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Multiple sclerosis 2015
- 1. Each patient ought to feel somewhat the better after the physician's visit, irrespective of the nature of the illness. ~Warfield Theobald Longcope
- 2. Multiple Sclerosis: Diagnosis and Treatment Monique Canonico DO Assistant Clinical Professor John A. Burns School of Medicine April 2015
- 3. Objectives • 1. Learn the disease characteristics and demographics. • 2. Discuss the pathophysiology. • 3. Learn the clinical presentation. • 4. Become familiar with MS therapeutics algorithms
- 6. It's not what you look at that matters, it's what you see. -Henry David Thoreau
- 7. Epidemiology • Peak age 15 to 45 • Women : Men 3 : 1 • Geographic variation • USA prevalence 0.1% • Approx. ½ million MS patients in USA • Life expectancy essentially normal
- 8. -avg person US has 1/750 risk of MS (.1%) -risk in child or sibling of pt~ 4% -Monozygotic twins: 30% -over 159 genetic variations related to MS have been identified GENETICS
- 9. What Is MS? • An chronic inflammatory demyelinating disorder of the CNS of uncertain etiology, likely autoimmune, associated with destruction of myelin sheaths and axons Trapp, 1998
- 10. -Described in late 1800s by Dr. Charcot -Perivascular inflammation and demyelination -Plaques occur anywhere in the CNS -Most frequent: optic nerve, brainstem, cerebellum, spinal cord -Above lesions correlate with clinical sxs -Axon sparing within the plaques Pathological Hallmarks
- 11. -Disruption of blood-brain barrier -Unknown if demyelination precedes or follows inflammation -Acute inflammatory response of lymphocytes, plasma cells, macrophages -Macrophages contain myelin breakdown product -Lymphocytes: antibody- and cell-mediated immunity (direct), secretion of lymphokines or cytokines (indirect) Plaque evolution
- 12. Conduction block at site of lesion Slower conduction time along affected nerve Increased subjective feeling of fatigue secondary to compensation for neurologic deficits Results of Demyelination
- 15. Spinal MS
- 16. CASE 2
- 19. Abnormal MRI Optic Nerve
- 20. Dawson’s Fingers
- 21. Abnormal MRI of Cerebellum
- 23. Symptoms are the body's mother tongue; signs are in a foreign language. ~John Brown
- 24. -Episodes of neurologic dysfunction followed by stabilization/remission -Relapses can be rapid or gradual onset -May persist or resolve over weeks to months -Relapsing-remitting pattern is most common in MS Clinical Presentation
- 25. MS Signs and Symptoms • Fatigue • Heat intolerance • Visual symptoms • Numbness, tingling, loss of sensation • Weakness • Imbalance • Urinary and sexual dysfunction • Cognitive deficits
- 26. -Ascending numbness starting in feet -Bilateral hand numbness -Hemiparesthesia/dysesthesia -Generalized heat intolerance -Dorsal column signs -Loss of vibration/proprioception -L’hermitte’s sign Sensory Symptoms
- 27. -Unilateral or bilateral partial/complete internuclear ophthalmoplegia -CN VI paresis -Optic neuritis -Central scotoma, headache, change in color perception, retro orbital pain with eye movement) Visual Disturbances
- 28. -Weakness (mono-, para-, hemi- or quadriparesis) -Increased spasticity -Pathologic signs (Babinski, Chaddock, Hoffman) -Dysarthria Motor Disturbance
- 29. -Urinary incontinence, incomplete emptying -Set up for UTI’s -Cognitive dysfunction -Fatigue -Sexual dysfunction Other Symptoms
- 30. Pain • Trigeminal neuralgia in 2 percent • L'hirmitte's sign in 9 percent • Dysesthetic pain in 18 percent • Back pain in 16 percent • Visceral pain in 3 percent • Painful tonic spasms in 11 percent
- 31. Anxiety and Depression • Anxiety most prevalent • 2/3 may have depression • Euphoria • Dysphoria • Depression may severely impact the already present cognitive dysfunction that is associated with MS
- 32. Signs • L’hirmitte’s Sign • Uhtoff’s phenomenon
- 33. Neuro Exam • Afferent pupillary defect • Internuclear ophthalmoplegia • Weakness • Dysmetria • Dysdiadochokinesia • Increased reflexes • Upgoing toe
- 34. Differential Diagnosis • Metabolic: SCD (B12 def), Adrenomyeloneuropathy • Connective Tissue Diseases: Sjogren’s, SLE • Infectious: HIV, HTLV1, Lyme disease, Syphilis • Structural: Chiari malformation, spinal cord compression • Genetic: ataxias, paraplegias, mitochondrial • Neoplastic: CNS lymphoma, paraneoplastic • “MS variants”: ON, TM, ADEM, NMO • Other: Neurosarcoidosis, CNS vasculitis • Psychiatric
- 35. MS DIAGNOSIS “DISSEMINATION IN SPACE AND TIME”
- 36. DIAGNOSTIC WORK UP • History & Physical Exam • Brain and Spinal Cord MRI • Labs: rule out mimics of MS • Connective tissue diseases, infections, metabolic disorders • Cerebrospinal Fluid (when clinical and MRI evidence inconclusive) • Evoked Potentials: • Identify damage to visual, auditory, & touch perception systems • Less sensitive than MRI or cerebrospinal fluid
- 37. labs • ANA • ACE • Lyme • Anticardiolipin ab • ESR • HIV • Syphilis IgG • SSA, SSB • Neuromyelitis optica antibody(AQP4 ab)
- 38. New Diagnostic Criteria • Incorporate use of MRI • Clinically Isolated Syndrome + MRI Dissemination in space + MRI Dissemination on time = Earlier MS Diagnosis AugustAugust NovemberNovember DIS DIT
- 39. Summarized Diagnostic Criteria 1. Dissemination in space: Objective evidence of neurological deficits localized to two separate parts of the CNS 2. Dissemination in Time: Onset of neurological deficits separated by at least one month 3. Rule out other explanations! AugustAugust NovemberNovember
- 40. 3 of the following: • 9 T2 or 1 Gd+ • 3 Periventricular • 1 Infratentorial • 1 Juxtacortical lesion MRI - Dissemination in Space
- 41. T2 MRI - Dissemination in Time CIS > 1 month > 1 month Gd > 3 months Polman, 2005 Gd T2
- 42. CSF Analysis • Elevated IgG Index >0.7 • Increased CNS IgG synthesis, with normal serum IgG consistent with MS • Oligoclonal Bands • Presence of ≥2 distinct bands in CSF is consistent with MS • Most helpful for suggesting an alternative Dx -high protein, marked pleocytosis, PMNs
- 43. CSF OCB are not specific to MS! • Lupus 25% • Sarcoidosis 51% • Behcet’s dz 8% • Syphilis • CJD • Whipple’s disease • Lyme disease • Vasculitidies • Devic’s disease • Healthy siblings of MS patients adapted from a lecture by Peter Riskind MD PhD 11/19/05
- 47. TREATMENT ACUTE Steroids IVIG Plasma exchange DISEASE MODIFYING 11 treatments CAM Recent evidence based guide lines published by the American Academy of Neurology
- 48. HOW TO IDENTIFY A RELAPSE? • CRITICAL, compare with previous examinations (history and examination), when ever possible • Relapses can be precipitated by infections and fever • Check U/A for occult UTI
- 49. TREATMENT OF RELAPSE • INPATIENT • Severe deficits • Risk of fall or other injury • Poor social support • OUTPATIENT • All other relapses
- 50. TREATMENT OF RELAPSE: • IV methylprednisolone one gram daily for 5 days • Severe cases: up to 2 grams daily x 7d • Oral Prednisone for special circumstances • poor veins, insurance issues, travel, etc…
- 51. TREATMENT OF RELAPSE: PLASMAPHERESIS • Severe relapses not responding to steroids • 5 to 7 courses done on alternate days for 2 weeks • One course takes place over 3 to 4 hours
- 52. Nonpharmacologic Management • Exercise (avoid overheating) • Physical / occupational therapy • Nutrition (avoid extremes of weight) • Avoid excess heat exposure or elevated core temperature • Prompt tx of fever with antipyretics • Cool environment / cool bath
- 53. PHARMACOLOGIC MGT • MANY OPTIONS NOW
- 54. FDA-Approved Disease-Modifying Agents Aubagio (teriflunomide) Avonex (interferon beta-1a) Betaseron (interferon beta-1b) Copaxone (glatiramer acetate) Extavia (interferon beta-1b) Gilenya (fingolimod) Novantrone (mitoxantrone) Rebif (interferon beta-1a) Tecfidera (dimethyl fumarate) Tysabri (natalizumab) Lemtrada (alemtuzumab)
- 56. The Big Guns Tysabri (natulizumab) Gilenya (fingolimod) Lemtrada (alemtuzumab)
- 57. Generic Copaxone is Here • Data presented at the ACTRIMS/ECTRIMS mtg Sept 14 Randomized study comparing Copaxone with a generic version of glatimer acetate in 735 pts and vs placebo -The GATE study found NO SUCH DIFFERENCES -The numbers of enhancing MRI lesions were the same over 7-9 mos (the primary endpoint) -Both groups showed superiority over placebo -Adverse effects similar
- 58. Stem Cell Therapy • Mesenchymal stem cell therapy for MS passed safety and feasibility in a Phase I study at the Mellen Center for MS • This paves the way for larger studies • The strategy is REPAIR of damaged tissues • 24 patients (14 secondary progressive and 10 with relapsing remitting • Tx was with autologous adult mesenchymal stem cells from the bone marrow
- 59. Neuropsychiatric Symptoms : MS • Prozac/Paxil for depression • Venlafaxine or mirtazapine for depression • Can add methylphenidate if needed • ECT is OK in MS (but carries risk of relapse) • Anxiety is the most common MS symptomCognitive Behavioral Therapy is helpful • Bipolar disease is twice as common in MS tx with valproate or Li or antipsychotics
- 60. AGENTAGENT MECHANISMMECHANISM ROUTEROUTE PHASEPHASE RituximabRituximab Anti CD20Anti CD20 IV (2 x year)IV (2 x year) Phase IIPhase II CampathCampath Anti CD52Anti CD52 IV (1 x year)IV (1 x year) Phase IIPhase II DaclizumabDaclizumab Anti CD25Anti CD25 IV or SC (q mo)IV or SC (q mo) Phase IIPhase II Anti IL-12Anti IL-12 Anti IL-12Anti IL-12 SC (qw or qow)SC (qw or qow) Phase IIPhase II StatinsStatins immunomodulatorimmunomodulator oraloral Phase IIPhase II TeriflunomideTeriflunomide immunomodulatorimmunomodulator oraloral Phase IIIPhase III Anti VLA-4Anti VLA-4 SAM inhibitorSAM inhibitor oraloral Phase IIIPhase III FTY 720FTY 720 immunomodulatorimmunomodulator oraloral Phase IIIPhase III Oral CladribineOral Cladribine immunosuppressanimmunosuppressan tt oraloral Phase IIIPhase III MinocyclineMinocycline immunomodulatorimmunomodulator oraloral Phase IIPhase II EstriolEstriol immunomodulatorimmunomodulator oraloral Phase IIPhase II MBP 8292MBP 8292 immunomodulatorimmunomodulator IV (q month)IV (q month) Phase IIIPhase III Therapeutic Agents Under InvestigationTherapeutic Agents Under Investigation
- 61. We cannot become what we need to be by remaining what we are. -Max De Pree
- 62. CAM • AAN guideline Feb 2014 • Knowledgeable advice should be given • Counseling is part of the evaluation and mgt • ( part of “Cognitive care” ) • -CPT code 99201 (new) • -CPT code 99241 (est)
- 64. CAM and MS • Gingko biloba- NOT helpful for cognition but probably helpful for fatigue • Reflexology Possibly effective for MS paresthesia • Vit D-may decrease exacerbations (5000 IU daily) • Cigarette smoking increases progression in MS • Cannibis-probably effective for pain and possibly effective foe spasticity • Magnet therapy • Pulsed magnetic fields probably effective for decreasing MS fatigue
- 65. Pulsed magnetic Field Therapy may help with MS fatigue
- 67. CAM in MS: SLeep •No melatonin! •Theanine Serene (oral supplement)
- 71. PROGNOSIS
- 72. Time (Years) DiseaseParameter INFLAMMATORY ACTIVITYINFLAMMATORY ACTIVITY NEURODEGENERATIONNEURODEGENERATION PROGRESSIONPROGRESSION RelapsesRelapses Active WMLActive WML Time (Years) Pre-Pre- ClinicalClinical ClinicallyClinically IsolatedIsolated SyndromeSyndrome Relapsing-Relapsing- RemittingRemitting SecondarySecondary ProgressiveProgressive Rx effectRx effect Poor Rx effectPoor Rx effect No New WMLsNo New WMLs CLINICALLYCLINICALLYRadiographicallyRadiographicallyPathologicallyPathologicallyRx ResponseRx Response AtrophyAtrophy
- 73. PreclinicalPreclinical Relapsing-remittingRelapsing-remitting Secondary progressiveSecondary progressive Adapted from Goodkin DE. UCSF MS Curriculum. January 1999. Natural History of Multiple Sclerosis Relapses and impairmentRelapses and impairment cMRI activity (T2, T1+Gd)cMRI activity (T2, T1+Gd) Axonal lossAxonal loss Measures of brain volumeMeasures of brain volume
- 74. Weinshenker, 1989 15% PPMS15% PPMS 85% RRMS85% RRMS 50% SPMS and 50% need a cane 90% SPMS 11-15 years 26 years from onset 50% need a cane 5 years Natural History of RRMS and PPMS 30 years from onset 83% need cane ~ 34% bed bound 22 years from onset 50% bed bound
- 75. Weinshenker, 1989 85% RRMS85% RRMS 50% SPMS and 50% need a cane 90% SPMS 11-15 years 26 years from onset Natural History of RRMS and SPMS 30 years from onset 83% need cane ~ 34% bed bound
- 78. Summary • Demographics • Presentation • Differential • Evaluation • Treatment
- 80. Have PAtients call the Hawaii MS SOciety 808 532 0811
Editor's Notes
- Notes for speaker: MS is a biphasic disease, from an inflammatory process (and axonal transection – grey line) to a neurodegenerative process Inflammation predominates early in MS and gradually lessens Notice loss of axons early in the disease The inflammatory process and demyelination of nerves are predominantly mediated by T- and B-cells1 Neurodegeneration, which includes the axonal, dendritic, and neuronal loss,2 is present before the first clinical event and progressively worsens,3 reaching a critical point and then predominating later in the course of disease Inflammation may occur independently, highlighting the need for early treatment with disease-modifying therapies (DMTs) that exert direct effects on inflammation and indirect effects on axonal injury3-5 Notes References: Wilson HL. Biologics. 2012;6:117-23. Dutta R and Trapp BD. Prog Neurobiol. 2011;93(1):1-12. Bergsland N, et al. AJNR Am J Neuroradiol. 2012 Apr 12. doi.org/10.3174/ajnr.A3086. Trapp BD, et al. Annu Rev Neurosci. 2008;31:247-69. Kuhlmann T, et al. Brain. 2002;125:2202-12. MS.US.PO516.0712/ext
- The peak age of onset is about five years earlier for women than for men In support of a possible autoimmune basis for MS, some [24,25] but not all [26] studies have observed that patients with MS are more likely than controls to have other autoimmune disorders, such as autoimmune thyroid disease. In addition, patients with other autoimmune disorders are more likely to have MS. As an example, a large Danish study found that patients with type 1 diabetes mellitus had an increased risk for developing MS compared with the general population [27]. Another large, well-designed cohort study found that patients with inflammatory bowel disease have an increased risk for demyelinating diseases, including MS [28 There is also a widely held belief of an association between latitude and MS, with the risk of MS increasing from south to north [20]. In an analysis from the Nurses' Health Study, for example, the adjusted rate ratios were 3.5 for the northern United States and 2.7 for the middle tiers relative to the southern tier [62]. Persons migrating from a high to low-risk area after the age of puberty are thought to carry their former high risk with them, while those that migrate during childhood seem to have the risk associated with the new area to which they migrated. However, the universal association between latitude and risk of MS has been challenged by findings from a 2010 systematic review and meta-analysis of epidemiologic studies of MS [21]. The results showed that, while the prevalence of MS increased with geographic latitude in Western Europe, North America, and Zealand, the incidence of MS increased with latitude only in Zealand, and not in Western Europe or North America. Thus, there was no latitudinal gradient for MS incidence in the northern hemisphere. In the absence of association with incidence, the observed latitudinal gradient of MS prevalence could be explained by other factors, such as survival time, diagnostic accuracy, and ascertainment probability. — One proposed explanation for the possible association of MS with latitude is that exposure to sunlight may be protective, either because of an effect of ultraviolet radiation or of vitamin D [63]. The following observations support of this hypothesis: A number of studies have found an inverse relationship between sun exposure, ultraviolet radiation exposure, or vitamin D serum levels, and the risk or prevalence of MS [64-68]. An analysis of data from the Nurses' Health Study and Nurses' Health Study II observed that the risk of developing MS was significantly reduced for women taking ≥400 international of vitamin D (relative risk 0.59, 95% CI 0.38-0.91) [69]. A longitudinal cohort study of 469 subjects with MS found that vitamin D levels were inversely associated with the risk of new T2-weighted or gadolinium-enhancing T1-weighted lesions on brain MRI [70]. — Environmental triggers unrelated to geography may be involved in the development of MS [71]. A number of studies have suggested an association between smoking and MS [71]. As examples, a cross-sectional study of 22,312 people in Norway found a higher risk of MS in ever-smokers than in never-smokers (relative risk 1.81, 95% CI 1.13-2.92) [72], and a case-control study in the United Kingdom found similar results [73]. Smoking may also be a risk factor for disease progression [63,73-75]. Month of birth has been implicated as a possible risk factor for MS, though the literature is conflicting. A 2013 meta-analysis and systematic review found that the risk of MS was increased for those born in April and May and decreased for those born in October and November [76], suggesting that the gestational or neonatal environment influences the risk of MS later in life. However, it is possible that studies finding a month of birth effect are actually false positive results that result from confounding caused by seasonal variation in birth rates, with data from Europe and North America showing excess births in March, April, or May, and reduced births in November, December, and January [77].
- — A possible infectious stimulus of the immune system has received more support than vaccines in the literature For purposes of genetic counseling, the sibling risk of MS is 3 to 5 percent. Studies of unaffected family members that have noted abnormalities on MRI scanning suggest that the risk may be even higher. Accumulating data suggest that transmission of MS is influenced by the sex of the affected parent [93-99]. Most studies have found a maternal parent-of-origin effect, with an excess of maternal transmission observed when examining half-sibling pairs with MS and unaffected parents, patients with MS in extended pedigrees, or avuncular pairs of patients with MS [93,97,98]. In contrast, studies of parent-child pairs with MS have found that paternal transmission is equal to or greater than maternal transmission [94-96]. The explanation for this discrepancy is unclear, but epigenetic mechanisms (eg, DNA modifications such as histone acetylation and DNA methylation that do not modify the DNA sequence) transmitted through cell division may be involved in direct transmission from an affected parent [99]. Dr. Philip De Jager (Harvard) presented the Consortium’s latest findings – a replication of its pivotal genetics study published in 2013. Gene research is grueling – data from thousands of people with and without MS need to be gathered in massive numbers, and then all those data must be replicated. Dr. De Jager announced that after studies involving over 80,000 people, they now have identified more than 159 genetic variations related to MS, and more importantly, have begun to identify the specific immune cells and proteins involved, and how much weight each one carries. “We have created a reference map of MS susceptibility,” said Dr. De Jager. “Now we turn to the task of understanding the biology of MS susceptibility.” (Read the complete abstract.)
- Immuno-fluorescent confocal micrographs showing segmental demyelination and axonal swelling in acute MS lesion.
- Inflammation in conjunction with blood-brain-barrier disruption, characterized by gadolinium enhancement on MRI, is seen in the early stages of most demyelinating lesions in patients with relapsing-remitting and secondary progressive MS. (See "Diagnosis of multiple sclerosis in adults", section on 'Magnetic resonance imaging'.) Inflammatory T cells, B cells, and macrophages are typically seen on histopathologic examination of MS lesions at biopsy and autopsy [4]. At least four histopathologic subtypes of MS demyelinating lesions have been described. Increased oligoclonal IgM and IgG levels are found in the cerebrospinal fluid (CSF) of patients with MS. (See "Diagnosis of multiple sclerosis in adults".)
- 3 patients with confirmed PML : 2 of 1171 MS patients (SENTINEL study: Natalizumab and INFβ-1a IM) 1 of 248 Crohn’s disease patients Incidence ~1:1000 for PML with Natalizumab
- Notes: The study was a retrospective review of prospectively collected data. RRMS patients with a spinal cord MRI performed during the first 3 years of the disease, a control MRI 5 years later, and who have been followed up at least 10 years were included Patients in the study were grouped according to the T2 spinal cord MRI into: Nodular pattern:If one or more focal lesions were present Sharply demarcated areas of signal intensity Diffuse pattern:Defined as a poorly demarcated high signal area. Homogeneously increased signal intensity without demarcated lesions The end point was defined as the time to reach an EDSS score of 4.0 Reference: Coret F et al. Early diffuse demyelinating lesion in the cervical spinal cord predicts a worse prognosis in relapsing–remitting multiple sclerosis. Mult Scler 2010;16(8):935-941. Design: A prospective study of RRMS patients (N=25) with baseline spinal cord MRI performed during the first 3 years of disease onset and control MRI performed ~5 years later who were followed up for at least 10 years Results: Patients with initial diffuse pattern in spinal cord MRI reached EDSS 4.0 sooner than those with nodular pattern (mean: 11.4 years vs. 6.2 years; p=0.001)
- — Frank dementia is an uncommon feature of MS, occurring in less than 5 percent of patients. It is usually only encountered in severely affected individuals. However, 34 to 65 percent of patients have cognitive impairment on the basis of neuropsychological testing, and cognitive impairment may be common even at the onset of MS. The most frequent abnormalities are with abstract conceptualization, recent memory, attention, and speed of information processing. The degree of cognitive decline in patients with MS correlates with the severity of cerebral pathology on MRI, and cortical atrophy on MRI (image 1) correlates with cognitive impairment. Acute cerebral lesions occasionally manifest as a confusional state associated with progressive focal paralysis. Cognitive dysfunction in MS is discussed separately. (S
- — Cross-sectional studies have shown some degree of affective disturbance in up to two-thirds of patients with MS [31]. Depression is the most common manifestation; it occurs in part due to the burden of having to cope with a chronic, incurable disease. Euphoria is usually associated with moderate or severe mental impairment. Patients may also manifest a dysphoric state with swings from depression to elation. Depression may be more common in patients with MS than in others with chronic medical conditions [19,32]. In addition, the risk of suicide in patients with MS may be increased compared with the general population, as shown in most [33-36] but not all [37] studies. The median life expectancy in patients with MS is reduced by about 5 to 10 years compared with that of the general population [38,39], and suicide probably has only a small effect on the diminished life expectancy in MS. As already noted, depression appears to have a major deleterious impact on cognitive function in patients with MS (see 'Impact of depression' above). It is not known whether depression in MS patients reflects a comorbid association with bipolar illness or an effect of frontal or subcortical white matter disease. Early trials suggested that treatment with interferon beta may contribute to the development of depression, but subsequent studies have not found such an association [40-43]. Treatment of depression in patients with MS is frequently effective with pharmacotherapy or psychotherapy, although the former may be preferred should depression arise during a course of treatment with a disease modifying agent [44]. However, data are limited, and a systematic review published in 2011 identified only two small randomized trials of limited quality evaluating the pharmacologic treatment of depression in patients with MS
- — Lhermitte's phenomenon is a transient sensory symptom described as an electric shock radiating down the spine or into the limbs with flexion of the neck [123]. It may be infrequent or occur with the least movement of the head or neck. Although most frequently encountered in MS, this symptom also can be seen with other lesions of the cervical cord, including tumors, cervical disc herniation, post radiation myelopathy, and following trauma - — Heat sensitivity (Uhthoff phenomenon) is a well known occurrence in MS; small increases in the body temperature can temporarily worsen current or preexisting signs and symptoms [128]. This phenomenon is presumably the result of conduction block developing in central pathways as the body temperature increases [129]. Normally, the nerve conduction safety factor decreases with increasing temperature until a point is reached at which conduction block occurs; this point of conduction block is reached at a much lower temperature in demyelinated nerves
- Notes: The study reports findings based on a retrospective analysis of 1,800 patients diagnosed with MS, of whom 44 met the inclusion criteria: CSF studies done at presentation Preserved polyacrylamide gels at the time of review Minimum follow-up of 10 years Excluded patients included those who had died by the time of analysis, and had indistinct OCBs in both serum and CSF Included patients were categorized as benign, mild, moderate or severe based on their level of disability as assessed by their EDSS scores. The 44 patients who met the inclusion criteria had “benign” (EDSS <3.5; n=14) or “severe” (EDSS >7.5; n=30) disease. All patients had more than 1 clinical attack. The mean follow-up for the benign and severe groups was 15.8 and 16.2 years, respectively Reference: Avasarala JR et al. Oligoclonal band number as a marker for prognosis in multiple sclerosis. Arch Neurol 2001;58(12):20
- IgM OCMBs have been reported as an important prognostic marker in MS The presence of intrathecal (local CNS) IgM antibodies directed against myelin lipids (shown by IgM OCBs) predict a severe evolution in MS IgM OCB antibodies that do not recognize myelin lipids represent a transient immune response related to a more benign disease course
- Mos Sq ambulatory pts cAlthough copax approved in 97 no generic is available It is a complex polypeptide the standard pharmacokinetic comparisons used in generic equivalence studies are not possible Small differeneces in the compound could lead to significant changes in the safety or efficacy The GATE study. FDA is deciding
- Cells were expanded in culture, cryopreserved and then thawed and given IV as a single dose Follow up over 6 mos showed no new lesions on MRI(enhancing lesions) Launching phase 2. The theory is that cells seek out and repair damaged tissue STEM CELLS ARE DIRECTED AT REPAIR!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
- Stu pt expect advice will be given Pt has to pay, increasing the chance they will seek advice Chronic dz unlike acute problems andwhciare self limited, lead pts to seek unconventional txs Lisen Knowledge Studies have shown that expectations of provider ignorance or dismissive attitude will decrease the chance they will bring it up at appts
- Magnet therapy is an umbrella term that includes several techniques. TMS-transcranial magnetic stimulation is a lg coil placed on scalp to create electric current to stimulate neurons. PMF or Pulsed magnetic field therapy is the therapy which was evaluated in the AAN guideline and there are subthreshol stimuli that can modify cortical hyperexcitability
- Notes: Forty-five patients, recruited after MS diagnosis, were followed for 7 years by yearly EDSS and Multiple Sclerosis Functional Composite (MSFC) evaluations, and were classified as cognitively impaired (CI) or unimpaired (CU) according to neuropsychological testing at baseline. At baseline, 47.8% of patients were CI, with deficits mainly in memory and information processing speed (IPS) A multivariate analysis showed correlations between the EDSS change over 5 and 7 years and two baseline tests evaluating information processing speed and verbal memory, respectively. The deterioration of the EDSS after 7 years was significantly correlated with verbal memory testing at baseline after adjustment for age and baseline EDSS. In conclusion, in this sample of MS patients early in the disease, impairments in baseline information processing speed and verbal memory as measured by the Symbol Digits Modality Test (SDMT) and Consistent Long-term Retrieval (CLTR) cognitive tests predict the EDSS score 5 and 7 years later Reference Deloire M et al. Early cognitive impairment in multiple sclerosis predicts disability outcome several years later. Mult Scler 2010;16:581-587.
- Inflam dam occurs in early RRMS Brain dam by recur bouts of inflam even during ‘remission’ Accum disability at least in part 2/2 early active inflam dz We can treat inflam, At later dz stage, Rx not as effective
- Not completely ascertained cohort. from longitudinal natural history studies that have been done 50% (majority) will require assistance to walk in 10 years 20-25yrs is important because you are talking about a person who is maybe 40-50 years old.
- Not completely ascertained cohort. from longitudinal natural history studies that have been done 50% (majority) will require assistance to walk in 10 years 20-25yrs is important because you are talking about a person who is maybe 40-50 years old.