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Induction of hydrocephalusand its relation to Cell death, axonal damage, and cell birth in the immature rat brain

Presented by:Monique Ferguson

Bio 475

Del Bigio, M.R, and Y.W. Zhang. 1998. Cell death, axonal damage, and cell birth in the immature rat brain following induction of hydrocephalus. Exp. Neurol. 154:157-169.

hydrocephalus what is it
Derived from Greek words: “hydro”=water “cephalus”=headHydrocephalusWhat is it?
  • It is a condition in which the primary characteristic is excessive accumulation of fluid in the brain resulting from a blockage in CSF route of flow and reabsorption
cerebrospinal fluid
Cerebrospinal Fluid
  • The water/fluid is actually CerebroSpinal Fluid (CSF) which is a clear liquid surrounding the brain and spinal cord.
  • It also fills the ventricles or interior chambers of the brain.
  • CSF is produced by the choroid plexus

how to identify hydrocephalus
How to identify Hydrocephalus

When the circulation or absorption of CSF is blocked, or a large amount of

fluid is produced, the volume of the brain becomes excessively larger than

normal. The picture above shows the flow of CSF in the ventricles of a

normal individual in comparison to an individual with Hydrocephalus,

displaying enlarged ventricles.

types of hydrocephalus
Types of Hydrocephalus

Congenital Hydrocephalus – present at birth and caused by pregnancy complications or genetic dispositionAcquired Hydrocephalus – develops at the time of birth or later in life

  • Communicating hydrocephalus
  • Obstructive hydrocephalus (non-communicating)
  • Normal Pressure Hydrocephalus or NPH
  • Dandy-Walker Malformation
types of hydrocephalus continued
Types of Hydrocephalus Continued
  • CommunicatingWhen the flow of CSF is blocked after it exits the ventricles. CSF can still flow between the ventricles which remain open
  • Obstructive (non-communicating)When the flow of CSF is blocked along one or more of the narrow pathways connecting ventricles
  • Normal PressureThe CSF is produced in normal amounts in this condition, but it is prevented from being normally re-absorbed because of obstruction to the flow of CSF
  • Dandy-Walker MalformationRare malformation of the brain that is present at birth and is characterized by an enlarged space at the back of the brain that interferes with the normal flow of cerebrospinal fluid through the openings between the ventricle and other parts of the brain.
what causes hydrocephalus
genetic inheritance

developmental disorders


blockage of the ventricles by hemorhaging

complications of premature birth

diseases (meningitis)

traumatic head injury

What causes Hydrocephalus?
symptoms of hydrocephalus
Symptoms of Hydrocephalus

Symptoms of hydrocephalus vary with:

  • Age
  • Disease Progression
  • Individual differences to CSF
symptoms in infants




sunsetting of the eyes (AKA downward deviation of the eyes)

Symptoms in Infants
An obvious indication of hydrocephalus in infants is the increase in head circumference. In infants the skull has not fully fused and the accumulation of fluid causes the head to enlarge due to the swelling of the ventricles.

symptoms in older children and adults



Papilledema (swelling of the optic disk which is part of the optic nerve)

Slowing or loss of development



Blurred vision

Diplopia (double vision)

Sunsetting of the eyes

Problems with balance

Gait disturbance

Urinary incontinence


Changes in personality or cognition including memory loss

Symptoms in older children and adults
how is hydrocephalus diagnosed
How is Hydrocephalus diagnosed
  • Clinical neurological evaluation
  • Cranial imaging techniques -ultrasonography -computed tomography (CT) -magnetic resonance imaging (MRI) -pressure monitoring techniques
current treatment
Current Treatment
  • Shunt System A shunt system diverts the flow of CSF from a site within the central nervous system to another area of the body where it can be absorbed as part of the circulatory system
  • Third ventriculostomy
shunt system
A shunt is a flexible but sturdy silastic tube

A shunt system consists of the shunt, a catheter, and a valve

One end of the shunt is placed within the CNS and the other end of the catheter is placed within the abdominal cavity, heart or lung cavity where the CSF can drain and be absorbed

The valve located along the catheter maintains one way flow and regulates the rate of CSF flow

Shunt System


third ventriculostomy
Third Ventriculostomy
  • Third ventriculostomy involves entering the brain through the bones at the top of the skull. The neurosurgeon passes an neuroendoscope through the lateral ventricle into the third ventricle and uses a laser to make a hole in its floor. Excess fluid drains through the hole into the subarachnoid space.
  • The overall success rate of third ventriculostomy is about 65%. When used to treat blockage caused by tumor success rates are slightly higher. In hydrocephalus caused by hemorrhaging or infection, they are slightly lower.
Cell death, axonal damage, and cell birth in the immature rat brain following induction of hydrocephalus
  • To test the hypothesis that hydrocephalus causes death of brain cells and that hydrocephalus is associated with the generation of new brain cells
materials and methods experimental model
Materials and MethodsExperimental model
  • 3 week rat with kaolin induced hydrocephalus
  • Note: At this age the rat brain is developmentally similar to that of a human infant.
  • Controls received sham injections with needle insertion only
materials and methods
Materials and Methods
  • Histological Studymicroscopic study of the animal tissues
  • Axonal Transport Study
  • Electron Microscope Studies
  • Immunoblot Studies
diagram of rat brain and cerebrospinal fluid system
Diagram of rat brain and cerebrospinal fluid system

The CSF is secreted in the ventricles by the choroid plexus. CSF flows through the ventricular system (black arrows) and out into the subarachnoid space via openings between the fourth ventricle and the cisterna magna.

  • By 2 weeks hydrocephalic rats weighed less than controls
  • By 3-4 weeks hydrocephalic rats exhibited unsteady gait, poor grooming and domed skulls due to progressive ventricular enlargement
results continued
Results continued
  • Reactive changes and Inflammation
  • Axonal damage
  • Cell death
  • Cell generation
anti g lial f ibrillary a cidic p rotein anti gfap and nestin immunoreactivity
Anti-Glial fibrillary acidic protein (anti-GFAP) and Nestin immunoreactivity
  • A=Immunohistochemical labelling of reactive astrocytes. At 3-4 weeks in hydrophalic rats there were abundant reactive astrocytes
  • B=Nestin immunoreactivity was studied with the hope that it might aid in the identification of progenitor cells



gelsolin immunohistochemical labeling of oligodendrocytes
The function of oligodendrocytes is to form myelin in brain and spinal cord

Reactive change in oligodendroglia was manifested immunohistochemically by increased expression of gelsolin in cell processes

Gelsolin is involved with the movement of myelin-forming cell processes.

Gelsolin immunohistochemical labeling of oligodendrocytes
microglial reaction by immunohistochemical labeling with ox 42
Microglial reaction by immunohistochemical labeling with OX-42



  • A=OX-42 amtibody in the white matter adjacent to the enlarged lateral ventricle of a rat that has been hydrocephalic for 4 weeks
  • B=No labeling in a comparable region for the control rat.
  • C=Plump activated microglial cell and reactiev astrocytes were identitfied in hydrocephalus


axons labeled with anti neurofilament
Axons labeled with anti-neurofilament
  • A=Shows the axons labeled with anti-neurofilament in hydrocephalic rat
  • B= At higher magnification the damaged axon profiles are round and varicose
  • C=the majority of swollen axons were found to be myelinated

Axons are specialized for rapid

conduction of nerve signals.

They are a part of the neuron.

damaged axons in white matter of control and hydrocephalic rat brains
Damaged Axons in White Matter of Control and Hydrocephalic Rat Brains
  • The controls had the least number of damaged axons and the smallest ventricle size
  • As the weeks progressed the number of damaged axons increased and ventricle size increased also

Axons are specialized for rapid

conduction of nerve signals.

They are a part of the neuron.

retrograde transport of fluorogold
Retrograde transport of FluoroGold
  • Retrograde transport of FluoroGold was used to asses the integrity of the axons
  • The number of retrogradely labeled neurons in the contralateral cortex tended to be greater in hydrocephalic rats than in the matched control rats

The labeling index estimated

the number of contralateral labeled neurons per mm3 of ipsilateral cortex injected with FluoroGold label

cell death in a rat that had been hydrocephalic for 4 weeks
Cell death in a rat that had been hydrocephalic for 4 weeks
  • A- shows a degenerating glial cell
  • B- shows a glial cell engulfing a dense apoptic body*



cell death in hydrocephalic rats
Cell death in hydrocephalic rats
  • There is a significant increase in cell death in hydrocephalic brains 3 to 4 weeks after kaolin injection
Ki67 Immunoreactivity and Histone mRNA as Indicators of Cell Activity in control and Hydrocephalic Rat brains
  • Demonstration of histone mRNAs showed many S phase cells. There were no statistically significant differences between hydrocephalic and control brains.
  • Labeling of Ki67 demonstrated abundant cycling cells in all regions of the control. One week after kaolin injection, the quantitiy of Ki67 immunoreactive cells increased significantlyNo such change was found in severely hydrocephalic rats 3 weeks after kaolin injection
fluorescence photomicrograph showing
Fluorescence photomicrograph showing
  • In controls and moderately hydrocephalic rats, 30-37% of transferrin-positive cells coexpressed Ki67



  • Kaolin induced hydrocephalus in neurologically immature rats was associated with progressive damage to axons in the periventricular white matter and gradual death of oligodendroglial cells
  • Multiple brain responses were observed: astroglial hyperplasia and hypertrophy, oligodendroglial reaction, microglial activation, and increased cell proliferation in the subependymal zone.
  • Oligodendrial cells did not appear to regenerate.