Diagnosis and treatment of Nystagmus: improving medical effectiveness and patient quality of care
Submitting InstitutionUniversity of Leicester
Unit of AssessmentPsychology, Psychiatry and Neuroscience
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Neurosciences, Ophthalmology and Optometry
Summary of the impact
Infantile nystagmus (IN), previously known as congenital nystagmus, is a
condition that impairs vision by causing continual and involuntary
oscillatory movements of the eyes. IN begins in infancy and is a lifelong
disorder, affecting over 88,000 people in the UK. Leicester is the leading
UK centre for research into the underlying mechanisms and treatment of IN:
discovering the genetic mutations behind some of the common forms of
nystagmus; pioneering early diagnosis of IN; and conducting randomised
clinical trials into drug treatments and other therapies. The centre
provides advanced scientific and medical knowledge, and support and advice
to sufferers of this physically and psychologically debilitating
condition. The work has resulted in new methods of diagnosis which are
more comfortable and convenient for patients and enable cost-savings for
healthcare providers; and has led to the testing and subsequent
prescription of pharmacological treatments which offer patients
improvements in quality of life.
Researchers in the Ophthalmology Group at the University of Leicester
have been focusing on understanding the eye disorder nystagmus for over
two decades, spearheading studies into the prevalence, causes and effects
of nystagmus, and treatments for these visual disorders.
Discovery of the FRMD7 gene
The cause of infantile IN has long been controversial. There are several
types of IN: it can arise from retinal or optic nerve abnormalities, such as
albinism (a lack of pigmentation), PAX6 mutations (which lead to a
wide spectrum of ocular defects, including the lack of an iris) or
achromatopsia (an inability to perceive colour). Alternatively, it may be
`idiopathic', with no obvious disease cause, and then it is unclear whether
the nystagmus is due to abnormalities of the retina or of areas of the brain
controlling eye movements.
Between 2003 and 2005 the group conducted numerous field studies
observing communities with large families in an effort to find the first
gene identified as causing idiopathic IN. The FRMD7 gene was
discovered in 2006 by Professor Irene Gottlob and Dr Shery Thomas in
collaboration with the University of Cambridge and the Sanger Institute (1,2).Further
research has shown that the FRMD7 gene plays a role in developing
nerve cells in the brain by encouraging growth and new connections in the
regions controlling eye movement.
The identification of the FRMD7 gene enabled the Leicester group to
differentiate subtypes of IN for the first time. The group compared
differences in eye movements between, first, idiopathic IN with and
without mutations in the FRMD7 gene (3) and, second, FRMD7-associated
IN and albinism. The group was also the first to systematically
characterise retinal abnormalities in idiopathic IN, albinism,
achromatopsia, PAX6 mutations and isolated foveal hypoplasia
(underdevelopment of the central part of the retina responsible for
high-resolution vision; 4). These developments have changed the
ease and accuracy with which IN is diagnosed, which is important for
clinical management of the disease because the various subtypes of IN have
different causes, prognoses and treatments.
As a result of this work, the group developed a genetic test for FRMD7
mutations in collaboration with the Nottingham NHS genetic lab in 2010;
this is now available to patients whose IN is believed to be idiopathic
(about 14% of IN sufferers) on the NHS in Nottingham and in labs around
the world, including the US, Israel, Germany, France and Spain.
Pioneering the use of a new method of diagnosis
In 2011 Leicester was chosen as the UK trial centre for a hand-held UHR
SD-OCT (ultra high- resolution spectral-domain optical coherence tomography)
scanner, manufactured by the US firm Bioptigen, for research and clinical
use in infants and young children. The device creates precise and highly
detailed three dimensional maps of the inside of the eye, including the
retina. The group had already developed expertise in diagnosing IN in adults
using head-fixed OCT, and recognised the potential of using the technology
to diagnose IN and characterise retinal abnormalities in infants and young
children, who have difficulty keeping still.
The group has tested hand-held OCT on 315 normal children and 120
children with IN and 75 premature babies born at less than 30 weeks (215
in total) to develop improved diagnostic strategies for young children (5).
Multiple recordings as children grow allow the charting of eye development
in these groups and provides parents with an early diagnosis of retinal
abnormalities (for most diseases sensitivity was >85% and specificity
>90%). They have also shown OCT measures to be an independent gauge of
the level of vision in adults. Currently they are assessing the ability of
OCT from infants and children to predict the severity of potential visual
deficits on maturation in later life.
Major trials for pharmacological treatment
The success of two medications, memantine (a treatment for Alzheimer's
Disease) and gabapentin (a drug to relieve neuropathic pain) for treating
acquired nystagmus, has led the group to complete the first randomised
controlled trial into pharmacological treatment for IN in 2007 (6).
The group measured the effect of memantine and gabapentin in an IN group in
comparison to a placebo group, showing for the first time that
pharmacological intervention can be beneficial in treating IN.
The study has been the springboard for a number of clinical trials,
including a large crossover trial for the two medications, which is
ongoing (2011 - 2014); a trial into the effects of a new medication
Neramexane through collaboration with MERZ Pharma (findings were negative)
(2007 - 2010); a randomised controlled trial comparing hard and soft
contact lens wear (2010 - 2012); and an evaluation of the effects of the
surgical procedure of `tenotomising' eye muscles for IN, at the request of
the National Institute for Health Care and Excellence (NICE; 2009 - 2014).
The group is developing ways to evaluate the impact of interventions on
patient-centred outcome measures, such as quality of life (7) and
measures of functional vision such as reading performance, in collaboration
with Claire Hutchinson and Applied Psychology groups in the College.
Key Contributors: Irene Gottlob, professor and head of group
(1999-date); Rebecca J McLean, research associate (1999-date); Frank A.
Proudlock, lecturer (2000-date).
Others: Nagini Sarvananthan, clinical research fellow (2002-2004);
Shery Thomas, clinical lecturer (2004-2008); Anil Kumar, clinical research
fellow (2007-2010); Mervyn Thomas, PhD student (2009- date); Rachel
Watkins, human geneticist (2010-2012); Sarim Mohammad, PhD student
(2011-date); Helena Lee, clinical research fellow (2012-date).
From other groups: Pierluigi Nicotera, MRC Toxicology Unit; Sue
Shackleton, Dept of Biochemistry
From other institutions: Patrick Tarpey, Wellcome Trust Sanger
Institute, Cambridge, UK (gene sequencing work); Lucy Raymond, Cambridge
Institute for Medical Research, University of Cambridge, UK (gene
sequencing work); Elizabeth Engle, Harvard Medical School, Harvard
University, USA (studies into PAX6 mutations); Susanne Kohl,
Institute for Ophthalmic Research, Eberhard Karls Universität Tübingen,
Germany (achromatopsia studies); MERZ Pharma, Frankfurt, Germany
(collaboration on Neramexane study).
References to the research
1. Tarpey P, Thomas S, Sarvananthan N, Mallya U, Lisgo S, Talbot CJ,
Roberts EO, Awan M, Surendran M, McLean RJ...Gottlob I. Mutations
in FRMD7, a newly identified member of the FERM family, cause
X-linked idiopathic congenital nystagmus. Nat Genet. 2006
Nov; 38 (11):1242-4.
2. Thomas MG, Crosier M, Lindsay S, Kumar A, Thomas S, Araki M,
Talbot CJ, McLean RJ, Surendran M, Taylor K, Leroy BP, Moore AT, Hunter
DG, Hertle RW, Tarpey P, Langmann A, Lindner S, Brandner M, Gottlob I.
The clinical and molecular genetic features of idiopathic infantile
periodic alternating nystagmus. Brain. 2011, Mar; 134(Pt 3):
3. Thomas S, Proudlock FA, Sarvananthan N, Roberts EO, Awan M, McLean
R, Surendran M, Kumar AS, Farooq SJ, Degg C, Gale RP, Reinecke
RD, Woodruff G, Langmann A, Lindner S, Jain S, Tarpey P, Raymond FL,
Gottlob I. Phenotypical
characteristics of idiopathic infantile nystagmus with and without
mutations in FRMD7. Brain. 2008 May; 131(Pt 5): 1259-67.
4. Thomas MG, Kumar A, Mohammad S, Proudlock FA, Engle EC, Andrews C,
Chan WM, Thomas S, Gottlob I. Structural grading of foveal
hypoplasia using spectral-domain optical coherence tomography a predictor
of visual acuity? Ophthalmology. 2011 Aug; 118(8): 1653-60.
5. Lee H, Sheth V, Bibi M, Maconachie G, Patel A, McLean RJ,
Michaelides M, Thomas MG, Proudlock FA, Gottlob I. Potential of
Hand-Held Optical Coherence Tomography to Determine Etiology of Infantile
Nystagmus in Children based on Foveal Morphology, Ophthalmology.
2013; (in press).
6. McLean R, Proudlock F, Thomas S, Degg C, Gottlob I. Congenital
nystagmus: randomized, controlled, double-masked trial of
memantine/gabapentin. Ann Neurol. 2007 Feb; 61(2): 130-8.
7. Rebecca Jane McLean, Kate C Windridge, Irene Gottlob.
Living with nystagmus: a qualitative study. Br J Ophthalmol. 2012;
96: 981e986. doi:10.1136/bjophthalmol-2011-301183
Genetic related studies: National Eye Research Institute
(2008-2011) £59,000; Ulverscroft Foundation (2007-2010) £205,000.
Optical Coherence Tomography: Medical Research Council (2012-2015)
£380,000; Ulverscroft Foundation (2012-1015) £140,000; Nystagmus Network
(2012-2015) £8,000; National Eye Research Institute (2009) £50,000;
Medisearch (2010-2012) £48,000.
Treatment of nystagmus: MERZ Pharma (2007-2010) £250,000, Fight
for Sight (2009-2014) £118,000; Nystagmus Network (2005) £5,000; College
of Optometrists (2010-2012) £13,000. Principal Investigator is Gottlob for
all except Medisearch and College of Optometrists (Proudlock)
Details of the impact
Infantile Nystagmus (IN) is a condition that has both physiological and
psychological effects. It is associated with reduced vision and decreased
motion perception. Most sufferers encounter practical difficulties in
everyday life: few can drive a car, and some lose out on education and
employment opportunities. It has a profound effect on self-esteem and
confidence in social situations.
Foremost centre for diagnosis and treatment
Long considered an untreatable condition with only limited options for
clinical intervention - and therefore largely ignored, IN is now much
better understood by the medical community, sufferers and their families,
following 13 years of collaborative clinical research by the group.
Leicester has become the foremost centre for the diagnosis and treatment
of IN in the UK and has made significant advances in meeting the clinical
needs of the UK's estimated 88,000 sufferers. The group sees more than 600
patients a year; some 53% of patients, and 66% of new referrals, come from
outside the service area, including private referrals from Europe and
The Development Manager for the Nystagmus Network, says: "The Group's
strengths come from the experience, breadth of skills and dedication of
its members... The combination of clinical and research activities in
Leicester is a huge advantage to the tens of thousands of families in
the UK affected by nystagmus. Not only is the Group able to provide
patients with much needed information about nystagmus (often not
routinely available elsewhere), they also offer treatment and the hope
of new treatment options in the future." (A)
Widespread use of the gene test
The discovery of the FRMD7 gene has opened up new avenues for
identifying the mechanisms underlying the development of IN, which are
currently unknown. The genetic test is used in eight centres in the UK,
US, Israel, Germany, France and Spain (B). A paper in Nature
Genetics about the gene sparked major interest from the research
community. There are now a total of 36 publications about mutation of
function in the gene. The group was asked to write the gene review about
IN in 2009 and updated this in 2011 (C).
The group discovered that IN caused by FRMD7 mutations is
inherited in an X-linked manner. Women who are carriers have a 50% chance
of transmitting the mutation to their sons, and 50% of their daughters
will become carriers. Once the disease-causing mutation has been
identified in the family, carrier testing for at-risk female relatives and
prenatal testing for pregnancies at increased risk are possible. This
enables parents and prospective parents to know what to expect from future
pregnancies and plan accordingly.
Use of new technology
Optical Coherence Tomography (OCT) is a non-invasive and safe diagnostic
method, which has resulted in considerable time-saving for the patient and
cost-saving for the NHS. Measurements and collection of genetic material
can be performed in 20-30 minutes with minimal discomfort. OCT can be used
to visualise the eyes in 3D, in a way that has not been possible
previously, even in premature infants. The development has received
considerable interest from the media (D).
Development of drug treatments
Leicester is the leading centre internationally for testing
pharmacological treatments for nystagmus. The 2007 trial has led to the
prescription of the drugs memantine and gabapentin for control of the
symptoms of IN, and they have been shown to improve visual acuity and
dampen movement, leading to improvements in quality of life, including
enabling some sufferers to start learning to drive. Gottlob is the only
ophthalmologist in the UK with a licence to prescribe these drugs
(normally available from a neurologist). She is currently formulating
national guidelines on the diagnosis and management of IN for the Royal
College of Ophthalmologists, aiming at accreditation by NICE.
Insight and support
Nystagmus sufferers reveal almost universally negative feelings about
themselves and their condition. Many feel abandoned by health
professionals. "'Go away and forget about it' ...that's basically what
I've been told all my life" and "I went for 40 years and nobody
touched me, nobody discussed it. It's on my medical records and yet
nobody was out there for me. So there was no help." are some of the
responses to a quality-of-life survey.
The group works closely with Europe's leading nystagmus charity, the
Nystagmus Network, in providing crucial information to sufferers and the
general public about how nystagmus affects daily lives. One parent wrote
via the Network, letter: "Through the Nystagmus Network I came into
contact with Professor Gottlob and her incredible team at Leicester
Hospital. I have never met anyone more inspiring, and knew from that day
forward my daughter was being seen by the best person in the world on
the subject of Nystagmus." (A) The group has contributed to a
book commissioned by the Network and available on Amazon: The Challenge of
Sources to corroborate the impact
A. Letter from Information Manager, Nystagmus Network.
B. GeneDx, Gaithersburg, USA; GGA - Galil Genetic Analysis Kazerin,
HaZafon, Israel; Medizinisch Genetisches Zentrum München, Munich, Germany;
Oregon Health and Science University, Casey Eye Institute Molecular
Diagnostic Laboratory, Portland, USA; Pronto Diagnostics Ltd., ProntoLab -
MLPA Lab, Tel Aviv, Israel; Nottingham University Hospitals NHS Trust
(City Hospital), Nottingham, UK; CHU de Nantes, Institut de Biologie,
Nantes, France; Sistemas Genómicos S.L, Sistemas Genómicos S.Lalencia,
C. Thomas MG, Thomas S, Kumar A, Proudlock FA, Gottlob I. FRMD7-Related
Infantile Nystagmus. In: Pagon RA, Bird TD, Dolan CR, Stephens K,
editors. GeneReviews [Internet]. Seattle (WA): University of Washington,
Seattle; 1993-. 2009 Feb 12 [updated 2011 Sep 29].
D. BBC News: Device aids eye disease research in young children. 31
August 2012 http://www.bbc.co.uk/news/uk-england-leicestershire-19436194
The Challenge of Nystagmus: Proceedings of the Nystagmus Network
Research Workshop, Abingdon, UK, 2-5 September. Irene Gottlob,
Chris Harris, Larry Abel and Andrea Barreiro. 19 Sep 2012