CASE 6 - Multiple Sclerosis Flashcards
Epidemiology of MS for the following categories:
- Sex
- Age of onset
- Ethnicity
- Sex: females > males (3:1)
- Age of onset: 20-40 years
- Ethnicity: caucasian, mostly
MS prevalence is _______ in those who live FURTHER away from the equator
MS prevalence is greater in those who live FURTHER away from the equator
The presence of which allele is associated with greater MS risk?
HLA-DRB1
Which allele appears to be PROTECTIVE against MS?
HLA-A*02
List 4 environmental risk factors for MS
- Smoking
- Obesity in early life
- Low vitamin D levels
- Infection (EBV, HHV6)
List the 3 key pathophysiological mechanisms that are responsible for MS (DIA)
- Inflammation
- Demyelination
- Axonal degeneration
Explain the pathophysiology behind the most commonly-accepted theory of MS
MS is a Type IV Hypersensitivity reaction (cell-mediated)
- Activation of autoreactive T lymphocytes (which is activated by myelin)
- Inflammation: release of various cytokines that increase permeability of BBB
- These cytokines damage the oligodendrocytes AND allow more immune cells in
- Destruction of oligodendrocytes
- No myelin to cover neurons
- Leaves behind scar tissue / plaques / sclera
Inadequate remyelination means poor neuronal function
The focal demyelinated plaques of MS tend to occur in which CNS locations?
- Optic nerves
- Brainstem
- Spinal cord
- Cerebellum
- Juxtacortical and periventricular white matter
What is typically the earliest manifestation of MS?
Optic neuritis (caused by lesions in CN II)
Describe the clinical features of optic neuritis (earliest manifestation of MS)
- Typically unilateral
- Can be painful
- Decreased visual acuity
- Colour blindness
- Marcus Gunn pupil / relative afferent pupillary defect (RAPD)
Describe what is meant by a ‘Marcus Gunn pupil’
Marcus Gunn Pupil / Relative Afferent Pupillary Defect:
When a flashlight is swung between both eyes, the pupil with the RAPD will NOT constrict and may DILATE in response to light being shone in that eye.
The affected eye will still constrict as a consensual response (i.e. when the light is in the unaffected eye)
Internuclear ophthalmoplegia results from a lesion in which tract?
Medial longitudinal fasciculus
Describe what is seen in internuclear ophthalmoplegia
Impaired ADDUCTION of the AFFECTED eye, causing minimal adduction when trying to gaze contralaterally
(e.g. if the right eye is affected, trying to gaze to the left will cause the right eye to adduct minimally - it will stay in the middle. Meanwhile, the left eye adducts with no problem, but nystagmus is present)
- Intact convergence reflex
- More frequently bilateral than unilateral
https://en.wikipedia.org/wiki/Internuclear_ophthalmoplegia
What phenomenon is experienced by the patient who has internuclear ophthalmoplegia?
Diplopia
Describe the visual changes that can occur in MS (SIGNS)
- Optic neuritis
- Internuclear ophthalmoplegia
Describe the visual changes that can occur in MS (SYMPTOMS)
- Colour blindness
- Vision loss / blurred vision
- Central scotoma
- Pain
- Diplopia
List 5 clinical manifestations of Spinal Cord Demyelination in MS
- Lhermitte sign
- Pyramidal tract lesion (UMNL Sx)
- Involvement of dorsal spinal column (loss of vibration and fine-touch sensation, paresthesia, sensory ataxia)
- Neuropathic pain
- Absent abdominal reflex
What is Lhermitte sign?
A shooting electric sensation that travels down the spine upon flexion of the neck
Which clinical features can be present in someone with pyramidal tract lesions?
Upper motor neuron weakness:
- Spasticity
- Hyperreflexia
- Positive Babinski sign
Which clinical features can be present in someone with lesions of the dorsal spinal column?
The dorsal spinal column (proprioception, vibration, and fine touch) is the first sensory tract to be affected in MS.
- Sensory ataxia (e.g. positive Romberg’s)
- Paresthesias, numbness
- Loss of fine touch sensation
What is the Charcot neurological triad, and what are its clinical features? (SIN)
Charcot neurological triad: can occur in any cerebellar lesion.
- Scanning speech (slowed speech, recurrent pauses between syllables and emphasis on other syllables)
- Intention tremors
- Nystagmus
MS cranial nerve palsies can present with which clinical features?
- Diplopia
- Trigeminal neuralgia
- Facial palsy
Autonomic dysfunction as a result of MS can cause which clinical features?
- Bladder and bowel neurogenic disorders
- Impaired sexual function
Approximately __ to __% of patients with retrobulbar neuritis go on to develop MS
Approximately 20 to 50% of patients with retrobulbar neuritis go on to develop MS
Name the 3 patterns of MS
- Relapsing-remitting MS (RR-MS)
- Secondary progressive MS (SP-MS)
- Primary progressive MS (PP-MS)
Which pattern of MS is the most common?
Relapsing-remitting MS
Describe the 3 patterns of MS
- Relapsing-remitting MS (RR-MS): exacerbations occur, then symptoms improve and remain dormant for months-years.
- Secondary progressive MS (SP-MS): starts off similar to RR-MS with exacerbations followed by improvement, but the immune attack becomes more constant and disability progresses consistently.
- Primary progressive MS (PP-MS): one constant attack on myelin, causing consistent progression of disability
https: //www.youtube.com/watch?v=yzH8ul5PSZ8
What is the definition of an MS exacerbation?
New symptoms or significant worsening of existing symptoms, both of which last at least 24 hours and are preceded by at least 30 days of relative clinical stability.
What is the McDonald criteria?
A diagnostic criteria for MS, based on dissemination of CNS lesions in TIME and SPACE
Describe the DIT component of the McDonald criteria
- DISSEMINATION IN TIME = presence of NEW lesions over time, as evidenced by one of the following:
- 2 or more exacerbations at least 30 days apart
- MRI demonstrates the presence of both gadolinium-enhancing and non-enhancing lesions at any time or a new hyperintense T2 or enhancing lesion on follow-up MRI
- Positive CSF oligoclonal bands w/no serum oligoclonal bands
https: //www.amboss.com/us/knowledge/Multiple_sclerosis/
Describe the DIS component of the McDonald criteria
- DISSEMINATION IN SPACE = presence of lesions in DIFFERENT REGIONS of the CNS that can be confirmed by one of the following:
- Presence of 2 or more lesions w/objective clinical
evidence (e.g. symptoms correlate with imaging) - Presence of 1 or more hyperintense
lesions on MRI in T2 sequence in at least 2 of the following regions: periventricular, juxtacortical, infratentorial, spinal
A diagnosis of MS is suspected when symptoms are spread out over time and space. What is meant by this?
SPACE = Damage in different areas of the CNS (producing different symptoms)
TIME = there are exacerbations and remissions
What is the investigation of choice for MS?
Plain MRI of brain and spinal cord
What could be seen in a CSF analysis of someone with MS?
- Lymphocytosis
- Oligoclonal bands (indicates poorer prognosis)
- Increased myelin basic protein
What feature can be typically be seen in the MRI of someone with MS?
Multiple sclerotic plaques, commonly seen in the periventricular white matter.
With finger-like radial extensions (Dawson’s fingers)
Caused by demyelination and reactive sclerosis
Explain the difference between a T1 and T2 MRI
T1 and T2 are both basic types of MRI images:
T1-weighted images make FAT appear HYPERINTENSE (bright)
T2-weighted images make FAT and WATER appear HYPERINTENSE (bright). *note that in T2, fat is LESS hyperintense than in T1
(in T2, 2 things are bright)
https://www.youtube.com/watch?v=mOt2FeGHjaY
Sclerotic plaques are _________ in T1 and _________ in T2
Sclerotic plaques are HYPO/ISOINTENSE in T1 and HYPERINTENSE in T2
What is the use of adding FLAIR to T2 images?
In a T2 with FLAIR, non-free-flowing water is BRIGHT (e.g. oedema) but free-flowing water (e.g. CSF) is DARK - signals from CSF are suppressed.
It is useful for delineating lesions near VENTRICLES since OEDEMA will be BRIGHT whereas CSF will be DARK.
https://www.radiologymasterclass.co.uk/tutorials/mri/mri_sequences
What information is conveyed by the DCML?
Fine touch Vibration Proprioception Discriminative touch 2-point touch
From peripheral nerves to the cerebral cortex (it is an ascending tract)
https://www.youtube.com/watch?v=gDw6hiM69c4
When does the DCML decussate?
Medulla
What are the 2 components of the DCML and what type of information do they convey?
Fasciculus Cuneatus - located more laterally, carries sensation from the UPPER limbs.
Fasciculus Graciis - located more medially, carries sensation from the LOWER limbs.
What information is conveyed by the spinothalamic tract?
Where does it decussate?
Pain and temperature
Decussates immediately upon entering the spinal cord
How do the tremors differ between cerebellar lesions and Parkinsonism?
CEREBELLAR = intention tremor (<5z, worsens with goal-directed movement)
PARKINSONISM = resting tremor (4 - 6 Hz, reduced with target-directed movement)
What is Romberg’s test and how can it be useful in a patient with MS?
Romberg’s test: the patient stands from a sitting position (without using their arms) with their eyes open, then closed.
Positive Romberg’s indicates cerebellar involvement
What are the basic principles of MRI scanning?
MRI involves imaging protons in vivo. Protons emit a signal when a radio frequency pulse is applied in a magnetic field; the MRI device then forms an image from these signals.
T1 and T2 weighted images are the basic images produced. T1 eliminate signals from fat.
Brisk reflexes, spasticity, and extensor plantar reflexes are an indication of damage to which tracts?
Pyramidal tract damage
The pyramidal tracts contain which 2 tracts? What are their functions?
Pyramidal tracts are descending motor tracts that contain the corticospinal and corticobulbar tracts.
They are responsible for controlling VOLUNTARY motor movements of the face (corticobulbar) and body (corticospinal)
What are the extrapyramidal tracts? What are their functions?
Extrapyramidal tracts are: reticulospinal, rubrospinal, vestibulospinal, and tectospinal.
Functions: INVOLUNTARY / AUTOMATIC control of musculature (e.g. tone, balance, posture, locomotion)
Motor symptoms in MS more commonly occur in the _____ extremities and are typically __________.
This is due to…
Motor symptoms in MS more commonly occur in the LOWER extremities and are ASYMMETRICAL.
This is due to lesions of the descending motor tracts.
RIS vs. CIS
RIS = radiologically isolated syndrome (a person has no apparent MS symptoms but has MS-like brain damage)
CIS = clinically isolated syndrome (a single demyelinating event without evidence of changes over time - NO further clinical events or new MRI changes)
The risk of MS in the general population is __%. The first-degree relatives of a patient diagnosed with MS have a _ to __% risk.
The risk of MS in the general population is 0.1%. The first-degree relatives of a patient diagnosed with MS have a 3 to 4% risk.
The emphasis on treating MS has 3 main components. Describe them.
- Starting IMMUNOTHERAPY early to slow or minimise disability
- CORTICOSTEROIDS for acute inflammatory clinical events (relapse)
- Treatment for neurological damage (e.g. pain)
What types of immunotherapy drugs are used for MS?
Monoclonal antibodies, e.g. Alemtuzumab, natalizumab (both IV) + dimethyl fumarate, fingolimod (oral)
What is the difference between monoclonal antibodies and oral drugs for MS?
MABs are higher potency, more effective, but have a higher risk profile and since they are IV it can raise issues with compliance.
Oral drugs have moderate potency.
How does pregnancy affect MS?
There is a decreased relapse rate during pregnancy, followed by increased relapse in the postpartum period.
The long-term clinical course remains unchanged.
When are MS relapses treated with corticosteroids?
When they are moderate-severe
What constitutes a mild vs. moderate-severe MS relapse?
MILD = no signs of disability (e.g. no objective neurological signs, no increase in urinary symptoms or bowel dysfunction)
MODERATE-SEVERE = objective neurological signs
Which corticosteroid is given in moderate-severe cases of MS relapse?
IV Methylprednisolone sodium succinate 1 g over 1 hour
Once daily for 3 days.
When are MRIs with IV gadolinium performed?
MRI w/gadolinium contrast is useful for enhancing active lesions
It can enhance active lesions during and up to 6 weeks after the exacerbation
What is MRI with STIR?
STIR = short tau inversion recovery
It is used to suppress signals from fat. Better for spinal cord lesions?
Similar to FLAIR (but flair suppresses water)
Which spinal tract is usually first to be affected in MS?
DCML
Contrast the benefits of older MS drugs (e.g. interferons and glatiramer acetate) vs. immunotherapy (monoclonal antibodies)
Interferons and glatiramer acetate are less predictable and relapses are more common when compared to MABs.
What is the MOA for interferons that are used in MS treatment?
Immunoregulatory actions:
- Reduced cytokine release
- Antagonism of gamma interferon
- Activation of suppressor T cell function
What is the MOA of Alemtuzumab? (MAB for MS)
Targets CD52 on T and B cells, depleting the T and B cells and preventing them from causing inflammatory damage
Name 3 types of MS immunotherapy drugs
- Monoclonal antibodies (e.g. Alemtuzumab) - IV
- Interferons & glatiramer acetate - IM or subcut
- Oral drugs (e.g. fumarates, fingolimod)
Why is baclofen used for MS? How is it prescribed?
To mitigate the spasticity caused by corticospinal tract damage.
Start at low doses and gradually increase. Taken TDS.
What is the MOA of baclofen?
Baclofen is a GABA-B agonist; it inhibits transmission at the spinal level and depresses the CNS
What is the Uhthoff phenomenon?
A reversible exacerbation of neurological symptoms following an increase in body temperature, e.g., physical exertion, a warm bath, or fever
What is sensory ataxia? How can it be tested?
Ataxia resulting from impaired proprioception (problems with DCML).
Can be tested using Romberg’s test. Sensory ataxia worsens when the eyes are closed because the lack of sensory control can be somewhat compensated with vision
Name an important differential for optic neuritis (not MS). What investigation should be done to confirm it?
Neuromyelitis optica spectrum disorders (NMOSD) - autoimmune chronic inflammatory disorder of the CNS primarily affecting the brain and spinal cord
Aquaporin-4 antibody test
Name 4 short-term and 4 long-term adverse effects of corticosteroids
SHORT-TERM: sodium and water retention, oedema, hypertension,
LONG-TERM: weight gain, hirsutism, acne, osteoporosis, delayed wound healing, menstrual irregularity
https://amhonline-amh-net-au.proxy.library.adelaide.edu.au/chapters/immunomodulators-antineoplastics/immunosuppressants/corticosteroids/methylprednisolone
