Cerebral Palsy Flashcards
Definition of cerebral palsy
A group of movement disorders characterised by dysfunction of movement or posture caused by insult to the cerebrum
What are the causes for hypoxia in the 2/3rd trimester?
- Bleeding from the uterus
- Impaired placental function
- umbilical cord obstruction
- compressed aorta (leading to less blood in uterine arteries)
Aorta
the main artery that carries blood away from the heart to the rest of the body
Non-hypoxic causes of cerebral palsies
- genetic mutations related to metabolism
- environmental toxins such as mercury or alcohol
- infections of the uterus
What is the incidence of cerebral palsy?
2-2.5 per 1,000 live births
(the most prevalent perinatal injury)
Survival is increasing due to success of newborn intensive care units
3rd trimester hypoxia
Characterised by injury (neuronal death, abnormal myelination, gliosis) to the striatum,
+ additional injury to other regions (Cortex/HPC) in 50% of cases
What are the pathological changes that occur in 3rd trimester hypoxia?
Neuronal death, gliosis, abnormal myelination
Gliosis
Increase in reactive astrocytes and microglia (Iba1+ve)
Other names for 3rd trimester hypoxia
Status marmoratus due to the marbled appearance of the striatum
+
Extrapyramidal/dyskinetic cerebral palsy due to extra-pyramidal damage causing movement deficits
Symptoms of 3-TH
- dyskinesia
- chorea
dyskinesia
difficulty executing voluntary movement
chorea
sudden, uncontrollable, jerky motions
prevalence of 3-TH
accounts for 25% of cerebral palsies
Rice-Vannucci hypoxic-ischaemic model
Rats ligation of the unilateral common carotid artery following by exposure to hypoxic conditions
3-TH: PN7 rats exposed to 8% oxygen
why rat post-natal day 7?
Resembles the developmental stage of the human brain in the 3rd trimester
Why is ligation used alongside oxygen deprivation in the Rice-Vannucci model?
Oxygen levels cannot be decreased below 8% as the animals stop breathing and die, so ligation of one of the common carotid arteries allows for brain damage without prevention of breathing
What aspects of human brain damage does the Rice-Vannucci model exhibit?
- neuronal loss, primarily in the basal ganglia and secondarily in the cortex
- increased gliosis
- abnormal striatal myelination
- locomotion problems
Mechanism of 3-TH
- Decreased oxygen
- Decreased ATP
- disruption of acid:base balance due to anaerobic respiration
- disruption of ion homeostasis due to malfunctioning of ATP-dependent cation pump
= greater Na+ influx - depolarisation, primarily in the glutaminergic neurons due to their excitable tendencies
- excessive glutamate release
- NMDA activation
- excitotoxicity due to excessive calcium influx
- activation of kinases/proteases and free radical generations
- membrane disintegration
- cell death
Neuroprotective treatments
aim to prevent the pathological cascades that cause cell death
eg: antioxidants
Neurorestorative treatments
aim to replace the dead neurons and restore damaged tissue through formation of new neurons
eg: stem cells
Existing treatment for cerebral palsy
Therapy aimed at minimising movement issues
- physiotherapy, occupational therapy, surgery
Why was gentle hypothermia investigated as a treatment for 3-TH?
Evidence has shown that it decreases glutamate release, and free radical production, as well as inhibiting apoptosis
Mild hypothermia
a decrease from normal body temperature by 1-3°C
moderate hypothermia
a decrease from normal temp by 4-7°C
systemic hypothermia
cooling of the whole body
selective hypothermia
cooling of the head
Animal model/Clinical trials of gentle hypothermia for 3-TH show…
- gentle hypothermia prevents neuronal death in animal models
- moderate improvement in disability in humans
- benefits in middle childhood
Why was antioxidants/gentle hypothermia investigated as a treatment for 3-TH?
Antioxidants act to scavenge free radicals, which was hypothesised to have an additive effect to the hypothermic decrease in free radical production
Animal model/Clinical trials of antioxidant + gentle hypothermia for 3-TH show…
- long term neuroprotective effect that restored # of neurons to healthy levels in Rice-Vannucci model
- functional restoration in performance on staircase test
Staircase test
mouse is placed in box, and has to reach to sugar pellet that are placed on a staircase apparatus. # of pellets reached for/eaten is measured.
- one of the best test for measuring motor skills after striatal injurt
Why was Xenon/gentle hypothermia investigated as a treatment for 3-TH?
Xenon is a NMDA antagonist and an anaesthetic gas, thus may help mitigate hypoxic excitotoxicity
Animal model/Clinical trials of Xenon + gentle hypothermia for 3-TH show…
- rescuing of normal motor skills at 7-9 weeks in Rice-Vannucci model
- improvement in pathology in rats, but not = to healthy ctrls
- no adverse effects but also no therapeutic effect shown in humans (potentially due to lag in treatment)
Caveat of Xenon treatment
It is expensive
(but can be recirculated to reduce costs)
Why was Erythropoietin/gentle hypothermia investigated as a treatment for 3-TH?
Erythropoietin (EPO) is anti-excitotoxic, anti-oxidant, and anti-apoptotic
Animal model/Clinical trials of Erythropoietin + gentle hypothermia for 3-TH show…
- decreased extent of cerebral palsy in primate models
- improves outcome in 12mo humans compared to just hypothermia
Potential Neuroprotective Treatments for 3-TH
- gentle hypothermia (standard of care)
+ Antioxidant
+ Xenon
+ Erythropoietin
Stem cells
unspecialised cells that are able to divide and differentiate into specialised cells depending on the context
Intrinsic sources of stem cells
- the sub-ventricular zone
- sub-granular zone of the hippocampus
stem cells of the SVZ
typically migrate via the rostral-migratory stream (RMS) to the olfactory bulb where they differentiate to become olfactory neurons
stem cells of the SGZ
form the neurons of the dentate gyrus
Extrinsic sources of stem cells
embryonic stem cells are pluripotent and obtained from the inner cell mass of embryos
adult mesenchymal stem cells (MSCs) are multipotent, and are obtained from bone marrow (typically the femur)
adipose tissue - MSCs have 90% identical growth factor section to bone-marrow derived MSCs & are more effective at treating stroke
Which stem cells show the most potential in treatment of 3-TH and why?
Bone marrow derived mesenchymal cells (MSNs) due to ease of collection (from self) and low chance of immune response
Animal model/Clinical trials of stem cells for 3-TH show…
- decreased lesion size and functional improvement on cylinder test following MSN treatment in rice-vannucci model
- restored # SPNs to level healthy ctrl in Rice-Vannucci + trend towards functional improvement in cylinder test
hypothesised mechanism underlying treatment of 3-TH with stem cells
sub-ventricular zone stem cells preferentially differentiate into striatal SPNs in the presence of MSCs due to growth factor release
Stain used to identify dividing cells
BrdU
Stain used to identify SPNs
DARPP
2nd trimester hypoxia
characterised by FOCAL PERIVENTRICULAR LEUKOMALACIA which describes the preferential injury to the white matter near the lateral ventricles
What are the pathological changes that occur in 2-TH
- Death of oligodendrocytes
- axonal injury
(grey matter is less affected in 3-TH; there is a loss of striatal volume but generally no cell death)
- 15% exhibit cell death in the cerebral cortex
Symptoms of focal periventricular leukomania caused by 2-TH
spastic displegia: unco-ordinated contraction of the skeletal muscle in the legs due to damage to the leg region of the pyramidal tract
what is the prevalence of 2-TH?
It accounts for ~40% of cerebral palsies
Oligodendrocyte precursor/progenitor cell are defined by presence of…
A2B5
What are the forms of oligodendrocyte in development?
- oligodendroglial precursor/progenitor cell
- pre-oligodendrocyte
- immature oligodendrocyte
- mature oligodendrocyte
pre-oligodendrocytes are defined by presence of…
O4 (sulfatide)
immature oligodendrocytes are defined by presence of…
O1
Oligodendrocyte precursor/progenitor cell are defined by presence of…
MBP (myelin basic protein)
What types of oligodendrocytes are present in the 2nd trimester?
pre-oligodendrocytes (O4+ve) abnd immature oligodendrocytes (O1+ve)
What is the proposed mechanism underlying 2-TH?
Oligodendrocytes are extremely susceptible to glutaminergic excitotoxicity and free radical which occur in hypoxia.
Expression pattern of glutamate receptors on oligodendrocytes
AMPA - soma
NMDA - processes
Why rat post natal day 2?
Equivalent to human brain development in second trimester
- shown by dominant O4+ve staining, indicating a large proportion of pre-oligodendrocytes
What treatments have been investigated for 2-TH
- memantine (NMDA antagonist)
- UDP glucose
- glial derived neurotrophic factor
(2&3 induce differentiation of SVZ NSPCs into oligodendrocytes)
What evidence supports the use of memantine/UDPG/GDNF for 2-TH
All treatments were shown to decrease white matter pathology and reduce hind leg motor dysfunction in PN5 Rice-Vannucci model
What factors are important when examining treatments for 2-TH
- The use of PN2 rats in a Rice-Vannuci model
- Measurement of O4 (pre-oligodendrocytes) positive cells
Why should gentle hypothermia NOT be used for 2-TH?
Premature babies are ineffective at coping with changes in body temperature
diffuse periventricular leukomalacia (PVL)
Mild injury to the white matter of the cerebrum caused by repeated insults of short duration during the second trimester
What is the pathology of diffuse PVL?
- oligodendrocyte death
- axonal injury
- long-lasting decreases in cerebral white matter & myelin
- potential injury to dopamine neurons of the SNpc
- loss of striatal and cortical volume (but no death of neurons)
What are the symptoms of diffuse PVL?
ADHD & memory deficits
What is the prevalence of diffuse PVL?
~1.2% of all live births, with increased representation in males
What causes diffuse PVL?
Premature birth and repeated short duration hypoxic exposures due to underdeveloped control of breathing by brainstem neurons
Animal model of diffuse PVL
14/15 min periods of exposure to 1.5% O2 every 2hours for three days (PN1-3)
How does the animal model of diffuse PVL reflect the presentation in humans?
Animal models show
- decreased O4 (pre-oligodendrocytes) in the white matter
- decreased myelin surface area
- make slightly more error on the radial arm test for short term memory
- are hyperactive to delayed reward, but are NOT inattentive
radial arm test for short term memory
A maze composed of 8 arms radiating from a centre point. Each arm contains a treat. The animal must remember where it has been (and which snacks it has eaten). Each incorrect entry is recorded.
dopaminergic pathways innervating the cerebrum (2)
- mesolimbic (VTA-> cortex)
- nigrostriatal (SNpc -> striatum)
dopaminergic pathway implicated in ADHD hyperactivity
mesolimbic, death of dopaminergic VTA neurons observed in rat model of diffuse PVL
Why are different cell types affected by hypoxic damage in different trimesters?
The biochemistry differs between cells and regions throughout development causing different cell types of be more vulnerable to hypoxia.
What contributes to the vulnerability of striatal SPNs in the 3rd trimester?
Have a high level of glutamate receptors comparative to other cells in the 3rd trimester, thus are more vulnerable to glutaminergic excitotoxicity
What contributes to the vulnerability of oligodendrocytes/VTA dopamine neurons in the 2rd trimester?
low levels of antioxidant enzymes
RMTg
rostromedial tegmental nucleus: provides GABAergic input to the dopaminergic neurons of the VTA
Potential mechanism of cerebral hypodopaminergia in ADHD + evidence
Increased inhibition of dopaminergic VTA neurons by the RMTg
- transmission electron microscopy showed an increase in length and thickness of the post-synaptic density between RMTg & DA nRs of VTA
Hypothesised mechanism of schizophrenia + evidence
Decreased inhibition from RMTg to dopaminergic VTA cells
decrease in volume of pre-synaptic terminals in RMTg
+
decreased in length and volume of post-synaptic density of RMTg GABA- VTA DA synapse
The maternal immune activation model
based on the fact that immune activation in mothers is a risk factor for schizophrenia
Involves the injection of poly I:C at gestational day 15 in rats
- results in ‘schizophrenic’ offspring that show dopaminergic hyperfunction and response to anti-psychotics
