Correction: Management of nystagmus in children: a review of the literature and current practice in UK specialist services.

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Management of nystagmus in children: a review of the literature and current practice in UK specialist services.

Nystagmus is an eye movement disorder characterised by abnormal, involuntary rhythmic oscillations of one or both eyes, initiated by a slow phase. It is not uncommon in the UK and regularly seen in paediatric ophthalmology and adult general/strabismus clinics. In some cases, it occurs in isolation, and in others, it occurs as part of a multisystem disorder, severe visual impairment or neurological disorder. Similarly, in some cases, visual acuity can be normal and in others can be severely degraded. Furthermore, the impact on vision goes well beyond static acuity alone, is rarely measured and may vary on a minute-to-minute, day-to-day or month-to-month basis. For these reasons, management of children with nystagmus in the UK is varied, and patients report hugely different experiences and investigations. In this review, we hope to shine a light on the current management of children with nystagmus across five specialist centres in the UK in order to present, for the first time, a consensus on investigation and clinical management.

Supranuclear eye movements and nystagmus in children: A review of the literature and guide to clinical examination, interpretation of findings and age-appropriate norms.

Abnormal eye movements in children, including nystagmus, present a significant challenge to ophthalmologists and other healthcare professionals. Similarly, examination of supranuclear eye movements and nystagmus in children and interpretation of any resulting clinical signs can seem very complex. A structured assessment is often lacking although in many cases, simple clinical observations, combined with a basic understanding of the underlying neurology, can hold the key to clinical diagnosis. As the range of underlying diagnoses for children with abnormal eye movements is broad, recognising clinical patterns and understanding their neurological basis is also imperative for ongoing management. Here, we present a review and best practice guide for a structured, methodical clinical examination of supranuclear eye movements and nystagmus in children, a guide to clinical interpretation and age-appropriate norms. We also detail the more common specific clinical findings and how they should be interpreted and used to guide further management. In summary, this review will encourage clinicians to combine a structured assessment and a logical interpretation of the resulting clinical signs, in order to recognise patterns of presentation and avoid unnecessary investigations and protracted delays in diagnosis and clinical care.

Infantile nystagmus and late onset ataxia associated with a CACNA1A mutation in the intracellular loop between s4 and s5 of domain 3.

PURPOSE: Mutations in the 1A-subunit of the brain P/Q-type calcium channel gene CACNA1A are responsible for spinocerebellar ataxia type 6 (SCA6), familial haemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). Considerable clinical and genetic overlap exists between these 3 allelic disorders. Clinical findings are varied and may include nystagmus. OBJECTIVE: To study the clinical phenotype and identify a causative mutation in a family who presented when the youngest member was diagnosed with apparent isolated congenital nystagmus (age 3 months). PATIENTS AND METHODS: 8 patients from one family underwent detailed clinical phenotyping comprising; ophthalmic and neurological examination, nystagmology, electrodiagnostic tests and brain imaging. The CACNA1A gene was screened for mutations by direct sequencing in one patient. Co-segregation of the disease and an identified sequence variation was shown using direct sequencing. RESULTS: Phenotyping revealed isolated atypical nystagmus in 4 family members and nystagmus in addition to late onset ataxia in 1 family member. Direct sequencing of the CACNA1A gene identified a novel missense mutation; (c.4110T>G p.Phe1370Leu (NM_000068.3)). CONCLUSIONS: We have shown that a mutation in the intracellular domain between s4 and s5 of repeat 3 can cause atypical nystagmus/cerebellar phenotypes, including isolated nystagmus in an infant. We also illustrate the necessity for detailed examination of relatives in cases of apparent isolated congenital nystagmus.

Spontaneous reversal of nystagmus in the dark.

AIM: To report five children with horizontal jerk nystagmus in whom eye movement recordings in the dark revealed a spontaneous reversal in the direction of the nystagmus beat. Three patients were blind in one eye and were diagnosed as having a manifest latent nystagmus (MLN), and two patients had strabismus and congenital nystagmus (CN). METHODS: Eye movements were recorded using DC electro-oculography with simultaneous video recording, including infrared recording in total darkness. RESULTS: Four patients had decelerating velocity slow phase jerk nystagmus when recorded under natural lighting conditions; the fifth case had accelerating velocity and linear slow phase jerk nystagmus. Under absolute darkness, nystagmus reversed in direction of beat with a mixture of linear and decelerating velocity slow phase waveforms. One child with unilateral anophthalmos could wilfully reverse the beat direction of his nystagmus by trying to look with his blind eye in the light and dark. CONCLUSIONS: These observations support the theory that LN/MLN beat direction is determined by the "presumed" viewing eye and may be consciously controlled. The spontaneous reversal of beat direction in the dark suggests eye dominance is predetermined. Eye movement recordings identified mixed nystagmus waveforms indicating that CN (accelerating velocity slow phases) and LN/MLN (linear/decelerating velocity slow phases) coexist in these subjects.

A study of the effects of contrast change on pattern VEPS, and the transition between onset, reversal and offset modes of stimulation.

We studied the relationship between the visual evoked potential (VEP) components by tracing the transition from onset/offset mode of stimulation to the reversal mode by a series of contrast change steps. VEPs on the ipsilateral and contralateral side of the scalp with respect to the left half-field checkerboard stimulus (checksizes: 12', 50' and 80') were recorded in 15 subjects. Eight contrast steps for each checksize were recorded. Each test step consisted of the alternation of a constant high contrast checkerboard (A), with a second checkerboard (B) in which the contrast was changed. Checkerboard B was initially of identical spatial phase to A, but contrast was reduced systematically until B was a uniform grey field (i.e. onset/offset). In subsequent steps checkerboard B was of opposite spatial phase and contrast was increased until the final step when B was of equal high contrast (i.e. full reversal). All ipsilateral and contralateral onset components, ipsilateral offset components, and the reversal P100 component significantly enlarged with increasing contrast. The extent of amplitude change with contrast was greatest for offset, followed by onset and then reversal. A clear association could be discerned between all offset and reversal components. Onset CI and CII appeared to be related to the reversal P100 and N145, respectively. When small 12' checks were used, onset Co appeared to have common features with the reversal N80. The contralateral onset P105 component did not have a comparable component in the reversal mode.

Vertical or asymmetric nystagmus need not imply neurological disease.

AIM: To indicate that congenital idiopathic nystagmus (CIN) and sensory defect nystagmus (SDN) can be vertical or asymmetric in some children. METHODS: Of 276 children presenting with nystagmus for electrophysiological testing, 14 were identified as having CIN or SDN, yet had a nystagmus which was either vertical (n=11) or horizontal asymmetric (n=3). Flash electroretinograms and flash and pattern visual evoked potentials (VEPs) were recorded in all patients. Eye movement assessment, including horizontal optokinetic nystagmus (OKN) testing, was carried out in 11/14 patients. RESULTS: Eight patients (seven with vertical, one with asymmetric horizontal nystagmus) had congenital cone dysfunction. One patient with vertical and another with asymmetric nystagmus had cone-rod dystrophy. One patient with vertical upbeat had congenital stationary night blindness. Two patients (one downbeat, one upbeat nystagmus) had normal electrophysiological, clinical, and brain magnetic resonance imaging findings and were classified as having CIN. One patient with asymmetric nystagmus showed electrophysiological and clinical findings associated with albinism. Horizontal OKN was present in 80% of patients tested, including the three cases with horizontal asymmetric nystagmus. This is atypical in both CIN and SDN, where the OKN is usually absent. CONCLUSIONS: Vertical and asymmetric nystagmus are most commonly associated with serious intracranial pathology and its presence is an indication for neuroimaging studies. However, such nystagmus can occur in children with retinal disease, albinism, and in cases with CIN. These findings stress the importance of non-invasive VEP/ERG testing in all cases of typical and also atypical nystagmus.

Visual-evoked potential evidence of chiasmal hypoplasia.

PURPOSE: To show that chiasmal hypoplasia or aplasia need not be an isolated developmental anomaly and to examine the spectrum of associated clinical findings to explore the possibility that these patients may represent a phenotypic manifestation of a developmental gene anomaly. DESIGN: An observational case series. PARTICIPANTS: Five infants, between several weeks and 7 months of age, in whom the electrophysiologic characteristic of chiasmal hypoplasia had been noted were included. METHODS: Flash electroretinography and flash and pattern visual-evoked potentials (VEPs) were elicited from all patients. Clinical ophthalmologic examinations, including funduscopy, were performed, and all patients had magnetic resonance imaging (MRI) brain scans. MAIN OUTCOME MEASURES: The occipital distribution of monocular VEP response peaks was studied. The symmetry of lateral channel responses was compared for monocular stimulation. RESULTS: All five patients had a crossed asymmetry in the monocular VEP occipital distribution, which is consistent with a paucity of fibers crossing at the chiasm. The MRI findings supported this electrophysiologic observation, illustrating degrees of chiasmal hypoplasia and variable coincidence of other midline abnormalities of the brain. Optic disc appearances varied from normal to hypoplastic and colobomatous. CONCLUSIONS: The ophthalmologic and MRI findings of five patients who showed a crossed asymmetry in monocular flash VEPs are consistent with a paucity of axons crossing at the chiasm. The similarities between achiasmia in humans and mice due to a Pax2 gene anomaly are discussed.

Saccadic strategies in children with hemianopia.

Multiple hypometric (undershooting) saccades are generally reported as a compensatory strategy in adults with homonymous hemianopia. However, hypermetric (overshooting) saccades have been reported to develop spontaneously as a beneficial strategy in response to predictable targets. We examined the saccades of 10 children (aged 5 to 16 years) with homonymous hemianopia to determine the type of compensatory eye-movement strategies employed 6 months to 16 years after hemianopia onset. Homonymous hemianopia was identified using perimetry and/or pattern visual evoked potentials and supported with results of neuroimaging. Eye movements were recorded using bitemporal electrooculography. Saccades were elicited to a red light source in a semipredictable paradigm. We found that hypermetria was not a consistent compensatory strategy in our patients. In spite of the predictability of our paradigm and the long follow-up period, multiple hypometric saccades into the blind field appeared to be the preferred strategy.

Familial congenital saccade initiation failure and isolated cerebellar vermis hypoplasia.

The underlying lesion in congenital saccade initiation failure (c-SIF) ('congenital ocular motor apraxia', 'Cogan's apraxia') is uncertain. Often no abnormality can be found, yet in others a midline cerebellar abnormality has often been reported. We examined this cerebellar association in a brother and sister. In addition to standard ophthalmological and neurological examinations, both siblings underwent ocular motor testing and neuroradiological investigations including CT and MRI. Both siblings exhibited the typical signs of c-SIF, including headthrusting, synkinetic blinking, missed-nystagmus quick phases, mild developmental delay, and speech difficulties. CT and MRI revealed cerebellar vermis hypoplasia in the brother, but appeared normal in the sister. No other neuroradiological abnormalities were detected. These cases highlight the wide variability in the association of vermis abnormalities with c-SIF, despite the inheritance and similar clinical manifestations. They show that either: (1) the vermis is causal in saccade triggering, but that c-SIF may result from very subtle damage that is beyond MRI resolution in some cases; or (2) that a vermis abnormality per se is not causative but only a marker of another subtle abnormality, either structural or possibly biochemical.

Comparison of pattern-onset, -reversal and -offset VEPs in treated amblyopia.

PURPOSE: There are differences in the properties of visual evoked potentials (VEPs) to various forms of pattern stimulation and it is not clear how these differences reflect macular and parmacular function in amblyopic and normal eyes. We assessed pattern-onset, -reversal and -offset VEPs from amblyopic eyes and compared them with the responses from the fellow eyes, and from controls, to gauge the relative effectiveness of these stimulus modes. METHODS: The three modes of pattern stimulation were presented sequentially in a single recording run to enable direct comparisons to be made for identical recording conditions. Half-field stimulation was used, as this elicits components over the ipsilateral and contralateral occipital scalp relative to the stimulated half-field, which reflect stimulation of macular and paramacular areas of the visual field. Eighteen amblyopes treated by occlusion and 20 control children were studied. RESULTS: Multivariate analysis of variance showed significant differences between ambylopic and fellow eyes in amblyopes: pattern-onset components were significantly attenuated and ipsilateral reversal components were significantly prolonged in amblyopic eyes. When fellow eyes of amblyopes were compared with the eyes of controls, the reversal P100 and offset P110 and N165 components showed significant differences. CONCLUSIONS: Ipsilateral reversal components and onset CII and contralateral P105 were the most affected in amblyopic eyes. The subnormal findings for the fellow eyes of amblyopes suggest that occlusion may have a long-standing physiological effect on the patched eye, not normally clinically apparent.

Sequential pattern-onset, -reversal and -offset VEPs: comparison of effects of checksize.

The effects of checksize on individual components of half-field pattern-onset, -reversal and -offset VEPs were studied by presenting these three modes of stimulation sequentially in a single recording epoch so as to provide near identical recording and subject conditions. Components on the side of the scalp ipsilateral and contralateral to the stimulated half-field were measured so as to separate the macular and paramacular contributions. Ten checksizes were used (6'-110'). MANOVA showed a significant effect of checksize: small checksizes enhanced onset ipsilateral CII and contralateral P105, as well as all ipsilateral reversal components and offset N85 component, suggesting they are reflecting macular function. Onset CI, and contralateral reversal N105 and offset N115 components increased in amplitude with increasing checksize, suggesting they are predominantly of paramacular origin. The morphology of the contralateral onset P105 component was checksize dependent: small checks (< 35') produced a sharply defined positivity (macular sub-component), whereas larger checks produced a broadened/bifid waveform, suggesting the emergence of a later paramacular sub-component.

Smooth pursuit development in infants.

PURPOSE: We set out to assess the development of pursuit eye movements in normal infants in an objective, longitudinal fashion. We asked whether smooth pursuit (SP) was present under 2 months of age and how the saccade ratio changed with increasing infant age. METHODS: Smooth pursuit was recorded longitudinally from 25 infants aged 1-7 months, using DC electro-oculography, in a clinically practical manner. Four uninstructed adults acted as controls. RESULTS: Smooth pursuit was present under 2 months of age. The gain of SP increased with increasing infant age. However, it had still not reached adult levels by 6 months of age. Latency decreased with increasing infant age. Monocular SP asymmetry was present in the younger infants. CONCLUSIONS: Smooth pursuit is present under 2 months of age, but at 6 months SP has still not reached adult levels. The traditional model of SP development is questionable.

Eye movement abnormalities in a case of Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder that is characterised by the presence of multiple vocal, facial, and motor tics which change with time, and a number of other behavioural phenomena. Previous studies have not revealed any ocular-motor abnormalities. We report the eye movement studies of a patient with TS, using electrooculography and simultaneous video recording. Intrusive saccades occurred during smooth pursuit and optokinetic nystagmus. Reflexive and voluntary saccades were dysmetric and there was a complete failure of antisaccades. These abnormalities are characteristic of disease of the frontal lobes and basal ganglia. We review the literature with respect to the eye movement abnormalities associated with TS.

Interocular interaction assessed by VEPs to pattern-onset, -reversal, and -offset in normally sighted and amblyopic subjects.

The extent of interocular interaction reflected in sequentially averaged VEPs to checkerboard onset, reversal and offset stimulation was investigated to assess the relative efficacy of the three modes of pattern stimulation. Thirty-one controls and 18 amblyopic children were studied. Components on the side of the scalp ipsilateral and contralateral to the stimulated left half-field were measured for checksizes 12', 20', 50' and 80'. Binocular:monocular amplitude ratios for normals were compared with 'binocular:good eye' amplitude ratios for amblyopes. The reversal P100 ratio was found to differ significantly between normals and amblyopes for 12', 20' and 50' checks. Ipsilateral (CII) and contralateral (P105) onset components also differed significantly but for the smallest 12' checks only. In controls, onset components (P105 and CIII) and, reversal components (N80 and P100) showed significantly shorter binocular as compared with monocular latencies. These latency differences were not found in amblyopes. Our results show that interocular interaction in normals is best shown by potentials which predominantly reflect macular pathway activation, and are most conspicuous for reversal N80 and P100 components. Similarly, these components demonstrated the clearest differences when comparing binocular interaction effects between controls and amblyopic subjects.

Effects of experimental scotomata on sequential pattern-onset, pattern-reversal and pattern-offset visual evoked potentials.

The effect of experimental scotomata on visual evoked potentials to half-field stimulation using sequential checkerboard onset, reversal and offset was investigated in 10 normal subjects to assess the relative sensitivity of the three stimulus modes, and the contributions of pathways subserving macular and paramacular parts of the visual field. Four scotoma sizes (0-1.5 degrees , 0 degrees - 2 degrees, 0 degrees -3 degrees and 0 degrees -4.5 degrees ) were used to mask the central part of the stimulus field (0 degrees -12 degrees ). Five check sizes (6', 12', 20', 50' and 80') were presented for each scotoma size. Peak-to-peak amplitudes and peak latencies of components on the ipsilateral and contralateral sides of the scalp to the stimulated half-field were measured. Scotoma size was highly significant in influencing component amplitude (p < 0.0001) and latency (p < 0.03) of all ipsilateral and contralateral onset components and all ipsilateral reversal and offset components. Components that were attenuated to the greatest extent with the smallest 0 degrees -1.5 degrees scotoma were the contralateral onset P105 and ipsilateral reversal P100 and N145. Onset CIII, reversal N80, and offset N85 and P110 only showed a significant attenuation after the use of scotomata of 0 degrees -3 degrees and larger. Our results show that scotoma size is a significant factor in influencing all the major visual evoked potential components, with the exception of reversal and offset contralateral potentials (N105 and N115), probably reflecting their paramacular origins. Reversal, ipsilateral P100 and N145, and onset, contralateral P105, appear to be predominantly of macular origin and the most sensitive potentials for detecting effects of small central scotomata.

Intermittent horizontal saccade failure ('ocular motor apraxia') in children.

BACKGROUND: Ocular motor apraxia (OMA) in childhood is a poorly understood condition involving a failure of horizontal saccades. OMA is thought to be rare but the literature indicates wide clinical associations. OMA is often identified by abnormal head movements, but failure of reflexive quick phases has been reported in all but a few patients. The extent of this oculomotor disorder was examined in a large group of children with diverse clinical backgrounds. METHODS: The degree of quick phase failure during horizontal vestibular and optokinetic nystagmus was measured using DC electro-oculography and video in 74 affected children, aged 17 days to 14 years. RESULTS: All children showed an intermittent failure of nystagmic quick phases, except for total failure in one case. Other visuomotor abnormalities were common including saccadic hypometria (85%), low gain smooth pursuit (70%), neurological nystagmus (28%), strabismus (22%), and vertical abnormalities (11%). Non-ocular abnormalities were common including infantile hypotonia (61%), motor delay (77%), and speech delay (87%). There was a wide range of clinical associations including agenesis of the corpus callosum, Joubert syndrome, Dandy-Walker malformation, microcephaly, hydrocephalus, vermis hypoplasia, porencephalic cyst, megalocephaly, Krabbe leucodystrophy, Pelizaeus Merzbacher disease, infantile Gaucher disease, GM1 gangliosidosis, infantile Refsum's disease, propionic acidaemia, ataxia telangiectasia, Bardet-Biedl syndrome, vermis astrocytoma, vermis cyst, carotid fibromuscular hypoplasia, Cornelia de Lange syndrome, and microphthalmos. Perinatal and postnatal problems were found in 15% including perinatal hypoxia, meningitis, periventricular leucomalacia, athetoid cerebral palsy, perinatal septicaemia and anaemia, herpes encephalitis, and epilepsy. Only 27% were idiopathic. CONCLUSION: Quick phase failure is a constant feature of OMA, whereas abnormal head movements were detected in only about half, depending on the underlying diagnosis. This oculomotor sign is better described as an intermittent saccade failure rather than as a true apraxia. It indicates central nervous system involvement, has wide clinical associations, but it is not a diagnosis.

The role of ERG/VEP and eye movement recordings in children with ocular motor apraxia.

Ocular motor apraxia (OMA) is characterised by an intermittent inability to initiate voluntary saccades, and a failure to produce optokinetic and vestibular quick phases. Some patients have no other abnormalities (idiopathic OMA), whereas in others it appears associated with a variety of neurological conditions which may affect the sensory visual pathway. Electroretinograms (ERGs), flash and pattern visual evoked potentials (VEPs) and eye movements were assessed in 53 children with OMA (age range 17 days to 14 years) to determine their efficacy in helping to distinguish between idiopathic and non-idiopathic cases. Seven patients (13.2%) had idiopathic OMA and the remaining 46 (86.8%) had other associated clinical conditions. All patients had episodes of absent quick phases ('lock up') during optokinetic nystagmus (OKN) and/or vestibular testing. Flash ERGs were abnormal in only 7 patients (13.2%); 6 had syndromes involving a pigmentary retinopathy (Joubert's, Bardet-Biedl, infantile Refsum's, Kearns-Sayre's), and the seventh had a cone dystrophy with vermis hypoplasia. VEPs were normal in all 7 patients with idiopathic OMA. Thirty-three (72%) patients with OMA in association with neurological conditions had abnormal VEPs and 13 had normal VEPs (28%). There was a significant positive correlation between VEP abnormality and poor OKN gain. VEP/ERG testing and eye movement studies are useful when OMA is suspected as they help in distinguishing isolated idiopathic cases from those with more widespread neurological abnormalities.

Delayed visual maturation in infants: a disorder of figure-ground separation?

Delayed visual maturation (DVM) is characterised by visual unresponsiveness in early infancy, which subsequently improves spontaneously to normal levels. We studied the optokinetic response and recorded pattern reversal VEPs in six infants with DVM (aged 2-4 months) when they were at the stage of complete visual unresponsiveness. Although no saccades or visual tracking with the eyes or head could be elicited to visual objects, a normal full-field rapid buildup OKN response occurred when viewing biocularly or during monocular stimulation in the temporo-nasal direction of the viewing eye. Almost no monocular OKN could be elicited in the naso-temporal direction, which was significantly poorer than normal age-matched infants. No OKN quick phases were missed, and there were no other signs of "ocular motor apraxia." VEPs were normal in amplitude and latency for age. It appears, therefore, that infants with DVM are delayed in orienting to local regions of the visual field, but can respond to full-field motion. The presence of normal OKN quick-phases and slow-phases suggests normal brain stem function, and the presence of normal pattern VEPs suggests a normal retino-geniculo-striate pathway. These oculomotor and electrophysiological findings suggest delayed development of extra-striate cortical structures, possibly involving either an abnormality in figure-ground segregation or in attentional pathways.

Neuroradiological and eye movement correlates in children with intermittent saccade failure: "ocular motor apraxia".

Ocular motor apraxia (OMA) is a clinical sign involving the intermittent inability to initiate saccades, and a failure of quick phases during optokinetic nystagmus (OKN) and vestibular nystagmus (VN). Some patients have no other associated abnormalities (idiopathic), whereas others have a variety of neurological conditions. We quantified the severity of the saccade failure and correlated it with neuro-radiological and other oculomotor findings in 62 children (aged 17 days - 14 years). Saccades, smooth pursuit, OKN and VN were recorded using electrooculography and the extent of "locking up" (absent quick phases during OKN and VN) was measured. Saccades were usually hypometric. Pursuit and OKN gains were normal in the majority of the idiopathic cases but were low in those with other neurological conditions. Twenty-four patients had essentially normal scans, whereas 38 had abnormal scans: Delayed myelination, cerebellar abnormalities (particularly involving the vermis), and agenesis of the corpus callosum were the most common findings. A significant positive correlation was present between increasing neuro-radiological deficits and severity of "locking up" during OKN. Principal component analysis showed that brainstem and cerebellar vermis abnormalities were the main factors involved. A pathophysiological basis of OMA is discussed in the light of animal and clinical studies.