Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 94
Encephalitis KAREN L. ROOS* Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA
INTRODUCTION Encephalitis is an infectious or inflammatory disorder of the brain manifest by fever and headache and associated with a depressed level of consciousness, an altered mental status (confusion, behavioral abnormalities), focal neurologic deficits, or new onset seizure activity. This chapter will address the viral etiologies of encephalitis. Other chapters in this volume address the bacterial, fungal, spirochetal, and parasitic etiologies of encephalitis. The California Encephalitis Project was initiated in 1998 to improve the identification of infectious etiologies of encephalitis. Although in the majority of cases a specific causative agent was not identified, of the cases in which an infectious agent was identified, the majority of them were viruses. Between 1998 and 2005 a total of 1570 patients were enrolled; a confirmed or probable etiologic agent was identified for 16% of cases, of which 69% were viral (Glaser et al., 2006).
ETIOLOGY The identifiable etiologic agents of encephalitis can be divided into those that we can diagnose and treat and those that we can diagnose, but for which there is supportive care only. The most common causative agent of sporadic encephalitis is herpes simplex virus 1. Primary infection occurs in childhood and is typically asymptomatic. Initial infection with herpes simplex virus 1 generally occurs in the oropharyngeal mucosa. When primary infection is symptomatic, it is characterized by fever with difficulty swallowing due to vesicles on the buccal and gingival mucosa (Whitley et al., 1998). The virus establishes latent infection in the trigeminal ganglion and periodically reactivates. Reactivation may lead to infection. This typically involves the medial
and inferior temporal lobe and insula. Herpes simplex virus 1 may also cause a brainstem encephalitis. Similar to herpes simplex virus 1, varicella zoster virus is transmitted from human to human by direct contact with secretions and enters the host through the oropharyngeal mucosa. Primary infection with varicella zoster virus causes chicken pox. Varicella zoster virus establishes latency in the cranial and dorsal root ganglia. When varicella zoster virus reactivates, it may cause shingles or an encephalitis. Varicella zoster virus may produce a large vessel ischemic infarction, small vessel ischemic or hemorrhagic infarctions in the deep white and gray matter, demyelinating lesions or a ventriculitis/periventriculitis (Gilden et al., 2000). Large vessel stroke or so-called large vessel encephalitis is a granulomatous arteritis which most commonly develops after ophthalmic (V1) trigeminal distribution zoster. Small vessel encephalitis may occur after zoster or may occur without a history of a rash and is characterized by an altered level of consciousness and focal neurologic deficits due to ischemic and hemorrhagic infarctions in cortical and subcortical gray and white matter. Demyelinating lesions have also been observed (Gilden et al., 2000). Cytomegalovirus causes an encephalitis in immunocompromised individuals, the most common of which is a microglial nodule encephalitis, but there is also a rather unique entity which is cytomegalovirus ventriculoencephalitis. Cytomegalovirus encephalitis should be a consideration in immunocompromised patients who develop rapidly progressive altered mental status, which may include focal neurologic deficits (Arribas et al., 1996). Human herpesvirus 6 causes exanthem subitum (sixth disease) in childhood and can reactivate in immunocompromised individuals causing encephalitis. The role of human herpesvirus 6 as a causative agent of encephalitis in immunocompetent individuals has been one of constant controversy and remains unclear.
*Correspondence to: Karen L. Roos, M.D., Indiana University School of Medicine, Indiana University Hospital, Suite 1711, 550 N. University Boulevard, Indianapolis, Indiana 46202, USA. E-mail: [email protected]
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Epstein–Barr virus may cause an encephalitis as a complication of infectious mononucleosis. Progressive multifocal leukoencephalopathy caused by the polyomavirus JC virus has been known for a long time to cause brain infection in patients with human immunodeficiency virus and in the past several years has been recognized to cause brain infection in patients on a number of immunomodulating agents, including natalizumab (Tysabri), rituximab, methotrexate, cyclophosphamide, azathioprine, and interferon b-1A (Avonex) (LangerGould et al., 2005). Similar to herpes simplex virus 1 and varicella zoster virus, JC virus is acquired in childhood and establishes latent infection in bone marrow, kidneys, spleen, and brain. Similar to the herpesviruses there is intermittent reactivation of JC virus, but the development of progressive multifocal leukoencephalopathy is typically associated with an immunocompromised state. A number of arthropod-borne viruses may cause encephalitis, including: West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, La Crosse virus, Murray Valley encephalitis virus, Powassan virus, Tickborne encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, and the recently identified deer tick virus (Tavakoli et al., 2009). The possibility of an arthropod- borne viral etiology to the encephalitis depends on the time of the year, specifically when mosquitoes and ticks are biting, place of residence, travel history, and occupational and recreational activities. A specific arthropod-borne virus may be identified by unique clinical features which will be discussed below. A rare etiologic agent of encephalitis, but one that should be considered in patients that have hypo- or agammaglobulinemia, are the enteroviruses (these include the coxsackieviruses, echoviruses, enterovirus 71 and other numbered enteroviruses). Other less common causes of viral encephalitis are measles virus, Nipah virus due to exposure to infected pigs, herpesvirus B transmitted by the bite of a macaque, influenza virus, and adenovirus. An important cause of encephalitis is rabies virus. In underdeveloped countries, rabies is most often the result of a dog bite. In the US and Canada, rabies is most often the result of the bite of a bat, although a bat bite may not be recognized. Rabies virus infection has also been transmitted through solid organ and tissue transplantation (Burton et al., 2005).
CLINICAL PRESENTATION Encephalitis should be a consideration in every patient with an altered level of consciousness or an altered mental status, such as behavioral abnormalities or confusion. Fever is expected, but fever is never a constant clinical
feature. The absence of fever on presentation does not rule out the possibility of encephalitis. Headache is a common complaint and many patients have a prodromal illness that is described as a flu-like illness with myalgias, nausea, vomiting, diarrhea or respiratory symptoms. Encephalitis should be a consideration in every patient with new onset seizures. There are unique clinical features to the viral agent. Herpes simplex virus 1 encephalitis presents with a subacute progression of fever, hemicranial headache, behavioral abnormalities, focal seizure activity, and focal neurologic deficits, most often difficulty with word finding. Patients with varicella zoster virus encephalitis present with headache, confusion, and focal neurologic symptoms and signs. Varicella zoster virus ventriculitis manifests with altered mental status and gait abnormalities. The symptoms of encephalitis due to an arthropod-borne virus are typically preceded by an influenza-like prodrome of fever, malaise, myalgias, nausea, and vomiting. These symptoms are followed by confusion and seizures. Patients with West Nile virus encephalitis may have tremor or a maculopapular or roseolar rash. Patients with West Nile virus encephalitis, St. Louis virus encephalitis, or Japanese encephalitis may have parkinsonian features or an acute asymmetric flaccid weakness due to anterior horn cell disease. Rabies virus encephalitis presents with focal neurologic deficits, altered mental status, seizures, hallucinations, choreiform movements, and myoclonus. Examination of the retina is very useful in patients with suspected cytomegalovirus encephalitis. In the organ transplant recipient with encephalitis, review the donor history as that often provides significant clues to the etiologic agent.
DIAGNOSIS The expected cerebrospinal fluid (CSF) abnormalities in the patient with encephalitis are a lymphocytic pleocytosis, a mild to moderate increase in the protein concentration, and a normal glucose concentration. In the patient with an altered level of consciousness, an opening pressure should be measured. In herpes simplex virus 1 (HSV-1) encephalitis, on magnetic resonance imaging (MRI) there is an area of increased signal intensity on fluid attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI) and T2-weighted images in the temporal lobe and often involving the insula. The absence of a temporal lobe abnormality on FLAIR and DWI 48 hours after symptom onset should prompt reconsideration of the diagnosis. The EEG will demonstrate focal stereotyped sharp and slow wave complexes, periodic lateralized epileptiform discharges, typically between the second and fifteenth
ENCEPHALITIS days of illness. Spinal fluid analysis will demonstrate an increased opening pressure, a lymphocytic pleocytosis, a mild to moderate increase in the protein concentration, a normal or slightly decreased glucose concentration and red blood cells or xanthochromia. The CSF HSV-1 PCR has a high sensitivity and specificity. The PCR may be negative in the first 24–72 hours after symptom onset and may be falsely negative 10 days after symptom onset. Serum and CSF should also be sent for antibodies. Intrathecal production of antibodies can be detected beginning at 8 days after symptom onset and for as long as 3 months. A serum to CSF ratio of less than 20:1 is diagnostic of herpes simplex virus encephalitis. In varicella zoster virus encephalitis there may be evidence of large vessel ischemic infarctions, small vessel ischemic and hemorrhagic infarctions, and/or demyelinating lesions. In varicella zoster virus ventriculitis there is increased periventricular signal abnormalities on T2-weighted imaging. The preferred diagnostic test is the detection of IgM antibodies in CSF. Varicella zoster virus PCR can also be obtained on CSF, but is less sensitive. In cytomegalovirus encephalitis, increased periventricular signal abnormalities may be seen on T2 weighted MR images. The recommended diagnostic test is the CSF PCR. The diagnosis of Epstein–Barr virus (EBV) encephalitis is made based on a combination of the results of serologic testing and the presence of a CSF lymphocytic pleocytosis in association with infectious mononucleosis. Epstein–Barr virus DNA can be found in peripheral blood latently infected mononuclear cells and may be positive in CSF in any CNS inflammatory disorder; therefore, in the immunocompetent patient with encephalitis not associated with acute Epstein–Barr virus infection, a positive CSF PCR for EBV DNA should be interpreted cautiously. Acute Epstein–Barr virus infection is confirmed by the detection of antiviral capsid antigen (VCA) IgM antibodies and the absence of antibodies to virus-associated nuclear antigen (anti-EBNA IgG). The detection of human herpesvirus 6 (HHV-6) nucleic acid in CSF is not definitive evidence that HHV-6 is the etiologic organism of the encephalitis. Send CSF for HHV-6 IgM. The diagnosis of progressive multifocal leukoencephalopathy is made by detection of JC virus DNA in CSF. This is a noninflammatory infection of oligodendrocytes and thus there is rarely an increased number of white blood cells in CSF. When there are white blood cells in the CSF, they are predominantly mononuclear cells. Diagnosis is based on a positive CSF PCR. T2weighted and FLAIR MR images demonstrate multifocal asymmetric increased signal abnormalities in the white matter that are nonenhancing and not typically associated with edema.
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In flavivirus encephalitis (West Nile virus, Japanese encephalitis virus, and St. Louis encephalitis virus) on T2 and FLAIR MR imaging, increased signal abnormalities can be seen in the thalami, basal ganglia, and substantia nigra. There is a CSF lymphocytic pleocytosis with a normal glucose concentration, although a polymorphonuclear pleocytosis may be present in West Nile virus encephalitis. The best diagnostic test for West Nile virus encephalitis is the CSF IgM antibody test. It may take several days to detect IgM antibodies, and thus serial serum and CSF samples should be sent for diagnosis. A positive serum West Nile virus IgM is evidence for recent West Nile virus infection but not definitive evidence of neuroinvasive disease. Although detection of West Nile virus IgM in CSF is the preferred diagnostic test, there is also a CSF West Nile virus PCR that is available. The PCR has a low sensitivity. As demonstrated in Table 94.1, the diagnosis of the arthropod-borne viral encephalitides can be made by the detection of IgM antibodies to the virus in serum or CSF or by the detection of a fourfold increase in IgG antibodies between acute and convalescent serology. Convalescent serology is obtained 4 weeks after the acute serology. Eastern equine encephalitis has a slightly different CSF formula than the other arthropod-borne viral encephalitides in that there may be a predominance of neutrophils rather than lymphocytes or mononuclear cells. The diagnosis is similarly made to the other arthropod-borne viral encephalitides by the detection of IgM antibodies in serum or CSF or by a fourfold increase in IgG antibodies. MRI may show areas of increased signal abnormality in the basal ganglia and thalamus. Classically the diagnosis of rabies was made by a biopsy of the nape of the neck for rabies virus antigen. Rabies virus can be cultured from saliva and rabies virus RNA can be detected by reverse transcriptase-PCR from CSF and saliva.
TREATMENT In the patient with headache, fever and a depressed or altered level of consciousness, empiric therapy for bacterial and viral encephalitis and a tick-borne infection (during the season when ticks are biting) is initiated and continued until either an infectious etiology is ruled out or a causative organism is identified. Empiric therapy includes dexamethasone (infants and children 2 months of age and older: 0.15 mg/kg of bodyweight intravenously every 6 hours for 2–4 days; adults 10 mg intravenously every 6 hours for 4 days), a third or fourth generation cephalosporin, either ceftriaxone (pediatric dose: 100 mg/kg/day in a 12 hour dosing interval; adult dose: 2 g every 12 hours) or cefepime (pediatric dose: 150 mg/kg/day in an 8 hour dosing interval; adult dose:
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Table 94.1 Serology and cerebrospinal fluid diagnostic studies for viral encephalitis Virus
Serology
Cerebrospinal fluid
Herpes simplex virus 1 Varicella zoster virus Cytomegalovirus Epstein–Barr virus Human herpesvirus 6 JC virus (PML) West Nile virus St. Louis encephalitis virus La Crosse virus Japanese encephalitis virus Western equine encephalitis virus Eastern equine encephalitis virus Venezuelan encephalitis virus Powassan virus Tick-borne encephalitis virus Rabies Enteroviruses
Positive VCA IgM antibodies Negative anti-EBNA IgG
West Nile virus IgM IgM Acute and convalescent sera (obtained 4 weeks later) to detect a fourfold increase in IgG antibodies
IgM Acute and convalescent sera
PCR for HSV-1 Serum: CSF ratio of less than 20:1 VZV IgM PCR for VZV PCR for CMV *PCR for EBV HHV-6 IgM PCR for JC virus DNA West Nile virus IgM PCR for West Nile virus IgM
RT-PCR for rabies virus RT-PCR for enteroviruses Viral culture
*Epstein–Barr virus DNA can be found in peripheral blood latently infected mononuclear cells and may be positive in any CNS inflammatory disorder.
Table 94.2 Treatment Virus
Intravenous antiviral therapy
Herpes simplex virus 1 Acyclovir-resistant HSV-1 Varicella zoster virus Cytomegalovirus
Acyclovir 10 mg/kg every 8 hours for 21 days Foscarnet 60 mg/kg every 8 hours for 21 days Acyclovir 10–15 mg/kg every 8 hours for 10–14 days Ganciclovir 5 mg/kg every 12 hours plus foscarnet 60 mg/kg every 8 hours for 21 days followed by maintenance therapy Ganciclovir or foscarnet or both Acyclovir is not recommended
Human herpesvirus 6 Epstein–Barr virus (Based on the recommendations in Tunkel et al., 2008.)
2 g every 8 hours) plus vancomycin (pediatric dose: 40–60 mg/kg/day in a 6 or 12 hour dosing interval; adult dose: 45–60 mg/kg/day in an 8 hour dosing interval) plus ampicillin (in select patient groups) plus doxycycline (100 mg every 12 hours). Therapy is modified when the causative organism is identified. Herpes simplex virus 1 encephalitis is treated with acyclovir 10 mg/kg every 8 hours for 21 days. Although
acyclovir-resistant HSV-1 has only been identified to date in immunocompromised patients, most hospital laboratories do not test for resistance. The routine use of acyclovir, famciclovir and valaciclovir to prevent the recurrence of orolabial and genital herpesvirus infections would be expected to produce resistant strains. Although patients with HSV-1 encephalitis can progress or fail to respond to treatment with acyclovir for any of a
ENCEPHALITIS number of reasons, consideration can be given to substituting foscarnet for acyclovir in these patients. Varicella zoster virus encephalitis is treated with acyclovir 10–15 mg/kg every 8 hours for 10–14 days. Cytomegalovirus encephalitis is treated with a combination of ganciclovir and foscarnet as therapeutic failures have been reported in patients treated with only one of these agents. An attempt should be made to decrease immunosuppression if possible. For the treatment of HHV-6 encephalitis in immunocompromised patients, ganciclovir or foscarnet can be used alone or in combination. In clinical trials, acyclovir has not been demonstrated to be efficacious for encephalitis complicating infectious mononucleosis and is not recommended (Tunkel et al., 2008). A number of agents have been investigated for the treatment of arthropod-borne viral encephalitis, many of which have been specifically investigated for West Nile virus encephalitis. These agents include ribavirin, interferon, and intravenous immunoglobulin containing high titers of anti-West Nile virus antibodies. None of these agents has been shown to be efficacious to date, but trials are ongoing. The recommended antiviral therapy is listed in Table 94.2. In the initial stages of encephalitis, patients should be monitored in the intensive care unit. Serial neurologic examinations should be performed in anticipation of the complications of increased intracranial pressure and seizure activity.
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REFERENCES Arribas JR, Storch GA, Clifford DB et al. (1996). Cytomegalovirus encephalitis. Ann Intern Med 125: 577–587. Burton EC, Burns DK, Opatowsky MJ et al. (2005). Viral encephalitis transmitted from donor to organ recipient. Arch Neurol 62: 873–882. Gilden DH, Kleinschmidt-Demasters BK, Laguardia JJ et al. (2000). Neurologic complications of the reactivation of varicella zoster virus. N Engl J Med 342: 635–645. Glaser CA, Honarmand S, Anderson LJ et al. (2006). Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis 43: 1565–1577. Langer-Gould A, Atlas SW, Green AJ et al. (2005). Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353: 375–381. Tavakoli NP, Wang H, Dupuis M et al. (2009). Fatal case of deer tick virus encephalitis. N Engl J Med 360: 2099–2107. Tunkel AR, Glaser CA, Bloch KC et al. (2008). The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 47: 303–327. Whitley RJ, Kimberlin DW, Roizman B (1998). Herpes simplex viruses. Clin Infect Dis 26: 541–555.
Chapter 94
Encephalitis KAREN L. ROOS* Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA
INTRODUCTION Encephalitis is an infectious or inflammatory disorder of the brain manifest by fever and headache and associated with a depressed level of consciousness, an altered mental status (confusion, behavioral abnormalities), focal neurologic deficits, or new onset seizure activity. This chapter will address the viral etiologies of encephalitis. Other chapters in this volume address the bacterial, fungal, spirochetal, and parasitic etiologies of encephalitis. The California Encephalitis Project was initiated in 1998 to improve the identification of infectious etiologies of encephalitis. Although in the majority of cases a specific causative agent was not identified, of the cases in which an infectious agent was identified, the majority of them were viruses. Between 1998 and 2005 a total of 1570 patients were enrolled; a confirmed or probable etiologic agent was identified for 16% of cases, of which 69% were viral (Glaser et al., 2006).
ETIOLOGY The identifiable etiologic agents of encephalitis can be divided into those that we can diagnose and treat and those that we can diagnose, but for which there is supportive care only. The most common causative agent of sporadic encephalitis is herpes simplex virus 1. Primary infection occurs in childhood and is typically asymptomatic. Initial infection with herpes simplex virus 1 generally occurs in the oropharyngeal mucosa. When primary infection is symptomatic, it is characterized by fever with difficulty swallowing due to vesicles on the buccal and gingival mucosa (Whitley et al., 1998). The virus establishes latent infection in the trigeminal ganglion and periodically reactivates. Reactivation may lead to infection. This typically involves the medial
and inferior temporal lobe and insula. Herpes simplex virus 1 may also cause a brainstem encephalitis. Similar to herpes simplex virus 1, varicella zoster virus is transmitted from human to human by direct contact with secretions and enters the host through the oropharyngeal mucosa. Primary infection with varicella zoster virus causes chicken pox. Varicella zoster virus establishes latency in the cranial and dorsal root ganglia. When varicella zoster virus reactivates, it may cause shingles or an encephalitis. Varicella zoster virus may produce a large vessel ischemic infarction, small vessel ischemic or hemorrhagic infarctions in the deep white and gray matter, demyelinating lesions or a ventriculitis/periventriculitis (Gilden et al., 2000). Large vessel stroke or so-called large vessel encephalitis is a granulomatous arteritis which most commonly develops after ophthalmic (V1) trigeminal distribution zoster. Small vessel encephalitis may occur after zoster or may occur without a history of a rash and is characterized by an altered level of consciousness and focal neurologic deficits due to ischemic and hemorrhagic infarctions in cortical and subcortical gray and white matter. Demyelinating lesions have also been observed (Gilden et al., 2000). Cytomegalovirus causes an encephalitis in immunocompromised individuals, the most common of which is a microglial nodule encephalitis, but there is also a rather unique entity which is cytomegalovirus ventriculoencephalitis. Cytomegalovirus encephalitis should be a consideration in immunocompromised patients who develop rapidly progressive altered mental status, which may include focal neurologic deficits (Arribas et al., 1996). Human herpesvirus 6 causes exanthem subitum (sixth disease) in childhood and can reactivate in immunocompromised individuals causing encephalitis. The role of human herpesvirus 6 as a causative agent of encephalitis in immunocompetent individuals has been one of constant controversy and remains unclear.
*Correspondence to: Karen L. Roos, M.D., Indiana University School of Medicine, Indiana University Hospital, Suite 1711, 550 N. University Boulevard, Indianapolis, Indiana 46202, USA. E-mail: [email protected]
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K.L. ROOS
Epstein–Barr virus may cause an encephalitis as a complication of infectious mononucleosis. Progressive multifocal leukoencephalopathy caused by the polyomavirus JC virus has been known for a long time to cause brain infection in patients with human immunodeficiency virus and in the past several years has been recognized to cause brain infection in patients on a number of immunomodulating agents, including natalizumab (Tysabri), rituximab, methotrexate, cyclophosphamide, azathioprine, and interferon b-1A (Avonex) (LangerGould et al., 2005). Similar to herpes simplex virus 1 and varicella zoster virus, JC virus is acquired in childhood and establishes latent infection in bone marrow, kidneys, spleen, and brain. Similar to the herpesviruses there is intermittent reactivation of JC virus, but the development of progressive multifocal leukoencephalopathy is typically associated with an immunocompromised state. A number of arthropod-borne viruses may cause encephalitis, including: West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, La Crosse virus, Murray Valley encephalitis virus, Powassan virus, Tickborne encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, and the recently identified deer tick virus (Tavakoli et al., 2009). The possibility of an arthropod- borne viral etiology to the encephalitis depends on the time of the year, specifically when mosquitoes and ticks are biting, place of residence, travel history, and occupational and recreational activities. A specific arthropod-borne virus may be identified by unique clinical features which will be discussed below. A rare etiologic agent of encephalitis, but one that should be considered in patients that have hypo- or agammaglobulinemia, are the enteroviruses (these include the coxsackieviruses, echoviruses, enterovirus 71 and other numbered enteroviruses). Other less common causes of viral encephalitis are measles virus, Nipah virus due to exposure to infected pigs, herpesvirus B transmitted by the bite of a macaque, influenza virus, and adenovirus. An important cause of encephalitis is rabies virus. In underdeveloped countries, rabies is most often the result of a dog bite. In the US and Canada, rabies is most often the result of the bite of a bat, although a bat bite may not be recognized. Rabies virus infection has also been transmitted through solid organ and tissue transplantation (Burton et al., 2005).
CLINICAL PRESENTATION Encephalitis should be a consideration in every patient with an altered level of consciousness or an altered mental status, such as behavioral abnormalities or confusion. Fever is expected, but fever is never a constant clinical
feature. The absence of fever on presentation does not rule out the possibility of encephalitis. Headache is a common complaint and many patients have a prodromal illness that is described as a flu-like illness with myalgias, nausea, vomiting, diarrhea or respiratory symptoms. Encephalitis should be a consideration in every patient with new onset seizures. There are unique clinical features to the viral agent. Herpes simplex virus 1 encephalitis presents with a subacute progression of fever, hemicranial headache, behavioral abnormalities, focal seizure activity, and focal neurologic deficits, most often difficulty with word finding. Patients with varicella zoster virus encephalitis present with headache, confusion, and focal neurologic symptoms and signs. Varicella zoster virus ventriculitis manifests with altered mental status and gait abnormalities. The symptoms of encephalitis due to an arthropod-borne virus are typically preceded by an influenza-like prodrome of fever, malaise, myalgias, nausea, and vomiting. These symptoms are followed by confusion and seizures. Patients with West Nile virus encephalitis may have tremor or a maculopapular or roseolar rash. Patients with West Nile virus encephalitis, St. Louis virus encephalitis, or Japanese encephalitis may have parkinsonian features or an acute asymmetric flaccid weakness due to anterior horn cell disease. Rabies virus encephalitis presents with focal neurologic deficits, altered mental status, seizures, hallucinations, choreiform movements, and myoclonus. Examination of the retina is very useful in patients with suspected cytomegalovirus encephalitis. In the organ transplant recipient with encephalitis, review the donor history as that often provides significant clues to the etiologic agent.
DIAGNOSIS The expected cerebrospinal fluid (CSF) abnormalities in the patient with encephalitis are a lymphocytic pleocytosis, a mild to moderate increase in the protein concentration, and a normal glucose concentration. In the patient with an altered level of consciousness, an opening pressure should be measured. In herpes simplex virus 1 (HSV-1) encephalitis, on magnetic resonance imaging (MRI) there is an area of increased signal intensity on fluid attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI) and T2-weighted images in the temporal lobe and often involving the insula. The absence of a temporal lobe abnormality on FLAIR and DWI 48 hours after symptom onset should prompt reconsideration of the diagnosis. The EEG will demonstrate focal stereotyped sharp and slow wave complexes, periodic lateralized epileptiform discharges, typically between the second and fifteenth
ENCEPHALITIS days of illness. Spinal fluid analysis will demonstrate an increased opening pressure, a lymphocytic pleocytosis, a mild to moderate increase in the protein concentration, a normal or slightly decreased glucose concentration and red blood cells or xanthochromia. The CSF HSV-1 PCR has a high sensitivity and specificity. The PCR may be negative in the first 24–72 hours after symptom onset and may be falsely negative 10 days after symptom onset. Serum and CSF should also be sent for antibodies. Intrathecal production of antibodies can be detected beginning at 8 days after symptom onset and for as long as 3 months. A serum to CSF ratio of less than 20:1 is diagnostic of herpes simplex virus encephalitis. In varicella zoster virus encephalitis there may be evidence of large vessel ischemic infarctions, small vessel ischemic and hemorrhagic infarctions, and/or demyelinating lesions. In varicella zoster virus ventriculitis there is increased periventricular signal abnormalities on T2-weighted imaging. The preferred diagnostic test is the detection of IgM antibodies in CSF. Varicella zoster virus PCR can also be obtained on CSF, but is less sensitive. In cytomegalovirus encephalitis, increased periventricular signal abnormalities may be seen on T2 weighted MR images. The recommended diagnostic test is the CSF PCR. The diagnosis of Epstein–Barr virus (EBV) encephalitis is made based on a combination of the results of serologic testing and the presence of a CSF lymphocytic pleocytosis in association with infectious mononucleosis. Epstein–Barr virus DNA can be found in peripheral blood latently infected mononuclear cells and may be positive in CSF in any CNS inflammatory disorder; therefore, in the immunocompetent patient with encephalitis not associated with acute Epstein–Barr virus infection, a positive CSF PCR for EBV DNA should be interpreted cautiously. Acute Epstein–Barr virus infection is confirmed by the detection of antiviral capsid antigen (VCA) IgM antibodies and the absence of antibodies to virus-associated nuclear antigen (anti-EBNA IgG). The detection of human herpesvirus 6 (HHV-6) nucleic acid in CSF is not definitive evidence that HHV-6 is the etiologic organism of the encephalitis. Send CSF for HHV-6 IgM. The diagnosis of progressive multifocal leukoencephalopathy is made by detection of JC virus DNA in CSF. This is a noninflammatory infection of oligodendrocytes and thus there is rarely an increased number of white blood cells in CSF. When there are white blood cells in the CSF, they are predominantly mononuclear cells. Diagnosis is based on a positive CSF PCR. T2weighted and FLAIR MR images demonstrate multifocal asymmetric increased signal abnormalities in the white matter that are nonenhancing and not typically associated with edema.
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In flavivirus encephalitis (West Nile virus, Japanese encephalitis virus, and St. Louis encephalitis virus) on T2 and FLAIR MR imaging, increased signal abnormalities can be seen in the thalami, basal ganglia, and substantia nigra. There is a CSF lymphocytic pleocytosis with a normal glucose concentration, although a polymorphonuclear pleocytosis may be present in West Nile virus encephalitis. The best diagnostic test for West Nile virus encephalitis is the CSF IgM antibody test. It may take several days to detect IgM antibodies, and thus serial serum and CSF samples should be sent for diagnosis. A positive serum West Nile virus IgM is evidence for recent West Nile virus infection but not definitive evidence of neuroinvasive disease. Although detection of West Nile virus IgM in CSF is the preferred diagnostic test, there is also a CSF West Nile virus PCR that is available. The PCR has a low sensitivity. As demonstrated in Table 94.1, the diagnosis of the arthropod-borne viral encephalitides can be made by the detection of IgM antibodies to the virus in serum or CSF or by the detection of a fourfold increase in IgG antibodies between acute and convalescent serology. Convalescent serology is obtained 4 weeks after the acute serology. Eastern equine encephalitis has a slightly different CSF formula than the other arthropod-borne viral encephalitides in that there may be a predominance of neutrophils rather than lymphocytes or mononuclear cells. The diagnosis is similarly made to the other arthropod-borne viral encephalitides by the detection of IgM antibodies in serum or CSF or by a fourfold increase in IgG antibodies. MRI may show areas of increased signal abnormality in the basal ganglia and thalamus. Classically the diagnosis of rabies was made by a biopsy of the nape of the neck for rabies virus antigen. Rabies virus can be cultured from saliva and rabies virus RNA can be detected by reverse transcriptase-PCR from CSF and saliva.
TREATMENT In the patient with headache, fever and a depressed or altered level of consciousness, empiric therapy for bacterial and viral encephalitis and a tick-borne infection (during the season when ticks are biting) is initiated and continued until either an infectious etiology is ruled out or a causative organism is identified. Empiric therapy includes dexamethasone (infants and children 2 months of age and older: 0.15 mg/kg of bodyweight intravenously every 6 hours for 2–4 days; adults 10 mg intravenously every 6 hours for 4 days), a third or fourth generation cephalosporin, either ceftriaxone (pediatric dose: 100 mg/kg/day in a 12 hour dosing interval; adult dose: 2 g every 12 hours) or cefepime (pediatric dose: 150 mg/kg/day in an 8 hour dosing interval; adult dose:
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Table 94.1 Serology and cerebrospinal fluid diagnostic studies for viral encephalitis Virus
Serology
Cerebrospinal fluid
Herpes simplex virus 1 Varicella zoster virus Cytomegalovirus Epstein–Barr virus Human herpesvirus 6 JC virus (PML) West Nile virus St. Louis encephalitis virus La Crosse virus Japanese encephalitis virus Western equine encephalitis virus Eastern equine encephalitis virus Venezuelan encephalitis virus Powassan virus Tick-borne encephalitis virus Rabies Enteroviruses
Positive VCA IgM antibodies Negative anti-EBNA IgG
West Nile virus IgM IgM Acute and convalescent sera (obtained 4 weeks later) to detect a fourfold increase in IgG antibodies
IgM Acute and convalescent sera
PCR for HSV-1 Serum: CSF ratio of less than 20:1 VZV IgM PCR for VZV PCR for CMV *PCR for EBV HHV-6 IgM PCR for JC virus DNA West Nile virus IgM PCR for West Nile virus IgM
RT-PCR for rabies virus RT-PCR for enteroviruses Viral culture
*Epstein–Barr virus DNA can be found in peripheral blood latently infected mononuclear cells and may be positive in any CNS inflammatory disorder.
Table 94.2 Treatment Virus
Intravenous antiviral therapy
Herpes simplex virus 1 Acyclovir-resistant HSV-1 Varicella zoster virus Cytomegalovirus
Acyclovir 10 mg/kg every 8 hours for 21 days Foscarnet 60 mg/kg every 8 hours for 21 days Acyclovir 10–15 mg/kg every 8 hours for 10–14 days Ganciclovir 5 mg/kg every 12 hours plus foscarnet 60 mg/kg every 8 hours for 21 days followed by maintenance therapy Ganciclovir or foscarnet or both Acyclovir is not recommended
Human herpesvirus 6 Epstein–Barr virus (Based on the recommendations in Tunkel et al., 2008.)
2 g every 8 hours) plus vancomycin (pediatric dose: 40–60 mg/kg/day in a 6 or 12 hour dosing interval; adult dose: 45–60 mg/kg/day in an 8 hour dosing interval) plus ampicillin (in select patient groups) plus doxycycline (100 mg every 12 hours). Therapy is modified when the causative organism is identified. Herpes simplex virus 1 encephalitis is treated with acyclovir 10 mg/kg every 8 hours for 21 days. Although
acyclovir-resistant HSV-1 has only been identified to date in immunocompromised patients, most hospital laboratories do not test for resistance. The routine use of acyclovir, famciclovir and valaciclovir to prevent the recurrence of orolabial and genital herpesvirus infections would be expected to produce resistant strains. Although patients with HSV-1 encephalitis can progress or fail to respond to treatment with acyclovir for any of a
ENCEPHALITIS number of reasons, consideration can be given to substituting foscarnet for acyclovir in these patients. Varicella zoster virus encephalitis is treated with acyclovir 10–15 mg/kg every 8 hours for 10–14 days. Cytomegalovirus encephalitis is treated with a combination of ganciclovir and foscarnet as therapeutic failures have been reported in patients treated with only one of these agents. An attempt should be made to decrease immunosuppression if possible. For the treatment of HHV-6 encephalitis in immunocompromised patients, ganciclovir or foscarnet can be used alone or in combination. In clinical trials, acyclovir has not been demonstrated to be efficacious for encephalitis complicating infectious mononucleosis and is not recommended (Tunkel et al., 2008). A number of agents have been investigated for the treatment of arthropod-borne viral encephalitis, many of which have been specifically investigated for West Nile virus encephalitis. These agents include ribavirin, interferon, and intravenous immunoglobulin containing high titers of anti-West Nile virus antibodies. None of these agents has been shown to be efficacious to date, but trials are ongoing. The recommended antiviral therapy is listed in Table 94.2. In the initial stages of encephalitis, patients should be monitored in the intensive care unit. Serial neurologic examinations should be performed in anticipation of the complications of increased intracranial pressure and seizure activity.
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