Visual signs & symptoms of Multiple System Atrophy: ageing vision part 6 course code: C-15734 O.
In this final article on ageing vision, the visual features of Multiple System Atrophy (MSA) are discussed and described. Previous articles in the series have shown how systemic ageing changes, particularly those affecting the brain, can have significant detrimental effects on vision. MSA is a rare movement disorder and a member of a group of neurodegenerative diseases, which include Parkinson's disease (PD) and progressive supranuclear palsy (PSP), and are referred to as the 'Parkinsonian syndromes'. Although primarily a neurological disorder, patients with MSA may also develop visual signs and symptoms that could be useful in diferential diagnosis. In addition, the eye care practitioner may contribute to the management of visual problems of patients with MSA and therefore help to improve quality of life.
Visual signs and symptoms
Several of the brain areas affected in MSA may be involved in visual function (Figure 1) including areas of the cerebral cortex, striatum, midbrain, and cerebellum. A variety of visual problems have been reported in patients with MSA, involving these brain areas, and the major signs and symptoms identified to date are summarised in Table 1.
There is little detailed information concerning changes in visual acuity (VA) in MSA. Patients with PD and PSP, however, will often complain of poor vision especially as the disease progresses, and this is also possible in MSA. In PD, vision has been reported to be blurred in response to coloured stimuli, (1) with reduced colour fusion times, (2) which indicates the acuity of perception of monochromatic contours. There is little evidence however, that colour vision itself is affected in MSA. Consistent with this suggestion, abnormal visual evoked potentials (VEP) using coloured stimuli have not been reported in MSA. (3) There have been few studies of visual field defects in patients with any of the Parkinsonian syndromes, a reflection of the specific difficulties of conducting such tests in patients with a movement disorder.
Eye movement problems are an important aspect of the Parkinsonian syndromes in general. For example, spontaneous and voluntary eyelid mobility are often abnormal in PSP but are usually less affected in PD and MSA. (4) Abnormal ocular fixation, however, may occur in a significant proportion of patients with MSA. (5) In a patient with MSA where a combination of olivopontocerebellar atrophy and striato-nigral degeneration was present, the typical impairments of eye movement characteristic of PD were evident, viz., abnormal eye movements, (6) in combination with a vertical optokinetic nystagmus. (7) However, smooth pursuit and saccadic movements in the vertical direction were only slightly affected. In a recent study of oculomotor function in thirty patients with MSA, (8) excessive square-wave jerks were observed in 21 of the patients, a mild supranuclear gaze palsy in eight patients, a gaze-evoked nystagmus in 12 patients, a positioning down-beat nystagmus in 10 out of 25 patients, mild-moderate saccadic hypometria in 22 patients, impaired smooth pursuit movements in 28 patients, and reduced vestibulo-ocular reflex (VOR) suppression in 16 out of 24 patients.
The VOR is a reflex eye movement that stabilizes images on the retina during movements of the head. This is achieved by the central nervous system, which induces an eye movement in the opposite direction to that of the head. It can be tested by the 'rapid head impulse test' in which the head is rapidly moved to the side. Normally the eyes will remain looking in the same direction but in diseases such as MSA, no compensatory eye movement may be apparent. The 'gain' of the VOR is the ratio of the change in eye angle to head angle during a head turn. If the gain is impaired (ratio not equal to unity), head movements result in image motion on the retina and blurred vision. The gain of the VOR in the dark may be cancelled by fixation. Both patients with MSA and PSP show this cancellation compared with both normal subjects and patients with PD, (5) which could be related to cerebellar dysfunction.
Hence, eye movement problems and especially those related to oculomotor dysfunction are likely to be an important feature of MSA. Nevertheless, many of the visual signs and symptoms associated with eye movement are controversial and may not occur in all patients. Hence, some authors believe that oculomotor anomalies are not present in MSA consistently enough to make them useful in differential diagnosis. (9)
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Examination of the pupil reactions is an opportunity to detect disturbances in autonomic innervation of the eye, a likely feature of MSA. (10) Infra-red pupillography can be used to measure pupil diameter in the light and dark, the light reflex response, and pupil reactions associated with the administration of pharmacological agents. (10) In a study of pupil reactivity in MSA, about a quarter of patients tested had abnormal pupil reactions and in the majority, the defects were bilateral and symmetrical. Pupil defects were not usually apparent to the patients themselves or to their physicians. In addition, in normal subjects, pupil size will often increase in response to stress but no such change is apparent in MSA. (11) Horner's syndrome (abnormally small pupil diameter) has rarely been observed in neuropathies such as MSA, although such a change has been reported in one case. (12)
Contrast sensitivity (CS) is affected in PD at least in a proportion of patients (13,14) but there is little evidence to date for an effect in MSA. Visual spatial contrast threshold and suprathreshold contrast match to high-contrast sine-wave gratings have been compared in patients with PD and MSA to normal control subjects. (15) The response of patients with PD was reduced compared with the controls but this was not the case in patients with MSA.
Visual evoked potentials
Evoked responses to motor stimuli have been reported to be normal in MSA. (16) Similarly, although significant effects on the electroretinogram (ERG) and VEP have been found in PD and PSP, the results reported in MSA are more controversial. For example, the pattern reversal ERG to a coloured stimulus (ChPERG) was recorded in both PD and MSA. (3) Although reduced amplitude and increased latency of evoked components were observed in PD, especially when a blue-yellow horizontal grating was used as a stimulus, no such effects were seen in MSA. (3) Similarly, using a horizontal sinusoidal grating, there were no effects on the VEP in MSA although effects were demonstrated in PD. (17) Significantly less impairment has also been observed in MSA to a full-field flash stimulus compared to PD and PSP. (18) Nevertheless, in some studies, VEP abnormalities have been reported in patients with MSA, with no detectable differences between the MSA-C and MSA-P subtypes. (16)
Event-related evoked potentials
There have been a number of studies of event-related potentials in MSA, which elicit the 'P300' evoked response, believed to reflect orientation, attention, stimulus evaluation, and memory. These evoked responses may be associated with neural activity in the temporal lobe, pre-frontal lobe, limbic system, and thalamus. (19) In one of the first studies of event-related potentials in MSA,20 it was observed that the P300, elicited using visual stimuli, could be recorded even when a severe motor disability was present. Reaction times to rare target stimuli were significantly decreased in PD and MSA compared with PSP. (19) Kamitani (21) studied event related potentials in MSA-C and MSA-P. No significant change was found in the latency of the N1 or N2 components in either subtype of the disease suggesting that the early stages of visual processing were preserved in MSA. Nevertheless, the P3a peak was more difficult to distinguish and there were decreases in amplitude of the response in both MSA subtypes. By contrast, the P3b component was only affected in the MSA-C subtype and exhibited both increased latency and reduced amplitude. The reduced size of the pons, claustrum, perisylvian area and the deep cerebral gray matter in MSA may be responsible for these responses.
Complex visual functions
Speech abnormalities are common in all of the Parkinsonian syndromes and in MSA, and there is often a mixed dysarthria (problems in articulating speech) with ataxic and spastic elements. (22) Maximum phonation time and reading speed are also affected in MSA but to a lesser extent than in PSP. (22) There is also 'idiopathic rapid eye movement' (iREM) disorder (abnormal behaviour during sleep accompanied with rapid eye movements) in MSA, which probably results from neuronal losses in the pigmented monoaminergic nuclei such as the locus caeruleus and substantia nigra. (23) So common is this type of disorder in the Parkinsonian syndromes generally, that the presence of iREM is often regarded as a strong indicator that a patient may be developing a Parkinsonian-type disorder. Visual hallucinations, unrelated to medication, are rare in MSA however, compared with the other Parkinsonian syndromes, and especially
The Parkinsonian syndromes often exhibit overlapping signs and symptoms and therefore, can be very difficult to diagnose correctly. Hence, there is the question of whether visual symptoms can help in the clinical diagnosis of these disorders. A summary of the most useful visual features in differential diagnosis is shown in Table 2. Patients with MSA often exhibit a combination of extrapyramidal, cerebellar, pyramidal, and autonomic dysfunction signs, many of which can also be seen in other Parkinsonian disorders. The presence of visual hallucinations, unrelated to medication, however, are rare in MSA and their presence can often exclude MSA as a possible diagnosis. (24) In addition, there is greater retinal pathology in PD, which results in significant defects in CS, and in the early components of the VEP, which are also not likely to be seen in MSA. Colour VEPs are also affected in PD but not in MSA. (3) Where defects in the VEP are seen in MSA, they will normally involve event-related evoked potentials such as the P300. (19,20) Additional features that may be helpful in differential diagnosis include fixation, which is abnormal in a significant proportion of PSP and MSA cases but less so in PD, (5) eyelid mobility which is abnormal in PSP but more likely to be normal in PD and MSA, (4) and the slowing of saccadic movements especially in the vertical direction which occurs most significantly in PSP. (25)
Anderson et al. (8) have recently published a list of 'red flag' criteria that are strongly suggestive of a diagnosis of MSA and include excessive square-wave jerks, mild to moderate hypometria of saccades, impaired VOR, and nystagmus. By contrast, if clinically slow saccades are present together with a moderate to severe vertical gaze palsy, the diagnosis is more likely to be one of the other Parkinsonian syndromes such as PSP.
Discussion and conclusions
Middle-aged to elderly patients who have not been diagnosed with MSA may exhibit visual signs and symptoms suggestive of a Parkinsonian-type disorder. The most important of these signs are related to the primary defects of the disease, viz., extrapyramidal, cerebellar, pyramidal, and autonomic dysfunction. The most important visual signs include oculomotor dysfunction and pupil reactivity, but with relatively preserved primary vision. Hence, a patient with unexplained signs of this type should be referred for neurological examination. Nevertheless, the exact presentation of MSA is highly variable and patients can be visually asymptomatic. It is difficult to separate MSA from other disorders with Parkinsonism such as PD and PSP especially before visual symptoms become apparent. If ocular signs and symptoms are present, then they may aid differential diagnosis. Atypical features of MSA include slowing of saccades, presence of vertical gaze palsy, and absence of square-wave jerks. Particularly useful in separating MSA from other Parkinsonian syndromes is the presence in the former of excessive square-wave jerks, mild to moderate hypometria of saccades, impaired VOR, and nystagmus.
Patients who have been diagnosed with MSA may develop a range of visual problems during the course of the disease. Visual deficits in Parkinsonian-type syndromes are often important in influencing overall motor function. Hence, identifying and correcting the visual problems of a patient with MSA as far as possible can significantly improve quality of life. Clinical examination requires sensitivity to the physical and mental state of the patient and the problems involved in the Parkinsonian syndromes have been described in detail by Naylor. (26) In addition, some of the visual problems may be adverse reactions to treatment. Side effects may occur relatively rapidly at the beginning of, or after a change in, drug treatment, but can also occur after a long latent period. It is important that those symptoms due to adverse reactions are distinguished from those due to the disease process itself. If ocular side effects are identified in a patient with MSA and become severe, then it is essential that these be monitored and the patient referred back to their physician for further clinical assessment.
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Course code: C-15734 O
1. Which of the following statements regarding the primary aspects of vision in MSA is FALSE?
(a) Poor vision is likely to be observed in MSA
(b) Blurred vision in response to coloured stimuli has been reported in Parkinsons's disease
(c) Abnormal VEP to coloured stimuli have been reported in MSA
(d) The degree to which visual fields may be affected in MSA is largely unknown
2. Which of the following features occurs in a significant proportion of MSA patients?
(a) Abnormal fixation
(b) Abnormal eyelid mobility
(c) Abnormal vertical saccadic eye movements
(d) Abnormal vertical smooth pursuit movements
3. Which of the following VEP abnormalities have been reported in MSA?
(a) Motor evoked responses
(c) Pattern-reversal VEP
(d) Event-related VEP
4. Which of the following statements regarding complex visual functions in MSA is FALSE?
(a) Speech abnormalities are common in MSA
(b) A mixed dysarthria with ataxic and spastic elements may be present in MSA
(c) Reading speed is affected to a greater extent in MSA compared with PSP
(d) Idiopathic rapid eye movement (iREM) disorder is present in MSA
5. Which of the following statements regarding the differential diagnosis of MSA is TRUE?
(a) Visual hallucinations are common in MSA
(b) There is greater retinal pathology in MSA compared with PD
(c) The early components of the VEP are significantly affected in MSA
(d) Fixation is abnormal in a significant proportion of MSA patients compared with PD
6. Which of the following is NOT a 'red flag' criterion for the identification of MSA?
(a) Excessive square-wave jerks
(b) Impaired vestibulo-ocular reflex (VOR)
(c) Moderate to severe vertical gaze palsy
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For the module questions to this article, please turn to page 59.
About the author
Richard Armstrong was educated at King's College London and St. Catherine's College Oxford. He has been a lecturer in Botany, Microbiology, Ecology, Neuroscience, and Optometry during his 34 years at Aston University. His research interests include the neuropathology of neurodegenerative diseases with special reference to vision and the visual system. He also has a particular interest in the application of statistical methods in research.
Dr. Richard A. Armstrong BSc DPhil
Table 1 Visual changes in Multiple System Atrophy (MSA). Abbreviations: iREM = idiopathic rapid eye movement sleep disorder, PERG = pattern elctroretinogram, VEP = Visual evoked responses, VOR = Vestibulo-ocular reflex Ocular aspect Change in MSA Primary vision Little evidence at present for defects in acuity, colour vision, or visual fields Eyelid mobility Spontaneous and voluntary eyelid mobility normal Fixation Abnormal in many patients Square-wave jerks Present in a significant proportion of patients Supranuclear gaze Mild defect in some patients palsy Nystagmus Gaze-evoked nystagmus in a proportion of patient Saccadic hypometria Mild to moderate Smooth pursuit Impaired in a significant number of patients movement VOR Reduced suppression in a proportion of patients Pupil reactivity Abnormal pupils in many patients No response due to stress Contrast sensitivity No evidence for impairment Evoked potentials Normal motor-evoked potentials Normal chromatic PERG VEP defects controversial Abnormal event-related potentials in some patients (P300) Sleep disorder iREM in many patients Reading speed Mildly affected Visual hallucinations Rare, unrelated to medication Ocular aspect References Primary vision - Eyelid mobility VallSole et al., 1991 Fixation Rascol et al., 1991 Square-wave jerks Anderson et al., 2008 Supranuclear gaze Anderson et al., 2008 palsy Nystagmus Anderson et al., 2008 Saccadic hypometria Anderson et al., 2008 Smooth pursuit Anderson et al., 2008 movement VOR Anderson et al., 2008 Pupil reactivity Kuruda et al., 1998 Contrast sensitivity van Elst et al., 1997 Evoked potentials Abele et al., 2001 Sartucci et al., 2006 Delalande et al., 1998 Delalande et al., 1998 Wang et al., 2000 Sleep disorder Turner, 2002 Reading speed Sachin et al., 2008 Visual hallucinations Kumbler and Kornhuber, 2002 Table 2 Summary of features that can be used to provide a differential diagnosis of 'parkinsonian'syndromes (MSA = Multiple system atrophy, PD = Parkinson's disease, PSP = Progressive supranuclear palsy) based on visual signs and symptoms. A = Amplitude, L = Latency, VEP = Visual evoked potential, VOR=Vestibulo-ocular reflex, OKN = Optokinetic nystagmus, ? indicates no reliable data known to the author Syndrome Feature MSA PD Eyelid mobility Normal Normal Saccadic eye Mild-moderate Normal movements hypometria Vertical gaze palsy Rare Rare Fixation Abnormal Normal Square-wave jerks Frequent Present Contrast sensitivity Normal (?) Abnormal (high to intermediate frequencies) VEP (early) Normal Abnormal VEP (colour) Normal Abnormal VEP (P300) Increased L ? Reduced A ? Visual hallucinations Rare, unrelated to Common medication VOR Impaired gain Normal Nystagmus Various present Abnormal OKN Feature PSP Eyelid mobility Eyelid opening apraxia Saccadic eye Abnormal, slow movements Vertical gaze palsy Present Fixation Abnormal Square-wave jerks Present Contrast sensitivity ? VEP (early) Normal VEP (colour) ? VEP (P300) Increased L Reduced A Visual hallucinations Rare VOR Impaired gain Nystagmus Abnormal OKN