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Super MS lecture. Basic Facts about MS. Demyelinating Conditions. Multiple Sclerosis Progressive Multifocal Leukoencephalopathy Acute Disseminated Encephalomyelopathy (ADEM) Post infectious, post-vaccinial leukoencephalitis Infection induced demyelination

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super ms lecture

Super MS lecture

Basic Facts about MS

demyelinating conditions
Demyelinating Conditions
  • Multiple Sclerosis
  • Progressive Multifocal Leukoencephalopathy
    • Acute Disseminated Encephalomyelopathy (ADEM)
  • Post infectious, post-vaccinial leukoencephalitis
  • Infection induced demyelination
  • Demyelination of autoimmune disease eg “lupoid sclerosis”, Hashimoto’s related demyelination
  • Dysmyelinating Conditions
  • Transverse Myelitis
  • Tropical Spastic Paraparesis
  • Progressive mulitfocal leukoencephalopathy
  • SSPE
slide3
ADEM
  • Problem diagnosis is it MS or ADEM??
  • ADEM fulminent single attack
  • Post viral or post vaccination esp Rabies
  • Can be acute hemorrhagic leukoencphalitis
  • May require aggressive therapy e.g. iv Cyclophosphamide or plasmapheresis
dysmyelination
Dysmyelination
  • Disturbance in the formation and preservation of myelin so that its proper functioning is never established. These disorders are also termed leukodystrophies, and almost all of them manifest themselves early in life and are genetically determined.
metachromatic leukodystrophy
Metachromatic Leukodystrophy
  • Most common of these disorders
  • Autosomal recessive disorder
  • Both central and peripheral white matter involved
  • Predominantly a disease of infancy, but juvenile and adult forms do exist
  • Course is progressive, usually fatal in a few years
  • Pathology is diffuse, confluent loss of myelin that is most advanced in the cerebrum.
  • Due to inborn error of metabolism in which arylsulfatase A, although present, is enzymatically inactive. Leads to breakdown of myelin and the accumulation of sulfatide-rich lipids that appear as small globules of metachromatic material in the white matter.
krabbe s disease
Krabbe’s Disease
  • Usually appears in early months of life and progresses to death in one to two yearsAutosomal recessive caused by a deficiency of galactocerebroside, B-galactosidaseExpressed histologically by the presence of perivascular aggregates of globoid cells
schilder s sudanophilic leukodystrophy
Schilder’s Sudanophilic Leukodystrophy
  • Clinical symptoms (motor, sensory and cognitive) develop in the first decade and progress insidiously.The central nervous system is depleted of myelin, and the peripheral nervous system to a lesser degree.Ordinarily X-Linked
alexander s disease
Alexander’s Disease
  • characterized pathologically by lack of formation of myelin and innumerable Rosenthal fibers.
adrenoleukodystrophy
Adrenoleukodystrophy
    • Progressive nervous system deterioration
    • paralysis
    • hearing loss
    • visual impairment or blindness
    • deteriorating fine motor control
    • vegetative state
  • Seizures
    • Symptoms of adrenal gland failure
    • muscular weakness (asthenia)
    • wasting (loss of weight, muscle mass)
    • decreased appetite
  • increased skin pigmentation
adrenoleukodystrophy 2
Adrenoleukodystrophy 2
  • X-linked or neonatal recessive types
  • Increased Long Chain Fatty Acids
  • Special (‘Lorenzo Oil’) Diet
  • EMG, Skin test, blood for long chain fatty acids,MRI, make diagnosis
  • Chromosome defect in 7q21-q22 : Neonatal form
  • Treat Adrenal failure
tropical spastic paraparesis
Tropical Spastic Paraparesis
  • Now Ass’d with HTLVI
  • i.v. drug use, positive sexual partner, breast milk, blood transfusion
  • No known established treatment
  • Trials with Steroids Interferon Beta 1a
  • HTLV ass’d myelopathy (HAM)/TSP
tsp ham
TSP/HAM
  • Progressive muscle weakness
  • Sensory disturbance
  • Sphincter dysfunction
  • Urinary incontinence
  • Uveitis
  • Arthritis
  • Pulmonary lymphocytic alveolitis
  • Polymyositis
  • Keratoconjunctivitis sicca
  • Infectious dermatitis
progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
  • Immunosuppressed
  • Multifocal confluent white matter abnormalities
  • Relentlessly progressive with no cure
  • Human papilloma virus, JC virus
  • Vision loss, speech disturbance, ataxia, paralysis, depressed sensorium, seizures
slide16
PML

Bizarre bodies in oligos,

Transformed astrocytes

demyelination

slide17
MS
  • A disease leading to the destruction of Central Nervous system Myelin. Myelin speeds electrical conduction through axons.
  • Recent work has revived concept of destruction of axon cylinders as well as myelin.
  • Characterized by relapses and remissions in 85% of cases at presentation
ms what it is
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
what is ms
What is MS?

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.

  • .
clinical features
Clinical features
  • In 80-85% of persons MS is characterized by relapses and remissions. These are new symptoms that persist at least days and often weeks. Most patients early on have good recovery from attacks but they do not fully recover.
highly characteristic symptoms
Highly Characteristic Symptoms
  • There are some highly characteristic i.e. common symptoms that are so frequently part of the disease they are easily recognized and help confirm the diagnosis
characteristic symptoms signs
Characteristic Symptoms/signs
  • Optic Neuritis
  • LHermitte’s phenomenon
  • Double Vision
  • Evidence for spinal cord attack
      • Band like sensation
      • Loss of abilitities with both legs
  • Tic Doloreux esp on both sides or in young
  • INO
  • LE spastic weakness
  • Heat exacerbation of neurological symtoms/signs
  • Fatigue Related Neurologic Dysfunction (FRND)
optic neuritis
Optic neuritis
  • Eye pain on movement
  • Usually one eye
  • Central (macular visual loss)
  • Color vision, acuity affected
  • Afferent pupillary defect
  • Anterior: Papillitis, Posterior: retrobulbar
  • Attack in optic nerve lasts weeks
  • More common in young women
  • Positive vs. negative MRI scans
afferent marcus gunn pupil
Afferent (Marcus-Gunn) Pupil
  • Swinging flashlight
  • Consensual light response>> direct response
  • Affected pupil dilates when you shine light in eye
  • Optic atrophy, optic neuritis
lhermitte phenomenon
LHermitte Phenomenon
  • Ephaptic transmission
  • Neck flexion yeilds electrical shock sensation
  • Increased proximity of denuded axons
charcot triad
Charcot Triad
  • Scanning speech
  • Nystagmus
  • Intention tremor
vague symptoms
Vague Symptoms
  • Fatigue
  • Tingling
  • Muscle, joint aches and pains
  • Depression
  • Dizziness
vague symptoms30
Vague Symptoms
  • Many persons with vague symptoms may lack MRI or spinal fluid abnormalities and do not have MS
  • Often persons with vague symptoms will eventually be diagnosed to have MS.
symptoms
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.
diagnosis depends on
Diagnosis Depends on:
  • History
    • Relapses and remissions
    • Multiple Attacks
    • Characteristic symptoms
  • Physical Exam
  • MRI
  • Blood Tests
    • Mostly to exclude other entities
diagnosing ms
Diagnosing MS
  • Dissemination in time and space.
  • MRI scans
  • Laboratory supported esp. 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
slide34
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 patientscan be seen in other neuro disease.
csf continued
CSF continued
  • Immunoglobulin: IgG synthesis rateIndicates activity of Plasma cells>3 in 80-90% of MSelevated in 12% of normal individual, and 30-50% of CNS infections
  • Immunoglobulin: IgG index>0.7 in 86-94% of MSfirst CSF abnormality in early MS
  • Oligoclonal bandspresent in over 90% of definite MSseen in other inflammatory diseasesseen in 7% of normal control
what causes ms
What Causes MS??
  • We don’t know
  • Best Theory: MS is a chronic infection but we don’t yet know the agent which reacts like all infections do to affect the nervous system in a vulnerable host.
  • The Immune system plays a role.
    • Immune system helps to destroy myelin
    • Myelin destruction may also be part of chronic infection.
    • People with MS have certain inherited characteristics of their immune system e.g. HLA types
candidates
Candidates
  • Measles, dystemper
  • Herpes 6
  • Chlamidia pneumoniae
  • Other viruses and bacteria
slide38

Distinct patterns of multiple sclerosis pathology indicates heterogeneity in pathogenesisLucchinetti, et al.BRAIN PATHOLOGY6: (3) 259-274 JUL 1996

  • demyelination with relative preservation of oligodendrocytes
  • myelin destruction with concomitant and complete destruction of oligodendrocytes or primary destruction or disturbance of myelinating cells with secondary demyelination.
  • Primary Selective demyelination followed by secondary oligodendrocyte loss in the established lesions.
  • Destructive lesions with loss of myelin, oligodendrocytes, axons and astrocytes.
slide39

NEJM 349(2):139-145July 10, 2003Antimyelin Antibodies as a Predictor of Clinically Definite Multiple Sclerosis after a First Demyelinating EventThomas Berger,MD et al

  • myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in patients with a clinically isolated syndrome predicts the interval to conversion to clinically definite multiple sclerosis.
  • RR in dual Ab Pos pts was 76.5!!
  • All Pts had clinically isolated syndrome pos MRI and Pos CSF
symptoms40
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.
diagnosing ms41
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
classes of proof
Classes of Proof
  • History of two attacks with positive oligoclonal bands or increased IgG in CSF; no clinical or para clinical evidence of a disease. =Probable MS with laboratory support
  • History of two attacks without laboratory abnormalities.---Clinically probable MS
  • History of two attacks with clinical and para clinical evidence of one lesion; Oligoclonal bands or increased IgG present in CSF=Laboratory-supported definite MS
  • History of at least two attacks; Clinical evidence of at least one lesion and clinical or para clinical evidence of another lesion=Clinically-definite MS
mcdonald criteria
McDonald Criteria
  • Idea: Dissemination in time and space
    • 2 attacks (time), 2 lesions (space)
    • 2 attacks, one lesion: need MRI to find other lesions
    • 1 attack, 2 lesions: need to wait for 2nd attack
    • 1 attack, 1 lesion “clinically isolated syndrome” need 2nd attack, 2nd lesion
mcdonald criteria44
McDonald Criteria
  • Insidious progression sugg’v for MS
    • 1) 9 or more T2 lesions in brain, or 2) 2 or more lesions in spinal cord, or 3) 4-8 brain lesions plus 1 spinal cord lesion; or
    • Abnormal visual evoked potentials, and MRI demonstrating 4-8 brain lesions, or fewer than 4 brain lesions plus 1 spinal cord lesion; or
    • Dissemination in time demonstrated by MRIb; or
    • Continued progression for 1 year PLUS
    • Positive CSF
slide45
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 patientscan be seen in other neuro disease.
csf cont d
CSF cont’d
  • Immunoglobulin: IgG synthesis rateIndicates activity of Plasma cells>3 in 80-90% of MSelevated in 12% of normal individual, and 30-50% of CNS infections
  • Immunoglobulin: IgG index>0.7 in 86-94% of MSfirst CSF abnormality in early MS
  • Oligoclonal bandspresent in over 90% of definite MSseen in other inflammatory diseasesseen in 7% of normal control
types of ms
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.

types of ms 2
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.

secondary progressive ms
Secondary Progressive MS
  • Over half of RR MS patients enter secondary progressive phase:
  • Exacerbations no longer prominent or identifiable
  • Gradually increasing mostly LE dysfunction
kurtzke expanded disability scale
Kurtzke Expanded Disability Scale
  • -Normal neurologic exam.
  • 1.0-No disability, minimal signs on one FS
  • 1.5-No disability minimal signs on >1 FS
  • 2.0-Minimal disability in 1 FS
  • 2.5-Minimal disability in 2 FS
  • 3.0-Moderate disability in 1 FS; or mild disability in 3-4 FS, though fully ambulatory
  • 3.5-Fully ambulatory but with moderate disability in 3-4 FS.
  • 4.0-Fully ambulatory without aid, up and about 12hrs./day despite relatively severe disability. Able to walk without aid 500meters
  • 4.5-Fully ambulatory without aid, up and about much of day, able to work a full day, may otherwise have some limitations of full activity or require minimal assistance. Relatively severe disability. Able to walk without aid 300meters
  • 5.0-Ambulatory without aid for about 200m. Disability impairs full daily activities
  • 5.5-Ambulatory for 100m, disability precludes full daily activities
  • 6.0-Intermittent or unilateral constant assistance required to walk 100m with or without resting
  • 6.5-Constant bilateral support required to walk 20m. without resting
  • 7.0-Unable to walk beyond 5m even with aid, essentially restricted to wheelchair, wheels self, transfers alone
  • 7.5-Unable to take more than a few steps, restricted to wheelchair, any need aid in transfer, wheels self but may require motorized chair for full day\'s activities
  • 8.0-Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed much of day, retains self care functions, generally effective use of arms
  • 8.5-Essentially restricted to bed much of day,some effective use of arms, some self care functions
  • 9.0-Helpless bed patient, can communicate and eat
  • 9.5-Unable to communicate effectively or eat/swallow
  • 10.0-Death
mri order of age of lesions
MRI: Order of Age of lesions
  • Gad-enhancement – acute lesion
  • FLAIR imaging and T2
    • Periventricular “Dawson Fingers” follow WM tracts.
  • T2 Accumulation of areas;Volume affected
    • “lesion burden”
    • Involution of some lesions
  • T1 “black holes”, Atrophy - axonal
slide56
MRI
  • Newer techniques such a magnetization transfer show that even FLAIR underestimates disease activity!!
  • MS is constantly active on MRI
mri scan
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.
attack inflammation
“Attack” = inflammation

Series of MRI scans in one patient

mri scan61
MRI Scan
  • Most sensitive test, abnormal in 85-97% of definite MS
  • MR is not Specific!!
  • Rule: You cannot make the dx of MS on MRI alone!
ms mri
MS MRI
  • 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.
inflammation
Inflammation
  • MS “attack” = Area of inflammation that you can see on an MRI scan
  • One or more Areas in the Nervous system is inflamed
acute attack
Acute Attack
  • Steroids
    • Solu-Medrol intravenous
    • Prednisone
    • ACTH
  • Controversial
    • Plasmapheresis
    • IvIg
acute attack65
Acute Attack
  • Methylprednisolone 1000 mg i.v. in diminishing dosages for 3 days to 2 wks
  • Decadron starting at 200 mg i.v. may be substituted
  • Prednisone
  • ACTH (rarely used not available)
abcr drugs
“ABCR drugs”
  • Avonex Interferon Beta-1a: 30mcg. Im q week
  • Betaseron:Interferon Beta-1b: .25 mg. sq q 2days
  • Copaxone (CopI)
  • Rebif 44 mcg s.q. t.i.w.
early vs late treatment
Early vs late treatment
  • Early treatment critical
  • CHAMPS study with Avonex
    • Half the amount to definite MS in treated group
  • ETOMS: European study with 22 mcg q week of Rebif
interferons
Interferons
  • Decrease relapses by about 1/3
  • Extremely effective to reduce MS lesions on MRI “lesion burden”
  • Decrease Atrophy (Avonex)
  • Decrease Cognitive Decline (Avonex)
  • Decrease Disability (Avonex, Betaseron)
avonex
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
betaseron
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
  • 28 million units antiviral activity/ week
betaseron71
Betaseron
  • injected subcutaneously every other day
  • Highest dose interferon
  • more pronounced side effects
  • some skin reactions
  • start slow and with anti-inflammatory meds
copaxone
Copaxone
  • Quite safe, almost without side effects
  • Daily sq injection 20mcg
  • effective over long term
  • Category B drug in pregnancy
copaxone73
Copaxone
  • Novel Mechanism of action
  • Very well-tolerated
  • ? As much MRI effect (black holes effect)
  • ? Effect on Disability
rebif
Rebif
  • Beta-Interferon 1a given sq t.i.w. at 44mcg per injection=12 MIU or 36 MIU/wk
  • Compare to Avonex at 30 mcg (=6 MIU given qWeek i.m.
  • Higher dose option
rebif evidence trial
Rebif (EVIDENCE Trial)
  • 24 and 48 weeks
  • 677 pts randomized
  • Proportion of patients not suffering relapse 75% (Rebif) vs 63% (Avonex) at 24 wks, 62% vs. 52% at 48 wks
  • Acute MRI data looked at (blinded) approx 1/3 relative difference in gps
  • Study not completely blinded
  • Difference diminishes over time
  • Extension study compared pre to post Avonex to Rebif change also positive
        • Panitch H et al. Neurology 2002; 59: 1496-1506
comparing abc s
Comparing ABC’s
  • INCOMIN Study: Avonex vs. Betaseron
  • EVIDENCE: Avonex vs. Rebif
  • PRISM
  • Early Betaseron trial
  • All show some dose response effect
  • ??Try drug with the highest dose?
  • Betaseron and Rebif are close to equivalent doses
  • Rebif and Betaseron have much higher incidence of neutralizing antibodies and skin reactions.
natalizumab
Natalizumab

Humanized monoclonal antibody against α4-Integrin on lymphocyte surface

Preliminary trial in 72 patients over 24 weeks, a Phase II trial showed decrease in T2 MRI lesions

Blocks the attachment of WBC to endothelium preventing migration into the CNS

natalizumab antegren
Natalizumab “Antegren”
  • 213 Patients randomized
  • New lesions: 9.6 per patient in the placebo group, 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg/KG (P<0.001).
  • Twenty-seven patients in the placebo group had relapses, 13 at 3 mg (P=0.02) and 14 at 6 mg?KG (P=0.02).
      • Miller DH et al NEJM 348:15-23January 2, 2003
comparing abc s79
Comparing ABC’s
  • Neutralizing Antibodies
  • Betaseron:
    • Synthesized in E.coli not CMO cells
    • No side chains
    • ?more immunogenic??
novantrone
Novantrone
  • NOVANTRONE is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary progressive, progressive relapsing and worsening relapsing-remitting MS.
novantrone81
Novantrone
  • i.v. infusion once every three months
  • Decreased e.f. and CHF seen in oncology patients: Implies careful cardiac monitoring necessary
novantrone mitoxantrone
Novantrone (mitoxantrone)
  • Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding,
  • causes crosslinks and strand breaks.
  • Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA.
  • It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.
novantrone83
Novantrone
  • Shuts down Gad enhancing new lesions
  • Slows disability
  • Improves ambulation index
  • 2 small studies
dosage
Dosage
  • 12 mg/m2 iintravenous infusion every 3 months.
  • Evaluation of LVEF (by echocardiogram or MUGA) prior to administration of the initial dose of NOV ANTRONE and qDosage after 100mg/M2
  • Stop at cumulative Dose of 140 mg/m2,
preventing attack progression
Preventing attack/progression
  • Interferons
    • Betaseron
    • Avonex
  • Copaxone
  • Immune-suppressing drugs
    • Methotrexate, Imuran. Cytoxan, Cyclosporine, Cell-Cept
when immunomodulators inadequate
When immunomodulators Inadequate
  • Add therapy
  • MTX, Cell-Cept, Imuran,
  • Add monthly Solu-Medrol
  • IVIg
azathioprine
Azathioprine
  • An open-label study was performed to assess the effectiveness of oral azathioprine (AZA) on augmenting the response to interferon ß-1b (IFNß-1b) in patients with treatment-refractory relapsing–remitting MS. Six IFNß-1b-treated MS patients with continued disease activity were studied on IFNß-1b and AZA therapy for a median period of 15 months. A 69% reduction in the number of contrast-enhancing lesions was observed during the combination therapy (p = 0.002).
  • Neurology 2003;60:1849-1851
  • Yudkin PL, Ellison GW, Ghezzi A, et al. Overview of azathioprine treatment in multiple sclerosis. Lancet . 1991; 338: 1051–1055
azathioprine89
Azathioprine
  • We randomized 59 patients with relapsing-remitting multiple sclerosis to receive azathioprine (AZA) 3.0 mg/kg daily or placebo in a double- masked therapeutic trial. Analysis of data for predetermined primary outcome measures demonstrated a significant difference favoring AZA for observed mean exacerbation rate after 2 years of therapy and time to deterioration in both Ambulation Index and Kurtzke Expanded Disability Status Scale score. This study confirms a modest therapeutic benefit for azathioprine previously reported by other investigators
  • Goodkin et alNeurology, Vol 41, Issue 1 20-25,1991
lesion burden
“Lesion Burden”

More lesions = Greater Effect

pathology
Pathology
  • Courtesy path.upmc.edu/divisions/neuropath/ bpath/cases/case6/dx.html
  • Demyelinated optic nerve
interferons96
Interferons
  • Betaseron, Avonex
  • Cut attacks by about one third
  • Flu-like side effect
  • ?Depression
  • Hold in pregnancy
symptomatic treatment
Symptomatic Treatment
  • Many Symptoms
  • You have to get a history, therefore time consuming
  • Here’s where you get to actually talk to the patient
ms issues
MS Issues
  • Neuromuscular function
  • Gait
  • Vision
  • Nutrition
  • Bladder Function
  • Sexual Function
  • constipation
ms issues cont d
MS Issues (cont’d)
  • Pain/Paresthesia
  • Energy
  • Spousal/ Social/Relationships
  • Psychiatric
  • Cognition
  • Spiritual Needs
neuromuscular function prob s
Neuromuscular Function/prob’s
  • Weakness
  • Fatigue
  • Spasticity
  • Incoordination
    • tremor
    • Ataxia
    • Dyscontrol
nm fxn weakness sol ns
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
nm fatigue
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?
fatigue
Fatigue
  • Fatigue Related Neurological Dysfunction (FRND)
  • As you use muscles you get weaker
fatigue etiologies
Fatigue etiologies
  • Induced by humoral factor??
  • Related to handling weakness/disability
  • Depression or sleep related
  • FRND
  • May take time to determine cause
nm fatigue sol ns
NM/Fatigue/Sol’ns
  • Drugs:
    • Amantadine
    • Activating antidepressants
      • Prozac, Wellbutrin
    • Stimulants
      • Ritalin, Cylert,
    • 4-Aminopyridine
    • Provigil (modafinil) 200-400 mg
fatigue106
Fatigue
  • Determine etiology
  • Non-Drug regimens
  • Budgeting energy with rest pds
  • Improving rest/sleep
  • Addressing relationships
  • Deconditioning and exercise
  • Heat/cold
nm fatigue sol ns107
NM/Fatigue/Sol’ns
  • Exercise
    • Preemptive - Goal to increase Stamina
  • Budgeting Energy
    • Energy-Saving Strategies
ms pain
MS Pain
  • Sensory perversions
  • Bands
  • LHermitte
  • Trigeminal neuralgia model
  • Painful tonic spasm
  • Body mechanics-positioning
trigeminal neuralgia model
Trigeminal neuralgia Model
  • Anti-convulsants
    • Neurontin, Tegretol, Topamax, Lamictal
  • Tricyclic anti-depressants
  • Judicious use of narcotics
nm spasticity why
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
nm spasticity sol ns
NM/Spasticity/Sol’ns
  • Physical/occup Therapies
  • “Limbering” loosening up
  • Drugs:
    • Baclofen
    • Tizanidine (Zanaflex)
    • Valium
    • Dantrium
    • Botox
nm incoord problem
NM/incoord./problem
  • Disconnection of:
    • Cerebellum
    • Other motor areas
  • Tremor
    • Postural: trunk and head
    • in arms and legs
  • Disorganization of Movement
nm incoor sol s
NM/Incoor/Sol’s
  • Physical Therapy
    • Mov’t Strategies and Synergies
    • Assistive Devices
  • Drugs
    • Tremor
    • Coordination
    • anti-spastic
nm tremor surgery
NM/Tremor/Surgery
  • Thalamotomy/Pallidotomy
  • Tremor pacing device
tremor device
tremor device
  • placed in the VIM of thalamus
  • Consider also lesioning
gait problems
Gait/Problems
  • Weakness
  • lowers affected more than uppers
  • Control
  • Loss of Balance
  • Ataxia
gait weakness
Gait/Weakness
  • Therapy
  • Exercise for muscle strengthening
  • Stretches and Drugs for Spasticity
gait balance
Gait/Balance
  • Usually temporary
  • Balance Exercises
  • cane /walker
  • vestibular medications
  • attention to incoordination
vision
Vision
  • Loss of Vision in one eye (optic Neuritis)
  • Double Vision
  • Problems in coordinating moving eyes
  • Complex visual perceptive problems
vision123
Vision
  • Fortunately most problems are temporary
nutrition
Nutrition
  • Regular well-balanced diet recommended
  • Low saturated fats
  • Vitamin Supplement
  • Avoid Obesity
bladder
Bladder
  • Spastic Bladder
  • Flaccid Bladder
  • “Dyssynergia”
bladder spastic
Bladder/Spastic
  • Bladder is small and tight
  • urgency, frequency
  • many voids with small volumes
  • Goes with spasticity in legs
  • Ditropan (XL), Detrol
  • Botox into bladder - slick
bladder flaccid
Bladder/flaccid
  • Late in disease and less frequent
  • Bladder is large and empties poorly
  • Chronic change
  • Intermittent Catheter usually recommeded
bladder dyssynergia
Bladder dyssynergia
  • Sphincter and bladder contract together
  • Trouble pushing urine out against a closed sphincter
  • Training and medication that affects contraction of both elements
  • Sphincter meds
    • Flomax (tamsulosin), Cardura
slide129
Sex
  • Complex Issue
  • Psychiatric aspects
    • Anxiety
    • Performance
    • Relational
  • Physical Issues
    • Motor dysfunction
    • Sensory Loss
    • Ass’d with bladder/ spinal cord
sex sol s
Sex (Sol’s)
  • Drugs
    • Newer agents
    • Stopping certain drugs
  • Relational (counseling)
  • Techniques
    • Methods to get around specific problems
  • Openness!!
sex drugs
Sex: Drugs
  • Sildanifil (Viagra ©) 50-100mg
  • Muse© 125-1000mcg pellet intraurethr.
  • Wellbutrin ©buporopion up to 450mgm
energy
Energy:
  • Chronic effect of inflammation
  • ?Viral Illness?
energy solutions
Energy (Solutions)
  • Exercise (Incr. Stamina)
  • Amantadine
  • Activating Antidepressants
  • Stimulants
    • Provigil 100-200mg
    • Concerta, Ritalin, Cylert
  • anti-inflammatories
  • 4-AP
cognition more common than previously realized
Cognition: More common than previously realized
  • Attention
  • Concentration
  • Short-term memory
  • Information Processing
  • Executive Function/Organization
  • Perception
  • Speech
  • 50+% of patients
lesion burden135
“Lesion Burden”

More lesions = Greater Effect

cognition solutions
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.
subcortical dementia
Subcortical Dementia
  • Classically does not involve cortical fx:
    • Aphasia, agnosia, apraxia
  • Associated with motor impairment
  • Speed of mental processing
  • Multi-tasking
  • Associated with disease states aff’g WM
    • Mutli-infarct state
    • Huntington Chorea
    • MS
subcortical dementia139
Subcortical Dementia
  • Disconnections
  • Speed of Transmission
  • Motor impairments
cognition sol s 2
Cognition: Sol’s 2
  • Aids:
    • Notes
    • Organizers
    • Alarms
    • Keyboards
    • Personal Assistants
cognition sol s 3 let people know
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
paresthesias
Paresthesias
  • Discomfort to severe pain
  • “Painful tonic spasms”
  • Anticonvulsants
    • Tegretol, Dilantin, Neurontin
  • Antidepressants
psychiatric
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
psychiatric144
psychiatric
  • Talk it out
  • support groups
  • avoid whipping yourself
  • help with medication
  • Developing outlets
    • pleasures
    • hobbies
    • “purpose”
spiritual needs
Spiritual Needs
  • Developing a personal context
  • Creating a “network” of acquaintances or one empathic person
  • Refuse to be defined by your illness
  • Taking charge
betaseron in progressive ms
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
antegren
Antegren
  • Elan drug
  • monoclonal antibody
  • attaches to alpha 4 Integrin
    • protein on lymphocyte
    • protein is receptor for lymphocyte attachment to blood vessels
genetics and ms
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.

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