Pa to Log i of Central Nervous St Stem

8/13/2019 Pa to Log i of Central Nervous St Stem

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Disorders of the central nervoussystem

Common pathological featuresIntracranial herniationIntracranial herniation is the movement of part of the

brain from one space to another with resultant damage.It usually occurs following a critical increase in

intracranial pressure caused by an expanding lesion,e.g. tumour or haematoma. However, it may be

inadvertently precipitated by withdrawing

cerebrospinal fluid (CSF) at lumbar puncture.Fig. 5.1 shows a diagrammatical representation of

the sites of intracranial herniation.

Cerebral oedemaThis is an abnormal accumulation of fluid in the

cerebral parenchyma. It is usually the result ofbreakdown of the bloodbrain barrier, and it may

occur following damage initiated by several different

causes: Ischaemia, e.g. from infarction. Trauma, e.g. from head injury.

Inflammation encephalitis or meningitis.

Cerebral tumours (primary or secondary). Metabolic disturbances, e.g. hyponatraemia or

hypoglycaemia.

The condition results in cerebral swelling, and it is

associated with raised intracranial pressure.Treatment is by minimizing the formation of

oedema by use of osmotic agents or steroids.

HydrocephalusHydrocephalus is an increase in the volume of CSF

within the brain resulting in the expansion of thecerebral ventricles. It can occur by one of threemechanisms:

Obstruction to flow of CSF (commonest form). Impaired absorption of CSF at arachnoid villi

(rare). Overproduction of CSF by choroid plexus

neoplasms (very rare).

Obstructive hydrocephalus is either congenital or

acquired.

Congenital hydrocephalusThis occurs in 1 per 1000 births. The principal causes

are congenital malformations, for example:

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5. Pathology of the NervousSystem

falx cerebri

midbrain

ponscerebellum

medulla

dura

skull

tentoriumcerebelli

herniation of cingulate gyrusbeneath falx cerebri

collapse ofventricle

herniation of medialpart of temporal lobeover tentoriumcerebelli

herniation of lower partof cerebellum throughforamen magnum

expandinglesion

herniation ofswollen brainthrough any

defect in duraand skull

C

B

DA

A

B

C

D

lateralventricle

Fig. 5.1 Sites of intracranialherniation. (A) Herniation of thecingulate gyrus beneath the falxcerebri. (B) Herniation of themedial part of the temporal lobeover the tentorium cerebelli.(C) Herniation of the lower part of

the cerebellum through the foramenmagnum. (D) Herniation of swollenbrain through any defect in thedura and skull.


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Pathology of the Nervous System

42

ArnoldChiari malformation (see p. 43). Congenital stenosis of the cerebral aqueduct. Atresia of the foramina of Magendie and Luschka

(DandyWalker syndrome). Some genetic causes associated with X-linked

inheritance.

Acquired hydrocephalus

This may result from any lesion that obstructs theCSF pathway such as: Tumoursespecially if located in the posterior

fossa, as the fourth ventricle aqueducts are easilyobstructed.

Scarringpostinflammatory fibrosis of themeninges at exit foramina, following meningitis orsubarachnoid haemorrhage.

Haemorrhageintraventricular or in the posteriorfossa.

Diagnosis

Severe forms of congenital hydrocephalus may bediagnosed antenatally via ultrasound. Less severe

forms may present with considerably enlarged headsat birth.

In acquired hydrocephalus, enlargement of the headis prevented by the inability of the skull to expand, butthis leads to massive dilatation of the ventriclesresulting in increased intracranial pressure.

Associated features are dementia with gaitdisturbances and incontinence.

Treatment and management

A ventricular shunt with one-way valve system can

be inserted to drain CSF into the peritoneum.

Prognosis

Untreated patients may suffer irreversible braindamage, and the condition is often fatal.

Special types of hydrocephalusSecondary or compensatory hydrocephalus

Here, an increase in CSF occurs as a compensatorymeasure following loss of brain tissue, e.g. due toinfarction or atrophy. There is no associated increase

in CSF pressure.

Normal pressure hydrocephalus (intermittent

pressure hydrocephalus)

This is a rare condition of progressive dementiaassociated with ventricular dilatation. Randomsampling shows normal CSF pressure, butcontinuous monitoring reveals intermittentincreases.

Malformations, developmental

disease, and perinatal injuryNeural tube defects and posterior fossaabnormalitiesThe aetiology of central nervous system (CNS)malformations includes genetic factors, maternalinfections, toxicity, metabolic factors, and irradiation

in utero. Neural tube defects are the commonestcongenital abnormalities of the CNS, and they arecaused by defective closure of the midline structuresover the neural tube. Screening for neural tubedefects can be performed with ultrasound or bymeasurement of -fetoprotein in the maternal serumor amniotic fluid. This is raised in 90% of cases.Posterior fossa abnormalities are the second mostcommon development abnormality of the CNS. Fig.5.2 illustrates the types of congenital abnormalities.

Syringomyelia and hydromyeliaSyringomyelia is a rare condition in which a cyst(syrinx) develops within the spinal cord, usuallyposterior to the central canal (Fig. 5.3). The cavity is

lined by gliosis (astrocytes). It is most common in thecervical spinal cord, but it may extend into themedulla (syringobulbia).

Hydromyelia is the term used to denote cases inwhich the dilatated central canal contains CSF, and islined by ependyma.

The causes of these conditions are either: Acquired (majority of cases)secondary to

trauma or ischaemia, or occurring in associationwith tumours of the spinal cord.

Congenitalmay be associated withmaldevelopment of the cord or otherdevelopmental abnormalities of thecraniocervical junction, especially inArnoldChiari syndrome.

Obstructive hydrocephalus isby far the most commonform of hydrocephalus. Itis commonly subdivided

into: Non-communicating hydro-

cephalusobstruction within theventricular system leading toblockage of CSF flow from theventricles to the subarachnoid space.

Communicating hydrocephalusextraventricular obstruction withinsubarachnoid space.


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Disorders of the Central Nervous System

43

The clinical manifestations are muscle weakness

and atrophy in the upper limbs due to compressionof the anterior horn cells. There is loss of the

sensations of pain and temperature, butpreservation of those of position and vibration, due

to damage to nerve fibres crossing the cord in the

lateral spinothalamic tracts.Surgery may arrest or alleviate symptoms by

decompression or by draining the fluid in the cystic

cavity.

Perinatal injuryCerebral palsyCerebral palsy describes brain malformation ordamage affecting motor areas of the brain. It is the

leading cause of crippling handicap in children,affecting 2 per 1000 live births. Damage may occur

during fetal life, may be birth related, or may occur

postnatally (Fig. 5.4).The different types of cerebral palsy are outlined

in Fig. 5.5.

Fig. 5.2 Types of congenitalabnormality.

Condition

Neural tube defects with cranial involvement

Anencephaly

Encephalocoele

Neural tube defects with spinal involvement

Spina bifida occulta

Spina bifida cystica

Posterior fossa abnormalities

ArnoldChiari malformation

DandyWalker malformation

Types of congenital abnormality

Features

Absence of the cranial vault and failure in the development ofthe cerebral hemispheres

Ossification defects in the bones of the skull results inherniation of the brain and meninges. Most common form isoccipital

Abnormal development of the vertebral arches but the cordand meninges are normal. Usually asymptomatic

Presents as either meningomyelocoele (90% of cases) ormeningocoele (10% of cases). Abnormal development of the

vertebral arches results in cystic outpouching

Prolongation of the cerebellum downwards through theforamen magnum often resulting in obstructivehydrocephalus

Obstruction of the foramina of Luschka and Magendie (exit ofthe fourth ventricle) results in the formation of a cyst-likestructure between the cerebellar hemispheres

early late

A B

Fig. 5.3 Syringomyelia. (A) Early effects: damage to the

decussating sensory fibres, with loss of temperature andtouch in local segments. (B) Late effects: destruction ofgrey matter and gradual affection of long tracts with lossof local reflexes, severe sensory loss, and spastic paralysis.

Cerebral malformationCerebrovascular accidentHypoglycaemiaHypoxiaInfectionKernicterus (bilirubin-induced brain damage)PoisoningToxinsTrauma (peri- and postnatal)

Causes of cerebral palsy

Fig. 5.4 Types of cerebral palsy and their associatedcharacteristics.


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Ischaemia and hypoxia

Ischaemia and hypoxia are major causes of severeperinatal brain damage. Perinatal hypoxia is usuallydue to asphyxiation associated with the trauma ofbirth, whereas perinatal ischaemia is commonlycaused by intracranial haemorrhages.

Premature infants are highly susceptible todeveloping intracranial haemorrhages because ofdisturbances in the cerebral circulation possiblycaused by in-utero hypoxia/ischaemia.

In full-term infants, intracranial haemorrhageswith the formation of small haematomas mayoccur during difficult deliveries, although this isless common now because of improved obstetriccare.

Mortality is high; one third of survivors maydevelop cerebral palsy, epilepsy, or mentalretardation.

Traumatic injuries to the central

nervous systemSkull fracturesSkull fractures occur in approximately 80% of fatalcases of head injuries. The most common are linearfractures of the vault of the skull (62%); suchfractures may extend into the base of the skullcausing cranial nerve laceration.

The other types of skull fracture are: Penetratingincreased risk of infection due to

tearing of the dura. Compoundincreased risk of infection due

to laceration of the scalp and tearing of the dura. Depressedincreased incidence of epilepsy. Comminuted (fragmented)increased incidence

of massive brain damage.

Parenchymal damageConcussion

This is an abrupt transient loss of consciousness dueto temporal neuronal dysfunction following arelatively slight impact. It is caused by an enormous,

but short-lived, increase in pressure within thecranium at time of impact. Full recovery usuallyensues, although repeated concussion may result inpermanent brain damage.

Contusions and lacerations

A contusion is a bruise with extravasation of bloodbut with the pia-arachnoid intact. A laceration iswhere the pia-arachnoid is torn.

Both are focal types of brain damage occurring at themoment of injury, caused by striking the brain against

adjacent bone. They are most common at the frontaland occipital poles and mainly affect the crests of gyri.Both lesions are characteristically haemorrhagic.

Types of contusion: Fracture contusionoccurs at the site of fracture. Coup contusionoccurs at point of impact in

absence of fracture. Contrecoup contusionoccurs diametrically

opposite to the site of impact. Herniation contusionoccurs when the

hippocampi or cerebellar tonsils (or both)

are impacted and bruised by the free edge of thetentorium and foramen magnum, respectively.

Gliding contusionoccurs at the superior marginsof the cerebral hemispheres; usually caused byinterference of the dura with a rotationalmovement of the brain.

Diffuse axonal injury

The condition is produced as a result of rotationalmovements of the brain within the skull during angularacceleration or deceleration. It often occurs in the

absence of any skull fracture or cerebral contusions.There are two main features:

Small haemorrhagic lesions in the corpus callosumand the dorso-lateral quadrant of brainstem(macroscopic).

Widespread tearing of axons (microscopic).

This type of injury occurs in almost 50% of patientswith a severe head injury, and in almost all fatal headinjuries. It is associated with head injuries involvingvehicular accidents.

Traumatic vascular injuryBleeding from craniocerebral trauma is oftenassociated with high mortality, and it may take place


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Type

Spastic cerebral palsy (70%)

Dystonic (athetoid) cerebralpalsy (10%)

Ataxic cerebral palsy (10%)

Mixed cerebral palsy (10%)

Types of cerebral palsy and their associated characteristics

Characteristics

Hypertonia, ankle clonus and

extensor plantar response

Irregular, involuntary musclemovements

Hypotonia, weakness,uncoordinated movementsand intention tremor

Fig. 5.5 Causes of cerebral palsy.


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in one or more of the potential spaces surrounding

the brain, e.g. extradural and subdural.

Extradural (epidural) haemorrhageThis type occurs in 2% of all head injuries and in 15%

of fatal cases. Haemorrhage occurs between the skulland dura, and gradually stripping dura from boneforming a large, saucer-shaped haematoma (Fig. 5.6).

This injury is almost always the result of skullfracture, usually a linear fracture of the thin

squamous part of the temporal bone, which contains

the middle meningeal artery (a branch of themaxillary artery).

It is associated with a post-traumatic lucid intervalof several hours followed by a rapid increase in

intracranial pressure.

Subdural haemorrhageHaemorrhage occurs between the dura and the outersurface of the arachnoid membrane. It is usually

caused by a rupture of the small bridging veins or thevenous sinuses. The resulting haematoma is often

extensive because of the loose attachment of the

dura and arachnoid membranes.Subdural haemorrhage may be acute or chronic.

Acute subdural haemorrhage is associated with: Severe head injury, subarachnoid haemorrhage,

and cerebral contusions. A rapid increase in intracranial pressure.

Chronic subdural haemorrhage has the following

characteristics: More common in the very young and elderly.

Usually occurs as a result of minimal trauma, oras a result of cerebral atrophy (in the elderly),

which causes a gradual widening of thesubdural space leading to rupture of the bridging

veins. Blood typically accumulates slowly over a period

of days or weeks.

Presents with personality change, memory loss,and confusion.

Subarachnoid haemorrhageArterial rupture is usually secondary to superficial

contusions or lacerations of the brain. Small amounts

of blood can be disposed of by arachnoid granulations.Larger haemorrhages cause arachnoid fibrosis leading

to meningeal irritation and raised intracranial pressure.It can also occur as a result of hypertension, aneurysms,

embolisms, or infarction.

Intracerebral haemorrhageThis is caused by direct rupture of the intrinsiccerebral vessels at the time of injury.

Resulting haematomas are classified into three

types:

Solitaryoccur in association with corticalcontusions; common in temporal and frontalpoles.

Multipleassociated with severe contrecouplesions; often fatal.

Burst lobeintracerebral or intracerebellarhaematoma in continuity with subdural

haematoma; most common in temporal andfrontal lobes; rapidly fatal.

Spinal cord injuries

Most spinal injuries occur in males aged under 40years. Road traffic accidents account for more than80% of such injuries.

There are two types of spinal cord injuriesopenand closed.

Open injuries

These are rare, and they are a result of direct traumato the spinal cord and nerve roots. They can be either

perforating (i.e. with extensive disruption andhaemorrhage) or penetrating (i.e. with incomplete

cord transectionBrownSquards syndrome).

Closed injuriesThese are in the majority, and they are associated

with fracture or dislocation of the spinal column


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scalp

skulldura

arachnoid

CSF

pia

brain

skullfracture middle

meningealartery

extradural

haematoma

Fig. 5.6 Extradural haemorrhage. (Redrawn with permissionfrom Pathology by A Stevens and J Lowe, Mosby.)


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causing compression of the cord by distortion of thespinal canal.

Primary damage: Contusions. Nerve fibre transection. Haemorrhagic necrosis.

Secondary damage: Extradural haematoma. Infarction. Infection. Oedema.

The consequences depend mainly on the site andseverity of the lesion. Cervical lesions result intetraplegia; lower thoracic lesions result inparaplegia.

Cerebrovascular diseaseCerebrovascular disease is the third leading cause ofdeath in the UK.

Stroke is a common outcome of cerebrovasculardisease, and it is defined as a sudden event in which aneurological deficit occurs over minutes or hours andlasts for longer than 24 hours.

If CNS disturbance lasts for less than 24 hours,

then the condition is termed a transient ischaemicattack.

The incidence is 1 or 2 per 1000 per year, but it ismuch higher in the elderly, affecting males more thanfemales.

Causes of stroke are: Cerebral infarction (80%). Intracerebral haemorrhage (10%). Subarachnoid haemorrhage (10%).

Pathological effects occur because of extensive

hypoxic neuronal damage. The area of brainaffected can be readily localized since the bloodsupply of the brain has a fairly constant anatomicdistribution. Fig. 5.7 shows the territories of themajor arteries.


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anterior cerebral artery

internal carotid artery

posterior communicating artery

superior cerebellar artery

vertebral artery

basilar artery

A B C

posterior cerebral artery

deep branches

superficial branches

middle cerebral artery

anterior communicating artery

key

anterior cerebral arterymiddle cerebral arteryposterior cerebral artery

1

2

Fig. 5.7 Territories of the majorarteries. (1) Main cerebral arteriesforming circle of Willis. (2) Their ter-ritories: (A) Lateral view. (B) Inferiorview. (C) Medial view. (Reproducedwith permission from AndersonsPathology, Damjanou, ed., Mosby.)


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Clinical features of stroke depend on localization

and the nature of the lesion. Risk factors areatheroma, heart disease, hypertension, and diabetes

mellitus.

Hypoxia, ischaemia and infarctionCerebral infarction is the process whereby a focal

area of necrosis is produced in the brain in response

to a decreased supply of oxygen (and glucose) in theterritory of a cerebral arterial branch.

There are two main causes of infarction: Hypoxiathe reduction of oxygen supply to

tissues despite an adequate blood supply, e.g.following respiratory arrest.

Ischaemiablood supply to tissues is absent, orseverely reduced, usually as a result of

constriction or obstruction of a blood vessel.

Ischaemia accounts for the majority of cases ofcerebral infarction.

Mechanisms of ischaemiaIschaemia may be caused by: Vascular diseasee.g. thrombosis, embolic

occlusion or vasculitis. Cardiac diseasee.g. prolonged hypotension or

cardiac embolism. Traumahead injury leading to vascular

occlusion, dissection, or rupture.

Infarcted tissue becomes swollen and soft with

the loss of definition between grey and white matter.The infarcted tissue undergoes colliquative necrosis

and shows microglial macrophage infiltration.Eventually, the necrotic tissue is completely

phagocytosed to leave a fluid-filled cystic cavity witha gliotic wall. Fig. 5.8 shows the macroscopic and

microscopic pathological features of cerebral

infarction.Strokes caused by cerebral infarction clinically

present with slowly evolving signs and symptoms.

Atraumatic haemorrhageIntracerebral haemorrhageThe majority of intracerebral haemorrhages are

thought to arise from CharcotBouchardmicroaneurysms associated with hypertension and

diabetic vascular disease. These haemorrhages occurmost frequently in the basal ganglia (80%),

brainstem, cerebellum, and cerebral cortex.The resulting haematoma acts as a space-

occupying lesion leading to increased intracranialpressure and herniation. The clinical picture is

often indistinguishable from a cerebral infarction,but the raised intracranial pressure commonly

gives rise to sudden headache, vomiting, andimpairment of consciousness. Mortality is about

80%.

Subarachnoid haemorrhageThis can occur at any age, but it is an important cause

of death and disability in the 2040 year age group.The majority of subarachnoid haemorrhages are

caused by saccular berry aneurysms, which develop

at proximal branch points in the major cerebralvessels on the circle of Willis (Fig. 5.9).

These aneurysms occur in 12% of the population,but they are more common in the elderly and

hypertensives.The clinical picture is one of sudden onset of

severe headache accompanied by neck pain/stiffnessand vomiting. Only 3040% survive for a few hours;

among those who survive longer, there is a 30%mortality rate within the first month.

Time

Before 24 h

After 24 h

After a few days

After weeks/months

Macroscopic

No naked eye abnormalities

Softening and swelling (oedema) of affected tissue

Necrotic tissue

Fluid-filled cystic cavity with gliotic wall

Pathological features of cerebral infarction

Microscopic

Some neuronal damage

Line of demarcation between normal and abnormal myelinin white matter

Infiltrating macrophagesProliferating astrocytes and capillaries

Necrotic tissue removedThickened capillary wallsOnly astrocytes remain

Fig. 5.8 Pathological features of cerebral infarction.


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Hypertensive cerebrovascular diseaseSystemic hypertension can affect the CNS resultingin neurological dysfunction, thus:

Atheroma of the larger cerebral vessels leads to aloss of autoregulation of cerebral blood flow.

Aneurysms, both saccular and microaneurysms,may cause spontaneous intracerebralhaemorrhage.

Encephalopathypathogenesis is uncertain butdamage to the bloodbrain barrier leads to forcedcerebral hyperperfusion.

Infections of the central nervoussystemBacterial meningitisMeningitis refers to inflammation of the meninges.There are two classes: leptomeningitis withinflammation centred on the subarachnoid space,and pachymeningitis with inflammation centred onthe dura.

Acute pyogenic (bacterial) meningitisThis is infection of the leptomeningespia andarachnoid materand the CSF, which diffuselyaffects the whole meninges and subarachnoid space.Organisms that typically cause this condition vary

between age groups (Fig. 5.10).The clinical features are headache, drowsiness,

vomiting, fever, petechial rash, and neck stiffness.The complications are:

Ventriculitis. Intracerebral abscess (see below). Cerebral infarction. Subdural empyema. Epilepsy. Disseminated intravascular coagulation (DIC). Adrenal haemorrhage.

Diagnosis and managementThe CSF is cloudy dueto increased numbers of neutrophils (>1000cells/mm3). CSF protein levels increase and glucoseconcentrations fall. Treatment is with vigorousantibiotic therapy.


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90% of total

10% of total

middlecerebral

artery

posteriorcerebral

artery

anteriorcerebral

artery

basilarartery

30% occurhere

30%occur here

10% occurhere

30% occurhere

Fig. 5.9 Berry aneurysmsapproximate frequency anddistribution. The dotted line separates anterior fromposterior circulation. (Redrawn with permission fromAndersons Pathology, Damjanou, ed., Mosby.)

There are four possiblemechanisms of meningealinfection: Direct spreadfrom

penetrating trauma (e.g.compound skull fractures) oradjacent focus of infection(e.g. sinusitis, middle ear ormastoid infection).

Blood-borne spreadfromsepticaemia or septic emboli fromother infections such as bacterialendocarditis.

Iatrogenic infectionfollowing the

introduction of organisms into CSFat lumbar puncture. Congenital abnormalities, e.g.

meningomyelocoeles.

Neonates

Escherichia coliGroup B StreptococcusListeria monocytogenes

Infants

Neisseria meningitidisHaemophilus influenzae

Streptococcus pneumoniae

Meningitis-causing bacteria

Young adults

N. meningitidisS. pneumoniae

Elderly

S. pneumoniaeN. meningitidisL. monocytogenes

Fig. 5.10 Meningitis-causingbacteria.


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PrognosisMortality ranges from 3% for

Haemophilus influenzae to 60% for Streptococcuspneumoniae, and it is highest in the very young and

the elderly.

Aseptic (viral) meningitisThis is the commonest cause of meningitis. It is abenign and self-limiting illness, usually less severe than

bacterial meningitis. It may occur as a complication ofviral infection, e.g. mumps or measles.

Common causative organisms

The common causative organisms are enteroviruses(e.g. echoviruses, coxsackie viruses, and polioviruses)

and mumps virus.The illness clinically presents with acute onset of

headache, irritability, and rapid development ofmeningeal irritation.

Diagnosis and managementThe CSF is clear andcolourless. It contains excess lymphocytes but

normal glucose and protein. Treatment involves

control of symptoms only.PrognosisComplete recovery usually occurs

without specific therapy.

Brain abscessA brain abscess is a severe focal infection of the brain

and is typically 12 cm across. It starts as an area ofcerebritisinflammation of the brain parenchyma

and develops into a pus-filled cavity walled off by

gliosis and surrounded by cerebral oedema. It oftenresults in raised intracranial pressure.

The aetiology of brain abscesses is as follows: Middle ear infection (60%)temporal lobe and

cerebellar abscesses. Frontal sinusitis (20%)frontal lobe abscess.

Bacteraemia/septicaemia (10%)usually frontallobe abscess.

Penetrating skull trauma. Secondary to meningitis.

Unknown causes.

Common causative organisms are Streptococcus

vividans, Staphylococcus aureus, andKlebsiella, butit may also be caused by fungal infection.

The clinical presentation is similar to that of acute

bacterial meningitis but focal neurological signs,epilepsy, and fever are common manifestations.

Complications include: Meningitis.

Intracranial herniation. Focal neurological deficit.

Epilepsy.

Treatment is with antibiotic therapy at an early

stage, with surgical aspiration or excision of thecapsule.

PrognosisOverall mortality is about 10%.

Subdural empyemaThis is a collection of pus in the subdural space and itis relatively uncommon. In adults it usually results

from frontal sinusitis, whereas in infants it is usuallysecondary to meningitis.

Clinically, patients with subdural empyema areusually very ill. The pus spreads rapidly on the

surface of a hemisphere, producing hemiparesis,

raised intracranial pressure, fits, and meningism.

Chronic meningoencephalitisTuberculous meningitis

This is meningitis due to infection byMycobacteriumtuberculosis. It is rare in the UK but a major problem

in developing countries.The disorder is almost always secondary to

tuberculosis elsewhere in the body; infection usuallyreaches the CNS via the bloodstream.

PathogenesisGranulomatous inflammationaffects the basal meninges, large arteries and cranial

nerves.

It presents clinically with slow-onset, subacutemeningitis. It may be accompanied by isolated cranial

nerve palsies.Hydrocephalus may result from impaired

reabsorption of CSF or obstruction of CSF outflowfrom the fourth ventricle.

CSF shows an initial increase in polymorphs, thenan increase in lymphocytes.

PrognosisUntreated, the disease is usually fatal.Intensive treatment with antituberculous drugs

lowers mortality to 1520%.Chronic meningitisThis is a rare condition, which usually occurs in the

middle-aged and elderly.Neisseria meningitidis isthe most common cause. The patient can be unwell

for weeks or even months with recurrent fever,sweating, joint pains, and transient rash.

NeurosyphilisThis is caused by invasion of the CNS by Treponema

pallidum weeks, months, or years after initialinfection. Meningitic illness occurs in only

approximately 25% of cases of syphilis. It is usuallymild or even asymptomatic, but it may be severe

with transient cranial nerve palsies and convulsions.


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Lyme disease

This disorder is caused by the tick-borne spirochaete

Borrelia burgdorferi. It is a systemic illnesscharacterized by skin lesions and neurological features.

Viral encephalitisThis is a virally induced diffuse inflammation ofthe brain, which is usually concomitant withinflammation of the meninges. It is a commoncomplication of many viral illnesses. Commoncausative viruses are: Arboviruses. Herpes simplex virus I and II. Measles. Cytomegalovirus. Polio and enterovirus. Rabies. Human immunodeficiency virus (HIV).

Most cases are mild and self-limiting. However, somecases (e.g. those involving herpes simplex virus type Iand rabies) result in extensive tissue destruction andmay be fatal.

Mortality for the more severe type is 50%, and themajority of survivors have severe, permanent braindamage.

Fungal infectionsThese are relatively rare and occur mainly in theimmunosuppressed (e.g. associated withchemotherapy, steroid treatment, acquired immunedeficiency syndromeAIDS), but some organisms,e.g. Cryptococcus neoformans, can produce disease inthe absence of immunosuppression.

The spread can be haematogenous (e.g. fromthe lungs, which is the most common) or direct

(e.g. from the nose and paranasal sinuses, which israre).Causative organisms are:

Cryptococcus neoformansfungal meningitis. Aspergillus fumigatusfungal abscesses usually

accompanied by pulmonary infection. Candida albicansfungal abscesses. Phycomycosisthrombosis and associated

infarction; commonly affects uncontrolleddiabetics.

Protozoal infectionToxoplasmosis

This is caused by infection with Toxoplasmagondii. It may be acquired by eating poorly-

cooked infected meat or food contaminated withfeline faeces. It has two forms: congenital andacquired.

The incidence of congenital toxoplasmosis showsgeographical variation, e.g. 1 per 4000 births in the

US; 1 per 100 births in France. The organism istransmitted to the fetus through the placenta duringmaternal infection.

The infection can cause: Abortion or stillbirth. Severe brain damage leading to early death. Moderate brain damage and chorioretinitis;

compatible with life but with permanentdisability.

Acquired toxoplasmosis is the commonestopportunistic infection of the CNS in adults withAIDS. It results in: Necrotizing cerebritis. Chronic abscesses. Meningoencephalitis.

However, in healthy subjects, it rarely causescerebral symptoms.

Other protozoan organisms that may causeinfection of the CNS are:

Amoebae. Plasmodium falciparum. Trypanosomes.

Progressive multifocal leucoencephalopathyMultifocal destruction of oligodendrocytes results indemyelination with minimal inflammation andminimal damage to axons. It is caused by the DNAJC papovavirus, and it occurs in association withunderlying diseases such as AIDS, chroniclymphocytic leukaemia, carcinoma, and systemic

lupus erythematosus.Patients present with progressive dementia. The

disease is progressive and death usually occurs withina few months.

Subacute sclerosing panencephalopathyThis subacute encephalitis occurring in children isdue to persistent measles infection. It presents withprogressive neurological dementia, and death usuallyoccurs within two years of onset.

Spongiform encephalitis (CreutzfeldtJakobdisease)This is rapidly progressive dementia, ataxia, andmyoclonus, and it is rare in the UK (at 1 per 1 000 000


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51

per year). The infectious agent is not precisely

known, but it is most likely to be non-nucleic acidtransmission by prion (or proteinaceous infectious

agent) protein (see page 33). The condition has anincubation period of up to 30 years but it is always

fatal, usually within 6 months.A recently described variant appears to be the

human manifestation of bovine spongiform

encephalopathy.

Demyelination and degenerationDemyelinating diseasesThis group of diseases has a common factor ofprimary damage to myelin of nerves while the axons

and nerve cells remain relatively intact.

Multiple sclerosisMultiple sclerosis (MS) is the commonest

demyelinating disorder of the CNS affecting 50 per100 000 in the UK. Peak incidence is between 20

and 40 years with a slight female predominance.MS is characterized by relapsing and remitting

episodes of immunologically mediateddemyelination within the CNS. Recovery from each

episode of demyelination is usually incomplete,leading to progressive deterioration. There is an

association between the disease and certain HLA

antigens (A3, B7, DR2 & DQ1). However theaetiology is unknown but current theories are: Myelin abnormality. Autoimmune disorder.

Toxin damage. Viral infection of the CNS, e.g. measles.

PathogenesisAcute demyelination occurs in the

central white matter in discrete areas known asplaques. Abnormalities are confined to the CNS; the

peripheral nervous system (PNS) is usually spared.Common sites are the optic nerve, brainstem,

cerebellum, periventricular regions, and cervical

spinal cord.Fig. 5.11 gives a list of the clinical manifestations

of MS and their causes.Diagnosis and managementClinical evaluation

and computed tomography (CT) and magneticresonance imaging (MRI) scans can show areas ofdemyelination within the brain. CSF examination

shows increased lymphoid cells and oligoclonalbands of IgG. There is no specific treatment

but corticosteroids may accelerate remission inrelapse. Beta-interferon has also been used to some

success.The diseases progress is variable. In about 5% of

patients, the disease is rapidly progressive and fatalwithin 5 years. However, others may survive for

more than 20 years with only minor disability.

Degenerative disordersCorticalAlzheimers disease

This is the most common cause of dementia inWestern countries. In the UK it affects 5% of

people over 65 years, and 15% of people over 80years; females more than males. Also of significance

is the subgroup of early onset patients (4060years). Genetic studies have shown that there is an

increase in incidence of sporadic cases in individualswith ApoEe4 genotype on chromosome 19. The

amyloid precursor protein (APP) gene onchromosome 21 has been implicated in the familial

cases.However, the aetiology and pathogenesis are

unknown; some cases (5%) are familial but most

(95%) are sporadic. Current theories involve: Infectious agents.

Toxins, e.g. aluminium. Traumatic injury.

Manifestations

Early clinical symptoms. blurring of vision. incoordination. abnormal sensation

Late stages. blindness, paraplegia and incontinence. ataxia. intellectual dysfunction

Clinical manifestations of MS and their causes

Causes

Optic nerve diseaseCerebellar peduncle diseaseDisease of long ascending sensory tracts

Spinal tract involvementSpinal and cerebellar involvementLoss of hemispheric white matter

Fig. 5.11 Clinical manifestations ofmultiple sclerosis (MS) and theircauses.


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53

Metabolic disorders and toxinsVitamin deficienciesVitamin B1 (thiamine) deficiencyThis is common in chronic alcoholics, resulting in:

Wernickes encephalopathy: memory impairment,

ataxia, visual disturbances, and peripheralneuropathy.

Korsakoff s psychosis: confused state, memory

loss, and confabulation.

If both occur, it is known as WernickeKorsakoff

syndrome.

Vitamin B12 (cyanocobalamin) deficiencyThis produces weakness and paraesthesia in the

lower limbs resulting from subacute combined

degeneration of the spinal cord (Fig. 5.13).Replacement therapy at an early stage reverses thedegenerative process, but long-standing cases show

irreversible axonal damage with reactive gliosis.

Iodine deficiencySevere iodine deficiency causes hypothyroidism; it is

the most important endocrine disorder to affect theCNS in children. In the fetus, severe iodine deficiency

causes cretinism characterized by dwarfism, mentaldefect, and spastic diplegia. This can be prevented by

iodine supplements during pregnancy.

ToxinsCarbon monoxideCarbon monoxide (CO) binds irreversibly to

haemoglobin, rendering erythrocytes incapable ofoxygen transport. CO poisoning, therefore, results in

brain damage due to hypoxia. This poisoning may beaccidental or associated with attempted suicide.

The amount of carbon monoxide-boundhaemoglobin (HbCO) with corresponding clinical

symptoms are as follows:

>20%Dyspnoea and slight headache.

30%Severe headache, fatigue, and impairedjudgement.

6070%Loss of consciousness. >70%Rapidly fatal.

PathogenesisHypoxia results in neuronal necrosis

with a predilection for globus pallidus. Other

selectively vulnerable regions are the hippocampus,and cerebral and cerebellar cortices.

MethanolMethanol is highly toxic to the CNS. It is lipid

soluble, so it readily diffuses into the CSF andaqueous humour in concentrations higher than in

plasma.

Methanol is metabolized into formic acid andformaldehyde. It is the formaldehyde that is thoughtto be the mediator of toxic effects. There are two

types of methanol poisoning: Acutesudden death with multiple haemorrhagic

lesions in the cerebral hemispheres. Chronicatrophy of retinal ganglion cells with

secondary degeneration of the optic nerve.

EthanolThe consequences of excessive ethanol intake on the

CNS are manifold (Fig. 5.14).

Neoplasms of the central nervoussystemGliomasGliomas are tumours that arise from glial supportive

tissue of brain. They are the most common primarybrain tumours, accounting for 50% of all CNS

tumours.

Astrocytoma

This is a glioma derived from astrocytes, and it ismore common in children, usually occurring in thecerebellum. It accounts for 10% of all primary

tumours in adults, usually in the cerebralhemispheres.

Common types of astrocytomas and theircorresponding tumour grading:

Benign juvenile pilocytic astrocytoma (grade I). Astrocytoma (grade I/II).

Anaplastic astrocytoma (grade III).

Glioblastoma multiforme (grade IV).

Prognosis depends on the degree of tumourdifferentiation and the size of the neoplasm. For

example:

Degeneration of:posterior columnsandcorticospinal tracts

Fig. 5.13 Subacute combined degeneration of the spinalcord. Degeneration of posterior columns leads to sensoryloss (vibration and proprioception) causing ataxia.Degeneration of corticospinal tracts leads to upper motorneuron damage causing spastic paralysis.


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Grade I: survival times of 2030 years are possible. Grade IV: 20% survive for 1 year.

Oligodendrogliomas

These ill-defined, slow-growing tumours arise fromoligodendrocytes in the white matter of the cerebralhemispheres, especially the temporal lobe. Theyaccount for 5% of all primary CNS neoplasms in

adults, but they are rare in children.The prognosis is relatively good.

Ependymoma

These tumours arise from the ependymal cells liningthe ventricle and central canal of the spinal cord.Ependymoma is the most common tumour of the spinalcord, accounting for 5% of all primary CNS neoplasms.It is common in children and young adults.

Medulloblastoma

This tumour of primitive neuroepithelial cells arisesin the cerebellum in children, in whom it is the mostcommon CNS tumour. It is malignant, with a rapidgrowth rate; obstruction of the fourth ventricleresults in hydrocephalus.

Other tumoursPrimary brain lymphomas

Associated with immunosuppression, especiallyAIDS, most primary brain lymphomas are highgrade, non-Hodgkins lymphomas of B cell type with

a poor prognosis.

Germ cell tumours

These rare tumours are seen mainly in children;males more than females. Most arise near the

pineal gland, and they behave as malignantteratomas.

Meningiomas

These account for approximately 15% of adultintracranial tumours; females more than males.Tumours arise from the arachnoid mater, and theyare usually benign but may invade adjacent bone

resulting in erosion and hyperosteosis. Meningiomasproduce symptoms by compression of brain tissuerather than by invasion.

Metastatic tumours

The CNS is a common site for metastasis, andtumours are usually multiple. They may arise fromhaematogenous or direct spread. The cerebellum isthe preferred site but they can affect any part of thebrain as well as other intracranial structures,especially meninges (hence malignant meningitis).

Metastases often occur at the boundary betweengrey and white matter.The most common neoplasms to metastasize to

the CNS are: Breast carcinomas. Bronchus carcinomas. Kidney carcinomas. Colon carcinomas. Malignant melanoma.

Disorders of the peripheralnervous system

Disorders of peripheral nerves are termedneuropathies, and they can be predominantly


54

Disease

Fetal alcohol syndrome

Acute intoxication

Cerebral and cerebellar atrophy

Nutritional disorders

Hepatocerebral syndromes

Demyelinating disorders

Features

Cerebral malformations

Facial and somatic malformationsGrowth retardation

Cerebral oedemaPetechial haemorrhages

Neuronal loss

Wernicke s encephalophathy

Hepatic encephalopathyChronic hepatocerebral degeneration

Central pontine myelinolysis

Consequences of excess ethanol intake on the central nervous system

Mechanism

Direct toxicity

Direct toxicity

Direct toxicity

Deficiency of vitamin B1

Hepatic toxicity with secondary effects on CNS

Electrolyte disturbances

Fig. 5.14 Consequences of excess ethanol intake on the CNS. (Adapted from Underwood, 2000.)


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sensory, predominantly motor, or mixed depending

on which nerves are affected.

Hereditary neuropathiesHereditary motor and sensory neuropathies

(HMSN)Peroneal muscular atrophy (HMSN I+II;CharcotMarieTooth disease)This disorder is characterized by pronounced atrophyof the calf muscles with associated sensory deficits as

a result of slowly progressive symmetric neuropathy.It is the commonest of the hereditary neuropathies,

and it is usually autosomal dominant. It impedesambulation and causes foot deformities (pes cavus),

but it does not shorten the lifespan.

Fig. 5.15 provides a table of the different types

of peroneal muscular atrophy and theircharacteristics.

DejerineSottas disease (HMSN III)This severe, chronically progressive symmetric

peripheral neuropathy is caused by hypertrophy ofperipheral nerves, followed by gradual axon

degeneration. There is delayed onset of motor skills(e.g. in walking) and gradual progression to

wheelchair confinement in young adult life.

Hereditary sensory and autonomicneuropathies (HSAN)This group of autosomal inherited diseases produce

mainly sensory and autonomic neuropathies. Thereare three major types as described in Fig. 5.16.

Traumatic neuropathiesLacerationsLaceration refers to a jagged tear of the peripheral

nerve in which there is partial or complete loss of

continuity of the nerve. It occurs most commonly

from a penetrating injury such as a knife wound, or a

misplaced intramuscular injection, or from bone

fractures.

AvulsionThis is the tearing of nerve fibres from the surface of

the spinal cord or from a muscle. It may be partial orcomplete depending on whether all or only some of

the rootlets contributing to the spinal nerve areinvolved.

Nerve roots may be avulsed from the spinal cord

in two ways: Tensile stresses from cervical plexus transmitted

centrally can stretch and finally avulse the nerveroots.

A spinal cord injury, such that displacement of thecord acts directly on the nerve roots between their

attachment to the cord and their entry into theintravertebral foramen.

Both laceration and avulsion injuries cause the

severed ends of the damaged nerve to retract and

then to undergo Wallerian degeneration forming a

Disorders of the Peripheral Nervous System

55

Note that: Disorders affecting many

peripheral nerves are termedpolyneuropathies, and they

usually cause symmetricaldeficits.

Disorders affecting only one(mononeuropathy) or a few(multiple mononeuropathies)peripheral nerves typically causeasymmetrical deficits.

Radiculopathies are disorders ofnerve roots.

Type of neuropathy

Relative occurrence

Type of axonal loss

Nerve conduction velocity

Time of onset

Effects

HMSN I

Demyelinating neuropathy

75%

Large calibre axons

Impaired (45 m/s)

Later (second decade)

Weakness and wasting less marked

Fig. 5.15 Different types ofperoneal muscular atrophy and theircharacteristics.


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traumatic neuroma. Subsequently, the proximalportion of the nerve develops neuritic sprouts which,if sited in proximity to the severed distal nerve, mayreinnervate by regrowth along the nerve sheath.

If continuity of the nerve is completelyinterrupted, basal laminae sheaths no longer formcontinuous tubes to guide regeneration sprouts andso the potential for recovery is limited.

Compression/entrapment neuropathyCompressed nerves undergo segmental

demyelination with decreased nerve conductionvelocity. If compression is prolonged or severe,axonal degeneration may occur. Symptoms of nervecompression are paraesthesia, anaesthesia, and loss ofmuscle strength.

Carpal tunnel syndrome

This is a disorder in which the size of the carpaltunnel is significantly reduced causing compression

of the median nerve. Causes include inflammationof the flexor retinaculum, arthritic changes, etc.

Saturday night palsy

Radial nerve compression (in the middle of the arm),which may result from improper positioning of theupper limb during sleeping, especially in intoxicatedpersons.

Inflammatory neuropathiesGuillainBarr syndrome (acute inflammatorydemyelinating polyradiculopathy)

This is the commonest form of acute neuropathycaused by immune-mediated demyelination ofperipheral nerves, usually occurring 24 weeks afterviral illness.

Affected patients develop motor neuropathy withlesser sensory changes due to widespreaddemyelination of the peripheral nerves. Recovery(i.e. remyelination) occurs over 34 months and isusually complete.

Infectious neuropathiesLeprosy (Hansens disease)A chronic granulomatous disease caused by

Mycobacterium leprae. It is the most common causeof peripheral neuritis worldwide, affecting about 10million patients in total.

The clinicopathological features of leprosy aredependent on the hosts response to infection, with aspectrum of disease ranging from tuberculoid tolepromatous form (Fig. 5.17).

Varicella-zoster virus (VZV)An invasion of cutaneous sensory nerves duringprimary infection with VZV (chickenpox) leads toinfection of the dorsal root ganglia where the virusenters a latent state. Reactivation of VZV may occur

Clinical syndrome

Eponym

Inheritance

Affected neurons

HSAN II

Congenital sensory neuropathy

Giacci s

Autosomal recessive

Degeneration of large andsmall myelinated fibres

Types of hereditary sensory and autonomic neuropathies (HSANs)

HSAN I

Ulcerative acropathy due to numbness

Morvan s

Autosomal dominant

Degeneration of large myelinated fibresof both peripheral nerves andposterior columns of spinal cord

HSAN III

Familial dysautonomia

RileyDay

Autosomal recessive

Degeneration of non-myelinated fibreswith preservation of myelinated fibres

Loss of neurons of autonomic ganglia

Fig. 5.16 Types of hereditary sensory and autonomic neuropathy.

Common sites of nervecompression are: Nerve roots in the

intervertebral foramina byprolapsed intervertebral discsor osteophytes due toosteoarthritis of the spine.

Median nerve in carpal tunnel at thewrist.

Ulnar nerve in flexor carpal tunnelat medial epicondyle of humerus.

Common peroneal nerve at theneck of the fibula.


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Disorders of the Peripheral Nervous System

57

years later causing shingles. The reason forreactivation is unknown, but there is increased

incidence in the immunocompromised.In shingles, VZV migrates down the nerves into

the skin and causes vesicular lesions identical to those

of chickenpox but confined to one or two adjacentdermatomes usually on the trunk.

Metabolic and toxic neuropathiesPeripheral neuropathy of diabetes mellitusThis occurs in both type I and II diabetes mellituswith a prevalence of 1060% clinically, but up to

100% when evaluated by nerve conduction studies.

There is increased prevalence with increasedduration of the disease.

PathogenesisVascular occlusion of the blood vessels supplying the

nerves results in neuronal atrophy.There are four types:

Symmetrical and predominantly sensory

polyneuropathy. Autonomic neuropathy.

Proximal painful motor neuropathy. Cranial mononeuritis (mainly CN III, IV

and VI).

Metabolic and nutritional causesUraemic neuropathy in renal failureApproximately 60% of patients with chronic renalfailure have symptoms of uraemic neuropathy at

onset of dialysis. It is expressed as pain andparaesthesia with the lower extremities

preferentially involved. Dialysis usually improvessymptoms.

Thyroid dysfunctionMild chronic sensorimotor neuropathy is sometimes

seen in both hypothyroidism (more commonly) andhyperthyroidism.

Vitamin deficienciesVitamin deficiencies are important causes of

peripheral neuropathies. Especially important aredeficiencies of vitamins B1 (thiamine), B12, B6(pyridoxine), and E.

Toxic neuropathiesMany toxins cause damage to peripheral nerves. Themost common toxins are: Drugsisoniazides, sulphonamides, vinca

alkaloids, dapsone, and chloroquine. Alcoholin cases of chronic abuse. Industrial toxinsacrylamide, hexane,

organophosphates, lead, arsenic, mercury.

Most toxins produce a dying back pattern of axonaldamage resulting in a distal symmetric pattern of

sensorimotor involvement. There is a stockingglove distribution at onset but continued exposure

to the toxin extends the deficit to the lower calvesand forearms.

Immune mechanism

Spread of organisms

Distribution in nerves

Nerve enlargement and damage

Neurological deficit

Prognosis

Lepromatous

Minimal immune response (occurs in

patients with low cellular immunity)

Bacteraemia occurs in peripheral sites

Widely disseminated diffuse nerveinvolvement

Intense infiltration of nerves byvacuolated macrophages

Sensory and motor involvementPatchy loss of sensation

Progressive and lethal

Comparison of peripheral nerve damage by lepromatous and tuberculoid forms of leprosy

Tuberculoid

Vigorous T cell mediated (delayed) hypersensitivity

Bacteraemia rare

One or a few sites (asymmetrical)

Hallmark of nerve involvement is discrete, well-formedgranulomas

Sensory, motor and autonomic involvementPeripheral nerve palsiesAnaesthetic areas prone to injury and secondary infection

Progression slow, but immune response produces extensive

destruction of tissue resulting in severe disfigurementEventually heals spontaneously

Fig. 5.17 Comparison of peripheral nerve damage by lepromatous and tuberculoid forms of leprosy.


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Disorders of the Autonomic Nervous System

59

Beneficial effectsOf benefit is the reduction of acid and pepsin

secretion by abolishing direct vagal drive (and

to a minor degree by reducing antral gastrin

secretion).

Harmful effectsImpairment of antral motility is caused by abolishing

receptive relaxation in the gastric corpus, andreducing the power of antral contractions.

The harmful effects of truncal vagotomy can nowbe largely overcome by performing a selective

vagotomy instead, but this is less effective and it hasa higher incidence of ulcer recurrence.

Fig. 5.18 Peripheral nervoussystem tumours.

superior

cervicalganglion

middlecervicalganglion

salivaryglands

eye

lungs

inferiorcervical

ganglion

olfactoryglands

Fig. 5.19 Sympathetic innervation to the eye and faceshowing the relationship of the sympathetic trunk to theapex of the lungs.

Tumour

Schwannoma

Neurofibroma

Neurofibromatosis type I

Neurofibromatosis type II

Tuberous sclerosis

Von HippelLindau disease

Peripheral nervous system tumours

Features

Benign tumour of schwann cells of the nerve

sheaths. Most common site is the vestibular branch ofCN VIII

A tumour of the neural crest cells derived from theepineurium and endoneurium

An autosomal dominant neurocutaneous syndrome.Characterized by multiple neurofibromas

Autosomal dominant disorder affecting CN VIII

Autosomal dominant disease causing epilepsy andmental retardation

Autosomal dominant disease characterized by

multiple haemangiomas

Truncal vagotomy means asection of the trunk of thevagus nerve.

Selective vagotomy means

a vagotomy where onlythose vagal fibres that passto the body of the stomachare divided, while thosesupplying the antrum,pylorus, and otherabdominal viscera arespared.


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Describe the common pathological features of the CNS. What are the congenital malformations and developmental diseases of the CNS? Give examples of types of traumatic injury that affect the CNS. What is the pathogenesis of cerebrovascular disease? Name the infections of the CNS. Describe CreutzfeldtJakob disease. Give examples of diseases of demyelination and diseases of degeneration. Name the vitamin deficiencies and toxins that damage the CNS. What are the consequences of excess ethanol intake on the CNS? Name the neoplasms of the CNS. Name the different types of hereditary neuropathies. What are the causes and outcomes of traumatic neuropathies? Outline the pathology of GuillainBarr syndrome (inflammatory neuropathy). Name infections that can cause neuropathies.

Give types of metabolic and toxic neuropathies. Name the neoplasms of the peripheral nerves. What are the characteristics and causes of Horners syndrome? Give indications for performing sympathectomies and describe their effects. Describe the pathology of phaeochromocytomas. What are the effects of vagotomies?

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