Evaluating the feasibility and preliminary efficacy of a Cognitive Occupation-Based programme for people with Multiple Sclerosis (COB-MS): an update to the protocol for a feasibility cluster-randomised controlled trial.

BACKGROUND: Cognitive difficulties experienced by people with multiple sclerosis (MS) impact on quality of life and daily functioning, from childcare and work to social and self-care activities. The Cognitive Occupation-Based programme for people with MS (COB-MS) was developed as a holistic, individualised cognitive rehabilitation intervention to address the wide-ranging symptoms and functional difficulties that present in MS, including the ability to maintain employment, social activities, home management and self-care. The aim of the research is to evaluate the feasibility and preliminary efficacy of COB-MS for people with MS. METHODS: Due to the impacts of COVID-19, trial activities that were planned for in-person delivery were completed remotely. One hundred and twenty people with MS will be assigned to participate in either the COB-MS programme or a treatment-as-usual, wait-list control group as part of this single-blind, cluster-randomised controlled feasibility and preliminary efficacy trial of the COB-MS programme. The COB-MS group will participate in an eight-session occupational-based cognitive rehabilitation programme over 9 weeks. The COB-MS intervention was planned for in-person delivery but was delivered online by occupational therapists to small groups of people with MS. The primary outcome measure is the Goal Attainment Scaling at 12 weeks. Participants will be assessed pre-intervention, post-intervention, 12 weeks post-intervention and 6 months post-intervention. Qualitative evaluations of participants' perspectives will also be examined as part of the feasibility study. Data, due to be collected in-person, was collected online or by post. The original study design, including the statistical analysis plan, remains unchanged despite the shift to a remote trial conduct. DISCUSSION: Results will provide recommendations for a future definitive trial of COB-MS, with respect to both feasibility and preliminary, clinical efficacy. TRIAL REGISTRATION: ISRCTN ISRCTN11462710 . Registered on 9 September 2019 and updated on 23 September 2020 to account for changes outlined here.

Endoplasmic Reticulum Stress-Regulated Chaperones as a Serum Biomarker Panel for Parkinson's Disease.

Examination of post-mortem brain tissues has previously revealed a strong association between Parkinson's disease (PD) pathophysiology and endoplasmic reticulum (ER) stress. Evidence in the literature regarding the circulation of ER stress-regulated factors released from neurons provides a rationale for investigating ER stress biomarkers in the blood to aid diagnosis of PD. The levels of ER stress-regulated proteins in serum collected from 29 PD patients and 24 non-PD controls were measured using enzyme-linked immunosorbent assays. A panel of four biomarkers, protein disulfide-isomerase A1, protein disulfide-isomerase A3, mesencephalic astrocyte-derived neurotrophic factor, and clusterin, together with age and gender had higher ability (area under the curve 0.64, sensitivity 66%, specificity 57%) and net benefit to discriminate PD patients from the non-PD group compared with other analyzed models. Addition of oligomeric and total α-synuclein to the model did not improve the diagnostic power of the biomarker panel. We provide evidence that ER stress-regulated proteins merit further investigation for their potential as diagnostic biomarkers of PD.

Identifying monitoring information needs that support the management of fish in large rivers.

Management actions intended to benefit fish in large rivers can directly or indirectly affect multiple ecosystem components. Without consideration of the effects of management on non-target ecosystem components, unintended consequences may limit management efficacy. Monitoring can help clarify the effects of management actions, including on non-target ecosystem components, but only if data are collected to characterize key ecosystem processes that could affect the outcome. Scientists from across the U.S. convened to develop a conceptual model that would help identify monitoring information needed to better understand how natural and anthropogenic factors affect large river fishes. We applied the conceptual model to case studies in four large U.S. rivers. The application of the conceptual model indicates the model is flexible and relevant to large rivers in different geographic settings and with different management challenges. By visualizing how natural and anthropogenic drivers directly or indirectly affect cascading ecosystem tiers, our model identified critical information gaps and uncertainties that, if resolved, could inform how to best meet management objectives. Despite large differences in the physical and ecological contexts of the river systems, the case studies also demonstrated substantial commonalities in the data needed to better understand how stressors affect fish in these systems. For example, in most systems information on river discharge and water temperature were needed and available. Conversely, information regarding trophic relationships and the habitat requirements of larval fishes were generally lacking. This result suggests that there is a need to better understand a set of common factors across large-river systems. We provide a stepwise procedure to facilitate the application of our conceptual model to other river systems and management goals.

Stridor: a rare presentation of motor neuron disease.

A 74-year-old farmer presented to the emergency department with a subacute history of progressive dyspnoea, wheeze and dysphonia. He was treated for an exacerbation of asthma with poor response to pharmacological therapy. Investigation of dysphonia via laryngoscopy identified a bilateral vocal cord palsy. Subsequently, the patient developed an episode of life-threatening stridor and hypercapnic respiratory failure requiring an emergency tracheostomy. Neurology input identified evidence of widespread muscle fasciculations on clinical examination. MRI of the brain and cervical spine were unremarkable. Electromyogram testing identified changes of acute denervation in several limbs consistent with a diagnosis of motor neuron disease (MND). Bilateral vocal cord palsy has been rarely reported in the literature as the heralding symptom resulting in the diagnosis of MND. In patients with a subacute onset of dysphonia, dyspnoea and stridor, MND should be a differential diagnosis.

Severe amnestic syndrome due to theophylline toxicity.

We report a case of severe amnestic syndrome following theophylline overdose. A woman in her early 30s was admitted to hospital where she developed status epilepticus following an intentional overdose of theophylline and lansoprazole. She developed a profound acidosis and required intubation in the intensive care unit. Following extubation the patient was noted to have a severe amnestic syndrome with poor short-term memory. A work-up to exclude infectious, autoimmune and paraneoplastic causes for encephalitis was undertaken. Cerebrospinal fluid analysis was normal and autoimmune encephalitis titres were negative. Initial MRI brain imaging demonstrated hyperintensities of the mesial temporal lobes bilaterally. Follow-up imaging at 4 months identified further interval reduction but persistent hippocampal hyperintensities. Theophylline toxicity with corresponding amnestic syndrome and hippocampal hyperintensities has been rarely reported. We believe this case with persistent abnormal Montreal Cognitive Assessment Score at 12 months correlates with persistent hippocampal abnormalities seen on imaging.

Applicability and tolerability of electrical stimulation applied to the upper and lower leg skin surface for cueing applications in Parkinson's disease.

Due to possible sensory impairments in people with Parkinson's disease, several methodological aspects of electrical stimulation as a potential cueing method remain to be explored. This study aimed to investigate the applicability and tolerability of sensory and motor electrical stimulation in 10 people with Parkinson's disease. The study focused on assessing the electrical stimulation voltages and visual analogue scale discomfort scores at the electrical sensory, motor, discomfort, and pain thresholds. Results show that sensory electrical stimulation at the tibialis anterior, soleus, hamstrings, and quadriceps stimulation sites was applicable and tolerable for 6/10, 10/10, 9/10, and 10/10 participants, respectively. Furthermore, motor electrical stimulation at the tibialis anterior, soleus, hamstrings, and quadriceps stimulation sites were applicable and tolerable for 7/10, 7/10, 7/10, and 8/10 participants, respectively. Interestingly, the thresholds for the lower leg were higher than those of the upper leg. The data presented in this paper indicate that sensory and motor electrical stimulation is applicable and tolerable for cueing applications in people with Parkinson's disease. Sensory electrical stimulation was applicable and tolerable at the soleus and quadriceps sites. Motor electrical stimulation was not tolerable for two participants at any of the proposed stimulation sites. Therefore, future studies investigating motor electrical stimulation cueing, should apply it with caution in people with Parkinson's disease.

Co-incident primary progressive multiple sclerosis and hereditary spastic paraplegia (SPG4) - a case report.

The cause of progressive disability in Primary Progressive Multiple Sclerosis (PPMS) is unknown. Pathogenic genes have been described in some MS cases that may contribute to progressive disability, independent of immune - mediated mechanisms (Jia et al., 2018). The autosomal dominant SPG4 (Spastin) mutation is the most common genotype in Hereditary Spastic Paraplegia (Solowska and Baas, 2015) and has been found in some patients with Relapsing Remitting Multiple Sclerosis (Mead et al., 2001, Yazici et al., 2013). Here, we describe the novel association of PPMS and the SPG4 (Spastin) mutation, in a patient with a family history of Hereditary Spastic Paraplegia, and discuss the therapeutic implications. While this single case report cannot discrimiate between simple co-occurence and the possibility of a pathogenic association, our report invites larger scale investigation.

Autoimmune encephalitis associated with Ma2 antibodies and immune checkpoint inhibitor therapy.

Immune checkpoint inhibitors have transformed the treatment of advanced malignancy, while increasing the risk of immune-related adverse events. A 56-year-old woman who had received nivolumab for stage 4 renal cell carcinoma subsequently developed altered behaviour, memory deficits and worsening of previously stable epilepsy. MR scan of the brain showed bilateral FLAIR (fluid-attenuated inversion recovery) hyperintensity of the mesial temporal lobes, and there were anti-Ma2 antibodies in both serum and cerebrospinal fluid. She was treated with corticosteroids but developed further clinical relapses requiring immunoglobulin and rituximab. The immune-related adverse events relating to immune checkpoint inhibitors are an emerging challenge for the neurologist. Some cases are refractory and require serial immunosuppression.

Evaluating the feasibility and preliminary efficacy of a Cognitive Occupation-Based programme for people with Multiple Sclerosis (COB-MS): protocol for a feasibility cluster-randomised controlled trial.

BACKGROUND: Cognitive difficulties experienced by people with multiple sclerosis (MS) impact their quality of life and daily functioning, from childcare and work, to social and self-care activities. Despite the high prevalence of cognitive difficulties seen in MS, there is a lack of developed programmes that target cognition, while also supporting patients by helping them to function well in everyday life. The Cognitive Occupation-Based programme for people with MS (COB-MS) was developed as a holistic, individualised cognitive rehabilitation intervention. It addresses the wide-ranging symptoms and functional difficulties that present in MS, including the ability to maintain employment, social activities, home management and self-care. The aim of the current research is to evaluate the feasibility and preliminary efficacy of COB-MS for people with MS. The focus is on feasibility outcomes as well as functioning associated with cognitive difficulty and secondary outcomes related to cognition, fatigue and quality of life. METHODS: One hundred and twenty people with MS will be assigned to participate in either the COB-MS programme or a treatment as usual, wait-list control group as part of this single-blind, cluster-randomised controlled feasibility and preliminary efficacy trial of the COB-MS programme. The COB-MS group will participate in an eight-session occupational-based cognitive rehabilitation programme over 9 weeks. The primary outcome measure is the goal attainment scaling at 12 weeks. Participants will be assessed pre-intervention, post-intervention and at 12 weeks post-intervention and 6 months post-intervention. Qualitative evaluations of participants' perspectives will also be examined as part of the feasibility study. DISCUSSION: Results will provide recommendations for a future definitive trial of COB-MS, with respect to both feasibility and preliminary, clinical efficacy. In the event that results indicate efficacy, study findings will suggest that COB-MS requires consideration as a means of enhancing cognitive and daily functioning in people living with MS. TRIAL REGISTRATION: ISRCTN: ISRCTN11462710. Registered on 9 September 2019.

Estimating dyskinesia severity in Parkinson's disease by using a waist-worn sensor: concurrent validity study.

Our research team previously developed an accelerometry-based device, which can be worn on the waist during daily life activities and detects the occurrence of dyskinesia in patients with Parkinson's disease. The goal of this study was to analyze the magnitude of correlation between the numeric output of the device algorithm and the results of the Unified Dyskinesia Rating Scale (UDysRS), administered by a physician. In this study, 13 Parkinson's patients, who were symptomatic with dyskinesias, were monitored with the device at home, for an average period of 30 minutes, while performing normal daily life activities. Each patient's activity was simultaneously video-recorded. A physician was in charge of reviewing the recorded videos and determining the severity of dyskinesia through the UDysRS for every patient. The sensor device yielded only one value for dyskinesia severity, which was calculated by averaging the recorded device readings. Correlation between the results of physician's assessment and the sensor output was analyzed with the Spearman's correlation coefficient. The correlation coefficient between the sensor output and UDysRS result was 0.70 (CI 95%: 0.33-0.88; p = 0.01). Since the sensor was located on the waist, the correlation between the sensor output and the results of the trunk and legs scale sub-items was calculated: 0.91 (CI 95% 0.76-0.97: p < 0.001). The conclusion is that the magnitude of dyskinesia, as measured by the tested device, presented good correlation with that observed by a physician.

The expanding spectrum of paroxysmal movement disorders: update from clinical features to therapeutics.

PURPOSE OF REVIEW: This review will discuss the expanding clinical spectrum of paroxysmal movement disorders and therapeutic options in light of emerging genotypic heterogeneity in these conditions. RECENT FINDINGS: Paroxysmal movement disorders comprise a heterogeneous group of rare neurological conditions characterized by intermittent episodes of abnormal movement associated with various triggers. As the clinical and genotypic spectrum of these disorders evolves, so also has the range of therapeutic options. Triheptanoin has recently been shown to be a very promising alternative to the ketogenic diet in paroxysmal exercise-induced dyskinesia. Four-aminopyridine is now considered first-line symptomatic therapy for episodic ataxia type-2, with pre-clinical findings indicating cerebellar neuroprotection. SUMMARY: In light of the newly emerging therapies, careful clinical phenotyping is needed to ensure diagnostic precision and timely initiation of appropriate therapies.

Can data from disparate long-term fish monitoring programs be used to increase our understanding of regional and continental trends in large river assemblages?

Understanding trends in the diverse resources provided by large rivers will help balance tradeoffs among stakeholders and inform strategies to mitigate the effects of landscape scale stressors such as climate change and invasive species. Absent a cohesive coordinated effort to assess trends in important large river resources, a logical starting point is to assess our ability to draw inferences from existing efforts. In this paper, we use a common analytical framework to analyze data from five disparate fish monitoring programs to better understand the nature of spatial and temporal trends in large river fish assemblages. We evaluated data from programs that monitor fishes in the Colorado, Columbia, Illinois, Mississippi, and Tallapoosa rivers using non-metric dimensional scaling ordinations and associated tests to evaluate trends in fish assemblage structure and native fish biodiversity. Our results indicate that fish assemblages exhibited significant spatial and temporal trends in all five of the rivers. We also document native species diversity trends that were variable within and between rivers and generally more evident in rivers with higher species richness and programs of longer duration. We discuss shared and basin-specific landscape level stressors. Having a basic understanding of the nature and extent of trends in fish assemblages is a necessary first step towards understanding factors affecting biodiversity and fisheries in large rivers.

Mortality after emergency Hartmann's procedure in octogenarians: a propensity score-matched analysis.

BACKGROUND: Complicated diverticulitis is associated with a postoperative mortality rate of 20%. We hypothesized that age ≥80 was an independent risk factor for mortality after Hartmann's procedure for diverticular disease when controlling for baseline comorbidities. METHODS: Patients who underwent an urgent or emergent Hartmann's procedure (Current Procedural Terminology codes 44143 and 44206) for diverticular disease (International Classification of Diseases-9:562.xx) were identified using the American College of Surgeons National Surgical Quality Improvement Project 2005-2013 user file. Using propensity score matching to control for baseline comorbidities, a group of patients ≥80 years old was matched to a group of those <80 years old. Univariate and multivariable logistic regression were performed. A P value <0.05 was considered statistically significant with a confidence interval (CI) of 95%. RESULTS: From a total of 2986 patients, 464 patients (15.5%) were ≥80 years old. Two groups of 284 patients in each study arm were matched using propensity-matching. The mean age of the ≥80 group and <80 group was 84.4 ± 3.3 versus 63.77 ± 911.8; P < 0.0001, respectively. There was no statistical difference in baseline comorbidities or operative time between the groups. There was a significant difference in mortality with 19% and 9.2% in the >80 group versus <80 groups, respectively (P = 0.001). Factors associated with mortality included ascites (odds ratio [OR] 4.95, confidence interval [CI] 1.64-14.93, P = 0.005), previous cardiac surgery (OR 3.68, CI 1.46-9.26, P = 0.006), partially dependent or fully dependent functional status (OR 2.51, CI 1.12-5.56, P = 0.02), albumin <3 (OR 2.49, CI 1.18-5.29, P = 0.01), and American Society of Anesthesiologist class >3 (OR 2.10, CI 1.10-4.46, P = 0.05). CONCLUSIONS: Octogenarians presenting with complicated diverticulitis requiring an emergent Hartmann's procedure have a higher mortality rate compared to those <80, even after controlling for baseline comorbidities. STUDY TYPE: This is a retrospective, descriptive study.

The "Cinderella Syndrome": A narrative study of social curfews and lifestyle restrictions in juvenile myoclonic epilepsy.

Several factors are thought to contribute to inadequate seizure control in patients with juvenile myoclonic epilepsy (JME), including drug resistance, neuropsychiatric comorbidity, and poor lifestyle choices. Recent evidence supports the existence of frontal lobe microstructural deficits and behavioral changes that may contribute to poor seizure control in a minority of patients. Counseling patients on the importance of adequate sleep hygiene and alcohol restriction is an important part of the management strategy for patients with JME. However, information is lacking on how these lifestyle restrictions impact on patients with JME. We conducted a qualitative descriptive analysis of the social impact of JME on 12 patients, from their own perspective. We identified four prominent themes: the importance of alcohol use as a social "norm", how JME affected relationships, decision making (risk versus consequences), and knowledge imparting control. Given that these restrictions were interpreted by patients as social "curfews", we suggest that the term "Cinderella Syndrome" encapsulates the perceived imperative to be home before midnight. Our findings underscore the importance for clinicians to recognize that in counseling patients with JME about lifestyle adjustments, there may be a significant social consequence unique to this patient group.

Corrigendum: Analysis of Correlation between an Accelerometer-Based Algorithm for Detecting Parkinsonian Gait and UPDRS Subscales.

[This corrects the article on p. 431 in vol. 8, PMID: 28919877.].

Clinically isolated syndromes or clinically isolated patients? A patient and clinician perspective on the utility of CIS as a diagnosis.

BACKGROUND: The term "Clinically Isolated Syndrome" (CIS) was introduced to describe a first clinical neurologic episode suggestive of an inflammatory demyelinating CNS disorder. Thereafter, the risk of developing clinically definite multiple sclerosis ranges from 20% to 80%, depending on a number of prognostic factors. Although the concept of CIS has been an important component in improving our understanding of risk levels in Multiple Sclerosis and prognosis, communicating uncertainty in this context remains a challenge for both patients and their clinicians. We therefore wished to explore both the patients understanding of the concept of CIS and the subsequent impact of a diagnosis. We also explored the concept of CIS from the clinician's perspective. METHODS: The study uses a qualitative descriptive design involving both a semi-structured interview of patients with CIS as well as a short questionnaire sent to practising clinicians in the Republic of Ireland. Narrative data was coded onto themes. RESULTS: Thirty CIS patients were interviewed. The majority of patients understood the term "CIS" but not the link between CIS and MS. Two themes were identified: emotional reactions following CIS diagnosis; and terminology and communication. Confusion and anxiety among patients due to inconsistent communication of CIS was identified. Of the thirty-three clinicians surveyed, only thirty-nine per cent found the term "CIS" clinically useful. Eighteen per cent of clinicians diagnosed MS from the CIS case vignette provided. CONCLUSION: In the diagnosis of a first demyelinating event, use of the term "CIS" is confusing to patients and inconsistent among clinicians. We suggest that the term "CIS" be abandoned in favour of terminology that reflects both its pathogenesis and inherent risk of subsequent MS.