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Infantile Idiopathic Nystagmus: for professionals


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:
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 diagnosisNext generation sequencing
  • Targeted gene panels (nystagmus and eye movement disorders)
  • Whole exome sequencing
  • Whole genome sequencing
ManagementOcular
  • 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 researchCurrent RCTPrevious RCT’s

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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.

A right beating jerk nystagmus with accelerating exponential slow phases to the left. Red lines mark the period of foveation. Green dotted lines denote the fast phase and the orange dotted lines denote the slow phase.

Credit: Mr Vijay Tailor-Hamblin, Clinical PhD Fellow and Extended Role Orthoptist, Moorfields Eye Hospital, London 

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

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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
The patient's gaze was looking to the right prior to surgery. After surgery, the gaze has been straightened.
The principles of the Anderson Kestenbaum surgery

Credit: American Academy of Ophthalmology

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

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

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Further information and support

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References

  1.  Sarvananthan N, Surendran M, Roberts E, et al. The Prevalence of Nystagmus: The Leicestershire Nystagmus Survey. Investigative ophthalmology & visual science. 2009;50:5201-5206
  2.  Cesarelli M, Bifulco P, Loffredo L, Bracale M. Relationship between visual acuity and eye position variability during foveations in congenital nystagmus. J Documenta Ophthalmologica. 2000;101(1):59-72
  3.  Abadi RV, Worfolk R. Retinal slip velocities in congenital nystagmus. J Vision Research. 1989;29(2):195-205
  4.  Dell’Osso LF, Jacobs JB. An expanded nystagmus acuity function: intra- and intersubject prediction of best-corrected visual acuity. Doc Ophthalmol. 2002;104(3):249-276
  5.  Theodorou M. Predicting visual acuity in early onset nystagmus. Seminars in ophthalmology. 2006;21(2):97-101
  6.  Abadi RV, Whittle J. The nature of head postures in congenital nystagmus. J Archives of ophthalmology. 1991;109(2):216-220
  7.  Thomas MG, Crosier M, Lindsay S, et al. Abnormal retinal development associated with FRMD7 mutations. Human molecular genetics. 2014;23(15):4086-4093
  8.  Abadi RV, Whittle JP, Worfolk R. Oscillopsia and tolerance to retinal image movement in congenital nystagmus. Investigative Ophthalmology & Visual Science. 1999;40(2):339-345
  9.  Thomas MG, Maconachie G, Hisaund M, Gottlob I. FRMD7-related infantile nystagmus. In: GeneReviews®[Internet]. University of Washington, Seattle; 2018
  10.  Tarpey P, Thomas S, Sarvananthan N, et al. Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus. Nature genetics. 2006;38(11):1242-1244
  11.  Liu JY, Ren X, Yang X, et al. Identification of a novel GPR143 mutation in a large Chinese family with congenital nystagmus as the most prominent and consistent manifestation. J Hum Genet. 2007;52(6):565-570
  12.  Gottlob I. Infantile nystagmus. Development documented by eye movement recordings. Invest Ophthalmol Vis Sci. 1997;38(3):767-773
  13.  Ospina LH. Dealing with Nystagmus. J Binocul Vis Ocul Motil. 2018;68(4):99-109
  14.  Self JE, Dunn MJ, Erichsen JT, et al. Management of nystagmus in children: a review of the literature and current practice in UK specialist services. Eye (Lond). 2020;34(9):1515-1534
  15.  Jayaramachandran P, Proudlock FA, Odedra N, Gottlob I, McLean RJ. A randomized controlled trial comparing soft contact lens and rigid gas-permeable lens wearing in infantile nystagmus. Ophthalmology. 2014;121(9):1827-1836
  16.  Theodorou M, Quartilho A, Xing W, et al. Soft contact lenses to optimize vision in adults with idiopathic infantile nystagmus: a pilot parallel randomized controlled trial. Strabismus. 2018;26(1):11-21
  17.  Simonsz HJ, Kommerell G. The effect of prolonged monocular occlusion on latent nystagmus in the treatment of amblyopia. Bull Soc Belge Ophtalmol. 1989;232:7-12
  18.  Shery T, Proudlock FA, Sarvananthan N, McLean RJ, Gottlob I. The effects of gabapentin and memantine in acquired and congenital nystagmus: a retrospective study. Br J Ophthalmol. 2006;90(7):839-843
  19.  Sarvananthan N, Proudlock FA, Choudhuri I, Dua H, Gottlob I. Pharmacologic Treatment of Congenital Nystagmus. Archives of Ophthalmology. 2006;124(6):916-918
  20.  McLean R, Proudlock F, Thomas S, Degg C, Gottlob I. Congenital nystagmus: randomized, controlled, double-masked trial of memantine/gabapentin. Ann Neurol. 2007;61(2):130-138
  21.  Hertle RW, Dell’Osso LF, FitzGibbon EJ, Thompson D, Yang D, Mellow SD. Horizontal rectus tenotomy in patients with congenital nystagmus: results in 10 adults. Ophthalmology. 2003;110(11):2097-2105
  22.  Hertle RW, Dell’Osso LF, FitzGibbon EJ, Yang D, Mellow SD. Horizontal rectus muscle tenotomy in children with infantile nystagmus syndrome: a pilot study. J aapos. 2004;8(6):539-548
  23.  Lingua RW, Liu CY, Gerling A, Zhang Z, Nalbandian A. Myectomy of the Extraocular Muscles Without Reattachment as a Surgical Treatment for Horizontal Nystagmus. J Pediatr Ophthalmol Strabismus. 2016;53(3):156-166
  24.  Lingua RW, Liu CY, Gerling A, Zhang Z, Nalbandian A. Further Considerations in the Management of Nystagmus with Myectomy. J Pediatr Ophthalmol Strabismus. 2016;53(4):255
  25.  Stahl JS, Plant GT, Leigh RJ. Medical treatment of nystagmus and its visual consequences. Journal of the Royal Society of Medicine. 2002;95(5):235-237
  26.  Dell’Osso LF, Orge FH, Jacobs JB. Effects of augmented tenotomy and reattachment in the infantile nystagmus syndrome. Digit J Ophthalmol. 2016;22(1):12-24
  27.  Tailor V, Dahlmann-Noor AH, Theodorou M, Greenwood J. Visual crowding in congenital nystagmus, sensory deficit or image motion? Investigative Ophthalmology Visual Science. 2018;59(9):1080-1080

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Updated on November 30, 2020

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