Artigo de Revisao Encefalite e Meningite

8/2/2019 Artigo de Revisao Encefalite e Meningite

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Meningitis and

EncephalitisKaren L. Roos, MD, FAAN; John E. Greenlee, MD, FAANABSTRACT

Purpose of Review: Neurologists have a vital role in the recognition of meningitis andencephalitis, the accurate evaluation and interpretation of CSF studies, and the man-agement and prevention of the neurologic complications of CNS infectious diseases.Recent Findings: Although the tetravalent meningococcal glycoconjugate vaccine hasdecreased the incidence of meningococcal meningitis, the vaccine does not contain sero-group B, which is responsible for one-third of cases of meningococcal disease. Thus, menin-gitis due to Neisseria meningitidis is still a concern in a vaccinated individual. Empiric therapyfor meningitis associated with sinusitis, otitis, or mastoiditis should include antibiotic therapyfor anaerobes. An organism that classically causes a subacute or chronic meningitis, such asMycobacterium tuberculosis, may on occasion present with an acute onset of symptoms.Summary: Unlike most other diseases, the management of patients with suspectedmeningitis or encephalitis begins with empiric therapy. The etiologic organism cannotalways be identified. The goal is to identify those that are treatable, provide supportivecare for those that are not, and, when possible, prevent the neurologic complicationsof these infections.

Continuum Lifelong Learning Neurol 2011;17(5):10101023.

INTRODUCTION

Meningitis and encephalitis are neuro-logic emergencies. In the hospital set-ting, the initial realization that a patienthas a CNS infectious disease is usuallymade by the emergency department phy-sician or, if the patient is already ad-mitted, by the primary service. For thisreason, neurologic consultation may bedelayed, and time is almost always of theessence in reaching an accurate diagno-

sis and initiating treatment.

ACUTE MENINGITISBacterial Meningitis

Bacterial meningitis is most commonlycaused by hematogenous spread ofbacteria from a remote site of infection.Meningitis may also develop from thespread of organisms through emissaryveins from infected sinuses, middle ear,or mastoid. Bacteria may enter the sub-

arachnoid space following penetrating

trauma or neurosurgical procedures orthrough congenital or acquired defectsin the skull or spinal column. Meningitisdue to entry of organisms throughcongenital or acquired defects in theskull or spinal column should be sus-pected in patients with recurrent epi-sodes of meningitis. Acquired defectsare usually the result of closed headtrauma and occur at sites where thebones of the skull are thinnest: over

the frontal, ethmoidal, or sphenoidalsinuses or bony structures adjacent tothe middle ear or mastoid. Acquiredskull base defects may be accompaniedby CSF rhinorrhea or otorrhea if themeninges are breached, but not all skullbase defects are associated with rhino-rrhea or otorrhea. It is important toremember that an interval of many yearsmay separate an episode of significantclosed head trauma and the onset of

meningitis.

Address correspondence toDr John E. Greenlee, ClinicalNeuroscience Center, 175 NMedical Drive E, 5th Floor, SaltLake City, UT 84132,

[email protected] Disclosure:Dr Roos is the editor-in-chiefof Seminars in Neurology andhas received compensationfor legal work. Dr Greenleehas received personalcompensation for activities

with Perseid Therapeuticsas a consultant and hasserved in an editorial capacityfor Medlink.

Unlabeled Use ofProducts/InvestigationalUse Disclosure: Dr Roosand Dr Greenlee report no

disclosure.Copyright* 2011,

American Academy ofNeurology. All rightsreserved.

1010 www.aan.com/continuum October 2011

Review Article

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


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Causative agents of acute bacterial

meningitis. The agents causing bacte-rial meningitis vary with the age of the

patient, the route by which infection isacquired, and the presence of associ-ated or predisposing conditions.

The most common etiologic organ-ism of bacterial meningitis in neonatesand infants is Streptococcus agalactiae(group B streptococci), followed in orderof frequency by Escherichia coli, othergram-negative bacilli, and Listeria mono-cytogenes. Meningitis due to S. agalactiaeoccurs at two points in time: within 48

hours of the postnatal period or at 7 daysto 6 weeks of age. Cases occurring in theimmediate postnatal period are due to ac-quisition of the organism from the motherat the time of birth, and meningitis oftenoccurs as part of a systemic infection.Cases of S. agalactiae meningitis in olderneonates are usually not accompanied byother evidence of systemic infection.

The most common causative organ-isms of bacterial meningitis in childrenand adults are Streptococcus pneumo-niae and Neisseria meningitidis. Thetetravalent meningococcal glycocon-jugate vaccine has decreased the inci-dence of meningococcal meningitis.The vaccine does not contain serogroupB, which is responsible for one-third ofcases of meningococcal disease.1

Meningitis associated with sinusitis, oti-tis, or mastoiditis may be due to strepto-cocci, anaerobes,Staphylococcus aureus,

Haemophilus, or Enterobacteriaceae.

Meningitis in the postneurosurgicalpatient may be due to staphylococci,

gram-negative bacilli, or anaerobes. S.aureus is a common causative organ-ism in patients with penetrating head

trauma.The organisms associated with bacte-

rial meningitis in patients who are im-munocompromised vary with the typeof immune deficiency. Individuals withdefects of cell-mediated immunity,which includes very young infants, preg-nant woman, the elderly, and patientswho are immunocompromised as a re-sult of organ transplantation, malignancy,AIDS, or immunosuppressive medica-

tions, have an increased prevalence ofmeningitis due to L. monocytogenes ormycobacteria. Patients with defects of hu-moral immune response (and patientswho have undergone splenectomy) are atrisk for fulminant meningitis with S.

pneumoniae or, less frequently, N. men-ingitidis. Patients with neutropenia aresusceptible to meningitis caused by Pseu-

domonas aeruginosa and by gram-negative enteric bacteria.

Chronic meningitis presenting

acutely. A number of etiologic organ-isms that typically cause a subacute orchronic meningitis may on occasionpresent with acute onset of symptoms.This is especially true for tuberculousmeningitis but may occasionally occurwith fungal meningitides due to Cryp-tococcus neoformans, Histoplasmacapsulatum, Coccidioides immitis, orother agents. The most urgent of these istuberculous meningitis, and presumptive

treatment should be initiated if thecondition is suspected (Case 3-1).

KEY POINTS

h The most common

causative organisms of

bacterial meningitis in

children and adults areStreptococcus

pneumoniae and

Neisseria meningitidis.

h The tetravalent

meningococcal

glycoconjugate vaccine

does not contain

serogroup B, which

is responsible for

one-third of cases of

meningococcal disease.

h Meningitis associated

with sinusitis,

otitis, or mastoiditis

may be due to

streptococci, anaerobes,

Staphylococcus aureus,

Haemophilus, or

Enterobacteriaceae,

and empiric coverage

should include

meropenem or

metronidazole.

h Patients with defective

cell-mediated

immunity, such as

infants, the elderly,

and individuals who are

immunosuppressed,

may develop meningitis

due to Listeria

monocytogenes.

Case 3-1A 21-year-old Laotian woman presented to the emergency department withsevere headache, fever, confusion, and difficulty with gait. Examinationrevealed confusion, nuchal rigidity, bilateral Babinski signs, and ataxia. CTscan demonstrated basilar meningeal inflammation and a mild increase inventricular size. CSF analysis revealed 150 white blood cells/mm3, 45%

Continued on page 1012

1011Continuum Lifelong Learning Neurol 2011;17(5):10101023 www.aan.com/continuumCopyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


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Viral Meningitis

Many of the viruses causing viral men-ingitis have a seasonal distribution(Table 3-1). Most cases of viral menin-

gitis are due to enteroviruses and occur

in summer or early autumn, although

occasional cases may occur throughout

the year. Meningitis associated withWest Nile virus has a similar seasonaldistribution, as does meningitis asso-ciated with other arthropodborne vi-ruses. The exception to this rule is

Colorado tick fever, which tends tooccur in late spring or early summer.

Clinical Presentation ofAcute Meningitis

Bacterial meningitis may be precededby 3 to 5 days of insidiously progressivemalaise, fever, irritability, or vomiting;develop over 1 to 2 days; or have afulminant presentation.2 Bacterial men-ingitis remains one of the few condi-

tions in which a previously healthy

young person may go to sleep with

mild symptoms and never awaken.Typical symptoms are fever, headache,photophobia, vomiting, and an alteredlevel of consciousness (Case 3-2). Pa-tients may or may not complain of neckstiffness. Seizures may occur early inmeningitis in up to 40% of affectedchildren and may also occur in adults.Presentation with focal seizures or focalneurologic symptoms, however, shouldraise concern of brain abscess, cere-

britis, or cerebrovascular complications.Cases of mycobacterial or fungal men-ingitis presenting acutely may resemblebacterial meningitis. Patients with viralmeningitis are usually less overtly ill,and they never have an altered levelof consciousness or new-onset seizureactivity unless encephalitis has devel-oped. Neurologists are critical in helpingnon-neurologists distinguish between apatient with bacterial meningitis, who

should be admitted to and observed in

KEY POINTS

h Empiric therapy for

tuberculous meningitis

should be initiated in

patients with fever,headache, and stiff

neck; a CSF lymphocytic

pleocytosis; and a mild

to moderate decrease in

glucose concentration

(less than 40 mg/dL but

greater than 20 mg/dL).

h Cases of mycobacterial

or fungal meningitis

presenting acutely may

resemble bacterial

meningitis.

Continued from page 1011

polymorphonuclear leukocytes and 55% mononuclear cells, a protein of230 mg/dL, and a glucose of 30 mg/dL. No organisms were seen on Gramstain, and both acid-fast smear and PCR for mycobacteria were negative.The patient was treated with isoniazid (300 mg/d), rifampin (600 mg/d),pyrazinamide (2 g/d), and ethambutol (2.5 g/d) on suspicion of tuberculousmeningitis. CSF was obtained by high cervical puncture, and 3 weeks laterMycobacterium tuberculosis grew in culture. A chest x-ray demonstratedinnumerable small pulmonary opacities consistent with miliary tuberculosis.

Comment. Ancillary studies such as a chest radiograph are helpful inpatients with CNS infections. Skin testing with purified protein derivativemay initially be negative but then become positive as the patient improvesduring the course of therapy. In patients with fungal or tuberculousmeningitis, a high cervical puncture may demonstrate the organism whenlumbar puncture does not.

Therapy for tuberculous meningitis is recommended in the patient withfever, headache, and stiff neck, with or without cranial nerve deficitsassociated with a CSF lymphocytic pleocytosis and a mild to moderatelydecreased glucose concentration (less than 40 mg/dL but greater than20 mg/dL). Evidence of basilar meningeal enhancement and hydrocephaluson neuroimaging further supports the need for empiric therapy fortuberculous meningitis.


Meningitis and Encephalitis



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the intensive care unit, and a patientwith viral meningitis, who is not at riskfor additional complications.

Bedside Diagnosisof Meningitis

Bacterial meningitis should be consid-ered in any patient presenting with fever,

alteration in consciousness, and nuchalrigidity, keeping in mind that thesefindings are not present in all patients.Presentation in coma is an ominousprognostic sign. The classic tests formeningeal irritation are resistance topassive flexion of the neck (nuchalrigidity), Kernig sign, and Brudzinski

Case 3-2A 62-year-old woman had been in good health until 4 days prior to admission, when she reported shakingchills, cough, and purulent sputum production to her husband. Two days prior to admission she reporteda headache. On the day of admission, her husband found her unresponsive in the early morning hoursand called an ambulance. She was brought first to an outlying facility and then transferred.

On examination, the patient was diaphoretic and unresponsive. Pulse was 108 beats/min, bloodpressure was 108/84 mm Hg, and temperature was 39.8-C (103.6-F). General physical examination wasunremarkable except for rales over the right lower lung field and nuchal rigidity with a positiveBrudzinski sign. Fundi showed flat disks but absent venous pulsations. Blood cultures were obtained,and empiric therapy for bacterial meningitis and herpes simplex virus type 1 encephalitis was initiatedwith dexamethasone, ceftriaxone, vancomycin, ampicillin, and acyclovir.

Continued on page 1014

TABLE 3-1 Major Agents of Viral Meningitis

Family Genus Agents

Mechanism

of Spread Peak Season

Picornaviridae Enterovirus Coxsackieviruses Fecal-oralcontamination

Summer toearly autumn

Echoviruses

Enterovirus 71 and othernumbered enteroviruses

Herpesviridae Herpesvirus Herpes simplex virus type 2a Human contact No seasonaldistribution

Togaviridae Flavivirus West Nile virus Mosquito Summer toearly autumn

St. Louis virus

Bunyaviridae Orthobunyavirus California virus/La Crosse virus Mosquito Summer to

early autumnReoviridae Orbivirus Colorado tick fever Tick Late spring to

early summer

Arenaviridae Arenavirus Lymphocytic choriomeningitisvirus

Airborneb Autumn andwinterb

Retroviridae HIV Human contactc No seasonaldistribution

aHerpes simplex virus type 2 meningitis may occur as an isolated event or may be recurrent.bLymphocytic choriomeningitis virus is classically associated with exposure to infected wild mice and is most common during autumn orwinter when mice tend to move indoors. Infection may also occur year-round after exposure to infected pet hamsters.cMeningitis in HIV usually has its onset early in the course of systemic infection, at the time of seroconversion.



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sign. Kernig sign is present when resis-tance to passive extension of the leg atthe knee is present. Although Brudzinskideveloped several tests to detect menin-geal irritation, the maneuver most com-monly referred to as Brudzinski signinvolves spontaneous flexion of the hipsand knees when the neck is passivelyflexed. Brudzinski sign is the more sen-sitive of the two. Both signs, when pres-ent, are strongly suggestive of meningealirritation; however, they were developedin the preantibiotic era when meningitiswas frequently advanced at the time ofpresentation and may not be detectedearly in the course of infection. In awakepatients, a more sensitive test is to askpatients to put their chin on their chestwith the mouth closed. Keeping themouth closed is important, because

patients experiencing pain on flexionmay hold their neck still but touch theirchin to their chest by opening the jawwidely. One of the most sensitive testsof nuchal rigidity is a test that was de-veloped during the days of the polioepidemic and involves asking the pa-tient to kiss his or her knee (in children,who consider this request perfectlyreasonable) or, in adults, to touch theforehead to the knee. This test will of-

ten detect meningeal irritation at a time

when other tests are negative. It is im-portant to keep in mind that elderlypatients with extensive cervical spinedisease may have neck stiffness, andoccasionally patients with influenza andsevere myalgias may also report neckpain. In both groups of patients, painand resistance to movement usually oc-cur not only upon flexion but also uponlateral rotation. Patients with meningi-tis, however, can usually turn the headeven if neck stiffness to flexion is pres-ent. Particular attention should be paidto the presence of cutaneous rashes,petechiae, or purpura suggestive of me-ningococcemia; pulmonary consolida-tion suggestive of pneumonia due to

S. pneumoniae; or cardiac murmurssuggestive of endocarditis.

Atypical Presentationsof Meningitis

In neonates, bacterial meningitis maypresent with tachypnea, apneic spells,changes in heart rate, atypical seizures,or simply vague decline. Although afeeble, high-pitched cry in an infant hasbeen said to suggest meningitis, this isnot a reliable sign. Similarly, a bulgingfontanelle is a late sign, indicating sig-nificantly increased intracranial pressure.

Individuals whoare immunocompromised,

Continued from page 1013

Complete blood count showed a white blood cell count of 15,000 2/L with 85% neutrophils and 5%bands. CT scan was unremarkable. Lumbar puncture revealed an opening pressure of 430 mm H 2O,turbid fluid, 2290 white blood cells/mm3, 95% polymorphonuclear leukocytes, a protein of 410 mg/dL,and a glucose of 28 mg/dL with a blood glucose of 125 mg/dL. Gram stain showed innumerablepolymorphonuclear leukocytes and occasional lancet-shaped gram-positive diplococci.

The patient was treated with dexamethasone, ceftriaxone, vancomycin, and ampicillin pendingcultures, and subsequently antimicrobial therapy was modified after Streptococcus pneumoniae wasisolated and antibiotic sensitivities demonstrated the organism was sensitive to ceftriaxone.

Comment. Empiric adjunctive and antimicrobial therapy is initiated for bacterial meningitis, herpessimplex virus type 1 encephalitis, and tickborne bacterial infections (during the season when ticks arebiting) immediately after blood cultures are obtained and prior to CT and CSF analysis. Empiric therapy isthen modified when the results of CSF analysis and antimicrobial sensitivity testing are known.





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such as neonates, may not develop feveror nuchal rigidity. Patients with alcohol-ism presenting in the setting of severe

inebriation may have meningitis withoutclearly detectable signs. Meningitis mayalso be deceptively asymptomatic in theelderly, and the only sign of meningitismay be confusion in a previously alertolder patient or altered responsiveness ina patient who already has dementia. Inthese patients, as well as in neonates, thethreshold for CSF analysis should be low.However, patients with alcoholism andelderly patients are also at risk for falls and

subdural hematomas. In such patients,it is appropriate to begin antimicrobialtherapy and obtain a head CT scan or MRIbefore CSF analysis. The onset of bacterialmeningitis following neurosurgical proce-dures is often insidious, developing overhours or days. Patients in this setting areat increased risk, as an alteration ofconsciousness or neck stiffness may beattributed to the expected postoperativecourse.

Laboratory Diagnosisof Meningitis

Although bacterial meningitis is sus-pected on the basis of the clinicalpresentation and physical examinationfindings, definitive diagnosis is made byanalysis of the CSF. If intracranial pres-sure is greatly increased, there is a risk ofbrain herniation independent of, butalso associated with, lumbar puncture,and the likelihood of fatal herniation

cannot be reliably predicted from CT orMRI.3 In severely ill patients in whomvery high intracranial pressure is sus-pected, the most prudent course is tobegin empiric therapy and wait untilCSF pressure has been controlled be-fore performing lumbar puncture. Theorganism can often be identified inblood cultures. CSF should be sent forcell count with differential, protein andglucose concentration, Gram stain, cul-

ture, and PCR. Simultaneous blood glu-

cose should also be sent to determinethe CSF:blood glucose ratio. Expedi-tious handing of CSF by the laboratory

is important because cells may adhereto the collecting tube over time, result-ing in lower CSF cell counts, andleukocytes may lyse in extremely puru-lent CSF.4

Typical CSF findings in bacterialmeningitis include elevated openingpressure, fluid that is often, but notalways, turbid, elevated white blood cellcount consisting predominantly of poly-morphonuclear leukocytes, elevated

protein concentration, and depressedCSF:blood glucose ratio. A CSF:bloodglucose ratio of less than 0.3 is highlycorrelated with bacterial meningitis. Inevaluating CSF glucose concentrations,it is important to remember that CSFglucose values will be higher in moder-ately to severely hyperglycemic patientsand that changes in CSF glucose con-centrations may lag 30 to 120 minutesbehind those in blood. Protein con-centrations in meningitis are a reflec-tion of blood-brain barrier injury butusually range between 100 mg/dL and500 mg/dL.4

Specific identification of the infect-ing organism involves Gram stain, cul-ture, and PCR. Gram stain providesthe most rapid initial identification ofthe organism. Detection of organismson Gram stain requires approximately100,000 organisms/mm3.5 Errors inGram stain may result from careless

handling of CSF, inadequate efforts toresuspend bacteria if CSF has beenallowed to settle, and errors in de-colorization or reading of the slide.A 16S ribosomal RNA conserved se-quence broad-based bacterial PCR isroutinely available in most hospitallaboratories. Additionally, a numberof meningeal-specific PCRs detect

N. meningitidis or S. pneumoniae nu-cleic acid in CSF, as well as a number

of other meningeal pathogens, but

KEY POINTS

h The causative organisms

of bacterial meningitis

can often be detected in

blood cultures.

h CSF should be

examined for white

blood cells within 90

minutes of collection.

h CSF glucose

concentrations will be

higher in moderately to

severely hyperglycemic

patients. In these

patients, the CSF:blood

glucose ratio should be

used to determine the

true CSF glucose

concentration. The CSF

glucose concentration

is low when the

CSF:blood glucose ratio

is less than 0.6.

h CSF bacterial PCRs are

increasingly available.

Specific diagnosis of the

causative organism of

bacterial meningitis anddetermination of

antibiotic sensitivity

require bacterial culture.



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these are not routinely available. Speci-fic diagnosis of the causative organismof bacterial meningitis and determina-tion of antibiotic sensitivity requirebacterial culture. Although this is rou-tine in most hospitals, it may be help-ful to alert the laboratory in advanceif anaerobic infection or other un-usual organisms or culture require-

ments are anticipated. Yield on culturecan be reduced by prior antibiotic ther-apy. Table 3-2 is a list of the expectedCSF results in meningitis due to bac-teria, viruses, mycobacteria, and fungi.

Treatment of Acute Meningitis

Antibiotic therapy for bacterial men-

ingitis. Antibiotic therapy for bacterialmeningitis is initially empiric and thenspecific once the pathogen has been

identified and the results of antimi-

crobial sensitivity testing are known(Table 3-3).

Therapy of chronic meningitis pre-

senting acutely. Specific diagnosis oftuberculous meningitis can be difficult:yield by PCR approaches 50%, andsensitivity of culture (which may takeup to 6 weeks) is only 70%.4 Thus, ther-apy for tuberculous meningitis should

be initiated presumptively if the diagnosisis suspected (Table 3-4). Treatment offungal meningitis is usually not begunempirically unless organisms are seenin CSF.

Treatment of viral meningitis. Mostcases of viral meningitis resolve spon-taneously. The headache may persistfor months and can be managed withamitriptyline and nonsteroidal anti-inflammatory agents. Limited data sug-

gest that pleconaril may shorten the

TABLE 3-2 CSF Abnormalities in Acute Meningitis

Type of

Meningitis Cellsa Protein Glucose Specific Diagnosis

Bacterialmeningitis

Polymorphonuclearleukocytes

Elevated G50% ofbloodglucose

Gram stain

Bacterial culture

PCR

Tuberculousmeningitis

Variable pleocytosis,usually withlymphocytes 9polymorphonuclearleukocytes

Elevated G50% ofbloodglucose

Acid-fast stainb

PCR

Culture

Fungalmeningitis

Lymphocytes Elevated G50% ofblood

glucose

Cryptococcal polysaccharide antigen

Histoplasma polysaccharide antigen Coccidioidesimmitis complement fixation antibody

India ink and culture

Viralmeningitis

Lymphocytesc Elevated 950% ofbloodglucose

Reverse transcriptase PCR for enteroviruses

PCR herpes simplex virus type 2

Immunoglobulin M (West Nile or other arboviruses)

aCell count, glucose, and protein may be minimally abnormal in patients who are severely immunocompromised.bIn tuberculous meningitis, diagnosis by CSF acid-fast smear has a low sensitivity, diagnostic reliability of PCR is only 50%, and culturerequires up to 7 weeks. For this reason, tuberculous meningitis is treated as described in Case 3-1.cCSF during the first 24 to 48 hours of viral meningitis may exhibit a mixed pleocytosis with predominance of polymorphonuclear leukocytes.





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duration of headache in enteroviralmeningitis, but the drug is not rou-tinely available.5 Acyclovir is efficaciousin treating herpes simplex virus type 2(HSV-2) meningitis, and prophylactictherapy with acyclovir, valacyclovir, orfamciclovir is efficacious in preventing

recurrent meningitis due to HSV-2.

Corticosteroid therapy in meningi-

tis. The realization that neurologic injuryin bacterial meningitis is due to the hostinflammatory response has led to a focuson controlling this aspect of men-ingitis. Early studies in children with

Haemophilus influenzae meningitis

who were treated with cefotaxime plus

TABLE 3-3 Antibiotics for Empiric Therapy of Bacterial Meningitis

Age and Associated

Conditions Probable Organism Antibiotic Therapy

Preterm infants Staphylococcus aureus (nosocomial) Vancomycin plus ceftazidime

Gram-negative bacilli

Neonates Group B streptococci Ampicillin plus cefotaxime

Escherichia coli

Other gram-negative bacilli

Listeria monocytogenes

Children and adults Streptococcus pneumoniae Third-generation (ceftriaxone orcefotaxime) or fourth-generation(cefepime) cephalosporin plus

vancomycin

Neisseria meningitidis

Adults over the age of 55 S. pneumoniae Third-generation (ceftriaxone orcefotaxime) or fourth-generation(cefepime) cephalosporin plusvancomycin plus ampicillin

L. monocytogenes


Haemophilus influenzae

Meningitis in the settingof sinusitis, otitis, or knownCSF leak

S. pneumoniae Third-generation (ceftriaxone orcefotaxime) or fourth-generation(cefepime) cephalosporin plusvancomycin plus meropenem ormetronidazole

Haemophilus


Anaerobic or microaerophilic streptococci

Bacteroides fragilis

S. aureus

Head trauma, neurosurgicalprocedures, shunt infections

S. aureus Vancomycin plus ceftazidime orvancomycin plus meropenem

Staphylococcus epidermidis


S. pneumoniae

States of impaired cellularimmunity, including AIDS

L. monocytogenes Third-generation (ceftriaxone orcefotaxime) or fourth-generation(cefepime) cephalosporin plusvancomycin plus ampicillin


S. pneumoniae

H. influenzae



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dexamethasone demonstrated an

effect on the CSF inflammatory re-sponse and a decreased incidence ofdeafness compared with those treatedwith cefotaxime alone.6 More recently,studies from EuropeVincluding a na-tionwide prospective study from theNetherlands in which dexamethasonewas used in all patients above 16 yearsof age with pneumococcal meningitisVdemonstrated reduced mortality ratesand neurologic sequelae in patientswith pneumococcal meningitis treatedwith dexamethasone begun at the ini-tiation of antibiotic therapy (class IIIevidence).7,8 Dexamethasone is givenas 10 mg intravenously, beginning im-mediately prior to or with the initialdose of antibiotics, followed by 10 mgintravenously every 6 hours for 4 days.Early institution of dexamethasone andantibiotic therapy appears to be cru-cial, and dexamethasone has not beenshown to be effective in less-developed

countries where patients tend to pres-ent later in the course of their dis-ease.8 The role of dexamethasone intuberculous or fungal meningitides isless well established. In tuberculousmeningitis, dexamethasone has been re-ported to decrease mortality but notneurologic sequelae in survivors.9 Aswith bacterial meningitis, however,the utility of dexamethasone may de-pend on its use early in the course of

infection.

Other measures to treat cerebral

edema. Patients presenting with papil-ledema or signs of impending brainherniation warrant emergent treatmentfor increased intracranial pressure. Ele-vation of the head of the bed to 30degrees will often reduce pressuresomewhat. Hyperventilation to a PCO2of 27 mm Hg to 30 mm Hg will causeintracranial vasoconstriction and may belifesaving over the short term. Thisusually requires intubation and paraly-sis, and in some cases the patient willalready be hyperventilating to that level.In children, 0.5 g/kg to 2.0 g/kg ofmannitol is given intravenously over 30minutes and repeated as needed. Theadult dosage is a 1.0 g/kg bolus re-peated as needed every 3 to 4 hours or0.25 g/kg every 2 to 3 hours. Pentobar-bital coma has been used in extremecases, but no controlled data exist forits use in meningitis. Decompressivecraniectomy is not normally used in

meningitis because the cerebral involve-ment is diffuse rather than focal. Surgerymay be required, however, to drain anaccompanying brain abscess or para-meningeal focus of infection. For moreinformation, refer to the article Eval-uation and Management of IncreasedIntracranial Pressure in this issue of

.Other complications of meningitis

requiring treatment. Bacterial menin-

gitis may be accompanied by a variety

TABLE 3-4 Antimicrobial Therapy for Tuberculous Meningitisa

Drug Usual Daily Dose Maximum Dose Duration

Isoniazid 5 mg/kg to 10 mg/kg 300 mg 6 to 9 months

Rifampin 10 mg/kg to 20 mg/kg 600 mg 6 months

Pyrazinamide 15 mg/kg to 30 mg/kg 2000 mg 2 months

Ethambutol 15 mg/kg to 25 mg/kg 2500 mg 2 months

Streptomycin 15 mg/kg 1000 mg 2 monthsaMultiple drug regimens (four or more) should be used when a high probability of drug resistance exists.





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of neurologic and systemic complica-tions, many of which may also occur intuberculous meningitis. Bacterial men-

ingitis arising from sinusitis or otitis maybe complicated by epidural abscess,subdural empyema, brain abscess, orvenous sinus thrombosis, any of whichmay require emergent surgery. Seizuresrequire emergent treatment with lora-zepam, phenytoin (fosphenytoin), ormore aggressive therapy such as phe-nobarbital or pentobarbital coma inpatients who fail to respond. Hypona-tremia may be caused by cerebral salt

wasting, the syndrome of inappropriatesecretion of antidiuretic hormone, or IVfluids. Subdural effusions are commonin children with meningitis; these donot usually require drainage and may befollowed by CT or MRI. Patients maydevelop cerebral vasculitis, stroke, orspontaneous intracranial hemorrhage.10

Myelitis, although not usually consid-ered a complication of bacterial men-ingitis, has been reported in 2.3% ofpatients with pneumococcal meningi-tis.10 Bacterial sepsis and shock may bepresent, as may disseminated in-travascular coagulation, and, in thecase of N. meningitidis, Waterhouse-Friderichsen syndrome with wide-spread hemorrhage and adrenal failure.Cases of meningitis associated with

S. aureus and, less often, S. pneumo-niae may be a complication of bacterialendocarditis. Meningitis in the presenceof S. pneumoniae endocarditis is often

accompanied by rapid destruction ofthe aortic valve. Basilar meningitis withbasal ganglia ischemia or infarction canoccur in both tuberculous meningitis andcryptococcal meningitis. The basilar men-ingitis that occurs in tuberculous menin-gitis may produce obstructive rather thancommunicating hydrocephalus.

Fungal meningitis. Recommenda-tions for the antimicrobial therapy offungal meningitis are readily available,

but neurologists must be vigilant about

the presence and development of in-creased opening pressure. Openingpressure should be measured at the

time of the initial lumbar puncture andany time a change in the neurologic ex-amination occurs. A time-honored prac-tice has been to perform daily lumbarpunctures and reduce the opening pres-sure by 50% using a manometer. Inreality, daily lumbar punctures are oftennot effective, and it is best to use aventriculostomy instead.

Prognosis

In most series, mortality has correlatedwith obtundation or coma. Factors as-sociated with poor prognosis includeage older than 60 years, concomitantdebilitating diseases, low GlasgowComa Scale score on admission, focalneurologic deficits, and low CSF cellcount.10Y12 Seizures have predicted aworse outcome in some studies, as haslow CSF:serum glucose ratio.11 Mortal-ity in tuberculous meningitis is in therange of 25%, with good recovery inonly 50% of patients.13 As in bacterialmeningitis, prognosis is significantlyinfluenced by the level of conscious-ness on presentation and the rapidinstitution of appropriate therapy. Viralmeningitis is usually self-limited.

ENCEPHALITIS

In patients with an altered level ofconsciousness or an acute confusionalstate, the first question to ask is

whether the patient has encephalitisor an encephalopathy. If the patient hasencephalitis, the next question to ask iswhether he or she has encephalitis thatcan be treated with antimicrobial agentsor encephalitis that is treated with sup-portive care only (Case 3-3).

Etiology

The presence of fever and headachewith an altered level of consciousness

makes encephalitis more likely than

KEY POINTS

h In the patient with

basilar meningitis

with basal ganglia

ischemia or infarction,tuberculous meningitis

and cryptococcal

meningitis should be

considered.

h In patients with

bacterial, mycobacterial,

or fungal meningitis,

prognosis is influenced

by the level of

consciousness at the

time of presentation

and the rapidity ofantimicrobial therapy

initiation.



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encephalopathy. The etiologic organ-ism of the encephalitis can be predictedbased on the following: (1) the time ofyear, (2) prodromal symptoms (eg,flulike illness in West Nile virus infec-tion), (3) area of residence, (4) traveland occupational and recreational activ-ities, (5) rash (eg, varicella, meningo-coccemia, Rocky Mountain spottedfever), (6) contact with animals, and

(7) immunosuppression from medica-tions, malignancy, chronic corticoste-roid use, or organ transplantation.14

The most common identifiable etio-logic organisms of encephalitis arethe reactivation of a latent herpesvirusinfection (eg, HSV-1 or varicella-zostervirus), a tickborne bacterial infection, oran arthropodborne virus.

In the organ transplant recipient, it iscritical to obtain the donor history from

the donors file. Cytomegalovirus, West

Nile virus, and rabies have been trans-mitted from organ donor to recipient.

Clinical Presentation

Patients with encephalitis have feverand headache and one or more of thefollowing: confusion, behavioral ab-normalities, depressed level of con-sciousness, focal neurologic deficits,and new-onset seizure activity.

Certain features, or a combinationof features, suggest a specific etiology.Patients with West Nile virus may have atremor, a history of diarrhea, or a macu-lopapular rash. The three most clini-cally significant flaviviruses (West Nilevirus, St. Louis encephalitis virus, andJapanese encephalitis virus) may presentwith a flaccid, weak limb (a poliomyelitissyndrome) or parkinsonian features.Confusion and word-finding difficulty

are common in HSV-1 encephalitis.

KEY POINTS

h The most common

identifiable etiologic

organisms of

encephalitis areherpesviruses

(eg, herpes simplex

virus type 1 or

varicella-zoster virus),

a tickborne bacterial

infection, or an

arthropodborne virus.

h Neuroinvasive disease

due to West Nile virus,

St. Louis encephalitis

virus, or Japanese

encephalitis virusmay present with

encephalitis, a flaccid,

weak limb (a

poliomyelitis syndrome),

or parkinsonian

features.

Case 3-3A 20-year-old college junior was brought to the emergency department byher boyfriend because of a 3-day history of fever, headache, andintermittent confusion. On examination, she had a temperature of 38-C(100.4-F), was oriented to self but not to date or place, and had difficultyfollowing commands. The boyfriend denied alcohol or illicit drug use.Complete blood count with differential was normal. Noncontrast cranialCT scan was normal. CSF analysis demonstrated 100 white blood cells/mm3,lymphocytic predominance, 700 red blood cells/mm3, a glucoseconcentration of 47 mg/dL, and a protein concentration of 56 mg/dL.

The patient was treated empirically with acyclovir for herpes simplex virus(HSV) encephalitis based on her clinical presentation and CSF analysis. CSFPCR for HSV-1 DNA was obtained as well as serum and CSF immunoglobulin G(IgG) antibodies to determine a serum:CSF antibody ratio.

Comment. The CSF PCR should be positive, as she is 3 days into her illness,but it is likely too early to detect the intrathecal synthesis of antibodies.Antibodies do not appear in CSF until 8 days after symptom onset but maybe detectable for up to 3 months. HSV IgG on serum and CSF should beobtained. A serum:CSF ratio of less than 20:1 is diagnostic of HSV encephalitis.Fluid-attenuated inversion recovery (FLAIR) sequences and diffusion-weightedimaging (DWI) magnetic resonance scans are indicated and would beexpected to demonstrate an area of increased signal intensity in the temporallobe. In 90% of adults with HSV encephalitis, an area of increased signalintensity is seen in the temporal lobe on T2-weighted images, FLAIRsequences, and DWI within 48 hours of symptom onset.





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Varicella-zoster virus presents with focalneurologic deficits due to ischemic andhemorrhagic infarctions. Although vari-

cella-zoster virus encephalitis may followshingles, encephalitis due to varicella-zoster virus may occur in the absence ofa history of shingles. The rash of RockyMountain spotted fever typically beginson the wrists and ankles and thenspreads centrally to the face, chest, andabdomen. This is in contrast to the rashof an enterovirus, which begins on theface and chest and then spreads to thelimbs. Borrelia burgdorferi, the causa-

tive spirochete of Lyme disease in NorthAmerica, does not cause encephalitis.Thus, the appearance of a single erythe-matous lesion on the trunk or extrem-ities is not a clue to the etiologic agent.

Diagnosis

Although the specific tests for encepha-litis are magnetic resonance (MR) scan,CSF analysis, blood cultures, and com-plete blood count with differential andserologies, routine tests for encephal-opathy should be sent as well, includingserum electrolytes, glucose, creatinine,liver function test, ammonia, and serumand urine toxicology screens. An MRscan is more sensitive than a CT scan forencephalitis.

The importance of serologies (acutephase immunoglobulin M [IgM] andacute and convalescent immunoglobu-lin G [IgG] titers) cannot be overstated.One of the biggest impacts that PCR has

had on the diagnosis of neurologic in-fectious diseases has been the increasedawareness of other serum and CSF teststhat have been available for years butwere often overlooked because of theemphasis on neuroimaging abnormali-ties in diagnosing encephalitis.

Herpes simplex virus type 1. In 90%of adults with HSV encephalitis, an areaof increased signal intensity is seenin the temporal lobe on T2-weighted

images, fluid-attenuated inversion re-

covery (FLAIR) sequences, and diffusion-weighted imaging MR scan within 48hours of symptom onset (Figure 3-1).

CSF analysis demonstrates a lympho-cytic pleocytosis with a normal glucoseconcentration. Red blood cells or xan-thochromia may be seen in the CSF asthis is hemorrhagic, necrotic encepha-litis. The CSF PCR may be falselynegative in the first 72 hours of HSVencephalitis symptoms, and detectionrates decrease 10 days after the onsetof symptoms. Serum and CSF HSV IgGantibodies should be obtained to de-

termine whether intrathecal synthesisof antibodies is present. A serum:CSFratio of less than 20:1 is diagnostic ofHSV encephalitis. It takes at least 8days for antibodies to be detected inCSF, and antibodies may be detectablefor up to 3 months. The EEG demon-strates periodic sharp-and-slow wavecomplexes occurring at regular 1- to3-second intervals. These abnormalitiesare most typically seen between thesecond and fifteenth days of illness.

For HSV-1 encephalitis, CSF PCRfor HSV-1 and CSF and serum anti-bodies should be sent.

FIGURE 3-1 T2-weighted MRI demonstratinga hyperintensity in the lefttemporal lobe in a patient with

herpes simplex virus type 1 encephalitis.



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Varicella-zoster virus. The best diag-nostic test for varicella-zoster virus en-cephalitis is the detection of varicella-

zoster virus IgM in CSF.Mosquitoborne viruses. In encepha-

litis due to any of the flaviviruses, hy-perintense lesions may be seen in thethalami, substantia nigra, and basal gan-glia on T2-weighted and FLAIR sequen-ces. The best test for West Nile virusencephalitis is the detection of CSF IgMantibodies specific for the virus. SerumIgM and IgG antibodies cannot be usedto diagnose neuroinvasive disease.

For the other mosquitoborne viral en-cephalitides, acute and convalescent serol-ogy remain the mainstay of diagnosis.

Epstein-Barr virus. Diagnosis ofEpstein-Barr virus (EBV) depends on acombination of serology and CSF PCR.If serology demonstrates a positive vi-rus capsid antigen (VCA) and negativeEpstein-Barr nuclear antigen (EBNA) andthe CSF PCR for EBV DNA is positive,a diagnosis of EBV encephalitis can bemade. If serology demonstrates a neg-ative VCA IgM and a positive EBNA andthe CSF PCR is positive, a diagnosis ofEBV encephalitis cannot be made, as theCSF PCR may be positive for EBV nucleicacid in an immunocompetent individualin any inflammatory CNS disorder.

Rocky Mountain spotted fever. Theserologic tests for the rickettsial infec-tions have a low sensitivity early in thedisease. It is important to biopsy any skinlesions that are present and to repeatedly

send serology. A number of differentserologic tests are available, including theindirect fluorescent antibody test, ELISA,and flow immunoassays.

Progressive multifocal leukoence-

phalopathy. The CSF should be non-inflammatory. To diagnose progressivemultifocal leukoencephalopathy, CSFPCR should be sent for JC virus DNA;sensitivity may only be around 60%.

Cytomegalovirus encephalitis. To

diagnose cytomegalovirus encephalitis,

CSF PCR for cytomegalovirus nucleicacid should be sent.

TherapyHSV-1 encephalitis is treated with10 mg/kg of IV acyclovir every 8 hoursfor 3 weeks. Varicella-zoster virus ence-phalitis is treated with 10 mg/kg of IVacyclovir every 8 hours for 10 to 14 days.Acyclovir is not recommended for EBVencephalitis, as it is felt to providelittle or no benefit.15 Rocky Mountainspotted fever is treated with 100 mg ofdoxycycline twice daily for at least

3 days after the patient becomes afe-brile. Cytomegalovirus encephalitis istreated with a combination of 60 mg/kgof IV foscarnet every 8 hours and 5 mg/kgof IV ganciclovir every 12 hours.

Noninfectious Encephalitis

Patients with noninfectious encephalitishave headache, confusion, behavioralabnormalities, gait abnormalities, andinvoluntary movements. CSF analysisdemonstrates a lymphocytic pleocytosiswith an increased protein concentrationand a normal glucose concentration.The hyperintensity in the temporal lobeon T2-weighted and FLAIR MR imagesof paraneoplastic limbic encephalitis hasa similar appearance to that of HSV-1encephalitis. Serology and CSF shouldbe sent for antineuronal antibodies, and,when positive, diagnostic studies shouldbe performed for the malignancy asso-ciated with the antineuronal antibody.

Nonvasculitic autoimmune inflam-matory meningoencephalitis (NAIM)steroid-responsive encephalopathy(previously referred to as Hashimotoencephalopathy) has been associatedwith a number of antibodies, includingthyroperoxidase antibodies, thyroidmicrosomal antibodies, thyroglobulinantibodies, extractable nuclear anti-gen antibodies, antistriatal antibodies,antinuclear antibodies, antiphospholi-

pid antibodies, and gliadin antibodies.

KEY POINTS

h To diagnose herpes

simplex virus type 1

encephalitis, CSF PCR

for herpes simplex virustype 1 and CSF and

serum antibodies should

be obtained.

h The best diagnostic

test for varicella-zoster

virus encephalitis

is the detection of

varicella-zoster virus

immunoglobulin M

in CSF.





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NAIM is treated with 1000 mg of IVmethylprednisolone for 5 days followedby oral prednisone therapy.

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