Viral encephalitis: a review of diagnostic methods and guidelines for management

European Journal of Neurology 2005, 12: 331–343 E F N S T A S K F O R C E / C M E A R T I C L E Viral encephalitis: a review of diagnostic methods and guidelinesfor management I. Steinera, H. Budkab, A. Chaudhuric, M. Koskiniemid, K. Sainioe, O. Salonenf andP. G. E. KennedycaLaboratory of Neurovirology, Department of Neurology, Hadassah University Hospital, Jerusalem, Israel; bInstitute of Neurology, Medical University of Vienna, Vienna, Austria; cDepartment of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK; dDepartment of Virology, Haartman Institute, eDepartment of Clinical Neurophysiology, and fHelsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland Viral encephalitis is a medical emergency. The spectrum of brain involvement and the prognosis are dependent mainly on the specific pathogen and the immunological state of the host. Although specific therapy is limited to only several viral agents, correct immediate diagnosis and introduction of symptomatic and specific therapy has adramatic influence upon survival and reduces the extent of permanent brain injury in survivors. We searched MEDLINE (National Library of Medicine) for relevant literature from 1966 to May 2004. Review articles and book chapters were alsoincluded. Recommendations are based on this literature based on our judgment of therelevance of the references to the subject. Recommendations were reached by con-sensus. Where there was lack of evidence but consensus was clear we have stated ouropinion as good practice points. Diagnosis should be based on medical history,examination followed by analysis of cerebrospinal fluid for protein and glucose con-tents, cellular analysis and identification of the pathogen by polymerase chain reaction(PCR) amplification (recommendation level A) and serology (recommendation levelB). Neuroimaging, preferably by magnetic resonance imaging, is an essential aspect ofevaluation (recommendation level B). Lumbar puncture can follow neuroimagingwhen immediately available, but if this cannot be obtained at the shortest span of timeit should be delayed only in the presence of strict contraindications. Brain biopsyshould be reserved only for unusual and diagnostically difficult cases. All encephalitiscases must be hospitalized with an access to intensive care units. Supportive therapy isan important basis of management. Specific, evidence-based, anti-viral therapy, acy-clovir, is available for herpes encephalitis (recommendation level A). Acyclovir mightalso be effective for varicella-zoster virus encephalitis, gancyclovir and foscarnet forcytomegalovirus encephalitis and pleconaril for enterovirus encephalitis (IV class ofevidence). Corticosteroids as an adjunct treatment for acute viral encephalitis are notgenerally considered to be effective and their use is controversial. Surgical decom-pression is indicated for impending uncal herniation or increased intracranial pressurerefractory to medical management.
pathogen, the immunological state of the host and a range of environmental factors. Although specific Clinical involvement of the central nervous system therapy is limited to only several viral agents, correct (CNS) is an unusual manifestation of human viral diagnosis, and supportive and symptomatic treatment infection. The spectrum of brain involvement and the (when no specific therapy is available) are mandatory to outcome of the disease are dependent on the specific ensure the best prognosis (for reviews see Koskiniemiet al., 2001; Chaudhuri and Kennedy, 2002; Redingtonand Tyler, 2002; Whitley and Gnann, 2002). This Correspondence: Dr I. Steiner, Department of Neurology, Hadassah document addresses the optimal clinical approach to University Hospital, PO Box 12 000, Jerusalem, 91 120, Israel (tel.: 972 2 6776952; fax: 972 2 6437782; e-mail:
Classification of evidence levels used in these guide- This is a Continuing Medical Education paper and can be found lines for therapeutic interventions and diagnostic with corresponding questions on the Internet at: http://www.
measures was according to Brainin et al. (2004) and Certificates forcorrectly answering the questions will be issued by the EFNS.
Table 1 Evidence classification scheme for a therapeutic intervention Table 4 Evidence classification scheme for the rating of recommen-dations for a diagnostic measure Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative Level A rating (established as useful/predictive or not population OR an adequately powered systematic review of useful/predictive) requires at least one convincing class I study or prospective randomized controlled clinical trials with masked at least two consistent, convincing class II studies outcome assessment in representative populations.
Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or b. Primary outcome(s) is/are clearly defined.
c. Exclusion/inclusion criteria are clearly defined.
Level C rating (established as possibly useful/predictive or not d. Adequate accounting for dropouts and crossovers with numbers useful/predictive) requires at least two convincing class III studies sufficiently low to have minimal potential for bias.
e. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriatestatistical adjustment for differences.
Class II: Prospective matched group cohort study in a representative We searched MEDLINE (National Library of Medi- population with masked outcome assessment that meets a–e above ora randomized, controlled trial in a representative population that cine) for relevant literature from 1966 to May 2004.
The search included reports of research in human Class III: All other controlled trials (including well-defined natural beings only and in English. The search terms selected history controls or patients serving as own controls) in a were: Ôviral encephalitisÕ, ÔencephalitisÕ, Ômeningoen- representative population, where outcome assessment is independent cephalitisÕ and ÔencephalopathyÕ. We then limited the search using the terms ÔdiagnosisÕ, ÔMRÕ, Ôpositron Class IV: Evidence from uncontrolled studies, case series, case reports, emission tomographyÕ (PET), Ôsingle photon emission (EEG), Ôcerebrospinal fluidÕ, ÔpathologyÕ, ÔtreatmentÕand Ôantiviral therapyÕ. Review articles and bookchapters were also included if they were considered to Table 2 Evidence classification scheme for the rating of recommen-dations for a therapeutic intervention provide comprehensive reviews of the topic. The finalchoice of literature and the references included was Level A rating (established as effective, ineffective, or harmful) based on our judgment of their relevance to this requires at least one convincing class I study or at least two subject. Recommendations were reached by consensus of all Task Force participants (Tables 1–4) and were Level B rating (probably effective, ineffective, or harmful) requires also based on our own awareness and clinical experi- at least one convincing class II study or overwhelming class IIIevidence ence. Where there was lack of evidence but consensuswas clear we have stated our opinion as good practice Level C (possibly effective, ineffective, or harmful) rating requires at least two convincing class III studies Table 3 Evidence classification scheme for a diagnostic measure Encephalitis is the presence of an inflammatory process Class I: A prospective study in a broad spectrum of persons with the in the brain parenchyma associated with clinical evi- suspected condition, using a Ôgold standardÕ for case definition, where dence of brain dysfunction. It can be due to a non- the test is applied in a blinded evaluation, and enabling the infective condition such as in acute disseminated assessment of appropriate tests of diagnostic accuracy encephalomyelitis (ADEM) or to an infective process, Class II: A prospective study of a narrow spectrum of persons with the which is diffuse and usually viral. Herpes simplex virus suspected condition, or a well-designed retrospective study of a broad type 1 (HSV-1), varicella-zoster virus (VZV), Epstein– spectrum of persons with an established condition (by ÔgoldstandardÕ) compared with a broad spectrum of controls, where test is Barr virus (EBV), mumps, measles and enteroviruses applied in a blinded evaluation, and enabling the assessment of are responsible for most cases of viral encephalitis in Class III: Evidence provided by a retrospective study where either 2001). Other non-viral infective causes of encephalitis persons with the established condition or controls are of a narrow may include such diseases as tuberculosis, rickettsial spectrum, and where test is applied in a blinded evaluation disease and trypanosomiasis, and will be discussed in Class IV: Any design where test is not applied in blinded evaluation the differential diagnosis section.
OR evidence provided by expert opinion alone or in descriptive Encephalitis should be differentiated from encephalo- pathy which is defined as a disruption of brain function Ó 2005 EFNS European Journal of Neurology 12, 331–343 that is not because of a direct structural or inflamma- relevance. Thus, certain viral and non-viral pathogens tory process. It is mediated via metabolic processes and cause encephalitis only or much more frequently in im- can be caused by intoxications, drugs, systemic organ munosuppressed individuals such as patients with AIDS dysfunction (e.g. liver, pancreas) or systemic infection or those who receive medications that affect the immune system (e.g. cancer and organ transplant patients).
The structure of the nervous system determines a The mode of disease course up to the appearance of degree of associated inflammatory meningeal involve- the neurological signs may provide clues to the aetiol- ment in encephalitis, and therefore symptoms that re- ogy. For example, enterovirus infection has a typical biphasic course. An associated abnormality outside the encephalitis. Moreover, in textbooks and review articles nervous system (bleeding tendency in haemorrhagic the term viral meningo-encephalitis is often used to fever, the hydrophobia in rabies patients) may also denote a viral infectious process of both the brain/spi- Viral infection of the nervous system is almost always part of a generalized systemic infectious disease. Thus, The diagnosis of viral encephalitis is suspected in the other organs may be involved prior or in association context of a febrile disease accompanied by headache, with the CNS manifestations. Evidence for such an altered level of consciousness, and symptoms and signs involvement should be obtained either from the history of cerebral dysfunction. These may consist of abnor- or during the examination. Skin rashes are not in- malities that can be categorized into four: cognitive frequent concomitants of viral infections, parotitis may dysfunction (acute memory disturbances), behavioural be associated with mumps, gastrointestinal signs with changes (disorientation, hallucinations, psychosis, per- enteroviral disease and upper respiratory findings may sonality changes, agitation), focal neurological abnor- malities (such as anomia, dysphasia, hemiparesis, hemianopia etc.) and seizures. After the diagnosis issuspected, the approach should consist of obtaining a meticulous history and a careful general and neuro-logical examination.
The findings relate to those of meningitis and disruptionof brain parenchyma function. Thus, signs of meningealirritation and somnolence reflect meningitis, while behavioural, cognitive and focal neurological signs and The history is mandatory in the assessment of the seizures reflect the disruption of brain function. Addi- patient with suspected viral encephalitis. It might be tional signs may include autonomic and hypothalamic important to obtain the relevant information from an disturbances, diabetes insipidus and the syndrome of accompanying person (relative, friend, etc.) if the inappropriate antidiuretic hormone secretion. The patient is in a confused, agitated and disoriented state.
symptoms and signs are not a reliable diagnostic The geographical location as well as the recent travel instrument to identify the causative virus. Likewise, the history could be of relevance to identify causative evolution of the clinical signs and their severity depend pathogens that are endemic or prevalent in certain on host and other factors such as immune state and age geographical regions (the recent example being severe and cannot serve as guidelines to identify the pathogen.
acute respiratory syndrome). Likewise, seasonal occur- In general, the very young and the very old have the rence can be important for other pathogens such as most extensive and serious signs of encephalitis.
polio virus. Occupation may well be important (as in acase of a forestry worker with Lyme disease). Contact with animals such as farm animals would sometimespoint to the cause, as animals serve as reservoirs for certain viruses (e.g. West Nile fever and the 1999 out-break of the disease in New York). A history of insect or Peripheral blood count and cellular morphology, are other animal bites can be relevant for arbovirus infec- helpful in separating viral from non-viral infections.
tion as well as rabies. Past contact with an individual Lymphocytosis in the peripheral blood is common in afflicted by an infective condition is important. The viral encephalitis. Erythrocyte sedimentation rate is medical status of the individual is of the utmost another non-specific test that is usually within normal Ó 2005 EFNS European Journal of Neurology 12, 331–343 range in viral infections. Other, general examinations such as chest X-ray, blood cultures, belong to the In brain-stem encephalitis the EEG mainly reflects the lowered consciousness and the abnormalities can be The auxiliary studies that examine viral infections of mild compared with the clinical state of the patient.
the nervous system include studies that characterize the Intermittent rhythmic delta activity (IRDA) has also extent and nature of CNS involvement (EEG and neuroimaging), microbiological attempts to identify thepathogen and histopathology will be discussed here.
EEG is generally regarded as a non-specific investi- In cerebellitis the EEG is mostly normal (Schmahmann gation, although it is still sometimes a useful tool in certain situations. Thus, leucoencephalitides showsmore diffuse slow activity in the EEG and polioen- cephalitides shows more rhythmic slow activity (Vas The EEG pattern in human immunodeficiency virus and Cracco, 1990; Westmoreland, 1999). However, in (HIV) infection of the brain is very variable, with practice this hardly helps in the differential diagnosis.
Likewise, the EEG findings in post-infectious en- (Westmoreland, 1999). Likewise the findings in ADEM cephalitides differ from infectious encephalitis only in are unspecific encephalitic abnormalities (Tenembaum the time schedule of the abnormalities. The main benefit of EEG is to demonstrate cerebral involvement duringthe early state of the disease. Only in rare instances does the EEG show specific features that may give clues to The EEG in subacute sclerosing panencephalitis (SSPE) shows a typical generalized periodic EEG patternrepeating with intervals between 4 and 15 s and syn- chronized with myoclonus of the patient (West- The EEG is an early and sensitive indicator of cerebral involvement and usually shows a background abnor-mality prior to the initial evidence of parenchyma involvement on neuroimaging. This may in some in-stances be helpful in the differential diagnosis of aseptic meningitis. Often, focal abnormalities may be observed.
Magnetic resonance imaging (MRI) is more sensitive During the acute phase, the severity of EEG abnor- and specific than CT for the evaluation of viral malities do not usually correlate with the extent of the encephalitis (Dun et al., 1986; Schroth et al., 1987; disease. However, a fast improving EEG indicates a Dale et al., 2000; Marchbank et al., 2000, class IIIC).
good prognosis, while lack of improvement of the EEG The advantages of MRI include the use of non-ion- recording carries a non-favorable prognosis (Vas and izing radiation, multiplanar imaging capability, im- Cracco, 1990, class IV). Although there may be seizures proved contrast of soft tissue, and high anatomical in the acute phase, interictal epileptiform EEG activity resolution. On the basis of previous data it should be is a rarity. The EEG abnormalities usually subside more the imaging technique of choice in determination of slowly than the clinical symptoms (Westmoreland, encephalitis. It allows earlier detection and treatment of inflammatory processes. MRI also provides valu-able information for patient follow-up. However, in practical terms many patients with suspicion of In 80% of the patients there is a typical finding in the encephalitis often undergo CT scanning before neuro- EEG. In addition to the background slowing there is a temporal focus showing periodic lateralized epilepti- A typical MRI protocol consists of routine T1 and form discharges. This finding is temporary; it can be found during days 2–14 from the beginning of the dis- inversion recovery (FLAIR) sequence, which is con- ease, most often during days 5–10 (Lai and Gragasin, sidered extremely sensitive in detecting subtle changes 1988). Detection of this EEG finding often requires in the early stages of an acute condition. Gradient- serial recordings. The repetition interval of these pseu- echo imaging, with its superior magnetic susceptibil- doperiodic complexes is from 1 to 4 s; in newborns it can be faster with a frequency of 2 Hz. Also the local- ization in newborns may be other than temporal (Sainio New MR imaging techniques are being applied to the study of various brain diseases. These technologies Ó 2005 EFNS European Journal of Neurology 12, 331–343 include procedures that can increase sensitivity to small, 2002, class IIIC). Involvement of cingulate gyrus and yet clinically relevant lesions, these techniques may be contra lateral temporal lobe is highly suggestive of useful for imaging protocols of patients with suspicion herpes encephalitis. Typical early findings include gyral oedema on T1-weighted (T1WI) imaging and high signal (i) Diffusion-weighted MRI (DWI) enables separation of intensity in the temporal lobe or cingulate gyrus on cytotoxic from vasogenic oedema and distinguishes re- T2WI, FLAIR and DWI and later haemorrhage.
cent from old insult, which can often be difficult on Hypointense on T1, hyperintense on T2WI, FLAIR, high signal on DWI are additional findings (Ito et al., (ii) Low magnetization transfer ratio (MTR) reflects 1999; Tsuchiya et al., 1999). In acute lesions, MRS re- myelin damage, cell destruction or changes in water veals metabolic changes in relation to neuronal death such as a decrease of N-acetyl aspartate (NAA) signal.
(iii) Magnetic resonance spectroscopy (MRS) identifies Resultant gliosis is reflected as an increase in inositol and quantities concentration of various brain metabo- and creatine resonances. The reinstitution of a normal lites. Spectroscopy is capable of differentiating normal spectrum over time could then potentially be used as a from pathological brain and provides tissue specificity marker of treatment efficacy (Menon et al., 1990; Salvan greater than that of imaging instances.
(iv) Functional MRI (FMRI) uses very rapid scanning Neonatal HSV-2 infection often causes more wide- techniques that in theory can demonstrate alterations in spread signal abnormalities than HSV-1 encephalitis, with periventricular white matter involvement andsparing of the medial temporal and inferior frontal CT is recommended only as a screening examination HIV-1. CT demonstrates normal/mild atrophy with with subtle clinical suspicion of encephalitis or when white matter hypodensity. MRI usually shows atrophy MRI is unavailable (Dun et al., 1986; Schroth et al., and non-specific white matter changes. MRS detects 1987; Marchbank et al., 2000, class IV).
early decreases in levels of NAA and increases in cho-line-containing phospholipids (Cho) levels, even before abnormalities are detected by MRI and prior to clinical SPECT is more readily available than PET and has symptoms. Later, with cognitive dysfunction, further been utilized in the study and diagnosis of encephalitis reductions in NAA and increases in Cho levels may be (Launes et al., 1988). It can provide information about seen (Rudkin and Arnold, 1999). In the later stages of brain chemistry, cerebral neurotransmitters and brain AIDS, the most common diseases affecting the brain function. It can also demonstrate hypoperfused tissue parenchyma are secondary to opportunistic infection or that seems normal on structural imaging.
malignancy and are predominantly focal. Neuroimag-ing is an important diagnostic tool for opportunistic infections. Toxoplasmosis (ring enhancing mass(es) in Although the gold standard in acquiring functional basal ganglia), cryptococcosis (gelatinous Ôpseudo- imaging data, remains a complex, costly and not readily In summary, structural information is provided by CT scan and MRI while functional and metabolic data enhancement), progressive multifocal leucoencephal- are provided by MRS, FMRI, SPECT and PET.
opathy (PML, white matter hyperintensities whichusually do not enhance), lymphoma (solitary or multi- focal solid or ring-enhancing lesions either in deep grey Herpes simplex encephalitis. CT obtained early is often and white matter or less frequent in subcortical areas) normal or subtly abnormal. Low attenuation, mild mass (Thurnher et al., 2001; Yin et al., 2001). MRS may effect in temporal lobes and insula, haemorrhage and be able to distinguish between these different space- enhancement are late features. Follow-up scans 1– occupying lesions based on their chemical profiles.
2 weeks after disease onset demonstrate progressively 1H-magnetic resonance spectroscopy can serve to more widespread abnormalities with the involvement of monitor the efficacy of antiretroviral therapy and may contra lateral temporal lobe, insula and cingulate gyri.
even be used to predict the responsiveness to drug Contrast enhancement and changes of subacute hae- morrhage may become readily apparent. MRI is much VZV. CNS complications of VZV infection (usually more sensitive in detecting early changes (Schroth et al., caused by reactivation) include myelitis, encephalitis, 1987; Marchbank et al., 2000; Chaudhuri and Kennedy, large- and small-vessel arteritis, ventriculitis, and Ó 2005 EFNS European Journal of Neurology 12, 331–343 meningitis (Gilden et al., 2000). Large vessel arteritis Paraneoplastic limbic encephalitis. In paraneoplastic presents with ischemic/haemorrhagic infarctions and limbic encephalitis MRI FLAIR and DWI depict MRI supported by angiography usually reveals these bilateral involvement of the medial temporal lobes and complications (Gilden et al., 2000; Redington and multifocal involvement of the brain. T2-weighted turbo spin-echo images fail to show changes (Thuerl et al., Miscellaneous viral infections. In polio and coxsackie virus infections, T2-weighted MRI may show hyperin-tensities in the midbrain and anterior horn of spinal cord (Shen et al., 2000). In EBV infection hyperinten-sities in the basal ganglia and thalami may be observed on T2-weighted MRI (Shian and Chi, 1996). West Nile The gold standard of diagnosis in encephalitis is virus virus (WNV) can be associated with enhancement of isolation in cell culture, now to be replaced by the leptomeninges, the periventricular areas, or both, on detection of specific nucleic acid from CSF or brain MRI (Sejvar et al., 2003). T2-weighted MRI of Japan- (Rowley et al., 1990; Echevarria et al., 1994; Lakeman ese encephalitis can show hyperintensities in bilateral and Whitley, 1995; Tebas et al., 1998, class Ia). Intra- thecal antibody production to a specific virus is simi- ADEM. Initial CT may show low density, flocculent, larly a strong evidence for aetiology (Levine et al., asymmetric lesions with mild mass effect and contrast 1978; Koskiniemi et al., 2002, class Ib). Virus detection enhancement multifocal punctate or ring-enhancing from throat, stool, urine or blood as well as systemic lesions. However, CT is normal in 40% of cases. MRI is serological responses like seroconversion or a specific more sensitive and an essential diagnostic tool. T2WI IgM provides less strong evidence (Burke et al., 1985; and FLAIR scans present multifocal, usually bilateral, Koskiniemi et al., 2001, class III). The CSF is a con- but asymmetric and large hyperintense lesions, invol- venient specimen and is recommended for neurological ving peripheral white and grey matter. They do not viral diagnosis in general (Cinque and Linde, 2003).
usually involve the callososeptal interface. Contrast- Brain biopsy is invasive and not used in routine clinical enhanced T1-weighted images may show ring-enhan- practice. At autopsy brain material will be obtained for cing lesions. Cranial nerves may enhance. DWI is virus isolation, nucleic acid and antigen detection as variable. On MRS, NAA is transiently low and choline well as for immunohistochemistry and in situ hybridi- is normal (Schroth et al., 1987; Dale et al., 2000; Bizzi et al., 2001).
PML. MRI is also the most sensitive imaging tool for PML (Berger and Major, 1999). T2-weighted sequences Viral cultures from CSF and brain tissue as well as from initially show multiple, bilateral, non-enhancing, oval throat and stool specimens are performed in four dif- or round subcortical white matter hyperintensities in ferent cell lines: African green monkey cells, Vero cells, the parietooccipital area. Confluent white matter dis- human amniotic epithelial cells and human embryonic ease with cavitary change is a late manifestation of skin fibroblasts. Cells are evaluated daily for cytopathic PML. Less common imaging manifestations of PML effect and the findings are confirmed by a neutralizing are unilateral white matter and thalamic or basal gan- or an immunofluorescence antibody test. Viral cultures from CSF are positive in young children with entero- viral infection but only seldom, in <5%, in other cases (RE) typically involves only one cerebral hemisphere, (Muir and van Loon, 1997; Storch, 2000, class III). As which becomes atrophic. The earliest CT and MRI brain biopsy is reserved only for unusual and diagnos- abnormalities include high signal on T2-weighted MR tically difficult cases, viral cultures are only rarely images in cortex and white matter, cortical atrophy that usually involves the fronto-insular region, with mild orsevere enlargement of the lateral ventricle and moderate atrophy of the head of the caudate nucleus. Fluorode- For nucleic acid detection, polymerase chain reaction oxyglucose PET has been reported to present hypo- (PCR) technology provides the most convenient test.
metabolism; Tc-99m hexamethylpropyleamine oxime Assays for HSV-1, HSV-2, VZV, human herpesvirus 6 SPECT decreased perfusion and proton MRS reduction and 7, CMV, EBV, enteroviruses and respiratory vir- of NAA in the affected hemisphere. However, PET and uses as well as for HIV can be performed from CSF SPECT findings are non-specific. MRI may become a samples or brain tissue. The primers are selected from a valuable early diagnostic tool by demonstrating focal conserved region of the viral genome and the PCR disease progression (Chiapparini et al., 2003).
product is identified by hybridization with specific Ó 2005 EFNS European Journal of Neurology 12, 331–343 probes or by gel electrophoresis. Respiratory virusesÕ tests for measles, mumps and rubella are only occa- nucleic acid as well as Chlamydia pneumoniae and sionally needed in countries with effective vaccination Mycoplasma pneumoniae can also be detected from programmes. Tests for arboviruses and zoonoses will be throat samples and enterovirus nucleic acid from stool useful in endemic areas (Burke et al., 1985; Wahlberg samples. However, these cannot confirm the aetiology of encephalitis. PCR for C. pneumoniae can also beperformed from a CSF sample. Detection of specific nucleic acid from the CSF depends on the timing of Antigens of HSV, VZV and RSV, influenza A and B, CSF sample. The highest yield is obtained during the parainfluenza 1 and 3, and adenoviruses can be studied transient appearance of the virus in the CSF compart- from throat specimens with a conventional immuno- ment during the first week after symptom onset, much fluorescence (IF) test or with an EIA test and may less in the second week and only occasionally after that provide a possible aetiology for encephalitis. In spite of (Lakeman and Whitley, 1995; Koskiniemi et al., 2002, promising initial results these tests are not helpful in class I). In herpes simplex encephalitis (HSE) the sen- sitivity is 96% and the specificity 99% when CSF is In conclusion, in a patient with suspected encephalitis studied between 48 h and 10 days from the onset of obtaining serum and CSF for virological tests is the symptoms (Lakeman and Whitley, 1995; Tebas et al., core of diagnostic procedure. Tests should include: PCR (single, multiplex or microarray) test for nucleic Instead of the single PCR tests, the multiplex PCR acid detection (from CSF) and serological tests for are gaining ground in diagnostics (Tenorio et al., 1993; antibodies (from CSF and serum samples). In undiag- Pozo and Tenorio, 1999). The sensitivity has been im- nosed severe cases, PCR should be repeated after 3– proved and it approaches that of the single PCR and 7 days, and serological tests repeated after 2–4 weeks to the specificities are equal. Real-time PCR makes it show possible seroconversion or diagnostic increase in possible to get the result in a shorter time while antibody levels. In children, viral culture from throat observing the yield cycle by cycle (Kessler et al., 2000).
and stool samples as well as antigen detection for herpes The usage of microarrays for detection of viral nucleic and respiratory viruses are recommended during the acid is still expensive, but has the potential to become a first week. Viral culture from CSF is useful in children regular diagnostic technique. Several microbes can be with suspected enteroviral or VZV disease if PCR tests studied at the same time and identification of the genotype will be easier than using the current conven-tional methods.
HistopathologyEncephalitis features a variety of histopathological changes in the brain, mainly depending upon the type Antibodies to HSV-1, HSV-2, VZV, CMV, HHV-6, of the infectious agent, the immunological response by HHV-7, CMV, EBV, respiratory syncytial virus (RSV), the host, and the stage of the infection. The aetiological HIV, adeno, influenza A and B, rota, coxsackie B5, spectrum is strongly influenced by geography. It should non-typed entero and parainfluenza 1 viruses as well as also be noted that primary encephalitic processes may Mycoplasma pneumoniae are measured from serum and secondarily involve the meninges as well, with inflam- CSF by using enzyme immunoassay (EIA) tests and matory infiltration resulting in usually mild CSF pleo- antibodies for Chlamydia pneumoniae by microimmu- cytosis (lymphocytes with variable degree of activation, nofluorescence test (MIF) (MacCallum et al., 1974; eventually plasmocytes). In encephalitis with a prom- Levine et al., 1978; Julkunen et al., 1984; Socan et al., inent necrotizing component, mixed CSF cellularity 1994; Koskiniemi et al., 1996; Gilden et al., 1998; may also include granulocytes; this is frequently seen in Koskiniemi et al., 2001, class II). These tests are sensi- HSV encephalitis, and CMV (peri)ventriculitis/myel- tive enough to detect even low amounts of antibodies from the CSF. The antibody levels in serum and CSF The histopathological basis of encephalitis is the triad are compared with each other in the same dilution of of damage to the parenchyma (usually nerve cell dam- 1:200. If the ratio of antibody levels is £20, it indicates age or loss, eventually demyelination), reactive gliosis intrathecal antibody production within the brain pro- and inflammatory cellular infiltration (by haematogen- vided that no other antibodies are present in the CSF, ous elements in the immunocompetent host) (Budka, i.e. the blood–brain barrier (BBB) is not damaged. The presence of several antibodies in the CSF suggests BBB This classical substrate is exemplified by (multi)nod- breakdown, while the presence of specific IgM in the ular encephalitis, as in the majority of viral encephali- CSF indicates CNS disease (Burke et al., 1985). The tides consisting of nerve cell damage, followed by nerve Ó 2005 EFNS European Journal of Neurology 12, 331–343 cell death and neuronophagia, focal/nodular prolifer- paraffin-embedded tissue by PCR may be blocked by ation of astro- and microglia, and focal/nodular infil- tration by lymphocytes, eventually macrophages. Thus, (iii)As PCR and ISH are very sensitive techniques, the classical encephalitic nodules are composed of positive results may just reflect the presence of genomic the mixture of microglia, astrocytes and lymphocytes information resulting from dormant or latent, and not usually around affected neuron(s) (Budka, 1997).
necessarily productive and pathogenic infection.
Distribution and spread of these inflammatory Therefore, prerequisites for the use of ICC, ISH or PCR changes are important for aetiological considerations: for neuropathological diagnosis of infections include six types of encephalitis may be distinguished, either simultaneous use of known positive and negative con- focal or diffuse affecting either the grey matter, the trol tissues which were identically processed as the white matter, or both (Love and Wiley, 2002). The material to be examined; availability of reagents (anti- bodies, probes, primers) with defined specificities; ade- cephalitis (e.g. in luetic general paresis) and patchy- quate testing of reagents on control tissues for highest nodular polioencephalitis (e.g. in poliomyelitis, rabies, sensitivity and sensitivity (optimal signal to noise ratio) acute encephalitis by flavi-, toga- and enteroviruses, in the respective laboratory and experience with im- HSV brainstem encephalitis), leucoencephalitis (e.g. in munocytochemical antigen retrieval techniques such as PML or HIV leucoencephalopathy), and panen- enzyme digestion, microwave treatment or autoclaving cephalitis (e.g. in bacterial septicaemia with micro- Viruses may exert damage to the nervous system not encephalitis, and herpesviruses such as HSV, CMV only by productive virus infection of the nervous sys- and VZV infection). Abscesses and granulomas may tem, but by indirect means as well. The best example is be randomly distributed in the brain. In addition to the immune-mediated ADEM or post-infectious/perive- the inflammatory quality and characteristic distribu- nous encephalitis as a sequel of exanthematous viral tion of tissue lesions, cytological features such as disease of childhood (e.g. measles, varicella, rubella, inclusion bodies (intranuclear in HSV, VZV enceph- mumps, influenza). This is very important for differ- alitis, PML and SSPE, cytoplasmic Negri bodies in ential diagnosis from productive viral encephalomyeli- rabies) or cytomegalic cell change in CMV disease give tis: multiple small demyelinated foci are arranged around small veins of the white matter, featuring involved cell type is considered: every viral infection of the nervous system usually features a fingerprint macrophages and microglia (Budka, 1997).
signature of selective vulnerability in the nervoussystem (Budka, 1997). However, immunosuppression and the effects of potent therapies have become notorious for being able to modify, blur or even wipe out the classical features of specific viral lesions.
Clinical distinction between viral encephalitis and non-viral infective meningoencephalitis is difficult, often The role of special techniques: immunocytochemistry, impossible. Epidemiological and demographic features, such as prevalent or emergent infections in the com- Arguably, it is in the field of infections where the munity, occupation, a history of travel and animal techniques of immunocytochemistry (ICC), in situ contacts may provide helpful clues. In acute bacterial hybridization (ISH) and PCR have the most profound meningitis, meningeal symptoms of intense headache, impact on neuropathological diagnosis. When per- photophobia and vomiting appear early and are usually formed appropriately with adequate controls and ade- more severe than the encephalopathic features. Presence quate tissue selection, they provide an aetiological of multiple cranial neuropathies is also suggestive of a diagnosis with high sensitivity and specificity (Budka, primary meningeal process. History of continued fever 1997; Johnson, 1998). Nevertheless, there are caveats and a subacute onset of symptoms with progressive for situations in which they may not be diagnostic: obtundation and/or features of raised intracranial (i)Production of the infectious agent may have burnt pressure are more typical of suppurative intracranial out, or its products may have become masked, resulting infections such as brain abscess. Tuberculous meningitis (TBM) also presents similarly, and in children, symp- (ii)Tissue preservation might be unsuitable for these toms of TBM are often subacute in onset. In a non- techniques, e.g. ICC or ISH may be falsely negative on epidemic setting, the most common cause of focal overfixed tissue, or nucleic acid amplification from encephalopathic findings is HSE; however, among cases Ó 2005 EFNS European Journal of Neurology 12, 331–343 with biopsy-proven herpes encephalitis, there were no association with migraine headache occur in familial distinguishing clinical characteristics between patients hemiplegic migraine (Feely et al., 1982). Sterile CSF positive for HSV and those who were negative (Whitley pleocytosis (pseudomigraine) has been reported in migraine patients who may present similarly (Schraederand Burns, 1980). It has been proposed that the CSFpleocytosis in some of these cases is due to recurrent predisposition to viral meningitis (Casteels-van Daele ADEM, an autoimmune disease, with evidence of cell- et al., 1981). Pseudomigraine with pleocytosis and mediated immunity to the myelin basic protein as its migraine coma are likely to represent reversible forms pathogenic basis (Behan et al., 1968), is characterized of ADEM (Chaudhuri and Behan, 2003).
by focal neurological signs and a rapidly progressivecourse in a usually apyrexial patient, usually with a history of febrile illness or immunization preceding theneurological syndrome by days or weeks (post-infec- tious or post-vaccinal encephalomyelitis). It may bedistinguished from infective encephalitis by the younger In two randomized controlled trials, acyclovir (10 mg/ age of the patient, prodromal history of vaccination or kg every 8 h given intravenously for 10 days) was found infection, absence of fever at the onset of symptoms and to be more effective than vidarabine (15 mg/kg/day) in the presence of multifocal neurological signs affecting improving survival rates of adult patients with biopsy- optic nerves, brain, spinal cord and peripheral nerve proven HSE (Skoldenberg et al., 1984; Whitley et al., roots. ADEM classically presents as a monophasic ill- 1986). Acyclovir is a safe treatment and given the higher ness developing after certain viral infections or immu- risk associated with diagnostic brain biopsy, it has be- nizations (post-infective and post-vaccinal ADEM). In come an established practice that treatment for viral the prodromal phase, patients experience migrainous- encephalitis is commenced on suspicion before a specific type headache with meningism. The disturbances of aetiological diagnosis is possible (Chaudhuri and Ken- consciousness range from stupor and confusion to nedy, 2002). When given early in the clinical course of coma. There is usually preservation of the abdominal HSE before the patient becomes comatose, acyclovir reflexes and patients have a mild fever often with per- reduces both mortality and morbidity in treated pa- ipheral blood pleocytosis. CSF shows lymphocytic tients. Acyclovir is also the treatment of choice for pleocytosis, with mildly raised protein and may appear neonatal HSE; however, there is no definitive evidence similar to the CSF in viral encephalitis. The clinical from trials that it is more effective than vidarabine.
course of patients with Hashimoto’s encephalopathy Acyclovir has a relatively short half-life in plasma and is would fit a less aggressive form of recurrent ADEM usually given intravenously 10 mg/kg every 8 h in adults (total daily dose 30 mg/kg). The daily dose ofacyclovir for neonatal HSE is 60 mg/kg (double theadult dose). As more than 80% of acyclovir in circu- lation is excreted unchanged in urine, renal impairment CNS vasculitis can be part of a systemic disease or be can rapidly precipitate acyclovir toxicity and thera- confined to the nervous system. Systemic symptoms, peutic doses should be adjusted according to the renal aseptic meningitis and focal neurological deficit may clearance. Rare relapses of HSE have been reported occasionally simulate viral encephalitis. This is seen in after weeks to 3 months later when the duration of both systemic vasculitis and primary CNS angiitis. In acyclovir treatment was 10 days or less (Davis, 2000).
systemic vasculitis affecting the CNS it is usually With conventional therapy, relapses of HSE may be possible to make a diagnosis based on a combination of higher than expected (5%) but do not occur if higher systemic and CSF serological and immunological tests doses were administered for 21 days (Ito et al., 2000).
and angiographic appearances of CNS vasculitis. In Although there have been no randomized trials, an isolated angiitis diagnosis may be more challenging and accepted policy in clinical practice is to give acyclovir even require brain and meningeal biopsy to secure the treatment for CSF PCR-positive HSE for 14 days in diagnosis where diagnostic uncertainties persist.
immunocompetent adult patients and 21 days for im-munosuppressed patients. Use of vidarabine for HSE islimited to the unlikely and rare patients who cannot receive acyclovir because of side-effects.
Acute confusion, psychosis and focal neurological Besides HSV, acyclovir is also effective against VZV deficit (hemiplegia, hemianaesthesia and aphasia) in and the doses and duration of therapy for VZV Ó 2005 EFNS European Journal of Neurology 12, 331–343 encephalitis are similar to HSE (GPP). In CMV (intravenous pulses of methylprednisolone) and/or encephalitis, combination therapy with ganciclovir plasma exchange is usually the recommended treatment (5 mg/kg intravenously twice daily) with foscarnet in ADEM (Cohen et al., 2001, class IV and GPP).
(60 mg/kg every 8 h or 90 mg/kg every 12 h) is currentlyadvised (GPP). Acyclovir is ineffective in CMV enceph- alitis. Antiretroviral therapy must be added or continuedin HIV infected patients (Portegies et al., 2004).
Surgical decompression for acute viral encephalitis is No antiviral therapy is particularly effective in epi- indicated for impending uncal herniation or increased zootic or enzootic viral encephalitis; however, because intracranial pressure refractory to medical management of the high mortality rate associated with B virus (cer- (steroids and mannitol, GPP). Such intervention has copithecine herpesvirus) encephalitis in humans, it is been shown to improve outcome in HSE in individual currently proposed (Whitley and Gnann, 2002) that patients should be treated with intravenous acyclovir organciclovir.
Newer antivirals like valciclovir appear promising in HSV and VZV encephalitis but remain to be evaluated All cases of acute encephalitis must be hospitalized. Like by formal trials (Biran and Steiner, 2002). Pleconaril is other critically ill patients, cases with acute viral a new Ôbroad spectrumÕ antiviral with potential for use encephalitis should have access to intensive care unit in enteroviral encephalitis and is undergoing clinical equipped with mechanical ventilators. Irrespective of the aetiology, supportive therapy for acute viral encephalitisis an important cornerstone of management (Chaudhuriand Kennedy, 2002). Seizures are controlled with intra- venous phenytoin. Careful attention must be paid to the Large doses of corticosteroids (dexamethasone) as an maintenance of respiration, cardiac rhythm, fluid bal- adjunct treatment for acute viral encephalitis are not ance, prevention of deep vein thrombosis, aspiration generally considered to be effective and their use is pneumonia, medical management of raised intracranial controversial. Probably the best evidence for steroid pressure and secondary bacterial infections. Secondary therapy is in VZV encephalitis. Primary VZV infection neurological complications in the course of viral may cause severe encephalitis in immunocompetent encephalitis are common and include cerebral infarction, children due to cerebral vasculitis (Hausler et al., 2002).
cerebral venous thrombosis, syndrome of inappropriate Vasculitis following primary and secondary VZV ADH secretion, aspiration pneumonia, upper gastroin- infection is recognized to lead to a chronic course in testinal bleeding, urinary tract infections and dissemin- immunocompetent children and adults (granulomatous angiitis). HSE is occasionally complicated by severe, Isolation for patients with community acquired acute vasogenic cerebral oedema with CT or MRI evidence of infective encephalitis is not required. Consideration of midline shift where high dose steroids may have a role.
isolation should be given for severely immunosup- Steroid pulse therapy with methylprednisolone has been pressed patients, rabies encephalitis, patients with an observed to be beneficial in a small number of patients exanthematous encephalitis and those with a conta- with acute viral encephalitis who had progressive dis- turbances of consciousness, an important prognosticfactor for outcome (Nakano et al., 2003).
Based on available data, combined acyclovir/steroid treatment may be advised in immunocompetent indi- Survivors of viral encephalitis and myelitis are a viduals with severe VZV encephalitis and probably in heterogenous group. Nature of the infective pathogen, other cases of acute viral encephalitis where progressive variability in anatomic lesions and time to treatment cerebral oedema documented by CT/MRI complicates contribute to outcome. Longitudinally designed case the course of illness in the early phase (GPP). High dose studies, reporting cognitive and psychosocial outcome dexamethasone or pulse methylprednisolone are both following mainly herpes simplex virus encephalitis were suitable agents. The duration of steroid treatment conducted prior to current era of early diagnosis and should be short (between 3 and 5 days) in order to effective therapy. While there are anecdotal case reports minimize adverse effects (e.g. gastrointestinal haemor- (Wilson et al., 2001; Miotto, 2002, and others) there rhage, secondary fever and infections).
are too few studies on the outcome of rehabilitation Although no randomized controlled trials have following encephalitis (Moorthi et al., 1999) to enable been performed, treatment with high dose steroids Ó 2005 EFNS European Journal of Neurology 12, 331–343 Recommendations for therapeuticinterventions Currently vaccines are available against a limitednumber of viruses with a potential to cause encephalitis.
The following are the specific and symptomatic thera- peutic measures available for viral encephalitis mumps, measles, rubella and poliovirus. Europeantravellers to specific geographical destinations (e.g.
Southeast Asia) should receive advice regarding vac- cination against rabies and Japanese encephalitis. Pre- ventive measures against exotic forms of emerging paramyxovirus encephalitis (Nipah and Hendra vir- uses) are entirely environmental (sanitation, vector Viral encephalitis is still an evolving discipline in medicine. The emergence of new, and re-emergence of old pathogens and the constant search for specific encephalitis cases, suggests that the following yearswill bring new developments in diagnosis and ther-apy. At present, adherence to a strict protocol These guidelines will be updated when necessary and of diagnostic investigations is recommended and in any case in not more than 3 years.
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