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CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Conference Proceedings

Conference Report: 9th International Summer School of Neurology

Author(s): Stephen D. Skaper

Volume 13, Issue 7, 2014

Page: [1121 - 1124] Pages: 4

DOI: 10.2174/187152731307141015103424


The International Summer School of Neurology provides a forum for a selected group of medical students and postgraduates specializing in neurology to interact with an internationally recognized faculty in the neurological sciences. Credit for having the vision to create the School goes to its founders and program coordinators, Dafin F. Mureşanu (Professor of Neurology and Chairman of the Department of Clinical Neurosciences, University of Medicine and Pharmacy "IuIiu Haţieganu", Cluj-Napoca, Romania) and Natan M. Bornstein (Professor of Neurology, Tel-Aviv University Sackler School of Medicine, Israel). This year’s edition of the School, its ninth, continued the tradition of integrating classes covering the latest developments in the neurological sciences with a tranquil setting on the shores of the Black Sea. Long-term support from academic organizations such as The Society for the Study of Neuroprotection and Neuroplasticity, Tel Aviv University, Uppsala Universitet, the Romanian Society of Neurology and World Federation for NeuroRehabilitation (among others) has been an important factor in sustaining the School over the years. This year’s program began on Sunday afternoon (July 6) with a series of basic research talks on advances in brain protection and recovery, including nanowired drug delivery for the treatment of traumatic and concussive brain injuries, the peripheral nerve microenvironment in chronic pain, and practical pharmacology in neurorehabilitation. It is of paramount important that physicians have a grasp of the basic science underlying clinical medicine. The first full day of the course, Monday July 7, was divided into morning and afternoon sessions covering the topics of neurorehabilitation and peripheral neuropathies, repectively. The high prevalence of back pain and its bearing on an individual’s quality of life, together with associated health care costs is a matter of common knowledge. The two principal factors in treatment of lower back pain are: to operate or not and how to alleviate pain. An interdisciplinary approach is recommended, which encompasses both morphological and functional findings. A clear diagnosis is of paramount importance in protecting the patient from unnecessary surgery and the fear of failed back surgery. Symptoms of peripheral neuropathy are common neurologic complaints. Peripheral neuropathy has an overall prevalence of 2 - 3% in the general population, which can reach 8% or more in those over 55 years of age. Understanding the cause(s) of peripheral neuropathy is important, as it may inform on treatment to prevent progression to disability and poor quality of life. Diabetic neuropathy is perhaps the most common peripheral neuropathy. A key clinical issue in the management of diabetic neuropathy is pain. Treatment options available for diabetic neuropathy should target both metabolic and vascular disturbances along with the clinical manifestations such as neuropathic pain and dysautonomic manifestations, and the role of advanced glycation end-products (AGEs), whose accumulation may be exacerbated by hyperglycemia. Non-steroidal anti-inflammatory drugs remain in the frontline of analgesic drugs prescribed for nociceptive pain, which is surprising given that clinical and experimental evidence shows that neuropathic pain syndromes in general respond poorly to the former or opioid analgesics. Thiamine (vitamin B1) is efficacious as an adjuvant medicine to treat neuropathic disorders, with its lipid-soluble form (benfotiamine) having much higher bioavailability compared to thiamine. At the preclinical level benfotiamine demonstrated lower toxicity in comparison to water-soluble vitamin B1. In clinical studies, benfotiamine restored nerve function in diabetic neuropathy, improved nerve conduction velocity, prevented diabetic retinal damage and halted the development of diabetic nephropathy without affecting blood glucose levels. It is believed that benfotiamine prevents progression of diabetic complications by increasing tissue levels of thiamine diphosphate. The resulted enhancement of transketolase activity can direct precursors of AGEs to the pentose phosphate pathway, thereby reducing tissue levels of AGEs. In addition, Alpha-lipoic acid, a water- and fat-soluble cell-penetrant antioxidant which scavenges mitochondrial reactive oxygen species blocks alternative pathways of glucose metabolism. Because beneficial effects of alpha-lipoic acid can be achieved at low micromolar concentrations, one cannot exclude that its therapeutic benefits are independent of its antioxidant status. This module concluded in the evening with a basic course in neurologic clinical examination. The course’s second day (July 8) focused on stroke. Lectures included a presentation on the updated and new recommendations of the 2014 American Stroke Guidelines, secondary stroke prevention, and advances in brain protection and recovery in acute and long-term stroke treatment. Patients with transient ischemic attacks (TIA) have a 43% chance of stroke within the next 7 days. In terms of early TIA management, there is an 80% risk reduction at 3 months when the patient is seen within the first 24 hours. In patients with TIA or ischemic stroke of non-cardiac origin anti-platelet drugs decrease stroke riskby 11-15%, myocardial ischemia and vascular death by 15-22%. Aspirin is the most widely used drug, given its affordability and effectiveness. Aspirin in combination with slow release dipyridamole surpasses aspirin alone in preventing stroke, with a 20-24% relative risk reduction of stroke and death. Clopidgrel (Plavix) is superior to aspirin (around 8.7%) in patients at high risk of recurrence. Dual anti-platelet therapy (aspirin + plavix) is not more effective than plavix alone for long-term secondary stroke prevention and has a higher risk of bleeding. These antiplatelet agents do not significantly reduce mortality. This was followed by highly informative lecture on atrial fibrillation (AF) and stroke prevention. Twenty to twenty-five percent of ischemic strokes are cardioembolic. Atrial fibrillation (AF), the most frequently found arrhythmia occurs in 0.4 – 0.7% of the general population. Its prevalence rises to approximately 6% in those over 65 years of age, and up to 10% in individuals older than 75 years. AF related-stroke accounts for something like 45% of all cardioembolic strokes. AF is a well-established independent risk factor for stroke, increasing the risk of stroke 5.6-fold. AF patients without antithrombotic treatment have a 12% risk per year of recurrent stroke. Non-anticoagulated AF patients run a 35% risk of an ischemic stroke occurring during their lifetime. Indeed, underuse of warfarin is greatest in elderly patients who are at the highest risk of stroke. Class I evidence tells us that adjusted-dose warfarin reduces stroke risk in AF patients by ~70% but aspirin by only 20%. A target INR of 2.5 (range 2.0-3.0) is recommended for warfain treatment. The novel anticoagulants (NOACs) dabigatran etexilate, rivaroxaban, apixaban, now approved in a number of countries for stroke prevention in AF are: associated with the same or lower rates of stroke, bleeding (intracranially, in particular) and death compared with warfarin; can be administered in fixed doses without routine coagulation monitoring – in contrast to warfarin. In comparing the effects of NOACs with warfarin, results are consistent in almost all populations and patients subgroups studied. In terms of statistical significance only dabigatran (150 mg/2 times a day) was superior to warfarin. Lack of NOAC antidotes in patients who experience major bleeding has not yet been linked to worse outcome among patients treated with NOACs compared with warfarin in secondary analysis. Multiple guidelines for AF management recommend NOACs for stroke prevention in AF patients at risk for stroke, along with periodic renal function assessment. Identifying the best therapeutic approach for brain protection and recovery in stroke remains difficult. Endogenous neurobiological processes than span neurotrophism, neuroprotection, neuroplasticity and neurogenesis are key to protection and recovery and form the core of endogenous defense activity. The pathological cascades of stroke comprise a limited number of pathophysiological processes: excitotoxicity, oxidative stress, inflammation and apoptotic-like processes. Identification of therapeutic modalities to limit brain damage and enhance recovery of motor function through neuroprotective and neurorestorative mechanisms, even with delayed initiation, is a critical goal. We may define neurorecovery as: positive outcome to yield clinically relevant results with both early functional and later structural effects; linked to adaptative plasticity of undamaged nervous tissue; depends on the non-affected elements of a functional network. The initial size and location of injury are key factors in determining the extent of brain recovery. Neurotrophic factors, produced by distinct brain cell types act in a pleotropic way against pathological cascades. The same molecules initially induce a endogenous neuroprotective effect, followed by neuroplasticity and neurogenesis actions, as well. One can thus say that they confer multimodal pleotropic activity. Neuroprotection, neuroplasticity and neurogenesis, although apparently independent, are actually sequences of the same endogenous defense activity, regulated by endogenous molecules. Today’s research continues to view drug activity in terms of single mechanisms and focus, which can ‘mask’ one’s vision of paradigms with greater explanatory power - thereby inhibiting development of more effective treatment strategies. From a pharmacological perspective, the best approach to achieve neurorecovery is to focus on molecules that mimic the endogenous molecules with multimodal and pleiotropic neuroprotective effects. Biological agents such as neurotrophic factors, with their modulating and multimodal effects are superior agents for brain protection and recovery, given an inherent pleiotropic neuroprotective effect. In other words, they pharmacologically ‘span’ the gap between acute neuroprotective processes and long-term recovery processes. As such, a change of concept is in order in terms of pharmacological brain protection and recovery stroke therapy. A fuller comprehension of the mechanisms underlying neuroplasticity will be needed to achieve a more efficient and comprehensive treatment. The presentation concluded by highlighting current and future needs in stroke therapy, including an integrated pharmacological approach which focuses on biological entities having multimodal activity and pleiotropic neuroprotective effects, rather than single mechanism drugs. The next presentation gave an overview on early and late neurorehabilitation in stroke therapy. Rehabilitation is a process through which each disabled person achieves his/her maximum physical, functional, cognitive and psychosocial recovery that are possible within the limits of one’s disability. As mentioned above, endogenous defense activity of the nervous system is acontinuum operating at the levels of neurotrophism, neuroprotection, neuroplasticity and neurogenesis. Neuroregeneration (neurorepair) is the morphological result of interactions between these basic neurobiological processes. Neurorecovery is the outcome that generates clinically relevant results. Restitution is a intrinsic process acting on biochemically and geneticallyinduced events, such as reduction of edema and restoration of axonal transport. Substitution depends on external stimuli that, through learning, drive activity-dependant plasticity. Compensation is intended to improve the mismatch between a patient’s impaired skills and his/her demand on the environment. The take-home message is that all basic biological processes can be activated endogenously or exogenously. This day’s module concluded in the evening with selected case presentations on stroke. The third day of the course (July 9) covered Parkinson disease (PD), the most common neurodegenerative movement disorder. PD is a complex and heterogeneous pathology whose lack of reliable biological markers complicates diagnostic criteria. It is now generally accepted that what we call PD is the result of phenotypic convergence. For example, molecular genetic analysis has been used to identify over 500 distinct DNA variants in five disease genes associated with familial PD. Knowledge dealing with the functions of the genes’ protein products has revealed pathways of neurodegeneration that may have features in common between inherited and sporadic PD. The main primary genetic lesions lead to abnormalities in the ubiquitinproteasome system function, or to mitochondrial respiratory chain abnormalities or to abnormalities in the mitochondrial life cycle. Studies from genetic association indicate that genetic variation in such genes may be susceptibility factors in sporadic PD, the most common form of parkinsonism. Environmental factors may have also an important role in PD etiopathogenesis. Exposure to pesticides may is increase the risk of developing PD. Chronic exposure to neurotoxic chemicals appears associated with epigenetic changes, protein aggregation and autophagy, which are important cellular and molecular correlates of neurodegenerative diseases. Dopaminergic neuron degeneration in PD is widely believed to result from a combination of multiple converging signaling pathways rather than a single unifying mechanism. Since the clinical manifestations of PD can be the result of quite divergent mechanisms, it is unlikely that an intervention can be developed which will is able to influence the disease development in all PD patients. Such disease-modifying therapy should be based not on clinical but rather on understanding the underling pathogenetic processes which differ among cases. Individualized therapy to interrupt, or at least slow, disease progression must be based on elucidation of the metabolic processes. It is becoming increasingly evident that non-motor symptoms (NMS) in PD are important and impact quality-of-life; these may be reported some years before PD is diagnosed. Unfortunately, NMS are not well-recognized in PD patients in the clinic and are often not reported spontaneously by the patient. The spectrum of NMS includes: neuropsychiatric symptoms, sleep disorders, gastrointestinal, sensory symptoms, autonomic dysfunction, sexual dysfunction, as well as fatigue, diplopia, and weight loss. Since the discovery of levodopa as the mainstay of pharmacotherapy in the early 1960s, the pharmacological treatment of PD has been continuously debated and adapted. Several treatment options for switching from intermittent to continuous dopaminergic stimulation (CDS) therapy were discussed. Duodenal infusion of levodopa (LCIG) or apomorphine (a nonselective dopamine agonist) infusions offer significant benefits to counteract the ‘off’ symptomatology and end-of-dose biphasic dyskinesia for selected patients. This can be considered an option prior to surgery (Deep Brain Stimulation). Notable improvements in motor and non-motor functioning can be achieved with CDS therapy, although limitations and unanswered questions remain (such as how early CDS therapies should be initiated). The final day of the course (July 10) began with a presentation by Ioana Ispas, the European Affairs Advisor for Bioethics, Genomics and Health International Cooperation, Department Ministry of National Education, Bucharest, Romania. She discussed European funding opportunities in the neurosciences in relation to Horizon 2020 – the European Union Framework Programme Horizon 2020. In addition, In addition, the rules and procedures for applying for research funding opportunities offered in a coordinated way by Member States through Joint Programming Initiative in the area of neurodegenerative diseases and joint programming initiatives was described. The remainder of the morning was dedicated to multiple sclerosis (MS), including: management of disease symptoms; cognition, fatigue and MS, and their significance and use as broader clinical indicators of treatment success; current treatments and new perspectives for MS therapy. MS is the most common non-traumatic cause of disability in young adults. In addition to the so-called 'classical' immunomodulators, oral disease-modifying therapies (teriflunomide, fingolimod, laquinimod, dimethyl fumarate) have been developed; there is also the possibility of regenerative or reparative therapies. Inflammation and oxidative stress are believed to be key features in the pathophysiology of MS and are associated with damage to the blood-brain barrier, myelin and axons.Cognitive impairment, fatigue, and depression often interact in a complex way in MS. MS-related fatigue is related to disturbances in cognitive function, leading to a perception of impaired overall health, mental state, and quality of life. Assessment of cognition and fatigue can be used as additional measures to evaluate treatment efficacy in the individual patient. For all patients with MS, particularly those developing cognitive issues, it is important to evaluate the depression and to treat accordingly. One of the most disruptive functional impairments in MS relates to mobility, which is influenced by other disese-associated deficits and symptoms. MS patients are most concerned by walking impairments, followed in importance by visual function and thinking/memory. Walking impairment hinders the patient’s ability to perform daily activities, decreases employment prospects and reduces health-related quality of life. As mobility is one of the most important aspects related to MS, the combination of a proper medication, the patients’ active attitude and exercise programs may improve significantly the profile of their disability and therefore quality of life. The students (some 200 in all, representing Romania, Ukraine, Uzbekistan, Vietnam, Russia, Chile, Egypt) received their course certificates of completion during the evening’s farewell dinner.

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