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-Pathophysiology-Treatments
Pr O Battisti, brain damage in neonates 1
Pr O Battisti, brain damage in neonates 222
Neuronal migration, blood brain barrier, cells ’ biochemistry, Cerebral blood flow autoregulation
Pr O Battisti, brain damage in neonates 3
Pr O Battisti, brain damage in neonates 4
Pr O Battisti, brain damage in neonates 5
Brain is 14-16 % of body weight
Brain is 60 % of body metabolism ( see glucose ) and 02 consumption
10 % of brain is CSF of which 6/7 is coming from choroid plexus and 1/7 from capillaries
3-5 % of brain is blood 40 % of brain is glial
cells 4% of brain is neurons 40% of brain is EC fluid
55
Pr O Battisti, brain damage in neonates 666
40 % glial cells , 4 % neurons, 4 % blood, 10 % CSF, 35 % ECF, 10 % variance
Microcirculation: observe differences between A and V- Radial cells;- oligodendrocytes- astrocytes- microglia
Pr O Battisti, brain damage in neonates 777
At 24 weeksAt 28 weeks
Pr O Battisti, brain damage in neonates 888
Extrinsic inflammationIn 25 – 33 % cases
iCDG
Pr O Battisti, brain damage in neonates 9
Oligodendrocytes:Perineuronal;;
Astrocytes:perivascular, in White and grey matter
Microcytes:travellers
Layers 1, 2 and 3 for intra-cortical associative relationships 1, 4, 5 , 6 for projective intra-cortical and subcortical relationships
Radial cells
Pr O Battisti, brain damage in neonates 10
20 % %
80 %50 %
40 %
4 %6 %
Pr O Battisti, brain damage in neonates 11
Function and integrity of cells, temperature;
10 glial cells for one neuron;
Neurone-glial cells unit; Surrounding capillaries
and the BBB; Differences in density of
capillaries; Differences in veins and
arteries networks; Differences in CMRO2 and
CMRG between neurons and glial cells
Late neuronal migration and transitory period of hypersensitivity
- Neurons: similarity of reactions -Oligodendrocytes: oxydative stress protection ;
trophins; myelin synthesis; non phagocytic
- Radial cells: guiders and helpers - Astrocytes: nutrition of neurons,
reservoir of beta-amyloid protein and chondroitine sulfate proteoglycan glutamate and TNF;« fibrous » in WM, « protoplasmic » in GM;
- Microglia ( < mesoderm ):
macrophage, reservoir of cytokins
1111
Pr O Battisti, brain damage in neonates 12
At BBB level: entry of small molecules (15 ‘ ) and big molecules ( 120 ‘); of neutrophils and monocytes ( 120 ‘ )
At neurons level: axones then dendrites edema ( 30-55 ‘ ), followed by retraction and hypersensitivity to EAA; body edema ( 50-75 ‘), action on peptides and nucleus;
At vessels’level :capillaries surrounded, , thrombosis;
At OL level: At astrocytes level:
glutamate, NO, FR, proteolytic enzymes
At microglia level:
Energy failure and oxydative stress:
Free radicals ( OFR, NO, Fe+++ )
EAA Release of NA from locus
ceorulus Activation of microglia and
LycT4 Genes activation ( CREB, JUN Relesa of toxins: AOAA, MPP,
3NPA Inflammatory products:- Proteolytic enzymes on matrix:
from neurons, astrocytes, microglia;
- Il 1,6,8,9, TNFa, complement, antithrombin III, factor V, protein C, antipohospolipid antibody
1212
Pr O Battisti, brain damage in neonates 13Prof Oreste BattistiProf Oreste Battisti 1313
CBF absent if: - respiratory distress; - circulatory distress; - hypoglycemia; - CNS infection; - brain trauma; Loosing the
independence 1° Systolic blood pressure; 2 °CO2 pressure (attention to
pCO2 < 27 for >= 1hr or > 65 for > 6 hrs );
3° O2 content;
Pr O Battisti, brain damage in neonates 14
Locus ceroelus
Pr O Battisti, brain damage in neonates 15
62#28#143822
44#19724010
29#13503015
2210362120
[aO2]-> W
[ aO2]->I[ aG ]-> W
[ aG ] ->ICbf ml/100g/m
Glycogen stores are enough for 30-60 minutes...
Hemoglobin from present blood stores O2 for 60 sec
Hb 12g/dL
Hb 15g/dL
term
Preterm « good »
Preterm sick
target
Pr O Battisti, brain damage in neonates 16
Pr O Battisti, brain damage in neonates 17
The functional unit in the brain:a close relationship between cells and vessels
Pr O Battisti, brain damage in neonates 18Prof Oreste BattistiProf Oreste Battisti 1818
Pr O Battisti, brain damage in neonates 191919
And also of volume andMyelination
Pr O Battisti, brain damage in neonates 202020
From protecting to damaging « biochemical attitudes »
Depending on the environmentalconditions, actual and preceding,factors can protect or damage
Appoptotic cascade :- if > 1h ofLow pCO2 ( < 27 mmHg; )- if > 6 h of high pCO2 ( > 65 mmHg )-if hypoxia ( > 65 mmHg? pO2 ) -for > 1 h ? Time ?
iCe and iNu Ca++FRCREB, CAMD, caspase 3 and 6
Pr O Battisti, brain damage in neonates 21
Similarity of reactions by neurons; more dependency of environment damage from inside CNS:--> astrocytes, loss of nutrition, of cytoskeletal compound,
activation of GAP3 and release of toxins--> microglia, release of toxins and activation of MHCII and CR3--> neurons: loss of targed-derived factors; dendritic and axons atrophy and loss of molecules
transport--> low synthesis of growth factors and low leullar
guidance impairement of BBB and arrival of cytokines
( lungs, digestive tract, blood cells, bone marrow )
Neurotrophic factors have specific targets;
their main roles are to prevent neuronal loss and maintenance of axons regrowth;
1. Neurotrophins family (NGF, BDNF )
2. Cytokins growth factors ( LIF, CNTF, CT-1 )
3. Fibroblats growth factors ( FGF1 and 2 ); mainly for layers II and III, hippocampus.
4. The insulin growth factors5. The transforming factor beta
family of growth factors;6. Epidermal growth factor7.Hepatocyte GF and
Immunophilins
2121
Pr O Battisti, brain damage in neonates 222222
Endotoxins coming from outside brain affects heartFunction and possibly CBF = « dual effects »
Or Inflammation
Pr O Battisti, brain damage in neonates 23
In about 75 % of cases, first trigger is iCDO2 giving rise to excitotoxycity and ifnflammatory cascade;
In about 25 % of cases, first trigger is inflammation cascade
The importance of iCDG per se is qualitatively well known, but its confounded and proportional place can’t be quantified
2323
EAA, Free radicals and cytokins
Pr O Battisti, brain damage in neonates 242424
Pr O Battisti, brain damage in neonates 25
Brain cells: neurons, astrocytes, microcytes,radial cells, oligodendrocytes;
Microcirculation; Ependyma and
villi; Arachnoids;
2525
Pr O Battisti, brain damage in neonates 262626
This is in about 15- 25 % of cases This is about in 70- 80 % of cases
- Late migration- CBF autoreg
Pr O Battisti, brain damage in neonates 27
Density of small vessels in germinal > cortex > white matter;
Capillaries in BBB are very rich in mitochondria;
All Brain cells can produce complement, cytokines and coagulation proteins;
MHC system in brain = HLA system outside brain;
Microglia works with CD4+ TH1 cells; can command astrocytes and endothelial cells.
Astrocytes can store toxins Ly B works with CD4+TH2
cells; Any cell works with CD8+T
cells Fibroblasts can produce
cytokines and stem cells.
2727
Distant interventionBy locus coeruleusAnd hippocampus
Pr O Battisti, brain damage in neonates 282828
factors
Pr O Battisti, brain damage in neonates 29
Pathology of leucomalacia: « end product »
Early and late neuronal migrations: their importance
Cerebral blood flow autoregulation impairement
Biochemical properties of brain cells
Metabolic differences between neurons and glial cells
pH, pCO2, BP, O2 intervention Cerebral blood flow, CMRG,
CMRO2 and extractions measurements
US diagnosis of PVL and classification
Epidemiological studies The inflammatory components
2929
Some important « apples »
Pr O Battisti, brain damage in neonates 303030
Values at 27 ° C !
Pr O Battisti, brain damage in neonates 31
The GLUT or glucose transporters
ATP and 5-Pentose; In- and out-cells
composition neurotransmission Defenses against FR
and EAA BMR Muscles ( FFA ) and
intestines ( glutamine and KB ) have alternatives
Pr O Battisti, brain damage in neonates 32
CBF [O2]
12 18 21
5 25 ( 75 ) 40 ( 120 ) 45 ( 135 )
10 50 ( 150 ) 75 ( 225 ) 90 ( 270 )
15 75 (225 ) 115 ( 375 ) 130 ( 390 )
20 100 (300 ) 150 ( 450 ) 175 ( 525 )
30 150 ( 450 ) 230 ( 690 ) 265 ( 795 )
40 200 ( 600 ) 300 ( 900 ) 350 ( 1050 )
Sec/ml CBF 5 ( 15 ) 8 ( 30 ) 9 ( 35 )
Prof Oreste Battisti, CHU-NDB, ULG 33
Pr O Battisti, brain damage in neonates 34
In normal cell: G + O2 Free radicals
ATP + CO2 + H2O
In cell with mitochondrial impairement:
G + O2 hypoxia reoxygenation
ATP + CO2 + lactic acid
> 95 %
coupled radicals
Loss of energy andElectrolytes disturbances
Free radicals
< 5%
FiO2 .21 1.0
stress oxydatif (-) ++
Flux sanguin cerebral = =<
Rétablissement de la microcirculation + ++
Metabolisme < <
circulation pulmonaire ++ ++
fonction myocardique + +
Survie > <
Pronostic neurologique = =
Prof Oreste Battisti, CHU-NDB, ULG 35From Saugstad, animal&clinical data
Pr O Battisti, brain damage in neonates 36
About nutritional needs and storages:
-> aminoacids, fat and Carbohydrates;
-> flow autoregulation; About cerebral
growth: - in preterms; - in case of retarded
growth; About muscles
growth: - in preterms; - in case of retarded
growth;
Pr O Battisti, brain damage in neonates 37
15 % body mass; 60 % BMR
muscles
24 % body mass
Pr O Battisti, brain damage in neonates 38
120
6-8
120
6-8
Kcal/kg/d
QO2 l/kg/m
50-6060-70% Gl
25-30< 5% Lp
10-1520-30% Pt
The last 3 weeks of pregnancy prepares the nervous andendocrine systems to neonatal adaptation,
mainly the autonomic nervous system
REM-periods: under adrenergic control; synthesis of proteins and neurotransmitters; high metabolic rate. Correlation with growth.
Non REM-periods: under vagal control; pauses in synthesis; lower metabolic rate.
Pr O Battisti, brain damage in neonates 39
Pr O Battisti, brain damage in neonates 404040
Neuronal migration, blood brain barrier, cells ’ biochemistry, Cerebral blood flow autoregulation
Pr O Battisti, brain damage in neonates 41
1. Brain damage is widespread in infants who die, and can be diffuse or focal, but white matter is the tissue most affected.
2. US evidence of white matter injury ... is the most important determinant of long-term outcome.
3. Thyroid hormone is the single most predictive measure of outcome obtainable on serum in the first week of life
4. Hypocapnia (PCO2 < 25) and perhaps hyperoxia (PO2 > 60) should be avoided.
5. The finding in the placenta most predictive of brain injury is fetal vasculitis; membrane inflammation alone is not associated with brain injury
4141
Comment:Amnionitis gives:an increased release of cytokines and a decreased expression of angiogenic factors
La chorioamniotiteLe RCIULa grande prématurité- La détresse respiratoire, la dysplasie
BP, hypothyroïdie, hyperbilirubinémie, les perturbations hémodynamiques
L’entérocolite nécrosante
Pr O Battisti, brain damage in neonates 42
Pr O Battisti, brain damage in neonates 43
Pr O Battisti, brain damage in neonates 44
Pr O Battisti, brain damage in neonates 45
Studying Brain Development
10 weeks premature Term 9 months
Pr O Battisti, brain damage in neonates 46
Prof Oreste Battisti, CHU-NDB, ULG 47
Effet structural de l ’hypoxie sur les cellules cérébrales
Pr O Battisti, brain damage in neonates 484848
And also of volume andMyelination
Pr O Battisti, brain damage in neonates 49
Pr O Battisti, brain damage in neonates 50
Voxel Labeling:Do you see the tracts
Cingulum Cingulum, arcuate fasciculus, uncinate fasciculus
Pr O Battisti, brain damage in neonates 51
Pr O Battisti, brain damage in neonates 52
Fiber tract clustering
MRI biomarkers have identified patterns of brain injury in newborn infants.– May be used to investigate characteristics of individuals or of groups of subjects.– Identified neuronal abnormalities as a significant feature of neonatalencephalopathy.– Determined timing of appearance of structural brain changes.
Pr O Battisti, brain damage in neonates 53
DTI and EEG concordance
Diffusion MRI andtractography indicates asymmetrical atypicalwhite matter tracts, concordant withincreased atypical spectral coherence on
Pr O Battisti, brain damage in neonates 545454