Ocular Motor Dysfunction Research Articles

An ipsilateral vestibulothalamic tract adjacent to the medial lemniscus in humans

We examined 14 patients with acute anteromedial pontomesencephalic infarctions for signs of vestibular and ocular motor dysfunction. In all cases, an isolated ipsilateral deviation of the subjective visual vertical (mean: 4.1, range: 2.7- 6.6) was found without any further signs of vestibular or eye movement disorders like ocular torsion or skew deviation. Distinct lesions in thin-slice brainstem MRI showed an overlap zone in the medial portion of the medial lemniscus. The finding of putative ipsilateral vestibular projections running adjacent to or within the medial lemniscus was subsequently confirmed by a reanalysis of an anterograde tracer labelling study in the primate after tracer injection in the vestibular nucleus complex. The major conclusions of this study are as follows: (i) there is evidence for an ipsilateral graviceptive pathway running from the vestibular nuclei close to and within the medial lemniscus to the posterolateral thalamus [ipsilateral vestibulothalamic tract (IVTT)], (ii) this pathway might be the human homologue of the three-neuron sensory vestibulocortical tract described in primates and (iii) unilateral lesions of this pathway cause only vestibulo-perceptive dysfunction in the roll plane in contrast to lesions of the crossed graviceptive pathways (in the medial longitudinal fascicle), which were described earlier and which manifest as a combination of tilt of the subjective visual vertical, ocular torsion and skew deviation.

Spectrum of infantile esotropia in primates: Behavior, brains, and orbits

Recent studies of human infants have described a spectrum of early-onset esotropia, from small angle to large heterotropias. We report here a similar spectrum of early-onset esotropia in infant monkeys, with emphasis on the relationship between visuomotor deficits, central nervous system circuitry, and orbital anatomy. Eye movements were recorded in macaque monkeys with natural, infantile-onset esotropia (n = 7) and in control monkeys (n = 2) to assess alignment, latent nystagmus, dissociated vertical deviation (DVD), and pursuit/optokinetic nystagmus (OKN) asymmetries. Acuity was measured by preferential-looking technique or spatial sweep visual-evoked potentials. Geniculo-striate pathways were then analyzed with neuroanatomic tracers and ocular dominance column labels. Extraocular muscles were examined by high-resolution magnetic resonance imaging (MRI) and anatomic sectioning of whole orbits. Esotropia ranged from 4 to 13.5 degrees (7-24(Delta)) with fixation preference (if any) varying idiosyncratically (as in human). Severity of ocular motor dysfunction (ie, nystagmus velocity, DVD amplitude, pursuit-OKN nasal bias index) increased as the magnitude of esotropia angle. Animals with greater ocular motor deficits tended to have greater visual area V1 (striate cortex) neuroanatomic deficits, evident as fewer binocular horizontal connections in V1. Orbital MRI/anatomic analysis showed no difference in horizontal rectus cross-sectional areas, muscle paths, innervation densities, or cytoarchitecture compared with normal animals. The infantile esotropia spectrum in nonhuman primates is remarkably similar to that reported in human infants. Concomitant esotropia in these primates cannot be ascribed to abnormalities of the extraocular muscles or orbit. These findings, combined with epidemiologic studies of humans, suggest that perturbations of cerebral binocular pathways in early development are the primary cause of the infantile esotropia syndrome.

Gaze Control and Foot Kinematics During Stair Climbing: Characteristics Leading to Fall Risk in Progressive Supranuclear Palsy

Does gaze control influence lower-extremity motor coordination in people with neurological deficits? The purpose of this study was to determine whether foot kinematics during stair climbing are influenced by gaze shifts prior to stair step initiation. Twelve subjects with gaze palsy (mild versus severe) secondary to progressive supranuclear palsy were evaluated during a stair-climbing task in a cross-sectional study of mechanisms influencing eye-foot coordination. Infrared oculography and electromagnetic tracking sensors measured eye and foot kinematics, respectively. The primary outcome measures were vertical gaze fixation scores, foot lift asymmetries, and sagittal-plane foot trajectories. The subjects with severe gaze palsy had significantly lower lag foot lift relative to lead foot lift than those with a mild form of gaze palsy. The lag foot trajectory for the subjects with severe gaze palsy tended to be low, with a heading toward contact with the edge of the stair. with severe gaze palsy were 28 times more likely to experience "fixation intrusion" (high vertical gaze fixation score) during an attempted shift of gaze downward than those with mild ocular motor deficits (odds ratio [OR]=28.3, 95% confidence interval [CI]=6.4-124.8). Subjects with severe gaze shift deficits also were 4 times more likely to have lower lag foot lift with respect to lead foot lift than those with mild ocular motor dysfunction (OR=4.0, 95% CI=1.7-9.7). The small number of subjects and the variation in symptom profiles make the generalization of findings preliminary. Deficits in gaze control may influence stepping behaviors and increase the risk of trips or falls during stair climbing. Neural and kinematic hypotheses are discussed as possible contributing mechanisms.

Episodic Ataxia Type 2

Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It manifests with recurrent disabling attacks of imbalance, vertigo, and ataxia, and can be provoked by physical exertion or emotional stress. In the spell-free interval, patients present with central ocular motor dysfunction, mainly downbeat nystagmus. A slow progression of cerebellar signs accompanied by a slight atrophy of midline cerebellar structures is commonly observed during the course of the disease. EA 2 is caused most often by the loss of function mutations of the calcium channel gene CACNA1A, which encodes the Ca(v)2.1 subunit of the P/Q-type calcium channel and is primarily expressed in Purkinje cells. To date, more than 30 mutations have been described. Two effective treatment options have been established for EA 2: acetazolamide (ACTZ), which probably changes the intracellular pH and thereby the transmembraneous potential, and 4-aminopyridine (4-AP), a potassium channel blocker. Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient. In an open trial, 4-AP prevented attacks in five of six patients with EA 2, most likely by increasing the resting activity and excitability of the Purkinje cells. These findings were confirmed by experiments in animal models of EA 2. Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.

Spectrum of infantile esotropia in primates: Behavior, brains, and orbits

Introduction: Recent PEDIG studies have described a spectrum of early-onset esotropia (ET), from small variable angle to “classical” large heterotropias. We report here a similar spectrum of early-onset ET in infant monkeys, with emphasis on the relationship between visuomotor deficits, central nervous system circuitry, and orbital anatomy. Methods: Eye movements were recorded in macaque monkeys with natural (n = 3) and optically induced (n = 7) ET to assess alignment, disparity-vergence, latent nystagmus, DVD, and pursuit/OKN asymmetries. Acuity was measured by SSVEP and stereopsis thresholds established using random-dot stimuli. Geniculo-striate pathways were then analyzed with neuroanatomic tracers and metabolic labels. EOMs were examined by high-resolution magnetic resonance imaging and anatomic sectioning of whole orbits. Results: ET ranged from 4° to 25° (7–44Δ) with fixation preference (if any) varying idiosyncratically (as in human). Severity of ocular motor dysfunction (ie, vergence insensitivity, nystagmus velocity, DVD amplitude, nasotemporal gain asymmetry), and severity of stereopsis deficit related to ET angle and duration (regression analysis; p = 0.036). Animals with marked behavioral deficits tended to have marked V1 neuroanatomic deficits, evident as fewer binocular horizontal connections and denser metabolic suppression. Orbital MRI/anatomic analysis showed no EOM/pulley or cranial nerve end-plate anomalies compared with (n = 3) controls. Conclusions: The ET spectrum in nonhuman primates is remarkably similar to that reported in human infants. Concomitant ET in these primates cannot be ascribed to abnormalities of the extraocular muscles or orbit. These findings, combined with epidemiologic studies of human, indicate that perturbations of CNS binocular pathways in early development are the primary cause of the infantile ET syndrome.

First a third, then a fourth nerve palsy in multiple intracranial aneurysms

Intracranial aneurysms may be a cause of ocular motor dysfunction, the third nerve being more often involved than the two other cranial ocular motor nerves. We report the unusual occurrence of an isolated fourth nerve palsy related to a cavernous carotid aneurysm, angiographically confirmed. The patient already underwent clipping of a ruptured posterior communicating artery aneurysm 17 years earlier, revealed at that time by a third nerve palsy. Endovascular treatment of the cavernous carotid aneurysm was performed, resulting in complete recovery of the palsy. Occurrence of an acquired fourth nerve palsy in a patient with a past history of aneurysm should prompt neurovascular imaging as multiple aneurysms may cause sequential ocular motor palsies.

Unusual ocular motor findings in multiple sclerosis

In multiple sclerosis (MS), nystagmus or internuclear ophthalmoplegia (INO) are the usual ocular motor dysfunctions. However, in patients with focal brainstem lesions, other rare manifestations may be observed, such as an isolated ocular motor nerve palsy or complex ocular motor disturbances. We report five MS patients with unusual ocular motor disturbances (bilateral third nerve palsy [ n = 2], opsoclonus, Horner's syndrome and one-and-a-half syndrome). We discuss possible correlations between clinical disturbances and MRI abnormalities. Patients were seen in two MS centres. They had a confirmed diagnosis of MS and underwent a brain MRI and a complete neuro-ophthalmological work-up. In one case (opsoclonus), ocular motor manifestations were the first manifestation of MS. In the other four cases they occurred 3 months (Horner syndrome), 6 years and 12 years (bilateral third nerve palsy) and 2 years (one-and-a-half syndrome) after the disease onset, respectively. Four out of five patients were still in a relapsing-remitting form of MS. In the opsoclonus case, there was no evidence of a brainstem lesion. A gadolinium-enhanced lesion (2 cases) or a new T2-weighted lesion located in the brainstem correlated with the clinical presentation. All patients completely or partially recovered after corticosteroid infusions. Our study shows some rare or previously undescribed complex ocular motor symptoms in MS.

Relative Atrophy of the Flocculus and Ocular Motor Dysfunction in SCA2 and SCA6

Two hereditary ataxia syndromes show distinct profiles of region-specific atrophy and ocular motor deficits. Selective pontine atrophy is associated with slowed saccades in ataxin-2 mutations, and selective floccular atrophy is associated with impaired pursuit and gaze-holding abnormalities in Ca(V)2.1 mutations. Although the flocculus seems to be spared relative to the pons in ataxin-2 mutations, and pursuit and gaze-holding appear to be relatively normal, these can be difficult to assess at the bedside, as corrective saccades are also slow and hard to discern. Here, we show the presence of significant floccular atrophy compared with controls in both ataxin-2 and Ca(V)2.1 mutations, which raises the possibility that abnormalities of smooth pursuit or gaze-holding are present in both conditions.

“Retinal diplopia” associated with macular wrinkling. Barton JJ. Neurology 2004;63:925–927

Binocular diplopia is usually attributable to ocular misalignment from ocular motor dysfunction. The author report three patients with chronic binocular vertical diplopia and small comitant hypotropic deviations because of macular displacement (heterotopia) associated with monocular retinal wrinkling. These observations emphasize that displacement of the macula by vitreoretinal traction can result in binocular diplopia, suggesting that diplopic patients require a careful funduscopic examination.—Valérie Biousse.

General vestibular testing

A dysfunction of the vestibular system is commonly characterized by a combination of phenomena involving perceptual, ocular motor, postural, and autonomic manifestations: vertigo/dizziness, nystagmus, ataxia, and nausea. These 4 manifestations correlate with different aspects of vestibular function and emanate from different sites within the central nervous system. The diagnosis of vestibular syndromes always requires interdisciplinary thinking. A detailed history allows early differentiation into 9 categories that serve as a practical guide for differential diagnosis: (1) dizziness and lightheadedness; (2) single or recurrent attacks of vertigo; (3) sustained vertigo; (4) positional/positioning vertigo; (5) oscillopsia; (6) vertigo associated with auditory dysfunction; (7) vertigo associated with brainstem or cerebellar symptoms; (8) vertigo associated with headache; and (9) dizziness or to-and-fro vertigo with postural imbalance. A careful and systematic neuro-ophthalmological and neuro-otological examination is also mandatory, especially to differentiate between central and peripheral vestibular disorders. Important signs are nystagmus, ocular tilt reaction, other central or peripheral ocular motor dysfunctions, or a unilateral or bilateral peripheral vestibular deficit. This deficit can be easily detected by the head-impulse test, the most relevant bedside test for the vestibulo-ocular reflex. Laboratory examinations are used to measure eye movements, to test semicircular canal, otolith, and spatial perceptional function and to determine postural control. It must, however, be kept in mind that all signs and ocular motor and vestibular findings have to be interpreted within the context of the patient's history and a complete neurological examination.

Neuro-ophthalmic manifestations of neurodegenerative disease.

Patients who have neurodegenerative disease frequently present to the ophthalmologist with visual complaints. The causes of the symptoms are varied and include visual sensory and ocular motor dysfunction. This article provides an overview of the neuroophthalmic manifestations of the most common neurodegenerative diseases presenting with visual dysfunction, including Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, and others. Evaluation of visual function in patients who have neurodegenerative disorder can be challenging, but familiarity with the type of visual dysfunction most commonly associated with each disorder will allow for a focused assessment and treatment when possible.

Development of generalized disease at 2 years in patients with ocular myasthenia gravis. Kupersmith MJ, Latkany R, Homel P. Arch Neurol 2003;60:243–248

The initial symptoms or signs of myasthenia gravis (MG) are ptosis, extraocular muscle weakness, or ocular misalignment in up to 65% of patients. Clinically apparent generalized disease develops in more than 50% of patients who present with ocular MG, typically within 2 years. The optimal treatment of ocular MG, including the use of corticosteroids, remains controversial. In addition, the prevalence of thymoma and the optimal performance of the edrophonium chloride test for ocular myasthenia remain unknown. The goal of this study was to assess the effect of oral corticosteroid therapy on the frequency of development of generalized MG within 2 years, the incidence of thymoma, and the amount of edrophonium needed for a positive test result in patients with ocular MG. The authors reviewed an MG database of 147 patients. Patients underwent measurement of acetylcholine receptor (AChR) antibody levels and chest computed tomography. Unless contraindicated, patients with diplopia were recommended for therapy with prednisone, up to 40 to 60 mg/day, with the dosage tapered for 5 to 6 weeks. Most continued to receive daily or alternate-day doses of 2.5 to 10 mg to prevent diplopia. Patients not given prednisone (untreated group) received pyridostigmine bromide or no medication. After the diagnosis, the authors documented the signs and symptoms of ocular and generalized myasthenia gravis and performed 2-year follow-up in 94 patients. The mean dose of edrophonium chloride to give a positive response was 3.3 mg (standard deviation, 1.6 mg) for ptosis and 2.6 mg standard deviation, 1.1 mg) for ocular motor dysfunction. Thymoma was diagnosed in 1 patient (0.7%). Generalized MG developed within 2 years in 4 of 58 treated and 13 of 36 untreated patients. The odds ratio (OR) for development of generalized disease in the treated group was 0.13 (95% confidence interval [CI], 0.04–0.45) compared with the untreated group. The AChR antibody level was not predictive of development of generalized MG at 2 years, but the risk was greater in patients with abnormal AChR antibody levels (OR, 6.33; 95% CI, 1.71–23.42). Logistic regression that included age, abnormal AChR antibody level, and prednisone therapy yielded significance only for abnormal AChR antibody level (OR, 7.03; 95% CI, 1.35–36.64) and treatment (OR, 0.06; 95% CI, 0.01–0.30). The authors conclude that at 2 years, prednisone treatment appears to reduce the incidence of generalized MG to 7% in contrast to 36% of patients who did not receive prednisone. Thymoma, although uncommon, may occur in ocular myasthenia gravis. Only small amounts of edrophonium are needed to diagnose ocular myasthenia gravis.—Valérie Biousse

Development of generalized disease at 2 years in patients with ocular myasthenia gravis.

Generalized myasthenia gravis will develop in more than 50% of patients who present with ocular myasthenia gravis, typically within 2 years. The optimal treatment of ocular myasthenia gravis, including the use of corticosteroids, remains controversial. In addition, the prevalence of thymoma and the optimal performance of the edrophonium chloride test for ocular myasthenia remain unknown. To assess the effect of oral corticosteroid therapy on the frequency of development of generalized myasthenia gravis within 2 years, the incidence of thymoma, and the amount of edrophonium needed for a positive test result in patients with ocular myasthenia gravis. We reviewed an ocular myasthenia gravis database of 147 patients. Patients underwent measurement of acetylcholine receptor (AChR) antibody levels and chest computed tomography. Unless contraindicated, patients with diplopia were recommended for therapy with prednisone, up to 40 to 60 mg/d, with the dosage tapered for 5 to 6 weeks. Most continued to receive daily or alternate-day doses of 2.5 to 10 mg to prevent diplopia. Patients not given prednisone (untreated group) received pyridostigmine bromide or no medication. After the diagnosis, we documented the signs and symptoms of ocular and generalized myasthenia gravis and performed 2-year follow-up in 94 patients. The mean dose of edrophonium chloride to give a positive response was 3.3 mg (SD, 1.6 mg) for ptosis and 2.6 mg (SD, 1.1 mg) for ocular motor dysfunction. Thymoma occurred in 1 patient (0.7%). Generalized myasthenia gravis developed within 2 years in 4 of 58 treated and 13 of 36 untreated patients. The odds ratio (OR) for development of generalized disease in the treated group was 0.13 (95% confidence interval [CI], 0.04-0.45) compared with the untreated group. The AChR antibody level was not predictive of development of generalized myasthenia gravis at 2 years, but the risk was greater in patients with abnormal AChR antibody levels (OR, 6.33; 95% CI, 1.71-23.42). Logistic regression that included age, abnormal AChR antibody level, and prednisone therapy yielded significance only for abnormal AChR antibody level (OR, 7.03; 95% CI, 1.35-36.64) and treatment (OR, 0.06; 95% CI, 0.01-0.30). At 2 years, prednisone treatment appears to reduce the incidence of generalized myasthenia gravis to 7% in contrast to 36% of patients who did not receive prednisone. Thymoma, although uncommon, occurs in ocular myasthenia gravis. Only small amounts of edrophonium are needed to diagnose ocular myasthenia gravis.

The vestibulo-ocular reflex and velocity storage in spinocerebellar ataxia 8.

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases characterized by progressive instability of posture and gait, incoordination, ocular motor dysfunction, and dysarthria due to degeneration of cerebellar and brainstem neurons. Among the more than 20 genetically distinct subtypes, SCA8 is one of several wherein clinical observations indicate that cerebellar dysfunction is primary, and there is little evidence for other CNS involvement. The aim of the present work was to study the decay of the horizontal vestibulo-ocular reflex (VOR) after a short period of constant acceleration to understand the pathophysiology of the VOR due to cerebellar Purkinje cell degeneration in SCA8. The VOR was recorded in patients with genetically defined SCA8 during rotation in the dark. Moderate to severely affected patients had a qualitatively intact VOR, but there were quantitative differences in the gain and dynamics compared to normal controls. During angular velocity ramp rotations, there was a reversal in the direction of the VOR that was more pronounced in SCA8 compared to controls. Modeling studies indicate that there are significant changes in the velocity storage network, including abnormal feedback of an eye position signal into the network that contributes to this reversal. These and other results will help to identify features that are diagnostic for SCA subtypes and provide new information about selective vulnerability of neurons controlling vestibular reflexes.

Sneeze-induced visual and ocular motor dysfunction

PURPOSE: The purpose of this report is to describe two neuroophthalmic complications that are related by their temporal association with a sneeze. DESIGN: We describe observational case reports of two patients. METHODS: Both patients were examined, and their conditions were diagnosed and treated according to standard indications for each neuroophthalmic condition. RESULTS: The first case describes a patient who had previously undergone intracranial surgery, including removal of the clivus and later developed a trochlear nerve paresis after a sneeze. The second case describes a patient who repeatedly demonstrates transient decreased perfusion to his right central retinal artery and an associated afferent papillary defect after sneezing. CONCLUSION: The mechanical and hemodynamic forces involved in sneezing are formidable and may cause permanent cranial neuropathy or temporarily alter ocular blood flow in certain patients.

VISUAL MANIFESTATIONS OF TEMPORAL ARTERITIS

Visual difficulties are common in patients with temporal arteritis. They may be the presenting manifestation of the disease or may occur at any time during its course. The visual deficits that occur in patients with temporal arteritis are most often loss of visual acuity or visual field; however, some patients develop double vision or other symptoms of ocular motor dysfunction. Knowledge of the visual deficits associated with temporal arteritis can aid in the diagnosis of the disorder, and early diagnosis of temporal arteritis can often prevent such deficits from developing.

Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, April 29???May 4, 2001

Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, April 29???May 4, 2001

Using biological indices to classify schizophrenia and other psychotic patients

Although classification of mental disorders using more than clinical description would be desirable, there is scant evidence that available laboratory tests (i.e. biological indices) would provide more valid classifications than current diagnostic systems (e.g. DSM-IV). We used cluster analysis of four biological variables to classify 163 psychotic patients and 83 nonpsychiatric comparison subjects. Analyses revealed a three-cluster solution with the first cluster reflecting electrodermal deviance, the second cluster representing nondeviant biological function, and the third cluster reflecting increased nailfold plexus visibility and ocular motor dysfunction. To assess the construct validity of proband clusters we examined ocular motor performance in 156 first-degree relatives as a function of proband cluster membership. First-degree relatives of third cluster probands exhibited worse ocular motor performance than relatives of other cluster probands. Additionally, better classification sensitivity and specificity were obtained for the relatives when they were grouped by proband cluster than by proband DSM-IV diagnosis. When a single proband characteristic (i.e. eyetracking performance) was used to group relatives, classification sensitivity and specificity failed to significantly increase over grouping by proband DSM-IV diagnosis. Multivariate biologically defined clusters may offer an advantage over DSM-IV classification when examining nosology and etiology of psychotic disorders.

Ocular motor dysfunction in lesch-Nyhan disease

Eye movements were assessed in 22 patients with varying degrees of hypoxanthine-guanine phosphoribosyltransferase deficiency. Ocular motility was clinically normal in seven patients with moderate enzyme deficiency but grossly abnormal in 15 patients with severe enzyme deficiency. In patients with severe deficiency, fixation was interrupted by frequent unwanted saccades toward minor visual distractions. Voluntary saccades were associated with an initial head movement and/or eyeblink in all of these patients. When head motion was prevented, voluntary saccades were often delayed and sometimes absent. In contrast, saccade speed, reflexive saccades, and other reflexive eye movements appeared clinically normal. Four patients with severe enzyme deficiency also experienced mild blepharospasm, and two had ocular tics. These disturbances of ocular motility are consistent with dysfunction of the basal ganglia or its connections with ocular motor centers in the prefrontal cortex or midbrain.

Clinical and biological concomitants of resting state EEG power abnormalities in schizophrenia

Background: This study investigated the clinical and biological concomitants of electroencephalogram power abnormalities in schizophrenia. Methods: We examined the power characteristics of resting electroencephalograms in 112 schizophrenic patients. Also collected were measures of psychotic symptomatology, brain morphology, ocular motor functioning, electrodermal activity, and nailfold plexus visibility. Seventy-eight nonschizophrenic psychosis patients (e.g., mood disorder patients with psychosis) and 107 nonpsychiatric control subjects were included for comparison. Results: Schizophrenic patients whose electroencephalograms were characterized by augmented low-frequency power and diminished alpha-band power had more negative symptoms, larger third ventricles, larger frontal horns of the lateral ventricles, increased cortical sulci widths, and greater ocular motor dysfunction compared with schizophrenic patients without these electroencephalogram characteristics. In nonschizophrenic psychosis patients, augmented low-frequency and diminished alpha-band powers failed to be associated with any clinical or biological indices. Conclusions: Results suggest that clinical and biological concomitants of low-frequency and alpha-band power abnormalities in schizophrenia are unique, perhaps indicating the presence of thalamic and frontal lobe dysfunction.