Daclizumab: Mechanisms of Action, Therapeutic Efficacy, Adverse Events and Its Uncovering the Potential Role of Innate Immune System Recruitment as a Treatment Strategy for Relapsing Multiple Sclerosis.

Daclizumab (DAC) is a humanized, monoclonal antibody that blocks CD25, a critical element of the high-affinity interleukin-2 receptor (IL-2R). DAC HYP blockade of CD25 inhibits effector T cell activation, regulatory T cell expansion and survival, and activation-induced T-cell apoptosis. Because CD25 blockade reduces IL-2 consumption by effector T cells, it increases IL-2 bioavailability allowing for greater interaction with the intermediate-affinity IL-2R, and therefore drives the expansion of CD56bright natural killer (NK) cells. Furthermore, there appears to be a direct correlation between CD56bright NK cell expansion and DAC HYP efficacy in reducing relapses and MRI evidence of disease activity in patients with RMS in phase II and phase III double-blind, placebo- and active comparator-controlled trials. Therapeutic efficacy was maintained during open-label extension studies. However, treatment was associated with an increased risk of rare adverse events, including cutaneous inflammation, autoimmune hepatitis, central nervous system Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) syndrome, and autoimmune Glial Fibrillary Acidic Protein (GFAP) alpha immunoglobulin-associated encephalitis. As a result, DAC HYP was removed from clinical use in 2018. The lingering importance of DAC is that its use led to a deeper understanding of the underappreciated role of innate immunity in the potential treatment of autoimmune disease.

Persistent Hemichorea and Caudate Atrophy in Untreated Diabetic Striatopathy: A Case Report.

BACKGROUND: Neurological complications of diabetes and hyperglycemia are relatively common but the specific manifestations can vary widely. Diabetic striatal disease or "diabetic striatopathy" is an uncommon condition usually thought to result from hyperglycemic injury to the basal ganglia, producing a hyperkinetic movement disorder, usually choreiform in nature. Symptoms are generally reversible with treatment of the hyperglycemia. CASE DESCRIPTION: We report the case of a 57-year-old woman presenting with a unilateral choreoathetosis of the left upper extremity, persistent for 4 years. Contemporaneous imaging demonstrated severe atrophy of the right caudate nucleus, while imaging obtained at the onset of symptoms was consistent with a right diabetic striatopathy. Symptoms improved with the use of dopamine antagonists and benzodiazepines. CONCLUSION: Although generally considered to be fully reversible, this case demonstrates that diabetic striatopathy can result in permanent structural lesions with persistent symptoms if left untreated.

Changes in Multidigit Synergies and Their Feed-Forward Adjustments in Multiple Sclerosis.

The authors explored the changes in multidigit synergies in patients with multiple sclerosis (MS) within the framework of the uncontrolled manifold hypothesis. The specific hypotheses were that both synergy indices and anticipatory synergy adjustments prior to the initiation of a self-paced quick action would be diminished in the patients compared to age-matched controls. The MS patients and age-matched controls (n = 13 in both groups) performed one-finger and multifinger force production tasks involving both accurate steady-state force production and quick force pulses. The patients showed significantly lower maximal finger forces and a tendency toward slower force pulses. Enslaving was increased in MS, but only in the lateral fingers (index and little). Indices of multifinger synergies during steady-state force production were lower in MS, mainly due to the lower amount of intertrial variance that did not affect total force. Anticipatory synergy adjustments were significantly delayed in MS. The results show that MS leads to significant changes in multidigit synergies and feed-forward adjustments of the synergies prior to a quick action. The authors discuss possible contributions of subcortical structures to the impaired synergic control.

Olfactory dysfunction in Multiple Sclerosis: A scoping review of the literature.

OBJECTIVE: Olfactory dysfunction in Multiple Sclerosis (MS) has been reported, but results have been inconsistent. In this review we describe, synthesize, and interpret the existing literature on olfactory dysfunction in Multiple Sclerosis and identify gaps in the current level of knowledge. METHODS: The study design was a scoping review of the literature covering several study designs. Systematic Searches of the PubMed, CINAHL, Cochrane Library, Web of Science, PsycARTICLES, PsycINFO and Google Scholar databases were conducted that included key words related to Multiple Sclerosis and Olfaction Disorders. Literature that met the criteria of pertaining to both Multiple Sclerosis and olfactory dysfunction was identified, with the aim of providing an overview of the extent and types of research available in this area. RESULTS: Sixty-one reports were identified in the initial search, with 40 meeting the study criteria. Twenty-five clinical studies were included. Among them, 23 studies measured for olfactory dysfunction in MS patients, ten evaluated MRI correlates of olfactory dysfunction, and five evaluated neurophysiology correlates of olfactory dysfunction. Six of the included studies were abstracts. In addition, thirteen reviews/commentaries and two case studies were included. The majority of the studies identified some degree of olfactory dysfunction in MS patients, and various aspects and correlations with olfactory impairment were observed. CONCLUSIONS: The overall weight of the literature suggests that olfactory dysfunction may occur in MS. Although there is variability in reported frequency, the more robust studies suggest the prevalence is significant, ranging from 20% to 45% in the MS population. Despite this, the mechanisms are unknown and the clinical relevance of this association has not been well explored. Interesting findings relating mood disorders, cognition, and olfactory dysfunction in MS are also suggested but remain poorly developed and require further investigation. Future studies are also warranted to understand the dynamic changes in olfactory function during the course of MS, and to correlate olfactory function with relapses/disease activity.

Capgras Syndrome in a Patient with Parkinson's Disease after Bilateral Subthalamic Nucleus Deep Brain Stimulation: A Case Report.

Capgras syndrome is a delusional misidentification syndrome (DMS) which can be seen in neurodegenerative diseases such as Lewy body dementia and, to a lesser extent, in Parkinson's disease (PD). Here, we report the case of a 78-year-old man with a history of idiopathic PD who developed Capgras syndrome following bilateral subthalamic nucleus deep brain stimulation (DBS) implantation. As the risk of DMS has been related to deficits in executive, memory, and visuospatial function preoperatively, this case highlights the importance of continuing to improve patient selection for DBS surgery. Capgras syndrome is a rare potential complication of DBS surgery in PD patients with preexisting cognitive decline.

History of smoking and olfaction in Parkinson's disease.

OBJECTIVE: Olfactory dysfunction is the most common pre-motor symptom in Parkinson's disease (PD), and smoking is known to be associated with lower risk of PD. This study tested the hypothesis that smoking is associated with better olfaction in PD. METHODS: Smoking history was obtained from 76 PD subjects (22 with a history of smoking [smokers], 54 who never smoked [nonsmokers]), and 70 controls (17 smokers, 53 nonsmokers). Olfaction was assessed using the 40-item University of Pennsylvania Smell Identification Test (UPSIT). The olfactory scores between groups and subgroups were compared using analysis of covariance with adjustment for age, gender, and monoamine oxidase B (MAO-B) inhibitor usage. RESULTS: Overall the olfactory score was lower in PD compared with controls (olfactory scores: 21.5 vs. 33.5, P < 0.0001). Among controls, there was no significant difference in olfaction between smokers and nonsmokers (olfactory scores, 33.2 vs. 34.2; P = 0.95). Among PD subjects, however, smokers scored significantly better regarding olfaction compared with nonsmokers (olfactory scores: 24.4 vs. 19.9, P = 0.02). CONCLUSIONS: These data suggest that a history of smoking is associated with better olfaction among PD patients. The finding may be related to why smoking may be protective against PD. Further studies are needed to confirm this finding and investigate the underlying mechanisms.

Effects of limb posture on reactive hyperemia.

To examine the role of limb posture on vascular conductance during rapid changes in vascular transmural pressure, we determined brachial (n = 10) and femoral (n = 10) artery post-occlusive reactive hyperemic blood flow (RHBF, ultrasound/Doppler) and vascular conductance in healthy humans with each limb at three different positions-horizontal, up and down. Limb posture was varied by raising or lowering the arm or leg from the horizontal position by 45°. In both limbs, peak RHBF and vascular conductance were highest in the down or horizontal position and lowest in the up position (arm up 338 ± 38, supine 430 ± 52, down 415 ± 52 ml/min, P < 0.05; leg up 1,208 ± 88, supine 1,579 ± 130, down 1,767 ± 149 ml/min, P < 0.05). In contrast, the maximal dynamic fall in blood flow following peak RHBF (in ml/s/s) in both limbs was highest in the limb-down position and lowest with the limb elevated (P < 0.05). These data suggest that the magnitude and temporal pattern of limb reactive hyperemia is in part related to changes in vascular transmural pressure and independent of systemic blood pressure and sympathetic control.