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.

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.

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.

Eye movement tics.

An 8-year-old girl presented with opsoclonus-like eye movement and an 18 month history of intermittent facial tics. Investigations were all normal. Electro-oculography showed the eye movements to be of variable amplitude (10-40 degrees), with no intersaccadic interval, and with a frequency of 3-4 Hz. Saccades, smooth pursuit, optokinetic, and vestibular reflexes were all normal. These abnormal eye movements eventually disappeared. It is thought that they were a form of ocular tics.

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.

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.

Electrophysiological and eye-movement abnormalities in children with the Bardet-Biedl syndrome.

We investigated 17 patients with clinical features of Bardet-Biedl syndrome by electroretinogram (ERG), visual-evoked potentials (VEP), and electro-oculographic (EOG) eye movement assessment. The ERGs were grossly abnormal in 16 cases. Pattern VEPs were generally well preserved, but showed a tendency to increase in latency and decrease in amplitude with age. These results confirm other reports that the retinopathy appears to be a progressive rod-cone dystrophy initially affecting mainly extramacular areas but involving the macula at later stages. Seven of 11 patients showed abnormalities of either optokinetic nystagmus, vestibulo-ocular reflex, or both. These eye-movement abnormalities have not been reported previously, and are further evidence of central nervous system involvement in this syndrome.

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.

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.

A comparison of flash electroretinograms recorded from Burian Allen, JET, C-glide, gold foil, DTL and skin electrodes.

Single flash scotopic and photopic electroretinograms (ERGs) were recorded from the same subjects using six types of corneal electrode, in order to assess their relative effectiveness. In addition, the ERG from a lower eyelid skin electrode was recorded to give an indication of the degree of attenuation to be expected from a skin electrode. On average, the scotopic ERG recorded from the Burian Allen electrode measured 471 microV (100%), and relative to this the b-waves recorded using other electrodes were as follows: JET (89%), C-glide (77%), gold foil (56%), DTL (46%) and skin (12%). Under photopic conditions the order was the same and the interelectrode proportions similar. The b-wave amplitude recorded using the Burian Allen electrode was 125 microV (100%), and with other electrodes was as follows: JET (93%), C-glide (78%), gold foil (60%), DTL (60%) and skin (14%).

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.

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.

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.

Centrifugal and centripetal mechanisms involved in the 'gating' of cortical SEPs during movement.

Pre- and post-central cortical SEPs were of reduced amplitude and altered wave form when the median nerve stimulus was delivered during active movement of the thumb. Peripheral, cervical and scalp far-field potentials were not significantly affected, apart from the positive wave following N13 at upper cervical level. The algebraic contribution of movement-related potentials was eliminated by wave form subtraction. Qualitatively similar effects were seen when the thumb was moved passively, suggesting that sensory input associated with the movement exerts a 'gating' effect which is at least as significant as that due to centrifugal influences. The effect was in some respects similar to that associated with interfering cutaneous stimulation, although an additional component was identifiable in the difference wave forms associated with active and passive movement. In contrast to passive movement, SEP gating during active movement was equally marked when the stimulus was delivered instantaneously with the first detectable displacement of the thumb. Thus the effect cannot have been entirely due to movement-related activity in distal cutaneous, muscle and joint receptors, since input from the latter could not have arrived at the CNS before the median nerve volley. Other centripetal mechanisms are not excluded, however, since arrival of the volley would be preceded by proprioceptive activity from proximal muscle receptors.

The use of video in assessing and illustrating abnormal eye movements in young children.

Eye movement studies can be useful in neuro-ophthalmological investigations of infants and young children. In our laboratory we use a combination of an electro-oculogram and video to record eye movements. A composite video image is created consisting of an image of the electro-oculographic eye movement trace superimposed on an image of the patient's eyes and face. This permits the qualitative clinical appearance of the case to be illustrated simultaneously with the quantitative eye movement trace.

The objective assessment of abnormal eye movements in infants and young children.

Recordings of eye movements from infants and young children can be of clinical value in patients with certain neuro-ophthalmological problems. This requires that the characteristics of normal eye movements in this same age-group are known. Using an electro-oculographic technique in a specially developed laboratory we have been able to assess the saccades, binocular and monocular smooth pursuit, binocular and monocular optokinetic nystagmus (OKN), and sustained vestibular rotation in infants and young children; these recordings were performed in one session lasting approximately 35 minutes. The recordings from four children with abnormal eye movements (delayed visual maturation, hemicerebral cyst, congenital ocular motor apraxia, and gaze-paretic nystagmus) are briefly reported and compared to normal eye movements of age-related children. The limitations of this procedure are discussed.

Contribution of cutaneous and muscle afferent fibres to cortical SEPs following median and radial nerve stimulation in man.

Somatosensory evoked potentials were recorded after stimulation of motor and cutaneous nerves in the upper limb. Stimulation of the thenar motor branch of the median nerve and the deep motor branch of the radial nerve produced only broad, ill-defined and small-amplitude scalp-recorded responses. In contrast, stimulation of purely cutaneous nerves (digital and the superficial radial) gave responses of large amplitude. The cortical responses following combined deep and superficial radial nerve stimulation were of smaller amplitude than the two individual responses combined. These findings suggest that, contrary to an earlier report (Gandevia et al. 1984), muscle afferents do not make a major positive contribution to the scalp-recorded cortical responses produced by electrical stimulation of mixed nerves in the upper limb.