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The Central Nervous System: II. Infections: Introduction

Infections of the nervous system are classified according to the infected tissue into

(1) meningeal infections (meningitis), which may involve the dura primarily (pachymeningitis) or the pia-arachnoid (leptomeningitis);

and

(2) infections of the cerebral and spinal parenchyma (encephalitis or myelitis).

In many cases, both the meninges and the brain parenchyma are affected to varying degrees (meningoencephalitis).

Meningeal Infections

Acute Leptomeningitis

Acute leptomeningitis is an acute inflammation of the pia mater and arachnoid.

Most cases are caused by infectious agents; rarely, release of keratinaceous contents from an intradural epidermoid cyst or

teratoma causes a chemical meningitis. When the term meningitis is used without qualification, it means leptomeningitis.

Classification

Acute meningitis may be classified according to etiology.

Acute Bacterial Meningitis

Etiologic Agents in Bacterial Meningitis.

Organism Patient Profile

Streptococcus pneumoniae Most common agent in patients over age 40 years

3050% of cases in adults

1020% of cases in children

5% of cases in infants

Neisseria meningitidis Most common agent in patients aged 540 years

2549% of cases in children aged 515 years


Haemophilus influenzae Most common agent in patients aged 15 years

4060% of cases in children aged 15 years


Listeria monocytogenes 1% of all cases of bacterial meningitis. Common in infants, elderly, or immunosuppressed

patients

Streptococcus agalactiae (group B) 40% of cases in neonates

Escherichia coli 40% of cases in neonates

Gramnegative bacilli (other than E

coli)

Posttraumatic postneurosurgical; 20% of cases in patients over age 50 years and in

debilitated patients

Staphylococcus aureus Postneurosurgical posttraumatic


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Staphylococcus epidermidis 75% of cases of meningitis complicating shunts

Neonatal meningitis is acquired during passage of the fetus through the birth canal. Organisms found in the maternal vagina,

commonly Escherichia coliand Streptococcus agalactiae (a group B streptococcus), are responsible.

In children up to 5 years of age, the most common pathogen causing meningitis is Haemophilus influenzae.

In adolescents, Neisseria meningitidis (meningococcus) is the most common cause.

Streptococcus pneumoniae (pneumococcus) causes meningitis in all age groups.

Listeria monocytogenes and gram-negative bacilli are important causes in older, debilitated, and immunosuppressed patients.

Acute Viral Meningitis

90% of these occur in patients under 30 years of age.

This is a mild, benign illness, which rarely causes death.

It is caused most commonly by enteroviruses, mumps virus, and lymphocytic choriomeningitis (LCM) virus.

An acute meningitis occurs in 10% of patients with human immunodeficiency virus (HIV) infection, most commonly at the time of

seroconversion.

Tuberculous Meningitis

Tuberculous meningitis is typically chronic; however, in the early stages there may be an exudative phase that resembles acute

meningitis.

Other Causes

The fungi Cryptococcus neoformans, Histoplasma, Blastomyces, and Candida albicans may cause meningitis in immunocompromised

patients. Free-living amebas belonging to the genera Naegleria andAcanthamoeba are rare causes of pyogenic meningitis.

Routes of Infection of the Meninges

Bloodstream spread accounts for the majority of cases; the primary entry site of the organism may be the respiratory tract (N

meningitidis, H influenzae, S pneumoniae, C neoformans, many viruses), skin (bacteria causing neonatal meningitis), or intestine

(enteroviruses).

Meningitis may also result from direct spread of organisms from an infected middle ear or paranasal sinus, especially in childhood.

Meningitis may be associated with skull fractures, especially those at the base of the skull causing free communication between the

subarachnoid space and the upper respiratory tract; brain surgery; or lumbar puncture.

Organisms may also gain entry through the intact nasal cribriform plate (eg, free-living soil amebas in stagnant swimming pools).

Tuberculous meningitis may occur during severe tuberculous bacteremia (miliary tuberculosis) or as a result of reactivation of a

meningeal focus, in which case the patient may have no evidence of tuberculosis elsewhere.

Pathology


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Grossly, the leptomeninges are congested and opaque and contain an exudate.

Microscopically, acute meningitis is characterized by hyperemia, fibrin formation, and inflammatory cells.

In bacterial meningitis, neutrophils dominate

in acute viral meningitis, neutrophils are rare and lymphocytes dominate . In acute tuberculous meningitis, there is an inflammatory

exudate that contains increased numbers of both neutrophils and lymphocytes.


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Clinical Features

Acute meningitis presents with fever and symptoms of meningeal irritation, which include headache, neck pain, and vomiting.

Physical examination reveals neck stiffness and a positive Kernig sign (inability to straighten the raised leg because of pain), both of

which are due to reflex spasm of spinal muscles, a consequence of irritation of nerves passing across the inflamed meninges.

In general, bacterial meningitis is a serious disease with considerable risk of death while viral meningitis is usually a mild, self-limited

infection. Tuberculous meningitis has an insidious onset and a slow rate of progression but is frequently a severe illness with a fataloutcome if not treated.

Diagnosis

The diagnosis is made by examination of the cerebrospinal fluid (CSF), a sample of which is obtained by lumbar puncture. The

leptomeningeal exudate becomes admixed with the CSF, which reflects the type of inflammatory response and contains the

infectious agent

Cerebrospinal Fluid Changes in Infections of the Central Nervous System.

Encephalitis Bacterial

Meningitis1

Viral

Meningitis

Tuberculous (Chronic)

Meningitis

Brain Abscess

Pressure Raised Raised Raised Raised May be very high

Gross appearance Clear Turbid Clear Clear; may clot Clear

Protein Slightly elevated High Slightly

elevated

Very high Elevated

Glucose Normal Very low Normal Low Normal

Chloride Normal Low Normal Very low Normal or low

Cells Lymphocytes ornormal

Neutrophils Lymphocytes Pleocytosis2

Pleocytosis

Gram stain Negative Positive in 90% Negative Negative Occasionally

positive

Acidfast stain Negative Negative Negative Rarely positive Negative

Bacterial culture Negative Positive in 90% Negative Negative Occasionally

positive

Mycobacterial

culture

Negative Negative Negative Positive Negative

Viral culture Positive in 30% or

less

Negative Positive in 70% Negative Negative

1Amebic and cryptococcal meningitis are diagnosed by the finding of these organisms in the smear.

2Pleocytosis is the presence of both neutrophils and lymphocytes in cerebrospinal fluid.


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Chronic Meningitis

Chronic meningitis is caused by facultative intracellular organisms such as Mycobacterium tuberculosis, fungi, and Treponema

pallidum.

Pathology & Clinical Features

Chronic tuberculous and fungal meningitis are characterized by caseous granulomatous inflammation with fibrosis.

Marked fibrous thickening of the meninges is the dominant pathologic feature. The entire brain surface is involved, with the basal

meninges more severely affected in cases of tuberculosis. The causative agent may be identified in tissue sections specially stained

for acid-fast bacilli and fungi.

The meningovascular phase of syphilis also causes a basal chronic inflammation with marked fibrosis and obliterative vasculitis,

with large numbers of plasma cells infiltrating the meninges; granulomas are not present.

Complications of chronic meningitis include

(1) obliterative vasculitis (endarteritis obliterans), which may produce focal ischemia with microinfarcts in the brain and brain stem;

(2) entrapment of cranial nerves in the fibrosis as they traverse the meninges, resulting in cranial nerve palsies; and

(3) fibrosis around the fourth ventricular foramina, causing obstructive hydrocephalus.

Clinically, chronic meningitis is characterized by an insidious onset with symptoms of diffuse neurologic involvement, including

apathy, somnolence, personality change, and poor concentration. These symptoms are thought to stem from a concomitant diffuse

encephalopathy.

Headache and vomiting are less severe than in acute meningitis, and fever is often low-grade. Focal neurologic signs and epileptic

seizures result from ischemia, cranial nerve palsies, or hydrocephalus.

Infections of the Brain Parenchyma

Cerebral Abscess

Cerebral abscess is a localized area of suppurative inflammation in the brain substance. The cavity contains thick pus formed from

necrotic, liquefied brain tissue and large numbers of neutrophils and is surrounded by a fibrogliotic wall.

Etiology

Cerebral abscesses are caused by a large variety of bacteria; several organisms may occur in a single abscess, and anaerobic bacteriasuch as Bacteroides and anaerobic streptococci are common. Nocardia, Staphylococcus aureus, and gram-negative enteric bacteria

may also be isolated.

Cerebral abscesses occur as complications of other diseases


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Cerebral abscesscommon sites and routes of infection.

(1) Chronic suppurative infections of the middle ear and mastoid air spaces and of the paranasal sinuses. The middle ear is

separated from the middle and posterior cranial fossas by thin bony plates that may be eroded by infection. The temporal lobeand the cerebellum are usually involved. Infections of the paranasal sinuses are occasionally associated with frontal lobe

abscesses.

(2) Infective endocarditis with embolization to brain. These patients commonly develop parietal lobe abscesses, which are often

small and multiple.

(3) Right-to-left shunts (eg, in patients with congenital cyanotic heart disease) may divert infected systemic emboli to the brain.

(4) Suppurative lung diseases such as chronic lung abscess and bronchiectasis are rarely complicated by embolization of infected

material to the brain, leading to parietal lobe abscesses.

Pathology

Grossly, a cerebral abscess appears as a mass lesion in the brain. It has a liquefied center filled with pus and a fibrogliotic wall whosethickness depends on the duration of the abscess. The surrounding brain tissue frequently shows vasogenic edema.

Clinical Features & Diagnosis

Cerebral abscess presents with

(1) features of a space-occupying lesion, including evidence of increased intracranial pressure (headache, vomiting, papilledema) and

focal neurologic


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(2) features relating to the source of infection, such as chronic otitis media, suppurative lung disease, and endocarditis; and

(3) general evidence of infection, such as fever, rapid (elevated) erythrocyte sedimentation rate, and weight loss in chronic cases.

In untreated cases, the abscess progressively enlarges and may cause death from increased intracranial pressure or rupture into the

ventricular system.

Diagnosis

The diagnosis of cerebral abscess is made clinically and confirmed by computed tomography (CT) scan or magnetic resonance

imaging (MRI). Lumbar puncture is dangerous because of the risk of precipitating tonsillar herniation.

Treatment

Surgical evacuation of the abscess followed by antibiotic therapy is effective treatment and has reduced the previously high

mortality rate of cerebral abscess to about 510%.

Viral Encephalitis

The frequency of viral encephalitis is difficult to estimate.

Most of these are presumptive diagnosesthe etiologic virus is identified in only about 30% of cases.

Causes of Viral Encephalitis.

Diffuse encephalitis

Epidemic (arbovirus) encephalitis

Eastern equine encephalitis

Western equine encephalitis

Venezuelan equine encephalitis

St. Louis encephalitis

California encephalitis

Japanese B encephalitis

Sporadic encephalitis

Herpes simplex encephalitis

Enterovirus encephalitis

Measles encephalitis

Varicella (chickenpox) encephalitis

Encephalitis in the immunocompromised patient

Herpes simplex encephalitis

Progessive multifocal leukoencephalopathy (PML)

Cytomegalovirus

HIV (AIDS) encephalitis

Specific types of encephalitis

Poliomyelitis

Rabies


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Subacute sclerosing panencephalitis (SSPE)

Prion (slow virus) infections

Pathology

The virus usually reaches the brain via the bloodstream. It infects brain cells, causing neuronal necrosis and marked cerebral edema,

which in turn leads to acute cerebral dysfunction and increased intracranial pressure.

Perivascular lymphocytic infiltration (perivascular cuffing) is characteristic.

Viral encephalitis, showing perivascular lymphocytic cuffing.

Clinical Features

Viral encephalitis has an acute onset with fever, headache, and signs of brain dysfunction, the nature of which depend on the areas

of brain involved.

Convulsions may occur. There may be papilledema if cerebral edema is severe. In many cases of viral encephalitis, there isconcomitant meningeal inflammation causing neck stiffness and CSF abnormalities typical of viral meningitis.

The diagnosis is based on the clinical picture. Lumbar puncture with examination and culture of CSF may provide an etiologic

diagnosis.

Treatment

Therapy is supportive. Control of cerebral edema with high doses of corticosteroids is important in preventing death in the acute

phase from increased intracranial pressure. The mortality rate from severe viral encephalitis is high, and patients who recover are

frequently left with permanent neurologic deficits due to irreversible neuronal necrosis.

Herpes Simplex Encephalitis

Incidence & Etiology

Herpes simplex encephalitis occurs in 3 classes of patients:

Neonates are infected during delivery to a woman with active genital herpes. The presence of herpes genitalis in the mother is an

absolute indication for cesarian section. Herpes simplex type 2 is responsible for most cases.


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Adults are infected through the bloodstream from a minor focus of viral replication, usually in the mouth. Herpes simplex type 1 is

commonly involved.

Immunocompromised persons, particularly patients undergoing chemotherapy for the treatment of cancer, have an increased

susceptibility not only to become infected by herpes simplex virus but also to develop viremia and encephalitis.

Pathology

Herpes simplex encephalitis affects the temporal and inferior frontal lobes selectively, producing a necrotizing, hemorrhagic acute

encephalitis that may rapidly cause death. Patients who survive frequently suffer permanent neurologic defects, the nature of which

depends on the neuronal loss.

Diagnosis

The diagnosis may be made by brain biopsy, which shows cerebral edema, necrosis, lymphocytic infiltration, and the presence of

intranuclear Cowdry A inclusions in infected cells. Electron microscopy or, preferably, immunohistochemical or in situ hybridization

tests demonstrate the virus in the majority of cases.

Herpes simplex encephalitis. This section has been stained for herpes simplex viral antigens by the immunoperoxidase technique. The

darkly staining (positive) cells are infected with the virus.

Treatment

Treatment of herpes simplex encephalitis with antiviral agents such as vidarabine improves prognosis if undertaken early.

HIV Encephalitis

HIV is a neurotrophic virus that causes subacute encephalitis characterized pathologically by small nodules composed of

demyelination, reactive astroglial proliferation, and infiltration by lymphocytes and microglial cells.

These microglial nodules occur in about 30% of patients with acquired immunodeficiency disease (AIDS). Their relationship to the

occurrence of dementia in AIDS patients is uncertain.

Poliomyelitis

Poliomyelitis is caused by the poliovirus, an enterovirus transmitted by the fecaloral route.


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The virus enters the body through the intestine and infects the brain and spinal cord via the bloodstream.

The poliovirus selectively infects

(1) the meninges, producing acute lymphocytic meningitis; and

(2) the lower motor neurons in the anterior horn of the spinal cord and medulla oblongata. Loss of motor neurons causes acute

paralysis of affected muscles. The paralysis is typically asymmetric and flaccid, with muscle atrophy and loss of deep tendon reflexes

With time, the atrophic muscles may undergo fibrous contracture.

Poliomyelitis is a very serious disease associated with a significant mortality rate in the acute phase, when paralysis of respiratory

muscle results in failure of ventilation. Patients who survive are commonly left with permanent muscle paralysis.

Poliomyelitis, showing the phases of infection. Patients who recover show a permanent neurologic deficit that corresponds to theneuronal necrosis in the acute phase.

Rabies

Rabies is rare in humans but occurs in a variety of wild animals and domestic pets, including dogs and cats, in whom it causes a fatal

illness called hydrophobia characterized by abnormal behavior, difficulty in swallowing, and convulsions.

Humans are infected when bitten by an infected animal.

The rabies virus enters the cutaneous nerve radicles at the site of inoculation and passes proximally to the central nervous system.

The incubation period is 13 months and is shortest in facial bites.

Rabies virus causes a severe necrotizing encephalitis that maximally affects the basal ganglia, hippocampus, and brain stem. Infected

neurons show diagnostic eosinophilic intracytoplasmic inclusion bodies (Negri bodies). The virus can also be identified in the

infected cells by electron microscopy and immunoperoxidase techniques.

Clinically, rabies presents with fever and generalized convulsions that are precipitated by the slightest of sensory stimulations such

as a gust of wind, a faint noise, or the sight of water. Death is inevitable.

Because there is no treatment, prevention is essential and consists of controlling the disease in wild animals, rabies immunization of

domestic pets, and administration of antirabies vaccine to humans immediately after viral exposure.


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Cytomegalovirus Encephalitis

Cytomegalovirus infection of the brain occurs in the fetus during the last trimester of pregnancy as a result of transplacental

infection.

Periventricular necrosis and calcification lead to microcephaly and mental retardation; chorioretinitis is common.

Cytomegalovirus encephalitis also occurs in immunocompromised persons, particularly patients with AIDS.

Progressive Multifocal Leukoencephalopathy (PML)

PML is caused by Jamestown Canyon (JC) virus, a specific serologic type of human papovavirus, and occurs particularly in patients

with AIDS and those undergoing chemotherapy for cancer.

PML is characterized pathologically by widespread focal demyelination of cerebral white matter.

Giant atypical astrocytes and intranuclear inclusions in oligodendroglial cells are typically present, along with a lymphocytic infiltrate

The JC virus can be identified by immunohistochemical techniques.

Clinically, PML presents as an acute, rapidly progressive illness associated with multifocal cerebral dysfunction. The diagnosis can be

established by brain biopsy. The mortality rate is high.

Subacute Sclerosing Panencephalitis (SSPE)

SSPE is an uncommon disease that affects children several years after a known attack of measles. Boys are five times more

commonly affected than girls.

The measles virus, which has been demonstrated in the cerebral lesions of SSPE, is the causal agent, and SSPE is therefore regarded

as a chronic measles virus infection.

The exact mechanism by which the virus causes encephalitis is unknown. Immunologic factors may play a role, or there may be some

alteration of the measles virus itself. The incidence has declined following measles vaccination.

Pathologically, SSPE is characterized by degeneration of neurons in the cerebral gray matter and basal ganglia. Intranuclear

inclusions are present in infected cells, and measles virus particles are present on electron microscopy. The white matter shows

demyelination, reactive astrocytic proliferation, and perivascular lymphocytic infiltration.

Clinically, patients present with personality changes and involuntary myoclonic-type movements. The disease is relentlessly

progressive, causing extensive brain damage and leading to death, usually within 12 years after onset.

Prion (Slow Virus) Infections

Creutzfeldt-Jakob disease and kuru are infections of the human brain that are characterized by a long latent period after infectionfollowed by a slowly progressive disease ending in death. Scrapie, an encephalopathy in sheep and goats, and bovine spongiform

encephalopathy (BSE), or mad cow disease) in cattle are apparently animal counterparts.

Kuru has occurred mainly among cannibalistic tribes in Papua New Guinea, where the disease is believed to be transmitted by the

ritualistic practice of eating brain tissue from deceased persons. The incidence of kuru is rapidly decreasing.

caused by an agent consisting solely of protein, a prion (forproteinaceous infectious particle). The mode of transmission and

whether or not activation of host genes is involved in pathogenesis remain unclear. About 10% of cases of Creutzfeldt-Jakob disease

may be inherited as a dominant trait; a gene responsible for production of prion proteins has been located in chromosome 20.


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Creutzfeldt-Jakob disease has occurred in patients who had received transplants of infected tissue (eg, corneal and dural

transplants). It is also important medically because the infectious agent is resistant to inactivation by formalin; this imposes a great

risk of infection on pathologists and other medical personnel who handle infected tissues.

Clinically, patients present with confusion and dementia followed by ataxia. Symptoms progress slowly but relentlessly to a fatal

outcome. There is no treatment.

Pathologically, both Creutzfeldt-Jakob disease and kuru are characterized by slowly progressive degeneration of the brain, with

neuronal loss, demyelination, and spongiform change in the cerebral white matter. There is no inflammatory cell infiltration.

Kuru tends to affect the cerebellum and is characterized microscopically by the presence of kuru plaques, which are amyloid bodies

with radially arranged spicules. The plaques appear to consist of filaments of prion protein.

Neurosyphilis

Congenital syphilis and adult syphilis in its late tertiary phase may involve the nervous system in many ways ; it has, however,

become relatively rare following the use of penicillin in the treatment of early syphilis.

Neurosyphilis: Pathologic and Clinical Features.

Type of

Disease

Time Elapsed

After Primary

Infection

Principal Pathologic Features CSF Clinical Features

Asymptomatic 23 years Mild lymphocytic meningeal

infiltrate

Positive VDRL1

Very common; discovered by

routine lumbar puncture in patients

with secondary syphilis; penicillin is

curative

Meningovascular syphilis

Diffuse 3+ years Chronic inflammation of

meninges with fibrosis and

endarteritis

Increased protein; mild

lymphocytosis; positive

VDRL

Meningeal symptoms; cranial nerve

palsies; penicillin may be effective

in early stage

Focal 3+ years Gumma formation Positive VDRL; increased

protein, lymphocytosis

Very rare; acts as a space

occupying lesion

Parenchymatous syphilis

General

paresis

10+ years Diffuse cerebral cortical neuronal

loss; chronic encephalitis;

spirochetes present

Positive VDRL; mild

lymphocytosis

Progressive dementia and

psychosis; cerebral atrophy with

ventricle dilatation; penicillin not

effective

Tabesdorsalis

10+ years Demyelination of spinal cord(posterior columns) and sensory

nerve root; spirochetes absent

Positive VDRL; mildlymphocytosis

Lightning pains, sensory loss,hypotonia, areflexia; penicillin not

effective

1VDRL = Veneral Disease Research Laboratory serologic test for syphilis. This is positive in about 50% of all cases of neurosyphilis. The

more sensitive FTAABS (fluorescent treponemal antibody test) is positive in over 90%.

The parenchymatous and meningovascular lesions of late syphilis may occur together in a given patient or separately.

Parenchymatous disease may affect the cerebral cortex (general paresis) and the spinal cord (tabes dorsalis). Spirochetes are

present in the brain in general paresis but not in the spinal cord in tabes dorsalis. Penicillin may prevent progression of neurosyphilis

but will not reverse deficits already present


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Parasitic Infections

Toxoplasmosis

Toxoplasma gondiiis a protozoal parasite that has its definitive cycle in the intestine of cats. Humans become infected through

contact with cat feces containing infective forms of the parasite. Cerebral toxoplasmosis occurs in two distinct forms, congenital and

acquired.

Congenital Toxoplasmosis

Fetal infection with T gondiioccurs transplacentally in the third trimester of pregnancy. The organism infects the fetal brain and the

retina, leading to extensive necrosis, calcification, and gliosis. Many infants die soon after birth, and those who survive have a variety

of defects such as microcephaly, hydrocephalus, mental retardation, and visual disturbances. Toxoplasma pseudocysts can be

identified in the brain and retinal lesions.

Acquired Toxoplasmosis

Acquired toxoplasmosis rarely causes cerebral lesions in normal individuals. It may, however, occur as an opportunistic infection in

patients with AIDS and in other patients with deficient cell-mediated immunity.

Cerebral toxoplasmosis in AIDS is characterized by the presence of multiple necrotic lesions ranging in size from 0.5 to 3 cm.

Toxoplasma pseudocysts and tachyzoites may be seen in biopsies of lesions. Diagnosis in tissues is aided by staining for Toxoplasma

antigens by immunoperoxidase techniques.

Clinically, patients present with fever and symptoms of acute cerebral dysfunction. Computerized tomography shows ring-enhancing

mass lesions that are often multiple. Treatment with anti-Toxoplasma agents is effective.

Other Parasitic Diseases

Other parasitic diseases rarely involve the brain in the United States. In other countries, the following parasitic diseases occur

commonly:

(1) Cerebral malaria, due to Plasmodium falciparum.

(2) African trypanosomiasis (sleeping sickness). This is caused by Trypanosoma rhodesiense in East Africa and Trypanosoma

gambiense in West Africa.

(3) Cysticercosis, due to the larval form ofTaenia solium, the pork tapeworm.

(4) Hydatid cyst, due to the larval form ofEchinococcus granulosus.

(5) Trichinosis, due to Trichinella spiralis.

(6) Schistosomiasis, due to Schistosoma haematobium and Schistosoma mansoni(in the Middle East).

(7) Amebiasis, due to Entamoeba histolytica, which causes brain abscesses. Free-living amebae of the generaAcanthamoeba and

Naegleria are rare causes of meningoencephalitis.


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The Central Nervous Syste1