Central and peripheral nervous systems

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 ). Neurones are highly specialised postmitotic cells that cannot be replaced. They are subject to unique metabolic demands, for example, maintaining an axon that may be up to 1 m in length, which makes neurones particularly vulnerable to a wide range of insults, for example, hypoxia and hypoglycaemia.

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 the ion channels allows an influx of sodium ions, which depolarises the membrane, forming an action potential that is transmitted rapidly down the axon by saltatory conduction. Transmission between neurones occurs at specialised junctions known as synapses (see Fig. 26.2 ). The most common excitatory neurotransmitter in the CNS is glutamate.

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

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.

Glial cells

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

• astrocytes

• oligodendrocytes

• ependymal cells

• choroid plexus cells.

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

• provision of a supportive framework for other cells in the CNS

• control of the neuronal microenvironment by influencing local neurotransmitter and electrolyte concentrations

• regulation of the blood–brain barrier by processes that are closely applied around capillary endothelium (see below)

• proliferation and enlargement in response to neuronal injury.

Oligodendrocytes are the most numerous cells in the CNS. On microscopy, they are visible as darkly staining nuclei located around neurones and nerve fibres (see Fig. 26.3 ). The most important function of oligodendrocytes is the synthesis and maintenance of myelin in the CNS, a lipid-rich protein that insulates myelin to facilitate rapid electrical conduction.

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 that may help regulate the flow of cerebrospinal fluid (CSF).

Choroid plexus cells form a cuboidal epithelial covering over the ventricular choroid plexus, where CSF is secreted.

Microglial cells

Microglia belong to the macrophage/monocyte system of phagocytic cells. They are normally quiescent, and inconspicuous on light microscopy, but can enlarge and proliferate in reaction to CNS injury, 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 contain fibroblast-like cells in the pia, arachnoid and dura mater, and arachnoidal cap cells, which form the main site of CSF absorption.

Blood vessels

The larger blood vessels in the CNS are similar in structure to those elsewhere; however, CNS capillaries differ from most other capillaries in several respects.

• They are nonfenestrated, with tight junctions between adjacent cells.

• Relatively few microvilli are present on the luminal surface of the endothelial cells, with only occasional pinocytotic vesicles present in the cytoplasm.

• The endothelial cell basement membrane is intimately surrounded by a network of astrocyte processes.

These special structural features are important constituents of the blood–brain barrier, a functional unit that controls the entry and exit of many substances — including proteins, ions, nonlipid-soluble compounds and drugs — to and from the CNS.

Neurones

Neurones can undergo various reactive changes to cell injury:

• central chromatolysis

• anterograde degeneration

• synaptic degeneration.

Central chromatolysis is a reaction that usually occurs in response to axonal damage ( Fig. 26.4 ). This reaction is accompanied by increased RNA and protein synthesis, suggesting a regenerative response.

Anterograde degeneration occurs as a result of axonal transection, and is usually accompanied by central chromatolysis (see Fig. 26.4 ). Degeneration of the distal part of the axon will occur following its separation from the intact perikaryon, for example, by transection. The myelin sheath surrounding the axon also fragments 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.

Synaptic degeneration occurs in many neurodegenerative disorders, for example, Alzheimer disease. Trans-synaptic neuronal atrophy may occur following the loss of afferent connections, for example, in neurones of the lateral geniculate body following damage to the optic nerve.

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 around areas of tissue damage, for example, at the edge of a cerebral infarct.

Microglia

Microglia and recruited blood monocytes are involved in the response to CNS damage, acting as phagocytes. When myelin is damaged, microglia ingest the breakdown products and become distended with droplets of lipid.

Diffuse brain swelling

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

Focal brain swelling

Expanding lesions of many types result in focal brain swelling, for example, cerebral abscesses, haematomas and intrinsic neoplasms. Expanding extrinsic lesions, for example, subdural haematomas and meningiomas, also exert a mass effect within the cranial cavity and act as SOLs.

Raised intracranial pressure

Raised intracranial pressure is an invariable consequence of expanding intracranial SOLs, as there is very little space within the rigid cranium to accommodate an enlarging mass. Initially, a phase of spatial compensation occurs by reductions in the CSF space and the blood volume within the skull. Pressure atrophy of the brain may occur around slow-growing extrinsic lesions, for example, meningiomas (see Fig. 26.36 ).

Any further increase in the volume of the intracranial contents will cause an abrupt increase in intracranial pressure. Characteristic signs and symptoms of raised intracranial pressure and their likely causes include:

• headache: due to compression of pain and stretch receptors around intracranial vessels and within the dura mater, usually worse on arising

• nausea and vomiting: due to pressure on vomiting centres in the brainstem

• visual disturbances: due to papilloedema, when axonal flow is impeded by raised pressure around the optic nerve

• impairment of consciousness, ranging from drowsiness to deep coma, related to the level of increased intracranial pressure

• ‘brain death’ when the intracranial pressure exceeds the cerebral arterial perfusion pressure.

Intracranial shift and herniation

Intracranial shift and herniation are the most important consequences of SOLs. They usually occur following a critical increase in intracranial pressure, which may be precipitated by withdrawing CSF at lumbar puncture. Lumbar puncture is contraindicated in any patient with raised intracranial pressure and a suspected intracranial SOL to prevent this potential complication.

Lateral shift of the midline structures is an early complication of supratentorial SOLs. Patients with acute lateral displacement of the brain have a depressed level of consciousness even in the absence of an intracranial herniation. The clinical features are summarised in Table 26.1 .

Herniations occur at several characteristic sites within the cranial cavity, depending on the location of the SOL ( Fig. 26.5 ). Axial displacement is frequently fatal because of secondary haemorrhage into the brainstem ( Fig. 26.6 ).

Epilepsy

Epileptic seizures may be focal or generalised ( p. 694 ), and are particularly common in patients with raised intracranial pressure due to cerebral abscesses and neoplasms.

Hydrocephalus

Hydrocephalus is a common complication of SOLs in the posterior fossa that compress the cerebral aqueduct and fourth ventricle ( p. 703 ).

Systemic effects

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

• hypertension and bradycardia

• pulmonary oedema

• gastrointestinal and urinary tract ulceration and haemorrhage

• acute pancreatitis.

Primary brain damage

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

Focal damage

The most common form of focal brain injury is contusions, which usually occur at an impact site, particularly if a skull fracture is present. Contusions are asymmetrical and may be more severe on the side opposite the impact — the ‘contrecoup’ lesion ( Fig. 26.7 ). Following injury, the brain moves within the skull and comes into contact with adjacent bone, resulting in local injury. Large contusions may be associated with intracerebral haemorrhage or cortical lacerations. Healed contusions are represented by wedge-shaped areas of gliosis that are yellow-brown due to the presence of haemosiderin. Severe forms of focal damage include tears of cranial nerves or the brainstem.

Secondary brain damage

Secondary brain damage results from complications developing after the moment of injury. These complications often dominate the clinical picture, and are frequently responsible for death.

• Intracranial haemorrhage. The mechanisms and clinical manifestations of traumatic intracranial haemorrhage are summarised in Table 26.2 .

  Table 26.2

  Mechanisms and clinical manifestations of traumatic intracranial haemorrhage

  Lesion	Mechanism	Clinical manifestations
  Extradural haematoma	Skull fracture with arterial rupture, e.g. middle meningeal artery	Lucid interval followed by a rapid increase in intracranial pressure
  Subdural haematoma	Rupture of venous sinuses or small bridging veins due to torsion forces	Acute presentation with a rapid increase in intracranial pressure
  		Chronic presentation with personality change, memory loss and confusion, particularly in the elderly
  Subarachnoid haemorrhage	Arterial rupture	Meningeal irritation with a rapid increase in intracranial pressure
  Intracerebral haemorrhage	Cortical contusions Rupture of small intrinsic vessels with intracerebral haematoma ‘Burst lobe’ with intracerebral haematoma contusions and subdural haematoma	May cause seizures Increased intracranial pressure with focal deficits; usually fatal Profound coma, usually rapidly fatal

• Traumatic damage to extracerebral arteries. Although uncommon, these are important because some cases can be treated surgically, for example, dissection of the internal carotid artery.

• Intracranial herniation. See above.

• Ischaemic brain damage. Ischaemic brain damage often results from severe systemic hypotension following blood loss, and raised intracranial pressure. Rarer causes include fat emboli and trauma to extracerebral vessels.

• Meningitis. This is particularly common in patients with an open skull fracture.

Outcome of nonmissile 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:

• posttraumatic epilepsy, which is the most common delayed complication of nonmissile head injury

• persistent vegetative state, in which patients remain severely neurologically impaired due to severe diffuse axonal injury and hypoxic brain damage

• posttraumatic dementia, due to severe neuronal loss and axonal damage.

Open injuries

Perforating injuries can cause extensive disruption and haemorrhage, but penetrating injuries may result in incomplete cord transection, which may result in the Brown–Séquard syndrome (flaccid paralysis and loss of position and vibration sense on the affected side, with contralateral loss of pain and temperature sense — see Fig. 26.21 ).

Closed injuries

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

• primary damage: contusions, nerve fibre transection, haemorrhagic necrosis

• secondary damage: extradural haematoma, infarction, infection, oedema.

Complications and outcome

Late effects of cord damage include:

• ascending and descending anterograde degeneration of damaged nerve fibres

• posttraumatic syringomyelia

• systemic effects of paraplegia: urinary tract and chest infections, pressure sores and muscle wasting.

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 with high cervical lesions have much higher morbidity and mortality.

Intervertebral disc prolapse

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

• disc rupture following strenuous exercise or sudden exertion in young adults

• disc herniation following minimal stress due to degenerative disc disease and spondylosis (see below) in older patients.

In both instances, a tear in the annulus fibrosus allows the soft nucleus pulposus to herniate laterally, causing nerve root compression. Central herniation is less common, but can cause direct cord damage. 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 affects around 70% of adults over 40 years of age, and is usually accompanied by degenerative disc disease. Bony outgrowths, known as osteophytes, develop 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 that is exacerbated by movement.

Obstructive hydrocephalus

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

Acquired hydrocephalus

Acquired hydrocephalus can result from any lesion that obstructs the CSF pathway (see Fig. 26.9 ). Expanding lesions in the posterior fossa are prone to cause hydrocephalus, as the fourth ventricle and aqueduct are small and easily obstructed. Some lesions may cause intermittent obstruction, for example, 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. 26.10 ). Intermittent pressure hydrocephalus is thought to result from defective CSF absorption at the arachnoid villi.

Cerebral infarction

Most infarcts occur within 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. Multiple cerebral infarcts may also result in dementia ( p. 698 ).

Pathological features

Around 24 hours after infarction, the affected tissue becomes softened and swollen, with loss of definition between grey and white matter. There may be oedema around the infarct, potentiating the local mass effect. Within 4 days, the infarcted tissue undergoes colliquative (liquifactive) necrosis. Histology shows infiltration by macrophages containing 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, leaving a cystic cavity with a gliotic wall ( Fig. 26.11 ). Some infarcts are haemorrhagic, due to reflow of blood through anastomotic channels. Anterograde degeneration of axons occurs distal to the site of infarction, for example, in the ipsilateral cerebral peduncle in infarcts involving the internal capsule.

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

Intracerebral haemorrhage occurs most frequently in the basal ganglia (80% of cases), the brainstem, cerebellum and cerebral cortex. Most occur in hypertensive adults over 50 years of age. The haematoma acts as an SOL, causing a rapid increase in intracranial pressure and intracranial herniation ( Fig. 26.12 ). In survivors, resorption of the haematoma eventually occurs, and a cyst with a gliotic wall is formed. The mortality from spontaneous intracerebral haemorrhage is greater than 80%, and many survivors suffer severe neurological deficits.

Most intracerebral haemorrhages occur following rupture of the lenticulostriate branch of the middle cerebral artery. Recent studies have found that the ruptured vessels are arterioles, which show replacement of smooth muscle by lipids and fibrous tissue (lipohyalinosis), 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 deposition in the vessel walls (amyloid angiopathy), which is associated with Alzheimer disease ( pp. 697-698 ).

Pathological features

Saccular aneurysms occur in 1% to 2% of the general population, but are more common in the elderly. Most patients with ruptured saccular aneurysm are between 40 and 60 years of age; males are affected twice as often as females. The role of hypertension in the pathogenesis of saccular aneurysms is uncertain, but it appears that hypertensive patients are more likely to have multiple aneurysms than are normotensive patients. Local vascular abnormalities, for example, atheroma, are also important. Their pathogenesis is thought to relate to 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.

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 10 mm in diameter, but some may be partly filled by thrombus, which can obscure their true size on radiological studies ( Fig. 26.13 ).

Bacterial meningitis

The clinical term ‘meningitis’ usually refers to inflammation in the subarachnoid space involving the arachnoid and pia mater, for example, leptomeningitis. However, inflammation of the meninges may involve predominantly the dura mater (pachymeningitis).

Diagnosis and complications of bacterial meningitis

Examination of the CSF following lumbar puncture is essential; the CSF changes in the CNS infections are summarised in Table 26.4 . The CSF in bacterial meningitis usually contains many organisms, although these are sometimes detected only on culture. In fatal cases, pus is present in the cerebral sulci and around the base of the brain, extending down around the spinal cord ( Fig. 26.14 ).

Table 26.4

Cerebrospinal fluid parameters in health and infection

	Cells	Protein (g/L)	Glucose (mmol/L)	Appearance
Normal	0–4 lymphocytes/mm 3	0.15–0.40	2.7–4.0	Clear and colourless
Bacterial meningitis	↑↑ polymorphs	↑	↓ or absent	Opaque and turbid
Tuberculous meningitis	↑ polymorphs initially, then lymphocytes	↑	↓ or absent	Clear or opalescent
Viral meningitis	↑ polymorphs initially, then ↑↑ lymphocytes	↑	Normal	Clear and colourless
Viral encephalitis	↑ polymorphs initially, then lymphocytes	↑	Normal	Clear and colourless

The meningeal and superficial cortical blood vessels are congested, often with small foci of perivascular haemorrhage. The CSF is usually turbid, even in the ventricles, which often show signs of acute inflammation with fibrin deposition. Common complications of bacterial meningitis are:

• cerebral infarction

• obstructive hydrocephalus

• cerebral abscess

• subdural empyema

• epilepsy.

Cerebral abscess

A cerebral abscess usually develops from an acute suppurative encephalitis in three ways.

• Direct spread of infection, usually Gram-negative bacilli, from the paranasal sinuses or middle ear.

• Septic sinus thrombosis due to spread of infection from the mastoid cavities or middle ear via the sigmoid sinus.

• Haematogenous spread, for example, in patients with infective endocarditis (particularly in congenital heart disease) or bronchiectasis. Haematogenous abscesses are most often found in the parietal lobes, and are often multiple.

Abscess formation occurs when suppuration is accompanied by local tissue destruction ( Fig. 26.15 ). A pyogenic membrane is formed and the abscess develops a capsule composed of granulation tissue, surrounded by reactive gliosis. The adjacent brain is markedly oedematous, containing perivascular collections of lymphocytes and plasma cells. Cerebral abscesses frequently enlarge and become multiloculate.

The clinical presentation is similar to that of acute bacterial meningitis, but focal neurological signs, epilepsy and fever are more common. Abscesses act as SOLs; a lumbar puncture should not be performed as an initial investigation on a patient with a suspected cerebral abscess as this may precipitate intracranial herniation. Antibiotic therapy is useful in the treatment of abscesses in an early stage, but surgical aspiration or excision is usually necessary once a capsule has formed. Complications of cerebral abscesses include:

• meningitis

• intracranial herniation

• focal neurological deficit

• epilepsy.

Tuberculosis

Tuberculous infection of the CNS is always secondary to infection elsewhere in the body, usually in the lungs. CNS involvement takes two main forms: tuberculous meningitis and tuberculomas.

Syphilis

Syphilis is now rare in the UK. After the initial infection, Treponema pallidum gains access to the CNS by haematogenous spread. CNS involvement includes:

• clinically silent meningitis during primary and secondary stages

• meningeal thickening in the tertiary stage, causing cranial nerve palsies

• gummas (focal inflammatory lesions) causing cerebral or spinal compression

• tabes dorsalis due to degeneration of dorsal spinal columns.

Viral meningitis

Although acute in onset, viral meningitis is usually clinically less severe than bacterial meningitis. In most instances, the viruses reach the CNS by haematogenous spread. Common organisms are:

• echovirus 7, 11, 24, 33

• Coxsackie B1 to 5

• Coxsackie A9

• mumps virus

• other enteroviruses.

Characteristic changes are present in the CSF (see Table 26.4 ), and serology or polymerase chain reaction (PCR) techniques are often used to confirm the diagnosis.

Viral meningitis is characterised by infiltration of the leptomeninges by mononuclear cells (lymphocytes, plasma cells and macrophages), along with perivascular lymphocytic cuffing of blood vessels in the meninges and superficial cortex.

Viral encephalitis

Infection of the brain is a well-recognised complication of several common viral illnesses, for example, measles and mumps. Most cases are mild, self-limiting conditions, but others, for example, rabies and herpes simplex type I infections, result in extensive tissue destruction and are often fatal. Herpes simplex encephalitis is the most common variety of acute viral encephalitis in the UK. Despite these differences in severity, all viral infections of the brain and spinal cord produce similar pathological changes in the CNS:

• mononuclear cell infiltration by lymphocytes, plasma cells and macrophages; this is often noticeable as perivascular cuffing which usually extends into the parenchyma ( Fig. 26.16 )

  

• reactive hypertrophy and hyperplasia of astrocytes and microglia

• cell lysis (cytolytic viral infection) and phagocytosis of cell debris by macrophages; when neurones are involved, for example, in poliovirus infection, this process is known as neuronophagia

• viral inclusions, which can be present in infected neurones, for example, Negri bodies in rabies, or glia.

Latent viral infections

Antenatal viral infections

The fetal CNS can be damaged during the first trimester of pregnancy following maternal infection with cytomegalovirus or rubella virus; the latter is becoming less common following immunisation in schoolgirls. Both viruses cause a necrotising encephalomyelitis resulting in developmental damage and microcephaly.