Download to read offline
![Clinical Presentation
• The classic presentations of MS include
• unilateral optic neuritis (blurred vision with associated pain),
• partial myelitis (extremity and torso impaired sensation, weakness,
and/or ataxia),
• focal sensory disturbance (limb paresthesia , abdominal or chest
banding [dysesthesia]),
• or brainstem syndromes (intranuclear ophthalmoplegia, vertigo,
hearing loss, facial sensory disturbance) (](https://image.slidesharecdn.com/20july2022diagnosisandtreatmentofmultiplesclerosis-220809172948-c2f2b8f9/75/20-July-2022-Diagnosis-and-Treatment-of-Multiple-Sclerosis-pptx-13-2048.jpg)
![Disease-Modifying Therapies [DMT]
• DMTs for MS decrease the frequency of relapses and reduce short
term disability.
• Currently available DMTs have a range of mechanism of actions,
administration routes, and degrees of efficacy.
• All DMTs modulate the immune system through mechanisms that
include sequestration of lymphocytes, TH1/TH2 shift, interference
with DNA synthesis in lymphocytes, depletion of immune cells,
and/or changes in cytokine secretion pattern](https://image.slidesharecdn.com/20july2022diagnosisandtreatmentofmultiplesclerosis-220809172948-c2f2b8f9/75/20-July-2022-Diagnosis-and-Treatment-of-Multiple-Sclerosis-pptx-58-2048.jpg)
![common adverse effects
• S1P modulators are associated with an increased risk of herpetic
infections (2.1%-8.7%), increased liver enzyme levels (10%-15%),and
macular edema (1.6%-2%) due to increased vascular permeability
(1.6%-2%)
• The most common adverse effects associated with the fumarates
(dimethyl fumarate and diroximel fumarate) are skin flushing and
gastrointestinal disturbances. Monitoring is required for lymphopenia
less than 0.5 × 109 /L (6%).
• An adverse effect with teriflunomide is hepatotoxicity (ALT level >3
times upper limit of normal [6%]); therefore monthly hepatic testing
for the first 6 months is required.](https://image.slidesharecdn.com/20july2022diagnosisandtreatmentofmultiplesclerosis-220809172948-c2f2b8f9/75/20-July-2022-Diagnosis-and-Treatment-of-Multiple-Sclerosis-pptx-67-2048.jpg)
![Relapse Treatment
• The primary role of DMTs is to prevent relapses and future disability.
• However, none of the DMTs suppress all relapses.
• If relapse symptoms are mild and do not impair function, treatment
not be necessary.
• For moderate or severe relapses, first-line treatment is typically high-
dose systemic steroids (intravenous methyl prednisolone [500 mg-
1000 mg]) for 3 to 5 days to accelerate relapse recovery.](https://image.slidesharecdn.com/20july2022diagnosisandtreatmentofmultiplesclerosis-220809172948-c2f2b8f9/75/20-July-2022-Diagnosis-and-Treatment-of-Multiple-Sclerosis-pptx-79-2048.jpg)
![DMT Treatment Duration
• Once an individual has started a DMT, the treatment is lifelong unless
breakthrough disease or adverse effects occur that require a
medication switch.
• Several observational studies have suggested that older individuals
receiving injectable or oral DMTs who have been stable clinically and
radiographically for an extended period (4 years) have a low
reoccurrence of disease activity and may benefit from treatment
discontinuation.
• An ongoing randomized trial (DISCO-MS [NCT03073603]) is evaluating
whether discontinuing therapy in patients with “nonactive” disease is
beneficial](https://image.slidesharecdn.com/20july2022diagnosisandtreatmentofmultiplesclerosis-220809172948-c2f2b8f9/75/20-July-2022-Diagnosis-and-Treatment-of-Multiple-Sclerosis-pptx-81-2048.jpg)
![Future Directions
• New therapies under evaluation include cell-based (hematopoietic
and mesenchymal stem cells) and remyelination therapies with the
potential to further improve MS treatment.
• High-dose immunosuppressive therapy with autologous
hematopoietic stem cell transplantation is not part of routine
practice, but there is evidence it may have therapeutic effects.
• An ongoing clinical trial (BEAT-MS [NCT04047628]) will evaluate the efficacy and safety of this treatment. Therapies
promoting remyelination have potential to slow or reverse disability. There have been several studies with a variety of
compounds (eg, biotin, clemastine , and opicinumab , mesenchymal stem cells) evaluating remyelination potential, but
data are limited.102-106](https://image.slidesharecdn.com/20july2022diagnosisandtreatmentofmultiplesclerosis-220809172948-c2f2b8f9/75/20-July-2022-Diagnosis-and-Treatment-of-Multiple-Sclerosis-pptx-89-2048.jpg)
More Related Content
Similar to 20 July 2022 Diagnosis and Treatment of Multiple Sclerosis.pptx
More from manjujanhavi
20 July 2022 Diagnosis and Treatment of Multiple Sclerosis.pptx
- 1. Diagnosis and Treatmentof Multiple Sclerosis Clinical Review & Education JAMA | Review-Methods MEDLINE was searched for articles from January 1, 2008, to October 27, 2020 A total of 108 articles were included, of which 21 were meta-analyses or reviews, 2 were guideline documents, 34 were randomized clinical trials, and 51 were other article types. JAMA February 23, 2021 Volume 325, Number 8 Dr Deshpande Janhavi J
- 2. content • Epidemiology • Pathophysiology •Clinical Presentation • Diagnosis:McDonald Criteria for Diagnosis of Multiple Sclerosisa • Multiple Sclerosis Terms and Definitions • Natural History • Disease Outcomes • Treatment: • Comorbidities
- 3. Multiple Sclerosis • MSis an autoimmune disease of the CNS characterized by chronic inflammation, demyelination, gliosis (scarring) and neuronal loss; the course can be relapsing , remitting or progressive • Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. N Engl J Med 2018 Jan 10;378(2):169–80. Available from: https://doi.org/10.1056/NEJMra1401483
- 4. • Lesions ofMS typically develop at different times and in different CNS locations (i.e., MS is said to be disseminated in time and space)
- 5. Epidemiology • MS presentsin young adults (mean age of onset, 20-30 years). The prevalence of MS worldwide ranges from 5 to 300 per 100 000 people and increases at higher latitudes.
- 6. Etiology of MS •The etiology of MS is unknown, but environmental, lifestyle, and genetic factors may contribute to development and outcomes. • Latitude effects may be explained by greater sun exposure and higher vitamin D levels, which are associated with a lower prevalence of MS. • The increased prevalence of MS within families also supports genetic factors. • The HLA-DR1*15:01 allele is the most frequent genetic factor associated with MS.
- 7. • Childhood obesity(age 13 years, body mass index >95th percentile) is associated with an increased risk. • Meta-analyses primarily composed of case-control studies also indicate that cigarette smoking and Epstein-Barr virus infection are associated with an increased risk of developing MS
- 8. Pathophysiology • MS isan autoimmune CNS disorder with lesions (discrete brain areas affected by MS) throughout the CNS. • The most characteristic lesions are focal areas of demyelination and inflammation in the white matter identified on magnetic resonance imaging (MRI). • Grey matter and cortical lesions are also common on pathologic tissue but may not be reliably visualized with current imaging modalities.
- 11. • After theacute inflammatory phase, MS lesions may enter a chronic state that can include remyelination, inflammation resolution without repair, or a “smoldering” state in which inflammation and myelin degeneration coexist • Early research demonstrated the role of T cells in development of inflammation and demyelination in MS.
- 12. • More recentstudies and the effectiveness of B-cell–depleting treatments such as ocrelizumab also support a pathogenic role of B cells most likely through regulation of T cells. • Inflammation and neurodegeneration are identified in varying degrees in individuals with MS at disease onset and can change within an individual over time.
- 13. Clinical Presentation • Theclassic presentations of MS include • unilateral optic neuritis (blurred vision with associated pain), • partial myelitis (extremity and torso impaired sensation, weakness, and/or ataxia), • focal sensory disturbance (limb paresthesia , abdominal or chest banding [dysesthesia]), • or brainstem syndromes (intranuclear ophthalmoplegia, vertigo, hearing loss, facial sensory disturbance) (
- 14.
- 16. • Objective findingsthat may be present on neurologic examination include • afferent pupillary defect, • impaired sensation, • motor weakness, • ataxia, and gait impairment often in the context of hyperreflexia.
- 17. Table 1. MultipleSclerosis Terms and Definitions
- 19. A clinical attackor relapse in MS • A clinical attack or relapse in MS is defined as a single clinical episode with symptoms and objective findings reflecting a focal or multifocal inflammatory demyelinating event in the CNS, developing acutely or subacutely, with a duration of at least 24 hours, with or without recovery, and in the absence of fever or infection.
- 21. Diagnosis • The diagnosisof MS is based on a combination of clinical findings, imaging, and laboratory data using the current diagnostic criteria known as the Revised McDonald Criteria/ • The diagnosis of MS is defined by the demonstration of dissemination of MS disease characteristics in space and time. • Dissemination in space refers to the presence of lesions in distinct CNS anatomical locations including infratentorial, juxtacortical, cortical, periventricular, and spinal cord. These lesions can be identified either through multiple clinical events implicating different areas in the CNS, multiple T2-hyperintense lesions on MRI, or both.
- 23. • Dissemination intime refers to the development of new lesions over time. • MRI can demonstrate dissemination in time through the simultaneous presence of gadolinium-enhancing (acute) and nonenhancing lesions (chronic) at one time or development of a new T2 lesion on follow-up MRI. • Dissemination in time can also be defined by multiple distinct clinical attacks. • In patients with a single clinical attack, the presence of cerebrospinal fluid– specific oligoclonal bands can also fulfill the criterion of dissemination in time, because it reliably indicates intrathecal antibody synthesis and is associated with higher risk of a second attack.
- 25. D/D • In aprospective cohort of patients (N = 251) with a first classic clinical attack, the sensitivity of the 2017 diagnostic criteria for a clinically definite MS diagnosis was 68% and specificity 61%. • In addition to meeting these criteria, alternative diagnoses must be excluded, including other CNS inflammatory conditions (eg, neuromyelitis optica spectrum disorder), systemic inflammatory conditions (eg, sarcoidosis), hereditary disorders (eg, Fabry disease), infections (eg, syphilis), toxic and nutritional disorders (eg, B12 deficiency), neoplastic diseases (eg, glioblastoma), and vascular diseases
- 26. Natural History • MSis a chronic condition with a variable course. • Relapsing remitting MS (RRMS) starts with clinical relapses with near or complete recovery, but over time recovery may be incomplete, and disability often accumulates. • Approximately 20% of patients with RRMS develop progressive neurologic decline later in the disease and transition to secondary progressive MS (SPMS). • A small proportion of individuals (15%) have progression from onset defined as PPMS
- 27. • Prior tothe availability of current DMTs, natural history cohort studies of people with RRMS and PPMS reported a median time from onset to requiring a walking aid of 20 and 7 years, respectively. • In untreated RRMS, a second clinical attack typically occurs within the first 2 years, and the median time to conversion to SPMS from onset is 15 years.
- 53.
- 54. Disease Outcomes • Diseaseactivity and progression are typically measured by relapses, MRI activity, and short-term progression of disability. • A relapse is defined as new or worsening neurologic symptoms such as weakness, sensory disturbances, and gait impairment persisting 24 hours or longer in the absence of fever or infection to rule out “pseudo relapses.”
- 55. Treatment: • Overview ofTreatment, • Disease-Modifying Therapies: Injectable DMTs, Oral DMTs & Monoclonal Antibody DMTs • Treatment Strategy • Relapse Treatment • DMT Treatment Duration • Pregnancy and Breastfeeding • Lifestyle Modifications • Symptomatic Treatment • Future Directions
- 56. Overview of Treatment •Treatment of MS includes DMTs, acute relapse treatment, comorbidity management, symptom control, psychological support, rehabilitative strategies, and lifestyle modifications.
- 57. several broad spectrumimmunosuppressive options • The first DMT, interferon beta-1b, was approved by the FDA in 1993. • Prior to approval of interferon beta-1b, several broad spectrum immunosuppressive options were used including azathioprine, methotrexate, mycophenolate mofetil, intravenous immunoglobulin, and corticosteroids. • Effectiveness of these therapies was based on studies that were not definitive because of small sample sizes. • Currently, these therapies are less frequently prescribed now that DMTs are available.
- 58. Disease-Modifying Therapies [DMT] •DMTs for MS decrease the frequency of relapses and reduce short term disability. • Currently available DMTs have a range of mechanism of actions, administration routes, and degrees of efficacy. • All DMTs modulate the immune system through mechanisms that include sequestration of lymphocytes, TH1/TH2 shift, interference with DNA synthesis in lymphocytes, depletion of immune cells, and/or changes in cytokine secretion pattern
- 59. DMTs : arange of mechanism of actions
- 60. Efficacy, Safety Profile,and Adverse Effects
- 61. • Adverse effectsof DMTs are listed in Table 3 shown below. • Monitoring for adverse effects is needed for DMTs. • Because of their effects on the immune system, most DMTs are associated with an increased risk for infection, typically urinary tract infections , upper respiratory tract infections ,and pneumonias
- 65. Injectable DMTs Injectable medications(interferons, glatiramer acetate) reduce the relapse rate by 29% to 34% compared with placebo. • They are generally considered to be safer than alternative therapies, owing to a lower incidence rate of infections compared with oral and infusion therapies • but have limitations of frequent injections (daily to every 2 weeks) and adverse effects of injection site reactions and flu-like symptoms
- 66. Oral DMTs • Oralmedications (S1P modulators, fumarates, teriflunomide) vary in their effects on relapse reduction from 36% to 58% over 2 years. • The S1P receptor modulators (fingolimod, siponimod, ozanimod) are administered once daily, such as bradycardia and heart block are a result of initial activation of the S1P receptor. • In subsequent dosing, the S1P modulator acts as a functional antagonist, leading to downregulation of the receptors • Each S1P modulator selectively binds the 5 S1P receptor subtypes with varying affinity. • and their main adverse effects Interaction with the subtype 1 receptor on cardiac myocytes may result in first-dose bradycardia (0.5%-4%) and heart block (1.2%- 3%)
- 67. common adverse effects •S1P modulators are associated with an increased risk of herpetic infections (2.1%-8.7%), increased liver enzyme levels (10%-15%),and macular edema (1.6%-2%) due to increased vascular permeability (1.6%-2%) • The most common adverse effects associated with the fumarates (dimethyl fumarate and diroximel fumarate) are skin flushing and gastrointestinal disturbances. Monitoring is required for lymphopenia less than 0.5 × 109 /L (6%). • An adverse effect with teriflunomide is hepatotoxicity (ALT level >3 times upper limit of normal [6%]); therefore monthly hepatic testing for the first 6 months is required.
- 68. • Tuberculosis hasoccurred during treatment with teriflunomide; therefore tuberculosis screening is required prior to initiation. • Cladribine has several common adverse effects, primarily infections, and may increase risk of malignancy (pancreatic carcinoma, malignant melanoma, ovarian cancer) • Fingolimod and dimethyl fumarate have been rarely associated with Progressive multifocal leukoencephalopathy (PML) may occur because of reactivation of the John Cunningham virus (JCV) in MS. • Cases of PML have been reported among patients receiving cladribine for oncologic indications
- 69. Monoclonal Antibody DMTs •Monoclonal antibody infusions (natalizumab, ocrelizumab, ofatumumab, alemtuzumab) have higher efficacy than injectable and oral DMTs and reduce relapse rate by 68% (absolute reduction, 0.5) compared with placebo and by 46% to 59% (absolute reduction, 0.11- 0.26) compared with active comparators (interferon beta-1a).
- 70. • All ofthese therapies can cause infusion reactions characterized by headache, nausea, urticaria, pruritus, and flushing, • which can be mitigated by pre-medications including antihistamines, antipyretics, and steroids. • Infusion reactions are less common for natalizumab (24%) compared with ocrelizumab (34%-40%) and alemtuzumab (92%)
- 71. • Alemtuzumab isassociated with autoimmune adverse effects. • These include frequent (40%) thyroid conditions (hypothyroidism and hyperthyroidism) and more serious rare conditions including immune thrombocytopenia (3.2%) and anti glomerular basement membrane disease (0.2%). • There has been postmarking reports of cerebrovascular events (13 reported to the FDA since 2014). • Because of these potential adverse effects, there is a Risk Evaluation and Mitigation Strategy (REMS) program for alemtuzumab, with monthly laboratory monitoring required until 48 months after the last drug dose to facilitate timely detection of autoimmune conditions.
- 72. • The mostserious risk for treatment with natalizumab is PML. Among patients who take the drug for longer than 24 months, the risk is estimated to be 0.09 cases per 1000 in JCV-seronegative patients and 2 per 1000 among JCV-seropositive patient • The risk can be further stratified based on the index level of JCV, prior immunosuppressant use, and number of years receiving treatment. Natalizumab has a REMS program that includes every 6-month JCV serology testing and monitoring for signs and symptoms of PML. There have also been reports of PML with alemtuzumab.
- 73. • Herpetic infectionsare common (16%) with alemtuzumab; therefore, herpetic prophylaxis with acyclovir (200 mg twice daily) is required starting on the first day of dosing and continuing for a minimum of 2 months after therapy completion or until the CD4+ lymphocyte count is more than 200/μL. • Ocrelizumab and natalizumab are associated with less than a 10% risk of herpetic infection; prophylaxis is not required but under certain circumstances may be offered
- 74. • Hepatitis Breactivation has occurred with other CD20 monoclonal antibodies, alemtuzumab, and in 1 participant in a cladribine clinical trial of 806 participants. • Therefore ocrelizumab and alemtuzumab are not prescribed for individuals with hepatitis B. • Pulmonary tuberculosis is a rare infection with alemtuzumab (0.3%). Tuberculosis testing prior to initiation is recommended.
- 75. Treatment Strategy • Thereare 2 main treatment approaches for RRMS that are based on evaluating the risks and efficacy of the DMTs. • Historically, the most common treatment approach was escalation, starting with the least potent medications with relatively few adverse effects. • People with MS are monitored with neurologic examinations and MRIs;
- 76. • if thereis evidence of disease activity with treatment or breakthrough disease (eg, relapse orMRI activity), treatments are escalated to amore potent medication. • This approach minimizes risks but may result in undertreatment, defined as breakthrough disease and accumulated disability.
- 77. to initiate amedication with greater efficacy at the time of diagnosis. • An alternative option is to initiate a medication with greater efficacy at the time of diagnosis. • The rationale for this treatment approach is to provide better relapse control and delay accumulation of disability. • However, a limitation of this approach is that patients are exposed to higher risks of adverse events and some patients may not require such intensive treatment. • Observational data suggest that initial treatment with a higher-efficacy medication may be associated with a lower risk of conversion to SPMS; • ongoing randomized trials will provide more definitive data to inform treatment choices
- 79. Relapse Treatment • Theprimary role of DMTs is to prevent relapses and future disability. • However, none of the DMTs suppress all relapses. • If relapse symptoms are mild and do not impair function, treatment not be necessary. • For moderate or severe relapses, first-line treatment is typically high- dose systemic steroids (intravenous methyl prednisolone [500 mg- 1000 mg]) for 3 to 5 days to accelerate relapse recovery.
- 80. Relapse Treatment………… • Arandomized noninferiority trial concluded that oral therapies were noninferior to intravenous steroids for clinical improvement of MS and had a similar safety profile for relapse treatment. • If relapses are severe and refractory to steroids, treatment with plasma exchange may be warranted.
- 81. DMT Treatment Duration •Once an individual has started a DMT, the treatment is lifelong unless breakthrough disease or adverse effects occur that require a medication switch. • Several observational studies have suggested that older individuals receiving injectable or oral DMTs who have been stable clinically and radiographically for an extended period (4 years) have a low reoccurrence of disease activity and may benefit from treatment discontinuation. • An ongoing randomized trial (DISCO-MS [NCT03073603]) is evaluating whether discontinuing therapy in patients with “nonactive” disease is beneficial
- 82. Pregnancy and Breastfeeding •Pregnancy and Breastfeeding Women are often diagnosed with MS during childbearing years; therefore, pregnancy and breastfeeding are important considerations regarding treatment • In a prospective study that followed up 254 women with MS through pregnancy, mean relapse rates (not receiving DMT) were significantly lower during the first and third trimesters of pregnancy compared • The mean rate of relapse increased during the first 2months postpartum to 1.2 (SD, 2.0) (P < .001); however, only 28% of participants experienced a relapse
- 83. Pregnancy and Breastfeeding……………… •Several studies have suggested that pre pregnancy DMT use may decrease postpartum relapse rates. A recent meta-analysis that included 7034 pregnancies in 6430 women showed a similar association. • Pre pregnancy DMT use was associated with annualized relapse rate decreasing • All DMTs except glatiramer acetate should be discontinued at least 4 months prior to conception (this duration depends on the medication). Birth control should be used during receipt of DMT.
- 84. Comorbidities • In peoplewith MS, comorbidities (eg, psychiatric and cardiovascular) and other health behaviors (eg, tobacco use) are associated with increased disability, • MRI changes such as lower brain volume, increased mortality, and decreased quality of life. • These may be due to direct biological effects such as accelerated neurodegeneration, decreased neuronal repair, and increased peripheral immune activation, or to indirect effects such as delay in diagnosis, added morbidity, and altered treatment responses. •
- 85. Comorbidities…………. • Therefore, specificinterventions such as smoking cessation, hypertension management, and overall health maintenance are important. • Despite the high prevalence of these psychiatric disorders, these patients are still at risk for underdiagnosis and undertreatment. • Treatment is associated with improved mood and quality of life in people with MS and may improve DMT adherence. • Vascular comorbidities such as hyperlipidemia, hypertension, heart disease, diabetes, and peripheral artery disease can lead to worse outcomes in MS
- 86. Lifestyle Modifications • Lifestylemodifications may reduce comorbidities and improve outcomes. Based on observational data and a small pilot study • physical activity is associated with improved symptoms and anti inflammatory effects and may be associated with larger brain volume. • In 1 randomized clinical pilot exercise intervention study (N = 42), significant improvements in fitness as measured by peak oxygen consumption and 6-minute walk distance, as well as improvements in depression symptoms, fatigue, and tested verbal learning and memory, were observed
- 87. Lifestyle Modifications……….. • Currentlythere is no high-quality evidence to support dietary modification to improve MS outcome • People with MS should be encouraged to remain active in intellectually challenging activities, since these activities are associated with improved cognitive function. • Cigarette smoking cessation is important in people with MS because smoking may be associated with a worse prognosis.
- 88. Symptomatic Treatment • Managementof symptoms including spasticity, pain, fatigue, cognitive impairment, bladder and bowel issues, gait dysfunction, mood dysregulation, and sleep disturbance is integral in treatment. • Treating these symptoms should include a combination of pharmacological and nonpharmacological treatments.
- 89. Future Directions • Newtherapies under evaluation include cell-based (hematopoietic and mesenchymal stem cells) and remyelination therapies with the potential to further improve MS treatment. • High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation is not part of routine practice, but there is evidence it may have therapeutic effects. • An ongoing clinical trial (BEAT-MS [NCT04047628]) will evaluate the efficacy and safety of this treatment. Therapies promoting remyelination have potential to slow or reverse disability. There have been several studies with a variety of compounds (eg, biotin, clemastine , and opicinumab , mesenchymal stem cells) evaluating remyelination potential, but data are limited.102-106
- 90. Conclusions • MS ischaracterized by physical disability, cognitive impairment, and other symptoms that affect quality of life. Treatment with DMT can reduce the annualized relapse rate by 29% to 68% compared with placebo or active comparator.