated with retinal dystrophies or OCA, these findings might be noted prior to the development of other signs and symptoms. Foveal hypoplasia is associated with OCA and aniridia but can also be seen in isolation or in retinopathy of prematurity (ROP). Peripheral vascular nonperfusion and macular dragging can be seen in prematurity and ROP but also in FEVR. Vitritis can be present secondary to intraocular infections, infiltrative diseases (eg, leukemia), or retinal dystrophies.22

    1. Ancillary testing

    No single test is universally recommended in the workup of congenital nystagmus. However, in addition to the clinical examination, usually one or more tests, including genetic testing, is necessary for making an accurate diagnosis. Tools available for use on awake or sedated patients are as follows:

      1. Full-field electroretinography (ERG). This test can be performed awake on most infants and young children, using DTL (Dawson, Trick & Litzkow ) or skin type electrodes. This test has tremendous value in narrowing the diagnosis when specific patterns are identified. A nonrecordable light- and dark-adapted ERG is highly suggestive of early childhood onset retinal dystrophy (most commonly LCA). Decreased amplitudes or nonrecordable light adapted full-field ERG is suggestive of achromatopsia, blue cone monochromacy, retinitis pigmentosa (RP), and/or related disorders. Electronegative full-field ERG is suggestive of X-linked retinoschisis or CSNB. Combinations of the above patterns are often seen with some more specific than others. Electrophysiology testing should be performed and interpreted by specialized professionals in the context of the patient’s age and clinical presentation.
      2. Macula optical coherence tomography (OCT). This test is difficult to perform awake in young children but can be performed under sedation using a handheld OCT. Older children (approximately 3 years and older) are able to perform awake OCT; however, they may have difficulties with fixation due to nystagmus. These difficulties should be considered when interpreting the images. Motion tracking such as is found on Heidelberg OCT may be helpful. OCT can be instrumental in the diagnosis of X-linked retinoschisis, foveal hypoplasia (as seen in OCA, aniridia, prematurity, etc.), cystoid macular edema (CME) associated with RP, and other retinal dystrophies.
      3. Visual fields. Visual field testing is valuable when possible to be performed. It is uncommon for young children to be reliably tested on automated perimetry. Some children, usually older than 5 years, can be tested on Goldmann visual fields by someone experienced in perimetries. On older patients (8 years and older), automated perimetry should be part of the examination.
      4. Full-field stimulus testing (FST). AdaptDX dark adaptation testing is not possible to perform in very young children but valuable when possible.
      5. Visually evoked potential (VEP), flash and pattern. This is easier to perform than ERG or OCT. It evaluates the visual system globally – retina, optic pathways, and visual cortex. This test has some value in isolation but is mostly useful in addition to other testing. Serial flash VEP evaluation can be used to monitor improvement or worsening of optic nerve and/or retinal function over time.
      6. MRI of the brain and orbits. This is most valuable in the workup of INS only when nystagmus is associated with neurological abnormalities,1 including, but not limited to, optic nerve abnormalities, systemic extraocular abnormalities, abnormal head circumference, and/or developmental delay. Unusual patterns of nystagmus, such as vertical nystagmus, and specific patterns of nystagmus (eg, opsoclonus) require a brain MRI as part of the workup. Dissociated and monocular nystagmus and suspected spasmus nutans syndrome always require MRI imaging, as all have been associated with intracranial processes. It is never wrong to perform the MRI but is often times unnecessary and should never be the only step in the workup of INS unless findings are clearly diagnostic and match the phenotype.
      7. Genetic testing. This plays an important role in establishing the final diagnosis. It can be complex deciding which tests to order, how to interpret the results, and when all options have been explored. Because of that, having a narrow clinical hypothesis is helpful, when possible. Various panels, including known pathogenic genes, for certain disorders are available. It is usually reassuring when complete genotype matches the phenotype. Parental segregation should always be performed for confirmation. Careful interpretation should be given to new mutations not reported previously or to negative results. Interpreting the tests is the responsibility of the ordering physician. When ordering genetic tests, one should know how comprehensive the results are and whether the study includes copy number variants and parental testing. Very comprehensive genetic testing such as whole exome sequencing (WES) or whole genome sequencing (WGS) is available. Positive and negative results should be carefully analyzed and only true disease-causing mutations should be reported.18 Pre-and post-test genetic counseling is also part of the testing and interpretation. Giving a family an erroneous diagnosis could be stressful and dangerous. It might lead to additional unnecessary testing, enrolling the patient in wrong clinical trials, misleading family planning, and missing the correct diagnosis. It is strongly recommended to refer patients to an ocular geneticist or pediatric geneticist for testing and counseling.
      8. Metabolic testing. This should be done when developmental and neurological abnormalities are present and MRI is abnormal; peroxisomal biogenesis disorders (PBDs),23 hypomyelinating leukodystrophy24 and carbohydrate-deficient glycoprotein syndromes25 should be considered. Usually a metabolic geneticist and a pediatric neurologist are involved in the workup and management.

     

    Figure 1. Infantile nystagmus syndrome (INS) workup algorithm.
    Abbreviations: MRI, magnetic resonance imaging; OCT, optical coherence tomography; ONH, optic nerve head; ROS, review of systems; TIDs, transillumination defects. 
    *Abnormal ERG can be “electronegative” in conditions like CSNB or juvenile X-linked retinoschisis (JXLS); nonrecordable or very low amplitudes in all testing conditions in severe cone and rod disease, likely LCA or retinitis pigmentosa (RP); abnormal cone responses are seen in achromatopsia and cone dystrophies.

    For children with INS and decreased vision vs. good vision, the sequences of these workups are summarized below.

    • INS with obviously decreased vision can follow these steps:
    1. Abnormal anterior segment. Corneal dystrophies, cataract, aniridia, and congenital glaucoma can be diagnosed on clinical examination. Some of these diseases also have associated foveal hypoplasia, and a macula OCT should be considered when possible. All of these disorders have a genetic component and are heritable. The workup should not end with the clinical diagnosis. Referral to an ocular genetic specialist or pediatric geneticist, as well as genetic testing and counseling, are mandatory part of the workup for these children and their families.
    2. Skin, adnexa, and fundus pigmentation in rapport with ancestry is abnormal. If iris TIDs are present, a macula OCT is the next step. If it shows foveal hypoplasia, then genetic testing for pigmentation disorders is recommended. Iris TIDs can be subtle, and some patients have reasonable pigment but less than the rest of the family. In these cases, a macula OCT is a very important part of the workup. If it is not possible to obtain an macula OCT, a careful clinical examination looking for macular pigment anomalies and a lack of a foveal reflex is important in making the diagnosis. Children with OCA have increased risk for skin cancer, and up to 4% have Hermansky-Pudlak syndrome (HPS) with most of them not being of Puerto Rican ancestry, so complete diagnosis including genetic testing is important.
    3. Normal pigmentation, paradoxical or normal pupils, normal fundus. Next step is full field ERG. If abnormal, it can be diagnostic. A normal ERG is reassuring for retinal function.
    4. Abnormal fundus. Optic nerve hypoplasia or pallor, macular/retinal scarring, retinal folds or detachment, abnormal retinal pigmentation (eg, salt-and-pepper, etc.) and/or lacunae, colobomas; next step is brain and orbit MRI. If MRI findings are not convincing or if MRI is normal, then a combination of full field ERG and VEP can be used to evaluate the retinal function, optic nerve function, and cortical function. In this context, electrophysiology is useful in determining the origin of decreased vision (ie, retina, optic nerve/optic pathway, or both). Clinical context, HPI, and ROS should be used when evaluating fundus findings that may be seen in traumatic injuries.

    Confirmation of the clinical diagnosis with genetic testing and parental testing is the final step of the workup for all of the above scenarios. Some of these diseases have treatments, including gene replacement therapy, and an early, accurate diagnosis is important. If complete genetic testing (appropriate for the clinically suspected disease) is negative, the differential can be expanded with additional testing (ERG for previously suspected pigmentation disorder) or broader genetic testing like WGS. 

    • INS with relatively normal vision can follow these steps:
    1. Abnormal anterior segment. Corneal dystrophies, cataract, aniridia, and congenital glaucoma can be diagnosed on clinical examination. All of these diseases can have large phenotypic variation and sometimes result in only mild visual impairment. Macular OCT and genetic testing is still recommended for confirmation of diagnosis and for genetic counseling. It is known that diseases can have variable expressivity and severity within the same family, and having a mildly affected child does not guarantee the same mild phenotype for subsequent affected children.
    2. High refractive errors can cause nystagmus by affecting vision at young ages. They are correctable with glasses, but complete diagnosis and prognosis require additional workup, including axial length measurements and monitoring for clinical signs of possible underlying disease associated with high refractive errors.
    3. Skin, adnexa, or fundus pigmentation is abnormal, iris TIDs are present, or a positive family history of albinism; macula OCT is the next step. If there is foveal hypoplasia – genetic testing for pigmentation disorders is recommended. Some patients with OCA can have good vision (20/25-20/30 range) despite the nystagmus.
    4. Normal skin and adnexa pigmentation, paradoxical or normal pupils, normal fundus. Next step is full-field ERG even if vision seems close to normal. If abnormal, it can be diagnostic. If normal, it is reassuring for retinal function.
    5. Abnormal fundus including optic nerve hypoplasia, colobomas, scars, and pigment abnormalities. Next step is MRI.

    Idiopathic infantile nystagmus is a diagnosis of exclusion. FIN must be confirmed with genetic testing for FRMD7 mutations.

    Acquired nystagmus in childhood

    1. Clinical examination, history, and review of systems

    Clinical examination is the first step in the diagnosis and must include for each patient:

      1. A detailed evaluation and description of nystagmus including onset, direction, frequency, amplitude, conjugation, pattern, and eye movement recordings when possible. Sometimes this is diagnostic and has localizing value.
      2. Visual acuity using age-appropriate testing with each eye separately at both distance and near. The examination includes vision assessment with proper optical correction. Changes in vision from prior examinations are important findings.
      3. Ocular motility abnormalities like oculomotor apraxia, new-onset strabismus, cranial nerve palsies, diplopia, ptosis (acquired or progressive).
      4. IOP measurements.
      5. Pupil evaluation with attention to presence of an afferent pupillary defect or anisocoria.
      6. Detailed slit-lamp examination of the anterior segment, including presence or absence of Lisch nodules or inflammation.
      7. Color vision.
      8. Cycloplegic refraction.
      9. Detailed fundus examination with attention to optic nerve (edema, pallor), presence of coloboma, inflammation, infectious or infiltrative processes.
      10. Family pedigree.

    History should include onset (or when nystagmus was first noted), history of prematurity or trauma, new-onset associated symptoms such as headaches or seizures, birth history, metabolic newborn screening history, congenital infections, current medication and exposure, illnesses, thick bites, skin rashes, regression of skills.

    General physical examination and review of systems including, neurologic focal deficits, cranial nerve evaluation, head circumference, growth/size for age, gait, headaches, milestones, regression of skills, presence of diplopia, abnormal head posture, fevers, pain with eye movements, flulike symptoms, altered mental status, vertigo, dizziness, hearing changes, tinnitus, and ataxia.

    1. Ancillary testing:
      1. Nystagmus recording - when possible, either by videography or wavelength recording is useful for documentation and for detailed review of monocular versus binocular, direction of movement, stability, amplitude, frequency, slow phase, and null point.
      2. Imaging (brain, spine) usually with MRI scans, is almost always necessary.
      3. Visual field when possible. In some circumstances shows specific patterns and has localizing value (quadranopsia, hemianopia, etc.).
      4. Lumbar puncture (LP) with opening pressure, constituents, serology, antibodies (aquaporin, MOG, etc.) and cultures should be performed if increased intracranial pressure (without herniation), inflammation, or infections are suspected.
      5. Electroencephalogram (EEG) if seizure activity is noted or suspected.
      6. Blood cultures if infection is suspected.
      7. Serology for drug levels, heavy metals, etc.
      8. Inflammatory markers
      9. Genetic testing is confirmatory if positive, in neurodegenerative diseases (eg, Batten disease or Rett syndrome) or syndromic disease (eg, Joubert syndrome), or neurofibromatosis if they are under consideration.

    All this information plays an important role in the workup; however, acquired nystagmus is almost exclusively secondary to a neurologic disease, medication, trauma, inflammation, infection, or exposure, and requires involvement of pediatric neurologist and neuro-ophthalmologist in the diagnosis and workup. Almost invariably, imaging is part of the workup. Frequently, specific sequences or cuts, or detailed evaluation of certain areas of the brain, or nonroutine testing is necessary, and for that reason it is preferable that imaging is ordered and interpreted by experienced professionals (neuro-ophthalmologist or pediatric neurologist and neuroradiologist). An incomplete or inadequate test might be falsely reassuring and completely misleading for the diagnosis.

    Beside imaging, additional testing including electroencephalogram (EEG), serology (serum and/or cerebrospinal fluid), infectious workup, serum levels of drugs, and metabolic testing are often necessary. Nutritional and toxic neurodegenerations (B12 and/or folate deficiency, heavy metal poisoning). 

    A pediatric neuro-ophthalmologist and/or a pediatric neurologist are essential part of the team for these cases and should be involved early in the process.

    Some forms of acquired nystagmus are very specific, but most of their etiologies overlap to some extent.

    Figure 2. Acquired nystagmus workup algorithm
    Abbreviations: APD, afferent pupillary defect; ERG, electroretinography; OCT, optical coherence tomography; ROS, review of systems. 
    *Abnormal ERG can be “electronegative” in conditions like CSNB or juvenile X-linked retinoschisis (JXLS); nonrecordable or very low amplitudes in all testing conditions in severe cone and rod disease, likely LCA or retinitis pigmentosa (RP); abnormal cone responses are seen in achromatopsia and cone dystrophies

    Below is a very brief review of most common forms of acquired nystagmus.

    Spasmus nutans syndrome (SNS) presents as acquired nystagmus in infancy with intermittent small-amplitude high-frequency variable or dissociated nystagmus, variable torticollis, head shaking/bobbing, and usually a normal-appearing fundus. Generally, vision is good and with time, the nystagmus tends to resolve. Most of the time, however, SNS is a clinical diagnosis and the work up is limited to MRI. We would like to stress the fact that retinal disease needs to be ruled out before making a final diagnosis of SNS. It has been reported that SNS can mimic retinal diseases26 and it is conceivable that some cases of SNS are actually retinal diseases, like CSNB. 

    Latent nystagmus (or fusion maldevelopment nystagmus syndrome [FMNS]), occurs commonly in patients with infantile esotropia.27 It is predominantly a bilateral, horizontal jerk nystagmus elicited by occluding either eye and leads to deterioration of visual acuity under monocular conditions. The slow phase is always toward the side of the occluded eye with an exponential decrease in the slow-phase velocity.27

    Gaze-evoked nystagmus and rebound nystagmus can be physiologic when present at extreme horizontal fields of gaze, especially in a patient with history of strabismus. However, primary position nystagmus, nystagmus that is sustained (>20 seconds), or asymmetric gaze-evoked nystagmus are usually pathologic.28,29 Etiologies may include intoxication (eg, sedatives, anticonvulsants, alcohol, illicit drug or hypnotic use), trauma, stroke, demyelination, Chiari malformation, or tumors.

    Vestibular nystagmus - peripheral or central is associated with infections, inflammation, trauma, toxicity (eg, aminoglycosides, phenytoin, pentobarbital, carbamazepine, salicylates, etc.), or central causes, such as demyelination or hypoxic ischemic encephalopathy.30 Hypoxic ischemic injury (HII) can lead to damage of the brainstem and vestibular nuclei and manifest with nystagmus.31 Primary congenital hydrocephalus or hydrocephalus secondary to intraventricular hemorrhage is occasionally associated with vestibular nystagmus, due to direct pressure effects on vestibular pathways in the brainstem.32

    Special forms of nystagmus, including downbeat nystagmus, upbeat nystagmus, seesaw nystagmus, periodic alternating nystagmus, convergence-retraction nystagmus, pendular nystagmus, and dissociated nystagmus have localizing value and always require imaging plus further workup with pediatric neurology, neuro-ophthalmologist, or other specialties. There are many conditions manifesting with these special forms of nystagmus. If the pathway for each type of nystagmus might be specific, the conditions in which these types of nystagmus are seen overlap dramatically. Arnold-Chiari type I malformation, tumors at the foramen magnum (meningioma, cerebellar hemangioma), demyelination, stroke, cranial trauma, brain irradiation, intrathecal methotrexate, and drugs (alcohol, lithium, anticonvulsants) have all been associated with various types of nystagmus.16

    Saccadic intrusions and oscillations including square-wave jerks and oscillations; dissociated ocular oscillations, hypermetric saccades, macrosaccadic oscillations, ocular flutter, opsoclonus, psychogenic (voluntary) flutter, and superior oblique myokymia all have variable etiology and outcome.

    Some of these conditions have both retinal/visual involvement in addition to systemic and neurologic abnormalities. Joubert syndrome is an example of conditions that can present with INS or acquired nystagmus. Patients have various degrees of neurologic and systemic abnormalities and some develop retinal dystrophies that can range from LCA type disease to retinitis pigmentosa (RP).33 Other syndromic retinal dystrophies (such as Batten disease)34 and syndromic optic neuropathies35 can have neurologic abnormalities associated, and can present with acquired nystagmus of childhood.

    In conclusion, all types of nystagmus require a step-by-step workup, directed by clinical examination. Almost all nonphysiologic forms of nystagmus have an underlying cause that can be ocular, neurologic, or both. Genetically determined motor nystagmus is either a diagnosis of exclusion or has to be proven with genetic testing. Analyzing eye movements alone can add clinical value and help guide the rest of the workup but should not be interpreted in isolation. A negative first step (especially MRI) should not be the last step of the nystagmus workup. Even in cases of acquired nystagmus (especially if the onset is in the first year of life or SNS is suspected), if the MRI is nondiagnostic, the entire INS algorithm should be explored to complete the workup.

    A complete workup will lead to a correct and complete diagnosis. Giving a family an erroneous diagnosis could be stressful and dangerous or falsely reassuring. It might lead to:

    • misinformed family-planning decisions and/or unexpected outcome when inherited ocular or neurologic conditions are missed; or
    • additional unnecessary testing when neurologic or syndromic ocular pathology is overcalled; or
    • missing an early diagnosis of a neurological or life-threatening condition.

    References:

    1. Bertsch M, Floyd M, Kehoe T, Pfeifer W, Drack A V. The clinical evaluation of infantile nystagmus: What to do first and why. Ophthalmic Genet. 2017;38(1):22-33. doi:10.1080/13816810.2016.1266667.
    2. TY - JOUR AU  - Hertle R PY  - 2001/01/01 SP  -  T1  - A Classification of Eye Movement Abnormalities and Strabismus (CEMAS) ER  -. https://www.researchgate.net/publication/242497706_A_Classification_of_Eye_Movement_Abnormalities_and_Strabismus_CEMAS/citation/download. Accessed December 15, 2019.
    3. Sarvananthan N, Surendran M, Roberts EO, et al. The prevalence of nystagmus: the Leicestershire nystagmus survey. Invest Ophthalmol Vis Sci. 2009;50(11):5201-5206. doi:10.1167/iovs.09-3486
    4. Ehrt O. Infantile and acquired nystagmus in childhood. Eur J Paediatr Neurol. 2012;16(6):567-572. doi:10.1016/j.ejpn.2012.02.010
    5. Nash DL, Diehl NN, Mohney BG. Incidence and Types of Pediatric Nystagmus. Am J Ophthalmol. 2017;182:31-34. doi:10.1016/j.ajo.2017.07.006
    6. Dumitrescu A V, Moga DC, Longmuir SQ, Olson RJ, Drack A V. Prevalence and characteristics of abnormal head posture in children with Down syndrome: a 20-year retrospective, descriptive review. Ophthalmology. 2011;118(9):1859-1864. doi:10.1016/j.ophtha.2011.02.026
    7. Self J, Lotery A. A Review of the Molecular Genetics of Congenital Idiopathic Nystagmus (CIN). Ophthalmic Genet. 2007;28(4):187-191. doi:10.1080/13816810701651233
    8. Choudhuri I, Sarvananthan N, Gottlob I. Survey of management of acquired nystagmus in the United Kingdom. Eye (Lond). 2007;21(9):1194-1197. doi:10.1038/sj.eye.6702434
    9. Li H, Liu LY, Xu H, Xu F, Jiang RX, Sui RF. [Clinical features of congenital stationary night blindness]. Zhonghua Yi Xue Za Zhi. 2012;92(39):2756-2759. http://www.ncbi.nlm.nih.gov/pubmed/23290162. Accessed December 22, 2019.
    10. Bowen M, Peragallo JH, Kralik SF, Poretti A, Huisman TAGM, Soares BP. Magnetic resonance imaging findings in children with spasmus nutans. J AAPOS. 2017;21(2):127-130. doi:10.1016/j.jaapos.2017.03.001
    11. Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010;18(3):643-650. doi:10.1038/mt.2009.277
    12. Thurtell MJ, Leigh RJ. Nystagmus and saccadic intrusions. Handb Clin Neurol. 2011;102:333-378. doi:10.1016/B978-0-444-52903-9.00019-4
    13. Calhoun JH, Harley RD. Surgery for abnormal head position in congenital nystagmus. Trans Am Ophthalmol Soc. 1973;71:70-83; discussion 84-7. http://www.ncbi.nlm.nih.gov/pubmed/10949591. Accessed August 18, 2019.
    14. Carruthers J. The treatment of congenital nystagmus with Botox. J Pediatr Ophthalmol Strabismus. 1995; 32(5):306-308. http://www.ncbi.nlm.nih.gov/pubmed/8531035. Accessed December 8, 2019.
    15. Zwergal A, Strupp M, Brandt T. Advances in pharmacotherapy of vestibular and ocular motor disorders. Expert Opin Pharmacother. 2019;20(10):1267-1276. doi:10.1080/14656566.2019.1610386
    16. Thurtell MJ, Tomsak RL, Daroff RB. Neuro-Ophthalmology. Oxford University Press; 2011. doi:10.1093/med/9780195390841.001.0001
    17. Blechschmidt T, Krumsiek M, Todorova MG. The effect of acupuncture on visual function in patients with congenital and acquired nystagmus. Med (Basel, Switzerland). 2017;4(2). doi:10.3390/medicines4020033.
    18. Tsang DK, Spors F, Shen J, McNaughton LE, Egan DJ. Optical rehabilitation of a patient with keratoconus and nystagmus. Med hypothesis, Discov Innov Ophthalmol J. 2018;7(4):183-189. http://www.ncbi.nlm.nih.gov/pubmed/30505870. Accessed December 8, 2019.
    19. Zeitz C, Robson AG, Audo I. Congenital stationary night blindness: An analysis and update of genotype–phenotype correlations and pathogenic mechanisms. Prog Retin Eye Res. 2015;45:58-110. doi:10.1016/J.PRETEYERES.2014.09.001
    20. McCafferty BK, Holleschau AM, Connett JE, Summers CG. Visual development during the second decade of life in albinism. J Pediatr Ophthalmol Strabismus. 2018;55(4):254-259. doi:10.3928/01913913-20180327-02
    21. Mets MB. Eye manifestations of intrauterine infections. Ophthalmol Clin North Am. 2001;14(3):521-531. http://www.ncbi.nlm.nih.gov/pubmed/11705152. Accessed October 5, 2019.
    22. Stunkel M, Bhattarai S, Kemerley A, et al. Vitritis in pediatric genetic retinal disorders. Ophthalmology. 2015;122(1):192-199. doi:10.1016/j.ophtha.2014.07.037.
    23. Rosini F, Vinciguerra C, Mignarri A, Di Giovanni M, Federico A, Rufa A. Eye movement abnormalities in a patient with Zellweger spectrum disorder. Neurol Sci. 2016;37(6):1013-1015. doi:10.1007/s10072-016-2499-8.
    24. Mendes MI, Green LMC, Bertini E, et al. RARS1ÔÇÉrelated hypomyelinating leukodystrophy: Expanding the spectrum. Ann Clin Transl Neurol. 2020; 7(1):83-93. December 2019:acn3.50960. doi:10.1002/acn3.50960.
    25. Stark KL, Gibson JB, Hertle RW, Brodsky MC. Ocular motor signs in an infant with carbohydrate-deficient glycoprotein syndrome type Ia. Am J Ophthalmol. 2000;130(4):533-535. doi:10.1016/s0002-9394(00)00569-9.
    26. Khan AO. Magnetic resonance imaging findings in children with spasmus nutans. J AAPOS. 2017;21(4):345. doi:10.1016/j.jaapos.2017.06.004.
    27. Richards M, Wong A, Foeller P, Bradley D, Tychsen L. Duration of binocular decorrelation predicts the severity of latent (fusion maldevelopment) nystagmus in strabismic macaque monkeys. Invest Ophthalmol Vis Sci. 2008;49(5):1872-1878. doi:10.1167/iovs.07-1375.
    28. Strupp M, Kremmyda O, Adamczyk C, et al. Central ocular motor disorders, including gaze palsy and nystagmus. J Neurol. 2014;261 Suppl 2(S2):S542-58. doi:10.1007/s00415-014-7385-9
    29. Association for Research in Vision and Ophthalmology. J, Schwarze H, Simonsz HJ, Mühlendyck H. Investigative Ophthalmology & Visual Science. Vol 31. C.V. Mosby Co; 1977. https://iovs-arvojournals-org.proxy.lib.uiowa.edu/article.aspx?articleid=2199573. Accessed October 5, 2019.
    30. Leigh RJ, Zee DS, eds. The Neurology of Eye Movements, Oxford University Press, 2015.
    31. Volpe JJ, Preceded by (work): Volpe JJ. Volpes Neurology of the Newborn, Sixth Edition. Elsevier, Philadelphia 2018.
    32. Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification for midbrain-hindbrain malformations. Brain. 2009;132(12):3199-3230. doi:10.1093/brain/awp247
    33. Brancati F, Dallapiccola B, Valente EM. Joubert syndrome and related disorders. Orphanet J Rare Dis. 2010;5(1):20. doi:10.1186/1750-1172-5-20
    34. Katata Y, Uematsu M, Sato H, et al. Novel missense mutation in CLN8 in late infantile neuronal ceroid lipofuscinosis: The first report of a CLN8 mutation in Japan. Brain Dev. 2016;38(3):341-345. doi:10.1016/j.braindev.2015.09.008
    35. Jarius S, Ruprecht K, Kleiter I, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin. J Neuroinflammation. 2016;13(1):279. doi:10.1186/s12974-016-0717-1