Infantile Idiopathic Nystagmus: for professionals

• Overview
• Clinical phenotype
• Genetics
• Key investigations
• Diagnosis
• Management
• Current research
• Further information and support
• References

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Overview

Prevalence	1.9 in 10,000[1]
Inheritance	X-linked typically Autosomal dominant less common
Genes involved (OMIM No.)	2 genes and 5 chromosome loci have been identified to cause IIN with variability in inheritance patterns: FRMD7 (#300628), GPR143 (#300808), NYS5 locus (#300589) – X-linked NYS2 (#164100), NYS3 (#608345), NYS4 (#193003), NYS7 (#614826) loci – Autosomal dominant
Symptoms	Visual impairment of variable severity Reduced 3D vision
Ocular features	Infantile nystagmus Variable reduction of visual acuity Strabismus Astigmatism Compensatory head position +/- Foveal hypoplasia (grade 1 usually if present) Intra- and interfamilial variability in disease severity
Systemic features	None
Key investigations	Orthoptic assessment and refraction VEP: To exclude chiasmal misrouting OCT: To exclude foveal hypoplasia Eye movement recording
Molecular diagnosis	Next generation sequencing Targeted gene panels (nystagmus and eye movement disorders) Whole exome sequencing Whole genome sequencing
Management	Ocular Amblyopia management Correction of refractive errors Surgical management may be required to address significant compensatory head postures utilised to optimise vision using a null point Systemic Multidisciplinary approach if indicated (ophthalmology and educational) Early referral to practitioners familiar with young children with visual impairment to optimise development and access to education
Therapies under research	Current RCT Biofeedback in IIN (NCT 04142307) Previous RCT’s Contact lenses (ISRCTN 80219391) Brinzolamide (NCT 01312402) Gabapentin and Memantine (NCT 00928954; NCT 01744444) Neramexane (NCT 00661440) Surgery (NCT 00001866)

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Clinical phenotype

Presenting features

Infantile idiopathic nystagmus (IIN) is diagnosed in the absence of any ophthalmological and systemic abnormalities.

Children usually present with infantile nystagmus syndrome (INS), which can lead to reduced visual acuity (VA).^[2] VA has been known to range from normal levels (0.00 logMAR) to severely sight impaired (1.00 logMAR or less), however it is usually better than 0.30 logMAR. VA has been shown to correlate with periods of foveation^[3-5] , which is determined by the speed and position of the eye that allow the target/stimulus of interest to land on the fovea. Visual function does not usually deteriorate over time with IIN. Some children may present with an anomalous head posture instead due to utilisation of a null point (an area of minimum nystagmus and better vision) to optimise vision.^[6] Patients tend to have good binocular vision and normal colour vision.

Other ocular features

• Refractive errors
• Strabismus (uncommon; affecting approx. 10% of individuals)
• Occasionally grade 1 foveal hypoplasia^[7]

Oscillopsia is rarely described by IIN patients due to stabilising of moving images through either extra-retinal feedback^[8] or periods of foveation.^[9] Affected individuals may perceive the moving images if the nystagmus waveform increases (speed and position) in different positions of gaze.

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Genetics

So far, 2 genes are associated with infantile idiopathic nystagmus – FRMD7 ^[10] and GPR143 ^[11]. Both are inherited through an X-linked manner. Five other genetic loci have been mapped but no responsible genes have been identified yet.

Gene/Locus (OMIM no.)	Phenotype (OMIM no.)	Inheritance
FRMD7/NYS1; Xq26.2 (#300628)	Nystagmus 1, congenital, X-linked (#310700); Nystagmus, infantile periodic alternating, X-linked (#310700)	X-linked
NYS2; 6p12 (#164100)	Nystagmus 2, congenital, autosomal dominant (#164100)	AD
NYS3; 7p11.2 (#608345)	Nystagmus 3, congenital, autosomal dominant (#608345)	AD
NYS4; 13q31-q33 (#193003)	Nystagmus 4, congenital, autosomal dominant (#193003)	AD
NYS5; Xp11.4 (#300589)	Nystagmus 5, congenital, X-linked (#300589)	X-linked dominant
GPR143/NYS6; Xp22.2 (#300808)	Nystagmus 6, congenital, X-linked (#300814); Ocular albinism, type I, Nettleship-Falls type (#300500)	X-linked recessive
NYS7; 1q31.3-q32.1 (#614826)	Nystagmus 7, congenital, autosomal dominant (#614826)	AD

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

1) Orthoptic assessment and refraction

To assess current level of vision and determine if amblyopia therapy and/or refractive correction are required to optimise vision.

2) Optical coherence tomography (OCT)

OCT can detect the presence/absence of foveal hypoplasia to support the clinical diagnosis and document its severity if present.^[7]

3) Electrophysiology

Visual evoked potentials can be requested to look for evidence of chiasmal misrouting. Full-field and pattern electroretinogram (ERG) readings are required to exclude retinal and/or macular dystrophies.

4) Eye movement recordings

INS waveforms are pathognomonic. The recordings tend to demonstrate conjugate horizontal oscillations with either a jerk or pendular waveform and the slow phase typically has an increasing velocity.

In some very early cases where nystagmus may be absent or not prominent, saccadic instabilities (square wave jerks) can be noted instead before evolving to more typical waveforms (conjugate pendular/jerk types) as the child gets older.^[12]

Systemic

IIN typically is not associated with any ocular or systemic causes. Certain red flag signs may indicate an acquired pathology instead that will require neuro-imaging^[13,14]:

• Later onset nystagmus (in the absence of signs in keeping with an ocular disorder)
• Constant oscillopsia in older children/adults
• Dysconjugate/gaze evoked/see-saw/convergence-retraction nystagmus
• Vertical/torsional nystagmus (in the absence of retinal pathology)
• Presence of neurological signs and/or a systemically unwell child

If these features are absent, referral to a paediatrician and other relevant specialists should be considered if patients show signs of developmental issues or based on the results of genetic testing.

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Diagnosis

Diagnosis of IIN is usually made clinically through eye movement recordings and full ophthalmological examination. Genetic testing should be undertaken to obtain a molecular diagnosis which can help in directing further clinical management, facilitating genetic counselling and providing accurate advice on prognosis and future family planning.

This can be achieved through a variety of next generation sequencing (NGS) methods:

• Targeted gene panels (nystagmus and eye movement disorders)
• Whole exome sequencing
• Whole genome sequencing

Related links

• Genomics England PanelApp for albinism or congenital nystagmus
• Clinical genetic testing: for professionals

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Management

Ocular

1) Refractive treatment

• Correction of refractive errors with either glasses or contact lenses
  • Contact lenses can benefit patients with large refractive errors or large head postures (through impairment of the spectacle frames)
  • Contact lenses may also provide a proprioceptive effect to dampening the nystagmus, however results from RCT’s have not been consistent^[15,16]

2) Amblyopia treatment

• Correct any refractive error for the optical treatment period (16-24 weeks)
• If a difference of 0.20 logMAR is present between the 2 eyes then start conventional amblyopia treatment (either occlusion therapy or Atropine penalisation)
• In some cases prolonged occlusion^[17] may be of benefit if there is confirmed visual improvement and dampening of nystagmus on eye movement recordings

3) Medical treatment

• Oral gabapentin or memantine have been shown to improve VA by reducing nystagmus intensity^[18,19], with a larger treatment effect observed in patients with IIN compared to those with a secondary cause in a randomised placebo-controlled trial^[20]
• Evidence in children is lacking

4) Surgical treatment

• Can be considered if a significant head posture/head turn is adopted to utilise the null point. The aim is to shift the null point centrally (i.e. towards the direction of the head turn) and therefore reduces the extent of head posture
• The Anderson-Kestenbaum technique(recession of the horizontal recti at the direction of the head turn and resection of the corresponding horizontal recti) is standard in the UK but other methods ^[21-24]have been reported

Development

Visual impairment can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.

The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents.

Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.

Family management and counselling

Most IIN cases are inherited in an X-linked pattern while autosomal dominant inheritance is less common.

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients in clinic. They provide emotional and practical support to help patients deal with their diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

• Coping with sight loss
• Education and learning
• Family support service

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research in nystagmus

Currently there is only one RCT recruiting in Toronto investigating the effect of a biofeedback system to improve visual outcome in idiopathic nystagmus (NCT 04142307). Other research areas have included the use of refractive^[15,16,25], drug^[18,19] and surgical^[23,24,26] treatments to improve visual outcome. Other pre-clinical work that is being undertaken is the investigation of visual crowding in idiopathic nystagmus and how the basis of these deficit reflects the eye movements seen in nystagmus^[27].

Related links

• Research Opportunities at Moorfields Eye Hospital UK
• Searching for current clinical research or trials

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Further information and support

• Nystagmus Network
• Royal National Institute of Blind People (RNIB)
• IN-vision

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References

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