Introduction

Encephalitis is defined as a neurological dysfunction caused by inflammation of the brain (Tunkel et al. 2008; Venkatesan et al. 2013). Previously the gold standard for diagnosis rested on obtaining brain tissue sampling for pathological analysis. However, it is currently widely accepted to rely on surrogate clinical markers demonstrating the presence of inflammation (e.g., cerebrospinal fluid (CSF) analysis, neuroimaging) (Kneen et al. 2012). Encephalitis can be categorized into the following main disease processes: (1) direct infection of the brain parenchyma, (2) postinfectious inflammatory or autoimmune processes such as acute disseminated encephalomyelitis (ADEM), and (3) other noninfectious diseases like anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis (Venkatesan et al. 2013). The latter two categories are beyond the scope of this chapter which will focus on the first category, direct infection of the brain parenchyma.

Encephalopathy is defined as a clinical state of altered mental status with or without inflammation of the brain parenchyma. In general, this entity is related to metabolic or toxic disorders but may also be related to infectious agents. As the definition of both these entities shows significant overlap, the International Encephalitis Consortium recently submitted a consensus statement offering a definition capturing both encephalitis and encephalopathy (Venkatesan et al. 2013). The presence of altered mental status lasting more than 24 h without an alternative etiology is a required major criterion. Also, there must be two minor criteria for possible encephalitis or at least three minor criteria for probable encephalitis. The following findings are considered minor criteria: (1) fever equal or greater than 38 °C (100.4 °F) in the 72 h around presentation, (2) seizure (generalized or partial) not due to known preexisting seizure disorder, (3) new focal neurological deficit, (4) CSF white blood cell (WBC) count equal or greater to 5/mm3, (5) neuroimaging showing new or acute appearance of brain parenchyma abnormality, and (6) abnormal electroencephalogram consistent with encephalitis. The diagnosis of confirmed encephalitis needs the presence of the major criterion, at least three minor criteria and one of the following additional findings: (1) brain tissue sampling showing parenchymal inflammation consistent with encephalitis; (2) pathologic, microbiologic, or serologic evidence of infection with microorganism capable of causing encephalitis; or (3) evidence of autoimmune disorders associated with encephalitis (Venkatesan et al. 2013). Future use of this precise definition should allow better collection and comparison of data.

In this chapter, we will focus on viral encephalitis and will elaborate on some of the most commonly encountered viruses in Western industrialized nations such as: (1) herpes simplex virus; (2) arboviruses (e.g., West Nile, Japanese, Zika, St. Louis, La Crosse); and (3) enteroviruses. We will not discuss bacterial, fungal, tuberculosis, HIV, or parasitic infections as these will be discussed in other sections of this textbook. We will briefly mention immunization recommendations for international travel as they relate to viral encephalitides. Lastly, a section of this chapter will summarize the role of the neurosurgeon in the management of viral encephalitis including brain tissue sampling and treatment of increased intracranial pressure.

Viral Encephalitis

The accurate incidence of infectious encephalitis in the pediatric population is difficult to establish due to the disparate definitions and methodologies used in the literature. Kneen et al. (2012) reports an incidence of 10.5–13.8 per 100,000 in Western industrialized settings.

In 2008, the Infectious Diseases Society of America (ISDA) published guidelines for the assessment and management of patients with encephalitis based on a consensus of a panel of experts (pediatric and adult infectious disease and neurology specialists) (Tunkel et al. 2008). In 2012, the Association of British Neurologists and British Paediatric Allergy, Immunology and Infection Group published guidelines for the management of viral encephalitis with a focus on the pediatric population (Kneen et al. 2012). These experts graded their recommendations as per the Canadian Task Force on the Periodic Health Examination (A = good evidence to recommend use; B = moderate evidence to recommend use; C = poor evidence to support recommendations; I = evidence from one or more good randomized controlled trial; II = evidence from one or more well-designed nonrandomized trial, cohort or case-control study, multiple time-series or important results in uncontrolled study; III = evidence from expert opinions, clinical experience, descriptive studies, or expert committees). Table 1, adapted from the work of these experts, summarizes the epidemiology, geographic location, mode of transmission, clinical manifestation, diagnostic evaluation, and general management for selected viruses capable of causing encephalitis. The reader is encouraged to refer to the publication by the IDSA for further details (Tunkel et al. 2008) .

Table 1 Summary of selected viral encephalitides (Adapted from Tunkel et al. 2008)
Full size table

Clinical Manifestations of Viral Encephalitis

In general, children affected by encephalitis most commonly present with fever (67–80%), new focal neurological deficit (36–78%), altered mental status or changes in personality (40–76%), and seizures (33–78%) (Kolski et al. 1998; Wang et al. 2007; Kneen et al. 2010). In a study by Wang et al. (2007) of 101 children diagnosed with encephalitis, only 22% had signs of meningismus. It is important to highlight the possible differences in clinical presentation between children and adults affected with encephalitis. Infants and younger children are unable to express their complaints as readily as older children and adults. Also, they frequently present with various nonspecific findings such as feeding difficulties, irritability, or symptoms of concomitant infections. For example, in a study by Wang et al. (2007), clinical manifestations of respiratory infection and gastrointestinal disturbances were present in 54% and 21%, respectively (Wang et al. 2007). The Association of British Neurologists and British Paediatric Allergy, Immunology and Infection Group recommends that any combination of these signs and symptoms that could raise suspicion of encephalitis should initiate proper investigations (Grade A, level II) (Kneen et al. 2012). It is prudent to consider noninfectious encephalopathic processes and autoimmune encephalitis for the child presenting in a subacute fashion. Certain risk factors should be considered to help clarify the etiology. For example, exposure to possible mosquito or tick bites and recent traveling could suggest arbovirus or tick-borne encephalitis and geographic-specific viruses. Questions about HIV risk factors, other immunocompromise, immunization status, and recent vaccinations should also be considered. Finally, attention to skin examination for presence or absence of rash can be suggestive of particular pathogens (e.g., enterovirus, varicella zoster, Neisseria meningitidis, etc.) (Solomon et al. 2007; Kneen et al. 2012) .

Diagnostic Investigations

After initial stabilization, the patient suspected of having encephalitis should undergo a lumbar puncture (LP) as soon as possible if there are no contraindications (grade A, level II). Clinical findings suggestive of increased intracranial pressure (altered level of consciousness, papilledema, bradycardia with hypertension, posturing), focal neurological deficits, or seizure should prompt immediate evaluation with a head CT scan before considering LP (grade A, level II). The LP should be deferred if the basal cisterns are not visible, if there is significant cerebral edema or mass effect. If the LP is delayed or initially contraindicated, the authors of the Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines suggest starting IV acyclovir empirically (Kneen et al. 2012).

During the LP procedure, an opening pressure should be measured and CSF analyzed for protein and glucose levels as well as red blood cell count, white cell count, and differential and for microbiological investigations (grade A, level II). The latter should include bacterial cultures (grade A, level II) and polymerase chain reaction (PCR) testing for HSV-1, HSV-2, VZV, enterovirus, and parechovirus for all patients (grade B, level II). CSF analysis suggestive of viral infection could have the following findings: normal to high opening pressure; slightly increased cell count with differential favoring lymphocytes, normal CSF/plasma glucose ratio; and normal to high protein level (0.5–1 g/L) (Kneen et al. 2012). If clinically suspected, additional cultures for Mycobacterium tuberculosis or PCR testing for other pathogens (e.g., EBV, CMV, HHV6, influenza virus, measles, mumps, West Nile virus, etc.) should be considered. Furthermore, if the initial results are negative despite clinical suspicion of encephalitis, a repeat LP and CSF analysis should be done with possible CSF and serum testing for viral antibodies (IgM and IgG) for HSV-1, HSV-2, VZV, CMV, HHV-6, HHV-7, RSV, enteroviruses, erythrovirus B19, adenovirus, influenza A and B (grade A, level II) (Kneen et al. 2012). Based on their review of available data and UK guidelines, Kneen et al. (2012) also recommend HIV testing for all patients with encephalitis even in the absence of risk factors (grade A, level II). On the other hand, certain authors recommend testing for HIV only in the immunocompromised patient (Venkatesan et al. 2013). Of course, CSF, serum, and other tissues sampling should be done in consultation with infectious disease and/or neurology specialists .

If indicated based on the presentation, a sampling of specific tissues (e.g., blood, nasopharynx, stool, skin vesicles, or sputum) for cultures, PCR testing, and/or histopathological examinations should be performed (Table 1) (Tunkel et al. 2008).

As soon as the patient’s condition allows, MRI of the brain should be obtained. Imaging protocols should at least include T1, T2, fluid-attenuated inversion recovery (FLAIR), diffusion weighted and postcontrast images. Preferably, imaging should be obtained within 24 h, but can be delayed up to 48 h if necessary (grade B, level II). An urgent CT scan is an acceptable initial alternative if the patient is too unstable to undergo MRI. However, an MRI should still follow as it is more sensitive than CT in detecting abnormalities in viral encephalitis (Tunkel et al. 2008; Kneen et al. 2012).The use of other imaging modalities such as MR spectroscopy, SPECT, and PET have not been thoroughly studied in this entity and are not currently recommended (grade B, level II) (Kneen et al. 2012).

Lastly, electroencephalography (EEG) is not recommended in all cases of suspected encephalitis as it is rarely diagnostic. It can be used in patients with clinical manifestations suggestive of nonconvulsive seizures or those with altered mental status to establish encephalopathic EEG findings (grade B, level II) (Kneen et al. 2012).

Herpes Simplex Virus Encephalitis

Description of Viral Structure

The alphaherpesviridae family includes herpes simplex viruses HSV-1 and HSV-2 among many others (Table 1). HSV contains linear double-stranded DNA surrounded by an icosahedral nucleocapsid. The presence of specific glycoproteins allows linking to and entry into cells leading to host immune reaction and antibody response (Pinninti and Kimberlin 2013).

Disease Classification and Clinical Manifestations

When discussing HSV infection and encephalitis, the age of the patient must be considered. The manifestations and outcomes differ between neonatal infections and children of older age.

Neonatal HSV infections, occurring 1 in 3,200 deliveries, can take place in the following settings: (1) intrauterine (5%); (2) peripartum (85%); or (3) postnatal (10%). The first scenario of intrauterine transmission of HSV has been reported to occur in 1 in 300,000 deliveries (Baldwin and Whitley 1989). Generally, the manifestations are present at birth and include a myriad of cutaneous, ophthalmologic, and neurologic findings. The latter may include intracranial calcifications, microcephaly, corpus callosum agenesis, and encephalomalacia (Jayaram and Wake 2010; Pinninti and Kimberlin 2013). Work by the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group (CASG) has elaborated three categories of clinical presentations of peripartum and postnatal HSV infections. This is referred to as the Whitley-Kimberlin disease classification (Whitley et al. 1991b; Caviness 2013). The first category, disseminated disease, occurs in 25% of neonatal infections and is typically present in the first 1–2 weeks of life. Concomitant encephalitis is present in two-thirds of these patients. They can manifest with poor feeding, respiratory disturbance (i.e., pneumonitis), sepsis-like state, abnormally elevated hepatic enzymes (i.e., hepatitis), thrombocytopenia, and coagulopathy. CNS involvement can present with altered mental status, seizures, and other signs of increased intracranial pressure such as bulging anterior fontanelle. Brain imaging may show evidence of edema and hemorrhage that can lead to encephalomalacia. With high-dose acyclovir (60 mg/kg/day), 12-month mortality rates have decreased from 85% to 29%. Deaths in the majority of these cases are caused by complications of coagulopathy, hepatic or respiratory failure.

The second category, skin, eye, or mouth (SEM) disease, represents 45% of neonatal HSV infections. It also tends to present in the first 10–12 days of life. Without antiviral treatment, 23% will show signs of CNS involvement and 37% will progress to disseminated disease (Caviness 2013). However, all those treated before the limited disease progresses to a more severe involvement will likely survive.

The third category, CNS disease, is responsible for 30% of neonatal herpes infection. It generally manifests later than the two previous categories at around 16–19 days of life. Manifestations of CNS involvement are the same as described above. Up to 30% of the patients will never develop skin lesions during their illness. On brain imaging, it is important to note that multiple areas of the brain can be involved unlike adult herpes encephalitis which often localizes to the temporal lobes. Again, acyclovir has made a significant impact decreasing mortality rates from 50% to 17% at 1 year. Unfortunately, in the NIAID CASG trials, 43% of the children presenting with CNS disease progressed to disseminated disease (Mennemeyer et al. 1997).

The risk of maternal transmission of HSV infection to the neonate is higher with first-episode maternal infections than with recurrent genital herpes. Maternal screening, antiviral suppressive treatment, and cesarean delivery are methods that can be recommended under certain conditions to reduce the infant’s risk of HSV infection. In 2013, Pinninti and Kimberlin published detailed approaches on the prevention of transmission of HSV and the management of infants born to women with active lesions or history of genital herpes.

In older children, HSV represents 10–20% of viral encephalitis with an incidence of about 1 case in 250,000 to 500,000 persons per year (Whitley 2006). There is no geographic or seasonal predilection. It can occur in the setting of primary infection or due to reactivation of previous HSV infection. Primary infections of the CNS occur in one-third of patients with the majority being less than 18 years of age. HSV encephalitis in the presence of preexisting antibodies from a prior herpes infection occurs with a known history of herpes labialis in only 10%. The pathophysiology remains unclear as the virus identified in the CNS can differ from the non-CNS site. In both primary and recurrent HSV infections, the involvement of the CNS is thought to result from transmission of the virus via olfactory tract and trigeminal nerves (Davis and Johnson 1979; Whitley 2006). Reactivation directly in the brain parenchyma remains hypothetical.

In both primary or reactivation infections, the clinical manifestations remain nonspecific with the majority showing an encephalopathic process with focal findings on exam, imaging, or EEG. About two-thirds of patients present with focal and/or generalized seizures. In general, a patient presenting with complaints of a headache, fever, changes in behavior or personality, and seizures concomitant with increased white blood cell count in the CSF with negative bacterial or fungal cultures should raise suspicion for herpes encephalitis (Whitley 2006).

HSV-Specific Investigations

As described previously, lumbar puncture for CSF HSV PCR testing should be attempted when the procedure is considered safe and not contraindicated. Its sensitivity and specificity in neonatal HSV infection has been reported to be 75–100% and 71–100%, respectively (Kimberlin et al. 1996; Pinninti and Kimberlin 2013). However, a negative result should be interpreted with caution as it can represent a false negative in the acute time period. The most common recommendation in the face of an initial negative result and suspicion of HSV encephalitis is to repeat the LP within 3–7 days. Analysis of HSV PCR should be repeated and testing for HSV antibodies should be considered, although the latter may not be contributory in the acute setting (Venkatesan et al. 2013). Serum HSV PCR can be obtained, but little data is available to estimate its current sensitivity and specificity in diagnosing HSV encephalitis (Kimura et al. 1991). On the other hand, serologic testing for HSV antibodies in the neonate is not recommended as transplacental transmission of maternal antibodies may confound the interpretation of the results. Other investigations to establish the diagnosis of HSV infection include serum hepatic enzymes as well as cultures and PCR analysis of vesicles or of suspicious skin lesions (Pinninti and Kimberlin 2013).

As recommended for the investigation of viral encephalitis in general, MRI of the brain should be obtained in the first 24–48 h when possible. In about 90% of cases, brain abnormalities related to the inflammatory process will be visible. Signal changes consistent with gyral edema seen on T1-weighted and FLAIR images located in the medial temporal lobe and cingulate gyrus are typically described in HSV encephalitis. With time, the affected brain may show hemorrhagic changes. Although medial temporal lobe involvement has been well described in HSV encephalitis, it may present differently (Kneen et al. 2012). Thus, HSV encephalitis should not be excluded based on multifocal or nonspecific pattern of signal changes on MRI.

Likewise, EEG abnormalities are generally nonspecific other than when seizure activity is recorded. Findings have included diffuse high-amplitude slow waves and can be occasionally localized to the temporal lobe with spike-and-wave activity. Previously, periodic lateralized epileptiform discharges (PLEDs) were considered pathognomonic for HSV encephalitis, but it is now frequently identified in various viral encephalitides (Kneen et al. 2012).

Additional investigations should be tailored based on presentation and suspicion of the category of disease. Organ-specific evaluations may include, for example, ocular or pulmonary (Caviness 2013) .

HSV-Specific Treatment

All children with confirmation of HSV encephalitis, with or without disseminated disease, should be treated with high-dose intravenous acyclovir (60 mg/kg/day given every 8 h, dose adjusted based on renal clearance) for 21 days. After the minimum duration of treatment, a repeat CSF HSV PCR should be obtained. Antiviral treatment should be continued until a negative result is obtained. Serologic PCR for following treatment response has not been well studied and is not currently recommended (Whitley et al. 1991a; Kimberlin et al. 2001; American Academy of Pediatrics 2009).

After initial treatment, suppressive treatment should be continued for 6 months for all neonatal HSV infections (SEM, CNS, and disseminated disease). The current regimen is oral acyclovir given at 300 mg/m2 per dose three times per day. One must follow dosing levels due to low bioavailability as well as monitor for neutropenia (Kimberlin et al. 2011; Pinninti and Kimberlin 2013; Caviness 2013).

Empiric antiviral treatment in the child assessed for sepsis remains controversial. Kneen et al. (2012) and Tunkel et al. (2008) both recommend initiating intravenous acyclovir in all patients suspected to have viral encephalitis (grade A, level II–III) since acyclovir has been shown to decrease mortality, and HSV encephalitis remains the most common viral encephalitis in industrialized countries. Acyclovir may be discontinued in the immunocompetent patient if: (1) diagnosis made for other etiology; (2) two negative CSF HSV PCR analyses (done 24–48 h apart) and neuroimaging not suggestive of HSV encephalitis (MRI, done at more than 72 h after clinical presentation); or (3) one negative CSF HSV PCR done more than 72 h after initial clinical symptoms concomitant with normal level of consciousness, normal MRI, and white cell count in CSF of less than 5 × 106/L (grade B, level III) (Kneen et al. 2012).

Outcome

Mortality rates for both disseminated HSV disease and CNS involvement have significantly decreased with the use of high-dose acyclovir in neonates (29% and 4% 12-months mortality, respectively). High-dose acyclovir has also led to an improved developmental outcome, with normal development measured at 1 year of age 6.6 times more likely (Kimberlin et al. 2001) .

Arbovirus Encephalitis

Common in lay media reports of encephalitis are the arboviruses. These include West Nile virus , Eastern equine encephalitis virus , Chickungunya virus, Japanese encephalitis virus , Saint Louis encephalitis virus, La Crosse encephalitis virus, and Zika virus (Salimi et al. 2016). The name arbovirus stems from these agents being arthropod-borne. Common carriers include mosquitoes and ticks, and some have an animal reservoir. These RNA viruses each have a geographic distribution as reviewed in Table 1. A review of United States arbovirus infections from 2003 through 2012 revealed 1,217 cases with a 1.8% mortality (Gaensbauer et al. 2014). Arboviruses implicated were La Crosse in 55%, West Nile in 41%, and Eastern equine in 2%, the latter having a mortality rate of 33%. Younger children were more commonly infected with La Crosse and older children with West Nile. West Nile cases were distributed across the USA, while La Crosse primarily occurred in the Midwest, and Eastern equine along the East coast.

The diagnosis and management of arbovirus encephalitis mirrors HSV encephalitis and, therefore, will not be separately discussed. Unlike HSV, however, the arboviruses typically have no specific therapeutic agent and treatment is generally supportive. In addition, arbovirus encephalitis can lead to lasting effects, including a 40–70% rate of cognitive issues at 5 years (Salimi et al. 2016). As of 2013, there is an approved vaccine for Japanese encephalitis which is discussed later in this chapter (CDC 2013). Prevention of the other arboviruses rests with control, avoidance, and repellants of the arthropod vectors.

Most recently, Zika virus has emerged as a worrisome threat. Spreading northward to the USA from Latin America, Zika infections in adults are usually mild. The glaring exception, however, is fetal infection which can be devastating. If the pregnancy carries to term, there may be significant cerebral developmental anomalies outwardly recognized as microcephaly. The consequences are variable, but notable neurologic deficit, seizure, and developmental delay are common (Salimi et al. 2016) .

Enterovirus Encephalitis

Enteroviruses are so named due to disease transmission via the enteral tract; however, respiratory spread is also possible (Jain et al. 2014). They have an RNA genome and belong to the family Picornaviridae. Although enteroviruses lead to encephalitis in only 3% of cases, morbidity and mortality can be significant. The typical pathogens include serotypes of the coxsackieviruses and echoviruses as well as enterovirus 71. Most enterovirus infection is mild, including hand, foot, and mouth disease. Enterovirus encephalitis has a predilection for the brainstem, but can also affect the thalami, putamina, dentate nuclei, and cervical spinal cord. These areas underscore the seriousness of enterovirus encephalitis. Unfortunately, specific antivirals are not available and treatment is supportive (Jain et al. 2014). Preventative efforts focus on sanitary measures to decrease disease transmission. There is currently an effort to develop a vaccine against the virulent subtype enterovirus 71 (Yee and Poh 2015) .

Traveling and Immunization

As international travel becomes more readily accessible, the differential diagnosis of infectious encephalitis must often be broadened to include unfamiliar exotic microorganisms. Patients intending to travel can be referred to infectious disease clinicians for a discussion about the risks of travel-acquired infections and the methods of prevention. In addition, the United States Centers for Disease Control and Prevention (CDC) website is a very informative resource (Centers for Disease Control and Prevention 2016).

It is widely accepted that vaccines have helped prevent and almost eradicate many diseases with dreadful CNS complications, such as mumps and polio. Additional vaccinations may be indicated for the traveling patient. Key among these is a Japanese encephalitis vaccine approved by the United States Food and Drug Administration (FDA) in 2013. It is a vero cell culture-derived vaccine approved for patients at least 2 months of age. It is recommended for travelers visiting endemic rural and agricultural areas, such as those in Southeast Asia, for 1 month or longer. It should be considered for shorter stays during high-risk seasons. It is not recommended for travelers to urban areas, especially outside of high-risk seasons (CDC 2013). In general, when considering immunization for traveling purposes, it is best to consider the following: (1) overall risk for travel-acquired infection based on itinerary, endemic areas, and activities; (2) the treatments available and possible morbidity and mortality if the disease occurs; and (3) the rates of seroprotection and risks of adverse events with vaccination .

Neurosurgical Implications

The neurosurgeon is occasionally involved in the care of children with encephalitis. Neurosurgical consultation may be sought for: (1) brain biopsy and (2) management of increased intracranial pressure.

Brain Tissue Sampling

As major improvements are being made in diagnostic PCR and antibody assays, the need for brain biopsy has become infrequent and is no longer routinely recommended. However, the procedure should be considered for patients with encephalitis of unknown origin without improvement or with rapid clinical deterioration despite appropriate medical treatment (grade B, level II) (Kneen et al. 2012). If brain biopsy is indicated, a 1989 study from the NIAID Collaborative Antiviral Study Group showed it was diagnostic and helpful in up to 67% of patients. It confirmed the diagnosis of suspected herpes simplex encephalitis in 45% of patients. Another 22% of the patients were diagnosed with an alternative etiology while only 33% of the 432 patients were left without a final diagnosis (Whitley et al. 1989).

In general, the neurosurgeon will plan an image-guided biopsy targeting a noneloquent region of abnormal cerebral parenchyma showing contrast enhancement. The choice of surgical technique is based on surgeon preference, the location of biopsy target, and clinical status of the patient. A retrospective case series of 58 patients at the University of California, San Francisco, did not show an association between the choice of surgical technique (stereotactic biopsy, open biopsy, or open resection) and the identification of a specific cause of encephalitis (Gelfand et al. 2015). If only nonfocal abnormalities are evident on neuroimaging, an open approach with biopsy of nondominant and noneloquent tissue is favored (grade B, level II) (Kneen et al. 2012).

When performing an open biopsy, the neurosurgeon should attempt to obtain at least 1 cm3 of tissue. The tissue should be sharply dissected if possible to avoid histology artifacts. Enough specimen should be obtained for culture, PCR, immunofluorescence, and histopathologic examination (Tunkel et al. 2008). Proper personal protective precautions must be observed, especially when the differential diagnosis includes HIV or prion disease.

Although the risk of surgical complication is low, it is not zero. A retrospective study of 39 patients undergoing open or stereotactic biopsy for nonneoplastic disease (7 for suspected encephalitis) found low complication rates. None were observed for stereotactic biopsy (n = 11). The two in the open biopsy group (n = 28) were transient focal neurological deficit and transient exacerbation of seizure activity (Pulhorn et al. 2008). Another study including 550 subjects undergoing stereotactic biopsy for various space occupying lesions (8.0% for inflammatory processes) found 2.4% intracranial hemorrhages, 1.2% intraoperative seizures, 4.2% transient neurological deficits, and no deaths (Yu et al. 2000). Therefore, although the neurosurgeon should always be cautious, the overall complication rates for brain biopsy appear acceptable if the procedure is indicated .

Management of Increased Intracranial Pressure

In the setting of generalized brain edema with increased intracranial pressure (ICP), a stepwise approach from medical management to surgical interventions can be utilized. An important initial step is to treat seizures, which can at times present in the form of status epilepticus. By causing increased metabolic activity, acidosis, and vasodilatation, seizure activity can lead to worsening intracranial hypertension . It may even lead to fulminant cerebral edema (Lan et al. 2016). Other basic maneuvers include raising the head of the bed to 30°, ensuring proper cerebral venous drainage by maintaining the neck straight and free of constrictions, and maintaining a low-normal arterial carbon dioxide level (such as 35–40).

The use of corticosteroids in infectious encephalitis remains controversial. Animal studies in mice with HSV encephalitis have shown a beneficial effect (Meyding-Lamadé et al. 2003). A retrospective study of 45 patients with HSV encephalitis (mean age 46 years old, range 17–77 years old) demonstrated that the addition of corticosteroids to acyclovir was associated with better outcomes at 3 months (Kamei et al. 2005). However, others disagree with its use as the immunomodulatory effects of the drug could possibly negatively impact the host response to infection and could enable viral replication (Openshaw and Cantin 2005; Kneen et al. 2012). In general, it is typically added when faced with increased intracranial pressure and severe cerebral edema. A double-blind, randomized, placebo-controlled trial on the use of corticosteroids and acyclovir in adults with HSV encephalitis is currently underway and will hopefully clarify recommendations (Martinez-Torres et al. 2008).

An additional step in the management of increased intracranial pressure is the use of hyperosmolar agents. In a study of 23 Kenyan children with cerebral malaria, mannitol was able to control the ICP of 9 children with intermediate intracranial hypertension (defined as ICP greater than 20 mm Hg and cerebral perfusion pressure less than 50 mm Hg for more than 15 min) (Newton et al. 1997; Solomon et al. 2007). Although there is little published data on hyperosmolar therapy for viral encephalitis, it remains a reasonable option for ICP control (Kneen and Solomon 2008).

When considering aggressive medical management of increased intracranial pressure, considerable thought should be given to the use of ICP monitoring. Recommendations for the use of ICP monitoring are broadly based on traumatic brain injury guidelines. Monitoring is generally indicated in a patient with a Glasgow Coma Score 8 or less and severe diffuse cerebral edema on neuroimaging (Helbok et al. 2014). There is currently little data on the kind of ICP monitor to use (external ventricular drain (EVD) vs. intraparenchymal monitor) or on ICP values to target (Glimaker et al. 2014). Further research on the use of such measures in viral encephalitis is needed.

For severe intractable intracranial hypertension with impending herniation, surgical decompression via hemicraniectomy with or without temporal lobectomy can be considered. It has been described in multiple case reports in children ranging from 7 months to 16 years of age (Singhi et al. 2015). Considering the gravity of the condition when surgery is contemplated, the outcome reported in these cases has been relatively favorable. Mild cognitive difficulties including memory and attention impairments have been described (Singhi et al. 2015). The decision to escalate care should be contemplated and individualized on a case by case basi s.

Conclusion

In summary, encephalitis is a disease process caused by the inflammation of the brain and is generally manifested by altered neurological function. Its causes include various infectious pathogens and inflammatory or autoimmune processes. Viruses that can lead to encephalitis are myriad. Attempts are being made to standardize the definition, investigation, and treatment of viral encephalitis. Rapid recognition and early treatment is key to decreasing mortality and improving outcomes in affected children.