Intractable Conditions Research Articles

The genetics of developmental disorders

Abstract Children with developmental disorders often have complex health needs and require frequent input from many different paediatric services. Genomic technologies have revolutionised how these disorders are diagnosed and have real potential to transform the management of previously intractable paediatric conditions. For paediatricians to fully harness these benefits for their patients, and to work productively with their clinical genetics colleagues within the multi-disciplinary team, they must be genomically literate and aware of the technical and ethical challenges. In this review article, we summarise the current understanding of the genetic architecture of developmental disorders; discuss the different types of genetic tests currently available, their strengths and limitations in clinical practice; and discuss the challenges and future opportunities in paediatric genomic medicine.

A Prospective, Randomized Cross-Over Trial of T2 Paravertebral Block as a Sympathetic Block in Complex Regional Pain Syndrome

Background: Sympathetic block is commonly performed in clinical practice for management of intractable pain conditions. However, stellate ganglion block (SGB) alone often does not achieve sufficient sympatholysis of the upper extremity. The paravertebral space continues up to the cervical sympathetic chain and includes the stellate ganglion. We compared the sympatholytic and analgesic effect of paravertebral block performed at the T2 level (T2 PVB) with that of SGB in patients with complex regional pain syndrome (CRPS) of the upper extremity. Objectives: The aim of this study was to compare the sympatholytic property of T2 PVB with that of the conventional SGB in patients with CRPS of the upper extremity. Study Design: Prospective, randomized cross-over trial. Setting: University hospital pain center in Korea. Methods: Fifteen patients with upper extremity CRPS were randomly assigned to 1 of 2 intervention methods (SGB or T2 PVB). After effects of the first block receded, the patients were crossed over to the second procedure. A difference in temperature increase between the treated side and the opposite side (ΔT) ≥ 1.5°C was considered as a successful primary outcome. Rate of successful primary outcome, degree of pain reduction, duration of effect, and patient satisfaction scores were compared between the 2 intervention methods. Results: Rate of successful primary outcome (ΔT ≥ 1.5°C) was significantly higher in the T2 PVB cases than in the SGB cases (80.0% vs. 20.0%; P = 0.003). Numeric Rating Scale scores after the procedure were significantly lower in the T2 PVB group. Patient satisfaction scores were significantly higher, and the duration of the block was significantly longer in the T2 PVB cases than in the SGB cases. Limitations: The relatively small sample size from a single center, and the lack of standardization of the injected volume of T2 PVB and SGB were limitations. Conclusions: T2 PVB showed superior sympatholytic effect than SGB; other clinical outcomes were also better with T2 PVB than with SGB. T2 PVB can be a useful option for producing sympatholytic and analgesic effect in patients with CRPS of the upper extremity. Key words: Sympathetic block, Complex Regional Pain Syndrome, paravertebral block, stellate ganglion block

New-onset Refractory Status Epilepticus Involving the Limbic System, Spinal Cord, and Peripheral Nerves

A healthy 28-year-old woman presented suddenly with intractable status epilepticus: a focal seizure evolved into a generalized seizure preceded by a high fever. Brain magnetic resonance imaging indicated bilateral hyperintensities in the hippocampus on T2-weighted imaging. Electroencephalograms continuously demonstrated diffuse sharp waves and poly-spikes. Comprehensive immunomodulation therapies and anti-epileptic drugs did not lead to any improvements. We therefore diagnosed her with cryptogenic limbic encephalitis and new-onset refractory status epilepticus (NORSE). We detected positive anti-ganglioside antibodies, IgG-GQ1b, GD1a, and GT1b, which were negative at six months after the onset. We emphasize the heterogeneous pathogenesis and intractable conditions of NORSE.

Extracorporeal Membrane Oxygenation (ECMO)-A Lifesaving Technology. Review and Single-center Experience.

ObjectiveExtracorporeal membrane oxygenation is used to bypass the cardiopulmonary system in a severe heart or/and lung failure, mainly in intractable conditions where all other therapy options fail or are unfeasible. Extracorporeal membrane oxygenation (ECMO) is a well-established therapeutic option in such circumstances for neonatal, pediatric, and adult patients. Managing a patient with ECMO requires dedicated and specific management. The importance and necessity of this essential technology in life-threatening cardio-respiratory rescue prompted Rambam Health Care Campus to implement it and make it available as a service to the population in northern Israel. This article includes a brief review of extracorporeal life support and a report of our single-center experience since the establishment of the service.MethodsThe ECMO unit was established in 2014 under the responsibility of the Cardiac Surgery Department. The ECMO service was initiated by a well-planned program with consideration of all aspects including economics, education and training, the specialist team and equipment needed, strategies for medication, and ethical challenges.ResultsBetween February 2014 and May 2018, 65 patients were treated with ECMO; 43 patients received veno-arterial ECMO for cardiac support (66%), while 22 received veno-venous ECMO for respiratory support (34%). The in-hospital mortality was 56%.ConclusionsExtracorporeal membrane oxygenation is an effective therapy that is constantly growing in use and provides a therapy that can replace previous options. To establish such a service requires a planned program and concerted effort. Our single-center experience presented a good learning curve and showed the feasibility as well as the efficacy of the ECMO procedure in life-threatening conditions.

New Advances in Neuromodulation

The purpose of this article is to illustrate the recent advances made in the field of neuromodulation for chronic pain management and it provides a brief review of the literature supporting their safe and efficacious use. Spinal cord stimulation (SCS) has been an effective therapy for the management of intractable pain conditions including complex regional pain syndrome (CRPS), peripheral neuropathy, and failed back surgery syndrome (FBSS). With the introduction of high-frequency and burst SCS waveforms, there has been a noted improvement in the treatment outcomes of these pain syndromes. Dorsal root ganglion stimulation and peripheral nerve stimulation have made it possible to achieve pain relief in the focal areas of pain, which was difficult before with the use of conventional SCS. Chronic pain conditions afflict a large population and are the leading causes of disability among industrialized nations. Conditions such as CRPS, peripheral neuropathy, and FBSS are often difficult to treat with conservative medical measures. This has been one of the factors that have led to increased opioid prescribing and has contributed to the current opioid crisis. Neuromodulation offers a relatively safe and effective therapy for the chronic pain patients that have failed conservative pain measures or are unwilling to undergo higher risk options such as spine surgery or opioid therapy.

Cannabis Therapeutics and the Future of Neurology.

Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.

Future of Smart Cardiovascular Implants.

Cardiovascular disease remains the leading cause of death in Western society. Recent technological advances have opened the opportunity of developing new and innovative smart stent devices that have advanced electrical properties that can improve diagnosis and even treatment of previously intractable conditions, such as central line access failure, atherosclerosis and reporting on vascular grafts for renal dialysis. Here we review the latest advances in the field of cardiovascular medical implants, providing a broad overview of the application of their use in the context of cardiovascular disease rather than an in-depth analysis of the current state of the art. We cover their powering, communication and the challenges faced in their fabrication. We focus specifically on those devices required to maintain vascular access such as ones used to treat arterial disease, a major source of heart attacks and strokes. We look forward to advances in these technologies in the future and their implementation to improve the human condition.

Why Weight? An Analytic Review of Obesity Management, Diabetes Prevention, and Cardiovascular Risk Reduction.

In this review, we examine one of the ironies of American health care-that we pay more for disease management than disease prevention. Instead of preventing type 2 diabetes (T2DM) by treating its precursor, obesity, we fail to provide sufficient insurance coverage for weight management only to fund the more costly burden of overt T2DM. There is a vital need for expanded insurance coverage to help foster a weight-centric approach to T2DM management. This includes broader coverage of anti-diabetic medications with evidence of cardiovascular risk reduction and mortality benefit, anti-obesity pharmacotherapy, bariatric surgery, weight loss devices, endoscopic bariatric therapies, and lifestyle interventions for the treatment of obesity. The fundamental question to ask is why weight? Why wait to go after obesity until its end-stage sequelae cause intractable conditions? Instead of managing the complications of T2DM, consider preventing them by tackling obesity.

MRI compatible MS2 nanoparticles designed to cross the blood–brain-barrier: providing a path towards tinnitus treatment

Fundamental challenges of targeting specific brain regions for treatment using pharmacotherapeutic nanoparticle (NP) carriers include circumventing the blood–brain-barrier (BBB) and tracking delivery. Angiopep-2 (AP2) has been shown to facilitate the transport of large macromolecules and synthetic nanoparticles across the BBB. Thus, conjugation of AP2 to an MS2 bacteriophage based NP should also permit transport across the BBB. We have fabricated and tested a novel MS2 capsid-based NP conjugated to the ligand AP2. The reaction efficiency was determined to be over 70%, with up to two angiopep-2 conjugated per MS2 capsid protein. When linked with a porphyrin ring, manganese (Mn2+) remained stable within MS2 and was MRI detectable. Nanoparticles were introduced intracerebroventricularly or systemically. Systemic delivery yielded dose dependent, non-toxic accumulation of NPs in the midbrain. Design of a multifunctional MRI compatible NP platform provides a significant step forward for the diagnosis and treatment of intractable brain conditions, such as tinnitus.

Cannabis for the treatment of paediatric epilepsy? An update for Canadian paediatricians

The plant Cannabis sativa produces over 140 known cannabinoids. These chemicals generate considerable interest in the medical research community for their possible application to several intractable disease conditions. Recent reports have prompted parents to strongly consider Cannabis products to treat their children with drug resistant epilepsy. Physicians, though, are reluctant to prescribe Cannabis products due to confusion about their regulatory status and limited clinical data supporting their use. We provide the general paediatrician with a brief review of cannabinoid biology, the literature regarding their use in children with drug resistant epilepsy, the current Health Canada and Canadian Paediatric Society recommendations and also the regulations from the physician regulatory bodies for each province and territory. Given the complexities of conducting research on Cannabis products for children with epilepsy, we also discuss outstanding research objectives that must be addressed to support Cannabis products as an accepted treatment option for children with refractory epilepsy.

Improvement of ischemic or congested wound conditions by reconstruction with microsurgical flaps.

Intractable chronic wounds share the basic problem of the environment being unfavorable for wound healing and prone to infection, inflammation, and recurrences. Microsurgical flap provides a healthy, well-vascularized normal tissue to compromised intractable environment, and promotes wound healing. In this report, we present the results of microsurgical flaps used for the reconstruction of chronic intractable conditions including chronic ulcer with an ischemic environment and pathologic lesions with a congestive environment. From 1997 to 2015, 18 patients received microsurgical flaps for chronic intractable conditions. Among them, three patients had radiation ulcers with an ischemic environment and 15 had pathologic lesions with a congested environment, such as vascular malformations. Nine patients were male, and nine were female. The mean age was 31.9 years. All patients were treated using radical excision and reconstruction with microsurgical tissue transfer. All flaps survived completely. Among three patients with radiation ulcers, two had minor wound disruptions, which were managed conservatively. No further episodes of infections or breakdowns occurred. Among 15 patients who had pathologic lesions, one suffered facial palsy of the forehead. No complications in terms of infection, or recurrences were noted, and resolution of the residual surrounding lesions was observed on follow-ups. No donor related problems occurred in any patients. The mean follow-up period was 10.7 years. In this report, we present the results of reconstruction of chronic intractable conditions using microsurgical flaps. The reconstruction using microsurgical flaps was clinically successful, with long-term improvement of surrounding tissues and no recurrence.

Inferring the Dysconnection Syndrome in Schizophrenia: Interpretational Considerations on Methods for the Network Analyses of fMRI Data.

Schizophrenia has long been considered one of the most intractable psychiatric conditions. Its etiology is likely polygenic, and its symptoms are hypothesized to result from complex aberrations in network-level neuronal activity. While easily identifiable by psychiatrists based on clear behavioral signs, the biological substrate of the disease remains poorly understood. Here, we discuss current trends and key concepts in the theoretical framework surrounding schizophrenia and critically discuss network approaches applied to neuroimaging data that can illuminate the correlates of the illness. We first consider a theoretical framework encompassing basic principles of brain function ranging from neural units toward perspectives of network function. Next, we outline the strengths and limitations of several fMRI-based analytic methodologies for assessing in vivo brain network function, including undirected and directed functional connectivity and effective connectivity. The underlying assumptions of each approach for modeling fMRI data are treated in some quantitative detail, allowing for assessment of the utility of each for generating inferences about brain networks relevant to schizophrenia. fMRI and the analyses of fMRI signals provide a limited, yet vibrant platform from which to test specific hypotheses about brain network dysfunction in schizophrenia. Carefully considered and applied connectivity measures have the power to illuminate loss or change of function at the network level, thus providing insight into the underlying neurobiology which gives rise to the emergent symptoms seen in the altered cognition and behavior of schizophrenia patients.

English

Retail pharmacies operating in developing and emerging nations are faced with a myriad of intractable macro-economic conditions including over-regulation, government interference, inept policy implementations and intensive competition. These conditions demand that retail pharmacies become strategic in their approach to business management in order to diminish the impact of macro-economic conditions conspiring to influence their performance in the market. From that perspective, this study investigates the specific strategic management approaches employed by retail pharmacies in Zimbabwe to navigate the country’s harsh economic conditions. In order to examine their management approaches, a questionnaire survey consisting of 90 retail pharmacies was carried out. Data collected from the survey was analysed using regression analysis. From this, the study developed a nuanced strategic management model that can be applied in managing businesses operating in unpredictable markets either in developing, emerging or advanced nations. Key words: Developing and emerging nations, retail pharmacies, strategic management, macro-economic conditions

The SAGE encyclopedia of stem cell research

Stem cells are the engine rooms of multi-cellular organisms. While fascinating in and of themselves, they are also clearly fuelling excitement and potential in traditional areas of developmental biology and in the field of regenerative medicine, where they are believed to hold much promise in addressing any number of intractable medical conditions. However, along with exciting breakthroughs, frustration and controversies swirl through this rapidly moving area of research. What does the average person make of all this, and how can an interested scholar probe the vast sea of new information? The first edition of the Encyclopedia of Stem Cell Research, published in 2008, gave general readers a reference manual to gain a clear understanding of basic concepts in stem cell biology along with socio-political issues facing the field. Much has happened since the articles for the first edition were written in 2007, and to capture developments, the updated second edition will expand from two to three volumes and will present more than 470 articles (320 revised from the first edition, augmented by 150 entirely new) that explore major topics in ways accessible to non-scientists, thus bringing readers up-to-date with where stem cell biology stands today, including new and evolving ethical, religious, legal, social, and political perspectives. Key features include: * A Reader's Guide, Further Readings, Cross References, Resource Guide, Chronology and Index * A Glossary that will elucidate stem cell terminology for the non-scientist. * Appendices that include statistics and selected reprints of major journal articles that pertain to milestones achieved in stem cell research as well as documents from hearings and reports on stem cells and cloning, and more.

Study of extra-articular manifestations and disease severity in patients with rheumatoid arthritis

Background: The prevalence of chronic diseases in modern industrialized nations is increasing and among these intractable conditions, rheumatoid arthritis (RA) stands out as a major cause of multiple medical problems. Rheumatoid arthritis is an inflammation of synovial tissue and is characterized by symmetric involvement of peripheral joints, with hands, feet and wrists being most commonly affected. RA also presents with systemic disturbances and extra-articular manifestations. The prevalence of RA is reported to be 0.5-1% in the population worldwide, affecting women more frequently than men. One study carried out in India reported a figure of 0.5%. Although considered a “joint disease”, rheumatoid arthritis is also associated with extra-articular manifestations. Prevalence of these manifestations is seen in about 40% of patients at any time during the course of the disease. The objective was to study extra-articular manifestations and disease severity in patients with rheumatoid arthritis. Methods: A Cross sectional study carried out among RA patients in inpatients and outpatients of tertiary care hospital. Based on the criteria, patients were selected and clinical history and examination was done. Locomotor system was examined and the total number of swollen and tender joints were counted and patient’s perception of pain was analysed using visual analogue scale ( 0-100 mm) and disease severity was calculated using disease activity score 28 (DAS 28 score ). Results: The results showed the mean age of rheumatoid arthritis to be 52.61 years, with the minimum age being 20 years and the maximum age being 81 years. Among 100 patients, 84% were females and 16% were males. Among 100 patients, 27% of patients had extra articular manifestations. The most common extra articular manifestation seen in the study was interstitial lung disease, a pulmonary manifestation, which was present in 11% of patients. There was a statistical significance between the association of extra-articular manifestation and disease severity. Conclusions: Extra articular manifestations was seen in 27 % of patients , most common was interstitial lung disease, indicating more extensive investigative protocol warranted for diagnosing milder presentation of these serious manifestations.

Peripheral Nerve Stimulation for Back Pain.

Peripheral nerve stimulation (PNS) generally refers to stimulation of a named nerve via direct placement of a lead next to the nerve either via a percutaneous or open approach; in peripheral nerve field stimulation (PNFS), leads are subcutaneously placed to stimulate the region of affected nerves, cutaneous afferents, or the dermatomal distribution of the nerves which converge back to the spinal cord. Recently, there has been a renewed interest in using the PNS approach for many otherwise refractory pain conditions; however, PNFS appears to be more effective for the management of low back pain and therefore more attractive. Here we discuss procedural details of PNFS trial and implant, and provide scientific and clinical rationale for placing PNFS electrodes at a certain depth under the skin. We also summarize results of published studies on use of PNFS in the management of low back pain and list the criteria that are used for proper patient selection. Our experience and the published studies provide evidence that PNFS is a safe and well-tolerated pain control option for intractable pain conditions, including chronic low back pain. Notably, achieving efficacious pain relief relies on correct patient selection and the optimal placement of the leads, ensuring, in particular, a lead depth of 10-12 mm from the surface to maximize the target sensation (mediated by fast-adapting Aβ fibers) of PNFS, which is believed to be most effective for the pain relief.

Deep Brain Stimulation in Neurological and Psychiatric Disorders.

Deep brain stimulation (DBS) is the chronic electrical stimulation of selected target sites in the brain through stereotactically implanted electrodes. More than 150 000 patients around the world have been treated to date with DBS for medically intractable conditions. The indications for DBS include movement disorders, epilepsy, and some types of mental illness. This review is based on relevant publications retrieved by a selective search in PubMed and the Cochrane Library, and on the current guidelines of the German Neurological Society (Deutsche Gesellschaft für Neurologie, DGN). DBS is usually performed to treat neurological diseases, most often movement disorders and, in particular, Parkinson's disease. Multiple randomized controlled trials (RCTs) have shown that DBS improves tremor, dyskinesia, and quality of life in patients with Parkinson's disease by 25% to 50%, depending on the rating scales used. DBS for tremor usually involves stimulation in the cerebello-thalamo-cortical regulatory loop. In an RCT of DBS for the treatment of primary generalized dystonia, the patients who underwent DBS experienced a 39.3% improvement of dystonia, compared to only 4.9% in the control group. Two multicenter trials of DBS for depression were terminated early because of a lack of efficacy. DBS is an established treatment for various neurological and psychiatric diseases. It has been incorporated in the DGN guidelines and is now considered a standard treatment for advanced Parkinson's disease. The safety and efficacy of DBS can be expected to improve with the application of new technical developments in electrode geometry and new imaging techniques. Controlled trials would be helpful so that DBS could be extended to further indications, particularly psychiatric ones.

Spinal and Nucleus Caudalis Dorsal Root Entry Zone Lesioning for Chronic Pain: Efficacy and Outcomes

The role for nucleus caudalis (NC) and spinal dorsal root entry zone (DREZ) lesioning in the management of chronic pain emanating from increased electrical activity in the dorsal horn of the spinal cord and brainstem remains largely uncharted. All patients who underwent NC and spinal DREZ lesioning by a single surgeon were identified and follow-up was obtained by telephone questionnaires. Patient demographics, surgical details, outcomes, and complications were critically reviewed for all patients identified. Of 83 patients identified, 53 (63.9%) were male. Indications for NC DREZ lesioning included trigeminal neuropathic pain (6), trigeminal deafferentation pain (3), glossopharyngeal or occipital neuralgia (3), post-herpetic neuralgia (3), and trauma (1); for spinal DREZ lesioning, indications included brachial plexus avulsion (20), post-herpetic neuralgia (19), spinal cord injury (11), phantom limb pain (8), pelvic pain (5), and complex regional pain syndrome (4). Pain relief was most significant among patients with trigeminal pain, traumatic brachial plexus avulsion injuries, spinal cord injury, and traumatic phantom limb pain. Mean pain reduction averaged 58.3% at a mean follow-up of 8.3 years. Complications included 3 cases of paresis, 3 cases of neuropathy/radiculopathy, 2 cases of ataxia, 3 general medical conditions (colitis, 2; atelectasis, 1), and 2 cases of persistent incisional site pain. Pain relief lasted an average of 4.3 years. Spinal and NC DREZ lesioning can provide effective relief in well-selected patients with intractable chronic pain conditions arising from trigeminal pain, spinal cord injury, brachial plexus avulsions, post-herpetic neuralgia, and phantom limb pain.

Targeting the body to protect the brain: inducing neuroprotection with remotely-applied near infrared light

The incidence of intractable age-related neurodegenerative conditions such as Alzheimer's and Parkinson's diseases and age-related macular degeneration is projected to increase substantially over the coming decades with the ageing of the global population. While the burden of disease associated with other chronic conditions has decreased in recent times due to improved diagnosis and treatment, current therapies for neurodegenerative diseases still fall short in that they are only effective in treating signs and symptoms – they do little to slow or prevent disease progress. Thus, there is an urgent need for treatments that address disease progression.

Dendritic spine dysgenesis in neuropathic pain.

The failure of neuropathic pain to abate even years after trauma suggests that adverse changes to synaptic function must exist in a chronic pathological state in nociceptive pathways. The chronicity of neuropathic pain therefore underscores the importance of understanding the contribution of dendritic spines--micron-sized postsynaptic structures that represent modifiable sites of synaptic contact. Historically, dendritic spines have been of great interest to the learning and memory field. More recent evidence points to the exciting implication that abnormal dendritic spine structure following disease or injury may represent a "molecular memory" for maintaining chronic pain. Dendritic spine dysgenesis in dorsal horn neurons contributes to nociceptive hyperexcitability associated with neuropathic pain, as demonstrated in multiple pain models, i.e., spinal cord injury, peripheral nerve injury, diabetic neuropathy, and thermal burn injury. Because of the relationship between dendritic spine structure and neuronal function, a thorough investigation of dendritic spine behavior in the spinal cord is a unique opportunity to better understand the mechanisms of sensory dysfunction after injury or disease. At a conceptual level, a spinal memory mechanism that engages dendritic spine remodeling would also contribute to a broad range of intractable neurological conditions. Molecules involved in regulating dendritic spine plasticity may offer novel targets for the development of effective and durable therapies for neurological disease.