Multiple Sclerosis

Question 1

Describe the pathogenesis of MS

Answer 1

t cells activated in peripheries, migrate to CNS and bind

Question 2

What is the triad of MS?

Answer 2

Inflammation, demyelination and gliosis (non-specific reactive change of glial cells) in response to damage to CNS

Question 3

What is the genetic link in MS?

Answer 3

VERY HIGH- 150x in monozygotic twin

HLA-DR2 of MHC? IL2 or 7 receptor genes (balance between pathogenic effector T cells and protective regulatory T cells)

Question 4

What cells are the problem in MS?

Answer 4

TH17 T cells that react against self myelin antigens and secrete cytokines.
TH1 cells secrete IFNgamma, which activates macrophages, and TH17 cells
promote the recruitment of leukocytes. The demyelination is caused by these activated leukocytes and their injurious
products.

Question 5

What is a possible mechanism of MS? (hint measles)

Answer 5

1˚ event – measles infection -> induction of measles specific T cells reacting with peptide EISDNLGQE (7/9 similar to myelin basic protein
EISFKLGQE)
2˚ event – meningitis/trauma (disruption of BBB) allows presentation of myelin basic protein EISFKLGQE to measles-primed T cells -> results in demyelination

Question 6

What are the common initial complaints of MS?

Answer 6

focal weakness, numbness, tingling, unsteadiness in a limb, sudden loss or blurring of vision in one eye, diplopia, disequilibrium or bladder function disturbance (urgency or hesitance)

Question 7

What are the investigations of MS?

Answer 7

Dianosis is mainly clinical (2 events disseminated in space and time)
1st: Brain/spine MRI and general tests for exclusion of other conditions (FBC, vit B12, TSH, LFT, comprehensive metabolic panel)
2nd line: CSF evaluation, evoked potentials

Question 8

What are the areas that need to be affected in MS?

Answer 8

periventricular
juxtacortical
infratentorial
spinal cord

Question 9

What are some good prognostic factors for MS?

Answer 9

Optic neuritis or sensory symptoms at onset.
oPatients <2 relapses in the first year of onset.
Patients with minimal impairment after 5 years.
Long intervals between attacks
Complete recovery from early attacks
Sensory attacks

Question 10

What is the prevelence of MS?

Answer 10

39/10 000

Question 11

How is vibration sensed?

Answer 11

The higher frequency vibratory signals originate from the pacinian corpuscles in the skin and deeper tissues, but lower frequency signals (below 200 per second) can also originate from Meissner’s corpuscles.
These signals are transmitter only in the medial lemniscus pathway, therefore vibration is used to test functional integrity of the dorsal columns.

Question 12

How is proprioception sensed?

Answer 12

At extremes of joint angulation, stretch of the ligaments and deep tissues around the joints is important. Pacinian corpuscles, Ruffini’s endings and Golgi tendon receptors found in muscle tendons are used for this.
Pacinian corpuscles and muscle spindles are especially adapted for detecting rapid rates of change. These are the receptors most responsible for detecting rate of movement.
Proprioceptive information is relayed via the spinocerebellar pathway to the cerebellum.

Question 13

How is pain sensed?

Answer 13

Three types of nociceptors: thermal, mechanical, polymodal. (fast carreid in type A delta fibres)
Neospinothalamic tract: dorsal horn cross immediately and pass to brain in the anterolateral columns
Paleospinothalamic: Dorsal horns (SG) cross and join neo

Question 14

What can go wrong at neuromuscular junction?

Answer 14

Myasthenia gravis:
Autoantibodies act against ACh receptors, causing them to be internalized and degraded, therefore the neuromuscular junction becomes abnormal and there is a defect in the conduction of nerve impulses at the neuromuscular junction.
The patient gets clinical features of chronic fatigable weakness but no muscle wasting.
Diagnosis can be made by administering anticholinesterases which allows optimal stimulation of receptors and improved muscle strength is observed.

Question 15

What is polyneuropathy?

Answer 15

Sensory loss is generally symmetric and is greater distally than proximally, as suggested by ‘sock and glove’ sensory loss.
Can be caused by idiopathic inflammatory neuropathies, uremia, vitamin B12 deficiency, diabetes, Guillain Barre syndrome and alcoholism.

Question 16

What is Guillain Barre syndrome?

Answer 16

Autoimmune disorder that causes peripheral nervous system demyelination and longterm neurodegenerative changes.
Motor features of paralysis, hyporeflexia/areflexia and nerve conduction studies show motor conduction slowing.

Question 17

What happens in complete spinal sensory syndrome?

Answer 17

With a complete transverse disruption of the spinal cord, the most striking loss is of power.
Most characteristic is a loss of all forms of sensation below a level that corresponds to the lesion.
There may be a narrow zone of hyperesthesia at the upper margin of the anesthetic zone.
Loss of pain, temperature and touch sensation begins one or two segments below the level of the lesion. Vibratory and position senses have less discrete levels

Question 18

What happens in Hemisection of the spinal cord (brown sequard syndrome)

Answer 18

Pain and thermal sensation are affected on the opposite side of the body, and proprioceptive sensation is affected on the same side of the lesion.
The loss of pain and temperature sensation begins one or two segments below the lesion.
An associated spastic motor paralysis on the side of the lesion completes the syndrome.

Question 19

What happens in a lesion of the grey matter> (syringomyelic syndrome)

Answer 19

Because fibers conducting pain and temperature sensation cross the cord in the anterior commissure, a lesion of the considerable vertical extent in this location characteristically abolishes these modalities on one or both sides over several segments (dermatomes) but spares tactile sensation.
This type of dissociated sensory loss usually occurs in a segmental distribution, and because the lesion frequently involves other parts of the grey matter, varying degrees of segmental amyotrophy and reflex loss are usually present as well.
If the lesion has spread to the white matter, corticospinal, spinothalamic and posterior column signs will be conjoined.

Question 20

What happens in Posterior column syndrome?

Answer 20

Paresthesias in the form of tingling and pins and needles sensations or girdle and band-like sensations are common complaints with posterior column disease.
Loss of vibratory and position sense occurs below the level of the lesion, but the perception of pain and temperature is affected relatively little or not at all.
The loss of sensory function that follows a posterior column lesion may stimulate a parietal “cortical” lesion, but differs in that vibratory sense is also lost in spinal cord syndromes.
The loss of sensory function includes impaired two point discrimination, figure writing, detection of size, shape, weight and texture of objects, and ability to detect the direction and speed of a moving stimulus on the skin.

Question 21

What happens in an anterior myelopathy?

Answer 21

With infarction of the spinal cord in the territory of supply of the anterior spinal artery or with other lesions that affect the ventral portion of the cord predominantly, as in some cases of myelitis, one finds a loss of pain and temperature sensation below the level of the lesion but with relative or absolute sparing of proprioceptive sensation.
Because the corticospinal tracts and the ventral grey matter also lie within the area of distribution of the anterior spinal artery, spastic paralysis is a prominent feature.

Question 22

What are the functions of CSF?

Answer 22

1. Buoyancy
2. Protection
3. Chemical stability
4. Prevention of brain ischaemia

Question 23

What are the characteristics of CSF?

Answer 23

Osmotic pressure approx. equal to that of plasma.
Sodium ion concentraltion also approx. equal to plasma.
Chloride about 15% greater than in plasma.
Potassium, approx. 40% less than in plasma.
Glucose, approx. 30% less than in plasma

Question 24

Describe the formation and flow of CSF

Answer 24

see notes

Question 25

What is Cushing’s triad and what is it for?

Answer 25

Raised ICP :hypertension, bradycardia and irregular respirations
Can also have headache, nausea, vomiting and progressive mental status decline

Question 26

How do glucocoritcoids work?

Answer 26

Enter cell- bind to GR alpha (normally has heat shock protein attached)- HSP dissociates and undergoes a confirmational change that exposes a DNA binding site. Forms heterodimers or homodimers and translocates to the nucleus- upregulates anti inflamm and deregulates proinflam (decreased COX, IL1-8, TNF)

Question 27

How do interferons work?

Answer 27

Periphery: decreases suppression of MCH, increases anti and decreases pro cytokines
CNS: Acts on blood brain barrier by interfering with T cell adhesion to the endothelium by binding VLA-4 (an integrin normally expressed on leukocyte plasma membranes) on T cells, or by inhibiting the T cell expression of MMP (matrix metalloproteinases). Reduction in T cell activation by interfering with HLA class II costimulatory molecules. Immune deviation of TH2 over TH1 cytokine profile.

Question 28

How does Glatiramer acetate work?

Answer 28

A synthetic polypeptide. Its mode of action is not completely understood but it may block presentation of certain myelin antigens to T lymphocytes

Question 29

Natalizumab

Answer 29

monoclonal antibody to alpha-4 integrins. Its exact mode of action is unknown, however it is thought to inhibit leukocyte migration from blood into CNS, thus reducing inflammation and demyelination.