Herpes Simplex Encephalitis

Author: Wayne E Anderson, DO; Chief Editor: Karen L Roos, MD

Background

Despite advances in antiviral therapy over the past 2 decades, herpes simplex

encephalitis (HSE) remains a serious illness with significant risks of morbidity and

death.[1, 2, 3]

Herpes simplex encephalitis occurs as 2 distinct entities:

In children older than 3 months and in adults, HSE is usually localized to the

temporal and frontal lobes and is caused by herpes simplex virus type 1

(HSV-1).

In neonates, however, brain involvement is generalized, and the usual cause is

herpes simplex virus type 2 (HSV-2), which is acquired at the time of

delivery.

Except where otherwise specified, this article describes HSE as it occurs in older

children and adults (as opposed to neonatal HSE). HSE must be distinguished from

herpes simplex meningitis, which is more commonly caused by HSV-2 than by HSV-

1 and which often occurs in association with a concurrent herpetic genital infection.

Like other forms of viral meningitis, herpes simplex meningitis usually has a benign

course and is not discussed in this article.

Patients with HSV may require long-term antiviral treatment if they have recurrent

lesions or if other organ systems are involved (as in herpes simplex keratitis). HSV

remains dormant in the nervous system; rarely, it presents as encephalitis, possibly by

direct transmission through peripheral nerves to the central nervous system (CNS).

This encephalitis is a neurologic emergency and the most important neurologic

sequela of HSV.

Pathophysiology

The pathogenesis of HSE in humans is poorly understood. Neurons are quickly

overwhelmed by a lytic and hemorrhagic process distributed in an asymmetric

fashion throughout the medial temporal and inferior frontal lobes. Wasay et al

reported temporal lobe involvement in 60% of patients.[4]

Fifty-five percent of

patients demonstrated temporal and extratemporal pathology, and 15% of patients

demonstrated extratemporal pathology exclusively. Involvement of the basal ganglia,

cerebellum, and brainstem is uncommon.

The exact mechanism of cellular damage is unclear, but it may involve both direct

virus-mediated and indirect immune-mediated processes. The ability of HSV-1 to

induce apoptosis (programmed cell death, or “cellular suicide”) in neuronal cells, a

property not shared by HSV-2, might explain why the former causes virtually all

cases of herpes simplex encephalitis in immunocompetent older children and adults.[5,

6]

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

immunohistologic autopsy study of patients succumbing to HSE over periods of days

to weeks in the era prior to acyclovir: The 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 3 weeks and resulting in

severe necrosis and inflammation in infected parts of the brain.[7]

Brain 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 HSE are unknown. The prevalence of HSE is not increased in

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

patients. HSV-2 may cause HSE in patients with HIV-AIDS.[8, 9, 10]

HSE represents a primary HSV infection in about one third of cases; the remaining

cases occur in patients with serologic evidence of preexisting HSV 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 HSV in the

brain. In a postmortem study, HSV was present in the brains of 35% of patients with

no evidence of neurologic disease at the time of death.[11]

Neonatal HSE may occur as an isolated CNS infection or as part of disseminated

multiorgan disease.

Etiology

As noted (see Pathophysiology), HSE is caused by HSV, an enveloped, double-

stranded DNA virus. HSV-1 and HSV-2 are both members of the larger human

herpesvirus (HHV) family, which also includes varicella-zoster virus (VZV, or HHV-

3) and cytomegalovirus (CMV, or HHV-5). HSV-1, or HHV-1, is the more common

cause of adult encephalitis; it is responsible for virtually all cases in persons older

than 3 months. HSV-2, or HHV-2, is responsible for a small number of cases,

particularly in immunocompromised hosts.

HSV-1 causes oral lesions (so-called fever blisters); these are common and may

respond to antiviral medications, though they spontaneously remit in most cases.

HSV-2 causes genital lesions. It was previously thought to appear within 1-2 weeks

of primary infection, then to recur with lessening severity. That lesions may appear

clinically at any interval after primary infection is now known. HSV-2 may be treated

with antiviral medications.

In adults, the host immune response, combined with viral factors, determines

invasiveness and virulence. Mitchell et al showed that the invasiveness of HSV-1

glycoprotein variants is controlled by the host response.[12]

Geiger et al used

interferon-gamma–knockout mice to show how interferon-gamma protected against

HSV-1–mediated neuronal death.[13]

These data suggested that the presentation and

severity of encephalitis vary.

Evidence from a European study suggested that socioeconomic status and geography

might affect levels of virus seropositivity. However, clinical correlation is difficult,

because HSE can occur at any time, regardless of the patient’s socioeconomic status,

age, race, or sex.

In children, encephalitis often results from primary infection with HSV.

Approximately 80% of children with HSE do not have a history of labial herpes.

Cathomas et al report a case of HSE as a complication of chemotherapy for breast

cancer.[14]

Neonatal herpes simplex encephalitis

The predominant pathogen is HSV-2 (75% of cases), which is usually acquired by

maternal shedding (frequently asymptomatic) during delivery. A preexisting but

recurrent maternal genital herpes infection results in 8% risk of symptomatic

infection, usually transmitted at the second stage of labor via direct contact. Should

the mother acquire genital herpes during pregnancy, the risk increases to 40%.

The absence of a maternal history of prior genital herpes does not exclude risk; in

80% of cases of neonatal HSE, no maternal history of prior HSV infection is present.

Prolonged rupture of the membranes (>6 h) and intrauterine monitoring (eg,

attachment of scalp electrodes) are risk factors.

Epidemiology

In the United States, HSE is the most common nonepidemic encephalitis and the most

common cause of sporadic lethal encephalitis. Incidence is 2 cases per million

population per year. HSE may occur year-round. HSV-1 is ubiquitous, and HSV-2 is

also common. International incidence is similar to that in the United States.

Age-, sex-, and race-related demographics

HSE has a bimodal distribution by age, with the first peak occurring in those younger

than 20 years and a second occurring in those older than 50 years. HSE in younger

patients usually represents primary infection, whereas HSE in older persons typically

reflects reactivation of latent infection. One third of HSE cases occur in children.

Herpes affects both sexes equally, though genital herpes may be more apparent in the

male because of anatomy. No racial predilection exists.

In about 10% of cases, HSV (often type 1) is acquired post partum by contact with an

individual who is shedding HSV from a fever blister, finger infection, or other

cutaneous lesion.[15, 16]

Presentation - History

Herpes simplex encephalitis (HSE) is an acute or subacute illness that causes both

general and focal signs of cerebral dysfunction. It is sporadic and occurs without a

seasonal pattern. Although the presence of fever, headache, behavioral changes,

confusion, focal neurologic findings, and abnormal cerebrospinal fluid (CSF)

findings are suggestive of HSE, no pathognomonic clinical findings reliably

distinguish HSE from other neurologic disorders with similar presentations (see

Workup).[23]

Patients may have a prodrome of malaise, fever, headache, and nausea, followed by

acute or subacute onset of an encephalopathy whose symptoms include lethargy,

confusion, and delirium. The following are typically the most common symptoms of

HSE[24]

:

Fever (90%)

Headache (81%)

Psychiatric symptoms (71%)

Seizures (67%)

Vomiting (46%)

Focal weakness (33%)

Memory loss (24%)

Signs and symptoms of neonatal HSE develop about 6-12 days after delivery, at

which time lethargy, poor feeding, irritability, tremors, or seizures may be noted.

Those with disseminated disease also have abnormal liver function test results and

thrombocytopenia. In contrast to older patients, neonates often have herpetic skin

lesions.

The initial presentation may be mild or atypical in immunocompromised patients (eg,

those with HIV infection or those receiving steroid therapy).

Physical Examination

The most frequent findings on physical examination are fever and mental status

abnormalities. Meningeal signs may be present, but meningismus is uncommon.

Typical findings on presentation include the following[24]

:

Alteration of consciousness (97%)

Fever (92%)

Dysphasia (76%)

Ataxia (40%)

Seizures (38%) - Focal (28%); generalized (10%)

Hemiparesis (38%)

Cranial nerve defects (32%)

Visual field loss (14%)

Papilledema (14%)

A causal or temporal relationship between peripheral lesions (eg, herpes labialis) and

HSE does not exist. In addition, many febrile diseases may precipitate herpes labialis.

Therefore, the presence or absence of such lesions neither confirms nor excludes the

diagnosis.

Unusual presentations occur. Both herpes simplex virus type 1 (HSV-1) and herpes

simplex virus type 2 (HSV-2) may produce a more subacute encephalitis, apparent

psychiatric syndromes, and benign recurrent meningitis. Less commonly, HSV-1 may

produce a brain stem encephalitis, and HSV-2 may produce a myelitis.

Ku et al discussed the unique presentation of HSE in a bilingual patient, who

developed global aphasia for 1 language (his most recently learned language) but

retained most of his birth language ability.[25]

McGrath et al reported on 4 patients with confirmed HSE, each with an anterior

opercular syndrome, and observed that the syndrome (ie, paralysis of the masticatory,

facial, pharyngeal, and lingual muscles) occurred as the primary manifestation of

HSE in 2 patients and as part of the encephalitis picture in the other 2 patients.[26]

The

authors suggested that unique presentations (eg, anterior opercular syndrome), should

alert the clinician to the possibility of HSE.

Mondal et al reported basal ganglia involvement in a child with HSE, demonstrating

extrapyramidal symptoms.[27]

Li and Sax reported HSE-associated cerebral

hemorrhage in an HIV-positive person.[28]

Approach Considerations

A high index of suspicion is required to make the diagnosis of herpes simplex

encephalitis (HSE), and expeditious evaluation is indicated after the diagnosis is

considered. In the absence of any other identifiable cause, consider HSE in any

febrile patient with encephalopathy and CSF pleocytosis. Start empiric acyclovir

therapy promptly in patients with suspected HSE pending confirmation of the

diagnosis because acyclovir, the drug of choice, is relatively nontoxic and because the

prognosis for untreated HSE is poor.

Failure to consider the possibility of HSE can result in delayed diagnosis and

treatment, with subsequent increased risks of mortality and morbidity. A single-center

study from a high-volume academic emergency department (ED) reported that only

29% of patients with a presentation suggestive of viral encephalitis (fever,

neuropsychiatric abnormalities, cerebrospinal fluid [CSF] pleocytosis, and a negative

CSF Gram stain) received acyclovir in the ED.[37]

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) of the brain is the preferred imaging study.

Proton-density and T2 images may be more helpful than T1 images. MRI can

noninvasively establish many of the potential alternative diagnoses of HSE.

Abnormalities are found in 90% of patients with HSE; MRI may be normal early in

the course of illness. Temporal lobe involvement (see the images below), sometimes

hemorrhagic, and early involvement of white matter are typical. The inferomedial

portion of the temporal lobe is most commonly affected on MRI, sometimes in

association with abnormalities of the cingulate gyrus.

Axial proton density-weighted image in 62-year-old woman with confusion and

herpes encephalitis shows T2 hyperintensity involving right temporal lobe.

Axial gadolinium-enhanced T1-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.

Axial diffusion-weighted image reveals restricted diffusion in left medial temporal

lobe consistent with herpes encephalitis. This patient also had positive result on

polymerase chain reaction assay for herpes simplex virus, which is both sensitive and

specific. In addition, patient had periodic lateralized epileptiform discharges on

electroencephalography, which supports diagnosis of herpes encephalitis.

Findings of localized temporal abnormalities are highly suggestive of HSE, but again,

confirmation of the diagnosis depends on the identification of herpes simplex virus

(HSV) by means of PCR or brain biopsy.

Computed Tomography

Approximately one third of patients with HSE have normal CT findings on

presentation. Head CT may show changes in the temporal and/or frontal lobe, but CT

is less sensitive than MRI.

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

lobes, but they may not appear until 3-4 days after onset. Edema and hemorrhages

may be present. After 1 week, contrast enhancement may be detectable.

Electroencephalography

Electroencephalography (EEG), though lacking in specificity (32%), has 84%

sensitivity to abnormal patterns in HSE. Focal abnormalities (eg, spike and slow- or

periodic sharp-wave patterns over the involved temporal lobes) or diffuse slowing

may be observed.

Periodic complexes and periodic lateralizing epileptiform discharges (PLEDs), in the

proper clinical context, are strongly suggestive of HSE. However, Beneto et al

reported 9 patients with confirmed HSE who had no PLED activity or had other EEG

patterns.[29]

Analysis of Cerebrospinal Fluid

Once a space-occupying lesion has been excluded by imaging, lumbar puncture

always should be performed in suspected HSE. In general, CSF yield is proportional

to the volume analyzed; an adequate volume of CSF should be obtained (>10 mL).

Acutely, a typical “viral profile” is identified. Red blood cells (RBCs) and

xanthochromia may be seen. Patients typically have mononuclear pleocytosis of 10-

500 white blood cells (WBCs)/µL (average, 100 WBCs/µL). As a result of the

hemorrhagic nature of the underlying pathologic process, the RBC count may be

elevated (10-500/µL). Protein levels are elevated to the range of 60-700 mg/dL

(average, 100 mg/dL). Glucose values may be normal or mildly decreased (30-40

mg/dL).

In about 5-10% of patients, especially children, initial CSF results may be normal.[30]

However, on serial examinations, the cell counts and protein values increase.

Viral cultures of CSF are rarely positive and should not be relied on to confirm the

diagnosis. However, HSV can be cultured from the CSF in about one third of affected

neonates.

Polymerase chain reaction

CSF should be sent for HSV-1 and HSV-2 polymerase chain reaction (PCR) study.

PCR analysis of CSF for the detection of HSV DNA has virtually replaced brain

biopsy as the criterion standard for diagnosis.[31, 32]

Schloss and colleagues report that

whereas quantitative PCR is more rational than a nested PCR, the former has little

prognostic use.[33]

PCR is highly sensitive (94-98%) and specific (98-100%). Results become positive

within 24 hours of the onset of symptoms and remain positive for at least 5-7 days

after the start of antiviral therapy.

Clinical severity and outcome appear to correlate with viral load as assessed by

quantitative PCR techniques,[34]

but not all investigators have confirmed this

correlation.[35]

False-negative findings may occur early in the course of the disease when viral DNA

levels are low (within 72 hours of the onset of symptoms) or when blood is present in

the CSF, because hemoglobin may interfere with PCR.[36]

Pretest probability should be considered in interpretation of results. A negative result

obtained less than 72 hours after the onset of symptoms in a patient with a high

pretest probability (on the basis of fever, focal neurologic abnormalities, or CSF

pleocytosis) should be repeated.

False-positive test results are rare and usually reflect accidental contamination of the

specimen in the laboratory.

Brain Biopsy

Brain biopsy was once considered the only definitive means of diagnosing HSE. The

results of brain biopsy can also establish alternative diagnoses, both treatable (eg,

brain tumor) and nontreatable (eg, non-HSV viral encephalitis). Currently, with the

advent of PCR technology, the role of brain biopsy is diminishing. Studies have

demonstrated that PCR testing of CSF is as accurate as brain biopsy in confirming the

diagnosis of HSE.

When the diagnosis of HSE cannot be established by other means (eg, when lumbar

puncture is precluded or nondiagnostic), brain biopsy can yield a definitive diagnosis

and may be considered. However, with the availability of nontoxic and effective

antiviral medications, brain biopsy is rarely used today. The procedure carries a

complication rate of about 3%.

Orbitofrontal or limbic encephalitis may be seen. One hallmark of the condition is

significant hemorrhage in these locations. On pathology specimens, Cowdry A

inclusions are seen.

Serologic analysis

Serologic evaluation of blood or CSF may be useful for retrospective diagnosis, but it

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

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

serum and CSF have not proven to be clinically useful.

Tzanck preparations

HSV can sometimes be confirmed by Tzanck preparations taken from vesicular

lesions in neonates with herpes simplex encephalitis.

Quantification of intrathecal antibodies

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

system (CNS) antibody response.

Approach Considerations

A high index of suspicion is required to make the diagnosis of herpes simplex

encephalitis (HSE), and expeditious evaluation is indicated after the diagnosis is

considered. In the absence of any other identifiable cause, consider HSE in any

febrile patient with encephalopathy and CSF pleocytosis. Start empiric acyclovir

therapy promptly in patients with suspected HSE pending confirmation of the

diagnosis because acyclovir, the drug of choice, is relatively nontoxic and because the

prognosis for untreated HSE is poor.

Failure to consider the possibility of HSE can result in delayed diagnosis and

treatment, with subsequent increased risks of mortality and morbidity. A single-center

study from a high-volume academic emergency department (ED) reported that only

29% of patients with a presentation suggestive of viral encephalitis (fever,

neuropsychiatric abnormalities, cerebrospinal fluid [CSF] pleocytosis, and a negative

CSF Gram stain) received acyclovir in the ED.[37]

Initial Management

Prehospital care consists of supportive management of the patient’s airway,

breathing, and circulation (ABCs). General nutritional and fluid support is important.

Universal precautions are appropriate. Monitor for increased intracranial pressure

(ICP) and seizures.

Intensive care unit (ICU) care may be required, especially if seizure activity or

increased ICP is present. Depending on the availability of local expertise (eg,

infectious disease, neurology, neurosurgery specialists), transfer to a tertiary care

facility may be appropriate. Hospitalization is not routine for uncomplicated herpes

simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2) infection.

Management of increased intracranial pressure

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

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

mannitol and steroids, intubation with hyperventilation).

Management of seizures

Behavioral manifestations of HSE may resemble seizures, which are also common.

Should seizure activity become apparent or should electroencephalography (EEG)

show evidence of nonconvulsive seizures, begin anticonvulsant therapy.

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

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

preferable.

Antiviral Therapy

Pharmacotherapy for HSE is available in the form of acyclovir. Patient outcome is

improved after treatment with this agent. Acyclovir is the treatment of choice for

HSE.[1, 3, 38]

When the diagnosis of HSE is suspected or has been established,

acyclovir (typically 30 mg/kg/d intravenously [IV] in adults) should be initiated

immediately.

Through a series of in vivo reactions catalyzed by viral and host cellular enzymes,

acyclovir is converted to acyclovir triphosphate, a potent inhibitor of HSV DNA

polymerase, without which viral replication cannot occur. Human cells are not

affected.

Acyclovir has relatively few serious adverse effects. Because of its high pH, IV

acyclovir may cause phlebitis and local inflammation if extravasation occurs.

Gastrointestinal (GI) disturbances, headache, and rash are among the more frequent

adverse reactions.

The drug is excreted by the kidney, and the dose should be reduced in patients with

renal dysfunction. Crystal-induced nephropathy may occur if the maximum solubility

of free drug is exceeded. Risk factors for this are IV administration, rapid infusion,

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

doses. The risk of renal toxicity is reduced by adequately hydrating the patient (eg, 1

mL/d of fluid for each 1 mg/d of acyclovir).

Acyclovir is considered appropriate for serious infections during pregnancy. The

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

benefits outweigh the potential risks. However, a prospective registry of acyclovir use

in pregnancy between 1984 and 1999, including 756 first-trimester exposures,

demonstrated a 3.2% rate of birth defects, similar to that expected in the general

population.[39]

In immunocompetent patients, viral resistance to acyclovir has been clinically

insignificant, with a reported prevalence of less than 1%.[40]

However, in

immunocompromised patients, this figure rises to 6%. Degree of immunosuppression

and duration of exposure to acyclovir appear to be the most important risk factors for

the development of resistant strains.

Since most relapses occur within 3 months of completing an initial course of IV

acyclovir, a prolonged course of an oral antiviral agent (eg, valacyclovir) has been

suggested after initial treatment. An ongoing clinical trial is currently evaluating a 90-

day course of valacyclovir versus placebo after treatment with acyclovir in patients

with HSE.[41]

A 2009 Cochrane database review of data from 17 trials that compared interventions

used for the prevention and treatment of HSV in patients being treated for cancer

concluded that acyclovir is effective in preventing and treating HSV infections.

Valacyclovir was not found to be more effective than acyclovir, nor did a higher dose

of valacyclovir make a difference. Some evidence indicated that placebo, as a

prophylaxis, is more effective than prostaglandin E, but the risk of bias was unclear in

all trials.[42]

If long-term suppressive therapy is needed, acyclovir or famciclovir can be used

orally.

Neonatal herpes simplex encephalitis

Acyclovir in doses of 20 mg/kg IV every 8 hours (60 mg/kg/d) is currently

recommended for neonatal HSE. This dosage is higher than that used in older

children and adults (30 mg/kg/d), but, in neonates, it has been shown to improve

mortality and morbidity when compared with the lower dosage. Because the higher

dosage is associated with neutropenia, the white blood cell (WBC) count should be

monitored closely.

Steroid Therapy

The role of steroids in the treatment of HSE remains uncertain. To the extent that

cellular damage in HSE is the result of immune-mediated inflammatory processes

triggered by the viral infection, the anti-inflammatory effects of steroids may be

beneficial. However, there is also concern that steroids might suppress immune

responses of the host that are necessary to limit viral replication.

Animal studies have demonstrated a beneficial effect of steroids on outcome, without

evidence of increased viral replication or dissemination.[43, 44]

Steroids have been used

to reduce cerebral edema in patients with severe HSE.

One nonrandomized, retrospective human study compared the outcomes of patients

with HSE who received steroids in addition to acyclovir with the outcomes of those

who received acyclovir alone.[45]

The steroid group had improved outcomes at 3

months. Although these results suggest a possible role for steroids in HSE, definitive

recommendations must await the results of larger prospective studies.

The German trial of Acyclovir and Corticosteroids in Herpes-simplex-virus-

Encephalitis (GACHE), a multicenter, randomized, placebo-controlled trial, is

currently enrolling patients with HSE in a study designed to assess the outcomes of

treatment with acyclovir against the outcomes of treatment with acyclovir plus

dexamethasone.[46]

Prevention

No measures are known to be effective for preventing HSE in adults and older

children. Person-to-person transmission does not occur. Prophylactic treatment of

close contacts and special isolation precautions are unnecessary.

Preventive measures for neonatal HSE include cesarean delivery in women with

active herpetic genital infections at the time of delivery and protection of neonates

from persons with active herpetic infections. Some authorities recommend a course of

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

genital herpes.

Consultations and Additional Care

HSE is a neurologic emergency. Consultation with a neurologist is required.

Neurosurgical consultation is helpful only if a brain biopsy is being considered. An

infectious disease consultation may be appropriate.

An evaluation for rehabilitation is often appropriate to deal with the long-term

neurologic sequelae of HSE. Depending on the nature and degree of any neurologic

deficits present, rehabilitation services may be required.

Medication Summary

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

disease, to prevent complications, and to prevent recurrences. Pharmacotherapy for

herpes simplex encephalitis (HSE) is available in the form of acyclovir. Patient

outcome is improved when this agent is used for treatment.

Class Summary

The 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.

Antivirals

Acyclovir (Zovirax)

Acyclovir is the drug of choice for HSE. It has demonstrated inhibitory activity

against both herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2

(HSV-2) and is taken up selectively by infected cells. Mortality from HSE before use

of acyclovir was 60-70%; since acyclovir, it is approximately 30%.

Famciclovir (Famvir)

After ingestion, drug is rapidly biotransformed into the active compound penciclovir

and phosphorylated by viral thymidine kinase. By competition with deoxyguanosine

triphosphate, penciclovir triphosphate inhibits viral polymerase, subsequently

inhibiting viral DNA synthesis/replication. Adjust the dose in patients with renal

insufficiency or hepatic disease.

Anticonvulsants

Class Summary

Anticonvulsants are used to terminate clinical and electrical seizure activity as rapidly

as possible and to prevent seizure recurrence.

Carbamazepine (Tegretol)

Carbamazepine is effective in treatment of complex partial seizures; it appears to act

by reducing polysynaptic responses and blocking posttetanic potentiation.

Phenytoin (Dilantin, Phenytek)

Phenytoin is a hydantoin. Its primary site of action appears to be the motor cortex,

where it may inhibit spread of seizure activity; it may reduce maximal activity of the

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

The dose should be individualized; if daily dosage cannot be divided equally, larger

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

available for parenteral use.

Diuretics

Class Summary

These agents are used for the management of increased intracranial pressure in

complications resulting from herpes simplex encephalitis.

Furosemide (Lasix)

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

the chloride-binding co-transport system, which, in turn, inhibits sodium and chloride

reabsorption in the ascending loop of Henle and distal renal tubule. It increases renal

blood flow without increasing the filtration rate. The onset of action generally is

within 1 hour. It increases potassium, sodium, calcium, and magnesium excretion.

Furosemide is used in the acute setting for reduction of increased ICP. The proposed

mechanisms in lowering ICP include following: (1) suppression of cerebral sodium

uptake, (2) carbonic anhydrase inhibition resulting in decreased CSF production, and

(3) inhibition of cellular membrane cation-chloride pump, thereby affecting the

transport of water into astroglial cells.

The dose must be individualized to the patient. Depending on the response,

administer at increments of 20-40 mg, no sooner than 6-8 hours after the previous

dose, until desired diuresis occurs. When treating infants, titrate with 1-mg/kg/dose

increments until a satisfactory effect is achieved.

Mannitol (Osmitrol)

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

blood viscosity, resulting in reflex vasoconstriction and lowering of ICP.

Prognosis

Untreated HSE is progressive and often fatal in 7-14 days. A landmark study by

Whitley et al in 1977 revealed a 70% mortality in untreated patients and severe

neurologic deficits in most of the survivors.[17]

Mortality in patients treated with acyclovir was 19% in the trials that established its

superiority to vidarabine. Subsequent trials reported lower mortalities (6-11%),

perhaps because they included patients who were diagnosed by polymerase chain

reaction (PCR) rather than brain biopsy and who thus may have been identified

earlier with milder disease.[1, 3]

The mortality of neonatal HSE is substantial, even with treatment; 6% in patients

with isolated HSE and 31% in those with disseminated infection.

Sequelae among survivors are significant and depend on the patient’s age and

neurologic status at the time of diagnosis. Patients who are comatose at diagnosis

have a poor prognosis regardless of their age. In noncomatose patients, the prognosis

is age related, with better outcomes occurring in patients younger than 30 years.

Significant morbidity exists among those treated. Neurologic outcomes in survivors

treated with acyclovir are as follows:

No deficits or mild deficits - 38%

Moderate deficits - 9%

Severe deficits - 53%

Anterograde memory often is impaired even with successful treatment of HSE.

Retrograde memory, executive function, and language ability also may be impaired.

A study by Utley et al showed that patients who had a shorter delay (< 5 d) between

presentation and treatment had better cognitive outcomes.[18]

Elbers and colleagues followed properly treated children for 12 years after the HSE.

They found seizures in 44% of the children and developmental delay in 25% of the

children. They concluded that HSE continues to be associated with poor long-term

neurologic outcomes despite appropriate therapy.[19]

Shelley and colleagues reported a case of intracerebral hematoma occurring in a

patient successfully treated with a full course of acyclovir after apparent eradication

of the virus. The hematoma occurred in the region of the encephalitis.[20]

Marschitz and colleagues reported a case of chorea after HSE.[21]

Relapses after HSE have been reported to occur in 5-26% of patients, with most

relapses occurring within the first 3 months after completion of treatment. Relapses

are more frequent in children than adults. It is unclear whether such relapses represent

recurrence of viral infection or an immune-mediated inflammatory process. Some of

the relapses reported in earlier studies may have been due to inadequate duration of

treatment rather than true recurrences of HSE.

A long-term follow-up study of patients with HSE suggested that the pathogenic

mechanisms present during relapses differ from those present during the initial

infection.[22]

Serial measurements of inflammatory markers as well as HSV viral load

in the CSF of relapsing patients demonstrated increased inflammatory markers

without detectable HSV during relapses. These findings suggest that immune-

mediated events, rather than direct viral-mediated neuronal toxicity, may predominate

in relapses.

Patient Education

The belief that HSV-2 lesions appear initially 2 wk after primary infection can lead to

false accusations of infidelity. The physician should emphasize that the initial

outbreak of lesions may occur at any time after infection, possibly even years later.

Education may help reduce the spread of HSV-2.

For patient education resources, see the Teeth and Mouth Center and the Brain and

Nervous System Center, as well as Oral Herpes, Cold Sores, and Encephalitis.

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