Case 6 Flashcards
what cells does the nervous system consist of?
The nervous systems consists of two main types of cells:
- Glia – insulate, support and nourish the neurons.
- Neurons – sense change in the environment, convey information and communicate these changes to other parts of the brain.
what are the two major types of glial cells in the nervous system?
- Microglia – CNS phagocytes.
2. Macroglia – scavenger cells that resemble macrophages and remove debris.
what are the 3 types of macroglial cells?
- Oligodendrocytes – myelin formation around axons in the CNS.
- Schwann Cells – myelin formation around axons in the PNS.
- Astrocytes – provide support for nerve fibres and maintain an appropriate neurotransmitter and chemical environment for neuronal signalling as well as maintaining the blood brain barrier.
microglia
- what are they
- what percentage of the total glial cell population
- what do they do
- what are they sensitive to
- how do they achieve this sensitivity
- These are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the CNS.
- 10-15% of the total glial cell population within the brain.
- Microglia are constantly scavenging the CNS for plaques, damaged neurons and infectious agents.
- In the case where infectious agents are directly introduced to the brain or cross the blood-brain barrier, microglial cells must react quickly to decrease inflammation and destroy the infectious agents before they damage the sensitive neural tissue.
- Due to the unavailability of antibodies from the rest of the body, microglia must be able to recognise foreign bodies, swallow them, and act as antigen-presenting cells activating T-cells.
- Since this process must be done quickly to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS.
- They achieve this sensitivity in part by having unique potassium channels that respond to even small changes in extracellular potassium.
oligodendrocytes
- what are they involved in
- ratio of oligodendrocytes to axons
- what does it do
- These are involved in myelin formation around axons in the CNS.
- These provide layers of membrane that insulate axons (myelin), giving rise to a sheath.
- This sheath is interrupted at certain intervals – Nodes of Ranvier.
- One oligodendrocyte cell will provide myelin to several axons.
- Myelin speeds the propagation of nerve impulses down the axons – saltatory conduction.
Schwann cells
- what involved in
- ratio of Schwann cell to axon
- what does it do
- These are involved in myelin formation around axons in the PNS.
- These provide layers of membrane that insulate axons (myelin), giving rise to a sheath.
- This sheath is interrupted at certain intervals – Nodes of Ranvier.
- One Schwann cell will provide myelin to only a single axon.
- Myelin speeds the propagation of nerve impulses down the axons – saltatory conduction.
what are the most numerous glia in the brain and spinal cord?
astrocytes
astrocytes
- what are the subtypes
- what do they do
• There are two subtypes of astrocytes:
- Fibrous Astrocytes – found primarily in white matter.
- Protoplasmic Astrocytes – found primarily in gray matter.
- Both types of astrocytes send processes to blood vessels, where they induce capillaries to form the tight junctions making up the blood-brain barrier.
- They also send processes that envelop the synapses and the surface of nerve cells.
- Protoplasmic astrocytes have a membrane potential that varies with the external K+ concentration but do not generate propagated potentials.
- They produce substances that are tropic to neurons, and they help maintain the appropriate concentration of ions and neurotransmitters by taking up K+ & glutamate & GABA.
- The precursors for astrocytes are radial glial cells.
what do neurones consist of?
Soma (cell body)
Axon
Dendrites (synapses)
Neuronal Membrane – encloses cytoplasm inside the neuron. This is studded with proteins and membrane-associated proteins that pump channels in and out of the cell.
Cytoskeleton – this is the scaffolding of the neuron. It gives the neuron its characteristic shape. It consists of microtubules, microfilaments and neurofilaments.
how can neurones be classified?
Unipolar - sensory neuron
Pseudounipolar– sensory neuron
Bipolar - interneuron (one axon and one dendrite)
Multipolar – motor neuron/ interneuron/ pyramidal cell (single axon and many dendrites - allowing for integration of lot of information from other neurones)
are nerve fibres in the CNS usually myelinated or unmyelinated?
unmyelinated
are nerve fibres in the PNS myelinated or unmyelinated?
Sympathetic nervous system fibres are myelinated.
Parasympathetic nervous system fibres are unmyelinated.
describe axonal transport of proteins and polypeptides
- The transport of proteins and polypeptides, from the soma to the axonal end, for secretion is by axoplasmic flow.
- The proteins are packaged into vesicles by the Golgi apparatus in the soma.
- Vesicles carried down the microtubule (polymer of tubulin) path by kinesin.
- Process is fuelled by ATP.
- Movement from soma to axonal end = Anterograde transport.
- Retrograde transport also occurs whereby terminals send signals to the soma about changes in their metabolic needs. Dyenin is used in this case instead of kinesin.
• Wallerian degeneration – this is a process that results when a nerve fibre is cut/crushed/damaged, in which the part of the axon separated from the soma degenerates distal to the injury.
what are the two types of potentials?
- Electrotonic Potential – this is a non-propagated local potential, resulting from a local change in ionic conductance (e.g. synaptic or sensory that produces a local current). When this spreads along a stretch of the neuronal membrane, it becomes exponentially smaller.
Neurons which are small in relation to their length, such as some neurons in the brain have only electrotonic potentials (e.g. amacrine cells in retina). - Action Potential – this is a propagated impulse.
Longer neurons utilise electrotonic potentials to trigger the action potential.
Initially, there is always an electrotonic potential in a neuron – when this propagates, it becomes an action potential.
describe and explain resting membrane potential
• In neurons, the resting membrane potential is usually about –70 mV, which is close to the equilibrium potential for K+.
• In order for a potential difference to be present across a membrane lipid bilayer:
o There must be an unequal distribution of ions of one or more species across the membrane.
o The membrane must be permeable to one or more of these ion species.
- The permeability is provided by the existence of channels or pores in the bilayer; these channels are usually permeable to a single species of ions.
- In neurons, the concentration of K+ is much higher inside than outside the cell, while the reverse is the case for Na+.
- This concentration difference is established by the Na+/K+ ATPase pump.
- Because there are more open K+ channels than Na+ channels at rest, the membrane permeability to K+ is greater.
- Consequently, the intracellular and extracellular K+ concentrations are the prime determinants of the resting membrane potential, which is therefore close to the equilibrium potential for K+.
explain depolarisation
- In response to a depolarizing stimulus, voltage-gated Na+ channels become active, and when the threshold potential is reached, the voltage-gated Na+ channels overwhelm the K+ and other channels and an action potential results (a positive feedback loop).
- The membrane potential moves toward the equilibrium potential for Na+ (+60 mV) but does not reach it during the action potential, primarily because the increase in Na+ conductance is short-lived.
- The Na+ channels rapidly enter a closed state (inactivated state) for a few milliseconds before returning to the resting state, when they again can be activated.
- In addition, the direction of the electrical gradient for Na+ is reversed during depolarization because the membrane potential is reversed, and this limits Na+ influx.
explain repolarisation & hyperpolarisation
- The voltage-gated K+ channels open.
- This opening is slower and more prolonged than the opening of the Na+ channels, and consequently, much of the increase in K+ conductance comes after the increase in Na+ conductance.
- The net movement of positive charge out of the cell due to K+ efflux at this time helps complete the process of repolarization.
Hyperpolarization
• The slow return of the K+ channels to the closed state leads to hyperpolarization.
Resting Membrane Potential
• This is brought about by the closure of the K+ channels, followed by the action of the Na+/K+ ATPase pump.
how decreasing the external Na+ concentration and increasing the external K+ concentration affect the resting membrane potential?
- Decreasing the external Na+ concentration reduces the size of the action potential but has little effect on the resting membrane potential.
- The lack of much effect on the resting membrane potential would be predicted, since the permeability of the membrane to Na+ at rest is relatively low.
- Increasing the external K+ concentration decreases the resting membrane potential.
how does an increase and decrease in extracellular Ca2+ concentration affect the excitability of nerves?
- Ca2+ ions appear to bind to the exterior surfaces of the sodium channel protein molecule.
- The positive charges of these calcium ions in turn alter the electrical state of the channel protein itself, in this way altering the voltage level required to open the sodium gate.
- A decrease in extracellular Ca2+ concentration increases the excitability of nerve and muscle cells.
- An increase in extracellular Ca2+ concentration can stabilize the membrane by decreasing excitability.
voltage-gated sodium channels
- what made up
- opening and closing
- This channel has two gates—one near the outside of the channel called the activation gate (m gate), and another near the inside called the inactivation gate (h gate).
- In this state normal resting membrane state, the activation gate is closed, which prevents any entry of sodium ions to the interior of the fibre through these sodium channels.
- The same increase in voltage that opens the activation gate also closes the inactivation gate.
- The conformational change that flips the inactivation gate to the closed state is a slower process than the conformational change that opens the activation gate.
what is the refractive period?
• This refractory period is divided into:
- An ‘absolute’ refractory period - No stimulus will excite the nerve.
- A ‘relative’ refractory period - Stronger than normal stimuli can cause excitation.
• The basis of the absolute refractory period, the time which a second action potential cannot occur under any circumstances, is Na+ channel inactivation.
o It is impossible to recruit a sufficient number of Na+ channels to generate a second spike unless previously activated Na+ channels have recovered from inactivation.
• The relative refractory period, during which a stronger than normal stimulus is required to elicit a second action potential, depends largely on delayed K+ channel opening.
o For a certain period after the peak of the action potential, the increased K+ conductance tends to hyperpolarize the membrane, so a stronger depolarizing stimulus is required to activate the population of Na+ channels that in the meantime have recovered from inactivation.
what are neurotransmitters classified into?
Amino Acids:
Glutamate, GABA, Glycine
Amines:
Acetylcholine, Noradrenaline, Dopamine, 5-HT (serotonin), Histamine
Peptides:
Substance P, Opioids (encephalin and dynorphin), NPY
what are receptors classified into?
Ionotropic - forms ion channels.
Metatrotopic - G-protein coupled
metabotropic activation
- when does it occur
- what happens
- how does it compare to ionotropic receptors
Metabotropic activation occurs when:
Binding of transmitter leads to activation of G-proteins.
G-proteins activate effector proteins:
Ion channels
Enzymes that generate 2nd messengers
Slower & longer lasting effects than ionotropic receptors
Neuromodulatory
what is primary and secondary demyelination?
- Primary Demyelination – myelin sheath is damaged or destroyed whilst axons remain intact.
- Secondary Demyelination – myelin sheath is damaged as a result of primary axonal damage.
what does damage in myelin sheaths result in?
- Damage in myelin sheaths results in impaired signal conduction.
- This results in a deficiency in sensation, movement, cognition and other functions.
how can demyelinating diseases be categorised?
Central Nervous System (CNS):
Inflammatory Demyelinating Disease: Multiple Sclerosis
CNS neuropathy: Vitamin B12 deficiency.
Central pontine myelinolysis.
Leukoencephalopathies.
Leukodystrophies.
Peripheral Nervous System (PNS):
Guillain-Baree Syndrome.
Charcot-Marie Tooth disease.
Copper deficiency.
multiple sclerosis
- what is it
- course
- lesions where
- what is spared
- underlying mechanisms
- cure
• Multiple Sclerosis – this is a disease characterised by inflammation, demyelination, and gliosis.
• Lesions are seen particularly in white matter of the CNS.
• The course may be relapsing or progressive.
• Lesions of MS are typically disseminated in time and space.
• Manifestations of MS vary from a benign illness to a rapidly evolving and incapacitating disease requiring lifestyle adjustments.
• The PNS is spared, and most patients have no evidence of an associated systemic illness.
• The underlying mechanisms are:
Destruction of myelin
Failure of myelin production
• There is no known cure.
what are the symptoms of MS? what do neurological symptoms depend on? patterns of symptoms?
• Neurological symptoms depend on the site of lesion.
• The most common symptoms affect the motor, visual, autonomic and sensory problems:
o Loss of sensitivity or changes in sensation: tingling, pins and needles, numbness.
o Muscle weakness, pronounced reflexes, spasms, difficulty in moving.
o Incoordination: ataxia, speech and swallowing problems (dysarthria and dysphargia), visual problems (nystagmus, optic neuritis or dyplopia).
o Feeling tired and acute or chronic pain.
o Bladder and bowel difficulties.
o Depression and unstable mood.
• Symptoms usually follow different general patterns:
o Episodes of sudden worsening - few days: relapses or exacerbations followed by improvement – 85% of cases.
o Gradual worsening over time of symptoms with little or no period of recovery: 10-15% of cases.
o Combination of both- starts are relapsing then becomes progressive.
o Relapses not predictable and occur without warning and do not occur more than twice a year.
what is the epidemiology of MS?
- Multiple Sclerosis is more common in women than men - 3:1
- Incidence = 1 in 500 in England (1 in 1000 in UK)
- The age of onset is typically between 20-40 years (slightly later in men than in women), but the disease can present across the lifespan.
what are the causes/risk factors of MS?
• Prevalence rates increase at higher latitudes:
One proposed explanation for the latitude effect on MS is that there is a protective effect of sun exposure. Low levels of vitamin D are common at high latitudes where sun exposure may be low, particularly during winter months.
Vitamin D deficiency is associated with an increase in MS risk.
• Genetic considerations
MS is not hereditary.
Caucasians are inherently at higher risk for MS than Africans, even when residing in a similar environment.
MS also aggregates within some families.
Specific genes have been linked:
Human Leukocyte Antigen (HLA) – group of genes on chromosome 6 that serves as MHC.
HLA changes account for 20-60% of genetic predisposition.
• Infectious Agents
o Hygiene hypothesis and prevalence hypothesis seem to be involved.
o Hygiene hypothesis is more prevalent.
o Viral cause evidence:
Previous exposure to Human Herpes virus and Epstein-Barr virus leads to a greater risk.
• Other
o MS risk also correlates with high socioeconomic status.
o Smoking, stress
what are the different types of MS?
- Relapsing and remitting MS (85–90%) – relapses (when symptoms worsen), followed by complete or partial recovery, alternate with remissions (when symptoms don’t worsen).
- Secondary progressive MS – this follows on from relapsing/remitting disease – begins with relapses alternating with remissions, followed by gradual progression of the disease.
- Primary progressive MS (10–15%) – progresses gradually from onset with no remissions or obvious relapses, although there may be temporary plateaus.
- Progressive-relapsing MS (< 5%) – progresses gradually, but progression is interrupted by sudden relapses. Rare.
- but no remitting after the attacks
what are three characteristic presentations of RRMS?
- optic neuropathy
- brainstem demyelination
- spinal cord lesions
what are the three main characteristics of MS?
- Inflammation
- Demyelination
- Lesions (plaques)
inflammation in MS:
- role and structure of BBB
- what happens during inflammation
- what happens with MS
- result of infammation
• Blood-Brain Barrier (BBB) - part of capillary system that prevents entry of T cells into the nervous system.
Can become permeable to T cells due to damage by virus or bacteria.
After repair, T-cells remain trapped.
• Structure of BBB:
Endothelial cells which line blood vessel walls of CNS.
ECs are connected by occludin and claudin which forms tight junctions in order to create a barrier.
To cross the BBB, molecules must be taken in by transport proteins/ adhesion molecules or alterations in BBB permeability.
• During Inflammation:
BBB is compromised to active recruitment of lymphocytes and monocytes and their migration across the barrier.
Chemokine release allows activation of adhesion molecules on the lymphocytes and monocytes resulting in interaction with ECs of BBB which then activate the expression of MMP to degrade the barrier.
Disruption of BBB occurs = swelling + activation and infiltration of macrophages and lymphocytes that directly attack myelin sheaths within CNS.
• Multiple Sclerosis:
BBB is disrupted and this enables entering of T-cells that attack the myelin.
Attack starts an inflammatory process whereby cytokines and antibodies are recruited.
This causes swelling, macrophage activation and further recruitment of cytokines etc.
• Result of Inflammation:
Stop neurotransmission by unaffected neurons.
Enhanced loss of myelin.
Cause axon to break down completely.
demyelination process - what happens during relapse?
- T–Lymphocytes are involved; mostly Th-1 and Th-17.
- IL-12 is responsible for the differentiation of naive Th cells into inflammatory T cells.
- Over-production of IL-12 is what causes the inflammation in MS patients, leading to too many inflammatory T cells.
- In MS, these lymphocytes cannot distinguish between normal and foreign myelin cells and thus attack the healthy myelin (oligodendrocytes). This triggers further inflammation with activation of more cytokines and macrophages and T-cells.
demyelination - what happens during remission?
- Oligodendrocytes cannot completely remyelinate or repair a destroyed myelin sheath.
- CNS thus recruits oligodendrocytes stem cells capable of proliferation and migration plus differentiation into mature myelinating oligodendrocytes.
- Newly formed myelin are however thinner and not as effective.
- Repeated attacks (“multiple”) make this worse until a scar-like plaque (“sclerosis”) is built up around the damaged axons.
- Inability of stem cells to myelinate properly can also be due to the astrocytes and prevailing inflammatory conditions.
lesions
- what also called
- what commonly affect
- what is rarely involved
- what is affected
- what takes place to some extent
- what forms the lesions
• Also known as ‘plaques’ and ‘scars’ that form in the nervous system.
• Most commonly affect the white matter in the:
Optic nerve, corpus callosum, cerebellum, brainstem, basal ganglia and spinal cord.
• PNS is rarely involved.
• CNS myelin is made of Oligodendrocytes and these are affected, therefore axons can no longer conduct information properly.
• Remyelination takes place to some extent but oligodendrocytes are unable to completely rebuild the myelin.
• Repeated attacks form scar-like plaque around damaged area.
lesions
- in an active plaque what is there evidence of
- what is there a relative preservation and depletion of
- what happens as lesions become calm
- what is there within an inactive plaque
- In an active plaque there is evidence of ongoing myelin breakdown with abundant macrophages.
- Active lesions are often centred on small veins.
- Within a plaque there is relative preservation of axons and depletion of oligodendrocytes.
- As lesions become calm, the inflammatory cells slowly disappear.
- Within an inactive plaque, little to no myelin is found, and there is reduction in the number of oligodendrocyte nuclei; instead, astrocytic proliferation and gliosis are prominent.
how is pathogenesis initiated? what causes demyelination? (which cells)
• Pathogenesis is initiated by CD4+ TH1 and TH17 T cells that react against self-myelin antigens and secrete cytokines.
TH1 cells secrete IFNγ, which activates macrophages.
TH17 cells promote the recruitment of leukocytes.
- The demyelination is caused by these activated leukocytes and their injurious products.
- The infiltrate in plaques and surrounding regions of the brain consists of T cells (mainly CD4+, some CD8+) and macrophages.
• B cell activation and antibody responses are also necessary for the full development of demyelinating lesions to occur.
what are the clinical manifestations of MS?
• Acute onset:
Impaired vision or sensation.
Fatigue, depression, bladder urgency, weakness, impaired balance, impaired coordination.
• Weakness of limbs – usually as a result of an upper motor lesion. This will result in the loss of tendon reflexes because an MS lesion disrupts the afferent reflex fibres in the spinal cord.
• Optic Neuritis (ON)
Presents as diminished visual acuity, dimness, or colour desaturation in the centre of vision.
These symptoms may be mild or may progress to severe visual loss.
Visual symptoms may be monocular but may be bilateral.
Periorbital pain is also felt.
Afferent pupillary defect is usually present.
Funduscopic examination may be normal or reveal optic disc swelling (papillitis). Pallor of the optic disc (optic atrophy) commonly follows ON.
Visual blurring in MS may result from ON or diplopia.
Diplopia may result from internuclear ophthalmoplegia (INO) or from palsy of the sixth cranial nerve. A bilateral INO is particularly suggestive of MS.
• Sensory Symptoms
Include both paresthesias and hypesthesia (reduced sensation).
Unpleasant sensations are also common.
Pain
Ataxia usually manifests are cerebellar tremors.
Bladder dysfunction and constipation.
- Cognitive Dysfunction - Memory loss, impaired attention etc
- Depression - 50% of patients experience this.
what is the diagnostic criteria for MS?
- Diagnostic criteria for clinically definite MS require documentation of two or more episodes of symptoms and two or more signs that reflect pathology in anatomically noncontiguous white matter tracts of the CNS.
- Symptoms must last for >24 h and occur as distinct episodes that are separated by a month or more.
DIAGNOSIS OF MS: 2017 MCDONALD CRITERIA - Two attacks at two different times Dissemination in Space: - The development of lesions in distinct anatomical locations within the CNS i.e. indicating a multifocal CNS process -brainstem -juxtacortical (next to cortex) -periventricular -spinal cord
Dissemination in Time:
- The development or appearance of new CNS lesions over time
- Positive oligoclonal bands – takes some time for bands to appear, so having positive oligobands means the disease has been going on for a while
what are the diagnostic tests for MS?
• MRI
An increase in vascular permeability from a breakdown of the BBB is detected by leakage of intravenous gadolinium (Gd) (contrast medium) into the parenchyma.
Such leakage occurs early in the development of an MS lesion and serves as a useful marker of inflammation.
Lesions are multifocal within the brain, brainstem, and spinal cord.
• Evoked Potentials Test
These measure the electrical activity of the brain in response to stimulation of specific sensory pathways.
EP tests are able to detect the slowing of electrical conduction caused by damage (demyelination) along these pathways.
Method:
Wires placed on scalp, overlying areas of brain being stimulated.
Sensory input provided (light, sound and sensation).
Record response of brain activity
Visual Evoked Potentials Test – patient sits before a screen on which an alternating check board pattern is displayed.
• CSF
CSF abnormalities found in MS include:
Elevated levels of IgG antibodies.
Oligoclonal bands (due to the degeneration of oligodendrocytes) – detected by electrophoresis.
Proteins that are breakdown products of myelin.
what is the prognosis for MS?
- The effects multiple sclerosis has and how quickly it progresses vary unpredictably.
- Remissions can last months up to 10 years or more.
- Nonetheless, about 75% of people who have multiplesclerosis never need a wheelchair, and for about 40%, normal activities are not disrupted.
Better prognosis:
- Caucasian
- Monofocal onset
- Females
- Onset with optic neuritis or isolated sensory symptoms
- Low relapse rate first 2-5 years
- Long interval to second relapse
- No or low disability at 5 years
- Abnormal MR with low lesion load
- Habits: vitamin D
Poorer prognosis:
- Afro-american or non-white
- Multifocal onset
- Males
- Onset with motor, cerebellar or bladder or bower symptoms
- High relapse rate first 2-5 years
- Short inter attack latency
- Disability at 5 years
- Abnormal MR with
- > _ 2 contrast esiosn
- > _ 9 T2 lesions
- Habits: smoking, high salt intake
- Increase BMI
what is the treatment for MS?
- There is no cure for MS.
- Vitamin D3 supplements
- Methylprednisolone (1g/day for 3days)
- There are drugs that aid in the disease modification: Beta interferons/ Glatiramer acetate/ Fingolimod/ Natalizumab
what’s the treatment for acute relapses?
• Short course of high dose corticosteroids for anti-inflammatory effects.
Methylprednisolone 1g/day for 3 days
or Prednisone 500mg for 5 says.
• Avoid long-term use of frequent steroids.
- High dose corticosteroids either orally or intravenously (i.e. 1gm Methylprednisolone IV once daily for 3 days) can accelerate recovery by reducing inflammatory activity/stabilising the BBB
- BUT:
- no significant effect on MS disease progression
- beneficial effects of successive steroid courses tend to diminish
- steroid side effects such as gastritis, osteoporosis, hypertension, low mood, avascular necrosis of the femoral head, infection
how are relapses and disability prevented in MS?
- beta-interferon
- glatiramer acetate (copaxone)
- fingolimod (gilenya)
- natalizumab (tysabri)
- alemtuzumab (lemtrada)
- other drugs
- immunosuppressants
- teriflunomide (aubagio)
- dimethyl fumarate (BG-12)
beta-interferon
- what used for
- how administered
- what does it do
- mechanism of action
Beta-interferon (1a and 1b) is used for relapsing and remitting diseases.
It is administered by a subcutaneous injection (alternating days).
This is defined as at least 2 attacks of neurological dysfunction over the previous 2/3 years followed by reasonable recovery.
Interferon-beta reduces relapse rates and prevents increase in lesions.
Mechanism of Action:
- Inhibiting T cell activation
- Preventing T cell proliferation
- Blocking T cell migration across the BBB
glatiramer acetate
- what does it do
- mechanism of action
- how administered
This is an immune-modulator which has been shown to reduce relapse frequency.
Mechanism of Action:
1. Binding to MHC class 2 molecules preventing the binding of other antigens.
2. Competing with myelin basic protein (MBP), because it has a similar structure, for binding to T-cell receptor.
Myelin basic protein – protein believed to be important in the process of myelination of nerves in the nervous system by maintaining correct structure of myelin.
3. Inhibiting activation of MBP-reactive T-cells shifts the population of T cells from pro-inflammatory Th1 cells to regulatory Th2 cells that suppress the inflammatory response
It is administered by subcutaneous injection.
fingolimod
- what is it
- how is it administered
- mechanism of action
Fingolimod is a sphingosine 1-phosphate receptor modulator indicated for the treatment of patients with relapsing-remitting multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.
It is given as a tablet, usually 0.5mg.
Mechanism of Action:
1. Fingolimod binds with high affinity to sphingosine 1-phosphate receptor 1.
2. This blocks the capacity of autoreactive lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood; it reduces lymphocyte migration into the central nervous system.
It is thought to reduce annualised relapse rate by approximately 50%.
natalizumab
- mechanism of action
- what useful for
- adverse side effect
α4-integrins are found on the surface of lymphocytes and monocytes and they are required for white blood cells to move into organs (i.e. from blood across the BBB into the brain).
α4-integrins (particularly α4β1) interact with Vascular Cell Adhesion Molecule (VCAM-1), on vascular endothelial cells, to mediate adhesion and migration of immune cells across the BBB.
Natalizumab is a monoclonal antibody which inhibits migration of leucocytes into the CNS.
Mechanism of Action:
1. Prevents binding of lymphocytes to vascular endothelium via α4β1 ligands such as osteopontin and fibronectin which are involved in priming, activation and survival of leucocytes in CNS.
It is useful in severe relapsing remitting MS that is unresponsive to other treatments.
It is, however, associated with a risk of progressive multifocal leukoencephalopathy (PML) (due to reactivation of John Cunningham Virus (JVC) which 70-90% of the population are affected by) and all patients need close monitoring for this and hypersensitivity reactions.
alemtuzumab
- what is it
- how administered
- what does it do
- adverse side effects
Another drug similar to natalizumab, alemtuzumab, is an anti-CD52 monoclonal antibody IV injection once yearly.
It depletes T and B cells and modulates their activity with preservation of neutrophils and NK cells.
Reconstitution enriches for regulatory and memory T cells.
However, adverse side effects include thyroid disorders.
teriflunomide
- what is it
- how does it work
Teriflunomide (Aubagio) is an oral immunomodulator.
- Blocks pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), and thereby T-cell function.
- However, vital salvage pathways are preserved allowing generalized immune surveillance.
dimethyl fumarate
- how does it work
- Activates Nrf-2 transcriptional pathway, a central mechanism of the body’s cellular defence.
- This decreases inflammation and tissue damage.
glucocorticoids
- examples
- what used for
- how do they work
- mechanism of action
- side effects
• Example – Methylprednisolone/ Prednisone
• Methylprednisolone is a synthetic glucocorticoid or corticosteroid drug.
• Used for its anti-inflammatory effects because glucocorticoids have a wide range of effects, including changes to metabolism and immune responses.
• Glucocorticoids also inhibit the generation of some (PGE2 and PGI2) vasodilators.
• Glucocorticoids dramatically reduce the manifestations of inflammation inhibiting both the early and the late manifestations of inflammation. This is due to their profound effects on the concentration, distribution, and function of peripheral leukocytes & lymphocytes and to their suppressive effects on the inflammatory cytokines and chemokines and on other mediators of inflammation.
Glucocorticoids also inhibit the functions of tissue macrophages and other antigen-presenting cells.
Glucocorticoids influence the inflammatory response by reducing the prostaglandin, leukotriene, and platelet-activating factor synthesis that results from activation of phospholipase A2.
Glucocorticoids reduce expression of COX-2 reducing the amount of enzyme available to produce prostaglandins.
• Mechanism of glucocorticoid action: Block the arachidonic pathway by: Enter cells Bind to intracellular receptors in cytoplasm – GRα and GRβ Receptor complex move to nucleus Binds to DNA in nucleus Alters gene transcription (transactivation or transsupression) E.g. induction of lipocortin E.g. repression of IL-3
• Side effects include:
hyperglycemia, decreased resistance to infection, swelling of face, weight gain, congestive cardiac insufficiency, fluid and sodium retention, edema, hypertension.
how can depression by diagnosed?
- Depression can be diagnosed using a Patient Heath Questionnaire (PHQ-9).
- This is used to highlight the symptoms and their frequency in the last 2 weeks.
- If the 5 or more ticks are plotted in the green areas (with one definitely being in the dark green area), then the patient is very likely to be diagnosed with ‘clinical depression’ (MDD).
Patient health questionnaire (PHQ-9) – based on DSM-IV criteria for MDD
- Little interest or pleasure in doing things
- Feeling down, depressed or hopeless
- Trouble falling or staying asleep, or sleeping too much
- Feeling tired or having little energy
- Poor appetite or overeating
- Feeling bad about yourself
- Trouble concentrating on things
- Moving or speaking so slowly that others have noticed
- Thoughts of suicide or hurting yourself
Questionnaire asks whether been bothered by any of these in last two weeks
5 or more of the symptoms present during same 2-week period and represent a change from normal
- Either anhedonia or depressed mood must be present
- Cause significant distress or impairment of functioning
- Not part of Bipolar Disorder
- Not due to the direct physiological effects of a substance (alcohol, drug, medication)
- Not better accounted for by bereavement
describe the epidemiology of depression
- Leading cause of disability worldwide.
- Affects women more commonly than men (50% higher for females).
- About 1 million people commit suicide each year. For every one who commits suicide, there are 20 or more who make an attempt.
- Depression is the leading cause of disease burden for women in both high-income and low- and middle-income countries
what are prominent negative cognitions associated with major depressive disorder (MDD)?
Self – a patient feels as if they aren’t worthy of anything.
World – a patient feels as if the world is too big for them to live happily in.
Future – a patient feels as if they have no future prospects and so there is no point in living.
