Neurocritical Care

5. Sorting Out and Treating Encephalitis

A 60-year-old woman was brought to the emergency department for evaluation of acute fever and confusion. She had psoriasis and rheumatoid arthritis, for which she was being treated with weekly doses of methotrexate and efalizumab and had recently received corticosteroids injections in her knees. Spiking fever had been first noticed one week before. Along with the fevers, she had been complaining of malaise and headache. Her primary internist suspected a urinary infection and had started her on levofloxacin two days before. She became more confused over the last 24 hours and was found in the neighbor’s garage at night. We are called to examine

her in the emergency department. She was tachycardic and had a temperature of 39.2˚ Celsius. She exhibited fluctuating level and content of consciousness. Her neck was rigid. Brainstem reflexes were preserved, and she had no lateralizing signs. CT scan showed low attenuation changes in the right temporal and insular regions (Figure 5.1 A and B).


FIGURE 5.1 Brain imaging in our patient with acute HSV-1 encephalitis. CT scan (A and B) showing low attenuation changes in the right temporal lobe and right insular region. Notice also the slightly hyperdense appearance in the Sylvian fissure, which may be confused for a fresh thrombus in the middle cerebral artery (A). The areas of brain swelling are much better visualized on the FLAIR sequence of the MRI (C and D), which also reveals the characteristic asymmetric bilaterality of the inflammation.

What do you do now?

The diagnosis of encephalitis as a syndrome is relatively straightforward. Patients present with headache, fever, confusion, and, when more advanced, abnormal consciousness. Seizures (focal or more generalized) are a common manifestation. Examination may show neck stiffness or focal deficits, but there may be no localizing signs. In fact the diagnosis may not even be considered if the patient is seen early in the course and is just “confused”. While the CT scan can be highly suggestive of certain forms of encephalitis (as illustrated by the temporal and insular areas of swelling in our patient with herpes simplex virus type 1 [HSV-1] encephalitis) (Figure 5.1), radiological changes are generally not characteristic of specific encephalitis etiologies. A brain MRI is far more helpful (Table 5.1). Cerebrospinal fluid (CSF) showing increased white blood cell count, and an increased protein concentration confirms the presence of encephalitis. A normal CSF strongly points towards alternative diagnoses (such as noninfectious limbic encephalitis).

TABLE 5.1 Causes of Acute Encephalitis with Characteristic Radiological Features


Characteristic radiological features

Herpes simplex virus type 1

Inflammatory lesions in temporal lobes, insula, and operculum

Varicella herpes zoster

Multifocal infarctions and irregularities of arterial lumen


Cerebellitis in children


Ventriculitis (subependymal enhancement). Brainstem inflammation

West Nile virus



Basilar meningitis

Fungal infections

Abscess formation**

Autoimmune limbic encephalitis

Inflammatory lesions in mesial temporal lobes

Acute disseminated encephalomyelitis

Bilateral white matter T2-hyperintense lesions. Corpus callosum involvement

Progressive multifocal leukoencephalopathy (JC virus)

Bilateral, confluent T2-hyperintense lesions in temporo-occipital white matter with involvement of U fibers and cortical sparing

* Presentation with acute flaccid paralysis may occur with or without radiological signs of myelitis.

 Also with fungal meningoencephalitis caused by Blastomycosis

** Aspergillus species is characterized by infarctions and hemorrhages

Recognizing a clinical presentation consistent with the diagnosis of acute encephalitis is just the first step. Encephalitis can be infectious, postinfectious, and noninfectious (Table 5.2). Autoimmune (paraneoplastic or not) and radiation-induced encephalitis are noninfectious examples. Defining the precise cause of the acute encephalitis is a much more difficult task that requires almost encyclopedic knowledge of neurological and infectious diseases, and working with a knowledgeable infectious disease consultant can be very helpful in these cases. Equally important is to narrow the differential diagnosis depending on the season, geographic area, specific exposures (including recent travel history) and risk factors.

Viral infection is the most common cause of acute encephalitis in adults. Epidemic outbreaks can be produced by the seasonal spread of arboviruses (i.e., viruses transmitted by arthropod vectors, such as mosquitoes). Most of these agents are constrained to specific geographical locations, but there are exceptions such as the West Nile virus or H1N1, which has been identified as a cause of outbreaks of encephalitis in all continents. Viral encephalitis can also be sporadic. Sporadic cases can occur in the immunocompetent and the immunodepressed patient.

HSV-1 is the most frequent cause of sporadic viral encephalitis in immunocompetent patients. HSV-1 encephalitis has a predilection for the temporal lobes, insula, and operculum. Consequently, it should be suspected when a febrile patient develops confusion or drowsiness associated with seizures or focal deficits referable to those locations. Aphasia, amnesia, hallucinations, agitation, visual field deficits and oral apraxia can be seen. When present, the typical distribution of swelling on brain MRI (Figure 5.1 C and D) strongly supports the diagnosis. Yet, the diagnosis should be established by confirming the presence of the virus in the CSF. Polymerase chain reaction (PCR) can detect HSV-1 DNA in the CSF with great sensitivity and specificity. If PCR is negative but the clinical-radiological presentation is suspicious for HSV-1 infection, the test should be repeated on a new CSF sample after 3–5 days.

TABLE 5.2 Main Causes of Acute Encephalitis, Diagnostic Test, and Principal Aspects of Management



Ab, antibodies; CMV, cytomegalovirus; CSF, cerebrospinal fluid; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; HSV-1, herpes simplex virus type 1; IMF, immunofluorescence; NMDA = N-methyl D-Aspartate; PML, Progressive multifocal leukoencephalopathy; PMN, polymorphonuclear; TPO, thyroid peroxidase; VZV, varicella-zoster virus; WNV, West Nile virus

*Serum antibodies are more sensitive than CSF antibodies.

 Bacterial infections that may present with acute encephalitis include Bartonella, Listeria (which characteristically causes a rhombencephalitis), Mycoplasma, and Tropherima whippeli.

** Sensitivity may not be optimal.

 Intrathecal amphotericin B may be necessary in severe cases.

Electroencephalography (EEG) should be performed in patients with HSV-1 encephalitis. It is not infrequent to see patients with encephalitis who exhibit fluctuating levels of alertness and awareness. In these cases we often pursue continuous EEG monitoring. Continuous EEG monitoring should also be considered in comatose patients with encephalitis. Nonconvulsive seizures are not uncommon but should be differentiated from periodic lateralized epileptiform discharges (PLEDs). Nonconvulsive seizures must be treated with antiepileptic drugs. When PLEDS are frequent or tend to become rhythmic, we also favor the use of antiepileptics to prevent seizures.

The role of brain biopsy has been relegated to very few selected cases thanks to the high yield of PCR. Brain biopsy in unexplained encephalitis is only considered once all noninvasive diagnostic alternatives have been exhausted and the patient continues to decline despite treatment with adequate doses of acyclovir. It is also advisable to search for other biopsy targets before invading the brain. Detailed physical examination with especial attention to the skin and lymph node chains; CT scans of chest, abdomen, and pelvis; and PET scan can deliver a more accessible site for tissue sampling. Brain biopsy should be guided by MRI findings, and we favor inclusion of a meningeal sample. When neuroimaging is unrevealing, the yield of random brain biopsy is much lower, but pathology may still be diagnostic in these cases. The most salient issue about the evaluation of unexplained encephalitis is how much of it may be without results—an intimidating assignment to say the least.

All patients with presumed acute encephalitis should be started immediately on intravenous acyclovir (10 mg/kg every 8 hours; longer intervals between doses in case of reduced glomerular filtration rate). This antiviral agent is the first choice for treating HSV-1, HSV-2, and varicella-zoster virus. Cytomegalovirus infection requires the combination of ganciclovir and foscarnet; these patients should also be tested for HIV infection. Ganciclovir and foscarnet are also the treatment for HSV-6 infection in immunosuppressed patients. No antiviral has proven effective against West Nile virus infection. HIV-infected patients must receive highly active antiretroviral therapy. In cases of progressive multifocal leukoencephalopathy (JC virus), the treatment consists of reversing immunosuppression. Main treatment measures for nonviral causes of encephalitis are summarized in Table 5.2.

Patients who develop severe brain swelling might require intracranial pressure monitoring. Intraparenchymal monitors are preferable when the ventricles are compressed by brain edema. Head of bed elevation and osmotic agents (mannitol, hypertonic saline) are the first step in cases of intracranial hypertension. The most severe cases may demand decompressive craniectomy. Corticosteroids do not have a role in the treatment of viral encephalitis.

The management of acute encephalitis may require admission to an intensive care unit. The major issues are recognition and treatment of seizures requiring video/EEG monitoring, mechanical ventilation in patients unable to protect the airway (due to abnormal consciousness or requirement of anesthetic drugs to control seizures or agitation), and treatment of brain swelling and medical complications. Even when the cause of the encephalitis is not treatable, aggressive supportive care increases the chance of a favorable outcome.

Our patient was started on intravenous acyclovir in the emergency department. An MRI of the brain (Figure 5.1 C and D) was obtained to delineate the degree of temporal lobe swelling before proceeding with lumbar puncture. The CSF contained 14 white blood cells (predominantly lymphocytes), a protein concentration of 58 mg/dL, and normal glucose level. Shortly after arrival to the ICU she was intubated because of progressive stupor and inability to protect the airway patency. Levofloxacin was stopped (it can reduce seizure threshold) and she was prophylactically started on intravenous levetiracetam. EEG demonstrated frequent periodic epileptiform discharges arising from the right temporal region but no electrographic seizures. Within hours we received confirmation that the PCR for HSV-1 was positive. She began to improve within the following 5 days. Two weeks later she was discharged home, where she continued recovering and completed a 21-day course of acyclovir. Her systemic immunosuppressive regimen was permanently stopped. Six months later she had regained full function.


· Always consider the diagnosis of encephalitis in a febrile and confused patient, regardless of the presence of meningealsigns or focal deficits.

· Start intravenous acyclovir in all patients with suspected viral encephalitis.

· PCR for HSV-1 should be performed in all CSF samples of patients with presumed encephalitis. If PCR is negative but the diagnosis is still suspected (clinical or radiological localization to the temporal lobes or insular/opercular region), acyclovir should be continued and PCR should be repeated after 3-5 days.

· MRI with gadolinium is the most informative neuroimaging modality for patients with suspected encephalitis.

· Every patient with HSV-1 encephalitis should have an EEG. In patients with fluctuating consciousness the option of continuous EEG monitoring should be considered to exclude nonconvulsive status epilepticus.

Further Reading

Barnett GH, Ropper AH, Romeo J. Intracranial pressure and outcome in adult encephalitis. J Neurosurg 1988; 68:585-588.

Kastrup O, Wanke I, Maschke M. Neuroimaging of infections of the central nervous system. Semin Neurol 2008; 28:511-522.

McGrath N, Anderson NE, Croxson MC, Powell KF. Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome. J Neurol Neurosurg Psychiatry 1997; 63:321-326.

Rosenfield MR, Dalmau J. Update on paraneoplastic and autoimmune disorders of the central nervous system. Semin Neurol 2010; 30:320-33.

Steiner I, Budka H, Chaudhuri A, Koskiniemi M, Sainio K, Salonen O, Kennedy PG. Viral meningoencephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol 2010; 17:999-1009.

Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld WM, Whitley RJ; Infectious Diseases Society of America. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008; 47:303-327.

Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. Lancet 2002, 359:507-513.