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.

Bacterial meningitis

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

Diagnosis and complications of bacterial meningitis

Examination of the CSF by lumbar puncture is essential in each case; the main CSF changes in the CNS infections are listed in Table 26.6. 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. 26.13).

Table 26.6CSF parameters in health and infection

Fig. 26.13 Bacterial meningitis: basal exudate. In this example of pyogenic meningitis due to Escherichia coli, a dense acute inflammatory exudate is present around the brainstem, cerebellum and adjacent structures at the base of the brain. Obstruction of the fourth ventricle exit foramina resulted in acute hydrocephalus in this case.

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 following:

Abscess formation in the brain, as in other tissues, occurs when pus formation is accompanied by local tissue destruction (Fig. 26.14). A pyogenic membrane is formed, and the abscess develops a capsule composed of granulation tissue, and reactive astrocytes and their fibrillary processes. The adjacent brain is markedly oedematous, containing a perivascular inflammatory infiltrate of lymphocytes and plasma cells. Cerebral abscesses frequently enlarge and become multiloculate.

Fig. 26.14 Cerebral abscess: space-occupying lesion. A large abscess in the left parietal lobe is surrounded by oedematous white matter. This has acted as an expanding lesion and displaced the midline structures to the right. Death in this case resulted from a transtentorial brainstem herniation, with a characteristic haemorrhage in the central pons.

The clinical presentation is similar to that of acute bacterial meningitis, but focal neurological signs, epilepsy and fever are common manifestations. Abscesses act as space-occupying lesions and it is important to remember that a lumbar puncture must never be performed as an initial investigation on a patient with a suspected cerebral abscess (or other space-occupying lesion) as this may precipitate a fatal intracranial herniation. Antibiotic therapy is useful in the treatment of abscesses at an early stage, but once a capsule has formed surgical aspiration or excision is usually necessary. Complications of cerebral abscesses include:

Tuberculosis

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

Syphilis

Syphilis is now rare; it occurs most frequently in male homosexuals. After the initial infection, Treponema pallidum gains access to the CNS by haematogenous spread. CNS involvement includes:

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:

Characteristic changes are present in the CSF (Table 26.6) and serology or 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. Most cases are mild, self-limiting conditions, but others, such as rabies and herpes simplex type I infections, result in extensive tissue destruction and are often fatal. Herpes simplex encephalitis is the commonest 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:

Fig. 26.15 Acute viral encephalitis due to herpes simplex virus. A blood vessel (V) in the grey matter is surrounded by a dense aggregate of lymphocytes and plasma cells, which have crossed the blood–brain barrier and migrated into the surrounding temporal lobe.

Latent viral infections

Antenatal viral infections

The commonest viruses to infect the CNS in utero are cytomegalovirus and rubella virus; the latter is becoming less common following immunisation in schoolgirls. Both viruses cause a necrotising encephalomyelitis resulting in developmental malformations and microcephaly, particularly when infection has occurred during the first trimester of pregnancy.

Persistent viral infections

Persistent viral infections are extremely rare diseases in which infection of the CNS occurs in early life, with neurological disease occurring years later.

Human immunodeficiency virus (HIV) infection

The CNS is commonly involved in HIV infection both in the acquired immune deficiency syndrome (AIDS) and in pre-AIDS stages. The mechanisms by which HIV gains access to the CNS are uncertain; many research workers believe that the virus is carried across the blood–brain barrier in monocytes or macrophages (the ‘Trojan horse’ theory). Once in the CNS, the virus appears to reside predominantly in microglial cells and multinucleate cells of the macrophage/microglial type (Fig. 26.16). Evidence for direct infection of nerve cells and other glia is not fully established and awaits further research.

Fig. 26.16 Giant cell encephalitis in AIDS. The giant cells (arrows) in the cerebral cortex are derived from macrophages which are infected with HIV and express viral proteins on the cell surface.

Patients with HIV infection frequently present with neurological abnormalities and at the time of death at least 80% of AIDS patients have CNS pathology resulting from:

Other organisms important in infecting immunosuppressed patients are listed on page 770. Dementia may occur in the absence of overt immunodeficiency (i.e. AIDS); diagnosis can then be made by serology on the blood, or by PCR analysis of CSF.

Prion diseases

Prion diseases are a group of rare transmissible neurodegenerative disorders also known as spongiform encephalopathies. One of these disorders, kuru, was at one time restricted geographically to a small number of islands in the East Indies and appeared to result from ritualistic endocannibalism; eating the brain of an infected individual resulted in the onset of the disease many years later. The disease is now virtually extinct.

Creutzfeldt–Jakob disease

Creutzfeldt–Jakob disease (CJD) usually presents in adult life as a rapidly progressive dementia often accompanied by myoclonus, visual abnormalities and ataxia. It occurs as a sporadic disorder in 1–2 in 1 000 000 per year worldwide; familial and iatrogenic (see below) forms occur more rarely. No specific treatment is available and the disease is uniformly fatal.

In 1968, the disease was found to be transmissible to primates, and further studies have found the infectious agent to be of very small size and highly resistant to heat, ultraviolet light and most chemicals. Its precise nature is as yet unknown. Increasing evidence supports the prion hypothesis, which states that the agent is composed entirely of a modified host protein, prion protein, which accumulates in the brain. Cases of iatrogenic human–human transmission of CJD have been recorded, attributed to implantation of intracerebral electrodes, corneal or dura mater grafts and, most recently, the administration of growth hormone extracted from human pituitary glands. These are, however, rare occurrences and the source of infection in most cases is unknown.

The brain from affected individuals often shows widespread cerebral cortical atrophy. Microscopy of the cortex shows a loss of neurones and a reactive proliferation of astrocytes. Numerous small vacuoles are present within neuronal and astrocytic processes, hence the term spongiform encephalopathy (Fig. 26.17). No inflammatory reaction occurs in this group of disorders.

Fig. 26.17 Creutzfeldt–Jakob disease. The cerebral cortex shows a characteristic spongiform vacuolation (arrows) accompanied by neuronal loss and reactive astrocytosis.

Variant Creutzfeldt–Jakob disease

A new variant form of CJD was identified in the UK in 1996, affecting young patients (average age 28 years). This new disease appears to result from the transmission of the bovine spongiform encephalopathy (‘mad cow’ disease) agent to humans, probably via contaminated beef products. Over 160 cases of variant CJD have been identified in the UK so far, including three cases that were transmitted by blood transfusion from infected donors, but the likely number of future cases is uncertain.

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis is an infrequent complication of measles, mumps and rubella infections, and may also occur following vaccination for smallpox and rabies. The onset of the disease is sudden, usually occurring 5–14 days after the initial infection or inoculation. This appears to be a T-cell-mediated delayed hypersensitivity response to a protein component of myelin, but the mechanism of sensitisation is unknown. The prognosis is good, with a complete recovery in 90% of cases.

Acute haemorrhagic leukoencephalitis is a related but more severe disorder which is accompanied by immune complex deposition in cerebral vessel walls and is usually rapidly fatal.

Clinical features

Most cases present between 20 and 40 years of age. The disease is slightly more common in females than in males, and the onset is usually characterised by the sudden development of a focal neurological deficit which spontaneously recovers. The relative incidences of initial manifestations are:

The disease follows a characteristic relapsing and remitting course. Recovery from each episode of demyelination (relapse) is usually incomplete, and a progressive clinical deterioration ensues. The effects of demyelination may be detected electrophysiologically as delays in the latencies of visual and auditory evoked responses because demyelinated axons conduct nerve impulses more slowly than normal. CSF analysis in multiple sclerosis shows oligoclonal bands of IgG, which is synthesised by plasma cells in the CNS. The progress of the disease is variable. Some patients (particularly children) follow a rapidly progressive course, while others may survive for over 20 years with only minor disability. Most patients die as a result of urinary tract infections, chest infections or pressure sores rather than during an acute episode of demyelination.

Morphological features

The primary abnormalities in multiple sclerosis are confined to the CNS; the peripheral nervous system is not involved. Patients with multiple sclerosis have numerous demyelinated plaques in the brain and spinal cord (Fig. 26.18), often closely related to veins and venules. In early lesions, the plaques are soft and pink with ill-defined boundaries. Histologically, there is myelin breakdown and phagocytosis by macrophages. Oedema is usually present, suggesting a local defect in the blood–brain barrier. Perivascular cuffing with inflammatory cells (plasma cells and T-lymphocytes) is widespread in the acute plaque. The plasma cells synthesise immunoglobulins, which can be detected in the CSF (see above). T-lymphocytes have also been identified at the edges of acute plaques.

Fig. 26.18 Multiple sclerosis: demonstration of demyelination in vivo. Coronal MRI image showing the typical appearances of multiple sclerosis plaques, particularly in a periventricular location (single arrow) and in the right middle cerebellar peduncle (double arrow).

(Courtesy of Dr D Summers, Edinburgh.)

As myelin breakdown eventually subsides, a reactive gliosis is established, giving rise to a chronic plaque. These lesions consist of sharply defined, grey, lucent areas of demyelination in which oligodendrocytes are scarce or absent. The inflammatory infiltrate also subsides, sometimes leaving small numbers of perivascular lymphocytes at the edge of chronic plaques (Fig. 26.19). Although it appears that oligodendrocytes have the capacity to proliferate in plaques, successful remyelination of established plaques probably never occurs. Axonal damage begins early in multiple sclerosis and correlates with the inflammatory activity in the white matter, contributing to progressive neurological debility.

Fig. 26.19 Multiple sclerosis: chronic plaque. The chronic plaque consists of a sharply defined area of myelin loss (which appears pale in this preparation) containing fibrillary astrocytes. A few lymphocytes and macrophages are present around blood vessels (V) in the plaque. Normal myelinated white matter appears blue.

Leukodystrophies

Although included as demyelinating conditions, it is known that most leukodystrophies result from a failure to synthesise normal myelin (sometimes called ‘dysmyelination’). Two of these disorders—metachromatic leukodystrophy and Krabbe’s globoid cell leukodystrophy—are due to inherited lysosomal enzyme deficiencies, and can be diagnosed antenatally. Others, such as adrenoleukodystrophy, are the result of an inherited abnormality in lipid metabolism, while in others the cause is unknown.

Methanol and ethanol

Both methanol and ethanol are toxic to the CNS. Acute poisoning with methanol can result in sudden death with multiple haemorrhagic lesions in the cerebral hemispheres, while chronic ingestion results in degeneration of neurones, e.g. in the retina, where loss of ganglion cells is accompanied by optic nerve atrophy. Ethanol can cause a wide range of CNS disorders (Table 26.8).

Table 26.8 Consequences of excessive ethanol intake on the CNS

Drugs

Drugs affecting the CNS can be considered in two main groups:

Drugs affecting CNS development include phenytoin and trimethadione, which can cause microcephaly and other congenital abnormalities following maternal ingestion. Drugs affecting the mature CNS include vincristine, which may cause axonal neuropathy.

Metals and industrial chemicals

Metals and industrial chemicals capable of affecting the CNS are listed in Table 26.9.

Table 26.9 Metal and industrial chemical toxins affecting the CNS

Malnutrition

Severe malnutrition may result in irreversible brain damage, particularly if it occurs in infancy during periods of CNS myelination, as the lack of normal myelin development cannot be reversed at a later date. Malnutrition later in life, e.g. kwashiorkor (Ch. 7), may result in encephalopathy and ultimately lead to coma. The underlying mechanisms in these events are uncertain, but may result from severe electrolyte disturbances.

Vitamin deficiency

The major vitamin deficiency states (Ch. 7) affecting the nervous system are shown in Table 26.10. The most important of these are discussed below.

Table 26.10 Major vitamin deficiency states affecting the nervous system

Vitamin B₁₂ (cyanocobalamin) deficiency

Vitamin B₁₂ deficiency is an important condition that can result from a variety of disorders. The pathogenesis of the CNS damage is unknown; impairment of CNS amino acid and fatty acid metabolism has been implicated. In severe cases, there is extensive degeneration of the posterior columns and lateral corticospinal tracts in the spinal cord (Fig. 26.20); this process is referred to as subacute combined degeneration of the spinal cord. The cerebral hemispheres are involved to a lesser extent. If replacement therapy is commenced at an early stage, the degenerative process is reversible. Longstanding cases show irreversible axonal damage accompanied by a reactive fibrillary gliosis.

Fig. 26.20 Sites of degenerations in the spinal cord. 1. Dorsal columns, involved in subacute combined degeneration, Friedreich’s ataxia and tabes dorsalis. 2. Anterior horn cells, involved in motor neurone disease and spinomuscular atrophy. 3. Lateral corticospinal tracts, involved in motor neurone disease, subacute combined degeneration and Friedreich’s ataxia. 4. Ventral corticospinal tracts, involved in motor neurone disease. 5. Spinocerebellar tracts, involved in Friedreich’s ataxia.

Wilson’s disease

Wilson’s disease, a disorder of copper metabolism, is inherited as an autosomal recessive condition. In some patients, liver disease is severe (Ch. 16) and may result in hepatic encephalopathy. In others, neurological signs predominate with tremor, rigidity and chorea; these abnormalities result from a marked loss of neurones in the basal ganglia, particularly the putamen. Deposition of copper in the cornea results in the characteristic Kayser–Fleischer ring.

Cranial involvement

Encephalocele and cranial meningocele usually occur in the occipital region, with herniation of the posterior cerebral hemispheres and their coverings respectively through a defect in the skull.

Anencephaly is the commonest of the neural tube defects. It is thought to occur when the developing brain is exposed to amniotic fluid as its coverings fail to develop. The calvaria is usually absent, but the base of the skull is thickened and partly covered by a mass of vascular granulation tissue. The anterior pituitary gland is present but hypoplastic, and several associated visceral and limb abnormalities have been described. The condition is fatal and often results in spontaneous abortion.

Arnold–Chiari malformation

Arnold–Chiari malformation is a complex disorder involving the cerebellum, brainstem and spinal cord, and is the commonest congenital malformation in the posterior fossa. It is often associated with a meningomyelocele. The main features are illustrated in Figure 26.22.

Fig. 26.22 Arnold–Chiari malformation: brain and cord abnormalities. The cerebellar tonsils (C) are displaced downwards from the shallow posterior fossa below the level of the foramen magnum (arrowheads). The brainstem is elongated and a syrinx (S) is present in the spinal cord commencing at the level of the third cervical vertebral body.

(Magnetic resonance image: courtesy of Professor B S Worthington, Nottingham.)

These abnormalities result in an obstructive hydrocephalus, usually of the communicating type (p. 759). There is no entirely satisfactory explanation for the Arnold–Chiari malformation.

Dandy–Walker malformation

Dandy–Walker malformation is the second most important congenital abnormality affecting the posterior fossa. The cerebellar hemispheres are of normal size, but the vermis is absent or hypoplastic. The fourth ventricle is markedly distended and forms a cyst-like structure. This results in obstructive hydrocephalus, which may be detectable antenatally by ultrasonography. The aetiology and pathogenesis of this malformation are unknown.

Agenesis and dysgenesis

Agenesis and dysgenesis may involve almost any structure within the CNS, but the commonest sites affected are the corpus callosum and the olfactory bulbs and tracts (arhinencephaly). These lesions may occur in isolation or in association with other malformations, for example agenesis of the corpus callosum with the Dandy–Walker malformation, and arhinencephaly with holoprosencephaly, a complex disorder of forebrain diverticulation.

Disorders of cell migration and corticogenesis

Failure of neuronal migration during CNS development results in a number of structural disorders, of which the most important are:

Destructive lesions

Destructive lesions occur most frequently in the developing CNS as a consequence of maternal infections and hypoxia. Extensive destruction of tissue may result in microcephaly, but focal lesions may also occur, such as ulegyria, with severe loss of neurones in the cerebral cortex.

Phakomatoses

Phakomatoses are a group of autosomal dominant inherited neurocutaneous disorders that result in CNS malformations. Important members of this group include neurofibromatosis, tuberous sclerosis and von Hippel–Lindau syndrome.

Chromosomal abnormalities

Chromosomal abnormalities frequently result in mental retardation. CNS malformations are often present in such cases, and are sometimes of sufficient severity to cause permanent disability or death. The best characterised of these disorders include Down’s syndrome, the principal features of which are:

Morphological features

The brain is reduced in weight, often to 1100 g, and shows cortical atrophy which is often most marked in the frontal and temporal lobes. There is loss of both cortical grey and white matter, with compensatory dilatation of the ventricular system (secondary hydrocephalus, Fig. 26.26). The cerebellum and spinal cord appear normal.

Fig. 26.26 Alzheimer’s disease cortical atrophy. The brain in Alzheimer’s disease shows severe cortical atrophy with narrowing of the gyri and widening of the sulci. White matter loss is accompanied by dilatation of the ventricular system (compensatory hydrocephalus).

The characteristic histological changes in Alzheimer’s disease are most pronounced in the limbic system (amygdala, entorhinal cortex and hippocampus) and cerebral cortex. The severity of these changes correlates with the clinical severity of the dementia. The histological hallmarks of Alzheimer’s disease are A-beta amyloid plaques and neurofibrillary tangles.

A-beta amyloid plaques

A-beta amyloid plaques are best demonstrated in specially stained histological sections of the CNS (Fig. 26.27A). They occur most frequently in the amygdala, hippocampus and cerebral cortex. These plaques can measure up to 200µm in diameter, and in their earliest stages comprise a collection of dilated presynaptic neuronal processes, which contain many organelles, around a diffuse aggregate of amyloid material. As the plaques mature, they enlarge and develop a core of A-beta amyloid protein, which eventually forms the major component of the ‘burnt-out’ plaque. Reactive astrocytes and microglia are usually present at the periphery of the plaque.

Fig. 26.27 Plaques and tangles in Alzheimer’s disease. The amyloid plaques in Alzheimer’s disease are composed of the A-beta protein, and form irregular rounded masses (brown) in the extracellular matrix in the cerebral cortex. In Alzheimer’s disease, abnormally phosphorylated tau protein (brown) accumulates intracellularly in neurofibrillary tangles (arrows) and in dystrophic neurites (arrowhead).

Aetiology and pathogenesis

Genetic factors are of major importance in the aetiology of Alzheimer’s disease in both familial and sporadic forms. Increasing evidence supports a primary role for A-beta amyloid in the pathogenesis of Alzheimer’s disease. A-beta amyloid is formed as part of the ‘amyloid cascade’ from APP (Fig. 26.25). This explains why individuals with trisomy 21 (Down’s syndrome) develop accelerated Alzheimer-like changes in the CNS as a consequence of their extra APP gene load.

Pathogenesis

The pathogenesis of most CNS neoplasms is unknown, but the following factors have been studied:

Classification

As in other organs, tumours of the CNS are classified according to their cellular differentation and presumed cell of origin (Table 26.13).

Table 26.13 Classification of CNS tumours according to presumed cell of origin

Clinicopathological features

Brain tumours may present clinically in two main ways:

Unlike neoplasms arising in other tissues, primary CNS neoplasms virtually never metastasise to other organs; the reasons for this are not clearly understood. However, infiltration of adjacent tissues both within the nervous system and its coverings (including the skull) is common, for example in meningioma, and seeding to remote parts of the nervous system by the CSF pathway is an important means of spread for certain intrinsic tumours, for example medulloblastomas. Spread by seeding can sometimes occur down a ventriculoperitoneal shunt, resulting in intra-abdominal tumour deposits.

Astrocytomas

Astrocytomas account for 10% of all primary CNS tumours in adults, but are relatively more frequent in children (Fig. 26.29). They commonly arise in the cerebellum in children, and in the cerebral hemispheres in adults. Astrocytomas are usually classified according to the predominant cell type and degree of differentiation (Fig. 26.30). It is thought that many anaplastic astrocytomas arise as a consequence of dedifferentiation within a pre-existing astrocytic neoplasm. The prognosis for patients with astrocytomas (and gliomas generally) depends on the degree of tumour differentiation, the age of the patient at diagnosis, and the site and size of the neoplasm.

Fig. 26.30 Astrocytoma. In this well-differentiated cerebral astrocytoma, most of the cells bear numerous cytoplasmic processes which are arranged around blood vessels in a manner similar to astrocytic processes in normal grey matter.

Glioblastoma

Glioblastoma accounts for 30% of all primary CNS tumours in adults, but is extremely rare in children. Most arise in the white matter of the cerebral hemispheres (Fig. 26.6). As its name implies, this neoplasm is characterised histologically by a pleomorphic cell population (Fig. 26.31). Although it is accepted that glioblastomas may arise de novo, it seems likely that many of these neoplasms arise as a consequence of dedifferentiation within a pre-existing astrocytic glioma. Dedifferentiation is accompanied by, or is the result of, a series of genetic events (Fig. 26.32). Mitotic activity in glioblastomas is abundant, and vascular endothelial proliferation is prominent. These features suggest a rapid growth rate; most patients die within 1 year of diagnosis.

Fig. 26.31 Glioblastoma. Areas of necrosis (arrows) are a characteristic feature of this neoplasm, and are usually surrounded by the nuclei of small malignant cells. The neoplastic cell population is pleomorphic, and also includes multinucleate cells. Vascular endothelial proliferation is another characteristic histological feature.

Fig. 26.32 Molecular genetic abnormalities in glioma progression.

Oligodendroglioma

Oligodendroglioma accounts for 3% of all primary CNS neoplasms in adults, but is rare in children. Oligodendrogliomas are usually ill-defined, infiltrating neoplasms, arising in the white matter of the cerebral hemispheres. Histologically, oligodendrogliomas present a spectrum of appearances which may be graded in a similar manner to astrocytomas. In a well-differentiated tumour, the neoplastic cells are small, rounded and uniform with a clear cytoplasm and prominent cell membrane. Small foci of calcification are common, and a characteristic interweaving vascular pattern is often present. Oligodendrogliomas exhibit a different set of genetic abnormalities to astrocytic gliomas, with losses of chromosomes 1p and 19q.

Ependymoma

An ependymoma arises from an ependymal surface, usually in the fourth ventricle, and projects into the CSF pathway (Fig. 26.33). Most ependymomas are well differentiated, and extensive invasion of adjacent CNS structures is uncommon. A special variant, the myxopapillary ependymoma, occurs in the cauda equina region in adults.

Fig. 26.33 Ependymoma: ventricular obstruction. The ependymoma (E) arising from the lining of the fourth ventricle has almost totally obstructed the CSF pathway and produced obstructive hydrocephalus. This results in characteristic clinical features that are common presenting symptoms for this group of neoplasms.

Choroid plexus papilloma

An uncommon intraventricular papillary growth, choroid plexus papilloma is most often found in a lateral ventricle and usually presents with obstructive hydrocephalus. Although showing little tendency to infiltrate locally, spread via the CSF may occur.

Primitive neuroectodermal tumours

The commonest variety of the primitive neuroectodermal group of tumours is the medulloblastoma, which arises in the cerebellum in children. The growth rate is rapid, and extensive local infiltration is common, often resulting in obstructive hydrocephalus. Meningeal infiltration frequently occurs and CSF seeding is common. As the name implies, these tumours are composed of poorly differentiated neuroepithelial cells which consist of small round nuclei surrounded by a scanty rim of cytoplasm. Mitotic figures are numerous, and evidence of differentiation into mature cell types, such as neurones or glia, is occasionally present. The prognosis for this group of tumours in children has improved in recent years as a consequence of improved treatment with radiotherapy; the 5-year survival rate is around 60%.

Haemangioblastoma

Haemangioblastoma is an uncommon neoplasm arising most often in the cerebellum and forming a well-defined, frequently cystic mass. Histologically, the tumour is composed of blood vessels, separated by stromal cells with clear cytoplasm containing lipid. CNS haemangioblastomas are an important component of von Hippel–Lindau syndrome, an autosomal dominant inherited disease with a genetic locus on chromosome 3p.

Lymphoma

Although an uncommon CNS tumour, there is much current interest in primary CNS lymphomas because of their greatly increased frequency of occurrence in immunosuppressed patients, for example in cardiac and renal transplant patients and in the acquired immune deficiency syndrome (AIDS). Recent studies have implicated the Epstein–Barr virus in the pathogenesis of these neoplasms. Most primary CNS lymphomas are ill-defined masses arising in the white matter or the cerebral hemispheres. Histologically, most are high-grade, non-Hodgkin’s lymphomas of B-cell type. Accordingly, the prognosis is poor and most patients are dead within 2–3 years.

Tumours of neuronal cells

Tumours comprising neuronal elements are rare; they occur most commonly around the region of the third ventricle in children. In gangliocytomas, the neoplastic cells all resemble mature neurones, but gangliogliomas include neoplastic glial cells (usually astrocytic cells).

Miscellaneous cysts

A variety of cystic lesions occur in the CNS which, although not all neoplastic, often present clinically with symptoms and signs similar to those of CNS tumours. Examples include:

Meningiomas

Meningiomas account for around 18% of intracranial neoplasms in adults; female patients outnumber males by 2:1. Meningiomas arise from cells of the arachnoid cap (a component of arachnoid villi). The most frequent sites are the parasagittal region, sphenoidal wing, olfactory groove and foramen magnum. Meningiomas are smooth lobulated masses, which are broadly adherent to the dura. Infiltration of the adjacent dura and overlying bone is not uncommon, but invasion of the brain is exceptionally rare. The brain, however, may be markedly compressed by a meningioma, resulting in considerable anatomical distortion (Fig. 26.34). Histologically, meningiomas display a variety of patterns, the most characteristic of which includes sheets of fusiform cells in a composite solid and whorled pattern. Small foci of calcification (psammoma bodies) are common.

Fig. 26.34 Meningioma: cerebral compression. Meningiomas do not usually invade CNS structures, but may produce clinical manifestations by compression of the adjacent brain. This neoplasm has the lobulated surface characteristic of meningiomas, and is sharply demarcated from the cerebrum.

Occasional meningiomas are frankly malignant and may metastasise outside the CNS, for example to the lung.

Schwannoma

As the name suggests, schwannomas derive from Schwann cells in the nerve sheath of the intracranial or intraspinal roots to sensory nerves. By far the commonest site is the vestibular branch of the 8th cranial nerve in the region of the cerebello-pontine angle; such neoplasms are often known as ‘acoustic neuromas’. As with meningiomas, schwannomas occur most frequently in adults, and are commoner in females. Bilateral 8th nerve tumours commonly occur in patients suffering from neurofibromatosis type 2. Histologically, schwannomas exhibit two main patterns: densely packed spindle-shaped cells with frequent nuclear palisading, and more loosely structured areas with a myxoid stroma which may contain cyst. Malignant change is very uncommon in these tumours.

Neurofibromas

In the CNS, neurofibromas usually arise on the dorsal nerve roots of the spinal cord, and occur most frequently in patients suffering from neurofibromatosis. Unlike schwannomas, neurofibromas are not encapsulated but tend to involve an entire nerve root, producing a localised or diffuse expansion (plexiform neurofibroma). Histologically, neurofibromas consist of a mixture of Schwann cells and fibroblasts, forming bundles of elongated cells with characteristically ‘wavy’ nuclei.

Compression and invasion

Tumours arising in adjacent organs may compress and invade the CNS, producing localising clinical signs, or presenting as space-occupying lesions. The commonest examples involving the brain are pituitary adenomas, which frequently cause visual impairment due to pressure on the optic chiasm.

Metastasis

The CNS is a common site for metastases, which may occur by haematogenous or direct spread. The commonest neoplasms to metastasise to the CNS are carcinomas of the breast, bronchus, kidney and colon, and malignant melanomas. Metastases often occur at the boundary between grey and white matter (Fig. 26.35) and may present as space-occupying lesions with or without focal signs. Metastatic carcinoma sometimes infiltrates the subarachnoid space producing ‘carcinomatous meningitis’. Patients with this condition present with the symptoms of subacute meningitis, often with multiple cranial nerve palsies. Metastatic deposits within the spinal cord are uncommon, but extradural metastases occur frequently and may present with paraplegia. CNS involvement occurs commonly in acute leukaemias and non-Hodgkin’s lymphomas (Ch. 22) with infiltration of the subarachnoid space and parenchyma. The prognosis for patients with a metastatic neoplasm within the CNS is extremely poor.

Fig. 26.35 Cerebral metastases: malignant melanoma. The darkly pigmented metastases from a malignant melanoma are present at several sites within the brain, mostly at junctions between grey and white matter. This is a characteristic pattern for metastases within the CNS.

Duchenne dystrophy

Duchenne dystrophy is an X-linked disorder affecting 1 in 3000–5000 live male births. Approximately one-third of cases represent new mutations. The gene for this disorder has been located to the p21 region of the X chromosome. The gene product, dystrophin, is a protein normally present at the interface between the cytoplasm and the muscle cell membrane. Gene deletions in Duchenne dystrophy result in a deficiency of dystrophin in muscle fibre membranes, causing muscle fibre damage by disruption of the cell membrane, leading to uncontrolled entry of calcium into the cell. Further understanding of the genetic defects in this disorder will allow for a fuller knowledge of its pathogenesis and hence potential for treatment.

The disease usually presents between 2 and 4 years of age, with proximal muscle weakness and pseudohypertrophy of the calves. The serum creatine phosphokinase (CPK) is elevated in the early stages of the disease, and is sometimes also elevated in female carriers. Most patients die before the age of 20, usually of the cardiomyopathy that occurs as part of this condition.

The characteristic biopsy findings are abnormal variation in the diameter of the muscle fibres, with many fibres showing hyaline degeneration or necrosis, with attempts at regeneration (Fig. 26.39). Partial or complete absence of dystrophin can be demonstrated by immunohistochemistry or western blotting of muscle biopsies. Eventually, as the muscle fibre destruction progresses, the muscle is almost totally replaced by fat and connective tissue.

Fig. 26.39 Muscle biopsy in Duchenne muscular dystrophy. Several enlarged densely staining hyaline fibres with numerous small necrotic fibres are present throughout. There is an increased quantity of fibrous and adipose connective tissue (top left) which contributes to the muscular pseudohypertrophy noted clinically in this disease. Compare with Fig. 26.37A.

Becker dystrophy

An X-linked disorder, Becker dystrophy exhibits many similarities to Duchenne dystrophy, but the onset occurs at a later age and the progress of the disease is slower, many patients surviving into adult life. Genetic studies indicate that this disorder is an allelic variant of Duchenne dystrophy, involving deletions in the p21 region on the X chromosome.

Limb girdle dystrophy

The group of disorders known as limb girdle dystrophy are inherited as autosomal recessive conditions. The onset can occur in childhood or adult life, usually with weakness in the pelvic girdle and, later, the shoulder girdle. The progress of the disease is variable, many patients surviving with only mild to moderate disability. Muscle biopsy shows the typical dystrophic features of fibre destruction and regeneration, but to a lesser degree than occurs in Duchenne dystrophy.

Facioscapulohumeral dystrophy

Facioscapulohumeral dystrophy is an autosomal dominant disorder, the genetic locus for which is chromosome 4q35. This disease usually presents in children and young adults with weakness of the face and shoulder girdle. The rate of progress is slow, and many patients survive with only mild disability. Muscle biopsy shows the features of a slowly progressive dystrophy, in which focal lymphocytic infiltration is occasionally present.

Myotonic dystrophy

Myotonic dystrophy is also an autosomal dominant condition, the gene for which has been localised to chromosome 19. The genetic abnormality is an unstable CTG repeat sequence in a cAMP-dependent protein kinase. It usually presents between 20 and 30 years of age with weakness and wasting of facial, limb girdle and proximal limb muscles. Myotonia (persistence of contraction after voluntary effort has ceased) is common in the involved muscles, and patients usually exhibit a number of systemic disorders, including cataract, balding, gonadal atrophy and diabetes mellitus. Characteristic changes are found on electromyography. Muscle biopsy shows dystrophic changes, in which many fibres contain internal nuclei and exhibit a variety of cytoskeletal abnormalities.

Polymyositis and dermatomyositis

Polymyositis is the commonest inflammatory muscle disorder, occurring most frequently in adults; females are affected more often than males. It may be associated with collagen vascular diseases (Ch. 25), for example systemic lupus erythematosus, or malignancies, for example bronchial carcinoma. Patients usually present with weakness, pain and swelling of proximal muscles. Dermatomyositis is a microangiopathy affecting skin and muscle, where complement deposition causes capillary lysis and muscle ischaemia. The serum CPK is usually elevated in the early stages of both diseases, and characteristic changes are usually present on electromyography.

Histology shows muscle fibre necrosis with phagocytosis of degenerate fibres by macrophages. T-lymphocytes are usually present within the endomysium and around blood vessels. Evidence of muscle fibre regeneration can usually be found, and fibre atrophy may be a striking feature in some cases, particularly in the perifascicular fibres in cases of childhood dermatomyositis.

The muscle fibre damage results from immunological injury by clonally expanded CD8 T-lymphocytes and macrophages. The mechanism of antigen sensitisation is unknown. Treatment with immunosuppressive drugs, such as corticosteroids and azathioprine, is beneficial in many cases.

Inclusion body myositis

Inclusion body myositis is most frequent in elderly patients and clinically resembles polymyositis. Its aetiology is unknown, but affected muscles show inflammation and fibre necrosis associated with small filamentous intracellular inclusions and vacuoles. Unlike polymyositis, it responds poorly to corticosteroids and azathioprine.

Lens-induced uveitis

Release of lens protein into the anterior chamber or vitreous (usually as a result of trauma) occasionally causes a giant cell granulomatous reaction involving the lens and uvea. This results from a delayed hypersensitivity reaction following sensitisation to lens antigens.

Sympathetic ophthalmitis

Trauma to one eye with damage to the iris or ciliary body may cause a delayed hypersensitivity reaction following sensitisation to uveal and retinal antigens. This results in a giant cell granulomatous inflammatory response in either the damaged eye or the second eye. Children are particularly susceptible to this uncommon complication.

Acute otitis media

Acute otitis media may result from primary or secondary bacterial infections; the latter occasionally complicate a viral illness. Acute bacterial otitis media is a suppurative inflammatory process most often caused by Haemophilus influenzae or Streptococcus pneumoniae. The inflammatory exudate can cause the tympanic membrane to bulge and rupture, and may spread to the mastoid air cells, causing acute mastoiditis. This condition usually responds rapidly to antibiotics.

Serous otitis media

Serous otitis media is a non-suppurative process in which fluid accumulates in the middle ear as a consequence of Eustachian tube obstruction. It is an important cause of hearing difficulties in children (‘glue ear’) and can be relieved by removing the Eustachian obstruction, for example in patients with tonsillar hyperplasia.

Chronic otitis media

Chronic otitis media usually results from persistent or repeated acute bacterial infections. Common complications include: