- pathophysiology - treatments pr o battisti, brain damage in neonates1

-Pathophysiology-Treatments

Pr O Battisti, brain damage in neonates 1


Neuronal migration, blood brain barrier, cells ’ biochemistry, Cerebral blood flow autoregulation


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


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


At 24 weeksAt 28 weeks


Extrinsic inflammationIn 25 – 33 % cases

iCDG


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


20 % %

80 %50 %

40 %

4 %6 %


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


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;


Locus ceroelus


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


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


And also of volume andMyelination


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


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


Endotoxins coming from outside brain affects heartFunction and possibly CBF = « dual effects »

Or Inflammation


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


Brain cells: neurons, astrocytes, microcytes,radial cells, oligodendrocytes;

Microcirculation; Ependyma and

villi; Arachnoids;

2525


This is in about 15- 25 % of cases This is about in 70- 80 % of cases

- Late migration- CBF autoreg


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


factors


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 »


Values at 27 ° C !


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


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


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

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;


15 % body mass; 60 % BMR

muscles

24 % body mass


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.



Neuronal migration, blood brain barrier, cells ’ biochemistry, Cerebral blood flow autoregulation


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

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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



Studying Brain Development

10 weeks premature Term 9 months

Prof Oreste Battisti, CHU-NDB, ULG 47

Effet structural de l ’hypoxie sur les cellules cérébrales


And also of volume andMyelination


Voxel Labeling:Do you see the tracts

Cingulum Cingulum, arcuate fasciculus, uncinate fasciculus


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.


DTI and EEG concordance

Diffusion MRI andtractography indicates asymmetrical atypicalwhite matter tracts, concordant withincreased atypical spectral coherence on

- pathophysiology - treatments pr o battisti, brain damage in neonates1

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