MS - Clinical, first 2 lectures Flashcards
MS epidemiology Prevalence numbers/ ratio: Women vs men: Age: Where does it seen in world:
Very common disease – 2-3 million has it.
Netherlands: similar to Europe, now becoming 1/500, getting more prevalent
diagnosis is really made in young age, between 20-40, female numbers peak earlier than men, so they usually get it earlier. Children/teenagers with MS is common.
MS is a western disease
America, Europe, Australia = very prominent, not common in Africa. Vit D might have an impact, but not strong enough to explain whole difference = lifestyle.
MS pathology = what is seen in lesions
MS is a disease of CNS (brain + spinal cord)
Demyelination is caused by lymphocytes + immune cells, and this is treated with Immunomodulatory drugs.
Demyelination later causes lesion formation. Demyelinated inflammatory lesions can be seen on MRI. Lesions are seen as white since they have edema accumulating around them due to the inflammation.
Continuous demyelination leads to neuronal
degeneration = neuronal loss leading to brain atrophy, brain getting smaller
Can’t be slowed down yet, only the inflammatory lesions can be treated.
Neuron structure
Neurons in CNS have axons, and axons are covered with myelin. Axons are signaling through Nodes of Ranvier, and jumping through them, with demyelination it’s lost and signals are transmitted very slow + gets easily damaged (missing also myelin protection).
MS risk factors
Genetics:
Environment/infections:
MS isn’t a Mendelian disease, but some alleles cause susceptibility.
Monozygotic twin gets it too. Exact same composition drives it no matter what! Dizygotic = %30.
Over 200 genes associated with MS / HLA/immune system related. - GWAS
Demyelination in MS is very similar to viral induced demyelination in Thelier’s disease.
But not a single virus causes MS.
EBV: if you have MS, you can’t be EBV negative. but %95 of population is infected. Might be due to molecular mimicry,
autoreactive cells get activated with cross reactivity between self Ag and foreign Ags. So virus has an epitope that’s very similar to self Ag, so immune system attacks this virus, and also as a bystander effect induces the autoreactive cells.
Same seen with measles viruses association.
Myelin basic protein and Measles virus P3 protein is almost same.
Virus infections increase MS relapses.
Western lifestyle:
Different diet & microbiome = maybe changing microbiome can help, fecal transplant studies are done.
Low sunlight : Low Vit-D = risk.
Smoking, early obesity.
Might be due to Hygiene hypothesis: poor countries have much less hygiene, developed countries are too clean, and their immune system is not properly trained.
MS symptoms
The optical nerve can get inflamed / demyelinated = optic neuritis. visual loss in one eye gradually, see less in the center, usually have pain behind the eyes, disturbed colors = one of the first symptoms, seen during relapse.
2nd common symptom: Diplopia (double vision) : two different nerves controlling two different eye muscles, are keeping the eyes looking at the same direction. The lesions disrupt the interaction, and cause diplopia.
3rd: Spinal cord problems/walking dissability. Lhermitte’s syndrome. Caused by spinal cord lesions. When the person stands, there’s no problem, but when it leans forward, it gets an electrical sensation in back. Can be caused by other problems in spinal cord too but can be MS too.
Motor dysfunction: If there’s a lesion in 1 hemisphere of the brain, you get onesided hemipheresis (1 sided loss of strength). But when its lower, in the spinal cord, problem will be bilateral (twosided), huge walking problems. In long term MS, patients usually have walking disability. Writing disability.
Bladder dysfunction: Very common. They constantly feel like they have bladder.
Sexual dysfunction: a very early symptom in MS, men - erectile dysfunction/women – orgasm problems, no sexual desire due to less signaling from the brain.
Cognitive dysfunction: no multitask, less memory/concentration, less attention, slow processing, disturbance of language = %65 of patients
Fatigue: super common, %80, cause unknown
MS types + Immunology + Animal models class
Sometimes patient only might have a first episode, but it doesn’t become chronic. = then it’s Clinically Isolated Syndrome, not MS yet. It can evolve to MS in follow up, but in minority of patients it doesn’t. (Preclinical stage)
There’s places in brain that if you get a lesion there, they don’t directly cause symptoms too. Not all lesions lead to clinical symptoms necessarily.
It’s not clear whether there’s gray matter lesions in preclinical phase, since MRI isn’t that sensitive to detect them. There’s some papers indicating that in very early stages gray matter pathology is observed though.
Relapsing Remitting MS = %80-85 of the patients have it. They have relapses + inflammatory lesions that comes and goes. Demyelination is observed.
Remyelination occurs a bit but it doesn’t have anything to do with remission.
Adaptive immunity, B/T cells observed.
A lot of inflammation/lymphocytes/macrophages/microglia/BBB disturbance is observed. New active CNS lesions are seen, also initial remyelination in active lesions observed.
With time & without treatment, in 15-20 years, patients will go continuous gradual progression/disability leading to Secondary Progressive MS (%10-15 people are diagnosed with primary progressive MS, skipping the relapsing
remitting phase, less common)
not all lesions on the MRI show symptoms.
Complete remyelination.
Lesions start to expand slowly, and more inactive types are seen (gliotic)
Meningeal inflammation is seen
Neurodegeneration occurs
Axon degeneration/brain atrophy is seen.
Innate immunity, eg. Local microglia get activated and causes ongoing tissue damage. Oligodendrocyte death is seen a lot.
Active MS = new lesions formed and sometimes goes, sometimes stays, progressive MS = neurological state continuously deteriorates
Criteria to see whether a patient has MS or not
McDonald Criteria:
Dissemination in space and time
1) Not all lesions are MS lesions, needs to be specifically demyelinating ones.
There should be at least lesions in 2 of the specific localizations where MS lesions are seen = dissemination in space
2)There needs to be 2 time points of occurring MS events, eg. 2 relapses on MRI, so 1 new 1 old lesion. = dissemination in time
new lesions mean disease progressing. New lesions light up in MRI and show up as “contrast enhancing lesions”, whereas older ones show as “non-contrast enhancing lesions”
Do lumbar puncture and check oligoclonal bands / Ig levels in CSF.
IgG can be seen in other diseases as well so not very sensitive, not very specific.
Oligoclonal bands: are sensitive %90 but not that specific.
If you don’t see dissemination in time and space, but see oligoclonal bands, you can diagnose MS, so lumbar puncture is done when not sure.
MS follow up = what to check?
MRI for lesions/atrophy
Symptom evaluation
Biomarkers are checked to see the progression, eg. NfL (neurofilament light) shows axon damage, can be measured from cerebrospinal fluid/blood.
MS treatment types
1st line of therapy: low efficacy
there was only 3 compounds for treatment. Mostly Interferons. long term effect + side effects aren’t known, only given when you are very sure that patient has MS + numerous relapses before. = treatment starts quite late after the onset
Low risk -low side effect
Higher efficacy 2nd line therapies: developed after 2000s = used if you can’t control the inflammation with 1st line therapies - High risk / effective. High side effects, eg. severe brain infection in Natalizumab
Newer compounds: 2004 Natalizumab -anti-integrin- Alemtuzumab - Ocrelizumab - Cladribine = after 2015.
With new compounds, right after diagnosis, drugs start to be administered.
Early treatment is important! = it even provides lower risk of secondary progression MS stage, no treatment = wheelchair bound in 20 years.
Costs of MS treatment
Therapy costs almost 15.000 dollars per patient per year. Costs also continue increasing as newer and more efficient drugs are developed, and there’s no competition. New therapy: Immunotherapy = 60.000 dollars.
First line treatment types
IFN beta – 4 diff types possible but all work similar. Injected every week, most common side effects are flu-like symptoms in the day of injection, skin reactions – known to be relatively safe, used for over 20 years. Can be used even in pregnancy/breastfeeding = so usually preferred by women
Copaxone (glatiramer acetate) – also injectable, most common side effect is skin reactions, that’s it. Can be used even in pregnancy/breastfeeding = so usually preferred by women at that age.
Dimethylfumarate – oral, no injection. Side effects, mainly GI tract, rare side effect, PML (severe brain infection) if you have low lymphocyte/leukocyte count using it. So every 3 months you need to get blood tests
Teriflunomide - %10 people stopped it due to nausea + diarrhea, causes a bit hair loss too. More side effects compared to others.
All first line: %30 reduction of relapse. Either can be picked dependent on personal preference of side effects. Safe + easy to apply. No added value when combined.
2nd line treatments in MS
Natalizumab Anti alpha integrin. Doesn’t allow lymphocytes to pass BBB, no immune surveillance = High risks of brain infection (Progressive multifocal leukoencephalopathy (PML)). They check the JCV (John Cunningham virus) presence in blood before giving to prevent brain infection. If you are JC positive and have a lot of virus count, your risk of getting a brain infection with Natalizumab usage gets much higher. JCV infection risk reduce its usage quite a lot, but it’s very effective, stabilizes MS completely with no inflammation over years. = so usage depends on virus presence/count. Monthly infusions (4-6 weeks)
Ocrelizumab B cell depletion, anti CD20. popular option for John Cunningham positive patients. As effective as Natalizumab. Also you need it once every 6 months, lot easier to introduce than Natalizumab.
Problem? Long term effects not known. Not very good for elderly, since might lead to strong opportunistic infections, in COVID there’s hesitancy. Neither of treatments except Ocrelizumab change the outcome of COVID infection, but Ocrelizumab might make it worse. Will be used much more once COVID passes.
Why use Ocrelizumab instead of Rituximab? (both anti-CD20)
It’s just because of the size of Phase III trials done for MS in Netherlands. Actually its cheaper. Ocrelizumab is humanized, maybe has less side effect, but no difference in USA.
- Fingolimod
–Alemtuzumab
restricted, only used as a very last resort): causes severe brain hemorrhage
Long term side effects is important to consider, drugs might be retracted from markets. New drugs aren’t really known well. People might decide to go for first line known drugs, and wait a bit until side effects are better evaluated.
Eg. Alemtuzumab restricted
Daclizumab (retracted): causing so severe autoimmune encephalitis, not sold.
MS treatment algorithm
1) Identification of Clinically Isolated Syndrome (CIS) or RRMS = can start with first line treatment usually, no longer wait and see, start treatment as early as possible.
If MS seems highly active with a lot of lesions, high inflammation/disability = go 2nd line directly.
Check every year.
