BLOOD BRAIN BARRIER;

CEREBRAL EDEMA
Ardik MD
Department of Neurosurgery
Ulin Hospital
Lambung Mangkurat University
Banjarmasin
 BLOOD BRAIN BARRIER
 Served only to protect the brain from harmful
substances
 A single cell layer regulates selectively both
the entry & exit of biologically important
substance in order to control the neural
environment & sustain normal function
 Location of the BBB

 Composed :
• endothelium of the
cerebral capillary
• & the juxtaposed glial
end feet
 Location of the BBB
 Electron dense markers
given either
intravascularly or in the
CSF are impeded from
passage  endothelial
cleft by interendothelial
tight junction
 Location of the BBB
 These tight junction
(zonulae occludentes)
appear during
developtment & are
functionally complete
before or shortly after
birth in most species
 Small area that have no BBB
 - Choroid plexus
 - Area postrema
 - Median Eminence
 - Neurohypophysis
 - Pineal Body
 - Sub fornical
 - Commisural organ
 - supraoptic crest
(less tight junction)
General properties of the cerebral
capillary
General properties of the cerebral
capillary
General properties of the cerebral
capillary
 Cerebral capillary cell contain
biologically important enzyme
 Adenosin triphospatase
(ATPase)
 Dehydrogeneses : succinate,  other associate with
lactate, glutamat dan glucose,amino acid &
glukose. neurotransmiter
 Non amine oxidase. metabolism
 Dopa decarboxylase  Some of these serve as
 Acid phosphatase the basis of transport
 Nikotinamide Adenin across the BBB
Dinucleotide (NAD)
 Gamma- glutamyl  Possess insulin & alpha
transpeptidase receptor
 innervation
 Have central innervation ( cholinergic and
adrenergic
 As well as peripheral innervation
(sympathetic and parasymphatetic)
 -receptors :found elsewhere in the
cerebral circulation
 -receptor : found at the BBB
 Rule of the innervation is poorly
understood
Carrier-mediated BBB movement
 Carrier-mediated BBB movement

 High lipid solubility (high oil –water partition coeffecien)

 rapidly penetrate BBB
 Ex. Anesthetic and analgesic
 Carrier-mediated BBB movement

 Heroin is taken up more easily than morphin

 Heroin is hydrolized to morphin (analgesic )  less lipid
soluble  more restricted
 exceptions

 Glucose and certain amino acid (usually

metabolic active)  penetrate easily
 Not because of lipid solubility but because of
particular molecular configuration
 Carrier-mediated BBB movement

 The movement requirement active transport (cellular

energy) or a facilitated diffusion process
 Stereospecificity : D-glucose and not L-glucose
 Competitive inhibition : D-glucose and D-mannose
 Saturation : limited transport capacity in high
concentration
 Carrier-mediated BBB movement
transport process

 Bidirectional : glucose, large neutral amino acid,

sodium ?
 Unidirectional : (brain to blood): small neutral amino
acid potassium , iodid, protein, and prostaglandin
F2
 Carrier-mediated BBB movement
transport process

 Maximal rate of glucose transport 1.9 mol/gram brain per min.

 Blood concentration 5-7 mM  transport glukosa across BBB : 0.5
max rate
 If fall to level 1.0 mM  symptoms hypoglycemia
 Coma in half this level
 250 % excess extracellular  transported back across the BBB
 Evaluation of BBB Function

 Integrity has been determine by the

external detection of radionuclide crystal
 Has been replaced by CT, MRI and
Positron Emission Tomography (PET)
 Perturbation (gangguan) of the BBB
 Anesthesia
 Starvation and hepatic
failure
 Sepsis and CNS
infection
 Brain Tumor and Barrier
Permeability
 Microwave and X-
Irradiation
 Loss of Cerebral Auto
regulation
 The BBB and drug
Modification
 Perturbation of the BBB
 Anesthesia  Although pentobarbital &
 Starvation and hepatic halothan do not affect
failure total glucosa influx into
the brain, carrier-
 Sepsis and CNS mediated portion fall with
infection 1.5 – 2.0 %
 Brain Tumor and Barrier  Suggested : compete
Permeability with the glucose carrier.
 Microwave and X-
Irradiation
 Loss of Cerebral Auto
regulation
 The BBB and drug
Modification
 Perturbation of the BBB
 Anesthesia  Starved for up 1 week,
 Starvation and hepatic transport of glucose
failure across the cerebral
capillary is enhanced 16-
 Sepsis and CNS 25 %
infection
 Ketone body up take
 Brain Tumor and Barrier increase
Permeability
 Unclear : accelerated
 Microwave and X- transport or increase in
Irradiation simple diffusion
 Loss of Cerebral Auto  No anatomic evidence
regulation
 The BBB and drug
Modification
 Perturbation of the BBB
 Anesthesia  Evidence support :
 Starvation and hepatic encephalopathy ~ liver
failure failure is primarily due to
altered amino acid
 Sepsis and CNS concentration in plasma
infection and brain rather than to
 Brain Tumor and Barrier the toxic effect of :
Permeability - Ammonia
 Microwave and X- - Fatty acid
Irradiation
- And mercaptans
 Loss of Cerebral Auto
regulation
 The BBB and drug
Modification
 Perturbation of the BBB
 Anesthesia  Infection  breakdown in
 Starvation and hepatic the physical integrity of
failure the BBB ( anatomic
substrate in not known )
 Sepsis and CNS
infection  Leucocytes-pass through
the barrier (acute
 Brain Tumor and Barrier untreated phase) of
Permeability bacterial meningitis 
 Microwave and X- BBB glucose transport is
Irradiation also deranged
 Loss of Cerebral Auto
regulation
 The BBB and drug
Modification
 Perturbation of the BBB
 Anesthesia  Growth of brain tumor >
 Starvation and hepatic few millimeters in
failure diameters required new
capillary development
 Sepsis and CNS
infection  Stimulation : tumor
angiogenesis factor (TAF)
 Brain Tumor and Barrier
Permeability  Not known whether:
 Microwave and X- - Malignant degeneration
Irradiation of the endothelial cell
 Loss of Cerebral Auto - Response of the cerebral
regulation capillary  metabolic
requirements of the
 The BBB and drug tumor
Modification
 Perturbation of the BBB
 Anesthesia  Large molecules
penetrate the BBB 
 Starvation and hepatic
failure basis of the abnormal up
take of radio nuclides &
 Sepsis and CNS contrast enhancements
infection (CT,MRI)
 Brain Tumor and Barrier  Poorly understood :
Permeability (anatomic or biochemical)
 Microwave and X- - Enhancement ~ normal
Irradiation appearing cerebral
 Loss of Cerebral Auto capillary
regulation - Inhibitory effect of steroid
 The BBB and drug on the contras
Modification enhancement
 Perturbation of the BBB
 Anesthesia
 Starvation and hepatic
failure
 Sepsis and CNS
infection
 Brain Tumor and Barrier
Permeability
 Microwave and X-  Primarily due to the
Irradiation hyperthermia ~ excessive
 Loss of Cerebral Auto exposure > 10 mW/cm2
regulation  Below this level 
 The BBB and drug thermal regulation to
Modification prevent cerebral “hot
spots”
 Perturbation of the BBB
 Anesthesia  A compensatory change in
 Starvation and hepatic cerebrovascular resistance in
failure response to variation in
vascular pressure (60-160
 Sepsis and CNS mmHg)
infection  Hypertensive : 200 mmHg
 Brain Tumor and Barrier  Due in part or totally :
Permeability
- Myogenic
 Microwave and X-
Irradiation - Autonomic

 Loss of Cerebral Auto - And metabolic mechanism

regulation Increase cerebral blood flow >
 The BBB and drug 400 %  open the barrier
Modification Rapid & greater the elevation of
blood pressure, alone or in
combination with a high
PCO2  BBB disruption
 Perturbation of the BBB
 Anesthesia  Ability to penetrate the
BBB ~ lipid solubility 
 Starvation and hepatic
failure oil water partition
coefficient
 Sepsis and CNS
 Less lipid soluble  more
infection
restricted
 Brain Tumor and Barrier
Permeability  Intra carotid arabinose
(1.6 M) or mannitol
 Microwave and X- (1.4M)  barrier opening
Irradiation without neurological
 Loss of Cerebral Auto sequelae.
regulation  ~ chemotherapeutic
 The BBB and drug agents  primary
Modification lymphoma of CNS
 CEREBRAL EDEMA (CE)

 The most common type of CE is due to

the breakdown of the BBB
 Definition : The excess accumulation of
water in the intra and/or extra cellular
spaces of the brain
classification
pathophysiology
 Diagnosis
Clinical feature

 Until the ICP reaches a level that produce local

ischemia, CE alone will not produce clinical
neurological abnormalities
 When reached : symptoms and sign are related
to the location of the inciting lesion
 Although remote effect are not uncommon
Diagnosis

Radiologic
Imaging
Diagnosis

Radiologic
Imaging
Diagnosis

Radiologic
Imaging
Diagnosis

Radiologic
Imaging
Diagnosis

Radiologic
Imaging
Diagnosis

Radiologic
Imaging
Diagnosis

Radiologic
Imaging
 Treatment
 Restoration or Improvement of BBB Breakdown

 Removal of the greater portion of the deranged

BBB  Edema fluid end then can be reabsorbed
 Decrease in lession bulk  improve rCBF 
edema resolution
 Effect of BBB disruption diminished by
decreasing the hydrostatic :
- Lowering blood pressure
- Increasing cerebrovascular resistance
 Treatment
 Restoration or Improvement of BBB Breakdown

 Drug (dexamethasone)  effect on ICP & CE

- by stabilizing cell membranes
- Restoring BBB integrity
- Inhibit plasma & tissue substances secondarily
increase local & distal cerebral vascular permeability
- High dose (150-400 mg/day) more effective than
standard or low dose (10-20 mg loading dose  16
mg/day)
 Treatment
 Restoration or Improvement of BBB Breakdown

 Dexamethasone : very effective for perifocal

Edema associated with :
- Focal infection
- tumor
 Questionably effective :
- Trauma
- Viral encephalitis
- Hypoxia ischemia
- & Rey’s syndrome
 Treatment
 Removal of tissue water

 Osmotherapy ( rapid and effective ) decreasing

tissue water & brain bulk
 Common agen used :

- Mannitol 20 % ( 0.25-1.0 g/kg BW)

- Some evidence  lower dose still effective

- Barrier intact.

- Osmotic effect can be prolonged by diuretics (

furosemid 0.7 mg/kg & ethacrinic acid )
oral glycerol 0.5 – 1.0 g/kg BW
The effect appears after few days
 Treatment
Compensation in vascular and CSF compartment

 Decreasing the rate of CSF formation

- Inhibit Na-K-ATPase activity
- Steroid (dexamethason 16 mg/day)
- Loop diuretics (furosemid 50 mg/kg)
- Carbonic acid inhibitors (acetazolamid 20-50 mg/kg)
- Glyserol (1.0 mg/kg)
- Dimethyl sulfoxid (DMSO)
 Decreasing the cerebral vascular volume
 Clinical aproach
 Possible with continuous measurement of
ICP & often effectively deal with CE
 Hyperventilation, PCO2 25 mmHg  often
effective in temporarily decreasing ICP
 Osmotic agents alone or with diuretic
 Barbiturate therapy (pentobarbital or
thiopental