DOCSLIB.ORG

Epilepsy and the Immune System

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Epilepsy and the Immune System NEUROLOGICAL REVIEW Epilepsy and the Immune System Johan A. Aarli, MD Objective: To discuss evidence that immune mecha- data to prove that immune mechanisms are involved in nisms are involved in the pathogenesis of some forms of the pathogenesis of intractable childhood epilepsies other epilepsy. than Rasmussen encephalitis. Epilepsy is more com- mon in patients with systemic lupus erythematosus who Data Sources: Computerized data sources and pub- have antiphospholipid antibodies, and it is possible that lished indexes and articles. these antibodies can lead to immune-mediated cortical damage. Immune defects in patients with epilepsy may Study Selection: Published reports showing disor- occur as a consequence of long-term antiepileptic treat- ders of the immune system in patients with epilepsy and ment or may represent a genetic coupling to the convul- in animals with experimental epilepsy. sive disorder. Data Synthesis: Rasmussen encephalitis is an ex- Conclusion: The finding of an immunological basis may ample of an autoimmune disorder of the central ner- offer new modalities for the treatment of selected cases vous system. Serum samples of patients with this dis- of intractable partial epilepsies. ease contain antibodies to the glutamate receptor GluR3, and immunization of animals with GluR3 induces a dis- order resembling the human disease. There are still few Arch Neurol. 2000;57:1689-1692 HE FINDING of immune sys- Rogers and coworkers3 demonstrated in tem activation in patients 1994 that immunization of rabbits with the with a seizure disorder has glutamate receptor GluR3 produces a con- lead to the suggestion that dition resembling Rasmussen encephali- immune mechanisms may tis. They also showed that serum samples play a role in the pathogenesis of some of patients with this disease indeed con- T 1 forms of epilepsy. For a long time, such tain antibodies to GluR3 and postulated theories lacked an experimental basis. The that Rasmussen encephalitis is an auto- results of recent studies, especially in pa- immune disorder.3 tients with Rasmussen encephalitis, have To establish that a disease has an au- given new information about the pos- toimmune etiology, Witebsky postulates sible relation between epileptic disorders require that an autoimmune response be and the immune system. recognized in the form of an autoanti- body or cell-mediated immunity, that the RASMUSSEN ENCEPHALITIS—AN corresponding antigen be identified, and AUTOIMMUNE DISORDER? that an analogous autoimmune response be induced in experimental animals. Fi- The clinical setting in Rasmussen encepha- nally, the immunized animals must de- litis is an apparently healthy child or young velop a similar disease.4 adult developing focal seizures that ini- The most straightforward evidence tially appear to be benign, but that gradu- for an autoimmune etiology of a disease ally develop into epilepsia partialis con- is to reproduce it in a normal recipient tinua with hemiparesis and mental by direct transfer of autoantibodies or From the Department retardation. A neuropathological exami- sensitized cells. This is seen as nature’s of Neurology, University nation reveals the typical picture of en- own experiment in neonatal myasthenia of Bergen, Haukeland Hospital, cephalitis with perivascular lymphocyte gravis, where placental transfer of mater- Bergen, Norway. cuffs and scattered microglial nodules.2 nal IgG anti–acetylcholine receptor anti- (REPRINTED) ARCH NEUROL / VOL 57, DEC 2000 WWW.ARCHNEUROL.COM 1689 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 bodies produces muscular weakness in the newborn. effect. Surprisingly, intraventricular infusion of inter- However, the blood-brain barrier represents an impedi- feron alfa reduced the seizure frequency dramatically in ment for antibodies to reach target antigens in the cen- a child with intractable Rasmussen encephalitis.11 This, tral nervous system. Opportunities for direct transfer of however, may relate to the demonstration that GluR3 an- autoimmune central nervous system disease are, there- tibodies exhibit greater immunoreactivity toward the fore, limited. interferon alfa receptor than toward GluR3.12 The classic strategy for documenting an autoim- These new data on Rasmussen encephalitis confirm mune etiology has been to identify and isolate the of- that immune factors may be central in the pathogenesis fending antigen and reproduce the essential features of of an epileptic disorder and may lead to an increased un- the disease by experimental immunization. This has been derstanding of the basis of other seizure disorders with im- accomplished with Rasmussen encephalitis. In raising an- munological concomitants. tibodies to glutamate receptors, Rogers et al3 demon- strated that 2 animals immunized with GluR3 devel- EPILEPSY IN PATIENTS WITH SYSTEMIC oped behavior typical of seizures and histopathological LUPUS ERYTHEMATOSUS (SLE) features mimicking Rasmussen encephalitis. This obser- vation has since been confirmed in other species.5,6 Between 10% and 20% of patients with SLE develop epi- Additional support that the autoantibodies are patho- leptic seizures at some stage of their disease. This is genic comes from the demonstration that IgG from rab- nearly 8 times the prevalence of epilepsy in the general bit antiserum to GluR3 binds to and activates a subpopu- population; epilepsy is, therefore, much more common lation of fetal murine cortical neurons in culture and that in patients with SLE than would be expected. Between this binding could be blocked by a competitive antago- 5% and 10% have onset of seizures several years before nist, CNQX.7 the clinical onset of SLE.13-15 This may mean that long- The experimental disease in these animals mirrors term treatment with antiepileptic drugs may precipitate several features of the human disease, such as the epi- SLE, or that epilepsy and SLE occur together as manifes- leptic seizures, the histopathological findings, and the se- tations of a genetically determined predisposition. lectivity of the immune response to GluR3. It differs, how- According to Mackworth-Young and Hughes,14 epilepsy ever, from Rasmussen encephalitis in humans in that the developing in patients before the other manifestations of latter is unilateral while the experimental disease in- SLE differs from that developing after the other manifes- volves both hemispheres. tations of SLE. Epileptic seizures occurring before the The neuronal cell death observed in vitro appears onset of other manifestations of SLE were more often not to be caused by excitotoxicity. IgG antibodies to GluR3 primary generalized, but seizures that occurred after the isolated from immunized animals (both ill and healthy) clinical onset of SLE were either focal or generalized- promote death of cultured cortical cells by a complement- tonic.14 dependent mechanism. IgG and complement factors of Seizures may occur in patients with SLE based on the membrane attack complex were found on neurons immune-mediated neuronal damage, because of throm- and their processes in the cortex of brains from patients botic events in cortical blood vessels, or they may be with Rasmussen encephalitis. Antibodies seem, there- secondary to hypertensive encephalopathy or renal fail- fore, to gain access to the central nervous system and trig- ure. Antibodies to transmitter receptors such as GluR3 ger complement-mediated neuronal damage. This pro- have never been convincingly demonstrated in patients cess may be of special importance in the initial, active with SLE. Epilepsy in patients with SLE is significantly phase of the disease.8,9 Genetic and species differences associated with antiphospholipid antibodies (aPLs).16 may exist, as Levite et al5 recently reported that murine Chapman et al17 reported recently that purified IgG GluR3 antibodies can mimic excess glutamate effect and containing aPLs depolarized synaptoneurosomes from induce neuronal death via activation of the receptor ion rat brainstem and suggested this as an additional channel, apparently independent of complement. mechanism in nonthromboembolic central nervous There is additional circumstantial evidence that au- system manifestations. toimmune mechanisms operate in Rasmussen encepha- Patients with aPLs are at risk of thromboembolic litis. Li et al10 have demonstrated restricted T-lymph- manifestations, intrauterine fetal loss, and thrombocy- ocyte populations in the brains of patients with Rasmussen topenia (antiphospholipid syndrome). Such antibodies encephalitis. Removal of antibodies by plasma ex- are commonly found in serum samples of patients with change transiently reduces the seizure frequency and im- SLE and are generally heterogeneous, and the different proves the neurologic function as the serum concentra- specificities may play causal roles in different clinical mani- 3 18,19 b tions of GluR3 antibodies decrease. As antibodies to festations. For example, anti– 2-glycoprotein I anti- GluR3 are found in serum samples from immunized ani- bodies may have a direct pathogenic role in thrombosis. b mals without apparent disease, a focal or a general dis- They recognize a 2-glycoprotein I structure on cellular ruption of the blood-brain barrier is essential for serum structures and are also significantly elevated in patients antibodies to reach the brain.1 with epilepsy.20,21 IgG antibodies to cardiolipin have been The finding of an immunological background for an found in 30% to 60% of unselected patients
Load more

Recommended publications
  • Inhibition of P38 MAPK Regulates Epileptic Severity by Decreasing Expression Levels of A1R and ENT1
    5348 MOLECULAR MEDICINE REPORTS 22: 5348-5357, 2020 Inhibition of p38 MAPK regulates epileptic severity by decreasing expression levels of A1R and ENT1 XUEJIAO ZHOU1*, QIAN CHEN1*, HAO HUANG1, JUN ZHANG1, JING WANG2, YA CHEN1, YAN PENG1, HAIQING ZHANG1, JUNWEI ZENG3, ZHANHUI FENG4 and ZUCAI XU1 Departments of 1Neurology and 2Prevention and Health Care, Affiliated Hospital of Zunyi Medical University; 3Department of Physiology, Zunyi Medical University, Zunyi, Guizhou 563003; 4Department of Neurology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China Received January 15, 2020; Accepted September 8, 2020 DOI: 10.3892/mmr.2020.11614 Abstract. Epilepsy is a chronic nervous system disease. of epilepsy. Status epilepticus (SE) is a state in which failure Excessive increase of the excitatory neurotransmitter glutamate of the epileptic termination mechanism or an abnormality in the body results in an imbalance of neurotransmitters and of the epileptic initiation mechanism leads to long-term excessive excitation of neurons, leading to epileptic seizures. epileptic seizures and requires emergency administration Long-term recurrent seizures lead to behavior and cognitive of antiepileptic drugs (2). Failure to terminate SE over time changes, and even increase the risk of death by 2- to 3-fold results in neuronal damage and death, and neural network relative to the general population. Adenosine A1 receptor changes (3). Pilocarpine injection can result in SE, which (A1R), a member of the adenosine system, has notable anti- triggers a series of molecular and cellular events that produce convulsant effects, and adenosine levels are controlled by the neuronal cell death and can culminate in the development of type 1 equilibrative nucleoside transporter (ENT1); in addition epilepsy (4,5).
    [Show full text]
  • The Emerging Clinical Potential of Circulating Extracellular Vesicles for Non-Invasive Glioma Diagnosis and Disease Monitoring
    Brain Tumor Pathology (2019) 36:29–39 https://doi.org/10.1007/s10014-019-00335-0 REVIEW ARTICLE The emerging clinical potential of circulating extracellular vesicles for non-invasive glioma diagnosis and disease monitoring Susannah Hallal1,2 · Saeideh Ebrahimkhani2,5 · Brindha Shivalingam3 · Manuel B. Graeber4 · Kimberley L. Kaufman1,2,3 · Michael E. Buckland1,2,5 Received: 9 February 2019 / Accepted: 27 February 2019 / Published online: 11 March 2019 © The Japan Society of Brain Tumor Pathology 2019 Abstract Diffuse gliomas (grades II–IV) are amongst the most frequent and devastating primary brain tumours of adults. Currently, patients are monitored by clinical examination and radiographic imaging, which can be challenging to interpret and insensi- tive to early signs of treatment failure and tumour relapse. While brain biopsy and histologic analysis can evaluate disease progression, serial biopsies are invasive and impractical given the cumulative surgical risk, and may not capture the complete molecular landscape of an evolving tumour. The availability of a minimally invasive ‘liquid biopsy’ that could assess tumour activity and molecular phenotype in situ has the potential to greatly enhance patient care. Circulating extracellular vesicles (EVs) hold significant promise as robust disease-specific biomarkers accessible in the blood of patients with glioblastoma and other diffuse gliomas. EVs are membrane-bound nanoparticles shed from most if not all cells of the body, and carry DNA, RNA, protein, and lipids that reflect the identity and molecular state of their cell-of-origin. EVs can cross the blood– brain barrier and their release is upregulated in neoplasia. In this review, we describe the current knowledge of EV biology, the role of EVs in glioma biology and the current experience and challenges in profiling glioma-EVs from the circulation.
    [Show full text]
  • Global Research Priorities for Infections That Affect the Nervous System
    nature.com/brain-disorders REVIEW OPEN Global research priorities for infections that affect the nervous system Chandy C. John1, Hélène Carabin2, Silvia M. Montano3, Paul Bangirana4, Joseph R. Zunt5 & Phillip K. Peterson6 Infections that cause significant nervous system morbidity globally include viral (for example, HIV, rabies, Japanese encephalitis virus, herpes simplex virus, varicella zoster virus, cytomegalovirus, dengue virus and chikungunya virus), bacterial (for example, tuberculosis, syphilis, bacterial meningitis and sepsis), fungal (for example, cryptococcal meningitis) and parasitic (for example, malaria, neurocysticercosis, neuroschistosomiasis and soil-transmitted helminths) infections. The neurological, cognitive, behav- ioural or mental health problems caused by the infections probably affect millions of children and adults in low- and middle-in- come countries. However, precise estimates of morbidity are lacking for most infections, and there is limited information on the pathogenesis of nervous system injury in these infections. Key research priorities for infection-related nervous system morbidity include accurate estimates of disease burden; point-of-care assays for infection diagnosis; improved tools for the assessment of neurological, cognitive and mental health impairment; vaccines and other interventions for preventing infections; improved understanding of the pathogenesis of nervous system disease in these infections; more effective methods to treat and prevent nervous system sequelae; operations research to implement known effective interventions; and improved methods of rehabili- tation. Research in these areas, accompanied by efforts to implement promising technologies and therapies, could substantially decrease the morbidity and mortality of infections affecting the nervous system in low- and middle-income countries. Nature 527, S178-S186 (19 November 2015), DOI: 10.1038/nature16033 This article has not been written or reviewed by Nature editors.
    [Show full text]
  • 7 Neurodegenerative Disorders
    1 7 NEURODEGENERATIVE DISORDERS 2 3 A number of studies have examined associations between exposure to electromagnetic fields and 4 Alzheimer‘s disease, motor neuron disease and Parkinsons‘s disease. These diseases may be classed as 5 neurodegenerative diseases as all involve the death of specific neurons. Although their aetiology seems different 6 (Savitz et al 1998 a,b), a part of the pathogenic mechanisms may be common. Most investigators examine these 7 diseases separately. In relation to electromagnetic fields, amyotrophic lateral sclerosis (ALS) has been studied 8 most often. 9 10 Radical stress, caused by the production of reactive oxygen species (ROS) and other radical species 11 such as reactive nitrogen species (RNS), is thought to be a critical factor in the modest neuronal degeneration 12 that occurs with ageing. It also seems important in the aetiology of Parkinson's disease and ALS and may play a 13 part in Alzheimer's disease (Felician and Sanderson, 1999). Superoxide radicals, hydrogen peroxide (H2O2) and 14 hydroxyl radicals are oxygen-centered reactive species (Coyle and Puttfarcken, 1993) that have been implicated 15 in several neurotoxic disorders (Liu et al., 1994). They are produced by many normal biochemical reactions, but 16 their concentrations are kept in a harmless range by potent protective mechanisms (Makar et al., 1994). 17 Increased free radical concentrations, resulting from either increased production or decreased detoxification, can 18 cause oxidative damage to various cellular components, particularly mitochondria, ultimately leading to cell 19 death by apoptosis (Bogdanov et al., 1998). 20 21 Several experimental investigations have examined the effect of ELF electromagnetic fields on calcium 22 exchange in nervous tissue and other direct effects on nerve tissue function.
    [Show full text]
  • The Role of Microglia and Macrophages in Glioma Maintenance and Progression
    REVIEW The role of microglia and macrophages in glioma maintenance and progression Dolores Hambardzumyan1, David H Gutmann2 & Helmut Kettenmann3 There is a growing recognition that gliomas are complex tumors composed of neoplastic and non-neoplastic cells, which each individually contribute to cancer formation, progression and response to treatment. The majority of the non-neoplastic cells are tumor-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, that create a supportive stroma for neoplastic cell expansion and invasion. TAMs are recruited to the glioma environment, have immune functions, and can release a wide array of growth factors and cytokines in response to those factors produced by cancer cells. In this manner, TAMs facilitate tumor proliferation, survival and migration. Through such iterative interactions, a unique tumor ecosystem is established, which offers new opportunities for therapeutic targeting. Solid cancers develop in complex tissue environments that dramati- monocytes7. Similar studies have also suggested that increases in cally influence tumor growth, transformation and metastasis. In the microglia density in response to CNS damage involve both the expan- microenvironment of most solid tumors are various non-neoplastic sion of endogenous resident microglia and the active recruitment cell types, including fibroblasts, immune system cells and endothelial of BM-derived microglial progenitors from the bloodstream8–12. cells. Each of these stromal cell types produce growth and survival Leveraging analogous methods, other reports demonstrated little factors, chemokines, extracellular matrix constituents, and angiogenic or no contribution of circulating progenitors to the brain microglia molecules with the capacity to change the local milieu in which neo- pool. These studies argued that the expansion of microglia during plastic cells grow and infiltrate.
    [Show full text]
  • Journal of Central Nervous System Disease a Review Of
    Journal of Central Nervous System Disease OPEN ACCESS Full open access to this and thousands of other papers at EXPERT REVIEW http://www.la-press.com. A Review of Eslicarbazepine Acetate for the Adjunctive Treatment of Partial-Onset Epilepsy Rajinder P. Singh and Jorge J. Asconapé Department of Neurology, Stritch School of Medicine, Loyola University Medical Center, Maywood, Illinois 60153, USA. Corresponding author email: [email protected] Abstract: Eslicarbazepine acetate (ESL) is a novel antiepileptic drug indicated for the treatment of partial-onset seizures. Structurally, it belongs to the dibenzazepine family and is closely related to carbamazepine and oxcarbazepine. Its main mechanism of action is by blocking the voltage-gated sodium channel. ESL is a pro-drug that is rapidly metabolized almost exclusively into S-licarbazepine, the biologically active drug. It has a favorable pharmacokinetic and drug-drug interaction profile. However, it may induce the metabolism of oral contraceptives and should be used with caution in females of child-bearing age. In the pre-marketing placebo-controlled clinical trials ESL has proven effective as adjunctive therapy in adult patients with refractory of partial-onset seizures. Best results were observed on a single daily dose between 800 and 1200 mg. In general, ESL was well tolerated, with most common dose-related side effects including dizziness, somnolence, headache, nausea and vomiting. Hyponatremia has been observed (0.6%–1.3%), but the incidence appears to be lower than with the use of oxcarbazepine. There is very limited information on the use of ESL in children or as monotherapy. Keywords: eslicarbazepine, licarbazepine, dibenzazepine, voltage-gated sodium channel, partial-onset seizures, epilepsy Journal of Central Nervous System Disease 2011:3 179–187 doi: 10.4137/JCNSD.S4888 This article is available from http://www.la-press.com.
    [Show full text]
  • Gene Transfer and Delivery in Central Nervous System Disease
    Neurosurg Focus 3 (3):Article 2, 1997 Gene transfer and delivery in central nervous system disease Gordon Tang, M.D., and E. Antonio Chiocca, M.D., Ph.D. Neurosurgical Service, Massachusetts General Hospital, and Molecular Neuro-Oncology Laboratory, Harvard Medical School, Boston, Massachusetts Gene transfer offers the potential to explore basic physiological processes and to intervene in human disease. The central nervous system (CNS) presents a fertile field in which to develop novel therapeutic modalities to treat intractable and pervasive malignant tumors and neurodegenerative disease. The extension of gene therapy to the CNS, however, faces the delivery obstacles of a target population that is postmitotic and isolated behind a blood-brain barrier (BBB). Approaches to this problem have included grafting of genetically modified cells to deliver novel proteins or introducing genes by viral or synthetic vectors geared toward the CNS cell population. Direct inoculation and bulk flow, as well as osmotic and pharmacological disruption, have been used to circumvent the BBB's exclusionary role. Once the gene is delivered, myriad strategies have been used to affect a therapeutic result. Genes activating prodrugs are the most common antitumor approach. Other approaches focus on activating immune responses, targeting angiogenesis, and influencing apoptosis and tumor suppression. At this time, therapy directed at neurodegenerative diseases has centered on ex vivo gene therapy for supply of trophic factors to promote neuronal survival, axonal outgrowth, and target tissue function. Despite early promise, gene therapy for CNS disorders will require advancements in methods for delivery and long-term expression before becoming feasible for human disease. Key Words * gene therapy * brain tumor * blood-brain barrier * neurodegenerative disorder Gene transfer offers a powerful and unique approach to the study and treatment of human disease.
    [Show full text]
  • Familial Risks for Main Neurological Diseases in Siblings Based on Hospitalizations in Sweden
    Familial Risks for Main Neurological Diseases in Siblings Based on Hospitalizations in Sweden Kari Hemminki,1,2 Kristina Sundquist,2 and Xinjun Li2 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 2 Center for Family Medicine, Karolinska Institute, Huddinge, Sweden ecent successes in identifying the underlying disease mechanisms have been discovered, including Rgenetic mechanisms for neurological diseases, DNA repeat expansions in coding and noncoding particularly for their Mendelian forms, have had pro- sequences, now found in over 40 neurological dis- found implications for their diagnostics, treatment eases (Gatchel & Zoghbi, 2005). Other achievements and classification. However, there has never been include molecular and pathophysiological characteri- an attempt to compare familial risks in a systematic zation of severe diseases such as Huntington’s chorea, way among and between the main neurological dis- hereditary ataxias, muscular dystrophies and eases. Familial risks were here defined for siblings myotonic disorders, all with a main heritable etiology who were hospitalized because of a neurological (Bertram & Tanzi, 2005; Dalkilic & Kunkel, 2003; disease in Sweden. A nationwide database for neu- Day & Ranum, 2005; Muntoni & Voit, 2004; rological diseases was constructed by linking the Ropper & Brown, 2005; Taroni & DiDonato, 2004). Multigeneration Register of 0- to 69-year-old siblings In the major neurological diseases including to the Hospital Discharge Register for the years Alzheimer’s disease, Parkinson’s disease, epilepsy and 1987 to 2001. Standardized risk ratios were calcu- migraine, some heritable subtypes have been noted, lated for affected sibling pairs by comparing them to but these explain only a small proportion of the etiol- those whose siblings had no neurological disease.
    [Show full text]
  • Mumps Meningoencephai'tis a Clinical Review of 119 Cases with One Death HENRY B
    Mumps Meningoencephai'tis A Clinical Review of 119 Cases with One Death HENRY B. BRUYN, M.D., HAROLD M. SEXTON. M.D., and HENRY D. BRAINERD, M.D., San Francisco MUMPS IS A generalized, systemic, virus infection in * Mumps is one of the most common viruses to which the salivary glands are commonly affected and affect the central nervous system and should be given primary consideration in the differential in which inflammation of the central nervous system diagnosis of aseptic meningitis. Many cases of occurs with such frequency that it can hardly be mumps infection do not involve the salivary considered a complication. In fact, the virus of glands. mumps could be said to be one of the most common The course of mumps meningoencephalitis is viral agents to affect the central nervous system. De- usually benign, with fever and signs of menin- geal irritation lasting less than five days. The spite the extensive literature attesting these facts, findings in the cerebrospinal fluid are usually there still exists the widespread impression that distinctive, with leukocyte content greater than mumps meningoencephalitis is a rare complication. 200 per milliliter, of which 80 per cent or more Hamilton10 in 1790 presented one of the first for- are lymphocytes. Sequelae, even of a minor na- ture, are rare. mal reports of "A Distemper, By the Common Peo- Death is extremely rare in recorded literature. ple in England Vulgarly Called the Mumps." In this A fatal case of mumps meningoencephalitis is very carefully written report he described the usual described herein. course of this disease and stressed the frequency of central nervous system involvement.
    [Show full text]
  • Biological Mechanisms of Brain Disorders Syllabus Credits: 3
    5/29/2019 NEUR 301/401: Biological Mechanisms of Brain Disorders Syllabus Credits: 3 Course Director: David M. Katz, PhD, Departments of Neurosciences & Psychiatry, School of Medicine Weekly schedule: 3 class meetings per week (MWF), 50 minutes each Course Description: This course is designed to introduce students to a broad range of neurological and neuropsychiatric diseases and disorders in order to understand how genetic and environmental perturbations can disrupt normal brain function. The primary focus will be on understanding the biological bases of nervous system dysfunction. For each disease discussed, the subject matter will be organized to explain how normal brain function is impacted, the biological mechanisms underlying dysfunction (including still-unanswered questions) and current efforts to develop effective treatments (translational research). With this approach, students will gain an understanding of disease presentation, how animal models and human studies are being used to elucidate pathophysiological mechanisms, and opportunities and challenges in the development of new therapies. The class format will be a mix of lecture-based sessions and discussions of scientific journal articles. Learning Objectives: After participating in this course, students should be able to: 1. Explain the biological mechanisms underlying a broad range of brain disorders 2. Critically analyze and interpret preclinical studies of human disease reported in the scientific literature 3. Illustrate the utility and limitations of animal models for
    [Show full text]
  • Two Ends of One Spectrum
    Review Article Annals of Pharmacology and Pharmaceutics Published: 13 Nov, 2017 Dopamine based Pharmaco-therapeutics of Schizophrenia and Parkinson’s Disease: Two Ends of One Spectrum Ashish Kumar Gupta1, Surabhi Swarnkar1, Gaurav Khunger Kumar1, Vinay Goyal2, Rakesh Kumar Chadda3 and Gururao Hariprasad1* 1Departments of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, India 2Department of Neurology, All India Institute of Medical Sciences, Ansari Nagar, India 3Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, India Abstract Schizophrenia and Parkinsons’s disease are two neuro-pathological end points of dopaminergic spectrum in the mid brain. While the symptoms of Parkinson’s disease results from the death of dopaminergic cells in substantia nigra, the psychotic symptoms of schizophrenia are related to dopaminergic hyperactivity in the striatum. Pharmacological intervention therefore involves normalizing the dopamine concentrations, wherein dopaminergic drugs are used to treat patients with Parkinson’s disease, dopamine antagonists are used to treat patients with schizophrenia. These pharmacological interventions in either of the two disease states, results in over shooting the optimum dopamine levels, therapy resulting in drug induced extra-pyramidal symptoms in schizophrenia and hallucinations in Parkinson’s disease. This review summarizes the side effects observed using dopamine modulating pharmaceuticals, and brings to light the clinical scenario of drug induced disease state at both ends of dopamine spectrum, that poses a challenge to patients and clinicians. Keywords: Schizophrenia; Parkinson’s disease; Dopamine; Adverse side effects; Treatment monitoring OPEN ACCESS Introduction *Correspondence: Parkinson's disease is a degenerative disorder of the central nervous system and schizophrenia Gururao Hariprasad, Departments of is a mental disorder characterized by a breakdown of thought processes with deficit of emotional Biophysics, All India Institute of Medical responses.
    [Show full text]
  • Adenovirus-Associated Central Nervous System Disease in Children
    ARTICLE IN PRESS THE JOURNAL OF PEDIATRICS • www.jpeds.com ORIGINAL ARTICLES Adenovirus-Associated Central Nervous System Disease in Children Kevin L. Schwartz, MD, MSc1,2, Susan E. Richardson,MD3, Daune MacGregor,MD4,5, Sanjay Mahant, MD, MSc4,6, Kamini Raghuram,MD4,6, and Ari Bitnun, MD, MSc4,7 Objective To characterize the spectrum and salient clinical features of adenovirus-associated neurologic disease in immunocompetent children. Study design Previously healthy children (aged 1 month-18 years) with central nervous system (CNS) disease associated with adenovirus infection were identified via the Encephalitis Registry (1996-2016) and Microbiology Database (2000-2016) at The Hospital for Sick Children, Toronto, and by systematic review of the literature. The data were pooled and analyzed to identify the spectrum of illness, clinical outcome, and risk factors for death or neurologic impairment. Results Neurologic complications associated with adenovirus infection in our institution included febrile sei- zures, encephalitis, acute disseminated encephalomyelitis, and aseptic meningitis. A total of 48 immunocompe- tent children with adenovirus-associated CNS disease were included in the pooled analysis—38 from the literature and 10 from our institution. In 85% of cases, the virus was detected in the respiratory or gastrointestinal tract, but not the cerebrospinal fluid. Eighteen of the 48 (38%) patients either died or suffered permanent neurologic se- quelae. Predictors of adverse outcome included younger age, coagulopathy, the absence of meningismus, sero- type 2 virus, and the presence of seizures. After multivariable adjustment, only seizures remained a significant risk factor. Conclusion Adenovirus is a rare cause of CNS disease in immunocompetent children. Disease spectrum is vari- able, ranging from mild aspetic meningitis and fully reversible encephalopathy to severe, potentially fatal, acute necrotizing encephalopathy.
    [Show full text]