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Flashcards in Multiple Sclerosis Deck (97):
1

What is the definition of MS?

A chronic inflammatory multifocal, demyelinating disease of the central nervous system of unknown cause, resulting in loss of myelin, and oligodendroglial and axonal pathology.

  • We know that autoimmune mechanisms play a key role in determining inflammatory lesions
  • But also the axonal degeneration and loss, which is the pathological basis of irreversible disability, represents a landmark features
  • Although historically MS has been regarded as a white matter disease, it is now well establish that these pathological processes involve also the grey matter (esp. the inflammation and neurodegeneration) 

 

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2

Give an introduction to the epidemiology of MS, and the prevelance in the UK

It affects around 2.5 millions individuals around the world and it is considered one of the most common causes of disability among young adults. It has an uneven geographic distribution, with a higher prevalence among white people of Nordic origin, living at high latitudes. This is called the latitude effect.

 

MS Prevalence in the UK.

Up until 2010 there were more than 120,000 cases in the UK, which had one of the highest incidence and prevalence among north European countries, along with Sweden and Denmark.

  • 258/100.000 women (affects women more than men)
  • 113/100.000 men

Incidence is 9.64/100.000 per year.

3

Discuss the mortality associated with MS

It is important to note that life expectancy among people with MS is not dramatically reduced compared to the general population on average reduced by 7-14 years. As the disease is usually diagnosed around the age of 30, the disease can last up to 40-50 years. It is the poor quality of life because of the unremitting disability that exerts the most significant burden on patients.

4

Quantify the social impact of MS

  • Probability of remaining in active employment after MS onset:
    • At 15 years: 31% MS patients vs. 89% controls
  • Probability of remaining in a relationship after MS onset:
    • At 24 years: 33% MS patients vs. 53% controls 

5

Give an introduction to the aetiology of MS

The cause of MS remains largely unknown. It is hypothesised that multiple factors contribute to its aetiology. The disease probably develops in genetically susceptible populations and it is triggered by the exposure to environmental factors, including sun exposure and viral infections.

 

Various factors influence MS aetilogy such as:

  • The latitude effect (more likely the further north of equator)
  • The viral hypothesis (EBV likely culprit)
  • The role of Vit-D (low Vit-D)
  • Time of expsosure (seasonal variation)
  • Genetic factors
  • The role of hormones

 

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6

Describe the Latitude effect in the aetiology of MS

The disease has a distinct latitudinal variation: the risk of developing the disease is higher in areas at high geographic latitude. This rule can be applied to the world distribution, as we looked at previously, but also within countries. For example, there are more cases of MS in Scotland and Northern Island, in comparison to England and Wales.

7

Describe the role of Vitamin D in the aetiology of MS

The latitude effect led to hypothesis that the incidence of MS might be related to the sun exposure. If we look at the UVB worldwide intensity, this is well known to be lower at higher altitudes. The striking similarities with the MS worldwide distribution strongly support a correlation between low UVB intensity and risk of MS. This correlation is possibly mediated by low vit D level, resulting from the low sun exposure UK, Scandinavian countries,

 

These observations support the hypothesis that vit D deficiency plays a primary role in determining the risk of MS.

Supporting evidence:

  • People with low vit D oral intake are more likely to develop the disease.
  • Low Vit D level probably associates with higher probability of having MS attacks (more severe disease course).

 

However, it is important to take into account the methodological difficulties of carrying out such studies. There any many confounding factors that affect serum vitD levels; smoking, intake of other nutrients, endocrinological diseases all influence vitamin D levels. Furthermore, black people are more likely to be vitamin D deficient, but have a lower incidence of MS in comparison to Caucasian people.

 

Despite it remaining a grey area, it is common practice recommending daily vit D dose to patients with MS, as this might exert a protective effect.

 

An observation from Norway offers interesting insight on the potential role of Vit D. In Norway the north-south gradient is inverted, as the incidence of MS is lower in the north, among people living by the coast. It has been demonstrated that the coastal communities spend more time in outdoor activities and consume large quantities of oily fish, which probably compensate for the lack of vit D.

8

Discuss the evidence of the role of Vitamin D in the aetiology of MS

Supporting evidence:

  • People with low vit D oral intake are more likely to develop the disease.
  • Low Vit D level probably associates with higher probability of having MS attacks (more severe disease course).

 

However, it is important to take into account the methodological difficulties of carrying out such studies. There any many confounding factors that affect serum vitD levels; smoking, intake of other nutrients, endocrinological diseases all influence vitamin D levels. Furthermore, black people are more likely to be vitamin D deficient, but have a lower incidence of MS in comparison to Caucasian people.

 

An observation from Norway offers interesting insight on the potential role of Vit D. In Norway the north-south gradient is inverted, as the incidence of MS is lower in the north, among people living by the coast. It has been demonstrated that the coastal communities spend more time in outdoor activities and consume large quantities of oily fish, which probably compensate for the lack of vit D.

9

Describe how the time of exposure affects the susceptability of MS

Although it appears clear that environmental factors influence the MS risk, it remains largely unclear when in life these factors affect the individual susceptibility. For instance, vit D deficiency is quite diffuse, but only few eventually develop MS.

 

John Kurtzke was a pioneer with his studies on MS people migrating from high risk to low risk area or the other way round.

  • He observed that those migrating after the age of 15 from north Europe to South Africa, which is an area of low risk, retained their original high risk of MS. Whereas when migration occurred before the age of 15, they would acquire the risk of the country they were moving too.
  • Therefore, it is hypothesised that there exists a period of susceptibility early in life.

 

Whether the age of 15 is the true cut off remains extremely controversial. For instance, some studies seem to suggest that environmental factors might act in utero.

  • This is the so called month of birth effect, supported by observations that there is a higher incidence of MS among those born in May and lower incidence among those born in November.
  • This is possibly because of the low sunlight exposure and vit d during pregnancies carried out in autumn/winter .
  • In line with this hypothesis, some studies suggest that MS activity exhibits a seasonal variation. New MS lesions at MRI are more likely to occur during summer time. MS attacks are more frequent during spring, as recently demonstrated in a very large study. Possibly explained by low vit D levels in previous winter months.

10

Describe the viral hypothesis in the aetiology of MS, and what evidence there is for it.

The virus hypothesis was initially proposed again by Kurztke, following the so-called epidemic of MS in the Faroe Islands. Here MS seems to have appeared for the 1st time only after British troops during the 2nd WW occupied the islands. Since then its been hypothesised that MS is a transmissible infection, or at least it is triggered off be a virus.

 
Among many viruses, EBV is the most likely candidate. (Note: 90-95% of human beings are EBV seropositive)

Evidence:

  • MS and infective mononucleosis share strikingly similar geographic and socioeconomic distribution
    • Latitude gradient
    • High income populations
    • Women more commonly affected
  • In addition, the risk of MS is strongly affected by EBV sero-status. Most interesting and compelling evidence linking EBV to MS.
    • It has been claimed that MS is virtually absent among EBV seronegative individuals (OR [odds ratio] = 0.18)
    • The risk of MS increases dramatically (OR [odds ratio] = 13) among seropositive. The problem is that 5-10% of world population is EBV negative, therefore it is difficult to establish a direct correlation.
  • Studies also showed that both the risk of MS and the disease severity are correlated with anti-EBNA abs titres (EBV titre/level)
  • More importantly, a previous history of mononucleosis associates with a 3 folds higher risk of MS. 

11

Describe the role of genetics in the aetiology of MS

No one gene has been implicated in MS. However, we know that genetic factors contribute 30% of the risk in developing MS. First-degree relatives have 10-25 times greater risk of MS than the general population. This risk correlates directly with the degree of kinship.

 

Further supporting evidence come from twin studies from different populations, consistently showing that a monozygotic twin of an affected individual has much higher risk of developing the disease than a dizygotic
Twin. Concordance rates:

  • 25-30% monozygotic twins
  • 2-3% dizygotic twins
  • 1.9% non-twin siblings

 

HLA-class ΙΙ genes exert the strongest effect, accounting for 20- 60% of the genetic risk, with a predominant role played by the HLA-DRB1*15 gene.

12

Discuss the role of hormones in the aetiology of MS

Finally, it is also believed that hormones might contribute to the disease susceptibility. At the beginning of last century the disease was equally distributed among men and women. However, the incidence of MS has steadily increased only among women and it almost doubled over the past 50 years. This was confirmed in two separate independent studies carried out in Canada and Denmark. It is now commonly accepted that that women are twice as likely then men to have MS

 

In support of a role of hormones, epidemiological studies demonstrated that the disease activity, in terms of
frequency of attacks, decreases during pregnancy and sharply increases the first 3 months after partum.

 

This can have practical implications as women with MS, who have stopped the therapy during pregnancy, often choose to avoid breastfeeding in order to restart the therapy immediately, as they fear a disease rebound after partum.

13

Summarise the types of clinical manifestations of MS

Relapses and progression are the two main clinical manifestations of MS. They are completely opposite phenomenon. As relapses are acute symptoms which, by definition, have to last more than 24 hours, and can be followed by remission. Whereas, progression (which shouldn’t be confused with worsening), is an insidious
relentless phenomenon leading to irreversible disability. In fact it requires retrospective assessment for at least 1 year.

This pattern of relpase and remission can be categorised into sub-types of MS.

14

Describe the concept of relapse in MS 

 

The demyelinated plaques represent the pathological substrate of relapses. These are areas of inflammation, with loss of myelin, which are scattered around the CNS. The inflammation leads to demyelination, which causes delay of the nerve impulse and eventually the neurological symptoms. 

 

Relapses are most of the time followed by remission, as a result of remyelination. As you can see from natural history registries spontaneous recovery occurs in most of cases, especially following the early attacks. Remission can occur over weeks and, in some cases, even after 12 months. During the late stage, remission is less likely.

 

Symptoms occurring during a relapse are extremely variable. The most common manifestations at onset are:

  • Optic neuritis
  • Motor weakness
  • Sensory disturbances 
15

What are the symptoms of MS, and to what lesion do they correlate to?

Optic neuritis:

  • Monocular vision loss

Spinal cord lesion:

  • Weakness of limbs with spasticity and hyper-reflexia
  • Paraesthesiae pain or sensory loss in limbs or trunk
  • Lhermitte's sign (electric shock radiating down back and triggered by neck flexion)
  • Urinary urgency and incontinence
  • Sexual dysfunction

Brainstem lesion:

  • Diplopia
  • Paraesthesiae, pain (neuralgia) or numbness of face or tongue
  • Vertigo and nsytagmus
  • Dysarthria

Cerebellar lesion:

  • Incoordination of limbs
  • Ataxic gait

Cerebral lesion:

  • Impairment of concentration or memory
  • Hemiparesis
  • Hemi-sensory loss
  • Visual field defect
  • Seizures
  • Psychiatric disturbances
  • Severe fatigue 

16

What are the subtypes of MS?

MS can present with different clinical phenotypes, which are characterised by relapses and progression in combination or alone. These are split into Relapsing-Remitting (RR), Secondary Progressive (SP) and Primary Progressive (PP).

 

  • Clinically Isolated Syndrome (CIS): is a first episode with neurologic symptoms caused by inflammation and demyelination in the central nervous system — which must last at least 24 hours — but does not yet meet the criteria for a diagnosis of the disease.
  • Relapsing Remitting Multiple Sclerosis (RRMS):  This is the most common form of MS with clear defined phases of relapse (repeat attacks or exacerbations), with progressive worsening of nerve functions with each attack, followed by phases of relief (or remission) where normal conditions are restored partially or completely.
  • Primary Progressive Multiple Sclerosis (PPMS):  This represents a condition with steady progression without early relapses or remissions, and temporary periods of stability.
  • Secondary Progressive Multiple Sclerosis (SPMS): This follows RRMS, with continued relapses and progressive neurological damage. Most patients will eventually transition to a secondary progressive course, with worsening of nerve damage, with or without remissions.

17

Describe the disease course of RRMS

RR MS is the most common form of MS (80-85%) with an age of onset around 30 years. Most patients start out with RR MS, but eventually progress to secondary progressive MS – this switch is completely unpredictable (after average of 15 years – but this is just an average, some cases never occurs or occurred after 40 years).

 

Common onset symptoms:

  • Optic neuritis
  • Sensory disturbances

 

Annualised relapse rate decreases over time (17% less every 5 years). Regression to the mean - 70% at least 5 years relapse-free period. The frequency of the attacks decreases over time, due to the regression to the mean phenomenon.

 

It is commonly believed that during the early phase of the disease, when relapses are more frequent, focal inflammatory phenomenon dominate in the pathophysiology of the disease. By the time the disease convert

to the SP phase, the axonal loss takes over and drives the accumulation of irreversible disability which characterises progressive MS.

18

Describe the epidemiology of PPMS and SPMS

Primary and secondary progressive MS start around the same age. Age at onset ~40 years each, leading to a controversial theory that PP MS has asymptomatic relapses. However, the sex ratio is different between the two:

  • SS MS = 2-3:1
  • PP MS= 1.3:1

19

Discuss the approach to diagnosing MS

The key to all diagnostic criteria is the absence of an alternative diagnosis in the context of an appropriate clinical presentation. It is a primarily clinical diagnosis which requires the fulfillment of 2 criteria for the CNS lesions:

  • Dissemination in time (DIT)
  • Dissemination in space (DIS)

 

This can be demonstrated by evidence from the history and the clinical examination, and can be supported by imaging/tests:

  • Radiological evidence (MRI)
  • Laboratory analysis (CSF)
  • Electrophysiology (evoked potentials) 

20

How can radiological tests be used to diagnose MS?

The MRI is an important tool for the diagnosis that can be used for demonstrating the dissemination in time and space of the lesions. The 4 typical locations where lesions occurs are:

  • Periventricular
  • Subcortical
  • Infratentorial (midbrain)
  • Spinal cord

The dissemination in time requires demonstration of new lesions compared to previous imaging, or the simultaneous presence of GAD enhancing and non enhancing lesions. 

Note: lesions as seem on an MRI look very similar to clots that happen in old patients. So it’s important to note where the lesions are, as it gives you a better idea of whether it is MS or clotting. Obviously clinical background is very important too.

 

New MRI lesions occur 5-10 more frequently than clinical attack. Most lesions are clinically silent.  This is the clinical-radiological paradox. Roughly estimated that a relapse occurs every 10-15 lesions.


We use gadolinium  (GAD) to enhance MRI. GAD is important because it implies damage of BBB, so GAD has entered the brain and taken up by the lesion. So if lesion lights up with GAD, it means the lesion is no older than 6 weeks, because after 6 weeks the BBB repairs and GAD can’t get into brain. This is used to identify newer/fresher lesions.

21

How can electrophysiological tests be used to diagnose MS?

Electrophysiology - visual evoked potentials (VEP) are helpful because they show evidence of dissemination in

space – e.g. if patient presents with arm weakness, can measure VEP in eyes and find a sub-clinical level of slowing down, indicating inflammation and demyelination even without the patient having noticed any symptoms from it.

22

How can CSF analysis be used to diagnose MS?

CSF analysis can be supportive of the MS diagnosis by showing:

  • Increased production of Immunoglobulin in CSF
  • Oligoclonal bands (OCB) in CSF only (not in serum, as that would indicate a global autoimmune disease rather than CNS confined one) 

 

White cells:

  • Normal or mildly increased (10-20 cells/mm3)
  • Note: if >50 WBC, suspect alternative diagnosis
  • 90% lymphocytes, 5% PMN [polymorphonuclear leukocytes - e.g. neutrophils]

Proteins:

  • 2/3 cases normal
  • 1/3 cases minor increase (0.5-0.7g/L)

IgG oligoclonal bands:

  • Positive in CSF only (unmatched with serum)
  • (If matched in serum it means the oligoclonal bands are from a different source, so unlikely to be MS)
  • Positive in >95% of clinically definite MS 

23

What differential diagnoses can share a similar symptomology with MS?

Main possibilities out of many CNS inflammatory disorders can be categorised into:

  • Systemic immune diseases affecting the CNS:
    • Neurosarcoidosis
    • Systemic lupus erythematosus (Neuro-lupus)
    • Anti-phospholipid syndrome
    • Sjögren’s syndrome
    • CNS vasculitis exist
    • Behçet’s syndrome
  • CNS-specific inflammatory syndromes
    • Acute disseminated encephalomyelitis (ADEM)
    • Neuromyelitis optica (NMO) 

24

Describe the prognosis of MS

We are unsure what affects the prognosis. The patient may have end up experiencing a relatively benign form of MS with little or no disability after 15 years, or a more malignant MS with severe disability 5 years after onset. The majority of patients fall within the middle ranges.

 

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25

How is disability mesaured in MS?

Disability here is measured using the Expanded Disability Status Scale (EDSS):

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26

What proprtion of patients convert from CIS to MS?

CIS is when there is only one lesion/symptom. It is not MS as MS needs two events separated by time and space. There is a risk of converting CIS to definite MS. The risk is extremely variable based on initial symptom. However, having a normal brain MRI is a good sign as only 20% then convert.

27

What are the good and bad prognostic indicators of MS?

No feature can predict the outcome in the single patient.

 

Good prognostic indicators:

  • Young onset
  • Female
  • Optic neuritis or only sensory symptoms at onset
  • Low frequency of early attacks
  • Complete symptom remission
  • Long first inter-attack interval

 

Bad prognostic indicators:

  •  >40 years at onset
  • Male
  • Insidious pyramidal tract involvement
  • Prominent cerebellar involvement
  • Frequent early attacks
  • Rapid development of fixed disability

 

Age at onset (old age) and a primary progressive course from onset are the most adverse prognostic factors. 

28

What are the causes of death, and secondary complications of MS?

Causes of death among MS patients

Because of slow disease progression, many MS patients die of other causes, such as cardiovascular disease or cancer. A considerable number also commit suicide because of the prospect of such a debilitating life.

 
Secondary Complications of MS
  • Depression
  • Urinary tract infection
  • Limb contractures due to spasticity
  • Gastroparesis and intestinal pseudo-obstruction
  • Accelerated lumbar spondylosis due to abnormal posture
  • Aspiration pneumonia and bronchopneumonia
  • Pulmonary thromboembolism
  • Pressure sores 
29

What are the four main types of pathology in MS?

  • Inflammation
  • Demyelination
  • Axonal Loss
  • ?Neurodegeneration (grey matter atrophy)?

30

Outline the evidence that supports the autoimmune hypothesis (or immune involvement) in MS

The autoimmune hypothesis in MS is supported by:

  1. Immunopathology of lesions
  2. Susceptibility associated with immune response genes
  3. CSF immunological abnormalities
  4. Subtle alteration of blood T cell functions
  5. Animal models of autoimmune disease
  6. Comorbidity and similarities with other autoimmune diseases
  7.  Response to immuno- suppressive and modulatory therapies
  8. Role of EBV in aetiology

31

Describe the immunopathology of lesions in CNS

  • By immunohistochemistry, we usually see CD4+ and CD8+ T cells infiltrates in the perivascular cuffs and intra-parenchymal areas.  

  • B-cells are also found in perivascular and meningeal locations where they can aggregate or form part of ectopic lymphoid follicles.

  • We also see lots of myelin-laden macrophages in and around lesions.

 

T-lymphocyte infiltration is seen during the very early stages of lesion formation and even during active demyelination only few T-cells are found in the brain parenchyma. B-lymphocytes may also be found in small numbers. The majority of inflammatory cells in the MS lesion are monocytes and macrophages.

The foamy macrophages contain numerous lipid droplets, stained here with oil red-O, which represent myelin breakdown products.

32

How is the immune system activated in MS?

Lymphocytes require activation to migrate into tissues, including CNS. The events leading to pathological immune activation in MS are unclear. Possible mechanisms induce infection or cross-reactivity with microbial, especially viral antigens (EBV - in particular). 

There are 4 major steps of the pathogeneic cascade:

  1. Activation of autoreactive T cells in the periphery; T cells that encounter their corresponding antigen associated with MHC secrete interleukin-2 (IL-2), which serves as an autocrine T-cell activator.
  2. Transmigration of proinflammatory T cells and monocytes through the BBB; Activated T cells readily cross the BBB, a process that is mediated by interaction of VLA-4 on the T-cell surface and VCAM-1 on the brain vascular endothelium
  3. Amplification of local inflammation and activation of resident APCs, such as microglia;  Infiltrating T cells increase the permeability of the BBB secretion by MMPs, which degrade the extracellular matrix. Activated immune cells in the brain interact with their responsive antigen presented by macrophages or microglia and secrete cytokines and chemokines that further permeablise the BBB and further reinforce the immune response.
  4. Effector stage of the disease, with damage of oligodendrocytes, myelin sheath and axons:

33

How does the immune system cause damage in MS?

Helper T cells (CD4) and cytotoxic T cells (CD8) are the predominant types of T cells in MS lesions.

The CD4 cells secrete TH-1 proinflammatory cytokines (IL-2 and IFN-γ), which further activates the immune response and may cause tissue damage.

Recent evidence has demonstrated that CD8 T cells can kill oligodendrocytes in culture and can also transect axons.

Macrophages are the predominant cell type along the periphery of lesions and secrete TNF-α and oxygen free radicals that lead to tissue damage.

B cells differentiate into plasma cells and secrete antibodies that can bind to their target antigen and bind complement, ultimately leading to myelin breakdown.

The targets of this immune cascade are believed to be directed at the oligodendrocytes and the neuron axons. The oligodendrocytes are damaged and lysed by a combination of cytokines released during the inflammatory reaction and possibly by direct cellular contact mediated through the Fas pathway leading to apoptosis. Axons may be damaged and transected by direct attack by inflammatory cells and their cytokines, or by loss of trophic support or protection provided by the oligodendrocytes and myelin membranes respectively.

In addition to the negative actions of the immune system, there is growing evidence that immune cells secrete cytokines and neuroprotective factors that may actually have trophic properties to neurons.

34

List the cells involved in MS autoimmunity

There is a very complex picture of autoimmunity - heterogeneity of Immune cells Involved in MS. Some are pro-inflammatory and others anti-inflammatory:

  1. Pro-inflammatory CD4+ TH1 cells
  2. Pro-inflammatory CD4+ TH17 cells
  3. Anti-inflammatory CD4+ Th2 & T reg cells
  4. Cytotoxic CD8+ T cells (CTLs)
  5. Pro-inflammatory CD8+ MAIT cells
  6. Regulatory CD8+ T cell subsets
  7. B-cells
  8. Microglia 

35

What is the role of Th1 cells in the automimmunity of MS?

IFNγ released by Th1 induces MHC class II expression in the CNS, triggers production of chemokines that attract macrophages and monocytes and activates macrophage function.

36

What is the role of Th17 cells in the automimmunity of MS?

CD4+ Th17 cells mainly produce IL-17A and IL-17F but also produce IL-22 and GM-CSF. They are epigenetically imprinted by RORγt, and require IL-23 for differentiation into pathogenic cells. Other signaling involved in their differentiation: IL-6, TFG-β, IL-1β, IL-21. They also express Homing Receptors CCR6 and CCR4.

 

Increased numbers of IL-17 transcripts and of IL-17 producing CCR6+ cells are detected in post mortem brain lesions of MS patients, in particular in chronic compared with either acute lesions or control.

 

It is thought that Th17 cells in particular play more of a role in initiating the autoimmune response in comparison to Th1 cells. This is because EAE mice deficient in IL-12,IFNγ  and TNF (Th1-mediated inflammation) can still develop severe EAE. However, IL-23-deficient mice are completely resistant to EAE. Transfer of Th17 cells seemed to induce more severe EAE than transfer of Th1

37

What is the role of Th2 and Treg cells in MS?

Th2 cells secrete anti-inflammatory cytokines (IL4, IL5, IL13) fight inflammation and slow it down or possibly prevent it.

Function of peripheral CD4+ Treg cells seems to be impaired in MS patients as they have decreased ability to inhibit the activation of myelin- specific T cells in the periphery

CD25, component of the IL-2 receptor and essential for Treg development, has been identified as a MS susceptibility gene in GWAS

38

What is the role of CD8 cells in MS?

We think they are involved after the initial phases mediated by CD4 cells. Frequency of CD8+ T cells recognizing myelin proteins is higher in the peripheral blood of patients with MS as compared to healthy controls.

 

CD8+ T cells are easily demonstrated at the edge of the inflammatory lesions and in the perivascular regions in post-mortem brain tissue of patients. T cell receptor analysis of the CD8+ T cells found in the lesion revealed clonal expansion of this population. MS lesion likely to be initiated by CD4+ T cells whereas amplification and damage is mediated by CD8+ T cells.

39

What is the role of B-cells in MS?

Source of pathological antibodies (IgG oligoclonal bands) found in the vast majority of MS patients’ CSF. IgG recognize components of myelin, axons or neurons contributing to demyelination or axonal damage.

  • Can act as antigen-presenting cells (APCs) for T cells specific for CNS antigens
  • The collaboration between CNS antigen-specific B and T cells was responsible for an aggressive form of autoimmune disease in a mouse model of MS

 

Ig are a component of the demyelinating plaques and of the B cell infiltrates detected in the MS post- mortem brain. Can have immuno-regulatory function (Transitional B cells) producing suppressive cytokines IL-10 and influencing regulatory T cell activity and possibly modulating the mechanisms leading to axonal injury.

 

In MS lesions (and CSF) there are clonally expanded B cells. Ectopic B cell follicles develop in meninges of patients with SP- MS. BAFF (B cell activating factor, also named BLyS), a member of the TNF family, is overexpressed in MS tissue by astrocytes. Subpial B cell follicles can re-stimulate inflammatory T and B cells. These ectopic B-cell follicles will also secrete of inflammatory mediators diffusing to the brain cortex.

40

What is the role of microglia in MS?

Microglia are part of the innate immune system. They are the first line of defense for CNS , responsible for maintaining its homeostasis (against any kind of injury).

 

M2 anti-inflammatory/regulatory phenotype is sustained in homeostatic conditions by neurons that actively produce anti-inflammatory signals aimed at inhibiting the acquisition of the inflammatory M1-like phenotype.

  • Sustained by Th2/Treg during CNS inflammation that both stimulates the acquisition of M2-like phenotype by microglia and attenuates the inflammatory cycle induced by M1-like; Th2 also contribute secreting IL4, which favours the production of neurotrophic factors by M2-like microglia and supports neuronal survival.

M1 inflammatory phenotype is induced after tissue injury or in autoimmune/neurodegenerative disorders by injured neurons that produced pro-inflammatory mediators. Activated microglia contributes to MS lesion development through phagocytosis, secretion of cytokines (TNF-α), oxidative radicals (ROS, RNS) that promote neuronal death.

 

In an MS lesion, you see lots of macrophages. Within an active region of MS, 45% of macrophage-like cells in active MS lesions are derived form the resident microglial pool, while the rest is from monocytes.

 

However, in an aminal model of MS (EAE), it suggests that monocyte derived macrophages associated with Nodes of Ranvier initiate demyelination, while microglial derived macrophages appear to clear debris.

41

How to Immune Cells get to the CNS?

The CNS is an immune privileged compartment, which is carefully shielded from potentially harmful immune reactions. There is not a classic lymphatic drainage of the parenchyma. To get to the CNS leukocytes must pass either of the two physiological barriers shielding the CNS:

  1. The Blood-Brain Barrier
  2. The Blood-CSF barrier

The multistep adhesion cascade:

  • Expression of cell adhesion molecules on the endothelium
  • Immune cells tether to the endothelium, roll on it, and adhere to the cell adhesion molecules
  • Then, they extravasate into the tissue and move by chemotaxis to the affected area

The Virchow-Robin spaces (VR spaces) also known as perivascular spaces, are spaces surrounding the walls of arteries, arterioles, veins, and venules as their course from the subarachnoid space through the brain parenchyma. They are spaces where immune cells reside. These spaces do not communicate directly with the subarachnoid space but they are filled with interstitial fluid which behaves similarly to CSF in MR. If many immune cells are extravasating, they can make the space bigger, occupy the space and get through the brain tissue (“outside-in hypothesis”).

 

In a pathological setting, lymphocytes are in direct contact with CSF. They can get out of the blood and into the CSF easily move around the brain using the CSF. Then they can go back inside the brain tissue. The blood-CSF barrier is at the site of the choroid plexus.

 

To get into the CNS, the immune cells move from the Choroid plexus → Sub-arachnoid space→ Pia mater→ Brain cortex. 

42

Explain the Susceptibility Associated with Immune Response Genes in MS

Whole genome scans in large populations have confirmed associations with immune genes, including:

  • HLA-class II (DRB1*1501, DRB5*0101; DQw6) - strongest
  • IL-7 Receptor
  • IL-2 Receptor alpha
  • CD58

 

The 6p21-23 is an area contains MHC class I, II and III, and also MOG

  • This has strong linkage and genetic association with susceptibility to MS, specifically with the class II, HLA-DRB1*1501 allele
  • Dose-effect on susceptibility
  • Possible modifier effects by genes mapped in the class I region
  • Possible assoc. with disease progression early in the course of the disease

 

GWAS studies

GWAS studies find that that MHC DRB1*1303, DRB1*03.01 and DRB1*15.01 increased risk. While MHC A02.21 reduced risk. Furthermore, many genes coding for T cell transcription factors/proteins were implicated in MS susceptibility. Apoptosis genes were also involved. Understanding what genes are associated with MS can help with development of gene therapy

  • There were other GWAS's in 2013 and 2014-2015 
43

How do CSF Immunological Abnormalities point to the immune involvement in MS?

Leukocyte counts can be normal but are often mildly increased above the normal of ≈3000 leukocytes/mL in the CSF. 

  • In MS 80% of total CSF cells are T-cells (45% in blood), mainly memory T cells (up to 30% of CSF cells during inflammation), 5% are monocytes, ≤ 1% B cells, plasma cells.
  • There can be a minor protein increase
  • Increased production of IgG in the CNS

Importantly, CSF oligoclonal bands are detected in >90% of MS cases and are stable over years 

44

How do Subtle Alterations in Blood T-Cell function point to the immune involvement in MS?

  • Slightly increased frequency and reduced requirements for activation of T cells responding to myelin antigens
  • Reduced activity of (CD4+/CD25+) regulatory T cells
  • Prevalence of T helper 1 over T helper 2 cytokine secretion by myelin antigen-specific T cells 

45

How do Animal Models point to the immune involvement in MS?

Experimental allergic encephalomyelitis (EAE): is induced by peripheral immunization with myelin protein antigens. Mediated by CD4+ myelin-specific T cells. These initiate the inflammation.

46

How do Co-morbities point to the immune involvement in MS?

Patients with MS have increased incidence of some autoimmune conditions (best evidence is for thyroiditis) and asymptomatic positivity for auto-antibodies. MS share similar features sich as high incidence with females, and initially relapsing course, with Rheumatoid Arthritis, Systemic lupus Erythematosus, autoimmune thyroiditis and other autoimmune disorders.

 

Genetic risk variants for related autoimmune diseases (Fortune et al.)

2015 analysis of four autoimmune diseases - T1D, RA, celiac disease and MS - identified 90 regions that were associated with at least one disease, 33 (37%) of which were associated with 2 or more disorders.

For 14 of these 33 shared regions, there was evidence that the causal variants differed

47

How does response to immunosuppressive and immune-modulating therapies point to the immune involvement in MS?

MS acute relapses maybe improved by high-dose corticosteroid administration. The clinical course of MS is attenuated [reduced in virulence] by:

  • Immuno-modulatory treatment (interferon-beta, GA, Gilenya, Dimethyl Fumarate, Teriflunomide)
  • By treatments blocking immune cell entry to the CNS (anti-alpha- 4 integrin: natalizumab)
    • Alpha-4 integrin plays a key role in T-cell transmigration. Therefore natalizumab locks the lymphocytes in the circulation.
  • Or modulating/neutralizing the activity of immune cells (daclizumab, alemtuzumab)
  • And by immuno-suppressive and cytotoxic agents (Mitoxantrone) 

48

Outline the main categories of treatments for MS

  • Education and counselling
  • Management of acute attacks
  • Prevention of disease activity (disease modifying treatments)
  • Symptomatic therapy
  • Physical therapy
  • Treatment of complications 
  • ?cure

49

How is education and councelling used in the treatment of MS?

This involves giving the patient information on MS and access to MS societies, web sites. It is important that patients maintain a well-balanced diet with regular exercise, avoid excessive heat. They may have to make work or habits adjustment and also need psychosocial and multidisciplinary management.

50

How are acute relapses managed?

An acute relapse refers to an episode of neurological disturbance, of the kind seen in multiple sclerosis, that lasts for at least 24 hours, and for which there is no other cause such as fever. [from http://pmj.bmj.com/content/81/955/302]

Neurological symptoms caused by heat or fever (pseudo-relapses) need to be excluded.

 

Decide on necessity for treatment. Are the symptoms disabling? Taking into account how the patient copes with the physical or psychological symptom.

 

The standard treatment given to accelerate recovery involves:

  • High-dose IV methylprednisolone (500-1000 mg/day x 3-5 days usually given in day hospital setting
  • But can also be given orally (La Page et al, Lancet 2015)
  • Standard-dose oral steroids (e.g. Prednisone 60mg od) not recommended 

51

What are the commonest problems in MS that bother patients?

The common symptoms that bother patients are:

  • Spasticity - muscles feel stiff, heavy and difficult to move. Involve spasm where muscle stiffens suddenly causing limb to move.
  • Sphincter disturbances
  • Pain - neuropathic pain.
  • Fatigue
  • Depression
  • In-coordination and tremor
  • Sexual dysfunction 

52

How is spasticity treated?

Spasticity can be treated with stretching and physical therapy. Pharmacological agents include:

  • Baclofen (muscle relaxant; GABA antagonist)
    • When given orally limited by side effects: drowsiness and hypotonia
    • Can be given intrathecally with implanted pump
  • Tizanidine (muscle relaxant; adrenergic antagonist)
  • Benzodiazepines
  • Botulinum toxin - More selective effect 

53

How is pain in MS treated?

It is important to establish the origin of pain. The type of pain commonly experienced in MS is neuropathic pain. Therefore narcotics and NSAIDs are ineffective and not recommended for neuropathic pain.

  • Paroxysmal pain can be treated with:
  • Chronic dysaesthetic pain (unpleasant abnormal sense of touch):
    • Amitriptyline 20-100 mg/day
    • Other antiepileptic and antidepressant drugs can be effective or better tolerated

54

How is fatigue in MS treated?

We unfortunately only have limited options in treating their fatigue. At the moment, we focus on “Energy savings” (day planning, devices etc.). Pharmacologically:

  • Amantadine (unconfirmed)
  • Some antidepressants      

55

How is mobility impairement treated in MS?

Mobility is a very important issue for MS patients. It is the leading concern for MS Patients. Our current approaches to mobility impairment include:

  • Encouraging increased activity straight from time of diagnosis. This can be tailored to ability.
  • Physiotherapy - Strengthening, Stretching, Re-training
  • Orthotics/aids
  • Functional stimulation
  • Managing spasticity

56

List the disease-modifiying drugs of MS

  • Interferon-β
  • Glatiramer Acetate
  • Fingolimod
  • Dimethyl Fumarate
  • Teriflunomide
  • Natalizumab
  • Alemtuzumab

  • Ocrelizumab

    • Daclizumab

57

How is interferon-b used to treat MS?

Often regarded as "First line" treatment.

  • Preparations: Interferon-β1b (Betaseron/Betaferon) and Interferon-β1a (Avonex and Rebif). Interferon-β1a is the human form and has higher specific activity than Interferon-β1b.
  • Subcutaneous/intramuscular injections every other day, three times a week or once a week.

58

What is the mechanism of action of inteferon-β?

IFN β is thought to act on several components of the immune response. Overall it:

  • Suppresses lymphocyte proliferation - due to downregulation of MHC Class II receptors, and other co-stimulatory receptors such as CD80 and CD28. 
  • T-helper immune deviation - increases the TH2 arm of the immune response and counters the effect of the TH1 arm. Treatment with IFN-β reduces the amount of TH1 proinflammatory cytokines (e.g., IL-2, IL-12, and IFN-γ) and shifts the immune response toward a TH2 profile, releasing IL-4 and IL-10.
  • Downregulation of MHC expression - MHC Class II receptors are upregulated after antigens are processed by APCs. These APCs include macrophages, microglia, B-cells and follicular cells. The MHC Class II molecules interact with, and activate T-cells via the TCR. The levels of MHC class II are upregulated by IFN-γ secreted by T cells.
  • Interference with cell adhesion. When T cells become activated, they upregulate cell surface expression of MMPs and VLA-4 (adhesion molecule that interacts with VCAM-1 on endothelium), which helps them migrate out of the vascular lumen and into the tissues.  IFN-β has also been demonstrated to decrease the expression of VLA-4 on the cell surface of T cells and to reduce the secretion of MMPs by T cells.

59

What are the pivotal trials in INF-b and what do they show?

  • The IFNB MS Study Group trial (comparing high and low doses of IFN beta-1b to placebo)
  • Multiple Sclerosis Collaborative Research Group trial (comparing once weekly IFN beta -1a to placebo)
  • PRISMS trial (comparing 22 and 44 mcg subcutaneous IFN beta-1a to placebo)
  • INCOMIN trial (comparing once weekly IFN beta-1a to every other day IFN beta-1b)
  • Danish MS Group trial (comparing once weekly subcutaneous IFN beta-1a to every other day IFN beta 1-b)
  • ADVANCE trial (comparing peginterferon beta 1-a to placebo)


The trials showed that:

  • Increasing the frequency of INF-β produces superior clinical responses.
  • IFNβ-1b and subcutaneous IFNβ-1a decreased ARR (relapse rate) by 34% when compared to placebo in RRMS.
  • Significantly positive effect on imaging outcomes, mainly in having fewer new and gadolinium enhancing lesions in RRMS.
  • Significant delay of sustained progression in RRMS but methodological concerns.
  • Inconsistent results on progression of disability (IFNb 1a>1b) in SPMS
  • Delayed and reduced risk of conversion to MS by up to ~50% in CIS (Clinically Isolated Syndrome).
  • Neutralising antibodies develop in 15-30% and may reduce efficacy 

60

How is Glatiramer Acitate (GA) used in the management of MS, and what is it's mechanism of action?

Glatiramer Acetate (GA) is a 4-amino acid synthetic co-polymer based on MBP (myelin basic protein). It is composed of random sequences of tyrosine, glutamate, alanine and lysine in a defined molar ratio; 40-100 aa length.

  • It is administered subcutaneously via daily injections.
  • It is very safe.

 

Approved for use in Relapsing forms of MS and in some countries for CIS (clinically isolated syndrome), where MRI is consistent with demyelination.

 

MoA

  • Binds to HLA-DR2
  • Inhibition/anergy of MBP reactive cells. Given its resemblance to MBP, it may act as a decoy, diverting the immune response away from myelin.
  • Cytokine shift Th1a→Th2 - This is a shift from a pro-inflammatory to less inflammatory phenotype
  • ?neuroprotection      

61

Describe some of the trials of GA, and what they showed

  • Copolymer 1 MS Study Group trial 29%-32% reduction in ARR  (relapse rate) in RRMS
  • Trials directly comparing GA to subcutaneous IFN beta 1-a (REGARD) and beta 1-b (BECOME and BEYOND) – no difference in relapses, MRI
  • PROMISe trial assessing sustained progression in PPMS patients: negative (+trend in males)
  • PRECISE trial showed 45% reduction in risk reduction of conversion to CDMS (Clinically Definite MS from CIS).

All the above trails involved GA administration daily subcutaneously.

  • GALA trial compared GA three-times a week SC to placebo and showed 34% reduction in the risk of confirmed relapse 

62

How is Fingolimod used to treat MS, and what is it's Mechanism of Action?

Fingolimod (Gylenia) was the first licensed oral treatment for MS.

  • It has a chemical structure similar to sphingosine and sphingosine-1- phosphate (S1P) , working as a agonist to the S1P receptor on T-cells (but a functional antagonist to the receptor).
  • It is effective at reducing active inflammation and relapse rate.
  • Good evidence that it reduces relapse-related irreversible disability in MS.
  • Currently licenced for highly active MS.

 

Mechanism of Action

It essentially works by keeping lymphocytes in lymph nodes. Ie Fingolimod interferes with T cell trafficking – has no effect on T cell activation, proliferation or cytokine production nor B cell ab production.

After dissociation of S1P from S1P1, the receptor is recycled to the cell membrane. Fingolimod-P has higher affinity to S1P leading to tight binding and less recycling of S1P1 and therefore proteosomal degradation of the drug-receptor complex  - so initial agonistic signal is terminated  and instead the “functional antagonism of S1P1). Internalisation of the S1P1 receptor reduces responsiveness of T cells to chemotactic cues and prevents exit from lymphoid organs.

63

Describe the clinical trials of Fingolimod

  • In the FREEDOMS trial, fingolimod significantly reduced ARR (Anualised Relapse Rate) when compared to IFN-β 1a and placebo, in patients with highly active RR-MS at 2 years; it also reduced the risk of disability progression after 3-6 months
  • In the TRANSFORMS trial, the same effect was seen with highly active RR- MS despite prior DMT (Disease Modifying Treatment)

64

How is Dimetyl Fumarate used to treat MS, and what is it's Mechanism of Action?

Dimethyl fumarate is an methyl ester of fumaric acid, which blocks pro-inflammatory cytokine production. It is taken orally (240mg) twice a day. It has clinical efficacy on active inflammation and relapse rates. Also good evidence that it reduces relapse-related irreversible disability. It is currently licensed for active MS. It blocks cytokine production by unknown mechanisms, but has antioxidant properties by activating a protein called Nrf2.

 

Flushing and gastrointestinal symptoms such as diarrhoea, nausea and upper abdominal pain are the most common side-effects.

65

Describe what the clinical trials of Dimetyl Fumarate show

  • DEFINE and CONFIRM trials both show that there is a significantly reduced annualised relapse rate compared to placebo.
  • DEFINE and CONFIRM trials both show that dimethyl fumarate also significantly reduces the number of new T2 lesions compared to placebo.
  • DEFINE study shows that dimethyl fumarate significantly reduces the probability of disease progression, though CONFIRM study did not find risk reduction statistically significant. 

66

How is Natalizumab used to treat MS?

Natalizumab (Tysabri®) Humanised mAb (monoclonal antibody) directed against α4 subunit of integrin on lymphocytes.

  • 300mg IV every 4 weeks
  • Clinical efficacy on active inflammation and relapse rate
  • Good evidence that it reduces relapse-related irreversible disability
  • Licensed for use in highly active MS 

67

What is the MoA of Natalizumab?

It blocks VLA-4 on TH1 cells so it can no longer interact with VCAM-1 on the endothelial cells and hence cannot get into CNS. Vascular endothelial cells lining the blood vessels normally have low affinity for circulating leukocytes. Inflammation leads to activation, which increased expression of surface antigens including VCAM-1. Blocking of this process means that T-cells can no longer cross the BBB to initiate lesion formation.

68

Describe the clinical trials of Natalizumab

Phase 3 Licensing trial AFFIRM (Natalizumab Safety and Efficacy in RRMS) where 942 pts randomised in 2:1 ratio to receive wither natalizumab (300mg) or placebo every 4 weeks for 116 weeks. 

  • Clinical relapses reduced by 68%
  • MRI activity reduced by 92%
  • Risk of sustained progression of disability reduced by 42% 

69

What are the adverse effects of Natalizumab?

  • Minor: nausea, headache
  • Hypersensitivity reactions
  • Rarely herpes infections
    • Fatal case of HSV encephalitis
    • Nonfatal case of HSV meningitis
    • 1 nonfatal case of HSV encephalitis
    • Several cases of cutaneous HSV reactivation
  • And, most importantly...Progressive Multifocal Leukoencephalopathy (PML)  - 698 cases!

70

Describe Progressive Multifocal Leukoencephalopathy (PML), and it's management

PML is caused by the JC virus (polyoma family) which actively replicates in the glial cells and causes oligodendrocyte death. Risk of PML: Initial incidence of 1/1000 patients after 18 months treatment. Risk increases with prior immunosuppressant use e.g. Cyclophosphamide, methotrexate, rituximab.

 

Clinical presentation: progressive and rapid deterioration (over weeks) cognitive, behavioural issues, language disturbance, hemiparesis and seizures. Outcomes reported for 242 cases: 21.5% deaths, majority of survivors had moderate-severe disability (Dong-Si et al. 2012)

 

Management of PML:

  • Stop natalizumab - *Problem: Immune Reconstitution Inflammatory Syndrome (IRIS) when natalizumab is suddenly stopped .
  • Plasma exchange – to remove natalizumab
  • Possible strategy??: combination of filgrastim (restore lymphocyte adhesion), oral maraviroc (modulates T cell recruitment) and mefloquin/mirtazepine (possible anti-JCV effects) 

71

How is Alemtuzumab used to treat MS?

Alemtuzumab is an anti-CD52 monoclonal antibody. The function of CD52 is unknown, but is widely expressed by T and B cells. Alemtuzumab selectively depletes circulating T and B cells. 

  • Administered IV 12mg/day on 5 consecutive days and on 3 consecutive days 12 months later.
  • Clinical efficacy on active inflammation and relapse rate
  • Good evidence that it reduces relapse-related irreversible disability
  • Licensed for active MS.

72

Describe the clinical trials for Alemtuzumab

  • CARE-MS 1 trial:
    • Reduced relapse rate by 55%
    • 78% were relapse free cf 59%
    • 8% had progressed (>1 EDSS pt) cf Rebif (NS)
  • CARE-MS 2: 42% reduction in 6 month sustained disability progression 

73

What are the adverse events associated with Alemtuzumab?

  • Infusion reactions
  • Infections (herpetic)
  • Autoimmunity (linked to increased IL-21?)
    • Hyperthyroidism/Graves’ disease (up to 25-30%)
    • Immune thrombocytopenic purpura (ITP)
    • Goodpasture’s syndrome 

74

How is Ocrelizumab used to treat MS

Ocrelizumab (Ocrevus) is a humanised monoclonal antibody anti-CD20 which targets CD20+ B-cells. Given intravenously every six months.

  • Clinical efficacy on active inflammation and relapse rate
  • Good evidence that it reduces relapse-related irreversible disability
  • Licensed for active relapsing and primary progressive MS.

75

Describe the clinical trials for Ocrelizumab

  • OPERA I and II studies showed that ocrelizumab significantly reduced remission compared to INF
  • Ocrelizumab significantly reduce the risk of confirmed disability progression, among PP MS patients

76

How is Daclizumab used to treat MS?

Daclizumab binds to CD25, the alpha subunit of the IL-2 receptors of T-Cells. Administered subcutaneously 150mg once monthly.

  • Clinical efficacy on active inflammation and relapse rate
  • Good evidence that it reduces relapse-related irreversible disability
  • Licensed for highly active MS (those that cannot tolerate lemtrada).

77

Give an overview of the evidence for Autologous Hematopoietic Stem Cell Transplantation (HSCT) Procedure for MS

As of Oct 2016, 916 patients have been treated with HSCT. The principle involves depletion of pathogenic T-cell repertoire followed by reconstitution of tolerant immune system via de-novo  differentiation of HCT.

 

A small clinical trial (2016) looking at 24 patients found:

Before Imunnoalbation and HSCT (I/HSCT), the patients had a total of 167 relapses and 188 Gd+ lesions. After I/HSCT, the patients had 0 relapses and 0 GD+ lesions.

Median follow-up was 6.7 years.

One of the 24 patients died of transplantation-related complications.

 

However, this is a single arm trial (not comparing to anything). And very small.

 

Furthermore, transplant-related mortality has been high in the past (3.6% in studies before 2005, 0.3 post-2005).

78

What are the clinico-pathological correlates of MS?

Relapses are linked to inflammatory activity of the CNS. Removing this inflammation through therapy, there is still a slow progression of the disease, but here the progression is linked to neurodegeneration.

  • Acute relapse = Inflammatory foci (even without inflammation)
  • Acute and chronic symptoms = Primary demyelination (also inflammatory in nature)
  • Progressive symptoms = Grey matter demyelination and Axonal loss in lesions
  • Fatigue = diffuse white matter changes
  • Motor, sensory and cognitive symptoms = Diffuse grey matter pathology
 
 

A image thumb
79

What is the gross pathology of MS

On the gross level, looking at the surface it looks normal except for slight atrophy. This is because the pathology is mainly in the white matter and can’t be seen on the surface of the cortex.

 

We can see that damage can occur anywhere in the brain and spinal cord. There is no direct pathology in the PNS, though the PNS can be affected because it is connected to the CNS. It is difficult to ascribe every symptom to a particular lesion and not all lesions cause symptoms - because damage can occur anywhere in the brain and spinal cord.


Extensive lesions often follow the lateral ventricles. Difficult to say which areas are more “susceptible”, but it does seem that extensive lesions often follow the lateral ventricles. 

80

Why are symptoms of MS so varied?

Because the amount and location of damage to the nervous system is different in each person with MS

Unless you do significant testing, you might not find any effect in the areas with pathology

 

The only generalisation we can make is that the more pathology, the shorter the disease duration (reduced lifespan).

81

How does Inflammation cause symptoms, and how does it relate to the clinical progression of MS?

Inflammation produces transient symptoms even without demyelination. This is why we think that acute relapses are due to inflammation, as it is too rapid for demyelination. Inflammatory cells release free radicals and cytotoxic mediators. This results in a reversible block of electrical signals and demyelination. Immunomodulatory treatments aim to stop these effects and are effective.

 

There are a number of suggested mechanisms for this inflammation:

  • Release of free radicals by peripheral immune cells and activated microglia: Nitric oxide (NO), peroxynitrite (OOND), hydroxyl radicals (OHD)
  • Glutamate release by microglia resulting in excitotoxicity (to oligodendrocytes as well as neurones as there are glutamate receptors at the nodes of Ranvier)
  • Hypoxia-like events
  • Mitochondrial dysfunction
  • Cytotoxic cytokine release by immune cells and microglia: TNF, lymphotoxin, IL1β, interferon-γ

82

Where are inflammatory cells found in MS?

In MS, there are variable-degrees of perivascular immune cell infiltration and intra-parenchymal infiltration by CD4+ and CD8+ T cells. B-cells are also found in perivascular and meningeal locations where they can aggregate or form part of ectopic lymphoid follicles. They cause a variable degree of perivascular and meningeal inflammation; if inflammation is at a very high level in the perivascular and meningeal areas, it’s usually the same throughout the CNS. 

 

While there are lots of lymphocytes in perivascular spaces, and in ectopic follicles, Looking at MS lesions themselves, you rarely see T-cells, instead the immune cells are predominantly macrophages. Macrophages are found around the neurons and also appear to be stripping off the myelin from neurons. Demyelination is largely macrophage mediated. There are also foamy macrophages at
the electron microscope level showing inclusions containing myelin debris. 

 

83

Describe the lymphoid-like structures in MS

The tertiary lymphoid structures appear in the depths of the cerebral sulci, leading to reduced CSF flow. This creates a protected microenvironment which favours the homing and retention of inflammatory cells.

84

Describe the nature of demyelination in MS

The hallmark of MS is a loss of myelin with relative preservation of axons. This distinguishes it from stroke, because in stroke you would have lost the axons as well. This demyleination is always accompanied by inflammation, and many of the mechanisms of inflammation in MS and demyelination in MS overlap.

 

Oligodendrocytes are generally absent from the centre of chronic lesions although increased numbers are often seen at the lesion edge. MOG-expressing cells are found in large numbers at the edge of some MS lesions - these are probably newly generated oligodendrocytes.

 

Demyelination is largely a macrophage-lead phenomenon. Active lesions can be identified by macrophages containing myelin-debris. There is no myelin-debris outside the lesion, indicating this stripping away of myelin is an active process.

 

Bare axons are surrounded by the fibrous processes of astrocytes in a chronic MS plaque. These fibrous processes are what gave MS the “sclerotic” title - early pathologists found that the lesions where hard - like scar tissue.

85

Describe the mechanisms of demyelination in MS

Demyelination is largely a macrophage-lead phenomenon. Active lesions can be identified by macrophages containing myelin-debris. There is no myelin-debris outside the lesion, indicating this stripping away of myelin is an active process.

There are a number of mechanisms for this demyelination. Many of these are shared with mechanisms of inflammation:

  • Release of free radicals by peripheral immune cells and activated microglia: Nitric oxide (NO), peroxynitrite (OOND), hydroxyl radicals (OHD)
  • Glutamate release by microglia resulting in excitotoxicity to oligodendrocytes. Oligodendrocytes express NMDA and AMPA receptors.
  • Cytotoxic cytokine release by immune cells and microglia: TNF, lymphotoxin are both toxic to complement.
  • Anti-myelin antibodies and complement though not yet proven, are likely to be the case. There are multiple possible antigens

86

How does demyleination relate to the clinical progression in MS?

Multiple episodes of demyelination occur throughout the course. When this reaches the clinical threshold, they are thought to contribute towards acute symptoms. However, still below the clinical threshold, they contribute towards chronic symptoms (progression) as it causes permanent injury to axons, leading to progressive axonal destruction, and eventually neuronal loss due to Wallerian degeneration.

87

Describe the lack of correlation of inflammation and demyleination to clinical progression

There is a lack of correlation between disease progression and inflammation/demyelination. This would have seen sensible because inflammation and demyelination in the white matter are key features of MS visible on MRI. But MRI lesion load and rate of appearance of new lesions correlates poorly with clinical progression. Though immunomodulatory therapies reduce relapse rate but fail to prevent long term progression of disability.

88

Describe the mechanisms of axonal loss in MS

Both inflammation and demyelination lead to axonal loss.

The mechanisms of axon degeneration in MS are similar to those leading to demyelination. Many factors in MS damage axons, the build-up of damaging factors will lead to the death of the axon. Damage here comes from:

  • Direct or bystander immune-mediated attack - TNFα or Fas ligand and other free radicals and cytotoxic mediators. 
  • Energy deficient: inherent mitochondrial defects or due to damage by inflammatory milieu (e.g. nitric oxide)
  • Glutamate excitotoxicity
  • Antibodies to neurofascin186, a component of the node/paranode.
    • The axon is particularly vulnerable at the Node of Ranvier.
  • Na+ and Ca2+ overloading in electrically active/ energy depleted axons. Alterations in ATP production, reduces the Na+/K+ exchange capacity, increasing the intracellular accumulation of Na+. This reverses the Na+/Ca2+ exchanger, causing an increase in Ca2+ in the cell. This activates proteolytic enzymes and eventually axonal death.

89

How does axonal loss relate to clinical progression in MS?

  1. In MOG-EAE, axonal loss correlates with chronic disability in RR-EAE. This is also found to be true for RR-MS looking at a longitudinal study (De Stefano et al 1998).
  2. However, this does not explain the build-up of neurological deficit that is not accounted for by WM tract lesions in progressive (PP and SC) forms of MS. (Reynolds et al 2011).

90

How does grey matter pathology correlate to clinical progression in MS

  1. There is a lack of correlation between disease progression and inflammation/demyelination. As MRI lesion load and rate of appearance of new lesions correlates poorly with clinical progression.
  2. Cortical grey matter pathology correlates better with long-term disability, compared to white matter pathology. (Fisniku LK et al 2008). 
  3. Organised meningeal inflammation and increased cortical demyelination are associated with early neurological disability and aggressive disease course in a large proportion of secondary progressive MS cases. There are worse clinical outcomes for patients who are follicular positive. Their mean age of duration is lower, mean age of wheelchair (36y F+, 51y F-).

91

Describe the role of B-Cells Follicules in cortical pathology

These germinal centres are found in the subarachnoid space with CSF. Lymphoid-like structures are a feature of meningeal inflammation in a large proportion of progressive MS cases. They contain proliferating CD20+ B-cells, Ki67+ B-cells and Follicular Dendritic Cells. This leads to the thought that there must have been antigen presentation for the proliferation to occur.

 

Majority of B cells appear to be CD27+ antigen experienced.

 

Similar (tertiary lymphoid) structures are characteristic of other chronic inflammatory and autoimmune conditions E.g. diabetes, Sjögren’s syndrome, rheumatoid arthritis, CPD, thyroiditis etc.

 

It is this meningeal inflammation which causes cortical demyelination and grey matter neurodegeneration. There is a gradient of cortical neurone loss in follicular positive cases, in terms of layers of cortical neurones.

The presence of inflammatory milleu by lymphoid-like structures causes global neurone expression downregulation, and upregulation of pro-inflammatory and pro-apoptotic gene expression. This is thought to be lead by TNF signalling.

92

Discuss if MS is a neurodegenerative disease

  • Cortical pathology has a major impact on clinical progression in MS
  • Presence of meningeal B-cell follicles leads to more extensive pathology and loss of neurons
  • Cytotoxicity mediated by factors released by B-cells and/or CD8 T-cells and/or microglia
  • Different pathogenetic mechanisms may be involved in WM & GM pathology, suggesting novel treatment options

Summary: Multiple sclerosis is an inflammatory demyelinating neurodegenerative disease 

93

Discuss the extent of remyelination in MS

Remyelination is a natural repair process that should occur in MS (taking only a week). It can be stopped by on-going inflammation and by the accumulating damage that affects axons. Remyelination restores conduction and protects axons. We do see some level of remyelination in the MS brain.

 

How does it work?

Repair in MS is indicated by the presence of thinly remyelinated sheaths. Remyelination is a frequent finding at the edge zones of inactive plaques. Suggested to be extensive in the early stages of MS and fails later on. Complete remyelination of lesions can occur.

 

Schwann cell remyelination is also found in the spinal cord.

 

Remyelination leads to the restoration of neurological function and may protect axons against damage. The adult mammalian brain and spinal cord has an enormous capacity for repairing myelin damage

94

Why is remyelination in animal models of MS good?

In animal models of non-diseased demyliantion, there is complete remyelination of axons. However in the MS brain, this is not seen as often, with there being chronic remyelination lesions (lesions that are always trying to remyelinate). Why does this happen?

 

The adult mammalian brain contains a widespread and numerous population of oligodendrocyte precursor cells. Glial progenitors in the adult CNS are cycling. When isolated into culture, they differentiate into oligodendrocytes. Glial progenitor cells are thought to be responsible for oligodendrocyte replacement following demyelination.

 

What are the ratios of oligodendrocytes:microglia:progenitors?

  • These ratios have significant implications for myelin repair
  • In the spinal cord, progenitors will need to undergo at least 2 cell divisions to replace oligodendrocytes
  • In the cerebral cortex, progenitors will only need to undergo 1 round of cell division

Remyelination is extremely efficient and complete in rodent models of MS. When axons are demyelinated by immune-mediated cytotoxicity, antibody-mediated autoimmunity or chemical toxin mediated, they still remyelinated. If the stimulus initiating demyelination is removed, then remyelination occurs, even after repeated demyelination in the same area

95

Why is remyelination not as great in human MS?

Oligodendrocyte progenitors in MS:

  • Some progenitor cells are present in most chronic plaques, in the complete absence of remyelination
  • Progenitor numbers are highly variable
  • Progenitor numbers are highest in lesions which still contain macrophages
  • Virtually nothing is known about the fate of progenitors in the acute lesion
  • There is some evidence from MS tissue studies that OPCs are able to differentiate, but that immature oligodendrocytes fail to form myelin
  • Many axons in the lesions appeared dystrophic with multiple swellings
  • Maybe the axons are not receptive to remyelination

 

Favourability of environment

  • Oligodendrocytes enter the lesion site to remyelinated neurons when there is a favourable environment
  • If the environment is hostile or unfavourable, or if there is too much inflammation, they will fail to migrate

96

What are the side-effects of Interferon-β?

Common side effects include: Injection site reaction, flu- like symptoms, depression, and raised LFTs. Overall good safety in the long term.

97

What are the side-effects of Fingolimod?

  • Herpes Infections
  • Skin cancers
  • Elevations of liver enzymes
  • Lymphopenia – an expected pharmacodynamic effect rather than an AE (due to sequestration of lymphocytes in LNs)
  • Cardiac (S1P1 and S1P3 atrial myocytes):
    • Bradycardia – transient, on treatment initiation (Day1). Hence need close cardiac monitoring.
    • 1st and 2nd degree AV conduction block
  • Macular oedema
  • Hypertension
  • Dyspnoea
  • Bronchitis
  • Diarrhoea