Flashcards in B06W07 Deck (282):
List the 4 most common types of eye disease in Australia
Macular degeneration, cataracts, glaucoma and diabetic retinopathy
Define vision impaiment
Any diagnosed condition of the eye or visual system that cannot be corrected to within normal limits
List the 6 causes of reading difficulties and comment on which are treatable
Cataracts, macular degeneration, glaucoma, diabetic eye disease and refractive error (cataract and refractive errors are treatable)
What is the most common cause of blindness?
What is the most common eye disease in Australia?
What is a cataract?
Loss of lens transparency
List 3 common types of cataracts
1. Capsular 2. Cortical 3. Nuclear
What is a nuclear cataract?
Hardening of the core of the lens that ex[ands thorugh the layers
Why are nuclear cataracts associated with yellowing/brunescence of the lens?
Due to accumulation of glutathione-3-hydroxy kynurenine glycoside
Explain why vision appears more reddish and blurry for a patient with a nuclear cataract
Causes reduced transmittance of light (especially blue), increased scatter and increased fluorescence
What occurs in cortical cataract development?
Changes to lens proteins that start at the margin of the lense and spread through the more superficial layers toward the optic axis
Which cataract type can occur subdequently to eye surgery?
What is a capsular cataract?
Modification of the lens capsule, either anteriorly or posteriorly
What is the leading cause of blindness in Indigenous Australians?
Cataracts (increased UV exposure)
Glaucoma is in a spectrum of related disorders characterised by what?
Progressive loss of ganglion cells and their axons (optic nerve)
Which section of the eye does glaucoma affect?
Anterior disorder that has impacts in the posterior segment, causing death of ganglion cells
Glaucoma is strongly associated with increased _____?
Intra ocular pressure (IOP)
Describe how glaucome affects the drainage of aqueous humour from the eye in angle closure glaucoma
Pressure on the posterior surface of the iris causes the iris to buckle, compressing the trabecular meshwork and restricting the drainage of aqueous
Describe how glaucoma affects the drainage of aqueous in open angle glaucoma
The trabecular meshwork and drainage network become clogged and restrict the passage of aqueous
Describe the pathophysiology in glaucoma that results in ganglion cell death
Increased IOP in the anterior segment is tranferred posterioly through the vitreous. Pressure distorts the sclera at the lamina cribrosa, compressing GC axons, leading to GC death
List the 3 mechanisms of ganglion cell death in glaucoma
1. Decline in retrograde supply of neurotrophins to GCs from their axon terminals 2. Release of exitotoxic amino acids by damaged GCs 3. Apoptotic death of GC
Explain why glaucoma is frequently unnoticed until late stage disease?
Tends to affect peripheral vision
The initial diagnosis of galucoma is based on assessment of which structure?
Describe the normal appearance of the optic disc
Has a distinct, reddish neural margin, where the majority of axons are located. The centre is paler (pallid)
Describe the appearance of the optic disc in glaucoma
Margin appears eroded (often inferiorly), dic appears enlarged and area of pallor increases, the normally shallow cupping of the disc increases over time with progression of disease
In glaucoma, increased IOP causes damage to the GC axons as they pass through which structure?
Describe the typical pattern of vision loss seen in glaucoma
Losses are patchy, beginning in the peripheral vision field and then progress centrally (losses compensated for by eye movements may not be registered)
What is the most efficacious strategy for treating glaucoma?
Management of IOP (but only when IOP is raised - limited options when IOP is not raised)
Describe the theory for why peripheral vision tends to be affected in glaucoma
Large diameter axons affected before smaller ones (i.e., parasol before midget cells) - hence, this occurs in periphery due to normal distribution of these cells
What is age-related macular degeneration?
Multi-factorial disease characterised by the loss of central (macular) vision
What causes vision loss in macular degeneration?
Degeneration of the photoreceptors, specifically in the macular region
Which 'spot's are one of the earliest signs of age-related macular degeneration? What is the other name for these?
White spots - drusen
What are the principle cell types affected in age-related macular degeneration?
Light-sensitive photoreceptors and their supporting pigmented epithelial cells
List two histological/imaging signs in emergent age-related macular degeneration
1. Subretinal deposits 2. Pigmentary disturbance
Describe the histopathology seen in dry/non-exudative age-related macular degeneration
Loss of photoreceptors and RPE cells in macular region, accumulation of leucocytes in the choriocapillaris, sharp transition into histologically normal photoreceptors
Describe the histopathology seen in wet/neovascular/exudative age-related macular degeneration
Breakdown of Bruch's membrane (BM) by phagocytic cells, sprouting of choroid vessels which breach BM and often also the RPE
What is the advantage of the normal 'leakiness' of the choirodal vessels?
Facilitates disffusion of oxygen and nutrients to photoreceptors
Discuss the implications of choroidal neovascularisation in wet age-related macular degeneration
New choroidal vessels leak serum constituents and blood cells into the outer retina, promoting retinal dysfunction and loss of vision
Discuss the implications of diet in the development of age-related macular degeneration
High intake of saturated fat and cholesterol increased risk of early AMD, high intake of fatty acids decreases risk of early AMD
Describe the onset and time progression of age-related macular degeneration
Insidious onset and develops over decades
How is age-related macular degeneration clinically diagnosed?
Via recognition of end-stage degeneration of neural tissue (cannot be repaired)
Describe the normal direction of signal passage through a neuron. Comment on the exception to this rule
Dendrite > cell body > axon (exception is neurogenic inflammation in pain)
What is the normal categor/type of primary sensory neuron?
Unipolar or pseudounipolar
Interneurons generally have which neuronal structure?
Motor neurons are which type/category of neuron structure?
Describe the structure of unipolar neurons
have one primary process that give rise to several branches. One of these is the axon and the rest serve as dendritic receiving structures. Unipolar cells have no dendrites arising directly from the cell's soma
Describe the structure of bipolar neurons
have two processes emerging from the cell soma: a peripheral process or dendrite which conveys information from the periphery and a central process, the axon, which carries information toward the brain
Describe the structure of multiipolar neurons
have a single axon and one or more dendritic branches emerging from all parts of the cell body. Multipolar cells vary in the number and length of their dendrites and the length of their axons. The number and extent of dendritic processes depend on the number of synaptic contacts that other neurons make onto it
What is the other name given to the cell body of a neuron?
Give some examples of specialised sensory receptors found in the nerve endings of unipolar neurons
Thermoreceptors, chemo-, mechano- and proprioceptors in the skin
Cell bodies of sensory nerves are located in ____ ____
Peripheral ganglia (i.e., dorsal root ganglia od spinal cord or ganglia associated with cranial nerves)
Dorsal root and cranial nerve ganglia do NOT contain ____
Which 3 cutaneous receptors are common to glaborous and hairy skin?
Merkel (Slow adapting superfifical - A1), Ruffini (Slow adapting deep - SA2) and free nerve endings
List the sensory receptors found in glabrous skin and comment on whether they are fast or slow adapting, and whether they are located superficically or deep
Meissner (FA1), Pacinan (FA2), Merkel (SA1), Ruffini (SA2) and free nerve endings
List the sensory receptors found in hairy skin and comment on whether they are fast or slow adapting, and whether they are located superficically or deep
Hair follicle afferents, Merkel (SA1), Ruffini (SA2) and free nerve endings
Comment on the location within the skin of Merkel and Ruffini receptors and free nerve endings
Merked and free nerve endings in upper dermis. Ruffini in lower dermis.
What is the only receptor type in the skin that is polymodal? What does this mean?
Free nerve endings - mechano-, chemo- and temp-receptors, not only mechanoreceptors like the other skin receptors
What do Meissner receptors respond to?
Changes in pressure
What do Pacinian receptors respond to?
Changes in changes in pressure (i.e., 3rd derivative)
What do Merkel receptors respond to?
Pressure status: differences in surfaces/curvatures
What do Ruffini receptors respond to?
Skin stretch or deformation of skin
What do free nerve ending receptors respond to?
Mechanical, temperature, tissue damage, sensitisation
What do hair follicle afferent receptors respond to?
Changes in hair position, trauma
What is the function/perception of Meissner cells?
Fine touch (texture/motion) and lower range vibrations
What is the function/perception of Pacinican cells?
Event detection and high frequency vibrations
What is the function/perception of Merkel cells?
Fine touch: shapes/form of edges and points/dots
What is the function/perception of Ruffini cells?
Proprioception, no conscious perception of stimulation
What is the function/perception of free nerve ending cells?
Noxious hot/cold, mechanical/trauma, itch, chemical irritants
What is the function/perception of hair follicle afferent cells?
Location of objects in close proximity, and pain
Which 3 specific receptor factors influence sensitivity of the skin?
Type of receptor, numerical density of receptors and distribution of receptors
What do golgi tendon organs (1b) sense?
Tension (either force of contraction or stretch)
What do golgi tendon organs inhibit?
Alpha motor neuron activity to reduce muscle tone
Describe what sort of information Pacinian-like and Ruffini-like receptors in a joint would sense
Pacinian like = joint movement. Ruffini-like = joint pressure/distortion
Within a muscle spindle, what do 1a and II fibres sense?
1a = degree and rate of stretch - i.e., muscle length) II = degree of stretch only (muscle length)
Ia and II neurons in muscle spindles sense stretch and result in activation of which type of neuron, which initiates myotactic jerk reflexes?
Which peripheral nerve fibres are responsible for the sensations of slow pain and itch in cold?
Which peripheral nerve fibres are responsible for the sensations of sharp pain and some touch in hear?
Which peripheral nerve group do Meissner corpuscles, Merkel endings and Pacinian corpuscles fit into?
Which is the only peripheral nerve fibre classification to include unmyelinated nerves?
List the 2 common characteristics of all sensory fibres carried by spinal nerves (first-order fibres)
1. Cell bodies in dorsal root ganglia 2. A central process that enters the spinal cord in the dorsal horn
Small diameter, slow-conducting C fibres send information into which tract of the spinal cord? What information do these fibres carry?
Spinothalamic tract - carry information about crude touch, pain and temperature
Large diameter, fast-conducting fibres send information into which part of the spinal cord? What information do these fibres carry?
Dorsal columns - carry information about touch, pressure and vibration
Second order sensory fibres all pass through which structure? IN which nucleus do they synapse?
Thalamus on opposite side, in the VP ventralposterior nucleus (before projecting to the somatosensory cortex)
Which structure subdivides the thalamus into 4 groups of nuclei?
Name the 4 nuclei groups in the thalamus
1. Anterior group 2. Lateral group 3. Medial group 4. Intralaminar nuclei
What is the only sensory information that does not pass through the thalamus on its way to the cortex?
The cortex ____ innervates the thalamus
What is the anterior nuclei of the thalamus repsonsible for?
Attention and learning
What is the medial group of nuclei in the thalamus repsonsible for?
Planning and active memory
What is the ventral anterior/lateral group of nuclei in the thalamus repsonsible for?
What is the ventral posterior group of nuclei in the thalamus repsonsible for?
What is the medial geniculate nuclei in the thalamus repsonsible for?
What is the lateral geniculate nuclei in the thalamus repsonsible for?
Which 2 nuclei of the thalamus give cortical output to the somatosensory cortex?
Ventral posterolateral and ventroposteromedial (VLP and VMP)
From which specific areas does the ventral posterolateral nuclei of the thalamus receive inputs?
Medial lemniscus (body), spinothalamic tract (Body)
From which specific areas does the medial posterolateral nuclei of the thalamus receive inputs?
Medial lemniscus (face) and trigeminal system
The caudal VPL of the thalamus receives information from which structures?
Spinal nerves from limbs and trunk
The caudal VPM of the thalamus receives information from which structures?
Trigeminal nerve from face, ocular surface, tongue, oral cavity and nasal cavity
Describe the projections of the dorsal column system to the SI area of the neocortex (primary somatosensory area)
Sensory information from tactile receptors and proprioceptors enters dorsal spinal cord on same side and ascends before decussating in the medulla, travelling upward through the pons and midbrain and entering the thalamus
Describe the projections of the spinothalamic tracts to the SI area of the neocortex (primary somatosensory area)
Sensory information from pain and temperature receptors enters the dorsal horn of the spinal cord before decussating to the opposite side and ascending to the thalamus. Some fibres synapse in the medulla and midbrain also
Which Broadmann areas are associated with the S1 region of the cortex? Briefly list the funciton of each area
3a: proprioception via muscle spindles. 3b: cutanous fine touch information. 1: cutaneous information for event/motion detection (FA1 and FA2). 2: deep receptors from muscles/joints for joint proprioception > complex responses and direction sensitive
List the 4 'multidimensional' functions/experiences of pain
1. Discriminative (where it hurts) 2. Affective (how it makes you feel) 3. Motivational (what you will do in response) 4. Cognitive/evaluative (appraisal and context)
Similarly to temperature, pain enables _____: a representation or sense of the body's physiological condition
What is hyperalgesia?
Augmented sensations of pain from a noxius stimulus
What is allodynia?
Perception of pain from an innoculous stimulus
Neuropathic pain describes pain that occurs in what condition?
In the absence of nociceptor stimulation
Give an example of neuropathic pain
Phantom limb pain - neuropathic pain which results from amputation
Give an example of neurogenic pain
Carpel tunnel - median nerve impinged by the carpel tunnel in the wrist (due to primary damage of a peripheral nerve). The pain resolves when impingement in removed.
Pain/temp is transduced by free nerve endings and carried by which fibre types?
A-delta and C
Nociceptors respond to what sort of information?
Tisseu damage and/or thermal stimuli
Mechanical nociceptors are selective for which stimuli?
Strong stimuli such as sinch and/or sharp objects that penetrate, squeeze or pinch the skin
Sharp or prickling pain is relayed by ____ fibres
How are mechanical nociceptors stimulated/mediated?
Mediated by mechanical deformation of the nociceptor membrane, leading to depolarisation
What are thermal nociceptors selective for?
Noxioud heat (temp above 45 degrees) and noxious cold (temp below 5 degrees)
Why are A-delta fibres most appropriate for transmitting information about hot pain?
Faster > thereforemore appropriate for withdrawal reflex
Chemical nociceptors are selective for which particular chemical irritants?
Histamine, capsaicin, mustard oil and acids
Itch and irritation sensation is transmitted by which fibres?
non-myelinated C fibres
What are the most common form of receptors linked to C fibres?
What information acitvates C-polymodal nociceptors?
Noxious mechanical stimuli, noxious hear, noxious cold and irritant chemicals
Slow dull burning or aching pain is transmitted via which fibres?
non-myelinated C fibres
What is unique about C-polymodal nociceptors?
Perception of stimulus persists long after stimulus is removed
What is a mechanohear-insensitive afferent?
A C fibre insensitive to noxious stimuli until sensitised
Describe what is meant by sensitisation in terns of the neurological response to injury
Chemical mediators induced by the injury module that excitability of nociceptors
Describe the effect of bradykinin on nociceptors
Directly depolarises nociceptors as well as stimulates long-lasting intracellular changes, making heat activated ion channels more sensitive
Describe the effect of prostaglandins on nociceptors
Generated by lipid membrane breakdown and increase nociceptor sensitivity
Describe the effect of substance P on nociceptors
Peptide prodiced by nociceptors causes vasodilation og adjacent capillaries and the release of histamine from mast cells
Describe the effect of histamine on nociceptors
Reeleased by mast cells and increases the excitability of the nerve ending membrane
What is neurogenic inflammation?
A peripheral mechanism whereby inflammation is caused by the liberation of chemical mediatiors (like substance P) released from peripheral nerve terminals
What is the consequence of pain and touch modalities being segregated at the level of the spinal cord?
Distinct neurological signs following spinal cord injury
What is the pain matrix?
Regions of the brain that are active during the experience of pain
List at least 3 structures that may be involved in the pain matrix
Somatosensory cortex (discriminative), Insular cortex (interoceptive), Amygdala (fear component) and anterior cingulate cortex (affective)
List the 3 components of discriminative pain provided by the somatosensory cortex
1. Localisation 2. Intensity 3. Quality
Discriminative pain information arrives at the somatosensory cortex via which structures? Distinguish between pain sensation brought from the body and face
Arrives at S1 via the VP thalamus. Body = VPL, face = VPM
The discriminative pain pathway that carries information from the body is also known by what name in the brainstem?
Pain, temperature afferents that give discriminative pain information from the face and head travel along which tract in the brainstem?
Spinal trigeminal tract
After synapsing in the spinal trigeminal nucleus of the brainstem, pain/temperature afferents then cross the midline and form which tract? What information does this tract carry?
Trigeminothalamic tract - carried both thermal/pain and touch information from the had
The trigeminothalamic tract joins the ___ ___ by tacking onto its dorsal border
List at least 3 central targets involved in the autonomic fight or flight response
Amygdala (conditioned fear memory), hypothalamus (regulates ANS), periaqueductal grey region (orchestrates behavioural, ANS and pain regulation), superior colliculus (head orientating reflexes) and reticular formation (arousal)
The medial pain pathway travels through which tract?
The medial pain pathway is responsible for what actions?
Arousal, to alert the CNS that there is a painful event
The reticular formation projects to which brain structure, before projecting on to many CNS regions?
The spinoreticular tract (medial pain pathway) gives rise to which projections which contribute to the control of pain transmission?
Descending reticulospinal projections
The periaqueductl grey area coordinates which responses to pain?
Behavioural, emotional and autonomic reponses and pain modulation (e.g., vocalisation and aversive behaviour)
The periaqueductal grey area projects to which 3 areas?
1. Amygdala (emotional response to pain) 2. Hypothalamus (ANS responses like heart rate) 3. Meduallary raphe (analgesia)
What are the ANS responses arising from pain from the skin?
Brisk movements, rise of pulse rate and sense of invigoration
What are the ANS responses arising from pain from deep structures
Quiescence, slowing of pulse rate, falling of blood pressure, sweating and nausea
What aspects of pain are provided by the anterior cingulate cortex?
Affective/motivational aspects of pain
What aspects of pain are provided by the insular cortex?
Interoceptive aspects of pain
Which thalamic nuclei are the relay nuclei for pain information to the cingulate and insular cortexes?
Midline thalamic nuclei
Afferent pain information from the viscera is via which pathways?
Visceral afferent signals for reflex control and homeostasis is via which pathways?
Primary afferents from viscera share what structure with sympathetic post ganglionic fibres before entering the dorsal horn of the spinal cord?
Which 2 afferents share the perineural sheath before entering the dorsal horn of the spinal cord?
Primary afferents from viscera and sympathetic postganglionic fibres
Discuss the entrance and pathway of visceral afferents as they enter the spinal cord
Enter via dorsal horn and cross to contralateral side where they ascend via the spinothalamic tract
Referred pain is believed to result from cross-talk between which pathways?
Nociceptive inputs from viscera result in the activation of cells normally carrying cutaneous information, resulting in pain perceived in those dermatomes
Visceral and which other afferents enter the spinal cord travel through the spinaothalamic tract?
Explain the specialised visceral pain pathway
Axons send collaterals to neurons in lamina X around the central canal. Axons of 2nd order neurons travel in the intermediate dorsal septum and synapse in the dorsal column nuclei. 3rd order neurons synapse in VP thalamus which project into the insular cortex
What is peripheral sensitisation?
Refers to the increased excitability at nerve endings, usually due to inflammatory infiltrate following injury
Give an example of at least 1 drug that is effective against peripheral sensitisation
NSAIDs and COX inhibitors
List at least 3 neuronal elements that are released in inflammation in the peripheries, and which cause vasodilation, swelling and release of histamine from mast cells
Substance P, calcitonin gene-related peptide and ATP
Describe the gate control theory of pain
The gate control theory of pain asserts that non-painful input closes the "gates" to painful input, which prevents pain sensation from traveling to the central nervous system. Therefore, stimulation by non-noxious input is able to suppress pain
Explain how the gate control theory of pain works at the level of the spinal cord
Stimulation of A-alpha and A-beta fibres > excited inhibitory neurons > release of GABA > inhibition of spinothalamic tract neurons (the interneuron plays a gating role)
What does central sensitisation refer to?
Increase in excitability of neurons centrally (usually in the dorsal horn)
What is the result of central sensitisation?
Transmission of nociceptive signals elicited by sub-threshold activation of nociceptive afferents > increase in pain sensitivity
Following administration of placebo with the expectation of pain relief, what is expressed in the pain matrix?
Endogenous opioid receptor acitvation
A great deal of pain modulation is centrally modulated via what mechanism?
Descending inhibition of ascending nociceptive pathways
List at least 3 sites of action within the dorsal horn that contribute to descending modulation of pain
1. Synaptic terminals of afferents 2. Excitatory or inhibitor interneurons 3. Synaptic terminals of descending projections 4. Directly onto STT cells
Within the PAG, ____ facilitates nociceptrion and pain modulation, whilst ____ inhibits nociception
Descending inputs from the PAG converge on which laminae in the spinal cord?
I and II
Which endogenous opioid receptor type is the target of morphine?
Where is the Mu opioid receptor found?
Dorsal horn, PAG, nucleus accumbens, amygdala
Describe the presynaptic and postsynaptic effects of endogenous opioids
Presynaptic: inhibits voltage-gated calcium channels to reduce NT release. Postsynaptic: increases postassium conductance to hyperpolarise the membrane
Dorsal horn enkephalin neurons regulate the release of ____ input to STT rojecting neurons by inhibition
What effect do exogenous cannabinoids (cannabis) have in the spinal cord?
Suppress nociceptive neurons in the dorsal horn
Explain how cannabinoids act as retrograde NTs
Released from the depolarised neurons and activate the CB1 receptor of presynaptic terminals > postsynaptic cells control the presynaptic cells (can also decrease the release of presynaptic GABA or Glu)
What is the definition of neuromodulators?
Substances or transmitters, which modulate/alter efficacy of synaptic transmission (i.e., the ability to increase or decrease firing rate of postsynaptic neurons)
Neuromodulators act mostly via which receptor type?
What are the 2 metabotropic targets of the catecholamine system?
Dopamine and noradrenaline
Catecholamines have a lack of pigments due to lack od which chemical substance?
What is the name of the dopamine precursor that can cross the BBB?
Can catecholamine transmitters cross the BBB? Why/why not?
No, as they are charged
Dopaminergic cells exist in the ____, and are co-released with _____
Which 2 nuclei in the midbrain house dopaminergic cells?
1. Substantia nigra 2. Nucleus in ventral tegmentum
Which disease has been linked to the dopamine system?
Dopaminergic cells from the substantia nigra and nucleus in the ventral tegmenum project to which areas?
Basal ganglia and forebrain and cortex
The noradrenergic system is predominantly located in which areas of the brain/spinal cord?
Locus coeruleus and lateral reticular formation (spinal cord)
Why does the locus coeruleus appear blue?
What is the function of the noradrenergic system?
Attention, vigilence and phasic changes in levels of attention
Which drug class can cause toxicity due to its effetcs on the noradrenergic system?
What are the metabotropic receptors of the serotonergic system?
What are the ionotropic receptors of the serotonergic system?
5-HT3 receptors (excitatory, not modulatory)
Which viatmin is required for the biosynthesis of serotonin (5-HT)?
5-HT of the serotonergic system is concentrated in which nuclei?
Raphe (rostral and caudal)
Which broad areas are innervated by the serotonergic (5-HT) system?
Densely sensory and limbic areas
What are the fucntions of the serotonergic system?
Sleep-wake cycle, aggression and impulsivity, anxiety and depression, descending pain control
List at least 1 pharmacological agent that can cause toxicity in the serotonergic ssytem
LSD, ergotalkaloids, psilocybe toxin
What are the ionotropic targets of the cholinergic system?
Pentamer of 2alpha: 1beta: 1 gamma: 1 delta subunits (not neuromodulatory)
What are the metabotropic targets of the cholinergic system?
ACh acts are an excitatory ____ and _____
Neurotransmitter and neuromodulator
ACh typically acts as a neuromodulator via what receptor types?
What is the main nicotonic neurotransmitter at the NMJ?
ACh breaks down into which substance in the synaptic cleft?
What are the 2 main cholinergic systems?
Basal forebrain complex (nucleus basalis and septal nuclei) and the pontomesencephalo-tegmental complex
What does the cholinergic system modulate?
What is the function of the cholinergic system?
Learning and memory (implicated in Alzheimers) and arousal and sleep/wake cycles
Histamine is synthesised simply from what substance? Which enzyme is responsible for this?
Histidine via decarbolylase
Which enzyme is involved in the break down of histamine?
Histamine exists in which hypothalamic nucleus?
Histamine signals via which receptors in the prefrontal brain? What is the function of this?
H(1-3) > project to cortex and thalamus and take part in arousal
The hitaminergic system (His) is involved in which functions?
wakefulness at the cortical level and sleep regulation
The histaminergic system has been implicated in which 2 pathologies?
1.Tourette's (mutation in H1-3 receptors) 2. Schizophrenia (antipsychotics like clozapine are sedative)
What are the metabotropic targets in the orexin/hypocretin system?
OX1 and OX2
Orexin/hypocretin is not synthesised in axon terminals, and requires _____ transport
How is orexin/hypocretin broken down?
Internalised as receptor/transmitter complex
The hypothalamix orexin/hypocretin system is most excitatory via which receptor?
What is the function of the orexin/hypocretin system?
Provides wakefulness and acts as an interface between CNS and ANS: metabolism, BP etc.
List 2 reasons why psychiatric disorders are not linked to a single transmitter system
1. Metabotropic complexity: dimerization of metabotropic monomers is not only within the same group of receptors 2. Iono-metabotropic complexity: ionotropic and metabotropic receptors may directly interact > unexpected extent of receptor promiscuity and signaling heterogeneity
Which area of the CAN plays a central tole in controlling neuromodulation?
Neurones in the locus coeruleus mostly produce which neuromodulator?
The neuromodulatory system in the ventral tegmental area releases which transmitter in the neocortex?
Which neuromodulatory transmitter is released from cells with somata in the raphe nuclei?
Which transmitter when released in the frontal cortex is synthesised by cells with somata in the nucleus basalis?
List at least 3 autoimmune diseases of the CNS and 3 of the PNS
CNS: MS, connective tissue disorders (SLE), vasculitis (giant cell arteriitis), acute disseminated encephalomyelitis. PNS: Guillain-Barre, connective tissue disorders (RA, SLE), PNS vasculitis
What is multiple sclerosis characterised by?
Episodes of demyelination affecting areas of the central nervous system separated by space and time (disseminated by time and location)
Describe the epidemiology of MS
More common in women with younger age of onset and relationship with distance from equator (Vitamin D). Also a genetic component
List at least 3 triggers for the unregulated immune response that leads to MS
Smoking, genetics, Vitamin D and viral trigger (EBV)
List the 5 steps involved in the evolution of a demyelinating plaque in MS
1. Immune engagement 2. Acute inflammatory damage 3. Repair 4. Post inflammatory gliosis 5. Further remyelination limited by gliosis
What is gliosis?
A non-specific reactive change of glial cells in response to damage to the CNS. In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes
List the 5 common characteristics seen in the CNS of a patient with MS
1. Inflammation beyong white matter lesions 2. Intrathecal Ig production with oligoclonal bands 3. Environemnt fostering immune cell persistance 4. Follicle-like aggregates in the meninges 5. Disruption to the BBB also outside of active lesions
What causes sclerosis in MS?
Scars produced by the astrocyte cells healing old lesions
Describe the steps in immune activation in MS
Autoreactive myelin-specific T helper cells (TH1 and TH17) are normally controlled by regulatory T cells. In MS, there is a failure of regulation when autoreactive T cells are stimulated by antigens. The T cells express adhesion molecules to BBB and penetrate the barrier. TH1 secretes IFN-gamma and Th17 secretes IL-17. Activated T cells then re-encounter myseling and activate microglia. Microglia express class II molecules which further promote T cells, microglia and PMN.
Th1 cells secrete ____, whilst Th17 cells secrete ____
IFN gamma; IL-17
List at least 4 presenting features of MS
Optic neuritis, sensory symptoms, motor deficit, cerebellar signs, brainstem signs (diplopia), transverse myselitis (motor, sensory or bladder) and fatigue
List the 3 classifications of MS, and comment on the clinical course of each
1. Relapsing-remitting (most common) - relapses that eventually become secondary progressive with no remaining relapses and progression of disease 2. Benign relapsing-remitting - relapses and remittances continue over time with no marked progression 3. Primary progressive - not makred by periods of remission, but slow progressive decline
List at least 4 factors that are associated with unfavourable prognosis in MS
Male gender, older age at onset, motor or cerebellar signs at onset, short interval between first and second attack, high relapse rate, incomplete remission after relapses, early disability and high lesion load (detected by early MRI of the brain)
What is needed for the diagnosis of MS?
At least 1 clinical episode, or episodes separated in time and place. Ancillary tests used to provie asymptomatic episodes and inclue MRI, CSF, evokes visual/somatosensory and brainstem potentials
What is the McDonald criteria for diagnosing MS?
2 or more episodes at least 30 days apart of symptoms attributable to demyelination at different sites in the CNS (but also allow incorporation of MRI results for evidence)
What are the 4 main treatment aims for MS?
1. Reduce relapses 2. Prevent permanent disability 3. Reduce disability from acute attacks 4. Symptomatic treatment
List at least 3 drugs that may be used to reduce relapses in MS
B-interferons, glutiramer acetate, azathioprine, natalizumab, fingolimod, tetriflunomide, dimethyl fumarate
Which pharmacological agent is used specifically to reduce disability from acute MS attacks?
What is ADEM?
Acute Disseminated Encephalomyelitis: autoimmune disease marked by a sudden, widespread attack of inflammation in the brain and spinal cord (also atackes nerves of CNS and damaged myelin insulation which destroys white matter
ADEM is more common in what age group?
After which events is ADEM associated?
Systemic viral illness or vaccination
What is the difference between lesions of MS and ADEM?
ADEM lesions look like MS lesions, but they are all the same age
What is the immune basis for ADEM?
T cells react to myelin basic protein (molecular mimicry)
What will the CSF show in a patient with ADEM?
Raised WCC and protein
How is ADEM treated?
With high dose methylprednisolone
What is NMO, and by which other name is this disease known?
Neuromyelitis optica: also known as Devic's disease
NMO has a predilection for which parts of the nervous system?
Spinal cord and optic nerves
Which autoantibodies are associated with over 50% of NMO cases?
ANA and Sjogrens
What is NMO?
heterogeneous condition consisting of the simultaneous inflammation and demyelination of the optic nerve (optic neuritis) and the spinal cord (myelitis). It can be monophasic or recurrent.
Describe the diagnostic criteria for NMO
1. Optic neuritis 2. Acute myelitis plus at least 2 of brain MRI exclusing MS, contguous lesion extending over 3+ vertebral segments on spinal cord MRI, NMO-IgG seropositive status
Acute attacks of NMO do not respond to steroids, but do respond to _____?
How is NMO treated in the long-term?
Long term immunosuppression (e.g., prednisolone, azothioprine or rituximab)
What may be seen in the spinalcord/brain MRI of a patient with NMO?
Long spinal lesions spanning over 3 levels, symmetrical cerebral lesions and often brainstem involvement with extension to thalami
Which age group and gender are more often affected by primary cerebral vasculitis?
Middle aged men
List some of the signs and symptoms of primary cerebral vasculitis
Headache, stroke, cognitive impairment, seizures
What is pleocytosis?
Iincreased cell count, particularly an increase in WBCs in a bodily fluid. It is often defined specifically as an increased WBC count in CSF.
Primary cerebral vasculitis patients often have CSF _____, but systemic inflammatory markers (ESR/CPR) are usually _____
Pleocytosis (increased WCC) but systemic markers usually normal
What is Guillain-barre syndrome?
Acute post-infectious autoimmune peripheral neuropathy
Describe the natural progression of Guillain-Barre syndrome
Post-infectious, progresses for no more than 4 weeks then plateaus, but recovery is slow
What is the most common presentation of Guillain-Barre syndrome?
Decribe the pathogenesis and resolution of Guillain-Barre syndrome
Exposure to infectious illness and antigen presentation leads to host response. Inflammatory activation targets myelin or axonal components and the inflammatory response then causes secondary axonal loss even in primary demyelinating disease. There is self-limiting immune acitvation and then remyelination and axonal regeneration
List at least 3 triggers for GBS
Viral infections, vaccinations and surgery
Which are the most common preceding infections that predispose to GBS?
Campylobacter jejuni, CMV, EBV
Lst at least 2 types of GBS
1. Acute inflammatory demyelinating polyradiculopathy (AIDP) 2. Acute motor and sensory axonal neuropathy (AMSAN) 3. Acute motor axonal neuropathy (AMAN) 4. Miller Fischer syndrome 5. Acute small fibre neuropathy 6. Acute autonomic neuropathy
56% of typically GBS cases start in which part of the body?
List the most common sites affected by typical GBS
Most often starts in legs, involves both upper and lower limbs as well as face commonly
List at least 4 differential diagnoses of ascending weakness
Diptheria, acute intermittent porphyria, heavy metal poisoning, lymphoma, acute spinal cord or brainstem lesion
List some of the presenting symptoms of GBS
Numbness, paraesthsia, weakness (ascending, facial and respiratory), tachycardia, postural hypotension, areflexia
Which 2 investigations are most helpful in the assessment of GBS? List at least 2 other investigations
CSF and nerve conduction studies - others include antinuclear antibodies, ESR/CRP, HIV, drugs and toxins, MRI spinal cord
Describe what investigations of CSF would show in a patient with GBS
Cytoalbuminaemic dissociation, rising with time and peaking at 7 days. Waised WCC (suggesting specific infections as the trigger), presence of oligoclonal bands. In 80% there will also be raised protein, but WCC should be less than 10
What would be experienced by a patient with deafferented lungs?
Why are ABGs a poor assessment tool for respiratory monitoring in GBS?
Because desaturation occurs just prior to respiratory failure/arrest
Discuss some ancillary management considerations in GBS
DVT management (as PTE major cause of death), cardiac monitoring for autonomic instability, BP and pressure sore management
What is IVIg?
Intravenous immunoglobulin (IVIg) is a solution of human plasma proteins and in particular IgG antibodies with a broad spectrum of antibody activity
A trial of which treatment has been shown to be more effective than plasmapheresis in the treatment of GBS?
List at least 4 prognostic indicators in GBS
Older age, campylobacter infection, CMV is worse for prognosis whilst EBV is better, intubation and bed bound
What are the 2 main treatment aims in the management of GBS?
Treat underlying disease and treat complications
If GBS occurs past 4 weeks, there is a possibility of progression to which other disease?
CIPD = chronic inflammatory demyelinating polyradiculoneuropathy
List the 4 types of CIDP
1. Chronic monophasic 2. Chronic relapsing (common) 3. Stepwise progression (common) 4. Steady progressive