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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 with the 26th Dr. Janez Faganel Memorial Lecture 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 Christopher Kennard: 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 Christopher Kennard: 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 5 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 DR. JANEZ FAGANEL MEMORIAL LECTURE 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 6 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 DR. JANEZ FAGANEL MEMORIAL LECTURE 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 Christopher Kennard (Great Britain): 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 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 8 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 Christopher Kennard (Great Britain): 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 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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]. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 10 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 11 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 12 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 13 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 1 Kandel ER. An introduction to the work of David Hubel and Torsten Wiesel. J Physiol 2009; 587: 2733–41. 2 Lewis JW, Van Essen DC. Corticocortical connections of visual, sensorimotor, and multimodal processing areas in the parietal lobe of the macaque monkey. J Comp Neurol 2000; 428: 112–37. 3 Lewis JW, Van Essen DC. Mapping of architectonic subdivisions in the macaque monkey, with emphasis on parieto-occipital cortex. J Comp Neurol 2000; 428: 79–111. 4 Hubel DH. Architecture of primary visual-cortex in monkey. J Opt Soc Am 1975; 65: 1216–7. 5 Hubel DH, Wiesel TN. Functional architecture of macaque monkey visual-cortex. P Roy Soc Lond B 1977; 198: 1–59. 6 Wiesel TN, Hubel DH, Lam DMK. Autoradiographic demonstration of ocular-dominance columns in monkey striate cortex by means of transneuronal transport. Brain Res 1974; 79: 273–9. 7 Marr D. Analyzing natural images – computational theory of texture vision. Cold Spring Harb Sym 1975; 40: 647–62. 8 Marr D. Early processing of visual information. Philos T R Soc B 1976; 275: 483–519. 9 Marr D. Artificial intelligence – personal view. Artif Intell 1977; 9: 37–48. 10 Marr D, Lal S, Barlow HB. Visual information-processing – the structure and creation of visual representations. Philos T R Soc B 1980; 290: 199–218. 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 York Rev Books 1987; 34: 25–34. 13 Schenk T, Zihl J. Visual motion perception after brain damage: II. Deficits in form-from-motion perception. Neuropsychologia 1997; 35: 1299–310. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 14 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. 24 Haxby JV, Grady CL, Horwitz B, Ungerleider LG, Mishkin M, Carson RE, et al. Dissociation of object and spatial visual processing pathways in human extrastriate cortex. Proc Natl Acad Sci USA 1991; 88: 1621–5. 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 non-human primates. Neuropsychologia 2006; 44: 2647–2667. 27 Orban GA, Van Essen D, Vanduffel W. Comparative mapping of higher visual areas in monkeys and humans. Trends Cogn Sci 2004; 8: 315–24. 28 Lyon DC, Nassi JJ, Callaway EM. A disynaptic relay from superior colliculus to dorsal stream visual cortex in macaque monkey. Neuron 2010; 65: 270–9. 29 Haxby JV, Gobbini MI, Furey ML, Ishai A, Pietrini P. Distinct, overlapping representations of faces and multiple categories of objects in ventral temporal cortex. Neuroimage 2001; 13: S891. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 15 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 16 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 17 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 18 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 19 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 20 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 21 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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]. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 22 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 23 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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]. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 24 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 25 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. REFERENCES 1. Halliday AM, Mc Donald WI, Mushin J. Delayed visual evoked response in optic neuritis. Lancet 1972; 1: 982–5. 2. Halliday AM, McDonald WI, Mushin J. Visual evoked response in the diagnosis of multiple sclerosis. Br Med J 1973; 4: 797–805. 3. Fortune B, Hood DC. Conventional pattern-reversal VEPs are not equivalent to summed multifocal VEPs. Invest Ophthalmol Vis Sci 2003; 44: 1364–75. 4. Holder GE, Gale RP, Acheson JF. Robson AG. Electrodiagnostic assessment in optic nerve disease. Curr Opin Neurol 2009; 2: 3–10. 5. Brecelj J. Visual evoked potentials and the localization of visual pathway lesions. Spektrum Augenheilkd 1991; 5: 114–22. 6. Brecelj J, Kakigi R, Koyama S, Hoshiyama M. Visual evoked magnetic responses to central and peripheral stimulation: simultaneous VEP recordings. Brain Topogr 1998; 10: 227–37. 7. Halliday AM. Evoked potentials in clinical testing. Churchill Livingstone, 1993. 8. Swanson JW. Multiple sclerosis: update in diagnosis and review of prognostic factors. Mayo Clin Proc 1989; 64: 577–86. 9. Shams PN, Plant GT. Optic neuritis: a review. Int MS J 2009; 16: 82–9. 10. Plant GT. Optic neuritis and multiple sclerosis. Curr Opin Neurol 2008; 21: 16–21. 11. Kidd D, Burton B, Plant GT, Graham EM. Chronic relapsing inflammatory optic neuropathy (CRION). Brain 2003; 126: 276–84. 12. Kupersmith MJ, Gal RL, Beck RW, Xing D, Miller N. Visual function at baseline and 1 month in acute optic neuritis. Predictors of visual outcome. Neurology 2007; 69: 508–14. 13. Tekavþiþ-Pompe M, Stirn-Kranjc B, Brecelj J. Optic neuritis in children – clinical and electrophysiological followup. Doc Ophthalmol 2003; 107: 261–70. 14. Jones SJ, Brusa A. Neuropysiological evidence for long-term repair of MS lesions: implications for axon protection. J Neurol Sci 2003; 206: 193–8. 15. Trip SA, Schlottmann PG, Jones ST, Altmann DR, Garway-Heath DF, Thompson AJ, et al. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol 2005; 58: 383–91. 16. Rinalduzzi S, Brusa A, Jones SJ. Variation of visual evoked potential delay to stimulation of central, nasal, and temporal regions of the macula in optic neuritis. J Neurol Neurosurg Psychiatry 2001; 70: 28–35. 17. Brusa A, Jones SJ, Plant GT. Long-term remyelination after optic neuritis: a 2-year visual evoked potential and psychophysical serial study. Brain 2001; 124: 468–79. 18. Holder GE. The incidence of abnormal pattern electroretinography in optic nerve demyelination. Electroencphalogr Clin Neurophysiol 1991; 78: 18–26. 19. Brecelj J, Kriss A. Pattern reversal VEPs in optic neuritis. Advantages of central and peripheral half-field stimulation. Neuro-ophthalmology 1989; 9: 55–63. 20. Brecelj J, Štrucl M, Hawlina M. Central fiber contribution to W-shaped visual evoked potentials in patients with optic neuritis. Doc Ophthalmol 1990; 75: 155–63. 21. Klistorner A, Fraser C, Garrick R, Graham S, Arvind H. Correlation between full-field and mutifocal VEPs in optic neuritis. Doc Ophthalmol 2008; 166: 19–27. 22. Fraser CL, Klistorner A, Graham SL, Garrick R, Billson FA, Grigg JR. Multifocal visual evoked potential analysis of inflammatory or demyelinating optic neuritis. Ophthalmology 2006; 113: 315–23. 23. Yang EB, Hood DC, Rodarte C, Zhang X, Odel JG, Behrens MM. Improvement in conduction velocity after optic neuritis measured with the multifocal VEP. Invest Ophthalmol Vis Sci 2007; 48: 692–8. 24. Rot U, Mesec A. Clinical, MRI, CSF and electrophysiological findings in different stages of multiple sclerosis. Clin Neurol Neurosurg 2006; 108: 271–4. 25. Lišþiü RM, Brecelj J. Visual evoked potentials in multiple sclerosis patients treated with interferon beta-1a. Croat Med J 2004; 45: 323–7. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 26 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 26. Niklas A, Sebraoui H, Heß E, Wagner A, Bergh FT. Outcome measures for trials of remyelinating agents in multiple sclerosis: retrospective longitudinal analysis of visual evoked potential latency. Mult Scler 2009: 15: 68–74. 27. Henderson APD, Trip SA, Schlottmann PG, Altmann DR, Garway-Heath DF, Plant GT, et al. An investigation of the retinal nerve fibre layer in progressive multiple sclerosis using optical coherence tomography. Brain 2008; 131: 277–87. 28. Šuštar M, Cvenkel B, Brecelj J. The effect of broadband and monochromatic stimuli on the photopic negative response of the electroretinogram in normal subjects and in open-angle glaucoma patients. Doc Ophthalmol 2009; 118: 167–77. 29. Holder GE. Chiasmal and retrochiasmal lesions. In: Heckenlively JR, Arden GB, editors. Principles and practice nd of clinical electrophysiology of vision. 2 ed. MIT Press, 2006; 857–65. 30. Brecelj J, Denišliþ M, Škrbec M. Visual evoked potential abnormalities in chiasmal lesions. Doc Ophthamol 1989; 73: 139–48. 31. Brecelj J, Stirn-Kranjc B. Electropysiologic evaluation of the visual pathway in children. Doc Ophthamol 1992; 79: 313–23. 32. Brecelj J, Denišliþ M, Škrbec M. Visual evoked potentials in compressive lesions of the optic chiasm. Neuroophthalmology 1992; 12: 207–14. 33. Brecelj J. A VEP study of the visual pathway function in compressive lesions of the optic chiasm. Full-field versus half-field stimulation. Electroenceph Clin Neurophysiol 1992; 84: 209–18. 34. Brecelj J. Electrodiagnostics of chiasmal compressive lesions. Int J Psychophysiol 1994; 16: 263–72. 35. Štrucl M, Brecelj J, Hawlina M. Visual evoked potential abnormalities in compressive chiasmal lesions: the relevance of central visual field defects. Neuro-ophthalmology 1997; 17: 91–100. 36. Brecelj J, Stirn-Kranjc B, Škrbec M. Visual electrophysiology in children with tumours affecting the visual pathway. Doc Ophthamol 2000; 101: 125–54. 37. Halliday AM, Halliday E, Kriss A, McDonald WI, Mushin J. The pattern-evoked potential in compression of the anterior visual pathways. Brain 1976; 99: 357–74. 38. Flasini B, Ziccardi L, Lazzareschi I, Ruggiero A, Placentino L, Dickmann A, et al. Longitudinal assessment of childhood optic gliomas: relationship between flicker visual evoked potentials and magnetic resonance imaging findings. J Neurooncol 2008; 88: 87–96. 39. Moradi P, Robson AG, Rose GE, Holder GE. Electrophysiological monitoring in a patient with an optic nerve glioma. Doc Ophthalmol 2008; 117: 171–4. 40. Danesh-Meyer HV, Carroll SC, Gaskin BJ, Gao A. Correlation of the multifocal visual evoked potential and standard automated perimetry in compressive optic neuropathies. Invest Ophthalmol Vis Sci 2006; 47: 1458–63. 41. Parmar DN, Sofat A, Bowman R, Bartlett JR, Holder GH. Visual prognostic value of the pattern electroretinogram in chiasmal compression. Br J Ophthalmol 2000; 84: 1024–6. 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 asymmetry and nystagmus. Brain 1995; 118: 1195–216. 43. Guillery RW, Okoro AN, Witkop CJ. Abnormal visual pathways in the brain of a human albino. Brain Res 1975; 96: 373–7. 44. Kriss A, Russell-Eggitt I, Harris CM, Lloyd IC, Taylor D. Aspects of albinism. Ophthalmic Paediatr Genet 1992; 13: 89–100. 45. Sami DA, Saunders D, Thompson DA, Russell-Eggitt IM, Nischal KK, Jeffery G, et al. The achiasmia spectrum: congenitally reduced chiasmal decussation. Br J Ophthalmol 2005; 89: 1311–7. 46. Taylor D. Developmental abnormalities of the optic chiasm. Eye 2007; 21: 1271–84. 47. Brecelj J, Stirn-Kranjc B, Peþariþ-Megliþ N, Škrbec M. VEP asymmetry with ophthalmological and MRI findings in two achiasmatic children. Doc Ophthalmol 2007; 114: 53–65. 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 27 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 28 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 29 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 30 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 31 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 32 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 33 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 34 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 35 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 36 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 37 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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]). ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 38 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 39 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 40 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 41 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. REFERENCES 1 Watanabe S, Kakigi R, Koyama S, Kirino E. Human face perception traced by magneto- and electro-encephalography. Brain Res Cogn Brain Res 1999; 8: 125–42. 2 Watanabe S, Kakigi R, Koyama S, Kirino E. It takes longer to recognize the eyes than the whole face in humans. Neuroreport 1999; 10: 2193–8. 3 Watanabe S, Kakigi R, Puce A. Occipitotemporal activity elicited by viewing eye movements: a magnetoencephalographic study. Neuroimage 2001; 13: 351–63. 4 Watanabe S, Miki K, Kakigi R. Gaze direction affects face perception in humans. Neurosci Lett 2002; 325: 163–6. 5 Watanabe S, Kakigi R, Puce A. The spatiotemporal dynamics of the face inversion effect: a magneto- and electro-encephalographic study. Neuroscience 2003; 116: 879–95. 6 Tanaka E, Inui K, Kida T, Kakigi R. Common cortical responses evoked by appearance, disappearance and change of the human face. BMC Neurosci 2009; 10 (1): 38. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 42 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 7 Miki K, Watanabe S, Honda Y, Nakamura M, Kakigi R. Effects of face contour and features on early occipitotemporal activity when viewing eye movement. Neuroimage 2007; 35: 1624–35. 8 Otsuka Y, Nakato E, Kanazawa S, Yamaguchi MK, Watanabe S, Kakigi R. Neural activation to upright and inverted faces in infants measured by near infrared spectroscopy. Neuroimage 2007; 34: 399–406. 9 Nakato E, Otsuka Y, Kanazawa S, Yamaguchi M, Watanabe S, Kakigi R. When do infants differentiate profile face from frontal face? A near-infrared spectroscopic study. Hum Brain Mapp 2009; 30: 462–72. 10 Honda Y, Nakato E, Otsuka Y, Kanazawa S, Kojima S, Yamaguchi KM, et al. How do infants perceive scrambled face? A near-infrared spectroscopic study. Brain Res 2010; 1308: 137–46. 11 Hoshiyama M, Kakigi R, Watanabe S, Miki K, Takeshima Y. Brain responses for the subconscious recognition of faces. Neurosci Res 2003; 46: 435–42. 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 43 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 44 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 45 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 46 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 47 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 48 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 49 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 50 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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). ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 51 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 2 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 3 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 4 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- E T AOCULA MUSCLES AND OCULA MOTILITY ranka Stirn- ranjc Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 . ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 6 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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) ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 7 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 8 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 9 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 . ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 60 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 . ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 61 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. EFE ENCES 1. Demer L. Mechanics of the orbita. Dev Ophthalmol 2007 40: 132– 7. 2. Spencer FR, Porter D. Structural organization of the extraocular muscles. In: ttner Ennever A, editor. Neuroanatomy of the oculomotor system. New ork: Elsevier Science Publishers, 1988: 33–79. 3. Scott A . Ocular motility. 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Mammalian skeletal muscle fiber type transitions. Int Rev Cytol 1997 170: 143–223. 31. Carlson M, Emerick S, omorowski TE, Rainin EA, Shepard M. Extraocular msucle regeneration in primates. Ophthalmology 1992 99: 82–9. 32. Mahdavi V, Strehler EE, Periasamy M, Wieczorek DF, Izumo S, Nadal-Ginard . Sarcomeric myosin heavy chain gene family: organization and pattern expression. Med Sci Sports Exerc 1986 18: 299–308. 33. Scott A . Adaptation of eye muscles to eye position. In: Scott A , editor. The mechanics of strabismus. San Francisco: Smith ettlewell, 1992: 263–8. 34. Stirn ranjc , Sketelj , D Albis A, Er en I. Long-term changes in myosin heavy chain composition after botulinum toxin A injection into rat medial rectus muscle. Invest Ophthalmol Vis Sci 2001 42: 31 8–64. 3 . amed LM. Strabismus presenting after cataract surgery. Ophthalmology 1991 98: 247– 2. 36. Lang T, Laver N, Strominger M , Witking A, Pfannl R, Alroy . Morphological findings of extraocular myopathy with chronic progressive external ophthalmoplegia. ltrastruct Pathol 2010 34: 78–81. 37. uwabara T, Lessel S. Electron microscopic study of extraocular muscles in myotonic dystrophy. Am Ophthalmol 1976 82: 303–8. 38. aminski , Al- akima M, Leigh R , atirji M , Ruff RL. Extraocular muscles are spared in advanced Duchenne dystrophy. Ann Neurol 1992 32: 86–8. 39. Ragusa R , Porter D. Extraocular muscle in the mdx mouse: absence of pathology correlates with superoxide dismutase activity. Molec iol Cell 1994 : 26a. 40. aminski , Maas E, Spiegel P, Ruff RL. Why are eye muscles frequently involved in myasthenia gravis Neurology 1990 40: 1663–9. 41. Sakharova AV, Popova LM. Morphology of oculomotor muscles and their nervous apparatus in lateral amyotrophic sclerosis in conditions during long-term artificial lung ventilation. Arkh Patol 2003 6 : 24–30. 42. Ahmadi M, Liu , r nnstr m T, Andersen PM, St l P, Pedrosa-Domell f F. uman extraocular muscles in ALS. Invest Ophthalmol Vis Sci 2010 1: 3494– 01. 43. eufelder AE, ahn RS. Detection and localization of cytokine immunoreactivity in retro-ocular connective tissue in Grave s ophthalmopathy. Eur Clin Invest 1993 23: 10–7. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 63 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 64 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 65 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 66 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 67 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 68 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 69 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 70 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 71 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 72 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 73 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 74 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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). ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 75 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 76 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- SURGICAL TREATMENT OF COMPLETE/TOTAL BINOCULAR OCULOMOTOR NERVE PALSY FOLLOWING CEREBROVASCULAR INFARCT – A CASE REPORT Dragica Kosec, Gregor Hawlina, Brigita Drnovšek Olup Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 77 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 78 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 79 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 80 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 81 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 82 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- IMAGING AND ELECTROPHYSIOLOGY IN STARGARDT DYSTROPHY Martina Jarc-Vidmar, Petra Popoviü, Eva Lenassi, Jelka Brecelj, Marko Hawlina Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 83 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- THE USE OF LARGE FIELD PERG IN ROUTINE ELECTROPHYSIOLOGY TESTING Eva Lenassi1,2, Anthony G. Robson2,3, Marko Hawlina1, Graham E. Holder2,3 1 Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 84 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- WHAT DOES CHROMATIC VEP RESPONSE TELL US IN CONGENITALY COLOUR DEFICIENT CHILDREN Manca Tekavþiþ Pompe, Branka Stirn Kranjc, Jelka Brecelj Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 85 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 86 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 87 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 88 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 89 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 90 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 91 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 92 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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]) ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 93 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. REFERENCES Corbett MC, Shilling JS, Holder GE. The assessment of clinical investigations: the Greenwich grading system and its application to electrodiagnostic testing in ophthalmology. Eye 1995; 9 (suppl.): 59–64. Holder GE. The pattern electroretinogram and an integrated approach to visual pathway diagnosis. Prog Retin Eye Res 2001; 20: 531–561. Brown M, Marmor M, Vaegan, Zrenner E, Brigell, M, Bach M. ISCEV Standard for clinical electro-oculography (EOG) 2006. Doc Ophthalmol 2006; 113: 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). Doc Ophthalmol 2009; 118: 69–77. Holder GE, Brigell MG, Hawlina M, Meigen T, Vaegan, Bach M. ISCEV Standard for Clinical Pattern Electroretinography – 2007 update. Doc Ophthalmol 2007; 114: 111–6. Odom JV, Bach M, Brigell M, Holder GE, McCulloch DL, Tormene AP, Vaegan. ISCEV standard for clinical visual evoked potentials (2009 update). Doc Ophthalmol 2009; 120: 111–9. nd Heckenlively JR, Arden GB, editors. Principles and practice of clinical electrophysiology of vision. 2 ed. Cambridge MA: MIT Press, 2006. Fishman GA, Birch DG, Holder GE, Brigell MG: Electrophysiologic testing in disorders of the retina, optic nerve, nd and visual pathway. 2 ed. Ophthalmology Monograph 2. San Francisco: The Foundation of the American Academy of Ophthalmology, 2001. Hood DC, Birch DG. Rod phototransduction in retinitis pigmentosa: Estimation of parameters from the rod a-wave. Invest Ophthalmol Vis Sci 1994; 35: 2948–61. Shiells RA, Falk G. Contribution of rod, on-bipolar, and horizontal cell light responses to the ERG of dogfish retina. Vis Neurosci 1999; 16: 503–11. Frishman LJ. Origins of the electroretinogram. In: Heckenlively JR, Arden GB, editors. Principles and practice of clinical electrophysiology of vision. 2nd ed. Cambridge MA; MIT Press, 2006: 139–83. Bush RA, Sieving PA. Inner retinal contributions to the primate photopic fast flicker electroretinogram. J Opt Soc Am A 1996; 13: 557–65. Bush RA, Sieving PA. A proximal retinal component in the primate photopic ERG a-wave. Invest Ophthalmol Vis Sci 1994; 35: 635–45. Sieving PA. Photopic ON- and OFF-pathway abnormalities in retinal dystrophies. Trans Am Ophthalmol Soc 1993; 91: 701–73. Arden GB, Carter RM, Hogg CR, Siegel IM, Margolis S. A gold foil electrode: extending the horizons for clinical electroretinography. Invest Ophthalmol Vis Sci 1979; 18: 421–26. Dawson WW, Trick GL, Litzkow CA. Improved electrode for electroretinography. Invest Ophthalmol Vis Sci 1979; 18: 988–91. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 94 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 17. Hawlina M, Konec B. New noncorneal HK-loop electrode for clinical electroretinography. Doc Ophthalmol 1992; 81: 253–9. 18. Berninger TA. The pattern electroretinogram and its contamination. Clin Vis Sci 1986; 1: 185–90. 19. Holder GE. Significance of abnormal pattern electroretinography in anterior visual pathway dysfunction. Br J 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 95 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 96 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 97 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 98 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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? ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 99 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- OPTHALMOLOGICAL TREATMENT OF DIPLOPIA Dragica Kosec Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 100 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 101 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 159 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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. ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 160 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- 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 ---------------------------------------------- Symposium on Electrophysiology of Vision and on Eye Movements, Ljubljana, 17–18 September 2010 ----------------------------------------------- INVITATION TO THE 2011 INTERNATIONAL COURSE ON F AND NERVE/MUSCLE ULTRASONOGRAPHY with the 27th Dr. Janez Faganel Memorial Lecture 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 ------------------------------------------------------------------------------------------------------- PROCEEDINGS ------------------------------------------------------------------------------------------------------- 163
