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.
what can severe depression involve?
psychosis:
- psychotic guilt – the patient blames themselves for everything bad that happens in the world (e.g. if they see a car accident on TV, they will blame themself for it).
- somatic delusions
- auditory hallucinations (telling yourself to kill yourself)
loss of colour vision
Catatonic retardation – the patient remains lying in bed for days without moving and so they die due to dehydration. (part of psychotic depression)
suicide
how common is recurrence with MDD and what increases it?
Recurrence is the norm (around 73% over 15 years).
Positive family history of depressive illness increases the risk of recurrence.
Earlier age of onset of index episode increases the risk of recurrence.
what is the kindling hypothesis?
- what is usually the cause of the first episode of depression?
MDD is a progressive disease (Kindling Hypothesis):
This hypothesis suggests that depressive episodes become more easily triggered over time:
As the number of depressive episodes increase, future episodes are predicted more by the number of prior episodes rather than by life stress.
Life stress is usually the cause of the first episode.
what are the two types of monoamines?
- Catecholamines – dopamine, noradrenaline, adrenaline
2. Indoleamines – serotonin (5-HT)
the amino acid tyrosine is taken in through our diet and metabolised into what?
noradrenaline (and further into adrenaline)
the amino acid tryptophan is taken in through our diet and metabolised into what?
serotonin (5-HT)
describe the production of dopamine, noradrenaline and adrenaline
- Tyrosine is hydroxilated into L-DOPA.
- L-DOPA is decarboxylated into Dopamine (in brain).
- Dopamine is hydroxilated into Noradrenaline.
- Noradrenaline is converted into Adrenaline.
describe the production of serotonin
- Tryptophan is hydroxilated into 5-Hydroxytryptophan.
2. 5-Hydroxytryptophan is decarboxylated into 5-Hydroxytryptamine (Serotonin).
describe the release, reuptake and degradation of serotonin and noradrenaline
• 5-HT and Noradrenaline released into synaptic cleft.
• Act at a range of pre- and postsynaptic receptors.
• Signal is terminated by 2 methods - reuptake and enzymatic degradation:
Serotonin (5-HT):
5-HT reuptake transporter (5HTT, SERT)
Monoamine oxidase (MAO-A)
Noradrenaline:
Noradrenaline reuptake transporter (NET, NAT)
MAO-A and Catechol-O-methyl transferase (COMT)
- MAO-A (and aldehyde dehydrogenase) breaks down serotonin into 5-Hydroxyindole acetic acid (5-HIAA).
- MAO-A and COMT breaks down serotonin into vanillylmandelic (VMA).
what are the two main classes of noradrenergic receptors?
Alpha receptors (α) – α1 (stimulatory effect), α2 (inhibitory effect)
Beta receptors (β) – β1, β2, β3 (all stimulatory effects)
what are the classes and sub-classes of 5-HT receptors?
overview of the different receptors
5-HT1 – 5-HT1A/ 5-HT1B/ 5-HT1C/ 5-HT1D/ 5-HT1E/ 5-HT1F 5-HT2 – 5-HT2A/ 5-HT2B/ 5-HT2C 5-HT3, 5-HT4 5-HT5 – 5-HT5A/ 5-HT5B 5-HT6, 5-HT7
- 14 receptors
- All G-coupled protein receptors except 1 – 5-HT3 receptor – acts by ligand-gated ion channel
- All of them are stimulatory except for two sub-families which are inhibitory
what is the interaction between serotonin and noradrenaline?
• NOTE: it is important to note that the noradrenaline and serotonin systems function independently BUT there are interactions between the two systems.
• Noradrenaline acts on noradrenergic receptors (α1 and α2) on serotonin neurones (serotonin system).
If noradrenaline binds to the α1 receptor on the cell body of the serotonin neurone, it causes an increase in the release of serotonin (stimulatory effect).
If noradrenaline binds to the α2 receptor on the pre-synaptic membrane of the serotonin neurone, it causes a decrease in the release of serotonin (inhibitory effect).
• This interaction allows for effective interaction between the two systems, with noradrenaline regulating the release of serotonin when needs be.
- Noradrenaline system regulates the serotonin system
- Noradrenaline alpha-2 autoreceptor switches off neurotransmitter release – switches off its own release
- Some of the noradrenaline acts at alpha1 receptors on the serotonin cell body
- So as well as regulating itself, it’s stimulating serotonin release
- However, when noradrenaline acts at alpha2 heteroreceptors on serotonin neurone, it switches off serotonin release
what is the monoamine hypothesis? what are the observations that lead to this hypothesis?
it suggests that depression might result from a problem with the central diffuse modulatory systems
Observations:
1. Resperine (a drug used to control blood pressure) depletes central catecholamines (adrenaline/ noradrenaline) and serotonin by interfering with their loading into synaptic vesicles.
Resperine was found to be a Vesicular Monoamine Transporter (VMAT) blocker.
- Iproniazid (developed for TB), caused a marked elevation in mood, thus acting as an antidepressant.
This was found to be a monoamine oxidase inhibitor (MAOI).
It inhibits the enzyme (MAO) that destroys monoamines, therefore causing an increase in the levels of monoamines (particularly serotonin). - Imipramine is an SNRI antidepressant – inhibits the reuptake of released serotonin and noradrenaline, thus promoting their action in the synaptic cleft.
- There is upregulation of the 5-HT2A receptor in patients with depression.
5-HT2A receptors are found on postsynaptic membranes on glutamate pyramidal neurons and GABA interneurons.
These receptors are upregulated after chronic 5-HT depletion.
Antipsychotics (SGAs) can act as 5-HT2A receptors antagonists, therefore reducing depression. - It is also observed that in patients suffering from recurrent episodes of depression, there is rapid tryptophan depletion. This is because the body is actively metabolising the tryptophan in your diet into serotonin.
Conclusion from observations:
Mood is closely tied to the levels of released “monoamine” neurotransmitters – noradrenaline and serotonin – in the brain.
According to this idea, called the monoamine hypothesis of mood disorders, depression is a consequence of a deficit in one of these diffuse modulatory systems.
Modern drug treatments for depression have in common enhanced neurotransmission at central serotonergic and/or noradrenergic synapses.
what is reserpine? how does it work?
- Vesicular Monoamine Transporter (VMAT) is a transporter protein that transports free cytoplasmic noradrenaline, serotonin and dopamine in the presynaptic nerve terminal into storage vesicles for subsequent release.
- Reserpine ‘irreversibly’ blocks VMAT.
- This causes the cytoplasmic monoamines in the presynaptic nerve terminal to be broken down by MAO and COMT, leading to long-lasting depression.
- It takes days-weeks to replenish depleted VMAT.
MAOI antidepressants
- give example
- describe
- what line of treatment
- iproniazid
These are chemicals which inhibit the activity of the monoamine oxidase (MAO) enzyme, and so are antidepressants.
Because of potentially lethal dietary and drug interactions, MAOIs are reserved as a last line of treatment, used only when other classes of antidepressant drugs (SSRIs or TCA) have failed.
what are the different types of MAOs?
There are two types of monoamine oxidase enzymes:
1. MAO-A
Deaminate (removes and amine group) serotonin, dopamine, melatonin, adrenaline and noradrenaline.
2. MAO-B
Deaminate phenylethylamine and dopamine.
what is the mechanism of action of MAOIs?
- what are MAO-A inhibitors and MAO-B inhibitors used for?
MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability.
Dopamine is equally deaminated by both types.
MAO-A inhibitors : antidepressants
MAO-B inhibitors: Parkinson’s Disease (↑ DA)
describe the reversibility of MAOIs
- why do patients on MAOIs have to go on a special diet
Some MAOIs covalently bind to the monoamine oxidase enzymes, thus inhibiting them ‘irreversibly’ – e.g. iproniazid, phenelzine, tranylcypromine.
The bound enzyme could not function and thus enzyme activity was blocked until the cell makes new enzymes.
Other MAOIs are reversible, meaning that they are able to detach from the enzyme to facilitate usual catabolism of the substrate – e.g. moclobomide.
The level of inhibition in this way is governed by the concentrations of the substrate and the MAOI.
NOTE: a person who is on MAOIs, their body cannot metabolise other monoamines. Therefore patients on MAOIs have to go on a diet (reduced tyramine diet).
Tyramine is a naturally occurring amino acid, involved in monitoring blood pressure.
If foods with tyramine are eaten, whilst on a MAOI, then the blodd pressure can increase drastically.
what are side effects of MAOIs?
The most common side effects of MAOIs include:
Dry mouth; Nausea/Headache; Drowsiness/Insomnia
Other possible side effects include:
Involuntary muscle jerks/muscle aches
Low blood pressure/weight gain/sleep disturbances/reduced sexual desire or difficulty reaching orgasm.
what do TCAs, SNRIs and SSRIs do? give examples of each
- Tricyclic Antidepressants (TCAs)
These block the reuptake of noradrenaline, 5-HT and dopamine.
Examples include: amitriptyline, clomipramine. - Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)
Found to reversibly block 5-HT reuptake transporter (SERT) AND the noradrenaline reuptake transporter (NET) proteins on the presynaptic membrane.
Examples include imipramine, venlafaxine. - Selective-Serotonin Reuptake Inhibitors (SSRIs)
Found to reversibly block 5-HT reuptake transporter (SERT) ONLY.
These result in sustained increase in extracellular 5-HT in a range of brain areas.
Examples include fluoxetine, sertraline, paroxetine, fluvoxamine, escitalopram, citalopram.
antidepressants have a range of differential affinities for what?
SERT (serotonin transporter), NET (norepinephrine transporter) and DAT (dopamine transporter) = all of these are MATs (monoamine transporters)
- all antidepressant can attach to all three transporters, but some have such low affinities that it doesn’t really count
- so SSRIs at clinical dosage just attach to SERT
mirtazapine
- what is it
- what does it cause
- This is a α2 adrenergic receptor antagonist.
- As a result the negative feedback loop to inhibit the release of noradrenaline is blocked.
- This means that there is an increase in the release of noradrenaline.
- Due to the interaction between the noradrenaline and serotonin systems, there is a subsequent increase in the release of serotonin.
ventral neural system
- what is important for
- what are its main structures
- how does this relate to MDD?
Important for identification of emotional significance of stimuli and the production of affective states.
The main structures that constitute the ventral neural system are:
- Ventromedial Orbitofrontal Cortex – deals with sensitivity to pain, anxiety, rumination (thoughtful consideration going on) and tension.
- Ventral Anterior Cingulate – deals with a depressive state of mood.
- Amygdala – modulates visual and attentional processing, particularly of facial expression.
In major depressive disorder (MDD):
- Ventromedial Orbitofrontal Cortex – increased sensitivity to pain, anxiety, depressive ruminations (thoughtful consideration going on) and tension.
- Ventral Anterior Cingulate – depressed mood.
- Amygdala – overly active when shown a sad stimuli, but underactive when shown positive stimuli.
Normalises with treatment.
dorsal neural system
- what important for
- what are its main structures
- how does it relate to MDD
Important for integration of emotional inputs and the performance of executive functions.
The main structures that constitute the ventral neural system are:
DLPFC and Dorsal Anterior Cingulate – deals with apathy, psychomotor function, attention and working memory.
Hippocampus – deals with memory consolidation.
In major depressive disorder (MDD):
DLPFC and Dorsal Anterior Cingulate – increased apathy, psychomotor retardation, deficits in attention and working memory.
Hippocampus – chronic depression leads to a reduction in the hippocampal volume. This is leads to a decrease in memory consolidation.
Normalises with treatment.
what happens with MDD in terms of ventral and dorsal neural systems?
In MDD, there is an overactive ventral neural system AND an underactive dorsal neural system.
what is meant by the diathesis-stress hypothesis? (each word)
- Evidence shows that mood disorders run in families and that our genes predispose us to this type of mental illness.
The medical term for predisposition for a certain disease is diathesis. - Early childhood abuse or neglect, or other stresses of life, are important risk factors in the development of mood disorders in adults.
Combining these two observations, the diathesis-stress hypothesis of mood disorders was proposed.
describe and explain the diathesis-stress hypothesis
- A consistent finding in patients with MDD is a high level of the stress hormone cortisol
- This cannot by physiologically suppressed (impaired dexamethasone suppression test), indicating dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis
- Exaggerated activity in the HPA (hypothalamic-pituitary-adrenal) system is associated with anxiety disorders.
- Anxiety and depression coexist.
- Hyperactivity of the HPA axis is associated with depression.
Chronic stress results in excessive release of glucocorticoids (Cortisol) in the blood. It released from the adrenal cortex in response to an elevation in the blood level of adrenocorticotropic hormone (ACTH).
ACTH is released by the anterior pituitary gland in response to corticotropin-releasing hormone (CRH).
CRH is released into the blood of the portal circulation by parvocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus.
Increased cortisol (glucocorticoids) dysregulate amygdala function.
Increased adrenal activity increases the sympathetic tone, causing a release of proinflammatory cytokines.
The proinflammatory cytokines and glucocorticoids increase the activity of the monoamine oxidase enzyme, resulting in decreased levels of serotonin, noradrenaline and dopamine.
The proinflammatory cytokines and glucocorticoids also reduce neurotrophic factors (neuron growth factors) such as BDNF.
A decrease in BDNF results in the reduction in neurogenesis and a decreased hippocampal volume.
Dysregulated amygdala and hippocampus maintain abnormal glucocorticoids, BDNF and cytokines – vicious cycle.
Increased pro-inflammatory cytokines results in physical illness symptoms. These increase the risk of developing inflammatory disorders such as cardiovascular disease, diabetes etc.
describe the genetic variability in the 5-HT reuptake (5-HTT) gene
There is a variety of alleles:
Short/short (s/s) – people who possess this combination of alleles have a far greater risk of developing depression.
Short/long (s/l) – this is the most common combination of alleles found in the population.
Long/long (l/l) - people who possess this combination of alleles have a far lesser risk of developing depression.
so overall, what does the diathesis-stress hypothesis suggest?
that a hyperactive HPA axis, together with specific genetic variability in the 5-HT reuptake gene can increase the risk of developing depression
what is treatment for mild depression?
• Don’t use antidepressants routinely to treat mild depression but consider using them if there is a history of moderate to severe recurrent depression or the depression has persisted for more then 2-3 months.
• Offer a low-intensity psychosocial intervention:
Individual guided self-help based on the principles of CBT.
Computerised CBT.
A structured group physical activity programme.
what is treatment for moderate or severe depression?
• Combination of antidepressant medication and high-intensity psychological intervention such as CBT.
• Antidepressants (example step-wise 8-10 week trials):
1. SSRI – sertraline or citalopram.
2. Venlafaxine (SNRI), mirtazapine (α2 antagonist)
3. Augmenting agents – e.g. antipsychotics (5-HT2A antagonists) then lithium (mood stabiliser).
4. TCA – amitriptyline or clomipramine.
5. MAOI – moclobomide (reversible) then phenelzine (irreversible).
• Antidepressants reduce the risk of relapse for as long as patients are on them, but protection wears off when stopped:
Odds reduced by around 70%.
Absolute risk reduced by around 50%.
• CBT and Antidepressants have equal acute efficacy, but CBT has a long-lasting protective effect after the end of the course.
electroconvulsive therapy
- what is it
- how effective
- advantages
- disadvantages
- This is the most effective treatment for depression and involves inducing seizure activity in the temporal lobes.
- In electroconvulsive therapy (ECT), electrical currents are passed between two electrodes placed on the scalp.
- Localized electrical stimulation triggers seizure discharges in the brain, but the patient is given anesthesia and muscle relaxants to prevent violent movements during treatment.
• Advantages:
relief can occur quickly, sometimes after the first treatment session
This attribute of ECT is especially important in cases where suicide risk is high
• Disadvantages:
Memory loss
Temporal lobe structures (including the hippocampus) play a vital role in memory
ECT usually disrupts memories for events that occurred before treatment, extending back 6 months, on average
ECT can also, temporarily, impair the storage of new information
• The mechanism by which ECT relieves depression is unknown; however, the hippocampus is affected which is involved in regulating CRH and the HPA axis.
what are different forms of psychotherapy?
Cognitive Behavioural Therapy (CBT), Interpersonal Psychotherapy (IPT) and Problem Solving Therapy (PST).
summary of depression
- is depression just due to low levels of monoamines
- what is depression associated with
- what can precipitate depression
- whether someone develops depression my depend on the relative balance of what
- what is elevated
- what is affected
- what do antidepressants do
- depression is assocated with an increased risk fo what
• Depression NOT simply due to low levels of monoamines.
• Depression is associated with a negative cognitive bias.
• Stress can precipitate depression - But not everyone who is stressed gets depressed
• Whether someone develops depression or not may depend on the relative balance between vulnerability and resilience factors:
One mechanism of resilience involves 5-HT pathways which maintain a positive emotional bias.
Vulnerability is mediated by genetic risk factors, early life adversity, and past episodes of depression etc, which may impair 5-HT mechanisms of resilience.
- Stress and genetic vulnerability elevate glucocorticoid steroids and alter cellular plasticity via downregulation of growth factors (e.g. BDNF) and glucocorticoid receptor sensitivity.
- The reduction in growth factors such as BDNF impacts negatively on the structural and functional processes within the limbic system, especially the hippocampus.
- Chronic and recurrent MDD may result in subsequent atrophy and further disruptions in neurocircuitry e.g. amygdala, ventral anterior cingulate, dorsolateral prefrontal cortex etc.
- Amygdala overactivity is associated with negative cognitive bias (treatable by cognitive therapy).
- HPA axis dysfunction leads to low synaptic levels of 5-HT and NA.
- Antidepressants increase synaptic 5-HT, NA and BDNF and prevent neurotoxic effect of glucocorticoids on hippocampus.
- Depression is also associated with increased inflammatory markers and increased risk of inflammatory disorders such as coronary artery disease.
what is coping and what does it involve?
- Coping is the process of managing stressors that have been appraised as taxing or exceeding a person’s resources.
- Coping has a dynamic nature which involves appraisal and reappraisal, evaluation and re-evaluation.
what does Leventhal’s self-regulatory model show are the two ways of coping? and what are the two other ways?
- approach coping
- avoidance coping
- problem focused
- emotion focused
describe approach and avoidance coping. when is each useful?
- Approach Coping – involves confronting the problem, gathering information and taking direct action.
- Avoidance Coping – involves minimising the importance of the event.
- People tend to show one of these forms of coping.
- The effectiveness of each type of coping is dependent on the nature of the stressor.
- Avoidance coping may be more effective for short-term stressors, but less effective for long-term stressors.
describe problem- and emotion-focused coping.
- These reflect types of coping strategies rather than opposing ways of coping.
- Coping Strategy – a deliberate, rationally planned programme of specific techniques employed to overcome, tolerate, reduce, or minimise stressful events.
- People can show both problem-focused and emotion-focused coping when facing a stressful event.
- Problem-Focused Coping – involves attempts to take action to either reduce the demands of the stressor or to increase the resources available to manage it.
- Emotion-Focused Coping – involves attempts to manage the emotions evoked by the stressful event.
- People use both behavioural and cognitive strategies to regulate their emotions.
- Behavioural strategies – talking to friends about a problem; drinking or smoking; shopping etc.
- Cognitive strategies – denying the importance of the problem; thinking about the problem in a positive way.
what is the Mental Capacity Act designed to do?
- The Mental Capacity Act is designed to protect people who can’t make decisions for themselves or lack the mental capacity to do so.
- This could be due to a mental health condition, a severe learning disability, a brain injury, a stroke or unconsciousness due to an anaesthetic or sudden accident.
what 5 key principles underpin the Act?
- A person must be assumed to have capacity unless it is established that he lacks capacity.
- A person is not to be treated as unable to make a decision unless all practicable steps to help him to do so have been taken without success.
- A person is not to be treated as unable to make a decision merely because he makes an unwise decision.
- An act done, or decision made, under this Act for or on behalf of a person who lacks capacity must be done, or made, in his best interests.
- Before the act is done, or the decision is made, regard must be had to whether the purpose for which it is needed can be as effectively achieved in a way that is less restrictive of the person’s rights and freedom of action.
what does an ‘advance decision’ need to have legal force? what is an advance decision?
To have full legal force, an AD must be in writing, signed by the patient or by another person in patient’s presence and by patient’s direction, the signature is made or acknowledged by patient in the presence of a witness, and the witness signs it, or acknowledges his signature, in patient’s presence.
An advance decision (sometimes known as an advance decision to refuse treatment, an ADRT, or a living will) is a decision you can make now to refuse a specific type of treatment at some time in the future.
“Advance decision” means a decision made by a person after he has reached 18 and when he has capacity to do so, that if:
at a later time and in such circumstances as he may specify, a specified treatment is proposed to be carried out or continued by a person providing health care for him, and
at that time he lacks capacity to consent to the carrying out or continuation of the treatment, the specified treatment is not to be carried out or continued.
when is an advance decision invalid?
• An advanced decision can be withdrawn by a person of capacity, and the power to decide can be given to another.
• It is also invalid if the patient “has done anything else clearly inconsistent with the advance decision remaining his fixed decision”.
• It also has no sway when capacity is present.
• There are other situations in which the advanced decision may not apply:
when treatment “is not the treatment specified in the advance decision”.
when any specified criteria do not obtain.
when “there are reasonable grounds for believing that circumstances exist which patient did not anticipate at the time of the advance decision and which would have affected his decision had he anticipated them.”
not applicable to life-sustaining treatment unless the decision is verified by a statement by patient to the effect that it is to apply to that treatment even if life is at risk, and the decision and statement comply with subsection 6 (which demands a written, signed, and witnessed refusal).
what is Lasting Power of Attorney?
- A legal tool that gives another adult the legal authority to make certain decisions for someone, if they become unable to make them themselves
- The person who is give LPA is known as an ‘attorney’
- They can manage finances, or make decisions relating to a person’s health and welfare
- Anyone who is over the age of 18 and has the mental capacity to do so can make an LPA
- Once a person has lost mental capacity, they will not be able to appoint an LPA – if the person’s family or friends then want to be able to make certain decisions on their behalf, they will need to apply for deputyship
- Lasting Power of Attorney (“LPA”) is a legal document which allows a person who is at least 21 years of age (‘donor’), to voluntarily appoint one or more persons (‘donee(s)’), to make decisions and act on his behalf as his proxy decision maker if he should lose mental capacity one day.
- A donee(s) can be appointed to act in two broad areas: personal welfare as well as property & affairs matters.
what are gamma globulins? what happens in MS?
- Gamma globulins are a class of globulins, identified by their position after serum protein electrophoresis – the most significant gamma globulins are immunoglobulins, although some immunoglobulins are not gamma globulins, and some gamma globulins are not immunoglobulins
- Analysis of CSF obtained during lumbar puncture can provide further supporting evidence of MS diagnosis
- In the CSF of most MS patients, gamma globulin level is elevated
- Due to proliferation of B cells within the nervous system
what does a longer than normal latency in VEP show?
- VEP measures the time that it takes for a visual stimulus to travel from the eye to the occipital cortex
- Longer latency means that it takes longer time for electrical signals to be conducted from the eyes, due to demyelination of the myelin sheath
- Abnormal VEPs are seen in MS patients due to the presence of optic neuritis (inflammation of the optic nerve)
- P100 wave normal latency: 107 msec
- P100 wave abnormal latency: 134 msec
what do lesions show up as on MRI scan?
- Lesions refer to an area of damage or scarring in the CNS
- Caused by inflammation that results from the immune system attacking the myelin sheath
- MRI scan can differentiate between active and non-active lesions
- Active lesions show up in the scan as white patches when a contrast fluid containing gadolinium is injected
- If the lesion doesn’t light up, then it’s likely to be an older lesions, and more than 3 months old
- With regular scans, a neurologist can tell how active your MS is, and to what extent your nerves are being damaged
- Sometimes, lesions will repair themselves and not be seen on subsequent scans
- Persistent lesions may eventually show up as ‘black holes’, where the underlying neuron has suffered irreparable damage
what is the criteria from DSM V for diagnosing depression?
A) 5 of 9 symptoms: - Depressed mood - Decrease interest/pleasure - Weight loss/gain - Inability to sleep or oversleeping - Psychomotor agitation or impairment - Fatigue - Feelings or worthlessness/guilt - Decrease concentration - Thoughts of death or suicidality B) Significant distress to daily life C) Not substance or medical condition D) Not better explained by other mental disorder E) No manic or hypomanic episodes
what is dysthmia?
persistent mild depression
- milder symptoms of depression that happen for long periods of time (2+ years with 2+ symptoms (change in appetite, change in sleep, fatigue/low energy, decrease self-esteem, decrease concentration, hopelessness/pessimism)
what is an Advanced Life Care Plan? what are the key points that should be covered?
- Advance Care Planning (ACP) is the term used to describe the conversation between people, their families and carers and those looking after them about their future wishes and priorities for care
- Key means of improving care for people nearing the end of life and of enabling better planning and provision of care, to help them live well and die well in the place and the manner of their choosing
- Enables people to discuss and record their future health and care wishes and also to appoint someone as an advocate or surrogate
‘Advance care planning is a process that supports adults at any age or stage of health in understanding and sharing their personal values, life goals, and preferences regarding future medical care. The goal of advance care planning is to help ensure that people receive medical care that is consistent with their values, goals and preferences during serious and chronic illness.’
- There are several key points that will usually be covered:
- beliefs and values
- hopes and fears
- involvement and wishes of relatives, carers, friends
- religious and spiritual needs
- wills, funeral arrangements
- organ and tissue donation
- palliative care
- specific treatments such as clinically assisted hydration and nutrition, ventilation
- place of care
- specifying wishes about treatment: advanced decisions, advanced statements, DNACPR decisions, allow natural death
- Lasting Power Attorney
why might antidepressants need to be stopped gradually?
Withdrawal symptoms:
- Dizziness
- Electric head
- Electric shock-like sensations
- Strange tingling or painful sensations
- Muscle spasms
- Nightmares or other vivid dreams
- Agitation
- Hallucinations
- Sensitivity to noises or visual stimuli, temperature, pain or mental stress
what is the forebrain made up of?
cerebrum & diencephalon
what is the most common type of neurone?
multipolar neurone
what type of neurones are long myelinated fibres?
unipolar
where do you find bipolar neurones?
olfactory, retina, ear
what receptors are usually used in glutamatergic synapses? which ones are also used and when?
- Most common excitatory neurotransmitter in the brain is glutamate
- Normally use AMPAR receptors as they’re open whereas NMDAR receptors are closed (because at negative membrane potentials they’re blocked by magnesium)
- However, as the membrane potential gets more positive, the magnesium gets kicked out channel as positive charges repel, so the channel opens
- This allows sodium and calcium to flow in – too much calcium kills cells
what ion is involved in inhibitory neurotransmission?
- Higher concentration of chloride outside the cell
- Chloride flows in making it more negative
what is spatial and temporal summation?
- Spatial summation
- adding of EPSPs (excitatory postsynaptic potential) generated simultaneously on multiple presynaptic inputs
- Temporal summation
- adding of EPSPs generated in quick succession at same synapse
what is stimulus intensity encoded as?
action potential frequnecy
what are the neuronal-glial interactions?
Glia on neurones: - Synapse formation - Synaptic strength - Co-ordination of activity Neurones on glia: - Proliferation - Differentiation - Myelination
what is MS?
Acute localised, and chronic diffuse, inflammation of the CNS and subsequent demyelination of neurons, following the infiltration of immune cells across the BBB
how does MS manifest?
- pain on eye movement, blurring of vision, red colour desaturation
- Uhthoff’s phenomenon – temporary worsening of symptoms caused by an increase in temperature
- Brainstem symptoms
- vertigo, slurred speech, ataxia (lack of muscle control during voluntary movements), incoordination, double vision
- Spinal cord
- sensory – Lhermitte’s sign – a sudden sensation resembling an electric shock that passes down the back of your neck and into your spine and may then radiate out into your arms and legs – usually triggered by bending your head forward towards your chest
- motor – upper and/or lower limb weakness
- bladder, bowels, sexual function
give an example of an upper and lower motor neurone disease
- Upper motor neuron disease:
- Acute central demyelinating disease; e.g. multiple sclerosis - Lower motor neuron disease:
- Acute peripheral demyelinating disease; e.g. Gullian burre syndrome
where are common sites of demyelination in MS?
- Corpus callosum
- Cerebellum
- Optic nerve
- Brainstem
- Spinal cord
what do the compare the CSF with when looking for oligoclonal bands?
- Oligoclonal bands = immunoglobulins within the CSF
- Compare the serum with the CSF
- You see bands in the CSF but no bands in the serum
what is the inheritance risk for MS?
- 1:500 – general risk
- If first degree relative has MS, risk is 1:25
- Monozygotic twins – 25%
- Both parents with MS – 30%
what’s the difference in the brain in relapsing-remitting and secondary progression?
relapsing-remitting = inflammation
secondary progression = nerve cell loss
what do you have to have to be eligible for MS treatment?
two relapses over two years
what is rapidly evolving severe RRMS?
> _ two relapses per year
what are low risk/gain to high risk/gain DMTs?
- Lower risk/gain – interferon B
- Medium risk/gain – alemtuzumab
- High risk/gain – natalizumab, mitoxantrone, ASCT
what are the injectable DMTs?
Beta interferon: 30% reduction in relapse rate
- Interferon beta 1a:
- Avonex: IM weekly
- Rebif: SC (subcutaneous) Thrice weekly
- Interferon beta 1b:
- Betaferon: SC alternate days
Glatiramer acetate: 30% reduction in relapse rate
- Copaxone: SC daily
Alemtuzumab (monoclonal antibody): 80% reduction in relapse rate
- Lemtrada: IV two courses
Natalizumab (monoclonal antibody): 80% reduction in relapse rate
- Tysabri: IV monthly
what are the oral DMTs?
Dimethyl Fumerate (BG2): 50% reduction in relapse rate - Tecfidera
Teriflunomide: 30% reduction in relapse rate
- Aubagio
Fingolimod: 50% reduction in relapse rate
- Gilenya
- Cladrabine: 50% reduction in relapse rate
- Mavenclad
whats’s the problem with alemtuzumab?
ALEMTUZUMAB – RISK OF OTHER AUTOIMMUNE DISEASES
- Antibody mediated autoimmune diseases
- Thyroid disease 30%
- hyperactive
- underactive
- Immune thrombocytopenia
- Goodpasture syndrome
- Alemtuzumab requires regular blood monitoring
what’s the composition of the myelin sheath?
Lipids
- Galactocerebroside
Glycoproteins
- Myelin basic protein (MBP)
- Myelin oligodendrocyte glycoprotein (MOG)
- Myelin associated glycoprotein (MAG)
where are voltage-gated Na+ channels only present along axons?
node of Ranvier
which chromosome is there a genetic association with MS?
6, which also contains MHC class genes and myelin proteins
what is the major histocompatibility complex? what is the problem with MS?
THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)
- Plays a pivotal role in the execution of the immune system
- Divided into three subgroups called class I, class II and class III
- Found on antigen-presenting cells (APCs)
- Anchored in the cell membrane of APCs, where they display short polypeptides to T cells, that are recognised by the T cell receptors (TCRs)
- T cells should ignore self-peptides while reacting appropriately to the foreign peptides
- Problem in MS: recognition of self-antigens (myelin proteins)
summarise the pathogenesis of MS
- An infection by a virus or bacteria
- Antigen gets into the blood stream, it is digested by a macrophage (APC)
- The macrophage cell displays the antigen with an MHC molecule
- The MHC-antigen can be recognised by special receptors on the surface of T cell
- The activate Th cells cross the BBB
- Once in the CNS, Th cells encounter local APCs (i.e. microglia)
- APCs present a MHC-antigen complex (containing myelin product) to T-cells; the Th cells are locally re-activated when they recognise their antigen on the surface of local ACPs (epitope-self-protein of the MBO, MOG or MAG)
- The activated Th cells secrete cytokines that
- >stimulate microglia and astrocytes
- >recruit additional inflammatory cells from peripheral blood (macrophages, B cells)
- >induce antibody production
- >complement system production - Demyelination, oligodendrocyte degeneration
what signs and symptoms does a lesion in the cerebrum cause?
symptoms:
- cognitive impairment
- sensory and motor deficit
- depression
- epilepsy (rare)
- focal cortical deficit
signs:
- deficit in attention, reasoning and executive function (early), dementia (late)
- upper motor neuron signs
what signs and symptoms does a lesion in the optic nerve cause?
symptoms:
- loss of vision
- delayed VEP
signs:
- scotoma
- reduced visual acuity
- colour vision
- pupillary defect
what signs and symptoms does a lesion in the cerebellum and cerebellar pathways cause?
symptoms:
- tremor
- clumsiness, poor balance
signs:
- postural and action tremor
- dysarthria
- limb coordination
- gait ataxia
what signs and symptoms does a lesion in the brainstem cause?
symptoms:
- vertigo
- impaired speech and swallowing
signs:
- dysarthria
what signs and symptoms does a lesion in the spinal cord cause?
symptoms:
- weakness
- stiffness and spasms
signs:
- upper motor signs
- spasticity
describe the noradrenaline system
- Tyrosine is a dietary, non-essential, large neutral amino acid (LNAA)
- Active transport across BBB
- Converted into NA (noradrenaline) in neuronal cell bodies in pons, particularly locus ceruleus
- NA packaged into vesicles and transported along axon to terminals for release
- NA system extends extensively to entire brain
describe the serotonin system
- Tryptophan is a dietary, essential, large neutral amino acid (LNAA)
- Active transport across BBB
- Converted into 5-HT in neuronal cell bodies in a chain of brainstem nuclei (raphe nuclei), particularly the dorsal and medial raphe
- 5-HT packaged into vesicles and transported along axon to terminals for release
- 5-HT system extends extensively to entire brain
describe the amygdala functionally and structurally in people with MDD?
AMYGDALA IN MDD (FUNCTIONAL)
- Amygdala modulates visual & attentional processing, particularly of facial expression
- In depression, the amygdala is overly active in people with MDD when shown sad stimuli, but under-active when shown positive stimuli like things that they would be rewarded by, or even smiling faces
AMYGDALA IN MDD (STRUCTURAL)
- Enlargement of the amygdala in patients with a first episode of major depression
- Possible that gets bigger due to being overactive
- All possible that people that already have a large amygdala are more prone to depression
what happens to the hippocampus in people with MDD?
REDUCED HIPPOCAMPAL VOLUME IN MDD
- Hippocampus is smaller, shrivelled and underactive in depression
- Longer durations during which depressive episodes go untreated with antidepressant medication are association with reductions in hippocampal volume
- Antidepressants may have a neuroprotective effect during depression
- Reduction comparing patients with chronic vs. recovered depression
- Hippocampal atrophy associated with chronicity and Rx resistance in other studies
- Hippocampi may be smaller to begin with (vulnerability) but get progressively smaller with MDD
what is the difference between an advanced decision and an advanced statement?
Advance Decision to Refuse Treatment – what you don’t want
Advanced Statement – what you would like
- a valid ADRT is legally binding
- an advance statement is not legally binding
when can an Advance Decision only be considered valid?
- You are aged 18+ and had the capacity to make, understand and communicate your decision when you made it
- You specify clearly which treatments you wish to refuse
- You explain the circumstances in which you wish to refuse them
- It is signed by you and by a witness if you want to refuse life-sustaining treatment
- You have made the advance decision of your own accord, without any harassment by anyone else
- You haven’t said or done anything that would contradict the advance decision since you made it (for example, saying that you have changed your mind)
