Rachel power MS Flashcards
Define Multiple sclerosis
Multiple sclerosis (MS) is a type IV hypersensitivity reaction characterized by an autoimmune response against the myelin sheath of axons in the central nervous system (CNS). It is marked by at least two regions of demyelination in the CNS, separated by time and space, leading to neurological symptoms that can vary widely depending on the location of the lesions.
Outline type IV hypersensitivity reactions
-Type IV hypersensitivity reactions are mediated by T cells, predominantly Th1, Th17, and cytotoxic CD8+ T cells.
-The hypersensitivity reaction is typically delayed in terms of manifestation, usually 48-72 hours after antigen exposure.
-These reactions develop following the presentation of an antigen (foreign or self) to a naive T cell, which can then differentiate into Th1, Th17, or cytotoxic T cells.
-Th1 cells cause tissue damage through the release of inflammatory cytokines, particularly IFN-gamma and TNF-alpha, which activate macrophages and amplify inflammation.
-Th17 cells contribute to inflammation through cytokines like IL-17, which recruits neutrophils.
-Cytotoxic CD8+ T cells cause inflammation and tissue damage through direct cytotoxic injury to tissue, using perforin and granzymes to kill target cells.
Examples:
MS
TB
Contact dermatitis
Type 1 diabetes
Describe the pathogenesis of multiple sclerosis
Multiple sclerosis (MS) pathogenesis involves the presentation of antigens related to the myelin sheath by antigen-presenting cells (APCs) on MHC class II molecules to naïve Th0 cells in peripheral lymphoid tissues.
Th0 cells differentiate into Th1 or Th17 cells, depending on the cytokine environment: IL-12 promotes Th1 differentiation, while TGF-β and IL-6 promote Th17 differentiation.
Autoreactive T cells produce cytokines that contribute to the disruption of the blood-brain barrier (BBB), facilitating the infiltration of immune cells into the central nervous system (CNS). This process is driven by an increase in the expression of adhesion molecules (e.g., VCAM-1) on the endothelial cells of the BBB in response to these cytokines. The interaction between integrins (e.g., alpha-4 integrin) on T cells and these adhesion molecules allows T cells to adhere to the BBB and transmigrate into the CNS
In the CNS, Th1 cells release IFN-γ, which recruits macrophages, NK cells, and other immune cells to attack the myelin sheath. IFN-γ also inhibits the differentiation of oligodendrocyte precursor cells (OPCs), limiting remyelination.
Th17 cells secrete IL-17, which exacerbates BBB disruption and recruits neutrophils and macrophages, amplifying inflammation.
B cells in the CNS contribute by producing autoantibodies against myelin, further driving demyelination.
Macrophages phagocytose myelin debris, while oligodendrocytes undergo apoptosis due to inflammation, oxidative damage, and excitotoxicity from excessive glutamate release. Axonal damage also occurs as a consequence of chronic demyelination. Partial remyelination may occur, but it is typically incomplete, leading to chronic neurodegeneration.
MS plaques appear as well-demarcated, glassy lesions in periventricular white matter, optic nerves, and spinal cord, representing areas of demyelination and gliosis
Give 3 reasons why remyelination is incomplete in MS
- Rate of demyelination > rate of remyelination
- Reduced maturation and differentiation of oligodendrocyte-precursor cells by effector T cells and IFN-y.
- Reduced absolute number of OPCs available –> because IFN-y gamma induces expression of immunoproteosome and MHC-1 in OPC’s which can then be target by CD8+ cytotoxic T cells.
What are dawsons fingers?
Dawson’s fingers are best seen on T2-weighted or FLAIR MRI sequences.
They are areas of hyperintensity oriented perpendicular to the lateral ventricles and often involve the periventricular region.
They are associated with perivenular demyelination, typically surrounding small veins.
List 3 findings on lumbar puncture which support a diagnosis of MS?
- Oligoclonal bands in the CSF
-Found following electrophoresis of CSF sample.
-Represents immune-mediated inflammation in the CNS involving the production of IgG antibodies which are not found in patient blood serum. - Increased amounts of Myelin basic protein
-Represents active demyelination. - Increased mononuclear cells (normal is <5mm/3) mainly lymphocytes and monocytes (macrophages) –> suggests ongoing CNS inflammation
How is demyelination of optic tracts detected by visual evoked potentials?
Visual evoked potentials involve placing an electrode on the occiput (visual cortex). The patient is then shown a visual stimulus in a darkened room, typically flashing checkered board.
The latency (time delay) and amplitude (strength) of the signals reaching the visual cortex is measured and graphed. This therefore represents how fast a signal can travel through the optic pathway.
Demyelination along optic pathway in MS (commonly optic neuritis) is characterized by delayed latency in the P100 wave and may also show reduced amplitude of P100 wave.
VEP’s can detect demyelination in clinically silent/assymptomatic plaques
List 4 abnormal findings found on neurological examination that may be seen in a patient with MS
Abnormal eye movements
(i)Nystagmus
–>internuclear ophthalmoplegia caused by demyelination of the medial longitudinal fasciculas (weak adduction of affected eye and abduction nystagmus of unaffected eye)
–>lesions in the cerebellar fibres can also cause nystagmus.
(ii) Optic neuritis
(iii) Conjugate lateral gaze disorder (failure of affected eye to abduct due to demyelination of abducens nerve)
Demyelination of dorsal column fibres
(iv) Sensory ataxia
–> broad base gait, foot slapping, positive rombergs test, difficult heel-shin test, impaired joint position sense
(v) Asterognosis
(vi) Decrease in 2 point discrimination
Demyelination of cerbellar fibres
DANISH
Dysdiadochokinesia
Ataxia
Nystagmus
Intention tremor
Scanning/staccato speech
Hypotonia
demyelination of descending motor tracts
–> Increased muscle tone/spacticity
–> increased deep tendon flexors
–> muscle weakness
List 4 contraindications to lumbar puncture
- increased ICP (papilloedema)
- spinal abcess/soft tissue infection at puncture site
- Risk of herniation e.g. arnold chari malformation
- Anticoagulant therapy
- Congential spinal abnormalities
- Thrombocytopenia
list 5 causes of acute vision loss and fundoscopic findings for each
(1) Optic neuritis
-fundoscopy may be normal or show disc swelling and hyperemia of retinal vessels.
(2) Retinal artery occlusion
-Pale retina + cherry red spot
-Retina is pale due to hypoperfusion, the fovea is avascular and so is not edematous, allowing for reflection of underlying choroidal vessels.
(3) Retinal vein occlusion
-Macular oedema
-blot haemorrages
-Cotton wool spots
-optic disc swelling
(4) Papillodema
-Bulging of optic disc
-blurring of disc margins
-engorgement of retinal veins
-Obscured view of vessels entering disc
(5) Retinal detachement
-billowing of sensory retina toward centre of globe
List the layers through which a needle passes to sample CSF
Skin –> Subcutaneous tissue –> supraspinous lig –> interspinous lig –> ligamentum flavum –> epidural space –> dura –> arachnoid –> sub arachnoid space + CSF
how is L4 found before a lumbar puncture?
With patient standing, a line is drawn between the highest point of top of the iliac crests marking L4
Describe the composition of myelin
Myelin refers to the plasma membrane of the oligodendrocyte or schwann cell which has encircled itself around and axon.
The composition differs slightly between oligodrocytes (CNS) and schwann cells (PNS)
CNS i.e. oligodendrocytes
(i) 50% proteolipid protein (PLP) which compacts the intraperiod line.
(ii) 30% Myelin basic protein: compaction at the major dense line
(iii) 1% Myelin associate glycoprotein: initial formation and maintenance of the myelin sheath by mediating interactions between oligodendrocytes and axons.
(iv) remainder is Myelin oligodendrocyte glycoprotein and cyclic nucleotide phosphodiesterase
PNS i.e. schwann cells
(i) Protein Zero (P0): 50-60% of the total protein in PNS myelin.
Formation, compaction, and maintenance of myelin structure by stabilizing the intraperiod line.
(ii) Myelin basic protein: compaction at the major dense line
(iii) 1% Myelin-Associated Glycoprotein (MAG):
plays a role in myelin-axon interactions and is critical during the early stages of myelination.
(iv) Myelin Protein 22 (PMP22):
Minor Component: PMP22 accounts for around 2-5% of PNS myelin protein: stability and integrity of the myelin sheath and is also involved in Schwann cell differentiation. Mutations in PMP22 are associated with disorders like Charcot-Marie-Tooth disease.
list 4 consequences of demyelination
(1) Conduction block
(2) slower conduction time
(3) increased fatigue due to compensatory efforts
(4) Muscle weakness, tremor, spasticity
List 4 drugs that can be used to relieve spaciticity and MOA
Botulinum toxin
*Enters into the presynaptic neuron’s end terminal via endocytosis and releases its light chain into the cytosol.
*The light chain then cleaves synaptobrevin/Syntaxin component of the SNARE protein associated with the neurotransmitter vesicle.
*This prevents appropriate docking and binding of the vesicle to the axon terminal meaning it can’t release acetylcholine into the synaptic cleft thereby preventing muscle contraction and relieving spasticity.
Baclofen
*Baclofen works within the spinal cord to reduce release of excitatory neurotransmitters, particularly glutamate, which ultimately prevents downstream excitation of motor neurons supplying skeletal muscle.
*It binds to the GABA-B receptor and inhibits opening of VG calcium channels in the pre-synpatic neuron, thereby preventing release of glutamate. It can also work post-synaptically to trigger opening of K+ channels leading to hyperpolarization. This inhibits mono and polysynpatic reflexes.
Diazepam
*Allosterically Binds to the GABA-A receptor of post synaptic neuron, between the alpha 1 and gamma 2 subunit.
*This enchances opening of chloride channels resulting in chloride influx and subsequent hyperpolarisation of the neuron.
*This makes neurons less excitable and less able to cause excitatory stimulation of lower motor neurons to skeletal muscle.
Dantrolene
-Works within the skeletal muscle, inhibiting the ryanodine 1 receptor of the SR which is responsible for mediating calcium release from SR.
-Calcium would normally bind to troponin to allow for interaction between actin and myosin to cause contraction
