MS Flashcards
Acute management of MS
Steroids (1 g IV solumedrol x 3-5 days), safe in pregnancy, including 2nd and 3rd trimesters
If fail IV methylprednisone, PLEX is second line treatment for acute flare
Injectable DMTs
Copaxone (glatiramer acetate)
Interferons
Kesimpta (ofatumumab)
Oral DMTs
Aubagio (teriflunomide)
Gilenya (fingolimid)
Mavenclad (cladribine)
Mayzent (siponimod)
Tecfidera (dimethyl fumarate)
All of the oral agents require laboratory monitoring, including blood counts and liver function testing.
Infused DMTs
Lemtrada (Alemtuzumab)
Novantrone (Mitoxantrone)
Ocrevis (Ocrelizumab)
Tysrabi (Natalizumab)
Most DMTs work in the periphery except…
Natalizumab (Tysrabi) works at the BBB Dimethyl fumarate (Tecfidera) and fingolimod (Gilenya) also penetrate the CNS.
Most DMTs work in the periphery except…
Natalizumab (Tysrabi) works at the BBB Dimethyl fumarate (Tecfidera) and fingolimod (Gilenya) also penetrate the CNS.
Interferons MOA and side-effects
Injectable
MOA: Suppresses T-cell activation, alters balance of pro- and anti-inflammatory cytokines
Notable side effects: 1) Flu-like symptoms 2) Depression 3) Neutralizing antibodies 4.) Increase miscarriage risk
The interferons as a class cause flu-like symptoms after injections and may cause injection site reactions. They require laboratory monitoring for liver function changes and hematologic abnormalities.
Interferons need to be stopped 1 month before conception
Higher-dose interferons tend to cause neutralizing antibodies in one-third of cases that may interfere with the efficacy of these medicines.
Glatiramer acetate (Copaxone)
Injectable
MOA: Similar to interferons
Side-effects: Lipoatrophy (can be permanent), safest during pregnancy
Ofatumumab (Kesimpta)
Injectable
MOA: mAb to CD20, depleting B cells
Side-effects: injection site reactions (fever, fatigue, myalgias, local reactions), headache
Fumarates
Oral
Dimethyl Fumarate (Tecfidera), Diroximel Fumarate (Vumerity), Monomethyl Fumarate (Bafiertam)
MOA: Induces Nrf2 pathway (anti-oxidant cascade)
Side effects: Flushing, GI upset
Dimethyl fumarate is a second generation fumaric acid ester with unclear exact mechanism of action, which may cause gastrointestinal upset and loose bowel movements as well as intermittent flushing. This tends to improve after the first 2 to 3 months on drug. Dimethyl fumarate is a pregnancy category C agent.
S1P modulators (-imod)
Oral
Fingolimod (Gilenya) - first dose observation
Siponimod (Mayzent) - CYP2C9 testing, contraindicated in patients homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype) because of substantially elevated siponimod plasma levels, modified dosing based on genetic result
Ozanimod (Zeposia) - no first dose observation or genetic testing
MOA: Sphingosine-1-phosphate receptor modulator -> cells can’t leave lymph nodes
Side-effects: bradycardia, macular degeneration, some forms of skin cancers
Fingolimod is an orally active modulator of four of the five sphingosine-1 phosphate (S1P) receptors. It acts as a superagonist at the S1P receptor on thymocytes and lymphocytes. It induces an uncoupling and internalization of that receptor. This makes these cells unresponsive to such signaling. They therefore lack the signal necessary for egress from the lymph nodes and secondary lymphoid tissues. In clinical trials, it reduces relapses of multiple sclerosis in patients with relapsing remitting multiple sclerosis, as well as reduces MRI measures of clinical activity. In addition, there appear to be direct effects on neurons and glial cells, which also express S1P receptors. It is unclear if this effect is active in vivo, but may indicate some potential for neuroprotection.
Fingolimod can cause macular edema and a first dose bradycardia, requiring 6-hour observation after first administration. Other potential side effects include bronchitis and elevation in liver enzymes. Fingolimod has also been associated with the risk of severe (potentially fatal) varicella zoster virus infections. Fingolimod is a pregnancy category C agent.
Patients being started on fingolimod will require baseline EKG and ophthalmologic examination. Adequate varicella zoster virus immunity is also recommended prior to starting fingolimod.
Aubagio (teriflunomide)
Oral
MOA: Dihydro-orotate dehydrogenase inhibitor -> decrease pyrimidine synthesis and T-cell proliferation
Side-effects: Hair thinning, diarrhea, hepatotoxicity, Pregnancy Cat X – washout with cholestyramine to minimize fetal exposure, peripheral neuropathy, decreased sperm count
Teriflunomide inhibits the mitochondrial enzyme dihydroorotate dehydrogenase, which plays a role in pyrimidine synthesis. This agent is associated with diarrhea, nausea, elevated liver enzymes, alopecia and may be teratogenic, considered as a pregnancy category X agent.
Natalizumab
Infusion
MOA: mAb to alpha-4-integrin on cells, blocking cxn with VCAM1 at BBB
Side-effect: PML
Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. It binds to lymphocytes and prevents adherence at the endothelial surface of blood vessels in the brain and gut. It therefore reduces the entry of immunologically active cells into the CNS compartment. Trials have shown a 60% to 70% reduction in exacerbation rate, reduced activity on MRI, and slowed progression with the use of this medicine in relapsing forms of multiple sclerosis. In the United States, it is indicated for relapsing forms of multiple sclerosis usually when patients have failed other forms of disease-modifying therapy. Use of natalizumab requires an FDA-approved monitoring program.
Anaphylaxis occurs in about 1 in 50 patients often by the second to fourth dose of natalizumab. Symptoms include shortness of breath, wheezing, hypotension, rash, and tachycardia. The infusion should be stopped immediately if this occurs, and treatment for anaphylaxis should be instituted. This is an absolute contraindication to restarting natalizumab. There is no desensitization procedure, nor should the medicine be retried with premedication or at a lower dose. This is not related to immunoglobulin A deficiency.
PML and PML-IRIS
PML:
MS on natalizumab OR HIV patient not on HAART-> Progressive cognitive, speech, motor decline
Treatment: STOP Tysabri or START HAART, plasma exchange
JCV, tropism for oligodendrocytes
PML-IRIS
Look for: worsening deficit after stopping Tysabri (or starting HAART)
Contrast enhancement on MRI
Treat with: corticosteroids
Alemtuzumab (Lemtrada)
Infused
MOA: Monoclonal Ab to CD52- depletes B and T cells
Notable side effects: delayed autoimmunity (thyroid, ITP)
Alemtuzumab is an FDA-approved medication for relapsing forms of multiple sclerosis in patients having broken through on treatment with two other disease-modifying therapies. It is a monoclonal antibody that specifically binds to CD52, an antigen that is present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, natural killer (NK) cells, and a subpopulation of granulocytes. The proposed mechanism of action is antibody-dependent cellular-mediated lysis of B and T cells causing immunomodulation and reduced immune injury in multiple sclerosis patients. It reduces relapses and new MRI lesion burden more effectively than interferon β-1a. Specific risks include hyperthyroidism and idiopathic thrombocytopenic purpura (ITP), probably on the basis of return of immune active B cells after treatment.
Ocrelizumab
Infusion
MOA: mAb to CD20, depleting B cells
Side-effects: Infusion related reaction
Mitoxantrone
Infusion
MOA: Topoli inhibitor, disrupts DNA synthesis
Side-effects: Cumulative cardio toxicity, leukemia
Fatigue in MS
Stimulants - amantidine, modafinil, Ritalin
Depression in MS
SSRIs (fluoxetine)
Pseudobulbar affect in MS
Dextromethorphan-quinidine
Neurogenic bladder in MS
Oxybutynin (urinary frequency w/ detrusor hyperreflexia)
Tamsulosin (incomplete emptying from dyssynergia)
Spasticity in MS
Baclofen/tizanidine
Both baclofen and tizanidine are indicated for multiple sclerosis- related spasticity. They have similar efficacy. Side effects of baclofen include fatigue, dizziness, and dose-related leg weakness at higher doses. Sudden cessation of baclofen may cause withdrawal seizures. Side effects of tizanidine include light- headedness and hypotension, fatigue, and, rarely, liver function changes.
Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons via agonist actions at Alpha-2 adrenergic receptor sites. This drug is centrally acting and leads to a reduction in the release of excitatory amino acids like glutamate and aspartate, which cause neuronal firing that leads to muscle spasm.
Baclofen is GABAb
Pain in MS
TCA and AEDs (Gabapentin, Trileptal, Tegretol, Topiramate, Zonisamide, Lamictal)
Sexual dysfunction in MS
PDE5 inhibitors
Gait issues in MS
Dalfampridine (ampyra)
Inhibitor of voltage-dependent K channels to improve conduction along demyelinated axons
Improves vision, strength, ambulation, endurance
Contraindicated in patients with seizures or GFR<50 (seizures at toxic levels)
Dalfampridine is FDA approved as an oral medication to improve walking in patients with multiple sclerosis. Dalfampridine is a symptomatic therapy, and can be used in combination with disease- modifying agents. It is an extended-release form of 4- aminopyridine (previously known as fampridine). Dalfampridine is a broad-spectrum inhibitor of voltage-sensitive potassium channels. In laboratory studies, dalfampridine has been found to improve impulse conduction in demyelinated nerve fibers and to increase synaptic transmitter release at nerve endings. Dalfampridine is administered as a 10-mg timed-release pill every 12 hours. In two phase III trials in patients with multiple sclerosis randomized to dalfampridine versus placebo, a significantly greater percentage of patients were “responders” on dalfampridine than on placebo. A responder was defined as a patient who showed faster walking speed while on therapy than while not on therapy. About one-third patients responded to dalfampridine in these studies. The increased response rate in the dalfampridine group was observed across all four major types of multiple sclerosis (relapsing-remitting, secondary progressive, progressive relapsing, and primary progressive).
Paroxysmal dystonic spasms in MS
From aberrant discharges from demyelinated nerves, treat with carbamazepine
MS in pregnancy
Decreased risk of relapse during pregnancy, but INCREASED risk in the postpartum period
Breastfeeding is protective
Steroids are OK (2nd and 3rd trimester)
Glatiramer acetate is the safest (or at least best-studied) in pregnancy
Teriflunomide is CATEGORY X–> wash out with cholestyramine!!!
MS in pregnancy
Decreased risk of relapse during pregnancy, but INCREASED risk in the postpartum period
Breastfeeding is protective
Steroids are OK (2nd and 3rd trimester)
Glatiramer acetate is the safest (or at least best-studied) in pregnancy
Teriflunomide is CATEGORY X–> wash out with cholestyramine!!!
Classifying MS
The classic clinical course of MS is the relapsing-remitting MS (RRMS) course which accounts for about 85% of patients
Most patients with RRMS will develop secondary progressive MS (SPMS)
25-40% of patients transition to SPMS within 15 years of disease onset in adults
Primary progressive MS(PPMS) accounts for 10-15% of MS patients
Ocrelizumab is the only DMT approved to treat PPMS
Classifying MS
The classic clinical course of MS is the relapsing-remitting MS (RRMS) course which accounts for about 85% of patients
Most patients with RRMS will develop secondary progressive MS (SPMS)
25-40% of patients transition to SPMS within 15 years of disease onset in adults
Primary progressive MS(PPMS) accounts for 10-15% of MS patients
Ocrelizumab is the only DMT approved to treat PPMS
CIS
Clinically Isolated Syndrome (CIS): an initial CNS event with a presumed demyelinating cause, can be multifocal, may or may not have MRI findings -> essentially an initial event, not meeting criteria for CDMS
Conversion rate to CDMS is about 43% at 5 years, 59% at 10 years and 63% at 20 years
If MRI shows evidence of another lesion, 56-88% of MS. If MRI is negative, 22% chance of MS
Start DMT to delay CDMS if high risk features
No indication for DMT if isolated, otherwise normal MRI
Positive OCBs in the CSF and spinal cord lesions are associated with increased risk of conversion to CDMS
RIS
MRI consistent with MS but no clinical symptoms.
Associated with 30% risk of MS
Spinal cord lesion significantly increases risk of developing MS
Do not necessarily need to start DMT at time of RIS
Serial imaging surveillance is recommended
MS Epidemiology
Most common cause of neurologic disability in young adults after trauma
Approximately 2.8 million people have MS worldwide
Onset often between 15-45 years of age
Female:Male = 3:1
Life expectancy is reduced by 7-14 years (narrowing in recent estimates)
Clinical features of MS
Clinical symptoms of MS are variable and result from involvement of sensory, motor, visual, and brainstem pathways
Most common disease course of MS is Relapsing Remitting MS (RRMS)
During disease course clinical episodes occur called “relapses”
Relapses are defined as episodes that last >24 hours and occur in absence of fever, infection, or clinical features of encephalopathy
Symptoms of a clinical attack typically have acute to subacute onset and reach peak severity within days to weeks, with recovery 2-4 weeks afterwards
ADEM
Susac syndrome
Triad of encephalopathy, hearing loss, vision loss (retinal branch occlusion)
MRI with corpus callosum lesions, but can be scattered throughout WM as well as leptomeningeal enhancement or deep GM (BG and thalamus) lesions
Thought to be from an autoimmune process against endothelial cells, not demyelination
Treatment:
Acute: Steroids, IVIG
Chronic: Azathioprine, mycophenolate, cyclophosphamide
CADASIL
Characterized by:
Migraine headaches
Recurrent Strokes
Progressive focal neurologic deficits
Cognitive deficits
Psychiatric disturbances
MRI with lesions in anterior temporal lobes and external capsule
Caused by mutation in NOTCH 3 gene, chromosome 19
Treatment: Aspirin for stroke prevention, standard migraine therapies (NO triptans), Acetazolamide (Diamox)
