Association of Clinically Evident Eye Movement Abnormalities With Motor and Cognitive Features in Patients With Motor Neuron Disorders

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012774
Author(s):  
Barbara Poletti ◽  
Federica Solca ◽  
Laura Carelli ◽  
Alberto Diena ◽  
Eleonora Colombo ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Motor Neuron ◽  
Eye Movement ◽  
Cognitive Behavioral ◽  
Cognitively Impaired ◽  
Clinical Markers ◽  
Behavioral Alterations ◽  
Neuropsychological Battery ◽  
Bulbar Onset ◽  
Als Patients

Objective:Although oculomotor abnormalities (OMAs) are not usually considered prominent features of amyotrophic lateral sclerosis (ALS), they may represent potential clinical markers of neurodegeneration, especially when investigated together with cognitive and behavioral alterations. The aim of our study was to identify patterns of clinically evident OMAs in ALS patients and to correlate such findings with cognitive-behavioral data.Methods: three consecutive, inpatient cohorts of Italian ALS patients and controls were retrospectively evaluated to assess the frequency of OMAs and cognitive-behavioral alterations. The ALS population was divided in a discovery and a replication cohort. Controls included a cohort of cognitively impaired individuals and of patients with Alzheimer’s disease (AD). Subjects underwent bedside eye movement evaluation to determine the presence and pattern of OMAs. Cognitive assessment was performed using a standard neuropsychological battery (discovery ALS cohort, and AD cohort), and the Italian Edinburgh Cognitive and Behavioural ALS Screen – ECAS (replication ALS cohort).Results:We recruited 864 ALS (635 discovery, 229 replication), 798 cognitively unimpaired, and 171 AD subjects. OMAs were detected in 10.5% of our ALS cohort vs 1.6% of cognitively unimpaired controls (p=1.2x10-14) and 11.4% of AD patients (p=ns). The most frequent deficits were smooth pursuit and saccadic abnormalities. OMAs frequency was higher in patients with bulbar onset, prominent upper motor neuron signs, and advanced disease stages. Cognitive dysfunction was significantly more frequent in patients with OMAs in both ALS cohorts (p=1.1x10-25). Furthermore, OMAs significantly correlated with the severity of cognitive impairment and with pathological scores at the ECAS ALS-specific domains. Lastly, OMAs could be observed in 35.0% of cognitively impaired ALS vs 11.4% of AD patients (p=6.4x10-7), suggesting a possible involvement of frontal oculomotor areas in ALS.Discussion:ALS patients showed a range of clinically evident OMAs, and these alterations were significantly correlated with cognitive, but not behavioral, changes. OMAs may be a marker of neurodegeneration and bedside assessment represents a rapid, highly specific tool for detecting cognitive impairment in ALS.

scholarly journals Eye Movement Abnormalities in Amyotrophic Lateral Sclerosis

2021 ◽  
Author(s):  
Xintong Guo ◽  
Xiaoxuan Liu ◽  
Shan Ye ◽  
Xiangyi Liu ◽  
Xu Yang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Eye Movement ◽  
Smooth Pursuit ◽  
Oculomotor System ◽  
Control Group ◽  
Clinical Markers ◽  
Square Wave ◽  
Movement Parameters ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Background and Purpose It is generally believed that eye movements are completely spared in amyotrophic lateral sclerosis (ALS). Although a series of eye movement abnormalities has been recognized in recent years, the findings are highly controversial, and the corresponding pattern has not yet been established. Furthermore, bulbar disabilities should be considered in relation to eye movement abnormalities. The present study aimed to determine whether eye movement abnormalities are present in ALS and, if so, to investigate their characteristics and their association with bulbar disability in ALS patients. Methods Patients with clinically definite, probable or laboratory-supported probable ALS (n=60) and a control group composed of their caregivers (n=30) underwent clinical assessments and standardized evaluations of the oculomotor system using videonystagmography. The gaze test, reflexive saccade test and smooth pursuit test were administered to all subjects. Results Eye movement abnormalities such as square-wave jerks, abnormal cogwheeling during smooth pursuit, and saccade hypometria were observed in ALS patients. Square-wave jerks (p<0.001) and abnormal cogwheeling during smooth pursuit (p=0.001) were more frequently observed in ALS patients than in the control subjects. In subgroup analyses, square-wave jerks (p=0.004) and abnormal cogwheeling during smooth pursuit (p=0.031) were found to be more common in ALS patients with bulbar involvement (n=44) than in those without bulbar involvement (n=16). There were no significant differences in the investigated eye movement parameters between bulbar-onset (n=12) and spinal-onset patients (n=48). Conclusion ALS patients showed a range of eye movement abnormalities, affecting mainly the ocular fixation and smooth pursuit systems. These abnormalities were observed more common in the ALS patients with bulbar involvement. Our pioneering study indicates that the region of involvement could better indicate the pathophysiological essence of the abnormalities than the type of onset pattern in ALS. Eye movement abnormalities may be potential clinical markers for objectively evaluating upper brainstem or supratentorial cerebral lesion neurodegeneration in ALS.

Association of Cortical Hyperexcitability and Cognitive Impairment in Patients with ALS

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011798
Author(s):  
Mana Higashihara ◽  
Nathan Pavey ◽  
Mehdi van den Bos ◽  
Parvathi Menon ◽  
Matthew C. Kiernan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cortical Excitability ◽  
Short Interval ◽  
Motor Evoked Potential ◽  
Intracortical Inhibition ◽  
Cognitively Impaired ◽  
Cortical Hyperexcitability ◽  
Multivariable Regression ◽  
Als Patients ◽  
Lateral Sclerosis

Objective:To determine whether cortical hyperexcitability was more prominent in cognitively impaired amyotrophic lateral sclerosis (ALS) patients.Methods:Threshold tracking transcranial magnetic stimulation (TMS) was utilised to assess cortical excitability, while cognitive function determined by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Cognitive impairment was defined by ECAS<105. ALS patients, defined by the Awaji criteria, were prospectively recruited. Patients unable to undergo TMS, or in whom TMS indices were compromised by coexistent medical conditions were excluded. Cortical hyperexcitability was defined by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation (SICF), index of excitability (IE) and motor evoked potential (MEP) amplitude. Student t-test determined differences between groups, while multivariable regression modelling was utilised to assess association between cognitive, clinical and TMS parameters. TMS results were compared to 42 controls.Results:Cognitive impairment was evident in 36% of the 40 ALS patents (23 males, mean age 62.1 years). Cortical hyperexcitability was more prominent in cognitively impaired patients as indicated by an increase in SICF (ECAS≥105 -15.3±1.7%; ECAS<105 -20.6±1.2%, P<0.01), IE (ECAS ≥105 80.9±7.8; ECAS <105 95.0±4.5, P<0.01) and MEP amplitude (ECAS≥105 28.7±3.3%; ECAS<105 43.1±5.9%, P<0.05). SICF was independently associated with the ECAS score (β=2.410, P<0.05). Reduced SICI was evident in ALS, being more prominent in patients with reduced executive score (ECASexecutive score>33 6.2±1.3%; ECASexecutive score<33 1.5±2.1%, P<0.01).Conclusion:Cortical hyperexcitability was more prominent in cognitively impaired ALS patients. Given that ECAS is a valid predictor of TDP-43 pathology, the increase in cortical hyperexcitability may be associated with TDP-43 accumulation.

Metabolic brain changes across different levels of cognitive impairment in ALS: a 18F-FDG-PET study

2020 ◽  
pp. jnnp-2020-323876
Author(s):  
Antonio Canosa ◽  
Cristina Moglia ◽  
Umberto Manera ◽  
Rosario Vasta ◽  
Maria Claudia Torrieri ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Fdg Pet ◽  
Rating Scale ◽  
Cognitive Status ◽  
Metabolic Changes ◽  
Cognitively Impaired ◽  
Neurodegenerative Process ◽  
Positron Emission ◽  
Brain Changes ◽  
Als Patients

ObjectiveTo identify the metabolic changes related to the various levels of cognitive deficits in amyotrophic lateral sclerosis (ALS) using 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) imaging.Methods274 ALS patients underwent neuropsychological assessment and brain 18F-FDG-PET at diagnosis. According to the criteria published in 2017, cognitive status was classified as ALS with normal cognition (ALS-Cn, n=132), ALS with behavioural impairment (ALS-Bi, n=66), ALS with cognitive impairment (ALS-Ci, n=30), ALS with cognitive and behavioural impairment (ALS-Cbi, n=26), ALS with frontotemporal dementia (ALS–FTD, n=20). We compared each group displaying some degree of cognitive and/or behavioural impairment to ALS-Cn patients, including age at PET, sex and ALS Functional Rating Scale-Revised as covariates.ResultsWe identified frontal lobe relative hypometabolism in cognitively impaired patients that resulted more extensive and significant across the continuum from ALS-Ci, through ALS-Cbi, to ALS–FTD. ALS–FTD patients also showed cerebellar relative hypermetabolism. ALS-Bi patients did not show any difference compared with ALS-Cn.ConclusionsThese data support the concept that patients with cognitive impairment have a more widespread neurodegenerative process compared with patients with a pure motor disease: the more severe the cognitive impairment, the more diffuse the metabolic changes. Otherwise, metabolic changes related to pure behavioural impairment need further characterisation.

scholarly journals Use radiography rarely, not routinely, for hip hemiarthroplasty

2021 ◽  
Author(s):  
Lucy Clare Maling ◽  
John Martin Lynch ◽  
Robert William Walker ◽  
Mark Ross Norton ◽  
Rory George Middleton
Keyword(s):  
Patient Safety ◽  
Cognitive Impairment ◽  
Limited Resources ◽  
Cognitively Impaired ◽  
Clinical Change ◽  
Index Procedure ◽  
Hip Hemiarthroplasty ◽  
Operative Care ◽  
Fluoroscopic Imaging ◽  
Retrospective Database

Abstract Purpose Hip hemiarthroplasty (HA) is a commonly performed operation. A post-operative radiograph forms part of the routine hip fracture pathway, although patients are often mobilised prior to this investigation. This study seeks to provide evidence for a pragmatic clinical change to optimise patient safety and allocate limited resources within the National Health Service (NHS). Methods We undertook a retrospective database review of 1563 HA procedures to assess whether the routine ordering of check radiographs played an important role in a patient’s post-operative care. Results 18 (1.2%) mechanical complications led to a return to theatre within 6 weeks of the index procedure. All were dislocations. Ten had a normal post-operative radiograph and five had documented suspicion of dislocation prior to radiography. The post-operative check radiograph was the sole identifier of dislocation in only three patients (0.2%). All three of these patients were pre-morbidly bed bound and non-communicative due to cognitive impairment (AMTS 0/10). Conclusion Unless a patient is pre-morbidly bed bound and cognitively impaired, routine post-operative radiography following HA surgery is of little clinical benefit, yet may carry considerable risk to the patient and cost to the NHS. A pragmatic compromise is to perform intra-operative fluoroscopic imaging.

Educational intervention to improve palliative care knowledge among informal caregivers of cognitively impaired older adults

2020 ◽  
pp. 1-9
Author(s):  
Hyunjin Noh ◽  
Lewis H. Lee ◽  
Chorong Won
Keyword(s):  
Older Adults ◽  
Palliative Care ◽  
Cognitive Impairment ◽  
Educational Intervention ◽  
Test Scores ◽  
Informal Caregivers ◽  
Cognitively Impaired ◽  
Significant Difference ◽  
Post Test ◽  
Seriously Ill

Abstract Objective Lack of palliative care knowledge among caregivers may pose an access barrier for cognitively impaired older adults, who may benefit from the specialized care. Therefore, this study aims to examine the effectiveness of an educational intervention in improving palliative care knowledge among informal caregivers of cognitively impaired older adults. Method Using a one-group, pre- and post-test intervention design, this study implemented an individual, face-to-face educational intervention with an informational brochure for 43 informal caregivers of chronically or seriously ill older adults (50+) with cognitive impairment, recruited from communities in West Alabama. Their level of knowledge about palliative care was assessed by the Palliative Care Knowledge Scale (PaCKS). The pre- and post-test scores were compared by the Wilcoxon signed-ranks test, and the racial subgroup (Whites vs. Blacks) comparison was made by the Mann–Whitney U test. Results There was a statistically significant difference between the pre- and post-test scores (z = 5.38, p < 0.001), indicating a statistically significant effect of the educational intervention in improving palliative care knowledge among participants. There was a significant difference (U = 143, p < 0.05) between Whites and Blacks in the pre-test, which, however, disappeared in the post-test (U = 173.50, p > 0.05), suggesting that the amount of increased PaCKS scores were significantly greater for Blacks (Mdn = 9.50) than for Whites (Mdn = 4.00, U = 130.50, p < 0.05). Significance of results This study demonstrated that a one-time educational intervention can improve the level of palliative care knowledge among informal caregivers of chronically or seriously ill older adults with cognitive impairment, particularly among Black caregivers. Therefore, further educational efforts can be made to promote palliative care knowledge and reduce racial disparities in palliative care knowledge and its use.

scholarly journals Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James C. Dodge ◽  
Jinlong Yu ◽  
S. Pablo Sardi ◽  
Lamya S. Shihabuddin
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Cholesterol Homeostasis ◽  
Cholesterol Oxidation ◽  
Therapeutic Approaches ◽  
Cellular Survival ◽  
Sporadic Als ◽  
Human Motor ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.

scholarly journals Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 906
Author(s):  
Nimeshan Geevasinga ◽  
Mehdi Van den Bos ◽  
Parvathi Menon ◽  
Steve Vucic
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cortical Excitability ◽  
Muscular Atrophy ◽  
Close Relationship ◽  
Bulbar Onset ◽  
Als Patients ◽  
Transcranial Magnetic Simulation ◽  
Cortical Dysfunction ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease.

scholarly journals Heterogeneity of Amyloid Binding in Cognitively Impaired Patients Consecutively Recruited from a Memory Clinic: Evaluating the Utility of Quantitative 18F-Flutemetamol PET-CT in Discrimination of Mild Cognitive Impairment from Alzheimer’s Disease and Other Dementias

2020 ◽  
pp. 1-14
Author(s):  
Yi-Wen Bao ◽  
Anson C.M. Chau ◽  
Patrick Ka-Chun Chiu ◽  
Yat Fung Shea ◽  
Joseph S.K. Kwan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Subjective Cognitive Decline ◽  
Cognitively Impaired ◽  
Memory Clinic ◽  
Pet Ct

Background: With the more widespread use of 18F-radioligand-based amyloid-β (Aβ) PET-CT imaging, we evaluated Aβ binding and the utility of neocortical 18F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. Objective: 18F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer’s disease (AD), and 2) MCI from other non-AD dementias (OD). Methods: 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included 13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). Results: The global mean 18F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aβ binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. Conclusion: 18F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force.

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