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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 l.jpg

Super MS lecture

Basic Facts about MS


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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


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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




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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.


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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.


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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


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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


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Alexander’s Disease

  • characterized pathologically by lack of formation of myelin and innumerable Rosenthal fibers.


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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


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    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


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    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


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    TSP/HAM

    • Progressive muscle weakness

    • Sensory disturbance

    • Sphincter dysfunction

    • Urinary incontinence

    • Uveitis

    • Arthritis

    • Pulmonary lymphocytic alveolitis

    • Polymyositis

    • Keratoconjunctivitis sicca

    • Infectious dermatitis


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    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


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    PML

    Bizarre bodies in oligos,

    Transformed astrocytes

    demyelination


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    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


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    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


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    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.

    • .


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    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.


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    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


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    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)


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    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



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    Afferent (Marcus-Gunn) Pupil

    • Swinging flashlight

    • Consensual light response>> direct response

    • Affected pupil dilates when you shine light in eye

    • Optic atrophy, optic neuritis


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    LHermitte Phenomenon

    • Ephaptic transmission

    • Neck flexion yeilds electrical shock sensation

    • Increased proximity of denuded axons


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    Charcot Triad

    • Scanning speech

    • Nystagmus

    • Intention tremor



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    Vague Symptoms

    • Fatigue

    • Tingling

    • Muscle, joint aches and pains

    • Depression

    • Dizziness


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    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.


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    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.


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    Diagnosis Depends on:

    • History

      • Relapses and remissions

      • Multiple Attacks

      • Characteristic symptoms

    • Physical Exam

    • MRI

    • Blood Tests

      • Mostly to exclude other entities


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    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


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    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.


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    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


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    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


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    Candidates

    • Measles, dystemper

    • Herpes 6

    • Chlamidia pneumoniae

    • Other viruses and bacteria


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    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.


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    NEJM 349(2):139-145 heterogeneity in pathogenesisJuly 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


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    SYMPTOMS heterogeneity in pathogenesis

    • 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.


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    Diagnosing MS heterogeneity in pathogenesis

    • 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


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    Classes of Proof heterogeneity in pathogenesis

    • 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


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    McDonald Criteria heterogeneity in pathogenesis

    • 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


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    McDonald Criteria heterogeneity in pathogenesis

    • 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


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    CSF heterogeneity in pathogenesis

    • 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.


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    CSF cont’d heterogeneity in pathogenesis

    • 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


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    Types of MS heterogeneity in pathogenesis

    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.


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    Types of MS (2) heterogeneity in pathogenesis

    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.


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    Secondary Progressive MS heterogeneity in pathogenesis

    • Over half of RR MS patients enter secondary progressive phase:

    • Exacerbations no longer prominent or identifiable

    • Gradually increasing mostly LE dysfunction


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    Types of MS at Presentation heterogeneity in pathogenesis


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    MS Prognosis in 15-20 Yrs. (Pre-ABC’s) heterogeneity in pathogenesis



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    Kurtzke Expanded Disability Scale heterogeneity in pathogenesis

    • -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


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    MRI: Order of Age of lesions heterogeneity in pathogenesis

    • 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


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    MRI heterogeneity in pathogenesis

    • Newer techniques such a magnetization transfer show that even FLAIR underestimates disease activity!!

    • MS is constantly active on MRI


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    Gad enhancement = acute lesion heterogeneity in pathogenesis


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    MRI scan heterogeneity in pathogenesis

    • 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.


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    “Attack” = inflammation heterogeneity in pathogenesis

    Series of MRI scans in one patient


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    MRI Scan heterogeneity in pathogenesis

    • 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!


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    MS MRI heterogeneity in pathogenesis

    • 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.


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    Inflammation heterogeneity in pathogenesis

    • MS “attack” = Area of inflammation that you can see on an MRI scan

    • One or more Areas in the Nervous system is inflamed


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    Acute Attack heterogeneity in pathogenesis

    • Steroids

      • Solu-Medrol intravenous

      • Prednisone

      • ACTH

    • Controversial

      • Plasmapheresis

      • IvIg


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    Acute Attack heterogeneity in pathogenesis

    • 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)


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    “ABCR drugs” heterogeneity in pathogenesis

    • 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.


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    Early vs late treatment heterogeneity in pathogenesis

    • 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


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    Interferons heterogeneity in pathogenesis

    • 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)


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    Avonex heterogeneity in pathogenesis

    • 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


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    Betaseron heterogeneity in pathogenesis

    • 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


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    Betaseron heterogeneity in pathogenesis

    • injected subcutaneously every other day

    • Highest dose interferon

    • more pronounced side effects

    • some skin reactions

    • start slow and with anti-inflammatory meds


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    Copaxone heterogeneity in pathogenesis

    • Quite safe, almost without side effects

    • Daily sq injection 20mcg

    • effective over long term

    • Category B drug in pregnancy


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    Copaxone heterogeneity in pathogenesis

    • Novel Mechanism of action

    • Very well-tolerated

    • ? As much MRI effect (black holes effect)

    • ? Effect on Disability


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    Rebif heterogeneity in pathogenesis

    • 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


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    Rebif (EVIDENCE Trial) heterogeneity in pathogenesis

    • 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


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    Comparing ABC’s heterogeneity in pathogenesis

    • 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.


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    Natalizumab heterogeneity in pathogenesis

    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


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    Natalizumab “Antegren” heterogeneity in pathogenesis

    • 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


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    Comparing ABC’s heterogeneity in pathogenesis

    • Neutralizing Antibodies

    • Betaseron:

      • Synthesized in E.coli not CMO cells

      • No side chains

      • ?more immunogenic??


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    Novantrone heterogeneity in pathogenesis

    • 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.


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    Novantrone heterogeneity in pathogenesis

    • i.v. infusion once every three months

    • Decreased e.f. and CHF seen in oncology patients: Implies careful cardiac monitoring necessary


    Novantrone mitoxantrone l.jpg
    Novantrone (mitoxantrone) heterogeneity in pathogenesis

    • 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.


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    Novantrone heterogeneity in pathogenesis

    • Shuts down Gad enhancing new lesions

    • Slows disability

    • Improves ambulation index

    • 2 small studies


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    Dosage heterogeneity in pathogenesis

    • 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,


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    Less lesion burden heterogeneity in pathogenesis


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    Preventing attack/progression heterogeneity in pathogenesis

    • Interferons

      • Betaseron

      • Avonex

    • Copaxone

    • Immune-suppressing drugs

      • Methotrexate, Imuran. Cytoxan, Cyclosporine, Cell-Cept


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    When immunomodulators Inadequate heterogeneity in pathogenesis

    • Add therapy

    • MTX, Cell-Cept, Imuran,

    • Add monthly Solu-Medrol

    • IVIg


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    Azathioprine heterogeneity in pathogenesis

    • 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


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    Azathioprine heterogeneity in pathogenesis

    • 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


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    “Lesion Burden” heterogeneity in pathogenesis

    More lesions = Greater Effect


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    Microscopic Picture of Axon and Myelin heterogeneity in pathogenesis


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    Pathology heterogeneity in pathogenesis

    • Courtesy path.upmc.edu/divisions/neuropath/ bpath/cases/case6/dx.html

    • Demyelinated optic nerve


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    Perivascular lymphs heterogeneity in pathogenesis


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    Hungry Macrophages heterogeneity in pathogenesis


    Astrocytosis gfap l.jpg
    Astrocytosis (GFAP) heterogeneity in pathogenesis


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    Interferons heterogeneity in pathogenesis

    • Betaseron, Avonex

    • Cut attacks by about one third

    • Flu-like side effect

    • ?Depression

    • Hold in pregnancy


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    Symptomatic Treatment heterogeneity in pathogenesis

    • Many Symptoms

    • You have to get a history, therefore time consuming

    • Here’s where you get to actually talk to the patient


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    MS Issues heterogeneity in pathogenesis

    • Neuromuscular function

    • Gait

    • Vision

    • Nutrition

    • Bladder Function

    • Sexual Function

    • constipation


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    MS Issues (cont’d) heterogeneity in pathogenesis

    • Pain/Paresthesia

    • Energy

    • Spousal/ Social/Relationships

    • Psychiatric

    • Cognition

    • Spiritual Needs


    Neuromuscular function prob s l.jpg
    Neuromuscular Function/prob’s heterogeneity in pathogenesis

    • Weakness

    • Fatigue

    • Spasticity

    • Incoordination

      • tremor

      • Ataxia

      • Dyscontrol


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    NM Fxn/ Weakness/sol’ns heterogeneity in pathogenesis

    • Attack: Treat Inflammation

      • Steroids, longer acting agents

    • Physical Therapies

      • Increase strength, endurance

      • Movement Strategies

      • Assistive Devices

    • Occup. Therapy: increase function


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    NM/ Fatigue heterogeneity in pathogenesis

    • 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?


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    Fatigue heterogeneity in pathogenesis

    • Fatigue Related Neurological Dysfunction (FRND)

    • As you use muscles you get weaker


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    Fatigue etiologies heterogeneity in pathogenesis

    • Induced by humoral factor??

    • Related to handling weakness/disability

    • Depression or sleep related

    • FRND

    • May take time to determine cause


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    NM/Fatigue/Sol’ns heterogeneity in pathogenesis

    • Drugs:

      • Amantadine

      • Activating antidepressants

        • Prozac, Wellbutrin

      • Stimulants

        • Ritalin, Cylert,

      • 4-Aminopyridine

      • Provigil (modafinil) 200-400 mg


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    Fatigue heterogeneity in pathogenesis

    • Determine etiology

    • Non-Drug regimens

    • Budgeting energy with rest pds

    • Improving rest/sleep

    • Addressing relationships

    • Deconditioning and exercise

    • Heat/cold


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    NM/Fatigue/Sol’ns heterogeneity in pathogenesis

    • Exercise

      • Preemptive - Goal to increase Stamina

    • Budgeting Energy

      • Energy-Saving Strategies


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    MS Pain heterogeneity in pathogenesis

    • Sensory perversions

    • Bands

    • LHermitte

    • Trigeminal neuralgia model

    • Painful tonic spasm

    • Body mechanics-positioning


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    Trigeminal neuralgia Model heterogeneity in pathogenesis

    • Anti-convulsants

      • Neurontin, Tegretol, Topamax, Lamictal

    • Tricyclic anti-depressants

    • Judicious use of narcotics


    Nm spasticity why l.jpg
    NM/Spasticity/Why? heterogeneity in pathogenesis

    • 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 l.jpg
    NM/Spasticity/Sol’ns heterogeneity in pathogenesis

    • Physical/occup Therapies

    • “Limbering” loosening up

    • Drugs:

      • Baclofen

      • Tizanidine (Zanaflex)

      • Valium

      • Dantrium

      • Botox


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    Baclofen heterogeneity in pathogenesis


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    Baclofen Pump heterogeneity in pathogenesis


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    NM/incoord./problem heterogeneity in pathogenesis

    • Disconnection of:

      • Cerebellum

      • Other motor areas

    • Tremor

      • Postural: trunk and head

      • in arms and legs

    • Disorganization of Movement


    Nm incoor sol s l.jpg
    NM/Incoor/Sol’s heterogeneity in pathogenesis

    • Physical Therapy

      • Mov’t Strategies and Synergies

      • Assistive Devices

    • Drugs

      • Tremor

      • Coordination

      • anti-spastic


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    NM/Tremor/Surgery heterogeneity in pathogenesis

    • Thalamotomy/Pallidotomy

    • Tremor pacing device


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    Activa tremor implant heterogeneity in pathogenesis


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    tremor device heterogeneity in pathogenesis

    • placed in the VIM of thalamus

    • Consider also lesioning


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    Gait/Problems heterogeneity in pathogenesis

    • Weakness

    • lowers affected more than uppers

    • Control

    • Loss of Balance

    • Ataxia


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    Gait/Weakness heterogeneity in pathogenesis

    • Therapy

    • Exercise for muscle strengthening

    • Stretches and Drugs for Spasticity


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    Gait/Balance heterogeneity in pathogenesis

    • Usually temporary

    • Balance Exercises

    • cane /walker

    • vestibular medications

    • attention to incoordination


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    Vision heterogeneity in pathogenesis

    • Loss of Vision in one eye (optic Neuritis)

    • Double Vision

    • Problems in coordinating moving eyes

    • Complex visual perceptive problems


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    Vision heterogeneity in pathogenesis

    • Fortunately most problems are temporary


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    Nutrition heterogeneity in pathogenesis

    • Regular well-balanced diet recommended

    • Low saturated fats

    • Vitamin Supplement

    • Avoid Obesity


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    Bladder heterogeneity in pathogenesis

    • Spastic Bladder

    • Flaccid Bladder

    • “Dyssynergia”


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    Bladder/Spastic heterogeneity in pathogenesis

    • 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 l.jpg
    Bladder/flaccid heterogeneity in pathogenesis

    • Late in disease and less frequent

    • Bladder is large and empties poorly

    • Chronic change

    • Intermittent Catheter usually recommeded


    Bladder dyssynergia l.jpg
    Bladder dyssynergia heterogeneity in pathogenesis

    • 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


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    Sex heterogeneity in pathogenesis

    • Complex Issue

    • Psychiatric aspects

      • Anxiety

      • Performance

      • Relational

    • Physical Issues

      • Motor dysfunction

      • Sensory Loss

      • Ass’d with bladder/ spinal cord


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    Sex (Sol’s) heterogeneity in pathogenesis

    • Drugs

      • Newer agents

      • Stopping certain drugs

    • Relational (counseling)

    • Techniques

      • Methods to get around specific problems

    • Openness!!


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    Sex: Drugs heterogeneity in pathogenesis

    • Sildanifil (Viagra ©) 50-100mg

    • Muse© 125-1000mcg pellet intraurethr.

    • Wellbutrin ©buporopion up to 450mgm


    Energy l.jpg
    Energy: heterogeneity in pathogenesis

    • Chronic effect of inflammation

    • ?Viral Illness?


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    Energy (Solutions) heterogeneity in pathogenesis

    • Exercise (Incr. Stamina)

    • Amantadine

    • Activating Antidepressants

    • Stimulants

      • Provigil 100-200mg

      • Concerta, Ritalin, Cylert

    • anti-inflammatories

    • 4-AP


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    Cognition: More common than previously realized heterogeneity in pathogenesis

    • Attention

    • Concentration

    • Short-term memory

    • Information Processing

    • Executive Function/Organization

    • Perception

    • Speech

    • 50+% of patients


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    “Lesion Burden” heterogeneity in pathogenesis

    More lesions = Greater Effect


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    Less lesion burden heterogeneity in pathogenesis


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    Cognition - solutions heterogeneity in pathogenesis

    • Problems with thought don’t make you less of a person

    • Just like a limp or problem with vision you have to get around.


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    Subcortical Dementia heterogeneity in pathogenesis

    • 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 l.jpg
    Subcortical Dementia heterogeneity in pathogenesis

    • Disconnections

    • Speed of Transmission

    • Motor impairments


    Cognition sol s 2 l.jpg
    Cognition: Sol’s 2 heterogeneity in pathogenesis

    • Aids:

      • Notes

      • Organizers

      • Alarms

      • Keyboards

      • Personal Assistants


    Cognition sol s 3 let people know l.jpg
    Cognition- sol’s 3 :Let people know... heterogeneity in pathogenesis

    • 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


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    Paresthesias heterogeneity in pathogenesis

    • Discomfort to severe pain

    • “Painful tonic spasms”

    • Anticonvulsants

      • Tegretol, Dilantin, Neurontin

    • Antidepressants


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    Psychiatric heterogeneity in pathogenesis

    • 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 l.jpg
    psychiatric heterogeneity in pathogenesis

    • Talk it out

    • support groups

    • avoid whipping yourself

    • help with medication

    • Developing outlets

      • pleasures

      • hobbies

      • “purpose”


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    Spiritual Needs heterogeneity in pathogenesis

    • Developing a personal context

    • Creating a “network” of acquaintances or one empathic person

    • Refuse to be defined by your illness

    • Taking charge


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    Betaseron in progressive MS heterogeneity in pathogenesis

    • 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


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    Antegren heterogeneity in pathogenesis

    • 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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    Genetics and MS heterogeneity in pathogenesis

    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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