p.9
Overview of Multiple Sclerosis (MS)
What is multiple sclerosis (MS)?
A common autoimmune demyelinating disease of the central nervous system.
p.12
Disease-Modifying Therapies for MS
What is cladribine reserved for?
MS refractory to at least two other treatments.
p.8
Disease-Modifying Therapies for MS
What is the significance of the ADVANCE study?
It evaluated pegylated interferon beta-1a for relapsing-remitting multiple sclerosis.
p.8
Disease-Modifying Therapies for MS
What type of study was conducted in the PRISMS study?
A randomised double-blind placebo-controlled study.
p.10
Pathophysiology of MS
What was believed to cause disability accumulation during the relapsing phase in the pretreatment era?
Incomplete recovery from relapses.
p.1
Role of B Cells in MS Pathogenesis
What has changed in the understanding of MS immune pathology?
Recognition that B cells have a key role in pathogenesis, moving away from a purely T-cell-mediated model.
p.8
Disease-Modifying Therapies for MS
What was the focus of the PRISMS study?
Interferon beta-1a in relapsing/remitting multiple sclerosis.
p.9
Treatment Approaches for Relapsing MS (RMS)
When do many experts recommend using MS therapies?
Early in the disease course to protect against late disability.
p.10
Pathophysiology of MS
What is 'silent progression' in the context of MS?
Insidious progression independent of relapse activity during the relapsing phase.
p.9
Disease-Modifying Therapies for MS
What is the significance of recently developed MS therapies?
They are highly effective in preventing attacks and can partially protect against progression.
p.12
Disease-Modifying Therapies for MS
What is the purpose of the therapeutic algorithm mentioned in the text?
To guide the use of disease-modifying therapy in MS based on the authors’ practice pattern.
p.10
Recent Advances in MS Treatment
What is the 'new' natural history of MS in the current treatment era?
Attacks are abolished in most patients, but silent progression occurs during the relapsing phase.
p.14
Clinical Manifestations and Diagnosis of MS
What demonstrates dissemination in space for MS diagnosis?
≥1 T2 lesion on MRI in at least 2 out of 4 MS-typical regions of the CNS or awaiting a further clinical attack implicating a different CNS site.
p.7
Disease-Modifying Therapies for MS
How much does ocrelizumab reduce progression of clinical disability in PPMS?
By approximately one-quarter.
p.15
Disease-Modifying Therapies for MS
What is the mechanism of action of Ocrelizumab?
Anti-CD20 monoclonal antibody (mAb).
p.7
Challenges in Treating Progressive MS
What factors may require switching therapies in MS treatment?
Suboptimal response, more than one relapse with active MRI scans in the prior year, and safety issues.
p.13
Clinical Manifestations and Diagnosis of MS
What are common symptoms of Multiple Sclerosis (MS)?
Sensory loss, unilateral painful visual loss, limb weakness, facial weakness, visual blurring, ataxia, vertigo, and fatigue.
p.10
Overview of Multiple Sclerosis (MS)
What does the top half of Figure 1 illustrate?
The natural history of relapse-onset MS in the pretreatment era.
p.10
Clinical Manifestations and Diagnosis of MS
What does SPMS stand for?
Secondary progressive multiple sclerosis.
p.14
Clinical Manifestations and Diagnosis of MS
What are the criteria for diagnosing multiple sclerosis in patients with an attack at onset?
≥2 attacks with objective clinical evidence of ≥2 lesions or 1 lesion with reasonable historical evidence of a prior attack.
p.4
Disease-Modifying Therapies for MS
What strategies were found effective in MS treatment?
Inhibiting lymphocyte access to the CNS or sequestering lymphocytes in primary lymphoid organs.
p.15
Disease-Modifying Therapies for MS
What is the administration route and frequency for Ocrelizumab?
IV infusion, every 6 months.
p.7
Challenges in Treating Progressive MS
What should be done if a patient experiences serious adverse events related to disease-modifying therapies?
Discontinuation of the therapies is required.
p.13
Clinical Manifestations and Diagnosis of MS
What cerebrospinal fluid (CSF) findings are associated with MS?
Oligoclonal immunoglobulin and modest inflammation with mononuclear cells.
p.13
Clinical Manifestations and Diagnosis of MS
What are some uncommon symptoms (red flags) of MS?
Seizure, dementia, and movement disorders.
p.1
Treatment Approaches for Relapsing MS (RMS)
What is required for effective management of MS?
A multifaceted approach to control acute attacks, manage progressive worsening, and remediate symptoms.
p.10
Clinical Manifestations and Diagnosis of MS
What does EDSS stand for?
Extended disability status score.
p.14
Clinical Manifestations and Diagnosis of MS
What indicates dissemination in time for MS diagnosis?
Simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions or a new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI.
p.11
Pathophysiology of MS
What are classic inflammatory white matter plaques associated with in Progressive MS?
They are typically associated with relapses but also occur in patients who progress gradually without acute attacks.
p.4
Disease-Modifying Therapies for MS
Which B-cell-depleting therapies have shown success in MS treatment?
Rituximab, ocrelizumab, and ofatumumab.
p.15
Disease-Modifying Therapies for MS
What are common adverse events associated with Ocrelizumab?
Infusion-related reaction, nasopharyngitis, upper respiratory tract infection, headache, and urinary tract infection.
p.5
Disease-Modifying Therapies for MS
What type of antibody is rituximab?
A chimeric anti-CD20 monoclonal antibody.
p.5
Disease-Modifying Therapies for MS
What is the mechanism of action of natalizumab?
It inhibits the α4β1 integrin, an adhesion molecule on lymphocytes.
p.13
Clinical Manifestations and Diagnosis of MS
What cognitive dysfunctions are commonly associated with MS?
Mild cognitive dysfunction, often referred to as 'brain fog', and difficulty with multitasking.
p.2
Clinical Manifestations and Diagnosis of MS
What are the two clinical paths MS can follow?
Relapsing or progressive.
p.3
Disease-Modifying Therapies for MS
What are the effects of disease-modifying therapies during the relapsing phase of MS?
They reduce the rate of relapses, accumulation of MRI lesions, and can stabilize or modestly improve disability.
p.16
Disease-Modifying Therapies for MS
What is the administration route for PeglFN β-1a (Plegridy)?
Subcutaneous injection, every 2 weeks.
p.16
Common adverse events
What are common adverse events associated with PeglFN β-1a (Plegridy)?
Injection-site erythema, influenza-like illness, pyrexia, and headache.
p.16
Common adverse events
What are common adverse events associated with IFN β-1b (Betaseron)?
Lymphopenia, flu-like symptoms, and injection-site reactions.
What are the two major components of multiple sclerosis?
Inflammation causing episodic attacks and neurodegeneration responsible for progressive worsening.
p.1
Disease-Modifying Therapies for MS
What type of drugs are now preferred for MS treatment?
Higher-efficacy drugs requiring less frequent administration.
p.14
Clinical Manifestations and Diagnosis of MS
What is required for evidence of dissemination in space in the brain for primary progressive MS?
≥1 T2+ lesions in the MS-characteristic periventricular, juxtacortical, or infratentorial regions.
p.7
Recent Advances in MS Treatment
What is the significance of early use of high efficacy therapy in MS?
It improves long-term outcomes.
p.11
Pathophysiology of MS
What causes slowly enlarging lesions in Progressive MS?
They are due to gradual concentric expansion of chronic plaques, characterized by a rim of activated microglia, astrocytosis, stressed oligodendrocytes, and progressive axonal injury.
p.4
Challenges in Treating Progressive MS
What is a significant unmet need in MS treatment?
The development of highly effective therapies against progressive MS.
p.6
Disease-Modifying Therapies for MS
What is Glatiramer acetate composed of?
A mixture of random polypeptides composed of four amino acids.
p.6
Management of Progressive MS (SPMS and PPMS)
What is Siponimod used for?
It is a selective S1P modulator approved for relapsing forms of MS, including active SPMS.
p.5
Recent Advances in MS Treatment
What pathway does dimethyl fumarate activate?
The nuclear factor (erythroid-derived 2)–like 2 (Nrf2) pathway.
p.2
Overview of Multiple Sclerosis (MS)
What is the prevalence of MS in North America compared to equatorial countries?
Highest in North America (>100 cases per 100,000) and lowest around the equator (<30 cases per 100,000).
p.2
Clinical Manifestations and Diagnosis of MS
How do symptoms of RMS typically present?
Acute or subacute over hours to days, sometimes followed by gradual spontaneous remission.
p.16
Common adverse events
What are common adverse events associated with Teriflunomide?
Nasopharyngitis, headache, diarrhea, and alanine aminotransferase increase.
p.1
Overview of Multiple Sclerosis (MS)
What is Multiple Sclerosis (MS)?
An autoimmune demyelinating and neurodegenerative disease of the central nervous system.
p.8
Disease-Modifying Therapies for MS
What type of study design was used in the ADVANCE study?
A randomised, phase 3, double-blind study.
p.12
Disease-Modifying Therapies for MS
Why are alemtuzumab and mitoxantrone not generally recommended?
Due to severe toxicities.
p.10
Clinical Manifestations and Diagnosis of MS
What does CIS stand for?
Clinically isolated syndrome.
p.6
Disease-Modifying Therapies for MS
What is a potential risk associated with Dimethyl fumarate treatment?
Progressive multifocal leukoencephalopathy risk.
p.11
Pathophysiology of MS
What are the hallmarks of classic inflammatory white matter plaques?
Perivenous inflammation dominated by lymphocytes and macrophages, demyelination with activated microglia, sharply demarcated plaques with glial scarring, and axonal loss.
p.4
Disease-Modifying Therapies for MS
What is the mechanism of action of ocrelizumab?
It selectively depletes CD20-expressing B cells while preserving humoral immunity.
p.7
Management of Progressive MS (SPMS and PPMS)
What is a notable exception for continuing treatment during pregnancy?
Glatiramer acetate can be continued during pregnancy.
p.13
Clinical Manifestations and Diagnosis of MS
What MRI findings are indicative of MS?
Multiple lesions in white matter, particularly in cerebral hemispheres, brainstem, and spinal cord, with recent lesions enhancing with gadolinium.
p.3
Clinical Manifestations and Diagnosis of MS
What do oligoclonal bands indicate in MS patients?
They reflect a highly focused immune response by activated B cells in the CNS.
p.2
Challenges in Treating Progressive MS
What is a significant challenge uncovered by controlling RMS?
A relapse-independent 'silent' progression.
What are the two pathological hallmarks of MS?
1) Inflammation with demyelination, and 2) Astroglial proliferation (gliosis) and neurodegeneration.
p.4
Disease-Modifying Therapies for MS
What were the first approved therapies for MS?
Interferons and glatiramer acetate.
p.4
Treatment Approaches for Relapsing MS (RMS)
Why were purely T-cell-based treatment approaches ineffective in RMS?
Clinical trials showed they did not yield effective results.
p.14
Clinical Manifestations and Diagnosis of MS
What is the significance of cerebrospinal fluid in diagnosing MS?
Positive cerebrospinal fluid indicates isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index.
p.11
Pathophysiology of MS
What is associated with widespread diffuse microglial inflammation in Progressive MS?
Astrogliosis throughout the CNS white matter, decreased myelin density, and ongoing axonal damage.
p.13
Clinical Manifestations and Diagnosis of MS
What do evoked potentials detect in MS diagnosis?
Conduction delay in visual, auditory, and sensory pathways.
p.15
Disease-Modifying Therapies for MS
What are common adverse events associated with Dimethyl fumarate?
Flushing, diarrhea, nausea, upper abdominal pain, decreased lymphocyte counts, and elevated liver aminotransferase.
p.2
Clinical Manifestations and Diagnosis of MS
What characterizes secondary progressive MS (SPMS)?
Gradual worsening after a decrease in the frequency of relapses.
p.16
Disease-Modifying Therapies for MS
What is the indication for IFN β-1a (Rebif)?
Clinically Isolated Syndrome (CIS) and Relapsing Multiple Sclerosis (RMS), first line.
p.12
Disease-Modifying Therapies for MS
What is hematopoietic stem cell transplantation reserved for?
Severe treatment refractory disease unresponsive to high efficacy treatments.
p.5
Disease-Modifying Therapies for MS
What is the administration frequency of ocrelizumab?
As an intravenous infusion every 24 weeks.
p.6
Disease-Modifying Therapies for MS
What are common adverse events associated with Teriflunomide?
Headache, diarrhea, nausea, alopecia, and increased hepatic alanine transferase.
p.13
Clinical Manifestations and Diagnosis of MS
What imaging technique is used in the diagnosis of MS?
Magnetic Resonance Imaging (MRI).
p.15
Disease-Modifying Therapies for MS
What are common adverse events associated with Natalizumab?
Fatigue and allergic reaction.
p.15
Disease-Modifying Therapies for MS
What are common adverse events associated with Fingolimod?
Bradycardia, atrioventricular conduction block, macular edema, elevated liver enzyme levels, and mild hypertension.
p.3
Clinical Manifestations and Diagnosis of MS
What is required for the diagnosis of Multiple Sclerosis (MS)?
Objective evidence of inflammatory CNS injury and details of dissemination in space and time.
p.3
Clinical Manifestations and Diagnosis of MS
What does gadolinium leakage indicate in MS diagnosis?
It indicates a breakdown in the blood-brain barrier and is a marker of acute inflammation.
p.2
Clinical Manifestations and Diagnosis of MS
How does the mean age of onset differ between RMS and PPMS?
RMS has a mean age of onset of ~30 years, while PPMS has ~40 years.
p.16
Disease-Modifying Therapies for MS
What is the mechanism of action for Teriflunomide?
Dihydroorotate dehydrogenase inhibitor.
p.16
Disease-Modifying Therapies for MS
What is the administration route for Glatiramer Acetate?
Subcutaneous injection, once daily or 3 times weekly.
p.1
Treatment Approaches for Relapsing MS (RMS)
What do many experts recommend for patients with early MS?
Use of higher-efficacy drugs as first-line treatment before permanent disability is evident.
What is the role of T cells in experimental autoimmune encephalomyelitis?
T cells play a critical role in the pathogenesis of CNS autoimmune diseases.
p.7
Treatment Approaches for Relapsing MS (RMS)
What has changed regarding first-line treatment options for active MS?
Highly effective disease-modifying therapies are now recommended as first-line options instead of traditional treatments like high-dose IFN β −1a and glatiramer acetate.
p.11
Pathophysiology of MS
What characterizes B cell rich lymphoid aggregates in Progressive MS?
They are found in the meninges, often in deep sulci, with underlying cortical demyelination and neuronal loss.
p.4
Treatment Approaches for Relapsing MS (RMS)
What benefits does ocrelizumab provide for RMS patients?
It is highly effective against relapses and silent progression, and halts new white matter lesions.
p.7
Future Directions in MS Research and Treatment
What remains an unmet need in MS treatment despite advances?
Effective treatment of progression.
p.5
Disease-Modifying Therapies for MS
What is fingolimod's mechanism of action?
It is an S1P inhibitor that prevents lymphocyte egress from secondary lymphoid organs.
p.3
Clinical Manifestations and Diagnosis of MS
What is characteristic of MS lesions on MRI?
A periventricular distribution of lesions and lesions in juxtacortical white matter, infratentorial white matter, and spinal cord.
p.2
Disease-Modifying Therapies for MS
What has been the impact of effective therapies on the progression of RMS?
They have lengthened the time to development of SPMS and reduced or eliminated relapses.
p.16
Disease-Modifying Therapies for MS
What is the indication for Teriflunomide?
Relapsing Multiple Sclerosis (RMS), first line.
p.16
Common adverse events
What are common adverse events associated with Glatiramer Acetate?
Injection-site reactions.
p.16
Common adverse events
What are common adverse events associated with IFN β-1a (Avonex)?
Flu-like symptoms, muscle aches, asthenia, chills, and fever.
p.7
Disease-Modifying Therapies for MS
What therapies can be used for patients with active Secondary Progressive MS (SPMS)?
Ocrelizumab, cladribine, and diroximel fumarate.
p.14
Clinical Manifestations and Diagnosis of MS
What are the criteria for diagnosing primary progressive multiple sclerosis?
Insidious neurologic progression for 1 year and 2 out of 3 criteria: evidence for dissemination in space in the brain or spinal cord, or positive cerebrospinal fluid.
What major advance changed the understanding of MS pathophysiology?
The recognition of the importance of humoral immunity and B cells in MS.
p.6
Disease-Modifying Therapies for MS
What enzyme does Teriflunomide inhibit?
Dihydroorotate dehydrogenase.
p.5
Disease-Modifying Therapies for MS
What complication has been recognized in post-marketing studies of ocrelizumab?
Serious herpes virus infections.
p.6
Disease-Modifying Therapies for MS
What are common side effects of Interferon beta?
Flu-like symptoms, mild lab abnormalities, and injection-site reactions.
p.15
Disease-Modifying Therapies for MS
What is the mechanism of action of Dimethyl fumarate?
Nuclear factor (erythroid-derived 2)-like 2 pathway inhibitor.
p.5
Recent Advances in MS Treatment
What is ozanimod?
A recently approved selective S1P receptor modulator effective in RMS.
p.2
Clinical Manifestations and Diagnosis of MS
What is the most common form of MS at onset?
Relapsing form of MS (RMS).
p.3
Clinical Manifestations and Diagnosis of MS
What additional tests can be useful in MS diagnosis?
Evoked potentials to assess nerve conduction and retinal imaging by optical coherence tomography.
p.16
Common adverse events
What are common adverse events associated with IFN β-1a (Rebif)?
Injection-site inflammation, flu-like symptoms, rhinitis, and headache.
p.12
Disease-Modifying Therapies for MS
What is ozanimod's current status according to the text?
Approved but not yet commercially available.
p.7
Treatment Approaches for Relapsing MS (RMS)
What is the recommended approach for initiating therapy in MS patients?
Initiate therapy in patients with a first attack who are at high risk for MS or in patients diagnosed with Relapsing MS (RMS).
p.6
Disease-Modifying Therapies for MS
What is Teriflunomide derived from?
It is the active metabolite of leflunomide, an immune suppressant used in rheumatoid arthritis.
p.5
Disease-Modifying Therapies for MS
What initial concern was raised in phase 3 trials of ocrelizumab?
A possible low risk of increased malignancies, including breast cancer.
p.6
Disease-Modifying Therapies for MS
What is the mechanism of action of Interferon beta (IFN-β)?
Immunomodulation through downregulating MHC expression, decreasing proinflammatory cytokines, and inhibiting T-cell proliferation.
p.5
Disease-Modifying Therapies for MS
How is ofatumumab administered?
By monthly subcutaneous injection at home.
p.5
Challenges in Treating Progressive MS
What is the risk associated with long-term treatment of natalizumab?
Progressive multifocal leukoencephalopathy (PML).
p.13
Clinical Manifestations and Diagnosis of MS
What is Lhermitte’s symptom?
Electric shock-like sensations evoked by neck flexion.
p.2
Clinical Manifestations and Diagnosis of MS
What is indicated if MS is suspected in a patient?
Prompt referral to a specialist.
p.16
Disease-Modifying Therapies for MS
How is IFN β-1a (Rebif) administered?
Subcutaneous injection, 3 times weekly.
p.11
Pathophysiology of MS
What role does age-related neurodegeneration play in Progressive MS?
It is one of the distinctive pathologies contributing to the disease.
p.6
Management of Progressive MS (SPMS and PPMS)
What is the role of autologous hematopoietic stem cell transplantation in MS treatment?
It can induce prolonged remission in many RMS patients but is not recommended for progressive MS.
p.3
Clinical Manifestations and Diagnosis of MS
What symptoms are indicative of MS diagnosis?
Symptoms must last for more than 24 hours and occur as distinct episodes separated by at least 1 month.
p.3
Clinical Manifestations and Diagnosis of MS
What CSF abnormalities are associated with MS?
Mononuclear cell pleocytosis and increased levels of intrathecally synthesized IgG.
p.16
Disease-Modifying Therapies for MS
What is the administration route for IFN β-1a (Avonex)?
Intramuscular injection, once weekly.
p.16
Disease-Modifying Therapies for MS
What is the administration route for IFN β-1b (Betaseron)?
Subcutaneous injection, every other day.
p.5
Challenges in Treating Progressive MS
What strategy can reduce the risk of PML in seropositive patients on natalizumab?
Extending the dosing interval from 4 to 6 weeks.
p.5
Disease-Modifying Therapies for MS
What are some adverse events associated with fingolimod?
Mild abnormalities in liver function tests, heart block, and bradycardia.
p.3
Clinical Manifestations and Diagnosis of MS
What main tests support the diagnosis of MS?
Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis.
p.3
Disease-Modifying Therapies for MS
What is the role of disease-modifying therapies in MS treatment?
They modify the course of MS through suppression or modulation of immune function.
p.2
Clinical Manifestations and Diagnosis of MS
What characterizes the symptoms of PPMS?
Slowly progressive symptoms from onset.
