Multiple sclerosis
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  • A list of possible diagnostic criteria for MS
  • 2 pictures of brain x-rays
  • 2 more pictures of brain x-rays
  • 2 pictures of side view head x-rays
  • The picture of a spine x-ray in the middle
  • A chart showing the visual evoked potentials
  • A diagram shows the absence of oligoclonal bands and the presence of them in CSF
  • Typical flu like symptoms can be treated with fever reducers.
  • Controlled High Risk Avonex Multiple Sclerosis Prevention Study In Ongoing Neurological Survelillance 13 47 83

Multiple sclerosis Multiple sclerosis Presentation Transcript

  • MULTIPLE SCLEROSIS - Recent perspectives: Prof. A.V. SRINIVASANDr.S.Arunan,Dr.C.T.Suresh,Dr.G.Mugundhan,Dr.G.Vikramraj. INSTITUTE OF NEUROLOGY MADRAS MEDICAL COLLEGE, CHENNAI-3 24th MAY 2008
  • LAND MARKS IN MS: Top Ten Events...Thus Far 1868: MS described by Jean-Martin Charcot. 1878: Myelin discovered by Louis Ranvier. 1916: Detailed microscopic description made by James Dawson revealed the basic damage done in MS. 1935: An animal form of NIS (EAE) developed by Thomas Rivers, ultimately suggesting an autoimmune basis for the disease. 1946: National Multiple Sclerosis Society founded by Sylvia Lawry.
  •  1948: Under an early NMSS grant, oligoclonal bands discovered in the spinal fluid by Elvin Kabat and others, provided a diagnostic test suggestive of MS and linking MS to immune system problems. 1965: Definite criteria for MS diagnosis developed by NMSS expert committee. 1969-1970: ACTH used to treat MS exacerbations. This was the first controlled trial of a successful treatment for MS: it used newly standardized diagnostic criteria and rating scales to evaluate the efficacy of treatment. Success is a prize to be won. Action is the road to it. Chance is what may lurk in the shadows at the road side. - O. Henry View slide
  •  1981: MRI first used to examine a person with MS. MRI revolutionized diagnosis and provided evidence that MS is a constantly active disease even when symptoms abate. 1993: Beta-interferon 1b (Betaseron) approved as the first drug to alter the course of MS. 2001:Macdonald’s criteria. Discipline Weighs Ounces Regret Weighs Tons View slide
  • THE MAGNITUDE: Most common nontraumatic neurologic cause of disability. 400000 persons in USA affected. USA spends 7 billion per annum(whetten- goldstein etal 1998). If extrapolated to current economic environment MS society – burden of 20 billion dollars."There is dignity in suffering; nobility in pain; but failure is a salted wound, that burns and burns again!"
  • MS epidemics:
  • EPIDEMIOLOGY: The peak onset of MS occurs in the late 30s. It has been suggested that pubertal and sex hormone factors play a role. MS clusters - in TIME- favored an environmental agent – kutzke etal,1995 and other investigators- unable to identify agent. North-south gradient- in northern hemisphere and south-north gradient in southern hemisphere. The power to believe in yourself, is the power to change fate
  •  VITAMIN D-PROBABLE PROTECTIVE ROLE. (Islam et al 2007,Van der Mei 2003) - also protective for animal model of EAE. Smoking – increased risk - odds ratio 1.81(Riise et al – Norwegian study) Hawkes et al 2007 – 1.22 – 1.51 odds ratio – increased risk of MS. EBV – Increased risk – 99% of MS patients have evidence of EBV while 90% of non MS patients have evidence of EBV. Brain infiltrating B and plasma cells – 100%evidence of EBV (Serfani etal 2007) – incidental association or causation? Memory, the daughter of attention , is the teeming mother of knowledge - Martin Tupper
  • Migration:
  • Unidentified gene – hunt still on:
  •  If migration occurs before 15 years – adopted country prevelance.(gale and martyn 1995) Samples – SMALL. Increased incidence - in monozygotic and dizygotic twins – Genetic predisposition ? Though in northern Europeans -HLA 2 association linked-other studies inconclusive (Ebers etal). Two loci in IL2 and IL7 – increased risk for MS(International MS genetics con 2007;gregory etal 2007)Our greatest glory is not in never failing, but in rising up every time we fail
  • MS IN INDIA: 1.33/100000 – Singhal etal. 2.54% of total neurology admissions between January93 to March98 -Syal,Khandelwal N, PGI Chandigarh. In the Parsi - a prevalence of 26/100,000 – Wadia etal. Optico spinal form more common than west -Pandit et al. Class II HLA association in 23 MS - non Parsi origin DRB1*1501 (50%) similar to western studies.11 Resistance drains energy Acceptance saves it Cheerfulness sustains it -- Anonymous
  • Where are We: The hunt continues. Handful of genes might be operative – ELUSIVE. An environmental agent – STILL UNIDENTIFIED. IS IT AN INTERPLAY BETWEEN BOTH – A PROBABLE YES. We do not know one millionth of one percent about anything – Thomas Edison
  • IMMUNO PATHOGENESIS:
  •  Initiating cause unknown. T cells activated – APC - TCR &MHC/ANTIGEN COMPLEX – Trimolecular complex – differentiates –CD4 and CD8 T h 1- pro inflammatory -TGF beta + IL 6 stimulates – CD4 – Th17. Treg cells – a subset of CD4 – expresses high level ofCD25 and transcription factor Foxp3 (Rose and Carlson 2007) Migration of Th1 to receptive CNS. “ Many Ideas grow better when transplanted into another mind than in the one where they sprang up” - O.W. Holmes
  •  Reactivation by auto antigens. Release of inflammatory cytokines. At this level there is significant contribution from by B cells. Result- axonal loss and demyelination. Success is a prize to be won. Action is the road to it. Chance is what may lurk in the shadows at the road side.
  • An active lesion:
  • LUCCHINETTI CATEGORISATION: Type 1- demyelination and macrophages relate products. Type 2-presence of immunoglobulin and complement. Type 3-lacks immunoglobulin and complement,early loss of myelin associate glycoprotein-oligodendrocyte dysfunction. Type 4-apoptosis of oligodendrocytes-DNA fragmentation. Every discovery contains an irrational element or 4 creative intuition
  • Current concepts: Axonal damage and demyelination. Remyelination does occur – transient – shadow plaque. MBP EXON 2 might be responsible – can be upregulated. Jagged notch pathway –active lesions-can be down regulated for remyelination. Chemockine ligand 1 can be targeted to prevent recruitment of T cells to Breach the BB barrier. Motivation is the Spark that lights the Fire of Knowledge and fuels the engine of Accomplishment”
  • Clinical course:
  • Clinical severity:  BENIGN AND MALIGNANT MS:  RELAPSING SUBTYPE.  FEMALE SEX & AGE LESS THAN 40.  PROLONGED REMISSION AFTER FIRST ATTACK( MORE THAN 1 YEAR)  INFREQUENT AND MILD RELAPSES WITH GOOD RECOVERY.  MILD DISABILTY OVER 25 YEARS AND LOW LESION LOAD IN MRI WITH LITTLE CORTICAL ATROPHY.Marriage and Private Practice are the two extinguishers of science
  • CLINICAL FEATURES: MOTOR. SOMATOSENSORY. VISUAL-ANTERIOR PATHWAY INVOLVED,UNILATERAL,CENTRAL SCOTOMA WITH PAIN-CHRACTERISTIC-IMPROVES BY 6 MONTHS. OTHER CARNIAL NERVES AND BRAIN STEM SYMPTOMS- INO,MONOCULAR NYSTAGMUS,OLFACTORY DISTURBANCE ,FACIAL WEAKNESS ETC.Expert is one who think to his chosen mode of ignorance
  •  COGNITIVE AND PSYCHIATRY DISTURBANCES – PREDOMINANTLY SUBCORTICAL(Kotterba etal 2003,Schltheis et al 2001) CORTICAL VARIANT DO OCCUR(Zerei and colleagues 2003) Depression – 75% suicide 15% of adult deaths(Feinstein 2002) “ By Nature All Men/ Women are alike but by Education widely different”
  •  FATIGUE-SYSTEMIC AND HANDICAP FATIGUE. PAIN – FREQUENT PRIMARY PAIN SYNDROMES- NEURALGIC PAIN(5TH NERVE,DYSESTHETIC PAIN OF LEGS,RADICULAR PAIN,TONIC SEIZURES,SPASTIC PAIN,OPTIC NEURITIS PAIN. SECONDARY PAIN SYNDROMES LIKE LOW BACK ACHE AND OSTEPOROSIS WITH FRACTURES. “ Medical School can be a tool of torture or an Instrument of Inspiration”
  • Paroxysmal symptoms: Trigeminal neuralgia. Tonic seizures. Paroxysmal dysarthria. Hemifacial spasm. Paroxysmal itching. Abrupt loss of muscle tone. Paroxysmal aphasia. Paroxysmal kinesogenic choreoathetosis. Lhermitte’s sign.
  • Favorable indicators: Early age of onset. Female sex. Optic neuritis as presenting episode. Sensory symptoms as presenting episode. Acute onset. Little residual disabilty. Long inter exacerbation period. Small lesion load.
  • Unfavorable indicators: Later age of onset. Progressive course. Male sex. Frequent exacerbations. Poor recovery. Involvement of cerebellar and or motor functions. More disease load in MRI. Positive oligoclonal bands.
  • DIAGNOSIS OF MULTIPLE SCLEROSIS
  • Schumacher Diagnostic Criteria (Schumacher G, et al. Ann NY Acad Sci 1965) The following 6 criteria are essential for a diagnosis of “definite MS”: – Age between 10-50 yrs – Objective abnormalities on exam – Two or more separate lesions in the CNS – CNS disease must reflect white matter involvement – Consistent time course  Attacks last > 24 hrs; spaced 1 mo apart  Slow/stepwise progression > 6 mo – No better explanation by a physician competent in clinical neurology
  • Poser Diagnostic Criteria(Poser C, et al Ann Neurol, 1983)
  • McDonald Diagnostic Criteria Primary Progressive MS Insidious course with steady progression of clinical deficits with paraclinical evidence: – DIS by MRI in combination with VER & positive CSF – DIT by MRI or continued progression for 1 yr Thought is the labour of the intellect; Reverie is its pleasure
  • McDonald Diagnostic Criteria MRI-High Specificity & Sensitivity for MS Typical MS demyelinating lesions meeting at least 3 of the following 4 criteria: – At least 1 Gd lesion or at least 9 T2 lesions – At least one infratentorial lesion – At least one juxtacortical lesion – At least 3 periventricular lesions
  • McDonald Diagnostic Criteria MRI-Dissemination in Space Stringent MRI Criteria – At least 3 of the 4 criteria must be met:  1 Gd enhancing lesion or 9 T2 lesions  > 1 Infratentorial lesion  > 1 Juxtacortical lesion  > 3 Periventricular lesions MRI + CSF Criteria – Both of the following must be met:  > 2 lesions consistent with MS  CSF showing OCB or increased IgG index
  • McDonald Diagnostic Criteria MRI-Dissemination in Time If the first MRI is performed 3 months after the clinical event, 1 of the 2 below must be found: – > 1 Gd lesion not at site of original attack; or – MRI 3 months later showing a new T2 or Gd lesion If the first MRI is performed < 3 months after the clinical event, then a second MRI done 3 months after the attack provides evidence for DIT if 1 of the 2 below must be found: – New Gd lesion on the second MRI – Later MRI showing new T2 or Gd lesion
  •  MRI Evidence Of Dissemination In Space is when three out of four criteria are seen: 1 Gd-enhancing or 9 T2 hyperintense lesions if no Gd-enhancing lesion 1 or more infratentorial lesions 1 or more juxtacortical lesions 3 or more periventricular lesions (1 spinal cord lesion can replace a missing infratentorial lesion and contribute to the 9 T2-lesions) It is a great misfortune not to posses sufficient wit to speak well nor sufficient judgement to keep silent. La Broyers Charactor
  •  The revised MRI criteria for dissemination in time are detection of gadolinium enhancement at least three months after the onset of the first clinical event or detection of a new T2 lesion appearing at any time compared with a reference scan done at least 30 days after the onset of the initial clinical event . Positive CSF is oligoclonal IgG bands in CSF (and not serum) or elevated IgG index. Positive visual evoked potentials (VEP) is delayed but well-preserved wave form Material Gains Soul Losses
  •  An Attack is defined as: Neurological disturbance of kind seen in MS Subjective report or objective observation 24 hours duration, minimum Excludes pseudo attacks, single paroxysmal episodes. Time Between Attacks is defined as 30 days between onset of event 1 and onset of event 2.
  • New Queensquare’s criteria In 2007, new criteria were proposed in which DIS requires at least one T2 lesion in at least two of four locations (juxtacortical, periventricular, infratentorial, and spinal- cord) and DIT requires a new T2 lesion on a follow-up scan “ Back pain – prize human beings pay for their UPRIGHT POSTURE”
  •  The specificity of all criteria for CDMS was high (2001 McDonald, 91%; 2005 McDonald, 88%; new, 87%). Sensitivity of the new (72%) and 2005 McDonald (60%) criteria were higher than the 2001 McDonald criteria (47%). “ You have got to be before you can do and do before you can have”
  •  The new criteria are simpler than the McDonald criteria without compromising specificity and accuracy. The presence of both DIS and DIT from two MRI scans has a higher specificity and risk for CDMS than either DIS or DIT alone. A true commitment is a heart felt promise to yourself from which you will not back down - D. Mcnally
  • McDonald Diagnostic Criteria Correct Application Clinical & lab findings typical of MS No better explanation of patient’s findings Unusual cases require close follow-up Criteria may be applied flexibly but not casually Revisions to criteria may be needed in future
  • McDonald Diagnostic Criteria Prospective Performance (Dalton, et al Ann Neurol 2002) Diagnosis of MS by McDonald Diagnostic Criteria in CIS patients at one year after presentation compared to reanalysis of these patients by Poser criteria at three years: – Sensitivity: 83% – Specificity: 83% – PPV: 75% – NPV: 89%
  • Focused Neurologic Exam (Adapted from Whitney D, Int J MS Care, 2001) MMSE: Attention, psychomotor slowing CN: VA, fundoscopic exam, VFs, swinging flashlight, EOM evaluating for paresis (INO) & nystagmus Reflexes: asymmetries, Babinski sign Motor: spasticity, pyramidal pattern of weakness Sensory: Thoracic or cervical level Gait: integrates many functions, 25’ timed walk Bladder: PVR (if symptomatic)
  • Imaging & Lab Work-up for MS (Modified from Fleming J, MS & Its Masquerades, AAN-2003) Brain MRI with Gd VERs CBC, Chem 7, Liver enzymes Lyme serology (based on exposure history) ANA, RPR, ESR B12 TSH HIV CSF (based on clinical and MRI) C & T Spine MRI (if Brain MRI nl or indicated clinically) CXR
  • MRI: FLAIR & T1 with Gadolinium (Noseworthy J, et al NEJM, 2000)
  • MRI: T1 “Black Holes”
  • MRI: Sagittal Views
  • MRI: Spinal Imaging
  • NON CONVENTIONAL MRI: MTI : Using MTI with gadolinium to improve lesion detection Distinguishing lesions of differing severity; Studying MTR in brain tissues that appear normal on conventional MRI. T1-hypointense lesions ("black holes") have a lower MTR than T1 iso intense lesions- Axonal damage. MTR values fall considerably when gadolinium enhancement occurs in lesions, with recovery of MTR over months, although not usually back to normal
  •  Diffusion tensor imaging: Chronic lesion : increased ADC and MD with decreased FA in chronic T1 hypo intense lesions - extensive tissue loss. Acute lesion : FA is lower in acute, gadolinium enhancing lesions - extracellular oedema - alters the anisotropic diffusion. ADC and MD values are raised, but the extent may depend upon the lesion age. ADC – Apparent diffusion co effecient. MD- mean diffusion. FA- fractional anisotrophy. Many Ideas grow better when transplanted into another mind than in the one where they sprang UP O.W. Holmos
  • Visual Evoked Potentials (Baker’s Clin Neurol 2003)
  • Oligoclonal Bands: Bakers Clinical Neurology, CDROM-2003
  • MS Variants: Balo’s concentric sclerosis. Neuromyeltis optica. Marburg Disease. Myelinoclastic Diffuse sclerosis. Tumefactive multiple sclerosis. Clinically isolated syndromes. “ Healthy Mind and Healthy expression of Emotion Go hand in Hand”
  • Balos concentric sclerosis: Pathologic diagnosis- rare acute variant-large concentric bands of demyelination separated by intact myelin – Leukoencephalitis periaxialis concentrica(Karaarslan etal2001. More common in Phillipines and China. Acute,monophasic,20-50 yrs,features of raised ICT,seizures,aphasia,decreased level of consiousness. CSF similar to MS. Differs from MS in clinical presentation,type of lesion & no involvement of Brainstem,optic nerve,spinal cord. Post mortem diagnosis
  • No Caption Found IANNUCCI, G. et al. J Neurol Neurosurg Psychiatry 2000;69:399-400Copyright ©2000 BMJ Publishing Group Ltd.
  • Neuro myelitis optica:
  •  NMO is considered - longitiduinally extensive myelitis.(more than 3vertebral segments) - optic neuritis. - Normal MRI or atypical brain lesions. Different from MS- clinically,readiologically and pathologically. Can be monophasic or relapsing. NMOIgG antibody - targets aquaphorin 4 water channel – 73%sensitive & 91%specific (Lennon &coworkers mayo clinic)
  •  NMO SPECTRUM DISORDER: Idiopathic relasping myelitis optic neuropathy. Asian optico spinal MS. These patients – histopathologically similar to NMO & Positive for NMO IgG. “Fools Admire but of men of sense approve”
  •  Eugene Devic (1858- 1930)- raised two questions- Why such a peculiar localisation? What is the intimate nature of the disease? Both the questions largely unanswered. Eugène Devic (1858–1930).
  • TUMEFACTIVE MS:
  •  MARBURG – ACUTE FULMINANT,DEATH BY 1 YEAR – DUE TO BRINSTEM INVOLVEMENT- FEW CASES- MATURE MYELIN CONVERTED TO CITRULLINATED AND IMMATURE FORM (WOOD etal 1996) TUMEFACTIVE MS – LARGE PLAQUES > 2CM WITH MASS EFFECT AND RING ENHANCEMENT – MIMICKING A TUMOR – NO CONSISTENT CLINICAL COURSE KNOWN. “ Social Isolation is in itself a pathogenic Factor for disease production” - Dr. Elsen Borg
  •  Concentric lacunar leukoencephalopathy – pathological diagnosis –rare disorder with extensive axonal damage and demyelination &features of cavitation separated with band of gliosis. Disseminated subpial demyelination – two cases are described – focal neurological deficits with mental status changes. “ My Opinions are founded on knowledge but modified by experience”
  •  Schilder’s disease: Handful of cases – childhood MS-rare condition. Bilateral symmetric hemispherical demyelinating lesions U fibers involved (Kotil etal 2002)
  • Monophasic syndromes within the spectrum of ADEM: Normal MRI and CSF – low risk for conversion into MS. MRI lesions & Positive CSF- High risk. (Fillipi etal 1994,Brex etal 2002) Optic neuritis – 12 - 85% conversion to MS. Complete transverse myelopathy – low risk (2 - 8%) Incomplete myelopathy (72 - 80%)
  • Factors related to risk ofdevelopment of MS after Acute ON: High Risk – Young adult(26-40 Yrs). Venous sheathing. Recurrent optic neuritis. Female sex. History of minor neurological symptoms. Brain MRI lesions. CSF oligoclonal bands or intrathecal IgG production.
  •  Lower risk: Age <10yrs. Macular star/exudates. Retinal or disc hemorrhage. Severe disc edema. No Brain MRI lesions. Normal CSF
  • Figure 4 Approach to the diagnosis of multiple sclerosis (MS) in a patient with a typical presentation of a clinically isolated syndrome (CIS). CSF, cerebrospinal fluid; MRI, magnetic resonance imaging. Trip, S A et al. J Neurol Neurosurg Psychiatry 2005;76:iii11-iii18Copyright ©2005 BMJ Publishing Group Ltd.
  • Three Categories of Treatment Treatment of disease activity. Treatment of exacerbations. Treatment of symptoms. A open foe may prove a curse ; but a pretended friend is worse
  • Rationale for disease modifying treatments in MS Relapsing remitting Secondary & primary MS progressive MSPrevent new inflammatory Prevent loss of nerve fibres:lesions: (neuroprotection)β-interferon ?lamotrigineCopaxone ?cannabinoidsMitoxantronePrevent development of Remyelination:secondary progressive MS: ?stem cells?possible with existingtreatments
  • Treatment of Underlying Disease Interferons vs. Glatiramer AcetateGlatirmer acetate is a substitute antigen that mimics myelinbasic protein. It inhibits the CNS immune reactions that areresponsible for tissue damage. Given subcutaneously daily injection Reduces number of attacks and brain lesions seen on MRI patients No flu-like side effects associated with interferons
  • Interferons : Discovered in 1957 Significant antiviral agents phenomenon where oneinfection with one virus interfereswith a subsequent infection withanother virus The Truth is fear and immorality are two of the greatest inhibitors of Performance too progress
  • What are they??A protein substance naturally produced in thebody and believed to function to modulate theimmune system. Interferons interact withreceptors on non-infected cells to promote thesynthesis of antiviral proteins that preventfurther infection. They belong to Cytokines,which are hormones of the immune system.
  • Beta InterferonBeta interferon-1a  Avonex – administered weekly by an intramuscularly injection (2003)  Rebif – administered subcutaneously three times a week (2002)Beta interferon-1b  Betaseron – administered subcutaneously every other day (1993)
  •  Early and aggressive treatment with immune stimulating interferons can delay diseae progression. Prevents crippling symptoms of MS “ Men of Genius Admired: Men of Wealth envied:women of power feared: But only women of character are trusted” -A- Friedman
  • Common Side Effects…  Typical Flu-like symptoms  headache, nausea, and fever  muscle aches Chills Irritation at the injection siteAlcohol and exposure to sunlight may irritate side effects
  • TRIALS:CHAMPIONS: Avonex altered long-term course MS in patientswho began treatment immediately after initial attack35% decrease in the rate of developing second attack42% reduction in new or enlarging T2 hyper intense lesions Avonex associated with fewer neutralizing antibodies. Binding antibodies decrease the medications efficacy. They hasten the drugs removal from the bloodstream. 10 0 80 Avonex 60 40 Rebif 20 Betaseron 0
  • June 18th 2003EVIDENCE: Showed that patients on Avonex who converted toRebif showed signs of relapse reduction  Patients taking Rebif had fewer active lesions per MRI scan for all studied activity July 21st 2003QUASIMS: Higher doses and frequencies of interferon beta arenot necessarily better with comparable disease progression  Annual Relapse rates Avonex - .52 Rebif - .69
  • Tysabri targets α4-Integrin (VLA4)adhesion molecule on white blood cells White blood cells White blood cells use Chemoattractant signal adhesion molecules VLA4 and VCAM1 to α 4 (VLA-4) cross the blood-brain barrier and enter the Blood Vessel Lumen brain and cause new Endothelial Cells inflammatory MS lesions Brain VCAM-1 Tysabri block the White blood cells VLA4 adhesion Chemoattractant Signal molecule on white blood cells so α 4 (VLA-4) should stop them Tysabri from getting in to the Blood Vessel Lumen brain and causing Endothelial Cells new MS lesions Brain VCAM-1
  • Other trials: AFFIRM STUDY- NATALIZUMAB MONOTHERAPY MORE EFFECTIVE THAN INTERFERONS IN TREATING RRMS. BEYOND TRIAL-DOUBLE DOSE INTERFERON BETA1B – NO ADVANTAGE OVER CONEVENTIONAL DOSAGE. REGARD TRIAL - THRICE WEEKLY INTERFERON SHOWED NO ADVANTAGE OVER GLATIRMER ACETATE. ETOMS TRIAL- EARLY TREATMENT WITH INTERFERONS REDUCED SECOND ATTACK BY 24%
  • COMBINATION THERAPY: NATALIZUMAB WITH IM BETA 1A OVER INTERFERON AND PLACEBO – FORMER WAS BETTER – REDUCED MRI LOAD AND RELAPSES (RUDICK ETAL 2006) PML WAS A DREADED SIDE EFFECT IN TWO PATIENTS. COMBINATION OF MINOCYCLINE AND GLATIRMER ACETATE IS UNDER WAY NOW. BETA1A COMBINATION WITH GA (TULLMAN AND LUBLIN) WAS SUCCESSFUL AND NOW A PHASE 3 TRIAL IS ONGOING – RESULTS EXPECTED IN 2011 “ Maintaining the right attitude is easier than regaining the right mental attitude”
  • Other drugs: MITOXANTRONE: Worsening forms of MS –SP,PRMS,RRMS WITH ACCUMULATING DISABILITY. Cytotoxic anthracenedione Multicenter observer blinded placebo controlled trial,5mg/m2 or12mg/m2 IV every 3 months for 2 years (Hartung etal 2002) – patients receiving 12mg/m 2 did better. Another European trial combining mitoxantrone with methyly prednisone – 86%reduction in new disease activity when compared with methyl pred group alone. Important cumulative dose dependent cardio toxic effect, kept below 140mg/m 2
  •  CYCLOPHOSPHAMIDE - No consistent benefit (canadian cooperative study group 1991). AZOTHIOPRINE - Modest effect on relapses.no convincing effect on relapses.commonest drug in progressive MS-cytostatic agent – More so due to lack of effective therapy(british and dutch MS AZT trial group1988:Ellison etal 1989:Goodkin etal 1991). METHOTHREXATE - A small trial in Prog MS at 7.5 mg orally modertae benefit in upper extremity function- no effect on ambulation. CLADIRIBINE - A large trial in PPMS,SPMS,- no benefit after 1 year but gadolinium enhancing lesions reduced(Rice etal 2000)
  •  Cyclosporine – in progressive MS modest effect with significant renal toxicity(MS atudy group 1990) Repetitive course of steroids- one study showed no benefit (goodkin etal 1998)while another study showed lessened accumulation of black holes,atrophy and disability (Zivadinov etal 2001) Success in life is a matter not so much of talent and opportunity as of concentration and perseverance - C.W. Wendte
  •  IVig – A double blind placebo controlled study in Austria (Fazekas etal 1997)-59%reduction in relapses. A study in denmark – reduction in Gad Enhancing lesions.relapse rate was not significantly reduced. (Sorenson etal) A study conducted in Israel- relapses decreased,number of exacerbation free periods decreased. A recently concluded European trial- no activity on disease activity. Mind is the great level of all things; Human thought is the process by which, Human ends are ultimately answered
  • WHOM TO START AND WHEN TO TREAT: When to start DMD- as early as possible. Interferons,glatirmer acetate- RRMS. IFN beta – relapsing form of SPMS (goodin etal 2002). MITOXONTRONE - Relaping MS (RR,SP,PROG.RELAPSING). NO SUCCESFUL TRIALS FOR PPMS.
  • UNANSWERED QUESTIONS: DOSE vs DOSING FREQUENCY. DOES TIME ON THERAPY MATTER. WHEN TO START NATALIZUMAB. HIGH DOSE IFN vs NATALIZUMAB. “ Peace Rules the day where reason Rules the mind” - Colling
  • Symptomatic therapy: Spasticity – baclofen 5mg bd (max dose80 mg in three divided doses). -Tizanidine 2mg(max dose 36 mg). Intrathecal baclofen and botulinium toxin are also used now. Weakness - 4 amino pyridine K channel opener – improves conduction in demyelinated nerve fibers- phase three trial is on. Truth comes out of error sooner than that of confusion
  •  Psychitaric manifestations:depression is commonest ,SSRI – citalopram,escitalopram,fluoxetine,sertaralin Norepinephrine and dopa reuptake inhibitors- bupropion . Bipolar disorder-lithium or valproic acid. Psychotherapy. Opinion is ultimately determined by the feelings and not by the intellect
  •  Fatigue -Psychotherapy. Amantadine. Acetyl L carnitine Pemoline – hepatotoxic. Acetly L carnitine more effective than amantadine in a recent double blinded trial(Tomassini etal) Experience can be defined as yesterday’s answer to today’s problems
  • Sexual Dysfunction: 90% have sexual dysfunction and more common in RRMS. Drugs used for treatment,might be a reason. Loss of libido &difficulty in attaining orgasm- bupropion 150mg-400mg –seizure side effect(crenshaw etal 1987). Erectile dysfunction:Sildenafil,vardenafil,tadalafil. Vardenafil faster onset while tadalafil longer duration of action.
  •  Eros therapy – USFDA appproved vacum device-increases blood flow and engorgement when placed on clitoris. Topical esterogen creams & lubricants to enhance sexual desire. Memory, Pity & Beauty are short lived in life, Tinged with emotions persist in life
  •  Cognitive dysfunction:donezipil- increases verbal memory(krupp etal 2004,small double lind placebo controlled trial) Bladder dysfunction- Detrusor hyopreflexia – rule out infection – intermittent self catherisation. detrusor hyperreflexia – anticholinergics, oral,extended release,transdermal patch.Being ignorant is not so much a shame as being unwilling to learn
  •  Detrusor sphincter dyssynergia- alpha adrenergic antagonists- Doxazosin,prazosin,tamsulosin,terazosin along with anticholinergics are used.alpha blockers prone to cause postural hypotension – if so intermittent self catherisation advised. Urologic evaluation – if symptoms suggestive of dterusor hyper reflexia an voiding dysfunction(continum of AAN 2007) Dual action of brain is reflected in the duality of god; Each is in-separable but has individual existence
  •  Bowel dysfunction – Constipation and fecal incontinence both are problems. bulk formers-methylcellulose,psyllium. Stool softener-docussate sodium. Stimulant laxatives-Senna,Bisacodyl. Osmotic laxatives-lactulose. High fiber diets-fecal impaction and overflow incontinence.
  • TREMOR: 35% HAVE TREMOR AND 25% are disabling. Carbamazepine,clonazepam,gabapentin,glu tethmide,INH,leviteracetam,primidone,propr anolol. DBS- not approved – Hooper etal 2002,showed improved function in 15 patients.“Give us the GRACE to accept with serenity the things that cannot be changed; T COURAGE to change the things that should be changed and; he T W he ISDOM to know the difference”
  • CONCLUSIONS: SIGNIFICANT ADVANCES HAVE BEEN MADE,IN IMMUNOPATHOLOGY,CATEGORISATION OF SEVERITY,DISEASE MODIFYING DRUGS AND THEIR USAGE. CRIPPLING DISABLTY CAN BE LIMITED,EARLIER DIAGNOSIS AND BETTER SYMPTOMATIC THERAPY ARE AVAILABLE NOW. RESEARCH IS STILL ON IN FINDING THE ELUSIVE GENE OR AN ENVIRONMENTAL AGENT OR BOTH. DESPITE ALL THESE ADVANCES TWO THINGS ARE STILL UNANSWERED – CURATIVE THERAPY & THE EXACT CAUSE FOR MS. OVER 140 YEARS MS REMAINS AN UNSOLVED PUZZLE AND AN ENIGMA.
  • Take home advances in MS: Queen square criteria – Earlier diagnosis of MS. DIS & DIT – Predicts conversion rate to Definite MS even in CIS. NMO & NMO spectrum disorder – distinct disorder from MS? In terms of Biological difference thin line separates PPMS & SPMS.
  •  TH 17 a Subset of CD4 and Treg cells(expressing CD25 & transcription factor Fox p 3) – pro inflammatory – a significant advance in immunopathogenesis. Two new gene loci IL2 and IL 7 - IDENTIFIED – needs substantiation. EBV, SMOKING – INCREASES RISK OF MS WHILE Vitamin D – Decreases risk of MS.
  •  Negative prognosticators are, bladder symtoms as presentation, incomplete recovery from an attack, shorter interval between first and second attack and early accumulation of disability. Benign MS – percentage of cases less – they eventually progress – not ACTUALLY BENIGN.
  •  A MAGIC PILL – BASED ON PHRMACOGENETICS(DNA LEVEL) AND PHRAMACOGENOMICS(RNA LEVEL)OF AN INDIVIDUAL.PROTEOMICS INFCAT RESEARCH BEYOND RNA LEVEL – FUTURE HOLDS PROMISE .
  • Dedicated to my familyfor making everything worthwhile
  • READ not to contradict or confute Nor to Believe and Take for Granted but TO WEIGH AND CONSIDERTHANK YOU My sincere thanks toDrC.T.SURESH,Dr.G.MUGUNTHAN,DR.G.VIKRAMRAJ Dr.S.ARUNAN. Institute of Neurology, Chennai-03