Current Neuropharmacology (v.9, #3)
Editorial [Hot Topic:Autoimmune Neurologic Disorders (Guest Editor: Sasa zivkovic)] by Sasa zivkovic (399-399).
Autoimmune disorders affect 5-10% of the general population,  and often involve central and peripheral nervous system. Inthis special issue of Current Neuropharmacology experts discuss pathophysiology, clinical features and treatment of variousneurologic autoimmune disorders. In the last decade we have witnessed remarkable scientific advances which have greatlyimproved our understanding of pathophysiology of the autoimmune disorders leading to an increasing number of treatmentoptions with many of new therapies already being used in the treatment of neurologic disorders as their role continues to evolve. The first article summarizes pathophysiology, diagnosis and treatment of neuromuscular autoimmune conditions includingGuillain Barre syndrome, myasthenia gravis and polymyositis. This is followed by a comprehensive review of treatment ofmultiple sclerosis by Drs. Loma and Heyman describing standard treatment protocols as well as newly approved treatments.The next article by Drs. Awad and Stuve highlights clinical features and pathophysiology of idiopathic transverse myelitis andneuromyelitis optica which often result in significant disability. Dr. David Lacomis discusses clinical features and treatment ofneurosarcoidosis which may affect central and/or peripheral nervous system, usually in combination with multisystemicdisease. Dr. Maria Cid and her colleagues provide a detailed review of systemic and primary CNS vasculitides and theirpathophysiology and treatment. Neuropsychiatric lupus is often called a great mimicker due to its wide spectrum of clinicalmanifestations, and Drs. Kao and Popescu review its pathophysiology and treatment. Over the last few years, autoimmunechannelopathies have become one of the hot topics of basic and clinical research, and Dr. Kleopa reviews paraneoplastic andnon-paraneoplastic autoimmune channelopathies. The issue concludes with a comprehensive review of toxicities ofimmunosuppressive treatment by Drs. Fadul and Lallana. Authors discuss potential risks of various therapies used in thetreatment of autoimmune neurologic disorders. I would like to thank the authors of this Current Neuropharmacology issue for all their time and effort in preparing their articlesto create a comprehensive and up-to-date collection of articles on the wide spectrum of autoimmune neurologic disorders.
Autoimmune Neuromuscular Disorders by Jessica Kraker, Sasa A. Zivkovic (400-408).
Autoimmune neuromuscular disorders affecting peripheral nerves, neuromuscular junction or muscle have awide clinical spectrum with diverse pathogenetic mechanisms. Peripheral nervous system may be targeted in the contextof complex immune reactions involving different cytokines, antigen-presenting cells, B cells and different types of T cells.Various immunomodulating and cytotoxic treatments block proliferation or activation of immune cells by differentmechanisms attempting to control the response of the immune system and limit target organ injury. Most treatment protocolsfor autoimmune neuromuscular disorders are based on the use of corticosteroids, intravenous immunoglobulins andplasmapheresis, with cytotoxic agents mostly used as steroid-sparing medications. More recently, development of specificmonoclonal antibodies targeting individual cell types allowed a different approach targeting specific immune pathways,but these new treatments are also associated with various adverse effects and their long-term efficacy is still unknown.
Multiple Sclerosis: Pathogenesis and Treatment by Ingrid Loma, Rock Heyman (409-416).
Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervoussystem. It affects approximately 400,000 people in the United States and onset is usually during young adulthood. Thereare four clinical forms of MS, of which relapsing remitting type is the most common. As the etiology of MS is unknown,finding a cure will remain challenging. The main mechanism of injury appears to be inflammation and 8 agents are nowFDA approved to help control MS. These agents for relapsing forms of MS target different parts of the immune system,with the end goal of decreasing and avoiding further inflammation. No agents are FDA approved for the primaryprogressive version of MS. FDA approved agents include four preparations of interferon β (Avonex, Rebif, Betaseron andExtavia), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri) and fingolimod (Gilenya).There are several drug undergoing phase II and III trials. The heterogeneity of the MS disease process, individual patientresponse, and medication toxicities continue to challenge the treating physician.
Idiopathic Transverse Myelitis and Neuromyelitis Optica: Clinical Profiles, Pathophysiology and Therapeutic Choices by Amer Awad, Olaf Stuve (417-428).
Transverse myelitis is a focal inflammatory disorder of the spinal cord which may arise due to differentetiologies. Transverse myelitis may be idiopathic or related/secondary to other diseases including infections, connectivetissue disorders and other autoimmune diseases. It may be also associated with optic neuritis (neuromyelitis optica), whichmay precede transverse myelitis. In this manuscript we review the pathophysiology of different types of transversemyelitis and neuromyelitis optica and discuss diagnostic criteria for idiopathic transverse myelitis and risk of developmentof multiple sclerosis after an episode of transverse myelitis. We also discuss treatment options including corticosteroids,immunosuppressives and monoclonal antibodies, plasma exchange and intravenous immunoglobulins.
Neurosarcoidosis by David Lacomis (429-436).
Neurosarcoidosis is an uncommon but potentially serious manifestation of sarcoidosis. While the cranial nervesare most frequently affected, neurosarcoidosis can involve other nervous system tissues including the meninges, brain parenchyma(especially the hypothalamic region), spinal cord, peripheral nerve, and muscle. Diagnosis may be particularlychallenging when neurosarcoidosis occurs in isolation. Diagnostic criteria usually include histologic identification of anoncaseating granuloma, supportive laboratory or imaging tests or both, and a compatible clinical course. Treatment hasnot been subjected to rigorous study, but corticosteroids are typically the first line of therapy and approximately half ofpatients have substantial benefit. For patients who are refractory to or intolerant of corticosteroid therapy, second-lineagents include azathioprine, methotrexate, cyclosporine, cyclophosphamide, mycophenolate, and even cranial irradiation.The combination of infliximab and mycophenolate mofetil is under study as well. Treatment options will likely evolve aswell-designed studies are undertaken.
Central Nervous System Vasculitis: Still More Questions than Answers by Marco A. Alba, Georgina Espigol-Frigole, Sergio Prieto-Gonzalez, Itziar Tavera-Bahillo, Ana Garcia-Martinez, Montserrat Butjosa, Jose Hernandez-Rodriguez, Maria C. Cid (437-448).
The central nervous system (CNS) may be involved by a variety of inflammatory diseases of blood vessels.These include primary angiitis of the central nervous system (PACNS), a rare disorder specifically targeting the CNSvasculature, and the systemic vasculitides which may affect the CNS among other organs and systems. Both situationsare severe and convey a guarded prognosis. PACNS usually presents with headache and cognitive impairment. Focalsymptoms are infrequent at disease onset but are common in more advanced stages. The diagnosis of PACNS is difficultbecause, although magnetic resonance imaging is almost invariably abnormal, findings are non specific. Angiography haslimited sensitivity and specificity. Brain and leptomeningeal biopsy may provide a definitive diagnosis when disclosingblood vessel inflammation and are also useful to exclude other conditions presenting with similar findings. However,since lesions are segmental, a normal biopsy does not completely exclude PACNS. Secondary CNS involvement bysystemic vasculitis occurs in less than one fifth of patients but may be devastating. A prompt recognition and aggressivetreatment is crucial to avoid permanent damage and dysfunction. Glucocorticoids and cyclophosphamide are recommendedfor patients with PACNS and for patients with secondary CNS involvement by small-medium-sized systemicvasculitis. CNS involvement in large-vessel vasculitis is usually managed with high-dose glucocorticoids (giant-cellarteritis) or glucocorticoids and immunosuppressive agents (Takayasu’s disease). However, in large vessel vasculitis,where CNS symptoms are usually due to involvement of extracranial arteries (Takayasu’s disease) or proximal portions ofintracranial arteries (giant-cell arteritis), revascularization procedures may also have an important role.
Neuropsychiatric Systemic Lupus Erythematosus by Alexandra Popescu, Amy H. Kao (449-457).
Neuropsychiatric systemic lupus erythematosus (NPSLE) is the least understood, yet perhaps the most prevalentmanifestation of lupus. The pathogenesis of NPSLE is multifactorial and involves various inflammatory cytokines,autoantibodies, and immune complexes resulting in vasculopathic, cytotoxic and autoantibody-mediated neuronal injury.The management of NPSLE is multimodal and has not been subjected to rigorous study. Different treatment regimensinclude nonsteroidal anti-inflammatory drugs, anticoagulation, and immunosuppressives such as cyclophosphamide,azathioprine, mycophenolate mofetil, and methotrexate. For refractory NPSLE, intravenous immunoglobulin (IVIG),plasmapheresis, and rituximab have been used. Adjunctive symptomatic treatment complements these therapies by targetingmood disorders, psychosis, cognitive impairment, seizures or headaches. Several new biological agents are beingtested including Belimumab, a human monoclonal antibody that targets B lymphocyte stimulator. This review focuseson the pathophysiology, treatment, and new potential therapies for neuropsychiatric manifestations of systemic lupuserythematosus.
Autoimmune Channelopathies of the Nervous System by Kleopas A. Kleopa (458-467).
Ion channels are complex transmembrane proteins that orchestrate the electrical signals necessary for normalfunction of excitable tissues, including the central nervous system, peripheral nerve, and both skeletal and cardiac muscle.Progress in molecular biology has allowed cloning and expression of genes that encode channel proteins, while comparableadvances in biophysics, including patch-clamp electrophysiology and related techniques, have made the functionalassessment of expressed proteins at the level of single channel molecules possible. The role of ion channel defects in thepathogenesis of numerous disorders has become increasingly apparent over the last two decades. Neurological channelopathiesare frequently genetically determined but may also be acquired through autoimmune mechanisms. All of theseautoimmune conditions can arise as paraneoplastic syndromes or independent from malignancies. The pathogenicityof autoantibodies to ion channels has been demonstrated in most of these conditions, and patients may respond well toimmunotherapies that reduce the levels of the pathogenic autoantibodies. Autoimmune channelopathies may have a goodprognosis, especially if diagnosed and treated early, and if they are non-paraneoplastic. This review focuses on clinical,pathophysiologic and therapeutic aspects of autoimmune ion channel disorders of the nervous system.
Toxicities of Immunosuppressive Treatment of Autoimmune Neurologic Diseases by Enrico C. Lallana, Camilo E. Fadul (468-477).
In parallel to our better understanding of the role of the immune system in neurologic diseases, there hasbeen an increased availability in therapeutic options for autoimmune neurologic diseases such as multiple sclerosis,myasthenia gravis, polyneuropathies, central nervous system vasculitides and neurosarcoidosis. In many cases, thepurported benefits of this class of therapy are anecdotal and not the result of good controlled clinical trials. Nonetheless,their potential efficacy is better known than their adverse event profile. A rationale therapeutic decision by the clinicianwill depend on a comprehensive understanding of the ratio between efficacy and toxicity. In this review, we outlinethe most commonly used immune suppressive medications in neurologic disease: cytotoxic chemotherapy, nucleosideanalogues, calcineurin inhibitors, monoclonal antibodies and miscellaneous immune suppressants. A discussion of theirmechanisms of action and related toxicity is highlighted, with the goal that the reader will be able to recognize the mostcommonly associated toxicities and identify strategies to prevent and manage problems that are expected to arise withtheir use.
Prenatal Cocaine Disrupts Serotonin Signaling-Dependent Behaviors: Implications for Sex Differences, Early Stress and Prenatal SSRI Exposure by Sarah K. Williams, Jean M. Lauder, Josephine M. Johns (478-511).
Prenatal cocaine (PC) exposure negatively impacts the developing nervous system, including numerouschanges in serotonergic signaling. Cocaine, a competitive antagonist of the serotonin transporter, similar to selective serotoninreuptake inhibitors (SSRIs), also blocks dopamine and norepinephrine transporters, leaving the direct mechanismthrough which cocaine disrupts the developing serotonin system unclear. In order to understand the role of the serotonintransporter in cocaine’s effect on the serotonergic system, we compare reports concerning PC and prenatal antidepressantexposure and conclude that PC exposure affects many facets of serotonergic signaling (serotonin levels, receptors, transporters)and that these effects differ significantly from what is observed following prenatal SSRI exposure. Alterations inserotonergic signaling are dependent on timing of exposure, test regimens, and sex. Following PC exposure, behavioraldisturbances are observed in attention, emotional behavior and stress response, aggression, social behavior, communication,and like changes in serotonergic signaling, these effects depend on sex, age and developmental exposure. Vulnerabilityto the effects of PC exposure can be mediated by several factors, including allelic variance in serotonergic signalinggenes, being male (although fewer studies have investigated female offspring), and experiencing the adverse earlyenvironments that are commonly coincident with maternal drug use. Early environmental stress results in disruptions inserotonergic signaling analogous to those observed with PC exposure and these may interact to produce greater behavioraleffects observed in children of drug-abusing mothers. We conclude that based on past evidence, future studies should puta greater emphasis on including females and monitoring environmental factors when studying the impact of PC exposure.
Raphe-Hippocampal Serotonin Neurotransmission In The Sex Related Differences of Adaptation to Stress: Focus on Serotonin-1A Receptor by Darakhshan Jabeen Haleem (512-521).
Stress is the major predisposing and precipitating factor in the onset of depression which is the most significantmental health risk for women. Behavioral studies in animal models show that female sex though less affected by an acutestressor; exposure to repeated stressors induces coping deficits to impair adaptation in them. A decrease in the functionof 5-hydroxytryptamine (5-HT; serotonin) in the hippocampus and an increased function of the 5-HT-1A receptor in theraphe nucleus coexist in depression. Pharmacological and neurochemical data are relevant that facilitation of serotoninneurotransmission via hippocampus due to desensitization of somatodendritic 5-HT1A receptors may lead to adaptation tostress. The present article reviews research on sex related differences of raphe-hippocampal serotonin neurotransmissionto find a possible answer that may account for the sex differences of adaptation to stress reported in preclinical researchand greater incidence of depression in women than men.