HSV Encephalitis

HSV encephalitis: EM-focused review

Author: Carla Sterling, MD (EM Resident Physician, SUNY Downstate Medical Center) // Edited by: Jennifer Robertson, MD and Alex Koyfman, MD (@EMHighAK)

Case (changed from original)⁹: A 56 year-old female with no significant past medical, psychiatric or family history is brought in to the emergency department (ED) by relatives. The family called 911 after the patient awoke in the morning with abnormal behavior, aphasia and later on, unconsciousness. The family also notes that she has had a 4-day history of nausea, vomiting and anorexia along with lethargy, paranoia, and morbid thoughts.

Upon arrival to the ED, the patient’s vital signs were within normal limits except for a mild fever of 38.2°C. Her exam showed that the right pupil was larger than the left without papilledema. She also had an increase in left upper and left lower extremity tone. While in the ED, the patient had a seizure with left-sided clonic movement, which was well controlled with 10mg diazepam.  Laboratory tests drawn at the time of arrival were unremarkable. In the ED, she regained consciousness but remained drowsy. The patient was subsequently admitted to the hospital.

The week following the patient’s admission, she developed meningismus and decreased alertness. Lumbar puncture (LP) performed at that time showed cerebrospinal fluid (CSF) containing predominant lymphocytes with no red blood cells (RBCs).  Repeat LP the following day showed increased lymphocytosis and protein. LP cultures grew no bacterial or viral isolates. Electroencephalogram (EEG) showed right-sided focus, with a brain scan showing increased uptake in the right temporal lobe.

On day 15 of hospitalization, a right temporal lobe biopsy showed necrosis. A retrospective CSF antibody assay demonstrated Herpes Simplex Virus (HSV) antibodies and consequently, treatment with acyclovir was initiated. On the day following initiation of treatment, the patient’s alertness improved, and within two months her mental state was essentially normal with only mild cognitive impairment. Her only significant neurological sequelae were occasional generalized seizures, controlled by phenytoin and phenobarbital.

Overview:

Herpes encephalitis (HE) is the most common form of sporadic encephalitis¹ and the most lethal encephalitic disease⁵. One third of cases are caused by primary herpes simplex virus (HSV) infection while two thirds are caused by reactivation of the virus⁸. HE carries a mortality rate of over 70% if untreated⁵. A high level of suspicion is needed to avoid a missed diagnosis. Over 50% of HE cases are undiagnosed due to the disease’s varied presentation.

Symptom presentation by age:

Neonatal HE presents with symptoms of poor feeding, lethargy, fever, and seizure.⁴ Ninety percent will present by day 21 of the disease process.⁴ There are three types of neonatal HSV infection: (1) Disseminated,^4,5 (2) HE with central nervous system (CNS) involvement +/- skin lesions, and (3) HE limited to skin, eyes, and mouth.⁴ Disseminated HE carries the highest mortality rate and types (2) and (3) can progress to disseminated HE. In neonates, skin lesions develop in 60% of cases.⁴ While C-section may prevent vertical transmission, C-section delivery does not rule out horizontal transmission of HSV.⁵

Adults and children over one year of age present with fever, lethargy, seizure, focal deficits, and behavioral changes. Only 10% of children older than one year have mucosal lesions.⁵ Presentations may involve multiple organ systems such as the eye, skin, and CNS.

When to suspect HSE:

Patients often present with flu-like symptoms such as fever, nausea, vomiting, and altered mental status (AMS). Often patients progress to seizure and focal neurological deficits. Disorientation, altered speech, and behavioral changes are common with 1/3 patients having seizure.⁸

Diagnostic testing:

Diagnostic tests for HE include CT, MRI and lumbar puncture

Lumbar puncture (LP) opening pressure may be elevated in encephalitis. False negatives can occur in up to 10% in the first twenty-four hours of disease or if antiviral medication is initiated >48hrs prior to LP. Studies have shown that cerebrospinal fluid (CSF) mononuclear pleocytosis is indicative of HE. CSF monopleocytosis is also known as elevated protein without organisms. It correlates with diagnosis of HSV to bacterial meningitis in a 2:1 ratio.⁵  In addition, ten to fifteen percent of patients with HSV will have no red blood cells (RBCs) in CSF. Therefore, RBCs in CSF does not necessarily indicate HSV, and is never a feature in neonatal HSV or HE⁵.

MRI is considered the gold standard for neuroimaging in encephalitis. Temporal lobe involvement is typical of HE, but patients may also have frontal or parietal involvement.⁸ Lack of temporal lobe involvement does not rule out HE.⁸

Physicians should use CT to rule out space-occupying lesions and other intracranial diagnoses that may present similarly.

Unexplained anemia⁴ in a neonate may be attributed to HSV, and liver function tests (LFTs), specifically aspartate transaminase (AST) levels >10x baseline, directly correlate with mortality in disseminated neonatal disease⁵. Hyponatremia is common in encephalitis secondary to Syndrome of Inappropriate Antidiuretic Hormone release⁸.

Management:

The Level I-A recommendation by the Infectious Disease Society of America is intravenous (IV) acyclovir for 21 days.¹ Neonatal dosing is 20mg/kg three times a day (TID).² Infant and pediatric dosing is split: infant 500mg TID; >1yr 10mg/kg TID. The adult dose is 30mg/kg per day (10mg/kg q8h x 21 days).⁵

Even one dose of acyclovir can cause acute kidney injury (AKI). Risk factors for AKI include high doses, older age, and concomitant use of other nephrotoxic or potentiating agents.⁶ IV hydration and doses </= 15mg/kg/dose decrease risk of renal injury. Acyclovir-induced kidney injury has been shown to be completely reversible by stopping the medication.

Acyclovir-induced neurotoxicity has also been observed as a dose-dependent phenomenon that is seen mostly in elderly and end-stage renal disease patients.⁷ Acyclovir-induced neurotoxicity can be differentiated by its sudden onset, lack of fever, and history of treatment with acyclovir. Patients with acyclovir induced neurotoxicity should also have normal CSF and no neurological symptoms.

Post-IV treatment regimen is oral acyclovir for 6-12 months after initial IV therapy is completed.⁵ Acyclovir is used for neonates, and valacyclovir (with better enteral absorption and higher concentrations in CSF) is used for children >1yr and adults.

Why do we miss the diagnosis of HE? ⁸

• Anchoring onto alternate diagnoses of infectious causes of altered mental status like urinary tract infection and pneumonia.
• Failure to retake vitals including temperature, and rectal temperature if needed because a patient is afebrile on arrival.
• Missing a part of the HPI that reveals recent infectious symptoms.
• Not examining the skin, and missing vesicles around the genitals, or anywhere on the body in neonates, including the scalp.
• If the LP is not bloody, we consider HE ruled out.

Bottom line: ⁸

Unfortunately, there is no clear consensus on who to test for HE or when to treat it. Consider LP and acyclovir for any patient presenting with fever and AMS, seizure, or focal neurological deficits. Neonates meeting sepsis criteria should prompt interviewing the mother about HSV infection, and if empiric treatment is initiated, acyclovir should be started and CSF should be tested for viruses. HSV has been found to have the same prevalence as bacterial meningitis in infants,⁵ and acyclovir treatment should be started at the same time as empiric antibiotics.

A note on VZV encephalitis:¹

Children usually have VZV encephalitis with cerebellar involvement. It is usually self-limited versus severe encephalitis with associated delirium. Seizures are rare.

Adults with VZV encephalitis usually have the disease from reactivation of the virus.  It typically presents with focal neurological deficits and seizures. Diagnosis is the same for HE with the addition of lesion biopsy for rashes. Level II recommended treatments are acyclovir and ganciclovir, with a level III recommendation for corticosteroids.

References/Further Reading

1. Allan R. Tunkel et al. (2008). The Management of Encephalitis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases 47, no. 3 (2008): 303–27.
2. Sharieff, G., & McCollough, M. (2003). The Nightmare Neonate: Life-Threatening Events In The First Month Of Life. Emergency Medicine Practice,5(9). Retrieved September 1, 2003, from ebmedicine.net
3. Claudius, I. (2010). An Evidence-Based Review Of Neonatal Emergencies. Emergency Medicine Practice,7(8). Retrieved September 1, 2003, from ebmedicine.net
4. Aronson, P. (2013). Evaluation Of The Febrile Young Infant: An Update. Emergency Medicine Practice,10(2). Retrieved September 1, 2003, from ebmedicine.net
5. Sanders, J., & Garcia, S. (2014). Pediatric Herpes Simplex Virus Infections: An Evidence-Based Approach To Treatment. Pediatric Emergency Medicine Practice,11(1). Retrieved January 1, 2014, from www.ebmedicine.net
6. Rao, S., & Abzug, M. (2015). Intravenous Acyclovir and Renal Dysfunction in Children: A Matched Case Control Study. Journal of Pediatrics. Retrieved February 21, 2015, from jpeds.com
7. Rashiq, L. Briewa, M. Mooney, T. Giancarlo, R. Khatib, F. M. Wilson, (1993). Distinguishing acyclovir neurotoxicity from encephalomyelitis. J Intern Med. November 1993; 234(5): 507–511.
8. Solomon T, Hart IJ, Beeching N. (2007). Viral encephalitis: a clinician’s guide. J Pract Neurol. 2007 Oct; 7(5):288-305.
9. Kapper PE, Cleator GM, Longson M. (1984). Mild Forms of Herpes Encephalitis. Journal Neurological Neurosurgery Psychiatry. 1984 Nov; 47(11): 1247-50.