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
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
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!"
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
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
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 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”
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
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
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).
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”
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
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