Siobhan Garbutt

Oculomotor function in frontotemporal lobar degeneration, related disorders and Alzheimer's disease

Frontotemporal lobar degeneration (FTLD) often overlaps clinically with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), both of which have prominent eye movement abnormalities. To investigate the ability of oculomotor performance to differentiate between FTLD, Alzheimers disease, CBS and PSP, saccades and smooth pursuit were measured in three FTLD subtypes, including 24 individuals with frontotemporal dementia (FTD), 19 with semantic dementia (SD) and six with progressive non-fluent aphasia (PA), as compared to 28 individuals with Alzheimers disease, 15 with CBS, 10 with PSP and 27 control subjects. Different combinations of oculomotor abnormalities were identified in all clinical syndromes except for SD, which had oculomotor performance that was indistinguishable from age-matched controls. Only PSP patients displayed abnormalities in saccade velocity, whereas abnormalities in saccade gain were observed in PSP > CBS > Alzheimers disease subjects. All patient groups except those with SD were impaired on the anti-saccade task, however only the FTLD subjects and not Alzheimers disease, CBS or PSP groups, were able to spontaneously self-correct anti-saccade errors as well as controls. Receiver operating characteristic statistics demonstrated that oculomotor findings were superior to neuropsychological tests in differentiating PSP from other disorders, and comparable to neuropsychological tests in differentiating the other patient groups. These data suggest that oculomotor assessment may aid in the diagnosis of FTLD and related disorders.

Medial Versus Lateral Frontal Lobe Contributions to Voluntary Saccade Control as Revealed by the Study of Patients with Frontal Lobe Degeneration

Deficits in the ability to suppress automatic behaviors lead to impaired decision making, aberrant motor behavior, and impaired social function in humans with frontal lobe neurodegeneration. We have studied patients with different patterns of frontal lobe dysfunction resulting from frontotemporal lobar degeneration or Alzheimers disease, investigating their ability to perform visually guided saccades and smooth pursuit eye movements and to suppress visually guided saccades on the antisaccade task. Patients with clinical syndromes associated with dorsal frontal lobe damage had normal visually guided saccades but were impaired relative to other patients and control subjects in smooth pursuit eye movements and on the antisaccade task. The percentage of correct antisaccade responses was correlated with neuropsychological measures of frontal lobe function and with estimates of frontal lobe gray matter volume based on analyses of structural magnetic resonance images. After controlling for age, gender, cognitive status, and potential interactions between disease group and oculomotor function, an unbiased voxel-based morphometric analysis identified the volume of a segment of the right frontal eye field (FEF) as positively correlated with antisaccade performance (less volume equaled lower percentage of correct responses) but not with either pursuit performance or antisaccade or visually guided saccade latency or gain. In contrast, the volume of the presupplementary motor area (pre-SMA) and a portion of the supplementary eye fields correlated with antisaccade latency (less volume equaled shorter latency) but not with the percentage of correct responses. These results suggest that integrity of the presupplementary motion area/supplementary eye fields is critical for supervisory processes that slow the onset of saccades, facilitating voluntary saccade targeting decisions that rely on the FEF.

Saccade Abnormalities in Autopsy-Confirmed Frontotemporal Lobar Degeneration and Alzheimer Disease

BACKGROUND Deficits in the generation and control of saccades have been described in clinically defined frontotemporal dementia (FTD) and Alzheimer disease (AD). OBJECTIVE To determine the saccade abnormalities associated with autopsy-defined cases of frontotemporal lobar degeneration (FTLD) and of AD, because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses. DESIGN An infrared eye tracker was used to record visually guided saccades to 10° targets and antisaccades in subjects with autopsy-confirmed FTD and subjects with autopsy-confirmed AD, a mean (SE) of 35.6 (10.0) months prior to death, and age-matched normal controls. Twelve subjects with FTD had an FTLD-TAR DNA-binding protein 43 pathology, 15 had an FTLD-tau pathology, and 1 subject showed an FTLD-fused in sarcoma protein pathology. Receiver operating curve statistics were used to determine the diagnostic value of the oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry. SETTING Memory and Aging Center, Department of Neurology, University of California, San Francisco. PARTICIPANTS A total of 28 subjects with autopsy-confirmed FTD, 10 subjects with autopsy-confirmed AD, and 27 age-matched normal controls. RESULTS All subjects with FTD or AD were impaired relative to normal controls on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually guided saccade abnormalities. The AD cases displayed prominent increases in horizontal saccade latency that differentiated them from the FTD cases. Impairments in velocity and gain were most severe in individuals with progressive supranuclear palsy but were also present in other tauopathies. By using vertical and horizontal saccade velocity and gain as our measures, we were able to differentiate patients with progressive supranuclear palsy from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume. CONCLUSION Decreased visually guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of progressive supranuclear palsy.

Neuro-ophthalmology of late-onset Tay-Sachs disease (LOTS)

Background: Late-onset Tay–Sachs disease (LOTS) is an adult-onset, autosomal recessive, progressive variant of GM2 gangliosidosis, characterized by involvement of the cerebellum and anterior horn cells. Objective: To determine the range of visual and ocular motor abnormalities in LOTS, as a prelude to evaluating the effectiveness of novel therapies. Methods: Fourteen patients with biochemically confirmed LOTS (8 men; age range 24 to 53 years; disease duration 5 to 30 years) and 10 age-matched control subjects were studied. Snellen visual acuity, contrast sensitivity, color vision, stereopsis, and visual fields were measured, and optic fundi were photographed. Horizontal and vertical eye movements (search coil) were recorded, and saccades, pursuit, vestibulo-ocular reflex (VOR), vergence, and optokinetic (OK) responses were measured. Results: All patients showed normal visual functions and optic fundi. The main eye movement abnormality concerned saccades, which were “multistep,” consisting of a series of small saccades and larger movements that showed transient decelerations. Larger saccades ended earlier and more abruptly (greater peak deceleration) in LOTS patients than in control subjects; these changes can be attributed to premature termination of the saccadic pulse. Smooth-pursuit and slow-phase OK gains were reduced, but VOR, vergence, and gaze holding were normal. Conclusions: Patients with late-onset Tay–Sachs disease (LOTS) show characteristic abnormalities of saccades but normal afferent visual systems. Hypometria, transient decelerations, and premature termination of saccades suggest disruption of a “latch circuit” that normally inhibits pontine omnipause neurons, permitting burst neurons to discharge until the eye movement is completed. These measurable abnormalities of saccades provide a means to evaluate the effects of novel treatments for LOTS.

Comparison of the main sequence of reflexive saccades and the quick phases of optokinetic nystagmus

BACKGROUND/AIMS Abnormalities in the saccadic main sequence are an important finding and may indicate pathology of the ocular motor periphery or central neurological disorders. In young or uncooperative patients it can be difficult eliciting a sufficient number of saccades to measure the main sequence. It is often assumed that the quick phases of optokinetic nystagmus (OKN) are identical to saccades. If this were the case, it would be feasible to use OKN, an involuntary response that is easily evoked, as a simple way of eliciting many saccades. The aim of this study was to determine whether reflexive saccades and the quick phases of OKN are indeed identical, and whether OKN quick phases could have a clinical role in identifying patients with slow saccades. METHODS OKN and reflexive saccades were recorded from 10 healthy adults using an infrared limbus eye tracker and bitemporal DC electro-oculography simultaneously. OKN was stimulated by rotating a full field patterned curtain around the subject at 10–50°/s. Reflexive saccades were elicited to red LED targets at 5–20° eccentricity. RESULTS OKN quick phases tended to have a longer duration compared to saccades, but these differences were not significant. OKN quick phases had a slightly lower peak velocity compared to saccades, which was statistically significant (p<0.05). CONCLUSION The main sequence for duration is the same for reflexive saccades and OKN quick phases. The main sequence for peak velocity is slightly faster for reflexive saccades than OKN quick phases, but the difference is unlikely to be of clinical significance. As an illustration of the potential of this technique, the authors demonstrate that OKN quick phases show similar slowness to saccades in a child with brainstem pathology caused by Gaucher disease type III. It is concluded that recording OKN may be a simple clinical means for approximating the main sequence.

Abnormalities of optokinetic nystagmus in progressive supranuclear palsy

Objectives: To measure vertical and horizontal responses to optokinetic (OK) stimulation and investigate directional abnormalities of quick phases in progressive supranuclear palsy (PSP). Methods: Saccades and OK nystagmus were studied in six PSP patients, five with Parkinson’s disease (PD), and 10 controls. The OK stimulus subtended 72° horizontally, 60° vertically, consisted of black and white stripes, and moved at 10–50°/s. Results: All PSP patients showed slowed voluntary vertical saccades and nystagmus quick phases compared with PD or controls. Small, paired, horizontal saccadic intrusions (SWJ) were more frequent and larger in PSP during fixation. Vertical saccades were transiently faster at the time of SWJ and horizontal saccades in PSP. During vertical OK nystagmus, small quick phases were often combined with horizontal SWJ in all subjects; in PSP the vector was closer to horizontal. Vertical OK slow phase gain was reduced in PSP but, in most PD patients, was similar to normals. The average position of gaze shifted in the direction of vertical OK stimulus in PSP patients with preserved slow phase responses but impaired quick phases. Conclusions: Vertical OK responses in PSP show impaired slow phase responses, and quick phases that are slowed and combined with SWJ to produce an oblique vector. SWJ facilitate vertical saccades and quick phases in PSP, but it is unclear whether this is an adaptive process or a result of the disease. A large OK stimulus is useful to induce responses that can be quantitatively analysed in patients with limited voluntary range of vertical gaze.

Abnormal vertical optokinetic nystagmus in infants and children

AIMS To determine if testing vertical optokinetic nystagmus (VOKN) has a role in the clinical assessment of infants and children. METHODS A large field projection system was developed with which optokinetic nystagmus (OKN) could be stimulated in any direction. Gross abnormalities in the response were detected simply by observation. RESULTS VOKN was tested in 144 children using this OKN projection system. 26 of these children had abnormal VOKN; 13 had a vertical saccade initiation failure “ocular motor apraxia” (in either direction, up/down, or in both) and 13 had absent VOKN (in either direction, up/down, or in both). Nine of the children with an up and/or down vertical saccade initiation failure (VSIF) had a neurometabolic disease (two had Niemann–Pick disease type C, five had Gaucher disease type III, one had Gaucher disease type II, and one had Gaucher disease type I). Five children with a VSIF had an abnormality identified by a magnetic resonance imaging (MRI) scan of the brain. In two of these children there was a focal lesion of the rostral midbrain. In 11 of the children with absent up and/or down VOKN an MRI scan revealed an abnormality. This involved the brainstem and/or the cerebellum in 10. Absent up and/or down VOKN was found in association with Joubert syndrome, Leigh disease, and cerebral palsy. CONCLUSION VOKN testing has a useful role in detecting neurological abnormalities in infants and children. Detection of abnormal VOKN should indicate further investigations for a neurometabolic disease or an abnormality involving the cortex, brainstem, and/or cerebellum. Abnormal VOKN but normal horizontal OKN is highly suggestive of a rostral midbrain lesion.

Directional Cuing of Target Choice in Human Smooth Pursuit Eye Movements

Perceptual attention and target choice for movement have many features in common. In particular, both generally are based on selection of a particular location in space. To ask whether motor control, like attention, also can exhibit target choice based on nonspatial features of the stimulus, we assessed the initiation of smooth pursuit eye movements when two targets move in different directions after human subjects have been cued which direction or color to track. The direction cue consisted of a patch of dots undergoing either 0% coherent motion or 50% coherent motion in the direction of motion of one of the subsequent targets. After a delay, the fixation spot was extinguished and two spots moved across the same small region of the visual field, one in the cued direction (“target”) and one in an orthogonal direction (“distracter”). After the 0% coherent cue, pursuit was approximately the vector average of responses to the two motions presented singly. After the 50% coherent cue, the initial pursuit response was biased strongly toward the target that moved in the cued direction. The impact of the cued direction persisted over delays of up to 1000 ms. Other cues about the direction of upcoming target motion biased the response similarly. Cues about target color also biased pursuit in the direction of motion of the cued target but were considerably less effective than cues indicating the direction of target motion. We conclude that target choice for movement, like perceptual attention, can be based on the features of the chosen target and not only its location in space.

Evaluating small eye movements in patients with saccadic palsies.

Slow saccades are an important diagnostic feature of a range of degenerative, metabolic, and genetic diseases of the nervous system. Many affected patients have difficulty initiating saccades, and the movements themselves may be small, making it difficult to make comparisons with control subjects. A large‐field optokinetic stimulus may elicit quick phases of nystagmus in patients who cannot initiate voluntary saccades, but these movements may also be small. We show that it is still possible to compare amplitude‐duration and amplitude‐peak velocity relations with controls if data are fit with a power function (rather than an exponential equation). When analyzed this way, the dynamic properties of small saccades and quick phases from patients with progressive supranuclear palsy (PSP) could be differentiated from fast movements made by patients with idiopathic Parkinsons disease or controls. Normal saccades show a fairly constant ratio: peak velocity/mean velocity (Q ∼1.6 for vertical saccades). This ratio was abnormally high (Q >3) for some larger saccades made by patients with PSP, suggesting that either these movements were not entirely saccadic or that they were composed of a series of small saccades.

Multicenter validation of a bedside antisaccade task as a measure of executive function

Objective: To create and validate a simple, standardized version of the antisaccade (AS) task that requires no specialized equipment for use as a measure of executive function in multicenter clinical studies. Methods: The bedside AS (BAS) task consisted of 40 pseudorandomized AS trials presented on a laptop computer. BAS performance was compared with AS performance measured using an infrared eye tracker in normal elders (NE) and individuals with mild cognitive impairment (MCI) or dementia (n = 33). The neuropsychological domain specificity of the BAS was then determined in a cohort of NE, MCI, and dementia (n = 103) at UCSF, and the BAS was validated as a measure of executive function in a 6-center cohort (n = 397) of normal adults and patients with a variety of brain diseases. Results: Performance on the BAS and laboratory AS task was strongly correlated and BAS performance was most strongly associated with neuropsychological measures of executive function. Even after controlling for disease severity and processing speed, BAS performance was associated with multiple assessments of executive function, most strongly the informant-based Frontal Systems Behavior Scale. Conclusions: The BAS is a simple, valid measure of executive function in aging and neurologic disease.