Multiple sclerosis Flashcards
1
Q
What is MS
A
- Chronic autoimmune disease
- Progressive disease
- Involves immune system and neurological system
- Multifocal areas of demyelination- presenting symptoms will depend on which neurones in which part of the brain in affected
- Disrupts ability of the nerve to conduct electrical impulses
- Leads to symptoms
2
Q
Epidemiology of MS
A
- First described in 1868 by Jean-martin Charcot
- Age onset 20-50 years old
- Women are twice as likely to develop MS
- Between 100-140 cases per 100,000 people
- 1800-3400 people in England and Wales
- Over 2.5 million world wide
- More prevalent in Caucasians
3
Q
Etiology of MS
A
- Genetic: MS is polygenic (not just one gene), MS susceptibility genes. MS associated genes, which may influence the overall clinical course of MS
- Vit D3
- Infection e.g. virus, EBV, chlamydia
- Environmental facots
4
Q
Role of vitD in MS
A
- US cohort study found that 3.5 times more women residing in northern states were diagnosed with MS than southern states
- The incidence of MS highest in North Temporal Climate
- MS more prominent in areas reporting less than 2000 hours of sunshine annually
- MS displays seasonable variability with increased activity in the Spring and lowest in. the Autumn.
- A Finnish study found in MS patients lower serum vitamin D levels in the Spring.
- A link between dietary intake of vitamin D and the incidence of MS has been suggested in Norway along the coastal areas where fatty fish, dairy products, and cereals are all rich in vitamin D consumed in higher amounts. The incidence is lower than the rest of Norway.
- Dietary information from the Nurses Health Study of 187,000 women showed those with a history of vitamin D supplementation as low as 400 units daily had a 40% less chance of developing MS
5
Q
Nerve condition in healthy myelinated cells in the CNS
A
- Healthy
6
Q
Speed of Ap in axons
A
- Unmyelinated axon conducted: 0.5 to 10 m/s
- Myelinated axon conducted up to 150 m/s
7
Q
Symptoms
generic symptoms shows why diagnosis can take a long time
A
- Vision disturbances
- Numbness
- Difficulty walking/ Co-ordination/ Balance problems
- Fatigue
- Depression/Emtionalchanges
- Vertigo and dizziness
- Spasticity
- Sexual dysfunction
- Pain
- Change in cognitive function
- Bowel/bladder dysfunction
8
Q
Lhermitte sign
A
- Lhermitte’s sign or Lhermitte’s syndrome is a sudden sensation resembling an electric shock that passes down the back of the neck and into the spinal column and can radiate out to the fingers and toes
- It is usually triggered by flexing the neck, that is, bending your head down, chin towards chest and is sometimes referred to as barber’s chair syndrome
- Lhermitte’s sign is rarely treated as the pain is so sharp and sudden that it does not usually last long enough for pain treatments to take effect
9
Q
Uhtoffs sign
A
- Uhthoff’s phenomenon or Uhthoff’s sign is the temporary worsening of symptoms, most often visual symptoms but sometimes motor or sensory - caused by an increase in temperature
- The visual symptoms may present as double vision, sharpness of vision, or black spots in the eyes
- The symptom takes its name from Wilhelm Uhthoff, a German neuro-opthamologist, who first described it in 1890
10
Q
Clinical presentations in MS
A
- Loss or reduction of vision in 1 eye with painful eye movements
- Double vision
- Ascending sensory disturbance and or weakness
- Problems with balance, unsteadiness or clumsiness
- Altered sensation traveling down the back and sometimes into the limbs when bending the neck forward
11
Q
Diagnosis (NICE)
A
- Be aware that usually people with MS present with neurological symptoms or signs as described
- Are often aged under 50 AND
- May have a history of previous neurological ssymptoms AND
- Have symptoms that have evolved over more than 24 hours AND
- Have symptoms that may persist over several days/weeks and then improve
- Do not routinely suspect MS if a person’s main symptoms are fatigue, depression or dizziness unless they have a history or evidence of focal neurological ssymptomsor signs
- Before referral to neurologist must rule out alternative diagnosis
12
Q
Diagnosis
A
- Referral to a neurologist
- Medical history
- Neurological examination
- Medical investigations including MRI to identify areas of sclerosis in the brain or spinal cord (Mcdonalds criteria)
- Lumbar puncture to test for abnormality of the CSF
- Evoked potentials, to measure time taken for nerves to respond to electrical stimulation
13
Q
Disease to rule out
A
- Viral infections
- Lyme disease
- B12 deficiency
- CVA
- Lupus
- RA
- Other connective tissue disorder
- Vasculitis
- Syphilis
- TB
- HIV
- Sarcoidosis
14
Q
Molecular pathology of MS
A
- Peripheral riming of T cells by environmental factors (e.g. viral proteins)
- Migration of T cells across BBB in genetically susceptible host
- Local expression of pro-inflammatory mediators leads, to myelin damage, leucocyte infiltration across the BBB, chemokine release= central damage
15
Q
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16
Q
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17
Q
Thats great but
A
- There’s goof evidence that self-Ag are extinguished
- So, no memory T cells should form against myelin
- Disease progression/Relapse associated with epitope spreading (autoimmunity) but not critical
- Is MS more complex than just too much inflammation
18
Q
Prognosis and progression
A
- Early symptoms of MS are a result of demyelination with associated oedema and inflammation
- Over time these symtpoms can abate as the inflammation resolves and partial re-myelination occurs
- Inflammation caused by activated leucocytes infiltrating the BBB resulting in hardening along the neurones (sclerosis) which blocks signal transmission to and from the brain and spinal cord
*
19
Q
Prognosis and progression
A
- 5-10% of all patients will develop benign MS
- 33% will have little or no disabilities allowing them to live independently whilst not in relapse
- 33% of patients will have severe disability
- Overall reduction in life expectancy 5-10 years
- Prognosis worse- older age of onset, male, progressive
20
Q
Clinical sub-types of MS
NB- you can move between sub-types
You are always symptomatic, on relapse these become worse
A
-
Relapsing-remitting MS (RRMS)
- Affects 85% of newly diagnosed
- Attacks followed by partial or complete recovery
- Symptoms may be inactive for months or years
-
Secondary-progressive MS (SPMS)
- Occasional relapse but symptoms remain constant no remission
- Progressive disability late in disease course
- ~50% of those RRMS develop SPMS during the first 10 years
-
Primary progressivee MS (PPMS)
- Affects 10-15% of MS population
- Slow onset but continuous worsening condition
- Symptoms become continuous
-
ProgressiveRelapsing MS (PRMS)
- Rarest form
- Affects ~5% of patients
- Steady worsening of conditions at onset
-
Benign MS
- 20% of MS patients
- Mild relapse followed by long periods of remission with little or no decline in function
21
Q
Types of treatment of MS
A
- Drug therapy
- Treatment of acute episodes
- Prevention of future attacks
- Slow or prevent disease progression
- Treatment the chronic symptoms of the disease
- Physical therapy
- Psychological support
22
Q
Treatment of acute MS episodes
A
- IV methylprednisolone, 500mg-1g daily, for between 3 and 5 days or high-dose oral methylprednisolone, 500mg-2g DD for 3-5 days up to 3 courses per year
- IV immunoglobulin- important for immunomodulation
- Azathioprine
- Mitoxantrone
- Intermittent (Monthly) short (1-9 days) courses of high-dose methylprednisolone
- Plasma exchange
- Physical therapy
23
Q
Prevention of future attacks and disease progression
A
- Immune modulating drugs
- Beta-interferon
- Glatiramer acetate
- Humanized mAb
- Immunosuppressant drugs
- Anti-cancer agents
- Combination therapies
- Current NICE guidance- nothing recommended
24
Q
Side effects of MS medication
A
- Local injection site/Irritation reactions
- Flu-like
- RA risein liver enzymes
- Decreased white cell count and platelets- immunosuppressant
- Opportunistic infections- immunosupressant
- Depression
- Progressive multifocal leukoencephalopathy (PML)
25
Disease modifying drugs- Interferons Beta1a
* Protein replica of human interferon
* Suppresses the immune system and helps maintain BBB
* Avonex IM weekly
* Rebif SC 3xweekly
* SE's include flu-like symptoms
* Used in definitive progressive MS
26
Interferon Beta-1-b
* Different human interferon
* The same action as beta-1-a injected SC every 48hrs
* SE's include: irritation, bruising and redness at the site of injection, flu-like symptoms
* Used in definitive progressive MS
27
Glatiramer acetate (Copaxone)
* Synthetic combination of 4 amino acids, resembling the myelin protein surrounding nerve fibres (immune system attacks drug not myelin)
* It is thought to lessen the immune reaction that attacks myelin
* Decreases the re-occurrence of relapse
* Administered SC daily
* There is no flu-like symptoms but occasional redness may occur at injection site. Few people experience brief shortness of breath
* All three of these drugs decrease relapse by 33% have manageable side effects, and injected, stabilize the disease and tend to be costly
28
Fingolimod FTY720 Gilenya
* First oral agent for prevention of relapse
* Second line therapy (NICE- not cost effective)
* 0.5mg daily
* Modulation of lymphocyte S1P1 receptors
* Inhibits lymphocyte gressfrom the lymph nodes
* Prevents lymphocytes from infiltrating iinflammatory lesions in the CNS
29
Other drugs
* **Cladribine:** Purine nucleoside analog preferentially depletes lymphocytes
* **Dimethyl fumarate (**BG12)- May have both anti-inflammatory and neuroprotective properties
30
Immunosupressents- Azathioprine
* Azathioprine- immunosuppressive antimetabolite drug, imidazolyl derivative of 6-mercaptopurine
* Cleaved in-vivo to mercaptopurine and converted to 6-thiouric acid by xanthine oxidase
* Generally used in treatment of organ and tissue transplantation; disease with auto-immune or inflammatory component
* It is used off-label for MS
* Toxicity
31
MTX
* An immunosuppressive anti-metabolite drug used for some neoplasias (including leukaemia), psoriasis and RA
* Interferes with DNA synthesis, repair and cellular replication
* Inhibits dihydrofolate reductase, which participates in the synthesis of thymidylate and purine nucleotides
* Off-label for MS
32
Mitoxantrone
* Type II topoisomerase inhibitor- disrupts DNA synthesis and DNA repair and engages in intercalation
* Has been shown to reduce relapse rate and slows disease progression in MS
* Toxicity limits the dose
33
Cyclosporine A
* Broad immunosupressant
* Some benefits have been shown, modest improvements
* Benefits outweighed by the toxicity of the doses required
* Nephrotoxic
34
mAb
* **Natalizumab-** binds to an alpha-4-beta-1 protein expressed by inflammatory cells, preventing lymphocyte passing the BBB
* Indicated for relapsing MS and to reduce symptom exacerbation frequency
* Reduce the relapse rate by 68% after one year
* **Alemtuzumab**- binds to Ag CD52 which is found on the surface of certain B and T cells and kills them (lymphocyte depletion\_
* Phase III trials
* Early reports of significant autoimmune side effects (~20%)
* **Ocrelizumab-** Anti-CD20 deplete B lymphocytes
* RRMS active disease defined by clinical or imaging features, only if: alemtuzumab is contra-indicated or otherwise unsuitable
35
Therapeutic targets in MS
36
Complementary
* People with MS should have 17-23g of linoleic acid may reduce progression of disability
* rich sources include sunflower, corn, soya
* BUT: mixed results in trials- proof-of concepttrial still needed
37
Symptoms management
* **Spasticity**- Baclofen, diazepam, dantrolene
* **Optic neuritis**- Methylpredinisolone, oral steroid
* **Fatigue**- antidepressant, amantadine
* **Pain**- opiate, aspirin
* **Sexual dysfunction**- sildenafil
* **Tremor**- isoniazid, primidone, propranolol
* **Counselling**
38
Fampridine
* 4-aminopyridine, a K+ channel blocker, which works by blocking some of the chemical processes in nerves. This seems to improve the transmission of messages along damaged nerves
* Shown to improve walking speed for some people with MS
* Granted a conditional licence by the EMA, in July 2011. Licence requires the manufacturer, to carry out further research into the benefits and long-term safety of fampridine. In particular, the research will provide information on benefits beyond the effect on walking speed
* In April 2013 NHS England, which funds specialist services, issued a policy statement in which it said " Fampridine is not considered to be a cost-effective use of NHS resources
39
Teriflunomide
* Dihydro-orotate dehydrogenase inhibitors, blocks pyrimidine synthesis
* Oral drug treatment for RRMS (experimental)
* Teriflunomide stops certain immune cells for dividing
* Results from phase II studies indicate that teriflunomide has similar effectiveness to current disease modifying treatments
* The most frequent side effects are
* Nausea and diarrhoea
* Increase liver enzyme
* Hair thinning
40
Laquinimod
* Believed to alter balanceof Th1 and 2 lymphocyte and cytokine profiles
* Modulates pro-inflammatory immune responses and interferes with cell trafficking, as well as potentially acting directly in the central nervous system to limit demyelination and axonal injury
* Phase III needed adjustment to receive a significant results
* Few serious side effects have occurred in clinical trials. The most common side effect have been
* Back pain
* Increased liver enzyme
* Headache
41
Sativex
* Sativex (nabiximols) is the first cannabis-based medicine to be licensed in the UK
* Used for MS -related spasticity when a person has shown inadequate response to other symptomatic treatments or found their side effects intolerable
* Can be used in addition to other anti-spasticity medication
* Prior to gaining a licence for use in MS -related spasticity, Sativex had been studied for its effects on a number of MS related symptoms including: spasticity and spasms, pain, bladder symptoms, tremor, and sleep disturbance
* Can only be prescribed by a specialist doctor with experience of treating MS spasticity
* Use currently limited to people who respond within 4 weeks of treatment. If no clear improvement in spasticity -related symptoms, treatment is stopped
* Sativex has not been assessed by NICE
