Herpes Simplex, including oral and labialis, encephalitis briefly (general)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has a herpes simplex virus infection? What should you expect to find?

Symptoms of herpes simplex virus (HSV) oropharyngeal infections vary with primary versus recurrent infection. Primary infection is associated with painful vesiculoulcerative lesions of the mouth and sometimes the face. Recurrences are often preceded by a prodrome of pain or tingling in the affected area.
Physical findings of orolabial herpes are vesicular lesions of the vermilion border of the lip.
Primary genital herpes infection can either be symptomatic or asymptomatic. Recurrences can also be either symptomatic or asymptomatic.

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Physical findings include a painful vesicular rash ranging from multiple lesions with primary infection to a few lesions with recurrent infection in the immune competent host.
Neonatal HSV infection occurs in the first month of life and can involve skin, brain, or multiple organs.
Herpes encephalitis is associated with altered mentation, bizarre behavior, and anosmia.
Findings with herpes simplex encephalitis are those of a focal encephalitis.

How did the patient develop disease? What was the primary source from which the infection spread?

Oropharyngeal and genital HSV infections are acquired by mucosal to mucosal transmission.
HSV infections, including encephalitis, occur at all times of the year with no seasonal predilection. They occur at a similar incidence between men and women. The seroprevalence of herpes simplex virus type 1 is in excess of 50% by 50 years of age in developed societies and higher in the developing world.

Which individuals are of greater risk of developing disease?

HSV infections are ubiquitous. The frequency of recurrences varies from one individual to another. Some individuals never experience a symptomatic recurrence (about 35%), whereas others may have episodes of recurrences monthly (less than 2%). Neonatal HSV infections are usually acquired by contact of the fetus with infected maternal secretions. There are no known predisposing factors for herpes simplex encephalitis.
The most common predisposing factor to recurrent oropharyngeal herpes is immunosuppression.

Beware: there are other diseases that can mimic herpes simplex infection:

Only an extreme variant of herpes zoster of the trigeminal nerve can mimic herpes labialis. In regards to herpes encephalitis, other causes of focal disease of the brain are common and include all the herpes viruses, arboviral disease, tuberculosis, and collagen vascular diseases, among others.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Laboratory studies done to confirm oropharyngeal or genital HSV infection include a culture or, preferably, polymerase chain reaction (PCR) detection of viral DNA.
To diagnose herpes simplex encephalitis, cerebrospinal fluid should be tested in a reliable laboratory by PCR for viral DNA.
Additional laboratory studies are not required.

Results that confirm the diagnosis

PCR detection of HSV DNA is the most sensitive and specific method of diagnosis. Importantly, the laboratory performing these tests must be reliable.

What imaging studies will be helpful in making or excluding the diagnosis of disease?

No imaging studies are required for oropharyngeal or genital HSV infections.
An MRI should be obtained in patients suspected of having herpes simplex encephalitis whether of the newborn or older individual. The MRI may reveal diffuse or localized involvement in the newborn, or a lesion of the temporal/parietal lobe with compression of the lateral ventricle and a midline shift in older individuals.
The cost of an MRI varies significantly from institution to institution.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

Infectious disease consultation can provide guidance in diagnosing and treating HSV infections, especially if the diagnosis is unclear, or if resistant or recurrent infections occur. Neurology consultation can assist in managing neurologic complications of HSV encephalitis.

If you decide the patient has herpes simplex infection, what therapies should you initiate immediately?

The management of oropharyngeal HSV infections is routine. A consult with an infectious diseases physician is required only if recurrences are more frequent than anticipated (more than 6-8 episodes annually). The consult should confirm the diagnosis and, potentially, offer suppressive therapy.

Primary genital herpes benefits from antiviral therapy. Therapy can be individualized for individual episodes, including suppressive therapy.

For neonatal herpes, infectious diseases should be consulted, intravenous antiviral therapy is mandatory.

For herpes simplex encephalitis, infectious diseases should be consulted, and neurology should also be involved in patient management, since these patients frequently have seizures and altered consciousness.

Therapy of oropharyngeal and genital HSV infections can be with acyclovir, valacyclovir, or famciclovir. Therapy of neonatal herpes and herpes simplex encephalitis is with intravenous acyclovir.

Whether oropharyngeal or central nervous system (CNS) infection, therapy must be initiated as soon after the onset of symptoms as possible.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Empiric therapy of oropharyngeal and genital HSV infections should utilize either valacyclovir or famciclovir (see Table I). These medications have superior pharmacodynamics and more convenient dosing as compared to acyclovir, but even the generic forms are costlier.

Table I.

Organism	Antibiotic	Dose	Alternative
Oropharyngeal herpessimplex virus infections	ValacyclovirFamciclovir	Two 1 g doses 12 hours apart1500 mg as a single dose	None
Herpes simplexencephalitis	Acyclovir	10 mg/kg/q every 8 hoursfor 21 days	None

For patients with focal encephalitis, therapy should consist of intravenous acyclovir and continued pending confirmation of the diagnosis by PCR. Similarly, neonatal herpes is treated with intravenous acyclovir.

Treatment of oropharyngeal and episodic genital HSV infections is now short course (either one day famciclovir or three days valacyclovir), but treatment must be initiated in the early stages of infection – during the prodrome – for healing to be accelerated.

For herpes simplex encephalitis, treatment must be administered intravenously. No benefit from long-term suppressive therapy with an oral antiviral drug has been established. On the other hand, following intravenous therapy of neonatal herpes, long-term suppressive therapy with acyclovir provides neurologic benefit.

2. Other key therapeutic modalities.

Some physicians recommend the use of topical corticosteroids with an oral antiviral drug; however, that is not the standard of care.
For herpes encephalitis, increased intracranial pressure and seizures must be considered on serial re-evaluation of the patient.

What complications could arise as a consequence of herpes simplex infection?

What should you tell the family about the patient's prognosis?

Complications of herpes labialis are trivial and only consist of neuritic pain.
Complications of primary genital herpes is aseptic meningitis, but this is rare.
However, the complications of herpes simplex encephalitis and neonatal herpes include neurologic impairment and a persistent seizure disorder.
Prognosis is relevant for herpes simplex encephalitis and neonatal herpes. For patients older than 30 years of age and with a Glasgow Coma Score less than 7, the probability of returning to normal function is 10%. Overall, only one in three patients returns to normal function. For neonatal herpes, if the disease is localized to the skin, the prognosis is excellent. With encephalitis, the mortality is approximately 5% and morbidity about 50%. With multiorgan disease, the mortality remains 50%.

What-if scenarios:

If the initial cerebral spinal fluid (CSF) PCR is negative but the patient appears to have all the classic findings of herpes encephalitis, continue to treat and repeat the PCR a few days later.
If the CSF examination is totally normal, do not exclude herpes encephalitis from your differential diagnosis as this will occur 5% of the time.

How do you contract this disease and how frequent is this disease?

Recurrent herpes labialis occurs in approximately 25-75% of the population.
Herpes simplex encephalitis occurs in approximately 1:200,000 individuals annually.
There is no seasonal variation.
Virus is spread by mucosa to mucosa contact.
Utilizing type-specific serology, the seroprevalence of herpes simplex type1 increases with age and occurs later in life in developed societies. In the developing world, by 10 years of age, most children have antibodies to this virus.
Genital herpes can be caused by HSV-2 or, increasingly, by HSV-1.

What pathogens are responsible for this disease?

There is only one etiology for oropharyngeal and brain infection, and that is HSV.

How does this pathogen cause disease?

The pathogenesis of HSV infections varies according to resultant disease. When involving the oropharynx or genital tract, this virus is spread by mucosal contact of a susceptible individual with another individual who is shedding the virus. Virus enters the host at mucosal surfaces and is transmitted to the sensory ganglia, where it replicates and is transmitted back down the axon to mucosal surfaces where it causes vesiculoulcerative lesions. With lesions of the vermillion border of the lip, vesicles evolve to pustules and ulcers followed by scabbing. The inflammatory response consists of polymorphonuclear leukocytes (PMNs), lymphocytes and macrophages.

The pathogenesis of herpes simplex encephalitis is less clear. Most adults are seropositive at the time of encephalitis. Whether the virus reactivates directly in the brain or is transported by either the olfactory or trigeminal nerves is unknown. Virus replication in the brain causes hemorrhagic necrosis. Microscopic evaluation reveals perivascular lymphocytic cuffing. Some cells may demonstrate Cowdry Type A intranuclear inclusions. Brain tissue may stain positive for herpes simplex antigens with appropriate antibodies.

Neonatal herpes is usually acquired by contact of the fetus with infected secretions intrapartum. A few babies acquire disease from invasive obstetrical procedures, e.g., fetal scalp monitoring, and then contact with infected maternal secretions. A few babies acquire infection postnatally by direct contact with an individual excreting virus.

Diagnosis of the newborn requires a high degree of suspicion.

What other clinical manifestations may help me to diagnose and manage herpes simplex infection?

The history of prodrome with herpes labialis is key to understanding the diagnosis.

The key to the diagnosis of herpes encephalitis is altered behavior and mentation in the presence of fever.

What other additional laboratory findings may be ordered?

No other tests are needed.

How can disease be prevented?

If a patient has frequently recurrent herpes labialis or genital herpes, suppressive therapy with either valacyclovir or famciclovir may be offered.

There are no vaccines to prevent HSV infections.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Kimberlin, DW,, Whitley, RJ,, Wan, W,, Powell, DA. “Oral acyclovir suppression and neurodevelopment after neonatal herpes.”. N Engl J Med. vol. 365. 2011. pp. 1284-92.

Whitley, RJ,, Roizman, B., Whitley, RJ,, Richman, D,, Hayden, FG. “Herpes simplex viruses”. Clinical virology. 2009. pp. 409-36.

Whitley, RJ,, Roizman, B,, Knipe, D, Knipe, DM,, Howley, PM,, Caputo, G. “Herpes simplex virus.”. Fields virology. 2012.

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