Multiple Sclerosis

Question 1

What is multiple sclerosis?

Answer 1

Multiple sclerosis is a chronic, immune-mediated inflammatory disease of the central nervous system.

Question 2

Multiple sclerosis (MS) is a … neuroinflammatory condition, which affects the central nervous system (CNS). The CNS comprises the brain, brainstem and spinal cord. The condition is most commonly seen in young adults.

Answer 2

Multiple sclerosis (MS) is a demyelinating neuroinflammatory condition, which affects the central nervous system (CNS). The CNS comprises the brain, brainstem and spinal cord. The condition is most commonly seen in young adults.

Question 3

Demyelination, which is the hallmark of MS, refers to damage to the protective … … that surrounds neurons. This can lead to scarring and secondary neuronal cell loss, which results in irreversible neurological damage.

Answer 3

Demyelination, which is the hallmark of MS, refers to damage to the protective myelin sheath that surrounds neurons. This can lead to scarring and secondary neuronal cell loss, which results in irreversible neurological damage.

Question 4

Due to the wide area of the CNS that can be affected, MS can present with a range of clinical manifestations and the disease course between individuals is unpredictable. MS is most commonly characterised by a …-…course, which may lead to progressive neurological disability overtime.

Answer 4

Due to the wide area of the CNS that can be affected, MS can present with a range of clinical manifestations and the disease course between individuals is unpredictable. MS is most commonly characterised by a relapsing-remitting course, which may lead to progressive neurological disability overtime.

Question 5

MS is 2-3 times more common in … than …

Answer 5

MS is 2-3 times more common in women than men.

Question 6

MS is predominantly a disease of young adults with a mean age of onset around … years old.

Answer 6

MS is predominantly a disease of young adults with a mean age of onset around 30 years old. It is estimated that 70% of patients with MS will present between 20-40 years old.

Question 7

Aetiology of MS

Answer 7

The aetiology of MS remains poorly understood.
Like most inflammatory conditions of unknown aetiology, the cause is thought to be due to an abnormal immune reaction to an unknown environmental trigger in a genetically predisposed individual.

Question 8

Genetics - MS

Answer 8

There is evidence of genetic susceptibility in MS with more than 200 polymorphisms (i.e. genetic variations).

In twin studies, the concordance rate is around 20-35% in monozygotic twins. Concordance means if one twin develops MS, what is the likelihood that the other twin, who has the same genetic material, also develops the condition. At 20-35%, it suggests genetics only play a modest role in the development of MS. The concordance rate in dizygotic twins of only 5%.

Question 9

When the aetiology of a condition is unknown, we look at different risk factors that may be associated with triggering an autoimmune response that subsequently leads to the disease.

What are some risk factors for MS?

Answer 9

Viral infections: several viruses linked with MS. Increased risk of MS following Epstein-Barr virus (EBV) infection (i.e. glandular fever)
Geographic latitude: prevalence of MS increases the greater the distance north or south from the equator. Migration after puberty carries risk from former geographic location.
Sunlight exposure: inverse relationship between MS, sunlight exposure and vitamin D levels.
Other: obesity during adolescence, smoking, gender (females at increased risk).

Question 10

MS is an inflammatory, demyelinating disease of the CNS, which is characterised by the presence of ….

Answer 10

MS is an inflammatory, demyelinating disease of the CNS, which is characterised by the presence of plaques.

Question 11

Pathophysiology of MS

Answer 11

MS is an inflammatory, demyelinating disease of the CNS, which is characterised by the presence of plaques.

The CNS is comprised of neurons, which contain a cell body and axons. Axons extend out and make connections with other neurons at synaptic junctions. These neurons are supported by glial cells, which are the most abundant cell type in the CNS.

One group of glial cells, known as oligodendrocytes, are important in formation of the myelin sheath that surrounds and insulates neuronal axons. In MS, oligodendrocytes are destroyed, which leads to demyelination and can cause axonal loss. Although there is no direct proof for an autoimmune cause, there is mounting evidence for involvement of the immune system in this pathological process.

Question 12

Pathological process

Answer 12

The exact mechanism of MS is still to be elucidated. However, there appears to be activation of myelin-reactive T lymphocytes and disruption of the blood brain barrier (BBB), which allows entry of autoreactive immune cells.

Within the CNS, there is then a pro-inflammatory response with recruitment of further inflammatory cells including B lymphocytes, macrophages and microglia. Microglia can be considered as ‘macrophages of the CNS’ and thus critical in cytokine release, phagocytosis and antigen-presentation.

There is a marked immune response including an antibody-mediated response with evidence of immunoglobulins, termed oligoclonal bands, in the cerebrospinal fluid (CSF). The continued immune reaction leads to damage to oligodendrocytes with subsequent demyelination and formation of ‘MS plaques’, which contain myelin reactive T cells, B cells and macrophages.

Within the focal areas of demyelination, or plaques, there is variable degrees of inflammation, scarring (i.e. gliosis) and axonal injury. The clinical manifestations of MS depend on the location of these plaques within the CNS.

Question 13

Classical plaque sites in MS

Answer 13

Optic nerves: affects 40% during course of disease. Presenting demyelinating event in 20%.
Spinal cord: affects 50-75% during course of disease. Majority associated with concomitant brain lesions. Predilection for cervical spine.
Brainstem: may present with ophthalmoplegia (e.g. intranuclear ophthalmoplegia - discussed below).
Cerebellum: characteristically causes ataxia and gait disturbance.
Juxtacortical white matter (near the cerebral cortex).
Periventricular white matter (near the ventricular system).

Question 14

Relapsing-remitting MS (RRMS)

How common is this subtype?

Answer 14

subtype in 85-90% of cases. Episodes of exacerbation in symptoms termed relapses followed by periods of recovery termed remissions. During early stages, symptoms may completely remit. As diseases progresses likely to retain residual damage with each relapse.

Question 15

Primary progressive MS (PPMS): subtype in…
Sustained progression of disease severity from onset. May have periods where disease is not active or non-progressive, but no evidence of clinical remission.

Answer 15

Primary progressive MS (PPMS): subtype in 10-15%. Sustained progression of disease severity from onset. May have periods where disease is not active or non-progressive, but no evidence of clinical remission.

Question 16

Secondary progressive MS (SPMS): 50% of patients with RRMS will develop this subtype within … years of onset. Following RRMS phenotype, disease course changes with gradual, sustained worsening in neurological function. Relapses may still occur but without remission.

Answer 16

Secondary progressive MS (SPMS): 50% of patients with RRMS will develop this subtype within 15 years of onset. Following RRMS phenotype, disease course changes with gradual, sustained worsening in neurological function. Relapses may still occur but without remission.

Question 17

Clinically isolated syndrome (CIS) - MS

Answer 17

CIS describes the first clinical episode of suspected MS. There is no previous evidence of demyelination clinically or on neuroimaging. Oligoclonal bands in cerebrospinal fluid may be used as supportive criteria to help come to the diagnosis (see supporting investigations).

Question 18

Clinical features associated with MS are determined by plaque locations within the ….

Answer 18

Clinical features associated with MS are determined by plaque locations within the CNS.

Question 19

There are a number of clinical features that are characteristic of MS including optic …, Lhermitte phenomenon (uncomfortable … …-like feeling triggered by neck flexion) and internuclear ophthalmoplegia (INO). Others may be common to numerous neurological pathologies including motor weakness, diplopia, … disturbance and … dysfunction

Answer 19

There are a number of clinical features that are characteristic of MS including optic neuritis, Lhermitte phenomenon (uncomfortable electric shock-like feeling triggered by neck flexion) and internuclear ophthalmoplegia (INO). Others may be common to numerous neurological pathologies including motor weakness, diplopia, gait disturbance and bladder/bowel dysfunction.

Question 20

Optic … and eye movement abnormalities commonly affect patents with MS.

Answer 20

Optic neuritis and eye movement abnormalities commonly affect patents with MS.

Question 21

Optic neuritis is due to inflammation of the optic nerve and characteristically presents with partial or total unilateral visual loss that develops over days.
Features include: (7)

Answer 21

Visual loss
Blurred vision
Pain: typically behind the eye and on movement
Scotoma: refers to partial visual field loss
Poor colour differentiation
Relative afferent pupillary defect
Optic nerve swelling: seen on fundoscopy

Question 22

… … is due to inflammation of the optic nerve and characteristically presents with partial or total unilateral visual loss that develops over days.

Answer 22

Optic neuritis is due to inflammation of the optic nerve and characteristically presents with partial or total unilateral visual loss that develops over days.

Question 23

Eye movement disorders may be due to brainstem lesions that affect cranial nerves or the pathways that connect visual tracts together. Two commonly seen are INO and Abducens palsy.

Answer 23

INO: disorder of conjugate lateral gaze due to demyelination of the medial longitudinal fasciculus (MLF). MLF is heavily myelinated. Connects the abducens nucleus complex with the contralateral oculomotor nucleus. If affected, when looking to the right, the right eye will abduct but the left will remain central (failure in adduction).
Abducens palsy: absence of lateral abduction of the eye. If the right abducens nerve is affected, when looking to the right, the right eye will remain central.

Question 24

absence of lateral abduction of the eye = … palsy

Answer 24

Abductees palsy = absence of lateral abduction of the eye. If the right abducens nerve is affected, when looking to the right, the right eye will remain central.

Question 25

INO: disorder of conjugate lateral gaze due to demyelination of the medial longitudinal fasciculus (MLF). MLF is heavily myelinated. Connects the abducens nucleus complex with the contralateral oculomotor nucleus. If affected, when looking to the right, the right eye will abduct but the left will remain central (failure in adduction).

Answer 25

INO: disorder of conjugate lateral gaze due to demyelination of the medial longitudinal fasciculus (MLF). MLF is heavily myelinated. Connects the abducens nucleus complex with the contralateral oculomotor nucleus. If affected, when looking to the right, the right eye will abduct but the left will remain central (failure in adduction).

Question 26

Motor & coordination in MS

Answer 26

Motor abnormalities can occur in any part of the body, but usually characterised by weakness and ataxia (lack of muscle coordination). The prominent motor feature in MS is progressive paraparesis and evidence of upper motor neuron signs (Spasticity, reduced power, hyper-reflexia).

Motor and coordination abnormalities may present as a typical clinical syndrome such as transverse myelitis or cerebellar syndrome.

Question 27

Transverse …: focal inflammation within the spine. Characterised by sensory and motor symptoms below the level of the lesion (e.g. paraesthesia, weakness). Bladder/bowel involvement may be present and usually there is a sensory level that corresponds to the level of the lesion. Must exclude compressive pathology in first instance (i.e. metastatic cord compression).

Answer 27

Transverse myelitis: focal inflammation within the spine. Characterised by sensory and motor symptoms below the level of the lesion (e.g. paraesthesia, weakness). Bladder/bowel involvement may be present and usually there is a sensory level that corresponds to the level of the lesion. Must exclude compressive pathology in first instance (i.e. metastatic cord compression).

Question 28

Cerebellar syndrome: a clinical syndrome characterised by disease of the cerebellum, which manifests with ataxia, … speech, … tremor, nystagmus, vertigo and ….

Answer 28

Cerebellar syndrome: a clinical syndrome characterised by disease of the cerebellum, which manifests with ataxia, slurred speech, intension tremor, nystagmus, vertigo and clumsiness.

Question 29

Cerebellar syndrome: a clinical syndrome characterised by disease of the cerebellum, which manifests with … (6)

Answer 29

Cerebellar syndrome: a clinical syndrome characterised by disease of the cerebellum, which manifests with ataxia, slurred speech, intension tremor, nystagmus, vertigo and clumsiness.

Question 30

There are a whole range of sensory and autonomic symptoms that should be explored in MS, including: (5)

Answer 30

Paraesthesia
Pain
Heat sensitivity (Uhthoff phenomenon)
Sexual dysfunction
Bladder & bowel dysfunction

Question 31

Up to 75% of MS patients report … dysfunction.

Answer 31

Up to 75% report bladder dysfunction. A range of Neurogenic bladder dysfunction may occur leading to incontinence, poor bladder emptying or urinary retention.

Question 32

Cognitive & psychological symptoms in MS

Answer 32

Cognitive impairment, depression and fatigue are all extremely common in MS. It is estimated that some degree of depression may affect up to two thirds of patients with MS and this can have a negative impact on memory, attention, and concentration.

Question 33

MS attack: defined simply as an episode of neurological symptoms that relate to an inflammatory demyelinating lesion. Lasts > … hours with or without recovery. Typically sensory disturbances, motor weakness, or visual complaints. There must be more than 30 days between attacks to count as a separate episode.

Answer 33

MS attack: defined simply as an episode of neurological symptoms that relate to an inflammatory demyelinating lesion. Lasts > 24 hours with or without recovery. Typically sensory disturbances, motor weakness, or visual complaints. There must be more than 30 days between attacks to count as a separate episode.

Question 34

MS attack: defined simply as an episode of neurological symptoms that relate to an inflammatory demyelinating lesion. Lasts > 24 hours with or without recovery. Typically sensory disturbances, motor weakness, or visual complaints. There must be more than … days between attacks to count as a separate episode.

Answer 34

MS attack: defined simply as an episode of neurological symptoms that relate to an inflammatory demyelinating lesion. Lasts > 24 hours with or without recovery. Typically sensory disturbances, motor weakness, or visual complaints. There must be more than 30 days between attacks to count as a separate episode.

Question 35

Objective clinical evidence: identification of an abnormality (usually on clinical examination or MRI), which corresponds to the … location suggested by the current, or past, symptoms of a MS attack.

Answer 35

Objective clinical evidence: identification of an abnormality (usually on clinical examination or MRI), which corresponds to the anatomical location suggested by the current, or past, symptoms of a MS attack.

Question 36

The … criteria provides recommendations for the diagnosis of MS based on MRI findings (brain +/- spinal cord) and clinical presentation. MRI is the imaging of choice for identification of demyelinating lesions within the CNS.

Answer 36

The McDonald criteria provides recommendations for the diagnosis of MS based on MRI findings (brain +/- spinal cord) and clinical presentation. MRI is the imaging of choice for identification of demyelinating lesions within the CNS.

Question 37

Revised McDonald criteria

OThe criteria can get quite niche, but these general principles apply:

Answer 37

≥2 attacks with objective clinical evidence of ≥2 lesions: MS diagnosed
≥2 attacks but objective clinical evidence for only one lesion: evidence of dissemination in time, but not space. MS diagnosed if dissemination in space shown on MRI or subsequent clinical attack representing new area.
Single attack with objective clinical evidence of one lesion: clinically isolated syndrome. MS diagnosed once proof of both dissemination in time and space.
Single attack with objective clinical evidence of ≥2 lesions: clinically isolated syndrome. MS diagnosed once proof of dissemination in time.

Question 38

The differential diagnosis of MS depends on the site of … and presentation of neurological symptoms.

Answer 38

The differential diagnosis of MS depends on the site demyelination and presentation of neurological symptoms.

Question 39

There are numerous conditions that present in a similar manner to MS. These may be other demyelinating conditions, infections, malignancy, metabolic disorder or even systemic inflammatory conditions.

List some demyelinating diseases (3)

Answer 39

Neuromyelitis optica
Transverse myelitis
Acute disseminated encephalomyelitis

Question 40

There are numerous conditions that present in a similar manner to MS. These may be other demyelinating conditions, infections, malignancy, metabolic disorder or even systemic inflammatory conditions.

List some infections which can present with similar symptoms (3)

Answer 40

Lyme disease
Human T-lymphotropic virus
Tertiary syphilis

Question 41

There are numerous conditions that present in a similar manner to MS. These may be other demyelinating conditions, infections, malignancy, metabolic disorder or even systemic inflammatory conditions.

What metabolic diseases may present in a similar way? (4)

Answer 41

B12 deficiency
Diabetic neuropathy
Adult-onset leukodystrophies
Copper deficiency

Question 42

There are numerous conditions that present in a similar manner to MS. These may be other demyelinating conditions, infections, malignancy, metabolic disorder or even systemic inflammatory conditions.

What systemic diseases may present in a similar way? (4)

Answer 42

SLE

Sarcoidosis

Question 43

Neuromyelitis optica (Devic’s disease)

Answer 43

Neuromyelitis optica spectrum disorders (NMOSD) is the new nomenclature for neuromyelitis optica, a condition with a very similar phenotype to MS. It refers to a series of neuroinflammatory demyelinating conditions, which preferentially affect the optic nerve and spinal cord.

Question 44

Neuromyelitis optica (Devic’s disease)

Answer 44

Neuromyelitis optica spectrum disorders (NMOSD) is the new nomenclature for neuromyelitis optica, a condition with a very similar phenotype to MS. It refers to a series of neuroinflammatory demyelinating conditions, which preferentially affect the optic nerve and spinal cord.

The hallmark of NMOSD is an acute attack of bilateral optic neuritis or transverse myelitis. These are two common clinical manifestations of MS, but in NMOSD the presentation is more severe. It is associated with formation of an IgG autoantibody to aquaporin-4 (AQP4). Treatment is similar to MS with corticosteroids, but plasma exchange may be required for refractory cases.

Question 45

Additional investigations in MS can be used to help support the diagnosis and exclude an alternative pathology.
What bloods?

Answer 45

Full blood count
CRP/ESR
LFTs, U&Es, Bone profile 
Glucose, HbA1c
TFTs
Haematinics
Blood-borne virus screen

Question 46

Oligoclonal bands - MS

Answer 46

Cerebrospinal fluid (CSF) can be analysed following a lumbar puncture to assess for CSF-specific oligoclonal bands.

Oligoclonal bands refer to bands of immunoglobulins. The test is considered positive if oligoclonal bands identified in the CSF are not present in the serum. Therefore, a paired serum sample should be taken at the time of the lumbar puncture. They are identified in up to 95% of patients with definite MS clinically, but the test is only needed as supporting evidence in equivocal cases.

Typically, they can be used in patients with CIS as a surrogate markers of dissemination in time or as a risk estimation for those not yet meeting criteria for dissemination in space.

Question 47

Oligoclonal bands refer to bands of immunoglobulins. The test is considered positive if oligoclonal bands identified in the CSF are … in the serum.

Answer 47

Oligoclonal bands refer to bands of immunoglobulins. The test is considered positive if oligoclonal bands identified in the CSF are not present in the serum. Therefore, a paired serum sample should be taken at the time of the lumbar puncture. They are identified in up to 95% of patients with definite MS clinically, but the test is only needed as supporting evidence in equivocal cases.

Question 48

MS supporting investigations

Cerebrospinal fluid (CSF) can be analysed following a lumbar puncture to assess for CSF-specific … bands.

Answer 48

Cerebrospinal fluid (CSF) can be analysed following a lumbar puncture to assess for CSF-specific oligoclonal bands.

Question 49

Oligoclonal bands refer to bands of immunoglobulins. The test is considered positive if oligoclonal bands identified in the CSF are not present in the serum. Therefore, a paired serum sample should be taken at the time of the lumbar puncture. They are identified in up to …% of patients with definitive MS clinically

Answer 49

They are identified in up to 95% of patients with definite MS clinically, but the test is only needed as supporting evidence in equivocal cases.

Question 50

There are many aspects to the general care of patients with MS. It should be emphasised that physiotherapy and occupational therapy are critical throughout the course of the disease, especially as the disease becomes more disabling and patients require assistance with their daily activities of living.

Answer 50

There are many aspects to the general care of patients with MS. It should be emphasised that physiotherapy and occupational therapy are critical throughout the course of the disease, especially as the disease becomes more disabling and patients require assistance with their daily activities of living

Question 51

…. …. : commonly seen in MS. May require anticholinergics such as oxybutynin for detrusor overactivity. Botulism injection is a second option if intolerant to medications. Patients with retention problems may require intermittent self-catheterisation or long-term catheters.

Answer 51

Bladder dysfunction: commonly seen in MS. May require anticholinergics such as oxybutynin for detrusor overactivity. Botulism injection is a second option if intolerant to medications. Patients with retention problems may require intermittent self-catheterisation or long-term catheters.

Question 52

Depression: treatment choices can be targeted depending on co-existing symptoms. For example, … may be preferred if co-existing neuropathic pain or fatigue. Selective serotonin reuptake inhibitors (SSRIs) commonly used.

Answer 52

Depression: treatment choices can be targeted depending on co-existing symptoms. For example, duloxetine may be preferred if co-existing neuropathic pain or fatigue. Selective serotonin reuptake inhibitors (SSRIs) commonly used.

Question 53

Fatigue: numerous non-pharmacological interventions should be attempted (e.g. physical activity) and treat co-morbidity such as depression. Some pharmacological options available like ….

Answer 53

Fatigue: numerous non-pharmacological interventions should be attempted (e.g. physical activity) and treat co-morbidity such as depression. Some pharmacological options available like modafinil.

Question 54

… impairment: occupational and physiotherapy input essential. Walking aids or wheelchair may be needed.

Answer 54

Gait impairment: occupational and physiotherapy input essential. Walking aids or wheelchair may be needed.

Question 55

Pain: neuropathic pain significant issue in MS. Treatment options include amitriptyline, … or …..

Answer 55

Pain: neuropathic pain significant issue in MS. Treatment options include amitriptyline, gabapentin or pregabalin.

Question 56

Spasticity: affects a large proportion of patients with MS. Can lead to functional disability. Degree of spasticity should be assessed and treatment involves physiotherapy and baclofen. … injections may be used.

Answer 56

Spasticity: affects a large proportion of patients with MS. Can lead to functional disability. Degree of spasticity should be assessed and treatment involves physiotherapy and baclofen. Botulism injections may be used.

Question 57

Acute relapse in MS

Answer 57

Before treating a relapse, it is essential to rule out infection, which can lead to a deterioration in symptoms. Furthermore, a true relapse must be distinguished from fluctuations in disease course or progressive disease. Patients may require hospital admission and should always be discussed with their specialist MS team.

Question 58

If a clinically significant relapse is confirmed:

Steroids: oral … 0.5 g daily for five days, OR Intravenous … 1 g daily for 3-5 days
Gastroprotection: proton pump inhibitor
Discuss risk/benefit of treatment: particular attention to acute changes in blood glucose and mental health

Answer 58

Steroids: oral methylprednisolone 0.5 g daily for five days, OR Intravenous methylprednisolone 1 g daily for 3-5 days
Gastroprotection: proton pump inhibitor
Discuss risk/benefit of treatment: particular attention to acute changes in blood glucose and mental health

Question 59

DMTs refer to immunomodulatory medications that aim to decrease the number of relapses and slow disease progression. The initiation of DMTs and ongoing care of patients on DMTs should be guided by MS specialists.

The initiation of DMTs have specific indications, but in general, the following principles should apply:

Answer 59

No evidence of non-relapsing progressive MS
Sustained disability due to MS: measured on Expanded Disability Status Scale (EDSS). The score should be < 7.0 (i.e. at least ambulant with two crutches).

Question 60

DMTs utilised in MS:

Answer 60

Interferon beta: injectable cytokine. Modulates immune response. First disease-modifying drug licensed for the treatment of MS.

Glatiramer acetate: injectable. Mechanism not fully understood. Thought to induce and activate T-lymphocyte suppressor cells for a myelin antigen

Teriflunomide: oral therapy. Inhibits pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects
Alemtuzumab: infusion. Monoclonal antibody targeted to CD52. Antigen is found on many immune cell lines. Immunomodulatory effect in MS.

Cladribine: oral therapy. Purine nucleoside analogue.
Cytotoxic effects on B and T lymphocytes through preventing DNA synthesis.

Natalizumab: infusion. Monoclonal antibody against the alpha-4 subunit of integrin molecules. Prevents migration of leucocytes across the BBB.

Question 61

Factors linked to prognosis in MS include:

Answer 61

Disease type: RRMS better prognosis than PPMS. Most patients with RRMS eventually develop SPMS.
Recovery following first attack: incomplete recovery associated with worse prognosis.
Clinical manifestations at onset: pyramidal, brainstem, and cerebellar symptoms (poor prognosis). Sensory symptoms, optic neuritis (favourable prognosis).
Pregnancy: protective during pregnancy. Increased risk of relapse in postpartum period.
Imaging: lesion load and cerebral atrophy linked to prognosis (higher burden and increased atrophy have worse prognosis).

Question 62

Pregnancy and MS

Answer 62

protective during pregnancy. Increased risk of relapse in postpartum period.

Question 63

Clinical manifestations at onset: pyramidal, brainstem, and cerebellar symptoms (… prognosis). Sensory symptoms, optic neuritis (… prognosis).

Answer 63

Clinical manifestations at onset: pyramidal, brainstem, and cerebellar symptoms (poor prognosis). Sensory symptoms, optic neuritis (favourable prognosis).