The cortex

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9 The cortex

Embryological development

Neuronal fate in the mammalian cortex is influenced by the timing of cell differentiation, which is dependent on both genetic and environmental factors (see Chapter 2). The cerebral cortex neurons are generated in the ventricular zone by the epithelial layer of progenitor cells that line the lateral ventricles. They migrate to the cortical plate, which eventually develops into the grey matter of the cortex. The final position assumed by these neurons depends on their ’birthmoment’, or time of last division. The migration occurs along radially organised glial cells called radial glia, which guide the migrating neurons to the cortex. The layering of the neurons in the cerebral cortex is established with an inside-first, outside-last manner so that the newest neurons must pass over and around the more mature neurons, probably gaining information from the previously established neurons as they pass.

The meninges

The meninges are layered structures that contain cerebrospinal fluid and give protection to the brain and spinal cord. The meninges are composed of three layers; the dura mater, the arachnoid mater, and the pia mater (Figs 9.1 and 9.2).

The dura mater is the tough fibrous outer component of the meninges and is composed of two layers. The periosteal layer is intimately attached to the inner surface of the skull bones. The second layer is the meningeal layer of the dura. The periosteal and meningeal layers of the dura are tightly connected in most areas except where the meningeal layer projects deep into the cranial cavity and forms tough fibrous sheets, the falx cerebri and the tentorium cerebelli, that divide the cranial space into well-defined sections. The falx cerebri divides the cerebral hemispheres along the median plane of the skull. The tentorium cerebelli forms a sheet-like structure that separates the cerebellum from the rest of the brain. This is an important landmark, as anatomical structures are referred to as infratentorial if they are below or inferior to the tentorium and supratentorial if they are superior or above the tentorium. Several important structures must pass through the tentorium in order to enter the brainstem and spinal cord. These structures pass through an opening in the tentorium referred to as the tentorial notch. This is an important clinical consideration because structures put under increased pressure due to space-occupying lesions or cerebral spinal fluid blockage can be squeezed into the notch, resulting in damage and dysfunction of the tissues passing through the notch and of the tissues forced into the notch. The falx cerebri is another structure that can be potentially damaging to neural tissue that gets forcibly pushed into or under it by increased intracranial pressure.

The arachnoid layer is composed of thin spider web-like attachments to the dura superiorly and the pia inferiorly. The pia mater adheres very closely to the surface parenchyma of the brain. This layer follows the surface of the brain into all of the surface gyri and sulci. Vessel must past through the pia to get to the parenchyma of the brain. As an artery enters the cortex, a layer of pia mater accompanies the vessel into the brain. With decreasing size of the vessel, the pia membrane becomes perforated and finally disappears at capillary level. The perivascular space between the artery and the pia mater inside the brain is continuous with the perivascular space around the meningeal vessel. Veins do not have a similar coating of pia mater.

The way in which the meninges connect to each other and the structures that they attach to gives rise to three clinically important spaces or potential spaces, the epidural space, the subarachnoid space, and the subdural space. The epidural space is a potential space that can form between the dura and the bone of the skull. The meningeal arteries run in the space between the tightly adherent dura and the skull. The middle meningeal artery passes under and along the temporal bone, which is the thinnest bone of the skull and thus the most easily fractured. Trauma to the temporal bone can cause tears in the meningeal arteries and result in blood escaping into the potential epidural space. As the blood builds up, it forces the periosteal layer of dura away from the bone and bulges into the arachnoid and pia layers, eventually exerting pressure on the brain. This process is referred to as an epidural haematoma (Fig. 9.3).

Epidural haematomas are usually rapidly growing and expanding as the arterial pressure spreads the periosteal dura from the bone of the skull. The dural separation continues until it reaches a cranial suture where the dura is much more tightly joined to the skull. This results in an expansile lesion that takes the shape of a biconcave lens. Clinically, the patient may experience a lucid interval following trauma to the skull where they may not have any symptoms. Within a few hours the expanding haematoma starts to compress the brain and results in increased intracranial pressure and death if not treated.

The subdural space is clinically important because of the many bridging veins leaving the brain parenchyma and exiting through the dura to the venous sinuses. Subdural haematoma (SDH) results when the bridging veins flowing from the cortex parenchyma to the sagittal sinus experience a trauma severe enough to tear them. This results in a slow-growing, low-pressure haematoma in the potential space between the dura and the arachnoid layers which often occurs in the parietal area of the cortex. There is no classic pattern of presenting symptoms but they are often trauma induced. The trauma need not be extreme and, in fact, trivial trauma is suspected in over 50% of cases.

The symptoms of SDH often mimic other cerebrovascular events or space-occupying lesions. Alcohol consumption reduces clotting mechanisms and often results in head trauma from falls. Anticoagulants can also increase the risk of SDH from minor trauma in the elderly (Fig. 9.4). Chronic subdural haematomas can take weeks to months in the elderly before they start to experience symptoms. This is mainly due to the low-pressure, slow leak from the veins and the fact that brain tissue shrinks somewhat as we age and allows a greater space for the blood to occupy before interference with function occurs. Acute subdural haematomas require a considerable amount of traumatic force to occur and as such are usually associated with other serious brain injuries such as traumatic subarachnoid haemorrhage and brain contusions.

The subarachnoid space, which is the space between the pia and arachnoid layers, is divided by trabeculae and contains the cerebrospinal fluid and the major blood vessels of the brain. A major clinical consideration of this area is the possibility of a subarachnoid haemorrhage. These most commonly occur when a pre-existing aneurysm located on the arteries traversing the subarachnoid space fails and blood leaks out into the space. The aneurysm can develop a slow leak or simply burst. Less than 15% of patients have symptoms prior to rupture, but following rupture the symptoms include the simultaneous onset of severe headache with nausea and vomiting. The headache is often described as the worse headache of their life. Photophobia and neck stiffness may also accompany the other symptoms. Because of the similarity of presentation with meningitis and migraine these must be considered as differential diagnoses until ruled out.

Any process that causes an increase in intracranial pressure, such as intracranial tumours, haemorrhages, oedema, and altered cerebrospinal fluid pressures, can result in compression of brain tissue. The portion of brain that becomes compressed and the way in which it responds to the compression is dependent on the mass effect. The mass effect can result in numerous ramifications in different individuals; however, three clinically relevant situations involving compression of brain tissues through anatomically ridged structures, a process called herniation, will be outlined below.

Cerebral spinal fluid (CSF)

Cerebral spinal fluid is normally a clear, colourless, and odourless fluid that diffuses over the brain and spinal cord. CSF probably functions to cushion the brain and spinal cord from external jarring or shocking forces that may be transmitted through the tissues to reach these structures. CSF may also function in some capacity as a metabolic transport medium, transporting nutrients to the neuraxial cells and metabolic waste products away from the neuraxial components. CSF may also function as a pressure distributor in cases where changes in intracranial volume have occurred such as in postoperative lesions where the removed tissue area fills with CFS. The CSF is formed by the dialysis of blood across the tissues of the choroid plexuses found in the ventricle of the brain and brainstem. The circulation of CSF occurs in two systems: the internal system which includes the two lateral ventricles, the interventricular foramens, the third ventricle, the cerebral aqueduct, and the fourth ventricle; and the external system, which includes all of the external spaces surrounding the brain and spinal cord including the various cisterns. Communication between the internal and external systems occurs via two lateral apertures in the fourth ventricle referred to as the foramens of Luschka, and a medial aperture also in the fourth ventricle referred to as the foramen of Magendie. The total volume of CSF in all systems measures about 150 cm3. The CSF is formed at the rate of about 20 cm3/hr or about 480 cm3/day. This means that all of the CSF in your body is replaced about 3.2 times per day. This is accomplished via absorption of the CFS by the arachnoid granulations located along the superior longitudinal sinus which allow the CSF to enter the venous drainage system and return to the general circulation (Fig. 9.6). The CSF circulates from the lateral ventricles, through the third ventricle, to the fourth ventricle where it then enters the external system and bathes the spinal cord and the external surface of the brain (Fig. 9.7).

image Quick facts 9.1

Summary of CSF examination

Finding Suspected condition
Neutrophils and decreased glucose Acute bacterial meningitis
Neutrophils and normal glucose Brain abscess
Lymphocytes and decreased glucose Virus, tuberculosis, or cryptococcal
Lymphocytes and normal glucose Virus, brain tumour, syphilis

Clinical examination of cerebral spinal fluid

Examination of the CSF can be a valuable tool in the diagnosis of several conditions such as infection that can affect the neuraxis. A common procedure utilised to obtain CSF is the lumbar puncture. This procedure provides direct access to the subarachnoid space of the lumbar cistern which contains the CSF (Fig. 9.8). This procedure can be used to obtain samples of CSF, measure the pressure of the CSF, remove excess CSF if necessary, and act as a conduit for the administration of medication or radiographic contrast material. The CSF is examined for a variety of different elements:

1. CSF pressure—Normal value is 100–200 mmH2O (7.7–15.4 mmHg). Elevated CSF pressure may be caused by blockage of the ventricular drainage system, overproduction, or space-occupying lesions. The two most common causes are meningitis and subarachnoid haemorrhage. Brian tumours and abscesses will cause an increase after a delay of days to weeks.

2. CSF appearance—Normal CSF is clear and colourless. CSF is generally white or cloudy if significant white blood cells (WBC) are present (over 400/mm3). CSF may appear red or pink if red blood cells (RBC) are present; however, if RBC have been in the CSF for more than 4 hours the fluid may appear yellow (xanthochromia). This is due to the breakdown of haemoglobin.

3. CSF glucose—Normal is 45 mg/100 mL or higher. The most significant clinical finding is a decrease in glucose concentration. This occurs in virtually every case of bacterial meningitis. Other causes of decreased glucose include:

Since a relationship exists between blood glucose and CSF glucose levels, a blood glucose concentration measure should be performed at the same time as the CSF sample is taken.

4. CSF protein—Normal value is considered to be 15–45 mg/100 mL in adults. In newborns it may range as high as 150 mg/100 mL. The most significant clinical finding is an elevation of protein concentration. Causes of increased protein concentration include:

5. CSF cell count—Normally the CSF contains no more than 5 cells/mm3. Under normal conditions virtually all of the cells present should be lymphocytes. Usually the highest leukocyte counts are found in acute bacterial infections such as meningitis. Usually the cell type most contributing to the leukocytosis in bacterial infections is the polymorphonuclear cell or neutrophil.


Meningitis is an inflammatory response to pathogen infection of the dura, arachnoid, and pia maters and the CSF. Leptomeningitis involves the pia–arachnoid layers and pachymeningitis involves the dura layer. Since the subarachnoid space and thus the CSF is continuous throughout the brain, spinal cord, and optic nerves the entire neuraxis is usually affected.

Access to the intracranial compartment is by way of the bloodstream, whereas access to the CSF is through the choroid plexus or directly through the blood vessels of the pia mater. Although the pia appears to be delicate and fragile it actually forms a remarkably efficient barrier against the spread of infection, and it generally prevents involvement of the underlying brain tissue.

Once a pathogen gains entrance to the CSF, the immune system’s counterattack is severely hampered, until a substantial population of the pathogen stimulates neutrophilic pleocytosis in the case of bacteria invasion or lymphocytic pleocytosis in the case of a virus invasion (Scheld 1994; Pryor 1995). Bacteria gain entrance to the CSF by one of three proposed mechanisms:

The primary results of bacterial invasion are:

Normal concentration of WBC in the CSF is 0–5 cells/mm3, and almost all are normally lymphocytes.

Meningitis may be caused by a variety of organisms, including Cryptococcus neoformans, which is a yeast found in the soil with a worldwide distribution. The incidence is about 5/1 000 000 and it is most often found in people with a compromised immune system. Risk factors of immune compromise include lymphoma, diabetes, and AIDS. Symptoms of cryptococcal meningitis include:

Treponema pallidum (Syphilis)

This condition can develop as a complication of untreated or poorly treated syphilis. It is characterised by changes in mental status and nerve function which involves a form of meningovascular neurosyphilis, which is a progressive life-threatening complication of syphilis infection. This condition resembles meningitis caused by other organisms but involves serious damage to the vascular structures of the brain, which result in stroke in a large percentage of patients. The symptoms include:

Haemophilus influenzae

The bacteria Haemophilus influenzae type B is the most common agent involved. This condition is the leading cause of meningitis in children from 1 month to 5 years of age, with the peak incidence from 6 to 9 months. The organism usually spreads from somewhere in the respiratory tract to the blood stream and then onto the meninges.

Risk factors for the development of this condition include recent history of otitis media, sinusitis, or pharyngitis. This also includes the history of a family member infected with H. influenzae in the past. Symptoms and examination findings may include:

Antibiotic treatment must be started as soon as meningitis is expected. Steroid medication may also be given to reduce damage to the auditory nerves, which occurs in about 20% of cases. The mortality of the condition is quite high with 3–5% of patients not surviving. Of those who do survive, some will develop brain damage, hydrocephalus, learning disorders, and behavioural problems. It is recommended that all family members start chemoprophylaxis as soon as possible.

Staphylococcus (aureus, epidermidis)

This condition is usually caused by the bacteria Staphylococcus aureus or Staphylococcus epidermidis. It may develop as a complication from surgery or from haematogenous spread from another site. Risk factors include brain surgery, CSF shunts, infections of the heart valves, and previous brain infections such as an abscess or encephalitis. The symptoms include:

CSF and serum cultures may show staph, and infections of this type often result in death.

Vascular accidents

Arteriovenous malformation (AVM)

These are congenital malformations of the arteriovenous junctions that result in large tangled areas that are often structurally delicate and can be ruptured with relatively minor trauma. The haemorrhage occurs in sinusoidal vessels that are under low pressure. These types of haemorrhage often result in focal neurological signs and headache, epilepsy, and occasionally hydrocephalus. The arachnoid villi can become blocked by blood from repeated subarachnoid haemorrhages and therefore impair CSF resorption, which leads to hydrocephalus.