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

Herpes simplex encephalitis is a severe viral infection of the central nervous system. Herpes simplex encephalitis may be classified according to origin of 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

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

Pathophysiology

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 thevirus 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

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

Differentiating Herpes simplex encephalitis from Other Diseases

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

Incidence

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

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

Gender

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

Race

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

Season

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

Risk Factors

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

Natural History

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

Complications

Common complications of herpes simplex encephalitis include:[20]

Prognosis

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

Diagnostic Criteria

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

History and Symptoms

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

Physical Examination

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

Laboratory Findings

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

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

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
  • 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
  • DWI/ADC
    • More sensitive than T2 weighted images
    • Restricted diffusion is common due to cytotoxic edema
  • GE/SWI

The following video demonstrates herpes simplex encephalitis on MRI:


Treatment

Medical Therapy

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

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

  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. PMID 16675036. doi:10.1016/j.antiviral.2006.04.002. 
  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 1765650Freely accessible. PMID 14978145. 
  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. PMID 21932127. doi:10.1007/s00415-011-6240-5. 
  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. PMID 11260760. doi:10.1080/026990501458335. 
  10. Soffer D (1976) Brain tumors simulating purulent meningitis. Eur Neurol 14 (3):192-7. PMID: 1278192
  11. 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. PMC 3059292Freely accessible. PMID 21371327. doi:10.1186/2045-8118-8-14. 
  12. 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
  13. Lee MC, Heaney LM, Jacobson RL, Klassen AC (1975). "Cerebrospinal fluid in cerebral hemorrhage and infarction.". Stroke. 6 (6): 638–41. PMID 1198628. 
  14. Birenbaum D, Bancroft LW, Felsberg GJ (2011). "Imaging in acute stroke.". West J Emerg Med. 12 (1): 67–76. PMC 3088377Freely accessible. PMID 21694755. 
  15. 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. PMID 21807345. doi:10.1016/j.jacr.2011.05.010. 
  16. 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. PMID 22482824. doi:10.1016/j.jns.2012.03.003. 
  17. Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. PMID 24365430. doi:10.1016/B978-0-7020-4088-7.00098-5. 
  18. Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–9. PMC 3746559Freely accessible. PMID 22421697. doi:10.1097/OLQ.0b013e31824ee574. 
  19. 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
  20. 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.
  21. 22.0 22.1 Herpes simplex encephalitis. Radiopaedia.org (2016). http://radiopaedia.org/articles/herpes-simplex-encephalitis Accessed on February 9, 2016.
  22. 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. PMID 6766039. doi:10.2214/ajr.134.1.61. 
  23. Bulakbasi N, Kocaoglu M (2008). "Central nervous system infections of herpesvirus family.". Neuroimaging Clin N Am. 18 (1): 53–84; viii. PMID 18319155. doi:10.1016/j.nic.2007.12.001. 
  24. Encephalitis: Treatment and drugs. Mayo Clinic. http://www.mayoclinic.org/diseases-conditions/encephalitis/basics/treatment/con-20021917 Accessed on February 11, 2016

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