Lehigh Valley Health Network - National Multiple Sclerosis ...

Lehigh Valley Health Network - National Multiple Sclerosis ...

Progressive MS Research Update David E. Jones, MD Director, MS Center Comprehensive Care of MS Multidisciplinary Symptom Mgmt MS Specialists Comprehensive MS Center Research Community Involvement History of Multiple Sclerosis

Saint Lidwina of Schiedam A Dutch nun from 1400s with intermittent pain, leg weakness, vision loss Augustus Frederick dEste Grandson of King George III whose diary (1822-1846) describes episodes of LE weakness, dizziness, bladder dysfunction, clumsiness Jean-Martin Charcot Clinicopathological treatise of patient with dysarthria, ataxia, and tremor in 1868 3 Multiple Sclerosis

Likely, a chronic, inflammatory condition of the CNS likely induced by an environmental trigger in a genetically susceptible patient Neurological lesions disseminated in time and space without an alternative explanation for symptoms Clinical MRI Paradox 36yo woman Avid hiker, recently completed PhD EDSS 2.0 42yo woman Cane and bilateral MAFO EDSS 6.0 5 Immunopathogenesis of RRMS

Early inflammation lead to demyelination and axonal loss; this may be what drives degeneration. Inflammation Regeneration Onset of Disease A Degeneration B Time C Compston A, et al. Lancet. 2008;372:1502-1517; Kuhlmann T, et al. Brain. 2002;125:2202-2212; Paolilo A, et al. J Neurol. 2004;251:432-439. Subtypes of MS 1. Relapsing-remitting Increasing disability

Increasing disability 2. Primary-progressive Time Time 3. Secondary-progressive Increasing disability Increasing disability 4. Progressive-relapsing Time Time Lublin FD, Reingold SC. Neurology. 1996;46:907-911. Relapsing Remitting MS

RRMS 85% of patients with MS start with a relapsing remitting course Exacerbations / Flares / Relapses Rapid onset of new symptoms Association with gadolineum enhancement on MRI May improve resolve over weeks to months (remission) Steroids (iv) speed up the improvement and likely delay future events Pseudo-exacerbation Previous symptoms can reoccur / worsen in setting of infection, heat, stress Inflammation plays a big role, but there is evidence of degeneration / atrophy in RRMS Treatment delays progression into SPMS 8

Progressive MS Degeneration plays more of a role in progressive MS Secondary Progressive Multiple Sclerosis (SPMS) Currently felt to be about 30% of MS patients Always follows relapsing-remitting MS (RRMS) Transition from episodic flares to slow, gradual worsening of symptoms independent of flares Often occurs 10-20 years after beginning of MS (highly variable) Primary Progressive Multiple Sclerosis (PPMS) ~10% of multiple sclerosis patients Gradual worsening of symptoms without preceding flares Can have mild fluctuations in symptoms Rare cases of PPMS will have occasional relapse (PRMS) 85% predominance of spinal cord symptoms (myelopathy) Slow worsening of gait is the most common presentation

Sex ratio 1:1 Later onset of symptoms (~45yo) 9 Treatment of Progressive MS All of our therapies work on the inflammatory component of the disease; however, progressive MS is felt to be more degenerative. None of the currently approved medications have been proven to alter the course of progressive MS Failed trials in PPMS Rituxan (OLYMPUS) possible response if <50yo, have relapses, or enhancing lesions Copaxone Mitoxantrone Trials suggesting effects in disease transitioning to SPMS Betaseron (European trial) Mitoxantrone Failed trials in SPMS Betaseron (North American trial) Dirucotide (MBP 8298) 10 Treatment of Progressive MS My approach Assess for amount of inflammation Gad-enhancing lesions, positive spinal fluid, response to iv corticosteroids If evidence of inflammation, consider off-label immunosuppressive drugs (Rituxan, Cellcept) Occasional pulses of steroids is another approach

Steroids come with risks 11 Natalizumab (Tysabri) Monoclonal VLA-4 Ab to Disrupts interaction with VCAM-1 Reduces ability of WBCs to cross the BBB Efficacy (vs placebo)

Reduces relapses by 67% Reduces disability progression by 42-54% Reduces enhancing lesions by 92% Reduces black holes by 76% Polman NEJM 354; 2006. 12 Natalizumab (Tysabri) Improvement in Disability (EDSS) 29.6% of patients had sustained improvement in physical disability (vs 18.7% placebo) Improvement in Disability (MSFC)

Improvement in 25 foot walk speed Improvement in 9 hole PEG test Improvement in cognitive function (PASAT) Improvement in quality of life (QOL) Both physical and mental components Progressive Multifocal Leukoencephalopathy (PML) Rare, opportunistic infection of brain myelin caused by JC virus Dysarthria, ataxia, cognitive impairment, cortical blindness Symptoms progress over 1-3 months JC virus is latent in many people (kidneys, bone marrow) 50% in recent studies (old studies suggesting 80% included BKV) Can reactivate in AIDS, CLL, organ transplant patients

No proven treatment, can be fatal AIDS patients can reverse infection if immune system restore PML with natalizumab 15 PML with natalizumab As of December, 2011 95,300 patients exposed, 55% of which in the US As of March, 2012 212 reported cases of PML with natalizumab, 38% in US 46 deaths; others with varying degrees of disability 10% mild, 50% moderate, 40% severe disability 42% of cases were previously treated with immunosuppressant

Per TYGRIS, 14% of US patients and 24% of EU patients previously on IS Novantrone 17 Imuran 5 Methotrexate 5 Cellcept 5 JC virus antibody assay 59/59 patients with serum collected before PML (or even starting natalizumab) were JCV positive 16 PML with Natalizumab 17 Natalizumab (Tysabri)

ASCEND SPMS Ongoing clinical trial of Tysabri in SPMS Rationale - CXCL13 May be a marker for SPMS May be involved in SPMS Is reduced by natalizumab 18 Fingolimod (Gilenya) First approved oral DMT disease for MS MOA traps ~70% of circulating immune cells in LN Proliferation and differentiation Afferent lymphatic vessel S1P

Activation Activated T cells S1P1 receptor Nave T cell Lymphatic sinus Sinus-lining endothelium Efferent lymphatic vessel Lymph node S1P1 downregulation Fingolimod Sinus-lining endothelial cell barrier enhancement Reduced T cell egress

Horga Expert Rev Neurother 8;2008. 19 Fingolimod (Gilenya) TRANSFORMS fingolimod vs. IM interferon-beta (Avonex) 52% reduction in ARR; 80-83% of patients relapse free No difference in disability (only 12 month trial) 2 deaths (herpetic infection), 15 cardiac conduction abnormalities, 8 macular edema, 3 melanoma FREEDOMS 1 EU fingolimod vs placebo 54-60% reduction in relapses

30-32% reduction in sustained disability (24 month trial) No significant difference in infection or malignancy, 3 cases macular edema, few asymptomatic cardiac conduction abnl FREEDOMS 2 US fingolimod vs. placebo 48% reduction in ARR 17-28% reduction in SAD (NS) 74% reduction in new T2; 70% reduction in Gd+ Cohen NEJM 2010; Kappos NEJM 2010. 20 Fingolimod (Gilenya) Airways hyperactivity (S1P13)

Bronchial smooth muscle S1 P Retina Vascular endotheli um Swelling (S1P2) Vasoconstriction, blood pressure increase (S1P13) Vascular smooth

muscle Atrial myocytes Angiogenesis (S1P1) Vasodilation (S1P1, 3) Barrier decrease (S1P23) Barrier enhancement (S1P1) Heart-rate reduction and regulation (S1P1, 3) Brinkmann Pharmacol Ther 115;2007. 21 Recent changes with

fingolimod (Gilenya) Defined patient selection: Appropriate - no pre-existing CV conditions, baseline EKG OK, no meds to lower HR Caution h/o CAD/CHF, CVD, HR-lowering drugs, recurrent syncope, severe OSA, mild dysryhthmias Avoid recent CAD/CHF, CVD, Class 1a or III antiarrhythymics, QTc > 500, Mobitz II or greater AV block Monitoring: Hourly 6 hours; ECG before and after Overnight with caution or with symptoms during monitoring Fingolimod (Gilenya) INFORMS clinical trial in PPMS Potential role in repair of myelin

S1P receptors in oligodendrocyte progenitor cells (OPCs) In vitro studies suggest can stimulate OPCs, inducing production of myelin 23 Dimethyl fumarate (BG00012) Presented to FDA 2/12 MOA Cytokine shift to more anti-inflammatory, Th2 cytokine milieu May be neuroprotective (activation of nrf2/keap1 antioxidant pathway) Phase II data

69% reduction in Gad lesions DEFINE study 2 year, placebo-controlled, Phase 3 study of BG12 240mg bid and tid in patients with RRMS (n=1,011) 54% reduction in relapses in bid group 38% reduction in disability progression 85% reduction in new MRI lesions; 90% reduction in gad Dimethyl fumarate (BG00012) CONFIRM trial 2 yr Phase 3 study of BG12 bid and tid vs Copaxone vs placebo 44% reduction in ARR in bid dose, 51% reduction in tid dose, 29%

reduction in Copaxone group (vs placebo) 65-7( % reduction in Gd+; 71-73% reduction in new T2 Disability chg NS (very little progression in placebo group) Safety Seemingly few issues; available for psoriasis (Fumaderm) in Germany since 1994 Flushing, especially first month (aspirin may reduce) GI side effects, including diarrhea initially Given potential neuroprotection, may be reasonable to study in progressive MS Laquinimod MOA Unclear; suspect shift in cytokine milieu to Th2; may be neuro-protective

ALLEGRO: 2 year, placebo-controlled, Phase 3 study of laquinimod 0.6mg in pts with RRMS (n=1,106) Efficacy 23% reduction in relapses; 36% reduction in disability progression Reasonable MRI data Safety data appears promising Reversible LFT elevations; back & abdominal pain BRAVO: 2 year, comparator (placebo or Avonex), Phase 3 study of laquinimod 0.6mg in pts with RRMS (n=1,331) Efficacy 21% reduction in ARR (after correcting for randomization dissimilarity) - NS 34% reduction in SAD; 28% reduction in brain atrophy Pooled analysis

21% reduction in ARR; 34% reduction disability; 30% reduction in atrophy Would be reasonable to study in progressive forms of MS Rituximab / Ocrelizumab MOA Humanized anti-CD20 monoclonal antibody; depletes B cells Efficacy HERMES Phase 2trial of rituximab in RRMS showed >50% reduction in relapses; 91% reduction in Gd+ 96 week trial of OCR (600 and 2000mg) vs placebo or Avonex in 220 patients with RRMS; 73-80% reduction in ARR; 89-96% reduction in T2 lesions at 24 weeks No gad or new T2 lesions weeks 24-96

67.3% of patients free of clinical activity at 96 week 78-80% of patients relapse free Ofatumumab (human) forms of rituximab 99% reduction in Gad lesions ORATORIO Trial in PPMS 27 Anti-LINGO Myelin-producing cells (oligodendrocytes) are dying in evolving MS lesions One of the key causes of axon loss is myelin damage Is it possible to make more oligodendrocytes? Oligodendrocyte Precursor Cells (OPCs) are not rare in MS lesions, are sitting at the periphery LINGO is a molecule that keeps OPCs quiet

Anti-LINGO molecule is under development Entering Phase II Stem Cells Autologous hematopoietic stem cell transplantation (AHSCT) Treat MS by resetting the immune system Remove immune stem cells from bone marrow Obliterate immune cells with high dose chemotherapy / radiation Replace stem cells to reset immune system This is treatment for RRMS Replacement of oligodendrocytes (myelin) Potential problem tumor formation

Replacement of neurons Problem creation of neural networks Adult human mesenchymal stem cells International MSCT Study Group Cells may be anti-inflammatory, promote repair, and potentially secrete substances that help protect axons / neurons Low Dose Naltrexone (LDN) Excitement at grass roots level Opioid agonist, increased -endorphins ? Placebo effect Compounding pharmacy Studies 17 patients with MS

Self-reported decreased disease activity 35 patients with PPMS (open-label) Improved fatigue and depression 80 patients with MS (randomized) Improved QOL, pain, cognition My take probably safe, may offer symptomatic benefit Cree, B. et al. Ann Neurol 2010, And The Bizarre Chronic Cerebrospinal Venous Insufficiency (CCSVI) Reports from Italy suggested abnormalities in venous drainage of the brain in patients with MS Zivadinov - >500 ultrasounds Approx. 55% of MS patients with CCSVI, 45% of pts with OND 22% of healthy controls with CCSVI Most recent papers - no CCSVI

No data to suggest CCSVI causes MS Studies of interventions correcting these narrowings have been initiated Liberation therapy Thus far, no positive data to support this practice Recent FDA warnings Treatment of Progressive MS There is even more hope In NY database of MS patients, up to 25% of patients with PPMS do not require a cane at 20 years. There are significant benefits of attainable with appropriate multidisciplinary management of symptoms in a comprehensive MS center 32 Physical Therapy / Exercise

Randomized trial of efficacy of resistance training in RRMS Exercise group 15% improvement in strength 21% improvement in functional status Mild improvements in mood, fatigue, QOL Biopsy increase in size of muscle fibers Obvious benefits of physical therapy in MS in other trials Fatigue Most common (and frequently most disabling) symptom of MS Physical lassitude that hits like a Mack truck and feels like carrying weights Compounded by increased energy expenditure needed to compensate for motor disability

Potential confounders, especially if sleepiness Obstructive sleep apnea Physical deconditioning Drug side effects Frequent nocturia Depression Treatment Non-pharmacological Maintain appropriate sleep Energy conservation pacing, planning activities Mild exercise to prevent physical de-conditioning Pharmacologic Amantadine, Provigil, stimulants, l-carnitine? Abnormal Mobility

Goal - safely maximize independence Ambulatory patients Strengthening Treat spasticity Treat foot drop Modified ankle-foot orthosis (MAFO) Peroneal stimulators - WalkAide, Bioness Assistive devices Ampyra Non-ambulatory patients Scooter, wheelchair to maintain independence Augment ability to transfer Transfer boards, Hoyer lift, grab bars Meticulous skin care 35

Spasticity Velocity-dependent resistance to muscle stretch Complications of spasticity Limitations in ability to walk / transfer Pain, muscle spasms Increased fatigue Joint changes Pressure sores Benefits Compensation for weakness Exacerbating factors Stress, infection, pain, temperature changes

Treatment is multifactorial PT / OT - ROM / stretching, strengthening Meds - baclofen, Zanaflex, BOTOX Baclofen pump Neurogenic Bladder 2 basic problems Failure to store spastic bladder Urgency, frequency, incontinence Treatment Timed void, pelvic floor therapy Avoid bladder irritants (caffeine, alcohol) Anticholinergics - Detrol, Ditropan, etc. Failure to empty atonic bladder or spastic sphincter Hesitancy, retention, UTIs, incontinence Treatment Double voids, pelvic-floor therapy

Clean intermittent catheterization Flomax? Combination > detrusor-sphincter dyssynergia Sexual dysfunction Lack of desire (Libido) Psychological issues, including altered identity roles Physical factors, including fatigue, bowel/bladder dysfunction, pain Lack of arousal Women Diminished sensation in pelvic floor may cause decreased arousal Vibrators, EROS device, bag of frozen peas Lack of lubrication Lubricants

Men Erectile dysfunction Phosphodiesterase inhibitors Viagra, Cialis, Levitra Caverject, prostheses Anorgasmia Psychological factors Fatigue Can respond to stimulants, alpha agonists Neuropsychiatric Issues Depression in MS Situational stressors AND neurotransmitter deficiencies More common in MS than in other neurological diseases Requires multi-disciplinary care

Psychologist Psychiatrist Activating antidepressants (Effexor, Prozac, Wellbutrin) Memory issues Difficulty with processing speed, multi-tasking, rapid word retrieval, problem solving, and maintaining attention Fatigue, depression, medications can worsen Pseudobulbar affect Spontaneous, inappropriate expression of emotion (laughter, crying) Can respond to TCAs, SSRI Neudexta Pain in MS

Common causes of primary MS pain Parathesias, including Lhermittes symptom Most common type of pain in MS Ephatic transmission between denuded axons Often, responds to anticonvulsants Often, lack of response to typical analgesics (i.e., narcotics) Trigeminal neuralgia Spasticity is painful! Secondary MS pain Osteoarthritis / joint pain can be attributed to abnormalities of gait Musculoskeletal pain, skin breakdown, compression fractures Psychiatric / emotional component to pain, especially chronic Duloxetine (Cymbalta) is approved for depression and neuropathic pain

Role for PT / OT, acupuncture, massage, exercise (yoga, aqua) Conclusions Relapsing multiple sclerosis has an inflammatory component which has been amenable to anti-inflammatory therapies Progressive MS may be more degenerative, a process that we do not understand as much Some of the drugs in development offer hope of neuroprotection Care of the MS should be multidisciplinary with some focus on symptomatic management 41

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