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Multiple Sclerosis:The Nurse Practitioner’s HandbookCarrie Sammarco, DrNP, FNP-C, MSCNDiana Logan, RN, MSN, FNP-C, BC, MSCNGina Remington, RN, BSN, MSCNRosalind Kalb, PhD, EditorA resource provided by:1 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 2Table of ContentsIntroduction .............................................4Chloe: Relapsing-Remitting MS .........................5Suzanne: Transitioning from Relapsing-Remitting MS to Secondary-Progressive MS ..................................9Owen: Primary Progressive MS ........................12Section I: Overview of MS ............17Chapter 1: Introduction to MS ........................17Chapter 2: Immunology ...................................26Chapter 3: Neuroimaging.................................30Section II: Diagnosis & Treatment ...................39Chapter 4: Diagnosing MS ...............................39Chapter 5: Treatment Strategies Over the Disease Course ..................................47Chapter 6: Bladder Dysfunction .......................64Chapter 7: Bowel Dysfunction .........................70Chapter 8: Cognitive Dysfunction ...................76Section III: Comprehensive Care for the MS Patient ................142Chapter 18: The Interdisciplinary Team Approach to MS Care ...........................142Chapter 19: The Nurse Practitioner in MS Care ...146Chapter 20: Coordinating Patient & Family Care ....................................150Chapter 21: Reproductive Issues.....................156Section II: Diagnosis & Treatment (cont’d)Chapter 9: Depression & Other Mood Changes ..................................83Chapter 10: Fatigue, Sleep Disorders & Energy Management ....................90Chapter 11: Mobility Restrictions — Gait, Balance, Coordination, Vestibular, Function & Spasticity.......................................96Chapter 12: Optic Neuritis & Eye Movement Disorders ...........................103Chapter 13: Pain & Sensory Abnormalities ....................................109Chapter 14: Sexual Dysfunction .....................117Chapter 15: Speech Disorders ........................123Chapter 16: Swallowing Disorders ..................129Chapter 17: Continuum of Care ....................1353 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 4Conclusion .............................................161Glossary...................................................171Author Biographical Sketches ....................196Appendix: Recommended Resources ............162National MS Society Resources for You ...........................................162National MS Society Resources for Your Patients .............................167IntroductionMultiple sclerosis (MS) is a complex, unpredictable disease that challenges patients and clinicians alike. As nurse practitioners (NPs), our role is to guide our patients on their journey with MS, providing education, treatment, and support. This book was designed as a practical reference tool — offering easy access to the information you need to help your patients manage their disease, enhance their quality of life, and make healthy, informed decisions. We structured this handbook to be accessible and user-friendly for the busy clinician. The book opens with case studies that are intended to set the stage for all that follows. They represent real people, living with all the challenges that they — and you — are likely to confront over the course of the disease. The case studies are followed by an Overview of MS and then chapters dealing with Diagnosis and Treatment. Each of the symptom chapters includes a Snapshot to give a quick overview, followed by expanded information on assessment and management. We know that no one — patient or clinician — can manage the complexities of MS alone so the section on Comprehensive Care for the MS Patient highlights the interdisciplinary healthcare team, strategies for engaging the patient’s family, and the pivotal role of the Multiple Sclerosis Nurse Practitioner in managing these intricate issues. 5 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 6Included throughout the book, and expanded upon in the final section, are recommended resources and suggestions for additional learning. Our goal is to offer you and your patients access to current, evidence-based resources that complement and enhance effective MS management. We hope that you will slip this book into your pocket as a quick reference during daily practice. For those of you who prefer electronic resources this text is located in its most up-to-date version on-line at involvement with patients with MS over the years has been challenging and ultimately incredibly rewarding for each of us. We hope that you find this book to be a useful and encouraging resource that enhances your ability to provide optimal care and support to your patients with MS.And now we’d like to introduce you to Chloe, Suzanne, and Owen.Chloe: Relapsing-Remitting MS (RRMS)Chloe is a 27-year-old right-handed high school teacher with no family history of MS. She is married with one child and has a history of anxiety and depression. Upon examination, she has a trace reduction in light touch distal RUE. Her cranial nerves, motor, sensory, reflexes, coordination, and gait are intact. History of Present Illness2007–2008• Episode of right-hand numbness and clumsiness followed by OS blurred vision and pain with eye movement (Ch. 12).• MRI of the brain/cervical spine consistent with active demyelinating disease (Ch. 2).• OS symptoms successfully treated with a short course of IV methylprednisolone (IVMP) (Ch. 12).• Diagnosed with RRMS and started on glatiramer acetate (Ch. 5). 2009–2010• Episodic fatigue managed with exercise (Ch. 10); ongoing depression managed with antidepressant medication and counseling (Ch. 9); vagin*l dryiness managed with lubricant (Ch. 14).• Clinically and radiologically stable on DMT, with no relapses; married; discontinued DMT upon becoming pregnant (Ch. 21).2011• Clinically stable during pregnancy; delivered healthy baby girl and breastfed x 3 months.• “Brain fog,” memory issues, and fatigue; referred for cognitive evaluation (Ch.8).• Episode of left leg weakness and altered gait; treated with IVMP for relapse and referred to PT for evaluation and management (Ch. 11).• Repeat brain and cervical imaging revealed new disease activity• Treatment initiated with natalizumab (Ch. 5).7 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 82012• Clinically and radiographically stable. Natalizumab continued, with antibody testing every six months (Ch. 5).• Returned to teaching job with accommodations recommended by OT for energy conservation and by neuropsychologist for memory and attention problems (Ch. 8 and 10).Management of Chloe’s MSOptimal Management Sub-Optimal Management2007–2008• Thorough workup • Treatment of presenting symptom(s)• Prompt diagnosis• Education about the disease• Initiation of disease- modifying therapy (following discussion of reproductive issues)• Continued management of depression• Follow-up appointments scheduled• “Wait and see” approach• Symptom management delayed• Diagnosis and education delayed• Treatment with DMT delayed, increasing risk for recurrent disease activity • Without scheduled follow-up, sub-clinical disease goes untreated 2009–2010• Referral to rehabilitation for fatigue evaluation and management• Ongoing management of depression• Monitoring of disease with yearly MRI and regular check-ups• Discussion of treatment options during pregnancy with patient/spouse• Support system for childbirth in place• Continued monitoring• Inadequately managed symptoms interfere with quality of life and primary roles • Uninformed about risk of postpartum relapse2011• Relapse management postpartum• Clinical and radiographic changes prompt treatment change• Referral for cognitive evaluation• Birth of first child, significant relapse, and initiation of treatment start simultaneously• Gait impairment, fatigue, and cognitive symptoms go unmanaged2012• Rehabilitation referral to support return to work• Ongoing monitoring and follow-up• Retires on disability instead of returning to work; marital stress; diminished quality of life9 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 10Suzanne: Transitioning from RRMS to SPMSSuzanne is a 36 old -year-old right-handed woman on short-term disability (jewelry engraver). She has a maternal aunt and nephew with MS. She is married with twin seven-year-old boys and has a history of osteoarthritis. Upon examination, she has cerebellar tremor with dysmetria in right upper extremity, a spastic, ataxic gait with bilateral hip flexor weakness and right foot drop and ambulates with right ankle foot orthotic (AFO). Recent episodes of choking on liquids.History of Present Illness2006:• Developed bilateral leg weakness three months after delivering twin boys. Diagnosed with multiple sclerosis, treated with IV methylprednisolone and initiated interferon beta 1a SC tiw (Ch. 5 and Ch. 21).2008:• Acute right leg weakness, spasticity and altered gait. Treated with IVMP with residual leg weakness and mobility limitation. Spasticity managed with baclofen and exercises recommended by PT. Began using cane for balance and weakness (Ch. 11). Continued interferon beta 1a SC tiw. 2009:• Acute bilateral leg weakness, spasticity and altered gait; referral to OT because of left-hand weakness and tremor; Treated with IVMP and switched to natalizumab monthly infusions (Ch. 11). 2010–2012:• Relapse-free on natalizumab, but increasing leg weakness and gait limitations over past 24 months. • Onset of right hand tremor and dysesthesias (Ch. 13). Gabapentin initiated and natalizumab discontinued in 2012. • Symptoms interfering with ADLs and impacting ability to function at work. Loss of ability to drive leads to strong grief reaction; referral for counseling (Ch. 9). • Extensive discussion of long-term treatment options focusing on intensive symptom management and rehabilitation. • Continued PT and OT to promote optimal function given her limitations. Referred to S/LP for dysphagia evaluation (Ch.16). 11 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 12Management of Suzanne’s MSOptimal Management Sub-Optimal Management2006• Comprehensive workup — to evaluate current symptom management strategies, general health, mood • Continue PT to ensure adequate gait evaluation, assess need for assistive devices for mobility• Continue OT to optimize hand function and ensure adaptation of work/home environments to enhance safety and function• Adequate management of dysphagia • Failure to do a thorough workup leads to inadequate management of symptoms• Gait limitations progress; limited function, mobility and increased disability• Failure to involve rehabilitation specialists, leading to reduced function at home and inability to remain in workforce• Increased risk for aspiration; increased social isolation2008• Discussion of medication options with Susan and her husband — addressing realistic expectations about use of DMTs in SPMS• Poor understanding of role of DMTs in disease management in SPMS may lead to unrealistic expectations2009• Referral to social worker to: – Discuss workplace options – Discuss financial/ insurance arrangements – Deal with loss of function and driving• Early departure from work force; financial implications; marital stress; unresolved grief potentially leading to severe depression2010–2012• Follow-up visits scheduled every 3-4 months to monitor: – Spasticity – Ambulation – Mood – Swallowing• Inadequate follow-up, possibly resulting in sub-optimal symptom management, unnecessary complications, reduced function and quality of lifeOwen: Primary Progressive MS (PPMS)Owen, a 42-year-old African American man, is retired on disability from his job as police chief. A divorced father of a 14-year-old daughter, he has a history of hypertension and hyperlipidemia. James now lives with his mother and father and requires full assistance with ADLs and IADLs. Upon examination, he presents in a manual wheel chair propelled by his father, with spastic quadriparesis.13 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 14History of Present Illness2004: • Conspicuous signs of gait instability; re-assigned to desk duty and started using cane. • Diagnosed with MS based on clinical and radiographic findings; started on interferon beta 1b in spite of no clinical or radiographic relapses (Ch. 4). 2005–2007:• Switched to glatiramir acetate due to intolerable side effects of interferon injections (Ch. 5). • Progressive lower extremity weakness, spasticity and balance necessitated bi-lateral assistance. Moved in with parents and retired on disability.• Continued progressive decline — with increased spasticity, lower > upper limb weakness, bladder and bowel dysfunction (Ch. 6 and 7). Assistance required with all ADLs. • IVMP pulse steroids tried with no benefit. • Began using manual wheelchair in- and outside the house. 2008:• Continued progressive decline without clinical or radiographic relapses, consistent with primary progressive MS (Ch. 1). • Glatiramir acetate discontinued due to lack of perceived efficacy.• Depression diagnosed; James reluctant to see a counselor or start medication (Ch. 9). 2009–2010:• Stage 1 sacral sores managed by visiting nurse• Supra-pubic catheter placed for neurogenic bladder; bowel incontinence• Spasticity in legs interfered with personal care; ITB pump implanted to address sedation caused by high-dose oral baclofen (Ch. 11).• Suicidal ideation; Lexapro prescribed but counseling again rejected.2012:• Mother had stroke; parents no longer able to act as caregivers.• Placement in long-term care (LTC) facility is recommended and arranged. 15 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 16Management of Owen’s MSOptimal Management Sub-Optimal Management2004–2011• Comprehensive work-up — to evaluate current symptom management strategies, treatment of pressure ulcer, general health, mood • Bowel regimen initiated to address constipation and control issues• Referral to PT for exercise (stretching, ROM) regimen• Referral to wheeled mobility specialist for suitable power chair with appropriate seating to ensure adequate comfort, safety, and independence• Failure to do a thorough workup, including issues subjects that patient may not mention (constipation/bowel control issues, skin breakdown, mood)• Inadequate bowel management, leading to increased discomfort, continued incontinence• Failure to involve rehabilitation specialists, leading to greater discomfort, skin breakdown, reduced independence2012• Discussion with James and parents about his health and theirs, leading to a conversation about possible placement in a long-term care facility • Follow-up discussion to address their fears and parents’ guilt feelings• Referral to social worker to: – Continue discussion – Identify nearby facilities – Discuss financial/ insurance arrangements – Assist with transition – Ensure that James, his parents, and his daughter will have regular visits• Follow-up visits scheduled every six months to monitor: – Spasticity/baclofen pump – Skin integrity– Bladder/bowel function – Mood• Delayed conversation with James and parents, resulting in subsequent emergency admission to LTC, without time for the family to prepare for transition, pick the optimal location, or deal with the financial implications• Inadequate attention to James’ deepening depression/suicidal ideation, potentially resulting in suicide• Inadequate follow-up, possibly resulting in sub-optimal symptom management, unnecessary complications, premature death17 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 18Section I:Multiple Sclerosis: A Brief OverviewChapter 1: Introduction to Multiple SclerosisMultiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system (CNS) — the brain, spinal cord, and optic nerves — and is a leading cause of disability in young adults.• MS is a chronic, often disabling disease of the CNS with unknown etiology. • It is hypothesized by many experts in the field to be an immune- mediated disease — in which the immune system attacks the central nervous system. Primary targets of this attack include the myelin coating that surrounds the nerve fibers (axons), the cells that make myelin (oligodentrodytes), and the nerve fibers themselves. • Damaged myelin (demyelination) forms scar tissue (sclerosis) in multiple sites in the CNS, giving the disease its name. The damaged myelin and axons interfere with the transmission of nerve signals, resulting in the symptoms of MS.• While always considered to be a disease of the white matter, it is now known that gray matter lesions also occur early in the disease, and may even precede damage to the white matter (Popescu & Lucchinetti, 2012; Lucchinetti et al., 2011) in some individuals. • The collective damage to white and gray matter results in a broad spectrum of clinical signs and symptoms. What causes MS? • The etiology of MS is unknown but believed to be multifactorial and immune-mediated. – MS may be the result of an abnormal immune response to some infectious or environmental trigger in a genetically susceptible individual. – Each of these factors — immunologic, environmental, infectious, and genetic — is the subject of intensive ongoing research.• The pathologic process in MS begins with the activation of CD4+ T cells in the periphery after they are presented with an antigen — possibly a virus. – These activated T cells cross the blood-brain barrier (BBB) with the help of intercellular adhesion molecules and become reactivated when encountering additional antigens in the CNS. – The activated CD4+ T cells along with B cells, macrophages, and CD8+ T cells interact to produce an inflammatory response and subsequent myelin damage through multiple mechanisms, including the B-cell — mediated antibody/complement pathway (e.g., antibodies to myelin basic protein), macrophage-induced oxidative damage, and TNF-alpha secretion. 19 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 20 – These cells interact to produce an inflammatory response directed at components of the CNS. This inflammation —considered the hallmark of MS — is followed by demyelination, tissue scarring (gliotic sclerosis), axonal degeneration, and neurodegeneration. Classifications of MSFour disease courses have been identified in MS (Lublin & Reingold, 1996):• Relapsing-remitting (RRMS): Episodes of acute worsening of neurologic function, with some amount of recovery (the most common form) and no progression in between. The remissions Figure 1. Precursor T cells become myelin-reactive following interaction with antigen presenting cells displaying myelin-cross-reactive antigens. Myelin-reactive T cells may express several chemokine receptors including CCR2, CCR5, and CXCR3. They breach the blood-brain barrier (BBB) and enter the CNS with the help of upregulated cell adhesion molecules and MMPs. In the brain they encounter myelin antigens, presented mainly by microglia, inciting an inflammatory response that damages or destroys oligodendrocyte-formed myelin sheaths and underlying neurons. [Figure adapted from Weiner, H.L. & D.J. Selkoe (2002) Nature 420:879.]can be months to years with no new signs of disease activity. Deficits suffered during attacks or exacerbations may either resolve entirely or result in ongoing deficits. About 85% of people are diagnosed with RRMS initially.• Secondary-progressive (SPMS): Following an initial relapsing- remitting course, the disease transitions in many people to a steadily progressive form with increased loss of function. Of the 85% who start with RRMS, more than 50% will develop SPMS within 10 years and 90% within 25 years.• Primary-progressive (PPMS): Continuing worsening of disease from onset, without distinct relapses. Approximately 10% of people are diagnosed with PPMS.• Progressive-relapsing (PRMS): Progressive steady neurologic decline with occasional acute relapses. About 5% of people appear to have PRMS at diagnosis.• Benign MS: About 10% of MS patients experience a ‘benign course’ of MS — which can only be determined retrospectively. – Patients who have rare attacks and are minimally disabled 20 years after being diagnosed with MS are said to have benign MS (Hutchinson, 2012). – However, with increasing awareness of the potential for significant cognitive impairment (Ch. 8) in patients with early MS (Khalil et al., 2011) and in patients with little or no physical disability (Reuter et al., 2011; Amato et al., 2006), defining benign MS, and determining the patients for whom early and ongoing treatment with a disease-modifying agent (Ch. 5) is appropriate, are the subject of some debate: Hawkins, 2012 vs. Amato, 2012; Pittock et al., 2006 vs.Frohman et al., 2006.21 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 22The Natural History of MSEpidemiologic studies show the following:• In the absence of treatment, most patients with MS exhibit progressive neurological deterioration.• Ten years after diagnosis, half of patients use a cane to ambulate, and 15% require a wheelchair. • In the same 10 year span, approximately half of patients convert to the secondary progressive phase of the disease where there is acceleration of disability and a paucity of effective therapy. • The risk of progression to disability over the first decade may be influenced by several factors. For instance, although MS is more common in women (3:1), men are more likely to have a progressive, even malignant, clinical course (Zaffaroni & Ghezzi, 2000). Further, African Americans have been shown to have a more rapidly progressive disease course (Kister et al., 2010).• MS relapse rates decrease by ~ 70% in the third trimester of pregnancy. The risk of exacerbation again increases following delivery of the baby. These observations underscore the principle that hormonal factors figure prominently in the mechanisms of immune modulation and the ultimate expression of MS. Table 1-1: Factors that Affect Prognisis (Mowry, 2011)Favorable Unfavorable• Female• Low rate of relapses per year• Complete recovery from first attack• Long interval between 1st and 2nd attack• Symptoms predominantly from afferent systems (i.e., sensory symptoms)• Younger age at onset• Low disability at 2–5 years from the disease onset• Later cerebellar involvement• Involvement of only one CNS system at the time of onset• Male• High rate of relapses per year• Incomplete recovery from first attack• Short interval between 1st and 2nd attack• Symptoms predominantly from efferent systems (i.e., symptoms of motor tract involvement)• Older age at onset• Significant disability at 2–5 years from the onset acute onset• Earlier cerebellar involvement• Involvement of more than oneCNS system at the time of onsetFigure 1-1 Disease Courses in MSProgressive-Relapsing MSSteady decline since onset with super-imposed attacks.Secondary Progressive MSInitial relapsing-remitting multiple sclerosis that suddenly begins to have decline without periods of remission.Primary Progressive MSSteady increase in disability with-out attacks.Relapsing-Remitting MSUnpredictable attacks which may or may not leave permanent deficits followed by periods of remission.23 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 24ReferencesAmato MP, Portaccio E. Truly benign multiple sclerosis is rare: let’s stop fooling ourselves – YES. Mult Scler 18(1) 13–14.Amato MP, Zipoli V, Goretti B, et al. Benign multiple sclerosis: cognitive, psychological and social aspects in a clinical cohort. J Neurol 2006 Aug;253(8):1054–9.Frohman EM, Havrdova E, Lublin F, et al. Most patients with multiple sclerosis or a clinically isolated demyelinating syndrome should be treated at the time of diagnosis. Arch Neurol 2006 Apr;63(4):614-9.Hawkins S. Truly benign multiple sclerosis is rare: let’s stop fooling ourselves — NO. Mult Scler 18(1) 11–12.Khalil M, Enzinger C, Langkammer C et al. Cognitive impairment in relation to MRI metrics in patients with clinically isolated syndrome. Mult Scler 2011 Feb;17(2):173–80.Kister I, Chamot E, Bacon JH et al. Rapid disease course in African Americans with multiple sclerosis. Neurology. 2010 Jul 20;75(3): 217–23.Lucchinetti CF, Popescu BF, Bunyan RF, et al. Inflammatory cortical demyelination in early multiple sclerosis N Engl J Med 2011 Dec 8;365(23):2188–97.Mowry, EM. Natural history of multiple sclerosis: early prognostic factors. Neurol Clin 2011; 29(2):279–92.Pittock SJ, Weinshenker BG, Noseworthy JH, et al. Not every patient with multiple sclerosis should be treated at time of diagnosis. Arch Neurol 2006 Apr;63(4):611–4.Popescu BF, Lucchinetti CF. Meningeal and cortical grey matter pathology in multiple sclerosis. BMC Neurol 2012 Mar 7;12:11.Reuter F, Zaaraoui W, Crespy L, et al. Cognitive impairment at the onset of multiple sclerosis. Mult Scler 2011 Jun;17(6):755–8. Zaffaroni M, Ghezzi A. The prognostic value of age, gender, pregnancy and endocrine factors in multiple sclerosis. Neurol Sci 2000;21(4 Suppl 2):S857–60.Recommended ResourcesNational Multiple Sclerosis Society — Consortium of Multiple Sclerosis Centers — www.mscare.orgRecommended ReadingsFrohman TC, O’Donoghue DL, Northrop D (eds.) Multiple Sclerosis for the Physician Assistant: A Practical Primer. National MS Society, 2011. B. Primer on Multiple Sclerosis. New York: Oxford University Press, 2011.25 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 26Recommended Resources for Your PatientsOrganizationsNational Multiple Sclerosis Society — www.nationalMSsociety.orgMultiple Sclerosis Association of America — www.msassociation.orgMultiple Sclerosis Foundation — BooksKalb R (ed.) Multiple Sclerosis: The Questions You Have; The Answers You Need (5th ed.). New York: Demos Health, 2012.Kalb R, Giesser B, Costello K. Multiple Sclerosis for Dummies (2nd ed.). Hoboken NJ: Wiley, 2012. Kennedy P (ed.). The Can Do Multiple Sclerosis Guide to Lifestyle Empowerment. New York: Demos Health, 2012. Chapter 2: ImmunologyThe Immune System• The function of the immune system is to protect against pathogens, which it accomplishes through: – Innate immunity • Immune response to certain pathogens, which occurs in all healthy individuals and does not require prior exposure to the pathogen • Immediate destruction of some pathogens by phagocytic cells such as macrophage and neutrophils – Adaptive immunity • Antibodies that are produced to pathogens serve as an ‘immunologic memory’ • Comprised primarily of lymphocytic B cells, which produce the antibodies that attach to specific antigens and T cells (Kasper, 2010)• The benefits of the immune system – Protection from outside invaders – Elimination of altered self• The risks of the immune system – Discomfort and collateral damage resulting from inflammation – Damage to self resulting from hypersensitivity or autoimmunityThe Immune System and MS• MS is thought to be an immune-mediated disease. • The cause of the immune mediated damage is unknown.27 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 28• Much of the evidence supporting autoimmunity is derived from the ability to replicate clinical and pathologic features of MS in animal experiments. The animal model of MS is experimental autoimmune encephalomyelitis (EAE).• The key difference between EAE and MS is that the cause of the autoimmunity in EAE is known (immunization with myelin antigens or insertion of transgenes to generate encephalitogenic T lymphocytes), whereas the cause of the autoimmunity in MS is unknown (Pender, 2007). • The immune mechanisms thought to contribute to the patho-genesis (development) of MS are as follows: – TH1 cells are stimulated/activated in the periphery by presentation with antigen, possibly a virus. – Once activated, these cells proliferate and release cytokines and metalloproteinases (MMP) that break down the extracellular matrix of the blood brain barrier (BBB). – Once in the CNS, TH2 cells are presented with myelin protein that is similar to the antigen presented in the periphery. – he reactivated T cells along with B cells, macrophages, and CD8+ T cells interact to produce an inflammatory response and subsequent myelin damage through multiple mechanisms, including the B-cell — mediated antibody/complement pathway (eg, antibodies to myelin basic protein), macrophage-induced oxidative damage, and TNF-alpha secretion. – These cells interact to produce an inflammatory response directed at components of the CNS. – This Inflammation leads to demyelination, as well as axonal degeneration followed by chronic neurodegeneration. It is this process that results in clinical manifestations (Cravens et al., 2011; Matsui, 2008). Evidence of Immune Response Seen in Clinical Practice• 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 (Bar-Or, 2007). • Inflammatory T cells, B cells, and macrophages are typically seen on histopathologic examination of MS lesions at biopsy and autopsy (Lucchinetti et al., 2000). • Increased oligoclonal IgM and IgG levels are found in the cerebrospinal fluid (CSF) of patients with MS. (Matsui, 2008)• Myelin reactive T cells are found in MS plaques and in the CSF and peripheral circulation of patients with MS (Oksenberg et al., 1993). ReferencesBar-Or A. Neuroimmunology of multiple sclerosis: current concepts. Adv Stud Med. 2007; 7(8):221–227).Cravens P, Eagar T, Karandikar N et al. Neuroimmunology of multiple sclerosis. In T Frohman, D O’Donoghue, D Northrop (eds.). Multiple Sclerosis for the Physician Assistant. National Multiple Sclerosis Society, 2011. Kasper LH, Shoemaker J. Multiple sclerosis immunology: The healthy immune system vs the MS immune system. Neurology 2010; 74 Suppl 1:S2–8.Lucchinetti C, Brück W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000; 47(6):707–717.29 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 30Matsui M. Multiple sclerosis immunology for clinicians. Neurology Asia 2008; 13:195–198. Oksenberg JR, Panzara MA, Begovich AB, et al. Selection for T-cell receptor V beta-D beta-J beta gene rearrangements with specificity for a myelin basic protein peptidein brain lesions of multiple sclerosis. Nature. 1993; 362(6415):68. Recommended ReadingsCostello K. State of knowledge: the immunopathophysiology of multiple sclerosis. In The Evolving Role of the Nursing Professional with New Multiple Sclerosis Therapies: Proceedings of a Roundtable discussion. International Journal of MS Care: 2008, Vol. 10, No. S3, pp. 4–10. Sospedra M, Martin R. Immunology of multiple sclerosis. Ann Rev immunol. 2005; 23:683–747.Chapter 3: NeuroimagingIntroduction Magnetic resonance imagining (MRI) currently offers the most sensitive, non-invasive way of imaging the brain, spinal cord, or other areas of the body. It is the preferred imaging method to help establish a diagnosis of MS and to monitor the course of the disease. And this technology has made it possible to visualize and understand much more about the underlying pathology of the disease.Although MRI helps to support the diagnosis of MS, is not diagnostic by itself (Ch. 4). The revised McDonald diagnostic criteria published in 2010 provide specific guidelines for making an MS diagnosis, based on clinical findings and objective evidence obtained from MRI. (p. 40)MRI Technology• How the technology works: – MRI uses a powerful magnetic field. Tissues in the body consist mainly of fat and water, which means that they contain an abundance of hydrogen atoms. – Each atom contains a proton that has a property called spin. The magnetic field causes the hydrogen protons in water molecules to line up. – Once the hydrogen protons are lined up, they are knocked out of line by a radiofrequency (RF) pulse that is transmitted to the person’s body in short bursts. – When the radio waves are stopped, the protons relax back into line, releasing resonance signals that are transmitted to a computer. 31 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 32 – The various types of MRI scans that are used — most commonly the T1-weighted scan and the T2-weighted scan — measure this relaxation time differently. Computer programs translate these data into cross-sectional pictures of the water in human tissue resulting in MRI images. • Why the technology is particularly useful in MS: – Subtle details in soft tissue might be missed using conventional imaging techniques such as CT scans or x-rays. Magnetic resonance imaging is very well tolerated and poses little or no risk to the average individual. – The layer of myelin that protects nerve-cell fibers is fatty and therefore repels water. In the areas where the myelin has been damaged by MS, the fat is stripped away. With the fat gone, the area holds more water, and shows up on an MRI scan as either a bright white spot or a darkened area, depending on the type of scan that is used. The magnitude and timing of the RF pulses can be manipulated in specific ways so protons in different tissues relax at varying rates. This produces images with greater contrast between different tissues types. • Types of scans used most commonly in MS: Conventional methods of MRI include T2 imaging, variations of T2 imaging such as FLAIR, T1 imaging, and T1 with gadolinium enhancement. – T2-weighted images • On T2 scans, gray matter appears lighter and brighter than white matter; cerebral spinal fluid (CSF) appears bright. • The information provided by T2 is often referred to as disease burden or lesion load (meaning the total amount of lesion area). • T2 images are sensitive to increased water content and are often superior at demonstrating pathological changes in the brain parenchyma. • T2 images have a high degree of sensitivity and allow us to detect lesions that might be missed on T1 scans. • A patient may have numerous T2 lesions while T1 hypo-intense areas may not be visible. • MS lesions are hyperintense or bright — which can make differentiation from ventricles challenging. • Hyperintense areas of T2 images are not specific — they may represent inflammation, edema, or mild demyelination as well as gliosis, severe demyelination, and axonal loss — making it difficult to assess the degree of irreversible tissue damage. Sagittal T2WI Image:Lesions in the cervical spinal cord. (courtesy of J. Wolinsky)Axial T2WI Image:Lesions in the spinal cord. (courtesy of J. Howard)Axial T2WI:Lesions throughout the brainstem and cerebellum in a patient with MS. Lesions in the brainstem and cerebellum are termed infratentioral lesions. These are best seen on T2-weighted MRIs.33 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 34 • T1 images are most useful in demonstrating the detailed anatomy of the CNS. • Gray matter appears dark and white matter is a lighter shade of gray. • Areas of abnormality are usually hypointense (dark) and referred to as black holes — which are thought to indicate areas of permanent damage. • T1 images emphasize tissue differences and show clear anatomic detail. – Gadolinium enhanced images • Gadolinium (gd), which acts as a marker for active inflammation, can be injected intravenously to further enhance the sensitivity of the T1-weighted MRI scan. • Gadolinium only penetrates the brain where the blood-brain barrier has been disrupted, which occurs in MS during active, inflammation. The result is enhancement or bright white areas that represent active lesions and provide an indication of current disease activity. • T1 background is utilized because areas that are enhancing will show the greatest amount of contrast on a T1 weighted image. • New and active lesions appear bright and easy to visualize with gadolinium enhancement. • MS lesions seen on a Gd-enhanced T1 scan may not be detected on a non-contrast T1 scan or T2-weighted images. • Enhancement may last from 1 to 4 weeks or even for months in some cases. • Gadolinium enhancing lesions are detected 5–10 times more frequently than clinical relapses — which suggests that most of the enhancing lesions are clinically silent. • Note: Many MRI centers request renal function testing prior to the administration of gadolinium; patients with acute or chronic renal insufficiency are at risk for nephrogenic systemic fibrosis after exposure to gadolinium-based contrast agents. Post-Contrast Axial T1 Weighted Image:Numerous enhancing lesions; incomplete ring- enhancing lesions highly suggestive of MS. (courtesy of J. Howard) – FLAIR (Fluid-Attenuated Inversion Recovery) Image • FLAIR is a type of T2 image that is better than standard T2 images at demonstrating demyelinating lesions because it shows both new and old lesions clearly. • The signal from the CSF is suppressed in FLAIR imaging so that it’s easier to visualize lesions. • FLAIR imaging best depicts lesions located along the lateral borders of the corpus callosum. – T1-weighted images Axial FLAIR ImageDemonstrates typical periventicular lesions in MS. (courtesy of J. Howard)Axial T1 Weighted ImageDemonstrates hypointentense lesions in the white matter. (courtesy of J. Howard)35 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 36• Where MS lesions are located – MS lesions can be found throughout the brain, but have a predilection for periventricular white matter (PVWM) and tend to have an ovoid configuration with the major axes perpendicular to the ventricular surface. – Early in MS, these PVWM lesions are typically thin and appear to be linear (referred to as “Dawson’s fingers”). – The corpus callosum, subcortical region, brainstem, U-fibers, optic nerves, and visual pathway are also regions where MS lesions occur with some frequency. The lesions in the corpus callosum, U-fibers,and optic nerve lesions can assist in differ-entiating MS from cerebrovascular disease. – White matter lesions occur more often than grey matter lesions. – Grey matter lesions are best detectedon FLAIR. – Optic neuritis (inflammation of optic nerve) can be detected by using a fat-suppression technique combined with contrast- enhanced imaging or by using long-echo short-tau inversion recovery (STIR) imaging.• The planes in which MRI images are provided: – Axial: a horizontal cut away slice of the body as seen from the top of the head. • Lesions are most likely to be seen in the optic nerve, the brain stem and the cerebellum. • Changes consistent with MS can be visualized on any plane but are most often viewed on the axial plane. – Sagittal: a vertical cut away slice of the body as seen from the left side of the head. • Lesions can be seen in the deep white matter in the periven-tricular area, brain stem, cerebellum, and spinal cord. • Juxtacortical lesions can also be viewed on the sagittal image. • White matter lesions are aligned perpendicular to the long axis of the lateral ventricle. This appearance in multiple sclerosis is known as Dawson’s fingers.Sagittal FLAIR image:Demonstrates characteristics Dawson’s fingers of MS. (courtesy of J. Howard) – Coronal: vertical cut away slice as seen from the front of the body. In addition to brain imaging, spinal cord imaging is very important in MS because many symptoms may be associated with cord pathology. Both axial and sagittal views of the spinal cord are used in MRI imaging for multiple sclerosis. • The role of MRI in MS Diagnosis – Because MRI is particularly useful in detecting central nervous system demyelination, it is a powerful tool in helping to establish the diagnosis of MS (Ch. 4). – It should be remembered, however, that approximately 5% of patients with clinically definite MS do not show lesions on MRI at the time of diagnosis. Axial FLAIR Image:Atrophy and ventricular enlargement in a patient with MS. Significant brain atrophy is typically a feature of advanced disease, however some degree of atrophy is often present even in early MS. (courtesy of J. Howard)37 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 38 – Also, since many lesions seen on MRI may be in so-called “silent” areas of the brain, it is not always possible to make a specific correlation between what is seen on the MRI scan and the patient’s clinical signs and symptoms. – With advancing age (probably over age 50), there are often small areas seen on MRI in healthy people that resemble MS but are actually related to the aging process.• The role of MRI in clinically isolated syndromes – MRI is particularly helpful in patients who have had a single demyelinating attack that is suggestive of MS, also called a clinically isolated syndrome (CIS). The number of lesions on an initial MRI of the brain (or spinal cord) can help the clinician assess the patient’s risk of developing a second attack (and therefore “clinically-definite MS”) in the future. Some of the treatments for MS have been shown to delay the occurrence of a second episode of symptomatic demyelination in patients who have had only one.• The role of MRI in assessing disease progression and prognosis – Once a diagnosis of MS has been established, there is no reason why an MS patient should have further diagnostic MRI scans. Subsequent scans, however, may be useful in tracking the progress of the disease, or possibly helping to establish a prognosis-a prediction of the course of a disease. For example, researchers have demonstrated that the degree of cognitive impairment as demonstrated by neuropsychologic testing can be correlated with the total amount of demyelination seen in certain areas of the brain on MRI.ReferencesGe Y. Multiple Sclerosis: The Role of MR Imaging. American Journal of Neuroradiology 2006; 27:1165–76 . Neuroimaging in Multiple Sclerosis: Key Concepts for Nurses, 2009. Educational DVD available at audio-visual/107. Recommended ReadingsFilippi M, Rocca M, Barkhof F, et al. Association between patho-logical and MRI findings in multiple sclerosis. Lancet Neurology 2012; 11(4):349-60. Resources for Patients -you-can-expect39 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 40Section II:Diagnosis & TreatmentChapter 4: Diagnosing Multiple SclerosisMultiple sclerosis (MS) can be challenging to diagnose because there are no unique symptoms, physical findings or laboratory tests that are specific to the diagnosis. The diagnosis is a clinical one, requiring several strategies to determine if a person meets the long-established diagnostic criteria. Multiple Sclerosis Diagnostic Criteria In order to make a diagnosis of MS, the clinician must:• Find evidence of damage in at least two separate areas of the central nervous system (CNS), which includes the brain, spinal cord and optic nerves (Dissemination in Space) AND• Find evidence that the damage occurred at least one month apart (Dissemination in Time) AND• Rule out all other possible diagnoses2010 Revised McDonald MS Diagnostic CriteriaWith the advent of increasingly sophisticated MRI technology, MRI findings have been incorporated into the diagnostic criteria in order to help speed the process of confirming dissemination in time and space.CLINICAL(ATTACKS) LESIONS ADDITIONAL CRITERIA TO MAKE DX2 or moreObjective clinical evidence of ≥ 2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attackNone. Clinical evidence alone will suffi ce; additional evidence desirable but must be consistent with MS2 or more Objective clinical evidence of 1 lesionDIS; OR await further clinical attack implicating a different CNS site1 Objective clinical evidence of ≥2 lesions DIT; OR await a second clinical attack1 Objective clinical evidence of 1 lesionDIS OR await further clinical attack implicating a different CNS site AND DIT; OR await a second clinical attack0(progression from onset)One year of disease progression (retrospective or prospective) AND at least two of: DIS in the brain based on ≥1 T2 lesion in periventricular, juxtacortical or infratentorial regions; DIS in the spinal cord based on ≥2 T2 lesions; or positive CSF2010 Revised McDonald MS Diagnostic Criteria11. Polman et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald Criteria. Ann Neurol 2011;69:292-302.* See reverse for DIS and DITDiagnosis of MS requires elimination of more likely diagnoses and demonstration of dissemination of lesions in space (DIS) and time (DIT)*Paraclinical Evidence in MS DiagnosisEvidence for Dissemination of Lesions in Space (DIS)2≥ 1 T2 lesion in at least two out of four areas of the CNS: periventricular, juxtacortical, infratentorial, or spinal cord• Gadolinium enhancement of lesions is not required for DIS• If a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded and do not contribute to lesion countEvidence for Dissemination of Lesions in Time (DIT)3• A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI or• Simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions at any timeEvidence for Positive CSFOligoclonal IgG bands in CSF (and not serum) or elevated IgG index2 Swanton KL et al. Lancet Neurology 2007;6:677-686 / Swanton KL et al. J Neurol Neurosurg Psychiatry 2006;77:830-8333 Montalban X, et al. Neurology 2010;74:427-434These diagnostic criteria were developed through the consensus of the International Panel on the Diagnosis of MS. See cited articles for details. Funding through National Multiple Sclerosis Society (USA) and European Committee for Treatment and Research in MS; additionalsupport from the Multiple Sclerosis International Federation and MS IrelandNational Multiple Sclerosis Society (USA)Professional Resource Center. 733 Third Avenue. New York, NY 10017-3288© 2011 National Multiple Sclerosis Society BR004041 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 42Tools for Making the MS Diagnosis• Medical history and neurologic exam – A systematic and extensive history should always accompany a careful and detailed physical and neurological examination as the cornerstones for making any neurologic diagnosis. – In many instances, the person’s medical history and neurologic exam provide enough evidence to meet the diagnostic criteria. • Laboratory testing – There is no definitive blood test for MS. – Blood tests can rule out other conditions that cause symptoms similar to those of MS, including Lyme disease, a group of diseases known as collagen-vascular diseases, certain rare hereditary disorders, and AIDS.• Magnetic Resonance Imaging (MRI) – MRI is the best imaging technology for detecting the presence of MS plaques or scarring (also called lesions) in different parts of the CNS. It can also differentiate old lesions from those that are new or active. – The diagnosis of MS cannot be made solely on the basis of MRI because there are other diseases that cause lesions in the CNS that look like those caused by MS. And even people without any disease — particularly the elderly — can have spots on the brain that are similar to those seen in MS. – Although MRI is a very useful diagnostic tool, a normal MRI of the brain does not rule out the possibility of MS. About 5% of people who are confirmed to have MS do not initially have brain lesions on MRI. However, the longer a person goes without brain or spinal cord lesions on MRI, the more important it becomes to look for other possible diagnoses.• Evoked potential testing (EP) – Evoked potential (EP) tests are recordings of the nervous system’s electrical response to the stimulation of specific sensory pathways (e.g., visual, auditory, general sensory). – Because damage to myelin (demyelination) results in a slowing of response time, EPs can sometimes provide evidence of scarring along nerve pathways that does not show up during the neurologic exam. – Visual evoked potentials (VEPs) are considered the most useful for confirming the MS diagnosis.• Cerebrospinal fluid analysis (Lumbar puncture [LP]) – Analysis of the cerebrospinal fluid, which is sampled by a spinal tap, detects the levels of certain immune system proteins and the presence of oligoclonal bands. – These bands, which indicate an immune response within the CNS, are found in the spinal fluid of about 90–95% of people with MS. But because they are present in other diseases as well, oligoclonal bands cannot be relied on as positive proof of MS.Because permanent neurologic damage can occur even in the earliest stages of MS — and subclinical disease activity is occurring even before clinical symptoms appear (See Figure 1) — it is important that a confirmed diagnosis is made so that the appropriate treatment(s) can be initiated early in the disease process (Coyle, 2008).Clinically Isolated SyndromeClinically isolated syndrome (CIS) is a term that describes a first clinical episode with features suggestive of multiple sclerosis (MS). It usually occurs in young adults and affects optic nerves, the brainstem, or the spinal cord. Although patients usually recover from their presenting episode, CIS is often the first manifestation of MS.43 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 44Table 4-1: Most Common Clinically Isolated Syndrome Presentations (Miller et al. 2008)Optic Neuritis Brainstem Spinal CordTypical for MS:Unilateral visual loss, orbital pain, afferent pupillary defect, retrobulbar or mild disc swelling, visual loss does not progress beyond two weekstBrain & Spinal MRI Typical for MS:Internuclear ophthalmoplegia 6th nerve palsy, multifocal signs (e.g., facial sensory loss, vertigo, hearing loss, ataxia, dysarthria)tBrain & Spinal MRItWithin 5 years:Typical for MS:Evolution over hours to days, partial myelitis, Lhermitte’s sign, partial Brown-Séquard, spontaneous remissiontBrain & Spinal MRI Figure 4-1: The Natural History of MSNormal brain MRI: 20% risk of conversion to clinically definite MS (CDMS).Abnormal brain MRI: (> 2 lesions consistent with demyelination) = 80–90% risk of conversion to CDMS, depending on CIS presentation.The most notable risk factors for MS are clinically silent MRI lesions and CSF oligoclonal bands; weak or uncertain risk factors include vitamin D deficiency, Epstein-Barr virus infection, smoking, HLA genes, and miscellaneous immunological abnormalities (Miller et al., 2012). Disease-modifying treatments delay the conversion of CIS to MS. Ruling Out Other Conditions that Mimic MS• The diagnosis of MS needs to exclude conditions that mimic MS and that can confuse the clinical picture. • Any conditions that can cause intermittent neurologic dysfunction can mimic MS. • As in any differential diagnosis, there are vascular, metabolic, autoimmune and physiologic processes that have symptoms reminiscent of MS. The typical workup for suspected demyelination disease includes a variety of tests. The exact battery may vary based on the presen-tation. Table I summarizes a standard workup that most patients should have, but is not comprehensive for all circ*mstances.Table 4-2: Basic workup for patients with suspected demyelinating diseaseTest ReasonBrain MRI Multifocal brain lesions suggest MSNMS IgG Neuromyelitis Optica (NMO)SSA/SSB Siogren’s Associated Transverse Myelitis45 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 46ANA Lupus Associated Transverse MyelitisAnticardiolipin Antibody Antiphospholipid Syndrome AssociatedTransverse MyelitisCopper and Zinc Copper Deficiency (and/or Zinc excess) Associated MyelopathyVitamin B12 Subacate Combined DegenerationRPR Tabes DorsalesChest CT Scan (consider galllium or indium scan); Angiotensin converting enzyme (ACE)SarcoidosisCSF Oligoclonal Bands/ IgG Index/IgG rateAssociated with MSReferencesCoyle PK. Early treatment of multiple sclerosis to prevent neurologic damage. Neurology 2008; 71: S3–S7.Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol 2012; 11(2):157–169.Miller DH, Weinshenker BG, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler 2008; 14(9):1157–1174Polman C et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Annals of Neurology 2011; 69:292–302) Recommended ReadingsAwad A, Hemmer B, Hartung HP, et al. Analyses of cerebrospinal fluid in the diagnosis and monitoring of multiple sclerosis. J Neuroimmunol 2010; 219(1–2):1–7.Barkhof F, Filipppi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain, 1997; 120:2059–2069ResourcesNational MS Society —• MS Clinical Care Network — – Free downloadable Diagnosis and Management App for smartphones. 47 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 48Chapter 5: Treatment Strategies Over the Disease CourseTreatment strategies in multiple sclerosis fall into five general categories (Reitman & Kalb, 2012).Treatment of Acute Exacerbations (relapses)An exacerbation of MS (also known as a relapse, attack, or flare-up) is caused by inflammation in the central nervous system (CNS) that causes damage to the myelin and slows or blocksthe transmission of nerve impulses. • To be a true exacerbation, the attack must last at least 24 hours and be separated from a previous exacerbation by at least 30 days — with most lasting from a few days to several weeks or even months. – A pseudo-exacerbation — a brief flare-up of old symptoms that is unrelated to new damage in the CNS — can result from an elevation in core body temperature caused infection (UTI, URI, viral infection), exertion during exercise, heat or humidity. Pseudo-exacerbations resolve once the body temperature returns to normal. • Exacerbations can be mild or severe enough to interfere with a person’s ability to function at home and at work. Severe exacerbations are most commonly treated with high-dose corticosteroids to reduce the inflammation. – Most common protocol: 3–5 day course of high-dose intra-venous (IV) corticosteroid (methylprednisolone) treatment, which may or may not be followed by a gradually tapering dose of an oral corticosteroid such as prednisone (Beck et al., 1992). – Steroids work to decrease acute inflammation in the CNS, but have no long-term benefits in MS. – Many people feel better while taking them, in part because steroids can sometimes have a mood-elevating effect. – Chronic use steroids causes serious side effects, including hypertension, diabetes, bone loss (osteoporosis), cataracts, and ulcers. • Short courses are generally well tolerated; side effects include: gastric problems; feeling ‘high’; insomnia; depression; mood swings (effectively treated with a low-dose mood stabilizing medication)• Other treatment options for exacerbations are available – High-dose oral corticosteroids are also used by some MS clinicians (Morrow et al., 2009). – ACTH (H.P. Acthar Gel — repository corticotropin injection) has been approved by the FDA for this purpose since 1978. Especially useful for patients who: are unable to tolerate high dose corticosteroids; have not responded to corticosteroids; do not have access to intravenous therapy; have insufficient venous access. The approved dosing schedule is 80–120 units daily for 2–3 weeks. – Plasmapheresis (Plasma exchange) may be considered for the 10 percent of very severe exacerbations that do not respond adequately to the standard steroid treatment.Symptom Management Symptom management is an essential component (Cohen, 2008; Henze et al., 2006) of comprehensive MS care. While disease management therapies reduce disease activity and slow progression for many people, it is the ongoing management of symptoms that allows people to function in their daily lives with optimal comfort, safety, participation, and quality of life. Given the wide variety of neurological symptoms that can occur in MS, interdisciplinary care is the key to effective management (Ch. 18). 49 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 50Working with patients to manage their symptoms requires awareness not only of the functional impact each symptom might be having, but also the ways in these visible and not-so-visible symptoms affect them emotionally, socially, and vocationally. The most common symptoms, discussed in detail in Chapters 6 –16, include:• Ambulation problems• Bladder dysfunction• Bowel dysfunction• Cognitive dysfunction• Fatigue• Mood disturbances• Pain and other sensory changes• Sexual dysfunction• Speech problems• Swallowing difficulties• Tremor• Vision problemsDisease ModificationSince 1993, the U.S. Food and Drug Administration (FDA) has approved several drugs for use in MS. These drugs do not cure MS or provide relief from current symptoms — in fact, the effects on the disease may not be immediately apparent. No medications have yet been approved for the treatment of primary-progressive MS.For the most current information on disease-modifying therapies, go to: 5-1: First-Line Disease-Modifying MedicationsGeneric Name & Brand NameInterferon Beta 1BBetaseron/ExtaviaManufacturer/ Distributor Bayer Healthcare Pharmaceuticals/ Novartis PharmaceuticalsApproval in US Betaseron: 1993 Extavia: 2009Frequency/Route of Delivery/DoseEvery other day; subcutaneous injection/ AutoinjectorUsual Dose 250 mcgCommon Side EffectsFlu-like symptoms following injection, which lessen overtime for many people; injection site reactions, about 5% of which need medical attention. Less common: depression, elevated liver enzymes, low white blood cell countWarnings & PrecautionsFor a complete listing, go to: Info & Financial Support ProgramsBetaplus 800-788-1467 betaseron.comExtavia Patient Support Program 866-925-233351 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 52Table 5-1 (cont’d): First-Line Disease-Modifying MedicationsGeneric Name & Brand NameInterferon Beta 1AAvonexManufacturer/ Distributor Biogen IdecApproval in US 1996Frequency/Route of Delivery/DoseWeekly; intramuscular injection/ AutoinjectorUsual Dose 30 mcgCommon Side EffectsFlu-like symptoms following injection, which lessen over time for many people. Less common: depression, mild anemia, elevated liver enzymes, liver toxicityWarnings & PrecautionsFor a complete listing, go to: Info & Financial Support ProgramsMS Active Sources 800-456-2255 / msactivesources.comTable 5-1 (cont’d): First-Line Disease-Modifying MedicationsGeneric Name & Brand NameInterferon Beta 1ARebifManufacturer/ Distributor EMD Serono, PfizerApproval in US 2002Frequency/Route of Delivery/DoseThree times per week; subcontaneous injection/AutoinjectorUsual Dose 44 mcgCommon Side EffectsFlu-like symptoms following injection, which lessen overtime for many people; injection site reactions. Less common: depression, elevated liver enzymes, low white blood cell countsWarnings & PrecautionsFor a complete listing, go to: Info & Financial Support ProgramsMS Lifelines 877-447-3243 / mslifelines.com53 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 54Table 5-1 (cont’d): First-LineDisease-ModifyingMedicationsGeneric Name & Brand NameGlatiramer AcetateCopaxoneManufacturer/ Distributor Teva PharmaceuticalsApproval in US 1996Frequency/Route of Delivery/DoseDaily;subcontaneousinjection/ AutoinjectorUsual Dose 20 mg (20,000 mcg)Common Side EffectsInjectionsitereactions.Lesscommon:a reaction immediately after injection that includes anxiety, chest tightness, shortness of breath, and flushing. This lasts 5–10 minutes and has no known long-term effectsWarnings & PrecautionsFor a complete listing, go to: Info & Financial Support ProgramsShared Solutions 800-877-8100 / / mswatch.comTable 5-1 (cont’d): First-LineDisease-ModifyingMedicationsGeneric Name & Brand NameFingolimodGilenyaManufacturer/ Distributor Novartis PharmaceuticalsApproval in US 2010Frequency/Route of Delivery/DoseDaily;capsuletakenorallyUsual Dose 0.5 mgCommon Side EffectsHeadache, flu, diarrhea, back pain, liver enzymeelevations,andcough.Lesscommon:slowed heart rate following first dose, infections, and macular edemaWarnings & PrecautionsFor a complete listing, go to: Info & Financial Support ProgramsGilenya Go Program 800-445-3692 gilenya.com55 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 56Managing Skin & Injection Site Reactions (McEwan et al., 2010)Five of the first-line medications are delivered by injection. Teaching optimal self-injectiontechniques and management of injection site reactions when they occur are key roles for the MS nurse. Injection-site reactions (ISRs), which can include pain and erythema, lipoatrophy, abscesses and infections, necrosis, rash, swelling, and lumps, are more common with subcutaneous injections than with intramuscular injections. Autoinjectors, when available, can be very helpful. • Erythema and pain – Pain may be reduced by applying warm compresses before injection and cold compresses after injection for up to 5 minutes. – Lidocaine/prilocaine cream has been shown to reduce pain/fear of pain after injection. – Pain may be reduced by use of a smaller, thinner needle.• Lipoatrophy – Emphasize importance of regular site rotation. – Emphasize importance of injecting only into healthy tissue. – Teach patient visual and manual inspection strategies. – Inspect injection areas at every visit.• Injection Site Infections: cellulitis and soft-tissue abscesses – Optimal skin preparation is the best prevention. – Antibiotic or surgical treatment may be warranted.• Induration, Swelling, Lumps, Rash, and Necrosis – Emphasize proper injection-site rotation. – Review preparation techniques and sites. – Substitute soap and water for alcohol, which can irritate indurations.Table 5-2: Additional Approved Treatment OptionsGeneric Name & Brand NameNatalizumabTysabriManufacturer/ Distributor Biogen Idec and Elan PharmaceuticalsApproval in US 2006Frequency/Route of Delivery/DoseIV infusion every 4 weeks in registered infuction facilityCommon Side EffectsHeadache, fatigue, UTI, depression, lower RTI, joint pain, chest discomfortWarnings & PrecautionsFor a complete listing, go to: increases a person’s risk for a rare brain infection called progressive multifocal leukoencephalopathy (PML), which usually results in death or severe disability. For the most current infor-mation about PML in Tysabri-treated patients, go to Info & Financial Support Programs800-456-2255 / biogenidec.com57 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 58Table 5-2: Additional Approved Treatment OptionsGeneric Name & Brand NameMitoxantroneNovantroneManufacturer/ Distributor Serono, Inc.Approval in US 2000Frequency/Route of Delivery/Dose4 times a year by IV infusion in a medical facility. Lifetime cumulative dose limit of 8–12 doses over 2–3 years.Common Side EffectsBlue-green urine 24 hours after administration; infections, bone marrow suppression, nausea, hair thinning, UTI, mouth soresWarnings & PrecautionsFor a complete listing, go to: of its potential long-term impact on cardiac function, the drug should only be used in those with normal heart function, and cardiac monitoring should continue for the duration of treatment and after treatment has been concluded.Mitoxantrone is also known to increase a person’s risk of acute myelogenous leukemia (AML).Patient Info & Financial Support ProgramsNone at this timeEmerging Therapies in Multiple SclerosisSeveral medications are expected to be approved for the treatment of MS in the months following the printing of this book. To ensure that you have the most current information, log on to for important updates or email to request these and other important announcements by email. Three medications are currently under review by the FDA, with expected approval by the end of 2013:• Teriflunomide (Genzyme/Sanofi-Aventis) is an oral, once-daily medication that decreases B-cells and T-cells to reduce inflammation. In a large, phase III trial in relapsing MS, two doses were compared. Both doses reduced the relapse rate by 37% and reduced total lesion volume by 39–67%. The high dose also reduced risk of disability progression by 30%. Overall adverse events were the same across treatment and placebo groups. The most common side effects were mild hair thinning, nausea, and diarrhea (O’Connor et al., 2011). Note: In September, 2012, both doses of teriflunomide were approved by the FDA for the treatment of relapsing forms of MS.• Alemtuzumab (Genzyme) is a monoclonal antibody that depletes circulating immune (T and B) cells that are thought to be responsible for MS relapses. It is given by intravenous infusion for 5 days initially and for 3 days one year later. In one phase III clinical trial, alemtuzumab significantly reduced relapse rates when compared to Rebif (interferon beta-1a). In a second phase III trial, alemtuzumab significantly reduced relapse rates and worsening of disability compared to Rebif over the two-year study period. In the trial, 15.9 percent of alemtuzumab- treated patients developed an autoimmune thyroid-related adverse event compared to 5.0 percent with Rebif, and 0.9 percent of alemtuzumab-treated patients developed immune thrombocytopenia (ITP).59 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 60• BG-12 (dimethyl fumarate — Biogen Idec) is an oral medication that appears to be neuroprotective and anti-inflammatory. In a phase III trial comparing two doses to placebo, both doses of BG-12 significantly reduced the risk of relapses, the annualized relapse rate, the risk of disability progression, and lesion activity on MRI, compared to placebo. The most common side effects were flushing or reddening of the skin and mild gastrointestinal issues, including diarrhea and nausea.Rehabilitation (to enhance & maintain physical function)Rehabilitation in MS involves the intermittent or ongoing use of multidisciplinary strategies to promote functional independence, prevent complications, and enhance overall quality of life (Kalb, 2010)• From disease onset (and intermittently throughout the disease course), providing education and treatment designed to promote good health and general conditioning, reduce fatigue, and maximize participation • Helping the person restore and/or maintain the highest possible level of functioning and realize his or her optimal physical, mental, and social potential • Targeting fatigue, mobility impairment (weakness, spasticity, imbalance, sensory loss, ataxia); tremor, pain, speech and swallowing problems, cognitive dysfunction, visual disturbances, and bowel and bladder problems • Reducing disablement by minimizing the impact of existing impairment(s) on day-to-day functioning and enhancing the person’s ability to carry out daily activities and participate to the fullest extent possible in all of his or her life roles• Providing structured, problem-focused interventions to manage advanced symptoms, enhance function, facilitate activities of daily living, identify appropriate assistive devices and environmental modifications, and prevent injuries and unnecessary complications. • Utilizing a team approach, rehabilitation specialists work collaboratively with each other, the person with MS and his or her care partners (significant other, other family members, paid assistant(s), to set achievable goals, assess outcomes, and establish new goals as the person’s condition changes.Psychosocial Support• Disease-related education/psychoeducation — a supportive educational process designed to enhance people’s understanding of the disease, adaptive coping strategies, and available resources)• Diagnosis/treatment of emotional and/or cognitive problems• Family interventions designed to support family members’ efforts to cope with the intrusion of MS into the household• Support for people’s efforts to remain productively employed as long as they are able and interested, and to transition out of the workforce when, and if, it is necessary to doso • Assistance for patients and families in accessing available resourcesThe Role of Complementary & Alternative Medicine (CAM) in MSCAM includes everything from exercise and diet to food supplements, stress management strategies, and lifestyle changes. Examples include yoga, hypnosis, relaxation techniques, traditional herbal healing, Chinese medicine, macrobiotics, naturopathy, and many others. (Bowling, 2007)Be sure to ask patients about their use of CAM therapies as they can interfere/interact with prescribed treatment regimens. 61 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 62The Key Role of the Nurse Practitioner in Treatment of MS The education, training, and support of patients to enhance adherence is critical given the often complex treatment regimens which are developed. • NPs need to provide patients with relevant, up-to-date information and guidance on new therapies or advances in existing therapies. • NPs can help patients interpret health information (and mis- information), leading to meaningful participation in their treatment decision-making process.• NPs may be the primary source of information for the patient and family members and is in the best position to involve them in the care continuum (Ch. 17).• “The proactive involvement of the MS APN can raise patients’ and their care partners’ awareness of, and access to, complementary non-drug modalities and resources, such as support groups, that may ameliorate some of the burden of disease.” (Costello & Halper, no date provided)ReferencesCohen BA. Identification causation, alleviation, and prevention of complications (ICAP): an approach to symptom and disability management in multiple sclerosis. Neurology. 2008 Dec 9;71(24 Suppl 3):S14–20.Costello K, Halper J. The APN in treatment decisions and symptom management. Advanced Practice Nursing in MS (3rd ed.)., pp. 20–23.Kalb R (Ed.) Multiple Sclerosis: A Focus on Rehabilitation (4th ed.). National MS Society, 2010.McEwan L, Brown J, Poirier J, et al. Best practices in skin care for the multiple sclerosis patient receiving injectable therapies. International Journal of MS Care 2010; 12(4):177–189. doi:’Connor P, Wolinsky J, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365:1293–1303.Reitman N, Kalb R (Eds.). Multiple Sclerosis: The Nursing Perspective (5th ed). National MS Society, 2012.Recommended ReadingsCohen JA. Emerging therapies for relapsing multiple sclerosis. Arch Neurol. 2009; 66(7):821–8Giesser B (Ed.). Primer on Multiple Sclerosis. Oxford: Oxford University Press, 2011. Kalb R (Ed.). Multiple Sclerosis: The Questions You Have; The Answers You Need (5th ed.). NY: Demos Health, 2012. Kalb R, Giesser B, Costello K. Multiple Sclerosis for Dummies. Hoboken, NJ: Wiley, 2012. Mohr DC, Cox D, Merluzzi N. Self-injection anxiety training: a treatment for patients unable to self-inject injectable medications. Mult Scler 2005; 11(2):182–5.63 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 64Resources from the National MS SocietyFor CliniciansMS Clinical Management: Modifying Therapy — Updated Information: Therapies Collaborative: Trial Listing: in-ms/index.aspx. Self-Injection for Anxiety Counseling (SIAC): Therapies Collaborative: in Clinical Trials: Multiple Sclerosis Society 64Chapter 6: Bladder Dysfunction SNAPSHOTPatient Presentation • Failure to Store – Subjective: “I can’t hold it.” or “I can’t get to the bathroom on time.” – Objective: Urinary urgency, frequency, or nocturia.• Failure to Empty – Subjective: “I can’t get it out.” Or “I have to push on my bladder.” – Objective: Urinary frequency, hesitation, double-voiding, and/ or dribbling Assessment• Rule out infection – Inquire about signs of symptoms of infection – Order UA with culture and CBC, if appropriate• Determine primary issue: Storage vs. Emptying – Obtain history of voiding patterns and episodes of incontinence• Check post-void residual (PVR): abnormal if >100ml• Refer to urology – Pelvic exam to rule out comorbidities – Urodynamic testingIntervention• Patient education and empowerment – Set goals for adequate hydration – Recommend dietary modifications: limit spicy or acidic foods, caffeine, alcohol – Recommend behavioral modifications: limit fluid intake 2–3 hours before bedtime – Discuss medication side effects – Other interventions: Kegel exercises, Valsalva, Interstim• Consider medications – Failure to Store: anticholinergics; antimuscarinics – Failure to Empty: alpha antagonists• Following pelvic exam, explore need for clean intermittent catheterization (CIC)• Complex or high-risk patients may require more invasive solutions (Litwiller & Kalota, 2012) – OnabotulinumtoxinA injections for refractory incontinence – Surgical interventions65 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 66Chapter 6: Bladder DysfunctionPatient Presentation• Failure to Store may be caused by an over-active detrusor muscle that contracts as soon as a small amount of urine enters the bladder — continually signaling the need to void. The bladder does not fill to normal capacity, which results in urgency, frequency, nocturia or incontinence.• Failure to Empty occurs when demyelination in the spine interrupts signals to the voiding reflex. The bladder fills, but the spinal cord is unable to send the signal to the brain to relax the sphincter, and/or the bladder to contract adequately, causing the bladder to retain urine and sometimes fill beyond normal capacity. Emptying dysfunction can lead to urgency, dribbling, hesitancy, incontinence or infection. • Combined Dysfunction is a combination of failure to store and empty. This occurs as a result of the lack of coordination between muscle groups. Urine is trapped in the bladder, leading to urgency, hesitancy, dribbling, incontinence, infection and renal injury.AssessmentClinical• Bladder emptying dysfunction increases patient’s risk for UTI. – Common UTI symptoms: urgency, frequency dysuria, abdominal or lower back pain, fever, increased spasticity, dark, foul-smelling urine – Careful attention should be paid to changes in the color or smell of urine, or any abrupt increase in other MS symptoms, because MS-related sensory loss my prevent people from noticing typical UTI symptoms.67 The Nurse Practitioner’s Handbook National Multiple Sclerosis Society 68Intervention: Algorithm for Analysis & Management of Bladder SymptomsIs UTI present?Is patient retaining urine?Are symptoms relieved?Anitcholinergic (AC) medication educationURINARY SYMPTOMSAre symptoms relieved?Are symptoms relieved?Are symptoms relieved?Add Anitcholinergic (AC) medication; consider onabotulinumA injections*Periodic re-assessmentContinue IC with periodic PVRContinue IC & AC medictaion with periodic PVRTreatmentIntermittent Catheterizable (IC) educationContinue AC medicationsUrologic consultationYESYESYESNONOPVR>200mlNONONOPVR>200mlYESYESYES*In 2011, onabotulinumtoxinA (Cruz et al., 2011) was approved to treat detrusor overactivity associated with a neurologic condition (
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