O Battisti, A Adant-François, E Scalais, M Kalenga, L Withofs, T Paquay, JP Langhendries,
B Reding, F Piérart, I Jordan, P Maton
Services de Néonatalogie Intensive et de Pédiatrie
CHC,
Clinique Saint-Vincent de Paul, 4000 Rocourt.
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This paper aims to update the pathophysiology of the most frequent acquired brain injuries in neonates: white matter damage ( leukomalacia ), peri- or intra- ventricular haemorrhage, total brain ischaemia ( brain asphyxia ) and local brain ischaemia ( occlusive vascular disorder ).
White matter damage is more than ischaemia, and the mechanism of cellular death is different in term and preterm infants. In order to understand these lesions, and hence to be more efficient in prevention, treatment and follow-up, one has to consider together biochemistry, cerebral and extracerebral haemodynamics, inflammation and immunology, cytology and development.
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The acquired brain injuries are potentially associated with long term difficulties such as cerebral palsy, major or minor impairements mainly concerning the cognitive functions and vision, and epilepsy. The abundant research on cellular death in brain of infants and adults, owing to the important consequences of it ( mortality, morbidities, impacts on health’s costs ) is largely justified. Hence, it not always easy for a given clinician, faced with numerous results or hypothesis coming from animal and human studies, to find a sufficient clear way of thinking and understanding about these lesions. This paper aims to give some more light to the practitioners.
Neuronal migration is ending its last phase at 4 months in cerebrum, and at 12 months in cerebellum. At these periods, the synaptic connections between upper and lower neurons are done, and the cellular hyperexcitability to certain transmitters ( i.e glutamate, aspartate ) or free radicals is normally ended. Till these periods, moreover, there is yet a mixture of neurons and glial cells in the periventricular zone ( 5 to 10 glial cells for 1 neuron ). Glucose and oxygen consumptions are roughly three times higher ( lower ) for neurons ( glial cells ).The metabolism of brain is high owing to its important mass and the high metabolic turnover, and that is for oxygen, glucose and proteins ( 56 %, 42 % and 60 % respectively of total needs ).
Major part ( about 90 % ) of oxygen and glucose is devoted to ATP synthesis in mitochondria, about 5 % being used to defenses against the unavoidable productions of free radicals, and about 5 % are used for synthesis of lipids and DNA. Oligodendrocytes are the glial cells responsible for defenses against free radicals, and that specific function is possible from 30 weeks gestational age. Astrocytes are the glial cells responsible for myelin synthesis, and that function is possible from 40 weeks gestational age. Microglia are the glial cells responsible for the specific within brain of immune and macrophagocytic responses.The brain, like any other growing or not growing tissue, is depending on body distribution of blood flow and metabolites deliveries, and also of the intra-tissue distribution of blood flow and deliveries.
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Cortex and brain stem are more protected zones, while white matter is the most disfavoured zone; basal ganglia have different responses according to type of disturbing entry ( decrease if this is hypoxia, increase if it is haemorrhage ). Any cell can maintain all functions in normal situations, as it may decrease them in abnormal conditions down to a maximal level below which the integrity of cells will be lost. This decrease of activity is a mechanism to avoid cellular death and may be obtained, under specific conditions, by anaesthesia , barbiturates or hypothermia. This is the concept of integrity or survival level, standby level, full activity level
( see Table 1 ).
Cerebral metabolic rates of oxygen ( CMRO2 ml/100g/m ) and of glucose ( CMRG mg/100g/min ) for full, standby and survival activities at 37 ° C.
.
Level
Full
Standby
Survival
CMRO2
3.5
1.8
0.53
CMRG
5
2.5
0.7
Hence, cerebral blood flow regulation is linked to metabolism regulation, which is a different concept according to a given gestational age, a given type of considered cell, a given zone in the brain, and a given level of activities offered to a cell.
As far the cerebral blood flow ( CBF ) autoregulation is concerned, this concept is relevant to the relative independency of CBF to possible changes of parameters such as blood pressure, cardiac output, blood pH, pCO2 or O2 content provided that sufficient amount of glucose and or oxygen are delivered to cells for standby activities. If this is not the case, then CBF will be dependent, within minutes to and in the following order: changes in systolic blood pressure ( and not mean blood pressure ), after that to changes in pCO2, and finally to changes in O2 content. These mechanisms are triggered mainly in the locus coeruleus, under noradrenaline and acetylcholine neurotransmission; sleep and substances such as melatonine and vasointestinal peptide are protecting factors.
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In the distressed neonate due most of the time to respiratory or circulatory failures, global
CBF is not well autoregulated, and hence is variable. The values found are rather low, going from 5-14 ml / 100 / min .
It is showing the arterial blood levels of glucose ( [ aG ] mg/dL ) and of O2 ( [ aO2 ] ml/dL ) required to survival ( I ) or full ( w ) level of activities in brain.
CBF ml/100g/m I -> [aG ]
20
15
10
5
21
30
40
82
W -> [aG ]
36
50
72
143
I -> [ aO2 ]
10
13
19
28 #
W -> [ aO2]
22
29#
44#
62#
As one can see, we can follow the demands for glucose, even if the concept of brain hypoglycaemia is around 70 mg/dL in the sick preterm infant . For oxygen, the status of the sick neonate is precarious, for the requirements during very low CBF ( see # ) of [aO2] for full or even survival activities are impossible to obtain. The concept of brain hypoxaemia in sick neonates is concerning cells survival and is an oxygen content of less than 14 ml/dL.
Hence, several aspects are running beside to explain periventricular haemorrhage and white matter damage: 1) the difficulties to defend against free radicals or excitatory factors such as glutamate, aspartate, nitric oxyde, calcium; 2) a disadvantageous place ( white matter zone ) for lately migrating neurons; 3) high metabolic demands for glucose and mainly oxygen; 4) the high capacity of response from microglia ( leading to inflammation and immunity ); 5) the very poor capacity to autoregulate blood flow and metabolism.
These facts lead in the acute phase to pure necrosis ( mainly concerning the mitochondria ), and in long and more silent phase to apoptosis ( mainly concerning the nucleus ).
Global ischaemia or occlusive vascular disorder has a special place, for in about 40-45 % of cases, one will find an elevated levels of factors V and VIII.
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The injuries to body part of cells ( necrosis and apoptosis ), but also to axons, to disorders of synaptic relays in subcortex with basal ganglia and cerebellum, to ependymal processes, to internal capsule, to optic radiations, and also the rosettes of neurons definitely wrong placed are the substrates of clinical findings in developmental delays or cerebral palsy.
In the acute phase, neuroprotection is mainly based on a good offer of glucose and oxygen arterial level and good cerebral blood flow ( a stable and sufficient systolic blood pressure ); beside that, when well applied in a at or near term neonate, brain hypothermia offer an aid to the clinician. Nevertheless, the most at risk infant remains the newborn infant of less than 30 weeks with respiratory and circulatory difficulties.
References ,discussions and remarks can be obtained from or addressed to Dr Oreste
Battisti, Clinique Saint-Vincent de Paul, 207 r Fr Lefèbvre, 4000 Rocourt or by E-mail at oreste.battisti@skynet.be
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