Proceedings2010

Transcription

Proceedings2010

Symposium
on
and on
Eye Movements
Clinical Neurophysiology of Vision
with the 26th Dr. Janez Faganel Memorial Lecture
Ljubljana, 17-18 September 2010
University Medical Centre, Lecture Hall II & Eye Clinic
SYMPOSIUM ON
ELECTROPHYSIOLOGY OF VISION AND ON EYE MOVEMENTS
Ljubljana, 17–18 September 2010
Organisers:
Section for Clinical Neurophysiology of the Slovenian Medical Association,
Slovenian Ophthalmological Society,
Institute of Clinical Neurophysiology at the Department of Neurology and Eye Hospital
of the University Medical Centre Ljubljana
Proceedings
Editors:
Jelka Brecelj, Janez Zidar
Technical Editors:
Tone Žakelj, Boštjan Kastelic, Ignac Zidar
Publisher:
Section for Clinical Neurophysiology of the Slovenian Medical Association
Front Cover Design:
Petra Petan
Front Cover Photo:
Bojan Brecelj – Trnovo lime tree, January/June 2010
Print:
Birografika Bori, Ljubljana
CIP - Kataložni zapis o publikaciji
Narodna in univerzitetna knjižnica, Ljubljana
616-009.7(082)
SYMPOSIUM on Clinical Neurophysiology of Vision and on Eye Movements
(2010 ; Ljubljana)
Proceedings / Symposium on Clinical Neurophysiology of Vision and on Eye
th
Movements with the 26 Dr. Janez Faganel Memorial Lecture, Ljubljana,
17-18 September 2010 ; [organisers Section for Clinical Neurophysiology of the
Slovenian Medical Association [and] Slovenian Ophthalmological Society [and]
Institute of Clinical Neurophysiology at the Department of Neurology and
Eye Hospital of the University Medical Centre Ljubljana ; editors Jelka Brecelj,
Janez Zidar]. - Ljubljana : Section for Clinical Neurophysiology of
the Slovenian Medical Association, 2010
ISBN 978-961-6526-38-8
1. Brecelj, Jelka 2. Dr. Janez Faganel Memorial Lecture (26 ; 2010 ; Ljubljana) 3.
Slovensko zdravniško društvo. Sekcija za kliniþno nevrofiziologijo 4. Slovensko
oftalmološko združenje 5. Kliniþni center (Ljubljana). Nevrološka klinika. Inštitut za
kliniþno nevrofiziologijo 6. Kliniþni center (Ljubljana). Oþesna klinika
252508160
---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 -----------------------------------------------
CONTENTS
Janez Zidar, Jelka Brecelj:
Foreword .............................................................................................................................. 5
PROGRAMME FRAMEWORK ................................................................................................ 6
DETAILED PROGRAMME ...................................................................................................... 7
VISUAL ELECTROPHYSIOLOGY – invited review lectures
Martin Štrucl:
The basic principles of the visual analysis ........................................................................... 10
Graham E. Holder:
Electrophysiology in retinal disease ..................................................................................... 16
Jelka Brecelj:
Electrophysiological evaluation of the visual pathway ......................................................... 17
Marko Hawlina:
The rational use of electrophysiology in neuroophthalmology ............................................. 28
Dorothy Thompson:
Paediatric visual electrophysiology – methods and indications ........................................... 31
DR. JANEZ FAGANEL MEMORIAL LECTURE
Ryusuke Kakigi, Kensaku Miki, Shoko Watanabe, Yukiko Honda,
Minoru Hoshiyama, Emi Tanaka:
Face recognition-related potentials: EEG, MEG, NIRS studies ........................................... 38
EYE MOVEMENTS – invited review lectures
Christopher Kennard:
The anatomy and physiology of eye movements ................................................................ 44
Ksenija Ribariü-Jankes:
Diagnostic procedures for detecting eye-movements defects
in vestibular and brainstem lesions ...................................................................................... 51
Wobbly eyes – saccadic oscillations and nystagmus .......................................................... 52
Branka Stirn-Kranjc:
Extraocular muscles and ocular motility .............................................................................. 55
Marko Korošec:
Blinking, its mechanisms and pathology .............................................................................. 64
Ulrich Ettinger:
Genetic and neuroimaging studies of eye movements ........................................................ 67
Chris M. Harris, Jithin S. George, Sreedharan Harikrishnan, Jonathan Waddington,
Andrew Smith, Martin T. Sadler:
Waveforms in type 2 epileptic nystagmus ........................................................................... 68
Abstracts of poster presentations
Maja Šuštar, Jelka Brecelj, Marko Hawlina, Branka Stirn-Kranjc, Barbara Cvenkel:
Evaluation of retinal function with electroretinographic ON- and OFF-response,
photopic negative response and S-cone response .............................................................. 69
Ivan ýima, Jelka Brecelj, Maja Šuštar, Frauke Coppieters, Bart P. Leroy,
Elfride De Baere, Marko Hawlina:
Unusually mild enhanced S-cone syndrome with preserved macular structure:
a case report ........................................................................................................................ 70
Satar Baghrizabehi, Teodor Robiü:
Optic nerve head drusen ..................................................................................................... 71
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Kensaku Miki, Shoko Watanabe, Mika Teruya, Yasuyuki Takeshima,
Tomokazu Urakawa, Masahiro Hirai, Yukiko Honda, Ryusuke Kakigi:
The development in the perception of facial emotion change using ERPs .........................
Denis Perko, Janja Pretnar-Oblak, Bojana Žvan, Marjan Zaletel:
Endothelial function of the posterior circulation supplying visual cortex ..............................
Marjan Zaletel, Andrej Fabjan, Martin Štrucl:
Visually evoked cerebral blood flow velocity responses ......................................................
Dragica Kosec, Gregor Hawlina, Brigita Drnovšek-Olup:
Surgical treatment of total binocular oculomotorius paresis after CVI –A case report ........
Igor Petriþek, Zlatko Juratovac, Rajko Pokupec, Branimir Cerovski, Goranka Petriþek:
Unilateral or asymmetric pigmentary retinopathy? A case report ........................................
RESEARCH REPORTS
Mitja Benediþiþ, Roman Bošnjak:
Cortical responses after intraoperative electrical stimulation of the optic nerve ..................
Marijan Palmoviü, Ana Branka Šefer, Magdalena Krbot, Velimir Išgum:
Eye-tracking as a measure of cognitive processes in children: two paradigms ..................
Miro Denišliþ, Zoran Miloševiþ, Metka Zorc:
Cerebrospinal venous outflow and eye movements ............................................................
Uroš Rot:
Dissemination in space in multiple sclerosis:
the role of VEP in different stages of the disease ...............................................................
Martina Jarc-Vidmar, Petra Popoviþ, Eva Lenassi, Jelka Brecelj, Marko Hawlina:
Imaging and electrophysiology in Stargardt dystrophy ........................................................
Eva Lenassi, Anthony G. Robson, Marko Hawlina, Graham E. Holder:
The use of large field PERG in routine electrophysiology testing .......................................
Manca Tekavþiþ-Pompe, Branka Stirn-Kranjc, Jelka Brecelj:
What does chromatic VEP response tell us in congenitally colour deficient children? ........
72
73
74
77
78
79
80
81
82
83
84
85
CONTRIBUTIONS TO THE ISCEV & EC-IFCN COURSES
Graham E. Holder:
Clinical visual electrophysiology: a practical overview ............................................................... 87
Vision, illusions and reality .................................................................................................. 96
Branka Geczy:
Nystagmus in a case of benign paroxysmal positional vertigo ............................................ 98
Petra Miklavþiþ, Ingrid Kompara-Volariþ, Iris Jurþiþ, Anton Grad:
Bilateral horizontal gaze paresis of unknown origin ............................................................ 99
Dragica Kosec:
Ophthalmological treatment of diplopia ............................................................................. 100
APPENDIX
ISCEV standards (reprinted from Documenta Ophthalmologica with permission) ............................. 101
AUTHORS INDEX ................................................................................................................. 159
ACKNOWLEDGEMENT ........................................................................................................ 160
Dr. Janez Faganel Memorial Lectures and Symposia 1985–2010 ................................... 161
Invitation to the Slovenian Neurophysiological Symposium 2011 .................................. 163
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FOREWORD
Dear Participants
We are pleased to welcome you at the 2010 Ljubljana Symposium on Clinical Neurophysiology
with the 26th Dr Janez Faganel Memorial Lecture, dedicated to Vision and Eye Movements.
It may be of some interest to note that (electrophysiology of) vision is the symposium topic for
the second time in the line of our 26 consecutive annual meetings. The revisiting is a result of
the continuous interest, efforts and accomplishments of some of our colleagues. However, it
cannot be overlooked that the Memorial Lecturers of either Symposia are of the Japanese origin:
Professor Hisako Ikeda from London, Great Britain, in 1993, and Professor Ryusuke Kakigi from
Okazaki, Japan, this year. In their laboratories they both also hosted and tutored our colleagues. We truly appreciate their hospitality and are honoured to have (had) them – the world
authorities in the field – lecturing here in Ljubljana.
We are grateful also to Professor Kennard who is contributing the keystones to the topic of eye
movements at the Symposium. We are sure that his talks – supplemented by the others on the
programme – will foster interest in the clinical field which seems neglected in our place.
We are thankful also to all other lecturers for their contributions to our Symposium.
The European Chapter of the International Federation of Clinical Neurophysiology (EC-IFC)
acknowledged the symposium as their Regional Course and generously supported it financially,
as well. We are indebted to the International Society of Clinical Electrophysiology of Vision
(ISCEV) for their approval of our ERG-VEP Practical Course.
And, finally, our appreciation goes also to all other financial supporters.
We have done our best to make your stay in Ljubljana professionally profitable and will try to
make it also enjoyable.
Janez Zidar and Jelka Brecelj
on behalf of the Programme & Organising Committee
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5
PROGRAMME FRAMEWORK
Friday, 17 September 2010
University Medical Centre Ljubljana, Zaloška cesta 7, Lecture Hall No. II
From 7:00 on
Registration
08:15–08:30
Opening
08:30–10:00
VISUAL ELECTROPHYSIOLOGY – review lectures I
10:00–10:30
Coffee break
10:30–11:30
VISUAL ELECTROPHYSIOLOGY – review lectures II
11:30–12:30
12:30–14:00
Lunch
14:00–16:25
EYE MOVEMENTS – review lectures
16:25–16:45
Poster session & Coffee break
16:45–17:55
Research reports
20:00
Symposium dinner (The Ljubljana Castle)
Saturday, 18 September 2010
Eye Hospital, Ljubljana, Grabloviþeva 46
From 07:30 on
Registration
08:00–10:30
ERG–VEP, an ISCEV approved course
10:30–11:00
Coffee break
11:00–13:00
Ocular movements in neurology, neuroophthalmology, and neurootology –
an EC-IFCN sponsored European Regional Course, together with Continuum
Neuroophtalmology by American Academy of Neurology
13:00
Closing of the Symposium
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6
DETAILED PROGRAMME
Friday, 17 September 2010
Venue: University Medical Centre Ljubljana, Zaloška cesta 7, Lecture Hall No. II
From 7:00 on
Registration
08:15–08:30
Opening
08:30–10:00
VISUAL ELECTROPHYSIOLOGY – review lectures I
Chairpersons: Marko Hawlina and Dorothy Thompson
08:30–09:00
Martin Štrucl (Slovenia):
The basic principles of the visual analysis
09:00–09:30
Graham E. Holder (Great Britain):
Electrophysiology in retinal disease
09:30–10:00
Jelka Brecelj (Slovenia):
Electrophysiological evaluation of the visual pathway
10:00–10:30
Coffee break
10:30–11:30
VISUAL ELECTROPHYSIOLOGY – review lectures II
Chairpersons: Branka Stirn-Kranjc and Graham E. Holder
10:30–11:00
Marko Hawlina (Slovenia):
The rational use of electrophysiology in neuroophthalmology
11:00–11:30
Dorothy Thompson (Great Britain):
Paediatric visual electrophysiology – methods and indications
11:30–12:30
Chairpersons: Tine S. Prevec and Jelka Brecelj
Ryusuke Kakigi (Japan):
Face recognition-related potentials: EEG, MEG, NIRS studies
12:30–14:00
Lunch
14:00–16:25
EYE MOVEMENTS – review lectures
Chairpersons: Janez Zidar and Ksenija Ribariü
14:00–14:25
Christopher Kennard (Great Britain):
The anatomy and physiology of eye movements
14:25–14:50
Ksenija Ribariü-Jankes (Serbia):
Diagnostic procedures for detecting eye-movements defects in vestibular and
brainstem lesions
14:50–15:15
Wobbly eyes – saccadic oscillations and nystagmus
15:15–15:40
Branka Stirn-Kranjc (Slovenia):
Extraocular muscles and ocular motility
15:40–15:55
Marko Korošec (Slovenia):
Blinking, its mechanisms and pathology
15:55–16:10
Ulrich Ettinger (Germany):
Genetic and neuroimaging studies of eye movements
16:10–16:25
Chris M. Harris, Jithin S. George, Sreedharan Harikrishnan, Jonathan Waddington,
Andrew Smith, Martin T. Sadler (Great Britain):
Waveforms in type 2 epileptic nystagmus
------------------------------------------------------------------------------------------------------- PROCEEDINGS -------------------------------------------------------------------------------------------------------
7
16:25–16:45
Poster No 1
Poster No. 2
Poster No. 3
Poster session & Coffee break
Chairpersons: Marjan Zaletel and Manca Tekavþiþ-Pompe
Maja Šuštar, Jelka Brecelj, Marko Hawlina, Branka Stirn-Kranjc,
Barbara Cvenkel (Slovenia):
Evaluation of retinal function with electroretinographic ON- and OFF-response,
photopic negative response and S-cone response
Ivan ýima, Jelka Brecelj, Maja Šuštar, Frauke Coppieters, Bart P. Leroy,
Elfride De Baere, Marko Hawlina (Croatia, Slovenia, Belgium):
Unusually mild enhanced S-cone syndrome with preserved macular structure: a case
report
Satar Baghrizabehi, Teodor Robiü (Slovenia):
Optic nerve head drusen
Poster No. 5
Kensaku Miki, Shoko Watanabe, Mika Teruya, Yasuyuki Takeshima,
Tomokazu Urakawa, Masahiro Hirai, Yukiko Honda, Ryusuke Kakigi (Japan):
The development in the perception of facial emotion change using ERPs
Denis Perko, Janja Pretnar-Oblak, Bojana Žvan, Marjan Zaletel (Slovenia):
Endothelial function of the posterior circulation supplying visual cortex
Poster No. 6
Marjan Zaletel, Andrej Fabjan, Martin Štrucl (Slovenia):
Visually evoked cerebral blood flow velocity responses
Poster No. 7
Dragica Kosec, Gregor Hawlina, Brigita Drnovšek-Olup (Slovenia):
Surgical treatment of total binocular oculomotorius paresis after CVI – Acase report
Poster No. 8
Igor Petriþek, Zlatko Juratovac, Rajko Pokupec, Branimir Cerovski,
Goranka Petriþek (Croatia):
Unilateral or asymmetric pigmentary retinopathy? A case report
16:45–17:55
RESEARCH REPORTS
Chairpersons: Martin Štrucl and Martina Jarc-Vidmar
16:45–16:55
Mitja Benediþiþ, Roman Bošnjak (Slovenia):
Cortical responses after intraoperative electrical stimulation of the optic nerve
16:55–17:05
Marijan Palmoviü, Ana Branka Šefer, Magdalena Krbot, Velimir Išgum (Croatia):
Eye-tracking as a measure of cognitive processes in children: two paradigms
17:05–17:15
Miro Denišliþ, Zoran Miloševiþ, Metka Zorc (Slovenia):
Cerebrospinal venous outflow and eye movements
Poster No. 4
17:15–17:25
17:25–17:35
17:35–17:45
Uroš Rot (Slovenia):
Dissemination in space in multiple sclerosis: the role of VEP in different stages of the
disease
Martina Jarc-Vidmar, Petra Popoviþ, Eva Lenassi, Jelka Brecelj, Marko Hawlina
(Slovenia):
Imaging and electrophysiology in Stargardt dystrophy
Eva Lenassi, Anthony G. Robson, Marko Hawlina, Graham E. Holder (Slovenia,
Great Britain):
The use of large field PERG in routine electrophysiology testing
17:45–17:55
Manca Tekavþiþ-Pompe, Branka Stirn-Kranjc, Jelka Brecelj (Slovenia):
What does chromatic VEP response tell us in congenitally colour deficient children?
20:00–23:00
Symposium dinner at the Ljubljana Castle
Saturday, 18th September
Venue: Eye Hospital, Ljubljana, Grabloviþeva 46
From 7:00 on
Registration
08:00–10:30
ERG–VEP, an ISCEV approved course
Organizers: Jelka Brecelj, Marko Hawlina, and Maja Šuštar
Technical support: Marija Jesenšek, Ana Jeršin
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8
08:00–08:20
Maja Šuštar (Slovenia):
Basic techniques for recording ERG and VEP according to ISCEV standards
(introduction to the course)
08:20–08:45
Discussion
08:45–09:10
Graham E. Holder (Great Britain):
Full-field electroretinography and the clinical relevance of S-cone and ON-OFF ERGs
08:45–09:10
Marko Hawlina (Slovenia):
PERG and MFERG and their application
09:10–09:35
Jelka Brecelj (Slovenia):
When to record flash, onset, pattern reversal full-field and half-field VEPs
09:35–10:00
Dorothy Thompson (Great Britain):
Recording skin ERG in babies and reasons for simultaneous VEP recording
10:00–10:30
Jelka Brecelj, Marko Hawlina, Graham E. Holder, Maja Šuštar, Dorothy Thompson
(Slovenia and Great Britain):
The role of visual electrophysiology in clinical practice (Round table discussion)
Maja Šuštar (Slovenia):
Individual practice of recording EOG, full-field ERG, MFERG, PERG and VEP
10:30–11:00
Coffee break
11:00–13:00
Ocular movements in neurology, neuroophthalmology, and neurootology – an
EC-IFCN sponsored European Regional Course, together with Continuum
Neuroophtalmology by American Academy of Neurology
Organiser: Marko Korošec
11:00–11:30
Vision, illusions and reality
11:30–12:00
Marko Korošec (Slovenia):
How to examine eye movements – bedside approach
12:00–12:45
Case presentations of various eye movement disorders:
Branka Geczy (Slovenia): Nystagmus in a case of benign paroxysmal positional
vertigo
Dragica Kosec (Slovenia): Eye movements – presentation of cases
Petra Miklavþiþ, Ingrid Kompara-Volariþ, Iris Jurþiþ, Anton Grad (Slovenia):
Bilateral horizontal gaze paresis of unknown origin
12:45–13:00
Dragica Kosec (Slovenia):
Ophthalmological treatment of diplopia
13:00
Closing of the Symposium
------------------------------------------------------------------------------------------------------- PROCEEDINGS -------------------------------------------------------------------------------------------------------
9
THE BASIC PRINCIPLES OF THE VISUAL ANALYSIS
Martin Štrucl
Institute of Physiology, University of Ljubljana Medical Faculty, Ljubljana, Slovenia
Abstract
The processing of visual information in the primate retino-geniculo-striate system is briefly described. Incoming visual
signals from the visual surroundings are reaching visual cortical areas through parallel subchannels, each one processing the distinct aspect of the visual stimulus. Early neurobiological strategy of visual analysis is functional segregation.
Some principles of visual analysis, like retinal tiling, hierarchical and parallel processing, receptive fields integration,
and functional modularity, are known and some interesting computational theories of information processing can be
applied. Ultimately, these parallel input signals must be elaborated upon and integrated within the cortex to provide a
unified and coherent percept. The psychological strategy of visual analysis is therefore integrative. The ongoing
percepts of the visual world are continuously constructed by the brain and these processes are still awaiting further
neurobiological explanations of the phenomena.
INTRODUCTION
Visual signals are processed in many regions of the brain, subserving a variety of important
functions. Retinofugal fibers project to subcortical structures for optical reflexes, regulation of
circadian rhythm, subcortical control of eye movements and visually guided actions.
This presentation is focused on the visual analysis in the retino-geniculo-cortical system, which
ultimately produces conscious awareness of the visual world.
It is a long journey from image-forming photons to a full explanation of visual perception. Nevertheless, scientific exploration of the visual system has led to the most exciting stories in sensory
neurobiology written by a number of excellent scientists and five Nobel Prize laureates [1]. Indeed, for several reasons, the visual system has become the most studied sensory system in
neurobiology. First of all, humans are members of the primate family, possessing an excellent
visual system with high spatial resolution and rich colour vision that allow us to admire beautiful
landscapes, to be motivated by supernatural stimuli, to recognize faces, to read the emotional
expressions, or even more importantly, to perform visually guided movements.
Visual analysis involves a huge number of neurons. The area of the cortex engaged in the
visual analysis in primate is considerably large, accounting for more than 30% in the macaque
monkey and almost 20% in humans. There are more than 30 distinctive retinal representations,
conjoined in complex networks by more than 300 major connections [2, 3]. The evolution of
visual processing in primates seems to have pushed towards a very costly and luxurious system,
obviously for some important adaptational advantages.
HOW CAN SUCH A COMPLEX SYSTEM BE STUDIED?
Several methodological approaches have been utilized to obtain the current knowledge of visual
processing: psychophysics, single-units recording, computational neuroscience, neuroimaging
methods and the study of patients with localized lesions.
Traditionally, there is good old psychophysics, which gave us the first valuable concepts and the
rules of visual perception (spectral sensitivity, trichromaticity, colour opponency and contrast).
Then, in the mid 20th century, single-unit recording revolutionized the exploration of visual
processing with the discovery of lateral inhibition, receptive field concept, and parallel processsing [4–6]. The real heroes of visual science became animal models (limulus, frog, rabbit, cat
and macaque monkey). For the first time, the black box approach could be upgraded with
computation theories of visual analysis and computational foundations of vision [7–10].
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10
Successively, mathematical scientists began to develop mathematical frameworks of informational theories of visual processing in neuronal networks, thereby contributing to the
flourishing of computational neurosciences.
Currently, modern neuroimaging methods (PET, EMG, MEG, fMRI) are being utilized that complement single-unit recordings [11]. In addition, some very interesting descriptions of patients
with rare, distinctive lesions of the visual system (visual agnosias, colour blindness, blindsight)
have been published that further the study of visual analysis [12–14].
HOW DOES THE BRAIN PERFORM VISUAL ANALYSIS?
Visual analysis is performed through the series of visual sensory processes from the retina to
the cortex of the brain. It is fairly well established how visual analysis takes place in its initial
processing, that is as the visual signals pass through 6 or 7 synapses (reception, transformation,
detection of elementary visual cues and abstraction of invariant features of image). However,
the ultimate challenge of sensory physiology is the very hard question as to the neurobiological
explanation of subjective experiences. In order to avoid the brain-mind problem, attention will be
focused on the most fruitful “bottom –up” approach to visual analysis. Basically, it is to design a
stimulus with such distinctive features as to stimulate the visual system and to detect the
response of the attuned single-unit (neurons) at different levels of visual analysis, layer by layer
and structure by structure, seeking for the preferential response of the unit in question. As
straightforward as it may be seen, this approach is far from being simple. The units must be
identified in demanding citoarchitectural, biochemical, anatomical, histological and in situ, in
vivo, or post mortem studies using several types of markers [6]. In short, the strategy is to follow
the visual streams of information from photoreceptors to the highest level of visual processing
[2, 3, 8]. Some essential questions must be resolved in bottom-up approach:
x How is a system, subsystem, group of neurons, single unit: structure, connections and
circuits to be defined?
x What aspects of visual information are represented within parallel subsystems?
x How is it represented (encoding and decoding modes)?
x What kind of processing (computation) is performed in a single unit or subsystem?
At successive levels, a representation is transformed into other forms of representation in a
meaningful way to assure stable visual perception over a wide range of variable conditions and
to allow for the flexible use of different representations of visual images by different functional
entities of the brain [10].
VISUAL STIMULUS
Out there is the visual world of physical stimuli. Light emitted from various sources within the
spectral domain of 400–800 nm is reflected from the surface of interest. A stimulus can be
described in radiometric intensity measurement as a function of space, time, spectral composition and left or right eye stimulation.
RETINAL PHOTOTRANSDUCTION
A visual image is focused on retinal detectors, where phototransduction takes place involving a
cis-trans isomerization of the miraculous retinen molecule. The mechanism of transduction is
basically identical for the human and insect eye.
At this level a visual stimulus can be described as primary sensory visual cues involving photometric intensity (luminance), spectral composition, and the feature based cues of contrast, 2D
position, orientation and left-right retinal disparity.
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11
RETINAL PROCESSING
For further retinal processing two major problems have to be solved by retinal circuitry. Only a
few tenth of millimetre thick, the retinal network has enormous computational power [15].
The first problem is wealth of visual information. Retinal mosaic of 120 million rods and 6 million
cones can transmit an enormous amount of information to the brain. Representing all of the
possible information would be too demanding a task, considering the anatomical bottleneck of a
system that consists of 126 million signalling receptors converging on only one million optic
nerve fibres with a limited transmission rate. The signals from the photoreceptors are therefore
compressed and reduced. The temporal aspect of the reduction is adaptation with the slow
events being filtered out.
The spatial aspect of compression is the formation of receptive fields. The signals from local
area integrate to form typical centre – surround structure of secondary receptive fields. The
same principle of receptive spatial integration is found beyond the retinal level. As the receptive
fields are synthesized from level to level, the properties of the receptive fields change from a
simple to an increasingly more complex form. In the striate cortex, we encounter simple and
complex receptive fields that have several new and more complex properties, including orientation (form perception) and binocularity (depth). At the advanced stage of object recognition in
the extrastriate cortical areas, the receptive fields are larger, with the neurons responding best
to the categories of shapes, object motion, and even faces [16, 17].
The second problem is the low intrinsic speed of nervous system processing, compared to
silicon chip serial processing. It is remarkable that human vision can recognize some very
complex objects in just a little more than 100 milliseconds [18]. The biological system must use
alternative strategies to speed up its performance, among others parallel processing. Therefore,
parallel processing is the second prominent feature of retinal circuits. By the first synapse, the
cone pedicle, a light signal is segregated into many parallel channels and transmitted onto two
types of horizontal cells and eight to ten different types of ON and OFF bipolar cells. Most
important for this synaptic diversity is the expression of different metabotropic and ionotropic
glutamate receptors at numerous (more than 500) synapses between the photoreceptors and
the postsynaptic bipolar and horizontal cells [19, 20].
The main output units of the retina are ganglion cells. More than 17 distinctive ganglion cells
types have been discovered in the mammalian retina, repeatedly representing the visual field
and sharing the photoreceptors, but conveying different aspects of visual stimuli. Most typical in
the mammalian retina are three types of ganglion cells with different origins, destinations and
characteristics. Parasol cells are the origin of the magnocellular pathway; midget cells originate
the parvocellular subsystem; and bistratified cells give rise to the koniocellular subsystem. As
we look at an image, each ganglion cell type filters out and signals its own distinctive attributes
of the visual stimulus. The observed image is literally tiled by different receptive field types [19–21].
THALAMIC LEVEL
The ganglion cells project to distinctive layers of the lateral geniculate nucleus (LGN). The retinotopic organization and separated L and R eye inputs are preserved together with segregated
stream projections.
CORTICAL LEVELS
The segregated streams from LGN reach V1 in different cortical layers [19–22].
From psychophysical, as well neurobiological studies, four principal perceptual attributes of
vision can be inferred: form, stereoptic depth, colour and motion.
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12
Form
The detection of edges is the early sensory cue for the perception of form. An object is very
likely represented in a form of scrambled edges and contours in the primary visual cortex. After
the sequential binding process, a holistic representation of the particular object is constructed at
higher levels of the visual cortex.
Depth
Stereoscopic (binocular) depth perception is based on left-right retinal picture disparity [10, 23].
Some points in the external space, whose distance differs from that of the fixation point, are
projected onto non-corresponding retinal points. The disparity of the projections is used by
binocularly driven cortical units to estimate the depth.
Colour
The perception of colour is based on differences in absorption spectra of three different types of
cones that combine two antagonistically organized colour channels [19]. Colour is further processed in area V1, V2 and V4 to differentiate between achromatic and chromatic contrast of the
image.
Motion
Motion analysis is a complex process combining the motion detection, the discrimination of
visual motion caused by body or eye movements from movements in the external world, and the
computation of object trajectories. It originates in directionally sensitive cells. Higher order visual
processes then combine low resolution motion with high resolution still pictures.
The central cortical visual pathways are found to be segregated in three parallel pathways:
depth and form, colour and movement. The description of the pathways is rather complex. The
segregated path of visual processing has been described as in the occipital lobe, encompassing
V1 (area 17), V2, V3 (area 18) V3a V4, V5 (area 19), as well as in some temporal (MT- area 5)
and parietal areas (V5a-MST, P7a).
MODULAR ORGANIZATION OF THE VISUAL CORTEX
Another feature of parallel processing in the visual cortex is the existence of functional modules.
Cortical cells with similar properties are aggregated together in a vertical columnar organization.
The cells in the primary visual cortex are grouped with respect to field axis orientation, ocular
dominance and wavelength sensitivity (blobs). Segregation is also clearly evident in the thick
and thin dark stripes of visual area V2 when it is stained for cytochrome oxidase [4].
“What” and “Where” visual streams
Accordingly to the central question of visual analysis, functional segregation at the higher level
of cortical processing can be reduced to the two principle “what” and “where” visual streams,
indentified by Mortimer Mishkin [24]. Fundamentally, vision is the process of discovering from
images what is present in the visual world, and where it is.
The “what” pathways terminate in the inferior temporal cortex, which is an area important for the
recognition of form (what) and receive inputs from parvocellular interblob (form) and blob (colour)
systems [25–27]. The “where” pathway terminates in the posterior parietal cortex and is important for the location of objects in space. It receives inputs from the magnocellular directionsensitive systems [28].
The two pathways represent the very limits of the “bottom-up “approach which links individual
units to the stimulus features. This approach provides us an insight into the fascinating parallel
subsystem and modular architecture of cortical regions. Regarding the higher level of visual
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13
processing, a new paradigm is needed that would account for the transformation from segregating to integrating visual information.
Highest level: From segregation to synthesis
At the highest levels, the perception of a visual object is integrative rather than segregative
process. The visual percept is constructed from multiple aspects of the visual object following
the rules of holistic synthesis [25]. That is why vision can easily be fooled. A number of popular
illusions can be experienced as a consequence of perceptual construction. For example, the
third dimension is essentially the construct of the brain by which the illusions of the perspective
(size-distance) is easily evoked.
Massive reciprocal interactions of different brain structures are dominating in the central
neuronal networks, and top-down strategies of processing become increasingly important [2].
Even at the level of LGN as much as 80% of excitatory synapses, with largely unknown
function, are driven by the primary visual cortex. The LGN also receives synaptic inputs from
neurons whose activity is related to alertness and attentiveness, representing the utmost
important functional bottleneck of visual analysis. At the higher stages of visual analysis
integration is the dominant strategy of the brain. Where does this integration take place? The
theory of receptive field synthesis would imply that perception is based on extremely selective
receptive fields such as those of a grandmother cell. However, it is highly unlikely that we have
a partition of cortex with a few cells tuned to each of the millions of object that we all recognize.
Instead, some other integrating mechanisms must be proposed for combining the activity of
many units, broadly tuned to the categories of visual percepts (faces, objects) [11, 24, 29].
CONCLUSION
The neurobiological strategy of visual analysis is segregative. Some principles of visual analysis
are known and some interesting computational theories of information processing can be applied.
The psychological strategy of visual analysis is integrative. The ongoing percepts of the visual
world are continuously constructed by the brain and these processes are still awaiting further
neurobiological explanations of the phenomena.
REFERENCES
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3 Lewis JW, Van Essen DC. Mapping of architectonic subdivisions in the macaque monkey, with emphasis on
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11 Haxby JV, Gobbini MI, Furey ML, Ishai A, Schouten JL, Pietrini P. Distributed and overlapping representations of
faces and objects in ventral temporal cortex. Science 2001; 293: 2425–30.
12 Sacks O, Wasserman R. The case of the colorblind painter + an essay on acquired cerebral achromatopsia. New
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13 Schenk T, Zihl J. Visual motion perception after brain damage: II. Deficits in form-from-motion perception. Neuropsychologia 1997; 35: 1299–310.
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14 Schenk T, Zihl J. Visual motion perception after brain damage: I. Deficits in global motion perception.
Neuropsychologia 1997; 35: 1289–97.
15 Wassle H. Parallel processing in the mammalian retina. Nat Rev Neurosci 2004; 5: 747–57.
16 Gobbini MI, Haxby JV. Neural systems for recognition of familiar faces. Neuropsychologia 2007; 45: 32–41.
17 Haxby JV, Gobbini MI. The perception of emotion and social cues in faces (vol 45, pg 1, 2007).
Neuropsychologia 2007; 45: 2416.
18 Holcombe AO. Seeing slow and seeing fast: two limits on perception. Trends Cogn Sci 2009; 13: 216–21.
19 Dacey DM, Packer OS. Colour coding in the primate retina: diverse cell types and cone-specific circuitry. Curr
Opin Neurobiol 2003; 13: 421–7.
20 Diller L, Packer OS, Verweij J, McMahon MJ, Williams DR, Dacey DM. L and M cone contributions to the midget
and parasol ganglion cell receptive fields of macaque monkey retina. J Neurosci 2004; 24: 1079–88.
21 Nassi JJ, Callaway EM. Parallel processing strategies of the primate visual system. Nat Rev Neurosci 2009; 10:
360–72.
22 Nassi JJ, Lyon DC, Callaway EM. The parvocellular LGN provides a robust disynaptic input to the visual motion
area MT. Neuron 2006; 50: 319–27.
23 Georgieva SS, Todd JT, Peeters R, Orban GA. The extraction of 3D shape from texture and shading in the
human brain. Cereb Cortex 2008; 18: 2416–38.
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25 Orban GA. Higher order visual processing in macaque extrastriate cortex. Physiol Rev 2008; 88: 59–89.
26 Orban GA, Claeys K, Nelissen K, Smans R, Sunaert S, Todd JT et al. Mapping the parietal cortex of human and
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27 Orban GA, Van Essen D, Vanduffel W. Comparative mapping of higher visual areas in monkeys and humans.
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28 Lyon DC, Nassi JJ, Callaway EM. A disynaptic relay from superior colliculus to dorsal stream visual cortex in
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15
ELECTROPHYSIOLOGY IN RETINAL DISEASE
Graham E. Holder
Moorfields Eye Hospital and Institute of Ophthalmology, London; Great Britain
Electroretinography is an indispensible tool in the characterisation, diagnosis and management
of patients with retinal disease, both acquired and inherited. After a short overview of the origins
of the ERG, which will demonstrate how alterations in stimulus parameters and the adaptive
state of the eye allow electroretinography to separate the function of different cell types and
layers within the retina, the presentation will utilise a case-based approach to demonstrate the
clinical value of ERG. Disorders addressed will include primary photoreceptor degenerations,
congenital stationary night blindness, Stargardt fundus-flavimaculatus, birdshot chorioretinopathy and others.
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ELECTROPHYSIOLOGICAL EVALUATION OF THE VISUAL PATHWAY
Jelka Brecelj
Unit for Visual Electrophysiology, Eye Hospital, University Medical Centre, Ljubljana, Slovenia
Abstract
The aim here is to review electrophysiological assessment in optic neuritis, chiasmal compressive lesions, achiasmia
and ocular albinism. In clinical investigations of these visual pathway disorders, it is relevant to define electrophysiological dysfunction as: (a) conduction block in the optic nerve axons; (b) prolonged conduction velocity due to demyelination of the optic nerve; (c) loss of optic nerve axons; (d) potential remyelination or subclinical demyelination of
the optic nerve; (e) degeneration of retinal ganglion cells; (f) abnormal conduction along crossed optic nerve fibres
due to compression of the optic chiasm; and (g) no decussation or excess decussation of the optic nerve fibres at the
chiasm.
The role of pattern electroretinography (PERG) and visual evoked potentials (VEPs) will be presented according to
three main aspects. The first provides an outline of the value of PERG and VEPs with pattern-reversal stimulation for
the understanding of a group of disorders that cause optic neuritis: (i) demyelinating optic neuritis, and the follow up
of remyelination; (ii) non-demyelinating optic neuritis; (iii) relapsing isolated optic neuritis, without multiple sclerosis
and myelitis; (iv) neuromyelitis optica, with serum antibody to aquaporin-4 water channels; and (v) optic neuritis, with
poor outcome. The second aspect will demonstrate the value of VEPs to pattern-reversal half-field stimulation in
cases of compressive lesions involving the optic chiasm: (i) without visual field abnormalities; (ii) where magnetic
resonance imaging appears to involve the optic chiasm, while VEP reveals dysfunction in one eye; (iii) in younger
age groups where visual-field testing is not always reliable; and (iv) follow-up and monitoring of stability, deterioration
and recovery after interventions. PERG defines a possible retrograde degeneration of retinal ganglion cells that can
occur, for example, during a longer period of gradual painless asymptomatic visual loss due to compression, and it
correlates with postoperative recovery. The third aspect will answer two questions relating to how VEP asymmetries
to flash and onset stimulation can define congenital abnormalities of optic nerve fibre decussation that are associated
with early onset nystagmus and poor visual acuity: (i) in achiasmia, is VEP ipsilateral asymmetry relevant for establishing the diagnosis of absent or reduced decussation; and (ii) in diagnosing ocular albinism, is VEP contralateral
asymmetry significant for detection of an excess of optic nerve fibre decussation at the chiasm.
In a look to the future, the considerations here include how clinically relevant VEP P100 can be combined with
multifocal VEP, thereby enabling the definition of more local visual pathway abnormalities. Furthermore, in addition to
PERG, future studies may include the new electroretinography method of photopic negative response (PhNR), along
with morphological measurement of the retinal nerve fibre layer by OCT, as markers of axonal degeneration.
INTRODUCTION
In clinical studies of today a relevant question is whether an electrophysiological assessment of
the visual pathway is needed when brain magnetic resonance imaging (MRI) is the investigative
technique of preference and VEPs are even not listed in diagnostic criteria of MS. In this review,
this will be discussed from my view and experience of visual evoked potentials (VEPs) as a
reliable diagnostic tool. This comes nearly 40 years after the first articles of Dr. Martin Halliday
that showed VEPs in acute optic neuritis after the recovery of the visual acuity, and in silent
demyelination due to multiple sclerosis [1, 2].
VEPs to flash, pattern-reversal and onset stimulation can be used to assess the global activity
of the visual pathway. A recent advance has been seen with multifocal VEP, which can identify
spatial detail of the visual pathway [3]. Pattern electroretinography (PERG) makes it possible to
assess the central retinal ganglion cells, and the new method of photopic negative response
(PhNR) can also identify ganglion cell function in cases without good fixation. Optical coherence
tomography (OCT) is a new method that defines morphology of the retina, including the thickness of the retinal nerve-fibre layer. Thus OCT enables the detection of axonal loss in optic
nerve diseases, although its relationship to PERG and PhNR has yet to be established. In
clinical assessments of the visual pathway is of greatest importance to record both the PERG
and VEPs, first to define the function at the level of the macula and ganglion cells, before
localising the dysfunction within the visual pathway.
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Pattern VEPs (to pattern-reversal or pattern-onset stimulation), flash VEPs and sweep VEPs
are well established in clinical assessments, while motion VEPs, colour VEPs and multifocal
VEPs (mfVEP) are relevant in clinical research. For descriptions of these PERG and VEP
electrophysiological methodologies, it is recommended to follow the published standards and
guidelines from the International Society for Clinical Electrophysiology of Vision (ISCEV) and
the International Federation of Clinical Neurophysiology (IFCN).
Electrophysiological assessment can provide objective evidence of the visual pathway dysfunction,
and can also characterise the nature and severity of the disease (for review, see 4). VEPs
enable the detection of dysfunction in the optic nerve, optic chiasm and retrochiasmal pathway [5].
For pattern-reversal stimulation, due to its robustness and reproducibility, P100 is a relevant
marker that is used in clinical assessment of the visual pathway. The P100 has been shown to
originate from the primary visual cortex [6]. In addition, pattern-reversal VEP stimulation with
bigger visual fields and large 50-minute checks to half-fields show paradoxical lateralisation of
P100 [7], which needs to be properly addressed for clinical interpretation.
The use of visual electrophysiology is also essential for many other visual pathway diseases
(e.g. Leber’s hereditary optic neuropathy, non-arteritic anterior ischaemic optic neuropathy,
dominant optic atrophy), to demonstrate normal functioning in non-organic visual loss, or to
define possible visual pathway dysfunctions that are associated with congenital nystagmus. A
recent review from Holder et al. [4] demonstrated well the role of electrophysiology in detecting
and localising dysfunction within the visual pathway.
The aim here is to review electrophysiological assessment in optic neuritis, chiasmal compressive
lesions, achiasmia and ocular albinism.
OPTIC NEURITIS – THE ROLE OF PERG AND VEP
Optic neuritis is the initial manifestation in 38% of patients diagnosed with multiple sclerosis [8].
Optic neuritis can occur in patients who do not develop multiple sclerosis as a monophasic or
recurrent illness, with poor outcome in some [9]. According to a recent review by Plant [10] on
optic neuritis and multiple sclerosis, which is of outstanding interest, there is a group of disorders
that can cause optic neuritis, although they remain to be fully understood. In cases of neuromyelitis optica (NMO), where the patients have optic neuritis and myelitis without multiple
sclerosis, a serum autoantibody to aquaporin-4 water channels (the NMO IgG antibody) has
been detected. Patients with NMO can have recurrent optic neuritis and myelitis of a different
aetiology to multiple sclerosis, which is likely to be autoimmune. Visual prognosis in NMO is
worse than in multiple sclerosis, and the management of optic neuritis in NMO has shown that
rather than following treatment according to protocols used in multiple sclerosis, long-term
immunosuppression appears to be more appropriate [10, 11]. There are also cases of optic
neuritis that are isolated and recurrent but not associated with multiple sclerosis or myelitis (with
no NMO IgG antibody). Furthermore, in patients presenting with isolated optic neuritis, the
incidence of MRI abnormalities that are suggestive of multiple sclerosis is high in the regions
with the high prevalence of multiple sclerosis. Where multiple sclerosis is rare, non-multiple
sclerosis optic neuritis becomes more common. About 5% of patients with optic neuritis will
have a poor visual outcome [10]. A trial of optic neuritis treatment showed that the patient
baseline measures of contrast sensitivity, visual acuity and visual field loss were poor predictors
of visual outcome at 6 months, whereas the measures obtained 1 month from onset of symptoms
were more useful [12]. Plant [10] concluded that within days of onset of symptoms, the visual
function can be very poor even in patients who will recover well, although if the recovery is not
well advanced within 1 month then the prognosis for the visual outcome is worse. Optic neuritis
in children is rare, and is bilateral in 60% of cases, with both eyes affected simultaneously or
within 2 weeks, with good prognosis for visual recovery and no further events [13].
Although it was in the 1970s that Halliday discovery that the pattern-reversal VEP is delayed in
optic neuritis [1], the role of electrophysiology is still very relevant today. Optic neuritis serves as
a model to study the effects of optic nerve demyelination, remyelination, and subclinical demyelination. Electrophysiology can define dysfunction in optic neuritis as: (a) conduction block in optic
nerve axons; (b) prolonged conduction velocity due to demyelination of the optic nerve; (c) loss
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of optic nerve axons; (d) potential remyelination or subclinical demyelination of the optic nerve;
and (e) degeneration of retinal ganglion cells.
We now have considerable understanding of PERG and VEP abnormalities in acute optic neuritis
and in the recovery phase [4, 14]. These can be seen as:
1 At the acute stage of optic neuritis, visual impairment can arise as a result of inflammation,
blood-brain barrier leakage, or oedema, during which the optic nerve fibres also become
demyelinated. This causes an acute blockage of conduction and delayed conduction in a
proportion of the optic nerve axons. Therefore, the VEP P100 amplitude is reduced and
latency prolonged; in some cases there is also a PERG P50 reduction. The association of
VEP amplitude with visual acuity suggests that both measures are likely to be influenced by
the optic nerve axonal integrity, although temporal dispersion caused by demyelination can
also contribute to reductions in these measures [15].
2 Clinical recovery of optic neuritis is followed by the resolution of inflammation within a few
weeks, which can lead to restoration of conduction along the optic nerve and a consequent
improvement of vision. At this time, the demyelination process is also likely to have ceased.
Along with the visual acuity improvement, there is also recovery in the VEP amplitude, while
the VEP latency is prolonged due to demyelinated optic nerve fibres. The central fibres are
those that are most affected by demyelination [16]. Within a month of the onset of symptoms,
remyelination by oligodendrocytes starts at the edges of plaques. The subsequent shortening
of the VEP latency represents a sign of remyelination (an increase in the conduction velocity
of the optic nerve) that is not associated with visual function improvement [17]. Thus, the
VEP latency can remain abnormal for many years, while there is a tendency for it to shorten
over a period of 2 years or more. This is through the ongoing process of remyelination, which
serves to protect demyelinated fibres from degeneration [14].
3 In optic neuritis without visual recovery, axonal loss is the major factor that influences the
visual deficit. The VEP amplitude is reduced, and this reflects the axonal loss. Also, a PERG
selective N95 reduction after 4–6 weeks reflects retrograde degeneration of the retinal ganglion
cells (in 85% of patients) [18]. The visual deficit following optic neuritis is not necessarily
associated only with axonal loss in the optic nerve: a conduction block in axons that are
preserved but are extensively demyelinated can also be responsible for loss of vision [10].
The aim here is to inform the clinician about the role of electrophysiology in the assessment
of optic neuritis. Some of this understanding is based on our own previous studies [13, 19, 20].
PERG and VEPs can be helpful for our understanding of groups of optic neuritis disorders: (i) demyelinating optic neuritis, and the follow up of remyelination; (ii) non-demyelinating optic neuritis;
(iii) relapsing isolated optic neuritis, without multiple sclerosis and myelitis; (iv) neuromyelitis
optica; and (v) optic neuritis with poor outcome. Findings relating to optic neuritis are presented
in Figures 1–3. In a typical case of demyelinating optic neuritis without any clinical signs and
symptoms of a systemic disease, it is not needed to record PERG and VEPs. However, when
following recovery, electrophysiology can follow the processes of myelin destruction and repair,
or of possible axonal degeneration. Also, when diagnosing atypical optic neuritis, a comprehensive
assessment needs to be undertaken [9], which may include electrophysiology.
Of recent interest, there is the application of the new method of mfVEP, which obtains 60 or more
local VEP responses simultaneously over a region of the visual field similar to that tested with
standard behavioural visual fields. In a study where VEP (P100) and mfVEP were correlated in
patients with recovered optic neuritis, 73% of the affected eyes were identified as abnormal
according to the VEP P100 amplitude and/or latency, while 89% were considered abnormal when
mfVEP was used [21]. This suggests that mfVEP is more sensitive, although in this particular
study, the level of 73% for the VEP P100 was low compared to most other studies [10]. In a
further study, abnormal mfVEP latency was found in 100% of patients with optic neuritis related
to definite multiple sclerosis, and in 33.3% of those with optic neuritis without evidence of multiple
sclerosis [22]. This study suggests a dichotomy between these VEP findings in multiple sclerosisrelated optic neuritis and in non-multiple-sclerosis-related optic neuritis, which could indicate
that the pathology in some of the patients with non-multiple-sclerosis optic neuritis is not pri
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19
marily demyelination [10]. Local improvements in conduction velocity have also been seen for
mfVEP in patients with optic neuritis multiple sclerosis [23].
Fig. 1. Demyelinating optic neuritis
The PERG P50, N95 and VEP P100 are shown at the acute stage of isolated unilateral optic neuritis and
after recovery. At the acute stage of left eye optic neuritis, the P100 amplitude was reduced in association
with reduced vision, mostly as a result of a block of conduction in a portion of optic nerve axons. In parallel
with the improvement in the acuity level, the P100 amplitude increased, while the P100 latency was prolonged, reflecting delayed conduction due to demyelinated optic nerve fibres. Normal PERG recordings reflect
preserved retinal ganglion cell function.
Fig. 2. Relapsing optic neuritis without multiple sclerosis and myelitis
A 19-year-old boy with normal brain MRI was first recorded 3 months after optic neuritis of the left eye.
Visual acuity was low (0.2) and the P100 was reduced and delayed, indicating some axonal loss and
demyelination. However, from ophthalmological notes it was seen that his left eye visual acuity recovered
from 0.2 to 1.0. At the second recording, three month later, first his right eye visual acuity dropped for
counting fingers (CF), and within days his left eye dropped to 0.4; at this time, the P100 was bilaterally
reduced and delayed. When followed, he noticed slight visual acuity improvement in the right eye (CF to
0.1), but again it dropped (CF), and for the left eye it deteriorated (0.4 to CF). VEP recordings showed no
improvements, with P100 severely reduced/ undetectable from both eyes. Serial PERG recordings
showed deterioration for the right eye, while for the left eye they were at first reduced, then with further
recordings improved, until the last recording (8 months later) showing reduced PERG N95, indicating
retrograde degeneration of the retinal ganglion cells.
Patients presenting with optic neuritis for the first time can develop multiple sclerosis; as seen in
up to 75% of female patients, and 35% of male patients [9]. In multiple sclerosis, axonal loss is
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associated with chronic disability, and therefore an early correct diagnosis is relevant for effective
therapy [24]. In our own study, VEP was used to follow the treatment of relapsing-remitting multiple
sclerosis [25]. Also, it has been proposed that for patients with multiple sclerosis, prolonged
P100 latency can be used as a surrogate outcome measure for remyelination trials [26]. Recent
studies in optic neuritis and multiple sclerosis have described the anatomical features of the
retinal nerve-fibre layer, which is composed largely of unmyelinated axons of retinal ganglion
cells. Thinning of the retinal nerve-fibre layer can occur in patients with multiple sclerosis, both
with and without a history of clinical optic neuritis [27], suggesting that axonal loss contributes to
optic nerve atrophy following a single attack of optic neuritis [15]. The new electrophysiological
method of PhNR also allows the study of ganglion cell function [28], and in the future, it can be
used to identify axonal loss in optic neuritis.
Fig. 3. Neuromyelitis optica
A 16-year-old girl with normal brain MRI was first recorded one month after symptoms of right-eye optic
neuritis and still low visual acuity (counting fingers; CF).The VEP P100 amplitude was severely reduced.
One year later, she had neurological symptoms and an MRI of the spinal cord showed transverse
myelitis, with NMO antibody IgG detected. After two years, the VEP P100 amplitude still showed no
improvements for the right eye, paralleling the minimal improvement in her visual acuity. At the last
recording, when she suffered acute optic neuritis in her left eye, the P100 was abnormal in amplitude but
normal in latency; the VEP was also abnormal for the right eye. Also at the last recording, the PERG N95
was reduced for both eyes.
In summary, when following optic neuritis, combining PERG and VEPs with OCT changes in the
retinal nerve fibre layer can provide a measure of the loss or preservation of the optic nerve
axons. Furthermore, when disease-modifying drugs are considered in patients at high risk of
developing multiple sclerosis, VEPs can be used to monitor demyelination with preservation of
axons, or remyelination of the optic nerve.
TUMOURS AFFECTING THE OPTIC CHIASM – THE ROLE OF VEP HALF-FIELD
STIMULATION
MRI is the main investigational method in patients with suspected chiasmal compressive lesions.
Tumours compressing the optic chiasm can reduce visual acuity, affect the visual field, and cause
optic atrophy. Bitemporal hemianopsia is a classical visual field defect that is due to compression of the decussating fibres from the nasal retina (this occurs in < 50% of patients with pituitary
tumours), although other types of visual field defects can result, including central scotoma. Approximately 13% of patients present with unilateral visual loss [29].
The significance of electrodiagnostics in the assessment of chiasmal compression is well established and has also been summarised in recent reviews [4, 29]. In patients with unilateral visual
loss or atypical symptoms, the pattern VEP is sensitive enough to reveal early chiasmal involvement, even before there are any visual field defects. Also, pattern VEP is relevant in the followup and management of patients with MRI-confirmed tumours that show any suprasellar extension.
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The aim here is to review the role of pattern-reversal VEP to half-field stimulation in the assessment of compressive lesions of the optic chiasm. In patients who can maintain accurate fixation
and perform half-field stimulation adequately, half-field stimulation is more sensitive than fullfield stimulation. The results presented here are based on our own studies [30–36].
Tumours that compress the visual pathway at the chiasm can slow conduction or block conduction
completely or to a limited degree, which can progress to nerve-fibre loss. The VEP abnormalities
are evidently related to tumour size and localisation, and to the longitudinal compression of the
optic chiasm. When the visual loss is severe and visual field defects are extensive, the VEP can
even not be recordable. However, it appears that the VEP is sensitive to the effects of an early
compressive lesion at a time when the visual acuity and visual fields are normal.
The abnormality that involves VEP responses from both eyes is typically seen as a crossed asymmetry distribution (with pattern reversal, full-field stimulation of 16-degree radius, 50-minute
checks, and multichannel recording with Fz reference). In crossed asymmetry distribution, the
P100 for the right eye is recordable over the left hemisphere, and from the left eye, over the
right hemisphere (Figure 1 in 30; Figure 1 in 32; Figure 5 in 34). The crossed asymmetry identifies any dysfunction of the crossed optic nerve fibres at the chiasm from both eyes, and it correlates with temporal-field defects and bitemporal hemianopsia [7, 37]. Chiasmal compressive
lesions have also been associated with high incidence of delayed P100 (34% of patients; 17/50);
however, the magnitude of the delays was smaller (1–32 ms) compared with delays in patients
with demyelinating disease [33]. Compression of the optic chiasm can produce asymmetrical
distributions in the responses from one eye only, or a P100 reduction and an altered waveform
[30, 34]. The involvement of a compressive lesion that is lateralised to one side, posterior of the
optic chiasm, and affecting both eyes, can be detected through a VEP asymmetrical distribution,
and is seen as uncrossed asymmetry [7].
VEPs to half-field stimulation can be of considerable value in clarifying the localisation and type
of dysfunction at the chiasm. First, VEP abnormalities that are revealed only to temporal half-field
stimulation can indicate compression of the crossed fibres. On the other hand, VEP abnormalities in the temporal and nasal half-field responses can indicate compression of the crossed and
non-crossed fibres at the optic chiasm. Secondly, half-field stimulation can reveal abnormalities
that are not detected under full-field stimulation, as shown in Figure 4. Thirdly, half-field stimulation
assists in the interpretation of responses to full-field stimulation. An example is seen with crossed
asymmetry distribution to full-field stimulation, which is associated with abnormal responses to
temporal half-field stimulation and with normal responses to nasal half-field stimulation (Figures 1
and 2 in 30; Figure 1 in 32; Figure 5 in 34).
In chiasmal compression, VEP abnormalities to half-field stimulation can differ between the eyes;
for example, for the temporal half-field stimulation from one eye, the P100 might not be recordable
(revealing a block in conduction of the majority of the crossed fibres), while from the other eye
the P100 latency might be prolonged (revealing a delay in conduction of the crossed fibres
(Figure 1 in 33). A further situation is to find P100 abnormalities to temporal half-field stimulation
in the asymptomatic eye, and also to confirm expected abnormalities to temporal and nasal halffield stimulation in the symptomatic eye (Figure 2 in 33). This electrophysiological dysfunction is
associated with a tumour affecting the distal part of the optic nerve from one eye, and spreading
across the chiasm and affecting the crossed fibres from the other eye. A reverse situation is
also relevant, when MRI suggests a tumour at the chiasm symmetrically compressing the fibres
from both eyes, while the P100 abnormalities can indicate that only a single eye is affected
(Figures 7 and 8 in 36).
Subjective visual-field testing is not easy with many children, and therefore objective and noninvasive, pattern-reversal VEPs can be valuable for diagnosing chiasmal compressive lesions in
children. We have shown that reliable recordings for half-field stimulation can be obtained in 5year-old, or even younger, children, to show chiasmal visual-pathway compression (Figure 3 in
31). In children with tumours involving the visual pathway, much better evaluation and prognosis
of visual dysfunction is possible when ophthalmological, neuroradiological and electrophysiological
findings are combined [36]. Recent studies have also shown that flicker VEP measures (elicited
by 8 Hz sine-waves) are more sensitive than MRI in childhood optic nerve gliomas that also
involve the optic chiasm [38].
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22
Fig. 4. Compression at the optic chiasm
The VEP from a patient with a confirmed pituitary tumour with normal visual fields and normal visual
acuity, while with both eyes, the VEP P100 was normal for full-field and nasal half-field stimulation and
severely delayed for temporal half-field stimulation.
Serial monitoring can also follow the progress of VEP abnormalities in the absence of significant
neuroradiological changes [36, 39], such as the recovery to a normal VEP that takes place very
soon after decompression (as a surgical and/or medical therapy). In a patient with a pituitary
tumour, the VEP P100 was absent from both eyes for temporal half-field stimulation, which was
in agreement with the bitemporal hemianopsia; after bromocriptine therapy, the visual fields and
VEPs returned to normal [33]. New studies have also confirmed that mfVEP correlates well with
visual field defects in compressive optic neuropathy from chiasmal lesions [40]. Thus, mfVEP
can produce an objective map of the visual field, which in clinical testing can become an alternative to half-field stimulation.
Abnormal PERG correlates well with a lack of postoperative recovery [29]. Indeed, PERG N95
reduction demonstrates significant retrograde degeneration of the retinal ganglion cells [41], as
can be used to monitor patient cooperation [34].
In summary, pattern-reversal VEP is more sensitive than visual acuity and visual fields. Half-field
stimulation can identify dysfunction of the crossing fibres in tumours that compress the optic
chiasm, and it can be used to follow prior functional deterioration of the visual fields and of acuity,
and improvements after medical or surgical therapy. Simultaneous PERG recordings are also
relevant, to confirm the correct cooperation and fixation during recording, to define possible
retrograde degeneration of ganglion cells, and to provide a prognostic indicator of visual outcome. In children, VEPs to half-field stimulation are more informative than visual fields.
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23
ALBINISM AND ACHIASMIA – THE ROLES OF FLASH AND ONSET VEPS IN DETECTING
CONGENITAL ABNORMALITIES OF OPTIC-NERVE-FIBRE DECUSSATION
In humans, the optic nerve fibres that originate from the nasal part of each retina decussate at
the optic chiasm (the crossing fibres) and project into the contralateral hemisphere. Those optic
nerve fibres that originate from the temporal part of each retina do not decussate at the optic
chiasm (non-crossing fibres), and therefore they project into the ipsilateral hemisphere. Failure
of all or the majority of the nasal retinal fibres to decussate at the optic chiasm is a congenital
disorder that is known as achiasmia. Apkarian et al. [42] initially detected this decussation abnormality by demonstration of an inter-hemispheric asymmetry of the monocular VEP response
to flash and onset stimuli. The decussation abnormality was confirmed by MRI, and reported as
a non-decussating retinal-fugal fibre syndrome. On the other hand, in humans with oculocutaneous
and ocular albinism, it has been anatomically verified that there is an excess of optic nerve fibre
decussation at the chiasm, as the majority of the temporal retinal fibres also decussate into the
contralateral hemisphere [43]. VEP responses to flash and onset stimuli demonstrate this socalled albino misrouting [44]. Achiasmia and ocular albinism are both congenital disorders that
are accompanied by early onset nystagmus. In both of these disorders, there is a spectrum of
clinical findings, and therefore VEPs to flash and onset stimulation are relevant for establishing
early diagnosis.
In isolated achiasmia, brain MRI reveals the complete absence of the chiasm, with normal-sized
optic nerves and optic tracts; however, the spectrum of achiasmia includes the absence of the
chiasm and chiasmal hypoplasia in association with small optic nerves and optic tracts and abnormalities of non-visual-system structures (e.g. absence of the septum pellucidum and posterior
displacement of the bright spot, midline facial clefting disorders, encephaloceles of the skull
base, and agenesis of the corpus callosum). The ophthalmological findings in achiasmia are
best correlated with the status of the optic nerve: the optic disc is normal or hypoplastic; visual
acuity varies from near 20/20 to 20/200; multidirectional or see-saw nystagmus is present; with
normal colour vision. Visual field testing shows constriction, hemianopsia, arcuate scotoma, and
bitemporal hemianopsia (for reviews, see 45–47).
However, the presence of achiasma has been documented in relatively few case studies, and
the purpose here is to report four additional cases of achiasma associated with optic nerve
hypoplasia and to emphasize the diagnostic features of VEP testing [47, 48]. In all of four
achiasmatic children, stable VEP asymmetries were seen over time. Ipsilateral asymmetry was
apparent in three children to flash stimulation, and in two to onset stimulation. This ipsilateral
asymmetry distribution was seen as flash N2 and P2 waves and onset C1 waves for right-eye
stimulation recordable over the right hemisphere, and for left-eye stimulation the waves were
recordable over the left hemisphere (Figure 5).
Thus, ipsilateral asymmetry defines the lack of optic-nerve-fibre decussation, and might have
correlated with bitemporal hemianopsia in two of these children. In the fourth child, the VEP to
flash stimulation revealed uncrossed asymmetry. This uncrossed asymmetry was compatible
with a right optic tractus anomaly, and at the same time, it suggested that some of the optic
nerve fibres from the right eye did cross over at the chiasm (here, MRI revealed achiasmia and a
right optic tractus anomaly). In the two achiasmatic children, onset VEP was not recordable from
the eye with severe optic nerve hypoplasia.
When relying only on clinical examinations, it is sometimes not possible to be certain whether
an infant with nystagmus has ocular albinism [49]. In oculocutaneous and ocular albinism, where
visual pathway decussation is in excess at the chiasm, this is defined as contralateral asymmetry to flash and onset stimulation [50]. This contralateral asymmetry distribution is seen as
flash N2 and P2 waves and onset C1 waves for right eye stimulation recordable over the left
hemisphere, and for left eye stimulation the waves were recordable over the right hemisphere
(Figure 6). In our study, contralateral asymmetry was found in 14/14 children to flash stimulation
and to onset stimulation in 2/9 children with ocular albinism (the infants could not cooperate for
onset stimulation) [48].
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24
Fig. 5. Child with achiasma
With a 10-year-old boy, VEP ipsilateral asymmetry was found to flash and onset stimulation. The N2 and
P2 waves to flash stimulation, and the C1 wave to onset stimulation, were clearly defined for right-eye
stimulation over the right hemisphere, and for left-eye stimulation over the left hemisphere. Channels O1’O2 showed the interocular inverse polarity (positive peak from one eye, and negative peak from the other
eye), which was opposite between the flash and onset stimulation.
Fig. 6. Child with ocular albinism
With a 10-year-old boy, VEP contralateral asymmetry was found to flash and onset stimulation. The N2
and P2 waves for flash stimulation, and the C1 wave for onset stimulation, were clearly defined, for right-eye
stimulation over the left hemisphere, and for left-eye stimulation over the right hemisphere. For channels
O1’-O2’, there was interocular inverse polarity, which was opposite between flash and onset stimulation.
In summary, achiasmia and ocular albinism are congenital disorders that are associated with
early onset nystagmus and a variety of ophthalmological features. VEPs to flash and onset
stimulation are important adjuncts to the clinical diagnosis. In achiasmia with brain MRI confirmation, VEP ipsilateral asymmetry can confirm absent or reduced decussation of the optic
nerve fibres at the chiasm. In contrast, in diagnosing ocular albinism, VEP contralateral asymmetry can define an excess of optic nerve fibre decussation at the chiasm.
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25
CONCLUSIONS
In optic neuritis, chiasmal compressive lesions, achiasmia and ocular albinism, electrophysiology
can support clinical and MRI examinations, and can add a dimension of function. It can be seen
as: a conduction block of the optic nerve axons; a slowed conduction velocity due to demyelination
of the optic nerve; a loss of optic nerve axons; possible remyelination or subclinical demyelination
of the optic nerve; degeneration of retinal ganglion cells; abnormal conduction in the crossed
optic nerve fibres due to chiasmal compression; no decussation of optic nerve fibres at the
chiasm; and an excess of decussation of the optic nerve fibres at the chiasm in albinism. For all
of these dysfunctions, it is even more relevant that they can be detected when the clinical
findings are atypical or asymptomatic.
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42. Apkarian P, Bour LJ, Barth PG, Wenninger-Prick L, Verbeeten B. Non-decussating retinal-fugal fibre syndrome.
An inborn achiasmatic malformation associated with visuotopic misrouting, visual evoked potential ipsilateral
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48. Brecelj J, Šuštar M, Peþariþ-Megliþ N, Stirn-Kranjc B. Detection of optic nerve fibre decussation in children with
achiasmia and albinism according to visual evoked potentials, unpublished data.
49. Russell-Eggitt I, Kriss A, Taylor D. Albinism in childhood: a flash VEP and ERG study. Br J Ophthalmol 1990;
74: 136–40.
50. Dorey SE, Neveu MM, Burton LC, Sloper JJ, Holder GE. The clinical features of albinism and their correlation
with visual evoked potentials. Br J Ophthalmol 2003; 87: 767–72.
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27
THE RATIONAL USE OF ELECTROPHYSIOLOGY IN NEUROOPHTHALMOLOGY
Marko Hawlina
Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
INTRODUCTION
It would have seemed logical that electrophysiology would play a major part in the diagnosis of
neuroophthalmic disorders. It is, however, not entirely part of the first-line diagnostic workup for
a few reasons: although it may be sensitive, information gained by electrophysiology may not be
very specific, or may be false negative. False positive results would usually suggest poor technical
workup. Ordering inappropriate electrophysiological methods for certain obvious diseases will
yield false negative results, i.e. full field electroretinography (ERG) will invariably be normal in
subtle Stargardt or Best disease whilst visual evoked potentials (VEP) may be delayed, leading
to diagnosis of optic nerve disease. Also, VEP may be normal in segmental optic neuropathies
with good central vision which does not rule out optic nerve disease. It is also believed that electrophysiology is very demanding and time consuming diagnostics, requiring expensive equipment
and invasive electrode placement and that this diagnostics has largely lost its place in the times
of accurate morphological imaging such as OCT and MRI. These reasons are not valid as only
electrophysiology can objectively assess visual function and therefore it has its role in neuroophthalmology, especially in preverbal children. However, proper tests should be ordered and
interpretation should always be done in conjunction to other clinical findings and information.
UNEXPLAINED VISUAL LOSS
In working with patients with occult retinopathies and optic neuropathies, it is, even to an experienced clinician, often difficult to determine the site of lesion. A good number of patients may
present without any or with very subtle macular changes that can mimic optic neuropathies in
many ways. As a rule of thumb, simultaneously bilateral cases are more often associated with
macular dystrophies or toxic conditions whilst unilateral or sequential bilateral involvement is
more suggestive of optic neuropathies. Also, RAPD and dischromatopsia is more suggestive of
optic neuropathy than retinopaty. There are however exceptions to this rule where
electrophysiology is very important to set the correct diagnosis.
As an example, when a patient with unexplained visual loss comes to the clinic, the first questions
relates to age, gender, nature and dynamics of visual loss. Presentation predominantly in female
patients under 45 years that have experienced unilateral visual loss with pain at movement,
positive relative afferent pupillary defect (RAPD), dyschromatopsia and central or centrocecal
scotoma with or without papillitis would suggest demyelinating optic neuritis. Electrophysiology
will invariably confirm this with prolongation of VEP latency, therefore it is not needed for clinical
diagnosis in typical cases. However, in patients of over 45, optic neuritis should be regarded as
diagnosis of exclusion. In such atypical cases electrophysiology may importantly add to the
diagnosis, especially in evaluation of retinal input and optic nerve conduction in diseases with
subtle visual loss due to lesions not picked up by routine morphological methods.
As maculopathies are not diagnosed by the full field ERG, abnormal VEP may be erroneously
interpreted as optic neuropathy. It is only after introduction of pattern ERG (PERG) and most
recently, multifocal ERG (mfERG) in electrophysiological armamentarium that we can evaluate
macular input to the VEP. In this respect it is very important to note that mfERG shows the
contribution of outer retinal layers (photoreceptors and bipolars) whilst PERG also reflects
ganglion cell function. Therefore, mfERG will be typically normal in optic nerve lesions whilst
PERG may not be, especially if disease is of longer duration. It is believed that P50 wave of
PERG is mostly generated by the outer retina whilst the wave N95 is generated entirely by the
ganglion cells. Therefore, in the diseases of outer retina, P50 is usually more affected whilst in
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28
the optic nerve diseases, N95 wave is predominantly affected. This is for example seen with
Leber hereditary optic neuropathy where the wave N95 is affected first and foremost as the
marker of primary ganglion cell loss in this disease.
Posterior ischaemic optic neuropathy (PION) may be diagnosed by the VEP in the absence of
other morphological signs if central vision is affected.
There are a number of miscellaneous clinical pictures where electrophysiology is of crucial importance to set the correct diagnosis. Such cases are paraneoplastic, autoimmune, toxic and
nutritive retinopathies and optic neuropathies.
Certainly, malingerers or uncooperative patients can be also ruled out with electrophysiology if
objective documentation is needed.
FOLLOW UP OF THE PATIENTS WITH ESTABLISHED DIAGNOSIS
In long standing optic neuritis or optic neuropathy, PERG N95 wave will be affected as secondary
epiphenomenon to ganglion cell loss, which is very useful for follow-up as VEP may or may not
recover in these cases if central vision is preserved or restored. In these cases mfERG will rule
out outer retinal involvement. However, as mf ERG and PERG are relatively small signals
dependent on good fixation, such distinctions are only possible if recording technique is well
controlled.
Also, follow up of the patients that are at risk of losing vision is important aspect of indications,
such examples may be optic nerve sheath meningeoma, compressive thyroid ophthalmopathy
or infiltrative optic neuropathies. Electrophysiology is probably not adding to diagnosis in ischaemic
optic neuropathy as if central vision is affected in the presence of obvious ischaemic oedema,
VEP will be invariably affected. Interestingly however, segmental arteritic optic neuropathy,
either anterior or posterior, in temporal arteritis may not show VEP abnormalities if central vision
is preserved, so VEP in such conditions is not useful for follow up. In temporal arteritis, note of
Ishihara colour vision testing at presentation, not in the affected eye (in which colour vision is
usually lost) but most importantly in the good eye is crucial for later follow up and judging
possible disease reactivation.
In cases of increased intracranial pressure and papilloedema, electrophysiology usually does
not add to clinical diagnosis, however it may be of use to detect optic nerve affection in long
standing idiopathic intracranial hypertension resistant to medical treatment to suggest proper
timing for surgical intervention.
CONCLUSIONS
In many traditional settings, the notion of »ERG and VEP« still means full-field flash ERG and
pattern VEP. However, electrophysiological techniques today give us a wide variety of options
and indications dependent on the presumed diagnosis: to differentiate between maculopathy
and optic neuropathy, mfERG and/or PERG is needed whilst full field (rod, cone and 30 Hz
flicker) responses give information on global retinal function in cone or rod dystrophies or acquired
conditions. It is therefore very important to note that VEP should no longer be recorded in the
absence of PERG. Simultaneous PERG recording with the same stimulus as for the VEP is also
excellent indication of the retinal input to the VEP and can also be used to judge fixation and
cooperativity of the patient. It is, however essential to interpret electrophysiological findings in
the full clinical context, where distance and near vision, color vision, visual fields, OCT and
autofluorescence imaging play essential roles.
SUGGESTED READING
Griffiths PG, Ali N. Medically unexplained visual loss in adult patients. Curr Opin Neurol 2009; 22 (1): 41–5.
Brecelj J. Electrodiagnostics of chiasmal compressive lesions. Int J Psychophysiol 1994; 16 (2–3): 263–72.
Fishman GA, Birch DG, Holder GE, Brigell MG. Electrophysiologic testing in disorders of the retina, optic nerve, and
nd
visual pathway. 2 ed. San Francisco: The Foundation of the American Academy of Ophthalmology, 2001.
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29
Holder GE. Pattern electroretinography (PERG) and an integrated approach to visual pathway diagnosis. Prog Retin
Eye Res 2001; 20 (4): 531–61.
Hood DC, Odel JG, Chen CS, Winn BJ. The multifocal electroretinogram. J Neuroophthalmol 2003; 23 (3): 225–35.
Brecelj J, Stirn-Kranjc B. Visual electrophysiological screening in diagnosing infants with congenital nystagmus. Clin
Neurophysiol 2004; 115 (2): 461–70.
Holder GE, Gale RP, Acheson JF, Robson AG. Electrodiagnostic assessment in optic nerve disease. Curr Opin Neurol
2009; 22 (1): 3–10.
Lenassi E, Jarc-Vidmar M, Glavac D, Hawlina M. Pattern electroretinography of larger stimulus field size and spectraldomain optical coherence tomography in patients with Stargardt disease. Br J Ophthalmol 2009; 93 (12): 1600–5.
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30
PAEDIATRIC VISUAL ELECTROPHYSIOLOGY – METHODS AND
INDICATIONS
Dorothy Thompson
Great Ormond Street Hospital for Children, London, Great Britain
Abstract
Electrodiagnostic tests can elucidate the underlying cause of unexplained low vision and/or unusual eye movements
in infants and children. This is valuable as evidence from other tests may be lacking e.g. the fundus examination can
be normal, & the child will not cooperate with psychophysical tests. Electrodiagnostic tests are objective, can be
adapted to provide overlapping complementary data with minimal co-operation. They can distinguish retinal from
post-retinal problems; screen for additional defects in cases of amblyopia, and help distinguish functional overlay in
these cases. Electrodiagnostic tests can complement clinical examination by suggesting the need for further more
expensive or invasive tests. This might mean metabolic studies in the case of patient with an abnormal ERG or
neuro-imaging, e.g., CT or MRI scans, in the case of a patient with an abnormal VEP.
INTRODUCTION
My aim is to present alternatives ways of carrying out visual electrophysiology with children to
obtain meaningful answers to the clinical questions of children with minimal ‘stress’ to the child,
or yourselves. Underpinning this is the approach and philosophy underlying our visual electrophysiology clinic at Great Ormond Street Hospital for Children (GOS) where we exclusively see
infants and children under 16 yrs.
The notes below are ‘a back to basics’ that reiterate much of what has been covered already
but hopefully will fill in any gaps. A lay reader can use them, and the aim is to supplement the
case studies I shall discuss.
RATIONALE AND INDICATIONS
Understanding why a baby cannot fix of follow, or why an infant has nystagmus are clinical
challenges, not least because it is difficult to obtain reliable behavioural information in such
young patients. Visual electrodiagnostic techniques are especially useful in paediatric eyecare,
because they provide reliable objective indices of retinal and visual pathway function.
I shall first describe how we apply electrodiagnostic techniques to babies and young children in
our unit, and along the way describe alternatives used in different centers across the world.
With the aid of case studies I hope to show the range and type of clinical questions that we can
help to answer.
It is enormously important to discover the cause of poor vision in infants and children as early
as possible in the course of their visual development. Surgical and medical intervention has a
better chance of succeeding. Genetic counseling has most value at a time when parents maybe
considering more children. An early diagnosis will also give more preparation time both for
emotional acceptance and provision of the child’s future educational needs.
Children seen in practice with acuities of LogMAR 0.2–0.3 (6/9, 6/12) or worse can be difficult to
manage. We often worry whether we can attribute reduced acuity simply to a child’s performance
reading the chart or identifying a shape, or if amblyopia can reasonably explain the vision level,
or if something sinister is going on. Some of these patients may also have strabismus or nystagmus,
may have been seen many times, but show no improvement to patching therapy. Although
babies and younger infants who are visually unresponsive or have unusual eye movements
more obviously require further investigations, children of all ages can benefit from the same
electrodiagnostic tests.
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THE TESTS
In these children objective measures of visual function complement clinical measures by
determining where in the visual system a defect may be, and also by giving an estimate of
vision level (n.b. differs from acuity). We use the ERG and VEP simultaneously. As you know
the ERG assesses retinal function and the VEP detects the electrical signal sent by the retina
along the optic nerve, as it reaches the visual cortex (striate cortex recipient layer 4a). Used
together these two tests can examine the functional integrity of the afferent visual pathway from
front to back; retina to cortex, (the hardware) and identify if a defect is a retinal or post-retinal
problem. Each test involves the detection of bioelectric potentials by electrodes after a visual
stimulus has occurred. These are most valuable for children, because they are non-invasive
tests that can be carried out rapidly without sedation.
METHODS OF RECORDING IN CHILDREN
ISCEV recommends contact lenses electrodes for ERG recording, dilated pupils and minimum
dark adaptation times of 20 minutes. For infants and toddlers such protocols would most
probably require sedation and/ or restraint with its associated risks. The VEP changes with the
state of alertness and can be affected by sedation and the pattern VEP can be affected by any
cycloplegia accompanying pupil dilatation. The recommended protocol requires separate
recording sessions for the ERG and VEP.
The protocol chosen will depend on local philosophy, resources and overarching philosophy.
There is an effect of inhalation anaesthesia on b-wave amplitudes and time to peak which
persists 2+hrs after finishes e.g. Ioham et al Eut J Anaesth. It is therefore very important that
whichever technique is applied there are normative data banks and an understanding of
potential confounders for each technique.
At GOS we have adapted the Ganzfeld to tip over the table and can carry out full and extended
ISCEV ERG protocols under anaesthesia, but do so only occasionally. Whilst it can easy when
babies and children are asleep to use corneal electrodes, it is quite another matter to apply the
ISCEV protocol rigorously in alert toddlers. At GOS we take a pragmatic approach; we record
the ERG and VEP simultaneously to maximise information capture in the examination time. No
sedation is used, and skin electrodes are placed on the cheek below the eyelid for ERG
recording. Parents and carers can stay with the children at all time.
Electrode placement
We place 4 standard 3–5 mm EEG electrodes across the back of the head; the middle one
placed 3 cm above the inion, another on the inion. The bony prominence found by following a
line up from the base of the neck. The others are put either side of this, (for babies this can be
halfway between the ear and midline). If only one eye is stimulated the relative activity on these
3 electrodes can help detect hemisphere anomalies and chiasmal anomalies e.g. the misrouting
of fibres in albinism. These ‘active’ electrodes, both ERG and VEP, are referenced to one common, relatively inactive, ‘reference’ electrode positioned at the top of the forehead. An ‘earth’
electrode is placed on top of the head.
Preparation
We reduce skin impedance by cleaning the skin with a slightly abrasive lotion (Skinpure) applied
with a cotton wool bud or tissue. A sticky, conductive paste (Elefix) then holds the electrodes in
position. For facial electrodes we use disposable gel electrodes; if circular we trim the top for
straight edge under lower lid, alternatively strip electrodes are available. A stretchy headband
(Coban 3M) over the electrodes prevents them being rubbed off. All sticky stuff is washed off with
cotton wool and warm water at the end of the test. NB sometimes oils and emoillients are used
for skin and hair and more wiping than usually or addition of alcohol swab will be needed.
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Visual stimuli
The brain and retina are constantly active and generating electrical activity. To make sure that
we are detecting activity due to visual processing we need to stimulate the eye with a known
amount of light at a known time. A bright flash can penetrate the eyelids so can give us valuable
information even in a sleeping or crying baby. We use a hand held Grass strobe to give a light
flash; this allows us some flexibility in following the head movement of more active toddlers to
ensure the stimulation actually reaches the eyes! The bright flash can provide basic information
about mixed rod/cone retinal function and activation of the post-retinal pathway. The use of
coloured filters, and photopic and scotopic ambient lighting helps distinguish rod and cone
activity in the retina (red peak 670 nm Grass intensity 4 and, dim blue 450 nm Grass intensity 1
mean amplitudes around 13 µV).
Pattern stimulation provides a qualitative estimate of vision. The size of the VEP elicited by
small patterns determines the ‘VEP acuity’ estimate. The patterns are usually high contrast
black and white checks. These checks can counterphase, black squares change to white then
to black again aka pattern reversal, or they may appear and disappear from a uniform grey
background aka pattern onset.
Pattern onset is a more effective stimulus if eye movements are unstable, (e.g. nystagmus) or
the stimulus is actively defocused, but the VEP morphology changes throughout childhood. As a
guide we suggest good vision levels to 50’ checks reversal and moderate if 50’ onset VEPs are
robust, large and normal latency.
The ERG and VEP to each flash or pattern reversal are extracted from other bioelectric potentials,
i.e., ongoing EEG and muscle activity, by averaging. A computer stores the 300 or 500 ms of
bioelectric activity that immediately follows the visual stimulus as a voltage vs time plot. This
process is repeated up to 100 times. Any activity time-locked to the stimulus will add together
whilst other activity occurring randomly in time will cancel out.
The responses are small (2–20 µV) and are therefore amplified. (Use of contact lens for ERG
records responses around 300–500 µV). Filters are use to narrow the activity recorded so that it
includes the response, but excludes very slow drifts and high frequency muscle activity. This
helps to smooth and better define the response.
Recording eye movements
Electrodes placed on the inner and outer canthi record the electro-oculogram (EOG). The front
of the eye is more positive than the posterior pole and a potential difference occurs between inner and outer canthi when the eyes make a saccade. The size of the potential depends upon
the size of the saccade and state of light adaptation of the eye. It reaches a minimum after about
8 min in the dark ‘the dark trough’ and a maximum after some 10 min in the light ‘the light rise’.
The Arden index is the ratio of amplitude in the light/ dark. Normal values are greater than 1.8,
depending on test conditions. The EOG is a response summed across the retina. It reflects the
interaction of photoreceptor membranes and pigment epithelium. It is essential in the diagnosis
of RPE dysfunction e.g. bestrophin disease, Best’s disease, where characteristically the Arden
index is 1, and the ERG is normal. Abnormal EOGs also occur in advanced Stargardt’s, RP and
myopic chorio-retinal degeneration, but the ERG is variably abnormal in these cases.
Eye movement recordings using the electro-oculogram (EOG) can describe nystagmus graphically
as a voltage vs time plot. An ‘accelerating slow phase’ signature can distinguish sensory defect
and idiopathic nystagmus from other causes e.g. acquired neurological problems. Most patients
having nystagmus with accelerating slow phases, who are examined in our department have a
sensory cause, i.e. sensory defect nystagmus. These include those with anterior pathway
problems, e.g., congenital cataract, optic nerve hypoplasia, and retinal problems, e.g., congenital stationary night blindness, cone dysfunction, or foveal hypoplasia found in albinism.
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Adaptation for children
An infant sits on a carer’s lap and is cuddled and encouraged to co-operate. The protocol is
sufficiently flexible to allow feeding and drinking during the test. Pattern testing is routinely
carried out first in a darkened room. This typically takes 10–15 min. The child can regard the TV
any which way; sideways e.g. roll on bed, in arms, over shoulder with parent’s back to screen.
The TV has a large screen to increase the chances of presenting the stimulus to the child
(28 deg). We use 28 deg in addition to 14 deg for the PERG in children. We use a wide range of
check sizes, (400’–6.25’) for the pattern VEP to bracket the ISCEV standard, e.g. 50’ that can
withstand up to 8 dioptres defocus or uncorrected refractive error. We maintain attention by
interleaving the pattern stimuli with cartoon videos and music, and encourage fixation by
tapping toys and rattles on the top of the screen. The audio is dissociated from the DVD into
separate speakers so the same screen can be used for the cartoon and the audio provides
continuity of songs etc. The child’s fixation is monitored by a close circuit TV camera and
averaging only occurs during periods of adequate fixation. An artefact reject facility removes
very large potentials due to movement. Flash testing is then carried out under fully darkened
conditions and then photopically (exceeding 45 cd/m2).
Summary of methodological adaptation for children
ERG and VEP same session, and simultaneously for flash
Three trans-occipital electrodes as minimum
Skin electrodes for ERG (scaling)
(DTL deep set eyes, dense corneal or lenticular opacities babies)
Alternative ERG protocol:
Natural pupils
Coloured Grass flashes
ERG Averaging
Two people to record
CCTV fixation monitor
Ability to interrupt and resume recording
Video splitter or equivalent produce cartoons, music interleaved with stimulus
Audio separated for cartoon continuity during stimulus presentation
Noisy toys, n.b. attention directors vs distractors
Flexible positioning to stimulus, (over shoulder, rolled on lap etc) – moveable chair
Food and drink during test session
Heightened awareness state of infant alertness
Slower stimulation rates under 6 weeks of age (e.g. 1/sec)
Maturational normative data.
Although eye movement recordings to characterise nystagmus can be successfully carried out
in neonates, routine EOG testing to establish an Arden index is unlikely to be successfully completed in children under 6 yrs. It can take 30 min, with 15 min dark adaptation, 15 min in the light
and saccades every 2 min. The vestibular reflex may be used in children. Similarly mfERG is
likely only in older children able to maintain fixation. For PERG we use two field sizes to enhance
information capture of central and peripheral retina.
RESPONSE ANALYSIS
ERGs and VEPs are produced as voltage size vs time graphs. The traces are analysed by the
shape, amplitude and time to peak of positive and negative peaks and also by the distribution of
the response over the occipital electrodes.
An ERG is characterised by a negative a-wave, from photoreceptors and positive b-wave from
the inner retina (depolarizing on-bipolars). ERG shape, size and b-wave time to peak change
according to light adaptation. The rod driven b-wave is later, larger and rounder, than the cone
mediated photopic ERG, which has a b-wave latency of 30–33 ms.
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The flash VEP is characterised by a positive peak at around 90–100 ms, but other components
are important especially on the lateral channels, e.g. in albinism. The pattern reversal VEP is
characterised by positive peak at 100 ms termed p100. This will increase in latency with uncorrected refractive errors and to smaller check sizes. The pattern onset VEP in infants is characterised
by large positivity. Towards adolescence the response morphology matures and becomes more
complex with 3 peaks p-n-p termed Cl, CII, and Clll, respectively. For this reason we prefer to
use pattern reversal VEP as a standard test, especially for serial monitoring, but pattern onset
can be a more effective stimulus in patients with nystagmus.
Consistency
The stimulus trials are repeated for consistency to each stimulus and across ranges of stimuli.
Non-stimulus trials are important in paediatric recording, particularly against a background of
large amplitude background EEG activity.
Response maturation
It is very important to compare a patient’s response with age appropriate normal responses.
Maturation of retinal organization, receptor sensitivity to light, pathway myelination, and cortical
synapses means that response latencies are slower in the newborn and the ERG is smaller,
(mixed rod cone flash grass intensity 4 a–b amplitude 25 µV in babies over 6 m, in infants
1 month age ERG broad and less than ½ this amplitude). In the newborn (under 6 weeks) the
VEP occurs at 150–240 ms and a slower stimulation rate of 1/s and time window of 500 ms
gives better-defined responses. Around six months of age response latencies approach adult
values for flash and pattern reversal 100’ and 50’ checks.
Macula representation in the PVEP – Transoccipital scalp distribution of the VEP
The macula maps to the tip of the occipital pole, closest to the midline electrode and dominates
the pattern VEP. Right and left half visual fields are represented on opposite hemispheres on
abutting sides of the calcarine sulcus. If both fields are stimulated together the electrical activity
on each side of the calcarine sulcus will sum together, and the biggest response will occur on
the midline electrode. A paradoxical localisation occurs with the large stimulus fields used for
children. The response from the left occipital electrode reflects activity from the right hemisphere,
the left half field. If the contribution from each hemisphere is unequal the largest response
occurs on a lateral electrode. This is an asymmetrical distribution. If the same asymmetry in
scalp distribution occurs if either eye is stimulated, it is termed ‘uncrossed asymmetry’. This
suggests a hemispheric dysfunction.
If the asymmetry in scalp distribution reverses when the other eye is stimulated it is termed
‘crossed asymmetry’. This distribution suggests that there is a chiasmal anomaly, e.g., misrouting of temporal retinal fibres in albinism (too many cross at the chiasm). A crossed asymmetry of flash VEP components (contra-lateral negativity around 80 ms) and the pattern onset
VEP (contra-lateral positivity MF ref) in older children, are pathognomic of albinism. A bitemporal
hemianopia will also result in a crossed asymmetry.
CLINICAL RESULTS
The more commonly encountered conditions in younger children are noted below. For visually
unresponsive infants and babies consider
x delayed visual maturation DVM
The infant is visually unresponsive until an abrupt onset of rapid improvement between 4–6
months. DVM can occur in isolation, when the infant will have normal ERG and pattern VEP
findings for age. It can occur also in association with other neurological or ophthalmic
problems. It may relate to a delayed development in extra-striate cortical structures and
attentional mechanisms. More simplistically an infant with visual problems may take longer to
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35
learn to use the vision they have. DVM is a diagnosis of exclusion: the infant needs to reach
adulthood without any subtle manifestation of neurological impairment before the diagnosis fits.
x ocular motor apraxia or congenital saccade initiation failure
The infant cannot make saccades and cannot make an orientating response of the eyes to a
target so appears not to fix or follow. It takes time for head-thrusting and blinking strategies
to develop.
x nystagmus
A roving almost triangular eye movement can precede the onset of frank nystagmus in the
first weeks of life.
Preretinal conditions
The bright flash ERG and VEP can give an indication of the functional integrity of the retina and
visual pathway in situations where the fundii are obscured. A bright flash will penetrate all, but
the most dense opacities, e.g., in cases of congenital cataract, hyperplastic primary vitreous
syndrome (PHPV), cryptophthalmos, anterior segment dysgenesis, and to judge the extent of
macula involvement in coloboma. Also useful to gauge the degree of visual impediment using
the pattern reversal VEP in corneal opacification e.g. deciding point to graft in congenital
hereditary endothelial dystrophy (CHED), intervene with congenital cataract.
Retinal dysfunction
x early onset severe retinal dystrophy EOSRD Lebers amaurosis
This is associated with hyperopia, roving eye movements, and eye poking. It is a severe retinal
dysfunction that affects both rods and cones. The mixed rod/cone ERG is extinguished or
severely attenuated. A small flash VEP is variably detected. Some phenotypic varaiability
e.g. OCT thick retina CRB1, residual ERG and variable preservation of pattern VEP.
x congenital cone dystrophy, achromatopsia, rod monochromatism
This is associated with nystagmus and photophobia. Cone mediated ERGs, (photopic, red
flash and flicker), are reduced or extinguished. Red scotopic flashes useful if photophobic.
x X-L congenital stationary night blindness
Boys with this condition usually are myopic, may have nystagmus and < 0.3 vision. The ERG
shape is described as negative: b-wave amplitude is reduced a-wave amplitude is preserved.
The defect lies at the junction receptors and inner retina. A negative ERG is also found in
boys with X-linked retinoschisis although fundal changes are characteristic in this condition.
Also AR CSNB i.e. girls.
x pigmentary retinopathy
This can occur in association with many metabolic, neurometabolic and other systemic
conditions. The ERG will be attenuated. Rod mediated ERGs are affected initially more than
cone ERGs. ERG changes can precede fundal changes. Association with kidney problems,
deafness e.g. cliliopathies.
The monocular flash and pattern VEP findings in post-retinal dysfunction
The VEPs are degraded and attenuated in cone dysfunction or in maculopathies, because of
the predominant contribution of the macular pathway to the VEP response at the occiput, (the
cone ERG is abnormal and the pVEP increased time to peak can be a complementary clue).
Optic nerve integrity
x optic nerve hypoplasia
The VEP is variably attenuated depending on the severity, but ERG is normal. If very severe
the child may have nystagmus. It is associated with other midline abnormalities. The child
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36
may be small for age, with growth retardation. It has also been associated with maternal
diabetes.
x dys- or demyelination
This affects nerve conduction and will delay the arrival of the electrical signal at the cortex
and be detected as an increase in the latency of the VEP. Childhood optic neuritis is
associated with a greater recovery to normal VEP latencies than optic neuritis in adults (90%
adults retain some delay on recovery) and is clinically considered a different disease.
x optic atrophy
With fewer functioning nerve fibres the VEPs are small and delayed. The severity of the optic
nerve compromise will reflect in the amount of VEP attenuation.
Chiasmal defects
These are associated with a crossed asymmetry in occipital distribution of the VEP:
x albinism
This can be a common cause of nystagmus, worthwhile check for iris transillumination and
foveal hypoplasia and examining parent’s fundi.
x compressive effects: gliomas (neurofibromatosis NF1), craniopharyngiomas
A recent review of 13 patients with craniopharyngiomas treated for strabismus showed 8/13
were concomitant. One of these children had a VEP when vision did not seem to improve
with patching. This revealed a crossed asymmetry suggesting a bitemporal field defect that
led to an MRI scan locating the tumour.
x achiasmia
This is rare, associated with midline developmental abnormalities and see-saw nystagmus –
or there is a spectrum of other type of nystagmus.
Hemisphere dysfunction
These are associated with an uncrossed asymmetry in occipital distribution of VEP.
QUALITATIVE ASSESSMENT OF VISION AND VISUAL ACUITY
The size of the pattern VEP to a range of check sizes we can give a qualitative idea of visual
acuity. A large well-defined VEP recorded to the smallest checks suggests that vision is good. A
degraded flash VEP and the absence of a consistent pattern VEP suggests only rudimentary
vision levels, but nevertheless is evidence of post-retinal activation. The VEP provides useful
information about children with communication difficulties, e.g., in cerebral palsy, which has
relevance for education and stimulation. Consider spatial tuning of the pVEP in hand with contrast
sensitivity curves.
The sweep VEP is an alternative fast method of presenting progressively smaller pattern sizes.
20–40 s of cumulative good fixation is needed to record a transient pattern reversal VEP. For sweep
VEPs the stimulus rapidly counterphases, e.g., 8 or 16 times /second, and every second the
pattern size decreases. 8 pattern sizes are presented in 8 seconds of fixation. Response amplitude
is plotted against pattern size and a regression is used to estimate the pattern size when no
response is detectable i.e. zero voltage or the noise level. Which is the sweep VEP acuity.
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37
26th Dr. anez Faganel Memorial Lecture
FACE
ECO NITION- ELATED OTENTIALS:
EE , ME , NI S STUDIES
Ryusuke akigi, ensaku Miki, Shoko Watanabe, ukiko
Minoru oshiyama, Emi Tanaka
onda,
Department of Integrative Physiology, National Institute for Physiological Sciences, Okazaki, Japan
Department of Physiological Sciences, School of Life Sciences, The Graduate University for Advanced Studies,
Hayama, Kanagawa, Japan
We have studied human face perception, mainly using electroencephalography (EEG) and
magnetioencephalography (MEG), that is, visual evoked potentials (VEPs) and fields (VEFs),
respectively 1– . Several recent topics for human face perception done in my department will
be introduced briefly.
COMMON CO TICAL
ES ONSES EVO ED Y A EA ANCE, DISA
CHAN E OF THE HUMAN FACE
EA ANCE AND
To segregate luminance-related, face-related and non-specific components involved in spatiotemporal dynamics of cortical activations to a face stimulus, we recorded cortical responses to
face appearance (Onset), disappearance (Offset), and change (Change) using magnetoencephalography 6 . Activity in and around the primary visual cortex (V1/V2) showed luminancedependent behavior. Any of the three events evoked activity in the middle occipital gyrus (MOG)
at 1 0 ms and temporo-parietal junction (TP ) at 2 0 ms after the onset of each event (Figure 1).
Fig. 1. Multi-dipole model of VEFs following onset stimulation of face. Six regions are activated
sequentially. LG: Lingual gyrus, Lateral gyrus, MOG: Middle occipital gyrus, FG: Fugiform gyrus,
TPJ: Temporo-parietal junction, L & R: Left and Right hemisphere (adapted from [6]).
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Onset and Change activated the fusiform gyrus (FG), while Offset did not. This FG activation
showed a triphasic waveform, consistent with results of intracranial recordings in humans.
Analysis employed in this study successfully segregated four different elements involved in the
spatio-temporal dynamics of cortical activations in response to a face stimulus. The results
show the responses of MOG and TP to be associated with non-specific processes, such as the
detection of abrupt changes or exogenous attention. Activity in FG corresponds to a face-specific
response recorded by intracranial studies, and that in V1/V2 is related to a change in luminance.
EFFECTS OF FACE CONTOU AND FEATU ES ON EA LY OCCI ITOTEM O AL
ACTIVITY HEN VIE IN EYE MOVEMENT
We investigated whether the early activity in the occipitotemporal region, corresponding to
human MT/V , is influenced by a face contour and/or features such as the mouth using magnetoencephalography (MEG) 7 . We used apparent motion as visual stimuli and compared four
conditions, as follows:
1. CDL: A schematic face consisting of a face Contour, two Dots and a horizontal Line
2. CD: The Contour and two Dots
3. DL: Two Dots and a horizontal Line and
4. D: Two Dots only (Figure 2).
Fig. 2. The course of stimulus presentation in the four conditions. (1) CDL: Schematic face consisting of a
Contour, two Dots and a horizontal Line, (2) CD: the Contour and two Dots, (3) DL: two Dots and a horizontal Line and, (4) D: two Dots only. Filler, which consisted of a scrambled image of the S1 stimulus
in the CDL condition, was presented between each stimulus session (adapted from [7]).
Subjects described a simple movement of dots for D, but eye movement for CDL, DL and CD,
though movement modalities were the same through all conditions. We used a single equivalent
current dipole (ECD) model between 14 –220 ms after stimulus onset and estimated the
location, dipole moment (strength) and peak latency. There were no significant differences in
the peak latency of the estimated dipoles between each condition, but the activity was
significantly stronger for CDL than for CD (p 0.0 ), DL (p 0.01), and D (p 0.01) in the right
hemisphere, and DL and D (p 0.01) in the left (Figure 3). These results indicated that there is
specific information processing for eye movements in the occipitotemporal region, the human
MT/V homologue, and this activity was significantly influenced by whether movements
appeared with the face contour and/or features, in other words, whether the eyes moved or not,
even if the movement itself was the same.
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39
Fig. 3. The upper image shows the waveforms recorded from 204 gradiometers of a representative
subject following S1 onset (static stimuli) in CDL condition. The head is viewed from the top, and in each
response pair, the upper trace illustrates the field along the latitude and the lower trace that along the
longitude of gradiometers. The lower image shows waveforms at sensors A and B in the upper image,
which showed a clear component in each hemisphere, horizontal and vertical eye movement is recorded
in red for CDL, blue for CD, light blue for DL, and green for D. A: representative waveforms at sensor A
on the right hemisphere of the upper image. : representative waveforms at sensor B on the left of the
upper image. Hori ontal: horizontal eye movement in all conditions. Vertical: vertical eye movement.
Black arrows show S1 onset and white arrows the response chosen for further analysis. Responses after
the onset of S1 are clearly larger in amplitude and shorter in latency in the CDL and CD than DL and D
in this subject (adapted from [7]).
FACE E CE TION IN INFANTS MEASU ED Y NEA INF A ED S ECT OSCO Y (NI S)
We have studied infants’ brain activity in response to faces using NIRS, which can non-invasively
record hemodynamic changes of the brain. NIRS is particularly useful for recording in infants,
since recordings can be made, even while the infants are awake, without fixing their body and
brain (Figure 4) 8–10 . For this objective, we used newly developed sensor probes of NIRS for
recording in infants. We measured changes in cerebral oxygenation in ten –8-month-olds’ left
and right lateral areas while they were looking at upright and inverted faces.
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40
The results are summarized as follows:
1. the concentration of oxyhemoglobin (oxy- b) and total-hemoglobin (total- b) increased significantly in the right lateral area during the upright face condition
2. the concentration of total- b in the right lateral area differed significantly between the upright
and inverted conditions
3. hemodynamic changes were maximal in the temporal region, probably in the superior temporal
sulcus (STS) in both hemispheres, and
4. the right hemisphere seems to be more important for recognizing upright faces. This is the
first evidence showing that there is an inter-hemispheric difference on the effect of face inversion in the infant brain using a hemodynamic method.
Fig. 4. An infant looking at face with NIRS probe.
VE AND VEF TO SU LIMINAL FACE STIMULATION
We have investigated the effects of subliminal stimulation on visible stimulation to demonstrate
the priority of facial discrimination processing 11–13 , for example, using a unique, indiscernible,
color-opponent subliminal (COS) stimulation. We recorded event-related magnetic cortical fields
(ERF) by magnetoencephalography (MEG) after the presentation of a face or flower stimulus
with COS conditioning using a face, flower, random pattern, and blank. The COS stimulation enhanced the response to visible stimulation when the figure in the COS stimulation was identical
to the target visible stimulus, but more so for the face than for the flower stimulus. The ERF
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41
component modulated by the COS stimulation was estimated to be located in the ventral temporal
cortex. We speculated that the enhancement was caused by an interaction of the responses
after subthreshold stimulation by the COS stimulation and the suprathreshold stimulation after
target stimulation, such as in the processing for categorization or discrimination. We also speculated that the face was processed with priority at the level of the ventral temporal cortex during
visual processing outside of consciousness.
INTERHEMISPHERIC DIFFERENCE FOR UPRIGHT AND INVERTED FACE PERCEPTION
IN HUMANS
It is difficult for humans to comprehend inverted face compared with other inverted objects, and
this phenomenon is termed “face inversion effect” [5]. To investigate interhemispheric difference
for upright and inverted face perception in humans in detail, we analyzed face-specific N170
component of event-related potentials (ERPs) by presenting upright and inverted unfamiliar
faces in the left or right visual hemifield in healthy subjects [14]. In the right hemisphere after the
stimulus was presented in the left hemifield, the N170 was longer in latency and larger in amplitude for inverted faces than upright faces, but such finding was not clearly identified in the left
hemisphere following stimulation of the right hemifield stimulation. N170 in the right hemisphere
showed double peaks, when the inverted face was presented in the left hemisphere, but did not
in other conditions. N170 recorded from the hemisphere ipsilateral to the stimulus hemifield
showed also new and unique findings. Therefore, we hypothesized that at least two temporallyoverlapping activities were generated in the right hemisphere only when the inverted face was
presented in the left hemifield. The summation of these activities causes an increase in amplitude and delay in latency of N170, that is, the “face inversion effect”.
EFFECT OF CONFIGURAL DISTORTION ON A FACE-RELATED ERP EVOKED BY
RANDOM DOTS BLINKING
Using random dots blinking (RDB), which reflects the activity of the higher visual area related to
face perception, the following stimuli were presented:
1. Upright: a schematic face;
2. Inverted: the Upright stimulus inverted, and
3. Scrambled: the same contour and features as in Upright but with the spatial relation distorted [15].
Clear negative components (N-ERP250) were identified at approximately 250 ms after stimulus
onset. At the T5 and T6 electrodes, the peak latency was significantly longer for Inverted and
Scrambled than for Upright. At the P4 electrode, the maximum amplitude was significantly larger
for Scrambled than for Upright and Inverted. These results indicate that the delayed latency for
Inverted and Scrambled reflects the involvement of the additional analytic processing caused by
the configural distortion, and that the increase in amplitude for Scrambled indicates the existence
of further processing caused by the distortion of the spatial relationship between the contour
and features.
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12 Hoshiyama M, Kakigi R, Takeshima Y, Miki K, Watanabe S. Priority of face perception during subliminal stimulation using a new color-opponent flicker stimulation. Neurosci Lett 2006; 402: 57–61.
13 Hoshiyama M, Kakigi R, Takeshima Y, Miki K, Watanabe S. Differential priming effects of color-opponent subliminal
stimulation on visual magnetic responses. Hum Brain Mapp 2006; 27: 811–8.
14 Honda Y, Watanabe S, Nakamura M, Miki K, Kakigi R. Interhemispheric difference for upright and inverted face
perception in humans: an event-related potential study. Brain Topogr 2007; 20: 31–9.
15 Miki K, Watanabe S, Takeshima Y, Teruya M, Honda Y, Kakigi R. Effect of configural distortion on a face-related
ERP evoked by random dots blinking. Exp Brain Res 2009; 193: 255–65.
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THE ANATOMY AND PATHOPHYSIOLOGY OF EYE MOVEMENTS
Christopher Kennard
University of Oxford, Oxford, Great Britain
INTRODUCTION
Many different disease processes affecting the central nervous system, from the brainstem to
the cortex, can give rise to supranuclear disorders of eye movements. Examination of eye
movements offer a number of advantages to the neurologist over skeletal movements. These
include: eye movements are directly related to the activity of brainstem neurons since the
extraocular muscles lack a stretch reflex; eye movements have limited degrees of freedom so
that disordered movements lend themselves to analysis (clinical or quantitative) in three planes,
horizontal, vertical and torsional; finally there are several functional classes of eye movements,
each with special physiologic properties that suit a particular purpose and which have a separate
and well segregated neural substrate. This enables the clinician to examine each of these
various types of eye movements and identify abnormalities which can then provide information
regarding anatomical, physiological and pharmacological lesions.
BRAINSTEM AND CEREBELLAR DISORDERS
Anatomy and physiology of horizontal and vertical gaze
There are two main features of the brainstem neural control of horizontal and vertical gaze: an
anatomic separation so that the neural substrate for horizontal gaze is located in the pons and
for vertical gaze in the midbrain, and the requirement to overcome viscous drag and resist elastic
restoring forces in the orbit when making dynamic eye movements. An understanding of the
neural mechanisms which generate a horizontal saccade will serve as an illustration of the
principles involved. A rapid phasic contraction of the extraocular muscle e.g. lateral rectus muscle,
is required to overcome the orbital viscosity, and a rapid, high frequency burst of nerve impulses,
the pulse, is transmitted to the muscle via the ocular motor nerve, in this example the abducens.
The premotor inputs to the motor neurons in the abducens nucleus arise from neurons in a
region of the reticular formation which lies ventral and anterior to the nucleus, the paramedian
pontine reticular formation (PPRF). The equivalent premotor region for vertical gaze is the
rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) in the midbrain, rostral to
the oculomotor nucleus at the level of the red nucleus. The pulse, a velocity signal, is generated
by cells called burst neurons, and must be of an appropriate size to ensure that the fovea of the
eye is aligned to the target. Once the saccade has been completed it is necessary to maintain
the new position of the eye against orbital viscoelastic restoring forces. The muscle must, therefore, now maintain a sustained tonic contraction to counter these forces and this is achieved by
the tonic innervation, the step, which is a position signal the motor neuron receive from so-called
integrator neurons (which integrate the step in a mathematical sense) lying in the nucleus
prepositus hypoglossi and the medial vestibular nucleus. The pulse and step must be perfectly
matched to prevent drift of the eye back to the primary position at the end of the saccade. Faulty
neural integration leads to an inadequately maintained step, and after a saccade the eye drifts
back in an exponential manner due to the unopposed orbital elastic restoring forces, followed by
a saccade to refixate the target. This pattern leads to gaze-evoked nystagmus and is observed
in cerebellar disease and anticonvulsant or sedative intoxication. An abnormal pulse may either
be of reduced duration or of reduced firing frequency. If the step is appropriately matched to the
abnormal pulse a reduced duration will result in a reduced amplitude (hypometric) saccade,
whereas if the firing frequency is reduced a saccade of reduced velocity but of normal amplitude
will be generated.
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The final neuron in the brainstem involved in saccade generation is the omnipause neuron,
located in the raphe interpositus nucleus (RIP). These neurons are tonically active and pause
before saccades in any direction. They are presumed to inhibit the burst neurons from firing
except when a saccade is required.
Abnormalities of horizontal eye movements
The abducens nucleus contains two populations of neurons, motor neurons innervating the
ipsilateral lateral rectus muscle and interneurons. The abducens nucleus is, therefore, the final
common pathway for horizontal gaze. The axons from the interneurons cross the midline and
ascend in the medial longitudinal fasciculus (MLF) to the contralateral medial rectus subdivision
of the oculomotor nerve nucleus. The final instructions for horizontal conjugate eye movements,
therefore, lie within the abducens nucleus itself, so that its activation results in an ipsilaterally
directed horizontal conjugate gaze movement.
Unilateral horizontal gaze palsy. A lesion of the abducens nucleus will result in a horizontal
gaze palsy for all types of ipsilateral conjugate eye movements (saccades, pursuit and vestibular). Vergence movements of the eyes are spared, however, so that adduction is possible with a
near stimulus. The palsy is usually associated with a ipsilateral lower motor neuron facial nerve
palsy, due to involvement of the genu of the facial nerve, which passes around the abducens
nerve. A selective horizontal gaze palsy involving all saccades, including the quick phases of
vestibular and optokinetic nystagmus, occurs when the lesion involves the PPRF in isolation,
since the vestibular and pursuit inputs pass directly to the abducens nucleus and are therefore
spared. The commonest causes for horizontal gaze palsies in adults are either vascular infarction
or haemorrhage in the distribution of the pontine paramedian penetrating arteries arising from
the basilar artery, demyelination, cavernous angiomas, or trauma. In children medulloblastomas
or pontine gliomas are the commonest aetiologies.
Bilateral horizontal gaze palsy. A bilateral pontine lesion involving the PPRF can cause a bilateral selective saccadic palsy with preservation of vestibular and optokinetic eye movements.
Such a lesion may impair vertical eye movements since signals for vertical vestibular and smooth
pursuit eye movements ascend in the MLF and other pathways through the pons. The commonest
causes of a bilateral horizontal gaze palsy, with sparing of vertical gaze, are neurodegenerative
diseases such as Huntington's disease or Gaucher's disease. In a patient presenting solely with
a gaze palsy other possible causes including the Miller Fisher variant of Guillian-Barre syndrome,
myasthenia gravis, Wernicke’s encephalopathy and thyroid disease.
Internuclear ophthalmoplegia. A lesion of the MLF produces an internuclear ophthalmoplegia
(INO), in which there is weakness of adduction ipsilateral to the side of the lesion. In a partial
INO adduction will be slowed, but will be completely absent in a complete lesion. Since the
fibres of the MLF carry the horizontal gaze commands subserving all types of conjugate eye
movements, this adduction paresis involves not only saccades but pursuit and vestibular eye
movements. The presence of intact convergence in the absence of voluntary adduction implies
that the medial rectus subdivision of the oculomotor nerve is intact, and that the INO is due to a
caudal lesion. Cogan (1970) called this a posterior INO in contrast to patients with an INO and
absent convergence which he called 'anterior'. However, such patients do not necessarily have
a lesion involving the medial rectus subdivision of the oculomotor nucleus.
The second major feature of an INO is the nystagmus on abduction in the contralateral eye.
This consists of a centripetal (inward) drift, followed by a corrective saccade. Several different
mechanisms have been proposed to explain the abducting nystagmus. These include, (a) a
gaze-evoked nystagmus, (b) impaired inhibition of the medial rectus contralateral to the lesion,
(c) an increase in convergence tone, (d) in response to the adduction weakness an adaptive
increase in innervation to the adducting eye, which because of Hering’s law of equal innervation
results in a commensurate change in the innervation to the abducting eye which leads to overshooting and postsaccadic drift giving the appearance of abducting nystagmus. The latter is
generally considered the most appropriate explanation.
A skew deviation (a vertical misalignment of the visual axes due to a disturbance of prenuclear
inputs) is often observed in patients with a unilateral INO, with the higher eye usually on the
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side of the lesion. Patients with bilateral INOs have bilateral adduction weakness and abducting
nystagmus. In addition, they also have impaired vertical pursuit and vestibular eye movements,
and impaired vertical gaze holding with gaze-evoked nystagmus on looking up or down.
Patients with an INO are usually asymptomatic, although if there is a complete adduction failure
they may complain of diplopia especially during shifts of horizontal gaze. Occasionally they may
complain of oscillopsia. A number of different aetiologies lead to an INO, but if unilateral the
commonest is ischemia, and if bilateral demyelination associated with multiple sclerosis.
One-and-a-half syndrome. A combined lesion of the abducens nucleus or PPRF and the adjacent MLF on one side of the brainstem results in an ipsilateral horizontal gaze palsy and INO.
The only preserved horizontal eye movement is abduction of the contralateral eye, and the
condition is therefore termed the 'one and a half' syndrome. Although the majority of patients
have no deviation or an esotropia in the primary position of gaze, some patients may habitually
fixate with the horizontally immobile ipsilesional eye, which results in exotropia of the contralesional eye that has intact abduction. This condition is called paralytic pontine exotropia. Convergence is often preserved. Some MLF lesions cause an adduction palsy due to INO that is
bilateral and and result in exotropia in the primary position, termed a 'wall-eyed' bilateral INO
(WEBINO).
The main causes of a one-and-a-half syndrome are brainstem ischemia, haemorrhage and tumour.
The syndrome can be mimicked by a bilateral INO with an ipsilateral abducens nerve palsy.
Lateropulsion. This is a feature of lateral medullary infarction (Wallenberg's syndrome), in which
there is a compelling sensation of being pulled toward the side of the lesion, accompanied by
appropriate eye movement signs. During voluntary eye closure and sometimes even during
blinks, the eyes deviate toward the side of the lesion, and have to make corrective saccades on
eye opening to refixate the target. All ipsilaterally directed saccades overshoot the target (hypermetric), and saccades directed away from the side of the lesion undershoot the target (hypometric).
Vertical saccades have a parabolic ipsiversive trajectory. This ipsipulsion is in contrast to the
overshooting of contralateral saccades (saccadic contrapulsion) observed in patients with infarction in the territory of the superior cerebellar artery. The eye signs of lateropulsion are considered to be due to damage to olivo-cerebellar projections in the inferior cerebellar peduncle.
Abnormalities of vertical eye movements
Disturbances of vertical gaze are usually associated with damage to one or more of three structures
in the mesencephalon, the posterior commisure, the riMLF and the interstitial nucleus of Cajal
(INC). The only exceptions are an apparent vertical gaze palsy due to mechanical restriction of
extraocular muscles in orbital disorders such as thyroid eye disease; large acute pontine lesions
involving the PPRF bilaterally producing a temporary vertical saccadic palsy, in addition to the
permanent horizontal saccadic palsy; and certain degenerative disorders of the nervous system
such as progressive supranuclear palsy or adult Niemann-Pick disease.
Dorsal midbrain syndrome (pretectal syndrome, Parinaud's syndrome). This syndrome is
due to a lesion which involves the posterior commissure and is associated with a variety of aetiologies and clinical features, some of which may not be present in an individual patient. The
essential sign is a loss of upward gaze involving all types of eye movement, although the VOR
and Bell's phenomenon may sometimes be spared. When acute, the eyes may be deviated
downwards (the setting-sun sign), and may be observed in premature infants following intraventricular haemorrhage, and when a ventricular shunt becomes acutely blocked. Downward
saccades and smooth pursuit may be impaired and downbeat nystagmus may be present.
The dorsal midbrain syndrome may also be associated with disturbances of vergence eye movements including an impairment of convergence, which is usually paralysed but may rarely be
excessive and cause convergence spasm, convergence-retraction nystagmus, eyelid retraction
(Collier's sign), and a pupillary light-near dissociation.
Selective vertical gaze palsy due to riMLF lesion. A unilateral or bilateral lesion of the riMLF
produces a downgaze palsy, mainly affecting saccades, or more rarely a complete vertical gaze
palsy. Patients with unilateral midbrain lesions can develop combined upgaze and downgaze
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palsies, isolated upgaze palsies, an uniocular upward ophthalmoplegia with no primary position
hypotropia (monocular double elevator palsy), and a vertical one-and-a-half syndrome which
describes the combination of a vertical gaze palsy in one direction and a monocular vertical
ophthalmoplegia in the other direction, with no primary position heterotropia.
The ocular tilt reaction and lesions of the INC. A lesion of the INC, which lies immediately
caudal to the riMLF and rostral to the oculomotor nucleus, produces two distinct deficits: an
ocular tilt reaction (OTR), and a deficit in vertical pursuit and vertical gaze holding. The OTR is a
head-eye postural synkinesis that consists of a skew deviation with a head tilt (towards the side
of the hypometric eye), and torsion of the eyes (incyclotropia of the hypermetric eye and excyclotropia of the hypometric eye). Such patients also show a deviation of their subjective
vertical. Although the OTR is produced by a lesion of the INC it can be found whenever peripheral or central lesions cause an imbalance of otolithic inputs.
Abnormalities of horizontal and vertical eye movements due to thalamic lesions
Lesions of the thalamus can give rise to disorders of both horizontal and vertical eye movements. Conjugate deviation of the eyes contralateral to the lesion (so-called wrong-way deviation) is associated with haemorrhage in the medial thalamus. Thalamic haemorrhage may also
lead to forced downward deviation of the eyes, associated with convergence and miosis. Caudal
lesions in the thalamus have been associated with esotropia, which although usually associated
with a downward gaze deviation may be present as an isolated finding. A paralysis of downgaze
is associated with a caudal thalamic infarction, due to occlusion of the proximal portion of the
posterior cerebral artery or its perforator branch, the thalamosubthalamic paramedian artery.
However, the ocular motor deficit may well be due to damage to the riMLF or its immediate premotor inputs.
The effect of cerebellar lesions upon eye movements
Although it is generally accepted that the cerebellum plays an important role in the control of
eye movements in man, pure lesions of the cerebellum without some brainstem involvement are
unusual. This creates some difficulty in determining eye movement abnormalities specific for
cerebellar dysfunction. It is appropriate to segregate lesions to three main regions of the cerebellum, each of which has a particular ocular motor syndrome: the dorsal vermis and underlying
fastigial nucleus, the nodulus and ventral uvula, and the flocculus and paraflocculus. The dorsal
vermis and underlying fastigial nucleus are involved in controlling saccadic accuracy and smooth
pursuit. Lesions in this region lead to saccadic dysmetria, usually hypermetria, and mild deficits
of smooth pursuit. The nodulus and ventral uvula are involved in the control of the low frequency
response of the VOR, and disorders in this region give rise to periodic alternating nystagmus,
positional nystagmus and impaired habituation of the VOR, with increased duration of the
vestibular responses. The flocculus and parafloculus are concerned with retinal-image stabilisation e.g. smooth tracking with the head still, gaze-holding, control of the VOR and it's suppression, and pulse-step matching. Lesions of this region, therefore, lead to impaired pursuit and
VOR cancellation with gaze-evoked, rebound, centripetal and downbeat nystagmus; and inappropriate amplitude of the VOR. Other signs which have been associated with cerebellar lesions,
although precise localisation is not available, include torsional nystagmus during vertical pursuit
(lesion in the middle cerebellar peduncle), square wave jerks, esotropia with alternating skew
deviation, divergent nystagmus, primary position upbeating nystagmus, centripetal nystagmus.
The cerebellum is also important in generating long-term adaptive responses which enable eye
movements to be maintained appropriate to the visual stimulus. For example, when wearing lens
corrections there is a magnifying or minifying effect which requires adaptive changes in the gain
of the VOR. These changes due to cerebellar adaptation take a few hours to days to occur and
explain why some individuals experience difficulties when prescribed new lens prescriptions.
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DISORDERS OF THE VOLUNTARY CONTROL OF GAZE
Anatomy and physiology of voluntary gaze
The cerebral hemispheres are extremely important for the programming and co-ordination of both
saccadic and pursuit conjugate eye movements. Since different areas are involved in these two
types of eye movements they will be dealt with separately, always realising that for fully effective
ocular motor control, co-ordination between these subtypes of eye movement is essential.
Saccadic system
There appear to be four main cortical areas in the cerebral hemispheres involved in the generation
of saccades. In the frontal lobe in man there is the frontal eye field (FEF) which lies laterally at
the caudal end of the second frontal gyrus in the premotor cortex (Brodmann area 8), and the
supplementary eye field (SEF) which lies mesially at the anterior region of the supplementary
motor area in the first frontal gyrus (Brodmann area 6). The third area is in the dorsolateral prefrontal cortex (DLPFC), which lies anterior to the FEF in the second frontal gyrus (Brodmann
area 46). Finally, a posterior eye field (PEF) lies in the parietal lobe, possibly in the superior part
of the angular gyrus (Brodmann area 39) and the adjacent lateral intraparietal sulcus. Studies in
monkeys reveal that these areas are all interconnected with each other, and they all appear to
send projections to the superior colliculus (SC) and the premotor areas in the brainstem controlling saccades.
It appears that there are two parallel pathways involved in the cortical generation of saccades.
An anterior system originating in the FEF projecting both directly, and via the SC, to the brainstem saccadic generators. This pathway also passes indirectly via the basal ganglia to the SC.
The second or posterior pathway originates in the PEF passing to the brainstem saccadic generators via the SC. Only after bilateral lesions to both the FEF and SC in monkeys is there a
failure to trigger saccades.
Although the precise functions of these various cortical areas in saccade generation have not
been determined, a number of general statements can be made. The FEF is involved in triggering volitional saccades which, for example, may be predictive (in anticipation of the appearance
of a target), memory-guided (to a previously seen target), or scanning (searching for a particular
target of interest). The PEF could be involved in triggering reflexive saccades to the sudden
appearance of novel visual or auditory stimuli, and appears to be involved in visuo-spatial
integration and shifting visual attention. The DLPFC may be responsible for maintaining a
spatial map of the environment in short-term memory providing spatial information for memoryguided saccades and other volitional saccades as well as playing an important role in antisaccades (when a saccade is made to the mirror image location of a novel visual target, by inhibiting
unwanted misdirected reflexive saccades to the target. The SEF appears to be involved in the
generation of sequences of memory-guided saccades and complex ocular motor behaviours.
A subsidiary neural circuit related to saccade generation is from the frontal lobe to the superior
colliculus via the basal ganglia. Projections from the frontal cortex pass to the substantia nigra,
pars reticular (SNpr), via a relay in the caudate nucleus. An inhibitory pathway from the SNpr
projects directly to the SC. This appears to be a gating circuit related to volitional saccades,
especially of the memory-guided type.
Smooth pursuit system
To maintain foveation of a moving target the smooth pursuit system has developed relatively
independently of the saccadic oculomotor system, although there are interconnections between
the two. To visually track a target it is first necessary to identify and code its velocity and direction.
This is carried out in the extrastriate visual area known as the middle temporal visual area (MT)
(also called visual area V5), which contains neurons sensitive to visual target motion. In man,
this lies immediately posterior to the ascending limb of the inferior temporal sulcus at the occipitotemporal border (Brodmann area 19/37 junction). Area MT sends this motion signal to the
medial superior temporal visual area (MST), which in monkeys is located on the anterior bank of
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the superior temporal sulcus, but in man is considered to lie superior and a little anterior to area
MT within the inferior parietal lobe. Damage to this area results in an impairment of smooth
pursuit of targets moving towards the damaged hemisphere. Evidence of a possible contribution
of the FEF to the generation of smooth pursuit has recently been obtained in the monkey.
Both areas, MST and the FEF, send direct projections to a group of nuclei, which lie in the basis
pontis of the pons. In the monkey, the dorsolateral and lateral groups of pontine nuclei receive
direct cortical inputs related to smooth pursuit. Lesions of similarly located nuclei in man result
in abnormal pursuit. These nuclei transfer the pursuit signal bilaterally to the posterior vermis,
contralateral flocculus and fastigial nuclei of the cerebellum. Finally, the pursuit signal passes
from the cerebellum to the brainstem, specifically the medial vestibular nucleus and nucleus
prepositus hypoglossi, and thence to the PPRF and possibly directly to the ocular motor nuclei.
This circuitry, therefore, involves a double decussation, firstly at the level of the midpons (pontocerebellar neuron) and secondly in the lower pons (vestibulo-abducens neuron).
THE DIAGNOSIS OF SPECIFIC DISORDERS OF EYE MOVEMENTS
Disorders of saccadic eye movements
Disorders of saccades can be considered in terms of abnormalities of the saccadic pulse-step
innervation pattern. A change in the amplitude (width x height) of the pulse, either too big or too
small, leads to saccadic hypermetria (overshoot) or hypometria (undershoot), respectively. Such
a saccadic pulse dysmetria is associated with a lesion of the dorsal vermis in the cerebellum. A
decrease in the height of the pulse, which implies disturbed function of the burst neurons in the
PPRF or riMLF, leads to slow saccades. Many causes of slow saccades, several of which involve
these areas, have been described. A mismatch between the size of the pulse and the step (pulsestep mismatch) results in post-saccadic drifts and glissades. They are observed in diseases involving the vestibulocerebellum. If the pulse is not followed by a step (called a saccadic pulse) the
eye drifts back to it's previous position in a decreasing velocity exponential smooth eye movement.
Both conjugate and monocular saccadic pulses may occur in patients with multiple sclerosis.
Disturbances in the initiation of saccades may lead to a prolonged latency, or the addition of a
head movement or blink to initiate the saccade. This may be seen in congenital or acquired oculomotor apraxia, and various degenerative conditions including Parkinson's disease, Huntington's
disease and Alzheimer's disease.
Saccades may also occur inappropriately, particularly during attempted fixation. Square wave
jerks (SWJ) are small amplitude (up to 5 deg) saccades that take the eyes off fixation, followed
some 200 ms later by a corrective saccade. Many normal subjects have low frequency SWJ
(< 15/min), but elderly subjects often have a higher frequency. They are most prominent in
cerebellar disease, progressive supranuclear palsy, multiple system atrophy and schizophrenia.
Macrosquare wave jerks (5–40 deg) are encountered in multiple sclerosis and olivopontocerebellar
degeneration. Patients with diffuse cerebral cortex damage often exhibit large amplitude saccades away from the object of regard. After an interval of several hundred milliseconds the
patient makes a saccade back to the target. These anticipatory saccades are particularly observed in Alzheimer's disease.
Disorders of smooth pursuit
A number of different disturbances of smooth pursuit are found. The commonest abnormality is
a low gain (gain = eye velocity / target velocity), which appears as deficient pursuit in which
pursuit is broken by small catch-up saccades. Low gain pursuit can occur as a result of tiredness and inattention, as a side-effect of medications such as sedatives and anticonvulsants, or
due to lesions in the vestibulocerebellum. Generally bilateral low gain pursuit has no localising
value. This is not the case with asymmetrical low gain pursuit, which usually occurs as a result
of a lesion in the ipsilateral parietal lobe, thalamus, midbrain tegmentum, dorsolateral nucleus of
the pons and vestibulocerebellum. Occasionally a disturbance of pursuit 'tone' (balance) occurs
due to cerebral hemisphere lesions, when the eyes drift towards the side of the lesion. Disturbances
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of direction can occur, for example, in congenital nystagmus in which there is an apparent
'inversion' of pursuit when the eyes move in an opposite direction to the motion of the target.
FURTHER READING
Kennard C. Ocular motor disorders. In: Donaghy M, editor. Brain’s diseases of the nervous system. 12th ed. Oxford
University Press, 2009: 331–66.
rd
Leigh RJ, Zee DS. The neurology of eye movements. 4 ed. Oxford University Press,2006.
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DIAGNOSTIC PROCEDURES FOR DETECTING EYE-MOVEMENT
ABNORMALITIES IN VESTIBULAR AND BRAINSTEM LESIONS
Ksenija Ribariü-Jankes
Institute of Neurology, Clinical Centre of Belgrade, Serbia
The focus of this presentation is the description of the observed and recorded eye movements
in patients who experience vertiginous sensations.
If the vestibular apparatus is suddenly unilaterally damaged, the spontaneous or the positionevoked nystagmus has two phases, fast and slow (jerk nystagmus). Its fast phase is the more
easily noted on examination. The amplitudes of jerks are equal in both sides and the direction of
nystagmus is not affected by changes in gaze direction or head position. This type of nystagmus
can readily be recorded by means of videonystagmography. Patients experience dizziness (that
of the surroundings turning around them), are unstable or cannot walk at all, and suffer from
nausea and vomiting.
The so called gaze-evoked nystagmus is not spontaneous but is evoked by gaze-fixation to the
right or left or up and down. The direction of the nystagmus changes with the gaze direction. It
is caused by a dysfunction of the neural integrator (nucleus prepositus hypoglossi and nucleus
vestibularis medialis) or by the dysfunction of flocculo-vestibular connections.
Similar to such gaze-evoked nystagmus is nystagmus found in the so called internuclear ophthalmoplegia (INO). On an attempt to direct the gaze to the right or left, the adducting eye is weak
or, rarely, unable to move, while the abducting partner eye on extreme positions shows compensatory nystagmus. The disorder is caused by injury of the medial longitudinal fasciculus that
allows conjugate eye movement. Weakness of adduction cannot always be observed clinically,
but the nystagmus of the abducting can. The eye-movement abnormalities in this case can, however, be recorded by electronystagmography. Patients with INO complain of blurred vision or of
diplopia, of the feeling of falling-down, and of the light-headedness. Sometimes they report on
the impression that the objects are quickly moving from one to the other side of the visual field.
Instability without lateropulsion may be caused by unilateral damage of the utriculus or of its
afferents. Such difficulties are named the ocular tilt reaction (OTR). Patients present with paradoxical head tilt, skew deviation and bilateral conjugate ocular torsion. An accompanying manifestation may be inability of judging what is vertical.
In case that the acute lesion affects the rostral interstitial nucleus of the medial longitudinal fasciculus, of the interstitial nucleus of Cajal, and of the posterior commissure (PC) a spontaneous
torsional ipsilesional or contralesional torsional nystagmus can be seen. A vertical or torsional
gaze-evoked nystagmus can persist for up to two months. Head tilt can be measured by a special
ruler, skew deviation by ophtalmological examination, and ocular torsion by fundus photographs.
The judgment of verticality can be measured by Subjective Visual Vertical test. Torsional nystagmus cannot, however, be recorded by means of video- or electronystragmography. It can be
recorded by means of (three dimensional) scleral search coil recording in a search coil system
with three orthogonal magnetic fields.
Having OTR, the patient describes instability. Patients with torsional nystagmus describe rotational
vertigo (the objects are rotating clock- or counter-clockwise).
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O
LY EYES
SACCADIC OSCILLATIONS AND NYSTA MUS
Christopher ennard
Department of Clinical Neurology, University of Oxford, Oxford, Great Britain
Rhythmic or arrhythmic sustained oscillations of the eyes – wobbly eyes – are classified as
either nystagmus or saccadic (rapid conjugate eye movements) oscillations. There is an important distinction between saccadic oscillations, which are initiated by saccadic eye movements,
and nystagmus where the oscillations are initiated by smooth eye movements i.e. the fast phase
in jerk nystagmus is corrective and not primary.
SACCADIC OSCILLATIONS
Saccadic oscillations are bursts of saccades, which may be intermittent or continuous, causing
a disruption of fixation. Two main types can be identified, those with intersaccadic intervals and
those composed of back-to-back saccades.
The oscillations with intersaccadic intervals include s uare ave oscillations consisting of
sequences of SW which can occur in Parkinson s disease and progressive supranuclear palsy.
Macrosaccadic oscillations straddle the intended fixation position. The amplitudes (up to 40
deg) of sequential saccades increase in amplitude and then decrease in a crescendo-decrescendo pattern. This type of oscillation is usually observed in acute damage to the dorsal cerebellum involving the deep cerebellar nuclei, as in demyelination, tumour or haematoma.
Oscillations without any intersaccadic interval (back-to-back) include opsoclonus, ocular flutter
and convergence-retraction saccadic pulses. Opsoclonus consists of multidirectional (including
oblique and torsional) back-to-back saccades of varying amplitude. It has been suggested that
the disorder arises due to disordered pause cell function in the PPRF. A variety of posterior
fossa disorders can give rise to the condition, including infective agents such as Coxsackie
virus and haemophilus influenza meningitis. It can also occur in neonates associated with myoclonus – dancing eye and dancing feet . This appears to be a maturational deficit which resolves
over approximately 6 weeks. Opsoclonus also occurs as a paraneoplastic (non-metastatic) disorder which in children is associated with occult neuroblastoma and in adults with small cell
carcinoma of the lung and carcinoma of the breast and uterus. Ocular flutter consists of bursts
of back-to-back saccades in the horizontal plane only. It can therefore be observed in patients
recovering from opsoclonus. Isolated ocular flutter is most often observed in patients with
multiple sclerosis and signs of cerebellar disease. A voluntary form of flutter (voluntary flutter)
can be induced by about eight percent of the population, usually by convergence. It consists of
salvoes of horizontal back-to-back saccades. Lesions of the dorsal midbrain are often associated
with upward gaze palsies and convergence-retraction nystagmus. This is incorrectly termed
a nystagmus since it actually consists of adducting saccades and should be redesignated
convergence-retraction saccadic pulses. Finally, a further type of saccadic oscillation is ocular
bobbing. This consists of rhythmic, sudden, downward jerks of the eyes followed by slow return
to the midposition, either immediately or after a short delay. The typical type, associated with
pontine haemorrhage or infarction, is associated with paralysis of horizontal eye movements.
Atypical bobbing is similar except horizontal eye movements are intact, and occurs in metabolic
encephalopathy, obstructive hydrocephalus or cerebellar haematoma. When the fast movement
is upward followed by a delayed slow return the condition is known as reverse bobbing.
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2
NYSTA MUS
Nystagmus is an oscillation which is initiated by a slow eye movement. When this slow movement is accompanied by a fast (saccadic) eye movement it is called jerk nystagmus. Although
the direction of the nystagmus is conventionally determined by the direction of the quick phases
it is important to remember that it is the smooth eye movement imbalance which is responsible
for the nystagmus. If both phases are smooth eye movements pendular nystagmus is observed.
The commonest form of jerk nystagmus is vestibular nystagmus which most frequently results
from labyrinth or vestibular nerve dysfunction. Tonic vestibular input on one side causes deviation of the eyes to the opposite side which is, however, quickly overcome by cerebral cortical
mechanisms concerned with saccadic eye movements so that there is a rapid recoil (saccade).
Thus a peripheral vestibular lesion may cause a spontaneous nystagmus with a slow phase
towards the side of the lesion and a saccade in the opposite direction. While the tonic vestibular
component of the nystagmus is the slow phase, it is customary in clinical practise to describe
the direction of nystagmus as being that of the fast phase, which is normally therefore away
from the affected labyrinth. In dysfunction of the semicircular canals or their peripheral neurons,
the nystagmus is always accompanied by vertigo, which is of limited duration due to central
compensation. If nystagmus persists for more than a few weeks, it is usually due to an abnormality of the central vestibular pathways.
Several different types of central vestibular nystagmus are described, all of which show no change
in intensity with the removal of fixation (by using Frenzel goggles). This is in contrast to peripheral vestibular nystagmus in which removal of fixation leads to an increased intensity of the
nystagmus.
Do nbeat nystagmus may or may not be present in the primary position if it is it beats directly
downwards and is often accentuated in lateral gaze. When it is present in the primary position a
disturbance of the cerebellar flocculus is found, commonly due to a disturbance at the craniocervical junction such as an Arnold Chiari malformation. Other causes include cerebellar
degenerations, anticonvulsant drugs, lithium intoxication and intra-axial brainstem lesions. In
about half of the patients with downbeat nystagmus, no cause can be found.
Upbeat nystagmus when present in the primary position, is usually associated with focal brainstem lesions in the tegmental gray matter, either at the pontomesencephalic junction or at the
pontomedullary junction, involving the nucleus prepositus hypoglossi or the ventral tegmental
pathway of the upward vestibulo-ocular reflex. Multiple sclerosis, tumour, infarction and cerebellar
degeneration are the commonest causes.
Torsional nystagmus is a jerk nystagmus around the anteroposterior axis. It is commonly
associated with other types of nystagmus. owever, when it is pure it indicates a lesion of the
lateral medulla involving the vestibular nuclei. Occasionally it may be due to a midbrain-thalamic
lesion, involving the INC.
eriodic alternating nystagmus (PAN) is a primary position horizontal nystagmus that changes
direction in a crescendo-decrescendo manner, characteristically approximately every 90 s.
etween each directional change there is a null period of 0 to 10 s. There is a congenital form,
and acquired forms are due to Chiari malformations, multiple sclerosis, fourth ventricle tumours,
spinocerebellar degenerations and anticonvulsant intoxication. aclofen has been shown to be
an effective treatment.
a e-evo ed nystagmus is a common clinical observation with limited localising value. It is a
jerk nystagmus which is absent in the primary position and is only present on eccentric gaze. It
usually signifies cerebellar parenchymal disease, particularly involving the flocculus or its projections to the brainstem. ilateral horizontal, together with vertical, gaze-evoked nystagmus
commonly occurs with structural brainstem and cerebellar lesions, diffuse metabolic disorders
and drug intoxication. A variant of gaze-evoked nystagmus is rebound nystagmus in which
there is a jerk nystagmus that beats away from the previous direction, present in eccentric gaze,
lasting for 3–2 s after the eyes return to the primary position. It is also associated with parenchymal cerebellar disease.
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3
endular nystagmus is either congenital or acquired due to cerebellar and brainstem disease,
usually multiple sclerosis. Acquired pendular nystagmus may have both horizontal and vertical
components, and the amplitude and phase relationships of the two sinewaves determine the
trajectory of the eyes e.g. oblique, circular or elliptical. It can affect one eye or both, equally or
unequally, and is often symptomatic resulting in oscillopsia. It may be associated with oscillations of other structures such as the palate, head or limbs. When it is present in association
with palatal myoclonus, oculopalatal myoclonus, the lesion is usually in Mollaret s triangle
which consists of the red nucleus, dentate nucleus and inferior olivary nucleus. The latter nucleus
usually shows pseudohypertrophic degeneration. A combination of a convergence induced
pendular nystagmus and synchronous jaw contractions, called oculomasticatory myorhythmia,
is characteristic of Whipple s disease. In see-sa nystagmus one eye intorts and rises while
the other eye extorts and falls in a rapidly alternating sequence. In this pendular form there is
often a bitemporal hemianopia and the condition is associated with large parasellar masses
which have expanded up into the third ventricle and are distorting structures in the mesencephalic-diencephalic region.
Congenital nystagmus is almost invariably a horizontal conjugate nystagmus, which is unaltered
by vertical position. It is generally of jerk type with accelerating slow phases, and has an eccentric
null position. Fixation effort enhances congenital nystagmus. Less commonly the nystagmus is
of a pendular type. Reversed optokinetic nystagmus, beating in the direction of the target motion,
is a feature of congenital nystagmus. Patients may show a head turn or occasionally a head
oscillation.
Latent nystagmus is a type of congenital nystagmus that is only present on monocular viewing
and which then beats toward the viewing eye. It is absent on binocular viewing. If the patient
has amblyopia in one eye latent nystagmus is present with both eyes viewing, when it is called
manifest latent nystagmus.
FU THE
EADIN
ennard C. Ocular motor disorders. In: Donaghy M, editor. rain’s diseases of the nervous system. 12th ed. Oxford
niversity Press, 2009: 331–66.
rd
Leigh R , ee DS. The neurology of eye movements. 4 ed. Oxford niversity Press,2006.
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4
E T AOCULA
MUSCLES AND OCULA
MOTILITY
ranka Stirn- ranjc
Abstract
The extraocular muscles (EOM) are unique in their structure and function. The extraordinary functional demands
including globe rotation, imposed upon these muscles made them the fastest and the most fatigue resistant skeletal
muscles. A short overview on EOM embryology, anatomy, structure, function and oculomotor control is given. To
better understand a specific EOM response to disease and manipulation, its regeneration and plasticity, EOM fibre
types with its histochemical profile, myosin heavy chain isoforms (My C), innervation are presented. In strabismus
singly innervated fibres in the orbital muscle layer (OL) seem to be the most important in ocular alignment. otulinum
toxin also affects these fibres, it has a long-term effect and causes a shift toward slower My C isoforms.
EOM are relatively spared in muscle dystrophies, however there is a distinctive muscle fibre response i.e. known in
progressive external ophthalmoplegia, myasthenia gravis, amyotrophic lateral sclerosis, dysthyroid ophthalmopathy.
INT ODUCTION
Six extraocular muscles (EOM) are the effectors of ocular motility of specific direction, velocity
and amplitude. The precision of eye movements is influenced not only by the activity of motoneurones in the extraocular motor nuclei in the brainstem and supranuclear structures, but also
by the unique structure of the striated extraocular muscles. The globe represents a fixed and
unchanging load for EOM which can be altered by disease, trauma, surgery. The small motor
unit size in EOM (10 muscle fibres/motoneuron) allows precise incrimination of force required in
fixation and eye movements. Vestibulo-ocular reflex compensates head/body movements
through signals from head accelerations and eye position changes to prevent blur. Optokinetic
movements also provide clear vision at low frequencies of head acceleration or during constant
velocity rotations. To maintain fixation and high binocular visual acuity EOM can execute
pursuit/saccadic and vergence eye movements. While pursuit and vergence movements (simultaneous movement of the eyes in opposite directions) track slowing moving visual targets (with
motoneuron tonic discharge rates 100 spikes/s), saccades rapidly reorient vision to new visual,
auditory, or somatosensory targets (by motoneurons at high frequency burst activity up to
600 spikes/s). These factors influence EOM structure which follows function and make EOM
among the fastest and most fatigue resistant skeletal muscles 1–4 .
EYE MOVEMENT CONT OL
To prevent diplopia oculomotor systems have a well-established feedback control in the adaptive
regulation of motor output. The information to the brain is provided from vision, efference copy
(corollary discharge) and muscle proprioception, in case of primate EOM present as palisade
endings – myotendinous cylinder as primary sensory receptor .
Muscle spindles are scarce in EOM, prevalent at the muscle-tendon interface. Their proprioceptive role and importance in eye position and EOM activity is still unclear.
The oculomotor system consists of a rather intricate mechanical arrangement comprised of pulleys, the inner elastic suspension supported by the rectus EOM and their associated connective
tissues. Rectus EOM and their pulleys implement kinematics in 2-D, largely corresponding to
the retina and subcortical visual system organization, while the oblique EOM generate torsion.
Pulleys prevent EOM sideslip during globe rotations and gaze related shifts of rectus pulleys
can occur. Oculomotor motor units are sequentially recruited to produce force levels adequate
to acquire and maintain the desired eye position 6, 7 .
EOM are innervated along their length with motor endplates and terminal axons. All rectus muscles
are innervated from the intraconal surface of the muscle belly. The third cranial – oculomotor
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nerve, the superior division innervates the levator palpebrae and the superior rectus, while the
inferior division innervates the medial and inferior rectus and inferior oblique EOM which receives
its innervation just lateral to the inferior rectus muscle. The parasympathetic fibres responsible
for pupillary constriction travel with the nerve to the inferior oblique muscle. The fourth cranial –
trochlear nerve innervates the superior oblique muscle, and the sixth cranial nerve – abducens
innervates the lateral rectus muscle 8 .
E T AOCULA
MUSCLE EM
YOLO Y AND ANATOMY
Myoblasts that form the EOM arise from cranial mesoderm, while the orbital connective tissue
originates from neural crest. Myogenesis follows in two waves to form primary and secondary
myofibres. The sequential development of EOM fibres is believed to be conserved across the
mammalian species, but may follow a different sequence in frontal and lateral-eyed species.
Despite considerable prenatal EOM development that occurs already in the first hundred embryonic days in primates, there is significant postnatal maturation of EOM 9 . There is postnatal
increase in size of all fibre types and in the mitochondrial content. owever, the mechanisms
responsible for neuromuscular junction formation in EOM (singly, multiply innervated fibres)
have not yet been fully elucidated. A critical period for EOM development and also greater insult
possibility may be 3–6 months postnataly when structural/functional muscle characteristics
demanded for binocular vision are established 10 .
Four rectus EOM (medial, lateral, superior, inferior) originate in the orbital apex from the fibrous
annulus of inn. The superior oblique muscle arises just above from the superonasal orbital
wall, while the inferior oblique originates from the maxillary bone, adjacent to the lacrimal fossa,
continuing laterally to enter its connective pulley inferior to the inferior rectus EOM. The rectus
EOM course anteriorly through loose lobules of fat and connective tissues that form sheathes
as the EOM penetrate posterior Tenon s fascia. Tenon s capsule is a fibroelastic membrane that
begins 1 mm from the limbus, where it is fused with the conjunctiva and then caps the globe
posteriorly to the optic nerve. Its inner surface is smooth and allows free gliding of the adjacent
structures within it. Although the rectus EOM insertions may vary, they insert into the sclera just
anterior to the equator of the globe. The medial rectus inserts closest to the limbus, followed by
the inferior, lateral, and superior rectus EOM. The superior oblique tendon inserts into the
posterior, superolateral sclera under the superior rectus EOM. The tendon insertion extends to
near the optic nerve and superotemporal vortex vein. The superior oblique sheath and tendon
pass through the trochlea, a cartilaginous rigid pulley attached to the superonasal orbital wall.
The inferior oblique muscle inserts into the posterior, inferolateral sclera in proximity to the macula
and the inferotemporal vortex vein 11 .
Pulleys consist of discrete rings of dense collagen encircling the EOM, transitioning gradually
into less substantial but broader collagenous sleeves which form slings to the orbital wall.
Elastic fibres in and around pulleys provide reversible extensibility. There are also bands of smooth
muscle in the pulley suspensions. All EOM pulleys cause pulling directions of the EOMs to change
by half the angle of ocular duction. This behaviour makes ocular rotations mathematically
cummutative so that binocular alignment during versions does not depend on the sequence of
eye rotations 12 .
The blood vessels that supply the rectus EOM are two anterior ciliary arteries from the ophthalmic
artery for each EOM. The exception is the lateral rectus which contains only one such artery,
but is also supplied by the lacrimal artery and the inferior oblique muscle also supplied by the
infraorbital artery. These vessel branches travel on the anterior surface of the rectus EOM and
pierce the sclera anterior to the rectus EOM insertions. They anastomose with conjunctival vessels at the limbus before connecting with the major arterial circle of the iris. The superior and
inferior orbital veins supply venous drainage for the EOM 13 .
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6
E T AOCULA
MUSCLE ST UCTU E AND FUNCTION
Six striated oculorotary EOM are configured as antagonist pairs. The medial and lateral rectus
form a horizontal antagonist pair, while the superior and inferior rectus a vertical pair with additional actions not strictly antagonistic, as well as oblique EOM implementing torsion around the
line of sight (Table 1).
Table 1. Extraocular muscle action and innervation
Direction of pull relative
to the visual axis
Action from primary
position
Innervation – cranial
nerve
Medial rectus
Lateral rectus
Superior rectus
90ƕ
90ƕ
23ƕ
lower III
VI
upper III
Inferior rectus
23ƕ
adduction
abduction
elevation
intorsion
adduction
depression
extorsion
adduction
intorsion
depression
abduction
extorsion
elevation
adduction
Muscle
Superior oblique
1ƕ
Inferior oblique
1ƕ
lower III
IV
lower III
EOM, but not the lid elevating levator palpebrae superioris, are arranged mainly into two layers.
The global layer (GL) is located adjacent to the globe in rectus EOM and in the central core of
the oblique EOM. It contains 10.000 to 1 .000 fibres in the belly of the EOM. The orbital layer can
be C shaped and is located on the orbital surface, containing around 30% or more EOM fibres.
EOM muscle bundles are surrounded by extensive layer of perimysium. The GL is wider than the
OL with fibre diameter range 7.1–40.3 m in the GL vs. 3.4–26.6 m in the OL (Fig. 1) 14–16 .
Global layer
Orbital layer
Fig. 1. Cross section of human ocular medial rectus muscle. Histochemical staining for D GPDH
(D glycerol-3-phosphate dehydrogenase) exhibiting low glycolytic activity especially in the thinner
peripheral orbital muscle layer (84 x)
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7
E T AOCULA
MUSCLE FI
E TY ES
Compared to other skeletal muscles EOM differ in their histochemical profile, type of innervation
and fibre type distribution and are not respecting the traditional fibre type classification schemes
of four fibre types in skeletal human muscles (I, II c, II a, II x). Several attempts at classification
of fibre types in EOM of different mammals and humans have been made by studying the morphology, histochemical characteristics and/or ultrastructure 17–20 . owever, the most pertinent
classification system used at present is still descriptive and incorporates different classification
schemes 2 . It distinguishes among six fibre types in EOM according to (i) their location in the
global (GL) or orbital layer (OL), (ii) type of innervation (i.e. singly (SIF) and multiply (MIF) innervated fibres), (iii) the staining for the myofibrillar adenosintriphosphatase (mATPase) reaction
after preincubation in acid and alkaline medium (slow or type I and fast or type II fibres), and (iv)
metabolic profile – depending on mitochondrial content (oxidative, oxidative-glycolytic, glycolytic).
The distinction between singly and multiply innervated fibre types was based upon the longitudinal separation of neuromuscular junctions on individual fibres. In MIF the histochemical localisation
of acethylcholinesterase revealed multiple small neuromuscular synaptic endings, distributed
irregularly along the longitudinal extent of individual fibres, while in SIF it revealed a restricted
focal innervation at a single locus 10 . sing several enzyme histochemical procedures, three
global layer SIFs were characterised as fast twitch fibres on the basis of their alkaline stable/acid
labile mATPase activity. Global MIFs resembled tonic fibres and were characterised as slow
fibres by their acid stable/alkaline labile mATPase activity, exhibiting low oxidative and low
glycolytic metabolic enzyme activities. The orbital layer contains one SIF and one MIF type. The
orbital SIFs are fast twitch and highly oxidative, while orbital MIFs are slow, of smaller diameter
and containing fewer mitochondria (Fig. 2) 16, 20 . Still this scheme remains limited in recognizing the full extent of the muscle fibre heterogeneity in EOM, not considering the myosin
heavy chain (My C) isoform composition, as suggested by McLoon and co-workers 21 .
In fact, My C isoforms are the one that determine the activity of mATPase and the shortening
velocity of myofibres. Two My Cs and four myosin light chains form a contractile protein myosin
present in thick filaments of muscle fibres. Till now more than ten My C isoforms are known,
coded by over 30 genes 22, 23 .
In spite of all complex research, the classification of muscle fibre types in EOM is still not fully
clarified neither is the correlation between its structure and function. ntil now only few studies
considered the My C composition of human EOM 14–16, 24–28 , however, the applied methods
were different and therefore the results are mostly not comparable. The reported expression of
My C isoforms in EOM is not consistent although it is generally agreed that EOM express all
the My C isoforms present in other striated muscles. eside these common My C isoforms,
the EOM specific extraocular (My C-eom), D-cardiac (My C-D), My C-2b, and developmental
My C isoforms, i.e. My C-embryonic (-emb) and -neonatal (-neo) are expressed in EOM as
well (Fig. 3) 16 . The majority of EOM fibres are hibrid fibres co-expressing two or more My C
isoforms. This EOM specific myosin gene expression may be crucial in muscle adaptation in
disease or as an expression of low EOM load demands.
At least four fibre types in the muscle global layer (GL) – one slow or type I fibres (multiply innervated fibres MIF), three fast or type II fibres (singly innervated fibres SIF), and two in the
orbital layer (OL) – one slow and one fast fibre type could be distinguished according to the
reaction for mATPase and the fibre metabolic profile as well (Table 2, Fig. 2, 3).
E T AOCULA
MUSCLE
E ENE ATION AND LASTICITY
Destroyed or damaged muscle fibres can regenerate from satellite cells which lie between basal
lamina and muscle fibre plasma membrane. Satellite cells are mitoticaly inactive in a developed
muscle. Their mitotic activity is most active a few days after muscle damage. They form myoblasts which join into myotubes and then into muscle fibres. Satellite cells are pluripotent, similar
in slow and in fast muscle. Muscle fibres present a dynamic structure and are able to change
their phenotype and to adjust to functional needs at the moment. The adaptation changes can
influence muscle fibre metabolism, its structural and contractile proteins and calcium regulation
with new gene expression. nfortunately this muscle plasticity is limited and different in several
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8
muscle groups even as an adaptation mechanism to the same noxis 29–31 . A complete adaptation ability would be a transformation possibility of fast muscle fibres i.e. II into slow fibres
type I or from glycolytic to oxidative fibres and vice versa. Factors that influence muscle fibre
transformation are: development, innervation, muscle load, ageing, hormones e.g. in hypothyroidism the amount of slow muscle fibres increases, while in hyperthyroidism fast muscle
fibres increase. Glucocorticoids, insulin, growth hormone, testosterone also influence muscle
plasticity, however it is not known whether they have a direct impact or there is a role of different muscle nerve activity 32 .
Table 2. Histochemical and immunohistochemical characteristics of human ocular rectus muscle fibres
Fibre type
Orbital layer
1 (SIF)
2 (MIF)
Global layer
3 (SIF)
4 (SIF)
(SIF)
6 (MIF)
MyHC isoform
a,x,b,eom,(neo)
1,a,x,b,eom,(neo)
a,x,eom
a,x,b,eom
b,x,eom
1,(x,b,eom,neo)
mATPase (pH)
9.4
4.4
D-GPDH
%
–
r
r
70–97
30–3
–
–
–
–
30–2
30–2
2 –20
10–30
SDH
–
–
r
r
r
SIF singly innervated fibre, MIF multiply innervated fibre, 1 My C (myosin heavy chain isoform) /slow, slow tonic, Dcardiac,
a
My C-2a, b
My C-2b, x
My C-2x, eom
My C-extraocular, neo
My C-neonatal, ( ) in some fibres
mATPase myofibrillar adenosinetriphosphatase, SD
succinil dehydrogenase, indicating oxidative activity, D-GPD
glycerol 3-phosphate dehydrogenase, indicating glycolytic activity Enzyme activity: - (none), r (very low),
(low),
(intermediate),
(high)
Fig. 2. Serial cross sections of the human ocular medial rectus muscle - orbital (OL) and global (GL)
muscle layer; histochemical staining assayed for succinil dehydrogenase (SDH) and for D GPDH (D
glycerol-3-phosphate dehydrogenase) activity; six fibre types are indicated in both muscle layers (1,2 in
the OL and 3,4,5,6 in the GL). In the OL fibre type 1 is fast, highly oxidative, singly innervated, fibre type 2
is slow, less oxidative, multiply innervated; in the GL fibre type 6 is slow, multiply innervated of low
oxidative and low glycolytic activity, fibres 3,4,5 are fast, singly innervated and of different metabolism
(oxidative, oxidative glycolytic and glycolytic). Scale bar 50 µm
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9
Fig. 3. Serial cross sections of the human ocular medial rectus muscle - orbital (OL) and global (GL)
muscle layer; immuno-peroxidase staining assayed for myosin heavy chain isoforms: MyHC-1 (ȕ slow)
(BAD-5 as monoclonal antibody), MyHC-2a (SC71), MyHC-2b (BF-F3), six fibre types are indicated in
both muscle layers (1,2 in the OL and 3,4,5,6 in the GL, classified as in histochemical staining above and
in Table 1). Scale bar 50 µm
E T AOCULA
MUSCLE ES ONSE TO DISEASE AND MANI ULATION
E traocular muscle changes in strabismus
It is still not clear whether the alterations in muscle structure are a primary or a secondary consequence of strabismus. According to research in monkeys prone to strabismus the orbital singly
innervated fibres seem to be involved in strabismus, what is likely due to constant activity of the
OL in maintenance of eye position. Strabismus surgery (muscle resection / recession) may have
myofibre contractile efficiency. Sarcomeric adaptation may have a role in long-term ocular realignment. In paralytic strabismus denervation muscle atrophy is produced, while in the antagonist
adaptation to decreased muscle length occurs 33 .
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60
otulinum to in
The A serotype as the most clinically useful pharmacologic agent blocks the calcium dependent
release of acetylcholine at the neuromuscular junction and weakens muscles, suggesting and
alternative to strabismus surgery. otulinum toxin does not produce the generalized atrophy of
all EOM fibre types, but specific long-term changes in orbital singly innervated fibres, especially
in developing EOM, possibly causing a static eye position change. In other skeletal muscles
fibres are restored after motoneuron sprouting reestablishes functional innervation after several
months. owever EOM do not regain their functional characteristics after new motor end plate
formation and recovery of muscle contraction, My C profile is shifted toward slower isoforms 34 .
Local anaesthetics
Aminoacyl anaesthetics (lidocaine, mepivacaine, bupivacaine) have myotoxic effect with sarcolemmal disruption and displacement of calcium which triggers proteases and fibre necrosis. Mitochondria can serve as a calcium sink, what explains a severe response to the applied aesthetic
in the global singly innervated glycolytic fibres 3 .
rogressive e ternal ophthalmoplegia ( EO)
It is the most common mitochondrial disorder affecting EOM, associated with pigmentary
retinopathy and cardiac conduction block known as earns Sayre syndrome. Cytochrome-c
oxidase deficiency is possible as well as increased staining for the mitochondrial succinate
dehydrogenase. With modified Gomori trichrome stain ragged red fibres are present, while
with an electron microscopy abnormal mitochondria are increased in number and size, are
dense, globular with no cristae. Ptosis usually requires correction, but diplopia might not be
problematic due to symmetry of ophthalmoplegia 36 .
Muscular dystrophy
Oculopharyngeal dystrophy specifically alters oculomotor function, but the sequelae for EOM are
poorly understood. Tubofilamentous intranuclear inclusion bodies can be seen in muscle biopsy.
In myotonic dystrophy EOM are affected, coloured cataracts like Christmas tree may be present.
The electromyogramme shows spontaneous high frequency bursts. The myofilaments and
sarcoplasmic reticulum are disrupted, accumulations of impaired mitochondria may be found. In
muscle fibres nuclei run in rows 37 .
In Duchenne muscular dystrophy, an
linked recessive disease with a deficiency of a subsarcollemmal protein dystrophin, rotatory EOM with absent dystrophin are spared. igher
capacity of EOM to scavenge free radicals is another protective mechanism. Superoxide dismutase activity in EOM is also higher than in other skeletal muscles 38, 39 .
Myasthenia gravis
It is an autoimmune disorder that targets acetylcholine receptors at the neuromuscular junction.
The EOM are vulnerable, early in the disease ptosis and diplopia are present. In skeletal muscle
the establishment of functional innervation serves to signal the replacement of the Ȗ subunit of
the embryonic acetylcholine receptor isoform by an İ subunit to yield the adult isoform, while the
adult EOM retains expression of the embryonic acetylcholine receptor isoform, most likely at the
neuromuscular junctions of the multiply innervated fibre types. This means controversion and no
stereotypical pattern of EOM involvement in myasthenia, for there are no MIF in the levator palpebrae superioris, but the ocular motility disorders are expected with positional deficit causing
diplopia with possible relationship to sensitivity resulting from normally high activation rates as
to acetylcholine receptor properties in EOM 40 .
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61
Amyotrophic lateral sclerosis
EOM are relatively spared in amyotrophic lateral sclerosis. Atrophic and hypertrophic fibres can
be found in clusters or scattered as well as increased amounts of connective tissue and areas
of fatty replacement. The population of fibres expressing My C slow tonic decreased mostly in
the orbital muscle layer 41, 42 .
Dysthyroid ophthalmopathy
In autoimmune disorder generally characterized by hyperthyroidism, Graves disease the EOM
enlarge due to abnormal accumulation of glycosaminoglycans in the connective tissue of the
endomysium and orbital fat. Alterations in the EOM may be secondary to elevated intraorbital
pressure and the absence of orbital lymphatic drainage, the process mediated by activated
fibroblasts and cytotoxicity. uman leucocyte antigen ( LA-DR) expressed in orbital fibroblasts
is crucial to antigen recognition by T cells. There are other protein interactions like interferon
gamma, interleukin I alpha, tumour necrosis factor, cytokines, intercellular adhesion molecule 1
(ICAM 1) that may control orbital infiltration and targeting by T cells 43 .
CONCLUSION
The extraocular muscles (EOM) are unique in their structure and function. The extraordinary
functional demands including globe rotation, imposed upon these muscles made them the
fastest and the most fatigue resistant skeletal muscles. A distinctive EOM muscle fibre response
is known in strabismus, experiment and disease, however many questions concerning EOM
arrangement, its functional consequence, and regeneration remain unclear.
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BLINKING, ITS MECHANISMS AND PATHOLOGY
Marko Koro ec
Institute of Clinical Neurophysiology, Department of Neurology,
University Medial Centre Ljubljana, Ljubljana, Slovenia
INTRODUCTION
A blink is a rapid bilateral eyelid closure with co-occurring small rotation of the eyes down
towards the tip of the nose and back up again. This generally unnoticed often repeated action is
not very spectacular. However if not for the occasional blink we would all be blind. Blinking is
necessary for maintenance of corneal tear film (spontaneous blinking) and eye protection (reflex
blinks). Healthy adult person in a relaxed state makes about 15 spontaneous blinks per minute.
Therefore every day we do about 15000 spontaneous blinks and an indefinable number of
voluntary and reflex blinks. If spontaneous eyelid closure lasts on average 150 ms, we spend at
least 9 days per year blinking. But we are rarely aware of our blinks, because during blinking,
brain activity was found to be suppressed in areas that respond to visual input (primary visual
cortex, parietal and prefrontal visual areas).
PHYSIOLOGY OF BLINKING
The physiology of spontaneous and voluntary blinking is not well known. The difficulty in identifying their neural origins is that blinking is a distributed process involving several brain regions.
Functional imaging studies reveal that primary motor cortex, supplementary motor area (confirmed
also with Bereitschaftspotential recordings), cingulate motor cortex, dorsolateral prefrontal
cortex, posterior parietal cortex, visual cortex, central thalamus, and cerebellum are all active
with spontaneous and voluntary blinking. One transcranial magnetic stimulation study results
provide evidence that the cortical center for the upper facial movements, including voluntary
blinking, is not principally located in the facial M1, but rather in mesial frontal region (the rostral
cingulated motor region, called M3). In turn, these structures activate brainstem interneurons
and motoneurons to produce the blink.
Reflex blinks are mainly elicited with external trigeminal, visual or acoustic stimuli, but can be
elicited also with peripheral nerve stimulation. The premotor areas involve pontine and medullary tegmental levels of the brainstem, influenced by basal ganglia. Most commonly, the blink
reflex is elicited with electrical stimulation of the supraorbital nerve. The orbicularis oculi (OO)
blink reflex consists of two components: an early, first response (R1) and a late, second response (R2). R1 is a brief unilateral response, ipsilaterally to the stimulated side, with a latency
of about 10 ms. R2 has a latency of about 30 ms, is longer in duration and appears bilaterally.
The afferent limb of OO R1 and R2 is the ophthalmic division of the trigeminal nerve, while the
efferent limb is the facial nerve. Based on analysis of human lesions, the central pathway for R1
is oligosynaptic, consisting of one ore two interneurones located in the vicinity to the main
sensory trigeminal nucleus. From there fibres impinge upon motoneurones within the intermediate subnucleus of the motor facial nucleus. For R2, afferent impulses are conducted
through the descending trigeminal spinal tract in the pons and dorsolateral medulla oblongata
before they reach the caudal spinal nucleus. From there, impulses are relayed via a medullary
ascending pathway ipsilateral to the stimulated side and an ascending route that crosses the
midline before it ascends contralaterally. Both routes connect with the facial nerve nucleus in
the pons on the two sides.
Blinks are one of the fastest movements in humans. During blinks, two skeletal muscles, levator
palpebrae superioris (LPS) and OO, and two smooth muscles, upper and lower tarsal muscles
(Müller’s muscles), are involved. LPS is innervated by motor neurones from central caudal subnucleus of the oculomotor nuclear complex, and OO from intermediate zone of facial nerve
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nucleus. LPS and OO act antagonistically in all types of blinks. Short inhibition of tonic LPS
activity and concurrent OO activation result in fast upper eyelid down movement and eye closure.
Immediately after cessation of OO activity return of tonic LPS activity opens the eyes. Eye
closure is about 3 times faster than eye opening. The kinematics of the superior eyelid during
blinks, explored by means of the electromagnetic search coil technique, consists of a first rapid
down-phase, followed by a slower up-phase with a variable total duration. Reflex blinks show a
duration of around 200 ms which is shorter than the voluntary (around 270 ms) and spontaneous
ones (around 330 ms). All types of blinks also have different amplitude and maximal velocity
and their amplitude-maximal velocity relationship is linear; i. e. larger blink amplitude results in
increased maximal blink velocity.
All types of blinks are associated with stereotyped eye movements. During blink the eye makes
a small retraction in the orbit and rotates in horizontal, vertical and lateral direction. A brief upward
movement of the eyes was first observed by Bell. However, more recent studies report that the
eye rotation during blink when looking straight is usually directed nasally/medially downward and
the degree of rotation is dependent from the initial eye position.
BLINKING ABNORMALITIES
Spontaneous blink rate shows a high interindividual variability (between 10–20 blinks per
minute in adults) and was shown to depend on the affective, attentional and cognitive state.
Blink rate has been proposed as a marker for the central dopaminergic activity, based on the
variations observed in different diseases with impairment of this neurotransmitter. In Parkinson’s
disease (PD), blink rate is generally decreased, although some patients also can have a significantly higher blink rate, not complaining of symptoms indicative of blepharospasm nor having a
form of off period dystonia. In progressive supranuclear palsy, blink rate is extremely reduced,
around 3 per minute. Patients with Huntington’s disease and schizophrenia show higher blink
rates than healthy subjects.
In one study, voluntary and reflex blink amplitudes tended to be smaller than normal for PD
patients, whereas eyelid kinematics (amplitude-maximum velocity relationship) for all three blink
types were normal. A significant positive correlation between spontaneous blink amplitude and
blink rate was also found. These observations imply that PD modifies a brainstem blink generator
circuit shared by spontaneous, voluntary, and reflex blinks.
Blepharoclonus consists of an abnormal rhythmic eyelid closure by the involuntary contraction
of the OO muscles. It is usually elicited with the eccentric or vertical gaze and the gentle voluntary closure of the eyes. It has been observed in multiple sclerosis with scattered periventricular
and brainstem lesions, on recovery from severe head trauma probably due to a cerebellar system
dysfunction, in PD and secondary parkinsonism, Arnold-Chiari malformation and some primary
headaches (e.g. migraine, tension and cluster headache).
Blepharospasm is a progressive focal dystonia characterized by excessive involuntary closure
of the eyelids due to spasm of the OO muscles. It is expressed as frequent and prolonged blinks
and later as clonic or/and tonic spasms of eyelids of different duration that may render the patient
functionally blind. Idiopathic blepharospasm can occur in isolation or together with other cranial
dystonias (Meige syndrome). It can be associated with other extrapyramidal diseases, e. g. PD,
progressive supranuclear palsy, postencephalitic parkinskonism, or induced by neuroleptic and
l-dopa treatment. It may also be secondary to focal central nervous system lesions, predominantly
the rostral brainstem and diencephalic regions. Simultaneous electromyographic recording of
LPS and OO muscles shows variable patterns, ranging from frequent and prolonged blinks with
an impairment in the timing and reciprocity of the activity of the two muscles, to clonic burst of
the OO to prolonged tonic activity of these muscles. Commonly, a precise co-contraction between both LPS and OO is observed. A localized contraction of pretarsal OO muscular portion
can result in so-called pretarsal blepharospasm and is only demonstrated by electromyography.
The blink reflex recording in blepharospasm shows the facilitation of the R2 recovery curve.
Some functional imaging studies reveal that a subregion of the putamen is active during blepharospasm but not during voluntary blinks. A change in the functional state of the putamen, that can
modify blinking through its actions on both cortical and brainstem pathways, could interrupt the
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blink system’s compensation to environmental triggers, thereby permitting the eyelid spasms. In
response to cornea drying, the nervous system improves tear film stability by increasing the
sensitivity of blink circuits to trigeminal stimuli and enabling a single trigeminal stimulus to evoke
multiple blinks. The blepharospasm could be an exaggeration of this compensatory response.
Thus, putamen dysfunction could predispose individuals to blepharospasm by failing to regulate
the nervous system’s compensatory response to dry eye appropriately or even by permitting
inappropriate blink circuit modifications in the absence of dry eye.
On the other hand, involuntary closure of the eyelids can also be caused by failure of LP contraction due to prolonged inhibition of the LP muscles in the absence of a demonstrated OO
contraction, a condition known as so-called apraxia of lid opening or blepharocolysis (from
Greek blepharon, eyelid; and colysis, inhibition). Although widely used, the term apraxia of
eyelid opening is inappropriate since the executive motor system is affected. Electromyographic
recordings show a prolonged intermittent or sustained overinhibition of the LPS activity with no
evidence of consistent OO discharges. The involuntary closure of the eyelids may last for long
period of time and like blepharospasm may render the patients functionally blind. Blepharocolysis can occur in isolation, but is more commonly associated with idiopathic blepharospasm
and can occur also in other extrapyramidal disorders (e. g. progressive supranuclear palsy,
Parkinson’s disease). The anatomical basis of blepharocolysis is unclear. The impairment of
some pons and rostral midbrain areas may be relevant and it can occur after a bilateral
subthalamotomy for the treatment of an idiopathic torsion dystonia.
FURTHER READING
Aramideh M, Ongerboer de Visser BW, Devriese PP, Bour LJ, Speelman JD. Electromyographic features of levator
palpebrae superioris and orbicularis oculi muscles in blepharospasm. Brain 1994; 117: 27–38.
Bour LJ, Aramideh M, de Visser BW. Neurophysiological aspects of eye and eyelid movements during blinking in
humans. J Neurophysiol 2000; 83: 166–76.
Esteban A, Traba A, Prieto J. Eyelid movements in health and disease. The supranuclear impairment of the palpebral
motility. Neurophysiol Clin 2004; 34: 3–15.
Evinger C, Manning KA, Sibony PA. Eyelid movements. Mechanisms and normal data. Invest Ophthalmol Vis Sci 1991;
32: 387–400.
Evinger C, Perlmutter JS. Blind men and blinking elephants. Neurology 2003; 60: 1732–3.
Bristow D, Haynes JD, Silvester R, Frith CD, Rees G. Blinking suppresses the neural response to unchanging retinal
stimulation. Curr Biol 2005; 15: 1296–300.
Hallett M. Blepharospasm: recent advances. Neurology 2002; 59: 1306–12.
Koro ec M, Zidar I, Reits D, Evinger C, VanderWerf F. Eyelid movements during blinking in patients with Parkinson's
disease. Mov Disord 2006; 21: 1248–51.
Schmidtke K, Buttner-Ennever JA. Nervous control of eyelid function. A review of clinical, experimental and pathological data. Brain 1992; 115: 227–47.
Sohn YH, Voller B, Dimyan M, St Clair Gibson A, Hanakawa T, Leon-Sarmiento FE, et al. Cortical control of voluntary
blinking: a transcranial magnetic stimulation study. Clin Neurophysiol 2004; 115: 341–7.
Yoon HW, Chung JY, Song MS, Park H. Neural correlates of eye blinking; improved by simultaneous fMRI and EOG
measurement. Neurosci Lett 2005; 381: 26–30.
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66
GENETIC AND NEUROIMAGING STUDIES OF EYE MOVEMENTS
Ulrich Ettinger
University of Munich, Munich, Germany
Eye movements have been studied as markers of genetic liability for schizophrenia since the
early 1970s. This work is based on the endophenotype (or intermediate phenotype) approach
and has flourished in the last years with the advent of modern molecular genetic methods. In
this talk I will summarise the evidence for impairments in eye movement control as endophenotypes for schizophrenia. In particular I will focus on two established oculomotor endophenotypes,
the smooth pursuit eye movement (SPEM) and antisaccade tasks. I will first present the tasks
as well as neuroimaging studies of their neural mechanisms in healthy humans. I will then summarise evidence from investigations aimed at validating these oculomotor tasks as schizophrenia
endophenotypes. These studies focus primarily on psychometric criteria as well as behavioural
genetic designs, such as the study of twins and families. Finally I will discuss recent molecular
genetic investigations which have studied oculomotor endophenotypes in relation to schizophrenia
candidate genes.
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67
WAVEFORMS IN TYPE
EPILEPTIC NYSTAGMUS
Chris M. Harris1, Jithin S. George2, Sreedharan Harikrishnan2, Jonathan Waddington1,
Andrew Smith3, Martin T. Sadler2
1
2
SensoriMotor Laboratory, University of Plymouth, Plymouth, Devon, Great Britain
3
Departments of Neurology and Neurophysiology, Plymouth Hospitals NHS Trust, Plymouth, Devon, Great Britain
Epileptic nystagmus (EN) is a paroxysmal oscillation of the eyes caused by focal seizures.
Many types of EN have been reported, but the most common is conjugate and horizontal and
has been subdivided into types 1 and 2. In EN-1 there is a gaze deviation (usually contraversion)
with poor gaze holding, and thought to be caused by abnormal excitation of the cortical saccade
centres. In EN-2 the slow phases cross the midline ipsiversively with resetting quick-phases,
and is usually associated with a seizure focus in the temporo-occipito-parietal region. The
mechanism is thought to be abnormal excitation of the smooth pursuit pathways in V5 (MT/MST).
We report a case of left-beating EN-2 with partial seizures in the right temporo-occipito-parietal
cortex confirmed by EEG. Unusually, we were able to video and record eye movements during
the seizure from the conscious patient using an infrared limbus eye tracker (IRIS system). We
found that as the seizure progressed, there was an evolution of nystagmus waveforms. Initially
slow phases were linear rapidly becoming accelerative with a gradual increase in slow phase
velocity and slow phase acceleration with time. After a few seconds, slow phases became decelerative before becoming jerk-pendular. There was also a period of convergence during the
seizure.
We draw two main conclusions from this rare examination. First, unilateral activation of human
V5 can generate conjugate horizontal nystagmus with a variety of waveforms and also disturb
the gaze-holding mechanism (eye position neural integrator). The concurrence of transient convergence leads us to suspect that the homologue of MST has been abnormally excited. Second,
the waveforms observed are typical of infantile nystagmus (INS) (‘congenital nystagmus’), although the patient did not have inter-ictal nystagmus. As with most types of nystagmus, INS has
been hypothesised to result from an abnormality in the subcortical gaze centres (cerebellum/
brainstem). This case clearly illustrates that we should consider the possibility that INS could be
caused by anomalous cortical activity in V5.
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68
EVALUATION OF RETINAL FUNCTION WITH
ELECTRORETINOGRAPHIC ON- AND OFF-RESPONSE,
PHOTOPIC NEGATIVE RESPONSE AND S-CONE RESPONSE
Maja u tar, Jelka Brecelj, Marko Hawlina, Branka Stirn-Kranjc, Barbara Cvenkel
Background. The human retina is a multi-layered tissue with several different types of neural
cells. The functions of many of these cell types can be evaluated with electroretrinography, performed according to the standards of the International Society for Clinical Electrophysiology of
Vision. Recent studies have indicated that the use of additional, non-standard, electrophysiological tests can support clinical diagnostics, although to date these have not been studied extensively. These tests include: (i) the ON- and OFF-response, which evaluate the function of the
retinal ON- and OFF-bipolar cells, respectively; (ii) the S-cone response, which evaluate the
function of the retinal S-cone system; and (iii) the photopic negative response, which test the
functioning of retinal ganglion cells.
Aim: The aim of this study was to optimize these novel responses for selective evaluation of
retinal dysfunction and to develop them for clinical diagnostics.
Sub ects and Methods. The investigation was performed on 81 control subjects, 14 control
subjects with high myopia, six patients with complete congenital stationary night blindness, two
patients with enhanced S-cone syndrome, and 16 patients with primary open angle glaucoma.
The novel electroretinograms (ON- and OFF-response, S-cone response, and photopic negative
response) were recorded while the stimulus parameters (duration, intensity and wavelength)
were modulated. The responses were analyzed and their values were compared using
statistical and mathematical tools.
Results. The ON- and OFF-response, S-cone response and photopic negative response were
observed under various recording conditions in the group of control subjects, with the optimal
stimulus conditions determined according to the largest response amplitudes.
The ON- and OFF-response in congenital stationary night blindness showed significant reduction
in the b-wave, consistent with ON-bipolar cell dysfunction. The d-wave, which is believed to
reflect the function of the OFF-bipolar cells, was also influenced in these patients, particularly at
higher background luminance. Therefore, the function of the ON- and OFF-bipolar cells might
be more selectively evaluated on darker photopic backgrounds with prolonged broadband white
stimuli of intermediate intensities.
The S-cone response showed similar relationships between stimulus intensity and response
amplitudes in patients with enhanced S-cone syndrome as was seen in healthy subjects at
lower stimulus intensities, on green, yellow and red backgrounds of appropriate luminance. This
indicates that these stimulus conditions selectively elicited responses of the S-cone system.
The photopic negative response in glaucoma patients showed the greatest relative amplitude
reductions for red monochromatic stimulus, as well as greater sensitivity and specificity, rather than
for broadband stimulus. These findings suggest that ganglion cell activities can be more efficiently
evaluated with the photopic negative response elicited with red rather than broadband stimuli.
Conclusion. Pathologies with specific retinal dysfunctions confirm that the origins of these novel
responses depend on the stimulus parameters chosen. Therefore, the physiological characteristics of these responses need to be extensively studied to assess the optimal stimulus conditions
for selective evaluation of the specific retinal neural-cell types.
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69
UNUSUALLY MILD ENHANCED S-CONE SYNDROME
WITH PRESERVED MACULAR STRUCTURE: A CASE REPORT
Ivan ýima1, Jelka Brecelj2, Maja u tar2, Frauke Coppieters3,
Bart P. Leroy3,4, Elfride De Baere3, Marko Hawlina2
1
University Eye Clinic, University Hospital Sveti Duh, agreb, Croatia
Eye Hospital Ljubljana, University Medical Centre Ljubljana, Slovenia
3
Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium
4
Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium
2
Purpose. We present ophthalmic features and genetic analysis findings of a 43-year-old
Croatian patient with enhanced S-cone syndrome (ESCS).
Methods. Complete ophthalmic examination, Ishihara colour vision test, dark adaptometry,
spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging
(FAI), Goldmann visual field and automated perimetry, full-field electroretinography (ERG),
multifocal ERG, S-cone ERG and ON-OFF ERG were performed. Mutation screening of the
NR2E3 gene, which encodes a photoreceptor-specific orphan nuclear receptor, was performed
with polymerase chain reaction amplification and direct sequencing.
Results. The patient has good visual acuity and normal colour vision. Fundus examination
showed normal posterior pole and nummular pigment depositions at the level of the retinal
pigment epithelium (RPE) in the mid-periphery of the retina. The SD-OCT images showed
normal macular structure and thickness. The ERG showed characteristic findings: photopic and
scotopic responses to the same stimulus had a similar waveform and were dominated by shortwavelength-sensitive mechanisms. Mutation analysis revealed the known NR2E3 mutation
c.481delA (p.Thr161HisFsX18) and the novel NR2E3 variant c.1120C T (p.Leu374Phe).
Conclusion To our knowledge, this is the only ESCS patient older than 40 years who phenoltypically has very mild form of the disease. Although the nature of the novel variant is not clear,
we suspect that the compound heterozygosity for the sequence changes described might be
associated with the patient's mild ESCS phenotype.
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70
OPTIC NERVE HEAD DRUSEN
Satar Baghrizabehi, Teodor Robiü
General Hospital Rakiþan, Murska Sobota, Slovenia
An 18 year-old patient initially experienced continued blurred vision in the left eye only. Believing
her contact lens correction to be too strong, she returned for another examination. A dilated
fundus examination revealed that the optic discs had a lumpy-bumpy appearance, suspicious
for optic disc drusen, and she was admitted to hospital for further evaluation. Mildly blurred
vision in her left eye was the only ocular symptom.
Most patients with optic nerve drusen are asymptomatic. However, optic nerve drusen may lead
to visual field deficits including enlargement of the blind spot and arcuate scotomas. Nevertheless,
loss of central visual acuity is rare.
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71
THE DEVELOPMENT IN THE PERCEPTION OF FACIAL EMOTION
CHANGE USING ERPs
Kensaku Miki1, Shoko Watanabe1, Mika Teruya1, Yasuyuki Takeshima1, Tomokazu Urakawa1,2,
Masahiro Hirai1,3, Yukiko Honda1, Ryusuke Kakigi1,2
1
2
Department of Integrative Physiology, National Institute for Physiological Sciences. Okazaki, Aichi, Japan
Department of Physiological Sciences, School of Life Sciences, The Graduate University of Advanced Studies
(SOKENDAI), Hayama, Kanagawa, Japan
3
Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo, Japan
Aim. We investigated the development in the perception of facial emotion change using eventrelated potentials (ERPs) in children and adults.
Material and Methods. To record time-locked ERP components, a first stimulus was replaced
by a second stimulus with no inter-stimulus interval. Two different conditions were presented:
(1) N-H: A neutral face changed to a happy face. (2) H-N: Reverse of N-H. (3) N-A: A neutral
face changed to an angry face. (4) A-N: Reverse of N-A.
Results. In the right and left temporal areas, a negative component was evoked by all conditions
in children (11–14 years old) and adults (23–33 years old) within 150–300 ms. Peak latency
was significantly shorter and amplitude was significantly smaller in adults than children.
Moreover, maximum amplitude was significantly larger for N-H than other conditions in adults.
Discussion. These differences between children and adults in the perception of facial emotion
change may be due to the following: The areas of the brain involved in the change of dynamic
facial emotion have not matured by 14 years of age.
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72
ENDOTHELIAL FUNCTION OF THE POSTERIOR CIRCULATION
SUPPLYING VISUAL CORTEX
Denis Perko, Janja Pretnar-Oblak, Bojana Žvan, Marjan Zaletel
Department for vascular neurology, Department of Neurology,
University Medical Centre Ljubljana, Ljubljana, Slovenia
Background. Visual function is depended upon intact posterior circulation. However, according
to some studies endothelial function of the anterior and posterior cerebral circulation is different
in healthy subjects. The function of cerebrovascular endothelium could be evaluated by cerebrovascular reactivity (CVR) to L-arginine. To our knowledge CVR to L-arginine has not been used
previously to compare endothelial function of the anterior and posterior cerebral circulation as
well as influence of gender on endothelial function.
Patients and Methods. Thirty healthy subjects, fifteen females (aged 32.1 ± 7.1 years) and
fifteen males (aged 32.2 ± 6.3 years), were included. Every subject underwent a complete
examination that included medical history, physical and neurological examination and ultrasound of precerebral arteries. Cerebral endothelial function was determined by CVR to L-arginine. The mean arterial velocity in the middle cerebral artery (MCA) and the posterior cerebral
artery (PCA) was measured by transcranial Doppler sonography before and after intravenous
infusion of L-arginine.
Results. CVR to L-arginine was significantly higher in PCA than in MCA (p 0.01). CVR to L-arginine
was also significantly higher in females compared to males in PCA (p 0.01) and MCA (p 0.01).
Conclusions. Our study suggests that in healthy subjects endothelial function of the anterior
cerebral circulation differs from the posterior circulation. Gender has an influence on cerebral
endothelial function.
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73
VISUALLY EVOKED CEREBRAL BLOOD FLOW VELOCITY
RESPONSES
Marjan Zaletel1, Andrej Fabjan2, Martin Štrucl2
1
Department of Neurology, University Medical Center Ljubljana, Ljubljana, Slovenia
Institute of Physiology, University of Ljubljana Medical Faculty, Ljubljana, Slovenia
2
INTRODUCTION
Activation of visual cortex with visual stimuli leads to an increase in blood flow velocity in posterior
cerebral arteries (PCAs), what is called the visually evoked cerebral blood flow velocity response
(VEFR). The underlying mechanism of VEFR is neurovascular coupling, which matches the
regional cerebral blood flow to regional neuronal activity and metabolism. The mechanism of
neurovascular coupling is not clear and currently there are no methods that can directly analyse
it. Neurovascular coupling is important in neuroimaging since methods like positron emission
tomography or functional magnetic resonance imaging are based on vascular response to brain
activity. It has also been proposed that impaired neurovascular coupling plays an important role
in the pathogenesis of certain neurologic disorders [1, 2].
The fenomenon of VEFR and its properties was first described by Aaslid in 1987 using noninvasive transcranial Doppler ultrasound technique (TCD) [3]. This blind (no B-mode morphology)
method alows real-time recordings of the Doppler signal arising from the PCA from which spectral
amplitudes and flow velocity can be calculated. Relative changes in the flow volume can be
obtained assuming a constant vessel diameter. The experimental approximations of flow volume
changes are therefore only relevant under steady-state conditions when the vessel diameter
changes are small [4].
VEFRs are a convenient method of studying neurovascular coupling due to noninvasive well
time-defined stimuli, good time resolution, the fact that the visual cerebral cortex is supplied
exclusively by the PCA and that it represents a great part of PCA teritory. Visual stimulus
produces no evoked response in the middle cerebral artery (MCA) blood flow and a simultaneous recording of contralateral PCA and ipsilateral MCA offers a way to detect changes in the
blood flow velocity that are not stimulus related (eg, cyclic changes of respiration rate) or are
stimulus related but nonspecific (eg, stimulus-dependent variation of blood pressure) that would
affect both vessels [5]. Trigger-related recordings enable the use of flow velocity averaging
algorithms, thus allowing detection and quantification of small responses in the presence of
noise and various coexisting random fluctuations [5].
It has been shown that the magnitude of VEFR is related to the complexity of visual stimulus,
with more complex stimuli resulting in a greater response [6–8]. This is probably due to the fact
that more complex visual stimuli activate larger areas of human cortex as shown in experiments
using PET [9]. VEFRs show less adaptation to stimulation with more complex visual stimuli [6].
VEFRs decrease with age [6, 10–12]. There is also a reduction of cerebral activation on BOLD
fMRI in older subjects [13]. Attenuated vascular response may therefore be a consequence of
decreased neurovascular coupling.
STUDIES
Our group conducted several studies using VEFRs. We have studied the specific influence of
colour, brightness and complexity on VEFRs [7]. A total of 31 healthy subjects aged 35.1 ± 7.7
years participated in the study. Mean arterial velocity was measured in the right PCA (vPCA) and
in the left MCA (vMCA) by Multi-DopX4 (DWL). Simple-white (SW), red (R) and complex-checkerboard (C) stimuli were used. VEFRs were determined by the difference of the vPCA:vMCA ratio
before and after stimulation. The VEFRs of SW with brightness of 21.4 cd/m2, 10.5 cd/m2 and
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74
2 cd/m2 were 8.7 ± 3.4%, 9.1 ± 3.0% and 8.0 ± 3.7%, respectively (p < 0.001). The VEFRs of R
and C stimuli were 10.4 ± 6.5% and 12.4 ± 6.1%, respectively (p < 0.001). ANOVA for repeated
measurements did not show significant variances (p = 0.295) between VEFRs of SW of different
brightness, but variances between VEFRs of SW, R and C stimuli were significant (p < 0.001).
We found significant differences between VEFRs of SW and of C stimuli (3.8 ± 1.9%, p < 0.001),
VEFRs of SW and of R stimuli (1.8 ± 2.4%, p < 0.008) as well as between VEFRs of C and of R
stimuli (2.0 ± 2.5%, p < 0.010). We have concluded that SW, R and C stimuli have a specific
influence on VEFRs. Brightness does not appear to affect VEFRs.
In the other study our aim was to establish whether visual contrast affects VEFR, whether VEFRs
relate to visually evoked potentials (VEP), and whether the relationship between VEP and VEFR
is altered in patients with migraine interictally [14]. The records were made from 30 healthy
volunteers of both sexes (8 men and 22 women), aged 38 ± 9.6 years, and 30 patients with
migraine (10 men and 20 women), aged 36.6 ± 10.4 years. 16 patients had migraine without
aura (MwA) and 14 had migraine with aura (MA). Also we analyzed the differences regarding
age in a group of healthy younger subjects (37.5 ± 9.4 years) as well as healthy older ones
(69.5 ± 5.9 years) [12]. The neurologic clinical examination as well as the general physical
status were normal in all of the subjects. The angiosonography of precerebral vessels did not
show any pathologic changes. The mean arterial velocity in the left MCA (vMCA) and the mean
arterial velocity in right PCA (vPCA) were monitored using TCD. Mean arterial pressure (MAP)
was detected by continuous blood pressure monitoring. End-tidal carbon dioxide (Et-CO2) was
measured by an infrared capnograph. Heart rate (HR) was determined using TCD signal. The
experiment took place in a dark, electric and soundproof room. The visual stimulus was a
checkerboard with changing contrast; there were 1, 10 and 100% visual contrasts applied. The
vMCA, vPCA, MAP, Et-CO2 and HR were recorded simultaneously with the VEP. VEP were
recorded from 3 occipital leads (Oz, O1 and O2). The parameters were calculated and
compared at the basal state and at 1, 10 and 100% visual contrast (įvMCA, įvPCA, įMAP, įEtCO2, įHR). The differences were tested with ANOVA for repeated measurements, paired t-test
and Student t-test. The relationships were analysed with linear regression and multivariant
regression. The differences between the regression slope lines were tested by t-test.
No significant difference in the basal velocity of blood flow in the PCA was found between the
healthy controls and migraine patients. In all subjects, visual stimulation produced an immediate
increase in vPCA with no adaptation. The pattern and absolute values of velocity changes on
visual stimulation were not statistically significantly different between the controls and migraineurs.
On visual stimulation with 1%, 10% and 100% visual contrast, the vPCA increased in healthy
controls by 3.1%, 8.4% and 10.2%, respectively, and in migraineurs by 6.3%, 11.1% and 16.3%,
respectively. The increase in vPCA was statistically different at different contrasts of visual stimulus (1%, 10% and 100%) and between controls and migraineurs. The differences between the
MwA and MA were not significant at any measuring point (p = 0.58). On increase of visual
contrast the amplitude of VEP increased in healthy controls, MwA and MA. The increase in VEP
amplitude was statistically different at different contrasts of visual stimulus (1%, 10% and 100%)
in all groups. The differences in the amplitude of VEP between the experimental groups were
not statistically significant at any measuring point (p = 0.31), except that VEP was significantly
higher in MA than in controls at 10% visual contrast (p = 0.03). In order to examine neurovascular
coupling we tested the relationship between the VEP and the VEFR in healthy controls and in
patients with migraine. Linear regression analysis showed a positive correlation between the VEP
and the VEFR (r = 0.66, p < 0.01) in both healthy controls and in patients with migraine (r = 0.63,
p < 0.01). The regression coefficient (slope) in the group of patients with migraine was 0.88
(SE = 0.08) and in healthy controls 0.55 (SE = 0.07), which was statistically significant (p = 0.04).
We did not find any significant differences between regression coefficients in MwA compared to
MA (p = 0.96). The other variables, i.e. įvMCA (p = 0.11), įMAP (p = 0.22), įEt-CO2 (p = 0.18)
and įHR (p = 0.17), did not show significant differences along the measuring points in healthy
subjects (p = 0.11, p = 0.22, p = 0.18, p = 0.17, respectively) or in patients with migraine (p = 0.32,
p = 0.42, p = 0.15, p = 0.26, respectively). The differences between the both subgroups (įvMCA:
p = 0.54; įMAP: p = 0.42; įEt-CO2: p = 0.38; įHR: p = 0.67) were also not significant. In addition
a linear regression analysis was performed which showed a significant positive association
between VEP and VEFR of the younger (r = 0.66, p < 0.01) and older subjects (r = 0.74, p < 0.01).
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75
The regression coefficient of the younger subjects was significantly higher (b = 0.54) than that of
the older ones (b = 0.40, p < 0.01).
We concluded that visual contrasts affect VEFRs. Higher contrast produces higher VEFR. Visual
contrast is associated with VEP and VEFR. Furthermore, VEP are positively linearly associated
with VEFR. Thus VEFR reflect neurovascular coupling very well. Interictally, the relationship
between VEP and VEFR is altered in patients with migraine. It seem that neurovascular coupling
activity in patients with migraine is higher than in healthy subjects. Furthermore, a simultaneous
recording of VEFR and VEP at graded visual contrasts indicates diminished neurovascular
coupling in older subjects.
REFERENCES
1. Iadecola C, Gorelick PB. Converging pathogenic mechanisms in vascular and neurodegenerative dementia.
Stroke 2003; 34: 335–7.
2. Napoli C, Palinski W. Neurodegenerative diseases: insights into pathogenic mechanisms from atherosclerosis.
Neurobiol Aging 2005; 26: 293–302.
3. Aaslid R. Visually evoked dynamic blood flow response of the human cerebral circulation. Stroke 1987; 18: 771–5.
4. Kontos HA. Validity of cerebral arterial blood flow calculations from velocity measurements. Stroke 1989; 20: 1–3.
5. Sturzenegger M, Newell DW, Aaslid R. Visually evoked blood flow response assessed by simultaneous twochannel transcranial Doppler using flow velocity averaging. Stroke 1996; 27: 2256–61.
6. Panczel G, Daffertshofer M, Ries S, Spiegel D, Hennerici M. Age and stimulus dependency of visually evoked
cerebral blood flow responses. Stroke 1999; 30: 619–23.
7. Zaletel M, Zvan B, Strucl M, Pogacnik T, Kiauta T. The influence of brightness, colour and complexity on visual
evoked doppler flow responses. Ultrasound Med Biol 2002; 28: 917–22.
8. Zaletel M, Strucl M, Zvan B. The influence of visual contrast on visually evoked cerebral blood flow responses.
Ultrasound Med Biol 2004; 30: 1029–34.
9. Gulyas B, Roland PE. Processing and analysis of form, colour and binocular disparity in the human brain:
functional anatomy by positron emission tomography. Eur J Neurosci 1994; 6: 1811–28.
10. Niehaus L, Lehmann R, Roricht S, Meyer BU. Age-related reduction in visually evoked cerebral blood flow
responses. Neurobiol Aging 2001; 22: 35–8.
11. Topcuoglu MA, Aydin H, Saka E. Occipital cortex activation studied with simultaneous recordings of functional
transcranial Doppler ultrasound (fTCD) and visual evoked potential (VEP) in cognitively normal human subjects:
effect of healthy aging. Neurosci Lett 2009; 452: 17–22.
12. Zaletel M, Strucl M, Pretnar-Oblak J, Zvan B. Age-related changes in the relationship between visual evoked
potentials and visually evoked cerebral blood flow velocity response. Funct Neurol 2005; 20: 115–20.
13. Langenecker SA, Nielson KA, Rao SM. fMRI of healthy older adults during Stroop interference. Neuroimage
2004; 21: 192–200.
14. Zaletel M, Strucl M, Bajrovic FF, Pogacnik T. Coupling between visual evoked cerebral blood flow velocity
responses and visual evoked potentials in migraneurs. Cephalalgia 2005; 25: 567–74.
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76
SURGICAL TREATMENT OF COMPLETE/TOTAL BINOCULAR
OCULOMOTOR NERVE PALSY FOLLOWING CEREBROVASCULAR
INFARCT – A CASE REPORT
Dragica Kosec, Gregor Hawlina, Brigita Drnovšek Olup
Introduction. A case of complete/total binocular oculomotor nerve palsy after cerebrovascular
infarction (CVI) following chronic atrial fibrillation and hypertension in a 69-year old woman is
presented. She had total/complete blepharoptosis and divergent paralytic squint with limitation
of adduction, elevation and depression on both eyes. Both pupils were dilated and did not react
to light. She had also nuclear and posterior subcapsular cataract. BCVA (best corrected visual
acuity) was counting fingers on right eye and 0–2 on the left eye.
Results. Nine months after CVI, surgery in general anesthesia was performed. The same procedure was done on both eyes: surgery/operation of blepharoptosis and transposition of lateral
rectus to the insertion of the medial rectus muscle. Paralytic divergent squint was corrected by
splitting lateral rectus muscle and then leading the superior half of the muscle beneath the
superior rectus and the inferior half of the muscle beneath the inferior rectus to the insertion of
the medial rectus. Both halves were attached to the sclera on the upper and lower side of the
insertion of the medial rectus. Afterwards, blepharoptosis was corrected with mersilene mesh
suspension to the frontalis muscle.
Conclusion. Three months postoperatively, the patient can open and close her eyes, she can
look straight ahead with residual 16 prisms of divergent deviation. With the exception of some
abduction, ductions are limited in all directions on both sides. BCVA is 0.2 on both eyes. Her
quality of life improved.
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77
UNILATERAL OR ASYMMETRIC PIGMENTARY RETINOPATHY?
A CASE REPORT
Igor Petriþek1, Zlatko Juratovac1, Rajko Pokupec1, Branimir Cerovski1, Goranka Petriþek2
1
2
Zagreb University Medical School Ophthalmology Dept., Zagreb University Clinical Hospital, Zagreb, Croatia
Zagreb University Medical School, Family Medicine Dept., Andrija Štampar School of Public Health, Zagreb, Croatia
Pigmentary retinopathy or retinitis pigmentosa (RP) is a term associated with a group of genetic
diseases that generally present with recognizable phenotypic retinal pigmentary changes.
The classical clinical triad of retinitis pigmentosa is arteriolar attenuation, retinal bone-spicule
pigmentation and waxy disc pallor. Patients develop progressive photoreceptor-cell degeneration
and, consequently, visual impairment.
One of the cardinal criteria for establishing the diagnosis of RP is bilateral retinal involvement.
Cases that show marked asymmetry or unilaterality are extremely rare, and are a great challenge to the clinician in establishing the proper diagnosis- RP or not? It must always be borne in
mind that it is most frequently a case of a young patient, and the visual prognosis, which should
be based on the eventual diagnosis, would determine his or hers future life and career.
A case of a highly asymmetric (or unilateral?) RP in a young male (19) is presented.
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78
CORTICAL RESPONSES AFTER INTRAOPERATIVE ELECTRICAL
STIMULATION OF THE OPTIC NERVE
Mitja Benediþiþ, Roman Bošnjak
Department of Neurosurgery, University Medical Center Ljubljana, Ljubljana, Slovenia
Introduction. The aim was to present cortical responses (CR) after electrical epidural stimulation of the optic nerve (ON) in individuals with normal preoperative vision undergoing surgery
for central skull base tumors.
Methods. Optic nerve evoked potentials (ONEP) after flash and electrical stimulation and flash
VEP were additionally recorded. CR and flash VEP were recorded with contact electrodes at Oz
with the reference at Fz. Monopolar ONEP were recorded with insulated platinum ball-tipped
wire electrode on the surface of ON and an extra-cephalic reference electrode. The distance
between stimulating and recording electrodes when recording ONEP after electrical epidural
stimulation of ON was 25 mm. Platinum blunt needle electrodes were attached epidurally to
both sides of ON when it enters or exits the optic canal and used for electrical stimulation and
used to deliver a rectangular current pulse (intensity 0.2–5.0 mA; duration 0.1–0.3 ms; rate
2 Hz). LED flash goggles were used for flash stimulation through the closed eyelids.
Results. CR after electrical epidural stimulation of ON consisted of a positive and a negative
deflection at 20 ms and 30 ms, respectively, and a smaller positive deflection at 40 ms. ONEP
after flash stimulation consisted of a positive deflection with a latency around 40 ms, followed by
a longer-lasting negativity with the peak at around 50 ms. ONEP after electrical epidural stimulation of ON consisted of a negative deflection at around 3 ms. Preliminary results showed
changes of the amplitude of CR after electrical epidural stimulation of ON, which were related to
the neurosurgical manipulation of ON.
Conclusions. Stable and repeatable CR after electrical epidural stimulation of ON could safely
be recorded in humans during neurosurgery. Further studies are needed to establish their role
in intraoperative monitoring of the visual function.
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79
EYE-TRACKING AS A MEASURE OF COGNITIVE PROCESSES IN
CHILDREN: TWO PARADIGMS
Marijan Palmoviü1, Ana Branka Šefer1, Magdalena Krbot1, Velimir Išgum2
1
2
University of Zagreb, Zagreb, Croatia
University Hospital Zagreb, Department of Neurology, Zagreb, Croatia
In the recent years eye-tracking has proved itself as a good instrument for studying cognitive
functions such as memory, attention or language. In language related studies two major paradigms have been developed: the listening paradigm and the reading paradigm. In the listening
paradigm subjects listen to a sentence while watching a scene or pictures related to the sentence.
In the reading paradigm subjects simply read a sentence presented on a computer screen. In
both paradigms a number of dependent measures can be obtained: fixation number, duration or
position, saccade number or the number of back saccades. The information about the cognitive
processes are obtained by manipulating the content of the sentences and pictures or grammatical complexity of the sentences etc.
For each paradigm an example is given: for the listening paradigm a study of anticipatory gaze
in children with typical language development (age 9–10) and in children with Specific Language
Impairment (SLI) will be presented. It is expected that the children with SLI are particularly affected in processing grammatical information and that the experiment would reveal their specific
weaknesses in language processing. In this study the anticipatory gaze depends on the fast
build-up of the syntactic structure (argument structure of the verb). The pictures that accompany
each sentence represent either the (syntactic) arguments of the verbs (in one experimental
condition) or objects of semantically related words (with the mismatch in gender so that they
cannot be grammatically correct arguments). Anticipatory gaze proved to be greater in the
group of children with typical language development (our control group) while the children with
SLI showed small anticipatory gaze in the syntactic condition and greater in the semantic condition. This indicated their compensatory strategy for the impairment that affects mainly morphosyntactic processing.
In the second experiment the reading paradigm was used to test the psycholinguistic reality of
the argument structure and the theory behind the concept of the Aktionsart (classification of the
verbs according to the type of action they encode and the number of arguments they have). To
this end the grammatical notion of the aspect in Croatian (or any other Slavic language) can be
well exploited since the majority of perfective/imperfective pairs show differences only in the
Aktionsart and, therefore, in the argument structure (e.g. while þitati 'to read: IMPF' can have
one argument, proþitati 'to read:PFV' must have at least two). Therefore, sentences that change
the verb from imperfective to perfective can easily be constructed with a violation in the constituent
(argument) structure. The number of back-saccades in the specific place in the sentence has
shown to be a good measure of cognitive processes that are related to the constituent (argument)
structure processing, i.e., they can be traced to specific syntactic processing.
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80
CEREBROSPINAL VENOUS OUTFLOW AND EYE MOVEMENTS
Miro Denišliþ1, Zoran Miloševiþ2, Marjeta Zorc3
1
Nevrit d.o.o., Ljubljana
Institute of Clinical Radiology, University Medical Centre Ljubljana, Ljubljana, Slovenia
3
Institute of Histology and Embryology of the University of Ljubljana Medical Faculty, Ljubljana, Slovenia
2
Background. Multiple sclerosis (MS) is a chronic autoimmune disease. A recent publication on
chronic cerebrospinal venous insufficiency (CCSVI) as a potential aetiologic factor of MS [1] has
stirred the professional and lay (especially patient) public. It seems there is a strong association
between MS and CCSVI. It is supposed that multiple stenoses of the extracranial venous pathway, as demonstrated by Doppler sonography and selective venography, cause obstruction of
the venous outflow resulting in an increased storage of iron in the brain.
Patient. We present a case of a female patient with relapsing-remitting MS and many episodes
of optic neuritis (ON). She was complaining of blurred vision, loss of colour vision and paresthesias
on the left side of the body. Additionally, she reported bladder dysfunction, manifested by urgency
and frequency. Neurological examination revealed internuclear ophthalmoplegia, brisk reflexes
bilaterally, and extensor plantar reflex left. EDSS was 2.0.
Methods. According to Doppler sonography, 2 of the 5 criteria required for the CCSVI were fulfilled. To rule out or demonstrate stenoses of the venous pathway, she approved to selective
venography. An angiographic catheter was introduced into the jugular veins and the azygous
venous system via transfemoral route.
Results. Selective venography demonstrated a 70% stenosis of the left jugular vein with rich
collateral flow. Percutaneous transluminal angioplasty resulted in evident amelioration of the
venous flow. No abnormality in the azygous venous system could be found. A few hours after
angioplasty, normal eye movements were noticed, and a few days later on, the patient reported
improvement of her colour vision.
Conclusion. In the presented MS case with eye movement limitation and colour vision impairment, both signs of the disease vanished after transluminal angioplasty, as documented also by
ophthalmologists. Following angioplasty, venous flow and drainage were found improved, venous
pressure in the brainstem and to the optic pathway was reduced. A clinical study on potential
role of CCSVI in the aetiology of MS, as indicated also in the presented case, has been proposed.
REFERENCE
1. Khan O, Filippi M, Freedman MS, Barkhof F, Dore-Duffy P, Lassmann H, et al. Chronic cerebrospinal venous
nsufficiency and multiple sclerosis. Ann Neurol 2010; 67 (3): 286–90.
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81
DISSEMINATION IN SPACE IN MULTIPLE SCLEROSIS:
THE ROLE OF VEP IN DIFFERENT STAGES OF THE DISEASE
Uro Rot
Department of Neurology, University Medical Centre, Ljubljana, Slovenia
The diagnosis of multiple sclerosis (MS) is based on objective determination of dissemination of
neurological symptoms/signs in space and time of the central nervous system. Early diagnosis
is important because immunomodulatory treatment is very effective in early stages of MS, especially
in patients with clinically isolated syndromes (CIS). Among paraclinical investigations for determination of dissemination in space, modern McDonald criteria use MRI imaging and visual evoked
potentials (VEP). MRI is very sensitive and shows typical lesions in nearly all patients with MS.
The value of VEP is mainly in determination of clinically silent lesions in patients without history
of optic neuritis. Clinically silent lesions not only help establishing the diagnosis of MS, but also
have prognostic importance. CIS patients with only two silent lesions almost invariably develop
MS as early as after two years. Furthermore, CIS patients with more than 10 brain MRI lesions
have worse prognosis after 5, 14 and even after 20 years of follow-up, as measured by an
EDSS score.
The aim of our analysis was to evaluate the importance of VEP in determination of dissemination
of space in different stages of MS and subgroups of CIS patients. In our first analysis we included 130 patients (90 women) with CIS (27 patients) and MS. Brain MRI showed typical MS
lesions in 95% of all patients (80% in patients with CIS). Prolonged latencies of VEP were seen
in 59% of patients, 29% of CIS patients, 66% of relapsing-remitting (RR), 75% of secondary
progressive (SP) and 63% of primary progressive (PP) MS patients. In second analysis we
compared characteristics of patients with the earliest MS (CIS patients with at least 2 clinically
silent lesions, 40 patients) with characteristics of patients with RRMS (95 patients) and found
that the former had less often prolonged latencies of VEP (32%) than the latter (67%). Among
CIS patients with only one or no brain MRI lesions and no evidence of optic nerve involvement,
abnormal VEP was found in only 22%. In our third analysis we compared characteristics of CIS
patients with high brain MRI lesion load ( 10 lesions) with characteristics of the remaining CIS
patients. Sixty-five patients were included in the analysis; 33 patients had high brain MRI lesion
load. Prolonged latencies of VEP were found in 50% of patients with high brain MRI lesion load
while compared to only 10% in the remaining CIS patients.
Our results show that sensitivity of VEP for determination of dissemination in space is lower than
sensitivity of MRI. The investigation is important in patients with PPMS where the course of the
disease is atypical, MRI sometimes unrevealing, but VEP often prolonged. We recommend VEP
be done in patients with CIS where brain MRI lesion load is often low, though positive results
are only expected to be found in approximately one third of patients. It is usually not necessary
to perform VEP in patients with RR or SPMS.
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82
IMAGING AND ELECTROPHYSIOLOGY IN STARGARDT DYSTROPHY
Martina Jarc-Vidmar, Petra Popoviü, Eva Lenassi, Jelka Brecelj, Marko Hawlina
Background. The aim of our study was to evaluate retinal function in patients with Stargardt
dystrophy with genetically determined mutation in the ABCR gene by correlating retinal function
with retinal morphology.
Patients and Methods. Twelve patients (10 F, 2 M, VA: 0.2 0.2) were included in the study.
The autofluorescence was recorded by scanning laser ophthalmoscope (HRA). The central 10
visual fields were tested with Octopus M2 TOP and microperimetry (MP1, Nidek technologies),
that enables one to compare central retinal sensitivity and fixation patterns in relation to the fundus
image. PERG and mfERG were recorded in all the patients according to the ISCEV standards.
Results. The patients had three patterns of fundus changes seen on autofluorescence: hyperfluorescent parafoveal ring (2 patients), hypo-hyperfluorescent flecks centrally in the macula
(SMD-6 patients) and extensive hyperfluorescent flecks all over the fundus (FF – 4 patients).
There was a high correlation found between microperimetry (MP) and static perimetry (MD,
r = 0.6, p = 0.008). Shift of fixation to the preffered retinal locus was found in 8 out of 16 eyes
tested with VA 0.2 and less. In patients with absolute central scotoma and shifting of fixation
(seen with MP) scotoma may erroneously be interpreted as eccentric when seen only with static
perimetry (Octopus M2 TOP). Full field ERG was normal in five out of six patients recorded, one
patient had abnormal cone-derived responses with normal rod activity. mfERG showed reduced
responses mostly in the inner three rings (ring 1: 33.9% of mean normal value, ring 2: 35.4%,
ring 3: 57.5%, ring 4: 75.5%, ring 5: 84% of mean normal value). There was good correlation
between mfERG and pattern P50 (r = 0.7, p = 0.0001) and N95 responses (r = 0.6, p = 0.004).
Conclusions. In patients with Stargardt dystrophy different pattern of fundus changes were
seen by AF – parafoveal ring, SMD, FF. Microperimetry is important in evaluating fixation shift.
In those with visual acuity 0.2 and lower, the fixation shift to the preferred retinal locus was
observed. mfERG was reduced mostly in the inner three rings. There was good correlation
between mfERG and PERG responses.
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83
THE USE OF LARGE FIELD PERG
IN ROUTINE ELECTROPHYSIOLOGY TESTING
Eva Lenassi1,2, Anthony G. Robson2,3, Marko Hawlina1, Graham E. Holder2,3
1
2
Moorfields Eye Hospital, London, Great Britain
3
UCL Institute of Ophthalmology, London, Great Britain
Background. Pattern electroretinography (PERG) provides an objective assessment of macular
function and is an important component of the management of patients with presumed macular
or generalized retinal disease. The International Society for Clinical Electrophysiology of Vision
(ISCEV) Standard for PERG recommends a stimulus field of 15 ( 3) degrees. Additional use of
a larger stimulus field could provide complementary information in diagnostic workup of patents
with macular diseases.
Aim. To report the large and standard field PERG data in an unselected sequential cohort of
277 patients referred for routine electrophysiological assessment.
Methods. PERGs to both 15 x 12 (ISCEV Standard) and 30 x 24 checkerboard field sizes
were recorded with gold foil electrodes in 277 consecutive patients, aged 10–79 years, sent for
electrophysiology testing. The most common referral diagnoses were unexplained visual acuity
loss (21%), macular disease (16%), Retinitis Pigmentosa (14%) and optic neuropathy (8%). The
Check size was 0.75 . Most patients had additional tests that included full-field ERG, electrooculography, multifocal ERG (mfERG) or visual evoked potentials. Additional data from 27 healthy
subjects were obtained to serve as controls.
Results. In normal subjects, the mean difference ( SD) between P50 amplitude to large and
standard field PERG was 4.8µV ( 1.5 µV; range 2.2–8.6 µV). The lower limit of normal was a
difference of 1.9 ȝV. PERG data from 24 patients (9%) were excluded due to poor compliance
(n = 17) or nystagmus (n = 7). The large field PERG provided clinically useful additional information in 53% (n = 261) of the eyes. In the eyes with macular disorders it enabled determination
of the extent of the dysfunction and eyes could be classified with central (29%), peripheral (2%)
or widespread macular dysfunction (59%). The spatial extent of spared macular function in
peripheral retinal degenerations could be estimated with the large field PERG. 15% of patients
had normal responses to both stimulus fields, indicating sparing of macular function; in 11%
large field PERGs were abnormal and standard PERGs normal, consistent with paracentral
macular dysfunction. Responses were abnormal to both stimuli in 63% of patients, consistent
with widespread macular dysfunction. MfERGs and retinal imaging, available in some cases,
correlated with the PERG findings.
Discussion. The large field PERG allowed additional assessment of eccentric macular function.
It was particularly useful in disorders such as Stargardt fundus flavimaculatus for assessing the
spatial extent of central macular dysfunction and in Retinitis Pigmentosa for assessing involvement of paracentral areas. The data corresponded well with mfERGs, and as the PERG is less
affected by unsteady fixation may be more useful in patients unable to maintain precise fixation.
In electrophysiological laboratories without mfERG, but with pattern stimulus facilities, the
recording of PERG to both stimulus fields provides detailed information about central retinal
function over a greater area.
Conclusion. The large field PERG helped to distinguish between localized central, predominantly
paracentral and widespread macular dysfunction. There was a good correspondence with the
results of mfERG and /or imaging. Routine use of the large field PERG enables improved management, both in diagnosis and counselling.
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WHAT DOES CHROMATIC VEP RESPONSE TELL US IN
CONGENITALY COLOUR DEFICIENT CHILDREN
Manca Tekavþiþ Pompe, Branka Stirn Kranjc, Jelka Brecelj
Congenital red-green colour vision deficiencies are present in 8–12% of male and in about 0.5%
of female population and are mostly X-linked recessively inherited [1, 2]. The most common
congenital colour vision deficiencies are deuteranomaly, protanomaly, deuteranopy and protanopy.
In deuteranomaly (5% of the population) there are all three cone pigments present, with medium
wavelength (M) cone pigment being abnormal. In protanomaly (1% of the population) there all
three cone pigments present, with long wavelength (L) cone pigment being abnormal. In deuteranopy (1% of the population) there are only two functional cone pigments, M being absent. In
protanopy (1% of the population) there are two functional cone pigments, L being absent [3].
With a battery of psychophysical tests, the exact axis and degree of colour vision deficiency can
be determined [1]. A small battery of psychophysical tests consisting of a screening test (the
Ishihara plates), a grading test (the D15 test) and a diagnostic test (the Nagel anomaloscope)
can provide a complete analysis of congenital red-green deficiency. The addition of the FM 100
hue test provides information about practical hue discrimination ability [1]. However, most of the
standard psychophysical tests are less suitable for testing children, since certain motor and
cognitive skills are required to perform them correctly.
The idea of using electrophysiological tests as an objective method to differentiate between a
person with congenital colour vision deficiency and a person with normal colour vision is not
new [4]. Many investigators have used chromatic stimuli with different stimulus and stimulation
characteristics, which produced many achromatic intrusions. Pioneer studies were mainly
focused on investigating stimulus characteristics for selective stimulation of the parvocellular
visual pathway [5–9].
Since there are no studies where more than a few children with congenital colour vision deficiency
have been investigated, the purpose of this study was to evaluate VEP responses to isoluminant
red-green stimulus in a group of schoolchildren with congenital red-green colour deficiency and
to compare these responses to normative data [10].
VEP responses of 15 colour deficient children were compared to 31 children with normal colour
vision. An isoluminant red-green stimulus composed of horizontal gratings was presented in an
onset-offset manner. The shape of the waveform was studied, as well as the latency and amplitude of positive (P) and negative (N) waves. cVEP response didn’t change much with increased
age in colour deficient children, whereas normative data showed changes from predominantly
positive to negative response with increased age. A P wave was present in 87% of colour deficient children (and in 100% of children with normal colour vision), whereas the N wave was
absent in a great majority of colour deficient children and was present in 80% of children with
normal colour vision. Therefore, the amplitude of the whole response (N-P) decreased linearly
in colour deficient children, whereas in children with normal colour vision it increased linearly. P
wave latency shortened with increased age in both groups.
This study has clearly demonstrated the difference between chromatic VEP responses of redgreen congenital colour vision deficient children and normal controls.
REFERENCES
1. Birch J. Diagnosis of defective colour vision. Oxford: Oxford University Press, 1993): 43.
2. Neitz M, Neitz J.Molecular genetics of color vision and color vision defects. Arch Ophthalmol 2000; 118: 691–
700.
3. Adams AJ. Color vision testing in optometric practice. J Am Optom Assoc 1974; 45: 35.
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85
4. Regan D, Spekreijse H. Evoked potential indications of colour blindness. Vis Res 1974; 14: 89–95.
5. Carden D, Kulikowski JJ, Murray IJ, Parry NRA. Human occipital potentials evoked by the onset of equiluminant
chromatic gratings. J Physiol (Lond) 1985; 369: 44.
6. Murray IJ, Parry NRA, Carden D, Kulikowski JJ. Human visual evoked potentials to chromatic and achromatic
gratings. Clin Vis Sci 1987; 1: 231–44.
7. Rabin J, Switkes E, Crognale M, Schneck ME, Adams AJ. Visual evoked potentials in three-dimensional colour
space: correlates of spatio-chromatic processing. Vis Res 1994; 34: 2657–71.
8. Robson AG, Kulikowski JJ. Verification of VEPs elicited by gratings containing tritanopic pairs of hues. J Physiol
1995; 475: 22.
9. Switkes E, Crognale MA. Comparison of color and luminance contrast: apples versus oranges? Vis Res 1999;
39: 1823–31.
10. Tekavþiþ Pompe M, Stirn Kranjc B, Brecelj J. Visual evoked potentials to red-green stimulation in schoolchildren.
Vis Neurosci 2006; 23: 447–51.
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CLINICAL VISUAL ELECTROPHYSIOLOGY: A PRACTICAL OVERVIEW
1
Graham E. Holder
Moorfields Eye Hospital and Institute of Ophthalmology, London; Great Britain
INTRODUCTION
Electrophysiological examination of the visual system provides objective information in relation
to the function of the visual pathways, often with a significant effect on the diagnosis and management of the patient [1]. The main test armamentarium consists of the electrooculogram (EOG),
which examines the function of the retinal pigment epithelium (RPE) and the interaction between
the RPE and the (rod) photoreceptors; the electroretinogram (ERG), the massed retinal responses to full-field luminance stimulation, which reflects the function of the photoreceptors and
inner nuclear layers of the retina; the pattern electroretinogram, which, in addition to being
“driven” by the macular photoreceptors, arises in relation to retinal ganglion cell function; and
the visual evoked cortical potential (VEP or VECP), which examines the intracranial visual
pathways. The interrelationships between PERG and ERG, and PERG and VEP, have recently
been addressed [2].
Electrophysiological recordings strongly relate to stimulus and recording parameters and the
adaptive state of the eye, and standardisation is therefore mandatory for meaningful scientific
and clinical communication between laboratories. The International Society for Clinical Electrophysiology of Vision (ISCEV) has published Standards for EOG [3], ERG [4], PERG [5], and the
VEP [6]. Typical normal ERG traces from the author’s laboratory are shown in Fig. 1.
Fig. 1. Nornal electroretinoghraphic recordings
A brief overview of each test modality is provided, with emphasis on response generation and
the clinical significance of the results. Referencing has been restricted; the reader is referred to
standard texts for further details [7, 8]. The multifocal ERG is, in the author’s view, a research
tool, and thus is not addressed.
THE ELECTROOCULOGRAM
The electrooculogram (EOG) is a measure of the function of the retinal pigment epithelium
(RPE), and the interaction between the RPE and the photoreceptors. The patient makes fixed
* Updated from a paper in the Journal of the College of Ophthalmologists of Sri Lanka
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30-degree lateral eye movements during a period of 20 minutes dark adaptation, and then
during a 12–15 minute period of light adaptation. The eye movements are made every 1–2 s for
approximately 10 s every minute. The amplitude of the signal recorded between electrodes
positioned at medial and lateral canthi reaches a minimum during dark adaptation, the dark trough,
and a maximum during light adaptation, the light peak. The development of a normal light peak
requires normally functioning photoreceptors in contact with a normally functioning RPE, and is
caused by progressive depolarisation of the RPE basal membrane by mechanisms which are
not fully understood. The EOG is quantified by calculating the size of the light peak in relation to
the dark trough as a percentage, the Arden index. A normal EOG light rise will be 175%.
THE ELECTRORETINOGRAM
The electroretinogram (ERG) is the mass electrical response of the retina to luminance stimulation. It is recorded using corneal electrodes with stimuli delivered by a Ganzfeld bowl, an
integrating sphere enabling uniform whole field illumination. The Ganzfeld provides both flash
stimulation and a diffuse background for photopic adaptation. The reference electrodes should
be positioned at the ipsilateral outer canthi if a bipolar contact lens electrode with a built-in
reference is not used. ISCEV defines a standard flash as 1.5–3.0 cd.s.m-2. The response to this
flash under scotopic conditions, with a fully dilated pupil, is the maximal or mixed response (Fig.
1). It is this maximal response that is often regarded as the “typical” ERG, but it should be noted
that although there is a cone contribution, the maximal response is dominated by rod driven
activity. The “maximal” ERGs herein were recorded to an 11.0 cd.s.m-2 flash better to view the
a-wave, the initial 8–10 ms of which principally reflects hyperpolarisation of the (rod) photoreceptors. Indeed, the slope of the a-wave has been related to the kinetics of phototransduction
[9]. The positive b-wave is generated post-receptorally in relation to depolarisation of the ONbipolar cells [10]. The origins of the ERG have been recently reviewed [11]. The oscillatory
potentials, the small oscillations on the ascending limb of the b-wave, are probably generated in
relation to amacrine cell activity. A rod-specific b-wave is obtained when the standard flash is
attenuated by 2.5 log units. At this luminance there is insufficient photoactivation to record an awave (Fig. 1).
Cone system ERGs are obtained under photopic conditions using both single flash and 30 Hz
flicker stimulation superimposed upon a rod-saturating background (17–34 cd/m2). At 30 Hz, the
poor temporal resolution of the rod system, in addition to the presence of a rod-suppressing background, enables a cone-specific waveform to be recorded. This response is perhaps the more
sensitive measure of cone dysfunction, but is generated at an inner retinal level [12]. Better
localisation within the retina may be obtained with the single flash cone response. Although
there is a demonstrated contribution of the hyperpolarising (OFF) bipolar cells to shaping the
photopic a-wave [13], this component is probably at least partly generated in relation to cone
photoreceptor function. The cone b-wave probably reflects post-phototransduction activity, and
to a short flash stimulus ON- and OFF- activity within the photopic system is effectively synchronised. There is no significant retinal ganglion cell contribution to the clinical (flash) ERG. As a
mass response, the ERG is normal when dysfunction is confined to small retinal areas, and,
despite the high photoreceptor density, this also applies to macular dysfunction; an eye with
disease confined to the macula has normal ERGs (e.g. Fig. 2).
Separation of the cone ON- (depolarising bipolar cells, DBCs) and OFF- (hyperpolarising bipolar
cells, HBCs) sub-systems can be achieved using a long duration stimulus with a photopic background [14]. The stimulus is usually generated either via a shutter system or by using light emitting diodes.
THE PATTERN ELECTRORETINOGRAM
The pattern electroretinogram PERG is the response of central retina to an iso-luminant stimulus,
usually a reversing black and white checkerboard. It allows both a measure of central retinal
function, and an evaluation of retinal ganglion cell function. It is thus of great value in the electrophysiological differentiation between optic nerve and macular dysfunction (see [2] for a com
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88
prehensive review). The PERG is recorded using non-contact lens electrodes in contact with the
cornea or bulbar conjunctiva to preserve the optics of the eye, and without mydriasis. The most
common electrodes are the gold foil [15], the DTL [16] and the H-K loop electrode [17]. Ipsilateral outer canthus reference electrodes are necessary to avoid the contamination from the
cortically generated VEP that results if forehead or ear reference electrodes are used [18].
Fig. 2. Typical patterns of ERG abnormality
The transient PERG has 2 main components: P50 at approx. 50 ms and a larger N95 at 95 ms
[19]. Measurement concentrates on the amplitude of P50, from the trough of the early negative
N35 component; the latency of P50 measured to peak; and the amplitude of N95, measured to
trough from the peak of P50 (Fig. 1). N95 is a contrast-related component in relation to the
retinal ganglion cells. Approximately 70% of P50 appears to be generated in the ganglion cells,
but the remainder is not related to spiking cell function and may be generated more distally [20].
The exact origins are yet to be ascertained. Although the PERG is generated in inner retina, the
P50 component reflects macular function.
For optimal recording of the PERG, an analysis time of 150 ms or greater is usually used with
approximately 150 averages per trial. It is a small response and stringent technical controls are
important during recording. These have been fully discussed elsewhere [8]. Binocular stimulation
and recording is usually preferred so the better eye can maintain fixation and accommodation,
but if there is a history of squint it is necessary to use monocular recording. P50 is sensitive to
optical blur, and accurate refraction is important. PERG amplitude is related almost linearly to
stimulus contrast at low stimulus frequencies. ISCEV recommends a high contrast black and
white reversing checkerboard with 40 minute checks in a 10–16 degree field.
THE VISUAL EVOKED POTENTIAL
The visual evoked potential (VEP) is mostly generated in relation to cortical function. The responses are recorded to monocular stimulation using occipitally placed electrodes, and are used
to assess the intracranial visual pathways, particularly the optic nerves and optic chiasm. The
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responses to patterned stimuli are most sensitive to visual pathway dysfunction. A reversing black
and white checkerboard is usually adopted as a routine stimulus. Pattern onset/offset is particularly effective in certain conditions (see below), and diffuse flash stimulation may also be useful.
The transient (< 2/sec recommended) checkerboard reversal VEP contains a prominent positive
component at approximately 100 ms (Fig. 3). This is known as P100. Stimulus parameters such
as contrast, luminance, check size, field size etc., are important determinants of the waveform,
and it is essential for each laboratory to establish their own normal controls. The size of the
stimulus field is particularly relevant to the use of hemi-field stimulation; there is paradoxical
lateralisation of the hemi-field pattern VEP with a large field, large check stimulus (as recommended by ISCEV), such that the hemi-field response is recorded over the hemisphere ipsilateral to the stimulated hemi-field, but anatomical lateralisation occurs with a small field, small
check stimulus. This latter small field, small check stimulus can be used to facilitate accurate
identification of the P100 component in case of doubt. A single midline recording channel is not
suitable for chiasmal assessment. The pattern appearance (onset/offset) VEP is most appropriate
for the assessment of visual acuity, and in the detection of the intracranial misrouting associated
with albinism. It is also less affected than the reversal VEP in a patient with nystagmus in the
primary position of gaze; under such circumstances pattern reversal VEP results must be treated
with considerable caution.
Fig. 3. Right optic nerve conduction delay following recovered optic neuritis. Note the reduction in the
right eye PERG N 5 component.
CLINICAL APPLICATIONS
Electrooculogram
Any disorder that affects rod photoreceptor function will affect the EOG, and the light rise is
typically severely reduced in RP and related photoreceptor degenerations. In general, the
reduction in EOG light rise reflects the degree of rod photoreceptor dysfunction, and any discrepancy between the level of EOG reduction and the (rod) ERG should alert to the probability
of generalised RPE dysfunction. The principal use of the EOG in clinical practice is in the diagnosis of Best vitelliform macular dystrophy (dominantly inherited; carriers also have abnormal
EOGs), where the diagnostic findings are a severely reduced or absent EOG light rise accompanied
by a normal ERG (Fig. 4). The EOG light rise in adult vitelliform macular dystrophy or pattern
dystrophy may be mildly subnormal, but is not reduced to the same extent as in Best disease. A
new disorder has recently been reported, autosomal recessive bestrophinopathy (ARB; [21])
where there is also severe loss of EOG light rise. ARB is a recessively inherited progressive
retinal dystrophy, like Best disease consequent upon mutation in BEST1. However, unlike Best
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disease, affected patients have abnormal ERGs, but not sufficiently abnormal to explain the
profound degree of EOG light rise reduction. In addition, ARB requires mutations on both alleles
and carriers do not show an EOG abnormality.
Fig. 4. Best disease. Normal ERGs but abolished EOG light rise
A further use of the EOG occurs in inflammatory disease in the diagnosis of AZOOR (acute
zonal occult outer retinopathy), which may occur consequent upon disorders such as MEWDS
(multiple evanescent white dot syndrome); mulitifocal choroiditis; punctate inner choroidopathy;
macular neuroretinitis etc. AZOOR remains poorly defined and poorly understood, but a recent
attempt to define some diagnostic criteria included the EOG [22].
Electroretinogram
Reduction in the rod specific ERG b-wave is a sensitive indicator of rod system dysfunction, but,
being generated in the inner nuclear layer, this does not allow localisation of the defect either to
those structures or the rod photoreceptors. It is the maximal response a-wave that directly reflects
activity of the photoreceptors. Genetically determined retinal degenerations, such as rod-cone
(retinitis pigmentosa) and cone-rod dystrophies, thus give overall ERG reduction consequent
upon photoreceptor degeneration (Fig. 2). RP initially may only affect the rod-derived ERGs. True
sector (restricted) disease may give amplitude reduction with no implicit time change, whereas
diffuse or generalised disease is usually also associated with abnormal implicit time. The fundal
appearance may not reflect the severity or nature of the disorder; the ERG enables accurate
diagnosis and may provide prognostic information. Cone dystrophies have normal rod responses,
but abnormal cone responses, with the 30 Hz flicker response usually showing both amplitude
reduction and delayed implicit time. Delayed 30 Hz flicker ERGs are also a feature of inflamamatory disorders such as birdshot chorioretinopathy, but there may be less marked amplitude
change. Indeed, the 30 Hz flicker in birdshot chorioretinopathy is not only a sensitive indicator of
generalised retinal dysfunction [23], but can also be used to guide management decisions by
objectively assessing retinal function [24]. Delay in the flicker ERG is also anticipated in AZOOR.
The presence of a “negative” ERG, where the a-wave is spared and there is selective b-wave
reduction, indicates dysfunction post-phototransduction, and probably post-receptoral. The
“negative” ERG in central retinal artery occlusion (CRAO) reflects the duality of the retinal blood
supply with RPE/photoreceptors supplied via choroidal circulation, but bipolar cells supplied via
central retinal artery. Other causes of negative ERG include X-linked congenital stationary night
blindness (CSNB, Fig. 2), X-linked retinoschisis, quinine toxicity, melanoma associated retinopathy (MAR), Batten disease, occasionally cone-rod dystrophy, and birdshot chorioretinopathy.
The causes of negative ERG have recently been extensively reviewed [25]. Carcinoma associated
retinopathy (CAR) does not usually give a “negative” ERG but profound global ERG reduction in
keeping with dysfunction at the level of the photoreceptor. This has been related to antibodies to
recoverin or enolase.
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Multifocal ERG
The multifocal ERG (mfERG) provides spatial information regarding cone system function in
central retina. The stimulus consists of multiple scaled hexagons displayed on a screen, each of
which flashes on with its own pseudo-random binary sequence (an M-sequence). Complex
mathematics derives the individual responses relating to each individual hexagon, generating
multiple cone system ERG waveforms from a single recording electrode. The mfERG can be of
use in disturbances of macular function and to assess the extent of central retinal involvement
in generalised retinal disease, but is highly susceptible to poor fixation, and the ability of a
patient accurately to maintain good fixation throughout the recording session is a pre-requisite
to obtaining clinically meaningful data. In the author’s laboratories mfERG is used in association
with the PERG.
Pattern ERG
Primary evaluation of macular function
In macular disorders, the P50 component of the PERG is abnormal, often with preservation of
the N95:P50 ratio. P50 amplitude is usually affected, with latency changes only occasionally
being seen, particularly in association with macular oedema or serous detachment at the macula.
In clinical practice, the PERG is best combined with the (full-field) ERG. The ERG assesses the
degree of peripheral retinal involvement, and the PERG the degree of central involvement. For
example, primary macular dysfunction will usually have a normal ERG and an abnormal PERG,
a common combination in Stargardt-fundus flavimaculatus, whereas generalised retinal dysfunction
with macular involvement will have an abnormal ERG and an abnormal PERG. This facilitates
the distinction between macular dystrophy, cone dystrophy and cone-rod dystrophy in a patient
with an abnormal macular appearance. It should be noted that some patients with Stargardtfundus flavimaculatus have additional full field abnormalities that may be of prognostic value [26].
In patients with rod-cone dystrophy, but normal central retinal function, the PERG may be
normal even when the ERG is almost extinguished. Further, the objective index of macular
function provided by the PERG can demonstrate early central retinal abnormalities prior to the
appearance of symptoms or signs of macular involvement.
Ganglion cell dysfunction
The N95 component (ganglion cell) of the PERG is usually selectively affected if the PERG is
abnormal in optic nerve disease (Fig. 3), but the PERG will often be normal. P50 latency may
be shorter in more severe optic nerve disease/ganglion cell dysfunction, but not in macular
dysfunction. Equally, PERG extinction may occur in macular dysfunction, but not optic neuropathy (providing adequate technical precautions are taken). Primary ganglion cell dysfunction is
associated with marked N95 component loss, particularly Leber hereditary optic atrophy, with
dominant optic atrophy (DOA) showing similar findings in advanced disease. Very severe optic
nerve disease will also reduce P50 amplitude, and the associated shortening of P50 latency
becomes an important factor. Complete extinction of the PERG in relation to optic nerve disease
rarely if ever occurs, providing at least one eye has enough vision to maintain fixation for binocular
PERG recording; the PERG may still readily be detectable in an eye with no light perception [2].
Visual evoked potential
The VEP is a sensitive indicator of optic nerve function. The pioneering work of Martin Halliday
in the early 1970’s showed that the pattern VEP (PVEP) is usually delayed in optic nerve demyelination (Fig. 3), and furthermore that this delay may be sub-clinical, i.e. it may occur with no
signs or symptoms of optic nerve involvement (see [27, 28] for reviews). This may significantly
affect clinical management in a patient with spinal cord disease and possible multiple sclerosis
(MS). The VEP is almost invariably delayed following symptomatic optic nerve involvement in
MS, even when vision has returned to normal. Ischaemic optic neuropathy (non-arteritic) gives
mainly amplitude reduction with minimal latency change. The VEP changes in swelling of the
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optic disc are consequent upon the nature of the underlying pathology, but papilloedema per se
does usually not result in a VEP abnormality unless secondary optic atrophy has occurred.
Chiasmal lesions, such as pituitary tumours, give a crossed asymmetry where there is an
abnormal distribution over the two hemispheres which is in an opposite direction for the two
eyes. Stimulus parameters are crucial for accurate localisation. In general, use of a large field,
large check stimulus gives paradoxical lateralisation, whereas a small field, small check
stimulus gives anatomical lateralisation. The VEP may contribute to the management of
hormonally active tumours as VEP changes may occur before visual fields or visual acuity
become abnormal. Retro-chiasmal lesions give an uncrossed asymmetry where there is an
abnormal distribution that is the same for the two eyes.
The diagnosis of the intra-cranial misrouting of albinism, where the majority of optic nerve fibres
from each eye decussate to the contralateral hemisphere, may be established by the VEP.
Abnormalities may occur in response to either pattern appearance or diffuse flash stimulation,
but the flash VEP appears to be more effective in infants and the appearance VEP in adults.
FVEP may also be useful in non-cooperative patients (infants, coma etc.), and where there is no
PVEP; FVEP and PVEP may be complementary.
The VEP, combined with other electrophysiological tests, is crucial to the diagnosis of nonorganic visual loss. Here, the contribution of electrophysiological testing is to demonstrate
normal function in the presence of symptoms that suggest otherwise. Great care is needed
while recording from such patients to ensure that any attempts voluntarily to affect the results,
by poor fixation, defocusing etc., are unsuccessful. Objective VA assessment is performed with
pattern appearance stimulation using a very brief appearance time in order to minimise the
possibility of voluntary defocusing.
The PERG in relation to VEP interpretation
The VEP to pattern reversal stimulation is a powerful clinical tool in the detection and assessment
of optic nerve dysfunction, and optic nerve disease is frequently associated with pattern VEP
latency delay or loss. However, similar abnormalities are also commonly present in macular
dysfunction, and a delayed PVEP must never be assumed necessarily to indicate optic nerve
dysfunction in a visually symptomatic patient. It should not be overlooked that a normal macular
appearance does not necessarily indicate normal macular function.
PERG
normal
normal
P50 normal
N95 abnormal
P50 abnormal
P50 abnormal
PVEP
PVEP
PVEP
ERG
ERG
normal
abnormal
abnormal
normal
abnormal
non-organic
optic nerve
dysfunction
optic nerve
dysfunction
maculopathy
generalised
retinal
dysfunction
Fig. 5. PERG as a determinant of diagnostic strategy in unexplained visual acuity loss (from [2])
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The different effects of macular and optic nerve dysfunction on the PERG allow the differentiation
between delayed VEP due to retinal/macular disease and that due to optic nerve disease. A
delayed or absent pattern VEP with a normal PERG or an abnormality confined to the N95 component indicates suggests optic nerve/ganglion cell dysfunction (Fig. 3), whereas pronounced P50
reduction usually indicates macular dysfunction (e.g. Fig. 2). Furthermore, a normal PVEP should
not be assumed to indicate normal macular function as mild macular dysfunction may give a
PVEP within the normal range but a pathological PERG (Fig. 5).
CONCLUDING REMARKS
The objective diagnostic information provided by electrophysiological examination of the visual
system is important to the diagnosis and management of visual pathway disease. The ability of
the ERG separately to assess retinal cell types and layers enables characterisation of acquired
and inherited retinal disorders, important when counselling patients who are affected by or at risk
of a genetically determined disorder. In inflammatory disease such as birdshot chorioretinopathy,
the ERG can be used not only to assess the degree of retinal dysfunction, but can assist in
determining both when to treat and the efficacy of treatment. The PERG complements the ERG
by providing a measure of central retinal function. The VEP allows assessment of optic nerve
and intracranial visual pathway function. However, both central retinal and optic nerve disease
can manifest VEP delay, and the distinction is enabled by the different effects of macular and
retinal ganglion cell dysfunction on the PERG, which therefore facilitates meaningful interpretation of an abnormal VEP.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
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Ophthalmol 1987; 71: 166–71.
20. Viswanathan S, Frishman LJ, Robson JG. The uniform field and pattern ERG in macaques with experimental
glaucoma: removal of spiking activity. Invest Ophthalmol Vis Sci 2000; 41: 2797–810.
21. Burgess R, Millat ID, Leroy BP, Urquhart JE, Fearon IM, De Baere E, et al. Biallelic mutation of BEST1 causes a
distinct retinopathy in humans. Am J Hum Genet 2008; 82: 19–31.
22. Francis PJ, Marinescu A, Fitzke FW, Bird AC, Holder GE. Acute zonal occult outer retinopathy (AZOOR): towards a
set of diagnostic criteria. Br J Ophthalmol 2005; 89: 70–3.
23. Zacks DN, Samson CM, Loewenstein J, Foster CS. Electroretinograms as an indicator of disease activity in birdshot retinochoroidopathy. Graefe’s Arch Clin Exp Ophthalmol 2002; 240: 601–7.
24. Holder GE, Robson AG, Pavesio CP, Graham EM. Electrophysiological characterisation and monitoring in the
management of birdshot chorioretinopathy. Br J Ophthalmol 2005; 89: 709–18.
25. Audo I, Robson AG, Holder GE, Moore AT. The negative ERG: clinical phenotypes and disease mechanisms of
inner retinal dysfunction. Surv Ophthalmol 2008; 53: 16–40.
26. Lois N, Holder GE, Bunce C, Fitzke FW, Bird AC. Stargardt macular dystrophy – Fundus flavimaculatus: Phenotypic
subtypes. Arch Ophthalmol 2001; 119: 359–69.
27. Holder GE. Multiple sclerosis. In: Heckenlively JR, Arden GB, editors. Principles and practice of clinical electrophysiology of vision. St. Louis: Mosby Year Book, 1991: 797–805.
28. Holder GE. Electrophysiological assessment of optic nerve disease. Eye 2004; 18: 1133–43.
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95
VISION, ILLUSIONS AND REALITY
Christopher Kennard
Department of Clinical Neurology, University of Oxford, Oxford, Great Britain
Since vision is our primary sense it is not surprising that a large part of the human brain is devoted
to processing the image of our visual world to generate our visual percept. However, it is wrong
to consider that our visual brain always provides us with a percept which is true to the external
visual world. Rather it actively participates in constructing what we see. Our visual percept,
obtained from the information it receives from the two eyes, may sometimes be distorted as a
result of physiological interactions amongst neurones in the visual brain due to the pattern of
their connections. This is best exemplified by the study of visual illusions – for example in the
Zöllner illusion parallel lines appear bowed or non-parallel when a series of short orthogonal
lines are added due to lateral interactions between orientation columns. Alternatively at other
times distortions arise from the generation of hypotheses by the visual brain about the visual
world– for example, when the two-dimensional metastable illusion, the Necker cube, is viewed it
appears three-dimensional but its forward face repeatedly changes between two alternatives.
As in the rest of science these hypotheses may not always be correct and individuals may
require other sensory inputs, eg tactile, to determine reality. The visual brain also has to restrict
what we see since to process all the visual information received by our eyes would require a
visual brain many times larger than is available to us. We, therefore, focus attention and hence
visual processing, on a restricted region of the visual world.
The visual world is made up of a number of visual attributes, such as orientation, colour, motion,
form and stereopsis, which are effortlessly identified by the visual brain. The use of electrophysiological recording in non-human primates and more recently the use of functional brain
imaging in normal human subjects has helped to settle the longstanding debate concerning the
functioning of the visual brain as to whether or not these different visual attributes are each
processed in separate areas or globally. Put more succinctly is there functional specialisation in
the visual brain? However, despite the sophistication of these techniques which have clearly
identified functional specialisation, the neurological patient with a small focal cortical lesion
(usually due to cerebral infarction) who shows a specific neurological deficit, as originally used
by Carl Broca in the nineteenth century in relation to identifying the dominant speech area, is
another required level of proof for deciding on the specific function of an area of the visual brain.
Functional brain imaging has identified a region of occipital ventral cortex, in the fusiform gyrus,
which is involved in colour processing – area V (visual) 4. Damage to this area gives rise to the
main central disorder of colour processing, achromatopsia, in which there is impaired colour
perception involving all or part of the visual field, with preservation of form and motion vision.
Discrimination of wavelength differences, however, may be intact. Patients describe the world,
for example, as drained of colour, a collection of shades of grey or that brightly saturated
colours look pale.
Although during functional imaging several different areas of the visual brain are activated by
motion perception the major site lies some way from V4 in the region of the lateral occipitotemporal junction – an area called V5 (or MT – middle temporal). Only one patient has been
well documented with bilateral lesions which affected this region causing a disturbance of
motion perception, akinetopsia. The disorder was highly specific for motion, the patient having
no difficulty in seeing colours, form or depth. She described how, for example, she experienced
problems in crossing the road because the exact position of moving cars were difficult for her to
judge, or pouring tea or coffee into a cup because the fluid appeared to be frozen.
Face perception is the most developed visual perceptual skill in humans, playing a critical role in
social interactions as well as enabling the recognition of the identity, background and mood of
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96
people around us. In view of this it is not surprising that regions of the visual brain have evolved
to become devoted to face recognition. Neurons have been recorded electrophysiologically in
the superior temporal sulcus of monkeys which respond selectively to the presentation of the
image of a face in their receptive fields. Functional imaging in man has similarly identified activation when viewing faces in the same region, as well as in the inferior occipital gyrus and the
lateral fusiform gyrus, the latter located anterior to the colour area V4. Damage to these areas
results in a very specific disturbance, prospagnosia, a term used to describe the inability to
recognise faces or their representation. Although prosopagnosia can occur in isolation, it is
often observed in association with other functional visual deficits such as achromatopsia and
visual agnosia. Although the most obvious disturbance in such patients is impaired facial
recognition, they may also show an inability to distinguish between objects belonging to other
object categories, such as buildings, animals or automobiles. Prospagnosia often occurs as a
result of a lesion in the occipital-temporal region which damages or disconnects the inferior
visual association cortex from the right temporal cortex.
Although an inability to visually recognise objects - visual agnosia or visual object agnosia – is a
relatively rare neuropsychological symptom, such cases have led to a considerable variety of
theories concerning higher visual processing. A categorisation, however, proposed by Lissauer
(1889), over a century ago, still serves as a useful framework to understand the main types of
visual agnosia. In apperceptive visual agnosia there is a breakdown in high-level visual perception leading to an inability to generate a stable perceptual representation of an object. Such
patients cannot name, copy or recognise visually presented objects, but can do so with auditory
or tactile cues. Tests of basic visual perception, for example, visual acuity, contrast sensitivity,
line orientation discrimination or colour identification are performed correctly. Lissauer also
described associative visual agnosia, which occurs when there is a breakdown in retrieving
stored knowledge about the object, which normally allows it to be recognised – a normal
percept stripped of its meaning (Teuber). Other high level visual processes such as copying
figures or written material, matching photographs taken from unusual views, or block design are
intact. Most cases have had bilateral lesions, due to stroke or tumour, advanced degenerative
dementia or carbon monoxide poisoning, which involve the ventral occipital-temporal lobe.
Recent functional imaging studies have identified areas in this region, which are specifically
activated when different categories of objects, such as houses or chairs, are viewed.
There is therefore, much evidence to suggest that there is marked functional specialisation in
our visual brain – indeed it is considered likely that there are over 30 different areas intercomnected and influencing each other in a very complex manner. It is no surprise, therefore, to conclude that the visual brain is not a mere chronicler of the external physical reality, but that as a
result of its own set of rules and programs it actively participates in generating our visual percept.
RECOMMENDED READING
Barton JJS, Rizzo M, editors. Vision and Brain I (and II). Neurol Clin North Am 2003 21 (2 and 3), WB Saunders,
Philadelphia, 2003.
Eagleman DM. Visual illusions and neurobiology. Nature Rev Neurosci 2001; 2: 920–6.
Gregory RL. Eye and brain: the psychology of seeing. Oxford: Oxford University Press, 1998.
Kennard C, editor. Bailliere's clinical neurology: International practice and research: Visual perceptual defects. Harcourt Brace and Co, 1993.
Sacks O. The man who mistook his wife for a hat. London: Picador, 1985.
Trobe JD. The neurology of vision. Oxford University Press, 2001.
nd
Zeki S. A vision of the brain. 2 ed. Oxford: Blackwell, 2003.
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97
NYSTAGMUS IN A CASE OF BENIGN PAROXYSMAL POSITIONAL
VERTIGO
Branka Geczy
Department of Otorhinolaryngology and Cervicofacial Surgery,
University Medical Centre Ljubljana, Ljubljana, Slovenia
Benign paroxysmal positional vertigo (BPPV) of the horizontal semicircular canal is a less
frequent form of BPPV. The majority of BPPV is due to posterior semicircular canal evolvement,
horizontal semicircular canal accounts for approximately 17% of all cases. This is a case of a
patient who was first thought to have posterior canal BPPV, but during the testing we assumed
that horizontal canal BPPV would be the proper diagnosis. The course of the disease, the
results of the videonystagmographic recording and the differences between the two forms of
BPPV will be discussed, as well as the proposed treatment and its effects.
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98
BILATERAL HORIZONTAL GAZE PARESIS OF UNKNOWN ORIGIN
Petra Miklavþiþ, Ingrid Kompara-Volariþ, Iris Jurþiþ, Anton Grad
Department of Neurology, General Hospital Izola, Izola, Slovenia
A 60-year-old right-handed patient with sudden onset of bilateral horizontal gaze paresis and
gait impairment was admitted to the hospital. The convergence and vertical eye movements
were normal. The gait was unstable and wide-based. Three months before he was diagnosed
with diabetes mellitus; since then he was on a diabetic diet and lost 20 kilograms in 3 months.
Cerebral MRI showed mild frontal and parietal atrophy and lacunar ischaemic lesions involving
right corona radiata. Results of the routine laboratory tests, CSF and anti-neuronal antibodies
were normal. The gait gradually improved, whereas the bilateral abduction and adduction
paresis persist. What shall we do?
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99
OPTHALMOLOGICAL TREATMENT OF DIPLOPIA
Dragica Kosec
Background. Diplopia (double vision) is one of the most troublesome visual disorders. It is
caused by paresis of the extraocular muscles following damage to the oculomotor nerves or
muscles themselves, either by various diseases or cranial or eye trauma. As the eyeballs are
not properly aligned, patient has troubles with reading, walking, and his/her common activities
are heavily disrupted.
Methods. Double vision can be treated by orthoptic therapy, prisms, surgery, or by their combination. The goal is to restore proper binocular vision. It may fully recover over time in some
patients, others need prisms, some surgical treatment. If therapy is inefficient, occlusion is indicated. Cases of diplopia with different aetiology (head trauma, eye injury, endocrine orbitopathy,
vascular diseases…) and different approaches to therapy will be presented.
Conclusion. Irrespective of aetiology, double vision can be cured, offering many patients not
only independent life, but also – at least partially – the ability to work. If therapy is not successful,
occlusion by semitranslucent glasses is indicated.
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100
STANDARDS
reprinted with permission from Documenta Ophthalmologica
Brown M, Marmor M, Vaegan, Zrenner E, Brigell M, Bach M. ISCEV. ISCEV Standard for Clinical Electrooculography (EOG) 2006. Documenta Ophthalmologica 2006; 113 (3): 205–12.
Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M. International Society for Clinical Electrophysiology of Vision. ISCEV Standard for full-field clinical electroretinography (2008 update). Documenta Ophthalmologica 2009;. 118 (1): 69–77.
Hood DC, Bach M, Brigell M, Keating D, Kondo M, Lyons JS, Palmowski-Wolfe AM.
ISCEV guidelines for clinical multifocal electroretinography (2007 edition). Documenta Ophthalmologica
2008; 116 (1): 1–11.
Holder GE, Brigell MG, Hawlina M, Meigen T, Vaegan, Bach M. International Society for Clinical Electrophysiology of Vision. ISCEV standard for clinical pattern electroretinography--2007 update. Documenta
Ophthalmologica 2007; 114 (3): 111–6.
Odom JV, Bach M, Brigell M, Holder GE, McCulloch DL, Tormene AP, Vaegan. ISCEV standard for
clinical visual evoked potentials (2009 update). Documenta Ophthalmologica 2010; 120 (1): 111–9.
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101
AUTHORS INDEX
Baghrizabehi, S
Benediþiþ, M
Bo njak, R
Brecelj, J
Cerovski, B
ýima, I
Coppieters, F
Cvenkel, B
De Baere, E
Deni liþ, M
Drnov ek-Olup, B
Ettinger, U
Fabjan, A
Geczy, B
George, JS
Grad, A
Harikrishnan, S
Harris, CM
Hawlina, G
Hawlina, M
Hirai, M
Holder, GE
Honda, Y
Honda, Y
Hoshiyama, M
I gum, V
Jarc-Vidmar, M
Juratovac, Z
Jurþiþ, I
Kakigi, R
Kennard, C
Kompara-Volariþ, I
Koro ec, M
Kosec, D
Krbot, M
71
79
79
5, 17, 69, 70, 83, 85
78
70
70
69
70
81
77
67
74
98
68
99
68
68
77
28, 69, 70, 83, 84
72
16, 84, 87
38
72
38
80
83
78
99
38, 72
44, 52, 96
99
64
77, 100
80
Lenassi, E
Leroy, BP
Miki, K
Miklavþiþ, P
Milo eviþ, Z
Palmoviü, M
Perko, D
Petriþek, G
Petriþek, I
Pokupec, R
Popoviþ, P
Pretnar-Oblak, J
Ribariü-Jankes, K
Robiü, T
Robson, AR
Rot, U
Sadler, MT
efer, AB
Smith, A
Stirn-Kranjc, B
trucl, M
u tar, M
Takeshima, Y
Tanaka, E
Tekavþiþ-Pompe, M
Teruya, M
Thompson, D
Urakawa, T
Waddington, J
Watanabe, S
Zaletel, M
Zidar, J
Zorc, M
van, B
83, 84
70
38, 72
99
81
80
73
78
78
78
83
73
51
71
84
82
68
80
68
55, 69, 85
10, 74
69, 70
72
38
85
72
31
72
68
38, 72
73, 74
5
81
73
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159
ACKNOWLEDGEMENT
The Organising Committee of the Symposium on Electrophysiology of Vision and on Eye
Movements gratefully acknowledges the assistance granted by the golden Sponsor Roland
Consult, financial supporters – Slovenian Research Agency and European Chapter of the
International Federation of Clinical Neurophysiology –, and companies who cooperated either
as exhibitors or advertisers (alphabetically): GSK d. o. o., Johnson & Johnson, Krka d. d.,
Optika Babnik, Pfizer, Medis d. o. o., and Neuroth.
Professional recognition of the Symposium Courses by the International Society for Clinical
Electrophysiology of Vision (ISCEV) and the International Federation of Clinical Neurophysiology
(IFCN) was much appreciated.
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160
Dr. JANEZ FAGANEL MEMORIAL LECTURES AND SYMPOSIA
1985–2010
1985
Brain Injury Satellite Symposium – BISS '85
P. D. Wall (London, Great Britain): Pain mechanisms
1986
Diagnostics in Neuromuscular Disorders
K.-G. Henriksson (Link ping, Sweden): Muscle pain in neuromuscular disorders and primary
fibromyalgia
1987
2nd Yugoslav Symposium on Neurourology and Urodynamics
J. K. Light (Houston, Texas, U.S.A.): Neurogenic bladder in patients with spinal cord injury
1988
Symposium on Quantitative Electromyography
E. Stålberg (Uppsala, Sweden): Electromyography – reflection of motor unit's physiology in
health and disease
1989
Symposium on Sensory Encephalography
A. M. Halliday (London, Great Britain): The widening role of evoked potentials in clinical
practice
1990
Symposium on Assessment of the Upper Motor Neuron Functions
A. M. Sherwood (Houston, Texas, U.S.A.): Brain motor control assessment
1991
Symposium on Neurophysiological Monitoring
V. Deletis (New ork, N. ., U.S.A.): Intraoperative monitoring of evoked potentials – current
status and perspective
1992
International Symposium on Evaluation and Treatment of Severe Head Injury
E. Rumpl (Klagenfurt, Austria): Neurophysiological evaluation of severe head injury patients
1993
Symposium on Neurophysiological Evaluation of the Visual System
H. Ikeda (London, Great Britain): Mammalian retinal neurotransmitters – as seen through the
eyes of a neurophysiologist
1994
Symposium on Extrapyramidal Disorders
J. Jankovic (Houston, Texas, U.S.A.): New horizons in dystonia
and
The First Lecture of the Slovene Basal Ganglia Club:
G. Stern (London, Great Britain): Amara lenta tempera risu
1995
Symposium on Multiple Sclerosis
W. I. McDonald (London, Great Britain): The clinical and pathological dynamics of multiple
sclerosis
1996
Symposium on Update in Neurogenetics
L. P. Rowland (New ork, N. ., U.S.A.): Molecular genetics and clinical neurology
1997
Symposium on Cognitive Neuroscience
G. Barrett (Farnborough, Great Britain): Cognitive neurophysiology, a tool for studying the
breakdown of mental processes
1998
9th European Congress of Clinical Neurophysiology, Ljubljana
J. Trontelj (Ljubljana, Slovenia): SFEMG – Sensitive optics in space and time
------------------------------------------------------------------------------------------------------- PROCEEDINGS -------------------------------------------------------------------------------------------------------
161
1999
Symposium on Electrophysiology of Hearing
A. Starr (Irvine, California, U.S.A.): Mysteries of the cochlea
2000
Symposium on Movement Disorders, “The Alpine Basal Ganglia Club”
A. J. Lees (London, Great Britain): The relevance of pleasure/reward dopamine circuits to
Parkinson’s disease
2001
EC-IFCN Ljubljana 2001 Regional EMG Refresher Course
E. Stålberg (Uppsala, Sweden): The role of conventional and advanced electromyography in
clinical neurology
2002
International Symposium on Clinical and Electrophysiologic Diagnostics of Epilepsy
P. Chauvel (Marseille, France): High-resolution electroencephalography in clinical
neurophysiology: applications to epilepsy and evoked potentials
2003
Symposium on Intraoperative Neurophysiology
V. E. Amassian (New ork, N. ., U.S.A): Essentials of neurophysiology of the motor system
2004
Symposium on Sleep Research
M. Billiard (Montpellier, France): Excessive daytime sleepiness: clinical impression versus
final diagnosis
2005
37th International Danube Symposium for Neurological Sciences and Continuing
Education
T. Prevec (Ljubljana, Slovenia): Sharp or kind stimulus to activate the sensory system?
2006
International Symposium on Spinal Cord Motor Control “From Denervated Muscles to
Neurocontrol of Locomotion”
G. Vrbová (London, Great Britain): Some observations on the biology of the neuromuscular
system and their possible usefulness for recovery of impaired function
2007
XVIth International SFEMG and QEMG Course and IXth Quantitative EMG Conference
J. Kimura (Kyoto, Japan): The use of late responses as a quantitative measure of nerve
conduction and motor neuron excitability
2008
Symposium on Amyotrophic Lateral Sclerosis
P. N. Leigh (London, Great Britain): ALS: Advances in the laboratory and in the clinic
2009
Symposium on Clinical Neurophysiology of Pain
G. Cruccu (Rome, Italy): Clinical Neuropohysiology of pain
2010
Symposium on Clinical Neurophysiology of Vision and on Eye Movements
R. Kakigi (Okazaki, Japan): Face recognition-related potentials: EEG, MEG, NIRS studies
------------------------------------------------------------------------------------------------------- PROCEEDINGS -------------------------------------------------------------------------------------------------------
162
INVITATION TO THE 2011 INTERNATIONAL COURSE ON F
AND NERVE/MUSCLE ULTRASONOGRAPHY
Ljubljana, Slovenia, 22–24 September 2011
Dear Colleagues and Friends,
We are happy to announce that the Institute of Clinical Neurophysiology of the University
Medical Centre Ljubljana will be hosting a Course on Single Fiber EMG and Nerve/Muscle
Ultrasonography. It will take place in Ljubljana, 22–24 September 2011, in the series of our
yearly Memorial Janez Faganel Meetings, but in addition and importantly, also part of the
SiNAPSA Neuroscience Conference ‘11, taking place at the same time and location (welcome
at www.sinapsa.org/SNC11/SFEMG.php).
The plan is to set up a practical SFEMG course in the original style of the early years of the
technique. This will mean, above all, a lot of hands-on practical exercise, at the end of which the
participants would be capable of recognizing pitfalls and perform a credible study. It would be
intended mainly for colleagues who already practice conventional EMG. In addition, the
participants will be introduced into basics of ultrasonography of nerves and muscles. The
course would take two and a half days, from Thursday to Saturday. Two mornings will be used
for lectures, and the rest of the time for practical work. The number of participants will be limited
in order to allow individualized guidance. A copy of the new edition of the book on Single Fiber
Electromyography by Stålberg, Trontelj and Sanders (2010) will be available. It is expected that
some travel grants could be made available to young colleagues from countries with developing
economies. Particularly welcome will be our young colleagues starting their career in this
exciting discipline of clinical neurosciences.
The faculty will be headed by Erik Stålberg. It will include Don Sanders, Jože Trontelj, Janez Zidar
and Simon Podnar. The 2011 Janez Faganel Memorial lecture will be delivered by Don B. Sanders.
The participants will also have the opportunity to consult the faculty on some other topics of
quantitative EMG, such as specifics of nerve and CNS conduction studies, multi-MUP analysis,
etc., and other applications that in many EMG labs are not yet a routine. At the moment, the list
of topics is preliminary; more suggestions are solicited. Considering the main topic, the keynote
lecture will be on diseases of the neuromuscular junction.
Cankarjev dom, the prestigious Congress Centre of Ljubljana, situated in the midst of the city
centre itself, will provide an excellent venue for our meeting. Its quality and other advantages
may still be remembered by participants of the IXth European Congress of Clinical Neurophysiology
in 1998 and the »Strawberry« SFEMG & QEMG Course and Conference of 2007. Ljubljana is a
hospitable city offering, in spite of its small size, all the essential facilities, as well as the cultural
and historical background of the capital of a prosperous and ambitious nation. It will provide a
pleasant and stimulating environment for work and pleasure, as well as a starting point for a
number of memorable sight-seeing tours in Slovenia.
Janez Zidar,
Jože Trontelj,
Chairman
Convener
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163

Proceedings2010

Transcription

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