module of meningitis 2013 student guidance

8/13/2019 Module of Meningitis 2013 Student Guidance

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Block VII : The Nervous System & Psychiatry

Module : Central Nervous System Infection

Course Period : Academic Year 20122013

4th

Semester

Name : Student

Guidance

Faculty of Medicine

Brawijaya University

2013


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Module :CNS Infection 2013 Page 2

STUDENT GUIDANCE

Course Period : 4th Semester

Module : Nervous System & Psychiatry

Sub-module : Nervous System

Topic : Central Nervous System Infection

1. Sub-Topics :

1. Basic and Clinical aspect of Central Nervous System Infection (CNS) Infection

2. Microbial Infection of Meningens

3. Neuroimaging in Meningitis

4. General Aspect of Antibiotic Treatment in Bacterial Meningitis

5. Neurological Examination in CNS Infection

2. Contributors

1. Masruroh Rahayu, Department of Neurology

2. Shahdevi Nandar Kurniawan, Department of Neurology

3. Widodo Mardi Santoso, Department of Neurology

4. Sri Winarsih, Department of Microbiology

5. Yuyun Yueniwati, Department of Radiology

6. Dian Nugrahenny, Department of Pharmacology

7. Nurdiana, Department of Pharmacology

8. Masdar Muid, Department of Pediatric

9. Agus Choirul Anab, Department of Neurosurgery

3. Competency Are

This module is a part of the elaboration of

1. The area of competence 2 i.e. The Clinical Skill

2. The area of competence 3 i.e. The Scientific-Base of Medical Sciences

3. The area of competence 4 i.e. The Management of Health Problems

4. The area of competence 7 i.e. The Professionalism.

4. Competency Component

1. The Clinical Skill : Neurological examination

2. The Scientific-Base of Medical Sciences: To apply the concepts and principle of

Biomedical Sciences, Clinical Sciences and Public Health in appropriate with Primary

Health Care.


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3. The area of competence 4 i.e. Management of Health Problems: To manage the

diseases, illness and patients problem as a individual person, a part of family and

community and To prevent diseases and illness

4. The Professionalism: to have professional attitude

5. Clinical Competence

In a vignette of a patient with a suspected CNS Infection the student is able to:

1. Make a clinical diagnosis of CNS Infection, to make simple aids and additional

investigation requested by student himself (such as simple laboratory or X-ray

investigation).

2. Make a judgment that an initial treatment is required before being referred and describe

to carry out an initial treatment and immediately refer to the relevant specialist

(emergency cases).

6. Learning Objectives

At the end of the Teaching-Learning Process of this topic, in a vignette of a patient with a

suspected infection of the central nervous system (CNS Infection) the student should be

able to:

A. Basic and Clinical aspect of CNS Infection

1. Describe the anatomy and physiology of the ventricles, cerebrospinal fluid and

meninges

2. Describe the type of CNS infections (meningitis, encephalitis, abscess, etc.)

3. Describe the pathophysiology of CNS Infection

4. Describe the signs and symptoms of CNS Infections.

5. Describe the outline a practical approach to diagnosis and initial management

6. Describe the prognosis

7. Demonstrate the neurological examination of the CNS Infection

B. Microbial Infection of Meningens

8. State the microbial agents (viruses, bacteria, fungi) that cause meningitis

9. Describe the epidemiology and pathomechanism of the species that the most

causative agents of meningitis

10.Describe how bacterial meningitis is diagnosed and prevented

C. Neuroimaging in Meningitis

11.Identify neuroimaging modality for meningitis


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7. Lecture Description

This topic is a part of Module of The Nervous System integratedly designed for medical

student of the 4th semester through Teaching-Learning Process in the 7th block both in

Lecture and Small Group Discussion. This part of Module will facilitate the student to have

an understanding and approach to the patient with CNS Infection.

8. Overview

Infections of the central nervous system are among the most important problems in

medicine because early recognition, efficient decision-making, and rapid institution of

therapy can be lifesaving. These distinct clinical syndromes include (A) acute bacterial

meningitis, (B) tuberculosis meningitis, (C) Viral infection, (D) HIV Infection in CNS, and (E)

focal infection such as brain abscess. The combination of fever, headache, and neurologic

signs or symptoms must be treated as a CNS infection until proven otherwise. Amanagement algorithm should be followed for suspected cases of CNS Infection. Empirical

treatment for bacterial causes should be done. Definitive treatment will be later be based on

the results of cultures or other diagnostic tests.


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1. BASIC AND CLINICAL ASPECT OF CNS INFECTION

1.1 ACUTE BACTERIAL MENINGITIS.

Epidemiology

The incidence of bacterial meningitis is estimated at 5 to 10 cases per 100.000 person

per year. Bacterial meningitis is much more common in developing countries and in specific

geographic area, such as the meningitis belt of Africa, where there is an estimated incidence of

70 cases per 100.000 people per year. The most common organisms are Haemophilus

influenza, Neisseria meningitidis and Streptococcus pneurnoniae, N. meningitidis tends to occur

in epidemics. Neonatal meningitis is usually due to Escherichia coli or group B. Streptococcus.

In developing countries, tuberculosis meningitis is also common but usually clinically distinct.

Pathophysiology and pathogenesis

Meningitis can occur with organisms crossing the blood-brain barrier during systemicinfection or as a result of a breakdown in the barrier, for example after skull fracture or a

neurosurgical procedure.

Once bacteria enter the subarachnoid space, they survive because immunoglobulin

concentration in the CSF is very low, and component components appear to be virtually absent.

Replication and autollysis of bacteria in the CSF leads to the release of bacterial components

into the CSF. Lipopolysaccharides, theichoic acids, and peptidoglycans are powerful stimuli for

the release of proinflammatory host factors. In addition to cell wall component, microbial toxins

(i.e., pneumolysin, pathogen-derived hydrogen peroxide) also may be involved in induction of

the inflammatory host response.

Clinical feature

The clinical features of meningitis are:

headache

fever

neck stiffness.

There may also be altered consciousness, seizures and focal signs in about 15% of patients.

Patients may have a positive Kernig's sign, another sign of meningism. Meningococcal

meningitis may be associated with a purpuric rash.

Diagnosis

The peripheral white blood cell count, C-reactive protein, and sedimentation rate are

usually elevated. From a lumbar puncture test, the opening pressure is elevated and the CSF

appears cloudy. There is typically a PMN with more than 1000 cells/l, a severe blood-CSF

barrier disruption (elevated total protein content > 120 mg/dl), and a low CSF glucose

concentration (


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meningococcal disease but negative microscopic and culture result, then the polymerase chain

reaction (PCR) assay to detect meningococcal DNA in the CSF should be done.

Differential diagnosis

Differential diagnosis of bacterial meningitis includes viral meningitis, viral encephalitis,

tuberculous meningitis, fungal meningitis, carcinomatous meningitis, parameningeal purulent

infectious foci, subarachnoid hemorrhage, and tumor in the posterior fossa.

Treatment

1. Empiric regimens are based on age, clinical setting, and local pattern of antibiotic

susceptibility

2. Once culture information is available from CSF or blood, tailor antibiotic regimens to cover

specific organisms.

Prognosis1. Early and late complications of bacterial meningitis can occur.

a. Early: cerebral edema, communicating hydrocephalus, infectious vasculitis with stroke,

dural sinius thrombosis, brain abscess, subdural abscess or effusion, hearing

loss.

b. Late: developmental delay or cognitive deficits, focal neurologic finding, and epilepsy.

2. Mortality is highest in streptococcus pneumoniae meningitis and in patients who present

with depressed level of consciousness.

1.2. TUBERCULOUS MENINGITIS

Epidemiology

Recent estimates from the WHO indicate that the global burden of tuberculosis is

enormous mainly because of a high incidence of disease in Southeast Asia, sub-Saharan Africa,

and Eastern Europe and because of high rates of M. Tuberculous and human immunodeficiency

virus coinfection in some African countries. In 2000, 16.377 cases (5.8 cases per 100.000

population) were reported to the centers.

Pathophysiology

1. May accompany primary infection. This is often the case in children.

2. May also result from reactivation of previous infection. During primary infection, the brain

and meningens may be seeded with low number of organisms. These foci of infection can

develop into larger caseous lesion or Rich Foci. When a meningeal lesions ruptures into

the CSF space, meningitis ensues.

3. Fibrosis of basal meningeal exudates can lead to communicating hydrocephalus.

Involvement of the ventricular system can lead to occlussion of the cerebral aqueduct and

noncommunicating hydrocephalus.

4. Vasculitis may develop in blood vessels transferring the meningeal exudates leading to

occlusion and stroke.


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Clinical features

The symptoms were anorexia, weight loss, cough, night sweats, headache,

meningismus, altered level of consciousness. Adenopathy, nuchal rigidity, pappiledema, focal

neurologic signs, and positive tuberculin test.

Diagnosis1. Symptoms and sign :

a. Early: low-grade fever, headache, malaise, nausea.

b. Later: severe headache, neck stiffness, cranial nerve palsies, vomiting, drowsiness,

seizures, change of mental status.

c. Late: coma, brainstem dysfunction.

2. Compared with patients with bacterial meningitis, patients with tuberculous meningitis

typically have been sick longer, are more likely tohave cranial nerve palsies and are less

likely to have elevated peripheral blood white blood cell counts.

3. Neuroimaging abnormalities are common: hydrocephalus, meningeal enhancement,

mass lesion and infarct.

4. CSF :

a. White blood count 100500 L, usually with lymphocytic predominance.

b. Protein 100500 mg/dL

c. Glucose less than 45 mg/dL

d. CSF culture positive.

e. CSF PCR specific but not sensitive

5. Abnormal chest radiograph findings seen in most children and about one half of adults.

Treatmenta. Isoniazid : adult : 300 mg p.o. qd; Child 1020 mg/kg/d

b. Rifampin : adult : 600 mg p.o. qd; Child 10 -2- mg/kg/d

c. Pyrazinamide : 1530 mg/kg

d. Streptomycin : adult 1 g once daily; Child 2040 mg/kg/d

Prognosis

Overall mortality in tuberculous meningitis is about 30 %, mortality highest in those with

low GCS score and whom therapy is delayed or interrupted.

1.3. HIV INFECTION IN CNS

1.3.1. Toxoplasmic enchephalitis

Epidemiology

Toxoplasma infection is prevalent world-wide. Seroprevalence in the general population

varies greatly from country to country, being in European countries (70% 90 %) than the

United States (10% - 40%).

Toxoplamosis encephalitis is the most common cause of a CNS mass lesion in patient

infected with HIV. Although a hystory of other AIDS defining conditions is present in many


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patient at the time of presentation with toxoplasmic encephalitis , this infection constitutes the

first opportunistic infection in 30% - 50% of patients.

Pathogenesis

Human become infected with T. Gondii by ingesting oocyts or raw or undercooked meat,

mainly pork, and limb, containing tissue cysts. After ingestion the cysts release the parasites inthe intestine. The parasites are then disseminated via lymphatics and the bloodstream. The

protozoan remains in a state of latency indefinitely, usually for life, unless there is a decrease in

the celluler immune respone of the host. Consequently, most cases toxoplasmic ecephalitis in

AIDS patients result from reactivation of a latent brain infection. This reactivation occurs in

severely immunosuppressed patients with CD4 counts below 100 cells/l, although some

patients may develop the infection with higher CD4 counts.

Clinical features

Toxoplasmic encephalitis may present with fever, headache, focal symptoms and signs

or as a subacute encephalopathy. Often focal neurologic disturbances are superimposed on aglobal encephalopathy. Focal manifestation such as hemiparesis, aphasia, and cranial nerve

palsy. Other common manifestation is seizures.

Diagnosis

- Ninety percent to 100% of HIV-infected patients with toxoplasmic encephalitis will have

detectable serum anti-toxoplasma IgG, but IgM rarely detectable.

- CSF examination is not helpful in establishing the diagnosis

- Neuroimaging shows round, isodense or hyperdense lesions in hemispheric gray-white

junction, deep white matter, or basal gangglia. More than 90% enhance with contrast in

ring, nodula, or homogenous pattern. MRI is more sensitive than CT an often identifiesmultiple lesions.

- For patients at high risk for CNS toxoplasmosis, presumptive diagnosis made by response to

a trearment trial. Diagnosis is established if clinical improvement occur within 1 to 2 weeks

and radiographic improvement within 2 to 3 weeks.

- Consider brain biopsy if no response to treatment trial or for patients at low risk for CNS

toxoplasmosis.

Treatment

Primary therapy (duration at least 6 week)

Pyrimetamine 100200 mg p.o load, and then 75 100 mg p.o. qd. plus Sulfadiazine

1,52 g p.o. q.i.d or clindamycin 600900 mg p.o. q.i.d. plus Folinic acid 1050 mg

p.o. qd.

Chronic suppresive therapy or secondary prophylaxis (duration determinate by response to

potent antiretroviral therapy).

Pyrimetamine 2550 mg p.o qd, plus Sulfadiazine 1 g p.o. t.i.d - q.i.d or clindamycin

300450 mg p.o. t.i.d. - q.i.d. plus Folinic acid 1050 mg p.o. qd.


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Prognosis

The following increase the risk of CNS toxoplasmosis in HIV-infected patients :

CD4 T cells bellow 200/L

Not receiving trimetroprim-sulfamethoxazole prophylaxis

Detectable serum anti-Toxoplasma antibody, particularly if titer is high

More than one abscess-like lesion on neuroimaging.

1.3.2. Fungal (Cryptocococcal Meningitis)

Epidemiology

Cryptococcal meningitis is the most common systemic fungal infection in HIV-infected

patients and the third most frequent opportunistic infection of the CNS. Although the incidence

of the infection varies among countries, 2 to 11 percent of all HIV-infected patients are

affected.

By many measures, the incidence of fungal disease has increased dramatically over the

past three decades. Several factors have contributed to an increase in fungal disease, including

the movement of populations into endemic region, such as the south western United States.

Antibacterial agents, cytotoxic chemotherapy, corticosteroids, organ transplantation, and HIV

infection have each resulted in large numbers of compromised patients at risk for fungal

disease. Also, seemingly immuno-competent individuals can aquire central nervous system

infection due to fungi such as Cryptococcus neoformans, Coccidioides immitis, and the

dematiacious mold, although other pathogens such as Histoplasma capsulatum, Blastomyces

dermatidis, Sporothrix schenkii and Candida spesies are increasingly reported.

Pathophysiology and pathogenesis

Fungal infections of the CNS most often are the result of hematogenous dissemination

of fungi from primary infection elsewhere in the body. Most fungi enter the host by inhalation

and establish a primary site of infection in the lungs. Among immunocompetent individuals, the

initial infection is often unrecognized and resolves without the need for anti fungal therapy.

However, due to genetic factors or immunocompromising conditions, certain fungi are able to

disseminate throughout the body and establish active sites of infection.

Clinical features

Fungal infection of the CNS vary from rapidly progressive mold infection in neutropenicpatients to indolent meningeal infections in immunocompetent hosts. However, most patients

with fungal meningitis have a chronic meningitis syndrome, defined as meningitis that fails to

improve or progress over 4 weeks of observation. Because the fungi have a tendency to infect

the basiler meningens, fungal meningitis may also present with cranial nerve palsies involving

the third, sixth, and seventh cranial nerve. Mental status abnormalities are common, including

stupor, confusion, personality changes and cognitive deficits.


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Diagnosis

1. Sign and simptoms generally over 12 weeks and include low grade fever, headache, neck

stiffness, malaise, and mental status changes.

2. Neuroimaging abnormalities include hydrocephalus, meningeal enhancement, and

occasionally infarcts.

3. CSF :a. Conventional analysis :

- WBC count 20 to 1,000 cells/L, lymphocytic predominance, but PMN may be

present.

- Protein 50 to 1,000 mg/dL

- Glucosa less than 40 mg/dL

b. Antigen and antibody test

c. Detection of H.capsulatum antigen in urine supports diagnosis.

4. Diagnosis often presumptive on the basis of the compatible clinical finding, CSF profile,

detectable serum antibody, and confirmed fungal infection at another site.

Treatment

Induction therapy : Amphotericin B 0,7 1,0 mg/kg/d IV to complete a 35 mg/kg course over

3 4 mo. Maintenance therapy fluconazole 800 mg/d p.o. for additional 9 12 mo if patient

not HIV-infected, for life if patient HIV-infected

Prognosis

1. Although most patients with cryptococcal meningitis respond to therapy with an acute

mortality of 5%, 25%, to 50% of patients with meningitis due to C. immitis,

H.capsulatum.

2. Worse outcome in immunosuppressed.

1.4. BRAIN ABSCESS

Epidemiology

Bacterial brain abscess occur in approximately 1500 to 2500 patients each year in the

United State. The mortality rate reported in the literature prior to antibiotics was between 60 to

80 %. Population studies over five decades determined an incidence rate of 1,3 per 100.000

person-years.

The epidemiology of the disease is also changing in the postantibiotic era. There has

been a decrease in the incidence of brain due to traditional causes, such as acute or chronic

sinusitis, chronic otitis media, penetrating cranial trauma, and the rise in the incidence seen

immunocompromised patient with organ and bone marrow transplantation, human

immunodeficiency infection and AIDS.

Pathophysiology

A brain abscess may develop in any of the three following ways : 1) by direct spread

from a contagious cranial side of infection, 2) following cranial trauma, either surgical, 3) as a

result of hematogenous spread from a remote site of infection. Brain abscess begins as a

localized area of cerebritis that evolves in to encapsulated infection over about 2 weeks. In the

setting of concomitant immunosuppresion, there may be poorer or slower capsule formation.


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Clinical feature

Headache the most common clinical finding. Focal neurologic abnormalities are seen in

one third to one half of cases. Fever is less common and may be absent in more than 50% of

patients.

Diagnosis

Computed tomography (CT) or magnetic resonance imaging (MRI) show ring enhancing

lesion with central low density and surrounding edema.

There may be high signal on diffusion-weighted MRI.

Bacteriologic diagnosis rests on culture of abscess material.

Blood culture are rare positive, but are worth collecting before antibiotics are given.

Lumbar puncture is ussualy contraindicated.

Treatment

Control elevated ICP : Use of steroid is controversial because they may decrease antibiotic penetration into the

area of infection. A short course of high dose corticosteroids is reasonable in the

presence of significant cerebral edema.

Aspiration or excision reduces ICP and provides a microbiologic diagnosis. Antibiotic

therapy can be delayed in clinically stable patients if aspiration can be done quickly.

After surgical drainage, parenteral antibiotics generally given for 6 8 weeks, followed

by 2 to 3 month of oral therapy.

Medical therapy alone generally suboptimal, but can be considered for abscesses smaller

than 2 cm in diameter, cerebritis without capsule formation, or multiple or surgical

inaccesible lesions. Duration of antibiotic regimens are generally longer for patients who

do not undergo surgical treatment.

Seizure are relatively frequent, consider prophylactic anticonvulsants.

Prognosis

Mortality is 15% to 20%. Prognosis is poorer for patients who present with significantly

depressed mental status. Rupture of abscess into the ventricular system has a mortality of more

than 80% and is more common when diagnosis is delayed. About 60% of survivors have no or

mild neurologic deficits. Of the remainder, about two thirds will have moderate and one third

severe neurologic disability.


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2. MICROBIAL INFECTION OF MENINGENS (MENINGITIS)

OVERVIEW

An inflammation of the meninges is called meningitis. An inflammation of the brain it self is

called encephalitis. If both the brain and the meninges are affected, the inflammation is calledmeningoencephalitis.

Both the brain and the spinal cord are covered and protected by three continuous

membranes called meninges. These are the outermost dura matter, the middle arachnoid

matter, and the innermost dura matter. Between the pia matter and arachnoid membranes is a

space called subarachnoid space which is filled by cerebrospinal fluid CSF has low levels of

complement or circulating antibodies and few phagocytic cells, bacteria can multiply in it with

few checks.

Pathogens capable of causing diseases of the CNS often have virulence have virulence

characteristics of a special nature that enable the to penetrate these defenses. For example, thepathogen can begin replicating in a peripheral nerve and gradually move into the brain and

spinal cord.

Meningitis can be caused by different types of pathogens including viruses, bacteria, fungi,

and protozoa. Viral meningitis (not to be confused with viral encephalitis) is probably much

more common than bacterial meningitis but tends to be a mild disease. The CNS is seldom

invaded by fungi. However, one pathogenic pathogen Cryptococcus neoformans, is well

adapted to growth in CNS fluid.

Historically, only three bacterial species have caused most of the cases of meningitis as

well as its related mortality. In adult patients, that is, older than 16 years, about 80% of the

cases are now caused by Streptococcus pneumonia, Neisseria meningitidis, and Haemophilus

influenzatype b (the latest bacteria has been nearly eliminated in the USA since introduction of

an effective vaccine).

Death from bacterial meningitis often occurs very quickly, probably from shock and

inflammation caused by the release of endotoxins of the Gram-negative pathogens.

Nearly 50 other species of bacteria have been reported to be opportunistic pathogens that

occasionally cause meningitis. Especially important are Listeria monocytogenes, group B

streptococci staphylococci, and certain Gram-negative bacteria.


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3. NEUROIMAGING IN MENINGITIS

Conventional Radiography

Findings

Plain Skull radiographs do not have diagnostic importance in bacterial meningitis.

Chest radiography may be obtained to look for signs of pneumonia or fluid in the lungs. As

many as 50% of patients with pneumococcal meningitis also have evidence of pneumonia on

initial chest images.

Computed Tomography

The most important role of CT scanning in imaging patients with meningitis is to identify

contraindications of a lumbar puncture and complications that require prompt neurosurgical

intervention; such complications include symptomatic hydrocephalus, subdural empyema, and

cerebral abscess.

Nonenhanced CT scan findings may be normal (>50% of patients), or the studies may

demonstrate mild ventricular dilatation and effacement of sulci, cerebral edema, and

focal low-attenuating lesions .

Obliteration of the basal cisterns may result from increased attenuation, perhaps owing

to the presence of exudate in the subarachnoid space or leptomeningeal yperemia.

Increased attenuation in the CSF spaces due to meningitis may simulate acute

subarachnoid hemorrhage on CT scans.

CT scans for patients with suggested meningitis must be performed with iodinated

contrast material. Diffuse enhancement of the subarachnoid space is characteristic .

Curvilinear meningeal enhancement over convexities, interhemispheric and sylvian

fissures, and obliteration of basal cisterns are usually seen on contrast-enhanced CT

scans. Dural enhancement also may occur.

Contrast-enhanced CT scans help in detecting complications of meningitis, such as

subdural effusion/empyema, venous thrombosis, infarction, cerebritis/abscess,

hydrocephalus, and ventriculitis.

CT scans may reveal the cause of meningeal infection. Otorhinologic structures and congenital

and posttraumatic calvarial defects can be evaluated, and coronal thin-section CT scanning is

useful for evaluating patients with recurrent bacterial meningitis; CT cisternography may depictCSF leaks, which may be the source of infection in cases of recurrent meningitis.

Sequelae from meningitis may be depicted on CT scans as periventricular and meningeal

calcifications, localized areas of encephalomalacia, porencephaly, and ventricular dilatation

secondary to brain atrophy.


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Degree of Confidence

The value of CT scanning in the early diagnosis of subdural empyema and effusion has been

controversial as this modality may not detect meningitis, especially nonenhanced CT scans in

the early stage. Normal results on CT imaging do not exclude the presence of acute meningitis.

False Positives/Negatives

Meningeal enhancement is nonspecific and may be caused not only by bacterial meningitis, but

also by neoplasm, hemorrhage, sarcoidosis, and other noninfectious inflammatory disorders.

Magnetic Resonance Imaging

Findings

Routine contrast-enhanced brain MRI is the most sensitive modality for the diagnosis of

bacterial meningitis because it helps to detect the presence and extent of inflammatory changes

in the meninges as well as complications. The increased sensitivity and specificity of MRI results

from direct multiplanar imaging, increased contrast resolution, and the absence of artifact

caused by bone.

Some authors suggest performing MRI with a high dose of contrast material (0.3 mmol/kg),

which is the most important factor. They also recommend imaging immediately after the

injection and then performing magnetization transfer imaging, which can help to depict

abnormal meningeal enhancement and which facilitates the diagnosis of early brain meningitis.

Nonenhanced MRI of patients with uncomplicated acute bacterial meningitis may

demonstrate obliterated cisterns and the distention of the subarachnoid space with

widening of the interhemispheric fissure, which is reported to be an early finding in

severe meningitis or may be unremarkable.o T2-weighted images are sensitive to abnormal tissue water distribution and,

thus, may show cortical hyperintensities that are reversible and believed to

represent edema.

o Diffuse enhancement of the subarachnoid space is characteristic.

Contrast-enhanced MRI has been shown to be more sensitive than CT scanning in the

detection of meningeal inflammation.

o Gadolinium-enhanced MRI studies can demonstrate abnormal leptomeningeal

enhancement that more closely approximates the extent of inflammatory cell

infiltration.

o Extension of enhancing subarachnoid exudate deep into the sulci can be seen in

severe cases.

o Dural enhancement may occur.

Revealing the cause of meningeal infection is best accomplished with MRI. MRI can help

to detect inflammatory changes in the paranasal sinuses and mastoid air cells, which are

usually depicted as areas of increased signal intensity on T2-weighted images.

Enhancement may be prominent.

MRI also can help to exclude congenital and post traumatic calvarial defects.


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Coronal and sagittal thin-section, heavily T2-weighted MRIs may show CSF leaks, which

may be the source of infection in cases of recurrent meningitis.

Plain and contrast-enhanced MRIs help to depict the complications of meningitis better

than other images. Such complications include empyema/effusion, cerebritis/abscess,

venous thrombosis, venous and arterial infarcts, ventriculitis, hydrocephalus, and edema

(with or without cerebral herniation).

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate

dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol

[ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or

nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic

Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-

stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or

MRA scans.

Degree of ConfidenceWith MRI especially, nonenhanced studies performed in patients with uncomplicated acute

bacterial meningitis may demonstrate unremarkable findings; however, such results do not

exclude acute meningitis.


Meningeal enhancement is nonspecific and may be caused not only by bacterial meningitis but

also by neoplasm, hemorrhage, sarcoidosis, and other noninfectious inflammatory disorders.

Ultrasonography

Findings

Bacterial meningitis is usually a clinical diagnosis. US is needed only to evaluate complications

or a deterioration in the patient's clinical situation. Commercially available equipment is used

with a 3- to 7.5-MHz transducer, depending on the size of the patient's head. Transducers of 5-

7.5 MHz are used for newborns, whereas transducers of 3-5 MHz are used for older infants.

In newborns and older infants, complications of meningitis that are depicted on cranial CT

scans and MRI can also be demonstrated on cranial sonograms obtained with a transfontanel

approach.

Important US findings in infants with bacterial meningitis have been described. These findings

include echogenic sulci, ventriculomegaly and obstructive hydrocephalus, ventriculitis,prominent leptomeninges, subdural effusions, empyema, parenchymal echogenicity, and

abscess formation. US can help to identify these complications, but the findings are usually not

specific.

Echogenic sulci that appear as a result of the accumulation of inflammatory debris are

the most common and transient US finding in meningitis; these resolve gradually as the

exudate is cleared.

Mild to moderate ventriculomegaly, which is usually reversible, can occur in the course

of meningitis. Exudates may produce CSF loculations and pathway obstruction, resulting

in a communicating hydrocephalus, whereas obstructive hydrocephalus may occur with
http://emedicine.medscape.com/article/1097889-overviewhttp://emedicine.medscape.com/article/1097889-overview


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ventricular obstruction or chronic inflammatory changes in the subarachnoid space.

Intraventricular septa formation may result in ventricular compartmentalization.

Progressive ventriculomegaly can be excluded with the use of serial sonograms.

Ventriculitis, which is seen in 65-90% of patients, is suggested by the US findings of

hydrocephalus, which include a thickened, hyperechoic, irregular ependymal surface and

echogenic debris and fibrous septa formation within the enlarged ventricles. The septaoccur over the 2 weeks following bacterial meningitis; US is best for identifying septa,

compared with CT scanning or MRI.

Subdural effusion is a common US finding in infants with H influenzae meningitis.

Subdural empyemas are uncommon findings and result when the effusions become

infected.

Areas of abnormal parenchymal echogenicity are a significant finding. The lesions

represent cerebritis, infarction, encephalomalacia, or, rarely, abscess formation.

Abscesses appear as homogeneous echogenic masses with a hypoechoic center that is

surrounded by a thin hyperechoic rim. Doppler US can easily demonstrate the major intracranial vessels via the anterior

transfontanel approach; however, in older children, these vessels can be demonstrated

via the transtemporal approach. The cerebral blood flow can be evaluated qualitatively.

Serial transcranial Doppler examinations performed to assess for disease-related arterial

narrowing have been described. An association between an unfavorable course of the

disease and increased cerebral blood flow velocity in intracranial arteries has been

suggested; this probably indicates vasospasm. Transcranial Doppler US can potentially

be used to identify high-risk patients who can benefit from adjuvant therapeutic

interventions.

Degree of Confidence

US is a heavily operator-dependent technique. Experience is needed to demonstrate the

meningeal and parenchymal findings of bacterial meningitis.


On US, inflammatory debris in the CSF creates low-level intraventricular echoes in acute

ventriculitis. This appearance may imitate that which is seen in the breakdown of

intraventricular hematomas; however, these 2 clinical settings can usually be distinguished

because ventriculitis has other signs of inflammation.

Nuclear Imaging

Findings

Although CT scanning and MRI are the most common imaging modalities used to evaluate

patients with a possible abscess, distinguishing brain abscesses with these 2 modalities is

occasionally difficult. Technetium-99 (99m Tc) hexamethylpropyleneamine oxime, which is a

radionuclide imaging label for leukocytes, and radiolabeled polyclonal immunoglobulin

antibodies may be helpful in select patients.99mTc hexamethylpropyleneamine oxime may also

be used in the evaluation of the cerebral blood flow velocity and perfusion in bacterial


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meningitis. In addition, radionuclide cisternography may depict CSF leaks, which may be the

source in cases of recurrent meningitis.

Angiography

Findings

Arterial angiography may demonstrate arterial spasm or may show focal areas of inflammation

that have manifested by hypervascularity.

If magnetic resonance venography is not available, a reliable and cost-effective method for

detecting venous sinus thrombosis is intravenous digital-subtraction angiography.

4. PHARMACOLOGICAL ASPECT OF CNS INFECTION

General Aspects of Antibiotic Treatment in Bacterial Meningitis

Most antibiotics employed in the therapy of bacterial meningitis, with the exception ofchloramphenicol, do not readily penetrate the non-inflamed blood-brain barrier. Meningitis

enhances the entry of penicillins and some other antimicrobial agents (e.g. vancomycin) into

the CSF and allows successful therapy with these drugs provided large parenteral doses are

administered. Antibiotics should be administered IV in divided doses at intervals that provide

high concentration gradients across the meninges. Dosage should not be decreased when

clinical improvement occurs, because the normalization of the bloodbrain barrier that

accompanies resolution of the infection reduces antibiotic concentrations that can be obtained

in the CSF.

The absence of intrinsic opsonic and bactericidal activity in infected CSF increases the

importance of providing bactericidal rather than bacteriostatic agents to treat bacterial

meningitis (Simberkoff et al. 1980). Although they are effective in vitro against many species

that are capable of causing meningitis, drugs such as clindamycin, erythromycin, and first- and

most second-generation cephalosporins (including cefamandole) should never be used in

bacterial meningitis. These agents cannot predictably achieve bactericidal concentrations in the

CSF. Vancomycin, a microbiostatic agent, should also not be routinely used in the treatment of

bacterial meningitis. It should be reserved for treatment of methicillin-resistant staphylococcal

infections and for penicillin-resistant S. pneumoniae.

WARNING

In the treatment of bacterial meningitis avoid:

Drugs with poor penetration within the CSF (e.g., clindamycin, erythromycin, first-

generation cephalosporins, and most second-generation cephalosporins)

Microbiostatic agents (e.g., vancomycin) unless no better alternative can be found.

Principles that should guide therapy for meningitis include the following:

The antibiotic must be capable of killing the pathogen.


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The pathogen must be shown to be highly susceptible to the selected antibiotic, asmeasured by quantitative dilution studies (e.g., in vitro CSF killing levels or in vitro MBC

tests). Because the antibiotic must reach local sites in concentrations sufficient to kill the pathogen,

the agent selected must readily penetrate into the infected CSF or, if not, be directlyinstilled into the CSF by intrathecal or intraventricular injection.

Empirical coverage with an appropriate antibiotic should be started as soon as possiblewhen clinical suspicion of meningitis exists.

Empirical choices should be based on age and predisposing conditions. The duration of antibiotic treatment for meningitis has not been standardized; however, the

duration of antibiotic therapy generally is based on the causative organism and theindividual case and may range from 7 to 21 days.

Table. Penetration of Antimicrobial Agents into Cerebrospinal Fluid

THERAPEUTIC ANTIBIOTIC CONCENTRATIONS

OBTAINED WITHOUT

INFLAMMED

MENINGES LIKELY WITH INFLAMED MENINGES

NOT LIKELY REGARDLESS OF

STATE OF MENINGES

rimethoprim Penicillin G Ceftizoxime sodium Amikacin sulfate First-generation

Sulfonamides Ampicillin Ceftazidimea,b Streptomycin

sulfate

cephalosporins

Chloramphenicol Nafcillin sodium Ceftriaxone sodium Gentamicin

sulfate

Cefamandole nafate

Isoniazid Cloxacillin sodium Imipenema,b obramycin

sulfate

Cefoxitin sodium

Rifampin icarcillin disodium Aztreonama,b Lincomycin HCl Cefotetan disodium

Flucytosine ( clavulanic acid) Ciprofloxacin HCl and

other quinolonesa,b

Clindamycin HCl Cefmetazole sodium

Carbenicillin indanyl

sodium

Vancomycin HCL

Fluconazole and other

bis-triazoles

Amphotericin B

Mezlocillin sodium

monohydrate

-Aminosalicylic acid

Piperacillin sodium Ethambutol HCl

Cefuroxime sodium

Cefotaxime sodiumaDoes not have FDA approval for treatment of CNS infection.bLimited data available.

SOURCE: Reproduced by permission from Young and Koda-Kimble 1988.Applied Therapeutics: The Clinical Use

of Drugs,4th edition. Vancouver, WA: Applied Therapeutics, Inc.

Intrathecal therapy is not needed to treat uncomplicated cases of the three most common typesof bacterial meningitis, since they can be treated with antimicrobials that enter the CSF in

bactericidal quantities. Only preservative-free gentamicin is available for intrathecal therapy.

WARNING

Always check to make sure that the preparation you are using for intrathecal therapy is

preservative free. If standard parenteral forms of aminoglycosides are used, a severe

arachnoiditis often occurs.

The patient's clinical course dictates the frequency needed for examination of the CSF. Repeat

examination should be performed 24 to 48 hours after the start of antibiotic therapy if progress


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seems unsatisfactory or if the cause of the meningitis remains uncertain. Meningococcal

meningitis should be treated until the patient remains afebrile for 5 to 7 days. With prompt and

satisfactory response to antibiotics, it is not necessary to repeat the examination of the CSF at

the end of the therapy. Patients with H. influenzae meningitis should be treated for at least 7

days after they have become afebrile. Again, a follow-up examination of the CSF is not

necessary in patients who show rapid and complete clinical recovery. Patients with

pneumococcal meningitis should be treated for 10 to 14 days. Prolonged therapy is necessary in

the presence of an underlying mastoiditis or if the patient has underlying immunosuppression

(e.g., neutrophil or B- or T-cell abnormalities or deficiencies).

Specific antimicrobial therapy

Bacterial meningitis is a life-threatening medical emergency that requires prompt therapy based

on examination of the gram-stained smear from the sediment of the CSF. Two serious but

common errors in managing a patient with suspected meningitis are to delay performing a

diagnostic lumbar puncture and to delay starting antibiotic therapy.WARNING

When imaging studies are needed to exclude an intracranial mass before a lumbar puncture is

performed, antibiotics should be initiated immediately after blood has been obtained for culture.

The choice of antibiotics depends at first on the suspected pathogen, and later on that which

ultimately is isolated. The scan and the lumbar puncture may be done while the patient is

receiving empirical antibiotic therapy. If a diagnostic lumbar puncture is performed after a mass

lesion has been excluded by CT scan and the Gram stain reveals bacterial types not covered by

the initial empirical therapy, the regimen can be appropriately altered. Animal models of

meningitis suggest that initial empirical therapy will not affect the subsequent results of culture

of CSF if the spinal fluid is sampled within 2 to 3 hours of the start of antibiotic therapy (Tauber

and Sande 1984).


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Table. Initial Antibiotic and Anti-inflammatory Therapy for Suppurative Meningitis of Unknown Cause

PATIENT GROUPSUSPECTEDPATHOGEN

PREFERRED THERAPYANTIBIOTIC

ALTERNATIVE THERAPYANTIBIOTIC

Neonate (1 month or younger) Group B streptococci Ampicillin pluscefotaxime

Ampicillin and gentamicin

Listeria

E. coli

S. pneumoniae

S. pneumoniae

Child N. meningitidis Ampicillin plus(cefotaxime orceftriaxone) plusdexamethasone

Chloramphenicol plusgentamicin plusdexamethasone

H. influenzae

Adult N. meningitidis (Ampicillin or penicillinG) plus ceftriaxone

Chloramphenicol or cefotaxime

S. pneumoniae

H. influenzae

Listeria

Adult or child resident in a communitywith >2% high level (2 g/ml)

penicillin-resistant S. pneumoniae

Penicillin-resistant Vancomycin plus(cefotaxime or

ceftriaxone)

Possibly meropenem

S. pneumoniae

N. meningitidis

Listeria

H. influenzae

Immunocompromised adult (e.g.,older than 60, with cirrhosis orneoplastic disease)

Listeria Cefotaxime plusAmpicillin

rimethoprim-sulfamethoxazole(TMP-SMX)plus chloramphenicol

Pseudomonas

S. pneumoniae

N. meningitidis

Postcraniotomy patient Staphylococcus

aureus

Nafcillin plus cefotaxime

plus gentamicin

Vancomycin and cefotaxime

and gentamicinStaphylococcusepidermidis

H. infleunzae Cefotaxime orchloramphenicol

Ampicillin only if isolate issusceptible

N. meningitidis Aqueous penicillin G orcefotaxime

Chloramphenicol

E. coli, Klebsiella,

Proteus,and similarorganisms

Gentamicin plus

cefotaxime

Chloramphenicol

Pseudomonas Ceftazidime plus

gentamicin

Ampicillin sodium, cefotaxime sodium, ceftriaxone sodium, chloramphenicol, dexamethasone, gentamicin,meropenem, nafcillin sodium, penicillin G, trimethoprim-sulfamethoxazole, vancomycin HCl.In communities with penicillin-resistant S. pneumoniae,initial therapy of suppurative meningitis should includevancomycin plus ceftriaxone or cefotaxime for all age groups. This combination will not treat Listeria.

Of Listeriaisolats, 30% are resistant to ampicillin. Alternative antibiotics include trimethoprim-sulfamethoxazole,doxycycline, and gentamicin.

Clinical studies suggest that optimal chemotherapy for bacterial meningitis requires the CSF

concentration of the antibiotic to be several fold greater (>10 times) than the MBC for the


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pathogen measured in vitro. Additional principles that should guide therapy for meningitis

include the following:

The antibiotic must be capable of killing the pathogen.

The pathogen must be shown to be highly susceptible to the selected antibiotic, as

measured by quantitative dilution studies (e.g., in vitro CSF killing levels or in vitro MBC

tests).

Because the antibiotic must reach local sites in concentrations sufficient to kill the

pathogen, the agent selected must readily penetrate into the infected CSF or, if not, be

directly instilled into the CSF by intrathecal or intraventricular injection.

Foci of suppurative parameningeal infection must be drained whenever the procedure

can be performed without causing serious neurologic damage. The extent to which

various antibiotics transport into the CSF during meningitis differs, and the practitioner

must know this. In general, concentrations of antibiotic are higher in the CSF of children

and neonates than in adults with meningitis.

The presence of local leukocytes, especially neutrophils, is probably necessary for the infectedmeninges to become permeable to antibiotics. For example, limited experience suggests that

vancomycin, which tends to accumulate in the CSF of otherwise healthy adults with bacterial

meningitis, does not enter the CSF as well in neutropenic patients with documented bacterial

meningitis. Therefore, serial determinations of the concentration of drug in the CSF or serial

studies of CSF bacterial killing should be performed in severely neutropenic patients to

document the presence of sufficiently high antibiotic concentrations. Otherwise, serial

intrathecal or intraventricular injections of the appropriate antibiotics must be given. The third-

generation cephalosporins usually achieve concentrations in CSF that are at least 10 times the

MBC against the common Enterobacteriaceae that cause meningitis (e.g., E. coli, Klebsiella

species, and Proteus mirabilis). Such a concentration appears to be needed in order to cure

meningitis (Sande 1981). It is questionable, however, whether these agents, when used alone,

can achieve 10-fold MBC concentrations in the CSF against such organisms as Pseudomonas,

Flavobacterium, Enterobacter, Serratia, and Acinetobacter species.

The appearance of penicillinase-producing H. influenzae type b strains that are highly resistant

to ampicillin (about 30% of isolates in the United States) has required a shift in the focus of

initial management of this form of meningitis. Ceftriaxone or cefotaxime is now mandatory as

empirical therapy for H. influenzae meningitis until the isolate has been demonstrated to be

susceptible to ampicillin in vitro.

Resistance to ampicillin in H. influenzae is caused by production of -lactamase, whereas

resistance to chloramphenicol is associated with production of acetyltransferase (Smith 1983). A

patient with S. aureus meningitis should be treated with a penicillinase-resistant penicillin such

as nafcillin or cloxacillin because 80 to 90% of S. aureus isolates are resistant to penicillin G.

Enterococcal meningitis requires the use of IV penicillin or ampicillin supplemented by

parenterally administered gentamicin. If a patient with enterococcal meningitis fails to respond

promptly to parenteral therapy with penicillin and gentamicin, adjunctive intrathecal gentamicin

(4 to 8 mg for an adult) may be given.


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9.MODULE TASK

Find out your answers to the following tasks by yourself after discuss it with your group or after

reading the suggested references below.

SUBTOPIC 1 : Basic and Clinical aspect of CNS Infection

1. Describe about anatomy of the meningens, structure of the ventricular system, and

cerebrospinal fluid production, circulation, and resorbstions.

2. What are the pathogenesis of the acute bacterial meningitis, tuberculous meningiitis, and

encephalitis ?

3. What are the kinds of the central nervous system infection?

4. What are the clinical presentation of the central nervous system infection?

5. Draw a schematic algorithm of the management of patient with suspected CNS Infection.

SUBTOPIC 2: Microbiological aspect of CNS Infection.1. What are the microbial agents (viruses, bacteria, fungi) that cause meningitis?

2. How do Cryptococcus neoformans cause meningitis?

3. How do Streptococcus pneumonia, Neisseria meningitidis, and Haemophilus influenzae

cause meningitis? What is the virulence factor?

4. How to diagnose meningitis (according to microbial examination)? What is the appropriate

specimen?

5. How to identify Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus

influenzae?

6. How the causative agents above can be transmitted from one to another? How to prevent

the dissemination of the disease?

SUBTOPIC 3 : Neuroimaging in Meningitis

1. What is the neuroimaging modality choice for diagnosed meningitis?

2. What is the most important role of imaging in meningitis patients?

SUBTOPIC 4 : General Aspects of Antibiotic Treatment in Bacterial Meningitis

1. Mention factors that influence the transfer of antibiotic from capillary blood into the CNS !

2. A 20 y.o. man complained of fever, chills, vomiting, photophobia, and severe headache

since 3 days ago. Physical examination: GCS 456, nuchal rigidity associated with Kernigs

and Brudzinskis signs. What would be the best management (diagnose and initial

treatment) of this patient? Draw a schematic algorithm.


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10. TEACHING-LEARNING PROCESS

1. Each student should work the tasks in a Student-Worksheet (written or typed in

some paper A4-size) prior to Small Group Discussion (home work).

2. The Student Worksheet will be collected before Small Group Discussion .

3. Student should discuss the tasks in Small Group Discussion. The conclusion of the

discussion will be collected at the end of the discussion.

4. The facilitators make notes on things the student discuss which need to clarify at the

end of each session or in lecture to achieve the learning objectives and collected the

report of discussion.

11. THE ASSESSMENT

1. The Formative Evaluation will be assessed through Observation Sheets elaborating the

Learning Skill and Content Mastery

2. The Summative Evaluation will be assesed together with the other modules in Middle

Semester Test and or End Semester Test scheduled.

12. REFERENCES

TOPIC 1 : Basic and Clinical Aspect of CNS Infection

Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J. , 2008.

Harrisons Principles of Internal Medicine 17thed Volume II. Mc GrawHill Medical.

USA.

Lindsay KW, Bone I, Callander L.,2004. Neurology and Neurosurgery Illustrated 4 thed.

Churchill Livingstone.

Martin AS., 2004 Manual of neurologic Therapeutics 7thed. Lippincott William and

Wilkins.

TOPIC 2 : Microbiological aspect of CNS Infection

Tortora G.J, Funke B.R., Case C.L.,2009. MicrobiologyAn Introduction, 10thEdition,

Pearson Benyamin Cummings, USA.

Brooks G.F., Carroll K.C., Butel J.S., Morse S.A., 2007. Jawetz, Melnicks & Adelbergs -

Medical Microbiology, 24thEdition (international Edition), The McGraw-Hill Co., USA

Topic 3: Radiological Aspect of CNS Infection

Barkovich, A. J., 2007. Diagnostic imaging pediatric neuroradiology. Amirsys Inc,

Salt Lake city, Utah.

Incesu, L. 2009. Meningitis bacterial, available athttp://www.emedicine.com , last update

mar 13, 2009.

Osborn, A., 2005. Diagnostic imaging brain. Amirsys Inc, Salt Lake city, Utah.

Sen, S. 2009. Magnetic resonance imaging in acute stroke,http://www.emedicine.com,

last update jul 15, 2009.
http://www.emedicine/http://www.emedicine/http://www.emedicine/http://www.emedicine/http://www.emedicine/http://www.emedicine/http://www.emedicine/http://www.emedicine/

module of meningitis 2013 student guidance

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