Week 42- Descending Pathways and Weakness Flashcards
1
Q
What are some clinical signs of an UMN lesion?
A
Muscle weakness Hyperreflexia Muscle rigidity (increased tone) Clonus (rhythmic muscle spasm) Positive Babinski's sign (plantar reflex)
2
Q
What are some clinical signs of a LMN lesion?
A
Muscle weakness but also with atrophy Decreased reflexes Fasciculations Flaccid paralysis (decreased tone) Negative Babinski's sign (plantar reflex)
3
Q
What are some clinical signs of Neuromuscular junction lesions?
A
Slowly progressive or fluctuating signs
Mixed UMN and LMN pattern
Bilateral proximal muscle weakness
Atrophy
4
Q
What are some clinical signs of disorder of the pyramidal motor pathways?
A
Spasticity Weakness slowing of rapid alternating movements Hyperreflexia Positive plantar reflex Babinski sign.
5
Q
What are some clinical signs of disorder of the extra-pyramidal motor pathways?
A
Akathisia –> feeling restless
Acute dystonia –> uncontrollable sudden muscle contraction (often head and neck + eyes)
Parkinsonism –> rigid limb muscles, tremor, slow movement, gait changes
6
Q
What is Hemiplegia gait?
A
foot is plantar flexed and leg is swung in the lateral arc –> caused my spasticity (normally from UMN lesion)
7
Q
What is a Parkinson’s gait?
A
hesitation to start, shuffling, freezing etc –> caused by extrapyramidal symptoms
8
Q
What is a Cerebellar gait?
A
drunken gait.–> wide based or reeling on narrow base, staggers towards the affected side if the is a unilateral cerebellar hemisphere lesion
9
Q
What is a Posterior column lesion gait?
A
clumsy slapping down of the feet on a broad base
10
Q
What is a high stepping gait?
A
high stepping gait to avoid tripping on foot –> person normally has foot drop –> injury to peroneal nerve or muscle weakness
11
Q
What is the gait like in Proximal myopathy
A
waddling gait –> leg extending has hip drop on that side to compensate the person will sway their trunk the other way
12
Q
What is a Prefrontal lobe (apraxic) gait?
A
feet appear glued to the floor when erect but move more easily when patient is supine
13
Q
What is a Conversion disorder (hysteria)
A
(choreiform gait)
bizarre inconsistent gait
14
Q
What is a Diplegic gait?
A
extensor spasm –> tip toe –> abduction spasm (legs close together) –> common in cerebral palsy
15
Q
What is the clinical symptoms of Multiple Sclerosis?
A
Numbness or weakness –> normally on one side of the body
Tremor
Lack of coordination
Unsteady gait
Vision problems common –> one eye at a time, double vision
Fatigue
Dizziness
16
Q
What is the clinical symptoms of Guillain-Barre Syndrome?
A
Weakness –> starts in legs and spreads upwards to arms etc –> can lead to respiratory depression
Pins and needles in extremities
Gait issues
17
Q
What is the clinical symptoms of Myasthenia Gravis?
A
Muscle weakness –> worsening as muscles are used
Commonly eye muscles are the first symptom –> ptosis (eyelid droop) and diplopia (double vision)
18
Q
What is the general pathology of MS?
A
Inflammatory reaction driving demyelination of axons
19
Q
What is the general pathology of GBS?
A
Inflammatory/autoimmune reaction to myelin of axons
20
Q
What is the general pathology of Myasthenia gravis?
A
Autoimmune attack on acetylcholine receptors at the NMJ –> drives weakness
21
Q
What is the general mechanism of LEMS?
A
Autoimmune attack on calcium ion channels on nerve side of NMJ –> drives weakness through less Acetylcholine release
22
Q
What is the easy way to tell MS, GBS, MG and LEMS apart?
A
MS –> normally vision symptoms
GBS –> very similar to MS –> but normally following a few weeks after a respiratory or GIT infection
MG –> weakness gets worse after using muscles –> improved with rest –> eye symptoms diplopia and ptosis are first
LEMS –> weakness gets better with muscle use “Warm UP” more nerve stimulation = more Ca+ = more ACh
23
Q
What the difference between cataracts and glaucoma?
A
Cataracts –> change in lens
(cloudiness)
Glaucoma –> build up of pressure in eye –> damage to optic nerve
24
Q
What cranial nerve is important for visual acuity and visual fields?
A
CN2
25
What cranial nerves are important for eye movements?
3,4,6
26
What is the normal water content of myelin in the body?
40%
27
What is the main components of myelin in both the CNS and PNS?
70-85% is lipid
| 15-30% is protein (lower than most other biological membranes
28
What are the major lipid types in myelin?
```
Cerebroside
Cholesterol
Plasmalogens
Lecithin
Sphinogmyelin (relatively low levels)
```
29
How does protein composition of CNS compare to brain membranes?
Much simpler
30
Is there protein in the PNS different to the CNS?
There is some crossover but the PNS does have some unique proteins
31
What accounts for 60-80% of the proteins in CNS myelin?
Myelin proteolipid protein (PLP) and Myelin basic proteins (MBP)
32
What is the role of myelin?
An electrochemically insulating sheath around all but the smallest axons in the white matter
--> increases speed of conduction and action potentials along the axon
33
How does thickness of myelin translate into speed of conduction?
Thicker = faster
34
What are some of the roles of enzymes discovered in myelin?
Ion transport --> to maintain its own structure but also buffering vicinity of the axon
35
What has been shown when CNP enzymes have problems?
Myelin axons will become swollen and degenerate
| Has not been shown to affect myelination though
36
What has MBP proteins been shown to mediate?
Signal transduction:
Sustained influx of Ca2+ followed by
Calcium dependant depolymerisation of microtubules and stabilisation of actin filaments
37
How does myelin affect neuron stiffness
Myelin provides extra support and makes the neurons stiffer
- -> significant support in the spinal cord
- -> partially dictates the tensile response of the tissue
38
What are some proteins that have a essential role in axonal maintenance and function?
PLP --> axon function --> absence causes axon swelling
MBP --> myelin compaction and thickening
MAG --> initiation of myelination
39
What is the type of conduction that myelination allows?
Saltatory conduction --> (saltare means to leap or hop)
| --> allows conduction to hop from one node of Ranvier to the next node
40
What is a node of Ranvier?
Gap in the myelin sheath of an axon
41
What are the segments of myelination each side of a node of Ranvier called?
Internodal segments --> or internodes
42
How many cells can a glial cell myelinate?
40 or more separate axons
43
What are the organised patterns of molecular domains on axons?
Nodes of Ranvier
Paranodal --> axoglial junctions (junction between axolemma and terminal ends of each myelin sheath layer)
Juxtaparanodes --> sites of K(voltage) ion channels
44
How are Na(voltage) channels clustered
| Protein interactions:
Axonal cell adhesion molecule (neurofascin 186 (NF186)) recruits ankyrin G
Ankyrin G binds voltage Na channels
45
Where are oligodendrocytes and where are Schwann cells?
Oligodendrocytes --> CNS
| Schwann --> PNS
46
How thick normally are the myelin sheaths as axon diameter increases?
They get thicker with larger diameter
47
How can several conditions like GBS be diagnosed?
Nerve conduction velocities
48
Within the axons how are misfolded and unnecessary proteins dealt with?
They are polyubiquitinated and degraded by the ubiquitin proteasome system (UPS)
49
What does the degradation of MAP8 and tubulin folding cofactor B (TFCB) control?
Microtubule organisation/dynamics
Also axon transport
--> if they are let to accumulate leads to a degradation of the axon
50
What gene has been identified to ensure the degradation of MAP8 and TFCB?
The gigaxonin gene
51
What is an important catabolic pathway for degradation?
Autophagy
52
What is Autophagy?
cytoplasmic contents are wrapped in a double membrane and fused with lysosomes for degradation
53
How is myelin formation initiated in the CNS?
Cell-cell interactions between the axon and the oligodendrocyte
Oligodendrocytes recognises a surface protein (eg VCAM-1)
54
How does an oligodendrocyte form its myelin sheath?
Produces a flattened sheet
Sheet wraps repeatedly around the axon
Layers of oligodendrocyte plasma membrane firmly pressed together
55
Where does the oligodendrocyte plasma membrane remain when it in myelin sheath?
Only in the innermost and the outermost turns
56
In the PNS which axons are myelinated?
Intermediate axons are
| Smallest diameter axons are not
57
How does Schwann cells form the myelin sheath for the PNS?
```
Attracted to axon segment
Wraps repeatedly --> compact sheath
Influenced by:
Contact, diameter, electrical activity
Signals originate from the axonal membrane
```
58
What is the differences of the PNS myelination to the CNS?
1. Small pockets of cytoplasm (schmidt-lanterman clefts)
Occurs at irregular intervals in PNS myelin --> small pockets of cytoplasm left behind during myelination
2. Basal lamina covers the external surface of Schwann cells
3. 1 Schwann cell --> 1 single internode of PNS
59
What encloses unmyelinated axons in the PNS?
Enclosed by canals formed by invagination's in Schwann cells
60
How does myelin increase speed of impulse propagation?
Electrical insulator --> current cannot leave the axon
| Myelin fibres lack voltage gated ion channels along the myelinated internodes
61
What is important for axons to remain in functioning order?
Delivery of new materials
| Removal of unwanted proteins
62
Where are most proteins needed in axons synthesized?
Cell bodies
63
How are proteins and waste transported to and from the axons?
Bidirectional transport along microtubules (fast or slow transport)
64
What proteins are essential for axonal transport machinery?
Microtubules (microtubule associated proteins (MAPs))
| Motor proteins
65
What does each branch of a motor neuron form a single junction with?
Muscle fibre
66
At the neuromuscular junction what happens to the axon?
Divides into several short processes that lie embedded in the groves on the sarcolemma
67
What kind of muscle fibre does a motor neuron make contact with?
Striated muscle fibres
68
What is the terms for the post synaptic region in a neuromuscular junction?
Motor end plate
69
What does the average human motor end plate contain?
15-40 million nicotinic acetylcholine receptors (NaChR)
70
What does each action potential release to the motor end plate?
Acetylcholine from synaptic vesicles
71
How is acetylcholine produced in colinergic neurons?
Synthesised by choline acetyltransferase from choline and acetyl-CoA.
72
What enzyme degrades Ach?
Acetylcholinesterase
73
Where is Acetylcholinesterase mainly present?
Abundant in the synaptic cleft
74
What is Acetylcholinesterase essential for?
Degrading Ach in synaptic cleft --> essential for proper muscle function
75
What is Myasthenia gravis?
Autoimmune disease:
| NaChR is internalised and degraded --> leads to impaired muscle contraction
76
What is a treatment for Myasthenia Gravis?
Acetylcholinesterase inhibitors --> ACh is not degraded as quickly --> signals can continue
77
What is the key features of motor neurons?
They are some of the longest cells in the body
| Myelin covers them --> except at the nodes of Ranvier and axon terminals
78
Are skeletal muscles voluntary?
Yes but not for individual muscles --> only muscle groups
79
Are smooth and cardiac muscle voluntary?
No they are involuntary --> action not normally consciously appreciated
80
Why are respiratory muscles special in terms of control?
They are under dual control
| Voluntary AND involuntary control
81
Which brain areas control skeletal muscle?
Precentral gyrus (anterior to the central sulcus) --> also known as M1 or Area4)
82
What side of the body does the precentral gyrus affect?
Contralateral side
83
What is the distribution of muscle control going from medial to lateral of the precentral gyrus?
```
Foot
Knee
Hip
Trunk
Shoulder
Elbow
Wrist
Hand (large area)
Neck
Face
Lips
Tongue
Swallowing
```
84
What is the tract where cortical signals are sent to the skeletal muscle?
Cortico-spinal (Pyramidal tract)
85
Describe the cortico-spinal tract (Pyramidal)?
Motor cortex cells (long axons) --> the medulla (pyramidal decussation)
Medulla --> Axons synapse on alpha motor neurons in the contralateral spinal cord at different segmental levels
Motor neurons travel to skeletal muscle groups
86
What is the capsula interna?
Where cortical axons gather within the brain
87
What will happen in Local damage to the motor cortex?
Paralysis or weakness in a limb/face (on the contralateral side)
88
What would happen if there was damage to the capsula interna?
Paralysis (hemiparesis/hemiplegia) and sensory losses on the contralateral side of the body --> as it can affect many axon groups
89
What happens in Brown-Sequard syndrome?
There is damage to half the spinal cord --> paraplegia or tetraplegia following cross sectional damage of the spinal cord
If damage is high enough (cervical) can cause respiratory paralysis
90
What is the general difference between upper and lower motor neurons?
Location:
Upper --> within the brain
Lower --> within the cortico-spinal tract
91
What happens to voluntary control in UMN vs LMN lesions?
They both lead to reduced or absent voluntary control
92
What kind of lesion leads to muscular atrophy?
Lower motor neuron lesions lead to muscle atrophy
93
What is the differences between muscular tone in UMN vs LMN?
UMN --> Increased tone --> spasticity
| LMN --> reduced tone --> flaccid paralysis
94
How does reflex responses compare between UMN and LMN lesions?
UMN --> Hyper-reflexia
| LMN --> reduced or absent
95
Where are alpha motor neurons located in the spinal cord?
Ventral horn
96
What is a motor unit?
Smallest functional unit for movement
97
What does a motor unit consist of?
Single alpha motoneuron
The alpha motoneurons axon
All muscle fibres innervated by the neuron
98
What is a motoneuron pool?
Group of neurons (a column) that innervate one muscle
99
What is the area in which nerves transmit signals to muscles?
Neuromuscular junction
100
What is a neuromuscular junction?
Synapse between motoneuron axon terminal and the muscle fibre
101
What neurotransmitter is released at a neuromuscular junction?
ACh
102
What receptor does ACh act on in the post synaptic region in a neuromuscular junction?
Nicotinic acetylcholine receptors nAChRs
103
What inactivates ACh in the synaptic cleft?
Acetylcholinesterase
104
What kind of ion channels are nAChRs?
Ligand gated ion channels --> allow the entry of Na+
105
What would be the effect of an ACh receptor blocker at the neuromuscular junction?
Paralysis
106
What would be the effect of a cholinesterase inhibitor at the neuromuscular junction?
Potentiation of ACh affect --> muscle overactivity --> spasm at overdose
Eg eserines and organophosphates (insecticides, pesticides etc)
107
What would be the effect of an ACh release blocker at the neuromuscular junction?
Paralysis
108
What is an example of an ACh release blocker?
Botulinum toxin (Botox)
109
What are some key features of skeletal muscle cells?
Long --> extend the whole muscle
Multiple nuclei --> results from myoblast fusion
Not electrically connected --> each fibre requires synaptic activation
110
What is the crucial ion for muscle contraction?
Ca2+
111
Where is intracellular Ca+ stored at rest in a skeletal myocyte?
Sarcoplasmic reticulum (SR)
112
How does Ca2+ get released from the SR?
```
DHP receptors (membrane Ca channels) --> Action potential arrives
DHP receptors are mechanically coupled to RyRs (intracellular Ca channel on the SR membrane)
DHP activation activates the RyRs
Ca2+ enters intracellular space from SR
```
113
What is the main components in an actin filament?
F-actin --> double strands --> have active sites with high myosin affinity
Tropomyosin --> wraps around F-actin
Troponin complex --> loosely attached to Tropomyosin to "shield" active sites from myosin head binding
114
What happens in the actin filament when there is an increase in intracellular Ca2+?
Ca2+ binds to Troponin C
Troponin C detaches from filament (revealing active sites on F-actin)
Active sites on F-actin can then bind myosin
115
How does actin and myosin interact to allow muscle contraction?
Myosin filaments have numerous myosin heads along its length
Pivoting myosin heads when bound to actin allows both filaments to slide over each other
Sliding --> muscle contraction
116
What is required to allow actin and myosin interaction for muscle contraction?
Ca2+ and ATP
117
In summary what is the flow from neuromuscular junction to muscle contraction?
```
ACh release at NMJ
AP generation in muscle cells
DHP receptors activation (activating RyRs on SR)
Ca2+ release from stores
Myosin-actin interaction
Contraction
```
118
What determines strength of a skeletal muscle contraction?
Frequency of motoneuron discharge
| Number of activated motor units
119
What are the 4 main factors that define muscular strength?
Cross-sectional area of recruited muscles (muscular component)
Intensity of recruitment (neural component)
Limb bone length (skeletal component)
Muscular fibre type (genetic component)
120
What are the two kind of twitch fibres in muscles?
Type 1 --> Slow
| Type 2 --> Fast
121
What is the different features of Type 1 and Type 2 muscle fibres?
Type 1 --> Slow --> Small twitch force --> Low glycogen content --> Endurance
Type 2 --> Fast--> Medium twitch force --> High glycogen content --> Short-term effort
122
What is a reflex?
Responses to sensory stimuli without participation of consciousness
123
How is reflex arc integrity assessed?
Examining motor reflexes eg knee patellar reflex
124
What is the role of sensory receptors in muscles and tendons?
Gives CNS information about position and movement so it can execute adequate motor control
125
What is an example of sensory proprioception in skeletal muscle?
Tension detection --> Golgi tension organ does this (sits in series)
126
What is self-tolerance important for?
Preventing autoimmunity
127
What kind of cells play a central role in self tolerance?
CD4+
128
What kind of tolerance is most important?
T cell tolerance --> more important than B cell tolerance in terms of autoimmunity
129
What are two processes of tolerance for T cells?
Thymic tolerance:
--> + and - selection leading to deletion of self reactive lymphocytes
--> weakly self reactive lymphocytes are rendered unresponsive (anergy)
Peripheral tolerance:
--> Ignorance --> self antigens are invisible
--> separation of autoreactive T cells and Ag (antigens)
--> Anergy and lack of co-stimulation
--> suppression induced by T reg cells (CD4+ AND CD25+)
130
What happens if self-tolerance breaks down?
Autoimmunity
131
What is the mechanism for T cell positive selection in the Thymus?
Selects for T-cells capable of interacting with MHC molecules
132
What is the mechanism of T cell negative selection in the Thymus?
Removes thymocytes that are capable of strongly binding with the "self" MHC peptides
133
What are the areas of B-cell tolerance?
In bone marrow
| Peripheral
134
How does Bone marrow B-cell tolerance happen?
The complex antigen receptor (IgM) is first expressed on 'immature' B cells
Central tolerance mechanisms remove B-cells that react to self-antigen
135
What are the two central tolerance mechanisms that remove B-cells that react to self-antigens?
High affinity binding to self antigen:
Receptors are edited --> so that it no longer binds to self antigen
Apoptosis --> self-reactive B cells are removed to prevent autoimmune responses
Low affinity binding to self antigen:
Decreased receptor expression and signalling --> leads to anergy --> B cells still present but do not respond
136
How does Peripheral tolerance of B-cells happen?
B cells undergo somatic hypermutation when encounter pathogen
During this process antibodies with higher binding efficiency are produced by can also form auto-reactive antibodies
B cells that do bind to self-antigen are removed by apoptosis
137
How does molecular mimicry act as an autoimmune trigger?
Antigens can have a structural similarity with self-antigens --> leads to an appropriate adaptive immune response to the pathogen but as it also reacts to self-antigen causes autoimmune disease after the infection is cleared
138
Why is the CNS classically considered to the an 'immune-privileged' area?
```
Existence of BBB
Absence of lymphatic drainage
Low expression of MHC class II
Low levels of dendritic cells and potent Antigen presenting cells (microglia)
Secretion of immunosuppressive TGF-beta
```
139
What is the reality of the brain and its immune privileged?
| It is not 100% true:
During infections --> breakdown in tolerance and peripheral T-cells gain access to the CNS through the BBB
Increasing evidence of CNS is an active surveillance site with bidirectional communication between the CNS and the immune system
140
What is the suspected mechanism between viral infections and autoimmunity in neurological diseases such as Multiple sclerosis (MS) in humans?
)
Genetic predisposition + molecular mimicry leads to the migration of Autoreactive T cells through the BBB to the CNS
Microglial cells present myelin peptides to activated T-cells
CD4+ (TH1 cells) active local macrophages and astrocytes to reduce myelin synthesis or triggering neuron apoptosis
CD4+ (TH2 cells) induce B-cell activation and formation of myelin reactive antibodies (triggering demyelination
141
What happens when there is an imbalance between tolerogenic and activating signals on autoreactive T cells?
They can escape tolerance traffic
Their activation can lead to tolerance or self-reactivity
Autoreactive T-cells can gain access to CNS and initiate tissue inflammation
Can further into autoimmune tissue destruction
142
What is the most common inflammatory neurological disease affecting young adults?
Multiple sclerosis (MS)
143
What are the hallmark features of MS?
CNS inflammation and neurodegeneration
144
What are some potential trigger aetiology?
Increased risk from specific HLA regions on chromosome 6
| Strong epidemiological link with Epstein-Barr virus (EBV)
145
What has mouse experimentation show?
Indicates strong role for CD4+ T cells (TH1 and TH17)
146
What antigens do T cells target in MS?
MBP --> myelin basic protein
PLP --> proteolipid protein
MOG --> myelin oligodendrocytes protein
147
Where can sclerotic lesions be found in MS?
Lesions/plaques develop in the white matter of the CNS
148
What destroys the myelin around the nerve axons in MS?
Inflammatory infiltrates of macrophages and lymphocytes surrounding blood vessels
149
Histologically what do the active plaques look like in MS?
High cellular density of Lymphocytes (T cells
| Foamy macrophages and astrocytes are sparse
150
What is the mechanism of immunopathogenesis of MS?
1. Autoreactive T cells specific to myelin antigens migrate to CNS
2. T cells encounter autoantigen peptides presented by MHC II on infiltrating macrophages and microglial cells (they activate in CNS or in periphery)
3. Local inflammation --> increases vascular permeability --> promotes infiltration of autoreactive TH17 and TH1 effector cells
4. Inflammatory cytokines increase recruitment of lymphoid and myeloid cells into CNS
5. Autoreactive B cells produce autoreactive antibodies with T cell help and exacerbate inflammation
151
What are some common presentations of MS?
```
Optic neuritis
Relapsing and remitting sensory symptoms
Subacute painless spinal cord lesion
Acute brain-stem syndrome
Subacute loss of function of upper limbs
CN6 palsy (abducens)
```
152
How is MS investigated?
Imaging --> MRI --> to check for lesions within CNS
Visual evoked potential/response --> speed of response to visual stimulus to visual cortex
CSF assessment --> increased protein, immunoglobin, T cells,
Exclusionary testing --> ruling out other causes
153
How is the clinical course of MS described?
Relapsing-remitting --> acute attacks and reduction in disease
154
What are the range of therapeutics for MS?
Symptomatic --> to address spasticity, ataxia, dysesthesias
Disease modifying --> reduce attack severity or frequency
Immunosuppressive --> reduce inflammation during attacks
155
What is Paraneoplastic-neurological disorders (PNDs)?
Neurological manifestations associated with cancer
156
What are some features of PNDs?
Do not originate from the tumour itself (caused by metabolic, toxic or infectious complications of malignancy or treatment)
Highly diverse in terms of tissue damage and clinical signs
Can develop naturally due to anti-tumour immune responses
157
What is Autoimmune Cerebellar Disease (anti-Hu)
A common PND
158
What cancer is Anti-Hu syndrome associated with mostly?
Lung cancer in 85% of cases --> mostly small cell lung cancer
159
What do Anti-Hu syndrome PNDs have as symptoms?
Highly diverse but --> psychiatric (depression , anxiety and hallucinations) and neurological (memory loss, weakness, seizures and coordination problems)
160
What are some typic brain regions that are preferentially targeted in autoimmune cerebellar disease? (Anti-Hu)
Hippocampus, lower brain stem, spinal cord, dorsal root ganglia
Structures that can also be affected --> cortex, medulla, amygdala, cingulate gyrus, pons
161
What is the pathogenesis of autoimmune cerebellar disease (anti-Hu)?
Adaptive immune response against antigen (HuD) which is normally neuron-restricted BUT can become ectopically expressed by small-cell lung cancer cells
Dendritic cells capture antigens from the malignant cells (including HuD)
Migrate to lymph nodes --> presented to antigen specific CD4+ and CD8+ cells
HuD-specific T cells circulate and acquire capacity to cross BBB
Neurons express MHC class I and present HuD, HuB, HuC proteins
Neurons are targeted by HuD specific CD8+ cells resulting in neuronal tissue damage
Leads to paraneoplastic neurological manifestations (PND)
162
What is Guillain-Barre Syndrome (GBS)?
Acute inflammatory or post-infective demyelinating polyneuropathy
163
What is some common history of people with GBS?
Respiratory infection or diarrhoea 1-4 weeks pre-onset in 70% of cases
164
What are some symptoms of GBS?
Weakness in legs --> spreading to upper body
Pins and needles in fingers, toes ankles or wrists
Difficulty with eye or facial movements (can be speech aswell)
Severe body aches
Rapid HR
Difficulty breathing
Low OR high BP
Difficulty with bladder or bowel function
165
What have 25-50% of patients with GBS been exposed to?
Campylobacter jejuni
166
What are some other causes of GBS?
Viruses such as Epstein-virus, HIV, cytomegalovirus (zika and chikungunya)
167
What is expected to be the immunological mechanism for GBS infection?
Molecular mimicry
168
How is nerve cells demyelinated in GBS?
Antibody-mediated effector pathways --> damaging myelin sheath --> includes complement activation
This mechanism causes glial or axonal membrane injury --> result in conduction failure
Caused by molecular mimicry between glycans in LPS generating antibodies that bind to GM1 and GD1a gangliosides --> leading to nerve conduction blockade
169
What happens in a less common variant of GBS?
There is immunological damage to the axon or motor nerve end plate terminals
--> mediated by anti-ganglioside IgG antibodies --> nerve damage caused by classical complement activation
170
How is GBS diagnosed?
```
Hard to do in early stages
Similar to other neurological disorders
Lumbar puncture
Electromyography
Nerve conduction studies
```
171
How is GBS treated?
Intensive care --> respiratory therapy, cardiac monitoring, safe nutritional supplementation, monitoring of infectious complications
Plasma exchange --> can remove certain antibodies that contribute to attack
Immunoglobin therapy --> high doses can block damaging antibodies that may be contributing to GBS
172
What is Myasthenia Gravis?
Progressive inability to sustain a maintained or repeated contraction of striated muscles
173
What is the cause of Myasthenia Gravis?
Acetylcholine receptors in the post-junctional membrane of neuromuscular junctions are blocked or internalised by a complement-mediated autoimmune reaction
174
What triggers the complement-mediated autoimmune reaction in myasthenia gravis?
Acetylcholine receptors bound by anti-acetylcholine receptor antibodies
175
Who is most at risk of Myasthenia Gravis?
15-50 years old and females are more affected
176
What are some symptoms of Myasthenia Gravis?
Abnormal fatigue and weakness of muscles with worsening symptoms at end of day or following exercise
177
Is there sensory signs and CNS involvement in Myasthenia Gravis?
No
178
What symptoms to people with myasthenia gravis normally present?
Intermittent ptosis, diplopia, weakness of chewing, swallowing, speaking and limb movement
179
How is myasthenia gravis diagnosed?
Neurological examination --> key sign is muscle weakness that improves with rest
Edrophonium test --> edrophonium chloride injection may result in temporary improvement of muscle strength (blocks degradation of acetylcholine)
Blood analysis --> presence of anti-acetylcholine receptor antibodies (80% of patient)
Electrophysiology --> repetitive nerve stimulation and electromyography
MRI --> exclusionary
180
What are the treatment options for myasthenia gravis?
Cholinesterase inhibitors --> inhibits acetylcholine degradation in synapse
Corticosteroids --> inhibit antibody production and immune cell activation
Immunosuppressants
Plasmapheresis --> remove auto-antibodies from circulation short term benefit
Intravenous immunoglobin --> dampens auto-immune antibody response
Monoclonal antibody --> suppresses overactive/dysfunctional B cells
Thymectomy --> 15% of patients have a tumour in thymus --> removal doesn’t have any immediate therapeutic benefit
181
What are the point of anatomical barriers to the brain?
Separate CSF from blood
182
What are the different anatomical barriers to separate blood from CSF in the brain?
Blood brain barrier
Blood-CSF barrier
Brain CSF barrier
183
What is the main role of the BBB?
Dynamic highly selective membrane --> regulates brain homeostasis
Insulates brain from toxins, invading pathogens, --> maintains immune status as immune privileged organ
184
Anatomically what is the BBB?
Capillaries with many tight junctions that seal the endothelial cells along with a thick basement membrane around the capillaries
185
What is the pericytes?
Sits next to the capillaries of the BBB
186
What does the pericyte regulate?
Endothelium tight junctions
Secrete basement membrane (basal lamina
Contractile properties of the pericyte regulate capillary blood flow
187
Where do the astrocytes sit in the BBB?
Astrocyte projections completely surround the capillaries
188
What is the role of astrocytes in the BBB?
Secrete chemicals that maintain endothelial tight junctions --> reinforces the highly selective membrane of the Endothelium
189
What is paracellular transport and what is it regulated by in the BBB?
Transport in between cells --> regulated by tight junctions
190
What is transcellular transport and what is it regulated by the BBB?
Molecules through the cells (apical and basolateral membrane) --> regulated by endothelial cells (membrane transporters, pumps and receptors)
191
What does clinical features of nervous system infections depend on?
Location --> meninges or the parenchyma of the brain and spinal cord
Cause --> virus, bacteria, fungus or parasite
Acute or chronic
192
What detects foreign pathogens in the CNS?
Macrophages and microglial detect and subsequently activate in response
193
How do T cells activate to detect pathogens in CNS?
Activated macrophages and microglia release chemokines and anti-viral cytokines in local environment
Chemokines attract T cell and myelomonocytic cells from periphery
Upregulation of MHC molecules and antigen presentation on infected microglia, macrophages, stromal cells and astrocytes
T cell mediated immune response is enhanced
What pathways are involved from increased expression of cytokines and chemokines?
Dopaminergic and glutamatergic pathways modulate brain function
194
What is the most common cause or meningitis?
Viral infections
195
What are some symptoms of Viral meningitis?
Elevation of body temperature
Headache
Meningism --> stiffness of neck + Kernig's sign (extension of the knee with hip joint flexed causes spasm in hamstring muscle
There is no associated focal signs (parenchymal tissue not involved)
196
What is the disease course of viral meningitis?
Self limiting and less severe than bacterial meningitis
197
What is the CSF results for viral meningitis?
Excess lymphocytes with normal protein and glucose levels
198
What is the treatment and recovery time for viral meningitis?
Symptomatic therapy as virus is self limiting
| Recovery is rapid compared to bacterial meningitis
199
What is the usual cause of bacterial meningitis?
Usually secondary to bacteraemia infections (blood infection)
Can be caused by direct spread from ear, sinus or skull fractures
200
What is the clinical signs of bacterial meningitis?
```
Fever
Headache
Drowsiness
Neck stiffness
Rapid progression to coma with focal neurological signs --> in severe infection
```
201
What is the prognosis of bacterial meningitis and what is essential in diagnosis?
Mortality rates are high --> early diagnosis via lumbar puncture is essential
202
What is a side effect of inflammation and adhesions in bacterial meningitis?
Obstructions to blood flow --> damage to cranial nerves, hydrocephalus, cerebral infarction
203
What are some CSF results in bacterial meningitis?
CSF pressure rapidly rises, cellular reaction varies depending on causative agent, increase in CSF protein content
204
How is bacterial meningitis managed?
```
Parenteral benzylpenicillin (given following blood culture)
Adjunctive steroid therapy +/- intensive care
```
205
What is Tuberculosis?
A mycobacterium tuberculosis (MTB) infection that predominantly affects the lungs but can affect other organs
206
What are classic symptoms of TB?
Fever
Night sweats
Weight loss
Cough with blood containing sputum
207
Where is TB meningitis more common?
Underdeveloped countries --> rare in the developed world
208
What increase the risk of TB meningitis?
```
AIDS
T2D (type 2 diabetes)
```
209
What is a common location for TB meningitis?
Caseous focus in the meninges adjacent to CSF pathway covered by exudate especially around the base with scattered tubercles
210
What is CSF analysis results in TB meningitis?
Raised lymphocytes
Reduction in glucose
Increased protein
Acid fast bacilli may be seen in smear (or upon culture)
211
What are the two immunological tests to detect exposure to MTB (tb)?
```
Mantoux test (Tuberculin Skin test) --> Tests for type 4 hypersensitivity through at site of purified protein intradermal injection (24-72 hours later)
Interferon Gamma Release Assay (IGRS) --> detects MTB-specific T cells
```
212
What is the type of virus in chickenpox?
Varicella Zoster Virus (VZV) (human herpesvirus)
213
What is the name for reactivated VZV later in life?
Shingles
214
How does herpes simplex virus enter and replicate in a human?
Infects epithelial cells
Enters sensory neurons (allow only limited replication as they are non-dividing)
Virus travels along neuron axon
Enters cell body and establishes latency (Anterograde transport)
Virus can be reactivated and travels back to epithelial cells and undergoes lytic replication (retrograde transport is recurrent)
215
What is meant by latency of herpes simplex virus? Eg chickenpox
Only latency associated transcripts are expressed to establish and maintain latency --> no infectious virus is produced, disease absent, transmission doesn’t occur
216
Where is VZV (herpes zoster virus) --> shingles dormant?
Dorsal root ganglion
217
What are the commonly affected dermatomes in shingles?
Thoracic and facial nerves
218
How does shingles present?
Ranging form discomfort to severe neuralgia
219
How is shingles treated?
Analgesics and Antivirals
220
What kind of disease in Rabies?
Parenchymal viral infection --> zoonotic disease
221
How is rabies spread?
Exposure to saliva or nerve tissue of infected animals with rabies or other lyssaviruses
222
What kind of virus is the Rabies virus?
Single stranded RNA (negative sense) virus
223
What is the incubation period for rabies?
3-8 weeks
224
How does rabies present in humans?
```
Encephalitic phase and signs of nervous system involvement include:
Aerophobia --> fear of flying
Hydrophobia --> extreme fear of water
Bizarre behaviours
Disorientation
Hyperactivity
```
225
What are some symptoms of autonomic instability in rabies?
Hypersalivation
Hyperthermia
Hyperventilation
226
What is the disease progression of Rabies?
Incubation 3-8 weeks
Neurological status deterioration for up to 12 days
Sudden death via cardiac or respiratory arrest or lapses into coma
227
What is the mechanism within the rabies single stranded - strand RNA virus?
Virus enters via receptor mediated endocytosis
Retrograde axonal transport to neuronal cell bodied
Ribonuclear protein released from endocytic vesicle --> transcription initiated
Viral transcripts --> translation of viral proteins
+ve sense viral RNA is used to make viral genomic RNA
Virus is released
228
What is the treatment options for Rabies?
Pre-exposure --> (PreP) --> 3 doses of vaccine
| Post-exposure --> (PEP) 4-5 doses + Human rabies immunoglobin (HRIG) at the same time as first dose
229
What is poliomyelitis?
Enterovirus (poliovirus) --> RNA virus colonising the oropharynx and intestine
230
What is the route of infection for poliomyelitis?
Nasopharynx
231
What is the incubation period for poliomyelitis?
1-2 weeks
232
What does poliomyelitis cause?
Meningitis
| Also infects grey matter of spinal cord, brain stem and cortex
233
What is grey matter vs white matter?
Grey matter --> numerous cell bodies and very few myelinated axons
White matter --> few cell bodies and long range myelinated axons
234
What is the clinical presentations and outcomes in poliomyelitis?
Mild forms --> mild fever and recovery
| Severe forms --> fever, headache, meningism, muscle weakness, respiratory failure
235
What is the mechanism behind a poliovirus infection?
Virus attaches to host cell receptors --> enters via endocytosis --> acidification opens capsid and viral RNA released into cytoplasm
VPg is removed from viral RNA which is then translated into polyprotein
Virion RNA serves as genome and viral mRNA
IRES allows direct translation of polyprotein
Viral RNA replication takes place in membrane bound vesicles derived from ER
New +sense viral RNA synthesised from complementary -ve sense RNA
New genomic RNA packaged into procapsids
Cells lysis releases virus
236
What are the ways poliovirus can gain access to the CNS?
1. Infect brain microvascular endothelial cells --> damages and crossed BBB
2. Trojan horse --> PV-infected leukocytes act as carriers
3. Hijack the retrograde axonal transport to enter CNS via muscles, motor neurons, spinal cord
237
What is the CSF analysis results in poliomyelitis?
Lymphocyte elevation
Increased protein
Normal sugar
Virus present in CSF
238
What is Herd immunity?
Form of indirect protection from infectious disease when a large percentage of a population has been immunised providing a measure of protection for individuals who are not immunised
239
What is an example of a Parenchymal bacterial infection?
Clostridium tetani (soil and gut organism)
240
How does clostridium tetani ender the body?
Cuts, child birth (umbilical stump or mother)
241
What is the mortality rate for clostridium tetani?
100% in newborns 40% in adults
242
What is the incubation time for clostridium tetani?
2 days - several weeks (shorter incubation time = worse prognosis)
243
How does clostridium tetani have its effect?
Bacilli produces exotoxin with affinity for motor nerve endings and neurons
244
What is the presentations of clostridium tetani?
Spasm of masseter muscles (locked jaw)
| Tonic rigidity --> mouth, board like abdominal wall, arched back, painful convulsions
245
How does clostridium tetani cause death?
Exhaustion, asphyxia, aspiration pneumonia
246
How is Clostridium tetani treated?
Tetanus anti-toxin, penicillin/erythromycin
247
What are the key infection risks of someone with clostridium tetani?
Spores of pathogen germinate upon infection in anaerobic environment --> where necrosis of tissues occur
248
What is limb drift?
Shut your eyes and hold your arms out straight --> now turn your palms upwards --> hold
249
What is some causes of limb drift?
Upper motor neuron (pyramidal) weakness --> drift from muscle weakness and tends to be downwards
Cerebellar disease --> drift is usually upwards --> includes slow pronation of wrist and elbow
Loss of proprioception --> drift only reallt affects fingers --> loss of joint position sense
250
What are fasciculations?
Irregular contractions of small muscle areas --> no pattern
251
What does increased tone suggest?
Upper motor neurone or extrapyramidal lesion
252
What does decreased tone suggest?
Frontal lobe or diffuse cerebrovascular disease
253
What is cogwheel rigidity and what is it suggestive of?
Alternating hypertonic --> suggests Parkinson's
254
What are the sensory dermatomes of the upper limb?
• C5 supplies the shoulder tip and outer part of
the upper arm.
• C6 supplies the lateral aspect of the forearm and
thumb.
• C7 supplies the middle finger.
• C8 supplies the little finger.
• T1 supplies the medial aspect of the upper arm
and the elbow.
255
What does the radial nerve innervate?
Triceps, brachioradialis, extensor muscles of the hand
256
What is a symptom of radial nerve palsy?
Wrist drop
257
How can you see where the lesion is for someone with radial nerve injury?
See if the triceps muscle is affected (test elbow extension to see)
258
Where to test for sensory loss in radial nerve damage?
Anatomical snuff box with a pin
259
What muscles does the medial nerve supply?
```
All muscles in the front of the forearm except flexor carpi ulnaris and the ulnar half of the flexor digitorum profundus
In the hand:
L --> lateral two lumbricals
O --> opponens pollicis
A --> Abductor pollicis brevis
F --> flexor pollicis brevis
```
260
What are some gait disorders?
Hemiplegia --> foot is plantar flexed and leg is swung in the lateral arc
Parkinson's disease --> hesitation to start, shuffling, freezing etc
Cerebellar --> drunken gait.--> wide based or reeling on narrow base, staggers towards the affected side if the is a unilateral cerebellar hemisphere lesion
Posterior column lesion --> clumsy slapping down of the feet on a broad base
Foot-drop --> high stepping gait to avoid tripping on foot
Proximal myopathy --> waddling gait --> leg extending has hip drop on that side to compensate the person will sway their trunk the other way
Prefrontal lobe (apraxic) --> feet appear glued to the floor when erect but move more easily when patient is supine
Conversion disorder (hysteria) (choreiform gait)--> bizarre inconsistent gait
Diplegic gait --> extensor spasm --> tip toe --> abduction spasm (legs close together)
261
What nerve is important for thenar atrophy (muscle thumb on palm near thumb)?
Medial nerve eg carpal tunnel
262
What is the nerve for the calf?
Tibial --> controls gastrocnemius
263
What is the difference between rigidity and spasticity?
Rigidity --> always stiff --> increased resistance to movement
Spasticity --> resistance is felt differently in flexion vs extension etc --> and also velocity dependant (faster is more resistance)
264
What does clonus look like?
Series of involuntary rhythmic muscular contractions and relaxations when a muscle group is stretched
265
What is the steps in the Reflex Arc?
Afferent pathway to the spinal cord
Afferent neurons enter dorsal nerve root
Passed to efferent neuron on ventral side of spinal cord
Effector organ muscles activated to move out of harm
Brain not involved
266
What are the features for upper limb neuro general observations ?
```
Scars
Abnormal/involuntary movements
Muscle wasting
Gait
Use of walking aids
```
267
How do you examine tone?
Wrists --> extension and flexion
Forearm --> pronation and supination
Elbow --> flexion and extension
268
What is lead pipe rigidity?
Limb is very ridged in every angle of its range of motion --> regardless of fast or slow motion
269
What is clasp knife rigidity?
Velocity and position of joint dependant tone/movement --> will be easier to move at speed and at certain joint areas
270
What is cogwheel rigidity?
elicits ratchet-like start-and stop movements through the range of motion of a joint
Series of "catches" during movement of a joint
271
How is muscle power graded?
0 --> no movement at all
1 --> flicker or small contraction
2 --> movement with no gravity
3 --> movement against gravity
4 --> movement possible against some resistance
5 --> power normal --> ask patient if they have noticed any issues -->
272
What is the issues with the muscle power grading system?
Very subjective and hard to reproduce
273
Where are nerve roots?
Where the peripheral nerve fibres come out of the spinal cord
274
What is between the nerve root and the peripheral nerve?
Plexus
275
What is the plexus?
Large group of intersecting nerves --> afferent and efferent fibres
276
How do you assess trapezius muscle?
Shrugging
| push down on patient
277
How do you assess deltoid?
Arms up like wings
| push down on patient
278
What are some considerations when assessing deltoid muscle?
Need to ensure arms are up at 90 degrees as first 20 degrees of elevation will be using supraspinatus
Also need to check if scapula is not stabilised (patient can use lots more muscles to keep arm elevated if it is not in normal position)
279
How is infraspinatus assessed of the shoulder?
External rotation of the shoulder --> elbow at 90 degrees and spin forearm out to abduct
(resist patients movement externally
280
How to assess biceps?
Patients elbow flexed at 45 degrees
| Pull down on forearm
281
How to assess forearm?
Patient attempts to extend at elbow
| Push up to resist
282
How to assess wrist extension and flexion?
Patients wrists cocked back --> They stop you from straightening them (extension)
Patients wrists folded down --> they stop you from straightening them (flexion)
283
Where do you hit for knee jerk reflex?
Just below patella onto the tendon
284
Where do you hit for ankle jerk reflex?
Back of the foot on the Achilles tendon
285
Where to hit for biceps jerk reflex?
Put your fingers on biceps tendon (near cubital fossa) --> wack your own fingers with hammer to elicit response
286
Where to hit for triceps jerk reflex?
Patients arm relaxed lying over their chest with shoulder relaxed
--> Wack just superior to the ulnar prominence (posterior side of elbow)
287
What affect does UMN have on Reflex arc?
Keeps the reflex under control
288
So what is the impact on reflexes for an UMN lesion?
Hyper reflexivity
289
How are reflexes graded?
0 --> no response
1+ --> a slight but definitely present response --> may or may not be normal
2+ --> a brisk response --> normal
3+ --> a very brisk response --> may or may not be normal
4+ --> a tap elicits a repeating reflex (clonus) (always abnormal)
290
What grades of reflex can be considered abnormal?
Every grade except 2+
291
What is the Jendrassik manoeuvre?
Supposed to distract the patient to help elicit a reflex --> eg get them to clench and unclench their hands
292
What is the plantar response?
Scratch up the underside of the foot
Normal --> no response
Abnormal --> great toe goes up and the other toes fan out
In sever spinal injury (eg cord transection) --> toes will fan, ankle will dorsiflex, knee and hip will flex
293
Is plantar response upper or lower motor neuron response?
UMN --> as spinal cord
294
What is the path for the pain and temperature pathway in the CNS?
```
Sensory neuron into dorsal root ganglion
Dorsal root ganglion into dorsal horn
Crosses to other side of spine (Spinothalamic tract)
Medial lemniscus
VPL nucleus of thalamus
Sensory cortex
```
295
What kind of fibres do pain and temperature travel in?
Small unmyelinated fibres
296
What is proprioception?
Ability to discriminate movement
297
What kind of fibres does proprioception travel in?
Large myelinated nerve fibres (same as vibration but they are slightly smaller)
298
What pathway does proprioception travel?
Dorsal column
299
How is vibration assessed in the lower limb?
Tuning fork placed on the medial malleolus (distal tibial prominence)
300
How is proprioception assessed in the lower limb?
Moving the toe up or down and asking the patient to tell you which way you moved it
301
What are the two cerebellar examination in the upper limb?
Finger to nose --> patient touches your finger and back to their nose etc
alternating movements --> patient can hit one of their hand with the other one and flip it front to back as they do so
302
What is the cerebellar exam in the lower limb?
Toe to finger
| Use heel to draw a line down their other legs shin
