1	MS 101 Basic Facts about MS
2	First thing to emphasize For the newly diagnosed Don’t be afraid. Treatment advances occur daily in MS Prognosis of those in the past, not prognosis of that in future.
3	Optimism vs. Pessimism Optimistic Persons do better clinically are they optimistic because they feel better or do they feel better because they are optimistic?? Optimists are willing to explore possibilities Keep trying Don’t reject therapies that may help Work with their professionals bring up issues pertinent to quality of life
4	Optimism: Rationale It works better More effective treatments than before New effective treatments on Horizon
5	Strategy Divide and Conquer
6	Problems have solutions Optimism Collaboration between patient and physician
7	What is MS? Now we get to the technical stuff. MS is a chronic, inflammatory disease of the CNS in which most patients incur disability over time. MS affects approximately 400,000 people in the United States, two thirds of whom are women. Disease onset typically occurs in young adults between the ages of 20 and 40. .
8	MS: What it is The disease is believed to be caused by the destruction of myelin by the immune system. Myelin is the fatty tissue that surrounds and protects CNS nerve fibers and facilitates the flow of nerve impulses to and from the brain. The loss of myelin disrupts the conduction of nerve impulses, producing the symptoms of MS
9	SYMPTOMS Disease symptoms vary. Common symptoms are weakness, numbness, fatigue, vision problems, slurred speech, poor coordination, short-term memory loss, and bladder dysfunction. Severe cases of MS can be characterized by partial or complete paralysis.
10	Diagnosing MS Clinical Presentation: A person has to have evidence of two separate attacks MRI scans Laboratory especially spinal fluid tests Evoked responses No other disease entity or other explanation for two separate abnormalities in the nervous system So-called possible, probable and definite MS
11	CSF Cell count: 1/3 have 5-50 mononuclears Myelin basic protein: Can be found in first 2 weeks after a substantial exacerbation in 50-90% of patients can be seen in other neuro disease.
12	CSF cont’d Immunoglobulin: IgG synthesis rate Indicates activity of Plasma cells >3 in 80-90% of MS elevated in 12% of normal individual, and 30-50% of CNS infections Immunoglobulin: IgG index >0.7 in 86-94% of MS first CSF abnormality in early MS Oligoclonal bands present in over 90% of definite MS seen in other inflammatory diseases seen in 7% of normal control
13	MS interrupts pathways
14	Types of MS There are distinctive disease patterns in MS. In each case a person experiences sudden deterioration in normal physical abilities that may range from mild to severe. This attack, sometimes referred to as an exacerbation of MS, may last a brief time or continue for months.About 80% of patients begin with Relapsing-Remitting (RR) MS, the most common pattern. In this form, patients experience a series of attacks followed by complete or partial disappearance of the symptoms (remitting) until another attack occurs (relapse). It may be weeks to years between relapses.
15	Types of MS (2) In Primary- Progressive (PP) MS, there is a gradual decline in physical abilities.About 20% of patients begin with PP-MS. At least half of patients starting with relapsing remitting MS eventually develop a secondary progressive pattern within 10 or so years. A rarer pattern is called Progressive-Relapsing (PR) MS is characterized by a steady decline in abilities accompanied by frequent attacks. Some patients, 10-30% have so called “benign” MS, a patient experiences an initial attack followed by little or no progression. Finally, there is a rare, rapidly progressive form of MS called malignant MS.
16	MS Pathology types (Lucchinetti et al) Type 1: T-cell and cytokine mediated demyelination with remyelination Type II: T cell antibody and complement mediated demyelination with remyelination Type III: plaques not centered on perivenule striking oligodendrocyte apoptosis Type IV: like type I an II but no remyelination and oligo apoptosis
17	MRI scan Has become the one of the best diagnostic methods Also a very good way to follow MS over time. Many patients have no obvious symptoms yet their MRI scans continue to show worsening.
18	“Attack” = inflammation
19	MRI Scan Most sensitive test, abnormal in 85-97% of definite MS In Patients with early, relapsing-remitting MS studied monthly MRIs 70% have at least one enhancing lesion during a 3 month period. frequency of contrast enhancing lesion activity fluctuates from month to month but average 12 per year.
20	New Diagnostic criteria (MRI) Three of the following: One Gd-enhancing lesion or 9 T2 hyperintensities if there is no Gd lesion At least one infratentorial lesion At least one juxtacortical lesion At least three perivetricular lesions One spinal lesion can substitute for brainstem McDonald Annals of Neurol, 2001 50:121-7
21	Dissemination in time First scan >=3 mos after clinical event Gd positive lesion: dissem in time if not same site Gd neg lesion: follow up MRI at >3 mos New T2 or Gd lesion : dissem in time
22	Dissemination in time First scan <3 mos after event compared with 2^nd scan >3 mos after clinical event Gd positive lesion:dissem in time if not at the same site Gd negative lesion follow up MRI at >3 mos New T2 or Gd +lesion dissemination in time
23	Spinal lesion in MS Spinal cord lesions are in 75% of MS Pts Predominantly in C-spine Usually dorsolat or central and 0.5cm by 1-2cm and 1-2 vertical segments Less likely to enhance or cause cord swelling More likely to cause progressive disease T2 less predictive or disability than atrophy
24	Types of Treatment Recall divide and conquer strategy Trying to think about everything at once and you become overwhelmed Treatment of MS Acute Attack Treating inflammation Symptomatic Treatment
25	Inflammation MS “attack” = Area of inflammation that you can see on an MRI scan One or more Areas in the Nervous system is inflamed
26	Problem: Reducing inflammation Acute attack Preventing attack
27	Diseases the Mimic MS on MRI ADEM HTN small vessel d CADASIL Sarcoid Vasculitis Migraine Age related change Organic Aciduria Histiocytosis HTLV-1 Lyme Disease Leukodystrophies Mitochondrial Disease Lupus Behcet’s Disease HIV
28	Predictive value of T2 lesion load Lesion Load>1.23 CC 90% developed CDMS 52% EDSS .=3 Lesion Load <1.23 CC 55% developed CDMS, 23%EDSS >=3 Normal MRI 6% developed d, )% EDSS=3/.0
29	Acute Attack Steroids Solu-Medrol intravenous Prednisone ACTH Controversial Plasmapheresis IvIg
30	Preventing attack/progression Interferons Betaseron Avonex Copaxone Immune-suppressing drugs Methotrexate, Imuran. Cytoxan, Cyclosporine, Cell-Sept
31	“Lesion Burden”
32	“ABC drugs” Avonex Interferon Beta-1a: 30mcg. Im q week Betaseron:Interferon Beta-1b: .25 mg. sq q 2days Copaxone (CopI) Rebif
33	Avonex Made in Mammalian Cells. Closest to natural product Injected weekly, very convenient Found to decrease disability Alters MRI scans Decreases brain atrophy Well tolerated Most popular ABC drug 6 million units of antiviral activity/wk
34	Betaseron Oldest drug Highly effective on MRI scan Hi dose and not as close to natural product, made in bacteria May become ineffective in some people due to antibody production (“neutralizing antibodies”) Hi rate of flue-like symptoms Some Skin reactions 28 million units antiviral activity/ week
35	Copaxone Quite safe, almost without side effects Daily sq injection No doubt effective over long term
36	Immunotherapies Betaseron (IFN-β1b) 875mcg or 28MIU SC every week Avonex (IFNβ1a)30mcg or 6MIU IM once a week Copaxone (glatiramer acetate) 20mg sc once a day Novantrone (Mitoxatrone) 140 mg /M2 IV lifetime dose Rebif (IFNβ1a)66mcg or 13.2 MIU or 132 mcg or 26.4 MIU sc every week
37	CHAMPS and ETOMS Trials Avonex (CHAMPS) and Rebif (ETOMS) tested in patients with First Attack Avonex or placebo once weeklyu(N=393) Rebif 22mcg or 4.4MIU vs placebo weekly Pts had high risk of developing MS by original MS criteria
38	Mitoxantrone FDA approved for SPMS and worsening RRMS IV pulses q 3 mos at 5-12 mg/M2 Acute less toxicity than Cytoxan Risk of Cardiomyopathy limits cumulative lifetime dose to 120 mg Increased leukemia in cancer pts exposed. Has not been seen in5-10 yr MS expc.
39	Less lesion burden
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41	MS interrupts pathways
42	“Attack” = inflammation
43	Inflammation MS “attack” = Area of inflammation One or more Areas in the Nervous system is inflamed
44	Problem: Reducing inflammation Acute attack Preventing attack
45	Acute Attack Steroids Solu-Medrol intravenous Prednisone ACTH
46	Preventing attack/progression Interferons Betaseron Avonex Copaxone Immune-suppressing drugs Methotrexate, Imuran
47	Interferons Betaseron, Avonex Cut attacks by about one third Flu-like side effect ?Depression Hold in pregnancy
48	Interferons Avonex Convenient once a week injection intra-muscular shown to decrease disability progression More minimal side effects ?lower dose
49	Interferons Betaseron First to be introduced injected subcutaneously every other day Highest dose interferon more pronounced side effects some skin reactions start slow and with anti-inflammatory meds
50	Copaxone Novel Mechanism of action Every day sq injection Very well-tolerated ? As much MRI effect ? Effect on Disability
51	MS Issues Neuromuscular function Gait Vision Nutrition Bladder Function Sexual Function
52	MS Issues (cont’d) Pain/Paresthesia Energy Spousal/ Social/Relationships Psychiatric Cognition Spiritual Needs
53	Neuromuscular Function/prob’s Weakness Fatigue Spasticity Incoordination tremor Ataxia Dyscontrol
54	NM Fxn/ Weakness/sol’ns Attack: Treat Inflammation Steroids, longer acting agents Physical Therapies Increase strength, endurance Movement Strategies Assistive Devices Occup. Therapy: increase function
55	NM/ Fatigue Causes more Weakness ?Due to prolonged inflammation ?similar to prolonged viral illness (cold) Something in the blood causes fatigue Damage to nerve fibers is not as important ? Does more fatigue mean more inflammation Does fatigue affect prognosis?
56	NM/Fatigue/Sol’ns Drugs: Amantadine Activating antidepressants Prozac, Wellbutrin Stimulants Ritalin, Cylert, 4-Aminopyridine
57	NM/Fatigue/Sol’ns Exercise Preemptive - Goal to increase Stamina Budgeting Energy Energy-Saving Strategies
58	NM/Spasticity/Why? Nervous system: Control through INHIBITION Brain connection to spinal cord inhibits reflexes Connections are broken Reflexes are dis-inhibited (liberated from higher control Reflexes are increased Spasticity=Resistance to Motion: Tightness
59	NM/Spasticity/Sol’ns Physical/occup Therapies “Limbering” loosening up Drugs: Baclofen Tizanidine (Zanaflex) Valium Dantrium Botox
60	Baclofen
61	Baclofen Pump
62	NM/incoord./problem Disconnection of: Cerebellum Other motor areas Tremor Postural: trunk and head in arms and legs Disorganization of Movement
63	NM/Incoor/Sol’s Physical Therapy Mov’t Strategies and Synergies Assistive Devices Drugs Tremor Coordination anti-spastic
64	NM/Tremor/Surgery Thalamotomy/Pallidotomy Tremor pacing device
65	Activa tremor implant
66	tremor device placed in the VIM of thalamus
67	Gait/Problems Weakness lowers affected more than uppers Control Loss of Balance Ataxia
68	Gait/Weakness Therapy Exercise for muscle strengthening Stretches and Drugs for Spasticity
69	Gait/Balance Usually temporary Balance Exercises cane /walker vestibular medications attention to incoordination
70	Vision Loss of Vision in one eye (optic Neuritis) Double Vision Problems in coordinating moving eyes Complex visual perceptive problems
71	Vision Fortunately most problems are temporary
72	Nutrition Regular well-balanced diet recommended Low saturated fats Vitamin Supplement Avoid Obesity
73	Bladder Spastic Bladder Flaccid Bladder “Dyssynergia”
74	Bladder/Spastic Bladder is small and tight urgency, frequency many voids with small volumes Goes with spasticity in legs Ditropan (XL), Detrol
75	Bladder/flaccid Late in disease and less frequent Bladder is large and empties poorly Chronic change Intermittent Catheter usually recommeded
76	Bladder dyssynergia Sphincter and bladder contract together Trouble pushing urine out against a closed sphincter Training and medication that affects contraction of both elements
77	Sex Complex Issue Psychiatric aspects Anxiety Performance Relational Physical Issues Motor dysfunction Sensory Loss Ass’d with bladder/ spinal cord
78	Sex (Sol’s) Drugs Newer agents Stopping certain drugs Relational (counseling) Techniques Methods to get around specific problems Openness!!
79	Energy: Chronic effect of inflammation ?Viral Illness?
80	Energy (Solutions) Exercise (Incr. Stamina) Amantadine Activating Antidepressants Stimulants anti-inflammatories 4-AP
81	Cognition: More common than previously realized Attention Concentration Short-term memory Information Processing Executive Function/Organization Perception Speech 50+% of patients
82	“Lesion Burden”
83	Less lesion burden
84	Cognition - solutions Problems with thought don’t make you less of a person Just like a limp or problem with vision you have to get around.
85	Cognition: Sol’s 2 Aids: Notes Organizers Alarms Keyboards Personal Assistants
86	Cognition- sol’s 3 :Let people know... You are not goofing off You still care about your work Slowness of decision making does not make you indecisive If you are distractible it is not because you don’t care
87	Paresthesias Discomfort to severe pain “Painful tonic spasms” Anticonvulsants Tegretol, Dilantin, Neurontin Antidepressants
88	Psychiatric Reaction to chronic disease Reaction to other person’s reaction spouse employer other Direct effect of MS on brain Effect of other meds especially interferons
89	psychiatric Talk it out support groups avoid whipping yourself help with medication Developing outlets pleasures hobbies “purpose”
90	Spiritual Needs Developing a personal context Creating a “network” of acquaintances or one empathic person Refuse to be defined by your illness Taking charge
91	Betaseron in progressive MS A large European clinical trial of interferon beta-1b (Betaseron®) in over 700 people with secondary-progressive MS was stopped early because the study showed the drug can slow the progression of disability. The U.S. FDA is reviewing study findings for possible approval of Betaseron for this new use
92	Antegren Elan drug monoclonal antibody attaches to alpha 4 Integrin protein on lymphocyte protein is receptor for lymphocyte attachment to blood vessels
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96	Genetics and MS MS is almost unheard of in European gypsies, Eskimos and African Bantus and rare in native Americans, Japanese and other Asian groups.. The chance of having MS increases in families where a first-degree relative has the disease. Thus, a brother, sister, parent, or child of a person with MS stands a one to three-percent chance of developing MS. Similarly, an identical twin runs a 30% chance of acquiring MS whereas a non- identical twin has only a four-percent chance if the other twin has the disease. These statistics suggest a strong role for both heredity and environmental factors.