Nervous System

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Chapter 14 Nervous System

Nervous System – Anatomy and Physiology 526, 527

Neuronal Damage 528

Glial Reactions 529

Increased Intracranial Pressure 530, 531

Cerebral Oedema 532

Increased Intracranial Pressure 533

Circulatory Disturbances 534

Cerebral Infarction 535, 536

Brain Damage due to Cardiac Arrest 536

Cerebral Infarction 537

Cerebral Haemorrhage 538

Subarachnoid Haemorrhage 539

Head Injury 540–543

Ageing and Dementia 544

Alzheimer’s Disease 545

Dementia 546

Infections 547

Bacterial Infection 548, 549

Virus Infections 550–554

Prion Diseases 555

Miscellaneous Infections and Infestations 556, 557

Demyelinating Diseases 558, 559

Parkinson’s Disease 560

Miscellaneous Disorders 561, 562

Diseases of the Spinal Cord 563, 564

Disorders of Motor Pathways 565

Motor Neurone Disease 566

Mixed Motor and Sensory Disorders 567

Sensory Disorders 567

The Peripheral Nerves/The Neuropathies 568

The Neuropathies 569

Hydrocephalus 570–572

Developmental Abnormalities 573

Tumours of the Nervous System 574

Secondary Brain Tumours 575

Primary Brain Tumours 576

Tumours of the Nervous System 577–579

Tumours of Peripheral Nerves 579, 580

Cerebrospinal Fluid 581

The Eye 582–584

Nervous System – Anatomy and Physiology

Considerations of anatomy and physiology have important applications to diseases of the central nervous system (CNS), particularly their effects and spread.

The anatomy of the various coverings is important.

The skull and vertebrae form a rigid compartment protecting the delicate CNS tissues.

This rigidity has serious disadvantages when pressure inside the skull increases, e.g. an expanding lesion soon takes up the small reserves of space available and the delicate brain tissues are progressively compressed, with very serious results.

Meninges and Cerebrospinal Fluid (CSF)

Diseases (particularly infections) at this site are usually widespread over the whole brain and cord surfaces, e.g. meningitis. Impediment to the flow of CSF causes serious effects hydrocephalus.

The pia is invaginated into the brain substance along with the small penetrating vessels.

The dura, arachnoid and pia act as barriers which selectively separate the CSF and the blood from the CNS tissues.

It is important to understand that, although the CSF is very similar in composition to the extracellular fluid of the brain, changes in the CSF only very indirectly reflect changes in the CNS in disease.

Thus the pia and the membrane formed by the foot processes of the astrocytes separate types of tissue derived from two embryological layers.

Neuronal Damage

NEURONES are sensitive to damage by a wide variety of agents including anoxia, hypoglycaemia, virus infections and intracellular metabolic disturbances (e.g. associated with vitamin B deficiencies).

There are two main types, depending on the rapidity of the changes.

1. Rapid NECROSIS – associated with acute failure of function.

2. Slow ATROPHIC CHANGES – associated with gradual loss of function.

The process of ageing involves cumulative atrophy and disappearance of neurones; in some individuals the process is speeded up resulting in presenile dementia.

Note: There is no regeneration of destroyed neurones.

A large group of disorders of cerebral function seen in psychiatric practice have (as yet) no morphological evidence of nerve cell damage. They are caused by disturbances of poorly understood biochemical control mechanisms within the brain.

In addition to the primary degenerations described above, neurones are subject to secondary degeneration in certain circumstances.

1. Retrograde degeneration – when the main axon is damaged there is degeneration of the neurone as well as the classical distal degeneration of the axon.

2. Trans-synaptic degeneration – in closely integrated neurone systems, neurone loss may be followed by degeneration of associated neurones across synapses.

Glial Reactions

The glial cells react vigorously in many diseases of the CNS.

1. The NEUROGLIAL cells have supportive and nutritive functions.

(a) The astrocytes with their numerous fibrillary processes give structural support. They are less susceptible to damage than neurones.

This process is called gliosis. It is a feature of many diseases and is analogous to scar tissue. These cells and fibres contain Glial Fibrillary Acidic Protein (GFAP), recognition of which, using antibodies, is useful in histological sections.

Note: Collagenous scar tissue is only formed in the CNS when mesodermal structures such as large blood vessels are damaged.

(b) The oligodendrocytes – small cells with short processes – have a nutritive function in respect of neurones and especially myelin. This reaction is best seen when neurones are damaged.

2. The MICROGLIAL cells are members of the mononuclear-phagocytic system. Reaction is best seen when there is necrosis of tissues.

Microglial cells are well seen in and around infarcts; the activated cells which have ingested lipids are strikingly different from the small inactive microglia.

These cells have been given a variety of names: e.g. ‘gitter’ cells, or lipophages (lipid phagocytes).

Increased Intracranial Pressure

INCREASED INTRACRANIAL PRESSURE (ICP) occurs in two main circumstances:

1. Due to the presence of an expanding lesion

2. Due to obstruction of the free flow of the CSF – this causes hydrocephalus and is dealt with on page 570.

Intracranial Expanding Lesions

These lesions may occur within the brain substance or in the meninges. Important examples are:

The situation is often aggravated by cerebral OEDEMA.

The severity of the effects is modified by two important factors:

(1) the size of the lesion and

(2) the rapidity of expansion.

There are three stages in the progress of increased intracranial pressure (ICP).

(1) The stage of Compensation

(2) The stage of Decompensation At this stage there are herniations and distortions of the brain with their associated complications including:

– reduction in level of consciousness

– dilatation of pupil ipsilateral to mass lesion and papilloedema

– bradycardia with raised blood pressure (‘Cushing’ effect)

– Cheyne-Stokes’ respiration

(3) A vicious circle is established leading to the stage of vasomotor paralysis.

Effects

Distortions and Dislocations of the Brain Substance

These are to some extent dependent on the site of the initiating lesion; the effects of a unilateral expanding lesion are illustrated.

Note: The sudden removal of even small amounts of CSF by lumbar puncture may precipitate medullary ‘coning’ with fatal results due to damage to the ‘vital centres’.

Cerebral Oedema

Swelling of the brain, of which oedema is the major component, is an important complication of many brain diseases because the enlargement either initiates or aggravates increased intracranial pressure.

The process may be localised or generalised depending on the type of initiating disorder.

Localised conditions	Generalised conditions
Examples:	Examples: Intoxications
Infarcts, and local ischaemia	Metabolic disturbances, e.g. hypoglycaemia
Haematomas (due to vessel rupture and injury)	Generalised hypoxia
Tumours	Severe head trauma
	Malignant hypertension

The pathological mechanism is as follows:

Notes

(a) Components (1) and (2) overlap.

(b) The oedema fluid tends to spread in the white matter.

(d) In clinical practice, therapy has two aspects:

1. Treatment of the initiating disorder by any appropriate means.

2. Minimising the formation of oedema by the use of

(i) osmotic agents, e.g. urea or mannitol

(ii) steroids.

Increased Intracranial Pressure

Secondary Complications

1. Vascular damage

(a) Compression of the central retinal vein causes papilloedema, an important clinical sign of raised ICP.

Note: Axonal flow in the optic nerve is reduced, contributing to swelling of the optic disc.

(b) Stretching and compression of blood vessels may cause haemorrhage and infarction quite remote from the initiating lesion – secondary midbrain and calcarine infarction and haemorrhage are common.

2. Intracranial nerve damage

Oculomotor (III) and abducens (VI) nerves are particularly prone to damage, giving rise to paralysis of ocular movements in varying combinations.

The VIth nerve is specially vulnerable due to its long subarachnoid course. It is often the nerve on the side opposite the lesion which is stretched giving rise to paradoxical signs.

3. Obstruction of flow of CSF

4. Changes in the skull bones

Long continued ICP causes bone erosion and thinning visible on X-ray.

(a) Erosion of posterior clinoid processes of sphenoid bone.

(b) In children, before the skull is fully ossified, the inner table is thinned at the sites of convolutional pressure giving a striking X-ray appearance.

Circulatory Disturbances

(1) Hypoxia and ischaemia and (2) intracranial haemorrhage are the important and common mechanisms causing brain damage.

Acute Hypoxic Disorders

When the cardiac output falls, an autoregulatory vascular control mechanism protects the cerebral blood supply the arterial BP must be kept above 50 mmHg.

There are no reserves of O₂ or glucose in the brain, therefore a constant delivery via arterial blood is necessary.

Neurones are very susceptible to hypoxia (and hypoglycaemia); with complete O₂ deprivation neuronal necrosis occurs in 5–7 minutes (at normal temperatures).

The following flow diagram illustrates the factors which influence availability of O₂ and the conditions giving rise to hypoxia.

Cerebral Infarction

This condition, the commoner of the two main types of stroke (the other is spontaneous intracerebral haemorrhage), is caused by failure of the supply of oxygen (and glucose) to maintain the viability of the tissues in the territory of a cerebral arterial branch. This is not always due to simple local arterial occlusion, and very often a component of central circulatory deficiency is contributory. The lesion is essentially necrosis of all the tissues in the affected territory.

Mechanism

Precipitating condition → Perfusion failure → infarction (ischaemic necrosis)

LOCAL ARTERIAL DISEASE (particularly atheroma) and its complications, are the most common.

1. Arterial occlusions

2. Arterial stenosis

atheroma – the widespread loss of arterial lumen potentiates cerebral perfusion deficiency in two ways: (1) by distributing the normal arterial flow and (2) by prejudicing anastomotic communications.

Atheromatous stenosis alone is not usually a cause of infarction, but when central circulatory deficiency is added, infarction is common, e.g. this may vary from the slight fall in BP during sleep to the severe hypotension of shock or myocardial infarction.

Other rarer causes of arterial stenosis are dissecting aneurysm and arteritis. Arterial spasm is even rarer.

Cerebral infarction can now be treated by administering ‘clot busting’ drugs. To avoid permanent damage these need to be given within 3 hours of the onset of symptoms. Tissue plasminogen activator which converts plasminogen to plasmin is most frequently used. Cerebral bleeding is a potential side effect. Alternatively thrombus can be surgically removed from the carotid artery. The success of these treatments is variable.

Sites

While infarcts may occur anywhere in the brain, depending on the vagaries of the precipitating arterial lesions, certain sites are more commonly affected.

1. In cases of local arterial occlusion, internal structures supplied by ‘end’ arterial branches are particularly vulnerable. The cortex is often protected in variable degree by anastomoses of other cerebral arteries. This is illustrated in the territory of the middle cerebral artery.

2. Boundary zones (see p.177)

The cortex in particular is damaged in boundary zone infarction. In these cases, central circulatory deficiency is an important component, e.g. hypotension.

Brain Damage Due to Cardiac Arrest

This is characterised by widely distributed selective neuronal necrosis – the neurones are more susceptible to hypoxia than the supporting cells.

Affected areas –	total cortical necrosis
	or
	most sensitive zones	– hippocampus
		– layers III, V, VI of cortex
		– within sulci
		– Purkinje cells of cerebellum.

Note:

(a) These changes do not become apparent unless the patient survives at least 12 hours after the arrest.

Cerebral Infarction

The diagram below illustrates the evolution of an infarct, e.g. in the territory of the middle cerebral artery. Up to 24 hours there is virtually no visible change.

Cerebral Haemorrhage

Spontaneous intracranial bleeding is the second main type of stroke. In the great majority of cases there is localised arterial disease aggravated by hypertension. A small number are associated with cerebral tumours, systemic bleeding diathesis or arteriovenous malformations.

In most hypertensives over middle age, microaneurysms are found in the very small cerebral arteries. It is believed that rupture of one of these aneurysms is the immediate cause of intracerebral haemorrhage.

Note: Intracerebral bleeding may track irregularly and often reaches the subarachnoid space and ventricles.

Subarachnoid Haemorrhage

This is commonly but not exclusively the result of rupture of a ‘berry’ aneurysm at or near the circle of Willis. The basic abnormality is a congenital weakness of the elastic tissues in the arterial wall; only rarely is an aneurysm present at birth, and while subarachnoid haemorrhage does occur in young people, the incidence increases with age. Hypertension is an important contributing factor.

Sites Often multiple, near arterial junctions.

Not all aneurysms rupture; they are found incidentally at autopsy.

Massive haemorrhage may be preceded by one or more small leaks – marked by headache without functional loss.

Head Injury

Head injuries of varying severity are common nowadays, particularly as a consequence of road traffic accidents. Immediate damage is caused by two main mechanisms which overcome the protection of the vulnerable cerebral tissues provided by the skull and the CSF ‘water cushion’.

1. Direct blows to the head (e.g. missile head injury)

Note:

It will be appreciated that more serious cerebral damage is the result of interaction of complex physical forces and anatomical features. An understanding of these mechanisms explains why serious cerebral injury is not uncommon in the absence of damage to the scalp or fracture of the skull, and also why brain damage may be remote from the site of impact: so-called ‘contre-coup’ injury is sustained when the brain tissue opposite the site of impact is contused.

Delayed Complications

In addition to damage sustained immediately at the time of impact, certain serious complications may supervene over the next hours or few days.

1. Haemorrhages

(a) Extradural haematoma

This type of haemorrhage classically occurs as a complication of linear fracture of the skull vault when the middle meningeal artery is torn.

The classic clinical association is a direct blow to the head from which recovery is rapid. After a lucid interval of varying duration up to several hours, signs of increased intracranial pressure supervene. This chain of events is explained by the time taken for the haemorrhage to accumulate by stripping the dura from the skull.

(b) Subdural haematoma. This may occur at any site and is often extensive because of the loose attachment of the dura and arachnoid membranes. It is usually due to rupture of small bridging veins.

These acute subdural haematomas are often associated with subarachnoid haemorrhage and cerebral contusions.

(c) Intracerebral haematomas occur in association with cortical contusions particularly in the temporal and frontal lobes (burst lobe); but also at random deep within the hemispheres due to shearing at the time of impact. Large haematomas are uncommon.

3. External leakage of CSF (and blood) from the ear and nose may complicate fractures of the skull base. This complication may be of long duration and is always a potential entry for infection.

4. Local infection may complicate compound fractures and progress to meningitis.

Late Complications

1. Epilepsy

Head injury is an important cause of epilepsy. The risk is highest in severe missile head injury and may be related to ischaemic brain damage.

2. Chronic subdural haematoma

A thick layer of fluid and partially clotted blood gradually accumulates between the dura and arachnoid membranes which show considerable reactive thickening.

The precise cause is not known; most cases occur in alcoholics or in elderly people already suffering from cerebral atrophy, and it is possible that the small bridging veins are unduly stretched and become more susceptible to damage.

The clinical signs are usually insidious in onset and progressive, and in many cases there is a history of either no or only very trivial injury.

Alzheimer’s Disease

This disease accounts for around 70% of cases of dementia. While typically a disease of the elderly, especially females, it is also seen in patients under 60 years, in whom there is often a family history. Almost all patients with Down’s syndrome who survive to 50 years develop Alzheimer’s (suggesting that chromosome 21 is important).

Pathology

The changes of Alzheimer’s resemble those of normal ageing, but are greatly exaggerated in the temporal and parietal lobes and in the hippocampus.

The histological hallmarks are:

1. Extracellular senile plaques.

Tangled aggregates of distended neurites presenting as black dots and rods with a centre core of amyloid β-protein.

2. Intracellular neuro fibrillary tangles.

Paired helical filaments composed of tau protein form around the nuclei of neurones.

3. Amyloid angiopathy.

Deposited in meninges and blood vessel walls.

4. Loss of neurones and synapses.

Pathogenesis – this is not fully understood but the theories include:

1. Amyloid Hypothesis – this theory postulates that amyloid products are the cause of the disease. Accumulation of amyloid triggers neuronal degeneration, disrupts calcium homeostasis, induces apoptosis and builds up in mitochondria where it inhibits enzyme function. The amyloid hypothesis is supported by genetic factors (see below).

2. Inflammatory Hypothesis – this theory postulates that when normal brain tissue is disrupted as a result of inflammation, this can cause misfolding and, subsequently, accumulation of amyloid . The effects may accumulate over many years as an acceleration of normal cellular senescence. Individuals who take anti-inflammatory drugs have a lower risk of Alzheimer’s disease.

Genetic factors – several genes are involved

1. Amyloid precursor protein (chromosome 21) – early onset Alzheimer’s.

2. Presenilin 1 and 2 (chromosome 14 and 1) – proteins involved in binding amyloid precursor proteins.

3. Apolipoprotein E – the E4 allele is associated with late onset disease.

– it may determine the age of onset.

– 40–80% of the those with Alzheimer’s disease have at least one Apo E4 allele.

4. α-2 macroglobulin – may be involved in clearance of amyloid proteins.

Dementia

Multi-Infarct Dementia

This form of dementia is associated with vascular disease – with infarcts often in the middle cerebral arterial distribution. The volume of brain loss appears to be important.

Loss of >100ml of brain correlates with dementia.

Hypertension is an important underlying factor. A stepwise progression is typical.

Lewy Body Dementia

This disorder accounts for 10–20% of dementias. Clinically there are overlapping features with Parkinson’s disease. There is widespread neuronal loss in the cerebral cortex. Characteristic Lewy bodies are identified in surviving neurones. Known components of Lewy bodies include alpha synuclein and ubiquitin.

Pick’s Disease

This uncommon form of dementia has a strong familial (autosomal dominant) component. There is typically severe atrophy of the temporal and frontal lobes. The histological marker in the surviving neurones is the Pick body.

Huntington’s Disease

This is an uncommon autosomal dominant condition beginning in the 3rd or 4th decade and characterised by psychiatric disorders, progressive dementia and in some patients bizarre writhing movements (chorea).

Pathology

The caudate nucleus is severely atrophic. The genetic locus is on chromosome 4 and consists of a trinucleotide repeat with up to 34 copies in unaffected patients. In Huntington’s disease the number of repeats increases with each successive generation resulting in earlier onset of symptoms (genetic anticipation). Genetic screening is available.

Punch Drunk Syndrome (Dementia Pugilistica)

Professional boxers may develop dementia due to neuronal damage caused by repeated blows to the head.

Infections

Compared with the high incidence of infection generally, infection of the central nervous system is uncommon. The pathological effects may be slight and wholly recoverable as in some virus infections, or severe, leading to permanent damage or death.

Anatomically, infections fall into two main groups which tend to remain separated due to the intervention of the pial barrier (see p.527).

Infections will be considered in three broad aetiological groups:

(1) Bacterial,

(2) Viral and

(3) Miscellaneous types.

Pyogenic Meningitis

The whole subarachnoid space contains purulent exudate which is maximal in sulci and around the brain base cisternae.

In untreated or ineffectively treated patients who survive, complications include cranial nerve damage, hydrocephalus and variable brain damage.

The CSF in the acute stage contains neutrophils and the infecting organism can usually be demonstrated.

Pyogenic Brain Abscess

The abscesses resulting from direct spread of adjacent infection or by blood borne infection – as seen particularly in bronchiectasis – are often well circumscribed by a pyogenic membrane.

Clinical note: An abscess is often silent early in its evolution, and the infection at the site of entry may have healed before the onset of serious complications causes clinical signs.

Multiple small abscesses occur in staphylococcal pyaemia and microabscesses may complicate bacterial endocarditis. The cerebral pathology in these circumstances is only one facet of serious systemic infection.

Tuberculosis

Infection of the nervous system is always secondary to disease elsewhere and may be a component of miliary tuberculosis. It may complicate AIDS and remains prevalent in many parts of the world. Without treatment tuberculous meningitis is invariably fatal.

TUBERCULOMA These localised tuberculous cerebral abscesses are now very rare.

SYPHILIS Neurological syphilis is rare nowadays. The main pathological lesions are described on p.76, 77.

Virus Infections

Compared with the incidence of virus infections in general, infection of the central nervous system is rare, even with viruses having an affinity for the CNS – NEUROTROPIC VIRUSES.

There are 3 broad groups:

1. Acute

Cell lysis occurs towards the end of the viraemic phase of infection. This is the common type of disease. Herpes simplex, mumps, poliovirus and togaviruses are examples.

2. Persistent

Viruses which usually cause damage outside the CNS behave uncharacteristically and cause continuing and active disease of the CNS over a long period (months – years). Measles, rubella and JC papovavirus are examples.

3. Latent virus infection is seen in herpes zoster and possibly plays a role in the demyelinating diseases.

Virus infection also has a possible role in oncogenesis within the CNS.

Routes of Infection

Most viruses arrive at the CNS via the blood, but the factors which potentiate the establishment of disease within the CNS are poorly understood.

Primary Portal of Entry

In rabies, the virus travels from the wound up the peripheral nerves to the CNS; a similar mechanism may be involved in herpes simplex encephalitis.

Basic Pathological Effects

(a) VIRAL MENINGITIS is the commonest form of meningitis; the disease is usually mild and only the meninges are affected. Recovery is usually complete.

(b) In more severe cases, the brain substance is also damaged in varying degree encephalitis (meningoencephalitis).

To these basic changes, damage to myelin and glial tissue may be added, and small focal haemorrhages may be seen. The damage is effected in two ways:

1. By the direct effects of virus on cells.

2. By a host cell-mediated and humoral response to the infected cell.

Diagnosis

Examination of the CSF is helpful in establishing a diagnosis of aseptic meningitis or meningoencephalitis.

Note: The findings in tuberculous meningitis are very similar except that in tuberculous meningitis the CSF sugar is low.

The specific virus aetiology is more difficult to establish. PCR of CSF is useful for some viruses (esp. HSV). In severe cases brain biopsy may be required.

Clinical Associations and Progress

In viral meningitis, the illness is mild with fever, headache and neck stiffness the main signs. Recovery is almost always complete.

In meningoencephalitis, signs of cerebral ‘irritation’ and neuronal damage are seen, e.g. mental confusion, delusion, stupor, convulsions and coma, and there may be localising signs. In mild cases, recovery is complete, but in more severe cases residual paralysis and other signs indicative of permanent brain damage may follow. Death in coma with respiratory failure occurs in very severe cases.

Herpes Simplex Virus (HSV) Encephalitis

This is the commonest form of severe acute viral encephalitis and is almost always due to Herpes Simplex Virus Type 1. It occurs in 2 forms:

1. In infancy, as part of a generalised HSV infection.

2. In adults, due to reactivation of the virus in the trigeminal ganglion.

Most cases are sporadic but immunosuppression increases the risk. The temporal lobes are most affected. Early treatment with antiviral drugs has now greatly reduced the previous high mortality.

Herpes Zoster (see also p.80)

This is a disease of adults, presenting as a painful vesicular rash, usually unilateral and affecting one or a few adjacent dermatomes only. It is due to recurrence of a latent varicella (chickenpox) infection.

Mechanism

Sequels

1. An occasional sequel is intense pain with varying paraesthesiae and anaesthesia long after the acute phase has healed.

2. In cases of Vth nerve herpes, serious damage to the eye may result.

Rabies

The rabies virus shows marked neurotropism and can infect most mammals. Various wild carnivores (fox, jackal, skunk, vampire bats) are the natural reservoir. Many human cases are contracted from dogs.

Mechanism

An unremitting encephalitis particularly affecting the grey matter is established. Diagnostic Negri bodies (virus inclusions) are found at autopsy in the pyramidal cells of the hippocampus and the Purkinje cells of the cerebellum.

Clinically, the encephalitis presents with extreme excitation of the sensory system. The classical hydrophobia (fear of water) is due to serious disturbance of the swallowing mechanism with muscular spasm. Without supportive therapy death occurs and is due to respiratory muscle spasm or paralysis.

Enteroviruses

These are small RNA viruses (picornavirus group) and include polioviruses, coxsackie viruses and echoviruses.

Infection is acquired by ingestion of faecally contaminated material followed by proliferation in the intestine. In only a small minority of infected cases does the virus pass the blood-brain barrier and cause disease of the CNS.

In addition to aseptic meningitis, the polioviruses (and very occasionally Coxsackie and Echo viruses) cause the classic paralytic disease, anterior poliomyelitis. Vaccination has dramatically reduced the global incidence of poliomyelitis.

Pathological Changes

The pathological changes are reflected in three clinical stages: (1) acute, (2) recovery and (3) permanent residual disability.

Persistent Virus Infections

Subacute sclerosing panencephalitis is a very rare disorder due to reactivation of latent measles virus. It affects children and young adults, often several years after uncomplicated measles, and is usually fatal within 6 months. The sequence is probably as follows:

Progressive Multi-Focal Leukoencephalopathy

JC papovavirus, a member of the polyoma virus group, may infect the oligodendrocytes of adults who are immunosuppressed. A rapidly progressive demyelinating disease follows with degenerative changes in the deep white matter.

HIV and the Brain

Despite the introduction of highly active antiretroviral therapy (HAART), brain involvement is still a major cause of death in AIDS patients.

(a) HIV infection of the brain. This may lead to a subacute encephalitis often with dementia. The incidence has not decreased with HAART.

(b) Opportunistic infections including toxoplasma, fungi (cryptococcus), viruses (cytomegalovirus).

The incidence of (b) and (c) has decreased dramatically with HAART.

Prion Diseases

Also known as the transmissible spongiform encephalopathies, this group of diseases is caused by abnormal, distorted PRIONS. A prion is a small protein molecule found in the brain cell membrane. Normal cellular prion protein is termed PrP^c whereas the distorted protein is termed PrP^sc (originally referring to scrapie but now a generic term).

The Prion Hypothesis

When a distorted prion molecule reaches the prions in the brain cell membrane of an individual, that molecule is able to act as a three-dimensional template to cause a normal prion molecule to adopt a similar distorted shape. This in turn can distort further proteins and so on.

Pathology

There are 4 characteristic histological features:

1. Spongiform change

2. Neuronal loss

3. Astrocytosis

4. Amyloid plaque formation.These are most frequently observed in the cerebellum.

They can be detected by immunohistochemistry with antibodies to PrP^sc.

Types of Prion Disease

1. Creutzfeld-Jacob Disease (CJD) this may be: (i) sporadic, (ii) acquired through contact with infected material, e.g. pituitary derived hormones, corneal grafts or (iii) familial due a point mutation of the PrP gene. Spongiform change is the most consistent histological features. Plaques occur in around 10% of cases.

2. Variant CJD – This occurs in younger patients with early psychiatric symptoms and a longer clinical course. The strain of PrP responsible for vCJD is identical to a bovine spongiform encephalopathy (BSE) and is caused by ingestion of products from infected cattle. In contrast with CJD florid plaques are a histological hallmark. Also, unlike CJD, PrP may be detected in lymphoid tissue.

3. Other – includes KURU (historical) due to ingestion of human brain by cannibalism in New Guinea; GERSTMANN-STRAUSSLER-SCHEINKER disease; a familial dementia.

Miscellaneous Infections and Infestations

1. FUNGAL INFECTIONS

(a) Primary infections. In healthy adults, fungal infections are rare. Occasionally in the presence of heavy exposure to fungus, localised infection, often clinically insignificant, may occur, and in very rare cases CNS infection is a complication. In cryptococcosis (C. neoformans), the fungus exhibits neurotropism and occasionally causes meningitis in otherwise healthy subjects.

(b) Opportunistic infections are becoming more common nowadays due to the use of immunosuppressive therapy and the increasing prevalence of AIDS. Various fungi including Candida, Aspergillus, Nocardia may cause serious cerebral damage. The incidence is decreasing in AIDS patients due to HAART.

2. PROTOZOAL INFECTIONS

(a) CEREBRAL MALARIA

Cerebral complications may occur in the severe acute malaria (falciparum type) which affects non-immune adults. Clinically, coma rapidly proceeds to death.

At autopsy the brain is swollen (oedema) and there may be petechial haemorrhages. Histologically, the capillaries are congested and malarial parasites and pigment are easily seen.

(b) TOXOPLASMOSIS

Although infection by T. gondii is common, serious nervous tissue damage is rare and is seen in two main circumstances. In both, it occurs as part of a systemic infection.

(i) In congenital toxoplasmosis, the infection is acquired by the fetus during a primary maternal infection.

(ii) Opportunistic infection in adult.

T. brucei infection is transmitted to humans from animal reservoirs by the Tsetse fly. The organism is neurotropic and a meningoencephalitis results. The infection is associated with excessive IgM production in CSF. The ‘cuffing’ infiltrate has a high component of plasma cells and also ‘Mott’ cells – plasma cells distended by eosinophilic globules (denatured Ig).

3. METAZOAL INFESTATION

Cysticercosis

The larvae of Taenia solium may encyst in the brain and can be the cause of epilepsy.

Hydatid cyst – also occurs in the brain (see p.360).

Demyelinating Diseases

Multiple Sclerosis (MS)

This is the commonest demyelinating disease – where the myelin sheath breaks down, leaving the axons healthy but with serious effects on their function. Multiple sclerosis is a chronic disease of young adults.

Clinical Associations

The neurological signs Pons reflect white matter damage – upper motor neurone Medulla weakness and paralysis; incoordination; visual disturbances; paraesthesia. (‘Grey matter’ signs, e.g. Spinal aphasia, fits and muscle cord atrophy are rare.)

Course of Disease

Variants are:

1. acute severe disease – rapid progress to death

2. chronic progression without remission

3. minimal signs with very long remissions.

Aetiology – This is unknown.

Geographically, the disease is common throughout temperate Europe and North America and is rare in the tropics.

A possible mechanism is:

Acute Disseminated Encephalomyelitis

An acute encephalitis in which demyelination is a prominent and characteristic feature is a very rare sequel to many natural viral diseases such as mumps, measles, chickenpox and rubella and to vaccination, historically against smallpox and rabies.

Clinically, there is fever, headache, vomiting and drowsiness followed by coma. There may be clinical evidence of focal neurological damage. Pathological changes are widespread in the brain and cord and rapidly progressive.

In ACUTE HAEMORRHAGIC LEUKOENCEPHALITIS, to these are added actual petechial haemorrhages from damaged vessels, particularly in the white matter; not all cases follow virus infection.

Mechanism. It is thought that in these disorders the damage to the myelin is not the result of direct virus attack but is an autoimmune reaction in which the antigen is a component of myelin and the virus in some unknown way acts as a trigger.

Diseases Due to Abnormal Myelin

In this group of rare ‘leukodystrophies’, the molecular structure of myelin is abnormal due usually to abnormal or deficient enzyme action. Most cases are genetically determined, present in early life and progress fairly rapidly.

Abnormal metabolites which can be specifically identified accumulate in macrophages, glial cells and sometimes neurones.

e.g.

1. In metachromatic leukodystrophy, the accumulation of a sulphatide gives a metachromatic staining reaction and characteristic EM appearance.

2. In Krabbe’s disease there are typical multinucleated histiocytes (called globoid cells) containing cerebroside.

Parkinson’s Disease

This is a disease of the extrapyramidal system which links the higher motor centres and effector motor cells of the spinal cord. Important neurotransmitters are DOPAMINE and γ-aminobutyric acid (GABA).

Aetiology – The disease occurs in 2 main circumstances:

(a) Idiopathic: The majority of cases occurring in the elderly population (1% of over 60s) are idiopathic and the cause remains unclear. Genetic and environmental factors may be involved.

Genetic: There is a 2–3 times increased risk of the development of Parkinson’s disease in the first-degree relatives of patients.

Environmental: Some pesticides can cross the blood-brain barrier and may be associated with Parkinson’s disease.

(b) Secondary:

1. Postencephalitic (historically) i.e. as a sequel to encephalitis lethargica which occurred in epidemic form in the 1920s.

2. Drug induced. The use of neuroleptic drugs may induce the syndrome temporarily (occasionally permanently), by disturbing the balance of the chemical transmitters.

3. Arteriopathy.

4. Heavy metal poisoning.

Clinically, Parkinsonism illustrates the classical features of extrapyramidal damage.

Pathological Mechanism

In all cases of long-standing Parkinsonism of any type, degenerative changes are seen in the extrapyramidal nuclei. In particular, there is depigmentation of the substantia nigra.

Histologically, there is loss of neurones, and the surviving nerve cells contain inclusions known as Lewy bodies (p.546).

Other extrapyramidal disorders include the choreas, of which there are 2 main types. Sydenham’s chorea occurs in children with rheumatic fever, while chorea is a manifestation in some patients with Huntington’s disease.

Miscellaneous Disorders

Nutritional and Metabolic Disorders (Encephalopathies)

In the last analysis, all disorders in this group are mediated by disturbed neuronal metabolism, so that exact classification may present some difficulty. However, it is convenient to consider them in 2 broad groups.

1. NUTRITIONAL DEFICIENCY

The vitamins of the B group are important coenzymes in several intracellular oxidative pathways. Deficiency, which may arise from primary malnutrition but more commonly in association with alcohol abuse, is the cause of degenerations of the brain, spinal cord and peripheral nerves.

Wernicke’s Encephalopathy

Clinically, this condition presents with disturbances of consciousness, ataxia and visual disturbances, and without prompt treatment progresses to death in coma. In Western countries, chronic alcoholism is usually present; often a particularly heavy bout of drinking precipitates the condition.

The lesions, which are focal, consist of glial proliferations with varying neurone loss. Petechial haemorrhages may be seen.

The lesions have a characteristic anatomical distribution:

Prompt treatment with thiamin minimises the damage, but if treatment is omitted or delayed, permanent damage results. The patient may have a persistent Korsakoff’s psychosis. At autopsy, there is visible shrinkage of the mamillary bodies.

2. METABOLIC DISORDERS

In the following examples, the metabolic defect causes neurological disorder, but in addition, other organs are seriously disturbed.

(a) Aminoacidopathies

A wide variety of hepatic enzyme defects in the complex metabolism of amino acids has now been described. When neurological damage occurs, it is essentially non-specific and developing in the immediate postnatal period, a critical time in the development of the brain which leads to mental retardation.

Phenylketonuria is an example.

The importance of this disease is that the effects can be prevented by dietary restriction of phenylalanine-containing substances, provided the treatment is begun within 60 days of birth.

(b) In the neuronal storage diseases, which usually present during the first decade, deficiency of lysozomal enzymes leads to accumulation of intermediate metabolites in the neurones. The diagnosis of the condition often depends on the identification of the abnormal metabolite by histochemistry or EM.

Tay-Sach’s disease (amaurotic familial idiocy) is an illustrative example.

Note: Involvement of the retinal ganglion cells causes blindness – a cherry red spot at the macula is seen.

In these disorders, other organs may be mildly affected by the enzyme defect but the neurological effects are predominant.

Diseases of the Spinal Cord

In purely spinal lesions, basic disease processes have important anatomical and functional implications. Lack of space for expansion produces important compression effects. Examples are:

Effects

At the level of the lesion, there is loss of the sensory and motor connections which constitute the spinal reflex.

In addition, severance of the longitudinal tracts cuts off the cerebral connections to all parts below the lesion.

Ascending And Descending Degenerations

The long tract fibres which are cut off from their neurones progressively degenerate.

Note: In transverse lesions of the cord, all the long tracts degenerate either upwards (sensory) or downwards (motor). These particular tracts are shown for illustrative convenience.

The commonest example of descending degeneration is seen following cerebral infarction involving the internal capsule; the degeneration extends from the lesion along the corticospinal axons to their terminations in the anterior horn.

Disorders of Motor Pathways

The concept of upper and lower motor neuronal activity, based on anatomical and physiological evidence, has great clinical value in diagnosis.

It will be appreciated that in its long course from the cerebral cortex to the anterior horn, the upper motor neurone is susceptible to damage from a variety of disease processes acting at various sites. The lower motor neurone may be damaged in the cord or in the peripheral nerve. Important illustrative examples are:

Note: Clinically, tendon jerks are increased and the plantar reflex is extensor.

Motor Neurone Disease

This is a disease of unknown aetiology occurring predominantly in adult males. In a few cases motor neurone disease is familial and is caused by a mutation in the gene encoding a free radical scavenger, superoxide dismutase 1. Other susceptiblity genes have been identified.

Three variants of MND are recognised according to the distribution of the disease process.

1. In progressive muscular atrophy, as the name implies, the main signs are of neurogenic atrophy due to degeneration of the anterior horn cells (LMN).

2. In amyotrophic lateral sclerosis there is both UMN and LMN damage: ‘lateral sclerosis’ indicates the degeneration of the pyramidal tracts.

The lesions are very rarely pure UMN type even initially, and with progression, the LMN lesions increase.

3. Progressive bulbar palsy

In a few cases, the disease begins with signs of cranial nerve dysfunction – swallowing and facial movements are impaired.

Progress

In motor neurone disease after a long progressive illness the stage is reached when the bulbar degeneration is severe enough to prevent elimination of secretions from the respiratory tract. Death is usually due to aspiration bronchopneumonia or respiratory failure.

Mixed Motor and Sensory Disorders

Subacute Combined Degeneration of Cord

Due specifically to vit B₁₂ deficiency. If replacement therapy is begun early enough, there is restoration to normal.

Syringomyelia

In this condition, a glial-lined cystic space gradually expands within the cord, usually in the cervical region. The pathogenesis is not certain, but it is suggested that the lesion is essentially an expansion of the central canal associated with a mild developmental abnormality of the distal end of the IVth ventricle. Some cases follow spinal trauma.

Effects

Damage to sensory fibres decussating in the cord. Loss of temperature and touch in local segments (dissociated anaesthesia).

Destruction of grey matter and gradual affection of long tracts. Loss of local reflexes. Severe sensory loss. Spastic paralysis

Spinocerebellar Degenerations

This is a large group of related disorders, usually familial, in which there is motor and sensory degeneration particularly affecting gait, posture, equilibrium and movement. There is sometimes optic nerve and retinal damage and intellectual disturbance.

Friedreich’s ataxia is the most common hereditary ataxia and is caused by expansion of a trinucleotide triplet repeat in the FRATAXIN gene on chromosome 9. Deficiency of frataxin leads to mitochondrial respiratory chain dysfunction. In addition to the effects of spinocerebellar degeneration there may be cardiomyopathy with arrhythmia.

Sensory Disorders

In TABES DORSALIS, a tertiary manifestation of syphilis in which the lumbar cord is commonly affected, there is degeneration of the posterior nerve roots and columns.

The Neuropathies

3. Polyneuropathy: where there is extensive and symmetrical disturbance of function, often peripheral in distribution and especially affecting the legs. There are many causes:

Toxic – diphtheria; lead; arsenic; drugs used in medicine.

Deficiency states – particularly vit B complex deficiency causing Beri-Beri.

Metabolic disorders – diabetes mellitus; porphyria, metachromatic leukodystrophy, associated with malignant tumours, in uraemia treated by dialysis.

Inflammatory/Immunological – Guillain-Barré syndrome where ascending paralysis occurs usually after a mild febrile illness. Respiratory failure requires supportive treatment but recovery is usually complete.

Other Neuropathies

Bell’s Palsy

This is a unilateral facial weakness of sudden onset. The cause is unclear but it may occur with draughts and chilling and is not uncommon in pregnancy. The mechanism is thought to be inflammation with swelling and compression of the facial nerve in its course in the bone adjacent to the internal auditory meatus. Progress: 75% of cases recover in about 4–8 weeks.

Leprosy

In the lepromatous form, there is a diffuse neuropathy involving the peripheries (which are at the lower temperature required for proliferation of M. leprae).

There is a low grade chronic inflammation of the nerve sheaths associated with fibrosis and nerve fibre degeneration.

Hydrocephalus

In hydrocephalus, the volume of the CSF is increased and the ventricles are dilated. In the majority of cases, there is an increase in intracranial pressure. Three possible mechanisms are considered.

1. Overproduction of CSF

The choroid plexus will secrete more CSF to compensate for any external leak, but overproduction is not a cause of hydrocephalus.

2. Obstruction to the flow of CSF is the common mechanism.

Sites of narrowing particularly

(1) Aqueduct of Sylvius

(2) Foramina of Magendie and Luschka

(3) The subarachnoid space between the midbrain and forebrain (interposition of tentorium cerebelli)

3. Defective absorption of CSF is a rare mechanism.

Causes

The diseases causing hydrocephalus fall into two groups:

1. Congenital (developmental) abnormalities

The common conditions are:

2. Acquired hydrocephalus

Of the many possible conditions causing hydrocephalus, the following are most common: (a) cerebral tumour (primary or secondary) and (b) scarring of the meninges following meningitis or subarachnoid haemorrhage.

As already explained, whether any particular disease produces hydrocephalus depends largely on the site affected.

Effects

In the infant and young child, the pliable skull expands to accommodate the enlarging brain – but these extreme changes do not occur if an effective shunt is inserted.

In the older child and adult, enlargement of the brain is prevented by the inability of the skull to expand. The main change is dilatation of the ventricles associated with the effects on the brain of increased intracranial pressure.

Special Types of Hydrocephalus

1. In cases of generalised cerebral atrophy, the ventricular system enlarges to compensate for the loss of cerebral tissue. This also happens locally when cerebral tissue is lost, e.g. following infarction.

No increase in pressure is involved and the pathological and clinical effects wholly reflect the primary loss of cerebral tissue. The condition is sometimes called secondary hydrocephalus.

2. Normal pressure hydrocephalus

In this rare condition, progressive mental deterioration (dementia) and disturbances of gait and micturition are associated with ventricular dilatation. CSF pressures are usually at the high end of the normal range. The exact mechanism is not understood but it is thought to be a form of communicating hydrocephalus with unpaired CSF reabsorption at the arachnoid granulations. The diagnosis has assumed importance because in some cases CSF shunt procedures have arrested the progress. The aetiology is obscure.

Developmental Abnormalities

Developmental abnormalities of the brain and cranium are relatively common. They range from anencephaly (absence of brain) to minor malformations, e.g. meningocele and encephalocele. There may be associated congenital defects elsewhere in the body.

Secondary Brain Tumours

In the general population the incidence of metastatic cerebral tumour is much higher than that of primary cerebral neoplasm. The two most common primary sites are lung and breast, but any malignant tumour can metastasise to the brain.

Secondary tumours may cause serious spinal damage by destroying the integrity of the vertebrae although the vertebral discs usually remain intact (cf. spinal TB). The prostate and cervix, in addition to lung, breast and kidney, are usual primary sites.

In contrast to tumours causing neurological damage by their physical presence and growth, less commonly non-metastatic effects of cancer are seen.

There is a wide range of disorders which are conveniently divided into two groups:

1. Neurological disorders in which the mechanism and association with cancer are known:

Examples		Mechanism caused by cancer
Opportunistic infections	_______________________	Immune depression
Metabolic and hormonal imbalance	_______________________	Destruction of organs, e.g. liver, kidney Inappropriate secretion
Vascular accidents	______________________	Coagulation disorders