B6W9 - Trigeminal System, Limbic System And Headache

Front 1

There are three types of genetic disorders: simple, polygenic and complex:
o What does it mean by simple inherited disease? Give an e.g.
o What is the definition of polygenic disorders? Give an example of a polygenic disorder.
o Complex disorders? E.g.

Back 1

• Simple “Mendelian” inheritance -> disorder which involved mutation of one gene which leads to defective one protein. E.g. triplet repeat disease, ALS.

• Polygenic disorders -> genetic disorders that results from the combined action of more than one gene. Mutations on different genes leads to similar phenotypes (multiple pathways). Each has simple Mendelian inheritance.
E.g. Epilepsies.

• Complex disorders -> involve multiple loci each contributing some effects in combination with environmental component.
E.g. MS, schizophrenia

Front 2

What is ALS?

What is the inheritance pattern of ALS?

How mutations in SOD1 contribute to the cause of ALS?

Back 2

ALS is a progressive motor neuron disorder characterized by degeneration of motor neuron with predominantly lower motor neuron manifestations.

o Rapid course: < 5 years
o Pathologic changes: anterior horn cells and pyramidal tracts

Inheritance pattern:
o 5% - 10% familial ALS
 20% of this is associated with SOD1
• SOD1 is inherited dominantly with age dependent penetrance with LAO (> 30 yo)
o 90% - 95% sporadic ALS

• Superoxide dismutase 1 (SOD1) produces SOD1 enzyme which is a powerful antioxidant that protects the body from free radical. Toxicity caused by oxygen free radicals is the primary pathogenetic mechanism. Basis of selective toxicity is damage from action of spinal cord specific factors that recruit mutant SOD1 protein to spinal mitochondria.

o Dramatic increase of ALS incidence in GUAM during 1950 – 1970 might open possibilities of dietary involvement (?calcium & magnesium, ?cycads)

Front 3

Epilepsy

o What environmental factors may trigger epileptic seizures?
o What kind of genetic disorder is associated with epilepsy?

Back 3

Environmental factors:
o Trauma
o Epileptiform agent (vaccination, alcohol) – mimic epilepsy
o Reflex seizure (tactile, visual, auditory, or musical)

Genetic disorders of epilepsy?
o Ligand gated channelopathies
o Voltage gated channelopathies
o Non-channel genes

Front 4

Huntington’s disease

o Autosomal dominant or recessive? AOO?
o What is anticipation (or Sherman paradox)?
o What gene is affected? What is the diagnosis method?

Back 4

Huntington’s disease – a triplet repeat disease (CAG)

o Autosomal dominant. Late AOO
o Anticipation => age of onset and severity of symptoms correlates with no of repeats. (no of repeats increase with every generation, especially from father to son.
o Gene: huntingtin. Diagnosis: PCR

Front 5

What is synaptic plasticity?

Back 5

Synaptic plasticity => the ability of chemical synapse to change their strength

Front 6

What is Long Term Potentiation (LTP)?

Back 6

LTP => long lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously

Front 7

What receptors are involved in formation LTP?

Back 7

Receptor: NMDA receptor. Glutamate ionotropic receptor. A Ca channel.

Front 8

Describe the process of LTP?

Back 8

o Rapid, intense stimulation of CA1 neurons in the hippocampus depolarizes them.
o Binding of Glu to their NMDA receptors opens them.
o Ca2+ ions flow into the cell through the NMDA receptors and bind to calmodulin.
o This activates calcium-calmodulin-dependent kinase II (CaMKII).
• CaMKII phosphorylates AMPA receptors making them more permeable to the inflow of Na+ ions and thus increasing the sensitivity of the cell to depolarization.
• In time CaMKII also increases the number of AMPA receptors at the synapse.
o Increased gene expression (i.e., protein synthesis — perhaps of AMPA receptors) also occurs during the development of LTP.
o Enlargement of the synaptic connections and perhaps the formation of additional synapses occur during the formation of LTP.

Front 9

Name the layers of the scalp and head.

Back 9

SCALP
Skin
subcutaneous Connective tissue
galea Aponeuretic
Loose areolar connective tissue
Pericranium (periosteum)

Skull

Meninges - PAD
Pia
Arachnoid
Dura

Front 10

In what layer of the meninges can you find blood vessels?

Back 10

Sub-arachnoid

Front 11

What are the common headaches?

Back 11

.

Front 12

What is the most common type of headache? What are the clinical features of this headache? Pathophys?

Back 12

Tension-type headache.

Clinical features:
- Constant and generalised pain
- Character: 'dull', 'tight', 'pressure'
- continue for weeks or months.
- Pain is less noticeable when the patient is occupied.

Pathophys:
Obscure. Emotional strain or anxiety is the common precipitant. Little evidence that it is caused by contraction of the muscles and neck.

Front 13

What is meningism? What are the common signs? Differential diagnosis?

Back 13

Meningism -> cluster of signs and symptoms indicating meningeal irritation or inflammation.

Signs:
- neck rigidity - HALLMARK
- Photophobia is common
- Positive Kernig's sign (pain on straightening legs with hips flexed
- Positive Brudzinski's sign (active flexion of hips/knees on passive flexion of neck)

DDx:
- Subarachnoid haemorrhage (SAH)
- Meningitis

Front 14

What are the clinical presentations of SubArachnoid Haemorrhage (SAH)?

Back 14

- sudden severe 'thunderclap' headache often occipital, which lasts for hours or days
- associated with vomiting, loss of consciousness
- symptoms of meningism: neck stiffness, photophobia, +ve Kernig's and Brudzinski's sign.
- Evidence of raised ICP:
- Headache worse on lying flat - Hallmark
- Compression of optic nerve - papilloedema leading to visual changes.
- Cushing's triad = HTN + ↓HR + ↓RR
- Described as the 'worst headache in my life' by patient.

Front 15

How is raised ICP diagnosed?

Back 15

- Imaging - CT brain, usually with CT venogram - look for a mass, compression of ventricles, midline shift, sulcal effacement.

Front 16

Why is it unsafe to treat high ICP due to mass lesion with lumbar puncture?

Back 16

Though raised ICP can often be checked and treated with lumbar puncture, but in the presence of mass lesion it may cause brain herniation compressing the brainstem.

Front 17

What are the causes of raise ICP?

Back 17

- SubArachnoid Haemorrhage
- Sagittal sinus thromboasis
- Obstructive hydrocephalus
- Benign intracranial hypertension
- Mass lesion (tumour)

Front 18

How do you treat raise ICP in the case of:
- Mass lesion (tumour)
- Sagittal sinus thrombosis
- Oedema
- High ICP as the main cause

Back 18

Mass lesion - removal of mass lesion.

Sinus thrombosis - anticoagulants

Oedema - corticosteroids

Benign raise ICP - Lumbar puncture, removal of CSF, neurosurgical drainage, craniectomy.

For urgent reduction - use mannitol and forced hyperventilation on ventilator.

Front 19

What is the compensation limit of ICP?

Back 19

25 mmHg.

Front 20

What is Cushing's triad? Describe Cushing's reflex?

Back 20

Cushing's triad is systemic response to raise ICP by raising blood pressure and cerebral vasodilation resulting in increase ICP and, lowring Cerebral perfusion pressure (CPP) further and continue the cycle.
= HTN + ↓HR (Cushing's reflex)+ ↓RR

Cushing's reflex:
When MAP < ICP -> hypothalamus increases sympathetic stimulation of the heart -> vasoconstriction + ↑ionotropic + ↑HR-> ↑CO -> HTN -> detected by baroreceptors in the carotid arteries -> vagal parasympathetic response -> bradycardia

Bradycardia may also due to impingement of brainstem.

Front 21

What is the formula for Cerebral Perfusion Pressure (CPP)?

Back 21

CPP = MAP - ICP

Front 22

Label.

Back 22

.

Front 23

Where is CSF produced?

Back 23

Choroid plexus. Lareral -> IIIrd vent. -> IVth vent.

Front 24

Through what structure does CSF leave the ventricular system to the spinal cord?

Back 24

Foramen of Magendie

Front 25

What is the function of arachnoid sinus?

Back 25

To absorb CSF.

Front 26

What are the 4 types of intracranial bleeds?

Back 26

- Extradural
- Subdural
- Subarachnoid
- Intraparenchymal bleed (Haemorrhagic stroke)

Front 27

Name the 2 innate barriers in the CNS against infection. Describe the characteristics of each barrier.

Back 27

- Blood Brain Barrier (BBB)
Characteristics:
- Intercellular tight junctions
- Limited pinocytic activity
- Specific carrier and transport sytem
- Basement membrane and astrocytes foot processes
- Blood CSF Barrier (BCB)
Characteristics:
- A layer of cuboidal epithelial cells continuous with ependyma with tight junctions restricting movement.
- Found in the choroid plexus.

Front 28

What are the common bacteria responsible for acute bacteria CNS infections in all ages and in neonates?

Back 28

All ages:
- Streptococcus pneumoniae
- Neisseria meningitidis
- Haemophilus influenzae

Neonates:
- Group B streptococci
- Eschericia colli
- Listeria monocytogenes

Front 29

Give example of viral CNS infections for:
Acute meningitis
Acute encephalitis

Back 29

Acute meningitis:
mumps, enteroviruses.

Acute encephalitis:
Herpesvirus (HSV)
VZV
Rabies
Mump
Rabies

Front 30

Lists the pathways by which pathogens can disseminate to CNS.

Back 30

- Physical pathways
- Haematogenous pathways
- Peripheral nerve pathways
- Olfactory nerve pathways

Front 31

Name the different pathways by which pathogens can spread haematogenously.

Back 31

1. Transcellular invasion
2. Paracellular invasion.
3. Transport within the circulating phagocytes.

Front 32

How does s. pneumoniae pass through the BBB?

Back 32

Haematogenous pathway by receptor mediated invasion.

Front 33

Describe the invasion pathway of strep. pneumoniae; starting from the gut -> blood vessels -> CNS.

Back 33

Invasion of gut:
- NanA - deglycosylate mucous exposing cell surface receptor for pneumococci.
- IgA1 protease - inactivates IgA.
- CbpA binds to host IgR => cross the epithelial barrier.
- Hyaluronate lyase - involve in tissue break down, increase tissue permeability.

Blood vessel:
- Capsule + PspA - prevent activation of C3b
- PspC - increase C3b degradation.
- Pneumolysin - binds to Fc region of IgG, cytotoxic to endothelial cells.

Invasion of BBB:
- Sp initially adheres and activates the endothelial cell surface - ↑PAF
- PAF binds to PPC => internalisation and invasion of Sp.

Front 34

What are the 2 phase variation of Sp?
What are the purpose of phase variations?

Back 34

Phase variants help aid variety to population.
1. Transparent variant - better colonisation and invasion.
2. Opaque variant - better survival in the bloodstream.

Front 35

Describe the dissemination of tetanus toxin.

Back 35

Clostridium tetani - produces the tetanus toxin locally in the wound during growth.

Punction wound
↓
C.tetani growth
↓
Toxin production
↓
Uptake by nerve
↓
Retrograde transport
↓
Blockage of actions of the inhibitory neurons - spare excitatory
↓
Continuous muscle contraction

Front 36

Name an example of pathogen disseminated through olfactory pathway.

Back 36

Protozoa - Naegleri fowleri.
Causes primary amoebic meningoencephalitis - very lethal.

Front 37

How is the CSF useful in diagnosis CNS infections.

Back 37

CSF is a clear sterile environment and high in protein.
Look for changes in levels of protein, glucose, leukocytes and predominant cell types.

Front 38

describe how does a triplet repeat expansion occurs.

Back 38

In mitosis, the DNA strands may misalign, creating a loop that includes that includes the triplet repeat (SSM-Slipped Strand Mitosis). Sometimes this section of DNA is excised (if from parent strand), but more often the DNA will separate creating an unpaired section of DNA (if from daughter strand)on each opposite strand. This acts as a template to form a complementary sequence on the other side, growing the length of the triplet repeat sequence.

Front 39

Name the 3 branches of trigeminal. State the characteristics of each; sensory or motor.

Back 39

V1: ophthalmic – purely sensory
V2: Maxillary – purely sensory
V3: mandibular – motor and sensory

Front 40

Label the sensory region of each branches in the following diagram.

Back 40

.

Front 41

What are the branches of the ophthalmic branch (V2)?

Back 41

Lacrimal nerve (L for Lateral)
• Sensory to lacrimal gland

Frontal nerve
• Supraorbital
• Supratrochlear

Nasociliary nerve
• Long ciliary nerve
• Infratrochlear nerve
• Ethmoidal nerve

Front 42

Locate the branches of the ophthalmic nerve on the diagram below.

Back 42

.

Front 43

Through what structures do branches of the trigeminal nerve leave the skull?
- Opthalmic n. (V1)
- Maxillary n. (V2)
- Mandibular (V3)

Back 43

Mneumonics - Single Room Occupancy (SRO)
Superior orbital fissure - V1
foramen Rotundum - V2
foramen Ovale - V3

Front 44

Name the 4 nuclei of the trigeminal nerve and what are their functions.

Back 44

1. Trigeminal motor nucleus
Mid pons; mediates jaw jerk reflex.

2. Mesencephalic nucleus
- Receives input from muscle spindle of the jaw mm and fibres from mechanoreceptors in the teeth and gums.
- The only sensory sensory nucleus withing CNS.

3. Principal sensory nucleus
- Mid pons
- Relays touch and proprioceptive (homologue to dorsal column)

4.Spinal trigeminal nucleus
- mid pons to C3 spinal cord
- Pain and temperature from V1, V2, V3. Blends into dorsal horn of the spinal cord and the lower tract blends into Lissauer's tract.

Front 45

What is the role of this branch of the trigeminal nerve?
Opthalmic nerve (V1)

Back 45

Opthalmic nerve (V1)

Purely sensory. Innervates skin of forehead,upper eyelid, eye and nose.
A branch of V1 (nasociliary n.) carries sympathetic fibres, picked up in the cavernous sinus, to the ciliary ganglion (of III) which are passed to dilator pupillae.

Front 46

What is the role of this branch of the trigeminal nerve?
Maxillary (V2)

Back 46

Maxillary nerve (V2)

Purely sensory. Innervates skin on cheeks, oral cavity, upper teeth and palate.

Front 47

What is the role of this branch of the trigeminal nerve?
Mandibular (V3)

Back 47

Mandibular (V3)

Motor and sensory.
Motor innervate muscles of mastication.
Sensory innervates lower teeth, anterior 2/3 tongue, taste fibres and provide parasympathetic supply to submandibular and sublingual salivary glands.

Front 48

N. caudalis, a part of the spinal trigeminal nucleus, process information of pain and temperature. From what nerves does it receive input from?

Back 48

V1, V2 V3
VII, IX, X - external ear

Front 49

Describe the sensory pathway to cortex - spinal trigeminal. From skin to cortex.

Back 49

V1-V3 -> 2nd order fibres x-over at the level of entry (medulla) -> project to VPM of the thalamus -> post central gyrus.

Front 50

Describe the sensory pathways to cortex for Principal nucleus.

Back 50

Large calibre fibres synapse in the principal nucleus
↓
most 2nd order fibres x-over at the level of synapse and join the medial lemniscus
↓
Fibres from mouth does not x-over and ascend I/L
↓
Synapse on VPM
↓
Projects to lower end of post central gyrus.

Front 51

What is the function of the limbic system?

Back 51

It is a very old system.
Related to natural rewards of food, drink, sex, sleep, memory and learning.
It is an interphase between hypothalamus and neocortex.

Front 52

Name some disorders associated with abnormal limbic cortex.

Back 52

- Mood disorders (commonly: depression, anxiety attacks, panic, OCD and phobias)
- Autism
- Schizophrenia
- Tourette's syndrome
- Social behaviour disorder

Front 53

What are the warning signs and symptoms of dangerous headaches?

Back 53

- Sudden and severe
- Febrile with menigism
- Focal neurology
- Chronic progressive
- Raised ICP
- Visual symptoms, polymyalgia, jaw claudication, temporal artery tenderness

Front 54

What are the characteristics of migraine headache?

Back 54

- Episodic
- Unilateral
- Throbbing headache
- Associated with photophobia

But it may not cause headache at all.

Front 55

What normally comes before migraine? In what forms does it normally come?

Back 55

Aura.

Central/focal deficit:
vertigo, dysphasia, hemiparesis, hemisensory change (migrating paraesthesia)
Visual change: zig-zag lines, dots/blobs, often moving/shimmering/shiny in nature.

Front 56

Name some of the triggers for migraine.

Back 56

- Food (chocolate, wine, cheese)
- Chemicals (MSG)
- Drugs (OCP)
- Exercise

Front 57

Giant cell arteritis

Age > 50

Headache characteristics:
localised, with arterial tenderness or visible/palpable swelling.

Other SS:
jaw claudication from ischaemia of chewing muscle, polymyalgia (rare), raised ESR/CRP.

Back 57

Diagnosis: biopsy

Treatment: steroids.

Front 58

How do you manage migraine?

Back 58

Prophylaxis:
propanolol and other beta-blockers, anti-epileptic (valproate), sandomigran, verapamil, dopamine antagonists (chlorpromazine)

Acute treatment:
- Analgesic
- Antimigraine agents (cafergot - caffeine plus ertogamine & triptans)

Front 59

What are some of the characteristics of tension headache?

Back 59

- Very common headache
- Diffuse and non throbing
- Worse near end of the day
- May respond to amitryptyline, or antimigraine drugs