REVIEW URRENT C OPINION
Ocular motor disorders Anna Willard and Christian J. Lueck
Purpose of review Studying eye movements can provide insight into how the normal brain works, how diseases affect eye movements, and how eye movement abnormalities can be used to study diseases and/or their treatments. In this review, we concentrate on recent studies looking at abnormalities of saccades in various diseases. Recent findings Various saccadic abnormalities have been found in Parkinson’s disease, Huntington’s disease, dementia, cerebellar disease, schizophrenia, and several other conditions. In some of these, saccadic abnormalities appear to be capable of distinguishing different subtypes (e.g., progressive supranuclear palsy from idiopathic Parkinson’s disease, Alzheimer’s disease from frontotemporal dementia, or one type of spinocerebellar ataxia from another). Several studies have looked at functional associations of saccadic abnormalities (e.g., reading in spinocerebellar ataxia or recovery from stroke), which may prove clinically useful. Studies on microsaccades have revealed abnormalities in various diseases, and suggest that they may provide a useful marker of fatigue. Summary Saccadic eye movements provide an excellent way of studying the human motor system in health and disease, as well as providing insight into various aspects of cognitive function. Assessment of saccades in the laboratory and at the bedside is likely to become increasingly useful clinically. Keywords dementia, eye movement, Huntington’s disease, microsaccades, Parkinson’s disease, saccades, spinocerebellar ataxia
INTRODUCTION There continues to be much interest in the study of eye movements, both in health and in disease. These studies provide increasing insight into how the normal brain works, how diseases can affect eye movements, how eye movement abnormalities can be diagnosed, and how they can be used to study diseases and/or their treatments. For example, there is much interest in studying both saccades and smooth pursuit in normal subjects to investigate attention [1 ,2–6], perception [7 ,8], and eye–hand co-ordination [9,10 ,11,12], and there has been some excellent work on anatomy [13 ] and physiology [14,15] of saccades. Unfortunately, space does not permit widespread coverage, so in this article we will concentrate on recent studies that have looked at saccadic eye movements in patients with various diseases. &
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SACCADES Saccades are the fast, refixating, eye movements that we make when looking from one object to another. They have been the subject of considerable research
ever since they were described toward the end of the 19th century (see Leigh & Zee [16]). There are, in fact, several different types of saccade, which can be classified into spontaneous, reflexive, and volitional (see Table 1). Each saccade type is generated by a slightly different pathway in the brain and so, not surprisingly, different diseases are associated with distinctive patterns of abnormality. The reader is referred to an excellent review by Anderson & MacAskill [17 ]. Figure 1 explains standard terms such as latency, amplitude, gain, and error rate, which are used when discussing saccades. Different laboratories have developed individual paradigms for eliciting the more complicated types of saccades. This means that it is often not &&
Department of Neurology, The Canberra Hospital and Australian National University, Canberra, Australia Correspondence to Dr Christian J. Lueck, PhD, FRACP, FRCP(UK), Department of Neurology, The Canberra Hospital, PO Box 11, Woden ACT 2606, Australia. Tel: +61 2 6244 2950; fax: +61 2 6244 4629; e-mail: [email protected] Curr Opin Neurol 2014, 27:75–82 DOI:10.1097/WCO.0000000000000054
1350-7540 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-neurology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Neuro-ophthalmology and neuro-otology
KEY POINTS There are several different types of saccade, which may be differentially affected by various diseases. Patients with Parkinson’s disease show impairment in anticipating target motion, which could relate to deficits of gait initiation and termination. The effects of DBS are somewhat conflicting, but there are significant effects on whole-body turning and associated saccadic eye movements. Saccadic abnormalities may be useful in distinguishing patients with different types of dementia. Patients with stroke show abnormalities of voluntary saccades, which can lag behind motor recovery, raising the possibility that they could provide a way of monitoring cognitive/nonmotor recovery from stroke.
possible to compare the results of different studies, nor is it possible to combine datasets to perform meta-analyses. To address this extremely important issue, Antoniades et al. [18 ] report the outcome of a meeting that produced an internationally standardized protocol for antisaccades. Global standardization will greatly enhance research by facilitating more direct comparison of results obtained in different laboratories. &&
PARKINSON’S DISEASE Parkinson’s disease, like many other neurodegenerative conditions, has significant effects on the ocular motor system. Although some abnormalities can be detected in the course of routine clinical examination (e.g., abnormalities of vertical gaze in progressive supranuclear palsy), other abnormalities are more subtle, often evident only on laboratory testing (e.g., hypometria of voluntary saccades). In the early stages, idiopathic Parkinson’s disease can be difficult to distinguish from other forms of parkinsonism such as progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA-P). Linder et al. [19 ] looked at newly diagnosed patients with Parkinson’s disease, PSP, and MSA-P to see whether abnormalities of ocular motor function might distinguish the different groups. Subjects were studied within 3 months of diagnosis and again a year later. All groups with parkinsonism displayed abnormalities of saccadic latency, velocity, and/or gain, but none of the findings could reliably separate the different forms of parkinsonism. Overall, ocular motor abnormalities were more pronounced in PSP and MSA-P. Interestingly, no patient with PSP had a vertical saccade velocity above 2048 per second. &&
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Further work is needed to determine whether a cutoff value such as this could be useful in distinguishing PSP from Parkinson’s disease. Linder et al. [19 ] also found that Parkinson’s disease patients demonstrated a correlation between the total axial motor scores of the Unified Parkinson’s Disease Rating Scale (UPDRS) and the velocity and precision of both vertical and horizontal saccades. However, no correlation was found with the tremor, rigidity, or bradykinesia scores, so the significance of this finding is not clear. Similarly, Helmchen et al. [20] found no correlation between ocular motor abnormality and either disease severity or duration looking at the role of anticipation and prediction in eye movement control. The study was principally concerned with smooth pursuit, although predictive saccades and antisaccades were also studied. During smooth pursuit, patients with Parkinson’s disease showed lower initial eye drift velocity before target onset and prolonged latency of initial acceleration. However, once pursuit had been initiated, Parkinson’s disease patients predicted target velocity as well as controls. Consistent with findings elsewhere in the literature, predictive saccades were hypometric and there was an increased antisaccade error rate. The authors suggested that the impairment in anticipating target motion could relate to deficits in gait initiation and termination. The effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on eye movements have been studied by several groups with conflicting results. Nilsson et al. [21] found that saccade accuracy and peak velocity were increased by DBS, and they also found significant improvements in both velocity and gain of smooth pursuit. Fridley et al. [22] reported decreased latency for both prosaccades and antisaccades following DBS of the STN (but not the globus pallidus). Pinkhardt et al. [23], on the contrary, did not report any improvement in prosaccades, volitional saccades, or smooth pursuit with DBS. One problem with these studies is that the numbers of patients were – understandably – low. Also, there is the possibility of subtle variation in stimulator position, which could have significantly influenced the effects on eye movements. Further work is needed to clarify the true effects of DBS. A different approach was taken by Lohnes and Earhart [24 ], who looked at the effect of STN DBS on the kinetics of whole-body turning and associated saccadic eye movements. During turning in healthy controls, eye movement precedes the sequential rotation of head, trunk, and then feet, whereas turning happens more en bloc in Parkinson’s disease, and saccadic amplitude during turns is reduced. Subjects were asked to perform a (seated) &&
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Volume 27 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Ocular motor disorders Willard and Lueck Table 1. The different types of saccade, including examples of conditions which show abnormalities Definition
Examples of conditions which demonstrate abnormality
Spontaneous saccades Microsaccades (
Ocular motor disorders Anna Willard and Christian J. Lueck
Purpose of review Studying eye movements can provide insight into how the normal brain works, how diseases affect eye movements, and how eye movement abnormalities can be used to study diseases and/or their treatments. In this review, we concentrate on recent studies looking at abnormalities of saccades in various diseases. Recent findings Various saccadic abnormalities have been found in Parkinson’s disease, Huntington’s disease, dementia, cerebellar disease, schizophrenia, and several other conditions. In some of these, saccadic abnormalities appear to be capable of distinguishing different subtypes (e.g., progressive supranuclear palsy from idiopathic Parkinson’s disease, Alzheimer’s disease from frontotemporal dementia, or one type of spinocerebellar ataxia from another). Several studies have looked at functional associations of saccadic abnormalities (e.g., reading in spinocerebellar ataxia or recovery from stroke), which may prove clinically useful. Studies on microsaccades have revealed abnormalities in various diseases, and suggest that they may provide a useful marker of fatigue. Summary Saccadic eye movements provide an excellent way of studying the human motor system in health and disease, as well as providing insight into various aspects of cognitive function. Assessment of saccades in the laboratory and at the bedside is likely to become increasingly useful clinically. Keywords dementia, eye movement, Huntington’s disease, microsaccades, Parkinson’s disease, saccades, spinocerebellar ataxia
INTRODUCTION There continues to be much interest in the study of eye movements, both in health and in disease. These studies provide increasing insight into how the normal brain works, how diseases can affect eye movements, how eye movement abnormalities can be diagnosed, and how they can be used to study diseases and/or their treatments. For example, there is much interest in studying both saccades and smooth pursuit in normal subjects to investigate attention [1 ,2–6], perception [7 ,8], and eye–hand co-ordination [9,10 ,11,12], and there has been some excellent work on anatomy [13 ] and physiology [14,15] of saccades. Unfortunately, space does not permit widespread coverage, so in this article we will concentrate on recent studies that have looked at saccadic eye movements in patients with various diseases. &
&
&
&&
SACCADES Saccades are the fast, refixating, eye movements that we make when looking from one object to another. They have been the subject of considerable research
ever since they were described toward the end of the 19th century (see Leigh & Zee [16]). There are, in fact, several different types of saccade, which can be classified into spontaneous, reflexive, and volitional (see Table 1). Each saccade type is generated by a slightly different pathway in the brain and so, not surprisingly, different diseases are associated with distinctive patterns of abnormality. The reader is referred to an excellent review by Anderson & MacAskill [17 ]. Figure 1 explains standard terms such as latency, amplitude, gain, and error rate, which are used when discussing saccades. Different laboratories have developed individual paradigms for eliciting the more complicated types of saccades. This means that it is often not &&
Department of Neurology, The Canberra Hospital and Australian National University, Canberra, Australia Correspondence to Dr Christian J. Lueck, PhD, FRACP, FRCP(UK), Department of Neurology, The Canberra Hospital, PO Box 11, Woden ACT 2606, Australia. Tel: +61 2 6244 2950; fax: +61 2 6244 4629; e-mail: [email protected] Curr Opin Neurol 2014, 27:75–82 DOI:10.1097/WCO.0000000000000054
1350-7540 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-neurology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Neuro-ophthalmology and neuro-otology
KEY POINTS There are several different types of saccade, which may be differentially affected by various diseases. Patients with Parkinson’s disease show impairment in anticipating target motion, which could relate to deficits of gait initiation and termination. The effects of DBS are somewhat conflicting, but there are significant effects on whole-body turning and associated saccadic eye movements. Saccadic abnormalities may be useful in distinguishing patients with different types of dementia. Patients with stroke show abnormalities of voluntary saccades, which can lag behind motor recovery, raising the possibility that they could provide a way of monitoring cognitive/nonmotor recovery from stroke.
possible to compare the results of different studies, nor is it possible to combine datasets to perform meta-analyses. To address this extremely important issue, Antoniades et al. [18 ] report the outcome of a meeting that produced an internationally standardized protocol for antisaccades. Global standardization will greatly enhance research by facilitating more direct comparison of results obtained in different laboratories. &&
PARKINSON’S DISEASE Parkinson’s disease, like many other neurodegenerative conditions, has significant effects on the ocular motor system. Although some abnormalities can be detected in the course of routine clinical examination (e.g., abnormalities of vertical gaze in progressive supranuclear palsy), other abnormalities are more subtle, often evident only on laboratory testing (e.g., hypometria of voluntary saccades). In the early stages, idiopathic Parkinson’s disease can be difficult to distinguish from other forms of parkinsonism such as progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA-P). Linder et al. [19 ] looked at newly diagnosed patients with Parkinson’s disease, PSP, and MSA-P to see whether abnormalities of ocular motor function might distinguish the different groups. Subjects were studied within 3 months of diagnosis and again a year later. All groups with parkinsonism displayed abnormalities of saccadic latency, velocity, and/or gain, but none of the findings could reliably separate the different forms of parkinsonism. Overall, ocular motor abnormalities were more pronounced in PSP and MSA-P. Interestingly, no patient with PSP had a vertical saccade velocity above 2048 per second. &&
76
www.co-neurology.com
Further work is needed to determine whether a cutoff value such as this could be useful in distinguishing PSP from Parkinson’s disease. Linder et al. [19 ] also found that Parkinson’s disease patients demonstrated a correlation between the total axial motor scores of the Unified Parkinson’s Disease Rating Scale (UPDRS) and the velocity and precision of both vertical and horizontal saccades. However, no correlation was found with the tremor, rigidity, or bradykinesia scores, so the significance of this finding is not clear. Similarly, Helmchen et al. [20] found no correlation between ocular motor abnormality and either disease severity or duration looking at the role of anticipation and prediction in eye movement control. The study was principally concerned with smooth pursuit, although predictive saccades and antisaccades were also studied. During smooth pursuit, patients with Parkinson’s disease showed lower initial eye drift velocity before target onset and prolonged latency of initial acceleration. However, once pursuit had been initiated, Parkinson’s disease patients predicted target velocity as well as controls. Consistent with findings elsewhere in the literature, predictive saccades were hypometric and there was an increased antisaccade error rate. The authors suggested that the impairment in anticipating target motion could relate to deficits in gait initiation and termination. The effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on eye movements have been studied by several groups with conflicting results. Nilsson et al. [21] found that saccade accuracy and peak velocity were increased by DBS, and they also found significant improvements in both velocity and gain of smooth pursuit. Fridley et al. [22] reported decreased latency for both prosaccades and antisaccades following DBS of the STN (but not the globus pallidus). Pinkhardt et al. [23], on the contrary, did not report any improvement in prosaccades, volitional saccades, or smooth pursuit with DBS. One problem with these studies is that the numbers of patients were – understandably – low. Also, there is the possibility of subtle variation in stimulator position, which could have significantly influenced the effects on eye movements. Further work is needed to clarify the true effects of DBS. A different approach was taken by Lohnes and Earhart [24 ], who looked at the effect of STN DBS on the kinetics of whole-body turning and associated saccadic eye movements. During turning in healthy controls, eye movement precedes the sequential rotation of head, trunk, and then feet, whereas turning happens more en bloc in Parkinson’s disease, and saccadic amplitude during turns is reduced. Subjects were asked to perform a (seated) &&
&&
Volume 27 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Ocular motor disorders Willard and Lueck Table 1. The different types of saccade, including examples of conditions which show abnormalities Definition
Examples of conditions which demonstrate abnormality
Spontaneous saccades Microsaccades (
