The Value of Standardized Case Definitions in Encephalitis Clinical Research

Encephalitis is a poorly defined disease entity. Encephalitic symptoms may be vague and unspecific, especially in the neonatal and pediatric age groups. Early signs and symptoms such as fever, malaise, headache and fatigue are fairly common and shared with many disease entities, infectious and non-infectious. Even if neurologic symptoms prevail and an encephalitis diagnosis has moved to the top of the list of differential diagnoses, overlap with other disease entities remains a possibility in particular with meningitis, cerebellitis, myelitis and acute disseminated encephalomyelitis (ADEM). Encephalitis appears to be under-diagnosed and in the majority of cases of encephalitis, the pathogen or cause remain unknown.1-5 Furthermore, surveillance programs in Scandinavia revealed that 60% of the children with encephalitis had persisting symptoms at the time of discharge. Systematic evidence-based research and prospective surveillance are warranted to learn more about the clinical spectrum, underlying causes, and prognostic factors of encephalitis. The ultimate goal of encephalitis clinical research should be to improve treatment modalities and disease outcomes in all patients, regardless of age and geographic background. Meaningful epidemiologic investigations of encephalitis disease outcomes, incidence and prevalence require large-scale studies, multi-centric approaches, and the pooling and metaanalysis of significant amounts of data from different parts of the world. For data comparability purposes, pre-defined standards should be used for the inclusion of patients into encephalitis surveillance cohorts. Inclusion criteria for encephalitis studies should be based on observerindependent, widely accepted clinical case definitions and ideally, international consensus. This paper aims to raise awareness of the challenges of defining and diagnosing encephalitis as a disease entity, while presenting a number of practical approaches to facilitate encephalitis screening for pediatric clinical research and public health purposes.

Examples of key topics in encephalitis studies in recent years are:  The early detection of congenital encephalitis and TORCH infections  Regional and periodic epidemiologic surveillance of arbovirus infections  Polio surveillance (WHO)  Baseline prevalence of vaccine preventable disease  Monitoring of adverse events following immunization (AEFI)

Example 1: The discussion around Rotavirus Encephalitis/ Encephalopathy
Ever since the first cases of CNS involvement in rotavirus disease were reported, it has been discussed if and when one of the most common pathogens causing gastroenteritis in children under the age of 4 may also cause neurologic symptoms and complications. Table 1 illustrates a summary of the first case reports of rotavirus encephalitis in the medical literature.  Table 1.
Notably, thirty-three cases of rotavirus disease with CNS involvement had been reported up until the time when the new rotavirus vaccines were introduced in the United States. 16-22 25-28 Among these 32 cases, less than half (10/24; 42%) of the patients with reported outcomes recovered completely. Five children (21%) died from the disease, whereas the remaining 37% experienced neurological sequelae. 23 With increased awareness evidence has since grown further, and CNS involvement is slowly being recognized as a rare but potentially serious complication in rotavirus gastroenteritis. [29][30][31][32][33][34][35][36][37][38] Over time, in addition to viral diagnostics radiological features of www.intechopen.com rotavirus encephalitis are better understood, which may help in directing clinicians to the correct diagnosis. 23 56 and Saudi Arabia 57 . Parallel to increased efforts in developing a cytomegalovirus (CMV) vaccine [58][59][60][61] , attention has also shifted to further understanding the neurologic sequelae and disease burden of congenital CMV disease and non-immunocompromised hosts.  In addition, influenza has been increasingly recognized as a vaccine preventable cause of encephalitis, especially in children and adolescents. 67 Initial reports emerged from Japan and the United States [68][69][70][71][72][73][74][75] and recently, a number of case reports as well as surveillance reports by CDC have been issued on neurologic complications of Influenza A (in particular pandemic H1N1) disease. [76][77][78][79][80][81][82][83][84][85][86][87][88] Example 3: Encephalitis as an adverse event following immunization (AEFI) Encephalitis has not only been described as a viral and/or immunological illness, but also as an adverse event following immunization (AEFI) 89 . The British Pediatric Surveillance Unit conducted a 3-year prospective surveillance aiming to investigate encephalitis as an AEFI in the UK and Ireland 90 By nature, AEFI are rare events requiring large-scale studies, meta-analyses, or extensive (ideally active) surveillance programs to be detected. Reporting bias and awareness are major obstacles to the systematic assessment of AEFI. Resent research revealed that physicians are more likely to report a specific AE if the AE constitutes an event a vaccine in designed to prevent. Interestingly, this "reverse placebo effect" also applied to non-live vaccines. 91 When data have to be pooled from a number of different studies, the use of uniform diagnostic criteria is warranted allowing comparability among studies conducted at different sites. This demand has been met by the Brighton Collaboration, who published a clinical case definition for encephalitis as an AEFI in 2007. 89 The diagnostic criteria for encephalitis as an AEFI are listed in Table 2, below. The Brighton Collaboration criteria are designed to capture an adverse event independent from any potential triggers, but also to differentiate reliably and consistently between different kinds of CNS involvement, including meningitis, meningo-encephalitis, myleitis, ADEM and the like. The Brighton Collaboration case definitions for aseptic meningitis, encephalitis, myelitis and ADEM have since been evaluated in a retrospective analysis of 255 clinical cases of CNS disease in a Swiss children's hospital. 93 This evaluation study revealed that unless predefined clinical criteria are applied consistently, the demarcation of closely related but distinct CNS disease entities will be missed. ICD-10 coding and diagnoses mentioned in hospital discharge summaries are insufficient and all too often observer-dependent. 93

Brighton Collaboration Case Definition for Encephalitis as an AEFI 89 "Case definitions: encephalitis, myelitis, and ADEM" 1
Encephalitis -Level 1 of diagnostic certainty: 2 (a) Demonstration of acute inflammation of central nervous system parenchyma (± meninges) by histopathology.

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Encephalitis -Level 2 of diagnostic certainty: 3,4 (a) Encephalopathy (e.g. depressed or altered level of consciousness, lethargy, or personality change lasting >24 h), Encephalitis -Level 3A of diagnostic certainty: 7,9 (a) Insufficient information is available to distinguish case between acute encephalitis or ADEM; case unable to be definitively classified.

Encephalitis -Exclusion criterion for levels 2 and 3 of diagnostic certainty:
(a) Other diagnosis for illness present. 10 2 If the lowest applicable level of diagnostic certainty of the definition for a definitive category (i.e., Level 3, excluding Level 3A) is met and there is evidence that the criteria of the next higher level of diagnostic certainty (Level 2) are met, the event should be classified in the next category. This approach should be continued until the highest level of diagnostic certainty for a given event can be determined. Thus, if a case fits diagnostic criteria for both categories (encephalitis and ADEM), but reaches a higher level of diagnostic certainty in one, the higher level supercedes, and the case should be classified according to the category in which the higher diagnostic certainty level is reached. TheWorking Group recognizes that under this paradigm, it is possible to reach a higher level of diagnostic certainty forADEMwith less stringent criteria than it is for encephalitis e.g., Level 1 diagnostic certainty for encephalitis requires histopathologic diagnosis, whilst ADEM Level 1 does not require this. However, in the absence of a biological marker, the diagnosis of ADEM rests upon the proper neuroimaging findings in the appropriate clinical context, and the combination of appropriate neuroimaging and a monophasic pattern of illness are as close to a gold standard as exist for this clinical entity. Thus, one may have a higher level of diagnostic certainty of ADEM than of encephalitis, in the absence of other biologic data.

Assessment of the problem
Most of the attempts to standardize the diagnosis of encephalitis are focusing on adults whereas pediatric studies are facing specific challenges in the differential diagnosis, such as age-dependent symptoms while intellectual capabilities are still developing and the difficulty to distinguish acute neurologic impairment from consequences of perinatal asphyxia and congenital malformations, developmental delay, intoxication and other alternative possible non-infectious causes of encephalopathy. 2,5 Due to the immaturity of the immune system and the blood-brain barrier, children under the age of two are at a www.intechopen.com particularly high risk of developing encephalitis during bacterial sepsis or systemic infection with herpesviridae, Tb and many other pathogens. At the same time the chance of recurrence of HSV meningo-encephalitis is difficult to assess and consequences of premature discontinuation of antiviral therapy can be detrimental. [94][95][96][97][98][99] Even in older children, the difficulty to identify symptoms of encephalopathy such as behavioral outbursts, decreased responsiveness, and other subtle signs may delay the diagnosis and thus, treatment. 100,101 In other cases, the differentiation of autoimmune from viral causes of encephalitis causes problems. 100,4 Without the identification of potential causes of encephalitis, however, the treatment options and prognosis in different types of encephalitis will remain poorly understood. 1,102 With additional diagnostic and therapeutic options becoming available, and several types of encephalitis vaccine-preventable, the systematic surveillance of encephalitis in children has gained significance, also with respect to everyday clinical care. As indicated above, prospective and retrospective case ascertainment both provide a number of challenges. Prospective surveillance of large cohorts using predefined case definitions is key to avoid inter-rater variability and selection bias. The installment of active surveillance systems in specialized reference centers will ultimately improve the monitoring of encephalitis as an AEFI. Children with acute CNS adverse events are most likely to present in emergency rooms and tertiary care centers rather than private pediatric practices, where the child has usually been immunized. Unless immunizations are systematically captured at the time of investigation, rates of encephalitis and other CNS adverse events following immunization -as opposed to other triggers or causes -can hardly be established. 90,103 In addition, lumbar puncture is difficult to perform in infants and children, and even if CSF has been obtained, pathogens other than HSV and bacteria are rarely assessed in routine practice. Very little is known for example, about incidence rates of enterovirus infection in pediatric CNS disease. 104 However, effective enterovirus surveillance can also be utilized as a tool for regional polio disease surveillance, as is the case at the German National Reference Laboratory for Enteroviruses at the Robert Koch Institute in Berlin. 105,106 Hospital-based prospective surveillance systems have been introduced in several locations, including country-wide surveillance systems in the US 4 , France 107 , the UK 2 and Sweden 1 , as well as smaller programs in Taiwan 108 , Crete 109 , and India. 110 Unfortunately, each of these programs use their own case definitions for encephalitis. "The case definition included any person of any age admitted to hospital with encephalopathy (altered consciousness that persisted for longer than 24 h, including lethargy, irritability, or a change in personality and behaviour) and with two or more of the following:fever or history of fever (≥38ºC) during the presenting illness; seizures and/or focal neurological fi ndings (with evidence of brain parenchyma involvement); CSF pleocytosis (more than four white blood cells per μL); electroencephalographic (EEG) fi ndings indicative of encephalitis; and abnormal results of neuroimaging (CTor MRI) suggestive of encephalitis." Glaser 113 In and with no preexisting neurological conditions or evidence of bacterial meningitis by microscopy or culture of cerebrospinal fluid (CSF) samples, and no febrile convulsion (defined by a single convulsion lasting less than 15 minutes with regaining of consciousness within 60 minutes in a child between 6 months and 6 years of age) were eligible for inclusion in the study after provision of written informed consent by the patient's parents or legal guardians" Lee 108 Encephalitis

Summary and future perspectives
In conclusion, it may be stated that  prospective surveillance systems for encephalitis have been developed in several sites  universal case definitions or inclusion criteria are currently not being applied  clinical encephalitis case definitions are usually not adjusted to age  a large number of prospective studies are laboratory-based with clinical information added after the fact  evidence-based information on the multiple causes of encephalitis only slowly emerging. With the emergence of surveillance systems for encephalitis worldwide, it would be desirable to introduce the use of uniform case definitions and clinical criteria allowing metaanalysis and head-to-head comparisons between studies and sites. As a first step into this direction, a model surveillance system has been introduced in the pediatric emergency rooms at Charité University Medical Center in Berlin in collaboration with the adjacent Robert Koch Institute, as a first cohort to prospectively implement the neurologic case definitions by the Brighton Collaboration while assessing vaccine preventable neurologic disease along with neurologic adverse events following immunization in the same population.

The Charité Meningitis Surveillance at Charité (MenSCh ) Cohort: Prospective Surveillance Systems for CNS inflammation and natural infection.
At Charité, a prospective surveillance system has been put in place monitoring acute presentations of children and adolescents to one of the largest pediatric ERs in Europe. The ERs are located in two different areas of Berlin representing an ethnically diverse population, including up to 40% of children with migratory background (Turkish, Kurdish, Arab/North African, Eastern European). All patients fulfilling predefined case definitions while presenting on regular screening days are automatically enrolled, tested immediately in close collaboration with epidemiologists and the adjacent Robert Koch Institute and followed-up clinically. In the absence of an HMO system in most European countries, this is a powerful method to capture a comprehensive sample of a typical pediatric urban tertiary www.intechopen.com care population with "naturally occurring infection" and adverse events. Precise immunization histories are taken at the time of presentation. Case-control and other methodology can be used to compensate for lack of randomization. The MenSCh (Meningitis Surveillance at Charité) Cohort is a prospective cohort of children presenting with signs and symptoms of CNS inflammation/infection to the ER. Presentations are classified according to age-adjusted clinical and disease severity scores, but also classified according to standardized case definitions for meningitis, encephalitis, myelitis, ADEM, GBS, seizure and Bell's Palsy by the Brighton Collaboration. Confirmed clinical cases according to the definitions of the Brighton Collaboration, regardless of the trigger (infection, immunization, autoimmune disease), are followed until discharge. Again, detailed immunization histories and laboratory data are captured. After case ascertainment according to standardized case definitions, patients presenting with rare autoimmune AE following immunization will be studied in detail. Vaccines are among the most effective methodologies available to date for the prevention of infectious diseases of childhood. With declining vaccine acceptance in many parts of the world, it will become increasingly important to learn more about the causes of neurologic adverse events in children. It is hoped that the MenSch cohort will provide a useful contribution to the field while monitoring incidences of vaccine preventable disease alongside with adverse events following immunization.