Abstract
Introduction:
Though eye movements are relatively spared in motor neuron disease (MND), recent literature suggests patients may exhibit oculomotor dysfunction (OD). Frontal lobe involvement has been postulated based on oculomotor pathway anatomy and clinical overlap of amyotrophic lateral sclerosis (ALS) with frontotemporal dementia. We examined oculomotor characteristics in patients with MND presenting to an ALS Center, hypothesizing that patients with prominent upper motor neuron involvement or pseudobulbar affect (PBA) may demonstrate greater OD.
Methods:
This was a single-center prospective observational study. Patients with diagnosis of MND were examined at bedside. Center for Neurologic Study-Liability Scale (CNS-LS) was administered to screen for pseudobulbar affect. Primary outcome was OD and the secondary outcome was the association between presence of OD in patients with MND experiencing symptoms of PBA or upper motor neuron dysfunction. Wilcoxon rank-sum scores and Fisher’s exact tests were used to perform statistical analyses.
Results:
53 patients with MND underwent the clinical ophthalmic evaluation. On bedside examination, 34 patients (64.2%) presented with OD. There were no significant associations between locations of MND at presentation and the presence or type of OD. OD was associated with increased disease severity as measured by reduced FVC (p = 0.02). There was no significant association between OD and CNS-LS (p = 0.2).
Discussion:
Though our study did not find a significant association between OD and upper versus lower MND at presentation, OD may be useful as an additional clinical marker for advanced disease.
INTRODUCTION
Oculomotor dysfunction (OD) was traditionally thought spared in amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MND), but more recent reports suggest that ALS patients may exhibit eye movement abnormalities similar to those in other types of neurodegenerative diseases, such as progressive supranuclear palsy [1, 2]. Past studies have variably found oculomotor abnormalities in patients with ALS examined at bedside or more with sophisticated digital technology. There has not been a clear consensus on the extent of oculomotor involvement, the type of OD, or the pathophysiology of oculomotor involvement in ALS. This may due in part to differences in methodology, as well as the range of oculomotor abnormalities assessed. Studies have evaluated fixation [3, 4], others saccades or saccadic intrusions [1, 5–7], smooth pursuit [1, 8], nystagmus [4], Bell phenomenon [2], or a combination of these tests. Case reports, including one discussing progressive external ophthalmoplegia in a respirator-dependent patient, have also demonstrated OD in ALS [9]. In contrast, studies have suggested that oculomotor abnormalities in ALS patients may be reflective of other associated features such as Parkinsonism or cognitive dysfunction [10].
Eye movements are controlled by an intricate network of pathways involving cortical and subcortical areas, such as the frontal eye fields (FEF), dorsolateral prefrontal cortex, the brainstem, and cerebellum [1, 16–19]. The predilection for clinicopathologic overlap between frontotemporal dementia (FTD) and ALS implies a degree of frontal lobe dysfunction in both diseases. Consequently, eye movement abnormalities observed in ALS may be related to dysfunction in areas such as the FEFs, which are involved in the pathways for smooth pursuit and volitional saccades. On the other hand, ALS patients with bulbar dysfunction may be more likely to experience eye movement abnormalities controlled predominantly by pontine pathways, such as reflexive saccades and ocular fixation. These likely manifest clinically as slow saccades and saccadic intrusions [1, 6].
The differentiation between types of MNDs is predominantly clinical. These diagnoses may be imprecise using current clinical criteria or may change over time as other clinical features emerge during the course of the disease. Postmortem data indicated that 56% of patients with PMA, by definition a lower MND, actually had pyramidal tract involvement [12]. In a set of diseases that largely relies on clinical criteria, the characterization of eye movement abnormalities may serve as a useful clinical marker to aid in the diagnosis and differentiation of MNDs.
Because of the known pathophysiologic overlap between ALS and FTD, we aimed to study OD associated with upper and lower motor neuron involvement in people with MNDs. We hypothesized that people with MNDs that involved upper motor neurons, including ALS, PBP, and PLS, would exhibit higher frequencies of OD than those lower motor neuron presentations, specifically PMA. Further, due to the correlation between PBAs and lesions in the frontal lobes and corticobulbar and cortico-ponto-cerebellar pathways, we hypothesized that people with MNDs who demonstrate a PBA would exhibit higher frequencies of OD. By assessing OD in patients with MNDs, we hoped to identify a clinical marker for more advanced MNDs and provide insights into the pathogenesis, progression, and prognosis of MNDs to improve the care of this highly compromised patient population.
MATERIALS AND METHODS
Study design and cohort selection
This study was a single-center prospective observational study conducted with patients with MND presenting to the ALS Center at Mount Sinai Beth Israel. Consecutive incident and established cases were enrolled from 2019 – 2020, dependent on evaluator availability. Adults over the age of 18 years were eligible for the study if they had a diagnosis of ALS, PMA, PLS, or PBP. MNDs were defined by the El Escorial Criteria: (1) ALS was categorized as possible, probable, or definite, (2) PMA was defined as lower motor neuron signs in two or more bodily regions without upper motor neuron signs, (3) PLS was defined as upper motor neuron signs alone in two or more bodily regions, and (4) PBP was defined as progressive bulbar signs without upper or lower motor signs in the limbs, or limited to one bodily region. Diagnoses of ALS or PMA were supported by the presence of fibrillation potentials in three or more bodily regions, and PLS by the absence of fibrillation potentials.
Patients with intrinsic eye disease that may preclude them from bedside oculomotor examination, and patients with known or previously diagnosed cognitive or behavioral dysfunction that interfered with daily activities were excluded from the study. Cognitive dysfunction was screened for by assessing: (1) orientation, (2) language, (3) naming, (4) attention using WORLD backwards, (5) verbal fluency tested by the ability to perform ≥8 D words in 30 seconds, (6) recall by the ability to recall three of three objects in three – five minutes, and (7) praxis/constructional abilities. This study was reviewed and approved by the Institutional Review Board through the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai. All participants gave informed consent prior to inclusion in the study.
Outcome measures
The primary outcome of interest was the presence or absence of OD – whether patients with upper motor neuron involvement at presentation, those with ALS, PBP, and PLS, have more OD relative to those with lower motor neuron involvement at presentation, specifically PMA. OD was characterized by the presence of any abnormalities in optic assessments. Measurement of OD was conducted by clinically examining eye movements for the presence of (1) hypometric saccades, (2) nystagmus, (3) saccadic intrusions, (4) ophthalmoparesis, (5) ocular dysmetria, (6) saccadic pursuit, and (7) abnormal optokinetic nystagmus. Optic tests were conducted at bedside, at which time patients were asked to fixate on and visually track an object located at one meter of distance. The secondary outcome of interest was the association between the presence of OD in MND patients experiencing symptoms of PBA. Measurement of PBA was conducted using the Center for Neurologic Study-Liability (CNS)Scale.
Independent variables
The key independent variable was location of neuronal involvement at presentation in patients with MND categorized as upper and lower. A diagnosis of possible, probable, and definite ALS was grouped together with PLS and PBP to make up the cohort of patients with upper MND. A diagnosis of PMA was used to define the cohort of patients with lower MND. Medical history, clinical examination, nerve conduction studies, and electromyography were used to confirm a diagnosis of MND. As appropriate, ancillary testing was conducted to rule out other diagnoses. We examined patient characteristics such as age at study enrollment, sex (male and female), and disease duration (symptom onset to study enrollment). As a measure of disease severity, pulmonary function was evaluated using maximal negative inspiratory pressure (MIP; absolute value) and sitting forced vital capacity (FVC; % predicted). The ALS Functional Rating Scale-Revised (ALSFRS-R) and motor strength graded according to the Medical Research Council (MRC) grading system, specifically MRC grades in standardized muscles summated to generate an MRC sum-score, were also utilized as measures of disease severity.
Statistical analysis
Baseline patient characteristics were described using median with interquartile range [IQR] for continuous variables and frequencies with percentages for categorical variables. Wilcoxon rank sum tests for continuous variables and Fisher’s exact tests for categorical variables were performed to compare demographic and clinical characteristics across location of MND at presentation, as well as the total cohort stratified by the presence or absence of OD. P value <05 was considered significant. SAS software version 9.4 (SAS Institute Inc., Carey, NC) was used for statistical analyses.
RESULTS
Study cohort
Fifty-three patients diagnosed with MND, 32 with ALS, seven with PBP, three with PLS, and 11 with PMA participated in the study. Baseline characteristics for the patients with upper and lower MND at presentation are described in Table 1. The median [IQR] age at enrollment was 64 [56, 70] years and the study population was comprised of 30 (56.6%) males and 23 (43.4%) females. Demographically, there was no significant difference across location of MND at presentation in age (p = 0.43) and sex (p = 1).
Baseline characteristics of patients stratified by location of motor neuron disease at presentation
Continuous variables are presented as median (interquartile range) and categorical variables as frequency (%); patients with upper motor neuron disease include those with amyotrophic lateral sclerosis, primary lateral sclerosis, and progressive bulbar palsy; patients with lower motor neuron disease include those with progressive muscular atrophy; yr. – year; ALSFRS-R – ALS Functional Rating Scale-Revised; MRC Sum – Sum of Medical Research Council (MRC) grades in designated muscle groups (bilaterally: deltoids, biceps, triceps, wrist extensors, extensor digitorum communis, abductor pollicis brevis, iliopsoas, quadriceps, hamstrings, tibialis anterior, gastrocnemius); CNS-LS – Center for Neurologic Study-Liability Scale; MIP – Maximal negative inspiratory pressure (cmH20); FVC – Forced vital capacity (% predicted).
Clinically, there was no significant difference between cohorts in disease duration and ALSFRS-R, with a median [IQR] of 3 [1.8, 6] years and a 32 [26, 37] score, respectively (p = 0.32 and p = 0.28, respectively). Pulmonary function was the same across the groups as measured by MIP and FVC with median [IQR] values of –42 [–20, – 60] cmH20 and 56 [34, 71] % predicted, respectively (p = 0.67 and p = 0.55, respectively). In patients with upper MND at presentation the median [IQR] MRC sum score was 87.3 [71.5, 100], which was significantly higher than that of patients with lower MND at presentation, with a sum score of 67 [26, 90] (p = 0.03). Increased symptoms of PBA, as measured by higher CNS-LS was found in patients with upper MND relative to those with lower MND, with a median [IQR] score of 11 [9, 14] versus a core of 8 [7, 12] (p = 0.03).
Oculomotor dysfunction
Thirty-four patients (64.2%) exhibited OD on examination; details are described in Table 2. Relative to patients with lower MND, those with upper MND did not exhibit a higher frequency of OD (p = 1). In patients stratified by location of MND at presentation, there was no significant difference in the proportions of positive optic tests. Baseline characteristics of patients stratified by presence or absence of OD are described in Table 3. Demographically, patients with OD were not significantly older than those without OD (p = 0.07), and had a similar distribution of males and females (p = 0.16). Clinically, patients with and without OD did not have significantly different disease durations (p = 0.14), ALSFRS-R scores (p = 0.06), MRC sum scores (p = 0.85), CNS-LS (p = 0.09), and MIPs (p = 0.53). The median [IQR] FVC in patients with OD was significantly lower compared to patients without OD at 48.5 [25, 66] % predicted and 66 [50, 89] % predicted, respectively (p = 0.02).
Oculomotor characteristics of patients stratified by location of motor neuron disease at presentation
Categorical variables are presented as frequency (%); patients with upper motor neuron disease include those with amyotrophic lateral sclerosis, primary lateral sclerosis, and progressive bulbar palsy; patients with lower motor neuron disease include those with progressive muscular atrophy; OD – Oculomotor dysfunction.
Baseline characteristics of patients with ocular motor disease stratified by the presence or absence of ocular dysfunction
Continuous variables are presented as median (interquartile range) and categorical variables as frequency (%); OD – Ocular dysfunction; yr. – year; ALSFRS-R – ALS Functional Rating Scale-Revised; MRC Sum – Sum of Medical Research Council (MRC) grades in designated muscle groups (bilaterally: deltoids, biceps, triceps, wrist extensors, extensor digitorum communis, abductor pollicis brevis, iliopsoas, quadriceps, hamstrings, tibialis anterior, gastrocnemius); CNS-LS – Center for Neurologic Study-Liability Scale; MIP – Maximal negative inspiratory pressure (cmH20); FVC – Forced vital capacity (% predicted).
DISCUSSION
Though a large proportion of patients studied, 64.2%, did present with OD, this study did not find a significant association between the presence of OD and upper motor neuron dysfunction or PBA. Of note, square wave jerks and saccadic pursuit were the most frequent clinical signs of OD, occurring in 37.7% and 30.2% of patients, respectively. There was no association between the presence of OD and the length of disease. However, due to the heterogeneity of MND and its subtypes, disease duration is not always directly linked with disease severity. Our results did suggest a significant association between OD and measures of more severe or advanced disease, specifically respiratory function as measured by FVC.
There is immunohistologic evidence of ALS pathology (ubiquitin positive skein-like inclusions, Bunina bodies) in cranial nerve nuclei III and IV in 1/3 of patients with ALS [12]. This was more common in patients with ophthalmoplegia (and more advanced quadriparesis) but also in patients with dementia. However, clinically, ophthalmoparesis only occurs in patients with advanced, often long-standing (i.e., ventilator-supported) disease. Relative sparing of oculomotor nerves in MND has been attributed to lack of collaterals, faster firing rates, greater expression of calcium binding proteins (calbindin D and parvalbumin), lack of monosynaptic connections, differences in glutamate transmission, and androgen receptor expression [1, 3]. None of the patients in this study with more advanced disease had clinically significant ophthalmoparesis, though none were quadriplegic or ventilator-dependent.
Limitations of this study include small sample size, due in part to using a single-center to recruit patients as well as an interruption in recruitment during the early stages of the COVID-19 pandemic. While numerous patients were screened, the total cohort was relatively small and that may have decreased the power of the study to detect significant effects. Although patients were screened for cognitive dysfunction, validated cognitive instruments, such as the frontal assessment battery, were not used to identify cognitive and/or behavioral abnormalities. Consequently, subclinical cognitive deficits may have been overlooked, and due to the association between OD and cognitive dysfunction in patients with ALS, this may have confounded the relationship between OD and location of MND at presentation. The study was also limited by not assessing inter-rater variability in the evaluation of OD by bedside examination. Additionally, there was no control group, but there is little evidence that the oculomotor findings assessed occur in the healthy elderly. Lastly, medication status and comorbidities, including unknown non-motor signs of OD, were not collected and those are variables which may have also interacted with the relationship between the outcome and exposure of interest.
Past studies have widely varied on the utility of oculomotor examination as a marker for MND. Oculomotor abnormalities were noted in only 10.5% of patients by Poletti and colleagues [10]. However, that study was retrospective and did not assess for square wave jerks, which we found frequently in patients with MND. Though our study did not find a significant association between the presence of OD with different types of MND, OD may yet be useful as a clinical marker for more advanced MND. Though we did not find a concrete association between CNS-LS as a measure of frontal lobe dysfunction with OD, future longitudinal studies examining OD and its connection to neuropsychological measures utilizing a more formal battery of cognitive tests may provide further insight into the pathogenesis, progression, and prognosis of MND.
Footnotes
ACKNOWLEDGMENTS
Initial statistical analyses were performed with the help of Lan Mu at the Mount Sinai Neurology Biostatistics Clinic. Dr. Sergei Yakushin and Dr. Jun Maruta at the Human Balance Laboratory at the Icahn School of Medicine at Mount Sinai provided additional assistance with study design and review of early drafts of the manuscript.
CONFLICTS OF INTEREST
The authors have no conflict of interest to report.