Herpes simplex encephalitis B00.4+G05.1*

Primary herpetic encephalitis (HSVE) is a dreaded complication of primary, usually severe herpetic gingivostomatitis herpetica caused by HSV-1. However, this neurological complication can also occur in patients with low cutaneous or mucocutaneous involvement. In contrast to other encephalitides (e.g. TBE), HSVE does not occur preferentially at any particular time of year.

The annual incidence is 0.2-0.4/100,000.

In adults and older children, acute encephalitis is almost always caused by HSV type 1. Type 2 is more likely to cause benign meningitis. In newborns, type 2 induces diffuse hemorrhagic-necrotizing encephalitis.

30% of HSVE patients are < 20 years old.

A two-phase course is typical: a flu-like preliminary stage (headache, high fever), followed by an often short-term improvement. Later, psychotic, aphasic symptoms appear. Hemiparesis and seizures continue to occur; later, quantitative disturbances of consciousness up to coma.

CSF: detection of herpes simplex virus by PCR (sensitivity 95-100%; specificity). Detection of rising CSF antibodies (end of 2 weeks of infection); sensitivity 97%, specificity 73-100%.

The detection of the herpes simplex virus by PCR can become negative again in the further course of the disease.

In up to 25% of patients a recurrent course is observed (possible virus reactivation).

The following clinical constellation justifies the suspicion:

• Flu-like prodromal stage, often acute onset
• Rapid progression
• high fever, headache, organic psychosyndrome, vigilance disorders or epileptic seizure
• Inflammatory cerebrospinal fluid (lymphocytic pleocytosis); serological CSF diagnostics: intrathecal HSV antibody production (detectable from the 2nd week)
• EEG changes (temporal focal findings, general changes with periodic complexes
• MRT: positive at an early stage with evidence of a mediobasal focus
• CCT: hypodense lesions reaching temperomediobasal to frontal, often detectable only on the 3rd day after the onset of neurological symptoms

Important: Immediate therapy must be initiated even if there is sufficient clinical suspicion of herpes simplex encephalitis.

Aciclovir i.v.: Aciclovir i.v. 3x10 mg/kg/KG for at least 14 days (ensure sufficient hydration, dose reduction for renal insufficiency).

If the HSV-PCR in the CSF is negative, but the clinical suspicion persists, acyclovir therapy should be carried out for at least 10 days (Kennedy 2004, Steiner et al. 2010).

In patients with AIDS and after organ transplantation, acyclovir-resistant HSV strains may occur. In these cases foscarnet should be used as an alternative: 3x60 mg/kg i.v. for 3 weeks.

The efficiency of acyclovir has been confirmed in several studies (Sköldenberg et al. 1984; Whitley et al. 1986). Important: By starting therapy early, the lethality of herpes encephaltitis can be reduced to 20%. An increase in mortality can be expected if therapy is started late (Poissy et al. 2009).

Dexamethasone adjuvant: Preliminary (non-significant) data show that patients treated with the combination therapy (dexamethasone - acyclovir) have a better prognosis than monotherapy patients. The therapy is off-label.

Adjuvant immunosuppressants: The adjuvant use of highly potent immunosuppressants such as rituximab or cyclophosphamide is recommended (Armangue et al. 2014).

Oral follow-up therapy with valaciclovir for 90 days does not show an improved clinical outcome (Gnann et al. 2015).

Herpes simplex encephalitis is lethal in about 70% of cases if left untreated. The prognosis depends crucially on the immediate start of a specific therapy.

Important: Persons with recurrent cold sores do not frequently develop herpes encephalitis.

In contrast to HSV-1 infection, HSV-2 usually causes mild aseptic meningitis or primary neuropathy. HSV-1 is the most common cause of mollaret meningitis (recurrent aseptic meningitis).

1. Armangue T et al (2014) Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol 75: 317-23
2. Gnann JW et al (2015) Herpes Simplex Encephalitis: Lack of Clinical Benefit of Long-term Valacyclovir Therapy: Clinical Infectious Diseases 61: 683-691
3. Kennedy PGE (2004) Viral encephalitis-causes, differential diagnosis and management. J Neurol Neurosurg Psychiatry 75: i10-i15 (suppl.)
4. Meyding-Lamadé U (2015) Viral meningoencephalitis. Guidelines for diagnosis and therapy in neurology.
5. Poissy J et al (2009) Factors associated with delay to acyclovir administration in 184 patients with herpes simplex virus encephalitis. Clin Microbiol Infect 15: 560-564
6. Sköldenberg B et al (1984) Acyclovir versus vidarabine in herpes simplex encephalitis; randomised multicenter study in consecutive Swedish patients. Lancet 1984; 2: 707-11
7. Steiner I et al (2010) Viral meningoencephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol 2010; 17: 999-1009
8. Whitley RJ et al (1986) Herpes simplex encephalitis: vidarabine versus acyclovir therapy. N Engl J Med 1986; 314: 144-149