Core curriculum of multiple sclerosis

MS Section Education Working Group

Multiple Sclerosis (MS) is the most common demyelinating disease of the CNS and the second
most common cause of disability among young adults. The complex and interdisciplinary
management issues of the MS patient demand the participation of health care professionals from
a variety of intergrated and interactive disciplines, with coordination of care often provided by
the neurologist. It is therefore essential for the neurologist to have a thorough grounding in the
disease across its broad spectrum, from basic scientific underpinnings including
immunopathology to the broad array of its clinical manifestations and patient care needs.
Conventional neurologic training usually provides brief encounters in clinic and classroom
settings that foster fragmented exposure to the disease. Basic genetics, neuroimmunology and
epidemiology are covered in the first two years of medical school, but often without clinical
correlation. In the M3 and M4 years, emphasis is placed on clinical presentation and differential
diagnosis without exploring the full bench to bedside spectrum of demyelianting disorders. The
student clerkship experience with clinical MS care may be limited to interacting for a few days
with an MS patient who is hospitalized for an acute and limited care need; such as an IV steroid
infusion for an acute MS exacerbation. During residency, diagnosis and therapeutics are more
fully explored, but often with limited individual patient continuity for what is a lifelong disorder;
and often in departmental partitions that obscure the benefits of coordinated multi-disciplinary
disease management. Further, pro-active care approached such as wellness management so
actively favored by the MS patient are limited in the university setting. Scheduling demands and
time constraints contribute to this fragmentation in MS training of the student and resident
physician.With increasing financial pressures, and competition for health care resources, it is
important to demonstrate that the optimal care of persons with chronic neurologic conditions
such as MS is best implemented by specialist physicians (neurologists) who are most familiar
with all of the medical, rehabilitative, psychosocial and vocational needs proper MS disease
management requires.
The AAN Section on MS Core Curriculum is designed to provide a concise yet comprehensive
educational resource about MS, that may be utilized by neurologists to help understand and
manage multiple facets of this complicated and interdisciplinary disease process. Basic science
facts are presented and will serve as a context for understanding immunopathology and current
therapeutic approaches, including immunomodulatory and symptomatic treatments. Clinical
phenomenology and diagnostic evaluations are discussed in detail, including unusual
presentations and symptoms, and the expanding differential diagnosis of CNS demyelianting
disease beyond its "classic" and "conventional" borders. Finally, guidelines for the
comprehensive management of persons with MS are provided, using information from each of
the health care disciplines that are commonly involved. These latter include nursing,
psychosocial and vocational strategies that are often not extensively covered in standard
Multiple Sclerosis Section 2010-Core Curriculum Page 1 neurologic training. In addition to presenting factual information about MS, the Core Curriculum
will also allow neurologists access to the opinions and practices of MS specialists, and a brief
bibliography of selected references for further reading. Ideally, this knowledge base will also
have the breadth to be valuable to other health care professionals as well.
Training Curriculum in Multiple Sclerosis

The Core Curriculum is broadly written, and may have applicability at several levels of training.
It is anticipated that a fellowship training program in MS will provide access to both in-patient
and out-patient experiences, ideally within the setting of a dedicated MS clinic or rehabilitation
facility, with the presence of a multidisciplinary health care team. This will provide education in
the comprehensive management that is central to the care of persons with MS. Additionally,
there should be opportunity for research either in a clinical area, including didactic instruction in
clinical research methodoly and statistics, and/or in collaboration with a basic scientist ( e.g.,
immunology, pathology, neurophysiology).The fellow should have the capacity to :
*Recognize common and unusual presentations and manifestations of MS, NMO and CNS demyelinating disease variants. *Generate a differential diagnosis of the broad spectrum of Multiple Sclerosis, its variants, and its mimics *Describe the basic immunopathophysiology of MS *Discuss sensitivities, specificities, and indications for paraclinical and emerging tests that are used to help establish ( or rule out) a diagnosis of MS. *Manage primary and secondary symptoms of MS. *Describe treatment of MS with disease modifying agents. *Lead the health care team in the rehabilitative approach to caring for persons with MS. * Serve as an expert consultant for questions of complicated management issues in persons with MS. * Design innovative treatment approaches utilizing neurologic and rehabilitative * Provide a critical review of current literature regarding research and clinical * Implement clinical or basic science research in an MS or MS related area. * Appreciate the vital role played in comprehensice clinical care of the MS patient played by subspecialty and other medical providers; including physiatry and rehabilitative medicine, physical therapy, occupational therapy, speech pathology, neuropscycology, psychiatry, urology, neurosurgery and indications for device placement, and complementary and alternative therapies Prerequisites Fellowship candidates and practitioners should be board eligible or board certified in Neurology or other appropriate specialty. Allied health professionals, e.g., nurses, therapists, etc. should have had practical experience in the care of persons with MS for a period of no less than two years. Multiple Sclerosis Section 2010-Core Curriculum Page 2 Facilities
Exposure should be provided to patients in both in-patient and outpatient settings. Ideally, this
would include acute care hospitals, rehabilitation units or free-standing facilities, ambulatory
clinic settings and/or a dedicated MS center. There should be access to state of the art
neuroimaging and electrodiagnostic technology, as well as an appropriate medical library and
computer based information.
Medical personnel should include board certified neurologists who are board certified
Neurologists with subspecialty interest in MS or general Neurorehabilitation. Access to other
medical specialists who may be needed in the management of persons with MS, such as
ophthalmologists, gynecologists, urologists, psychiatrists or surgeons should be available.
Additional personnel should have representation from rehabilitation therapists, nurses,
psychologists and case managers who have training and/or certification in working with persons
with MS. Additionally, there should be input and access to basic scientists in the fields that are
relevant to MS research, e.g., immunology, pathology, neurophysiology, etc.
The fellowship program should be at least one year in duration.
Methods of evaluation
Fellows should be able to sit for an examination which will assess their knowledge of basic
science principles and clinical care. Practitioners should be eligible to take a shorter more
clinically based examination for which they may receive CME credit.
Methods of Evaluation
The AAN Section on MS will be available to help analyze comments and provide appropriate
solutions for areas of deficiency.
The overall goals of the Core Curriculum are as follows:
1. To provide a comprehensive knowledge base encompassing basic science and clinical aspects of Multiple Sclerosis. 2. To enable neurologists in fellowship training to become familiar with principles of comprehensive management of persons with MS 3. To be a resource for information about current research directions and clinical trials.
Each sub-topic will have a specific set of objectives, which relate to informational content. After
completing each unit, the trainee should be able to perform the following.
Multiple Sclerosis Section 2010-Core Curriculum Page 3 l. Genetics & Epidemiology . Provide a summary of current epidemiologic facts about MS. . Geography North-South gradient Clusters,epidemics Incidence and prevalence b. Migration studies c. Racial/ethnic distribution . Describe the genetics of MS, from population studies to molecular mechanisms. . HLA associated loci . Risk related to affected family member . Twin studies . Molecular sites of genetic contribution to susceptibility (TCR, MHC expression,  Emerging data on the proteomic profiles of MS lesions . Provide information regarding gender bias in MS. . Sex ratio . Differences in disease severity between sexes . Effects of pregnancy, menses, menopause breast feeding D. Discuss possible roles of stress and trauma and infection in etiology of MS ll. Neurophysiology . Discuss electrical transmission in normal nerves. . Architecture of normal myelinated nerves . Generation of action potentials . Saltatory conduction . Describe disorders of conduction in demyelinated nerves. . Decreased conduction velocity, conduction block, temporal dispersion . Ephaptic transmission . Heat sensitivity . Ion channel distribution lll. Neuroimmunology . Describe normal mechanisms for immune reactivity and self tolerance . Describe possible mechanisms for loss of self-tolerance (Autoimmunity) . List possible candidates for "MS antigen" ( e.g., MBP, MOG) . Discuss role of infections in etiology of MS . Describe role of cytokines in MS . Describe role of adhesion molecules in MS . Discuss T cell biology Regulatory mechanisms . Role of other immune cells Multiple Sclerosis Section 2010-Core Curriculum Page 4 Antigen presenting cells . Describe the role of the blood brain barrier in MS and trafficking of lymphocytes into the CNS lV. Neuropathology . Present gross pathologic and histologic findings associated with MS lesions. . Inflammation, edema, demyelination, gliosis, axonal transection . Distribution of plaques in the CNS . Histologic differences between acute and chronic plaques . Immunocytochemistry of the MS lesion Lassman/Luchinetti subtypes . Describe mechanisms of oligodendrocyte and myelin damage in MS. . Antibody/ compliment mediated . Cell mediated Role of T cell, astrocytes, macrophages . Cytokines . Chemokines C. Discuss possible mechanisms of axonal damage in MS. D. Discuss potential mechanisms of remyelination . List diagnostic criteria for diagnosis of MS . Schumacher . Poser, Paty, Scheinberg Mc Donald  Revised 2005 McDonal criteria (Polman) . Generate differential diagnosis of MS in several categories . Other autoimmune( e.g., collagen vascular) Sjogren's SLE RA Behcet's Undifferentiated connective tissue syndromes Overlap syndromes Neurosarcoidosis HIV HAART associated HIV myelopathy Lyme HTLV-1 Neurosyphilis and treponemal diseases Multiple Sclerosis Section 2010-Core Curriculum Page 5 Vasculitis ANCA associated vasculitides CADASIL Binswanger's Antiphospholipid Syndrome (APS) Susac's Syndrome Embolic disease Hypertensive disease . Hereditodegenerative Spinocerebellar ataxias and trinucleotide repeat disorders Multiple Systems Atrophy, cerebellar type (MSA-C) OPCA Metachromatic leukodystrophy Adrenoleukodystrophy Hereditary ataxias including Friedrich's ataxia Mitochondrial diseases Brainstem glioma ACM Syrinx Structural myelopathy ( tumor or disc) Primary brain tumor . Toxic/metabolic B 12 deficiency Cigeratoa intoxication Nitrous oxide toxicity syndrome Vitamin E deficiency Copper deficiency Balo's
Neuromyelitis Optica (NMO)
Diagnostic criteria Role of aquaporin-4 antibody Treatment options Opticospinal MS and NMO spectrum disorders C. Describe sensitivities and specificities of paraclinical tests . MRI Indications for specific MR sequences . Evoked potentials . Cerebrospinal fluid Electrophoretic and isoeletric focusing technologies for CSF analysis . Discuss indications for each testing modality Multiple Sclerosis Section 2010-Core Curriculum Page 6 D. List appropriate tests to exclude diagnosis of MS ( e.g. collagen vascular serologies) E. List several reasons why it is important to communicate a diagnosis 1. Clarify diagnosis 2. Begin treatment 3. Allay anxieties about possible other disease processes 4. Begin planning for the future A. Discuss natural history including different temporal and clinical courses . R/R . SP . PP . PR . Mild . Evidence for immunologic differences between above . Present guidelines for defining prognosis a. Prognostic indicators . Age . Gender . Race . Type of initial symptoms . Interval to next attack . Degree of recovery from attack . Disease subtype b. Statistics re: cumulative disability years after diagnosis c. Role of MRI in formulating prognosis and monitoring disease activity . Outcome measures . EDSS MSFC ?OCT . MRD . Quality of life scales . Composite scales D. Describe common and uncommon symptoms in MS Diplopia/Blurred vision Intranuclear ophthalmoplegia (INO) Decomposition of smooth pursuit eye movements Multiple Sclerosis Section 2010-Core Curriculum Page 7 Glissades on rapid saccadic eye movements from latent INO Nystagmus and oscillopsia Ophthalmoplegia Chiasmal and post chiasmal syndromes c. Sensory/pain syndromes L'hermitte's Sign Trigeminal neuralgia Anaesthesia dolorosa Musculoskeletal pain Spasticity Secondary lumbosacral pain syndrome Piriformis Syndrome Other pain syndromes d. Genitourinary Urgency,frequency, hestitancy, nocturia, incontinence Faiulre to store bladder Failure to empty bladder Bladder dyssynergia Constipation, tenesmus, fecal incontinence Impotence, anorgasmy, decreased libido, dyspareunia Ocular dysmetria Scanning/telegraphic speech Ataxia Vertigo/dizziness Neuropsychology profile of MS Multiple Sclerosis Section 2010-Core Curriculum Page 8 Attention and concentration Mood disturbances E. Describe common clinical signs Afferent pupillary defect Ophthalmopareses Opsoclonus Smooth pursuit decomposition Glissades Ocular dysmetria Hypereflexia Upper motor neuron findings in absence of hyper-reflexia Loss of posterior column modalities Peripheral facial weakness Trigeminal neuralgia Myokymia Tremor/incoordination . Spinal cord Transverse myelitis Brown-Sequard syndrome Sensory level Sweat level . Cognition/psychologic Impairment of higher intellectual function/dementia Emotional lability Pseudobulbar Palsy Depression Euphoria Multiple Sclerosis Section 2010-Core Curriculum Page 9 Absence of abdominal reflexes Hearing impairment/tinnitus Vll. Prophylactic management A. Present results from clinical trials of FDA approved immunomodulatory drugs 1. Beta-interferon 1b Relapsing remitting Secondary progressive 2. Beta interferon 1a Relapsing remitting CIS (CHAMPS) 3. Glatiramer acetate Relapsing remitting CIS(PROMISE) Secondary progressive Progressive/relapsing /Relapsing/remitting 6. Fingolimod
6. Rituximab/Ocrelizumab 7. Off label medications and immunotherapies 8. Emerging immunotherapies; oral, MAb, other B. Discuss guidelines for initiation and maintenance of therapy 1. AAN guidelines for indications for therapy; NMSS Consensus statement 2. Guidelines and interpretation of antibody testing for interferons and natalizumab 3. Indications for stopping or changing therapy C. List common side effects (and their management) for each of the above agents a. Fever, chills, myalgia c. Elevated liver function tests/leukopaenia d. Site reactions, site necrosis e. Menstrual irregularities Multiple Sclerosis Section 2010-Core Curriculum Page 10 a. Injection techniques b. Dose adjustments c. NSAIDs, acetaminophen, steroids 2. Glatiramer acetate a. Site reactions b. Immediate post injection vasomotor reaction (IPIR) Side effects Secondary leukemia Reduction of measured LVEF and cardimyopathy Leukopaenia Menstrual irregularities and premature menopause risk Fever/infection Hair loss CNS opportunistic infection Progressive Multifocal Leukoencephalopathy HSV encephalitis, meningitis CNS toxo, other . Provide information about on going trials and research of other immunomodulating . Clinical trials Relapsing remitting a. Blood borne infection b. Allergic reaction d. Aseptic meningitis . Thromboembolic phenomena Azathioprine . Cyclophosphamide . Methotrexate Mycophenolate Mofetil . Others . T cell/peptide vaccination . Hormone therapy . Adhesion molecule antibody . Others Rituximab Alemtuzumab Multiple Sclerosis Section 2010-Core Curriculum Page 11 Vll. Symptomatic management A. Discuss treatment of acute exacerbations 1. Steroid regimens 3. Plasmapheresis . Rehabilitative modalities Assistive devices Environmental and vocational modifications . Pseudoexacerbations Treat underlying precipitant, e.g., infection B. Present primary symptoms and discuss their management a. Pharmacologic b. Rehabilitative Assistive devices/Orthotics Functional Electrical Stimulation . Physiology Definition Final common pathway Denervation supersensitivity Loss of descending inhibitory pathways . Treatment a. Pharmacologic Baclofen/Baclofen pump b. Rehabilitative Therapies,exercise, stretching Assistive devices C. Spasticity scales, e.g. Ashworth Multiple Sclerosis Section 2010-Core Curriculum Page 12 . Types of pain syndromes Structural (e.g. compression) a. Pharmacologic Anti-convulsants Anti-depressants b. Rehabilitative Therapies; physical modalities . Intrathecal analgesic or baclofen pump . Genitourinary-Bladder a. Anatomy & physiology of normal micturition and defecation Structure of bladder, urethra, pelvic floor Sympathetic and parasympathetic pathways Cerebral, spinal centers for micturition b. Algorithm for diagnosis of bladder dysfunction PVR/Bladder scan c. Bladder history d. Treatment of failure to store bladder Anticholinergics e. Treatment of failure to empty Physical maneuvers, e.g. crede 5. Genitourinary-Bowel a. Bowel history b. Pharmacologic Anti-diarrheal agents c. Timed evacuations d. Nutritional and fluid intake guidelines 6. Genitourinary-Sexual dysfunction ( male) Multiple Sclerosis Section 2010-Core Curriculum Page 13 a. Normal male anatomy and innervation b. Physiology of normal sexual response c. Impotence/erectile dysfunction Other phosphodiesterase inhibitors Iatrogenic (medication related) c. Ejaculatory dysfunction d. Decreased libido 7. Genitourinary - Sexual dysfunction(female) a. Normal female anatomy and innervation . Physiology of normal sexual response . Symptoms of sexual dysfunction Decreased libido Inadequate lubrication Altered or painful sensation Alternative methods of stimulation a. Definition & characteristics of MS fatigue Incidence and impact Diurnal variation Relationship to heat b. Pharmacologic c. Rehabiltative Energy conservation Assistive devices Multiple Sclerosis Section 2010-Core Curriculum Page 14 9. Tremor/Ataxia a. Pharmacologic Deep brain stimulator b. Rehabilitative Assistive devices Therapeutic exercises c. Deep brain stimulation a. Diagnostic evaluation Videofluoroscopy Exercises/Swallow strategies Alteration of food/liquid consistencies a. Optic neuritis Treatment with steroids 12. Psychologic/Cognitive c. Emotional lability d. Personality changes e. Cognitive impairment Neuropsychologic testing Psychiatric/psychologic consultaion Multiple Sclerosis Section 2010-Core Curriculum Page 15 Anti-anxiety agents d. Social service assistance C. List secondary symptoms and prevention a. Acidification/antibiotic prohpylaxis b. Drainage of retained urine c. Adequate hydration a. Treatment of dysphagia b. Nutritional supplements 3. Impaired skin integrity a. Identify risk factors for skin breakdown a. Relieve spasticity b. Maximize mobility d. Surgical remediation a. Identify patients at risk b. Treat dysphagia a. Incidence in patients with MS b. Predisposing factors Immobility/decreased weight bearing Calcium supplementation Weight bearing exercises Increased mobility Multiple Sclerosis Section 2010-Core Curriculum Page 16 C. Describe tertiary symptoms and treatment approaches 1. Social/ Familial issues Marital difficulties Parenting issues Financial hardship Reasonable accommodations Employment modifications Vocational retraining Medical Power of attorney/advance directives Reimbursement for medical care Immunology/molecular biology Myelin/glial cell biology Infectious agents Therapeutic agents/clinical trials Neuroimaging modalities Health services delivery Clinical phenomenology Outcomes mesurement Database creation and utilization Multiple Sclerosis Section 2010-Core Curriculum Page 17


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Bhr185 1133.1138

Cerebral Cortex May 2012;22:1133--1138doi:10.1093/cercor/bhr185Advance Access publication July 28, 2011 Modulation of Inhibition of Return by the Dopamine D2 Receptor Agonist BromocriptineDepends on Individual DAT1 Genotype Ariel Rokem1, Ayelet N. Landau2, William Prinzmetal2, Deanna L. Wallace1,2, Michael A. Silver1,3 and Mark D'Esposito1,2 1Helen Wills Neuroscience Institute, 2Department of Psychology and 3School of Optometry, University of California, Berkeley,Berkeley, CA 94720, USA.