Intracranial infection can affect the arachnoid and pial membranes (meningitis) or the underlying brain itself (encephalitis). Viral, bacterial, protozoal, fungal and protein (prion) agents all contribute. Routes of entry into the CNS include:

Meningitis can be:

The microorganisms likely to be responsible vary with age and immunocompetence. Clinical symptoms include headache, neck stiffness, photophobia, irritability and altered consciousness. A skin rash may only be present with certain strains of meningococcal bacteria causing systemic sepsis. Biochemical analysis and microscopic examination of cerebrospinal fluid (CSF) obtained at lumbar puncture is helpful in discriminating the causative agent (Table 64). Bacteria and protozoa may be directly identified by microscopy.

The fixed skull volume allows very little room for the intracranial contents to expand in the presence of haemorrhage, tumour, abscess or oedema. Therefore a mild increase in intracranial mass can lead to increased intracranial pressure with serious consequences. Brain tissue becomes displaced (herniation). The site of herniation partly depends on whether mass increase is focal or diffuse (Figure 72):

Compression of blood vessels supplying the midbrain causes venous stagnation with haemorrhage, necrosis and irreversible neuronal injury in this vital area.

Normal brain function ceases within a few seconds of loss of oxygen supply; irreversible neuronal damage occurs after 6–8 minutes of anoxia. Most cerebrovascular disease results from focal impairment of blood supply causing cerebral infarction. This manifests clinically as a ‘stroke’ – a neurological deficit of sudden onset but lasting more than 24 hours, caused by vascular insufficiency (neurological symptoms caused by lack of blood flow but resolving within 24 hours are known as transient ischaemic attacks or ‘TIA’). Stroke can be due to thrombosis or embolus.

Thrombotic stroke usually complicates atherosclerosis in the basilar artery, proximal middle cerebral artery or at the carotid bifurcation. As thrombotic stroke arises on a background of atheroma, risk factors include hypercholesterolaemia, hypertension, diabetes mellitus and ischaemic heart disease.

When stroke occurs secondary to embolism, the source of the embolus is usually the heart. Cardiac mural thrombus can complicate myocardial infarction and atrial fibrillation. Thrombus may also embolise from abnormal heart valves, arterial walls (especially atherosclerotic carotid arteries) or from sites of cardiac surgery. Less commonly the embolus may consist of fat, air or tumour. Cerebral fat embolus should be suspected when neurological signs develop following non-head trauma with multiple bone fractures. Most embolic strokes affect the middle cerebral artery territory. Identification of the embolus at post mortem is often not possible, as a high percentage will have lysed.

Cerebral infarction can be haemorrhagic or non-haemorrhagic, as demonstrated by computed tomography (CT) or magnetic resonance imaging (MRI). The distinction is of therapeutic importance, as anticoagulation therapy is contraindicated in the presence of intracerebral bleeding. Thrombotic strokes are not usually complicated by bleeding. Haemorrhage can be secondary to reperfusion following an embolic stroke, but is more commonly seen in spontaneous intracerebral haemorrhage (ICH) associated with hypertension. ICH usually arises in:

Microscopically, the small arterial branches that rupture may show fibrinoid necrosis of the vessel wall and formation of microaneurysms known as Charcot–Bouchard aneurysms. Severe bleeding can cause rapid mass effect with an acute fatal rise in intracranial pressure. Haemorrhage may rupture internally into the ventricular system or externally into the subarachnoid space.

Hypertension can also result in small, often multiple lacunar infarctions (<15mm in diameter) in the basal ganglia, deep white matter and pons. In accelerated or malignant hypertension, an encephalopathy may develop with headaches, vomiting, convulsions and altered conscious level.

The sequelae of stroke depend on the area of the brain involved and the extent of the infarction. Anterior circulation infarcts (internal carotid supply) affect cerebral hemispheres and can cause hemiparesis, sensory loss, dysphasia, incontinence and hemianopia. Posterior circulation infarcts (vertebrobasilar circulation) affect the brainstem and cerebellum. Neurological deficits may include ataxia and gaze abnormalities. Even small posterior circulation infarcts can cause coma and death due to involvement of vital regulatory centres in the brainstem.

Rarer causes of intracerebral haemorrhage include:

Cerebral amyloid angiopathy occurs in the elderly and is associated with Alzheimer’s disease (see Section 27.4). Haemorrhage is usually peripheral (lobar) in distribution.

Diffuse cerebral ischaemia can result following profound systemic hypertension. Clinically this may manifest as transient confusion with no permanent damage, or may result in widespread cerebral infarction with coma and death. The watershed areas of the brain – at the margins of perfusion by the major circle of Willis arterial branches – are particularly susceptible to such global ischaemia. Other brain regions particularly sensitive to hypoxia include:

Subarachnoid haemorrhage is a relatively frequent natural cause of sudden unexpected death in young and middle-aged adults. The pathogenesis involves a congenital defect in the muscle wall of the cerebral arteries, which becomes manifest in later life as saccular dilatations known as ‘berry aneurysms’. There is an association with adult polycystic renal disease (see Ch. 23) and hypertension. The aneurysms develop mainly in the anterior part of the circle of Willis (Figure 73), around the origin and proximal branches of the anterior and middle cerebral arteries. In 25% of cases there are multiple aneurysms. Rupture causes subarachnoid haemorrhage and clinically manifests with a sudden very severe headache. Bleeding may be precipitated by an acute rise in blood pressure (e.g. during sexual intercourse). Females are more frequently affected than males.

As with aneurysms elsewhere in the vascular system, the risk of rupture increases in proportion with the aneurysm size. Re-bleeding is common in those who survive the initial insult. As the haemorrhage resolves, fibrosis of the meninges at the base of the brain can lead to subsequent hydrocephalus.

This is a progressive inherited dementia associated with uncontrolled movements (chorea). Onset is in middle age. Atrophy occurs in the caudate, putamen and frontal lobes. The involuntary movements result from loss of GABA-utilising inhibitory neurones, which regulate motor output in the basal ganglia. Huntington’s is an autosomal dominant condition with full penetrance, and new mutations are very rare. The gene responsible lies on chromosome 4 and contains repeats of the trinucleotide base sequence CAG. The normal allele contains 11–34 CAG copies, but in Huntington’s there is amplification of this base sequence, with up to several hundred copies. The age of onset of disease decreases with each successive generation as the number of CAG copies increases (this phenomenon is known as ‘anticipation’). A similar mechanism of disease is seen in X-linked spinal muscular atrophy, which is linked to trinucleotide repeats in the androgen receptor gene.

Parkinson’s disease is a movement disorder characterised by:

There is damage to dopamine-utilising neurones in the nigrostriatal tract. Loss of substantia nigra pigmentation can be identified at autopsy. Microscopically, Lewy bodies (cytoplasmic neuronal inclusions) can be seen in the brainstem nuclei, the cingulate gyrus and the hippocampus.

This is clinically manifest by progressive muscular atrophy, fasciculation and symmetrical weakness. There is atrophy of anterior motor roots of the spinal cord (lower motor neurones) and of corticospinal tracts (upper motor neurones). Patients are usually middle-aged men. Death is often due to respiratory complications.

Toxic and metabolic disorders of the nervous system include thiamine (vitamin B₁) deficiency and B₁₂ deficiency. The latter affects long tracts with lower-limb weakness, ataxia and sensory loss (known as subacute combined degeneration of the cord). Other uncommon but important causes of neurological damage include hypoglycaemia, hepatic encephalopathy and ethanol.

Fetal alcohol syndrome, which is caused by excess maternal ethanol intake during pregnancy, comprises:

Demyelinating disorders affect oligodendrocytes in the CNS or the myelin sheath of peripheral nerves.

Multiple sclerosis (MS) is characterised by repeated episodes of demyelination within the central nervous system. Neurological deficit is variable. It may be relatively mild, with relapses and remissions, or severe and chronically progressive. Unilateral optic neuropathy causing sudden visual deterioration is the commonest presentation, but the diagnosis is based on finding CNS lesions disseminated in time and space. The aetiology of MS is unknown. No specific infectious agent has been implicated, although there are increased serum and CSF antibody titres to common viruses. The pathogenesis may involve an immune reaction against myelin, possibly triggered by viral infection.

Neural tube defects (NTDs) affect 2 per 1000 pregnancies in the UK, although their frequency in live births is much lower (many such pregnancies are terminated). Many NTDs can be detected antenatally by serum α-fetoprotein measurement and ultrasound. Defects include anencephaly, encephalocele and spinal fusion defects (Table 65). The rate of recurrence in subsequent pregnancies is approximately 5%. The incidence of NTDs varies in different ethnic groups. Folate deficiency is a recognised aetiological factor. Spinal defects are commonest and usually involve the lumbosacral region, predisposing to infection and cord damage. Table 66 details other more common CNS malformations.

Is a non-progressive neurological defect arising in the perinatal period. The cause may not be apparent but intrauterine hypoxia, infection, birth trauma, kernicterus and hypoglycaemia may contribute. In premature babies, development of cerebral palsy is associated with cerebral haemorrhage and ischaemic damage to white matter (periventricular leucomalacia).

Inborn errors of metabolism in the CNS include neuronal storage diseases and white matter diseases (leucodystrophies) involving damage to myelin or oligodendrocytes. Storage diseases usually have an autosomal recessive pattern of inheritance. Enzyme deficiencies cause accumulation of substrate (e.g. mucopolysaccharides, sphingolipids) within neuronal lysosomes and ultimately cell death.

Friedreich’s ataxia is an inherited spinocerebellar degeneration with axonal loss in long tracts. Onset is usually in late childhood, with boys more commonly affected than girls. Symptoms include ataxia, dysarthria, sensory loss and progressive paralysis. There may be associated cardiomyopathy.

Intracranial tumours are 10 times more frequent than spinal neoplasms. About 20% of childhood cancers arise in the CNS. Primary tumours of the CNS cannot be labelled as ‘benign’ or ‘malignant’ using the same criteria as for tumours arising elsewhere in the body. Cytologically benign tumours can show locally extensive growth patterns preventing surgical excision. Slow-growing lesions can prove fatal due to their location or mass effect (e.g. benign tumour of the brainstem). Even microscopically high-grade tumours rarely metastasise outside the CNS, although dissemination can occur via the subarachnoid space and CSF pathways. Up to half of all CNS neoplasms are primary. The rest are metastases arising largely from carcinoma of the lung, breast, kidney, gastrointestinal tract and from malignant melanoma.

Paraneoplastic symptoms are defined as clinical phenomena associated with malignancy but not directly attributable to tumour infiltration. Paraneoplastic symptoms involving the CNS most commonly occur with small cell lung carcinoma. The pathogenesis is uncertain but may be immunologically mediated by antibodies against tumour expressed antigens cross-reacting against nervous system cells. CNS paraneoplastic syndromes include:

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