Case 6

Question 1

what cells does the nervous system consist of?

Answer 1

The nervous systems consists of two main types of cells:

1. Glia – insulate, support and nourish the neurons.
2. Neurons – sense change in the environment, convey information and communicate these changes to other parts of the brain.

Question 2

what are the two major types of glial cells in the nervous system?

Answer 2

1. Microglia – CNS phagocytes.

2. Macroglia – scavenger cells that resemble macrophages and remove debris.

Question 3

what are the 3 types of macroglial cells?

Answer 3

1. Oligodendrocytes – myelin formation around axons in the CNS.
2. Schwann Cells – myelin formation around axons in the PNS.
3. 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.

Question 4

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

Answer 4

• 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.

Question 5

oligodendrocytes

• what are they involved in
• ratio of oligodendrocytes to axons
• what does it do

Answer 5

• 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.

Question 6

Schwann cells

• what involved in
• ratio of Schwann cell to axon
• what does it do

Answer 6

• 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.

Question 7

what are the most numerous glia in the brain and spinal cord?

Answer 7

astrocytes

Question 8

astrocytes

• what are the subtypes
• what do they do

Answer 8

• There are two subtypes of astrocytes:

1. Fibrous Astrocytes – found primarily in white matter.
2. 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.

Question 9

what do neurones consist of?

Answer 9

 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.

Question 10

how can neurones be classified?

Answer 10

 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)

Question 11

are nerve fibres in the CNS usually myelinated or unmyelinated?

Answer 11

unmyelinated

Question 12

are nerve fibres in the PNS myelinated or unmyelinated?

Answer 12

 Sympathetic nervous system fibres are myelinated.

 Parasympathetic nervous system fibres are unmyelinated.

Question 13

describe axonal transport of proteins and polypeptides

Answer 13

• 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.

Question 14

what are the two types of potentials?

Answer 14

1. 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).
2. 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.

Question 15

describe and explain resting membrane potential

Answer 15

• 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+.

Question 16

explain depolarisation

Answer 16

• 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.

Question 17

explain repolarisation & hyperpolarisation

Answer 17

• 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.

Question 18

how decreasing the external Na+ concentration and increasing the external K+ concentration affect the resting membrane potential?

Answer 18

• 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.

Question 19

how does an increase and decrease in extracellular Ca2+ concentration affect the excitability of nerves?

Answer 19

• 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.

Question 20

voltage-gated sodium channels

• what made up
• opening and closing

Answer 20

• 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.

Question 21

what is the refractive period?

Answer 21

• This refractory period is divided into:

1. An ‘absolute’ refractory period - No stimulus will excite the nerve.
2. 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.

Question 22

what are neurotransmitters classified into?

Answer 22

Amino Acids:
 Glutamate, GABA, Glycine

Amines:
 Acetylcholine, Noradrenaline, Dopamine, 5-HT (serotonin), Histamine

Peptides:
 Substance P, Opioids (encephalin and dynorphin), NPY

Question 23

what are receptors classified into?

Answer 23

 Ionotropic - forms ion channels.

 Metatrotopic - G-protein coupled

Question 24

metabotropic activation

• when does it occur
• what happens
• how does it compare to ionotropic receptors

Answer 24

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

Question 25

what is primary and secondary demyelination?

Answer 25

* 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.

Question 26

what does damage in myelin sheaths result in?

Answer 26

* Damage in myelin sheaths results in impaired signal conduction. * This results in a deficiency in sensation, movement, cognition and other functions.

Question 27

how can demyelinating diseases be categorised?

Answer 27

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.

Question 28

multiple sclerosis - what is it - course - lesions where - what is spared - underlying mechanisms - cure

Answer 28

• 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.

Question 29

what are the symptoms of MS? what do neurological symptoms depend on? patterns of symptoms?

Answer 29

• 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.

Question 30

what is the epidemiology of MS?

Answer 30

* 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.

Question 31

what are the causes/risk factors of MS?

Answer 31

• 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

Question 32

what are the different types of MS?

Answer 32

1. Relapsing and remitting MS (85–90%) – relapses (when symptoms worsen), followed by complete or partial recovery, alternate with remissions (when symptoms don’t worsen). 2. Secondary progressive MS – this follows on from relapsing/remitting disease – begins with relapses alternating with remissions, followed by gradual progression of the disease. 3. Primary progressive MS (10–15%) – progresses gradually from onset with no remissions or obvious relapses, although there may be temporary plateaus. 4. Progressive-relapsing MS (< 5%) – progresses gradually, but progression is interrupted by sudden relapses. Rare. - but no remitting after the attacks

Question 33

what are three characteristic presentations of RRMS?

Answer 33

- optic neuropathy - brainstem demyelination - spinal cord lesions

Question 34

what are the three main characteristics of MS?

Answer 34

1. Inflammation 2. Demyelination 3. Lesions (plaques)

Question 35

inflammation in MS: - role and structure of BBB - what happens during inflammation - what happens with MS - result of infammation

Answer 35

• 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.

Question 36

demyelination process - what happens during relapse?

Answer 36

* 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.

Question 37

demyelination - what happens during remission?

Answer 37

* 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.

Question 38

lesions - what also called - what commonly affect - what is rarely involved - what is affected - what takes place to some extent - what forms the lesions

Answer 38

• 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.

Question 39

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

Answer 39

* 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.

Question 40

how is pathogenesis initiated? what causes demyelination? (which cells)

Answer 40

• 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.

Question 41

what are the clinical manifestations of MS?

Answer 41

• 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.

Question 42

what is the diagnostic criteria for MS?

Answer 42

* 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

Question 43

what are the diagnostic tests for MS?

Answer 43

• 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.

Question 44

what is the prognosis for MS?

Answer 44

* 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

Question 45

what is the treatment for MS?

Answer 45

* 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

Question 46

what's the treatment for acute relapses?

Answer 46

• 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

Question 47

how are relapses and disability prevented in MS?

Answer 47

1. beta-interferon 2. glatiramer acetate (copaxone) 3. fingolimod (gilenya) 4. natalizumab (tysabri) 5. alemtuzumab (lemtrada) 6. other drugs - immunosuppressants - teriflunomide (aubagio) - dimethyl fumarate (BG-12)

Question 48

beta-interferon - what used for - how administered - what does it do - mechanism of action

Answer 48

 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: 1. Inhibiting T cell activation 2. Preventing T cell proliferation 3. Blocking T cell migration across the BBB

Question 49

glatiramer acetate - what does it do - mechanism of action - how administered

Answer 49

 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.

Question 50

fingolimod - what is it - how is it administered - mechanism of action

Answer 50

 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%.

Question 51

natalizumab - mechanism of action - what useful for - adverse side effect

Answer 51

 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.

Question 52

alemtuzumab - what is it - how administered - what does it do - adverse side effects

Answer 52

 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.

Question 53

teriflunomide - what is it - how does it work

Answer 53

Teriflunomide (Aubagio) is an oral immunomodulator. 1. Blocks pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), and thereby T-cell function. 2. However, vital salvage pathways are preserved allowing generalized immune surveillance.

Question 54

dimethyl fumarate | - how does it work

Answer 54

1. Activates Nrf-2 transcriptional pathway, a central mechanism of the body’s cellular defence. 2. This decreases inflammation and tissue damage.

Question 55

glucocorticoids - examples - what used for - how do they work - mechanism of action - side effects

Answer 55

• 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.

Question 56

how can depression by diagnosed?

Answer 56

* 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

Question 57

describe the epidemiology of depression

Answer 57

* 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

Question 58

what are prominent negative cognitions associated with major depressive disorder (MDD)?

Answer 58

 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.

Question 59

what can severe depression involve?

Answer 59

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

Question 60

how common is recurrence with MDD and what increases it?

Answer 60

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.

Question 61

what is the kindling hypothesis? | - what is usually the cause of the first episode of depression?

Answer 61

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.

Question 62

what are the two types of monoamines?

Answer 62

1. Catecholamines – dopamine, noradrenaline, adrenaline | 2. Indoleamines – serotonin (5-HT)

Question 63

the amino acid tyrosine is taken in through our diet and metabolised into what?

Answer 63

noradrenaline (and further into adrenaline)

Question 64

the amino acid tryptophan is taken in through our diet and metabolised into what?

Answer 64

serotonin (5-HT)

Question 65

describe the production of dopamine, noradrenaline and adrenaline

Answer 65

1. Tyrosine is hydroxilated into L-DOPA. 2. L-DOPA is decarboxylated into Dopamine (in brain). 3. Dopamine is hydroxilated into Noradrenaline. 4. Noradrenaline is converted into Adrenaline.

Question 66

describe the production of serotonin

Answer 66

1. Tryptophan is hydroxilated into 5-Hydroxytryptophan. | 2. 5-Hydroxytryptophan is decarboxylated into 5-Hydroxytryptamine (Serotonin).

Question 67

describe the release, reuptake and degradation of serotonin and noradrenaline

Answer 67

• 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).

Question 68

what are the two main classes of noradrenergic receptors?

Answer 68

 Alpha receptors (α) – α1 (stimulatory effect), α2 (inhibitory effect)  Beta receptors (β) – β1, β2, β3 (all stimulatory effects)

Question 69

what are the classes and sub-classes of 5-HT receptors? overview of the different receptors

Answer 69

```  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

Question 70

what is the interaction between serotonin and noradrenaline?

Answer 70

• 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

Question 71

what is the monoamine hypothesis? what are the observations that lead to this hypothesis?

Answer 71

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. 2. 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). 3. Imipramine is an SNRI antidepressant – inhibits the reuptake of released serotonin and noradrenaline, thus promoting their action in the synaptic cleft. 4. 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. 5. 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.

Question 72

what is reserpine? how does it work?

Answer 72

* 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.

Question 73

MAOI antidepressants - give example - describe - what line of treatment

Answer 73

- 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.

Question 74

what are the different types of MAOs?

Answer 74

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.

Question 75

what is the mechanism of action of MAOIs? | - what are MAO-A inhibitors and MAO-B inhibitors used for?

Answer 75

 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)

Question 76

describe the reversibility of MAOIs | - why do patients on MAOIs have to go on a special diet

Answer 76

 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.

Question 77

what are side effects of MAOIs?

Answer 77

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.

Question 78

what do TCAs, SNRIs and SSRIs do? give examples of each

Answer 78

1. Tricyclic Antidepressants (TCAs) These block the reuptake of noradrenaline, 5-HT and dopamine. Examples include: amitriptyline, clomipramine. 2. 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. 3. 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.

Question 79

antidepressants have a range of differential affinities for what?

Answer 79

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

Question 80

mirtazapine - what is it - what does it cause

Answer 80

* 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.

Question 81

ventral neural system - what is important for - what are its main structures - how does this relate to MDD?

Answer 81

 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.

Question 82

dorsal neural system - what important for - what are its main structures - how does it relate to MDD

Answer 82

 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.

Question 83

what happens with MDD in terms of ventral and dorsal neural systems?

Answer 83

In MDD, there is an overactive ventral neural system AND an underactive dorsal neural system.

Question 84

what is meant by the diathesis-stress hypothesis? (each word)

Answer 84

1. 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. 2. 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.

Question 85

describe and explain the diathesis-stress hypothesis

Answer 85

- 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.

Question 86

describe the genetic variability in the 5-HT reuptake (5-HTT) gene

Answer 86

 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.

Question 87

so overall, what does the diathesis-stress hypothesis suggest?

Answer 87

that a hyperactive HPA axis, together with specific genetic variability in the 5-HT reuptake gene can increase the risk of developing depression

Question 88

what is treatment for mild depression?

Answer 88

• 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.

Question 89

what is treatment for moderate or severe depression?

Answer 89

• 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.

Question 90

electroconvulsive therapy - what is it - how effective - advantages - disadvantages

Answer 90

* 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.

Question 91

what are different forms of psychotherapy?

Answer 91

Cognitive Behavioural Therapy (CBT), Interpersonal Psychotherapy (IPT) and Problem Solving Therapy (PST).

Question 92

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

Answer 92

• 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.

Question 93

what is coping and what does it involve?

Answer 93

* 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.

Question 94

what does Leventhal's self-regulatory model show are the two ways of coping? and what are the two other ways?

Answer 94

1. approach coping 2. avoidance coping 1. problem focused 2. emotion focused

Question 95

describe approach and avoidance coping. when is each useful?

Answer 95

* 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.

Question 96

describe problem- and emotion-focused coping.

Answer 96

* 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.

Question 97

what is the Mental Capacity Act designed to do?

Answer 97

* 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.

Question 98

what 5 key principles underpin the Act?

Answer 98

1. A person must be assumed to have capacity unless it is established that he lacks capacity. 2. 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. 3. A person is not to be treated as unable to make a decision merely because he makes an unwise decision. 4. 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. 5. 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.

Question 99

what does an 'advance decision' need to have legal force? what is an advance decision?

Answer 99

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.

Question 100

when is an advance decision invalid?

Answer 100

• 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).

Question 101

what is Lasting Power of Attorney?

Answer 101

- 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.

Question 102

what are gamma globulins? what happens in MS?

Answer 102

- 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

Question 103

what does a longer than normal latency in VEP show?

Answer 103

- 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

Question 104

what do lesions show up as on MRI scan?

Answer 104

- 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

Question 105

what is the criteria from DSM V for diagnosing depression?

Answer 105

``` 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 ```

Question 106

what is dysthmia?

Answer 106

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)

Question 107

what is an Advanced Life Care Plan? what are the key points that should be covered?

Answer 107

- 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

Question 108

why might antidepressants need to be stopped gradually?

Answer 108

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

Question 109

what is the forebrain made up of?

Answer 109

cerebrum & diencephalon

Question 110

what is the most common type of neurone?

Answer 110

multipolar neurone

Question 111

what type of neurones are long myelinated fibres?

Answer 111

unipolar

Question 112

where do you find bipolar neurones?

Answer 112

olfactory, retina, ear

Question 113

what receptors are usually used in glutamatergic synapses? which ones are also used and when?

Answer 113

- 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

Question 114

what ion is involved in inhibitory neurotransmission?

Answer 114

- Higher concentration of chloride outside the cell | - Chloride flows in making it more negative

Question 115

what is spatial and temporal summation?

Answer 115

- 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

Question 116

what is stimulus intensity encoded as?

Answer 116

action potential frequnecy

Question 117

what are the neuronal-glial interactions?

Answer 117

``` Glia on neurones: - Synapse formation - Synaptic strength - Co-ordination of activity Neurones on glia: - Proliferation - Differentiation - Myelination ```

Question 118

what is MS?

Answer 118

Acute localised, and chronic diffuse, inflammation of the CNS and subsequent demyelination of neurons, following the infiltration of immune cells across the BBB

Question 119

how does MS manifest?

Answer 119

- 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

Question 120

give an example of an upper and lower motor neurone disease

Answer 120

1. Upper motor neuron disease: - Acute central demyelinating disease; e.g. multiple sclerosis 2. Lower motor neuron disease: - Acute peripheral demyelinating disease; e.g. Gullian burre syndrome

Question 121

where are common sites of demyelination in MS?

Answer 121

- Corpus callosum - Cerebellum - Optic nerve - Brainstem - Spinal cord

Question 122

what do the compare the CSF with when looking for oligoclonal bands?

Answer 122

- Oligoclonal bands = immunoglobulins within the CSF - Compare the serum with the CSF - You see bands in the CSF but no bands in the serum

Question 123

what is the inheritance risk for MS?

Answer 123

- 1:500 – general risk - If first degree relative has MS, risk is 1:25 - Monozygotic twins – 25% - Both parents with MS – 30%

Question 124

what's the difference in the brain in relapsing-remitting and secondary progression?

Answer 124

relapsing-remitting = inflammation secondary progression = nerve cell loss

Question 125

what do you have to have to be eligible for MS treatment?

Answer 125

two relapses over two years

Question 126

what is rapidly evolving severe RRMS?

Answer 126

>_ two relapses per year

Question 127

what are low risk/gain to high risk/gain DMTs?

Answer 127

- Lower risk/gain – interferon B - Medium risk/gain – alemtuzumab - High risk/gain – natalizumab, mitoxantrone, ASCT

Question 128

what are the injectable DMTs?

Answer 128

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

Question 129

what are the oral DMTs?

Answer 129

``` 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

Question 130

whats's the problem with alemtuzumab?

Answer 130

ALEMTUZUMAB – RISK OF OTHER AUTOIMMUNE DISEASES - Antibody mediated autoimmune diseases - Thyroid disease 30% - hyperactive - underactive - Immune thrombocytopenia - Goodpasture syndrome - Alemtuzumab requires regular blood monitoring

Question 131

what's the composition of the myelin sheath?

Answer 131

Lipids - Galactocerebroside Glycoproteins - Myelin basic protein (MBP) - Myelin oligodendrocyte glycoprotein (MOG) - Myelin associated glycoprotein (MAG)

Question 132

where are voltage-gated Na+ channels only present along axons?

Answer 132

node of Ranvier

Question 133

which chromosome is there a genetic association with MS?

Answer 133

6, which also contains MHC class genes and myelin proteins

Question 134

what is the major histocompatibility complex? what is the problem with MS?

Answer 134

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)

Question 135

summarise the pathogenesis of MS

Answer 135

1. An infection by a virus or bacteria 2. Antigen gets into the blood stream, it is digested by a macrophage (APC) 3. The macrophage cell displays the antigen with an MHC molecule 4. The MHC-antigen can be recognised by special receptors on the surface of T cell 5. The activate Th cells cross the BBB 6. Once in the CNS, Th cells encounter local APCs (i.e. microglia) 7. 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) 8. 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 9. Demyelination, oligodendrocyte degeneration

Question 136

what signs and symptoms does a lesion in the cerebrum cause?

Answer 136

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

Question 137

what signs and symptoms does a lesion in the optic nerve cause?

Answer 137

symptoms: - loss of vision - delayed VEP signs: - scotoma - reduced visual acuity - colour vision - pupillary defect

Question 138

what signs and symptoms does a lesion in the cerebellum and cerebellar pathways cause?

Answer 138

symptoms: - tremor - clumsiness, poor balance signs: - postural and action tremor - dysarthria - limb coordination - gait ataxia

Question 139

what signs and symptoms does a lesion in the brainstem cause?

Answer 139

symptoms: - vertigo - impaired speech and swallowing signs: - dysarthria

Question 140

what signs and symptoms does a lesion in the spinal cord cause?

Answer 140

symptoms: - weakness - stiffness and spasms signs: - upper motor signs - spasticity

Question 141

describe the noradrenaline system

Answer 141

- 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

Question 142

describe the serotonin system

Answer 142

- 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

Question 143

describe the amygdala functionally and structurally in people with MDD?

Answer 143

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

Question 144

what happens to the hippocampus in people with MDD?

Answer 144

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

Question 145

what is the difference between an advanced decision and an advanced statement?

Answer 145

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

Question 146

when can an Advance Decision only be considered valid?

Answer 146

- 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)