Neuropathology

1.         Briefly describe several pathologic responses of the nervous system to injury that are not seen in other tissues.

Zen Seeker S&L 434

The nervous system has several pathological responses to injury that are not seen in other tissues.

• Neuronal chromatolysis is a reparative response of neurons following damage to the axon (fig 21.1).  The neuronal cell body swells due to accumulation of neurofilaments and there is peripheral migration of the Nissl substance (material consisting of granular endoplasmic reticulum and ribosomes that occurs in nerve cell bodies and dendrites), associated with nuclear swelling.  Chromatolysis is part of the regenerative response whereby neurons can regrow a severed axon (see page 465).

• Phagocytosis.  Following cell death, removal of damaged tissues is achieved by phagocytic resident microglial cells, which are supplemented by recruitment of monocytes from the blood.  These phagocytic cells become vacuolated by accumulated lipid from dead cells, forming foam cells.

• Gliosis.  Astrocytes become activated, proliferation to fulfill metabolic roles in protecting neurons.  Following death of cells, and removal by phagocytes, damaged areas are replaced by proliferation of astrocytes, which form a glial scar.  In large areas of damage, astrocytic gliosis may not entirely replace a defect, and an area remains that is partly cystic and partly gliotic.

• Cerebral edema is accumulation of tissue fluid in between the cells of the nervous system.  Seen after damage from many different causes, it is the result of breakdown of the blood-brain barrier due to ischemia, trauma, inflammation, and metabolic disorders.  This breakdown also occurs around tumors.

Severe cerebral swelling is associated with a rise in the pressure within the skull (raised intracranial pressure).

Ky 434

Neuronal Chromatolysis:  reparative response of neurons following damage to the axon.  Neuronal cell body swells due to accumulation of neurofilaments and there is peripheral migration of the Nissl substance associated with nuclear swelling.  Chromatolysis is part of the regenerative response whereby neurons can regrow a severed axon.

Phagocytosis:  microglial cells, supplemented by recruited monocytes, remove damaged tissues.  Phagocytic cells become vacuolated by accumulated lipid from dead cells, forming foam cells.

Gliosis:  astrocytes become activated, proliferating to fulfill metabolic roles in protecting neurons.  Following cell death, and phagocytosis, damaged areas are replaced by astrocyted proliferation forming a glial scar.  Large areas of damage the defect is not entirely replaced and the area is partly cystic and partly gliotic.

Cerebral edema:  accumulation of tissue fluid in between cells of the nervous system.  Many causal agents exist, it is the result of breakdown of the blood brain barrier due to ischemia, trauma, inflammation, metabolic disorders, around tumors.

Sung K, S&L p.434

2.         Describe the process and consequences of cerebral herniation. (Note: you do not have to distinguish between the four types of cerebral herniation listed in the textbook.)

Zen Seeker S&L 434

Expanding intracranial lesions cause raised intracranial pressure

            The cranial cavity is divided into three spaces by the falx and tenorium cerebelli.  If a lesion expands within the brain substance, there is only a limited amount of room within the skull to accommodate it.  Initially, reduction in the size of the ventricles and subarachnoid space occurs, but once this volume is used, further increase in the size of a lesion is associated with increase in intracranial pressure.

Swellings within the brain are particularly dangerous when they lead to rapid local expansion of one part, causing it to shift from one brain compartment to another, a process termed cerebral herniation.  There are four types of cerebral herniation (fig 21.2a):

• Transtentorial herniation (c) is caused by lesions expanding in one cerebral hemisphere.  There is herniation of the medial part of the temporal lobe down over the tentorium cerebelli to compress the upper brain stem (fig 21.2b).  The third cranial nerve becomes first stretched, then compressed on the side of the lesion, giving rise to a fixed dilated pupil.  Branches of the posterior cerebral artery are also compressed as the brain herniates, causing secondary infarction of the occipital lobe.  As the midbrain is distorted by compression, small vessels are torn and secondary hemorrhage occurs into the brain stem leading to death.

• Cerebellar tonsillar herniation (e) is caused by expanding lesions in the posterior fossa.  There is herniation of the lower part of the cerebellum (cerebellar tonsils), which pushes down into the foramen magnum and compresses the medulla: this process is also known as coning.  As the medulla is compressed, it causes cessation of respiration and death.  This may be precipitated by performing a lumbar puncture in a person with a mass in the brain.  Withdrawal of CSF allows a pressure gradient to develop and there is rapid coning with death.  Lumbar puncture should never be performed until the possibility of a mass lesion in the cranial cavity bas been excluded.

• Cingulate gyrus (subfalcial) hernation (a) is caused by a lesion in one of the cerebral hemispheres, resulting in movement of the cingulated gyrus beneath the falx cerebri.  This is often associated with compression of the adjacent anterior cerebral artery, leading to secondary cerebral infarction.

• Diencephalic herniation is caused by generalized swelling of both cerebral hemispheres.  There is compression of the ventricles, with descent of the thalamus and midbrain through the tentorial hiatus. This causes tearing of vessels in the midbrain, with secondary hemorrhage.

a) Subfalcial (cingulate) herniation

b) uncal herniation

c) downward (central, transtentorial) herniation

d) external herniation

e) tonsillar herniation.

Types a, b, & e are usually caused by focal, ipsilateral space occupying lesions, ie., tumor or axial or extra-axial hemorrhage.

Ky 434

Defn:  there are three basic compartments in the brain.  Swelling within the brain is particularly dangerous when it leads to rapid local expansion of one part, causing it to shift from one brain compartment to another.

Process:  lesions expand from one compartment to another compressing nerves, occluding blood vessels etc.

Consequences:  dilated pupils, brain herniation, hemorrhaging, compress medulla:  cessation of respiration and death.  Cerebral infarction.

Sung K, S&L p.434-436

      PROCESS: the cranial cavity is divided into three spaces by the falx and tentorium cerebelli. If a lesion expands within the brain substance, there is only a limited amount of room within the skull to accommodate it. Initially, reduction in the size of the ventricles and subarachnoid space occurs, but once this volume is used, further increase in the size of the lesion is associated with increase in intracranial pressure. Swellings within the brain are particularly dangerous when they lead to rapid local expansion of one part, causing it to shift from one brain compartment to another, a process termed cerebral herniation (severe displacement of brain tissue).

      CONSEQUENCE: may cause infarction as herniated brain compresses against an artery, small vessel tears leading to hemorrhage, and ultimately death.

3.         Define the following terms: TIA, RIND, and stroke.

Zen Seeker S&L 437

Stroke is common in the general population

            Stroke occurs in 2 per 1000 of the general population.  A clinical diagnosis with several pathological causes, it is mainly seen in the elderly population.

• Clinical diagnosis of stroke is defined as a sudden onset of non-traumatic focal neurological deficit that causes death or lasts for over 24 hours.

• Minor stroke and reversible ischemic neurological deficit (RIND) are used when recovery of clinical features occurs after a period of time, usually defined as 7 days.

• Transient ischemic attacks (TIA) are defined as episodes of non-traumatic focal loss of cerebral or visual function lasting no more than 24 hours.

Ky 437

Stroke:  sudden onset of non-traumatic focal neurological deficit that causes death or lasts for over 24 hours.

TIA:  transient ischemic attacks.  Episodes of non-traumatic focal loss of cerebral or visual function lasting no more than 24 hours

RIND:  reversible ischemic neurological deficit.  Recovery of clinical features occurs after a period of time, usually defined as 7 days.

Sung K, S&L p.437    

4.         Distinguish between ischemic and hemorrhagic stroke, and describe typical causes of each.

Zen Seeker S&L 438-441

The causes of stroke can be divided into two main groups:

• ischemic (85%), caused by cerebral infarction

• hemorrhagic (15%), caused by intracerebral and subarachnoid hemorrhage.

            Hemorrhages and ischemic lesions caused by trauma are discussed later in this chapter (441 et seq.).

ISCHEMIC 

Regional cerebral infarction is caused by occlusion of named cerebral arteries

            Regional cerebral infarcts are caused by occlusion of main named arteries supplying the brain.  The most common causes originate outside the cranial cavity, e.g. emboli from the heart, aorta or carotid vessels, and thrombosis in the carotid or vertebral arteries (fig 21.5), predisposed by atheroma.  Less common causes of infarction are seen in younger stroke patients (see blue box on 438).

Cerebral infarcts correspond to the territory of supply of the occluded arteries.  It is difficult to see an infarct in the first 24 hours, as changes are limited to focal swelling and blurring of the normal demarcation between gray and white matter, termed a pale or anemic infarct.  If there is lysis of an occlusive thrombus, the infracted area may be reperfused with blood, resulting in a hemorrhagic infarct (fig 21.6).

            By about 1 week the infracted area becomes macroscopically soft and is infiltrated by macrophages, which remove dead tissue.  Proliferation of astrocytes occurs around the margins of the infarct, and these partly replace the dead tissue, usually being well established by about 2 weeks.  Larger regional areas of infarction invariably heal as fluid-filled spaces bounded by gliosis (fig 21.7).

            Although a number of clinical syndromes related to occlusion of individual arteries are described, the most important practical distinction is between those affecting the carotid territory (frontal, temporal, parietal lobes or basal ganglia/internal capsule) and those affecting the vertebrobasilar territory (occipital lobe, cerebellum or brain stem).

            Large cerebral infarcts may cause death by associated cerebral swelling, leading to herniation, and brain stem compression.  Infarcts in critical sites, particularly brain stem infarcts, may interfere with vital function and lead to death.  Immobility and difficulty in swallowing lead to development of pneumonia in many patients.

Lacunar infarction is caused by arteriolosclerosis of small vessels

            Lucunar infarcts are small, often slit-shaped, areas of infarction that are less than 1 cm in maximum diameter.  The are an important form of cerebral infarct, particularly in patients with hypertension and diabetes, being caused by hyaline arteriolsclerosis.

            Macroscopically, lesions are usually multiple and are seen in the sites normally supplied by fine perforating branches, such as the basal ganglia, internal capsule, thalamus and pons (fig 21.8).

            Clinically, lacunar infarcts can be asymptomatic or may cause very restricted neurological deficits such as monoparesis.  Multiple lacunar infarcts in the basal ganglia cause a syndrome of rigidity and abnormal gait, which superficially resembles Parkinson’s disease, termed vascular pseudo-Parkinsonism.  Lacunar infarction is also associated with ischemic white-matter degeneration, an important cause of dementia.  Because hypertension and diabetes are risk factors for ischemic heart disease and atheroma, lacunar infarcts are often seen in association with regional infarcts caused by large vessel disease.

Cortical laminar necrosis is caused by generalized failure of perfusion

            Diffuse necrosis of cerebral cortical neurons is the pattern of infarction seen in generalized failure of blood flow or oxygenation as seen, for example, following cardiac arrest, with severe hypoglycemia, and after carbon monoxide poisoning.

            Changes develop 24 hours after resuscitation from the damaging episode.  There is widespread damage to the cerebral cortex, with death of the majority of cortical neurons.  With time, there is phagocytosis of dead neurons with astrocytic gliosis.

            Macroscopically the cerebral cortex is shrunken and there is extensive loss of axons from the brain, causing white matter loss (fig 21.9).

            Patients who survive global laminar necrosis generally have severe brain damage, existing in a vegetative state devoid of higher cortical functions.  Lesser degrees of hypoxia or cerebral perfusion failure result in similar damage, limited to the particularly vulnerable areas of the hippocampus and cerebellar cortex.

Venous infarction is caused by venous sinus thrombosis

            Venous infarction is the least common pattern of cerebral infarction.  It occurs when there is occlusion of the venous sinuses and cerebral cortical veins by local thrombosis (fig 21.10).

            Predisposing factors include dehydration in children, spread of infection from adjacent foci in the head (nasal sinus and middle ear) and disorders that cause hypercoagulability of blood, particularly polycythemia, oral contraceptive therapy and pregnancy.  Macroscopically the affected brain shows severe hemorrhagic infarction caused by vascular congestion.

HEMORRHAGE

Spontaneous intracranial hemorrhage accounts for about 15% of all strokes and is caused by intracerebral hematoma and subarachnoid hemorrhage.  Petechial (small purplish spot on a body surface, such as the skin or a mucous membrane, caused by a minute hemorrhage and often seen in typhus) hemorrhage is a less common pattern.  Hemorrhage caused by trauma is considered in a later section (see page 443).

Cerebral hematomas are most commonly caused by hypertensive vascular damage

            The most common cause of cerebral hemorrhage is hypertensive vascular damage.  Prolonged hypertension results in arteriosclerosis and in the development of small microaneurysms (Charcot-Bouchard aneurysms), which predispose to vessel rupture, resulting in a hematoma.  The common sites for hypertensive intracerebral hematoma are those supplied by fine perforating vessels (basal ganglia, internal capsule, thalamus, cerebellium and pons).

            In patients over the age of 70 years, 10% of cerebral hemorrhages are caused by the presence of cerebral artery amyliod, which is composed of Aβ peptide (page 543).  This causes hematomas, seen in the periphery of cerebral hemispheres (lobar hemorrhages).  This type is associated with a better clinical outcome than the deep bleeds associated with hypertension.

            Less common causes of a cerebral hematoma are bleeding into a tumor, rupture of vascular malformations, cerebral vasculitis, bleeding associated with disordered coagulation, and bleeding occurring in association with leukemias.

            Macroscopically, hematomas appear as a large blood clot, causing compression and damage to adjacent brain (fig 21.11).  Large hematomas in the basal ganglia or thalamus often rupture into the ventricular system.  If the patient survives a bleed, the hematomas in the basal ganglia or thalamus often rupture into the ventricular system.  If the patient survives a bleed, the hematoma is removed by phagocytic cells; astrocytic gliosis takes place, leaving a cavity stained yellow-brown with hemosiderin.  Large bleeds that cause raised intracranial pressure, and those that rupture into the ventricular system, are usually fatal.

Subarachnoid hemorrhage is most often caused by a ruptured berry aneurysm

            Bleeding into the subarachnoid space (between the arachnoid and the pia) is termed subarachnoid hemorrhage.  A cause of stroke from adolescence to old age, it accounts for about 5% of all cases.  In most cases, the cause of subarachnoid bleeding is rupture of a berry aneurysm; less common causes are rupture of an intracerebral hematoma into the subarachnoid space or rupture of a vascular malformation.

            Macroscopically a layer of blood is present over the brain surface in the subarachnoid space (fig 21.12).  Blood is therefore present in the cerebrospinal fluid (CSF) and can be detected on lumbar puncture.  There are two effects of subarachnoid hemorrhage:

• Blood around vessels causes vascular spasm and leads to widespread cerebral ischemia and brain swelling.

• There may be blockage of CSF resorption, causing acute hydrocephalus.

            About 30% of patients die immediately; others who present with headache and signs of meningeal irritation may have surgical intervention and clipping of the aneurysm.  In the absence of operative intervention, 30% of patients have a rebleed within 1 year, most within 1 month of their first bleed.  A long-term complication is development of hydrocephalus caused by blockage and fibrosis in the CSF pathways.

Diffuse petechial hemorrhage in the brain is caused by damage to small vessels

            The least common form of cerebral hemorrhage is multiple petechial hemorrhages scattered throughout the brain.  These are 1-2 mm in size and are concentrated in the white matter.  They are caused by disease that disrupts the walls of small cerebral blood vessels, allowing extravasation of red cells.  Patients with this pattern of disease tend to present with confusion and decreased conscious level, rather than with focal neurological signs.  The main causes are acute hypertensive encephalopathy, fat embolism, vasculitis of small cerebral vessels (e.g. polyarteritis), cerebral malaria and acute hemorrhagic leukoencephalitis (allergic vasculitis of cerebral vessels).

Ky 437

Ischemic:  (85%) caused by cerebral infarction.  Failure of blood oxygenation, failure of blood flow, severe hypoglycemia.  Four types:  large vessel, small vessel, venous infarction, global ischemia.

            Large vessel:  regional infarction from embolism and thrombosis in cerebral arteries.

            Small vessel:  microinfarcts (lacunar) caused by arteriolosclerosis predisposed by HTN and DM.  Sites—basal ganglia/internal capsule region.

            Venous infarction:  causes hemorrhagic necrosis due to thrombosis in main cerebral venous sinus.  Risk factors:  polycythemia and dehydration.

            Global ischemia:  widespread neuronal necrosis leading to laminar cortical necrosis.  Risk factors:  ß cerebral blood flow with cardiorespiratory arrest.  Hypotension.

Hemorrahagic: (15%).  Caused by intracerebral and subarachnoid hemorrhage.  

Sung K, S&L p.437-441

5.         Describe the two main patterns of primary brain damage in closed head injury.

Zen Seeker S&L 441-442

Brain pathology from head injury may be primary (i.e. the immediate consequence of impact damage) or secondary (i.e. occurring as a delayed consequence of brain swelling, bleeding and hypoxia)(fig 21.13).

            There are two main patterns of primary brain damage in closed head injury.

1. Cerebral contusions occur when the brain moves within the cranial cavity, causing parts of the brain to be crushed by violent contact with the skull or dural membranes.  For the most part, these occur adjacent to the site of impact (coup lesions) and diagonally opposite (countercoup lesions).  The most common sites for this pattern of damage are the underside of the frontal lobes, the occipital poles, and the cerebellum (fig 21.14).  Early contusions appear as petecheal hemorrhage into cortical gray matter and underlying white matter.  Over a period of several hours there is oozing of blood, and contusions become hemorrhagic, with severe swelling of the brain (fig 21.15).  Severe contusions may be associated with extensive intracerebral, subarachnoid and subdural hemorrhage.  Contusions heal by gliosis, which is often associated with brown hemosiderin deposition (caused by the associated hemorrhage).

2. Diffuse axonal injury is the result of shearing of axons due to acceleration/deceleration/torsional forces, leading to severe damage to white matter tracts.  Patients with this pattern of damage who survive are generally severely disabled.  Most of the changes are seen histologically only, consisting of axonal tearing visible as swellings of the torn ends of nerve fibers (axonal retraction balls) (fig 21.16).  Petechial hemorrhages may also occur in the corpus callosum and brain stem, and their detection at these sites is a useful indicator of this type of severe head injury.

Ky 441

Non-missile trauma:  closed head injury.  Results from acceleration/deceleration forces to the head that cause movement of the brain within the skull.

            Cerebral contusions:  brain moves within cranial cavity causing parts of the brain to be crushed by violent contact with the skull or dural membranes.  Usually occur adjacent to site of impact (coup lesion) or diagonally opposite (contrecoup lesion).  Early contusions appear as petechial hemorrhage into cortical gray matter and underlying white matter.  Over several hours blood oozes and contusions become hemorrhagic.  Severe swelling can occur.  Contusions heal by gliosis which is often associated with brown hemosiderin deposition (associated with hemorrhage).

            Diffuse axonal injury:  result of shearing of axons due to acceleration/deceleration/torsional forces.  Causes severe damage to white matter tracts.  If survive then severely disabled.  “2^nd collision”.  Secondary hypoxic brain damage and cerebral edema.  4 types of hemorrhage:  intracerebral hematoma, subarachnoid hemorrhage, subdural hemorrhage, extradural hemorrhage.

Sung K, S&L p.441-442

6.         Compare and contrast extradural hemorrhage (aka: epidural hematoma) and subdural hemorrhage (aka: acute and chronic subdural hematomas).

Zen Seeker S&L 442-443

Extradural hemorrhage is caused by tearing of vessels running outside the dura

            Extradural hemorrhage causes a hematoma in the potential extradural space between the skull and the dura (fig 21.17) and is almost always the result of skull fracture, which tears an artery or a main venous sinus running outside the dura.  A vessel commonly involved is the middle meningeal artery (associated with fracture of the temporal bone).

            The extradural hematoma appears as a gelatinous layer of blood clot outside the dura.  This accumulation causes compression of the brain and development of transterntorial herniation.  In many cases, high-pressure arterial blood accumulates rapidly, leading to an acute decline in conscious level with raised intracranial pressure.  In other cases, blood accumulates over a period of hours and it is not uncommon to have a history of head trauma followed by gradual development of drowsiness, leading to coma and death.

Some subdural hematomas are caused by minor head trauma and have a chronic pattern of evolution

            Sudural hemorrhage results in a hematoma developing in the subdural space between the dura and the arachnoid (fig 21.18).  It is caused by traumatic tearing of venous vessels that traverse the subdural space.  There are two patterns.

            Acute subdural hematomas are usually seen after a severe head injury and are associated with other types of brain injury.  They cause rapid accumulation of blood, leading to acute neurological deterioration as a result of raised intracranial pressure.

            Chronic subdural hematomas usually occur as a result of minimal trauma and are mainly seen in the very young (including childhood non-accidental injury) and the elderly.  Blood typically accumulates slowly over a period of days or weeks, becoming localized by a membrane of fibrovascular granulation tissue.  In addition to the osmotic effects of degenerating blood clot drawing in fluid from the CSF, increase in the size of the hematoma occurs with further bleeding.  Clinical symptoms and signs may only become obvious weeks after an apparently trivial injury, as a result of raised intracranial pressure.

            Macroscopically a subdural hematoma is seen as a layer of gelatinous blood clot (acute type) or as an organized layer of dark liquefied clot surrounded by membranes (chronic type), which flattens and compresses the underlying brain, staining the outside of the arachnoid with hemosiderin.

Ky 442-443

Extradural Hemorrhage:  Fig p443.  causes hematoma in the potential extradural space between the skull and dura and is almost always the result of skull fracture which tears an artery or a main venous sinus running outside the dura.  Middle meningeal artery is commonly involved when the temporal bone is fractured.  High pressure arterial blood accumulates rapidly leading to an acute ß in consciousness with Ý intracranial pressure.  Or blood accumulates over a period of hours following head trauma with gradual drowsiness, coma and eventually death.

Subdural Hemorrhage:  results in a hematoma in subdural space between the dura and the arachnoid.  Caused by the traumatic tearing of venous vessels that traverse the subdural space.  2 patterns:

            Acute subdural hematoma:  after severe head injury.  They cause rapid accumulation of blood leading to acute neurological deterioration due to increased pressure.

            Chronic subdural hematoma:  occur as a result of minimal trauma and are mainly seen in the very young and elderly.  Blood accumulates slowly over a period of days or weeks becoming localized by a membrane of fibrovascular granulation tissue.  Macroscopically: seen as a layer of gelatinous blood clot (acute type) or as an organized layer of dark liquefied clot surrounded by membranes (chronic type) which flatten and compress the underlying brain.

Sarra V.  Swartz 442,43  extradural hemorrhage(epidural hematoma)-is caused by tearing of vessels running outside the dura. Extradural hemorrhage causes a hematoma in the potential extradural space between the skull and the dura and is almost always the result of skull fracture, which tears an artery or a main venous sinus running outside the dura.  A vessel commonly involved is the middle meningeal artery. The hematoma appears as a gelatinous layer of blood clot outside the dura.  This accumulation causes compression of the brain and development of transtentorial herniation.  In many cases, high-pressure arterial blood accumulates rapidly, leading to an acute decline in conscious level with raised intracranial pressure. In other cases, blood accumulates over a period of hours and it is not uncommon to have a history of head trauma followed by gradual development of drowsiness, leading to coma and death.

Subdural hemorrhage- results in a hematoma developing in the subdural space between the dura and the arachnoid.  It’s caused by traumatic tearing of venous vessels that traverse the subdural space.

Acute subdural hematomas-are usually seen after a severe head injury and are associated with other types of brain injury.  They cause rapid accumulation of blood, leading to acute neurological deterioration as a result of raised intracranial pressure.

Chronic subdural hematomas-occur as a result of minimal teauma and are mainly seen in the very young(including childhood non-accidental injury) and the eldrly.  Blood typically accumulates slowly over a period of days or weeks, becoming localized by a nenbrane of fibrovascular granulation tissue.  In addition to the osmotic effects of degenerating blood clot drawing in fluid from the CSF, increase in the size of the heamatoma occurs with further bleeding.  Clinical symptoms and signs may only become obvious weeks after an apparently trivial injury, as a result of raised intracranial pressure.

Tim Stevens&Lowe Pg. 442-443

            Extradural hemorrhage causes epidural hematoma in the extradural space between the skull and the dura and is almost always caused by skull fx which tears an artery or main venous sinus outside the dura.  Most commonly involves the middle meningeal artery due to temporal skull fx. Accumulation causes compression of the brain leading to herniation, with raised intracranial pressure and decline in conciousness.

            Subdural hemorrhage results in subdural hematoma in the space between the dura and arachnoid caused by traumatic tearing of venous vessels in the subdural space.

            Acute are usually seen  after severe head injuries and are associated with rapid accumulation of blood leading to increased intracranial pressure and neoro deterioration.

            Chronic occur as a result of minimal trauma and are seen in young and elderly. Blood accumulates slowly over days or weeks and draws fliud from CSF causing increase in hematoma.

7.         Define hydrocephalus, and describe some common examples.

Zen Seeker S&L 444

Excess CSF in the intracranial cavity is termed ‘hydrocephalus’ and most cases are caused by obstruction of the flow of CSF

            The term hydrocephalus is used to describe conditions in which there is increase in the CSF volume within the brain, with expansion of the cerebral ventricles.  The most common type, which is termed non-communication hydrocephalus or obstructive hydrocephalus, is caused by blockage of the CSF at the arachnoid villi along the dural venous sinuses, usually precipitated by previous infection or bleeding into the subarachnoid space.

• Among the main causes of obstructive hydrocephalus is congenital hydrocephalus, seen in about 1 in 1000 births.  Some cases have stenosis of the aqueduct of Sylvius, some have associated Arnold-Chiari malformation (page 457), and some are inherited as an X-linked trait.

Note that there are grades 1-4 and the book describes type 2

• Tumor may obstruct the ventricular system, particularly those located in the brain stem, cerebellum, or pineal region which block the cerebral aqueduct or fourth ventricle.

• Scarring and lockage of the CSF exit foramina at the base of the brain are common complications of meningitis or subarachnoid hemorrhage.

• Hemorrhage in the brain or subarachnoid space may obstruct CSF drainage pathways.

            Macroscopically, there is dilation of the ventricular cavities of the brain proximal to the site of obstruction (fig 21.21).  The effects of hydrocephalus depend on the speed of development of disease and age of the patient.

            In acute hydrocephalus, swelling of the brain may be rapid and may cause death due to cerebral herniation.

            In chronic hydrocephalus, signs and symptoms develop slowly and there are clinical features of raised intracranial pressure.  When hydrocephalus develops in children, before fusion of the skull bones, there is progressive enlargement of the head circumference.  In adults, where the skull is rigidly fused, prolonged disease causes thinning of the skull vault.  In the absence of treatment, long-standing disease causes axonal damage and gliosis in the white matter.  In children this leads to mental subnormality and in adults can lead to the development of a dementia syndrome, with early gait disturbance and incontinence as prominent features.

            Treatment of hydrocephalus involves placement of a permanent shunt to drain CSF into the peritoneal cavity.  This leads to other pathological complications because shunts become periodically blocked, leading to acute attacks of hydrocephalus.  Shunts also become infected with low-virulence organisms, producing signs and symptoms of infection, as well as immune-mediated glomerular disease.

Ky 444

Defn:  excess CSF in the intracranial cavity.  Most cases caused by obstruction of CSF flow.  Accompanies expansion of cerebral ventricles.  Examples:  non-communicating hydrocephalus or obstructive hydrocephalus is caused by blockage of CSF pathway from ventricles to the subarachnoid space or less commonly there is impairment of resorption at the arachnoid villi along the dural venous sinuses (precipitated by infection or bleeding).

Causes:  congential (most common); tumors; scarring; hemorrhage.

Sarra V. Swartz 444. Hydrocephalus-is a condition in which there is increase in the CSF volume within the brain, with expansion of the cerebral ventricles.  The most common type: non-communicating hydrocephalus or obstructive hydrocephalus, is caused by blockage of the CSF pathway from the ventricles to the subarachnoid space. Among the main causes of obstructive hydrocephalus is congenital hydrocephalus, seen in about 1 in 1000 births. Tumors may obstruct the ventricular system. Scarring and blockage of the CSF exit foramina at the base of the brain are common complications of meningitis or subarachnoid hemorrhage. Hemorrhage in the brain or subarachnoid space may obstruct CSF drainage pathways. The effects of hydrocephalus depend on the speed of development of disease and age of the patient. Acute hydrocephalus swelling of the brain may cause death due to cerebral herniation. Chronic hydrocephalus signs and symptoms develop slowly and there are clinical features of raised intracranial pressure. When hydrocephalus develops in children, before fusion of the skull bones, there is a progressive enlargement of the head circumference.

Tim Stevens&Lowe pg444

            Defined as excess CSF in the intracranial cavity and is caused by obstruction of drainage by tumor, scarring and hemorrhage.  Can also be due to malformation of sinus drainage (Arnold-Chaiari malformation)

8.         Describe the three major types of meningitis, and identify typical organisms associated with each.  (Note: don’t worry about the textbook’s distinction between leptomeningitis and pachymeningitis.)

Zen Seeker S&L 445-446

Acute purulent meningitis is almost always caused by bacterial infection

            Acute purulent meningitis is a severe infection that is nearly always caused by bacterial infection.  Patients are severely unwell and have signs of infection, neck stiffness and photophobia.  CSF examination shows turbid fluid with many neutrophil polymorphs and a low sugar; bacteria may be seen on special staining.

            Macroscopically, the subarachnoid space contains a cream-colored acute inflammatory exudates that is rich in neutrophils (fig 21.22).  The severe inflammation causes secondary thrombosis of superficial vessels and cerebral ischemic damage.  If treated early, there may be resolution of disease.  However, complications caused by organization of the inflammatory exudates may lead to obstruction of the CSF drainage pathways and to development of hydrocephalus.

            The main cause of acute purulent meningitis vary according to age.  In neonates Echerichia coli, streptococci and Listeria monocytogens  are responsible, and in children Haemophilus influenzae and Neisseria maningitidis are the principal causes.  Neisseria meningitides and Streptococcus pneumoniae type 3 are involved in adults, and in the elderly the main causative organisms are Streptococcus pneumoniae type 3 and Listeria monocytogens.

Lymphocytic meningitis is usually caused by viruses and is a benign self-limited disease

            Lymphocytic meningitis is a self-limited disease caused by several viral infections.  In most cases patients have clinical malaise and meningism (symptoms that mimic those of meningitis but without inflammation of the meninges), and require investigation to exclude the presence of a bacterial meningitis.  Typically the CSF is clear, has a normal glucose level, but has a mild elevation of protein and contains an increase in lymphoid cells.

            The cause of infection is ascertained by virological or serological examination of CSF and blood.  The most common causes are infection by the mumps, Coxsackie, ECHO, Epstein-Barr, lymphocytic choriomeningitis and polio viruses. No organism is detected in many cases.

Chronic and granulomatous meningitides are severe inflammatory diseases that lead to meningeal fibrosis and cranial nerve lesions

            Chronic and granulomatous meningitides are forms of severe productive chronic inflammation and fibrosis.  The CSF is typically opalescent, with a raised protein level, reduced glucose level, and an increased lymphocyte count with the presence of plasma cells.  The important causative organisms are Mycobacterium tuberculosis, Treponema pallidum (syphilis), Cryptococcus neoformans, and Borrelia burgdorferi (Lymes disease).

            Macroscopically there is thickening and opacity of the leptomeninges, with marked thickening and fibrosis in advanced disease.  Histologically, there is lymphocytic and plasma-cell infiltration of the meninges with fibrosis.  The cause of chronic meningitis may be apparent on examination.  In tuberculous meningitis, caseating granulomas are seen, and mycobacteria may be visible on Ziehl-Neelsen (ZN) staining.  In cryptococcal infection, fungi are usually clearly visible.

            Meningeal fibrosis and inflammation have two main effects: they lead to obstruction of the drainage pathways for CSF, causing hydrocephalus (page 444), and vascular lesions cause infarction and cranial nerve and spinal root palsies.

Ky 445

Acute purulent meningitis:  Mainly bacterial.   Severe infection, stiff neck, photopobia, CSF turbid fluid with neutrophil polymorphs and low sugar.  Neonates = E coli., Strep pneumon., and Listeria monocytogenes.  Children = Haemophilus influenzae and Neisseria mening.  Adults = Neisseria mening., Strep pneumon.  Elderly = strep pnuemon, and Listeria mononcyt.

Lymphocytic meningitis:  self-limited disease caused by viral infections.  Malaise, meningism, clear CSF with normal sugar, mild elevation of protein and lymphoid cells.  Causal organisms:  mumps, coxsackie, ECHO, EBV, lymphocytic shoriomeningitis and polio.  Often times no organism is detected.

Chronic and granulomatous meningitis:  severe inflammatory disease that lead to fibrosis and cranial nerve lesions.  Fibrosis causes obstruction of CSF drainage pathways resulting in hydrocephalus.  Vascular lesions cause infarction and cranial/spinal nerve root palsies.  CSF opalescent, Ý protein, Ý lymphocyte and ß sugar.  Causal orgs:  TB, syphilis, Crytpococcus neoformans and Lyme disease.

Sarra V. Swartz 445. Three types of meningitis: 

1.) acute purulent meningitis- severe infection that is nearly always caused by bacteria.  Signs are neck stiffness and photophobia.  CSF shows turbid fluid with many neutrophil polymorphs and low sugar.  Macroscopically, subarachnoid space contains a creamcolored acute inflammatory exudates that is rich in neutrophils.  Severe inflammation causes secondary thrombosis of superficial vessels and cerebral ischemic damage.  If treated early, there may be resolution of disease.  However, complications caused by organization of the inflammatory exudates may lead to obstruction of the CSF drainage pathways and to development of hydrocephalus.  Main causes of acute purulent meningitis vary accrording to age.  In neonates E-coli, streptococci, Listeria monocytogenes are responsible, and in children Haemophilus influenzae and Neisseria meningitides are the principal causes.  Neisseria meningitides and Streptococcus pnuemoniae type 3 are involved in adults, and in the elderly the main causative organisms are Streptococcus pneumoniae type 3 and Listeria monocytogenes.

2.) Lymphocytic meningitis- self- limited disease, caused by viruses, infected by mumps, Coxsackie, ECHO, Epstein-Barr, lymphocytic chriomeningitis and polio viruses.

3.) Chronic and granulomatous meningitis- severe inflammatory disease that lead to meningeal fibrosis and cranial nerve lesions.  CSF- opalescent, raised protein level, redused glucose level, increased lymphocyte count with the presence of plasma cells.  Causative organisms are Mycobacterium tuberculosis, Treponema palidum (syphilis), Cryptococcus neoformans, and Borrelia burgdorferi (Lyme disease).  Two main effects: lead to obstruction of the drainage pathways for CSF, causing hydrocephalus, and vascular lesions cause infarction and cranial nerve and spinal root palsies.

Tim Stevens&Lowe pg. 445

            Acute purulent meningitis is caused mainly by bacterial infection.   Sx include stiff neck, photopobia, CSF turbid fluid with neutrophil polymorphs and low sugar. In neonates E coli., strep pneumon., and listeria monocytogenes.  In children haemophilus influenzae and neisseria. In adults neisseria, strep pneumo. In elderly strep pnuemo, and listeria.

            Lymphocytic meningitis is a self-limited disease caused by viral infections.  Sx include malaise, meningism, clear CSF with normal sugar, mild elevation of protein and lymphoid cells.  Caused by mumps, coxsackie, ECHO, EBV, lymphocytic shoriomeningitis and polio.  Most times no organism is detected.

            Chronic and granulomatous meningitis is a severe inflammatory disease that lead to fibrosis and cranial nerve lesions.  Fibrosis causes obstruction of CSF drainage pathways resulting in hydrocephalus.  Vascular lesions cause infarction and cranial and spinal nerve root palsies.  CSF opalescent, incresed protein levels, increased lymphocyte and decreased sugar levels.  Caused by TB, syphilis, crytpococcus neoformans and Lyme disease.

9.         List the four main patterns of brain abscess.

Zen Seeker S&L 446

Cerebritis and cerebral abscess are examples of severe focal infection of the brain caused by a wide range of organisms

            Focal inflammation of the parenchyma of the brain, termed cerebritis, frequently leads to formation of a cerebral abscess.  These patterns of inflammation develop in four main ways:

1. Secondary to meningitis and caused by the same types of organism.

2. Local extension from sepsis in the middle ear or mastoid cavities.

3. Hematogenous, particularly associated with bacterial endocarditis, cyanotic congenital heart disease, and pulmonary bronchiectasis.

4. Trauma following open injuries to the CNS.

            Areas of brain affected by cerebritis appear as ill-defined areas of swelling, which are congested and soft on cut surface, being composed of necrotic brain infiltrated by neutrophils.  An abscess is a rounded cavity, typically 1-2 cm in diameter, filled with pus and walled off both by gliosis and by fibroblasts derived from tissue adjacent to blood vessels (fig 21.23).  Certain brain areas are preferred sites for abscess formation, according to etiology.  For example, infection of the middle ear causes abscesses in temporal lobe or cerebellum, nasal sinus infection causes abscesses in frontal lobes, and septic emboli tend to cause abscesses in parietal lobes.

            Microbiology usually reveals mixed bacterial organisms in cerebral abscesses, including a high frequency of anaerobic bacteria.  TB may form a localized caseous abscess termed a ‘tuberculoma’.  Cerebral abscesses may also be caused by fungal infection, e.g. Candida, Aspergillus and amebas, and some cases of cerebritis and abscess are due to Toxoplasma, predisposed by immunosupppression.

            With the exception of viral meningitis, all forms of meningitis can lead to development of cerebritis or cerebral abscess.  If they are not excised or drained surgically, abscesses may rupture to cause meningitis or ventricultis.

Ky 446

cerebritis:  brain abscess is a rounded cavity, typically 1-2cm in diameter, filled with pus and walled off both by gliosis and fibroblasts derived from tissue adjacent to blood vessels.  Patterns:

1.    secondary to meningitis and caused by the same types of organisms

2.    local extension from sepsis in the middle ear of mastoid cavities

3.    hematogenous, particularly associated with bacterial endocarditis, cyanotic congenital heart disease, and pulmonary bronchiectasis.

4.    Trauma following open injuries to the CNS.

Sarra V. Cerebritis and cerebral abscess are examples of severe focal infaction of the brain caused by a wide range of organisms.  

1. Secondary to meningitis and caused by the same types of organism.

2. Local extention from sepsis in the middle ear or mastoid cavities.

3. Hematogenous, particularly associated with bacterial endocarditis, cyanotic congenital heart disease, and pulmonary bronchiectasis.

4. Trauma following open injuries to the CNS.

Tim Stevens&Lowe pg. 446

1.  Secondary to meningitis and caused by the same types of organisms

2.  Local extension from sepsis in the middle ear of mastoid cavities

3.    Hematogenous, associated with bacterial endocarditis, cyanotic

       congenital heart disease, and pulmonary bronchiectasis.

4.   Trauma following open injuries to the CNS.

10.       Define encephalitis, and describe typical causes, patterns, and consequences of viral diseases of the nervous system.

Zen Seeker S&L 446-448

Encephalitis and myelitis are diffuse inflammatory processes leading to neuronal death and brain swelling

            Diffuse inflammation of the brain (encephalitis) and cord (myelitis) is caused by viral, rickettsial and certain bacterial organisms (mainly Listeria, Treponema, and Borrelia).  The main viral organisms responsible for this pattern of infection are herpes simplex, polio and rabies.  Clinically, diffuse inflammation causes neurological dysfunction manifest by myelopathy (motor and sensory signs) or encephalopathy (confusion and reduced level of consciousness).

            Macroscopically, there is hyperemia of the meninges, petechial hemorrhages in the brain, and brain swelling due to edema.  In some types, e.g. encephalitis due to herpes simplex, there is extensive brain necrosis.  The results of encephalitis or myelitis are death of neurons, cuffing of cerebral blood vessels by lymphoid cells, and astrocytic gliosis.  Depending on the cause, viral cellular inclusion bodies may be seen.  For example, cytoplasmic Negri bodies are seen in rabies, and nuclear viral inclusion bodies are seen in herpes encephalitis.

Viral disease of the nervous system are seen in four main patterns:

• Viral meningitis, characterized by the development of lymphocytic meningitis (page 445)

• Cytolytic,  in which there is cell destruction producing encephalitis or myelitis.  This is the most clinically severe pattern of involvement, most commonly seen with herpes simplex (fig 21.24).

• Latent, in which virus is integrated into the host cells, with the potential for reactivation as a cytolytic infection.  This is extremely common with herpes zoster, causing shingles.

• Persistent, in which there is slow, smoldering degeneration of neuronal tissues caused by viral infection in the absence of elimination by immune responses, e.g. measles virus infection causing subacute sclerosing panencephalitis.

            The main infections of the CNS are summarized in fig 21.25.  Diffuse parenchymal infections lead to headache, drowsiness, and, in severe cases, coma.  In addition to direct infection, systemic viral infections can predispose to immune-medicated demyelinization or vasculitis in the nervous system.

AIDS commonly affects the nervous system

            One of the most common causes of viral infection of the nervous system is HIV.  Not only does HIV directly affect the brain and spinal cord, AIDS also predisposes to several complications due to immunosuppression.

            The AIDS dementia complex (HIV cognitive/motor complex) is a clinical syndrome that has elements of intellectual impairment, and behavioral and motor changes.  Several pathologically defined changes underlie this clinical syndrome.

            Lymphocytic meningitis is seen in patients around the time of seroconversion and is defined as occurring in the absence of any demonstrable opportunistic pathogens.

            HIV encephalitis is a multifocal process characterized by inflammatory foci including multinucleate giant cells, mainly seen in white matter, basal ganglia and brain stem.

            HIV leukoencephalopathy is characterized by myelin loss, gliosis, phagocytic macrophages and scattered multinucleate giant cells in whiter matter.  There is little or no inflammatory infiltration.

            Diffuse poliodystrophy is the term applied to neuronal loss, microglial activation and gliosis in CNS gray matter.

            Vacuolar myelopathy is the term used to describe vacuolation (the state of having become filled with vacuoles) in myelin sheaths, with myelin loss in the spinal cord.

            Cerebral vasculitis is seen most prominently in childhood HIV disease of the brain.

            Clinically, patients with mild cases of cognitive impairment and motor slowing have myelin pallor and gliosis corresponding to HIV leukoencephalopathy, whereas those with severe cognitive impairment and motor slowing tend to have HIV encephalitis.  Patients with clinical signs of spinal cord disease have vacuolar myelopathy.  The cerebral atrophy often seen on imaging correlates with neuronal loss and diffuse poliodystrophy.

            The immunosuppression induced by AIDS predisposes to several opportunistic infections of the CNS, particularly atypical cycobacteria, cryptococcal meningitis, cytomegalovirus (CMV) (microglial nodular encephalitis describes the pattern of cortical inflammation seen due to CMV), herpes zoster encephalitis, toxoplasmosis, progressive multifocal leukoencephalopathydue to papovavirus, and Candida and Asperigillus infection.

            AIDS patients are at risk of developing primary cerebral lymphomas (page 464).

Fig 21.25  ain viral infections of the CNS

Ky 446-447

Defn:  diffuse inflammation of the brain.  

Caused: by viral (HSV, polio, rabies), rickettsial and certain bacterial organisms (listeria, treponema, borrelia).

Patterns:  hyperemia of meninges petechial hemorrhages in brain, brain swelling due to edema.

Consequence:  diffuse inflammation causes neurological dysfunction manifest by myelopathy (motor/sensory signs) or encephalopathy (confusion/reduced level of consciousness).  Myelopathy and encephalopathy cause death of neurons, cuffing of cerebral blood vessels by lymphoid cells, and astrocytic gliosis.  HSV causes extensive brain necrosis.

Sarra V.  Encephalitis and myelitis are diffuse inflammatory processes leading to neuronal death and brain swelling.  Caused by viral, rickettsial and certain bacterial organisms (mainly Listeria, Treponema, and Borrelia).  The main viral organisms responsible for this pattern of infections are herpes simplex, polio and rabies. Clinically, diffuse inflammation causes neurological dysfunction manifest by myelopathy ( motor and sensory signs) or encephalopathy ( confusion and reduced level of consciousness).

Tim Stevens&Lowe pg. 446

            Defined as diffuse inflammation of the brain cause by viral (HSV, polio, rabies), rickettsial and certain bacterial organisms (listeria, treponema, borrelia).  Patterns are hyperemia of meninges petechial hemorrhages in brain with swelling due to edema.  Consequences include diffuse inflammation leading to neurologic dysfunction by myelopathy (motor and sensory signs) or encephalopathy (confusion and reduced level of consciousness).  

11.       Describe spongiform encephalopathy and its association with prion protein.

Zen Seeker S&L 448

Spongiform encephalopathies are caused by an unconventional protein-only agent and can be genetic as well as transmissible

            Creutzfeld-Jakob disease (CJD) is an uncommon nervous system disorder.  It is characterized by accumulation of a modified normal cell-membrane protein, termed prion protein (PrP).  The precise way in which the protein is modified is unknown.

            The disease is associated with a rapidly progressive dementia in humans, with histological vacuolation in the brain, known as spongiform encephalopathy (fig 21.26).  It is similar to kuru in humans, scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle, which are also characterized by accumulation of PrP.  As these diseases were once thought to be caused by a virus with a long incubation, they were formerly termed slow-virus diseases.  It is now recognized that this is a protein-only infective disorder, a biologically unique phenomenon.

            New variant CJD has been caused by transmission of the agent causing BSE in cattle to man, by ingestion of contaminated meat in the diet.  This disease is characterized by early psychiatric symptoms followed by sensory symptoms, cerebellar ataxia and only late dementia.  The brain shows prominent accumulation of PrP amyloid plaques (fig 21.27a).  Importantly in this condition PrP also accumulates in the lymphoid tissues in affected patients allowing diagnosis by tonsil biopsy in life (fig 21.27b).

            Although most human disease is sporadic, cases have resulted from transplantation of tissue from an affected person, as well as from administration of growth hormone derived from cadavers.  Identical and transmissible disease can result from hereditary mutations in the gene coding for the prion protein in man (hereditary CJD and Gerstmann-Straussler syndrome, causing familial cases of ataxia and dementia).

Ky 448

Spong Encehp:  Histological vacuolation in the brain causing rapidly progressive dementia.  Caused by an unconventional protein-only agent and can be genetic as well as transmissible.  Characterized by an accumulation of prion protein (PrP).  PrP is a modified cell membrane protein.

Janelisa S&L 448 Spongiform encephalopathy is histological vacuolation in the brain, is associated with rapidly progressive dementia in humans, and is characterized by an accumulation of a modified normal cell-membrane protein (PrP). It is unknown how the protein is modified.

12.       Identify fungal and parasitic causes of infection of the nervous system.

Zen Seeker S&L 449

Fungal infection of the nervous system is usually seen in patients who are immunosuppressed

            Infection of the nervous system by fungi is frequently seen in patients who are immunosuppressed (most commonly following organ transplantation or anti-cancer chemotherapy, or with HIV infection and AIDS).

• Candidiasis causes multiple small cerebral abscesses in the CNS, usually secondary to septicemia caused by primary Candida infection elsewhere.  Aspergillus is another organism that affects the brain from hematogenous spread, usually from primary lung involvement, leading to formation of fungal abscesses.

• Phycomycosis (mucormycosis, zygomycosis) infect the brain by local spread from primary infection of the paranasal sinuses.  Fungi typically invade along vessels, causing vascular thrombosis and cerebral infarction.

• Cryptococcosis is due to a yeast-like organism that most commonly causes a fungal meningitis in immunosuppressed patients but may also affect patients with normal immune function (page 125 and fig 8.16)

Parasitic infection of the nervous system by protozoa and metazoan is increasing in western countries

            Infection of the nervous system by protozoa was formerly uncommon in western countries, but is being seen increasingly because of international travel and increased risk of infection in patients with immunosuppression.

• Toxoplasma can cause a congenital infection resulting in hydrocephalus and cerebral calcification.  It is also now frequently seen in patients with AIDS, causing cerebritis and brain abscesses (page 446 and fig 21.23).

• Malaria is the most common protozoan disease to involve the brain (particularly infection with Plasmodium falciparum), causing vascular thromboses with petecheal hemorrhages (cerebral malaria) (see page 133).

• Trypanosomiasis may be associated with an encephalomyelitis in acute disease.

• Entamoeba histolytica can cause an amebic abscess by spread from the gut, whereas a meningitis is caused by freeliving amebas such as Naegleria, usually acquired by swimming in contaminated pools in warm climates.

• Echinococcus granulosus (causing hydatid disease) and the larval form of the pork tapeworm, Taenia solium (causing cysticercosis) are the two main metazoan parasites to infect the brain (page 137).

Ky 449

Janelisa S&L 449 Fungal infection is more frequent in the immunosuppressed. Organisms include Candida, Aspergillus, Phycomycoses, and crytpococcus. Parasitic infection is becoming more common in the west due to international travel. Examples of protozoan infections are toxoplasma, malaria (Plasmodium falciparum), trypanosomiasis, Entamoeba histolytica, and Naegleria. The metazoan parasites are Echinococcus granulosus and Taenia solium.

13.       Describe the etiology, pathogenesis, and natural history of the following demyelinating diseases:

                        multiple sclerosis

                        Guillain-Barre syndrome

Zen Seeker S&L 450

            The demyelinating disorders are diseases in which the main abnormality is damage to CNS myelin.  Myelin loss is seen in many disease processes after axonal loss, but this type of secondary myelin loss is not considered as part of the group of demyelinating diseases.  The most important condition causing demyelination is multiple sclerosis.

            Multiple sclerosis is an immune-mediated disease of uncertain cause.

            Multiple sclerosis (MS) is a disease in which there are relapsing episodes of immunologically-mediated demyelination within the CNS.  Loss of myelin leads to failure of axonal function and neurological dysfunction.

            The lesions of MS are confined to the brain and spinal cord.  Areas of demyelination are termed plaques, best seen at the angles of the lateral ventricles, in the cerebellar peduncles, and in the brain stem, although they can occur at any site in the CNS.

            Areas of active recent demyelination appear as salmon-pink granular patches of softening in white matter.  Histologically, there is myelin loss associated with lymphocytic cuffing of small vessels.  Macrophages enter the lesion and phagocytose damaged myelin, accumulating lipid and forming foam cells.  Astrocytes around plaque margins become enlarged.

            Areas of old myelin loss appear as sharply demarcated patches of firm, gelatinous, grayish-pink discoloration (fig 21.28).  These inactive plaques, sometimes called burnt-out plaques, show loss of myelin, very few inflammatory cells, and are occupied by astrocytes.

            Although the axons that span a plaque are mostly preserved, there is clear-cut evidence of loss of a small proportion of axons from plaque areas.

            Most patients who develop MS are aged between 20 and 40 years.  The early common clinical symptoms are limb weakness, blurring of vision, incoordination, and abnormal sensation.  There is great variation in outcome.  Some patients have a benign form of disease, experiencing minor disability and few episodes of demyelination.  Others have frequent repeated episodes of myelin loss, progressing such that in the late stages of disease they are rendered blind, paraplegic and incontinent, with cognitive dysfunction caused by loss of hemispheric white matter.

Etiology and pathogenesis of multiple sclerosis

            MS has a peak incidence between the ages of 20 and 40 years, with a slight female predominance.  Many theories have been advanced to explain the disease, but the etiology of the condition is uncertain.

            Although viral infection gas been postulated, none has been consistently detected or directly implicated in disease.  Immunological mechanisms are central to disease pathogenesis, and an active immunological response is present in areas of demyelination.  The cause of immune response remains uncertain.  An association with certain HLA antigens (HLA-DR2) has also been demonstrated.  It is likely that the disease is the result of a genetic susceptibility, predisposing to mounting an inappropriate immune response to viral infections.

            In the region of active plaques, microglial cells show enhanced expression of Class II major histocompatibiliy antigens, suggestive of immune activation.  Lesions are infiltrated by T-cells, B-cells and macrophages, again emphasizing immune activation.  Trails with cytokine agents which modulate the immune response are under evaluation.

             S&L 466

Acute immune-mediated demyelination is the most common cause of an acute peripheral neuropathy.

            Guillain-Barré Syndrome, also known as acute postinfectious polyradiculoneuropathy is the most common form of acute neuropathy.  It is an immune-mediated demyelination of peripheral nerves, usually seen 2-4 weeks after a viral illness, but also triggered after a variety of infective processes.  Histologically, nerves show infiltration by lymphoid cells, with phagocytosis of myelin by macrophages.

            Widespread demyelination in peripheral nerves causes motor weakness, often leading to reparatory failure, with less prominent sensory changes.  Remyelination usually occurs over a period of 3-4 months and is associated with recovery in most cases.

Ky 450 & 466

Multiple Sclerosis:  (p450)  Idiopathic immune mediated disease.   

Guillain-Barre syndrome: (p466)  Disease of peripheral nerves.  Most common form of acute neuropathy.  Immune mediated.  Seen 2-4 weeks after viral infection, also triggered after a variety of infective processes.  Nerves infiltrated by lymphoid cells, with phagocytosis of myelin by macrophages.  Causes motor weakness, respiratory failure.  Remyelination occurs over 3-4 months, most cases fully recover.

Janelisa

multiple sclerosis - S&L 450 in MS, there are relapsing episodes of immunologically mediated demyelination within the CNS. This leads to failure of axonal function and neurological disfunction. The lesions are confined to the brain and spinal cord and are called plaques. Most patients are between 20 and 40 years. Symptoms include limb weakness, blurry vision, incoordination, and abnormal sensation. The disease can be fairly benign or progress to blindness, paraplegia, and incontinence.

Guillain-Barre syndrome - S&L 466 is also known as acute post-infectious polyradiculoneuropathy. It is an immune-mediated demyelination of peripheral nerves, usually seen 2-4 weeks after a viral illness. Symptoms include motor weakness, respiratory failure, and less prominent sensory changes. Remyelination usually occurs in 3-4 months and is associated with recovery in most cases.

14.       Describe the etiology, pathogenesis, and natural history of the following neurodegenerative diseases:

                        amyotrophic lateral sclerosis (ALS)

                        Parkinson’s disease

                        Huntington’s disease

                        Alzheimer’s disease

Zen Seeker S&L 451-454

amyotrophic lateral sclerosis (ALS) (Lou Gehrig's Disease internet)

Motor neuron disease (amyotrophic lateral sclerosis) causes paralysis due to death of motor neurons in the motor cortex, brain stem and spinal cord

            Motor neuron disease is a progressive neurodegenerative disease.  It is mainly seen in old age, a small number of patients presenting in middle age.  Disease typically begins as mild weakness in one limb.  There is then progression to severe paralysis, with loss of swallowing and respiration leading to death in 2-3 years.  The cause of the disease is unknown.

            Different sub-types related to the loss of different groups of motor neurons:

• Amylotrophic lateral sclerosis is the most common pattern, showing loss of both cortical motor neurons and lower motor neurons in the spinal cord and brain stem.

• Progressive bulbar palsy is common and shows loss of brain stem motor neurons.

• Progressive muscular atrophy is uncommon and shows loss restricted to spinal lower motor neurons.

• Primary lateral sclerosis is rare and shows loss of neurons restricted to the motor cortex.

            There is loss of motor neurons from cortex, brain stem and spinal cord, and gliosis with secondary degeneration of motor tracts (fig 21.29).  Inclusion bodies containing the protein ubiquitin are found in surviving neurons.

Parkinson’s disease

Parkinson’s disease results from loss of neurons from the substantia nigra

            Parkinson’s disease is a movement disorder that mainly affects patients over the age of 45 years.  It is clinically characterized by disturbance of movement with rigidity, slowness of voluntary movement (bradykinesis), and rest tremor.  Severity of disease is related to loss of the neuromelanin-containing nerve cells from the substantia nigra in the midbrain; these cells normally produce dopamine, there loss reducing the amount of dopamine in the basal ganglia.

            Macroscopically, there is loss of pigment from the substantia nigra, which is the result of death of the melanin-containing nigra, which is the result of death of the melanin-containing dopaminergic cells (fig 21.30).  The surviving cells in the substantia nigra contain spherical inclusions termed Lewy bodies (fig 21.31).

            The cause of Parkinson’s disease is unknown but rare cases are familial.  The disease may be symptomatically treated by administration of drugs that correct the neurotransmitter imbalance, e.g. L-dopa.  The natural history of the disease is for patients to develop failure of response to treatment, with death eventually occurring from wasting and poor nutritional intake.

loss of pigmentation in substantia nigra

damage and death of the dopaminergic pigmented neurons

Huntington’s disease

Huntington’s disease is an autosomal dominant disease causing chorea and dementia

            Huntington’s disease is a neurodegenerative disease causing choreiform movements and dementia, with onset in middle life.  The disease is an autosomal dominant disorder with a prevalence of approximately 1 in 20,000; the gene has been characterized at its location in the short arm of chromosome 4 (pink box page 452).

            Macroscopically the brain shows atrophy of the caudate and putamen due to cell loss and gliosis (fig 21.32), and careful measurements have shown subtle loss of neurons from the cerebral cortex.

            Pink box - Molecular genetics of Huntington’s disease

            The gene for Huntington’s disease is located on chromosome 4.  The cause of the disease is an abnormally long, tandemly repeated trinucliotide (CAG).  In normal individuals this gene has between 9 and 34 repeats, whereas in Huntington’s disease patients have around 70 repeats.  The protein produced by the gene, which has been named huntingtin, is expressed in many tissues but has no homology with other proteins; its function is at present unknown.  Protein accumulates inside neuronal nuclei forming inclusions as well as accumulating inside some nerve cell processes.

            The age of onset of disease is related to the length of the repeat sequence; patients with large repeat sequences have early onset. With passage of the gene through generations, the repeat sequence increases in length, resulting in progressively earlier ages at presentation, a phenomenon termed anticipation.

            Now that the gene has been identified, confident genetic testing for the disease is possible, with all the attendant ethical and social implications.

atrophy of the caudate nucleus

Alzheimer’s disease

Alzheimer’s disease is the most common cause of dementia

            Alzheimer’s disease is the most common neurodegenerative disease and the most common cause of dementia (An organic mental disorder characterized by a general loss of intellectual abilities involving impairment of memory, judgment and abstract thinking as well as changes in personality).  Clinically, patients develop progressive failure of memory, degeneration of temporal and parietal failure of memory, degeneration of temporal and parietal association cortex (causing dyspraxia (impaired or painful function of any organ of the body) and dysphasia) and, frequently, disturbances in emotions.  With progression of disease over many years, patients become immobile and emaciated, death commonly being due to the development of a pneumonia.

            The cause of the disease is unknown, but there are well-defined genetic predispositions (pink box 453)

            The brain in Alzheimer’s disease is smaller than normal and brain weight is reduced, evident as shrinkage of gyri and widening of sulci of the cerebral hemispheres (fig 21.33). Atrophy is most evident in the temporal lobe, particularly the parahippocampal gyrus, but also the motor cortex are generally spared.

            Histologically, there are several main abnormalities seen in Alzheimer’s disease.  Amylid, composed of Aβ-peptide, is deposited in the cerebral cortex as spherical deposits termed senile plaques (fig 21.34a).  Intraneuroanl inclusions comprising bundles of abnormal filaments termed neurofibrillary tangles develop in cortical neurons (fig 21.34b) Tangles are frequently flame-shaped and occupy much of the space within the neuronal cytoplasm, being largely composed of a microtubule-binding protein called Tau protein.  Cortical nerve-cell processes become twisted and dilated (neuropil threads) due to accumulation of the same filaments that form the tangles.  Neurofibrillary tangles and plaques can be seen in the brains of cognitively normal elderly individuals, one interpretation being that they are in an early stage of disease at the time of death.  The pathological diagnosis of Alzheimer’s disease is based on the presence of lesions in high density in patients with clinical dementia.

            The neurochemical analysis of brains from patients with Alzheimer’s disease has shown widespread neurotransmitter defects, particularly loss of acetylcholine from the cortex.  Treatment protocols that supplement cholinergic transmission have shown promising results in trials.

neuritic" plaques

neurofibrillary tangles

amyloid angiopathy

granulovacuolar generation

Hirano bodies

spongiform

ventricular dilatation

Pink box on page 453 talks about molecular pathogenesis of Alzheimer’s disease

Janelisa

• amyotrophic lateral sclerosis (ALS) S&L 451 ALS is the most common subtype of motor neuron disease characterized by loss of both cortical motor neurons and lower motor neurons in the spinal cord and brain stem. It is mainly seen in old age beginning with mild weakness in one limb and progressing to severe paralysis with loss of swallowing and respiration leading to death in 2-3 years

• Parkinson’s disease S&L 451-452 is mainly seen in those over 45 years. Clinically characterized by disturbance of movement with rigidity, bradykinesis, and rest tremor. The severity of the disease is related to loss of the neuromelanin-containing cells, which produce dopamine, from the substantia nigra in the midbrain. Treatment is with a synthetic neurotransmitter L-dopa. As patients develop a failure to respond to this, death occurs from wasting.

• Huntington’s disease S&L 452 is a neurodegenerative disease causing choreiform movements and dementia with onset in middle life. It is autosomal dominant with a prevalence of 1 in 20,000. Characterized by progressive cognitive decline, with increase in severity of the movement disorder. Death results from severe mental and physical capacity.

• Alzheimer’s disease - S&L 453-454 is the most common neurodegenerative disease and most common cause of dementia. Characterized by progressive memory failure, degeneration of temporal and parietal association cortex leading to dyspraxia and dysphasia, and emotional disturbance. Over time, patients become immobile and emaciated. Death is commonly due to pneumonia. Amyloid deposits are seen in the cerebral cortex called senile plaques. There are also widespread neurotransmitter defects, particularly acetylcholine from the cortex.

15.       Describe the effects of chronic alcoholism on the nervous system.

Zen Seeker S&L 455-456

The brain and peripheral nerves are frequently damaged in chronic alcoholism

            Acute alcohol intoxication causes neuronal depression and may lead to death through cessation of respiration.

            Chronic alcoholism is associated with several diseases of both the central and peripheral nervous system.  It has been difficult to determine whether this is due to direct toxicity or whether it is caused by the nutritional and vitamin deficiencies commonly seen in patients dependent on alcohol.

            The brains of alcoholic patients show generalized cerebral cortical atrophy, which sometimes causes cognitive decline.  Cerebellar ataxia in patients with alcoholism is usually caused by cerebellar degeneration associated with severe atrophy of the cerebellar cortex.

            Wernicke’s encephalopathy is caused by thiamine deficiency, commonly seen in patients dependent on alcohol.  It presents clinically as a triad of confusion, ataxia, and abnormal eye movements with ophthalmoplegia.  Pathologically, there are petechial hemorrhages from small vessels in the mammillary bodies (page 21.36), which are associated with necrosis and loss of neurons, leading to eventual shrinkage and gliosis.  Acute Wernicke’s encephalopathy may prove fatal unless B-complex vitamins (including thiamine) are administered.  Damage to the limbic system from repeated episodes of Wernicke’s encephalopathy causes a permanent impairment of recent memory, termed Korsakoff’s psychosis.

            Exposure of the fetus to alcohol, when the mother is dependent, leads to growth retardation and cerebral malformations (fetal alcohol syndrome).

Ky 455

Difficult to distinguish between toxic affects vs. nutritional deficiency.  Brains show generalized cerebral cortical atrophy that may cause cognitive decline.  Cerebellar ataxia usually caused by cerebellar degeneration associated with severe atrophy of cerebellar cortex.  Wernicke’s encephalopathy (acute is fatal) caused by thiamine deficiency (presents as confusion, ataxia, abnormal eye movements).  Korsakoff’s psychosis is the permanent impairment of recent memory due to repeated episodes of Wernicke’s enceph.

Janelisa S&L 455-456 The brains of chronic alcoholics show generalized cerebral cortical atrophy, which sometimes causes cognitive decline. Cerebellar degeneration can also occur. Wernicke’s encephalopathy is cause by thiamine deficiency commonly seen in alcoholics. It is characterized by confusion, ataxia, and abnormal eye movements with opthalmoplegia. This results from petechial hemorrhages associated with necrosis and loss of neurons. Repeated episodes of Wernicke’s cause permanent impairment of recent memory, called Korsakoff’s psychosis. 

16.       Describe the main neural-tube defects of the spinal cord.

Deb/S&L, pg.456

            Spina Bifida Occulta= abnormal development of bony arch of spinal column. Meninges and cord normal. May be assoc. sinus track of the skin surface or subcut. Lipoma

            Meningocele=abnormal development of bony arch of spinal cord, with cystic outpouching of meninges covered by skin, spinal cord may be normally or abnormally formed.

            Meningomyelocele= abnormal development of bony arch of spinal cord, with cystic outpouching of meninges including nerve roots and incorporating abnormally developed spinal cord.

            Myelocele= abnormal development of bony arch of spinal cord, with exposure of abnormally developed spinal cord. 

Zen Seeker S&L 456-457

Neural-tube defects are the most common form of developmental abnormality of the CNS

            Defects in the closure of the neural tube are the most common cause of congenital malformation of the nervous system.  Such defects may affect either the cranial or the spinal closure of the neural tube, and may be an open defect or one closed by meninges and skin.

            The most severe and common form of cranial neural-tube defect is anencephaly.  The cranial vault is generally not formed, although the face and eyes are usually well developed.  The brain is replaced by a disc of abnormally developed neural tissue.  A less severe cranial neural-tube defect is development of an encephalocele, in which a defect in the bone of the skull is associated with cystic out-pouchings of meninges, which may contain brain.

encephalocele

            Neural-tube defects of the spinal cord are most common in the lumbar region.  The severity of the defect is variable (fig 21.38).  The main defects include:

• Spina bifida occulta.   Abnormal development of the bony arch of the spinal column.  Meninges and cord normal.  There may be an associated sinus track to the skin surface, or subcutaneous lipoma.

• Meningocele. Abnormal development of the bony arch of the spinal cord, with cystic outpouching of meninges covered by skin.  Spinal cord may be normally or abnormally formed.

• Meningomyelocele.  Abnormal development of the bony arch of the spinal cord, with cystic outpouching of meninges including nerve roots and incorporation abnormally developed spinal cord.

• Myelocele.  Abnormal development of the bony arch of the spinal cord, with exposure of abnormally developed spinal cord.

            The neurological deficit associated with spinal neural-tube defects is related to the degree of severity of abnormality of the spinal cord and nerve roots.

Other developmental abnormalities may be present, particularly hydrocephalus caused by Arnold-Chiari malformation (page 444).

            Patients with spinal neural-tube defects commonly have paraplegia with urinary and fecal incontinence.  Without surgical correction, they develop spinal and limb deformities.  A major complication is recurrent urinary tract infection leading to chronic pyelonephritis and renal failure.

            Diagnosis can be made in utero by ultrasound scanning or by detecting raised levels of α fetoprotein (AFP) in serum or amniotic fluid.

Ky 456

Spina Bifida Occulta:  Abnormal development of the bony arch of the spinal column.  Meninges and cord normal.  There may be an associated sinus track to the skin surface or subcutaneous lipoma.

Meningocele:  Abnormal development of the bony arch of the spinal cord with cystic outpouching of meninges covered by skin.  Spinal cord may be normally or abnormally formed.

Meningomyelocele:  Abnormal development of the bony arch of the spinal cord, with cystic outpouching of meninges including nerve roots and incorporating abnormally developed spinal cord.

Myelocele:  Abnormal development of the bony arch of the spinal cord, with exposure of abnormally developed spinal cord.

Greg R.  S&L p. 456-7.  See Fig. 21.38.

Neural-tube defects of  the spinal cord are most common in the lumbar area.  Severity is variable.  The main defects include:

Spina bifida occulta - Abnormal development of the bony arch of the spinal column (incomplete closure).  Meninges and  cord normal.  May be an associated sinus track to the skin surface, or subcutaneous lipoma.

Meningocele - Abnormal development of the bony arch of the spinal cord, with cystic outpouching of meninges covered by skin.  Spinal cord may be normally or abnormally formed.

Meningomyelocele - Abnormal development of the bony arch of the spinal cord, w/ cystic outpouching of meninges including nerve roots and incorporating an abnormally developed spinal cord.

Myelocele - Abnormal development of the bony arch of the spinal cord, w/ exposure of abnormally developed spinal cord.

The neurological deficit associated with spinal neural-tube defects is related to the degreed of severity of abnormality of the spinal cord and nerve roots.  Other developmental abnormalities may be present.  Patients w/ spinal neural-tube defects commonly have paraplegia w/ urinary & fecal incontinence.

17.       Briefly describe the main features of neurofibromatosis 1 and neurofibromatosis 2.

Deb/S&L,pg. 459

            Neurofibromatosis1= an autosomal dominant disease causes multiple benign tumors of peripheral nerves and presence of pigmented skin lesions “café au lait spots”  Pts. Develop multiple polypoid skin nodules, from 1mm to 5cm, there is risk of development of malignant nerve tumors

            Neurofibromatosis2= autosomal dominant disease causes tumors on the acoustic nerves, clinical features are development of bilateral benign tumors “schwannomas” aka “acoustic neuromas”/ Also, a tendency to develop other brain tumors, meningiomas and glioma.  Pts. Present with tinnitus, deafness, or signs of mass lesion compressing lower cranial nerves and brain stem. 

Zen Seeker S&L 459

The phacomatoses are familial disorders in which there are developmental abnormalities associated with hamartomatous (relating to tumor like but nonneoplastic overgrowth of tissue that is disordered in structure) or neoplastic growths.  The main types of disease are neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), tuberous sclerosis, and von Hippel-Lindau syndrome.

NF1 is an autosomal dominant disease that causes multiple benign tumors of peripheral nerves

            NF1, formerly called ‘von Recklinghausen’s syndrome’, is an autosomal dominant disorder affecting 1 in 4000 individuals.  The main clinical features are development of benign tumors of peripheral nerves, termed neurofibromas (page 467), and the presence of pigmented skin lesions called café au lait spots.  Less prominent are hamartomas (tumor like but nonneoplastic overgrowth of tissue that is disordered in structure) of the iris, optic-nerve gliomas, and bone abnormalities.  Patients characteristically develop multiple polyploid skin nodules, which can vary from 1 mm up to 5 cm in diameter.  There is a risk of development of malignant nerve tumors (neurofibrosarcomas).  The gene defect in NF1 is located on chromosome 17 pink box 459

NF2 is an autosomal dominant disease that causes tumors on the acoustic nerves

            NF2 is an autosomal dominant disorder affecting 1 in 100000 individuals.  The clinical features are development of bilateral benign tumors (also termed schwannomas) of the eighth cranial nerve, which are also known as acoustic neuromas, hence the alternative name of bilateral acoustic neurofibromatosis (BANF).  There is also a tendency to develop other brain tumors, meningiomas and gliomas.  Patients present with tinnitus, deafness, or signs of a mass lesion compressing the lower cranial nerves and the brain stem.  The gene defect of NF2 is located on chromosome 22 (pink box 459).

            Pink box - genetics of neurofibromatosis syndromes

            Neurofibromatosis was once regarded as one disease, but is now considered to be two diseases, termed NF1 and NF2.

            NF1, or von Recklinghausen’s disease, is caused by mutation in a gene on chromosome 17.  The gene codes for neurofibromin, which is a guanidine-triphosphatase-activating protein (GAP protein).  These proteins normally convert the proto-oncogene p21-ras from an active GTP-bound form to an inactive GDP-bound form.  The ras proteins usually act to modulate cell proliferation, and their over activity has been implicated in tumor formation.  In NF1 it is likely that mutant forms of protein cannot inactivate ras and that activated ras therefore accumulates to promote cell growth.

            NF2 is caused by mutation in a gene on chromosome 22, which codes for a protein that has been termed schwannomin or merlin by different workers.

            The schwannomin protein acts as a tumor suppressor, but its mechanism of action is uncertain.  It has similarities with cytoskeletal proteins linking to the spectrin-actin complex (which normally braces the cell membrane), suggesting that lack of the protein causes abnormal cell-to-cell contact and interferes with normal contact-dependent inhibition of cell growth.  Screening of patients with NF2 has shown several different mutations in the gene, each predicted to result in syntheses of a truncated form of schwannomin.  Interestingly, mutations in this gene have been seen in meningiomas from patients not affected by NF2, raising the possibility of its involvement in sporadic cases of meningioma.

            The identification of these genes means that patients and families may be screened for mutations and given appropriate counseling.

Greg R.  S&L p. 459.

Neurofibromatosis 1 (NF1) - is  an autosomal dominant disease.  Main features:

— Multiple benign tumors of peripheral nerves (neurofibromas).

— Pigmented skin lesions (café au lait spots).

Less common features:

— Hamartomas of  the iris, optic nerve gliomas, & bone abnormalities.

Patients characteristically develop multiple polypoid skin nodules, which can vary from 1mm up to 5cm in diameter.

Neurofibromatosis 2 (NF2) - is an autosomal dominant disease.  Main features:

— Developoment of bilateral benign tumors (schwannomas) of the eighth cranial nerve known as acoustic neuromas (alternative name of bilateral acoustic neurofibromatosis (BANF)).

— There is also a tendency to develop other brain tumors, meningiomas and gliomas.

Patients present with tinnitus, deafness, or signs of a mass lesion compressing the lower cranial nerves and brain stem.

18.       List the four main types of tumors that are commonly seen in the CNS.

            (Note:  don’t try to learn all of the various tumors described in the textbook, but do pay attention to the primary sites of metastases to the brain and spinal cord, meningiomas, astrocytes and glioblastomas, and lymphomas.)

Deb/S&L,pg. 460

           Metastases= overall, the most common cause of a neoplasm affecting the brain

           Meningeal= tumors derived from epithelial cells of the meninges, termed “meningiomas”

           Neuroepithlial= tumors loosely termed “gliomas”, which are derived from astrocytes, oligodendrocytes, ependyma, neurons or primitive embryonal cells

           Non-neuroepithelial= tumors including cerebral lymphomas, germ-cell tumors, cysts and tumors extending from local growth in the skull and pituitary. 

Zen Seeker S&L 460

Primary neoplasms of the CNS are important as they commonly affect young patients; in incidence they are second only to the leukemias, accounting for about 10% of cancer deaths in those aged between 15 and 35 years.  Overall, they account for only about 2% of all deaths from cancer and, in general, are uncommon.  Tumors are derived from the various tissues that make up the CNS:

• Metastases.  Overall, the most common cause of a neoplasm affecting the brain

• Meningeal.  Tumors derived from epithelial cells of the meninges, termed ‘meningiomas’.

• Neuroepithelial.  Tumors loosely termed ‘gliomas’, which are derived from astrocytes, oligodendrocytes, ependyma, neurons or primitive embryonal cells.

• Non-neuroepithelial.  Tumors including cerebral lymphomas, germ-cell tumors, cysts and tumors extending from local growth in the skull and pituitary.

Greg R.  S&L p.460-464.

1)  Metastases - overall the most common cause of a neoplasm affecting the brain and spinal cord.  As well as focal neurological signs, metastases to brain cause signs of raised intracranial pressure.  The main primary sites of metastatic tumor to brain are lung, breast, and skin (melanoma).  Metastases are often multiple and commonly begin as lesions at the junction of the cortex and white matter.  Cerebral edema is often extensive around metastases, accounting for the main problem of raised intracranial pressure.  Metastatic tumor commonly affects the spinal cord as extradural deposits, causing compression.  The most common are metastases from carcinomas of the prostate, kidney, breast & lung, together with lymphoma and myeloma.

2)  Meningeal - benign tumors derived from epithelial cells of the meninges, termed ‘meningiomas’.  They are common intracranial tumors and have a female predominance.  Meningiomas are typically rounded lesions that arise from the dura and grow slowly to compress underlying brain (see fig 21.41). Tumors can vary in diameter from 1 or 2cm up to 7cm.  Usually solitary, but may be multiple.  Infiltration of the skull by tumor may occur, causing local bony thickening.  Meningiomas typically present w/ either focal neurological signs or w/ features of raised intracranial pressure.  Tumors arise anywhere in the meninges, the most frequent sites being next to the falx, over the cerebral convexities, or over the sphenoid wings. Less commonly, meningiomas arise from the spinal dura & compress the spinal cord.

— The majority are classed as benign meningiomas.  Slow-growing expansile lesions w/ low risk of recurrence after surgical removal.

— A small proportion are classed as atypical meningiomas, have many mitoses, cell pleomorphism and necrosis, and an increased risk of local recurrence after surgery.

— A rare group are classed as malignant meningiomas.  These are rapidly growing tumors that behave as locally invasive malignant tumors resembling sarcomas.

3)  Neuroepithelial - tumors of neuroepithelial origin are common primary brain tumors loosely termed ‘gliomas’.  The main types are derived from astrocytes, oligodendrocytes, ependyma, choroids plexus, neurons or primitive embryonal cells.  Tumors range from benign, slow-growing lesions to malignant, rapidly growing tumors known as anaplastic gliomas.  Gliomas tend infiltrate diffusely into adjacent brain, making surgical removal difficult and leads to frequent local recurrence.

— Astrocytomas are diffuse lesions that range from benign to highly malignant.  They may arise in the cerebral hemispheres, brain stem, spinal cord or cerebellum, and are derived from astrocytic cells.  They vary from tumors w/ no histological features  of atypia and a slow pace  of growth (astrocytoma) to lesions w/ high cellularity, mitoses, pleomorphism and a rapid pace of growth (anaplastic astrocytoma).  They appear as ill-defined, pale areas of softening in the tissue of the nervous system, which blend into adjacent normal brain.  These tumors may arise in children or adults, presenting w/ focal neurological signs or raised intracranial pressure.  Low grade tumors are associated w/ many years’ survival, anaplastic astrocytomas having a survival of 4-5 yrs.  Low grade tumors usually evolve into high grade tumors w/ time.

— Glioblastomas are highly malignant tumors derived from glial cells with a rapid pace of growth.  Seen most in elderly ~ 65yo.  These tumors are necrotic hemorrhagic masses, arising principally in the cerebral hemispheres, less frequently in the brain stem, and rarely in the cerebellum or spinal cord.  Necrosis is always present, as this is the feature that delineates this type of lesion from the anaplastic astrocytoma.  Tumors may present as glioblastomas or may have evolved into glioblastoma from a previously diagnosed lower grade astroglial tumor.  They usually cause death by rapid local growth, but may also spread w/in the neuroaxis.  Have a median survival of ~ 10 months from Dx.

4)  Non-neuroepithelial - tumors including cerebral lymphomas, germ-cell tumors, cysts and tumors extending from local growth in the skull and pituitary.

Lymphomas of the nervous system are increasing in incidence as a complication of immunosuppression.  Primary lymphomas o the nervous system are usually high-grade non-Hodgkin’s lymphomas of B-cell type. May arise sporadically, but are becoming more frequent and are associated with immunosuppression, particularly w/ AIDS.  Lesions are ill-defined and multifocal, usually seen deep in the hemispheric white matter.  Histology shows brain infiltrated by atypical lymphoid cells.  These tumors have a very poor prognosis, with most patients dead 5 years after Dx.