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 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. 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. 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. 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. 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.

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. 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. 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.

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:

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		?	Cancer cells	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		?	Xanthochromia	CT scan without contrast	?	?	?	?	?	?	?	?	Trauma/fall	Confusion, dizziness, nausea, vomiting
Stroke		?	Normal	CT scan without contrast		?	?		?	?		?	TIAs, hypertension, diabetes mellitus	Speech difficulty, gait abnormality
Neurosyphilis		?	? Leukocytes and protein	CSF VDRL-specifc CSF FTA-Ab -sensitive	?	?	?	?		?		?	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. Approximately 2,000 cases of herpes simplex encephalitis occur within the United States annually. 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.

Gender

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

Race

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

Season

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

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.

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.

Complications

Common complications of herpes simplex encephalitis include:

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

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.

Diagnosis

Diagnostic Criteria

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

History and Symptoms

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

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

Physical Examination

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

Laboratory findings consistent with the diagnosis of herpes simplex encephalitis include increased leukocytes in cerebrospinal fluid obtained via lumbar puncture. 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.

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. Subtleties become more apparent over time and may progress to hemorrhage, and may eventually spread to the other temporal lobe after 7-10 days.

MRI

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

• 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:

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Treatment

Medical Therapy

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

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.