European Journal of Cardiovascular Medicine

Nystagmus refers to involuntary, typically conjugate, often rhythmic oscillations of the eyes. There are three types of nystagmus that are most likely to be encountered in children: infantile nystagmus syndrome (INS), fusion maldevelopment syndrome nystagmus (previously known as latent/manifest latent nystagmus), and spasmus nutans. This review focuses on INS. Some believe that fusion maldevelopment syndrome nystagmus represents a monocular form in the same spectrum as INS. ^[1] The term congenital nystagmus is often used synonymously with INS; however, it is technically incorrect as nystagmus does not typically develop at birth but more likely at 2–3 months of age. INS may be associated with retinal or optic nerve maldevelopment (previously known as sensory nystagmus) or may occur in isolation (previously known as congenital motor nystagmus). Conditions commonly associated with nystagmus include albinism, aniridia, achromatopsia, cone dystrophy, optic nerve hypoplasia, foveal hypoplasia, congenital cataracts, corneal opacities, retinopathy of prematurity, Leber congenital amaurosis, and syndromic causes associated with early-onset retinal degenerations. The nystagmus associated with visual sensory deficit is identical to that which presents in isolation; however, acuity is typically worse in those with sensory deficit. ^[2]

When assessing an infant or child with nystagmus, it is important to determine the age of onset as well as the child’s birth, developmental, medical, and family history. It is imperative to identify an underlying etiology if present, as the associated ocular or associated systemic condition may require intervention. Newer high-resolution imaging modalities such as optical coherence tomography (OCT) are increasingly being used for determining the cause of INS in children. The ability to use imaging to augment the clinical evaluation is important as patients are often misdiagnosed as having idiopathic INS, when in fact there is an underlying ophthalmic diagnosis and foveal maldevelopment can be found on OCT. ^[3] Neuro-imaging should be considered when nystagmus onset is after 3 months and not associated with an underlying sensory deficit or when associated with optic nerve hypoplasia. ^[4]

Clinically, the evaluation of nystagmus includes measurement of best-corrected visual acuity and a description of characteristics of the waveform (eg, direction, type, amplitude, and frequency) as well as documentation about any head turns or tilts and location of the null point, if present. To further characterize nystagmus, eye movement recordings are utilized. These recordings may be used to determine change after medical or surgical intervention. There are at least three methods used to quantify foveation characteristics in patients with nystagmus.

Nystagmus with acceleration of movement during the slow phase is considered characteristic of infantile nystagmus. ^[6] The earliest form of infantile nystagmus seen tends to be pendular and develops into a jerk form in the first 2 years of life.8 The presence of a null point or zone is also characteristic of infantile nystagmus. The null point is typically within 10° of fixation with lateral head turns the most common adaptation. ^[7] How the null point develops is poorly understand and has received surprisingly little research attention. The absence of illusory movement of the visual world (oscillopsia) is a characteristic of infantile nystagmus, which separates it from acquired forms. Visual perception is normally suppressed during saccades to prevent smear of the visual image. ^[8] It has been postulated that the eye movement generation systems produce a copy of the nystagmus eye movement to be executed and send it to higher cortical areas. This “efference copy” serves as the template for the expected movement at the cortical level. ^[9] Since there is a match between the true eye movement and the expected eye movement, no perception of visual motion is generated. In acquired nystagmus, a mismatch between the expected and actual location occurs, or possibly, multiple signals are misinterpreted, resulting in the illusion of motion of the visual world.

This prospective, Single center cohort study was conducted in the Tertiary Care Teaching Hospital. Medical charts were selected by searching the keyword “nystagmus” in the fields “history,” “clinical examination,” and “diagnosis” of the electronic notes. Potential casepatients were manually screened by medical chart review. We included all patients referred to the PED with a history of ,30 days of an ocular movement abnormality in whom a diagnosis of nystagmus was confirmed. Exclusion criteria were (1) abnormal eye movements other than nystagmus (such as ocular flutter, opsoclonus, and/or supranuclear gaze disturbances), (2) patients attending the PED because of head injury or (3) epileptic seizures, and (4) patients affected by an already known neurologic condition explaining the nystagmus.

              We included both patients attending the PED complaining of the eye movement abnormality and patients complaining about other symptoms whose nystagmus was detected during the clinical examination. In the latter case, nystagmus was considered as new onset when it was reasonably linked with the same pathologic process causing the acutely presenting symptoms (eg, ataxia, vertigo, headache, altered mental status), it had neither been noticed before nor mentioned in medical records, and it was not explained by any of the known preexisting medical problems.

              From each medical record, information about demographic features, clinical history, examination findings, investigations performed, hospital admission, and length of stay (as applicable) was extracted. Accordant with Italian National Health Service guidelines, the priority of consultation on PED admission was based on a 4-color triage coding scale:

• red code: critical medical state, vital signs alteration needing immediate life-saving intervention, high-priority access to urgent care;
• yellow code: serious state, risk of evolution into critical conditions, intermediate-priority access and reevaluation needed in 5 to 15 minutes;
• green code: fair state, stable vital signs, medical consultation postponable without risk, lowpriority access and reevaluation needed in 30 to 60 minutes; and
• white code: good state, nonurgent consultation.

The triage code has to be assigned by a trained triage nurse at entrance in the emergency department and is periodically reevaluated during the waiting time. This system was enforced during the entire study period, which was conducted after the Italian Ministry of Health agreement with all Italian regions in 2001.

              The clinical and demographic features were described in the overall cohort and in the 2 subgroups (patients with and without UCs). Each variable was compared between the 2 subgroups to identify significant differences. After reviewing for appropriateness, x2 and Student’s t tests were used for statistical comparison of categorical and continuous variables, respectively

              To detect predictive variables associated with a higher risk of UCs in patients with AN, a logistic regression analysis model was applied. Clinical features revealing significant differences on x2 and t tests were selected as independent variables. Sex and age were included a priori to adjust the effect of each independent variable for the demographic characteristics of the cohort. Variables with extremely unbalanced distribution in the 2 groups (frequency 0% in 1 group) were excluded.

              Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were used as measures of effect. The statistical significance was set at P , .05 for all analyses. SPSS Statistics software package (IBM SPSS Statistics, IBM Corporation) was used to perform all statistical analyses.

A total of 90 patients meeting the inclusion criteria were identified (48 male patients; male-to-female ratio: 1.01). Demographic and clinical features of the whole cohort and the 2 subgroups with and without severe UCs are summarized in Table 1. The mean age at PED attendance was 8 years 11 months. Thirty-seven patients (33%) were, 2 years of age (25 of 37 were, 6 months), 34 children (38%) were aged between 2 and 12 years, and 82 (40%) were .12 years. In 77 cases (37%), patients attended the PED complaining of abnormal eye movements. In the remaining cases, nystagmus was detected during clinical examination in patients with other complaints. The mean time from symptoms onset to admission to the PED was 5 days, with 68% of the whole cohort reporting the onset of symptoms within 3 days before admission (median: 2 days). Nystagmus plane was horizontal in the vast majority of cases (71.4%). Less frequently, vertical (6.8%), torsional (1%), or combined (3.4%) nystagmus was reported. Nevertheless, in a significant proportion of patients, the oscillation plane was not reported in clinical records (17.4%). The symptoms most commonly referred during PED consultation were headache (43.2%) and vertigo and/or dizziness (42.2%), followed by nausea and vomiting (25.7%) and visual disturbances (16.02%). Many patients presented with a constellation of associated symptoms (Supplemental Fig 3). Clinical findings most commonly reported during examination included ataxia (18.45%), strabismus (13.1%), or a decreased level of consciousness (6.3%). Sixteen patients (7.8%) were febrile at PED admission (Table 2). In 54.9% of the cases, nystagmus was the only neurologic abnormality reported.

TABLE 1 Demographic and Clinical Feature of the Whole Cohort and the 2 Subgroups With and Without Severe UCs

TABLE 2 Frequencies of Signs and Symptoms Associated to Nystagmus in the Whole Cohort and in the 2 Subgroups

TABLE 3 Investigations Performed in the Whole Cohort and the 2 Subgroups

Specialist consultations were requested for 83.5% of the patients, mainly neurologic (61.2%) or ophthalmologic (35.4%) consultations. Approximately one-half of the patients underwent neuroimaging tests (53.9%); 60.4% of them performed the test directly in the PED (Table 3).

              A total of 118 patients (57.3%) were hospitalized after PED consultation. Migraine was the most common cause of AN (accounting for 25.7% of all cases), followed by vestibular disorders (14.1%) (Fig 1A). Transient, not otherwise identified vertigo accounted for 12.6% of the cases. Idiopathic infantile nystagmus (IIN) was responsible for 6.8% of the AN cases, representing the first cause of PED consultation for nystagmus in the first year of life (Fig 1B). Other rarer causes of AN included toxic ingestion, postinfectious cerebellar ataxia, and periodic syndromes (Fig 1A). Thirty-nine patients were diagnosed with a UC (18.9%). Brain tumors were the first UC causing AN (17 cases; 8.3% of the whole cohort). Other causes included idiopathic intracranial hypertension, demyelinating disorders, degenerative conditions, and CNS infections or malformations (Fig 1C).

              Patients with UCs were found to be significantly younger than non-UC patients (mean age: 6 years and 11 months versus 12 years and 4 months), with the highest frequency of UC cases occurring in children between 1 and 6 years of age (Fig 1D). Time delay from symptoms onset to PED presentation was significantly longer in UC compared with non-UC patients (Table 1). Diplopia, blurred vision, strabismus, cranial nerve palsy, ataxic gait, dysmetria, pyramidal weakness, and papilledema, as well as the absence of accompanying symptoms, were significantly more frequent in patients with UCs (Table 2). In contrast, vertigo and the absence of any neurologic sign were more commonly found in non-UC patients (Table 2), as well as the attribution of a nonurgent (green or white) triage code.

              On this basis, 14 variables were selected for the logistic regression model (Table 4), including 199 patients (96.6%). According to our model, the presence of cranial nerve deficits, ataxia, or strabismus was strongly associated with an underlying UC, increasing its risk by 46.82-, 9.29-, and 9.17-fold, respectively (P , .02) (Table 4). Though not reaching statistical significance, the presence of pyramidal weakness and abnormal head postures were also associated with an increased risk of UC (with an OR of 8.59 and 7.18, respectively). A longer time from symptoms onset to PED referral was found to raise the odds of an underlying UC, with a 9% increase of the risk by each day from nystagmus onset (OR = 1.09; P, .01). Despite the younger age at admission of patients with UCs, this variable was not associated with a greater risk of UC when adjusted for other variables in the logistic regression model (Table 4).

              On the other hand, the occurrence of vertigo was found to reduce the odds of an underlying UC (OR = 0.17; P, .01), as well as the attribution of a green or white triage code (OR = 0.30; P = .01).

Nystagmus is a worrying condition for the family and paediatricians. In child neurology, it may indicate severe intracranial pathology even in the absence of other neurological signs. However, in infancy the most frequent aetiology of nystagmus is eye or anterior visual pathways disorder allowing for SDN. ^[11] Infantile nystagmus without major ocular signs thus create a diagnostic challenge for the child neurologist.

              In the present study we collected a large cohort of children with infantile nystagmus uniquely characterized by the absence of pathognomonic ocular abnormalities and systematically evaluated with an integrated interdisciplinary neuro-ophthalmological approach including visual electrophysiology. Clinical, ophthalmological, and neurological examinations combined with electrophysiological assessments (electroretinogram-VEPs) and, in selected cases, full neurodiagnostic work-up enabled classification of all our patients into one of the four diagnostic subgroups: neurological nystagmus, MNSN, SDN, IIN.

              Our data confirmed that SDN is the most prevalent type of infantile nystagmus even in children without obvious ocular diagnoses, but about one-third of the infants in our cohort had a variety of neurological malformations and genetic disorders involving oculomotor circuits, as confirmed by MRI, manifesting early in life with nystagmus. We demonstrated that paediatric neurological nystagmus is not only due to ‘acquired’ brain damage, usually occurring in older children, but also to genetic disorders and brain malformations manifesting with infantile nystagmus. In agreement with recent literature, neurological pathophysiology should be considered in the diagnostic work-up of infantile nystagmus. Nystagmus may also be idiopathic in a minor proportion of infants, further complicating aetiological work-up.

              Vision loss can impact on psychomotor development; thus the evaluation of the infant’s level of vision coupled with basic neurological assessment is needed to assist clinicians in teasing apart the developmental consequences of visual impairment from neurological abnormality.

              Considering the neurological diagnoses associated with neurological nystagmus and MNSN, white matter, metabolic diseases, and cerebral malformations were the most prevalent disorders. The neurological examination was clearly abnormal in all but two infants both showing isolated nonprogressive pontine tegmental hyperintensities on MRI. Considering children with isolated SDN, none had clearly abnormal neurological signs; however, we observed transient developmental delay of gross motor skills resolving over time in some children with severe vision loss, attributed to the impact of low vision. From these results we suggest that nystagmus presenting early in life, and associated with abnormalities in the neurological examination, should undergo a complete neurological diagnostic work-up including MRI. At this early age, neurological signs of fronto-cerebellar involvement other than nystagmus may be non-specific (i.e. hypotonia instead of coordination disorder in cerebellar abnormalities) and may be missed on clinical grounds alone. MRI and a full neurometabolic and genetic work-up are fundamental to achieve the diagnosis in these children.

Electrophysiology should be performed before MRI in infants without neurological signs, in contrast with the practice reported by Bertsch. The authors showed that, in infantile nystagmus, MRI was usually performed as the first instrumental test. One other important finding of the present study was that 23% of the total number of infants with a primary neurological diagnosis had an associated sensory defect, classified as MNSN. These infants had a mixed pathophysiology of nystagmus involving both the oculomotor circuits function and the sensory systems such as the retina or optic nerve. Examples were the occurrence of rod-cone retinal dystrophy in some metabolic diseases and in Joubert syndrome, Leber congenital amaurosis in Galloway-Mowat syndrome, and early-onset optic atrophy in genetic syndromes. Vision impairment can be overlooked in such cases because of the predominance of the neurological features overshadowing abnormal visual clues. ^[12] Electrophysiological tests can be of paramount importance in the identification of the associated retina and anterior visual pathways disorders, representing diagnostic clues in the syndromic definition.

              Visual electrophysiology had an important role also in the subgroup with sensory defect, in line with research. ^[13] The electroretinogram identified photoreceptors’ dysfunction in all retinal dystrophies, giving different patterns of involvement, useful for genotype–phenotype correlations. ^[14] The VEPs supported the diagnosis of ocular albinism in infants without cutaneous findings, by identifying misrouting of optic nerve fibres, the so-called pattern of crossed asymmetry, provided that the electroretinogram excluded a retinal dystrophy. ^[15] Moreover, recent genetic advances report that, in the absence of albino fundus, the crossed asymmetry pattern can suggest variations in the gene SLC38A8. ^[16]

              The subgroup with SDN also included children with isolated foveal hypoplasia, in agreement with other studies. ^[17] In infancy, these patients fulfilled our diagnostic criteria for IIN, but foveal hypoplasia was subsequently diagnosed by means of OCT, at a median age of 8 years, thanks to longterm follow-up. Whole exome sequencing revealed GPR143 variants in three male siblings with foveal hypoplasia. The ophthalmological diagnosis of foveal hypoplasia may be difficult at fundus oculi inspection alone in very young infants due to retinal immaturity, abnormal ocular movements, and scarce cooperation. In infancy, the OCT technique is also not easy to perform and less reliable, explaining the late diagnosis in these patients.^[18-24]

In conclusion, infantile nystagmus in the absence of ophthalmological signs is subtended by a variety of ophthalmological and neurological disorders that require an interdisciplinary neuro- ophthalmological approach. We propose that electrophysiological testing could be performed early in the diagnostic pathway of these infants, in order to rule out retinal or optic nerve disorders both in children with and without neurological signs or symptoms. Brain MRI and a full neurometabolic and/or genetic work-up should be first considered in infants with abnormal neurological examination or developmental delay. When the neurological examination is fully normal, psychomotor development is appropriate for age, and the electroretinogram and VEPs are normal, the diagnostic hypothesis of IIN should be confirmed at follow-up when fundus oculi evaluation may be more reliable, and OCT can further support a possible diagnosis of foveal hypoplasia.

1. Leigh RJ, Rucker JC. Nystagmus and Related Ocular Motility Disorders. Walsh Hoyt’s Clin Neuro-Ophthalmology. 2005;(2):1–89.
2. Casteels I, Harris CM, Shawkat F, Taylor D. Nystagmus in infancy. Br J Ophthalmol [Internet]. 1992; 76(7):434–7. Available from: https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC504306/pdf/brjopthal0 0055-0050.pdf%0Ahttp://www.pubmedcentral.nih.gov/articleren der.fcgi?artid=504306&tool=pmcentrez&rendertype=abstract
3. Papageorgiou E, McLean RJ, Gottlob I. Nystagmus in childhood. Pediatr Neonatol [Internet]. 2014;55(5):341–51. Available from: https://doi.org/10.1016/j.pedneo.2014.02.007
4. Nash DL, Diehl NN, Mohney BG. Incidence and Types of Pediatric Nystagmus. Am J Ophthalmol [Internet]. 2017 Oct;182:31–4. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0002 93941730301X
5. Hvid K, Nissen KR, Bayat A, Roos L, Grønskov K, Kessel L. Prevalence and causes of infantile nystagmus in a large population-based Danish cohort. Acta Ophthalmol. 2020;98(5):506–13.
6. van Genderen M, Riemslag F, Jorritsma F, Hoeben F, Meire F, Stilma J. The key role of electrophysiology in the diagnosis of visually impaired children. Acta Ophthalmol Scand. 2006;84(6):799–806.
7. Cibis GW, Fitzgerald KM. Electroretinography in congenital idiopathic nystagmus. Vol. 9, Pediatric Neurology. 1993;84:369–71.
8. Lambert SR, Taylor D, Kriss A. The infant with nystagmus, normal appearing fundi, but an abnormal ERG. Surv Ophthalmol. 1989;34(3):173–86.
9. Banc A, Ungureanu MI. Normative data for optical coherence tomography in children: a systematic review. Eye [Internet]. 2020; Available from: https://doi.org/10.1038/s41433-020-01177-3

10. McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, et al. ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol. 2015;130(1):1–12.