Section 1 of 10
Authored by Larry I Lutwick, MD,
Director, Division of Infectious Diseases, Veterans Affairs New York Harbor
Health Care System, Professor, Department of Internal Medicine, State University
of New York at Downstate
Coauthored by Meena Seenivasan, MD, Fellow, Department of
Infectious Disease, State University of New York Health Science Center at
Larry I Lutwick, MD, is a member of the following medical societies:
College of Physicians, and
Infectious Diseases Society of America
Edited by Thomas J Marrie, MD, Chair, Professor, Department
of Medicine, Division of Infectious Diseases, University of Alberta College of
Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy
Editor, eMedicine; Charles V Sanders, MD, Edgar Hull Professor
and Chairman, Department of Internal Medicine, Louisiana State University Health
Sciences Center and School of Medicine; Eleftherios Mylonakis, MD, PhD,
Clinical and Research Fellow in Infectious Disease, Howard Hughes Physician
Postdoctoral Fellow, Department of Internal Medicine, Massachusetts General
Hospital, Harvard University; and Burke A Cunha, MD, Professor
of Medicine, State University of New York School of Medicine, Director of
Infectious Disease Fellowship, Chief, Division of Infectious Disease,
Vice-Chair, Department of Internal Medicine, Winthrop University Hospital
eMedicine Journal, December 21 2001, Volume 2, Number 12
Background: Herpes simplex
viruses (HSVs) are ubiquitous, extremely host-adapted pathogens that can cause a
wide variety of illnesses. Two types exist: type 1 (HSV-1) and type 2 (HSV-2).
Both are closely related but differ in epidemiology. HSV-1 is transmitted
chiefly by contact with infected saliva, whereas HSV-2 is transmitted sexually
or from a mother’s genital tract infection to her newborn.
Herpes simplex infections are asymptomatic in as many as 80% of patients, but
symptomatic infections may be characterized by significant morbidity and
recurrence. Moreover, infections can cause life-threatening complications,
particularly in immunocompromised hosts.
HSV infection appears to have increased in prevalence worldwide in the last 2
decades, making it a major public health concern. The availability of effective
chemotherapy underscores that the prompt recognition of the infection and early
initiation of therapy are of utmost importance in the management of the disease.
Pathophysiology: HSV, belonging to the family Herpesviridae
and to the subfamily Alphaherpesvirinae, is a double-stranded DNA virus
characterized by the following unique biological properties:
- Neurovirulence (the capacity to invade and replicate in the nervous
- Latency (the establishment and maintenance of latent infection in nerve
cell ganglia): In HSV-1 infection, the trigeminal ganglia are involved most
commonly, while in HSV-2 the sacral nerve root ganglia (S2-S5) are involved.
- Reactivation: The reactivation and replication of latent HSV can be
induced by a variety of stimuli (eg, fever, trauma, emotional stress,
sunlight, menstruation), resulting in overt or covert recurrent infection and
peripheral shedding of HSV. In immunocompetent patients with equal chances of
acquiring HSV-1 and HSV-2 both orally and genitally, HSV-1 reactivates more
frequently in the oral rather than the genital region. Similarly, HSV-2
reactivates 8-10 times more frequently in the genital region when compared to
orolabial HSV-2. Reactivation is more frequent and severe in immunocompromised
Dissemination of infection occurs in people with impaired T-cell immunity
such as organ transplant recipients and individuals with HIV-related disease.
Distribution of HSV is worldwide. Humans are the only natural reservoirs, and
no vectors are involved in transmission. Because of latent infection, periodic
reactivation, and virus shedding, endemicity is easily maintained in most human
The mode of transmission is by close personal contact, and infection occurs
via inoculation of virus into susceptible mucosal surfaces (eg, oropharynx,
cervix, conjunctiva) or through small cracks in the skin. The virus is readily
inactivated at room temperature and by drying; hence, aerosol and fomitic spread
- In the US: HSV is ubiquitous. Most individuals show
evidence of infection due to HSV. HSV-1 usually is acquired in childhood by
contact with oral secretions containing the virus. HSV-2 becomes an issue when
the individual becomes sexually mature. (The presence of HSV-2 is an indirect
measure of sexual activity.) Seroprevalence rates do not reflect how many of
these individuals have or will have symptomatic episodes of HSV recurrence.
Seroprevalence: Antibodies to HSV-1 increase with age starting in childhood
and correlate with socioeconomic status. By age 30 years, 50% of individuals
in a high socioeconomic status and 80% in a lower socioeconomic status are
seropositive. Antibodies to HSV-2 begin to emerge at puberty, correlating with
the degree of sexual activity. The lifetime seroprevalence can be 20-80%.
- Internationally: HSV is well distributed worldwide.
Mortality/Morbidity: Morbidity and mortality of HSV
infections are discussed in
Overall, the mortality associated with herpes simplex infections is related to 3
situations: perinatal infection, encephalitis, and infection in the
Race: No clear evidence indicates that the risk of infection
with HSV relates directly to race.
Sex: Differences in frequency of genital HSV infections
relate to sex only because infection relates to sexual activity, particularly
without appropriate barrier protection.
Age: HSV-1 infections transmitted via saliva are common in
children, although such primary herpes gingivostomatitis can be observed at any
age. HSV-2 infections are clustered perinatally (from a maternal episode at
delivery) and primarily once sexual activity begins. HSV-2 genital infections in
children can be an indication of sexual abuse.
History: The clinical course of the
disease depends upon the age and immune status of the host, the anatomic site of
involvement, and the antigenic type of the virus. While the primary infections
caused by HSV-1 and HSV-2 are accompanied by systemic signs, longer duration of
symptoms, and higher rate of complications, recurrent episodes are milder and
shorter. Both HSV-1 and HSV-2 can cause similar genital and orofacial primary
infections after contact with infectious secretions containing either HSV-1
(usually oral secretions) or HSV-2 (usually genital secretions).
- Acute herpetic gingivostomatitis
- This manifestation of primary HSV-1 infection occurs in children aged 6
months to 5 years.
- Infected saliva from an adult or another child is the mode of infection.
The incubation period is 3-6 days.
- Clinical features
- Abrupt onset
- High fever (102-104°F)
- Anorexia and listlessness
- Gingivitis is the most striking feature, with markedly swollen,
erythematous, friable gums.
- Vesicular lesions develop on the oral mucosa, tongue, and lips and
later rupture and coalesce, leaving ulcerated plaques.
- Tender regional lymphadenopathy
- Perioral skin also may be involved because of contamination with
- Course: Acute disease lasts 5-7 days, and the symptoms subside in 2
weeks. Viral shedding from the saliva may continue for 3 weeks or more.
Adults also may develop acute gingivostomatitis, but it is less severe and
is associated more often with a posterior pharyngitis.
- Acute herpetic pharyngotonsillitis
- In adults, oropharyngeal HSV-1 causes pharyngitis and tonsillitis more
often than gingivostomatitis.
- Fever, malaise, headache, and sore throat are presenting features.
- The vesicles rupture to form ulcerative lesions with grayish exudates on
the tonsils and the posterior pharynx.
- Associated oral and labial lesions occur in fewer than 10% of patients.
- HSV-2 can cause similar symptoms and is associated with orogenital
contact or can occur concurrently with genital herpes.
- This is the most common manifestation of recurrent HSV-1. A prodrome of
pain, burning, and tingling often occur at the site, followed by the
development of erythematous papules that rapidly develop into tiny,
thin-walled, intraepidermal vesicles that become pustular and ulcerate. In
most patients, fewer than 2 recurrences manifest each year, but some
individuals have monthly recurrences.
- Maximum viral shedding is in the first 24 hours of the acute illness but
may last 5 days.
- Genital herpes: The severity and frequency of the disease and the
recurrence rate depend on a number of factors that include viral type, prior
immunity to autologous or heterologous virus, gender, and immune status of the
- Primary genital herpes can be caused by both HSV-1 and HSV-2 and is
asymptomatic in most patients. The clinical features and course of primary
genital herpes caused by both HSV-1 and HSV-2 are indistinguishable, but
recurrences are more common with HSV-2.
- Primary genital herpes is characterized by severe and prolonged systemic
and local symptoms. The symptoms of persons with a first episode of
nonprimary HSV-2 infection are less severe and of shorter duration.
- Preexisting antibodies to HSV-1 have an ameliorating effect on disease
severity caused by HSV-2.
- Prior orolabial HSV-1 protects against genital HSV-1 but not HSV-2.
- Women’s symptoms are more severe, and women have a higher rate of
complications than men.
- Clinical features: The incubation period is 3-7 days (range = 1 d to 3
wk). Constitutional symptoms include fever, headache, malaise, and myalgia
(prominent in the first 3-4 d); local symptoms include pain, itching,
dysuria, vaginal and urethral discharge, and tender lymphadenopathy.
- Clinical features in women: Herpetic vesicles appear on the external
genitalia, labia majora, labia minora, vaginal vestibule, and introitus. In
moist areas, the vesicles rupture, leaving exquisitely tender ulcers. The
vaginal mucosa is inflamed and edematous. The cervix may be involved in
70-90% of patients and is characterized by ulcerative or necrotic cervical
mucosa. Cervicitis may be the sole manifestation in some patients. Dysuria
may be very severe and may cause urinary retention. Dysuria is associated
with urethritis, and HSV can be isolated in the urine. HSV-1 causes
urethritis more often than HSV-2.
- Clinical features in men: Herpetic vesicles appear in the glans penis,
the prepuce, the shaft of the penis, and sometimes on the scrotum, thighs,
and buttocks. In dry areas, the lesions progress to pustules and then crust.
Herpetic urethritis occurs in 30-40% of patients and is characterized by
severe dysuria and mucoid discharge. The perianal area and rectum can be
involved in persons who engage in anal intercourse, resulting in herpetic
- In men and women, the ulcerative lesions persist from 4-15 days until
crusting and reepithelialization occur. New lesions can occur during the
course of the illness in 75% of patients, usually forming in 4-10 days. The
median duration of viral shedding is about 12 days.
- The major morbidity of genital herpes is due to its frequent
reactivation rate. In one study, 90% of patients reactivated within the
first 12 months. For HSV-2 infection 38% had 6 recurrences in 1 year, and
20% had more than 10 recurrences in the first year.
- Both subclinical and symptomatic reactivation are more common with HSV-2
compared to HSV-1. Sixty percent of patients with primary genital HSV-2
experience recurrences in the first year.
- Patients who had severe primary genital herpes tend to have more
frequent recurrences of longer duration.
- Recurrent genital herpes is preceded by a prodrome of tenderness, pain,
and burning at the site of eruption that may last from 2 hours to 2 days. In
some patients, severe ipsilateral sacral neuralgia may occur.
- In women, the vesicles are found on the labia majora, labia minora, or
perineum. The lesions are often very painful. Fever and constitutional
symptoms are uncommon. The lesions heal in 8-10 days and viral shedding
lasts an average 5 days. The symptoms are more severe in women than men.
- In men, recurrent genital herpes presents as 1 or more patches of
grouped vesicles on the shaft of the penis, prepuce, or glans. Urethritis is
uncommon. Pain is mild, and lesions heal in 7-10 days. The frequency and
severity of recurrences decrease with time.
- Subclinical genital herpes
- The majority of primary genital HSV infections are asymptomatic, and
70%-80% of seropositive individuals have no history of symptomatic genital
herpes. Nevertheless, they experience periodic subclinical reactivation with
virus shedding, thus making them a source of infection.
- The rate of viral shedding may be 1-2% in immunocompetent persons and
may be as high as 6% in the first few months after acquiring the infection.
This fact is important in neonatal herpes because most mothers have no signs
and symptoms of genital herpes during pregnancy.
Physical: This section addresses the physical examination of
the herpetic lesion as it relates to primary and recurrent lesions of cutaneous
or mucosal HSV infection. This can be related to either oral or genital
- Primary mucocutaneous HSV infections
- Primary (first episode) infections present within several days of
exposure to secretions containing viable virus.
- Often painful, the lesions develop into vesicles quickly and can
continue to erupt over 1-2 weeks.
- The lesions are prominent and often are present internally on the
mucosal surface of the oral or genital area as well as on the surrounding
- Constitutional symptoms often are prominent with fever, malaise,
myalgias, and anorexia. Weight loss is not uncommon, either related to
illness or dysphagia (in primary gingivostomatitis).
- Individual vesicles on mucosal surfaces break down rapidly, forming
shallow painful ulcers (usually <8-10 mm in diameter). They may be covered
with a white exudate that can be confused with mucosal candidosis. Those on
cutaneous surfaces remain as vesicles longer, only to develop into crusted
ulcers that heal in 5-7 days.
- Recurrent mucocutaneous HSV infections
- Following the establishment of latency in the corresponding sensory
nerve ganglion cells, HSV can cause recurrent infection that can be
subclinical (manifest by viral excretion without lesions) or overt (manifest
by mucosal or cutaneous lesions with viral excretion).
- Oral recurrences often are triggered by recognizable stimuli such as
pyrexia (fever blisters and cold sores), stress, or sunburn. Genital
recurrences are more likely to be linked to stress and not pyrexia. Females
may relate a relationship to the menstrual cycle.
- Burning or paraesthesias at the point where the lesions are to occur may
herald recurrences. Unlike primary infection, constitutional symptoms are
minimal in most cases.
- Recurrences last 3-7 days and can occur numerous times per year or once
or twice in a lifetime. Overall, the number of yearly recurrences tends to
decrease over time.
- Although recurrent HSV may last much longer (>30 d) in immunocompromised
hosts, such as individuals with AIDS, frequent recurrences are not
necessarily a sign of an altered immune system.
- Because recurrences can be clinically unrecognizable, transmission to
susceptible individuals can occur without overt lesions being present. In
genital disease, this means barrier protection should be used whether
lesions are present or not, even if no history of genital HSV is present.
- Vesicles occurring in a sacral dermatomal distribution (zosteriform) can
occur in recurrent genital HSV disease and be confused with herpes zoster. A
history of similar recurrences should alert the clinician to this
- Sacral HSV recurrences also may present with signs and symptoms of
meningeal inflammation; and, in fact, an aseptic meningitis picture can be
found upon examination of the cerebrospinal fluid.
- The mode of transmission is by close personal contact.
- Infection occurs via inoculation of virus into susceptible mucosal
surfaces (eg, oropharynx, cervix, conjunctiva) or through small cracks in the
- The virus is inactivated readily at room temperature and by drying; hence,
aerosol and fomitic spread occur rarely.
- HSV-1 is transmitted chiefly by contact with infected saliva, whereas
HSV-2 is transmitted sexually or from a mother’s genital tract infection to her
Other Problems to be Considered:
Oral ulcerative disease
Genital ulcerative disease
- HSV infection is best confirmed by isolation of virus in tissue culture
(the criterion standard for diagnosis).
- Rapid diagnosis is possible by the histological appearance of the lesion.
- Multinucleated giant cells and epithelial cells containing eosinophilic
intranuclear inclusion bodies distinguish the lesions of herpesviruses.
- The characteristic cytologic changes induced by HSV can be demonstrated in
Tzank smears (see
- Punch biopsy provides more reliable material for histological examination,
particularly when lesions are infected with bacteria and fungi.
- Rapid detection of HSV DNA in clinical specimens is now possible with
polymerase chain reaction (PCR) techniques.
- In HSV encephalitis, PCR using cerebrospinal fluid (CSF) provides a
rapid, noninvasive diagnostic technique that is as sensitive as brain
- PCR has detected HSV-2 as the cause of recurrent meningitis (Mollaret)
and has shown a strong association of HSV-1 with Bell palsy.
- PCR can detect asymptomatic viral shedding.
- Tissue culture for HSV often is positive within 48 hours of inoculation.
- Characteristic cytopathic effect with ballooning of cells and cell death
are observed, and death of the entire monolayer of cells may be rapid.
- Immunofluorescent staining of the tissue culture cells can quickly
identify HSV and can distinguish between types 1 and 2.
- Antibody testing can demonstrate a primary seroconversion, particularly
with HSV-1 in childhood.
- Because of sero–cross-reactivity, HSV-1 and HSV-2 are not generally
distinguishable unless a glycoprotein G antibody assay is available.
- Antibody titer increases generally do not occur during recurrences of
HSV, which is in contradistinction to the situation in varicella-zoster
virus recurrence. Therefore, the test generally is not used for the
diagnosis of mucocutaneous HSV relapse.
- Brain imaging studies in simplex virus encephalitis generally demonstrate
focal localization in the temporal area that is associated with edema and
- Typically, an intact vesicle is used from which the vesicular fluid is
aspirated by puncture with a sterile tuberculin syringe. This fluid can be
used for viral culture.
- Aspiration should facilitate complete collapse of the vesicle because it
is not multiloculated as cutaneous poxvirus infections can be.
- After aspiration, the vesicle should be unroofed aseptically.
- Using a sterile instrument, the floor of the newly produced ulcer can
then be scraped. The obtained material can be spread on a glass microscope
slide and then dried and fixed for staining.
- Staining can be performed with a Papanicolaou smear stain. (In
actuality, whatever is available as Gram, Giemsa, or Wright stain will
- A positive result is the finding of multinucleate giant cells.
- Using appropriate immunofluorescent antibody reagents, the smear can
distinguish different herpesviruses and nonherpesviruses that may be present
(eg, vaccinia, smallpox).
- Overall, medical treatment of HSV revolves around specific antiviral
- In situations in which constitutional effects such as fever occur,
symptomatic treatment can be used.
- Appropriate wound care is needed, and treatment for secondary bacterial
skin infections may be required.
Diet: A diet high in the amino acid lysine has been
suggested as useful in preventing recurrences of HSV. Although viral yields in
tissue culture are lower in a high lysine medium, replication still occurs. No
objective clinical evidence exists to support this dietary manipulation.
The goals of pharmacotherapy are to reduce
morbidity and to prevent complications.
Drug Category: Antivirals -- Nucleoside
analogs are phosphorylated initially by viral thymidine kinase to eventually
form a nucleoside triphosphate. These molecules inhibit HSV polymerase with
30-50 times the potency of human alpha-DNA polymerase.
|Acyclovir (Zovirax) -- Synthetic purine
nucleoside analogue with activity against a number of herpesviruses,
including herpes simplex and varicella-zoster. Highly selective for
virus-infected cells because of its high affinity for viral thymidine kinase
enzyme. This effect serves to concentrate acyclovir monophosphate into
virus-infected cells. The monophosphate then is metabolized into the
triphosphate active form by cellular kinases.
Double dose is suggested for herpes simplex proctitis or ocular infections.
Ocular infections also can be treated with topical acyclovir. Oral
suspension available (40 mg/mL).
||First episode mucocutaneous herpes
simplex: 200 mg PO 5 times daily or 400 mg tid for 7-10 d or until clinical
Recurrent genital herpes: 200 mg PO five times daily for 5 d
Chronic suppressive therapy: 400 mg bid or 200 mg 3-5 times daily;
reevaluate after 1 y
Herpes simplex encephalitis: 10 mg/kg IV q8h for 10-14 d
Severe infection in immunocompromised host: 5-10 mg/kg IV q8h for 5-10 d
||First episode mucocutaneous herpes
simplex: 20-30 mg/kg/d in 5 divided doses for 7-10 d
Severe infections in immunocompromised children: 10 mg/kg/d IV q8h for 7 d
Herpes encephalitis: 20 mg/kg IV q8h for 10-14 d
||Concomitant use of probenecid or
zidovudine prolongs half-life and increases CNS toxicity
||B - Usually safe but benefits must
outweigh the risks.
||Renal dysfunction (usually reversible)
can occur during high-dose IV administration (primarily related to drug
crystalluria); effect can be minimized by slow infusion and adequate
neurological symptoms, including lethargy, agitation, myoclonus, or seizures
is observed in <1% of patients; appears to be dose-related phenomenon with
increased risk with azotemia
|Valacyclovir (Valtrex) -- Prodrug
rapidly converted to the active drug acyclovir. More expensive but has a
more convenient dosing regimen than acyclovir.
||First episode herpes simplex: 1 g bid
for 10 d, preferably beginning within 48 h of onset
Recurrent episode herpes simplex: 500 mg bid for 5 d beginning within 24 h
Suppressive dosing for HSV: 500 mg to 1 g/d
||Probenecid, zidovudine, or cimetidine
coadministration prolongs half-life and increases CNS toxicity of
||B - Usually safe but benefits must
outweigh the risks.
||Caution in renal failure and
coadministration of nephrotoxic drugs; associated with onset of hemolytic
|Famciclovir (Famvir) -- Prodrug that
when biotransformed into active metabolite, penciclovir, may inhibit viral
DNA synthesis/replication. Used against herpes simplex and varicella-zoster
||Recurrent genital HSV: 125 mg bid for 5
Recurrent genital HSV in HIV-infected patients: 500 mg bid for 7 d
Suppression of frequent recurrence of genital HSV: 250 mg bid up to 12 mo
||Coadministration of probenecid or
cimetidine may increase toxicity; coadministration increases bioavailability
||B - Usually safe but benefits must
outweigh the risks.
||Caution in renal failure or
coadministration of nephrotoxic drugs; dosage adjustment in renal impairment
recommended (half-life prolonged by 5-6 times if CrCl <20 mL/min)
- Because of the ubiquitous and cosmopolitan nature of HSV, avoiding contact
with individuals who (often asymptomatically) are excreting the virus in
saliva or sexual secretions is difficult.
- Although not easily applicable to oral-oral contact, barrier protection
using latex condoms is recommended to minimize exposure to genital HSV
- Because genital ulcers due to HSV may occur outside of areas covered by
the condom, transmission can occur in those areas.
- Herpetic whitlow can be avoided by the use of latex gloves when health
care workers insert their hands into the oral cavity of patients. Transmission
of genital virus to the hand, however, can occur during unprotected
finger-genital contact related to sexual exposures.
- Suppressive antiviral therapy is used for individuals with frequent and/or
particularly symptomatic relapses.
- Balanitis can occur in an uncircumcised male as a result of bacterial
infection of the herpetic ulcers.
- Candidal vaginitis has been described in as many as 10% of women with
primary genital herpes, particularly if they have diabetes. Care should be
taken to confirm the diagnosis of candidosis because ulcerative herpetic
disease can have whitish mucosal lesions that can be confused with yeast
- Ocular infections
- This complication is not uncommon in children as a result of
autoinoculation during acute herpetic gingivostomatosis or asymptomatic
oropharyngeal HSV infection.
- Ocular infection is caused primarily by HSV-1, except in neonates in
whom it may be caused by HSV-2, and manifests as unilateral follicular
conjunctivitis or as acute herpetic keratoconjuctivitis with dendritic
- Recurrences can occur in as many as 25% of patients and can be
associated with progressive scarring of the cornea. HSV has been the leading
infectious cause of blindness in the US.
- Skin infections: Various cutaneous complications related to HSV can occur.
- Eczema herpeticum: This occurs in individuals with underlying dermatitis
and may be localized (which can be confused with herpes zoster) or
disseminated. The process also can occur in patients with extensive skin
breakdown as with burns, pemphigus, or Sézary syndrome.
- Herpetic whitlow: HSV of the fingers of the hand occurs at or near the
cuticle or at other sites associated with trauma. When involving the nail
area, it has been confused with a bacterial felon and been subjected,
inappropriately, to incision and drainage. Herpetic whitlow is associated
with HSV-1 in health care workers and children related to saliva exposure
and with HSV-2 related to digital-genital exposure.
- Herpes gladiatorum: Scattered cutaneous HSV-1 lesions have been observed
in wrestlers who have had viral contact through exposure to infectious
saliva during a match.
- Visceral infections: HSV infection of the visceral organs usually results
from viremia, and multiple organ involvement is common. This may occur during
otherwise asymptomatic primary infections and sometimes in seemingly
immunologically normal hosts.
- In most cases of disseminated herpes, the lesions are confined to the
skin; however, fatal visceral dissemination can occur with or without
vesicular skin lesions. Multiple organs are involved, but fulminant HSV
hepatitis is usually clinically prominent.
- It is associated with leukopenia, thrombocytopenia, and disseminated
- Disseminated HSV-1 and HSV-2 infections also can result in herpetic
esophagitis, adrenal necrosis, interstitial HSV pneumonitis, HSV cystitis,
HSV arthritis, HSV meningitis, and HSV encephalitis.
- Central nervous system complications
- Aseptic meningitis: This condition is an acute, generally benign
lymphocytic meningitis. In 1 series, 36% of women and 13% of men with
primary genital HSV-2 had meningeal symptoms on 2 consecutive examinations.
It is more common with HSV-2 infection. Meningeal symptoms usually start
3-12 days after the onset of genital lesions; they reach a maximum 2-4 days
into the illness and recede over 2-4 days. Signs and symptoms of
encephalitis are unusual and neurological sequelae are rare. HSV-1 also has
been identified by PCR in the CSF of patients with benign lymphocytic
recurrent meningitis (Mollaret meningitis), suggesting that HSV may be the
cause of this so-called idiopathic syndrome.
- Ganglionitis and myelitis: Genital and anorectal HSV infections may be
complicated by urinary retention, sacral neuralgia, and sacral anesthesia.
This is due to associated ganglionitis and radiculitis. The symptoms usually
resolve in 1-2 weeks. Transverse myelitis rarely is reported.
- Herpes simplex encephalitis: This is an acute necrotizing viral
encephalitis that, beyond the neonatal period, is nearly always caused by
HSV-1. It accounts for 10-20% of all cases of encephalitis and is the most
common cause of sporadic acute necrotizing encephalitis in the United
States. Herpes simplex encephalitis occurs as a primary infection in about
50% of cases and may be due to recurrent infection or to reinfection with a
different strain of HSV-1 in the remainder. Clinical features include the
- Nonspecific findings common to all forms of encephalitis, which
include headache, signs of meningeal irritation, altered mental status,
and generalized seizures
- Changes referable to focal necrosis of the orbitofrontal and temporal
cortex and the limbic system, including anosmia, memory loss, olfactory
and gustatory hallucinations, and focal seizures
- Rapid development of hemiparesis and coma may occur. In some patients,
the clinical picture may be protracted, mimicking acute psychosis or
- The CSF has moderate pleocytosis with mixed mononuclear cells and
polymorphonuclear cells, moderate RBCs, and mildly elevated protein with
- MRI is the most sensitive imaging procedure.
- The most sensitive noninvasive method of diagnosis is the
demonstration of HSV DNA by PCR.
- The mortality rate is high (70%) in untreated patients. Even with
treatment, a high incidence of neurological sequelae remains.
- Genital herpes and pregnancy
- Recurrent genital herpes is similar in pregnant and nonpregnant women,
although an increase in the number of recurrences in the course of pregnancy
- Recurrent genital herpes accounts for 1-2% of all cases of neonatal
herpes. Considering the fact that a high serological evidence of herpes and
low incidence of neonatal herpes exists, recurrent herpes is not an
important risk factor. Hence, cesarean delivery is recommended only in
mothers who have active genital lesions during labor.
- First-episode infections have more severe consequences to the mother and
infant. Thus, identification of women at risk for primary infection (seronegative
for HSV-2) is of paramount importance.
- Serological discordance between partners may be 15-20%, so that the risk
of a seronegative mother becoming infected from the father during pregnancy
- Pregnant women may have widely disseminated infection with a high
mortality rate of 50%.
- Infection in the third trimester of pregnancy is associated with
neonatal HSV infections, intrauterine growth retardation, and prematurity.
- Neonatal HSV disease
- Ninety percent of infections are acquired perinatally, 5-8% are acquired
congenitally, and a few are acquired postnatally.
- Neonatal infection is caused by contact with infected genital
- In 70% of mothers, the infection is asymptomatic. The risk of
transmission from a mother with primary infection is about 50%.
- Neonates and infants (aged <6 wk) have a very high frequency of visceral
and CNS infections. Without therapy, the mortality rate is 65%, and a high
degree of neurological sequelae exists.
- The disease may be confined to the skin, eyes, or mouth, or it may
manifest as encephalitis or disseminated visceral disease involving the
lungs, liver, heart, adrenals, and skin.
- Suits over sexual transmission
- Legal actions have been taken over transmission of HSV through
unprotected sexual activity.
- Demonstration that both partners are infected with the same type of HSV
is not adequate to prove that one partner infected the other.
- The use of restriction endonucleases, which lyse DNA at very specific
base sequences, can strongly suggest an epidemiologic link between 2
isolates but does not indicate the direction of the transmission.
- The presence of genital HSV-2 infection in young children can be an
indicator of sexual abuse in parallel to gonococcal infections but is not
necessarily the case.
- Recognition of HSV encephalitis
- Because prompt treatment of HSV encephalitis appears to minimize
residual neurologic damage and death, considering this diagnosis early is
important in appropriate cases. Perform necessary diagnostic tests, and
institute early, usually empirical, antiviral therapy.
- Unsatisfactory outcomes can occur, however, even with the early use of
- Development of antiviral drug resistance
- Antiviral resistance of HSV can be selected for both in vitro and in
- Once these isolates are present, commonly representing thymidine kinase¡Vnegative
mutants, the usual treatments are not likely to be effective, and alternate
modalities of therapy must be sought.
- The use of prolonged suppressive therapy for HSV no doubt contributes
substantially to the risk of developing resistance.
- Because of the possibility of developing resistance, the decision to use
chronic suppression (or patient-driven relapse treatment) must be made while
carefully balancing the positive effect of suppression or any likely minimal
effect of therapy on an already overt mucocutaneous relapse against the
potential for resistance.
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glycoprotein G-specific immunodot enzyme assay for detecting antibodies to
herpes simplex virus types 1 and 2 in human sera. J Clin Microbiol 1988 Apr;
- Aurelius E, Johansson B, Skoldenberg B: Rapid diagnosis of herpes simplex
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