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Although, in common with any other organ system, the central nervous system (CNS) is susceptible to infection, trauma and the processes of infarction, inflammation and neoplasia, the anatomy and metabolic requirements of the CNS modify its response to common injurious agents and render it prone to unique pathological processes.
Neurones are the functional units of the nervous system ( E-Fig. 23.1 H ). A typical neurone is composed of a cell body (soma) rich in rough endoplasmic reticulum (Nissl substance) , short afferent cell processes (dendrites) and a main efferent cell process (the axon ). Except in development, neurones are not capable of replication and hence, once a neuronal cell body dies, regeneration is not possible. Damage to the axon with preservation of the soma can, however, be repaired by regeneration of the axon.
Specialised support cells (glial cells) are of four types: astrocytes, oligodendrocytes, microglia and ependymal cells. Astrocytes , ( E-Fig. 23.2 H ) with their delicate cytoplasmic processes, form a ‘fibrillary’ supporting framework for neurons and other cells of the CNS, participate in maintenance of the blood–brain barrier and proliferate following damage. Oligodendrocytes form myelin sheaths around axons in the CNS ( E-Fig. 23.3 H ). Their counterparts in the peripheral nervous system are the Schwann cells . Microglia ( E-Fig. 23.4 H ) are cells with short processes and are the CNS equivalent of quiescent macrophages. Ependymal cells ( E-Fig. 23.5 H ) provide a lining to the ventricles and central canal of the spinal cord.
Blood vessels in the brain have a specialised structure for maintenance of the blood–brain barrier . This limits transport and diffusion from the vascular compartment into the CNS. Connective tissues in the CNS are limited to the meninges ( E-Fig. 23.6 H ), choroid plexuses and around blood vessels. The relative paucity of fibroblastic cells means that healing in the CNS is generally not marked by fibrous scarring. In the peripheral nervous system, connective tissue and associated blood vessels are found in association with individual axons (endoneurium) , bundles of axons (perineurium) and peripheral nerves (epineurium) .
Neurones have a limited ability to survive significant changes in their metabolic or physical environment and are said to be selectively vulnerable compared to the more robust astrocytes or microglial cells. Neurones may undergo reversible cell damage, which is recognisable histologically by swelling of the cell body associated with loss of Nissl substance, a process termed chromatolysis . This process is particularly seen in the cell body of a neurone after damage to the axonal process. As discussed in Ch. 2 , necrosis of brain tissue usually results in liquefaction, leaving a fluid-filled space.
Following injury or necrosis, healing through granulation tissue and fibrous scarring is an uncommon event in the CNS, a result of a relative lack of fibroblasts. Initially, there is an exudative response with activation of local microglia and recruitment of phagocytic monocytes to phagocytose dead tissue. This is followed by proliferation of astrocytes to form an astrocytic scar . This process is generally termed gliosis and is a common end product of damage to the specialised structures of the CNS. If there is extensive tissue necrosis, for example following infarction, the gliotic response is insufficient to repair the whole defect and a fluid-filled space lined by gliosis (glia limitans) remains.
Where healing through granulation tissue and collagenous fibrosis occurs, it is in relation to healing of inflammatory processes such as around a cerebral abscess. It also occurs in disease involving the meninges, such as acute bacterial meningitis and tuberculous meningitis (see Fig. 5.7 ) ( E-Fig. 23.7 G ).
A astrocyte I ischaemic neurone N normal neurone
The brain is responsible for approximately 20% of total body oxygen consumption at rest. Under normal circumstances, cerebral blood flow is maintained through the process of cerebral autoregulation such that delivery of oxygen to the brain is not compromised. Where this process fails, the consequence is the ischaemic cell process , with decreasing vulnerability from neurones through glia to microglia and blood vessels. Hence, brief interruptions in blood flow are reflected in selective neuronal necrosis , whilst longer interruptions or cessation of flow result in cerebral infarction or stroke , a term used to describe the sudden onset of a persistent focal neurological deficit such as paralysis, disturbance of speech, coordination or sensation. The majority of strokes arise as a consequence of atheroma, thrombosis or embolism ( Fig. 23.2 ). Cerebral haemorrhage is also an important cause of stroke and may arise following reperfusion of a vessel occluded by thrombus or through rupture of small intracerebral vessels.
Cerebral infarction may follow thrombosis of a cerebral artery, often superimposed on atheroma of cerebral vessels. This is commonly seen in the vertebrobasilar territory, resulting in brainstem infarction. Cerebral infarction may also result from occlusion of a vessel by embolus. Such emboli most commonly arise from complicated atheroma of the carotid arteries (usually at the bifurcation), from the left side of the heart (frequently from mural thrombus after myocardial infarction), from atrial thrombosis in atrial fibrillation or from thrombotic vegetations on the aortic or mitral valves. More insidious disease results from progressive arteriosclerosis of small vessels in the brain causing degeneration of white matter with small areas of micro-infarction in the cerebral cortex. This is a common cause of dementia (progressive intellectual deterioration) in the elderly and is termed multi-infarct dementia .
Primary intracerebral haemorrhage is most often a complication of hypertension ( E-Fig. 23.8 G ). The muscular walls of small vessels in the brain are replaced by collagenous tissue, which leaves the vessels prone to rupture. Typically, hypertension related intracerebral haemorrhages occur in or around the basal ganglia. Where intracerebral haemorrhage arises elsewhere in the brain (lobar haematomas), other aetiologies should be considered. Accumulation of β-amyloid in the walls of small vessels in the superficial cerebral cortex and adjacent meninges, cerebral amyloid angiopathy , represents a further important pathology, which may predispose to intracerebral haemorrhage. Less common causes of primary intracerebral haemorrhage include congenital abnormalities of cerebral vessels forming arteriovenous malformations , saccular aneurysms, vasculitis and haemorrhage into primary or secondary brain tumours.
Intracranial haemorrhage may also occur from vessels outside the brain. Subarachnoid haemorrhage arises as a result of rupture of vessels in the subarachnoid space. The most common reason is rupture of a small aneurysm arising on one of the main cerebral arteries, descriptively termed a saccular (berry) aneurysm (see Fig. 11.4 ). Subdural haemorrhage results from bleeding from fragile veins, which traverse the subdural space. This most commonly occurs in the elderly as a result of trauma, which may be relatively trivial. Extradural haemorrhage ( E-Fig. 23.9 G ) is a result of bleeding from arterial vessels outside the dura, a common complication of trauma to the head, especially with skull fracture. The middle meningeal vessels are most vulnerable.
C cystic cavity E erythrocytes G glial tissue Inf infarcted area M macrophages N necrosis V proliferating astrocytes and blood vessels
Certain diseases of the CNS are characterised by progressive degeneration of neurones and/or white matter:
Alzheimer’s disease is a common cause of irreversible cognitive impairment (dementia), mainly in the elderly. The aetiology is unknown, but there are distinct histological abnormalities ( Fig. 23.3 ) that distinguish the condition from dementia with Lewy bodies and vascular dementia.
Parkinson’s disease ( Fig. 23.4 ) causes clinical features of tremor, slow movement and rigidity as a result of degeneration of nerve cells in the substantia nigra. The cause is unknown.
Dementia with Lewy bodies ( Fig. 23.5 ) is clinically similar to Alzheimer’s disease, though there are some key differences with fluctuating cognition, visual hallucinations and parkinsonism often encountered in this type of dementia. It has brainstem pathology identical to that seen in Parkinson’s disease but, in addition, similar neuronal pathology is present in cortical neurones and serves as the substrate for cognitive impairment.
Vascular dementia typically manifests clinically with a stepwise deterioration in cognitive function and focal neurological signs. A number of possible pathologies may be encountered in association with vascular dementias, reflecting whether the disease involves small or large vessels.
Motor neurone disease is the result of specific degeneration of motor neurones in the cerebral cortex, brainstem and spinal cord. Cells degenerate over a period of a few years resulting in progressive denervation of muscle with insidious paralysis and death. The cause of this disease is unknown.
Creutzfeldt-Jakob disease ( CJD ) is a cause of rapid onset, progressive dementia resulting from extensive death of neurones in the cerebral cortex ( Fig. 23.6 ). It is unique among degenerative diseases of the CNS in that a transmissible cause has been demonstrated (variant CJD) although poorly characterised. The infective agent, known as prion protein , is closely related to that which causes scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle.
CL cortical Lewy body L classical Lewy body P senile plaque
A amyloid plaque
Infections in the CNS may arise as a consequence of bacterial, viral or fungal agents and result in inflammatory processes, which may be divided into those involving the meninges (meningitis) or the CNS parenchyma ( encephalitis in the brain; myelitis in the spinal cord). Encephalomyelitis and meningo-encephalitis describe conditions where a mixed pattern of involvement occurs.
Bacterial meningitis may be a severe life-threatening disease. Survivors are commonly left with brain damage. The common infective agents are the meningococcus ( Neisseria meningitidis ), the pneumococcus ( Streptococcus pneumoniae ) and Haemophilus influenzae .
Histologically, there is an acute, purulent, neutrophilic response in the meninges with secondary thrombosis of many of the blood vessels supplying the CNS. Treatment with antibiotics may allow recovery. However, healing may be complicated by fibrosis in the meninges.
In the majority of cases, CNS infections arise as a consequence of haematogenous spread. In the remaining, small proportion of cases, infection may arise as a complication of a surgical procedure (including lumbar puncture) or as a consequence of local spread such as from an infected air sinus.
Where there is impairment in cell-mediated immunity, such as encountered in AIDS, organ transplantation, chemotherapy or haematolymphoid malignancy, there is an increased incidence of tuberculous meningitis. Typically, this takes the form of granulomatous meningitis (see Fig. 5.7 ), though the cellular response may be minimal in situations of severe immunological compromise.
Viral meningitis is commonly due to an enterovirus and is rarely fatal. Typically, it results in a transient lymphocytic response in the meninges.
Encephalitis and myelitis are usually caused by viral infections, some having a particular propensity to affect specific types of neurone. In viral encephalitis or myelitis, there are three main histological features:
Focal neuronal loss and phagocytosis as a direct result of viral infection.
Lymphocytic ‘cuffing’ of vessels with increase in microglial cells; this is because of a local immune response.
Astrocytic reaction with increase in number and size of astrocytes in response to loss of neurones.
The commonest acute necrotising encephalitis is herpes simplex type 1 (HSV-1) infection. Typically, the history is one of fever, confusion, headache and frontotemporal localising signs. This latter feature reflects the preferential involvement of the frontal and temporal lobes, which can be detected as an asymmetrical imaging abnormality on CT scanning. HSV-1 causes a severe form of generalised encephalitis with extensive necrosis of brain tissue ( Fig. 23.7 ).
In contrast, the polio virus tends to attack motor cells of the anterior horn of the spinal cord causing poliomyelitis and, for this reason, is termed a neurotropic virus . Rabies virus is also neurotropic and results in a meningo-encephalitis with virus inclusions visible in neuronal cells. Papovavirus infection of the CNS occurs in immunosuppressed patients and particularly affects oligodendroglial cells resulting in loss of myelin in white matter. The disease is termed progressive multifocal leukoencephalopathy . The human immunodeficiency virus (HIV-1), which causes AIDS, also affects the CNS and can result in HIV encephalitis ( Fig. 23.8 ). Persistent viral infection of the brain occurs in some cases of measles virus and results in a chronic degeneration of nerve cells in a disease termed subacute sclerosing panencephalitis .
Fungal infections of the CNS are rare and mainly confined to immunosuppressed patients. The most common causative organisms are Aspergillus , Rhizopus (causes mucormycosis) and Cryptococcus species (see Fig. 5.18 ). Lesions usually take the form of abscesses.
Typical cerebral abscesses may develop as a consequence of meningitis or may be the result of direct spread of infection from the skull (such as complicating middle ear infection) or of blood-borne spread from an infection elsewhere in the body, such as the lung. There is commonly a mixed infection including anaerobic organisms. Histologically, there is a pus-filled cavity walled off by fibrosis generated through granulation tissue derived from local blood vessels. Around this fibrous cavity wall, there is a reactive astrocytic response.
D demyelinated area G multinucleate giant cell L lymphocytes M mononuclear cells W white matter
Primary demyelinating diseases result in selective loss of myelin sheaths with (relative) preservation of axons. The commonest of these is multiple sclerosis (MS) , where episodes of demyelination occur in multiple different sites in the CNS and at different times (i.e. separated in place and time). The typical lesions of MS are well-defined foci of demyelination, plaques , distributed throughout the cerebral hemispheres, brainstem and spinal cord. It is postulated there is an abnormal immunological reaction, possibly triggered by a viral infection, resulting in focal myelin destruction.
There are three histological stages in the demyelinating process. First, during an acute episode, myelin breakdown occurs associated with lymphocyte and macrophage infiltration of the affected area, termed a plaque. At this stage there is clinical evidence of focal neurological dysfunction. Although the primary damage is against myelin, secondary damage to axons also occurs. In the second phase, astrocytes proliferate and gradually infiltrate the demyelinated area, which exhibits a continued lymphocytic infiltration. In the final phase of evolution of the plaque, cellularity is reduced, astrocytes shrink in size and the process becomes ‘burnt out’. This is illustrated in Fig. 23.9 .
Primary tumours of the CNS are uncommon, accounting for approximately 2% of cancer deaths in adults and 10% in children, although metastases to the brain from extracranial malignancies are, by contrast, relatively common. Despite their rarity, there are numerous different types of tumours arising from the CNS or its coverings with origins in neuroepithelial tissue (glia, neurones, embryonal tissues), meninges and lymphoid cells.
A unique system of classification and grading of tumours of the CNS exists that is regularly revised and updated (currently World Health Organization (WHO) 2016). The most recent update reflects the recent explosion in molecular knowledge of CNS tumours and integrates histological features (phenotype) with the results of specific molecular tests (genotype). Tumours are still graded on purely histological grounds from slow growing ( WHO grade I ), to rapidly growing and highly aggressive ( WHO grade IV ). However, molecular subtype is very important in some tumour types for prognostic information. The updated WHO classification contains a large number of entities but only some are considered in this chapter and an abridged classification is given in Table 23.1 .
|Tumour type||WHO grade||Tumour type||WHO grade|
|Diffuse astrocytic and oligodendroglial tumours (including molecular subtype)||Embryonal tumours (including molecular subtype)|
|Diffuse astrocytoma: IDH1 mutant/wild type/NOS||II||Medulloblastoma (abbreviated genomic classification)||IV|
|Anaplastic astrocytoma: IDH1 mutant/wild type/NOS||III||
|Oligodendroglioma (IDH1 mutant and 1p 19q co-deleted / NOS)||II||Neuronal and mixed glioneuronal tumours|
|Anaplastic oligodendroglioma (IDH1 mutant and 1p19q co-deleted/NOS)||III||Ganglioglioma||I or III|
|Glioblastoma (IDH1 mutant/wild type/NOS)||IV||Central neurocytoma||II|
|Oligoastrocytoma NOS||II||Nerve sheath tumours|
|Anaplastic oligoastrocytoma NOS||III||Neurofibroma||I|
|Other astrocytic tumours||Schwannoma||I|
|Pilocytic astrocytoma||I||Malignant peripheral nerve sheath tumour||II, III or IV|
|Pilomyxoid astrocytoma||II||Meningeal tumours|
|Ependymal tumours||Meningioma (various subtypes)||I|
|Anaplastic ependymoma||III||Anaplastic meningioma||III|
|Selective vulnerability||Neurones more vulnerable to hypoxic/ischaemic injury than glial cells. Shrunken, eosinophilic neurones in early stages, followed by phagocytosis of dead neurones and astrocytic proliferation.||23.1|
|Infarction||Most a result of atheroma, thrombosis or embolism. Haemorrhagic or anaemic. Large infarcts heal with cavitation and gliosis.||23.2|
|Haemorrhage|| Primary intracerebral haemorrhage most often a complication of hypertension. Other causes: cerebral amyloid angiopathy, vascular malformations, aneurysms, tumours.
Other intracranial haemorrhages: extradural, subdural, subarachnoid.
|Alzheimer’s disease||Most common cause of dementia. Unknown aetiology. Typically in elderly. Amyloid plaques and neurofibrillary tangles on microscopy.||23.3|
|Parkinson’s disease||Idiopathic destruction of neurones in substantia nigra. Motor symptoms/signs. Inclusions (Lewy bodies) in surviving substantia nigra neurones.||23.4|
|Dementia with Lewy bodies||Common cause of dementia. May be history of visual hallucinations, fluctuating cognition and parkinsonian symptoms. Inclusions in cortical and nigral neurones.||23.5|
|Prion diseases||Transmissible via abnormal prion protein. Most common – sporadic Creutzfeldt-Jakob disease. Also iatrogenic, variant and familial forms. Neuronal loss, spongiform change and gliosis.||23.6|
|Bacterial meningitis||Acute, purulent exudates in meninges. Most common organisms – meningococcus, pneumococcus, Haemophilus influenzae.|
|Herpes simplex encephalitis||Most common acute necrotising encephalitis. Neuronal death, astrocyte proliferation, lymphocytes round blood vessels and necrosis.||23.7|
|HIV encephalitis||Inflammation of white matter with clusters of mononuclear cells and occasional multinucleated cells.||23.8|
|Multiple sclerosis||Well-defined plaques of demyelination with relative preservation of neuronal elements and inflammatory cell response.||23.9|
|Tumours of CNS|
|Astrocytoma||Graded on histological features from grade I (lowest grade) to grade IV (highest grade, most aggressive; glioblastoma). IDH1 mutation, 1p and 19q intact.||23.10|
|Oligodendroglioma||Typically sheets of cells with round nuclei and cleared cytoplasm, fine vessels and foci of calcification. IDH1 mutation, 1p19q co-deletion.||23.11|
|Ependymoma||From ependymal cells lining ventricles. Perivascular pseudorosette arrangements of tumour cells and epithelial tubules.||23.13|
|Meningioma||From arachnoidal cells of meninges. Cells arranged in whorls with some containing psammoma bodies.||23.14|
|Leprosy||Nerve trunks infiltrated by macrophages filled with Mycobacterium leprae , with resulting loss of nerve fibres.||5.9|
|Schwannoma||Derived from Schwann cells. Biphasic appearance with Antoni A (with occasional Verocay bodies) and Antoni B areas.||23.15|
|Neurofibroma||May be solitary or multiple in association with NF1. Loosely arranged spindle cells with intervening connective tissue.||23.16|
|Neurogenic atrophy||Result of damage to nerve innervating muscle. Clusters of atrophic fibres.||23.17|
|Polymyositis||Inflammatory infiltrate with necrosis and phagocytosis of muscle fibres.||23.18|
|Duchenne/Becker muscular dystrophy||Mutation of dystrophin gene on X chromosome. Muscle fibre destruction with replacement by fibrous tissue and wide variation in fibre size.||23.19|
|Mitochondrial myopathy||Aggregates of abnormal mitochondria with trichrome stain (ragged red fibres) and mitochondrial inclusions in electron microscopy preparations.||23.20|
Over and above growth rate and tumour grade, any CNS tumour may exert harmful effects by growing into vital structures or by causing swelling of the brain around the tumour. Hence a small, WHO grade 1 (low grade) tumour may have serious consequences if it is located in or adjacent to the cardiorespiratory control centres of the brainstem.
CNS tumours are first assessed for histological features and graded accordingly. Following this, a number of specific molecular tests are employed depending on the histological type of tumour. Tests for diffuse gliomas are discussed in their relevant figures. In the new WHO classification, some molecular markers are an essential feature to diagnose a particular tumour type and essentially ‘trump’ histological features, e.g. a diagnosis of oligodendroglioma requires demonstration of both mutation of IDH1 (immunohistochemistry or sequencing) and co-deletion of chromosomal arms 1p and 19q (FISH). IDH1 also confers a better outcome in diffuse gliomas.
Particular molecular subtypes also give important prognostic information to better inform patients and provide options for more targeted therapies. For example, medulloblastoma is the commonest brain tumour in children, most often arising in the cerebellar vermis, and can show a variety of histological appearances. Recent genomic classification has shown four distinct molecular subtypes of medulloblastoma ( Table 23.1 ) that allow stratification of tumours into prognostic categories and allow for more aggressive treatment of poor prognostic tumours. In the future, histological diagnosis of ‘diffuse glioma’ may be all that is required at light microscopy and molecular tests will provide the basis of further classification and treatment.
E eosinophilic granular body P perivascular pseudorosette Ps psammoma body T tubule W cellular whorl V blood vessel VP vascular proliferation
Diseases of the peripheral nerves (peripheral neuropathies) result in abnormal motor or sensory function in the territory of the affected nerve. There are two main patterns of disease. Axonal neuropathies are due to primary damage to axons, while demyelinating neuropathies are a result of primary damage to Schwann cells and the myelin sheaths they form.
Generalised peripheral neuropathies may be found in association with a variety of diseases, such as diabetes mellitus, lead poisoning, alcoholism, uraemia and some malignancies. Several specific peripheral neuropathy syndromes are associated with segmental loss of myelin. These include post-infectious polyneuropathy (Guillain–Barré syndrome) and a large group of hereditary sensorimotor neuropathies . Axonal degeneration underlies other causes of peripheral neuropathy, for example those due to toxins, trauma or ischaemia. As a worldwide problem, an important cause of peripheral nerve disease is leprosy (see Fig. 5.9 ) in which nerve trunks are infiltrated by large numbers of macrophages filled with Mycobacterium leprae, with resulting loss of nerve fibres.
Tumours of peripheral nerve are common and are derived from Schwann cells (the cells forming peripheral myelin sheaths), fibroblasts and perineural cells. Examples are shown in Figs 23.15 and 23.16 .
A atrophic fibres AA Antoni A area AB Antoni B area L lymphoid infiltrate N normal sized fibres P phagocytosis Vb Verocay body