Shifting the point of view
Nij Bijvank, J.A.
2020
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citation for published version (APA)
Nij Bijvank, J. A. (2020). Shifting the point of view: Perspectives on eye movements in multiple sclerosis.
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General introduction
Partly based on:
Coric D*, Nij Bijvank JA*, van Rijn LJ, Petzold A, Balk LJ. *These authors contributed equally to the manuscript
The role of optical coherence tomography and infrared oculography in assessing the visual pathway and CNS in multiple sclerosis.
11
Preface
“Measure what is measurable, and make measurable what is not so.”
(Misattributed* to Galileo Galilei 1564-1642)
“Measurement is the first step that leads to control and eventually to improvement. If you can’t measure something, you can’t understand it. If you can’t understand it, you can’t control it. If you can’t control it, you can’t improve it.”
(H. James Harrington, 1999).
Measurement is considered an essential element in most (scientific) disciplines. Though, it is never an end in itself and the translation into interpretation of the underlying concept or construct can be challenging. Therefore, as a start of this thesis, the following quote is added:
“Measurement brings knowledge, but also requires knowledge.”
For measurement in healthcare, a first step in knowledge is the distinction between patient reported outcomes and performance-based methods. They both have their advantages and disadvantages, and have to be considered complementary to each other. Second, non-invasive, reliable and precise measurement instruments are indispensable for both clinical care and research purposes. In this view, the
measurement of eye movements is a simple and accurate performance-based method which can provide a new and broad perspective on the complex nature of the disease multiple sclerosis (MS). Important purposes of measurements in MS are monitoring of disease, prediction of disease and measurement of therapeutic effects. The potential of a new and comprehensive method of eye movement measurement in MS is described and discussed in this thesis.
Multiple sclerosis
Multiple sclerosis (MS) is a disease of the central nervous system. It is affecting more than 2 million people worldwide and in the Netherlands 1000-1500 new patients are diagnosed each year.1-4 It usually presents at a relatively young age, with a mean age of
onset of 30 years.3, 4 It is thereby regarded as one of the most common causes for
neurological disability in young adults, according to the World Health Organization. It affects more than twice as many women as it does men.3, 4 To date, the exact etiology
and pathophysiology of MS is unknown. Besides genetic predisposition, several environmental risk factors are revealed, such as previous infections, lack of sun exposure and diet factors.5
* This quote is widely misattributed to Galilei, but is actually from two French scholars, Antoine-Augustin Cournot and Thomas-Henri Martin
The disease is characterized by inflammatory as well as neurodegenerative
components.6 Inflammation is the main contributing factor in the early stage of the
disease, often resulting in a single episode of focal neurological dysfunction, which is referred to as a clinically isolated syndrome (CIS). For the majority of these patients this is followed by recurrent episodes of neurological worsening with a various degree of recovery and residual damage, which define the relapsing–remitting phase of the disease (relapsing-remitting MS [RRMS]). This phase is histopathologically marked by attacks of immune cells to the myelin, the coverage of axons.5 This will cause focal
demyelination in the affected grey and/or white matter of the brain. Eventually, most of these patients will enter the secondary progressive phase (secondary progressive MS [SPMS]), characterized by slowly progressive and permanent disability. A small proportion of patients have a primary progressive disease course (primary progressive MS [PPMS]). This is characterized by a progressive course from onset without having acute relapses. In SPMS and PPMS, neuroaxonal degeneration is thought to play the main role.7, 8 Neurodegeneration is considered as the main cause for the eventual
irreversible physical disability and cognitive decline.5
Several treatment options exist which target the neuro-inflammatory component of the disease. They aim to prevent inflammatory episodes and indirectly slow down the progression of the disease. However, the efficacy for reducing the development of brain atrophy in clinical trials has been moderate at best.2 These disease modifying
therapies are mainly available for RRMS and a few for active SPMS. For PPMS, ocrelizumab is the only FDA-approved disease modifying therapy, which has been shown to reduce the risk of disability progression in these patients.9 For particular
groups of patients (i.e. very active RRMS) recent trials which investigated hematopoietic stem cell therapy has shown promising result.10 It is however an
aggressive treatment option, and the risks and costs of treatment in relation to the efficacy have to be evaluated.11
Recently, a first successful treatment strategy to rebuild myelin around axons had been developed, with the anticholinergic drug clemastine fumarate.12, 13 The results of
the first randomised clinical trial in MS patients with this drug has been promising for rebuilding myelin in damaged optic nerves.14
As well as the disease course and therapy options, the range of symptoms in MS can be very heterogeneous. These can include muscle weakness, sensory disturbances, problems with coordination, fatigue and cognitive problems.15 The visual system is
particularly often affected in MS and this can cause disturbing symptoms for patients. This will be discussed in more detail in the next paragraphs.
13
Figure 1. Schematic overview of important structures and pathways in the visual system. The
afferent visual pathway (blue lines) originates in the retina, where bipolar cells connect with the retinal ganglion cells, which project to the lateral geniculate nucleus in the thalamus (dark blue lines). From the lateral geniculate nucleus, the signal continues through the optic radiations (light blue lines) toward the primary visual cortex. The efferent visual pathway (green lines) originates in a broad network of cerebral regions, extending from parietal and (pre)frontal areas, which connect through the thalamus to the superior colliculus (light green lines). Through connections with the three oculomotor nuclei (oculomotor, trochlear [both not shown] and abducens nucleus), signals are sent to cranial nerves (III, IV and VI) innervating the extraocular muscles (dark green line). The cerebellum (not shown) is also a key component in the efferent visual pathway, with well-networked connections to areas in both the brainstem and the prefrontal cortex, and is involved in fine motor and cognitive control of eye movements.
The visual system
Up to 80% of MS patients experience visual disturbances during the course of the disease.16-18 It is estimated that about a third of patients suffer from persistent visual
complaints, unrelated to a recent relapse. These deficits often lead to visual disabilities in daily life and reduced vision-related quality of life.17, 19 MS patients value visual
functioning as important as lower limb function when rating different dimensions of
physical bodily functions, especially in late MS.20 However, the impact of visual
complaints on daily functioning and quality of life is in sharp contrast with the number of outcome measures assessing visual function in clinical care and trials.21 In order to
get a better understanding of these disabling deficits, knowledge about the underlying mechanisms is essential.
Interpreting visual information from the world around us is a complex process that is facilitated by a comprehensive system.22 This visual system can be divided in the
afferent and efferent visual pathway (Figure 1). The afferent visual pathway originated in the retina, where bipolar cells connect with the retinal ganglion cells, which project to the lateral geniculate nucleus in the thalamus. From the lateral geniculate nucleus, the signal continues through the optic radiation toward the primary visual cortex. The primary visual cortex connects with a broad network of cerebral regions, which are involved in the efferent control of the visual system. These connect eventually to multiple brainstem regions (Figure 2), among which the superior colliculus, which is a critical structure for the initiation of eye movements. Through connections with the three oculomotor nuclei the six extraocular muscles that are responsible for the actual eye movement are innervated. The cerebellum is involved in fine motor and cognitive control of the eye movements.22
The visual system can take in detailed information about what is being looked at when the central fovea is pointed at the object of interest. This focus on a visual target is called visual fixation. When scanning the environment, the eyes makes rapid movements to displace the fovea from one point of interest to another. These fast eye movements are called saccades. Our perception is guided by alternating these sequences of fixation and saccades. Investigation of these types of eye movements will be the key part of this thesis.
Visual pathway disorders
In the afferent visual pathway, the optic nerve is often affected in MS. Inflammation of the optic nerve, optic neuritis, is the presenting symptom in approximately 20% of MS patients and about 50% of MS patients will experience one or more episodes during the course of their disease.23 Is characterized by an episode of loss of vision which
(partially) recovers over the course of a few days to weeks. In recent years, the value of use of retinal optical coherence tomography (OCT) in the assessment of optic neuritis has been proven, not only in diagnosis, but also in prognosis.24-29 Moreover, in
the recently proposed revisions of the diagnostic criteria for MS it is advocated to include the optic nerve as a fifth anatomical location (next to periventricular, juxta-cortical, infratentorial and spinal) to fulfil criteria for dissemination in space.30
15
Figure 2. Schematic overview of important brainstem areas of the efferent visual system. The sagittal cross section of the
brainstem is showing the three oculomotor nuclei (III, IV, VI), the nucleus prepositus hypoglossi (NPH), the interstitial nucleus of Cajal (INC), the superior colliculus, the paramedian pontine reticular formation (PPRF), the medial longitudinal fasciculus (MLF), the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and the mediadorsal nucleus (MD) in the thalamus. The nucleus raphe interpositus (not shown) lies close to the midline, at the level of the abducens nucleus (VI).
Disorders of the efferent pathway in MS are very diverse. Clinically evident disorders are listed in many case reports and narrative reviews31-34, although the prevalence
remains unknown. Estimations range from 36 to 84%.16, 35, 36 Two commonly
described groups of eye movement disorders are ocular misalignment (including internuclear ophthalmoplegia [INO]) and fixational instability.
In the latter category, pendular nystagmus is one of the most distressing oculomotor findings in MS. The eyes make constant sinusoidal movements, which can cause continuous complaints of oscillopsia and blurred vision. The prevalence in MS is unknown and the pathophysiology is not completely understood.37-39 In contrast, an
eye movement disorder in which the exact location of the lesion is known, is INO. A demyelinating lesion in the medial longitudinal fasciculus causes a delay in velocity of the adducting eye during horizontal saccades. Prevalence, mainly based on clinical examinations, is estimated between 24 and 55%.16, 40-42 Although not systematically
reported in literature, clinical consequences of INO can be absent, or include diplopia, blurred vision or oscillopsia during horizontal saccades.
Other eye movement abnormalities in MS that are reported in literature include
misalignment of the visual axes, saccadic dysmetria and impaired vestibulo-ocular reflex.
Besides some more or less demarcated visual pathway disorders, it is known that also higher order regions are involved in the complex and broad network of the visual system. In the next paragraph the utility of investigating this in multiple sclerosis with non-invasive methods will be discussed.
The visual pathway as a reflection of CNS processes
To understand the interplay between different disease mechanisms which contribute to (irreversible) disability in MS, focus has shifted from investigating MS as a white matter disease, to a broader perspective in which grey matter pathology and network dysfunction receive more attention. Brain atrophy, and especially thalamic atrophy, is strongly related to physical disability and cognitive decline, even in early phases of disease.43-45 Furthermore, functional magnetic resonance imaging (fMRI) and
magnetoencephalography (MEG) studies have shown that changes in functional connectivity of the brain, which are often interpreted as compensatory mechanisms for structural deficits46, 47, are shown to play a crucial role in early deterioration in
clinical and cognitive status.48-50 The increasing focus of this type of MS research on
cognitive decline besides physical disability is essential. It is difficult to localize lesions or disease processes which cause cognitive dysfunction, due to the complex nature of cognitive functioning, which require communication between a broad range of brain regions.51 Cognitive dysfunction is, however, increasingly recognized as an important
aspect of MS. The prevalence is estimated at 40–70% and it can be apparent at early stages of disease.50, 52-54 It has a great impact on daily functioning and quality of life of
MS patients.44, 52, 55 The ultimate goal is to study the brain in total as a functional and
structural network. However, the exact interplay between different pathogenic mechanisms, as atrophy and disruption of cortical networks, is unknown. There is need for non-invasive methods to investigate these interactions that contribute to (irreversible) disability, especially cognitive dysfunction.
In recent years, the knowledge on the use of OCT for assessing processes of the CNS has been expanded. Independent on the experience of an episode of optic neuritis, MS patients show more atrophy of the inner retinal layers than healthy contols.27 It is
believed that this atrophy is a reflection of the neuroaxonal damage in the CNS.56 This
atrophy of two inner retinal layers is associated with gray and white matter atrophy. 56-59 Furthermore, there is an association with cognitive impairment.60, 61 A major
challenge when applying OCT as a surrogate marker for neurodegeneration is the confounding effect of optic neuritis (ON). This problem can be bypassed by looking at
17 changes over time, since MS-associated ON (MSON) eyes seem to show the same amount of atrophy over time as eyes with no history of MS-associated ON (MSNON).62, 63 Finally, a lower peripapillary retinal nerve fiber layer (pRNFL)
thickness has been shown to predict disability worsening in 5 years of follow-up.64
As an extensive (cortical) network is involved in the control of eye movement, it would be desirable and promising to extend the findings on the afferent visual system in MS to the efferent visual system. Eye movements, especially saccades, show exceptional high velocities, short latencies and ballistic behaviour, compared to other movements. They rely on very precise integration of signals which initiate and control the movement and therefore even small disruptions in signal are expected to result in changes of eye movement parameters. Even though in various neurological and psychiatric disorder changes in eye movements were related to functioning of the brain65-68, there is not much data in MS. A few studies have shown an association
between eye movement parameters and cognitive functioning in MS.69, 70 With the
current insights in the mechanisms of eye movement control, investigation of eye movement measures represents a novel but promising strategy to investigate the integrity of cognitive processing networks in MS. For this purpose, a very precise and patient-friendly method is desirable, which will be discussed in the next paragraph. Assessment of eye movements
As already briefly mentioned in the previous paragraphs, examination of eye
movements could play an important role in the evaluation of MS patients. Besides the possible impact of eye movements disorders on visual functioning in daily life, it could be useful in making the diagnosis of MS, monitoring the progression of disease and studying fatigue and medication effects.22, 33, 35, 71, 72 Standard clinical evaluations of MS
patients often lack systematic eye movement testing. With the development of the King–Devick Test, a brief bedside screening tool of efferent visual dysfunction is provided.73 This rapid number-naming test depends on correct execution of saccades,
but also involves visual acuity, reading, language and attention. However, for more detailed discrimination and quantification of (subtle) eye movement disturbances, more sophisticated methods are needed.
The available methods to measure eye movements have grown substantially over the past decades. Starting halfway through the 20th century, the magnetic (scleral) search coils technique was developed, originally for horizontal and vertical movements only.74, 75 It is since then thoroughly investigated and therefore remains one of the
most reliable methods. However, a major disadvantage is that the subject must wear a special kind of contact lens, which has to be applied after topical anesthetic eye drops.
This is a major hindrance against application of this technique in large groups of patients. Another widely applied method is electro-oculography (EOG), which is still used because it allows measurement of a large range of movements, is relatively inexpensive and hardly stressful for the patient. It has some important limitations, including limited bandwidth, low sensitivity introduction of artefacts and inability to reliably measure vertical eye movements.22 In recent years, a precise and non-invasive
method has become more widely available. This technique, called infrared
oculography, uses the pupil and the corneal reflection (created by infrared light) to determine the gaze direction with high frequency bandwidth. Therefore, this
technique combines the advantages of the scleral search coils (accuracy and precision) with those of the EOG technique (hardly stressful for the patient), the (only)
disadvantage is that torsion cannot be measured. In Figure 3 examples of saccadic eye movements captured with infrared oculography are shown.
As mentioned before, our perception of the visual environment is largely guided by alternating sequences of fixations and saccades.22 Furthermore, saccades show unique
ballistic properties compared to other movements of the human body and are expected to have little within-subject variation.76
Figure 3. Recordings with infrared oculography of horizontal eye position of the left and right eye during
a pro-saccadic task. A. Leftward saccade of a healthy control. B. Hypometric leftward saccade (undershooting the target) of a patient with multiple sclerosis. C. Slightly hypermetric leftward saccade (overshooting the target) of a patient with multiple sclerosis. D. Internuclear ophthalmoplegia during a leftward saccade of a patient with multiple sclerosis. The velocity of the right eye is reduced and the left eye shows a dynamic overshoot of the target. E. A saccade with an increased latency (longer time period between the target jump and the movement of the eyes) of a patient with multiple sclerosis.
19 The dynamic features of a standard saccadic task have been well delineated in
literature.76-78 Consequently, more complex variations of saccadic tasks can give more
insight into higher order eye movement control. For several saccadic tasks the neurobiological substrates have been proposed.22, 79
Taken together, for this thesis we aimed to include visual fixation and saccades in a standardized measurement protocol. Contemporary studies on eye movements generally focus on only one or a few aspects of oculomotor controls and protocol differ considerably. Furthermore, there is a lack of transparency on the data analysis, which frequently depends on device specific eye-tracking software.
Key questions and outline of this thesis
The general aim of this thesis is the development of a standardized protocol of measurement of eye movements with infrared oculography and an exploration on usage in MS. Continuing on the content of the previous paragraphs, there is need for a systematic approach that can meet with: 1) the ballistic and extraordinary properties of saccadic eye movements and 2) the hypothesized broad potential of using them in the complex disorder of MS.
The outline of this thesis is divided in three main parts. Chapter 2 focuses on the development and validation of an open-source measurement and analysis protocol for infrared oculography. Key questions of this chapter are:
• What type of tasks can provide a broad impression on oculomotor function? • What type of analysis method does justice to the complexity of eye movements
and remains at the same time practical for a clinical setting?
• What is the physiological variation of fixational and saccadic eye movements in healthy subjects?
• How reproducible are fixational and saccadic eye movement parameters in healthy subjects?
In chapter 3 the added value of the use of infrared oculography in the demarcated brain stem disorder internuclear ophthalmoplegia (INO) in MS is discussed. The seven main questions of this chapter are:
• Can the ocular dysconjugacy of an INO (and INO variants) be reliably captured with infrared oculography?
• What are the best parameters and cut-off points for detecting an INO? • What is the prevalence of INO in MS?
• What are the clinical characteristic and consequence of INO?
• Can therapeutic effects on INO be reliably measured with infrared oculography?
• What MLF lesions can be found on MRI in patients with and without an INO? • How can INO be used to investigate the clinico-radiological paradox?
Next, the use of infrared oculography in MS extending from INO is explored in chapter 4. The four main question to be investigated in this chapter are:
• What type of fixational and saccadic abnormalities are present in MS in addition to the well-known INO?
• Can fixational and saccadic abnormalities distinguish MS patients with a more advanced disease course?
• How are fixational and saccadic abnormalities related to other measures of the visual system, including visual functioning?
• To what extent is saccadic fatigability present in MS and can it reflect on subjective fatigue?
In the final section (chapter 5) this thesis is concluded with a general discussion and summary of the results, as well as suggestions for future research.
21
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