Module 2 - Stroke and TBI

Question 1

Why are midline structures more susceptible to trauma?

Answer 1

Held rigidly in place by dura and at the centre resulting in shearing or tearing force generated by rotational trauma as the two hemispheres shift move separately to one another.

Question 2

Describe what effect raised intracranial pressure has had on the brain.

Answer 2

Midline deviation, ridge on the uncus of the right temporal lobe indicates it’s herniated through the tentorial notch. Also the top of the right cerebellum has been squashed by the herniated lobe.

Question 3

What can be seen on histology of diffuse axonal injury?

Answer 3

Axonal swellings, retraction bulbs?

Question 4

Where is DAI most likely to be seen?

Answer 4

Parasagittal parts of the brain, the corpus callosum, fornix, internal capsule, and the brain stem.

Question 5

What happens in transtentorial or uncinate herniation?

Answer 5

The medial aspect of the temporal lobe is compressed against the free margin of the tentorium. With increasing displacement of the temporal lobe, the third cranial nerve is compromised, resulting in pupillary dilatation and impairment of ocular movements on the side of the lesion.

Question 6

Where does hypertensive Intraparenchymal haemorrhage occur?

Answer 6

The putamen (50 to 60%) of cases, thalamus, pons, cerebellar hemispheres (rarely), and other regions of the brain.

Question 7

Describe the gross pathology of traumatic brain injury:

Answer 7

Contusions = bruise on brain
Lacerations = break in the pia mater
Different types of herniations, haematomas, etc. Diffuse axonal injury possible too.

Question 8

Describe the histology of TBI:

Answer 8

Blood, retraction bulbs, venous congestion, perivascular oedema, axonal changes and splitting of the ependymal layer from the rest of the grey matter.

Question 9

What is a mild, moderate and severe TBI using GCS scores?

Answer 9

>12 = mild
9-12 = moderate
<9 = severe

Question 10

What are some symptoms of base of skull fractures?

Answer 10

Otorrhea, rhinorrhea, raccoon eyes, Battle’s sign

Question 11

What midline structures are commonly affected and why?

Answer 11

Corpus callosum, rostral brainstem, septum pellucidum - they are held in place by the dura and then the rotational forces damage the structures as the two hemispheres move past each other.

Question 12

What are the gradings of DAI?

Answer 12

Grade 1: Parasagittal frontal, internal capsule, cerebellum.
Grade 2: + Corpus callosum
Grade 3: + Dorsal brainstem

Question 13

What is the pathogenesis of DAI?

Answer 13

Damage leads to calcium activated proteases such as calpain. The axon is completely severed in primary axotomy but stabilises in secondary axotomy, only to completely severe later on and produce a bulb.

Question 14

What causes the raised ICP?

Answer 14

Vasodilatation + increased CBV (congestion) + blood vessel damage (vasogenic oedema) + increased water content of cells (cytotoxic cerebral oedema)

Question 15

Role of immune system in TBI?

Answer 15

BBB breakdown + PMN infiltration + Macrophage/microglia activation -> ROS + oedema + cytokines + complement activation + phagocytosis -> apoptosis/necrosis/repair
Head trauma can cause a poor clinical outcome long after the immediate injury by initiating an inflammatory cascade causing damage to multiple neural cell-lines. This cascade up-regulates cytokines such as IL1ß inducing apoptosis and DNA fragmentation of oligodendrocytes and neurons via Fas ligands. This results in cell death followed by inflammation and further expansion of the initial neurological lesion of the brain parenchyma, thus worsening the resultant cognitive deficit.
Molecules such as TNFα are released after trauma and this predisposes astrocytes to apoptosis. While neural and synaptic damage from TBI creates the lesion, it is the lost trophic support from astrocyte-derived BDNF that limits regeneration/ recovery.

Question 16

What is the definition of CTE?

Answer 16

(i) foci of perivascular NFT and astrocytic tangles
(ii) irregular cortical distribution of NFT and astrocytic tangles with a predilection for the depths of sulci
(iii) clusters of subpial and periventricular astrocytic tangles in the cerebral cortex, diencephalon, basal ganglia and brainstem
(iv) neurofibrillary tangles in the cerebral cortex located preferentially in the superficial layers.

Question 17

Give some examples of primary and secondary damage in TBI:

Answer 17

Primary: Lacerations, fractures, contusions, haemorrhages, DAI
Secondary: Ischaemia, hypoxia, cerebral swelling, infection

Question 18

What are the different types of herniation?

Answer 18

Subfalcine herniation of cingulate gyrus
Transtentorial/uncinate herniation of media temporal lobe
Transforaminal herniation of cerebellar tonsil

Question 19

Describe the appearance of haematoma:

Answer 19

Extradural: dome shape
Subural: Crescent
Subarachnoid: white around edges in an MRI, lots of blood near vessels in post mortem

Question 20

Describe the gross pathology of stroke:

Answer 20

Haemorrhage within the parenchyma.

Question 21

Describe the histology of stroke:

Answer 21

Red neurons, neutrophil infiltration, macrophages, loss of myelin, gliosis.

Question 22

Define a stroke:

Answer 22

Acute-onset neurological symptoms or signs indicative of focal central nervous system dysfunction, due to vascular cause (ischemia/hemorrhage), lasting >24 hours.
2nd commonest cause of death after cancer (with heart disease)

Question 23

How does head trauma lead to post-traumatic epilepsy (6% epileptics)?

Answer 23

TBI can cause disruption to the blood-brain-barrier(BBB), resulting in neurological complications by reducing a patient’s seizure threshold, leading to post-traumatic epilepsy. Up-regulation of cytokines such as IL6 after injury increases the permeability of the BBB by disrupting the integrity of its tight junctions, causing albumin extravasation. This alters the local ionic environment as astrocytes cannot then buffer potassium ions, which increases neuronal excitability and thus lowers the seizure threshold.

Question 24

How is TBI pathology similar to AD pathology?

Answer 24

Reduced cognitive function also results from tau deposition after TBI. Trauma causes damage to the integral structure of microtubules resulting in peri-vascular tau deposition in brain parenchyma. Subsequent tau hyper-phosphorylation causes development of neuro-fibrillary tangles. These insoluble tangles limit axonal conduction, prevent axonal transport and eventually cause cell death. This then leads to memory and executive dysfunction which has a significant long-term impact on the patients’ ability to function, limiting their independence and quality of life. McKee 2009
The expression of the APOE gene is a genetic risk factor for deposition of Amyloid ß plaques post-TBI, and the expression of such genes confers a neurological risk factor for poor outcome after TBI. Amyloid ß deposition is a pathophysiological mechanism that contributes to symptoms of Chronic Traumatic Encephalopathy (CTE).
After TBI, axonal damage causes amyloid precursor protein to be deposited in cell bodies and axons. This then increases the local concentration of soluble amyloid ß locally through aberrant cleavage resulting in deposition of diffuse Amyloid ß plaques. It is hypothesised that this could play a role in the symptoms of disordered cognition and changes in mood and memory that patients experience in CTE. It is clear that head trauma is a key factor in the development of this syndrome; however, the APOE gene renders the individual more susceptible to this specific negative consequence of head injury, causing clinical outcome after TBI to worsen. Gavett 2010

Question 25

Define CTE and explain its stages:

Answer 25

a syndrome where many instances of mild TBI cause cumulative damage. CTE is a long-term consequence of TBI as symptoms start approximately 10 years after experiencing repetitive mild traumatic brain injury. CTE is a progressive disease, split into four stages. Initially symptoms are mild, and include disorientation and attention deficits. Disease progression manifests itself as memory loss, inappropriate and erratic behaviour, and poor judgment. Ultimately, it progresses to dementia, bradykinesia, speech deficits and deafness.

Question 26

What is the mechanism for TBI -> depression?

Answer 26

A specific mechanism for this remains somewhat elusive, though it has been proposed that trauma could damage neural circuits of the prefrontal cortex, amygdala, hippocampus, basal ganglia, and thalamus, and that this may be related to the development of depression due to TBI. TBI-associated depression is frequently characterized by irritability, anger and aggression rather than by sadness. A possible mechanism is that trauma often causes axonal damage in the frontal and anterior temporal lobes, potentially accounting for the higher rate of mood-related symptoms. Reeves 2011

Question 27

Use Virchow’s triad to discuss the type of thrombosis in stroke and their risk factors:

Answer 27

Endothelial injury - arterial thrombosis
Atherosclerosis
Hypertension - arteriosclerosis
Dissection
Dysplasia, fibromuscular
Vasculitis (autoimmune, sarcoid, infection)
Injury (iatrogenic, radiation, catheter)
Spasm (migraine)
Embolism, compression
Hypercoagulability - venous/arterial thrombosis
Hereditary (factor V leiden, prothrombin mutations)
Endocrine (oestrogen from HRT, OCP, testosterone, diabetes hyperosmolar nonketotic coma)
Polycythaemia and other haematological, including platelets, (paraproteinaemia, sickle cell anaemia, paroxysmal nocturnal haemoglobinuria, sticky platelet syndrome, Behcet’s syndrome)
Renal (neophrotic syndrome, volume depletion)
Infection (TB, chlamydia, otitis media of mastoiditis, etc.)
Neoplasia (adenocarcinoma, acute myeloid leukaemia, head-neck carcinoma)
Injury, fracture, sympathetic tissue response
Smoking
Exogenous, eg. chemo, COX-2 inhibitors
Stasis - venous thrombosis
Operation, especially orthopaedic, obstetric
Obesity
Overland flights
Reduced circulating volume
Right sided heart failure

Cardiac thrombosis (mural)
atrial fibrillation
aneurysm (congenital, MI)
cardiomyopathy

Question 28

What factors are involved in endothelial disruption?

Answer 28

Release of von Willebrand factor, fibronectin
Removal of prostaglandins I2 (-> platelet adhesion and vasodilation), heparin (->FIIa), anti-thrombin III (-> FIIa) (activated protein C via protein S and factor IIa ->) tPA (

Question 29

What are the different types of stroke?

Answer 29

Thromboembolism
Hypoperfusion - watershed/border zone infarction (between ACA and MCA territories or MCA and PCA = cortical border zones or between MCA and LCA = internal border zones)
Lacunar infarction - small, deep penetrating artery

Question 30

What is the pathophysiology of an ischaemic stroke in the acute phase?

Answer 30

Core - Penumbra model of stroke - <10ml/100g/min of blood flow in ischaemic core, <22 in ischaemic penumbra (maintain cell viability but not normal neuronal function) and >50 in normal brain (22-50 is olighaemia, likely to survive but depends on other factors eg. collateral flow

Hossmann 2006: Na+/K+ and H2O increase at around 10ml/100g/min, ATP and glucose utlisation at around 20ml/100g/min, protein synthesis decreases at around 75ml/100g/min

In minutes-hours:
Blood flow decrease leads to loss of tissue oxygen and CO2 accumulation. This leads to low levels of ATP which leads to ATP debt because of the switch to anaerobic respiration.
The Na+/K+/ATP pump stops working and this leads to an ionic homeostasis disturbance.
Na+ and Cl- enter the cell which causes H2O to enter the cell and this leads to cytotoxic oedema.
The Na+ also causes depolarisation of the cell and exit of K+ from the cell (which causes depolarisation of nearby cells)
L-type Ca2+ channels open (intracellular calcium increases).
This also leads to glutamate release and excitotoxicity (NMDA KO mice are less vulnerable to stroke, Calabresi) and the glutamate transporters become inactive due to the lack of ATP.
Zinc is also released from nerve terminals which is toxic to cells.
The glutamate allows calcium entry via the NMDA (•NR2A KO decreases infarct size (focal ischaemia) and •Interruption of signalling using a 2B subunit antibody
affecting PSD95 interaction reduces ischaemic damage, usually not through AMPA receptor but if GluR2 antisense knockdown then more Ca2+ permeable and this leads to increased global injury) receptor into the cell.
Calcium causes mitochondrial swelling, reduced
oxidative phosphorylation (loss of mitochondrial
transmembrane potential-proton motive force),
cytochrome c loss (mitochondrial transition pore)
leading to even more reduced ATP and activates the formation of an apoptosome complex (APAF1 + procaspase 9) and caspase 3 activation leading to DNA fragmentation (Caspase 3 selective inhibitors (zDEVD.FMK) are effective up to 9h after reversible ischaemia and Broad specificity caspase inhibitors (zVAD)/caspase 1 deletion protects against ischaemia.) Bcl-2 family of proteins: PROMOTE (Bax, Bak, Bad, Bim,
Bid) or PREVENT (Bcl-2, Bcl-XL) mitochondrial pore formation involved in cytochrome c release and basal Bcl-2 is high in ischaemia resistant pyramidal cells of CA3 and brainstem cells controlling autonomic function but low in ischaemia-sensitive cortical and hippocampal CA1 cells. Viral mediated gene transfer of Bcl-2 and Bcl-XL are neuroprotective
Proteases are also activated by the calcium influx, such as xanthine dehydrogenase and phospholipase A2 and cyclo-oxygenase and nitric oxide synthase activation which releases free radicals than cannot be controlled by glutathione scavenging. Sheng 1999 showed that SOD1 hyperexpression reduced the injury after ischaemia.
The free radicals cause DNA damage which leads to apoptosis. The free radicals also damage the cell membrane which causes protein misfolding and enzyme dysfunction and there is subsequent cell necrosis. The proteolytic enzymes also cause actin degradation which will break down the cell cytoskeleton for necrosis.
NB: nNOS retrograde messenger - Toxic levels of NO free radicals - neuronal lesion
eNOS vasodilator (relaxes sm. muscle) - Improves cerebral blood flow
iNOS immune mediator- Toxic effects enhanced in ischaemia
Exogenous SOD, or iNOS and nNOS KOs protect

The damage propagates from this focal point as K+ release from the ion homeostasis disruption causes cortical spreading depolarisation at 2mm/min which is why the penumbra is at risk but salvageable in the first few hours.

White matter is more vulnerable because it has generally lower cerebral blood flow, fewer collateral vessels, a higher metabolic demand and leaky sodium channels.

Question 31

Describe the RFs for lacunar infarcts and it’s presentations:

Answer 31

Acute Syndromes:

1. Pure motor
2. Pure sensory
3. Ataxia-hemiparesis
4. Dysarthria-Clumsy hand
   - hypertension, ageing, diabetes, renal disease, migraine, “Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy” (CADASIL)

Question 32

How does small vessel ischaemia present?

Answer 32

Chronic Syndromes:

1. Executive cognitive impairment, bradyphrenia
2. Lower body parkinsonism, gait apraxia

Question 33

What tests are for diagnosing strokes and after strokes?

Answer 33

CT (ASPECT score, Aberta Stroke Program Early CT score)
MRI
MRAngiogram
Clinical, pulse oximetry, BP, HR, ECG, FBC, coagulation, NIHSS stroke scale

Measure penumbra with 15O-PET, MRP, Xe-CT, SPECT

Afterwards:
Carotid dopplers
24 hour ECG
Maybe bubble echocardiogram
- Mural thrombus
- Aortic valve 
     vegetations 
- Inter-atrial shunt
- Myxoma

Question 34

What are the causes for primary intracerebral haemorrhages?

Answer 34

70% Hypertensive arteriolopathy 
5-20% cerebral amyloid angiopathy
Atrio-venous malformations
Tumour
Anticoagulants
Sinus thrombosis, vasculitis, drugs, alcohol, etc.

Question 35

What are the causes for subarachnoid haemorrhages?

Answer 35

Aneurysm (hypertension, genetic, adult polycystic kidney disease)
Dissection
Trauma

Question 36

What is the pathophysiology of a haemorrhagic stroke?

Answer 36

Arriesen 2008: in hypertension, there is smooth muscle proliferation of vessels which leads to hyperplastic arterial sclerosis. When the smooth muscle dies, they are replaced with collagen which is more likely to form aneurysms because it is more flexible which creates Charcot-Bouchard aneurysms.
small aneurysms of lenticulostriatal arteries in basal ganglia (<300µM)
Rebleeding is common - 26% in first 3 hours Brott 1997
Spot-Sign Definition: „tiny, enhancing foci within hematomas, with or without clear contrast extravasation in CT-A“ - poor sensitivity, 84% specificity but ongoing trials using this SPOTLIGHT, STOP-IT, STOP-AUST

Question 37

What is the treatment for ischaemic stroke?

Answer 37

IV Thrombolysis
rTPA - <4.5 hours, 0.9mg/kg over 60 mins (max 90mg) with 10% in 1 min and rest over next 60 mins.
OR = 2.6 at 90 mins, 1.6 at 160 and 1.2 at 360mins
EXTEND and Wake-up trials ongoing
But Proximal location of vessel occlusion lowers chance of recanalisation by thrombolytic and Rha 2007: 46% recanalisation with iv rTPA, 84% with mechanical
<6 hours Mechnical thrombectomy
Ultrasound (EKOS)
Shock-wave/ Vacuum: Angiojet
Retrieval devices (MERCI, Penumbra)
Laser devices (EPAR)
Stentretrievers
for every 30 min delay, 12% chance of worse clinical outcome Prabhakaran 2015
ESCAPE, MR RESCUE, MR CLEAN, IMS III, SWIFT-PRIME, EXTEND-IA Sardar 2015, Goyal 2016 favour mechanical over rTPA

Question 38

What is the modified Rankin scale?

Answer 38

0 - no symptoms
1 - despite symptoms able to perform all usual activities
2 - Can’t do all usual activities but can look after own affairs without assistance
3 - Requires help but can walk unaided
4 - needs help with mobility and attending own bodily needs
5 - bedbound, incontinent, nursing care
6 - dead

Question 39

What is the presentation and treatment for basilar artery thrombosis?

Answer 39

Atherothrombotic or embolic occlusion of basilar artery
Sudden onset or initial fluctuation of symptoms (“treacherous”)
Vertigo, brain stem signs, loss of consciousness
Spontaneous course: 50-90% mortality
Severe morbidity (e.g. locked-in syndrome)

Time window for thrombolysis is longer than for MCA stroke
Early recanalisation

Question 40

What is a malignant MCA infarct?

Answer 40

Space occupying MCA infarction - hemicraniectomy to relieve pressure
DESIRE showed better MRS if do surgery over conservative

Question 41

Why are specialist stroke units recommended?

Answer 41

Reduce morbidity and mortality
independent of age, sex, severity
better in designated and confined space
Shorten inpatient treatment
Lower number of patients surviving with severe disability and needing long-term care
Increase proportion of patients with complete recovery
Cochrane 2004
because Monitoring of patients with acute stroke (> 24 h, unstable phase)
immediate diagnostic work-up for cause of stroke
Immediate specific therapy (e.g. lysis) and secondary prevention
Immediate basic measures incl. continuous monitoring of vital sigs and aim for homeostasis
Prevention of secondary complications
Stay rarely eexceeding 5 days

Question 42

What is the treatment for haemorrhagic stroke?

Answer 42

Recombinant factor VIIa
FAST trial, Cochrane review 2009 - Volume reduction, but no improvement of death and disability (day 90), but increased risk thrombembolic events
Tranexamic acid in TICH-2 trial, shift in mRS at day 90
-> Currently no haemostatic drug recommended for spontaneous ICH
OAC-ICH - 10-15% ICHs, increased mortality, more frequent and prolonged haematomas, 2/3rs in therapeutic area Steiner 2006
Factors associated with haematoma growth
Shorter time from symptom-onset to CT
Longer time between imaging and therapy
Deep location of haematoma
INR level on first measurement
Systolic blood pressure Kuramatsu 2015
FFP - fast anticoagulation reversal has positive effect on haematoma growth. Steiner 2016
Idarucizumab (humanised Fab fragment) is highly specific for dabigatran (300x higher than dabigatran to thrombin), IV, short half life, small distribution volume, no intrinsic pro/anti-coagulant effect expected Stangier 2015, idarucizumab reduces haematoma growth of NOAC-ICH in experimental models Na 2015
Andexanet-alfa as FXa decoy - ANNEXA-4, Connolly 2016 - <40% reduction FXa baseline activity but good clinical haemostasis after 12 hours (80%).
INTERACT-2 s shows no difference to haematoma growth with intensive antihypertensive treatment
ATACH-2 shows no effect of very intensive (<120) anti-hypertensive therapy on income but (<140) has positive outcome and is safe.
STICH-II - no difference regarding survival if do surgery
MISTI-III for surgery (catheter) + rTPA

Question 43

Susceptibility to stroke post infection:

Answer 43

30 % (20-50) of all stroke patients develop infections
Pneumonia: 10%
UTI: 10%

Pneumonia = most important cause of death (subacute phase)
OR 5.5 (26% vs. 5%)

Classical predisposing factors
old age, severe stroke
dysphagia, immobility Westendorp 2011

Question 44

What is poststroke Immunodepression?

Answer 44

Hallmarks = Lymphocytopenia and Reduced responsiveness of monocytes
Spontaneous bacteremia and pneumonia in murine stroke model
Lymphocytopenia (blood, lymphatic organs: apoptosis)
Reduced responsiveness of innate and adaptive immune cells to in vitro stimulation
Stress hormones as mediators
RU 486 (glucocorticoid receptor blocker)
no lymphopenia, improved responsivenes of monocytes
Propranolol (β-Blocker)
no lymphopenia, normalisation of IFN-γ / IL-4 secretion
improved in vitro monocyte responsiveness
prevention of pneumonia and bacteremia
reduced mortality
Interferon-γ plays a key role in microbiological defence
Early (d1): massive activation of peripheral immune cells1
IL-6, IFNg, MCP-1↑
Splenocytes secrete more TNFa, IFNg, IL-6, and IL-10
Subacute (d4): splenic atrophy, thymic atrophy
in vitro proliferation of splenocytes ↓
lower expression of proinflamm. cytokines
Increased apoptosis of stimulated cells
Elkins 2016 - Natalizumab did not affect infarct volume compared to placebo - At days 30 and 90, natalizumab showed a meaningful benefit over placebo treatment on global clinical and cognitive function but not NIHSS score

Question 45

What is the issue with NMDA antagonists in stroke treatment?

Answer 45

NMDA, AMPA antagonists - HIGHLY effective up
to ~2h after insult BUT have psychotomimetic
(NMDA) and respiratory depressive properties
Window of therapeutic opportunity difficult to
translate to application in man.
Ca2+ channel (L, P/Q and N), Ca2+-dependent K+,
channel and proton activated Ca2+ permeable
channel (ASIC1a) blockers reduce brain injury.

Question 46

What is the rationale for NR1 antibodies?

Answer 46

In addition to the effect of tPA on fibrinolysis, tPA
also interacts with the NR1 subunit of the NMDA
receptor causing excitotoxic cell death
MCAO infarct size reduced by NR1 a-body (20
min and 4h) and by tPA at 20 min but at 4 hours
tPA causes neurotoxicity which can be prevent by
NR1 a-body treatment Macrez 2011

Question 47

What happens in stroke in the subacute an chronic phases?

Answer 47

In the subacute phase (hours to days) glutamate activates an extensive transcriptional cascade:
Ca2+-calmodulin kinase IV pathway (CAMKIV)
Phosphorylation of cAMP-response element binding protein (CREB)
CREB/CREB binding protein (CBP ) complex activates
transcription (transcription factors and neurotrophic factors):
• inducible transcription factors (IEGs) which activate/repress other genes
• enzymes such as COX-2 which underlie developmental and behavioural responses (COX-2 mRNA found in dendritic spines)
COX2 selective inhibitor reduces infarct volume (Nogawa et al 1997) but COX2 selective inhibitors, whilst lacking gastric toxicity, decrease prostacyclin
(vasdilator) and lack COX1 anti-thrombotic properties which potentiates cardiovascular events
• neuroprotective proteins e.g. HSPs which counter damaging effects
(Act as protein chaperones facilitating the transfer of proteins between subcellular compartments and following a noxious stimulus (heat, ischaemia) HSPs are induced which target abnormal proteins for degradation and are also anti-apoptotic and antioxidant (HSP27). Infarct size in MCAO is reduced in HSP70
and HSP27 transgenic mice. Van der Weerd 2005
Ischaemic PreConditioning is a process in which brief exposure to ischaemia provides robust protection/tolerance to subsequent prolonged ischaemia (~TIA) and HSP involvement in IPC has been
demonstrated in cardiac and cerebral ischaemia (Sun et al 2010) mediated through the NF-kB pathway(Tranter et al 2010). IPC reduces infarct size Stenzel-Poore 2004
The upregulation of injury response genes (e.g.
c-jun, ATF3, and heat shock proteins HSPs) extends area of infarct
There is also inflammation by neutrophils (O2
free radicals & proteolytic enzymes), macrophages, lymphocytes and microglia and cytokine and chemokine production as there is disruption of the BBB. iNOS is elevated and TNFalpha and IL-1beta cause upregulation of ICAM-1, p and E-selectins for adhesion to endothelial cell surfaces and neutrophil migration. There is vasogenic oedema and ICP increases. Macrez 2011
•CSF levels of IL-1, IL-6 and TNF at 24h correlate
with infarct size
- IL-1b receptor antagonists are protective
- TNFalpha neutralising antibodies and antisense nucleotides are protective
- However, Phase III anti-neutrophil drugs failed to improve stroke outcome and antiICAM (n=625) increased mortality (Becker et al 2002).
- TGFbeta and IL-10 produced by lymphocytes limit
leukocyte invasion and reduce immune responses
- Complex protective/harmful effects are seen due
to multiple sites of action. (Easton 2013)

In the chronic phase (weeks to months) there is necrotic debris removal with angiogenesis, neurogenesis and stem cell proliferation and differentiation. There is also gliosis, and reconnection of lost circuits via neuronal sprouting.
Growth factors are secreted by neurones, astrocytes, microglia, macrophages, vascular and peripheral
cells e.g. IGF1, erythropoietin
Glutamate-mediated synaptic activity increases BDNF transcription and secretion