encephalitis.docx

8/18/2019 encephalitis.docx

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Background

Encephalitis, an inflammation of the brain parenchyma, presents as diffuse and/or focalneuropsychological dysfunction. Although it primarily involves the brain, the meninges arefrequently involved (meningoencephalitis).

From an epidemiologic and pathophysiologic perspective, encephalitis is distinct frommeningitis, though on clinical evaluation both can be present, with signs and symptoms ofmeningeal inflammation, such as photophobia, headache, or stiff nec. !t is also distinctfrom cerebritis. "erebritis describes the stage preceding abscess formation and implies a highlydestructive bacterial infection of brain tissue, whereas acute encephalitis is most commonly aviral infection with parenchymal damage varying from mild to profound.

Although bacterial, fungal, and autoimmune disorders can produce encephalitis, most cases areviral in origin. #he incidence of encephalitis is $ case per %&&,&&& population in the 'nitedtates, with herpes simple virus (*+) being the most common cause. "onsidering thesubacute and chronic encephalopathies, the emergency department (E) physician is mostliely to encounter tooplasmosis in an immune-compromised host.

#he relatively common acute arboviral encephalitides vary widely in epidemiology, mortality,morbidity, and clinical presentation, and no satisfactory treatment eists for these infections.*owever, attempts to distinguish these acute arboviral encephalitides from the treatable acuteviral encephalitides due to herpes simple or varicella are important.

*erpes simple encephalitis (*E), which occurs sporadically in healthy and immune-compromised adults is also encountered in neonates infected at birth during vaginal deliveryand is potentially lethal if not treated. +aricella-oster virus encephalitis (++E) is lifethreatening in immune-compromised patients. wift identification and immediate treatment of*E or ++E can be lifesaving. From a ris-benefit standpoint, most authorities recommendinitiating E treatment with acyclovir in any patient whose central nervous system ("0)presentation is suggestive of viral encephalitis, especially in the presence of fever,

encephalopathy, or focal findings, and in all neonates who appear ill for whom a "0 infectionis being considered.

ee the following for more information1

• "alifornia Encephalitis

• "230E--+eneuelan Equine Encephalitis

• Eastern Equine Encephalitis

• Encephalitis

• *erpes imple Encephalitis

• *!+-Associated "ytomegalovirus Encephalitis

• 4apanese Encephalitis

•

t. 5ouis Encephalitis• +eneuelan Equine Encephalitis

• +iral Encephalitis

• 6est 0ile Encephalitis

• 6estern Equine Encephalitis

7athophysiology

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7ortals of entry are virus specific. 8any viruses are transmitted by humans, though most cases

of *E are thought to be reactivation of *+ lying dormant in the trigeminal ganglia.

8osquitoes or tics inoculate arbovirus, and rabies virus is transferred via an infected animal

bite or eposure to animal secretions. 6ith some viruses, such as varicella-oster virus (++)

and cytomegalovirus ("8+), an immune-compromised state is usually necessary to develop

clinically apparent encephalitis.

!n general, the virus replicates outside the "0 and gains entry to the "0 either by

hematogenous spread or by travel along neural pathways (eg, rabies virus, *+, ++). #he

etiology of slow virus infections, such as those implicated in the measles-related subacute

sclerosing panencephalitis (7E) and progressive multifocal leuoencephalopathy (785), is

poorly understood.

9nce across the blood-brain barrier, the virus enters neural cells, with resultant disruption in cell

functioning, perivascular congestion, hemorrhage, and a diffuse inflammatory response that

disproportionately affects gray matter over white matter. 3egional tropism associated with

certain viruses is due to neuron cell membrane receptors found only in specific portions of the

brain, with more intense focal pathology in these areas. A classic eample is the *+

predilection for the inferior and medial temporal lobes.

!n contrast to viruses that invade gray matter directly, acute disseminated encephalitis and

postinfectious encephalomyelitis (7!E), most commonly due to measles infection and associated

with Epstein-2arr virus (E2+) and "8+ infections, are immune-mediated processes that result

in multifocal demyelination of perivenous white matter.

Etiology

#he cause of encephalitis is usually infectious in nature. +iral agents, such as *+ types $ and

% (the latter much more common in neonates than adults), ++, E2+, measles virus (7!E and

7E), mumps virus, and rubella virus, are spread through person-to-person contact. *uman

herpesvirus : may also be a causative agent.;


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United States statistics

etermining the true incidence of encephalitis is impossible, because reporting policies are

neither standardied nor rigorously enforced. !n the 'nited tates, several thousand cases

of viral encephalitis are reported to the "" each year, with an additional $&& cases a year

attributed to 7!E. #hese figures probably represent a fraction of the actual number of cases.

*E, the most common cause of sporadic encephalitis in 6estern countries, is relatively rare>

the overall incidence is &.% per $&&,&&&, with neonatal *+ infection occurring in %-< per $&,&&&

live births.

#he arbovirus group is the most common cause of episodic encephalitis, with a reported

incidence similar to that of *+. #hese statistics may be misleading in that most people bitten

by arbovirus-infected insects do not develop clinically apparent illness and, of those who do,

less than $&? develop overt encephalitis.

Arboviruses require an insect vector, which is generally present between 4une and 9ctober. #he

% most common arboviruses result in ($) t 5ouis encephalitis, found throughout the 'nited

tates but principally in urban areas around the 8ississippi 3iver, and (%) the geographically

misnamed "alifornia virus encephalitis ("E)@in particular, 5a"ross encephalitis (5A")@which

affects children in rural areas in states of the upper 8idwest and 0orth East.

Among the other arbovirus-caused encephalitides, the deadliest (and, fortunately, rarest)

is eastern equine encephalitis (EEE), which is encountered in 0ew England and surrounding

areas> western equine encephalitis (6EE), a milder disease, is most common in rural

communities west of the 8ississippi 3iver. 7owassan virus is the only well-documented

arbovirus transmitted by tics.

5ess common causes of viral encephalitis include ++ encephalitis, with an incidence of

roughly $ in %&&& infected persons. 8easles produces % devastating forms of encephalitis1 7!E,

which occurs in about $ in $&&& infected persons, and 7E, occurring in about $ in $&&,&&&

infected patients. 3arest in the 'nited tates are the &-< unrelated annual cases of rabies

encephalitis, typically a consequence of the immigration of an infected person from 8eico or

"entral America during the long incubation period of the rabies virus but prior to the onset of

clinically apparent disease.

International statistics

4apanese virus encephalitis (4E), occurring principally in 4apan, outheast Asia, "hina, and

!ndia, is the most common viral encephalitis outside the 'nited tates.

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Age-related differences in incidence

!ndividuals at the etremes of age are at highest ris, particularly for *E. 0eonatal *E is a

manifestation of disseminated infection type $ or %, whereas older infants, children, and adults

are much more liely to have localiing "0 infection almost eclusively due to type $, in a

bimodal distribution of patients aged - conversely, 5A" is more common and is most severe in children younger than $: years.

EEE and 6EE disproportionately affect infants while EEE disproportionately affects children and

elderly persons.

7rognosis

#he prognosis is dependent on the virulence of the virus and the patientBs health status.

Etremes of age (C $ y or D y), immune-compromised status, and preeisting neurologicconditions are associated with poorer outcomes.

'ntreated *E has a mortality of &-?, and virtually all untreated or late-treatment survivors

have long-term motor and mental disabilities. #he mortality in treated *E averages %&?, and

the neurologic outcome correlates with the neurological disability present at the time of the first

dose of acyclovir or comparable antiviral agents. Approimately &? of survivors have minor-to-

maGor learning disabilities, memory impairment, neuropsychiatric abnormalities, epilepsy, fine-

motor-control deficits, and dysarthria.

9utcomes in arboviral 4E and EEE are catastrophic, similar to untreated *E, with high

mortality and severe morbidity, including mental retardation, hemiplegia, and seiures. 9ther

arboviruses cause substantially less morbidity and mortality. For eample, t 5ouis encephalitis

and 60E have a mortality rate of %-%&?, the higher rates found in patients older than :& years.

5ong-term sequelae with t 5ouis encephalitis include behavioral disorders, memory loss, and

seiures.

6EE is associated with few deaths and much less morbidity, although developmental delay,

seiure disorder, and paralysis occasionally occur in children, and postencephalitic

parinsonism may occur in adults. "E is typically associated with mild illness, and most patients

mae a full recovery> however, the minority of patients with severe disease have a %? chance

of focal neurologic dysfunction. eath rates from 6EE and 5A" are less than ?.

7!E secondary to measles is associated with a mortality rate approaching &? of cases, with a

high rate of neurologic sequelae in survivors. 7E is uniformly fatal, although the disease

course may last anywhere from several wees to $& years.


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++E has a mortality of $? in immune-competent patients and virtually $&&? in immune-

suppressed patients. #he mortality for E2+ encephalitis is H?, with substantial morbidity found

in approimately $%? of survivors.

3abies encephalitis and acute disseminated encephalitis are virtually $&&? fatal, although there

are rare survivors reported in the medical literature.

History

#he clinical presentation and course can be maredly variable. #he acuity and severity of thepresentation correlate with the prognosis. A history of mosquito or tic bites or eposure tomouse/rat droppings should be sought. 3ecogniing certain mammalian animal bite(s)associated with rabies or eposure to a bat in an enclosed space for which antirabies treatmentwas not obtained is very important.

#he viral prodrome is typically several days and consists of fever, headache, nausea andvomiting, lethargy, and myalgias. #he specific prodrome in encephalitis caused by varicella-oster virus (++), Epstein-2arr virus (E2+), cytomegalovirus ("8+), measles virus, or mumpsvirus includes rash, lymphadenopathy, hepatosplenomegaly, and parotid enlargement. ysuriaand pyuria are reported with t 5ouis encephalitis. Etreme lethargy has been noted with 6est0ile encephalitis (60E).

#he classic presentation is encephalopathy with diffuse or focal neurologic symptoms, includingthe following1

• 2ehavioral and personality changes, with decreased level of consciousness

• 0ec pain, stiffness

• 7hotophobia

• 5ethargy

• Ieneralied or focal seiures (:&? of children with "E)

• Acute confusion or amnestic states• Flaccid paralysis ($&? of patients with 60E)

9f note, severe headache is not always found. 5ess common is the complaint of paraspinalbacache.

ymptoms of herpes simple virus (*+) infection in neonates (aged $- d) may includelocalied sin, eye, or mouth lesions in the early phase of illness with encephalitis. iminishedalertness, irritability, seiures, and poor feeding develop later in the course of illness, anddisseminated disease and shoc are late findings.

*erpes simple encephalitis (*E) in older children and adults is not typically associated withactive herpetic eruptions and is characteried by the acute onset of more severe symptoms of

encephalitis early in the course of illness.

Toxoplasma encephalopathy accounts for as many as &? of *!+-positive patients withneurologic disease who present with a subacute headache, findings of subtle to remarableencephalopathy, and, often, focal neurological complaints/findings. 3arely, this may be thepresenting symptom comple of profound immune suppression due to *!+ infection.

Physical Examination


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5oo for supporting evidence of viral infection. #he signs of encephalitis may be diffuse or focal. At the etremes, H&? of patients with *E present with focal findings. #ypical findings includethe following1

• Altered mental status

• 7ersonality changes are very common

• Focal findings, such as hemiparesis, focal seiures, and autonomic dysfunction• 8ovement disorders (t 5ouis encephalitis, eastern equine encephalitis ;EEE=, western

equine encephalitis ;6EE=)• Ataia

• "ranial nerve defects

• ysphagia, particularly in rabies

• 8eningismus (less common and less pronounced than in meningitis)

• 'nilateral sensorimotor dysfunction (postinfectious encephalomyelitis ;7!E=)

Findings of *+ infection in neonates (aged $- d) may include the following1

• *erpetic sin lesions over the presenting surface from birth or with breas in the sin,

such as those resulting from fetal scalp monitors• JeratoconGunctivitis• 9ropharyngeal involvement, particularly buccal mucosa and tongue

• Encephalitis symptoms, such as seiures, irritability, change in level of attentiveness,

bulging fontanelles• Additional signs of disseminated, severe *+ include Gaundice, hepatomegaly, and

shoc As noted above, Toxoplasma infection causing encephalitis is found in immune-suppressedpatients. #hey ehibit significant encephalopathy with lethargy or personality changes, and ?present may present with focal neuropathology.

Complications

Encephalitis may be associated with a number of complications, including the following1

• eiures

• yndrome of inappropriate secretion of antidiuretic hormone (!A*)

• !ncreased intracranial pressure (!"7)

• "oma

ifferential iagnoses

• 2rain Abscess

• "atscratch isease

• *erpes imple

• *erpes imple Encephalitis

• *ypoglycemia

• 5eptospirosis in *umans

• 8eningitis

• 7ediatrics, 8eningitis and Encephalitis

• tatus Epilepticus

• ubarachnoid *emorrhage

• ystemic 5upus Erythematosus

• #ic-2orne iseases, 5yme

• #ic-2orne iseases, 3ocy 8ountain potted Fever

http://emedicine.medscape.com/article/781021-overviewhttp://emedicine.medscape.com/article/781320-overviewhttp://emedicine.medscape.com/article/783113-overviewhttp://emedicine.medscape.com/article/1165183-overviewhttp://emedicine.medscape.com/article/767359-overviewhttp://emedicine.medscape.com/article/788751-overviewhttp://emedicine.medscape.com/article/232915-overviewhttp://emedicine.medscape.com/article/802760-overviewhttp://emedicine.medscape.com/article/1164462-overviewhttp://emedicine.medscape.com/article/794076-overviewhttp://emedicine.medscape.com/article/332244-overviewhttp://emedicine.medscape.com/article/786767-overviewhttp://emedicine.medscape.com/article/785659-overviewhttp://emedicine.medscape.com/article/781021-overviewhttp://emedicine.medscape.com/article/781320-overviewhttp://emedicine.medscape.com/article/783113-overviewhttp://emedicine.medscape.com/article/1165183-overviewhttp://emedicine.medscape.com/article/767359-overviewhttp://emedicine.medscape.com/article/788751-overviewhttp://emedicine.medscape.com/article/232915-overviewhttp://emedicine.medscape.com/article/802760-overviewhttp://emedicine.medscape.com/article/1164462-overviewhttp://emedicine.medscape.com/article/794076-overviewhttp://emedicine.medscape.com/article/332244-overviewhttp://emedicine.medscape.com/article/786767-overviewhttp://emedicine.medscape.com/article/785659-overview


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*erpes simple virus (*+) cultures of suspicious lesions and a #anc smear should be

obtained. +iral cultures of "F, including *+, should be performed, although the incidence of

the latter being positive is rare. 2lood cultures for bacterial pathogens should be obtained.

"omplement fiation antibodies are useful in identifying arbovirus. "ross-reactivity eists among

a subgroup of arboviruses, the flaviviruses (eg, viruses that cause t 5ouis encephalitis,4apanese virus encephalitis ;4E=, and 6est 0ile encephalitis ;60E=), and the antibodies found

in persons inoculated with yellow fever vaccine.

*eterophile antibody and cold agglutinin testing for Epstein-2arr virus (E2+) may be helpful.

erologic tests for tooplasmosis can be helpful in light of an abnormal computed tomography

("#) scan, particularly in the case of single lesions. *owever, the overlap in titer levels between

eposed but currently uninfected and reactivated groups may complicate interpretation.

"omputed #omography, 8agnetic 3esonance !maging, and

Electroencephalography

7erformance of a head "# scan with and without contrast agent should be performed in virtually

all patients with encephalitis. #his should be done prior to 57 if there are focal complaints or

findings, signs to search for evidence of elevated intracranial pressure (!"7), obstructive

hydrocephalus, or mass effect due to focal brain infection. *ead "# scanning also helps

eclude brain hemorrhage or infarction as a cause of an encephalopathic state. 8agnetic

resonance imaging (83!) is more sensitive than "# scanning in demonstrating brain

abnormalities earlier in the disease course.

!n *E, 83! may show several foci of increased #% signal intensity in medial temporal lobes

and inferior frontal gray matter. *ead "# commonly shows areas of edema or petechial

hemorrhage in the same areas. EEE and tic-borne encephalitis may show similar increased

83! signal intensity in the basal ganglia and thalamus.

!n tooplasmosis, contrast-enhanced head "# typically reveals several nodular or ring-

enhancing lesions. 2ecause lesions may be missed without contrast, 83! should be performed

in patients for whom use of contrast material is contraindicated.

!n *E, electroencephalography (EEI) often documents characteristic paroysmal lateral

epileptiform discharges (75Es), even before neuroradiography changes. Eventually, 75Esare positive in H&? of cases> however, the presence of 75Es is not pathognomonic for *E.

Analysis of "erebrospinal Fluid

#he most important diagnostic test in the emergency department (E) to rule out bacterial

meningitis is prompt Iram staining and, if available, polymerase chain reaction (7"3) of the

"F in patients with suspected *+ encephalitis. 7"3 for *+ 0A is $&&? specific and -


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KH? sensitive within the first %- hours. #ypes $ and % cross-react, but no cross-reactivity

with other herpes viruses occurs. Arguably, a series of quantitative 7"3s documenting the

decline of viral load with acyclovir treatment is strongly supportive of the diagnosis of *+, and

selected patients my avoid need for brain biopsy.

2rain 2iopsy

Although most histologic features are nonspecific, brain biopsy is the criterion standard because

of its K:? sensitivity and $&&? specificity.

#he presence of 0egri bodies in the hippocampus and cerebellum are pathognomonic of rabies,

as are *+ "owdry type A inclusions with hemorrhagic necrosis in the temporal and

orbitofrontal lobes.

Emergency epartment "are

6ith the important eceptions of *E and varicella-oster encephalitis, the viral encephalitides

are not treatable beyond supportive care. #reatments for T gondii and cytomegalovirus ("8+)

encephalitis are available but generally not initiated in the E.

#he goal of treatment for acutely ill patients is administration of the first dose or doses of

acyclovir, with or without antibiotics or steroids, as quicly as possible. #he standard for acute

bacterial meningitis is the initiation of treatment within


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!ntraventricular !"7 monitoring is controversial. ome authorities believe that dangerous focal

edema with a pressure gradient between the temporal lobe and the subtentorial space usually is

not detected by the monitor and that this failure of detection can lead to a false sense of

security. !n fact, monitor placement may potentially aggravate a pressure gradient.

"reatment of systemic complications

5oo for and treat systemic complications (eg, hypotension or shoc, hypoemia, hyponatremia,

and eacerbation of chronic diseases), particularly in herpes simple encephalitis (*E),

eastern equine encephalitis (EEE), 4apanese virus encephalitis (4E).

Empiric treatment of HS# meningoencephalitis and #$# encephalitis

Empiric adult emergency treatment for herpes simple virus (*+) meningoencephalitis and

varicella-oster virus (++) encephalitis consists of acyclovir $& mg/g (infused over $ h) qHh

for $-%$ days. Iive acyclovir $&-$ mg/g !+ qHh for neonatal *+> for *+ encephalitis in thepediatric population, give acyclovir $& mg/g !+ qHh.

!n *!+-positive patients, consider foscarnet, given the increased incidence of acyclovir-resistant

*+ and herpes oster virus (*+).

Approach "onsiderations

Prehospital care

!n the prehospital setting, evaluate and treat for shoc or hypotension. Administer crystalloidinfusion in patients with evidence of circulatory compromise. "onsider airway protection in

patients with an altered mental status. eiure precautions are indicated. #reat seiures

according to usual protocols (ie, loraepam &.$ mg/g given intravenously ;!+=). All patients

should receive oygen and have intravenous access secured en route to the emergency

department (E).


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Pediatric Meningitis and Encephalitis

2acground

espite advances in antimicrobial and general supportive therapies, central nervous system("0) infections remain a significant cause of morbidity and mortality in children. As classical

signs and symptoms often are not present, especially in the younger children, diagnosing "0

infections is a challenge to the emergency department. Also, even for children who have had

prompt diagnosis and treatment, a high frequency of neurologic sequelae remains. #his often

leads to legal action. #he emergency clinician is faced with the daunting tas of separating out

those few children with "0 infections from the vast maGority of children who come to the E

with less serious infections.

7athophysiology

#o develop bacterial meningitis, the invading organism must gain access to the subarachnoid

space. #his is usually via hematogenous spread from the upper respiratory tract where the initial

coloniation has occurred. 5ess frequently, there is direct spread from a contiguous focus (eg,

sinusitis, mastoiditis, otitis media) or through an inGury, such as a sull fracture.

#he most common causative organisms in the first month of life are Escherichia coli and group

2 streptococci. Listeria monocytogenes infection also occurs in patients in this age range and

accounts for -$&? of cases. Neisseria meningitidisinfections occurring in the first month of life

have been reported. From


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Salmonella meningitis should be suspected in any child with this organism grown at any other

site in an unwell child or one younger than : months. 8others nown to be infected

with Salmonella during pregnancy may put their child at ris. As therapy is different

for Salmonella meningitis, while rare, it must be considered in the above situations.

#he bacteremic phase allows penetration of the cerebrospinal fluid ("F) through the choroidpleus. #he "F is poorly equipped to control infection because type-specific antibodies do not

penetrate the blood brain barrier well and complement components are absent or in low

concentrations.

#he cell walls of both gram-positive and gram-negative bacteria contain potent triggers of the

inflammatory response. !n the gram-positive bacteria, teichoic acid is considered the maGor

pathogenic component. !n gram-negative bacteria, lipopolysaccharide or endotoin is the maGor

pathogenic component. #hese components are released in the "F during bacterial growth and

especially with the lysis of bacterial cells. Antibiotic therapy causes a significant release of the

mediators of the inflammatory response.

#he mediators of the inflammatory response include cytoines (tumor necrosis factor, interleuin

$, :, H, $&), platelet activating factor, nitric oide, prostaglandins, and leuotrienes. #hese

mediators cause disruption of the blood brain barrier, vasodilation, neuronal toicity, meningeal

inflammation, platelet aggregation, and activation of leuocytes. #he capillary endothelial cell is

the main site of inGury in bacterial meningitis> thus, it is a vasculitis, which results in destruction

of vascular integrity. #he ultimate consequences are damage to the blood brain barrier, brain

edema, impaired cerebral blood flow, and neuronal inGury.

2ecause of the damage done by the bodyLs response to the infection, various anti-inflammatory

agents have been used in an attempt to decrease the morbidity and mortality of bacterialmeningitis. 9nly deamethasone occasionally has been proven effective.

+iral meningitis or aseptic meningitis is the most common infection of the "0. !t most

frequently occurs in children younger than $ year. Enterovirus is the most common causative

agent and is a frequent cause of febrile illnesses in children. 9ther viral pathogens include

paramyoviruses, herpes, influena, rubella, and adenovirus. 8eningitis may occur in up to half

of children younger than < months with enteroviral infection. Enteroviral infection can occur any

time during the year but is associated with epidemics in the summer and fall. +iral infection

causes an inflammatory response but to a lesser degree than bacterial infection. amage from

viral meningitis may be due to an associated encephalitis and increased intracranial pressure.

Fungal meningitis is rare but may occur in immunocompromised patients> children with cancer,

previous neurosurgery, or cranial trauma> or premature infants with low birth rates. 8ost cases

are in children who are receiving antibiotic therapy and, thus, usually are inpatients.

#he etiology of aseptic meningitis caused by drugs is not well understood. #his form of

meningitis is infrequent in the pediatric population.

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A similar effect occurs with the advent of pneumonococcal vaccine. #his is true for the

pneumococcal polysaccharide vaccines conGugated to various proteins. Iiven at ages %, , and

: months, this vaccine has reduced invasive disease more than K&?. Age groups most affected

are those younger than age % years and those aged %- years. #his was proven in a

surveillance study in 5ouisville, Jentucy.;$=0early half of those with pneumococcal disease are

caused by nonvaccine serotypes.;%,


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o 'p to


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• 8eningismus and a bulging fontanel may be observed but are not needed for

diagnosis.• A child who is quiet at rest but who cries when moved or comforted may have

meningeal irritation (paradoical irritability).• After age < months, the child may display symptoms more often associated with

bacterial meningitis, with fever, vomiting, irritability, lethargy, or any change in behavior.• After age %-< years, children may complain of headache, stiff nec, and

photophobia.• #he clinical course may be brief and fulminant with rapid progression of

symptoms or may follow a more gradual course with several days of upper respiratoryinfection progressing to more severe symptoms. #he fulminant course is more oftenassociated with N meningitidis infection.

• +iral meningitis

• !n areas with widespread vaccination of children, enteroviruses are the most

common causes of viral meningitis. #he onset is variable and may have several days of fever,anoreia, and general malaise. !t also may present as a rather abrupt onset of fever, nausea,vomiting, and headache.

• Additional symptoms are shared with enteroviral infections, such as pharyngitis,

conGunctivitis, and myositis.• 9ther causes of viral meningitis also may be associated with encephalitis.

Arboviral infections frequently have associated encephalitis and seiures.• Adenoviral, mumps, and varicella-oster infections tend to be more severe than

enteroviral infections, and often evidence of encephalitis is present.• !n areas with low vaccination rates, mumps virus is often the most frequent cause

of meningitis.• Fungal meningitis occurs in immunocompromised patients and has a variable

presentation.• Aseptic meningitis may be caused by drugs, usually nonsteroidal anti-inflammatory

drugs (0A!s), !+!I, and antibiotics. A recent report was of a pediatric patient with a

trimethoprim-sulfamethoaoleNinduced meningitis. ymptoms were similar to those of viralmeningitis. ymptoms may occur within minutes of ingestion of the drug.• Encephalitis

• iagnosis for the causative viral agent is aided by historical facts. !nformation

such as season of year, travel, activities, and eposure to animals helps with diagnosis.• A distinction between viral encephalitis and postinfectious encephalomyelitis is

important because management and prognosis are different. 6ith postinfectiousencephalomyelitis, the usual presentation is a nonspecific respiratory viral syndrome.

Physical

7hysical eamination findings are widely variable based on age and infecting organism. !t isimportant to remember that the younger the child, the less specific the symptoms.

• !n the young infant findings that definitely point to meningitis are rare.o #he infant may be febrile or hypothermic.

o 2ulging of the fontanel, diastasis of the sutures, and nuchal rigidity point to

meningitis but are usually late findings.• As the child grows older, the physical eamination becomes more reliable.

o 8eningeal signs (eg, headache, nuchal rigidity, positive Jernig and 2rudinsi

signs) should be sought, and their presence or absence recorded.


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o A definitive diagnosis of meningitis requires eamination of "F vialumbar

puncture. 7resence or absence of classic meningeal signs and symptoms should not beused as the sole criteria for referring patients for further diagnostic testing.;H=

o Focal neurological signs may be present in up to $? of patients and are

associated with a worse prognosis.o eiures occur in up to proimal muscle weaness> and flaccid paralysis. #his rash is commonlyfound in children.

o "ritically ill patients have neurological dysfunction, such as altered mental status

and cranial nerve dysfunction, as the maGor physical finding.

http://emedicine.medscape.com/article/80773-overviewhttp://emedicine.medscape.com/article/80773-overviewhttp://emedicine.medscape.com/article/80773-overviewhttp://emedicine.medscape.com/article/80773-overview


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Herpes Simplex EncephalitisBackground

espite advances in antiviral therapy over the past % decades, herpes simpleencephalitis (*E) remains a serious illness with significant riss of morbidity and

death.;$, %, rarely, it presents as encephalitis, possibly bydirect transmission through peripheral nerves to the central nervous system ("0). #hisencephalitis is a neurologic emergency and the most important neurologic sequela of*+.

7athophysiology

#he pathogenesis of *E in humans is poorly understood. 0eurons are quicly

overwhelmed by a lytic and hemorrhagic process distributed in an asymmetric fashion

throughout the medial temporal and inferior frontal lobes. 6asay et al reported temporal

lobe involvement in :&? of patients.;= Fifty-five percent of patients demonstrated

temporal and etratemporal pathology, and $? of patients demonstrated etratemporal

pathology eclusively. !nvolvement of the basal ganglia, cerebellum, and brainstem is

uncommon.

#he eact mechanism of cellular damage is unclear, but it may involve both direct virus-

mediated and indirect immune-mediated processes. #he ability of *+-$ to induceapoptosis (programmed cell death, or Ocellular suicideP) in neuronal cells, a property not

shared by *+-%, might eplain why the former causes virtually all cases of herpes

simple encephalitis in immunocompetent older children and adults.;, :=

A vivid description of the temporal course of tissue destruction is given in an

immunohistologic autopsy study of patients succumbing to *E over periods of days to

http://emedicine.medscape.com/article/1168529-overviewhttp://emedicine.medscape.com/article/1168529-overview


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wees in the era prior to acyclovir1 #he impression is of a rapidly spreading wave of viral

infection within limbic structures, probably starting on one side of the brain and

spreading within it and to the other side, lasting about < wees and resulting in severe

necrosis and inflammation in infected parts of the brain. ;=

2rain infection is thought to occur by means of direct neuronal transmission of the virus

from a peripheral site to the brain via the trigeminal or olfactory nerve. Factors that

precipitate *E are unnown. #he prevalence of *E is not increased in

immunocompromised hosts, but the presentation may be subacute or atypical in these

patients. *+-% may cause *E in patients with *!+-A!. ;H, K, $&=

*E represents a primary *+ infection in about one third of cases> the remaining

cases occur in patients with serologic evidence of preeisting *+ infection and are due

to reactivation of a latent peripheral infection in the olfactory bulb or trigeminal ganglion

or to reactivation of a latent infection in the brain itself. A substantial number of

neurologically asymptomatic individuals may have latent *+ in the brain. !n a

postmortem study, *+ was present in the brains of it is responsible for virtually all cases in persons older than < months.

*+-%, or **+-%, is responsible for a small number of cases, particularly in

immunocompromised hosts.

*+-$ causes oral lesions (so-called fever blisters)> these are common and may

respond to antiviral medications, though they spontaneously remit in most cases. *+-%

causes genital lesions. !t was previously thought to appear within $-% wees of primaryinfection, then to recur with lessening severity. #hat lesions may appear clinically at any

interval after primary infection is now nown. *+-% may be treated with antiviral

medications.

!n adults, the host immune response, combined with viral factors, determines

invasiveness and virulence. 8itchell et al showed that the invasiveness of *+-$


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glycoprotein variants is controlled by the host response. ;$%= Ieiger et al used interferon-

gammaNnocout mice to show how interferon-gamma protected against *+-$N

mediated neuronal death.;$


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Age-+ sex-+ and race-related demographics

*E has a bimodal distribution by age, with the first pea occurring in those younger

than %& years and a second occurring in those older than & years. *E in younger

patients usually represents primary infection, whereas *E in older persons typically

reflects reactivation of latent infection. 9ne third of *E cases occur in children.

*erpes affects both sees equally, though genital herpes may be more apparent in the

male because of anatomy. 0o racial predilection eists.

Prognosis

'ntreated *E is progressive and often fatal in -$ days. A landmar study by 6hitleyet al in $K revealed a &? mortality in untreated patients and severe neurologicdeficits in most of the survivors.;$=

8ortality in patients treated with acyclovir was $K? in the trials that established itssuperiority to vidarabine. ubsequent trials reported lower mortalities (:-$$?), perhapsbecause they included patients who were diagnosed by polymerase chain reaction(7"3) rather than brain biopsy and who thus may have been identified earlier withmilder disease.;$, :? in patients withisolated *E and


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helley and colleagues reported a case of intracerebral hematoma occurring in apatient successfully treated with a full course of acyclovir after apparent eradication ofthe virus. #he hematoma occurred in the region of the encephalitis. ;%&=

8arschit and colleagues reported a case of chorea after *E. ;%$=

3elapses after *E have been reported to occur in -%:? of patients, with mostrelapses occurring within the first < months after completion of treatment. 3elapses aremore frequent in children than adults. !t is unclear whether such relapses representrecurrence of viral infection or an immune-mediated inflammatory process. ome of therelapses reported in earlier studies may have been due to inadequate duration oftreatment rather than true recurrences of *E.

A long-term follow-up study of patients with *E suggested that the pathogenicmechanisms present during relapses differ from those present during the initialinfection.;%%= erial measurements of inflammatory marers as well as *+ viral load inthe "F of relapsing patients demonstrated increased inflammatory marers without

detectable *+ during relapses. #hese findings suggest that immune-mediated events,rather than direct viral-mediated neuronal toicity, may predominate in relapses.

History

*erpes simple encephalitis (*E) is an acute or subacute illness that causes bothgeneral and focal signs of cerebral dysfunction. !t is sporadic and occurs without aseasonal pattern. Although the presence of fever, headache, behavioral changes,confusion, focal neurologic findings, and abnormal cerebrospinal fluid ("F) findingsare suggestive of *E, no pathognomonic clinical findings reliably distinguish *E fromother neurologic disorders with similar presentations (see 6orup). ;%


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#he initial presentation may be mild or atypical in immunocompromised patients (eg,those with *!+ infection or those receiving steroid therapy).

Physical Examination

#he most frequent findings on physical eamination are fever and mental status

abnormalities. 8eningeal signs may be present, but meningismus is uncommon.

#ypical findings on presentation include the following ;%= 1

• Alteration of consciousness (K?)

• Fever (K%?)

• ysphasia (:?)

• Ataia (&?)

• eiures ( generalied ($&?)

• *emiparesis (


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Even in treated cases of *E, complications and sequelae (both focal and global) are

not uncommon. !f treatment of *E is delayed, permanent neurologic deficits may

develop in survivors.

"ommon sequelae among survivors include motor deficits, seiure disorders, and

changes in mental status. "ognitive and memory deficits are particularly common. o

too are recurrent seiures> some authorities recommend prophylactic treatment with

anticonvulsant drugs in patients with severe *E.

!n addition, patients with *E are subGect to the same complications as any other

seriously ill and immobilied patients with depressed levels of consciousness (eg,

aspiration, deep venous thrombosis, decubitus ulcers).

iagnostic Considerations

•

8yoclonus• 8anagement of increased intracranial pressure (!"7) in the neuro intensive care

unit (!"')

• 8anagement of intracranial hemorrhage (!"*) in the neuro !"'

• Electroencephalography (EEI) in coma

• !ncreased !"7

• 0euro-2ehQet disease

ifferential iagnoses

• Acute isseminated Encephalomyelitis

• Aphasia

• Aseptic 8eningitis

• 2enign "hildhood Epilepsy

• 2enign 0eonatal "onvulsions

• "hildhood 8igraine +ariants

• "omple 7artial eiures

• "onfusional tates and Acute 8emory isorders

• issection yndromes

• Early 8yoclonic Encephalopathy

• EEI in "ommon Epilepsy yndromes

• EEI in ementia and Encephalopathy

• EEI in tatus Epilepticus

• Epileptiform ischarges

• Frontal 5obe Epilepsy

• Frontal 5obe yndromes

• Ieneralied EEI 6aveform Abnormalities

• *aemophilus 8eningitis

http://emedicine.medscape.com/article/1147044-overviewhttp://emedicine.medscape.com/article/1135944-overviewhttp://emedicine.medscape.com/article/1169489-overviewhttp://emedicine.medscape.com/article/1181649-overviewhttp://emedicine.medscape.com/article/1175719-overviewhttp://emedicine.medscape.com/article/1178141-overviewhttp://emedicine.medscape.com/article/1183962-overviewhttp://emedicine.medscape.com/article/1135767-overviewhttp://emedicine.medscape.com/article/1160482-overviewhttp://emedicine.medscape.com/article/1176055-overviewhttp://emedicine.medscape.com/article/1138154-overviewhttp://emedicine.medscape.com/article/1138235-overviewhttp://emedicine.medscape.com/article/1138728-overviewhttp://emedicine.medscape.com/article/1138880-overviewhttp://emedicine.medscape.com/article/1184076-overviewhttp://emedicine.medscape.com/article/1135866-overviewhttp://emedicine.medscape.com/article/1140075-overviewhttp://emedicine.medscape.com/article/1164916-overviewhttp://emedicine.medscape.com/article/1147044-overviewhttp://emedicine.medscape.com/article/1135944-overviewhttp://emedicine.medscape.com/article/1169489-overviewhttp://emedicine.medscape.com/article/1181649-overviewhttp://emedicine.medscape.com/article/1175719-overviewhttp://emedicine.medscape.com/article/1178141-overviewhttp://emedicine.medscape.com/article/1183962-overviewhttp://emedicine.medscape.com/article/1135767-overviewhttp://emedicine.medscape.com/article/1160482-overviewhttp://emedicine.medscape.com/article/1176055-overviewhttp://emedicine.medscape.com/article/1138154-overviewhttp://emedicine.medscape.com/article/1138235-overviewhttp://emedicine.medscape.com/article/1138728-overviewhttp://emedicine.medscape.com/article/1138880-overviewhttp://emedicine.medscape.com/article/1184076-overviewhttp://emedicine.medscape.com/article/1135866-overviewhttp://emedicine.medscape.com/article/1140075-overviewhttp://emedicine.medscape.com/article/1164916-overview


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• *!+-$ Associated "0 "omplications (9verview)

• !ntracranial Epidural Abscess

• !ntracranial *emorrhage

• 5enno-Iastaut yndrome

• 5eptomeningeal "arcinomatosis

• 8igraine *eadache

• 8igraine *eadache1 7ediatric 7erspective

• 8igraine +ariants

• 0eurosyphilis

• 7araneoplastic Encephalomyelitis

• eiures and Epilepsy1 9verview and "lassification

• imple 7artial eiures

• tatus Epilepticus

• #emporal 5obe Epilepsy


!n suspected herpes simple encephalitis (*E), the worup must be initiated rapidly

and should not delay treatment. Ieneral laboratory studies are not helpful in diagnosis

but may show evidence of infection or detect renal disease (in which case treatment

must be adGusted). A high inde of suspicion is required in all immunocompromised

patients with febrile encephalopathy.

0o pathognomonic clinical findings are associated with *E. Focal neurologic deficits,

cerebrospinal fluid ("F) pleocytosis, and abnormalities on computed tomography ("#)scanning may be absent initially. #he diagnosis can be confirmed only by means of

polymerase chain reaction (7"3) or brain biopsy.

iagnostic modalities for neonatal *E are similar to those for *E in older children

and adults.

!agnetic )esonance Imaging

8agnetic resonance imaging (83!) of the brain is the preferred imaging study. 7roton-density and #% images may be more helpful than #$ images. 83! can noninvasively

establish many of the potential alternative diagnoses of *E.

Abnormalities are found in K&? of patients with *E> 83! may be normal early in thecourse of illness. #emporal lobe involvement (see the images below), sometimeshemorrhagic, and early involvement of white matter are typical. #he inferomedial portionof the temporal lobe is most commonly affected on 83!, sometimes in association withabnormalities of the cingulate gyrus.

http://emedicine.medscape.com/article/1167008-overviewhttp://emedicine.medscape.com/article/1165292-overviewhttp://emedicine.medscape.com/article/1163977-overviewhttp://emedicine.medscape.com/article/1176735-overviewhttp://emedicine.medscape.com/article/341389-overviewhttp://emedicine.medscape.com/article/1142556-overviewhttp://emedicine.medscape.com/article/1179268-overviewhttp://emedicine.medscape.com/article/1142731-overviewhttp://emedicine.medscape.com/article/1169231-overviewhttp://emedicine.medscape.com/article/1157060-overviewhttp://emedicine.medscape.com/article/1184846-overviewhttp://emedicine.medscape.com/article/1184384-overviewhttp://emedicine.medscape.com/article/908394-overviewhttp://emedicine.medscape.com/article/1184509-overviewhttp://emedicine.medscape.com/article/1167008-overviewhttp://emedicine.medscape.com/article/1165292-overviewhttp://emedicine.medscape.com/article/1163977-overviewhttp://emedicine.medscape.com/article/1176735-overviewhttp://emedicine.medscape.com/article/341389-overviewhttp://emedicine.medscape.com/article/1142556-overviewhttp://emedicine.medscape.com/article/1179268-overviewhttp://emedicine.medscape.com/article/1142731-overviewhttp://emedicine.medscape.com/article/1169231-overviewhttp://emedicine.medscape.com/article/1157060-overviewhttp://emedicine.medscape.com/article/1184846-overviewhttp://emedicine.medscape.com/article/1184384-overviewhttp://emedicine.medscape.com/article/908394-overviewhttp://emedicine.medscape.com/article/1184509-overview


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Aial proton density-weighted image in :%-year-old woman with confusionand herpes encephalitis shows #% hyperintensity involving right temporal lobe.

Aial gadolinium-enhanced #$-weighted image reveals enhancement of right anterior temporal lobe and parahippocampal gyrus. At right anterior temporal tip is hypointense,crescentic region surrounded by enhancement consistent with small epidural abscess.

Aial diffusion-weighted image reveals restricted diffusion in left medialtemporal lobe consistent with herpes encephalitis. #his patient also had positive result onpolymerase chain reaction assay for herpes simple virus, which is both sensitive and specific. !naddition, patient had periodic lateralied epileptiform discharges on electroencephalography, which

supports diagnosis of herpes encephalitis.Findings of localied temporal abnormalities are highly suggestive of *E, but again,confirmation of the diagnosis depends on the identification of herpes simple virus(*+) by means of 7"3 or brain biopsy.

"omputed #omography


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Approimately one third of patients with *E have normal "# findings on presentation.

*ead "# may show changes in the temporal and/or frontal lobe, but "# is less sensitive

than 83!.

5ow-density lesions may be found in two thirds of cases, especially in the temporal

lobes, but they may not appear until an adequate volume of "F should be obtained (D$& m5).

Acutely, a typical Oviral profileP is identified. 3ed blood cells (32"s) and anthochromia

may be seen. 7atients typically have mononuclear pleocytosis of $&-&& white blood

cells (62"s)/R5 (average, $&& 62"s/R5). As a result of the hemorrhagic nature of the

underlying pathologic process, the 32" count may be elevated ($&-&&/R5). 7rotein

levels are elevated to the range of :&-&& mg/d5 (average, $&& mg/d5). Ilucose values

may be normal or mildly decreased (


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"F should be sent for *+-$ and *+-% polymerase chain reaction (7"3) study. 7"3

analysis of "F for the detection of *+ 0A has virtually replaced brain biopsy as the

criterion standard for diagnosis.;


29/35

9rbitofrontal or limbic encephalitis may be seen. 9ne hallmar of the condition is

significant hemorrhage in these locations. 9n pathology specimens, "owdry A

inclusions are seen.

9ther #ests

Serologic analysis

erologic evaluation of blood or "F may be useful for retrospective diagnosis, but it

has no role in the acute diagnosis and treatment of patients.

trategies based on increases in antibody levels and on the ratio of antibody levels in

serum and "F have not proven to be clinically useful.

",anck preparations

*+ can sometimes be confirmed by #anc preparations taen from vesicular lesions

in neonates with herpes simple encephalitis.

uantification of intrathecal anti(odies

!ntrathecal antibodies can be quantified, thus giving evidence for a central nervous

system ("0) antibody response.


A high inde of suspicion is required to mae the diagnosis of herpes simple

encephalitis (*E), and epeditious evaluation is indicated after the diagnosis is

considered. !n the absence of any other identifiable cause, consider *E in any febrile

patient with encephalopathy and "F pleocytosis. tart empiric acyclovir therapy

promptly in patients with suspected *E pending confirmation of the diagnosis because

acyclovir, the drug of choice, is relatively nontoic and because the prognosis for

untreated *E is poor.

Failure to consider the possibility of *E can result in delayed diagnosis and treatment,

with subsequent increased riss of mortality and morbidity. A single-center study from a

high-volume academic emergency department (E) reported that only %K? of patients

with a presentation suggestive of viral encephalitis (fever, neuropsychiatric

abnormalities, cerebrospinal fluid ;"F= pleocytosis, and a negative "F Iram stain)

received acyclovir in the E.;


30/35

!nitial 8anagement

7rehospital care consists of supportive management of the patientBs airway, breathing,

and circulation (A2"s). Ieneral nutritional and fluid support is important. 'niversal

precautions are appropriate. 8onitor for increased intracranial pressure (!"7) and

seiures.

!ntensive care unit (!"') care may be required, especially if seiure activity or increased

!"7 is present. epending on the availability of local epertise (eg, infectious disease,

neurology, neurosurgery specialists), transfer to a tertiary care facility may be

appropriate. *ospitaliation is not routine for uncomplicated herpes simple virus type $

(*+-$) or herpes simple virus type % (*+-%) infection.

!anagement of increased intracranial pressure

#reatment of brain edema ranges from simple measures (eg, elevating head of bed,

gentle diuresis with medication such as furosemide) to more comple measures (eg,

mannitol and steroids, intubation with hyperventilation).

!anagement of sei,ures

2ehavioral manifestations of *E may resemble seiures, which are also common.

hould seiure activity become apparent or should electroencephalography (EEI)

show evidence of nonconvulsive seiures, begin anticonvulsant therapy.

2enodiaepines may be useful for aborting status epilepticus but, because of their

short duration, are ineffective at preventing further seiures. A longer-acting agent is

preferable.

Antiviral #herapy

7harmacotherapy for *E is available in the form of acyclovir. 7atient outcome is

improved after treatment with this agent. Acyclovir is the treatment of choice for *E. ;$,


31/35

Acyclovir has relatively few serious adverse effects. 2ecause of its high p*, !+ acyclovir

may cause phlebitis and local inflammation if etravasation occurs. Iastrointestinal (I!)

disturbances, headache, and rash are among the more frequent adverse reactions.

#he drug is ecreted by the idney, and the dose should be reduced in patients with

renal dysfunction. "rystal-induced nephropathy may occur if the maimum solubility of

free drug is eceeded. 3is factors for this are !+ administration, rapid infusion,

dehydration, concurrent use of nephrotoic drugs, underlying renal disease, and high

doses. #he ris of renal toicity is reduced by adequately hydrating the patient (eg, $

m5/d of fluid for each $ mg/d of acyclovir).

Acyclovir is considered appropriate for serious infections during pregnancy. #he

manufacturer cautions that it should be used in pregnancy only when the potential

benefits outweigh the potential riss. *owever, a prospective registry of acyclovir use in

pregnancy between $KH and $KKK, including : first-trimester eposures,

demonstrated a


32/35


33/35

suppressive acyclovir therapy near the time of delivery in mothers with a history of

genital herpes.

8edication ummary

#he goals of therapy are to reduce morbidity, to shorten the clinical course of the

disease, to prevent complications, and to prevent recurrences. 7harmacotherapy for

herpes simple encephalitis (*E) is available in the form of acyclovir. 7atient outcome

is improved when this agent is used for treatment.

Antivirals

Class Summary

#he goals of using antivirals are to shorten the clinical course, prevent complications,prevent development of latency and subsequent recurrences, decrease transmission,

and eliminate established latency.

+iew full drug information

Acyclo.ir /$o.irax0

Acyclovir is the drug of choice for *E. !t has demonstrated inhibitory activity against

both herpes simple virus type $ (*+-$) and herpes simple virus type % (*+-%) and

is taen up selectively by infected cells. 8ortality from *E before use of acyclovir was:&-&?> since acyclovir, it is approimately it appears to act by

reducing polysynaptic responses and blocing posttetanic potentiation.

http://reference.medscape.com/drug/zovirax-acyclovir-342601http://reference.medscape.com/drug/zovirax-acyclovir-342601http://reference.medscape.com/drug/tegretol-xr-equetro-carbamazepine-343005http://reference.medscape.com/drug/tegretol-xr-equetro-carbamazepine-343005http://reference.medscape.com/drug/zovirax-acyclovir-342601http://reference.medscape.com/drug/zovirax-acyclovir-342601http://reference.medscape.com/drug/tegretol-xr-equetro-carbamazepine-343005http://reference.medscape.com/drug/tegretol-xr-equetro-carbamazepine-343005


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Phenytoin /ilantin+ Phenytek0

7henytoin is a hydantoin. !ts primary site of action appears to be the motor corte,

where it may inhibit spread of seiure activity> it may reduce maimal activity of the

brain stem centers responsible for the tonic phase of grand mal seiures.

#he dose should be individualied> if daily dosage cannot be divided equally, larger

dose should be given before bedtime. A phosphorylated formulation, fosphenytoin, is

available for parenteral use.

iuretics

Class Summary

#hese agents are used for the management of increased intracranial pressure in

complications resulting from herpes simple encephalitis.


%urosemide /1asix0

Furosemide is a loop diuretic that increases the ecretion of water by interfering with the

chloride-binding co-transport system, which, in turn, inhibits sodium and chloridereabsorption in the ascending loop of *enle and distal renal tubule. !t increases renal

blood flow without increasing the filtration rate. #he onset of action generally is within $

hour. !t increases potassium, sodium, calcium, and magnesium ecretion.

Furosemide is used in the acute setting for reduction of increased !"7. #he proposed

mechanisms in lowering !"7 include following1 ($) suppression of cerebral sodium

uptae, (%) carbonic anhydrase inhibition resulting in decreased "F production, and

(


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!annitol /2smitrol0

8annitol reduces cerebral edema with the help of osmotic forces, and it decreases

blood viscosity, resulting in refle vasoconstriction and lowering of !"7.
http://reference.medscape.com/drug/osmitrol-mannitol-343061http://reference.medscape.com/drug/osmitrol-mannitol-343061

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