Secondary progressive MS: Diagnosis, symptomatic management, and outlook on potential therapies

Transcription

1 Secondary progressive MS: Diagnosis, symptomatic management, and outlook on potential therapies Maria Fides Pacheco, M.D. Shirley O Leary, MS APRN-C, MSCN Olaf Stüve, M.D., Ph.D. Neurology Section VA North Texas Health Care System Medical Service, Dallas Department of Neurology & Neurotherapeutics University of Texas Southwestern Medical Center at Dallas

2 Disclosures Dr. Olaf Stϋve serves on the editorial boards of the Multiple Sclerosis Journal, Therapeutic Advances in Neurological Disorders Dr. Stϋve has received grant support from Teva Pharmaceuticals and Opexa Therapeutics Dr. Stϋve has served on data monitoring committees for Pfizer and TG Therapeutics without monetary compensation Dr. Stϋve served on an advisory board for Sanofi Genzyme and Novartis

3 Learning Objectives At the conclusion of this activity, the participant will be able to: Provide an overview of SPMS pathogenesis Outline the different phenotypes of Multiple Sclerosis Identify the challenges of diagnosis and treatment of Progressive MS Outline current research in the treatment of progressive MS and the future of MS care Outline the most common symptoms and clinical challenges for patients with MS Create an Interdisciplinary Treatment Plan for patients with MS

4 Defining SPMS SPMS is diagnosed retrospectively: History of gradual worsening after an initial relapsing disease course With or without acute exacerbations during the progressive course Lublin et al. Neurology

5 Lublin et al. Neurology

6 Lublin et al. Neurology

7 Lublin et al. Neurology

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9 Defining SPMS SPMS is diagnosed retrospectively: History of gradual worsening after an initial relapsing disease course With or without acute exacerbations during the progressive course To date, there are no clear clinical, imaging, immunologic, or pathologic criteria to determine the transition point when RRMS converts to SPMS The transition is usually gradual This has limited the ability to study the imaging and biomarker characteristics that may distinguish this course Lublin et al. Neurology

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11 Conversion to a secondary progressive course is the key determinant of long-term prognosis, independent of: Disease duration 1, and Early relapse frequency 1 Pre- and post-progression relapses may accelerate time to disability milestones 2 Immunomodulatory therapies may benefit patients with SPMS who have ongoing relapses 2 1 Scalfari et al. Neurology Paz Soldan et al. Neurology

12 Pathogenesis All MS phenotypes are inflammatory

13 Neuropathol-web.org

14 Prineas. Science

15 Iadecola. Nat Rev Neurosci. 2004

16 Magliozzi et al. Brain

17 Lucchinetti et al. Ann Neurol

18 Lucchinetti et al. Ann Neurol

19 Lucchinetti et al. Ann Neurol

20 Lucchinetti et al. Ann Neurol

21 Chronic Acute Lucchinetti et al. Ann Neurol

22 80 Pattern I Pattern II Pattern III Pattern IV % of total

23 Pathogenesis All MS phenotypes are neurodegenerative

24 Active lesion Active lesion Green: Nonphosphorylated neurofilament Red: Myelin Trapp et al. NEJM

25 Axonal injury is often associated with demyelination 1 Axonal damage is detectable in early MS lesions 2,3 1 Trapp et al. NEJM Kornek et al. Am J Pathol Bitch et al. Brain

26 MRI measurement of brain atrophy Filippi et at. Curr Opin Neurol

27 MRI measurement of brain atrophy Unfractionated brain atrophy is typically measured from T1-weighted scans 1 Starting in late adolescence, unfractionated brain atrophy occurs in healthy individuals at a rate of % per year 2 In untreated clinically-stable MS patients, brain volume loss is accelerated at a rate of about 0.5 1% per year 1 1 Giorgio et al. J Magn Reson Imaging Miller et al. Brain

28 MRI measurement of brain atrophy Gray matter atrophy in MS has been demonstrated in several cross-sectional and longitudinal studies: Higher in RRMS than in SPMS 1 1 Roosendaal et at. Mult Scler

29 MRI measurement of brain atrophy Gray matter atrophy in MS has been demonstrated in several cross-sectional and longitudinal studies: Higher in RRMS than in SPMS 1 Correlates with disease clinical manifestations, particularly cognitive impairment 2 Predicts long-term clinical outcome (EDSS) 3 1 Roosendaal et at. Mult Scler Amato et al. Neurology Filippi et al. Neurology

30 Neurodegenerative changes in progressive MS MR spectrometry of n-acetylaspartate (NAA) levels has demonstrated diffuse neuronal loss from the earliest clinical stages of disease Fu et al. Brain Davie et al. J Neurol Neurosurg Psychiatry Bjartmar et al. Ann Neurol

31 Healthy Control MS NAA NAA NAA NAWM = normal-appearing white matter. NAA = N-Acetyl-Aspartate Courtesy of D. Arnold, MNI

32 Neurodegenerative changes in progressive MS MR spectrometry of NAA levels has demonstrated diffuse neuronal loss from the earliest clinical stages of disease 1-3 Additionally, cerebral spinal fluid (CSF) biomarkers of neuronal damage are emerging, including: Neurofilament autoantibodies Neurofilament phosphorylation 4,5 1 Fu et al. Brain Davie et al. J Neurol Neurosurg Psychiatry Bjartmar et al. Ann Neurol Eikelenboom et al. Neurology Petzold. J Neurosci

33 How are inflammation and neurodegeneration in MS related?

34 Causally? Just by association? What is the sequence of events?

35 Neuropathol-web.org

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37 Barentt & Prineas. Ann Neurol

38 There is no animal model that supports the Inside -> Out dogma

39 At least 200 genomic MS susceptibility regions have been identified Many of which are shared with other inflammatory diseases In contrast, strikingly few genetic associations are shared between MS and other neurodegenerative disorders dejager. ACTRIMS

40 PPMS

41 Recent work by the International Multiple Sclerosis Genetics Consortium (IMSGC) recently conducted a GWAS study on 15,317 cases and 29,529 controls RRMS and PPMS cohorts are genetically basically indistinguishable IMSGC. Am J Hum Genet. 2013

42 PPMS

43 dejager. ACTRIMS

44 Experimental Autoimmune Encephalomyelitis myelin Ag./CFA s/c +myelin Ag. CD4+ Th1 Slide provided by Nitin Karandikar, M.D., Ph.D.

45 Rivers et al. J.Exp.Med Baxter. Nat.Rev.Immunol

46 Experimental Autoimmune Encephalomyelitis myelin Ag./CFA s/c +myelin Ag. CD4+ Th1 Slide provided by Nitin Karandikar, M.D., Ph.D.

47 Paterson. J.Exp.Med Baxter. Nat.Rev.Immunol

48 Pathogenesis The exact mechanism(s) of disease progression in MS remains unknown A prevailing hypothesis involves a systemic adaptive inflammatory autoimmune process in the early stages that eventually results in the chronic activation of the CNS-intrinsic innate immune system that ultimately leads to neurodegeneration 1 1 Mahad et al. Lancet Neurol

49 Pathogenesis The exact mechanism(s) of disease progression in MS remains unknown A prevailing hypothesis involves a systemic adaptive inflammatory autoimmune process in the early stages that eventually results in the chronic activation of the CNS-intrinsic innate immune system that ultimately leads to neurodegeneration 1 Major factors suggested to drive neurodegeneration include: Microglia activation and associated oxidative injury 2 Mitochondrial insults and energy failure 3 Age-dependent iron accumulation in myelin and oligodendrocytes leading to oxidative tissue damage 1, 4 1 Mahad et al. Lancet Neurol Fischer et al. Brain Davies et al. Ann Neurol Hametner et al. Ann Neurol

50 Conclusion Clinical MS phenotypes are currently defined clinically Conversion to a secondary progressive course is the key determinant of long-term prognosis To date, there are no clear clinical, imaging, immunologic, or pathologic criteria to determine the transition point when RRMS converts to SPMS Importantly, it is also unknown why some patients convert to SPMS, and others do not

51 Conclusion CNS inflammation is present during all stages of MS CNS neuronal loss occurs during all MS disease stages Most scientific evidence suggest a peripheral immune deviation as the major causative factor

52 Clinical Conundrum of the Multiple Sclerosis Provider: Secondary Progressive MS SHIRLEY O LEARY MS APRN-C,MSCN

53 Disclosures Shirley O Leary has no disclosures

54 Objectives Defining SPMS from the clinical prospective Transition to SPMS, the diagnostic uncertainty for patient and provider When do providers discontinue or continue disease modifying treatments in SPMS? What are the factors to consider? The challenges of managing the SPMS patients Review of a SPMS case study

55 Defining SPMS 1996 US National Multiple Sclerosis Society Advisory Committee on Clinical Trial in MS purposed phenotypes based on clinical features. 4 core phenotypes/courses of MS were defined Acknowledgement that the landscape of MS would change over time, revisions would come 2014 publication in American Academy of Neurology, provides recommended revisions and refinements to the 1996 consensus (Lubin et al, 2014)

56 General Consensus Highlights The committee retained the phenotypes with some modifications Modification to utilize assessment of disease activity using clinical assessment or lesion activity on imaging Time period over which disability has occurred The committee added clinically isolated syndrome (CIS) as a phenotype Radiographically isolated syndrome (RIS) should not be considered a phenotype Recommended elimination of PRMS (Lubin et al, 2014)

57 Defining SPMS, Consensus Says? A retrospective diagnosis Begins with a RRMS course Gradual worsening, possible to have relapses Modifiers included active and progressing, active not progressing, not active but progressing, not active or progressing (Lubin et al, 2014)

58 Definitions of Progressive Disease Consenus Objective and steadily increasing neurological dysfunction, without recovery; may be times of stability Imaging measures less certain but some are under consideration including increases in T1 numbers and increasing size of lesions, brain volume loss (Lubin et al, 2014)

59 MRI Importance of MRI in diagnosis, clinical management, research Consortium of Multiple Sclerosis Centers offers guidelines/recommendations Importance of imaging in determining progression, active disease Monitoring patients is adversely affected by varying protocols, techniques, and quality (

60 What kind of MS do I have? SPMS Evolving definitions are becoming a bit confusing. Generally thought of as a progressive accumulation of disability over time. The 2014 Lublin paper suggests modifiers such as active or not active, with progression and without progression. Paraclinical evidence; MRI surveillance, accurate comparisons for new or enlarging lesions, consider brain volume loss Use of the EDSS in ascertaining confirmation of progression, what about the MSFC? Lublin paper suggests some clarification in terminology, worsening vs progressing. Is it tomato or tomato? What is the relevance to the patient s question How, as clinicians, do we define SPMS? What do patient s tell us? ( Lublin et al.,2014)

61 The Uncertainty of Transition Retrospective review and determination There is no on and off switch Subtle changes take place Some literature suggests, that RRMS patients who experience a decline without the presence of relapses for 6 months or more may have transitioned to SPMS Likely the MS provider will reflect much longer on confirming a transition to SPMS, why? (Sand et al.,2013)

62 Clinician Uncertainty of Transition It may be that the changes are to subtle, less tangible Neurological exam may not reflect change, or insufficient historical retrospective exams are available Insurance companies may withhold drug selections, with a label of SPMS; clinicians may prefer not to document SPMS The word progression sounds harsh and belies hope (Sand et al., 2013)

63 Challenges of Confirming the Transition to SPMS An interview study done by Davies et al (2016)looked at how healthcare professionals deal with the subject of SPMS How HCPs broached the subject How HCPs dealt with the patients response How HCPs provided support for patients and caregivers How important is the interdisciplinary team; to support patients and the neurology provider (Davies et al., 2016)

64 Responses Broaching the subject Discussing SPMS was recognized as needed Initiating the conversation was a challenge Patient response and how to manage Emotional impact and strategies that were used Providing support to the patient by HCPs Importance of interdisciplinary team

65 Why do we Continue or Discontinue DMTs in SPMS Patients? Literature in recent years supports a delay in transition to SPMS in treated RRMS. A questionnaire study involving 26 neurologists from Europe, North America, and New Zealand, completed in Ireland, asked the neurologists about their DMT stopping criteria Of the 26, 15 attempted to discontinue, 11 continued treatment. (Lonergan, et al., 2009)

66 Stopping DMTs in SPMS Study questions asked: If patients have transitioned to SPMS, are taking a platform therapy that is well-tolerated, what is your practice? If EDSS is 7.5 or higher do you continue treatment? What level of disability, if any, would you stop treatment? If you have stopped a treatment, in the presence of a relapse have you had to restart? (Lonergan et al.,2009)

67 Answering the Questions Most of the neurologists interviewed did not stop DMTs if patients resisted Some neurologists mentioned side effects as a reason to discontinue DMTs Others mentioned stopping for several months and reassessing Most of the neurologists had experience with a few patients experiencing relapse after DMT cessation and here the decision most often was to restart (Lonergan et al.,2009)

68 Discontinuing Disease Modifying Therapies Most of the DMTs for MS are labeled for relapsing forms of MS, which would include persons who have transitioned to SPMS but continue to have relapses or changes on MRI. Literature suggests that benefits of DMAs beyond an EDSS of 6.5 are not seen. Without clear benefit, risk of adverse events, monitoring, and cost become part of the discussion. (Lonergan et al., 2009)

69 Transitioned Patients Neurologists seem to recognize a need to stop after transition, but there are challenges. When do we discontinue disease-modifying treatments in a patient believed to have transitioned to SPMS? -Patients with ongoing progression, without relapses for a period of 2 or more years -Patients with ongoing progression, and no new or enhancing lesions for a period of 2 or more years. (Lonergan et al., 2009)

70 The Next Steps Problem solving patient concerns by treating the various symptoms; positively impacting quality of life with a multidisciplinary team approach Fatigue Gait/Mobility Psychosocial needs, depression Cognitive testing/rehabilitation

71 References Davies, F., et al. (2016), International Journal of MS Care. 18, Lonergan, R., Kinsella, K., Duggan, M., Jordan, S., Hutchinson, M., & Tubridy, N. (2009). Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we stop what we have started? Multiple Sclerosis, 15(12), Lubin, F., Reingold, S., Cohen, J., et al. (2014). Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 8, 1-9.

72 References Sand, I., Krieger, S., Farrell, C., & Miller, A. (2013). Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis. Multiple Sclerosis Journal, 20(12), Retrieved, June 26, 2017 from MS/Types-of-MS/Secondary-progressive-MS Retrieved, June 26, 2017 from /

73 MANAGING SYMPTOMS OF MULTIPLE SCLEROSIS: Interdisciplinary Care of Patients with MS Fides Pacheco, M.D. Co Director, MS Center of Excellence, Dallas VA Medical Center Clinical Operations Manager, SCI, Dallas VA Medical Center Assistant Professor, Dept. of PM&R, The University of Texas Southwestern Medical Center

74 Disclosures Dr. Fides Pacheco has no interest to disclose. PESG and PVA staff have no interest to disclose. This continuing education activity is managed and accredited by Professional Education Services Group in cooperation with PVA. PESG, PVA, and all accrediting organization do not support or endorse any product or service mentioned in this activity.

75 Learning Objectives Learn and understand the most common symptoms of multiple sclerosis and how it affects activities of daily living Create a Multidisciplinary / Interdisciplinary treatment plan for patients with Multiple Sclerosis

76 Multiple Sclerosis MS is the most common cause of non traumatic disability among young adults Onset typically between 2 nd and 6 th decades, mean age at onset is 30 At prime of life Affects approx. 2.5M worldwide and 400,000 in the US Reference: National Multiple Sclerosis Society. Available at the Society/MS Prevalence

77 Overview of Symptoms Generally Sensory, Motor, Cognitive or Emotional May be stable, fluctuating or progressing May be: PRIMARY (Fatigue) SECONDARY (Falls, UTI s) TERTIARY (Loss of Job, Divorce)

78 Most Common Symptoms Fatigue Major mobility impairments Spasticity Pain Tremors Sexual and Intimacy Issues Cognitive Issues Sensory symptoms / paresthesias Mood Disorders Bowel and bladder disturbances Speech and Swallowing Difficulties

79 FATIGUE IN MS Abrupt onset of exhaustion Described as lassitude, weakness, lethargy Prevents sustained physical functioning and interferes with ADL s May be acute or chronic

80 Fatigue Most commonly reported symptom in MS (affects 80 90% of people with MS) Over 50% describe fatigue as their worst MSrelated symptom Leads to other problems such as inactivity, depression, cognitive dysfunction, sexual dysfunction, pain

81 Fatigue Inactivity Deconditioning Physical Impairment Psychological Disturbances

82 Managing Fatigue 1) Address Secondary Causes Other medical or metabolic issues Poor Sleep Depression 2) Patient and Family Education and Counseling Energy conservation Use of appropriate assistive devices Regular exercise Proper nutrition Cooling strategies 3) Medications (Amantadine, Ritalin, Modafinil, Acetyl L Carnitine)

83 Heat Sensitivity 80% of patients develop increased symptoms with an increase in core temperature Cool environment (AC, fans) Cooling vest, appropriate clothing Cool drinks Use normal circadian rhythm (lowest core temp in am) Recognize red flags

84 Assistive Devices

85 Cognitive Dysfunction Cognition is defined as the process of acquiring knowledge. It is the mind s ability to organize, store and recall information Strong correlation exists between cognitive dysfunction and MRI lesion burden Prevalence rate of up to 65% most are mild

86 Cognitive Dysfunction Most common reason people with MS leave the workplace Can be worsened by fatigue and depression Memory changes, executive dysfunction Due to cerebral demyelination, axonal damage, atrophy of CC, enlarged ventricles

87 Cognitive Domains Affected Memory Processing Attention Problem Solving Visuospatial Abilities Verbal Fluency

88 Who can help? Neuropsychologists: Neuropsychological testing can pinpoint problem areas Speech Therapist and Occupational therapists: Cognitive Rehab which involves compensation and retraining techniques Physical Therapist: for home evaluation and safety strategies

89 Managing Cognitive Dysfunction Identify and treat / manage all possible causes (i.e. depression, fatigue, infection) Counseling and patient / family education Cognitive Rehab and compensatory strategies Medications (Aricept, Namenda)

90 Cognitive Rehab Strategies Attention: minimize distractions (reduce clutter, reduce noise and interruptions) Memory: notepads, personal alarms, tape recorder Word retrieval: describe item, substitute one word for another, gestures, picture board Executive functions (i.e. organizing, planning, reasoning, etc): make lists, prioritize lists, write things down

91 Assistive Devices

92 Spasticity involuntary, velocity dependent increase in muscle tone that causes resistance to movement Another common symptom in MS Consequences: Pain and discomfort Contractures Increased energy cost for activities Skin breakdown Interferes with gait and transfers Interferes with hygiene Sexual difficulties Insomnia

93 Considerations in treating spasticity Spasticity does not necessarily need to be treated Possible advantages of spasticity Maintains muscle tone / bulk Helps support circulatory function May prevent formation of DVT May assist in ambulation, transfers, ADL s May assist in postural control

94 Managing Spasticity Possible Interventions Stretching Gait training Positioning / posture Cooling Relaxation Patient education Avoiding noxious stimuli Medications (oral, injectable, intrathecal)

95 Intimacy and Sexuality in MS MS can affect the individual s sexual experience in a variety of ways Everyone (with MS) retains the capacity to give and receive love and pleasure, although creative problem solving is necessary to find avenues for intimacy and sexual expression Prevalence of sexual problems in women with MS is 40 80% and in men with MS is 50 90%

96 Most frequently reported changes MEN Erectile dysfunction Diminished capacity to attain or maintain Difficulty having an orgasm WOMEN Partial or total loss of libido/ desire Vaginal dryness Diminished orgasm Uncomfortable changes in the vaginal area

97 Sexual Dysfunction Causes and Contributing Factors: Loss of sensation (body mapping) Decreased libido (meds, testosterone, fatigue) Erectile dysfunction (testosterone levels) Difficulty reaching orgasm Spasticity Medications (antidepressants, sleep meds, pain meds) Fatigue (sleep, time of day) Pain Depression Mobility impairment, bowel / bladder problems

98 Top 10 Sex Tips for Men and Women with MS 1. Talk to your partner 2. Lubricate or use creams / suppositories as needed 3. Take medications for ED if needed 4. Experiment with positions and times 5. Feel beautiful or handsome or sexy 6. Takc care of your health 7. Expand your definition of sex 8. Time your medications 9. Talk to your doctor 10. Get creative and do not hesitate to use assistive devices, as needed

99 Assistive Devices

100 Pharmacologic and non pharmacologic interventions are necessary for multiple symptoms Interdisciplinary team approach can maximize outcomes for patients with MS Frequent reassessment and adjustment of management of symptoms Effective Management of Symptoms in Patients with MS

101 Summary Multiple Sclerosis is a chronic, disabling condition that affects multiple organ systems, causing various symptoms that impair mobility, activities of daily living, self care and quality of life. As such a multi and interdisciplinary approach to medical, rehabilitative and psychosocial care is necessary in the treatment of patients with MS.

102 CE/CME Credit If you would like to receive continuing education credit for this activity, please visit:

103 Case Study Mr. S is a 50 year old male engineer, diagnosed 12 years earlier, EDSS of 5 Past treatment includes interferon, glatiramer acetate, and the last 2 years, dimethyl fumarate His last clinical relapse was 3 years ago Recent brain MRI shows no new lesions on serial MRIs compared to 4 years previously Additionally, he has a positive cervical and thoracic spine, with no new or enhancing lesions in the past several years

104 Case study Mr. S states that he notices over the last 2 years that his right leg is more bothersome, he stumbles more. Last year he was able to walk a mile every day, now he can only do ½ of that His ability to take on new projects at work seems increasingly difficult, he does not understand why he is struggling, when he has had no relapses and he has been treated since his diagnosis Fatigue is a significant factor, his wife has noted his lack of energy this has created some strain in their relationship