Neurones

Neurones are the structural and functional units of the CNS, generating electrical impulses that allow rapid cell–cell communication at specialised junctions known as synapses (Fig. 26.2). Many millions of neurones are present, arranged in layers within the cortex on the surface of the cerebellum and the cerebral hemispheres. Groups of functionally related neurones within the subcortical grey matter are known as nuclei (Table 26.1). Neurones are highly specialised post-mitotic cells which cannot be replaced after cell death. They are subject to unique metabolic demands, having to maintain an axon (which may be up to 1m in length) by intracellular transport. This makes neurones particularly vulnerable to a wide range of insults, principally hypoxia and hypoglycaemia.

Fig. 26.2 Neuronal signal transmission at synapses. The transmission of the action potential down the axon (1) to the presynaptic membrane (2) results in opening of Ca ion channels, producing an influx of calcium. The subsequent phosphorylation of calcium-binding proteins allows the synaptic vesicles (3) to bind to the presynaptic membrane and release their neurotransmitter contents into the synaptic cleft (4). The neurotransmitters diffuse across the synaptic cleft and bind to receptors in the post-synaptic membrane (5), causing membrane depolarisation and eventually the formation of another action potential.

Neurones contain ion channels within the cell membrane that can be opened by either changing the voltage across the membrane or by the binding of a chemical (neurotransmitter) to a receptor in or near the ion channel. In the resting state, the neuronal cell membrane is relatively impermeable to ions. Opening of the ion channels allows an influx of sodium ions which depolarises the membrane, forming an action potential which is transmitted rapidly down the axon by saltatory conduction. Cell to cell transmission occurs at the synapse (Fig. 26.2). The commonest excitatory neurotransmitter in the CNS is glutamate. Excessive release of glutamate under certain conditions such as cerebral ischaemia and epilepsy can result in excitotoxic neuronal cell death.

Neurones, or nerve cells, vary considerably in size and appearance within the CNS. All possess a cell body, axons and dendrites.

The cell body or perikaryon is easily seen by light microscopy (Fig. 26.3). It contains neurofilaments, microtubules, lysosomes, mitochondria, complex stacks of rough endoplasmic reticulum, free ribosomes and a single nucleus with a prominent nucleolus. Some groups of neurones contain the pigment neuromelanin and are readily identifiable with the naked eye as darkly coloured nuclei, e.g. in the substantia nigra.

Fig. 26.3 Normal cerebral cortex. Figure shows the normal arrangement of neurones (1), astrocytes (2), oligodendrocytes (3) and capillaries in the cerebral cortex. Although the neuronal perikarya are visible, the cytoplasm of glial cells is best demonstrated by using special histological techniques.

Axons and dendrites are the neuronal processes that convey electrical impulses from and towards the perikaryon respectively. These processes vary enormously in size and complexity, and may be difficult to identify on routine microscopy.

Glia

Glia are specialised supporting cells of the CNS comprising four main groups:

Astrocytes are process-bearing cells which are poorly visualised by light microscopy (Fig. 26.3) unless special staining techniques are used. They perform several important roles:

Oligodendrocytes are the most numerous cells in the CNS. On light microscopy, they are visible as darkly staining nuclei located around neurones and nerve fibres (Fig. 26.3). The most important function of oligodendrocytes is the synthesis and maintenance of myelin in the CNS.

Ependymal cells form the single-cell lining of the ventricular system and the central canal of the spinal cord. They are short columnar cells that bear cilia on the luminal surface. Ependymal cells may participate in the absorption and secretion of cerebrospinal fluid (CSF).

Choroid plexus cells secrete CSF and contain large quantities of mitochondria, rough endoplasmic reticulum and Golgi apparatus within the cytoplasm. They form a cuboidal epithelial covering over the ventricular choroid plexus, and bear atypical microvilli.

Microglial cells

Microglia belong to the macrophage/monocyte system of phagocytic cells. They are normally quiescent, and inconspicuous on light microscopy, but are of major importance in reactive states, for example in inflammatory and demyelinating disorders.

Connective tissue

Connective tissue in the CNS is confined to two main structural groups: the meninges and perivascular fibroblasts.

The meninges comprise the pia, arachnoid and dura mater, and the arachnoidal granulations which are the main sites of CSF absorption. The meninges are composed of fibroblast-like cells which also extend around meningeal and cerebral blood vessels.

Blood vessels

Blood vessels in the CNS are similar in structure and function to those elsewhere in the body, with the important exception of the capillaries. The capillaries within the CNS differ from most other capillaries in several respects:

These special structural features are important constituents of the blood–brain barrier: this is a functional unit which restricts the entry and exit of many substances—including proteins, ions, non-lipid-soluble compounds and drugs—to and from the CNS.

Neurones

Neurones can undergo various reactive changes to cell injury:

Central chromatolysis is a distinctive reaction which usually occurs in response to axonal damage (Fig. 26.4). This reaction is maximal at around 8 days following axonal damage, and is accompanied by increased RNA and protein synthesis, suggestive of a regenerative response.

Fig. 26.4 Response to axonal injury: central chromatolysis and anterograde degeneration. Following axonal injury, the perikaryon swells and the nucleus migrates peripherally. The Nissl substance is dispersed to the periphery of the perikaryon, hence the term ‘central chromatolysis’. Anterograde degeneration of the axon occurs distal to the site of injury.

Anterograde degeneration occurs as a result of axonal transection, and is usually accompanied by central chromatolysis (Fig. 26.4). Degeneration of the distal part of the axon will occur following its separation from the intact perikaryon, e.g. by transection. Within 4 days, the distal segment degenerates and becomes fragmented. The myelin sheath surrounding the axon also fragments, but this usually occurs only after axonal degeneration is established. Axonal and myelin debris is then phagocytosed by macrophages, which often remain around the site of injury for several months. Attempts at axonal regeneration do not occur to a significant extent in the CNS.

Atrophy of neurones occurs in many slowly progressive degenerative disorders, e.g. motor neurone disease. Such neurones appear shrunken, and often contain excess lipofuscin pigment. Trans-synaptic atrophy occurs in neurones following loss of the main afferent connections, e.g. in neurones of the lateral geniculate body following damage to the optic nerve or retina.

Astrocytes

Astrocytes undergo hyperplasia and hypertrophy following almost all forms of CNS damage, in a response known as ‘reactive gliosis’. Gliotic tissue is translucent and firm, often forming a limiting barrier to sites of tissue damage, for example at the edge of a cerebral infarct.

Microglia

Microglia are also involved in the response to many forms of CNS damage, often acting as phagocytes (as in neuronophagia). When myelin is damaged, these cells ingest the breakdown products, resulting in an enlarged rounded cell body distended with droplets of neutral lipid.

Oligodendrocytes and ependymal cells

These cells show only a limited capacity to react to injury.

Diffuse brain swelling

Diffuse brain swelling denotes a generalised increase in the volume of the brain which results from either vasodilatation or oedema.

Focal brain swelling

Focal lesions of many types can produce an increase in cerebral volume, for example cerebral abscesses, intracranial haematomas and intrinsic neoplasms. Many extrinsic intracranial lesions, for example subdural haematomas and meningiomas, exert a mass effect within the cranial cavity and so act as space-occupying lesions.

Raised intracranial pressure

Raised intracranial pressure is an invariable consequence of enlarging intracranial lesions, as there is very little space within the rigid cranium to accommodate an expanding mass. Initially, however, there is a phase of spatial compensation, made possible in three ways:

Once this phase is passed, there is a critical period in which a further increase in the volume of the intracranial contents will cause an abrupt increase in intracranial pressure. The characteristic clinical signs and symptoms of raised intracranial pressure and their likely causes are:

Intracranial shift and herniation

Intracranial shift and herniation are the most important consequences of raised intracranial pressure due to space-occupying lesions. They usually occur following a critical increase in intracranial pressure, which may inadvertently be precipitated by withdrawing CSF at lumbar puncture. Lumbar puncture is therefore contraindicated in any patient with raised intracranial pressure and a suspected intracranial space-occupying lesion to avoid the risk of precipitating a potentially fatal brainstem herniation.

Lateral shift of the midline structures is a common early complication of intracranial space-occupying lesions. However, patients with acute lateral displacement of the brain due to a hemispheric mass show a depressed level of consciousness even in the absence of an intracranial herniation. The clinical features are summarised in Table 26.2.

Table 26.2 Clinical consequences of intracranial herniation

Herniations occur at several characteristic sites within the cranial cavity, depending on the site of the space-occupying lesion (Fig. 26.5). Transtentorial herniation is frequently fatal because of secondary haemorrhage into the brainstem (Fig. 26.6). This is a common mode of death in patients with large intrinsic neoplasms or intracranial haemorrhage.

Fig. 26.5 Sites of intracranial herniation. Space-occupying lesions in the cerebral hemispheres may cause herniation of the cingulate gyrus under the falx cerebri (1) or of the hippocampal uncus and parahippocampal gyrus over the tentorium cerebelli (2). Cerebellar tonsillar herniation through the foramen magnum (3) can occur with lesions in the cerebrum or cerebellum. A swollen brain will herniate through any defect in the dura and skull (4).

Fig. 26.6 Herniation effects in the brain. A large haemorrhagic neoplasm (glioblastoma) is present in the right cerebral hemisphere, causing shift of the midline structures to the left and compression of the right lateral ventricle. Transtentorial herniation at the base of the brain. A prominent groove surrounds the displaced parahippocampal gyrus (arrow). The adjacent 3rd nerve (N) is compressed and distorted and the ipsilateral cerebral peduncle (P) is distorted with small areas of haemorrhage.

Epilepsy

Seizures (fits) may be focal or generalised (p. 775), and are particularly common in patients with raised intracranial pressure due to cerebral abscesses and neoplasms.

Hydrocephalus

Hydrocephalus is a particularly common complication of space-occupying lesions in the posterior fossa that compress and distort the cerebral aqueduct and fourth ventricle (p. 759).

Systemic effects

The systemic effects of raised intracranial pressure are of major clinical importance, as they may result in a life-threatening deterioration in an already ill patient. These are thought to result from autonomic imbalance and overactivity as a result of hypothalamic compression and include:

Primary brain damage

Primary brain damage occurs at the time of injury. There are two main forms: focal damage and diffuse axonal injury.

Focal damage

The commonest type of focal damage is contusions. These often occur at the site of impact, particularly if a skull fracture is present. Contusions are commonly asymmetrical and may be more severe on the side opposite the impact—the ‘contrecoup’ lesions (Fig. 26.7). Movement of the brain within the skull brings these areas into contact with adjacent bone, resulting in local injury. Large contusions may be associated with an intracerebral haemorrhage, or accompanied by cortical lacerations. Healed contusions are represented by wedge-shaped areas of gliosis and cortical rarefaction which are yellow–brown due to the presence of haemosiderin.

Fig. 26.7 Head injury: contusions and haematomas. A severe blow to the frontal bone has resulted in contusions and haematomas in the frontal lobes. ‘Contrecoup’ contusions are present in the parietal lobes, and in the cerebellum.

Other forms of focal damage, e.g. tears of cranial nerves, pituitary stalk or brainstem, occur less frequently.

Secondary brain damage

Secondary brain damage occurs as a result of complications developing after the moment of injury. These complications often dominate the clinical picture, and are responsible for death in many cases:

Table 26.3 Mechanisms and clinical manifestations of traumatic intracranial haemorrhage

Outcome of non-missile head injury

Most patients with minor head injuries make a satisfactory recovery. However, only 20% of survivors of severe head injuries make a good recovery, while 10% remain severely disabled. Important causes of persisting debility are:

Open injuries

Open injuries cause direct trauma to the spinal cord and nerve roots. Perforating injuries can cause extensive disruption and haemorrhage, but penetrating injuries may result in incomplete cord transection which can be manifested clinically as the Brown–Séquard syndrome (hemisection of the cord resulting in an upper motor neurone lesion and loss of position and vibration sense on the affected side with loss of pain and temperature sense on the contralateral side, below the level of the injury—see Fig. 26.20).

Closed injuries

Closed injuries account for most spinal injuries and are usually associated with a fracture/dislocation of the spinal column which is usually demonstrable radiologically. Damage to the cord depends on the extent of the bony injuries and can be considered in two main stages:

Complications and outcome

Late effects of cord damage include:

The outcome of cord injuries depends mainly on the site and severity of the cord damage. Patients with incomplete lesions in the cauda equina have an almost normal life expectancy, while patients surviving a high cervical lesion have a much higher morbidity and mortality.

Intervertebral disc prolapse

Intervertebral disc prolapse (Ch. 25) occurs in two main ways:

In both instances, a tear in the annulus fibrosus allows the soft nucleus pulposus to herniate posteriorly. This usually takes place in a lateral direction, causing nerve root compression. Central herniation is less common, but can cause direct cord damage and may also compress the anterior spinal artery, resulting in infarction. Disc prolapse occurs most commonly at the C5/C6 and L5/S1 levels; nerve root compression in the latter results in sciatica.

Spondylosis

Spondylosis due to osteoarthritis (Ch. 25) of the vertebral column occurs commonly with age. It affects around 70% of adults over 40 years of age, and is usually accompanied by degenerative disc disease. It is characterised by bony outgrowths, known as osteophytes, on the upper and lower margins of the vertebral bodies. These may encroach upon the spinal canal or intervertebral foramina to produce nerve root pain which is exacerbated by movement.

Obstructive hydrocephalus

Obstructive hydrocephalus is by far the commonest form; it may be either congenital or acquired.

Acquired hydrocephalus

Acquired hydrocephalus can result from any lesion that obstructs the CSF pathway (Fig. 26.8). Expanding lesions in the posterior fossa are particularly prone to cause hydrocephalus, as the fourth ventricle and aqueduct are easily obstructed. Some lesions may cause intermittent obstruction, particularly colloid cysts of the third ventricle which may block the foramen of Monro. Obstructive hydrocephalus commonly results from the organisation of blood clot or inflammatory exudate in the CSF pathway following an episode of haemorrhage or meningitis (Fig. 26.9). Intermittent pressure hydrocephalus is thought to result from defective CSF absorption at the arachnoid villi.

Fig. 26.9 Longstanding hydrocephalus. The lateral ventricles are very dilated and contain a prominent choroid plexus (arrow). The overlying white and grey matter are atrophic. Fibrous adhesions are present in the ventricles posteriorly, suggestive of previous infection. In the same case, the cerebral aqueduct in the midbrain is completely obliterated by glial tissue as a consequence of a previous viral infection (arrow). This has resulted in obstructive hydrocephalus.

Cerebral infarction

The site and size of a cerebral infarct depend on the site and nature of the vascular lesion. Most infarcts occur within the cerebral hemispheres in the internal carotid territory, particularly in the distribution of the middle cerebral artery. Infarction of the corticospinal pathway in the region of the internal capsule is a common event, resulting in contralateral hemiparesis. Although many infarcts produce clinical symptoms, small infarcts may not result in any apparent neurological disturbance. These micro-infarcts are often found in apparently normal elderly individuals, but are also numerous in the brains of hypertensive patients. Multiple infarcts involving the cerebral cortex may result in dementia (p. 779).

Morphological features

At a very early stage after cerebral infarction, no naked-eye abnormalities are apparent. However, 24 hours after infarction the affected tissue becomes softened and swollen, with a loss of definition between grey and white matter. There may be considerable oedema around the infarct, resulting in a local mass effect. Within 4 days, the infarcted tissue undergoes colliquative necrosis. Histology shows infiltration by macrophages, which are filled with the lipid products of myelin breakdown. Reactive astrocytes and proliferating capillaries are often present at the edge of the infarct. Eventually, all the dead tissue is phagocytosed to leave a fluid-filled cystic cavity with a gliotic wall (Fig. 26.10). Some infarcts are haemorrhagic, possibly due to reflow of blood through anastomotic channels. Anterograde degeneration of nerve fibres occurs distal to the site of infarction, for example in the ipsilateral cerebral peduncle in infarcts involving the internal capsule.

Fig. 26.10 Cerebral infarct: cystic change. In this old infarct in the territory of the right middle cerebral artery, the necrotic tissue has been phagocytosed to leave a cystic cavity lined by glial tissue.

Intracranial haemorrhage

Intracerebral and subarachnoid haemorrhage together account for around 18% of strokes. Extradural and subdural haemorrhages usually occur following trauma and are considered in Table 26.3.

Intracerebral haemorrhage

The commonest cause of intracerebral haemorrhage is hypertensive vascular disease, in which haemorrhages occur most frequently in the basal ganglia (80% of cases), the brainstem, cerebellum and cerebral cortex. Most intracerebral haemorrhages occur in hypertensive adults over 50 years of age. The haematoma acts as a space-occupying lesion, causing a rapid increase in intracranial pressure and intracranial herniation (Fig. 26.11). In survivors, resorption of the haematoma eventually occurs, and a fluid-filled cyst with a gliotic wall is formed. The mortality from spontaneous intracerebral haemorrhage is greater than 80%, and many survivors suffer severe neurological deficit.

Fig. 26.11 Complications of intracerebral haemorrhage. An intracranial haemorrhage originating in the internal capsule on the left has ruptured into the ventricular system, which is filled with blood. The mass effect of the haematoma has resulted in a shift of adjacent structures to the opposite side.

The pathogenesis of spontaneous intracerebral haemorrhage is not fully understood. For many years, it was thought that most intracerebral haemorrhages in hypertensive patients occurred following rupture of micro-aneurysms on small arterioles, particularly on the lenticulostriate branch of the middle cerebral artery. Recent studies, however, have found that the ruptured vessels are arterioles, which show replacement of smooth muscle by lipids and fibrous tissue (lipohyalimosis), predisposing to rupture. Intracerebral haemorrhage in children and younger adults may occur as a consequence of trauma, or rupture of an arteriovenous malformation. In older adults, haemorrhage into the lobes of the brain may be due to amyloid depostion in the vessel walls (amyloid angiopathy), which is associated with Alzheimer’s disease (p. 779).

Subarachnoid haemorrhage

Subarachnoid haemorrhage usually occurs following rupture of a saccular or ‘berry’ aneurysm on the circle of Willis. Other causes are uncommon, but include trauma, hypertensive haemorrhage, vasculitis, tumours and disorders of haemostasis.

Saccular aneurysms

Saccular aneurysms occur in 1–2% of the general population, but are commoner in the elderly. Most cases of ruptured saccular aneurysm occur between 40 and 60 years of age; males in this age group are affected twice as often as females. Several predisposing factors for saccular aneurysms have been identified.

The role of hypertension in the pathogenesis of these lesions is uncertain, but it does appear that hypertensive patients are more likely to have multiple aneurysms than are normotensive patients. Local vascular abnormalities, such as atheroma, are important in the pathogenesis of saccular aneurysms by altering haemodynamics in affected vessels.

Saccular aneurysms are usually sited at proximal branching points on the anterior portion of the circle of Willis, particularly on the internal carotid, anterior communicating and middle cerebral arteries. Most are less than 10mm in diameter, but some may be partly filled by thrombus, which can obscure their true size on radiological studies (Fig. 26.12). Their pathogenesis is thought to relate to congenital defects in the smooth muscle of the tunica media at the site of an arterial bifurcation, where local haemodynamic factors act to produce a slowly enlarging aneurysm.

Fig. 26.12 Demonstration of a saccular aneurysm in vivo. This 3D digital subtraction angiogram shows a large grape-like saccular aneurysm (arrowhead) arising at the terminal region of the internal carotid artery (single arrow). The anterior cerebral arteries (double arrows) appear normal.

(Courtesy of Dr D Summers, Edinburgh.)

Clinicopathological features and prognosis

Subarachnoid haemorrhage often presents with the characteristic clinical history of sudden onset of severe headache. Blood accumulates in the basal cisterns and around the brainstem following rupture of a saccular aneurysm. Subarachnoid haemorrhage may be instantly fatal in as many as 15% of cases, with some patients dying later due to rebleed at the site of rupture, or arterial spasm (see below). One-third of survivors are permanently disabled as a consequence of hypoxic brain damage following haemorrhage.

Arterial spasm in the distal cerebral vasculature following rupture causes cerebral ischaemia and infarction, that is often accompanied by brain swelling due to oedema.

Hydrocephalus can occur acutely following rupture as blood accumulates in the basal cisterns, or at a later stage in survivors, where fibrous obliteration of the subarachnoid space or arachnoid granulations may occur.