Degenerative Neurological Diseases Research Articles

A Comparison of Estimand and Estimation Strategies for Clinical Trials in Early Parkinson’s Disease

Parkinson’s disease (PD) is a chronic, degenerative neurological disorder. PD cannot be prevented, slowed, or cured as of today but highly effective symptomatic treatments are available. We consider relevant estimands and treatment effect estimators for randomized trials of a novel treatment which aims to slow down disease progression versus placebo in early, untreated PD. A commonly used endpoint in PD trials is the MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), which is longitudinally assessed at scheduled visits. The most important intercurrent events (ICEs) which affect the interpretation of the MDS-UPDRS are study treatment discontinuation and initiation of symptomatic treatment. Different estimand strategies are discussed; Hypothetical or treatment policy strategies, respectively, for different types of ICEs seem most appropriate in this context. Several estimators based on multiple imputation which target these estimands are proposed and compared in terms of bias, mean-squared error, and power in a simulation study. The investigated estimators include methods based on a missing-at-random (MAR) assumption, with and without the inclusion of time-varying ICE-indicators, as well as reference-based imputation methods. Simulation parameters are motivated by data analyses of a cohort study from the Parkinson’s Progression Markers Initiative (PPMI).

Association between Human Blood Metabolome and the Risk of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common degenerative neurological disorder with limited therapeutic options. Therefore, it is particularly important to explore the potential biomarkers implicated in the occurrence and progression of AD prior to clinical testing. We selected 119 unique blood metabolites from 3 metabolome genome-wide association studies (GWASs) with 147,827 European participants. Summary data about AD were obtained from a GWAS meta-analysis with 63,926 European individuals from the International Genomics of Alzheimer's Project. MR analyses were performed to assess the associations of blood metabolites with AD, and a phenome-wide MR analysis was further applied to ascertain the potential on-target side effects of metabolite interventions. Four metabolites were identified as causal mediators for AD, including epiandrosterone sulfate (odds ratio [OR] per SD increase: 0.60; 95% confidence interval [CI]: 0.51-0.71; p=6.14 × 10-9 ), 5alpha-androstan-3beta-17beta-diol disulfate (OR per SD increase: 0.69; 95% CI: 0.57-0.84; p=1.98 × 10-4 ), sphingomyelin (OR per SD increase: 2.53; 95% CI: 1.78-3.59; p=2.10 × 10-7 ), and glutamine (OR per SD increase: 0.83; 95% CI: 0.77-0.89; p=2.09 × 10-6 ). Phenome-wide MR analysis showed that epiandrosterone sulfate, 5alpha-androstan-3beta-17beta-diol disulfate and sphingomyelin mediated the risk of multiple diseases, and glutamine had beneficial effects on the risk of 4 diseases. Genetically predicted increased epiandrosterone sulfate, 5alpha-androstan-3beta-17beta-diol disulfate, and glutamine might be associated with a decreased risk of AD, while sphingomyelin was associated with an increased risk. Side-effect profiles were characterized to help inform drug target prioritization, and glutamine might be a promising target for the prevention and treatment of AD with no predicted detrimental side effects. ANN NEUROL 2022;92:756-767.

The parallel tetrameric DNA G-quadruplex formed by the two-repeat C9orf72 GGGGCC sequence in solution

The abnormal expansion of G-rich hexanucleotide repeat, GGGGCC (G4C2), in chromosome 9 open reading frame 72 (C9orf72) is known to be the prevailing genetic cause of two fatal degenerative neurological diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It is well known that the DNA G4C2 repeat expansion with different lengths can form G-quadruplexes which affect gene transcription related to ALS/FTD, therefore it is crucial to understand DNA G4C2 G-quadruplex structures. Herein, by utilizing nuclear magnetic resonance (NMR) spectroscopy, we examined DNA G-quadruplex structure adopted by two G4C2 hexanucleotide repeats with an inosine substitution at position 4, d(G4C2)2-I4. We show that d(G4C2)2-I4 folds into an eight-layer parallel tetrameric G-quadruplex containing two parallel dimeric G-quadruplexes stacking together through π-π interaction via 5′-to-5′ mode in solution. Each dimeric G-quadruplex unit involves two propeller loops composed of two cytosine bases. This result is consistent with the observation in the crystal structure of d(G4C2)2. Our work not only sheds light on the structural diversity of G-quadruplexes adopted by d(G4C2)n but also provides a structural basis for drug design in treatment of ALS and FTD.

Toward the cholinesterase inhibition potential of TADDOL derivatives: Seminal biological and computational studies

Alzheimer's disease (AD) is a degenerative neurological disease characterized by gradual loss of cognitive skills and memory. The exact pathogenesis involved still remains unrevealed, but several studies indicate the involvement of an array of different enzymes, underlining the multifactorial character of the disease. Inhibition of these enzymes is therefore a powerful approach in the development of AD treatments, with promising candidates, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase. Interestingly, AChE is the target of a major pesticide family (organophosphates), with several reports indicating an intersection between the pesticide's activity and AD. In this study, various TADDOL derivatives were synthesized and their in vitro activities as AChE/BuChE inhibitors as well as their antioxidant activities were studied. Molecular modeling studies revealed the capability of TADDOL derivatives to bind to AChE and induce inhibition, especially compounds 2b and 3c furnishing IC50 values of 36.78 ± 8.97 and 59.23 ± 5.31 µM, respectively. Experimental biological activities and molecular modeling studies clearly demonstrate that TADDOL derivatives with specific stereochemistry have an interesting potential for the design of potent AChE inhibitors. The encouraging results for compounds 2b and 3c indicate them as promising scaffolds for selective and potent AChE inhibitors.

Methods to investigate advanced glycation end-product and their application in clinical practice.

Advanced glycation end-products (AGEs) are heterogeneous compounds of irreversible adducts principally derived from nonenzymatic glycation and glycoxidation of proteins. An increase in AGEs may be involved in the pathogenesis of metabolic and cardiovascular diseases, chronic degenerative diseases, neurological diseases and cancer, and it has been suggested as a biomarker of oxidative stress. AGEs have been evaluated in different biological fluids, as well as in tissues. The most utilized techniques for AGE measurement can be divided into immunochemical methods, such as ELISA, and bioanalytical methods, including fluorescence spectroscopy, high-performance liquid chromatography, liquid chromatography-mass spectroscopy, gas chromatography-mass spectroscopy. However, the lack of reference values, well-established standard molecules, and standardized methods to measure these compounds, could limit the application of AGE evaluation for clinical purpose. Aim of this review is to provide an overview on the state of the art of the most employed techniques for detection and measurement of AGEs and their application in clinical practice.

Outcomes of lung transplantation from organ donation after medical assistance in dying: First North American experience

Over 2.5% of deaths in Canada occur as a result from medical assisting in dying (MAID), and a subset of these deaths result in organ donation. However, detailed outcomes of lung transplant recipients using these donors is lacking. This is a retrospective single center cohort study comparing lung transplantation outcomes after donation using MAID donors compared to neurologically determined death and controlled donation after circulatory death (NDD/cDCD) donors from February 2018 to July 2021. Thirty-three patients received lungs from MAID donors, and 560 patients received lungs from NDD/cDCD donors. The donor diagnoses leading to MAID provision were degenerative neurological diseases (n=33) and end stage organ failure (n=5). MAID donors were significantly older than NDD/cDCD donors (56 [IQR 49-64] years vs. 48 [32-59]; p=.0009). Median ventilation period and 30day mortality were not significantly different between MAID and NDD/cDCD lungs recipients (ventilation: 1day [1-3] vs 2days [1-3]; p=.37, deaths 0% [0/33] vs. 2% [11/560], p=.99 respectively). Intermediate-term outcomes were also similar. In summary, for lung transplantation using donors after MAID, recipient outcomes were excellent. Therefore, where this practice is permitted, donation after MAID should be strongly considered for lung transplantation as a way to respect donor wishes while substantially improving outcomes for recipients with end-stage lung disease.

Pharyngolaryngeal semiology and prognostic factors in multiple system atrophy

IntroductionMultiple system atrophy (MSA) is a rare degenerative neurological disorder in adults. It induces parkinsonian and/or cerebellar syndrome associated with dysautonomia. Pharyngolaryngeal symptoms are common. Our aim is to describe the Pharyngolaryngeal semiology on one hand, and to ascertain whether the presence of these symptoms represents a prognostic factor for MSA on the other.MethodsThus, we carried out a retrospective, single-centre study, on a cohort receiving care at the centre of reference for MSA. The patients were referred for otorhinolaryngology assessment. The data was collected over the year 2020 with the help of computer software from the university hospital centre (UHC). Firstly, we described the Pharyngolaryngeal semiology specific to MSA by questioning patients, and by the results of nasofibroscopic examinations and swallowing tests. We then used multivariate analysis of variance to describe the prognostic factors of MSA progression (in UMSARS I and II points per month of progression) and survival (number of years between the first symptoms and death).ResultsThis study included a hundred and one patients and made it possible to define a Pharyngolaryngeal semiology profile of MSA, which is: a reduction in laryngeal mobility (primarily vocal cord abduction defects), abnormal movements (particularly at rest or when initiating a movement) and a defect in the protection mechanisms of the upper airways. The swallowing difficulties are moderate and the main mechanisms are delayed pharyngeal swallow and/or an oro-pharyngeal transport defect. In the multivariate analyses, the contributing factors are laryngeal anomalies, modification of solid food to fluid food and nutritional complication.ConclusionENT specialists should pay close attention to problems in the Pharyngolaryngeal dynamic and then consider a neurological cause. They can also itemize the clinical factors that could have a negative effect on the prognosis of the patient with MSA. Indeed, early detection makes it possible to provide care for respiratory and nutritional complications.

Why We Need an Alzheimer's Moonshot in 2022

Genetic Engineering & Biotechnology NewsVol. 42, No. 5 DepartmentsWhy We Need an Alzheimer's Moonshot in 2022Genuv calls for an urgent, all-hands-on-deck drug development effort to ameliorate the fast-worsening health crisis that is Alzheimer's diseaseSungho Han, PhD and Allan I. Levey, MD, PhDSungho Han, PhDSungho Han, PhD, is founder and CEO of Genuv, a clinical-stage biopharma company in Seoul, South Korea, that develops treatments for cancer and degenerative neurological diseases. Allan I. Levey, MD, PhD, is a neurologist and neuroscientist at the Emory University School of Medicine who advises Genuv. Website: https://genuv.com.Search for more papers by this author and Allan I. Levey, MD, PhDSungho Han, PhD, is founder and CEO of Genuv, a clinical-stage biopharma company in Seoul, South Korea, that develops treatments for cancer and degenerative neurological diseases. Allan I. Levey, MD, PhD, is a neurologist and neuroscientist at the Emory University School of Medicine who advises Genuv. Website: https://genuv.com.Search for more papers by this authorPublished Online:10 May 2022https://doi.org/10.1089/gen.42.05.06AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 42Issue 5May 2022 Information© 2022 by GEN PublishingTo cite this article:Sungho Han, PhD and Allan I. Levey, MD, PhD.Why We Need an Alzheimer's Moonshot in 2022.Genetic Engineering & Biotechnology News.May 2022.18-19.http://doi.org/10.1089/gen.42.05.06Published in Volume: 42 Issue 5: May 10, 2022PDF download

Image Segmentation with Priority Based Apposite Feature Extraction Model for Detection of Multiple Sclerosis in MR Images Using Deep Learning Technique

Multiple Sclerosis (MS) is a degenerative neurological disease caused by damage to the central nervous system's axons and myelin sheaths. MS lesions alter shape, position, and size over time in patients, therefore radiologists must be vigilant in detecting and evaluating MS lesions appropriately. Magnetic resonance imaging (MRI) has gotten a lot of attention from doctors for diagnosing MS, but there are other ways as well. The information provided by MRI modalities to doctors about the brain's anatomy and function is critical for making an MS diagnosis quickly. For automatic extraction of MS lesions from three-dimensional (3D) MR images, this work introduces a new feature selection approach. The approach described here can be used to treat a variety of MS lesions. MS MRI diagnosis takes a long time, is difficult, and is prone to human mistake. The design of a Computer-Aided Diagnosis System (CADS) based on Artificial Intelligence (AI) to diagnose MS incorporates standard machine learning and deep learning approaches. Traditional machine learning uses trial and error to extract, select, and classify features. Deep learning, on the other hand, uses deep layers with values that are automatically learned. In this research work, a Priority based Apposite Feature Extraction Model with Image Segmentation (PAFEM-IS) is proposed for segmentation and feature extraction. With proposed method, a large number of image attributes can be learned with little effort and bias on the part of the user. Apart from that, by using unlabelled data for feature learning, the classifier training can benefit from the significantly larger amount of generally available unlabelled data. The proposed model is compared with the traditional models and the proposed model exhibits better performance levels.

Cabotegravir, the Long-Acting Integrase Strand Transfer Inhibitor, Potently Inhibits Human T-Cell Lymphotropic Virus Type 1 Transmission in vitro.

Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus most prevalent in southwestern Japan, sub-Saharan Africa, Australia, South America, and the Caribbean. Latest figures approximate 10 million people worldwide to be infected with HTLV-1. This is likely a significant underestimation due to lack of screening in endemic areas and absence of seroconversion symptoms. The two primary diseases associated with HTLV-1 infection are adult T cell leukaemia-lymphoma, a malignant and, sometimes, aggressive cancer; and HTLV-1 associated myelopathy/tropical spastic paraparesis, a debilitating neurological degenerative disease. Unfortunately, despite the poor prognosis, there is currently no effective treatment for HTLV-1 infection. We previously showed that integrase strand transfer inhibitors (INSTIs) clinically used for human immunodeficiency virus type 1 (HIV-1) prophylaxis and treatment are also effective against HTLV-1 transmission in vitro. In 2021 a new INSTI, cabotegravir, was approved by the FDA for HIV-1 treatment. We thus set out to evaluate its efficacy against HTLV-1 infection in vitro. Strand transfer assays performed using recombinant HTLV-1 integrase treated with increasing concentrations of cabotegravir, effectively inhibited strand transfer activity, displaying an IC50 of 77.8 ± 22.4 nM. Furthermore, cabotegravir blocked HTLV-1 transmission in tissue culture; we determined an EC50 of 0.56 ± 0.26 nM, similar to bictegravir. Alu-PCR confirmed the block in integration. Thus, there are four INSTIs and one reverse transcriptase inhibitor approved by the FDA for HIV-1 treatment, that potently block HTLV-1 infection in vitro. This should strongly encourage the establishment of a new standard of HTLV-1 treatment – particularly for pre-exposure prophylaxis and prevention of mother-to-child transmission.

Neuropsychiatry as the interface of behavioral manifestations driven by brain dysfunction.

Neuropsychiatry mainly deals with processes of the mind related to neurological diseases. Only secondarily, it deal with depressive and anxiety syndromes, as reactions to the presence of an acute, chronic, or degenerative neurological disease. This review illustrate the most frequent neuropsychiatric disorders in the context of the main neurological diseases, focusing on secondary psychic reactions to the development of neurological diseases. The main purpose of this paper is therefore to amplify the sensitivity of psychiatric colleagues towards these clinical conditions in order to create a communication channel with fellow neurologists and neuroradiologists that is not limited to simple counseling.

Neural Network Aided Detection of Huntington Disease.

Huntington Disease (HD) is a degenerative neurological disease that causes a significant impact on the quality of life of the patient and eventually death. In this paper we present an approach to create a biomarker using as an input DNA CpG methylation data to identify HD patients. DNA CpG methylation is a well-known epigenetic marker for disease state. Technological advances have made it possible to quickly analyze hundreds of thousands of CpGs. This large amount of information might introduce noise as potentially not all DNA CpG methylation levels will be related to the presence of the illness. In this paper, we were able to reduce the number of CpGs considered from hundreds of thousands to 237 using a non-linear approach. It will be shown that using only these 237 CpGs and non-linear techniques such as artificial neural networks makes it possible to accurately differentiate between control and HD patients. An underlying assumption in this paper is that there are no indications suggesting that the process is linear and therefore non-linear techniques, such as artificial neural networks, are a valid tool to analyze this complex disease. The proposed approach is able to accurately distinguish between control and HD patients using DNA CpG methylation data as an input and non-linear forecasting techniques. It should be noted that the dataset analyzed is relatively small. However, the results seem relatively consistent and the analysis can be repeated with larger data-sets as they become available.

The importance of a multidisciplinary approach to improve the life quality for patients with Parkinson's disease

Parkinson's disease is defined as a complex degenerative neurological disease with progressive evolution, which is part of motor system of the brain disorders, being the second degenerative disease as a frequency after Alzheimer's disease. It is characterized by tremor when muscles are at rest (rest tremor), increased muscle tone (stiffness), slow voluntary movements and difficulty maintaining balance (postural instability). Occupational therapy helps Parkinson's patients im-prove their ability to perform daily tasks. The intervention consists in assisting patients in deve-loping a self-care routine, taking into account the limitations of functional mobility, encoura-ging patients to maintain maximum function of daily activities for as long as possible, learning adaptive techniques to reduce tremor. Materials and methods. The devices used for this purpose are commercially available but they are quite expensive, which is why we wanted to make devi-ces made of material as cheap and affordable as possible. Some of the devices can be successfully made of material that every person has in their home. We also took into account the variant of making them without the need to use complicated tools and devices that are not available to pa-tients. Starting from these premises, we thought and made in our occupational therapy laborato-ry various devices designed to offer patients a variety of techniques and exercises and also a fle-xible work environment. On a pallet plate we fixed a series of elements such as zippers, snap button, hook-and-eye closure, systems that patients use on a regular basis. We also manufactu-red a device designed to help patients with household chores such as dish washing. The device is provided at one end with a washing sponge, its handle being a detergent tank. The size and sha-pe have been adapted to the needs of patients with Parkinson's disease. Results and discussions. In order to obtain the devices, cheap materials were used at the disposal of every person eager to make them. It started with simple objects that any patient uses for personal hygiene and more. The technique of making the devices was a very simple one, from the very beginning the steps that must be followed in order to make them were clearly established. Conclusions. Using the devices made during the physiotherapy sessions, significant improvements of the life quality for patients with Parkinson's disease were observed. Keywords: Parkinson, Occupational therapy, Devices, ADL

Different strategies in pointing tasks and their impact on clinical bedside tests of spatial orientation

Deficits in spatial memory, orientation, and navigation are often early or neglected signs of degenerative and vestibular neurological disorders. A simple and reliable bedside test of these functions would be extremely relevant for diagnostic routine. Pointing at targets in the 3D environment is a basic well-trained common sensorimotor ability that provides a suitable measure. We here describe a smartphone-based pointing device using the built-in inertial sensors for analysis of pointing performance in azimuth and polar spatial coordinates. Interpretation of the vectors measured in this way is not trivial, since the individuals tested may use at least two different strategies: first, they may perform the task in an egocentric eye-based reference system by aligning the fingertip with the target retinotopically or second, by aligning the stretched arm and the index finger with the visual line of sight in allocentric world-based coordinates similar to using a rifle. The two strategies result in considerable differences of target coordinates. A pilot test with a further developed design of the device and an app for a standardized bedside utilization in five healthy volunteers revealed an overall mean deviation of less than 5° between the measured and the true coordinates. Future investigations of neurological patients comparing their performance before and after changes in body position (chair rotation) may allow differentiation of distinct orientational deficits in peripheral (vestibulopathy) or central (hippocampal or cortical) disorders.

Is sacral neuromodulation effective in patients with Parkinson's disease? A retrospective review.

Parkinson's disease (PD) is the second-most common degenerative neurologic disease worldwide. Overactive bladder (OAB) is prevalent in this population but can be challenging to treat. Sacral neuromodulation (SNM) is an attractive option but remains understudied. We have utilized SNM in PD patients and herein describe our outcomes. We performed a retrospective chart review of PD patients who underwent peripheral nerve evaluation (PNE) or Stage 1 SNM from 2000 to 2020. The primary outcome was progression to a permanent implant. The impact of PD stage and preprocedural urodynamic (UDS) parameters on test-phase outcome were investigated. Long-term efficacy was assessed using Wilcoxon matched-pairs test looking at a change in urinary symptoms (frequency, nocturia, incontinence episodes, and pad use) documented at follow-up visits and further need for treatment. Thirty-four patients underwent test phase SNM (7 PNE and 27 Stage 1). Median follow-up was 11 (interquartile range 5.8-29.8) months. Indications included refractory OAB (30/34) and nonobstructive urinary retention (4/34). Overall, 82% (28/34) of patients proceeded to a permanent implant. 71% (5/7) of PNEs were successful. Test-phase success did not differ based on PD disease severity or UDS parameters. In patients with OAB/urgency incontinence who progressed to the permanent implant, there was a statistically significant improvement in their urinary symptoms from baseline. Most (68%) patients were able to discontinue OAB medications post-implant. The overall lead revision rate was 14% (4/28) and 3 devices required removal. SNM is an efficacious treatment option for PD patients with a high percentage of patients having improvement in their urinary symptoms.

Connexin43 inhibition attenuated dopaminergic neuronal loss in the lipopolysaccharide-induced mice model of Parkinson’s disease

Studies using in vitro Parkinson’s disease (PD) models have found that lipopolysaccharide (LPS) induced reduction of connexin 43 (Cx43) gap junction communication and elevation of hemichannel function, which could cause neurotoxicity directly and indirectly via excessive ATP and glutamate release. However, in vivo study about Cx43 expression and function, as well as the efficacy of Cx43 inhibition for neuronal survival in PD is lacking. This study aimed to unravel the role of Cx43 in PD and understand the underlying mechanisms using an in vivo PD model. Male C57BL/6 mice received intranigral injection of LPS (5 μg) and 43Gap27 (4 μg), a Cx43 inhibitor, simultaneously. Results showed that following LPS treatment, total Cx43 expression decreased by about 60%, but the relative level of phosphorylated Cx43 increased to about double that controls (all p < 0.05). The administration of 43Gap27 significantly attenuated the loss of dopaminergic neurons and restored dopamine and its metabolites levels. Moreover, 43Gap27 treatment inhibited intense microgliosis and astrogliosis in nigrostriatal system induced by LPS and also ameliorated elevated levels of inflammatory mediators. Interestingly, Cx43 inhibition also increased nerve growth factors. In conclusion, Cx43 inhibition was able to prevent LPS-mediated dopaminergic neuronal death, possibly via neuroinflammation reaction reduction and neurotrophic factors elevation. Therefore, Cx43 may be a promising therapeutic target for degenerative neurological disorders such as PD.

AlzVNet: A volumetric convolutional neural network for multiclass classification of Alzheimer’s disease through multiple neuroimaging computational approaches

Alzheimer's disease is a degenerative neurological disease that causes a loss of cognitive skills and has no known treatment. Alzheimer's disease (AD) must be detected early, before symptoms appear, in order to be treated effectively. In this study, we used a deep learning approach called a convolutional neural network to classify Alzheimer's disease into three categories using a neuroimaging biomarker called T1w-MRI. Our research is the first to look at the results of three neuroimaging computational approaches in a systematic way (3D subject-level, 3D patch-based and slice-based). To show Alzheimer detection using deep convolutional neural networks, three distinct Slice Based methods are used (Subset selection method, uniform selection method, Interpolation zoom method). For 3D patch-based approaches, we investigated the classification accuracy of distinct non-overlapping patches ranging in size from small to medium to large (from 32, 40, 48, 56, 64, 72, 80, till 88). Our findings revealed that 1) our 3-class classification model performed best, with 98.3 percent accuracy percent (highest accuracy obtained until now as per our best knowledge); 2) The 3D Subject-level approach was the most efficient, followed by 3D-patch-based and then Slice-based approaches, with classification accuracy of 98.26 percent, 97.48 percent, and 95.40 percent, respectively; and 3) The same network had the most accuracy for bigger patches (size 72, 80, 88), followed by medium-sized (size 56, 64) to tiny patches (size 32, 40, 48). Large patches had a classification accuracy of 97.48 percent, while medium patches had a classification accuracy of 96.62 percent, and small patches had an accuracy of 86.49 percent. 4)) Even slice selection and interpolation selection exceeded subset slice selection with three-class classification accuracy of 95.37 percent and 94.57 percent, respectively, compared to 92.57 percent for subset slice selection.

Tone- Increase is an Answer after a Brain Damage: But How High Is Good?

Tone- Increase is an Answer after a Brain Damage: But How High Is Good?

Laryngeal silicone stent as a treatment option for laryngeal paralysis in dogs: a preliminary study of 6 cases.

BackgroundLaryngeal paralysis is a common idiopathic degenerative neurological disease in older medium-to-large breed dogs, with surgical correction of the obstruction being the treatment of choice.ObjectivesThis study evaluated the use of laryngeal silicone stents to treat canine laryngeal paralysis in dogs where classic surgical treatment was not accepted by the owners.MethodsDogs diagnosed with laryngeal paralysis, for which the owners refused arytenoid lateralization surgery as a first-line treatment, were treated with laryngeal silicone stents.ResultsSix dogs with bilateral laryngeal paralysis were included in the study. All dogs showed improvement in clinical signs immediately after the procedure. No clinical signs or radiographic changes were noted in four out of six dogs in the follow-up visit performed 1 wk later. One dog was suspected of aspirating water while drinking, but the signs disappeared after repositioning the stent. Another dog had a relapse of stridor due to caudal migration of the stent. This dog underwent arytenoid lateralization surgery because larger stents are not commercially available. At the time of writing, between seven and 13 mon after stent placement, no significant incidents have occurred in four dogs, and all owners report a satisfactory quality of life.ConclusionsLaryngeal silicone stenting is an interesting alternative for treating dogs with acquired laryngeal paralysis when the owners refuse classic arytenoid lateralization surgery. Furthermore, stent placement can be a temporary solution to stabilize these dogs until a permanent surgical treatment can be performed.

Workshop Compiled

Progressive supranuclear palsy (PSP) is a type of neurodegenerative extrapyramidal syndrome. The prevalence of PSP in studies is found to be 5.8-6.5 per 100,000 individuals with a slightly male preponderence. Onset is usually between 55 and 70 years of age and median survival is around 6 years after the onset of symptomatology.It is characterized by motor symptoms, such as postural instability, rigidity, akinesia, supranuclear gaze palsy, pseudobulbar palsy; levodopa-unresponsive parkinsonism, and behavioral and cognitive symptoms. Early PSP is also difficult to differentiate from PD; as it shares many features like abnormalities in gait, speech, and eye movements. Neuropsychiatric symptoms commonly observed in patients with PSP are dementia, apathy, depression, anxiety, disorders of sleep and disinhibition.A 60 year old man presented with impaired memory, disturbed sleep and restless behaviour for 2months in geriatric mental health outpatient department. He had a history of tremors on both the hands and stiffness of body which was gradually progressive for last 4 years. They consulted a neurologist 1.5 years back as his symptoms were severe enough to hamper in day to day functioning. He was diagnosed as a case of idiopathic Parkinson’s Disease and was prescribed Tab Levodopa 100mg and Carbidopa 25mg combination preparation thrice daily. On medication within 2months, family members reported decrease in his symptoms. For last 6months new symptoms like frequent falls during walking without any precipitant developed. Falls usually occurred within a few steps of walking mostly towards the left side and following which he sustained an injury over his left eye leading to lower lid ectropion. The activity of the patient became restricted and he started to remain confined to his bed for the fear of falls since last 3months. They consulted a physician again and he was prescribed Tab Trihexyphenydyl 2mg three times a day and dose of Tab Levodopa 100mg and Carbidopa 25mg combination increased to four times a day and Tab Levodopa 100mg and Carbidopa 25mg combination contolled relase preparation was added at bedtime. After taking those medications the frequency of falls increased, forgetfulness appeared, sleep got disturbed, at night he becomes restless and some confusion in behavior like pointing things, picking bed linen were noticed during evening hours.On examination the patient had prominent vertical wrinkling of forehead, wide opened eyes with reduced blinking, ‘procerus sign’ was present. His speech revealed hypophonia and reduced fluency. On the first two days his orientation was fluctuating; from the third day no abnormality was noticed in his mental state. Neurological examination revealed wide based festinating gait, intention tremor in upper limb, lead pipe rigidity in all four limbs bilaterally(right>left), axial rigidity and impaired balance and coordination; and supranuclear gaze palsy.During the hospital stay the anticholinergic drug (trihexyphenydyl 2mg) and Tab Levodopa 100mg and Carbidopa 25mg combination contolled relase preparation was withheld; Tab Melatonin 5mg was added along with other drugs were continued. Within 2days of hospitalization, his sleep improved, restlessness and confusion in behavior decreased, also his cognition was improved.Workshop Description:Approach to Parkinson plus syndromes presenting in Geriatric Psychiatric population.Case scenarios from the literature.Discussion on diagnostic and management issues.Methods/Issues:Progressive supranuclear palsy (PSP) is often difficult to discriminate clinically from idiopathic Parkinson’s disease (PD). Diagnosis in early stage is important for maximal benefit from disease modifying treatment for PSP. Delirium is defined as an acute organic brain syndrome which presents with decreased level of consciousness, varied psychomotor activity, wake-sleep rhythm disorders, cognitive impairment and attention deficits. High dose of Levodopa in Parkinson’s disease is reported to cause confusion and psychosis.Moreover dopaminergic drug in Progressive Supranuclear Palsy has response in only 20-40% cases.Anticholinergic drugs in ageing brain with comorbidities are known to cause confusion and delirium.Learning Objectives:Parkinsonism plus syndrome as a heterogeneous degenerative neurological disorders that differs from the classical idiopathic Parkinson’s disease in certain associated clinical features, poor response to levodopa, distinctive pathological characteristics and poor prognosis. Associated clinical features include symmetrical onset, infrequent or atypical tremor, prominent rigidity in axial musculature, bradykinesia, early postural instability, supranuclear gaze palsy, early autonomic failure, pyramidal affection, cerebellar involvement, alien limb phenomenon, apraxia and significant early cognitive dysfunction in some cases. Progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and dementia with Lewy body disease (DLB) are commoner disorders. Less frequent disorders are cortico-basal ganglionic degeneration (CBGD), frontotemporal dementia with chromosome 17 (FTDP-17), Pick’s disease, parkinsonian-dementia complex of Guam, Pallidonigral degeneration, Wilson’s disease and a rigid variant of Huntington’s disease.Conclusions/ Strategies:Patients with Parkinsonism-plus syndromes represent a relatively small portion of Parkinsonism patients.They have wide spectrum of disease phenotypes associated with these disorders and the often subtle clinical differences, establishing the correct diagnosis, especially at disease onset, can be difficult despite serial clinical observations and repeated neurological examination.