Herpes simplex encephalitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Cafer Zorkun, M.D., Ph.D. [2], Anthony Gallo, B.S. [3]

Synonyms and keywords: HSE; Herpes viral encephalitis; Herpes meningoencephalitis

## Overview[edit | edit source]

Herpes simplex encephalitis is a severe viral infection of the central nervous system. Herpes simplex encephalitis may be classified according to the origin of the disease into two subtypes: oral (HSV-1) and genital (HSV-2). The exact pathogenesis of herpes simplex encephalitis is not fully understood.[1] Herpes simplex encephalitis must be differentiated from other diseases that cause fever, headache, and altered mental status. Physical examination findings for herpes simplex encephalitis are generally unspecific. Herpes simplex encephalitis constitutes a medical emergency. If left untreated, approximately 70% patients with herpes simplex encephalitis progress to mortality.[2] Common complications of herpes simplex encephalitis include meningitis, increased intracranial pressure, and coma. Laboratory findings consistent with the diagnosis of herpes simplex encephalitis include increased leukocytes in cerebrospinal fluid.[3] Polymerase chain reaction is critical in the diagnosis of herpes simplex encephalitis, as there is a 95-98% specificity and sensitivity beginning as early as one day after symptoms first appear and lasting up to one week after treatment.[1] Magnetic resonance imaging is the imaging modality of choice for herpes simplex encephalitis. The mainstay of therapy for herpes simplex encephalitis includes antiviral therapy. The drug of choice is acyclovir.[4]

## Classification[edit | edit source]

Herpes simplex encephalitis may be classified according to origin of disease into two subtypes: oral (HSV-1) and genital (HSV-2).

## Pathophysiology[edit | edit source]

The exact pathogenesis of herpes simplex encephalitis is not fully understood.[1] It is believed that herpes simplex encephalitis is caused by the retrograde transmission of the virus from a peripheral site on the face to the brain along a nerve axon following HSV-1 reactivation.[2] The virus lies dormant in the ganglion of the trigeminal or fifth cranial nerve but the exact pathogenesis remains unknown. The olfactory nerve may also be involved in herpes simplex encephalitis.[5]

## Causes[edit | edit source]

Herpes simplex encephalitis may be caused by either HSV-1 or HSV-2.

## Differentiating Herpes simplex encephalitis from Other Diseases[edit | edit source]

Herpes simplex encephalitis must be differentiated from other diseases that cause fever, headache, and altered mental status, such as:[6][7][8][9]

Disease | Similarities | Differentials

|
|

Meningitis | Classic triad of fever, nuchal rigidity, and altered mental status | Photophobia, phonophobia, rash associated with meningococcemia, concomitant sinusitis or otitis, swelling of the fontanelle in infants (0-6 months)
Brain abscess | Fever, headache, hemiparesis | Varies depending on the location of the abscess; clinically, visual disturbance including papilledema, decreased sensation; on imaging, a lesion demonstrates both ring enhancement and central restricted diffusion
Demyelinating diseases | Ataxia, lethargy | Multiple sclerosis: clinically, nystagmus, internuclear ophthalmoplegia, Lhermitte's sign; on imaging, well-demarcated ovoid lesions with possible T1 hypointensities (“black holes”)

Acute disseminated encephalomyelitis: clinically, somnolence, myoclonic movements, and hemiparesis; on imaging, diffuse or multi-lesion enhancement, with indistinct lesion borders

Substance abuse | Tremor, headache, altered mental status | Varies depending on type of substance: prior history, drug-seeking behavior, attention-seeking behavior, paranoia, sudden panic, anxiety, hallucinations
Electrolyte disturbance | Fatigue, headache, nausea | Varies depending on deficient ions; clinically, edema, constipation, hallucinations; on EKG, abnormalities in T wave, P wave, QRS complex; possible presentations include arrhythmia, dehydration, renal failure
Stroke | Ataxia, aphasia, dizziness | Varies depending on classification of stroke; presents with positional vertigo, high blood pressure, extremity weakness
Intracranial hemorrhage | Headache, coma, dizziness | Lobar hemorrhage, numbness, tingling, hypertension, hemorrhagic diathesis
Trauma | Headache, altered mental status | Amnesia, loss of consciousness, dizziness, concussion, contusion

Herpes simplex encephalitis must be differentiated from other causes of headache, altered mental status and seizures such as brain tumors and delirium trmemns.

Diseases | Diagnostic tests | Physical Examination | Symptoms  | Past medical history | Other Findings

|
|
|
|
|

Na+, K+, Ca2+ | CT /MRI | CSF Findings | Gold standard test | Neck stiffness | Motor or Sensory deficit | Papilledema | Bulging fontanelle | Cranial nerves | Headache | Fever | Altered mental status
Brain tumour[10][11] |  | ?  | Cancer cells[12] | MRI  |  | ?  | ?  | ?  | ?  | ?  |  | ?  |  | Cachexia, gradual progression of symptoms
Delerium Tremens |  | ?  |  | Clinical diagnosis  |  | ?  | ?  |  | ?  | ?  | ?  | ?  | Alcohal intake, sudden witdrawl or reduction in consumption  | Tachycardia, diaphoresis, hypertension, tremors, mydriasis, positional nystagmus, tachypnea
Subarachnoid hemorrhage[13] |  | ?  | Xanthochromia[14] | CT scan without contrast[15][16] | ?  | ?  | ?  | ?  | ?  | ?  | ?  | ?  | Trauma/fall  | Confusion, dizziness, nausea, vomiting
Stroke |  | ?  | Normal  | CT scan without contrast  |  | ?  | ?  |  | ?  | ?  |  | ?  | TIAs, hypertension, diabetes mellitus  | Speech difficulty, gait abnormality
Neurosyphilis[17][18] |  | ?  | ? Leukocytes and protein | CSF VDRL-specifc

CSF FTA-Ab -sensitive[19]

| ?  | ?  | ?  | ?  |  | ?  |  | ?  | Unprotected sexual intercourse, STIs  | Blindness, confusion, depression,

Abnormal gait

Viral encephalitis |  | ?  | Increased RBCS or xanthochromia, mononuclear lymphocytosis, high protein content, normal glucose  | Clinical assesment  | ?  | ?  | ?  |  | ?  | ?  | ?  | ?  | Tick bite/mosquito bite/ viral prodome for several days  | Extreme lethargy, rash hepatosplenomegaly, lymphadenopathy, behavioural changes
Herpes simplex encephalitis |  | ?  |  | Clinical assesment  |  |  | ?  | ?  | ?  | ?  | ?  |  | History of hypertension  | Delirium, cortical blindness, cerebral edema, seizure
Wernicke’s encephalopathy |  |  | Normal  |  |  |  | ?  | ?  |  |  | ?  |  | History of alcohal abuse  | Ophthalmoplegia, confusion
CNS abscess |  | ?  | ? leukocytes >100,000/ul, ? glucose and ? protien, ? red blood cells, lactic acid >500mg  | Contrast enhanced MRI is more sensitive and specific,

Histopathological examination of brain tissue

| ?  | ?  | ?  |  | ?  | ?  | ?  | ?  | History of drug abuse, endocarditis, ? immune status  | High grade fever, fatigue,nausea, vomiting
Drug toxicity |  |  |  |  |  |  |  |  |  |  | ?  | ?  |  | Lithium, Sedatives, phenytoin, carbamazepine
Conversion disorder |  |  |  | Diagnosis of exclusion  |  | ?  |  | ?  |  | ?  | ?  | ?  |  | Tremors, blindness, difficulty swallowing
Electrolyte disturbance | ? or ? |  |  | Depends on the cause  |  |  |  |  |  | ?  |  | ?  |  | Confusion, seizures
Febrile seizures |  |  | Not performed in first simple febrile seizures  | Clinical diagnosis and EEG  |  |  |  |  | ?  | ?  | ?  | ?  | Family history of febrile seizures, viral illness or gastroenteritis  | Age > 1 month,
Subdural empyema |  | ?  |  | Clinical assesment and MRI | ?  | ?  | ?  | ?  | ?  |  |  | ?  | History of relapses and remissions  | Blurry vision, urinary incontinence, fatigue
Hypoglycemia | ? or ? |  |  | Serum blood glucose

HbA1c

|  | ?  |  |  |  | ?  |  | ?  | History of diabetes | Palpitations, sweating, dizziness, low serum, glucose

## Epidemiology and Demographics[edit | edit source]

### Incidence[edit | edit source]

The incidence of herpes simplex encephalitis is approximately 0.1-0.2 per 100,000 individuals worldwide.[2][6] Approximately 2,000 cases of herpes simplex encephalitis occur within the United States annually.[4] Approximately 90% of cases are caused by HSV-1, with 10% caused by HSV-2. HSV-2 infection is most commonly observed among immunocompromised individuals and neonates.

### Age[edit | edit source]

Approximately 50% of individuals who develop herpes simplex encephalitis are over 50 years of age.[3]

### Gender[edit | edit source]

There is no gender predilection to the development of herpes simplex encephalitis.[4]

### Race[edit | edit source]

There is no racial predilection to the development of herpes simplex encephalitis.[4]

### Season[edit | edit source]

Unlike other cases of encephalitis, there is no seasonal predilection to the development of herpes simplex encephalitis.[4]

## Risk Factors[edit | edit source]

The most potent risk factor in the development of herpes simplex encephalitis is immune deficiency. Other risk factors include age and extent of human contact.[4][20]

## Natural History, Complications and Prognosis[edit | edit source]

### Natural History[edit | edit source]

Herpes simplex encephalitis constitutes a medical emergency. If left untreated, approximately 70% patients with herpes simplex encephalitis progress to mortality.[2]

### Complications[edit | edit source]

Common complications of herpes simplex encephalitis include:[20]

* Meningitis
* Increased intracranial pressure
* Shock
* Coma
* Seizures
* Aspiration pneumonia
* Respiratory failure

### Prognosis[edit | edit source]

The prognosis for herpes simplex encephalitis is generally poor. Even with rapid treatment, it is fatal in approximately 20% of cases. In approximately 50% of surviving patients, long-term neurological damage is present. Only 2.5% of survivors regain full brain function.[3]

## Diagnosis[edit | edit source]

### Diagnostic Criteria[edit | edit source]

The diagnosis of herpes simplex encephalitis is based on the IDSA criteria, which can be found here.[21]

### History and Symptoms[edit | edit source]

If possible, a detailed and thorough history from the patient is necessary. Symptoms of herpes simplex encephalitis include:[4]

* Decreased alertness
* Confusion
* Fever
* Headache
* Drowsiness
* Lethargy
* Inability to produce or comprehend language
* Difficulty swallowing
* Seizures

### Physical Examination[edit | edit source]

Physical examination findings for herpes simplex encephalitis are generally unspecific. Common physical examination findings of herpes simplex encephalitis include:

* Fever
* Confusion
* Aphasia
* Coma
* Chorioretinitis
* Conjunctivitis
* Erythema multiforme
* Genital and/or oral ulcers

### Laboratory Findings[edit | edit source]

Laboratory findings consistent with the diagnosis of herpes simplex encephalitis include increased leukocytes in cerebrospinal fluid obtained via lumbar puncture.[3] Polymerase chain reaction is critical in the diagnosis of herpes simplex encephalitis, as there is a 95-98% specificity and sensitivity beginning as early as one day after symptoms first appear and lasting up to one week after treatment.[1]

### CT[edit | edit source]

Computed tomography may be helpful in the diagnosis of herpes simplex encephalitis. Findings on CT suggestive of herpes simplex encephalitis include subtle low density within the anterior and medial temporal lobe and the insular cortex.[22][23] Subtleties become more apparent over time and may progress to hemorrhage, and may eventually spread to the other temporal lobe after 7-10 days.[3]

### MRI[edit | edit source]

Magnetic resonance imaging is the imaging modality of choice for herpes simplex encephalitis. Findings on MRI suggestive of herpes simplex encephalitis include:[22][24]

* T1
* General edema in the affected region
* Hyperintense signal if complicated by subacute hemorrhage.
* T1 C+ (Gd)
* Early: enhancement is generally absent.
* Later: enhancement is variable and may appear as:
* Gyral enhancement
* Leptomeningeal enhancement
* Ring enhancement
* Diffuse enhancement
* T2
* Hyperintensity of affected white matter and cerebral cortex.
* DWI/ADC
* More sensitive than T2 weighted images.
* Restricted diffusion is common due to cytotoxic edema.
* GE/SWI
* May demonstrate blooming if hemorrhagic.

The following video demonstrates herpes simplex encephalitis on MRI:

{{#ev:youtube|OLQlsDCcD3Y}}

## Treatment[edit | edit source]

### Medical Therapy[edit | edit source]

The mainstay of therapy for herpes simplex encephalitis includes antiviral therapy. The drug of choice is acyclovir.[4] Supportive therapy for herpes simplex encephalitis includes breathing assistance, intravenous fluids, anti-inflammatory drugs, and anticonvulsant medication.[25]

### Primary Prevention[edit | edit source]

Effective measures for the primary prevention of herpes simplex encephalitis include abstinence from sexual contact, remaining in a long-term mutually monogamous relationship with an uninfected partner, use of latex condoms, and conversing with possible sexual partners regarding infections. Vaccines against herpes simplex have been developed but remain experimental.

## References[edit | edit source]

1. ↑ 1.0 1.1 1.2 1.3 Schlossberg D. Clinical Infectious Disease. Cambridge University Press; 2008.
2. ↑ 2.0 2.1 2.2 2.3 Whitley RJ (2006). "Herpes simplex encephalitis: adolescents and adults". Antiviral Res. 71 (2–3): 141–8. doi:10.1016/j.antiviral.2006.04.002. PMID 16675036.
3. ↑ 3.0 3.1 3.2 3.3 3.4 Whitley RJ, Gnann JW (2002). "Viral encephalitis: familiar infections and emerging pathogens". Lancet. 359 (9305): 507–13. PMID 11853816.
4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 M.D. JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Expert Consult Premium Edition. Saunders; 2014.
5. ↑ Dinn J (1980). "Transolfactory spread of virus in herpes simplex encephalitis". Br Med J. 281 (6252): 1392. PMID 7437807.
6. ↑ 6.0 6.1 Kennedy PG (2004). "Viral encephalitis: causes, differential diagnosis, and management". J Neurol Neurosurg Psychiatry. 75 Suppl 1: i10–5. PMC 1765650. PMID 14978145.CS1 maint: PMC format (link)
7. ↑ Davis LE (2000). "Diagnosis and treatment of acute encephalitis". The Neurologist. 6 (3).
8. ↑ Eckstein C, Saidha S, Levy M (2012). "A differential diagnosis of central nervous system demyelination: beyond multiple sclerosis". J Neurol. 259 (5): 801–16. doi:10.1007/s00415-011-6240-5. PMID 21932127.CS1 maint: Multiple names: authors list (link)
9. ↑ De Kruijk JR, Twijnstra A, Leffers P (2001). "Diagnostic criteria and differential diagnosis of mild traumatic brain injury". Brain Inj. 15 (2): 99–106. doi:10.1080/026990501458335. PMID 11260760.CS1 maint: Multiple names: authors list (link)
10. ↑ Soffer D (1976) Brain tumors simulating purulent meningitis. Eur Neurol 14 (3):192-7. PMID: 1278192
11. ↑
12. ↑ Weston CL, Glantz MJ, Connor JR (2011). "Detection of cancer cells in the cerebrospinal fluid: current methods and future directions". Fluids Barriers CNS. 8 (1): 14. doi:10.1186/2045-8118-8-14. PMC 3059292. PMID 21371327.CS1 maint: Multiple names: authors list (link)
13. ↑ Yeh ST, Lee WJ, Lin HJ, Chen CY, Te AL, Lin HJ (2003) Nonaneurysmal subarachnoid hemorrhage secondary to tuberculous meningitis: report of two cases. J Emerg Med 25 (3):265-70. PMID: 14585453
14. ↑ Lee MC, Heaney LM, Jacobson RL, Klassen AC (1975). "Cerebrospinal fluid in cerebral hemorrhage and infarction". Stroke. 6 (6): 638–41. PMID 1198628.CS1 maint: Multiple names: authors list (link)
15. ↑ Birenbaum D, Bancroft LW, Felsberg GJ (2011). "Imaging in acute stroke". West J Emerg Med. 12 (1): 67–76. PMC 3088377. PMID 21694755.CS1 maint: Multiple names: authors list (link)
16. ↑ DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF; et al. (2011). "ACR Appropriateness Criteria® on cerebrovascular disease". J Am Coll Radiol. 8 (8): 532–8. doi:10.1016/j.jacr.2011.05.010. PMID 21807345.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
17. ↑ Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG; et al. (2012). "Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients". J Neurol Sci. 317 (1–2): 35–9. doi:10.1016/j.jns.2012.03.003. PMID 22482824.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
18. ↑ Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. doi:10.1016/B978-0-7020-4088-7.00098-5. PMID 24365430.
19. ↑ Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–9. doi:10.1097/OLQ.0b013e31824ee574. PMC 3746559. PMID 22421697.
20. ↑ 20.0 20.1 Meningitis and Encephalitis Fact Sheet. National Institute of Neurological Disorders and Stroke. National Institutes of Health (2015). http://www.ninds.nih.gov/disorders/encephalitis_meningitis/detail_encephalitis_meningitis.htm Accessed on February 9, 2015
21. ↑ The Management of Encephalitis: Clinical Practice Guidelines by the Infectious Diseases Society of America. http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/Encephalitis.pdf Accessed on February 16, 2016.
22. ↑ 22.0 22.1 Herpes simplex encephalitis. Radiopaedia.org (2016). http://radiopaedia.org/articles/herpes-simplex-encephalitis Accessed on February 9, 2016.
23. ↑ Zimmerman RD, Russell EJ, Leeds NE, Kaufman D (1980). "CT in the early diagnosis of herpes simplex encephalitis". AJR Am J Roentgenol. 134 (1): 61–6. doi:10.2214/ajr.134.1.61. PMID 6766039.CS1 maint: Multiple names: authors list (link)
24. ↑ Bulakbasi N, Kocaoglu M (2008). "Central nervous system infections of herpesvirus family". Neuroimaging Clin N Am. 18 (1): 53–84, viii. doi:10.1016/j.nic.2007.12.001. PMID 18319155.
25. ↑ Encephalitis: Treatment and drugs. Mayo Clinic. http://www.mayoclinic.org/diseases-conditions/encephalitis/basics/treatment/con-20021917 Accessed on February 11, 2016