Multiple sclerosis treatment Flashcards
Spasticity
Baclofen
- GABA activation
Botulinum toxin B
- Prevents release of Ach
- Reduces calcium influx
- Suppresses release of excitatory neurotransmitters
Gait
FES - improves gait speed by 38%, reduces trips and falls
Dalfampridine - Inhibits voltage gated potassium channels between conduction along demyelinating axons, facilitates neuromuscular and synaptic transmission by relieving conduction blocks in demyelinating axons, better conduction along demyelinated axons improves walking and reduces disability
Bladder
Anticholinergic drugs - Block the parasympathetic nerves (frequency/urgency)
Artificial sphincter (emptying)
Treatment for acute relapses
Oral or intravenous methylprednisolone (Steroids)
- Hasten recovery but do not change overall disease progression
Plasma exchange short-term if steroids don’t work or it’s severe/worsening
Treatment for frequent relapses
Disease-modifying therapies reduce frequency and severity of relapses
Slow disability and reduce lesions
If 2+ relapses in 2 years consider DMA
Relapsing-remitting MS (for RRMS or CIS with MRI consistent with MS)
Interferon beta-1b (first treatment approved for RRMS, reduces relapse frequency after 2 years, decreases lesion burden, 5 year follow up disease progression 10% lower, well tolerated with few side effects)
Intramuscular Interferon beta-1a (Avonex) - (lowers disease progression, relapse rate, MRI lesion volume and number of lesions, well tolerate with few side effects)
Subcutaneous interferon beta-1a (Rebif) - higher doses reduce relapse rate more than lower doses, reduces disability and MRI lesion burden, well tolerated with few side effects)
Glatiramer acetate (copaxone) - synthetic polypeptide (substitutes itself as a target for the immune system), reduces relapses over 2 years and slows disability, continued effect for 6 years, well tolerated with few side effects)
Natalizumab - humanised monoclonal antibody that binds with alpha-4 intergrin inhibiting its adherence to receptors, reduces relapses and progression of disability over 2 years, used when don’t respond well to first-line therapy or in active disease, 300g IV infusion over 1 hour every 4 weeks. Risk of Primary multifocal leukoencephalopathy - caused by reactivation by the JC virus (increased if previous immunosuppression, exposure to natalizumab for > 2 years and JC virus) Re approved but only for those with rapidly evolving RRMS
Fingolimod - first oral DMT for RRMS. reduces lymphocyte migration into the CNS and reduces relapses and disease progression, better than interferon beta 1-a - adverse events include: bradycardia, atrio-ventricular block, increased risk of infection, headache, back pain. Only for second line treatment with no response to Interferon-beta.
Treating aggressive MS
High dose cyclophosphamide to stabilise MS
Followed by maintenance with Glatiramer acetate - well tolerated and reduced the risk of relapse, disability progression and new MRI lesions. Adverse events of cyclophosphamide: leukaemia, lymphoma, infection, and haemorrhagic cystitis
Mitoxantrone for SPMS, PRMS, worsening RRMS
- reduces neurological disability and/or frequency of relapses
- Induction treatment followed by long-term glatiramer acetate
- Black box warning for cardiotoxicity and secondary Leukaemia
Primary progressive MS
Currently no approved therapies for PPMS
Previous trials with various drugs showed no effect on the course of the illness
Ongoing trial using Fingolimod
Treating CIS
Reduced risk of developing MS following treatment with Teriflunomide
Reduced occurance of relapses and MRI lesions and total lesion volume and no. of gadolinium enhancing lesions
Benefit of early vs. delayed treatment on the rate of conversion to clinically definite MS
Early DMT not yet proven to prevent long-term disability, early interferon beta reduces disability progression at 3 years but not 5 years
Consider - occupation, family history, women, pregnancy, level of disability after each relapse, cerebellar involvement (aggressive), drug history
Normal MRI with no lesions but CIS = 22% chance of developing MS
Chance of MS 60-80% with present lesions
Increased risk of MS = OCB, young age, female, multiple systems affected, B cells
Treat someone with CIS - people may have side effects from the drug and they may never develop MS (only 50-60% sure that the person will develop MS)
Can reduce relapse rate but not long-term benefit
There is only a weak correlation between long-term disability and relapse frequency
Disadvantages of DMD (e.g. interferon beta)
Can become tolerant to it
It’s an injection (3 times a week) - reactions
Patient’s get flu like symptoms after the injection
Chest pain
Cardiac risk
Atrio-ventricular block (Fingolomod)
PML (alemtuzumab and natalizumab) - PML risk - need to test for JC virus and if + monitor patients very closely throughout treatment, there is no treatment for a reactivated JC virus so just need careful monitoring
Which drugs are best ?
Alemtuzumab and Natalizumab are high-effectiveness and reduce relapse rate by >50%, however they have more dangerous side effects
Moderate-effectiveness drugs include e.g. interferon beta, fingolimod - relapse rate reduction of around 30-50% between them all but with better tolerance and fewer side effects
Currently beta interferons are licensed for clinically isolated syndrome
Experimental agents
Alemtuzumab (monoclonal antibody targets CD52 cells) for RRMA reduces disability and relapses by >50% but does not alter disease progression
B12 (dimethylfumarate oral-therapy) - significantly reduced annual relapses and disability progression and lesions better than other drugs
Future therapies
Stem cell transplantation - mobilise stem cells, flush patients own stem cells from bone marrow to peripheral blood, harvest stem cell seive out stem cell from blood, abilation of immune system toxic chemotherapy drug to destroy immune system, transfuse stem cells replace stem cells into bone marrow (potent therapy, mortality was 7.5% but now only 1%, 70% disease free survival at 4 years NEDA achieved by 63% after 5 years, need to make stem cell flushing more potent but less toxic because 30% still not disease free after 5 years
Gene therapy - currently used for MSA. Remove defective cells, virus altered in the lab so it can’t reproduce, gene inserted into virus, altered virus mixed with cells from patient, cells become genetically altered, produce desired protein or hormone
Mouse model - MOG protein (part of myelin) injected into mice, mice develop serious allergic reaction (model for RRMS), give them bone marrow transplant, add MOG to stem cell - weakens recovery, MOG may be primary target antigen in MS. Antibodies against MOG may be important in the pathogenesis of MS. More specifically optic neuritis. MOG gene - adhesion molecule to provide structure to the myelin sheath.
Role of gut microbe. Gut bacteria role in development of autoimmune conditions. Mother and daughter share similar gut bacteria (genetic influence). Gut bacteria leaky and exposed to immune cells can cause inflammation of the brain. Gut bacteria influence BBB integrity and activate inflammatory cells. We may be able to treat autoimmune conditions by altering gut bacteria. MS patients show alterations in Gut bacteria compared to healthy controls.
