This document discusses recent developments in the treatment of multiple sclerosis (MS). It notes that early treatment with immunomodulatory therapies can slow disease progression and reduce future disability. Patients presenting with a clinically isolated syndrome or radiologically isolated syndrome, who have abnormal MRI findings but no or limited symptoms, are now treated early to prevent or delay their first clinical relapse of MS. The document reviews the inflammatory and demyelinating nature of MS and how the newly discovered glymphatic system may help immune cells enter the central nervous system to cause MS lesions.
Movement disorders are not only realm of chronic disorders that are treated without requiring emergent intervention, but also they can present acutely with more aggressive forms
This presentation contains information about Dementia in Young onset. Also it describes the etiologies, clinical feature of common YOD & their management.
Movement disorders are not only realm of chronic disorders that are treated without requiring emergent intervention, but also they can present acutely with more aggressive forms
This presentation contains information about Dementia in Young onset. Also it describes the etiologies, clinical feature of common YOD & their management.
Dr. Cavallari will present studies relevant to the recently discovered glymphatic pathway of clearance, with particular emphasis on ongoing studies at the Center for Neurological Imaging. The glymphatic pathway is considered to play a substantial role in the clearance of brain waste, including neurotoxins implicated in the pathobiology of neurodegenerative disease, such as Alzheimer’s disease. Studies in animal models showed that this mechanism of clearance is particularly active during sleep. The characterization of the glymphatic system in humans would have profound implications for our understanding of the core functions of sleep, as well as the pathogenesis of neurodegenerative diseases. Preliminary findings, including ours, support the presence of a similar mechanism of clearance in humans.
Multiple sclerosis: Introduction, Risk Factors, Diagnosis and TreatmentEnriqueAlvarez93
Introduction about Multiple Sclerosis.
Risk factors affect to Multiple Sclerosis.
When to Suspect Multiple Sclerosis.
Evaluation and Diagnosis of Multiple Sclerosis.
How to treatment of Multiple Sclerosis.
Treatment of Multiple Sclerosis with Monoclonal Antibody.
Metabolic encephalopathy diagnosis and managementRobert Robinson
Overview of the diagnosis and management of metabolic encephalopathy for third year medical students in the Personalized Education Program portion of the third year curriculum at SIU Medicine
Childhood demyelinating syndromes
In the past decade, the number of studies related to demyelinating diseases in children has exponentially increased. Demyelinating disease in children may be monophasic or chronic. Typical monophasic disorders in children are acute disseminated encephalomyelitis and clinically isolated syndromes, including optic neuritis and transverse myelitis. However, some cases of acute disseminated encephalomyelitis or clinically isolated syndrome progress to become chronic disorders, including multiple sclerosis and neuromyelitis optica. This review summarizes the current knowledge on monophasic and chronic demyelinating disorders in children, focusing on an approach to diagnosis and management.
A wonderful and interesting presentation on Multiple Sclerosis! It includes videos, pictures and great insight into the possible cure for MS. I truly hope whoever downloads it enjoys it as much as I do. Blessings!
Dr. Cavallari will present studies relevant to the recently discovered glymphatic pathway of clearance, with particular emphasis on ongoing studies at the Center for Neurological Imaging. The glymphatic pathway is considered to play a substantial role in the clearance of brain waste, including neurotoxins implicated in the pathobiology of neurodegenerative disease, such as Alzheimer’s disease. Studies in animal models showed that this mechanism of clearance is particularly active during sleep. The characterization of the glymphatic system in humans would have profound implications for our understanding of the core functions of sleep, as well as the pathogenesis of neurodegenerative diseases. Preliminary findings, including ours, support the presence of a similar mechanism of clearance in humans.
Multiple sclerosis: Introduction, Risk Factors, Diagnosis and TreatmentEnriqueAlvarez93
Introduction about Multiple Sclerosis.
Risk factors affect to Multiple Sclerosis.
When to Suspect Multiple Sclerosis.
Evaluation and Diagnosis of Multiple Sclerosis.
How to treatment of Multiple Sclerosis.
Treatment of Multiple Sclerosis with Monoclonal Antibody.
Metabolic encephalopathy diagnosis and managementRobert Robinson
Overview of the diagnosis and management of metabolic encephalopathy for third year medical students in the Personalized Education Program portion of the third year curriculum at SIU Medicine
Childhood demyelinating syndromes
In the past decade, the number of studies related to demyelinating diseases in children has exponentially increased. Demyelinating disease in children may be monophasic or chronic. Typical monophasic disorders in children are acute disseminated encephalomyelitis and clinically isolated syndromes, including optic neuritis and transverse myelitis. However, some cases of acute disseminated encephalomyelitis or clinically isolated syndrome progress to become chronic disorders, including multiple sclerosis and neuromyelitis optica. This review summarizes the current knowledge on monophasic and chronic demyelinating disorders in children, focusing on an approach to diagnosis and management.
A wonderful and interesting presentation on Multiple Sclerosis! It includes videos, pictures and great insight into the possible cure for MS. I truly hope whoever downloads it enjoys it as much as I do. Blessings!
Current Thoughts on Nutrition With Emphasis on Treating the Cause of Degenera...Visionary Ophthamology
Current Thoughts on Nutrition
With Emphasis on Treating the Cause of Degenerative Eye Disease, Safety Issues, B Vitamins and Essential Fatty Acids and Dry Eyes
Ellen Troyer, MT MA
This project was developed for a competitive intelligence company by mining data from the various information sources e.g. Company (News, Investor Section, SEC filings, Annual Reports, Presentations etc), Universities/Medical Schools/Organizations, Medical Affairs Companies, Non- Profit Medical Agency, Government Agencies, Drug Delivery Companies, Contract Manufacturing Organizations, Contract Research Organizations, Consultancies and Financial Institutions. The complete information available there complied into a single MS word document, listed in MS Excel and then by using MS publisher it was converted into the report which finally converted into PDF.
Herpes zoster infection in neurology: management updates and prevention懿恩 施
Varicella zoster cause a huge burden among patients with Post-herpetic nerlagia.
This lecture leads audience to deeper understanding of the disease nature and its association with multiple disciplines.
Concussions, TBI, Reading, Balance, Car-Sickness, Attention, Visual Fatigue Problems Vision Therapy 101 for the Primary Care Practitioner By Stan Appelbaum, OD
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
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1. WhatWhat’s New in Multiple’s New in Multiple
SclerosisSclerosis
David M Katz, MDDavid M Katz, MD
Bethesda Neurology, LLCBethesda Neurology, LLC
Associate Professor of Ophthalmology and Neurology atAssociate Professor of Ophthalmology and Neurology at
Howard University Hospital andHoward University Hospital and
Assistant Professor of Ophthalmology at GeorgetownAssistant Professor of Ophthalmology at Georgetown
UniversityUniversity
301-540-2700301-540-2700
Neuro-Ophthalmology ReviewNeuro-Ophthalmology Review
May 22, 2016May 22, 2016
2. DisclosuresDisclosures
Clinical MS research supported by BiogenClinical MS research supported by Biogen
and Novartisand Novartis
Clinical consultant for BiogenClinical consultant for Biogen
3. BackgroundBackground
Multiple sclerosis (MS) is an autoimmune diseaseMultiple sclerosis (MS) is an autoimmune disease
typically causing attacks followed by remissions involvingtypically causing attacks followed by remissions involving
the central nervous system only, most often the opticthe central nervous system only, most often the optic
nerve(s).nerve(s).
Symptoms and signs depend on where in the CNS theSymptoms and signs depend on where in the CNS the
lesion(s) are. For example, optic neuritis is caused bylesion(s) are. For example, optic neuritis is caused by
inflammation of an optic nerve, double vision due toinflammation of an optic nerve, double vision due to
brainstem lesions, transverse myelitis is caused bybrainstem lesions, transverse myelitis is caused by
inflammation of the spinal cord, ataxia is caused byinflammation of the spinal cord, ataxia is caused by
inflammation of the cerebellum or brainsteminflammation of the cerebellum or brainstem
Optic neuritis presents most often in young females withOptic neuritis presents most often in young females with
unilateral pain on eye movement soon followed byunilateral pain on eye movement soon followed by
declining visual acuity, color vision, contrast sensitivitydeclining visual acuity, color vision, contrast sensitivity
and visual field over 7-10 days. Vision recovers toand visual field over 7-10 days. Vision recovers to
>>20/40 by six months in 95% of patients with or without20/40 by six months in 95% of patients with or without
high-dose steroid treatment based on results of the Optichigh-dose steroid treatment based on results of the Optic
Neuritis Treatment Trial 1988-92 (ONTT) andNeuritis Treatment Trial 1988-92 (ONTT) and
Longitudinal Optic Neuritis Study 1999-2004 (LONS)Longitudinal Optic Neuritis Study 1999-2004 (LONS)
4. Pre- 1993 MS Treatment:Pre- 1993 MS Treatment:
“Diagnose and Adios”“Diagnose and Adios”
SymptomaticSymptomatic
treatment only:treatment only:
baclofen, benzos,baclofen, benzos,
Botox, gabapentinBotox, gabapentin
PT/OT/rehabPT/OT/rehab
IV Steroids toIV Steroids to
speedspeed
improvement fromimprovement from
relapses butrelapses but
ineffective atineffective at
reversing damagereversing damage
5. Martino et al. J Neuroimmunol 2000;109:3, Trapp et al. N Engl J Med 1998;338:278, Fisher et al. Neurology 2002;59:1412-20
Multiple Sclerosis:Multiple Sclerosis:
ImmunopathogenesisImmunopathogenesis
InflammationInflammation
Immune-mediatedImmune-mediated
Facilitated by the entry of auto-reactive T and B cells and auto-Facilitated by the entry of auto-reactive T and B cells and auto-
antibodies from the bloodstream into the CNSantibodies from the bloodstream into the CNS
DemyelinationDemyelination
Primarily immune- and antibody-mediatedPrimarily immune- and antibody-mediated
Mediated by cytokines produced by activated CD4 T cells andMediated by cytokines produced by activated CD4 T cells and
anti-myelin antibodies produced by activated B cells (ex. CD20)anti-myelin antibodies produced by activated B cells (ex. CD20)
Axonal injury and lossAxonal injury and loss
The effects of inflammation and demyelination lead to axonal injuryThe effects of inflammation and demyelination lead to axonal injury
and loss, and ultimately to brain atrophy and permanent disabilityand loss, and ultimately to brain atrophy and permanent disability
6. Environmental
factors
(ex. northern latitudes,
Low vitamin D?)
Abnormal immunologic response
Genetic
predisposition
(ex. HLA-Dw2)
Infectious agent?
(HHV-6, HSV, EBV,
CMV, etc)
MS
Potential Triggers for Multiple SclerosisPotential Triggers for Multiple Sclerosis
Gilden DH Lancet Neurol 2005;4:195-202, Noseworthy et al. N Engl J Med 2000;343:938
9. MS is Inflammatory Early on,MS is Inflammatory Early on,
Degenerative LaterDegenerative Later
RelapsingSubclinical Progressive
TimeTime
MRI total T2 lesion areaMRI total T2 lesion area
MRI activityMRI activity
Measures of brain volumeMeasures of brain volume
Relapses and impairmentRelapses and impairment
Therapeutic window of opportunity
10. The newly discoveredThe newly discovered “Glymphatic” system helps“Glymphatic” system helps
explain how immune cells enter the CNSexplain how immune cells enter the CNS
Louveau A, et al Nature 2015Louveau A, et al Nature 2015
11. ““Glymphatics”Glymphatics”
Before the first reports of a glympathic (glial-lymphatic)Before the first reports of a glympathic (glial-lymphatic)
system by Iliff et al in 2012, the CNS was thought not tosystem by Iliff et al in 2012, the CNS was thought not to
have a lymphatic system, yet we knew the immunehave a lymphatic system, yet we knew the immune
system somehow protects the CNS from infection and cansystem somehow protects the CNS from infection and can
cause autoimmune disease, ex. MScause autoimmune disease, ex. MS
Lymphatic vessels were recently detected lining the duralLymphatic vessels were recently detected lining the dural
sinuses in mice, subsequently in humans, which carrysinuses in mice, subsequently in humans, which carry
immune cells to and from the CSFimmune cells to and from the CSF
Classic MS lesions are typically perpendicular to theClassic MS lesions are typically perpendicular to the
lateral ventricles, termedlateral ventricles, termed “Dawson fingers” (1916), prior to“Dawson fingers” (1916), prior to
2012 the anatomic explanation was lacking for 96 years.2012 the anatomic explanation was lacking for 96 years.
The glymphatic system follows the same anatomicThe glymphatic system follows the same anatomic
distribution as Dawson fingersdistribution as Dawson fingers
12. Activation of Immune CellsActivation of Immune Cells
in the CNSin the CNS
Frohman EM et al. Arch Neurol 2005;62:1345-56, Martino et al. J Neuroimmunol 2000;109:3-9
Upon antigen presentation inUpon antigen presentation in
CNS, CD4+ T cells differentiateCNS, CD4+ T cells differentiate
into autoreactive Th1 cells thatinto autoreactive Th1 cells that
release proinflammatoryrelease proinflammatory
cytokinescytokines
This process leads to anThis process leads to an
inflammatory cascade andinflammatory cascade and
immune-mediated demyelinationimmune-mediated demyelination
13. When should MS treatmentWhen should MS treatment
begin?begin?
1993-4 the first MS treatment, interferon-beta-1993-4 the first MS treatment, interferon-beta-
1b sq QOD (Betaseron) was made available by1b sq QOD (Betaseron) was made available by
lottery only due to small supply until 1995lottery only due to small supply until 1995
1995-2001 Copaxone, Avonex, Rebif approved1995-2001 Copaxone, Avonex, Rebif approved
only for patients afteronly for patients after multiplemultiple clinical relapsesclinical relapses
2002- Interferon beta 1a IM qwk (Avonex)2002- Interferon beta 1a IM qwk (Avonex)
approved afterapproved after firstfirst clinical MS relapseclinical MS relapse
2014- MS treatment effective at2014- MS treatment effective at
delaying/preventing first clinical MS relapse indelaying/preventing first clinical MS relapse in
patients withpatients with “Radiological Isolated Syndrome”“Radiological Isolated Syndrome”
14. Clinically Isolated Syndrome (CIS),Clinically Isolated Syndrome (CIS),
i.e.i.e. “Single Sclerosis”“Single Sclerosis”
MRI lesion load at presentation stratifies patients into high and low riskMRI lesion load at presentation stratifies patients into high and low risk
groupsgroups
Even one lesion at presentation carries almost the same risk of MS at 5Even one lesion at presentation carries almost the same risk of MS at 5
years (80%) as >10 lesions at presentationyears (80%) as >10 lesions at presentation
0
20
40
60
80
100
5 10 14
0 Lesions
1-3 Lesions
4-10 Lesions
>10 Lesions
15. Early Treatment is important forEarly Treatment is important for
long-term control of MSlong-term control of MS
Multiple well controlled studies indicate that early treatmentMultiple well controlled studies indicate that early treatment
of MS with immunomodulatory treatment (IMT) slowsof MS with immunomodulatory treatment (IMT) slows
progression of disease and lowers the risk of future disabilityprogression of disease and lowers the risk of future disability
Patients with Clinically Isolated Syndrome (CIS), ie,Patients with Clinically Isolated Syndrome (CIS), ie, “Single“Single
Sclerosis” defined as a single event (ex. optic neuritis) withSclerosis” defined as a single event (ex. optic neuritis) with
an abnormal MRI have a lower risk of developing relapsingan abnormal MRI have a lower risk of developing relapsing
MS if treated with an IMTMS if treated with an IMT
““Radiological Isolated Syndrome (RIS)” ie, pre-symptomaticRadiological Isolated Syndrome (RIS)” ie, pre-symptomatic
MS includes patients undergoing MRI brain/spine forMS includes patients undergoing MRI brain/spine for
unrelated issues, most often trauma or migrainesunrelated issues, most often trauma or migraines
A 5-year study of 451 RIS patients showed that 34%A 5-year study of 451 RIS patients showed that 34%
developed a clinical relapse, especially males with spinaldeveloped a clinical relapse, especially males with spinal
cord lesionscord lesions
Kappos L et al Neurol 2006; Okuda D, et al PloSone 2014Kappos L et al Neurol 2006; Okuda D, et al PloSone 2014
16. Interferon beta-1a IM qw (Avonex) inInterferon beta-1a IM qw (Avonex) in
Clinically Isolated SyndromeClinically Isolated Syndrome
PatientswithSecond
Exacerbation(%)
3 15 27
0
10
20
30
40
50 Placebo
IFN-beta 1a
Study Month
6 9 12 18 21 24 30 33 36
44%
in risk of
developing
MS
P=0.002
Jacobs et al. N Engl J Med 2000;343:898
IFN-beta 1a 193 164 143 112 73 41
Placebo 190 146 131 98 58 26
No. of Patients at Risk
17. MRI may be more informative than theMRI may be more informative than the
clinical examination as to whether an MSclinical examination as to whether an MS
patient is responding to treatmentpatient is responding to treatment
Monthly MRIs on a large cohort of MS patients followedMonthly MRIs on a large cohort of MS patients followed
at the NIH showed lesions frequently developing andat the NIH showed lesions frequently developing and
spontaneously resolving (partially or completely) inspontaneously resolving (partially or completely) in
patients with no new symptoms or clinical findingspatients with no new symptoms or clinical findings
PatientPatient’s symptoms and clinical examination therefore’s symptoms and clinical examination therefore
represent the “tip of the iceberg”; 80% of MS lesions onrepresent the “tip of the iceberg”; 80% of MS lesions on
MRI are clinically silentMRI are clinically silent
A single MRI at diagnosis is therefore no longer felt to beA single MRI at diagnosis is therefore no longer felt to be
adequate to manage MS. Yearly or bi-annual MRIs areadequate to manage MS. Yearly or bi-annual MRIs are
now recommended. If new lesions are seen, a change innow recommended. If new lesions are seen, a change in
MS medication should be consideredMS medication should be considered
I use the analogy of HTN: if you donI use the analogy of HTN: if you don’t check the BP’t check the BP
regularly on BP medication, how do you know if theregularly on BP medication, how do you know if the
medication is working?medication is working?
18. MRI in same patient over one yearMRI in same patient over one year
withoutwithout symptoms or treatmentsymptoms or treatment
19. Currently approved MS treatmentsCurrently approved MS treatments
TheThe “platform treatments” first became available“platform treatments” first became available
in the mid-1990s and include interferon-betain the mid-1990s and include interferon-beta
injections (Betaseron, Avonex, Rebif, Extavia,injections (Betaseron, Avonex, Rebif, Extavia,
Plegridy), and a non-interferon, glatiramerPlegridy), and a non-interferon, glatiramer
acetate injections (Copaxone)acetate injections (Copaxone)
Oral medication: fingolimod (Gilenya) approvedOral medication: fingolimod (Gilenya) approved
in 2010, teriflunomide (Aubagio) in 2012, andin 2010, teriflunomide (Aubagio) in 2012, and
dimethyl fumerate (Tecfidera) in 2013dimethyl fumerate (Tecfidera) in 2013
The more potent MS medications: IVThe more potent MS medications: IV
natalizumab (Tysabri) and IV alemtuzumabnatalizumab (Tysabri) and IV alemtuzumab
(Lemtrada, aka Campath) unfortunately carry the(Lemtrada, aka Campath) unfortunately carry the
highest risk of serious side effects includinghighest risk of serious side effects including
Progressive Multifocal LeukoencephalopathyProgressive Multifocal Leukoencephalopathy
(PML) caused by the JC virus(PML) caused by the JC virus
20. Vitamin D and MSVitamin D and MS
Ascherio et al prospectively followed 465 early MS patients forAscherio et al prospectively followed 465 early MS patients for
5 years and measured vitamin D levels every 6 months5 years and measured vitamin D levels every 6 months
Those patients with vitamin D levelsThose patients with vitamin D levels >>50 nmol/L had significantly50 nmol/L had significantly
fewer active MS lesions on MRI, less brain volume loss andfewer active MS lesions on MRI, less brain volume loss and
lower disability score (EDSS) than patients with levels <30lower disability score (EDSS) than patients with levels <30
The well known finding of a higher incidence of MS furtherThe well known finding of a higher incidence of MS further
from the equator may be explained by lower vitamin D levelsfrom the equator may be explained by lower vitamin D levels
further from the equator. The contrary is also true: MS remainsfurther from the equator. The contrary is also true: MS remains
rare in countries near the equator.rare in countries near the equator.
Beginning 20 years ago, the incidence of MS in Africa and theBeginning 20 years ago, the incidence of MS in Africa and the
Middle East began to increased significantly, perhaps followingMiddle East began to increased significantly, perhaps following
the advent of air conditioning in these regions, allowing peoplethe advent of air conditioning in these regions, allowing people
in warmer climates to stay inside during daylight hours,in warmer climates to stay inside during daylight hours,
thereby less UV exposure, therefore lower vitamin D levelsthereby less UV exposure, therefore lower vitamin D levels
Ascherio A et al Lancet NeurolAscherio A et al Lancet Neurol
21. Natalizumab (Tysabri) IV q4wkNatalizumab (Tysabri) IV q4wk
Efficacy at six months: 90% reduction in new T2 and gad+Efficacy at six months: 90% reduction in new T2 and gad+
lesions (interferon-beta (IFB)=80% reduction)lesions (interferon-beta (IFB)=80% reduction)
Relapses were reduced by 68% at one year (IFB=30%)Relapses were reduced by 68% at one year (IFB=30%)
Progression of disability reduced by 42% at 2 yearsProgression of disability reduced by 42% at 2 years
(IFB=<30% at 2 years)(IFB=<30% at 2 years)
Natalizumab is a monoclonal antibody that inhibits alpha-4-Natalizumab is a monoclonal antibody that inhibits alpha-4-
mediated cell adhesion of leukocytes to the VCAM-1mediated cell adhesion of leukocytes to the VCAM-1
receptors and thereby blocks movement of inflammatory Treceptors and thereby blocks movement of inflammatory T
cells into the CNScells into the CNS
However, without adequate T cell migration into the CNSHowever, without adequate T cell migration into the CNS
the risk of infection rises: 1/200-500 develop PML if JCV+the risk of infection rises: 1/200-500 develop PML if JCV+
for > 2 yearsfor > 2 years
Goodin D, et al Neurol 2008Goodin D, et al Neurol 2008
23. Penetration of the blood-brain barrierPenetration of the blood-brain barrier
Breakdown of BBB permits entry from the glymphaticBreakdown of BBB permits entry from the glymphatic
system into the CNSsystem into the CNS
Auto-reactive T and B cellsAuto-reactive T and B cells
Antibody and complementAntibody and complement
Frohman EM et al. Arch Neurol 2005;62:1345-56
24. Fimgolimod (Gilenya)Fimgolimod (Gilenya)
Fimgolimod 0.5 mg/d was the first oral agentFimgolimod 0.5 mg/d was the first oral agent
approved for MS, in 2010. It is a sphingosine-1-approved for MS, in 2010. It is a sphingosine-1-
phosphate receptor blocker which inhibitsphosphate receptor blocker which inhibits
release of T cells from lymph nodesrelease of T cells from lymph nodes
Side effects:Side effects: macular edemamacular edema <3 months into<3 months into
treatment in 1/400, bradycardia <6 hrs first dose,treatment in 1/400, bradycardia <6 hrs first dose,
increased risk of infections, especially zoster,increased risk of infections, especially zoster,
UTIs, sinus infections, 5 cases of PML to dateUTIs, sinus infections, 5 cases of PML to date
25. Teriflunomide (Aubagio)Teriflunomide (Aubagio)
Second oral agent 14 mg/d, approved inSecond oral agent 14 mg/d, approved in
20122012
Inhibits pyrimidine synthesis therebyInhibits pyrimidine synthesis thereby
reducing inflammatory leukocytesreducing inflammatory leukocytes
Side effects: liver toxicity, alopecia,Side effects: liver toxicity, alopecia,
headache, diarrhea, category X forheadache, diarrhea, category X for
pregnancy (males and females)pregnancy (males and females)
Not as effective as fingolimod andNot as effective as fingolimod and
permanently affects the immune system,permanently affects the immune system,
so used less oftenso used less often
26. Dimethyl Fumarate (Tecfidera)Dimethyl Fumarate (Tecfidera)
Approved for MS in 2013, 240 mg po bidApproved for MS in 2013, 240 mg po bid
Used in Europe for 10 years for psoriasis andUsed in Europe for 10 years for psoriasis and
RA, and used to prevent mold buildup on leatherRA, and used to prevent mold buildup on leather
until banned in 1998 due to contact dermatitisuntil banned in 1998 due to contact dermatitis
Mode of action unclear: activation of nuclearMode of action unclear: activation of nuclear
derived factor 2, thereby acting as anti-derived factor 2, thereby acting as anti-
inflammatory and antioxidantinflammatory and antioxidant
Side effects: GI, flushing, leukopenia, increasedSide effects: GI, flushing, leukopenia, increased
LFTs. 4 cases of PML to dateLFTs. 4 cases of PML to date
27. MS treatments on the near horizonMS treatments on the near horizon
Rituximab blocks CD19 and CD20 B cells: available off-Rituximab blocks CD19 and CD20 B cells: available off-
label for MSlabel for MS
Ocrelizumab (humanized rituximab): FDA approvalOcrelizumab (humanized rituximab): FDA approval
expected 2016 for relapsing andexpected 2016 for relapsing and primaryprimary progressive MSprogressive MS
Daclizumab (Zinbryta, formerly Zenapax) blocks CD25Daclizumab (Zinbryta, formerly Zenapax) blocks CD25
and IL-2 activated T cells. FDA approval expected 2016and IL-2 activated T cells. FDA approval expected 2016
Vitamin D has anti-inflammatory properties. A trial of lowVitamin D has anti-inflammatory properties. A trial of low
dose vs high dose vitamin D with glatiramer (Copaxone)dose vs high dose vitamin D with glatiramer (Copaxone)
is ongoingis ongoing
Autologous bone marrow transplant is highly effective inAutologous bone marrow transplant is highly effective in
aggressive cases of MS but to date carries an 8% fatalityaggressive cases of MS but to date carries an 8% fatality
rate due to opportunistic infectionsrate due to opportunistic infections
28. Anti-LINGOAnti-LINGO
A monoclonal Ab that blocks a CNSA monoclonal Ab that blocks a CNS
-specific glycoprotein that inhibits-specific glycoprotein that inhibits
remyelination by oligodendrocytesremyelination by oligodendrocytes
Anti-LINGO IV 100mg/kg q4w x 24w in 33Anti-LINGO IV 100mg/kg q4w x 24w in 33
patients improved the latency on visualpatients improved the latency on visual
evoked potential test by 7.6 ms (p=0.05)evoked potential test by 7.6 ms (p=0.05)
over 36 placebo patients, suggesting anti-over 36 placebo patients, suggesting anti-
LINGO may promote remyelinationLINGO may promote remyelination
No effect on visual acuity or OcularNo effect on visual acuity or Ocular
Coherence Tomography (OCT) of theCoherence Tomography (OCT) of the
optic discoptic disc
29. Phenytoin (Dilantin) for MSPhenytoin (Dilantin) for MS
Blocks Na entry into demyelinated axons, thereby protectingBlocks Na entry into demyelinated axons, thereby protecting
them from further injurythem from further injury
A phase II trial in optic neuritis is ongoingA phase II trial in optic neuritis is ongoing
(don(don’t let Martin Shkreli find out, he’ll buy the rights to Dilantin’t let Martin Shkreli find out, he’ll buy the rights to Dilantin
and charge $5,000 a pill like he did with pyrimethamineand charge $5,000 a pill like he did with pyrimethamine
(Daraprim) for HIV patients…)(Daraprim) for HIV patients…)
30. SummarySummary
MS traditionally was, and in some cases still is a progressiveMS traditionally was, and in some cases still is a progressive
CNS disease causing disability over many yearsCNS disease causing disability over many years
Current immunomodulatory medication significantly reduceCurrent immunomodulatory medication significantly reduce
relapses, MRI progression, and slow disability but do not haltrelapses, MRI progression, and slow disability but do not halt
the disease in all patientsthe disease in all patients
Early treatment is more effective than delaying 2-5 years byEarly treatment is more effective than delaying 2-5 years by
reducing the risk of relapses and lowering the risk of long-reducing the risk of relapses and lowering the risk of long-
term disease progressionterm disease progression
Yearly neurological examination and MRIs help guideYearly neurological examination and MRIs help guide
immunomodulatory treatmentimmunomodulatory treatment
The current standard is NEDA (No Evidence of DiseaseThe current standard is NEDA (No Evidence of Disease
Activity) clinically and by MRI and can be achieved in 1/3 ofActivity) clinically and by MRI and can be achieved in 1/3 of
patients if treated early with an effective medicationpatients if treated early with an effective medication
The future holds promise for agents to reverse disability byThe future holds promise for agents to reverse disability by
repairing damaged myelin and axons (anti-LINGO?)repairing damaged myelin and axons (anti-LINGO?)
Inflammatory events occur early in MS disease progression, while degeneration appears later.
This slide diagrams the natural history of MS. Keep in mind that the only tools we have to assess MS progression are clinical assessment and MRI. What you observe depends on when you look.
MRI activity is highest early in the disease. Later, although MRI activity has fallen off, increased degeneration is present, leading to progression of disability. By the time you see progressive disability, a degenerative process is occurring for which there is no effective treatment currently available.
Hence, the therapeutic window of opportunity is early in the progression of the disease. Strong therapy, initiated early, has the potential to slow the progression of disability and maintain function.