Multiple Sclerosis Flashcards
What is the most common cause of neurological disability in young adults?
Multiple sclerosis
Where is there a significant amount of people living with MS, contributing to a significant proportion of people with severe disability?
▪️ Young onset
▪️ Long duration of illness
▪️ Very treatable - limited effect on mortality
What is MS?
▪️ An inflammatory demyelinating disease
▪️ In the CNS
▪️ Attacks separated in time and space
What are the benefits of viewing all the subtypes of MS as one illness?
Diagnosis and symptoms management
▪️ Similar clinical issues
▪️ Similar patient issues
What are the benefits of viewing all the subtypes of MS as separate illnesses?
For understanding pathogenesis and selecting therapies
▪️ Difference courses
▪️ Different pathology
▪️ Different response to treatment
What are the two main types of MS?
▪️ Relapsing-remitting (85% at onset)
▪️ Progressive
What is a monophasic illness?
An illness with only one event
What is secondary progressive MS?
MS that was initially relapsing-remitting but is now progressive
How should inflammatory demyelinating diseases be viewed?
As a spectrum
Monophasic -> relapsing -> progressive
How might relapsing-remitting MS develop into secondary progressive MS?
After a period of time (10-15 years?), they may not recover completely after relapse, so their disability slowly increases
Inflammation and demyelination becomes axonal loss and gliosis
Who is most likely to have progressive MS at onset?
▪️ Older age
▪️ No difference between genders
Who is most likely to have R-R MS at onset?
▪️ Younger age
▪️ More commonly female
Why is it important to distinguish between R-R and progressive MS?
To guide treatment
▪️ Very good treatment options to reduce inflammation in relapsing form
▪️ One one drug shown to slow progression
Is MS the same pathological process?
No
What are the four pathological patterns of MS?
- Inflammation and remyelination
- Inflammation and antibody/complement
- Oligodendrocyte apoptosis
- Oligodendrocyte damage including normal appearing tissue
How do white blood cells enter the brain?
Stick to epithelial cells on BBB and squeeze through junctions in the BBB in response to signals
What are the majority of genes associated with risk of MS associated with and what is the problem with this?
▪️ Impaired MHC (major histocompatibility complex)
▪️ Cannot present antigens therefore cannot activate immune system
Why might there be many attacks one after the other in MS?
More inflammation = more you expose antibodies = more complex immune response
How might antigen presentation result in inflammation and tissue damage?
▪️ Antigen presentation activates T cells
▪️ T cells stimulate B cells to become plasma cells produce antibodies which may lead to demyelination
▪️ T cells become cytotoxic T cells and release cytokines and nitrous oxide leading to tissue destruction
What is the main pathological cause of disability in MS?
Axonal damage due to loss of protective myelin (greater correlation with disability than inflammatory markers)
(Myelin can heal and grow back but axons cannot)
How does loss of myelin lead to axonal death?
▪️ Loss of support leaving axon exposed to NO and inflammatory cytokines
▪️ Increased number of Na+ channels to maintain function increases metabolic stress
Where is axonal loss found in MS?
▪️ Predominantly in areas of inflammation
▪️ At the lesions themselves (areas of active demyelination)
▪️ BUT ALSO in areas of normal-looking white matter
▪️ Associated with higher levels of neurofilament
Why does axonal transection occur predominantly in areas of inflammation?
Likely due to exposure to inflammatory mediators such as NO and cytokines
(Also loss of trophic factors and direct axonal damage?)
What is grey matter involvement related to in MS?
Cognitive dysfunction
What might explain the increased incidence of epilepsy in MS populations?
Cortical demyelination
What are the principles of MS diagnosis?
▪️ Dissemination in time (more than 1 attack)
▪️ Dissemination in space (lesions in more than 1 area)
▪️ Independent immune attack in CNS
▪️ Exclude mimics
How can MRI aid MS diagnosis?
Can allow us to spot lesions before attacks so can diagnose earlier without having to wait for a second attack
Where might you see lesions in MS?
▪️ Periventricular
▪️ Posterior fossa/infratentorial
▪️ Juxtacortical (beneath surface)
▪️ Spinal cord
▪️ Optic nerve
How can clinically silent lesions result in disability in MS?
As they accumulate, eventually affecting eloquent tissue
What MRI signs can be used as markers of new activity in MS?
New inflammatory lesions and gadolinium enhancing lesions
(Bright spots of FLAIR)
What MRI signs can be used as markers of disability?
T1 black holes and atrophy
What does enhancement mean on a scan?
There is breakdown of the BBB
What are CSF oligoclonal bands evidence of?
Independent production of antibodies within the BBB, suggestive of inflammation
In 97% of people with MS
BUT also seen with other infectious/inflammatory conditions so not specific
What is OCB negative in patients with MS an indicator of?
Better prognosis
How can you use visual evoked potentials to diagnosis of MS?
Evidence of delayed conduction of optic nerve (p100 latency) is evidence of demyelination, proving dissemination in space
(now use OCT)
What are the three components of MS pathogenesis?
- Predisposing genes
- Exposure during childhood (to infectious agent?)
- Precipitants in adulthood
What is the prevalence of MS in individuals with a 1st degree relative with MS?
3%
What is the risk of MS if your monozygotic twin has it?
30%
What racial differences are seen in MS and what might this suggest?
▪️ Much lower in Asian and indigenous populations
▪️ Variety of genes involved
How does MS differ between genders?
▪️ Greater prevalence in women
▪️ Especially for relapsing remitting
Why are women more vulnerable to almost all autoimmune conditions?
▪️ Immune system lowered when pregnant so not to reject foreign genes
▪️ Too low = autoimmune disease
▪️ Loss of protective effect after multiple pregnancies?
▪️ Hormones and contraception?
What happens to relapse rate of MS during pregnancy?
It decreases
BUT may get worse after birth (either maintain treatment throughout or treat immediately after)
How does risk of MS differ across the world and why?
▪️ Greater risk when more geographically north (further from equator)
▪️ Sunlight and vitamin D - lower exposure (especially in childhood) = greater risk
▪️ Thought to modulate immune system
What role does migration play in MS risk?
▪️ Very little - maintain protection if not too young when move
▪️ Risk declines if going from high-risk to low-risk country
BUT protection doesn’t extend to children
What is the relationship between MS and smoking?
Worse prognosis if already have MS - triggers inflammation? interacts with HLA genes?
What factors are associated with worse MS prognosis?
▪️ Low vitamin D
▪️ Smoking
▪️ Obesity
What virus has been associated with increased risk of MS?
Epstein-Barr Virus (EBV)
(Mono/glandular fever)
How might childhood infection of EBV effect risk of MS?
▪️ If living in dirty environment and get it very young, usually have no/mild symptoms but remain carrier
▪️ If living in clean environment, may not get it until your teens and can have worse symptoms as your immune system overreacts (glandular fever)
▪️ Greater risk of MS if had EBV and even greater risk if has glandular fever - triggers already sensitive immune system?
What is the hygiene hypothesis of MS?
▪️ Higher risk of MS if brought up in clean, urban areas compared to rural (as seen with asthma)
▪️ Lack of exposure to allergens and common pathogens when young makes immune system more sensitive?
▪️ Particularly then if exposed to infectious triggers such as EBV later on?
What factors are associated with better prognosis in MS?
▪️ Young
▪️ Female
▪️ Sensory/optic neuritis (numbness, tingling)
▪️ Fewer attacks at long intervals with good recovery
What factors are associated with worse prognosis of MS?
▪️ Older
▪️ Male
▪️ Motor/cerebella (weakness, clumsiness)
▪️ Frequent attacks with little recovery
▪️ Higher lesion load on MRI
▪️ Progressive course
How is MS disability measured?
Expanded Disability Status Scale (EDSS)
0 = normal
10 = dead
What is a score from 1-3.5 on the EDSS?
▪️ Score based on performance at examination (minimal, mild, moderate)
▪️ Look for weakness, clumsiness, reflexes, sensory dysfunction etc
What is the main factor determining score on the EDSS scale from 4-10?
Ability to walk - how far and what assistance is required
Gaps are not equal and do not spend an equal amount of time on each one
How does deterioration on the EDSS scale differ between MS subtypes?
▪️ Much quicker in progressive type to reach 4.0 (almost all by 10 years, 50% of RR)
▪️ BUT once at 4, all progress to 6 at the same rate (indicate transition to secondary progressive in those with RR at onset)
(Increased risk of deterioration if more early attacks)
What is Copaxone (glatyrimer acetate)?
▪️ Polymer designed to look like myelin
▪️ Immune system becomes more tolerant so stop attacking
▪️ Very safe as no immune suppression
▪️ Injection
What is Teriflunomide?
▪️ Immunosuppressant tablet
▪️ Modest benefits (~30% reduction)
▪️ Mostly tolerable but can cause liver problems and cannot fall pregnant on it
▪️ Need to be removed with activated charcoal to have baby
What used to be the mainstay treatment for MS until around 2010?
Beta interferons (injection, get flu-like symptoms)
Modulates immune response
What is DMF (dimethyl fumarate)?
▪️ Most widely use medication for MS in the world
▪️ Immunosuppressant tablet twice a day
▪️ Can cause stomach problems and skin flushing
What is Fingolimod?
▪️ Tablet once a day
▪️ Reduce relapse by around 50%
▪️ SIP inhibitor - white cells in lymph nodes cannot be mobilised, reducing number in system thus reducing damage
What is Cladribine?
▪️ Chemotherapy drug
▪️ Given for now for a week then in a years time for a week then never needed again
▪️ Good option for long-term treatment
▪️ BUT requires isolated room
What are the three main considerations when choosing which treatment to use for MS?
▪️ The disease (severity, type, disability)
▪️ The patient (attitude to risk, work/lifestyle, pregnancy)
▪️ Funding and NICE guidelines
What is the only drug that has been proven to delay deterioration in people with secondary progressive MS?
Siponimod (SIP inhibitor)
What are monoclonal antibodies?
Man-made antibodies that bind to very specific targets for targeted-drug therapy
What is Natalizumab?
▪️ Monoclonal antibody
▪️ Blocks gaps in BBB preventing WBC from entering
▪️ Double as effective as first line injectable therapies
What is the issue with Natalizumab?
When immune system is compromised and WBC unable to enter brain, JC virus can cause progressive multifocal leukoencephalopathy
(Can now test for JC)
What is Ocrelizumab?
▪️ Monoclonal targets CD20 on B cells
▪️ Damages them which stops production of antibodies and communication between B cells and T cells
▪️ 6 monthly drip
What is the first drug found to be effective in primary progressive MS?
Ocrelizumab (modest benefit)
BUT need evidence of inflammatory activity with new and enhancing lesions for treatment
What is Alemtuzumab?
▪️ Monoclonal antibody binds to CD52
▪️ Profoundly immunosuppressant
▪️ BUT 30% will get autoimmune disease and high risk of cardiac problems so only used now as a rescue treatment
How can stem-cell therapy be used for MS?
Autologous HSCT:
▪️ Aggressive MS and failed first line therapy
▪️ Chemotherapy stimulates bone marrow to make WBC which you harvest
▪️ Knock immune system out (severely immunocompromised)
▪️ Then give WBC/stem cells back, hoping to only give good ones
How effective is HSCT for MS?
Reduce relapses by 85%
BUT 1% die
How might statins help people with primary progressive MS?
▪️ Neuroprotection
▪️ Anti-inflammatory
▪️ Trials ongoing
How can you treat spasticity in MS?
▪️ Remove aggravating factors
▪️ Exercises, posturing etc
▪️ Medication such as baclofen, benzos, cannabinoids (Sativex!)
▪️ Botox or baclofen around spinal cord?
▪️ surgery?
How might the bladder be affected in MS and how can we manage it?
▪️ Damage along spinal cord decreasing communication between brain and bladder
▪️ Urinary incontinence
▪️ Increased risk of kidney infections
▪️ Can teach to self-catheterise
What is the prevalence of depression in MS?
▪️ 50% at some stage
▪️ 15% at any one time
What is the issue with diagnosing depression in MS?
Lots of overlap between MS and ‘organic’ depression symptoms such as poor sleep, fatigue, and cognition
Reliant on mood symptoms
What causes depression in MS?
▪️ Reactive response - effects on relationships, functioning, pain, self-esteem etc
▪️ Biological response - lesions, cognitive dysfunction, disability and duration etc
What is the main issue surrounding cognitive dysfunction in MS?
▪️ Especially in younger women with relatively low physical disability, exacerbated by having children
▪️ Makes them vulnerable
▪️ Memory services typically tailored for older people with dementia
▪️ Dementia drugs don’t work
What is neuropathic pain and where does it typically occur in MS?
Irritate nerve sending mixed messages, appears as pins and needles feeling
▪️ Trigeminal neuralgia (in face)
▪️ Limbs
▪️ Hug (corset pattern with spinal injury)
How do you treat neuropathic pain in MS?
▪️ Tricyclic antidepressants
▪️ Duloxetine (NRI)
▪️ Antiepileptics (carbamazepine, gabapentin, pregabalin)
What complications from MS may contribute to pain?
▪️ Spasticity
▪️ Musculoskeletal (e.g., sitting in wheelchair)
▪️ Psychogenic component
▪️ Bladder/bowel/bedsores
How common is fatigue in MS?
~80% (across all disease stages)
What factors are associated with worse fatigue in MS?
▪️ Relapses and immune activation
▪️ Afternoon - heat or exercise?
▪️ Poor sleep and depression
How can we treat fatigue in MS?
▪️ Limited role for medication
▪️ Possibly amantadine (PD drug)
▪️ Some evidence for modafinil (off licence)
▪️ Potentially helped by Copaxone?
