Update and new insights in encephalitis

Clinical Microbiology and Infection xxx (2017) 1e7

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Review

Update and new insights in encephalitis A. Mailles 1, 2, *, J.-P. Stahl 2, 3, K.C. Bloch 4 Sant
e publique France, Saint-Maurice, France ESCMID Study Group on infections of the Brain 3) Joseph Fourier University, University Hospital, Grenoble, France 4) Vanderbilt University Medical Center, Nashville, TN, USA 1) 2)

a r t i c l e i n f o

a b s t r a c t

Article history: Received 2 February 2017 Received in revised form 30 April 2017 Accepted 1 May 2017 Available online xxx

Infectious encephalitis is a rare but severe medical condition resulting from direct invasion of the brain by viruses, bacteria, fungi or parasites, or indirect post-infectious immune or inflammatory disorders when the infectious agent does not cross the bloodebrain barrier. Infectious encephalitis cases represent an interesting and accurate sentinel to follow up on trends in infectious diseases or to detect emerging infections. Using Pubmed and Embase, we searched the most relevant publications over the last years. We present here an update on the important findings and new data recently published about infectious encephalitis. A. Mailles, Clin Microbiol Infect 2017;▪:1 © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Editor: C. Pulcini Keywords: Autoimmunity Bornavirus Chikungunya Ebola Encephalitis Guidelines Lassa Naegleria fowleri Next-generation sequencing Zika

New and emerging viruses Variegated squirrel bornavirus 1 Bornavirus are neurotropic viruses that infect birds, horses, rodents and, more rarely, humans. In Germany, three individuals, aged 62e72 years, who knew each other, presented with encephalitis of unknown cause but highly similar presentation in the same hospital from 2011 to 2013 [1]. They presented with sub-acute onset, decreased consciousness then coma, and died in hospital after 2e4 months. All three experienced late ocular paresis, myoclonus and bilateral crural veinous thrombosis, and two of them experienced pulmonary embolism. Necropsy demonstrated brain necrosis, microglial activation and perivascular lymphocyte infiltration. The investigation revealed that all three were exotic squirrel breeders of Sciurus variegatoides (Fig. 1). This species originates


publique France, 12 rue du Val d'Osne, * Corresponding author. A. Mailles, Sante 94415 Saint-Maurice cedex, France. E-mail address: [email protected] (A. Mailles).

from South America and S. variegatoides are only rarely kept as pets in Europe. The three patients had exchanged some squirrels. A new Bornavirus, close to those usually infecting horses, was identified thanks to metagenomic analysis from brain samples of the three patients and named Variegated Squirrel Bornavirus 1 (VSBV1). The virus was also identified in various organs of a squirrel belonging to one of the three patients by metagenomic analysis. Finally, RT-PCR and serological diagnosis were developed and some other squirrels were found to be positive (serology and RTPCR) in zoos and private collections in Germany and the Netherlands [2]. This episode illustrates the risk of emerging diseases acquired from pet animals captured in the wild. Although bats are frequently cited as a potential reservoir for emerging pathogens, rodents should be considered too because they represent 40% of all mammals and account for 1700 species. It is not known if Variegated Squirrel Bornavirus 1 can be responsible for milder clinical presentations in humans. However, the virus was discovered because the cluster of encephalitis attracted attention, emphasizing the value of this syndrome as a sentinel of emerging infectious agents.

http://dx.doi.org/10.1016/j.cmi.2017.05.002 1198-743X/© 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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Fig. 1. Sciurus variegatoides in its natural environment in Costa Rica (courtesy of Dr Didier Boussarie).

A number of questions still remain unanswered about other possible reservoirs and the routes of transmission of the virus to humans. Of note is that no other human cases were reported despite the spread of these findings among the exotic pet breeding community. Lassa fever virus Lassa fever virus (LFV) is a highly transmissible Arenavirus and a biosafety-level-4 pathogen. LFV infection is endemic in West Africa with seasonal peaks and frequent outbreaks. LFV infection is most frequently asymptomatic but can result in a severe disease, including haemorrhagic fever, in 20% of patients. Survivors experience hearing deficit in 25%e30% of cases. Rare encephalitis cases caused by LFV infection have been reported [3]. In Sweden, during spring 2016, a woman in her 70s was hospitalized with encephalitis of unknown origin after returning from a 6-week stay in Liberia, where she had been exposed to rodents [4]. Magnetic resonance imaging demonstrated hypersignals but the cerebrospinal fluid (CSF) characteristics were normal. She received supportive standard healthcare. On day 26 of hospitalization, genome amplification on serum was positive for LFV and she was transferred to a reference hospital. She progressively recovered but was discharged with hearing loss. In all, 118 healthcare workers (HCW) and family members were considered possible at-risk contacts and were followed up for a 3-week period. Five of them presented with symptoms suggesting LFV infection but all tested negative. Encephalitis and encephalopathy are not common clinical presentations of Lassa fever. A number of other infectious agents possibly responsible for encephalitis are far more frequent both in Africa, including more usual causes like herpes simplex virus or malaria. These frequent causes of encephalitis need to be considered as first-line diagnosis also in returning travellers. However this case emphasizes the need for careful interview of patients returning from tropical areas with encephalitis. It is also important to note from this report that no secondary case was recorded although ‘only’ standard protection measures were used by HCW. Ebola virus and the brain From 2014 to 2016, the largest ever reported outbreak of Ebola virus diseases (EVD) occurred in West Africa. An unprecedented number of HCW were deployed in the affected countries, resulting in better management and more accurate description of the disease. Neurological syndromes during the course of EVD had been

described during previous outbreaks, but with only limited investigation [5]. During the 2014e16 outbreak, reports suggested that various neurological syndromes may be associated with EVD, namely encephalitis, encephalopathy or isolated seizures [6,7]. However, despite an increased number of HCW in the field and more sophisticated medical equipment, the neurotropism of Ebola virus (EV) was still difficult to assess, as some examinations such as electroencephalogram were not available in all treatment centres, or were difficult to perform in highly contagious patients (for example lumbar puncture or imaging). Moreover, at some point during the outbreak, the high number of patients in the treatment centres would have made it difficult if not impossible to perform a complete investigation. The neurological cases described during the last outbreak had some interesting details, and raised new questions (Table 1). The majority of cases had neurological onset during the second week of illness. In some cases [8], encephalopathy with metabolic disorders was the major hypothesis, whereas it was ruled out in a severe encephalitis case with white matter lesions [10]. In other cases, imaging [11] and high viral load in CSF [9,13] suggested a direct invasion of brain parenchyma. When both CSF and serum/plasma were tested, the results could be divergent, suggesting the existence of different pathophysiological mechanisms (Table 1). Finally, some authors suggested that experimental therapy could have driven neurological side effects in some patients [12]. Besides these acute cases, preliminary data from survivor patients suggest a high prevalence of persisting cognitive and neurological symptoms and complaints in both short and long term: - In Liberia, 82 patients included in the ‘Prevail III’ cohort still presented cognitive or neurological signs 6 months after the onset of EVD, with increased mRankin scores [14]. Main complaints were memory loss, headaches, weakness, myalgias and depressed mood. Tremors and sensory disorders were present in a third of cases and abnormal ocular movements in twothirds, frontal release in one of six patients. - In Guinea, among 105 survivors examined 4e9 months after acute EVD, 32% had mood disorders, 27% memory deficits, and 10% dizziness [15]. - In Sierra Leone, 38 patients were followed up after discharge: 1 year later, 74% complained of headache, 55% of sleep disorders and 29% of anxiety (Howlett, 26th ECCMID, Abstract OLB21). The pathophysiology of these ‘sequelae’ remains undetermined and more studies are needed to clarify these important preliminary findings, especially to distinguish between primary neurocognitive disorders and post-traumatic stress syndrome. However, their convergence is in favour of a systematic long-term follow up of Ebola survivors, including neurocognitive assessment by trained HCW, using tools that can be administered independently of the language of the patients and their ability to read. Another unexpected finding was the ability of the virus to persist in ‘protected’ body sites such as the eye or the brain. In early 2015, a 38-year-old HCW returning from Sierra Leone was successfully treated for EVD in the UK [16]. During her initial hospitalization, specific treatment included brincidofovir, convalescent plasma and ZAMb (Public Health Agency of Canada, MB, Canada). She was discharged with full recovery, but she was re-admitted 9 months later with severe meningo-encephalitis. Remarkably, RT-PCR on admission showed lower CT values in CSF than plasma, suggesting viral multiplication in CSF. Infectious virus could be cultured from CSF samples but not from blood samples. It was therefore considered that the virus was multiplying in the central

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Table 1 Reports of Ebola patients with neurological symptoms Symptoms

Cerebrospinal fluid

Imaging

Comments

Kreuels B, NEJM 2014 [8]

‘Encephalopathy’, hallucinations, delirium

no

Related to severe sepsis?

Sagui E, CID 2015 [9] Chertow D, Annals Intern Med 2016 [10]

‘Encephalopathy’, seizures, meningitis Speech disorders, frontal release signs, delirium, respiratory depression, deviated eyes, memory disorders, postural tremors, uveitis Sequelae on discharge

RT-PCR þ plasma, urine, sweat. No test on CSF RT-PCR þ CSF and blood No test on CSF

Neurological signs at Day 7 Systematic correction of metabolic disorders Full recovery after 7 months

Howlett P, EID 2016 [11]

Confusion, decreased consciousness

no White matter lesions suggestive of microvascular occlusion and ischaemia þ spinal cord lesions Cortical atrophy on tomodensitometry

Uyeki TM, NEJM 2016 [12]

Case series n ¼ 27 Encephalopathy/encephalitis in 1/3 Case series n ¼ 3 Case 1: headache, slowness of thoughts, frontal syndrome Case 2: photophobia, prostration, slowness of ideation, aggression. Case 3: disorders, slowness of thoughts, loss of inhibition, aggressiveness.

De Greslan T, CID 2016 [13]

RT-PCR þ CSF, Blood and urine (D41)

Investigational therapy in 70% All cases: positive RT-PCR on CSF and serum, CT-value higher in serum than CSF

none

Mild severity with regards to the systemic symptoms. Neurological symptoms developed on the second week of illness for two cases, but were present since onset for the third case.

Abbreviations: CSF, cerebrospinal fluid.

nervous system (CNS) only and that the patient was less contagious than during the initial EVD. She was discharged on day 52 of hospitalization with persisting neurological symptoms. Although many questions remain unanswered about neuroebola, some issues to address are clear: managing critical neurological syndrome in highly contagious patients, designing a way to obtain good-quality imaging and electroencephalograms in limited-resource settings. These issues are real challenges that need to be anticipated before the next EVD outbreak, taking into account that these may be ‘classical outbreaks’ involving fewer cases and occurring in remote places. Zika virus Zika virus (ZV) is a Flavivirus first identified in 1947 in Uganda. It is mainly transmitted by Aedes aegypti, or through human-tohuman transmission (maternoefetal and sexual transmission). ZV (re)emerged and spread in the Pacific region in 2013/14, then in South America, Central America, West Indies since late 2015, and recently in Florida. Since the re-emergence of ZV, its neurotropism has been demonstrated in newborns infected during the first-trimester of pregnancy, revealing an outbreak of severe brain malformations and microcephaly [17]. In adults, an increased incidence of
syndrome was reported in French Polynesia in 2013 GuillaineBarre [18]. Similar results were later reported in the Americas [19]. During the same outbreak, rare cases of encephalitis [20,21], encephalopathy [22], acute disseminated encephalomyelitis [23] and myelitis [24] were reported. Despite a large spectrum of neurological disorders in adults following ZV infection, the number of cases remains very low. Unlike other Flaviviruses, encephalitis seems to be a rare clinical presentation of ZV infection. An increased incidence of neurological conditions of unknown cause (International Classification of Diseases. 10th revision codes G040eG049) was reported in the national hospital discharge record in northeastern Brazil during the outbreak [25]. However, indepth investigations have to be carried out before any conclusion can be drawn from these data. Chikungunya virus Chikungunya virus (ChikV), an Alphavirus transmitted by Aedes mosquitoes, was identified in Tanzania in 1952. ChikV is known as

an endemic threat in Africa and Asia. The virus emerged in 2005 in the Indian Ocean and spread rapidly. More recently, outbreaks occurred in the Americas and Pacific Islands. Before 2005, ChikV was considered a cause of mild febrile self-limited disease, possibly complicated by chronic disabling arthritis of the joints. In
union 2005/6, an outbreak of ChikV infections occurred in La Re Island with unexpected neurological cases [26,27]. The estimated total number of Chikungunya cases was 300 000, and 57 were diagnosed with encephalitis (n ¼ 24) or encephalopathy (n ¼ 33). The case fatality rate was 10% among the patients with neurological presentation. CNS involvement occurred in infants <1 year old and in adults; the disease was more severe in adults. One adult died 3 months after discharge with acute disseminated encephalomyelitis. Three years after discharge, only four in ten adults had an apparent full recovery whereas one infant in 13 re-evaluated had developed cerebral palsy and four had a low developmental quotient [26]. A number of case reports with neurological involvement were published during the ChikV outbreaks in Asia [28,29], in the South Pacific [30], in Italy in 2007 [31], and more recently in the French West Indies [32] and in Brazil [33]. Most patients experienced encephalitis and were reported in patients over 60 years. However, Bandeira et al. reported severe encephalitis following a probable mother-to-child perinatal transmission in a 4-day-old newborn [33]. In India, a case of ChikV encephalitis was reported in a 12year-old boy [28]. Other reported neurological presentations included
syndrome, acute disseminated encephalomyelitis, GuillaineBarre encephalopathies and complex/simple febrile seizures. Although neurological presentations are rare among patients with ChikV infections, they are severe conditions and available data suggest a poor neurocognitive outcome [26,27]. Possible future threats in the field of encephalitis Powassan virus Powassan virus (PWV) is a Flavivirus sharing close characteristics with the European tick-borne encephalitis virus. PWV is present in North America (in the region of the Great Lakes, in New York State, in New England and in Ontario); and in the Far East of Russia. In North America, the virus is transmitted to humans by several Ixodes vectors.

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Like some other Flaviviruses, most infections by PWV are asymptomatic in humans. Encephalitis is a rare but severe presentation of PWV infection with a 10% case-fatality rate [34]. Although the disease remains rare, there is a growing concern that the incidence of PWV infections, including encephalitis, may be increasing. In the USA, at the national level, the incidence was 0.7 cases/year before 1998, but had increased up to 1.3 cases/year in 2005 [34]. In Maine and Vermont, four PWV encephalitis cases were diagnosed in 1999/2001 [35]. In New York State, four cases were diagnosed in 2013 compared with 14 cases between 2004 and 2012. In Massachusetts and New Hampshire, eight cases of PWV encephalitis were confirmed in 2013/15 [36]. Moreover, PWV encephalitis has been recently diagnosed in places where the disease was formerly not present, such as Tennessee [37] and Minnesota [38]. In New England, a recent study demonstrated a major increase of the seroprevalence of PWV antibodies in deer, from 25% before 1996 to 80%e90% in the years 2005 to 2009 [39]. PWV may become an important cause of encephalitis in the USA and another major tick-borne disease. Tick bite prevention is essential in the prevention of these diseases. More research is needed to confirm this apparent emergence, and understand its mechanism, including possible increased human exposure to ticks in the context of climate change. Primary amoebic meningoencephalitis Primary amoebic meningoencephalitis (PAM) is a fulminant, almost invariably fatal necrotizing brain infection caused by the free-living amoeba Naegleria fowleri. The high mortality has led to the organism being referred to as the ‘brain-eating amoeba’. The clinical presentation is indistinguishable from bacterial meningitis, although PAM does not respond to standard antibiotic therapy. Diagnosis is confirmed in only 27% of cases pre-mortem, and death due to cerebral oedema occurs a median of 5 days after presentation [40]. This organism thrives in warm water, with the preponderance of cases occurring during summer months among individuals with recreational exposure to standing bodies of freshwater. Most cases in the USA have occurred in southern states; however, in the last decade, cases have been reported in northern regions, potentially related to warming temperatures allowing growth of this thermophilic organism [41]. Transmission has also been documented through municipal water supplies, with cases associated with play on a lawn water slide [42], sinus lavage with a neti pot [43], and ritual nasal ablution [44]. The mortality from PAM exceeds 95%. Before 2013, there had only been three reported survivors among the 135 known cases. In 2013, two children with PAM survived after treatment with a multidrug regimen that included miltefosine [45,46]. This agent, which has been available internationally as a treatment for cutaneous leishmaniasis, is now commercially available in the USA. Outcome however is contingent on suspicion for PAM allowing early initiation of treatment, and PAM should be included in the differential diagnosis of any patient presenting with a rapidly progressive meningoencephalitis following water exposure or nasal lavage. Infection and autoimmunity in central nervous system Disordered immunological responses to a number of stimuli, including infection, vaccination, and malignancy, may result in the production of antibodies that cross-react to neural tissues, causing autoimmune encephalitis. In 2007, a cohort of young women with ovarian teratomas and paraneoplastic encephalitis was reported [47]. These patients had production of antibodies reactive with

both epitopes on the tumour as well as the N-methyl-D-aspartate receptor (NMDAR) present in neural tissue. Anti-NMDAR encephalitis typically has a subacute onset, and frequent findings include behavioural disturbances (including new-onset psychosis), choreoathetosis, seizures, aphasia and autonomic instability [48]. AntiNMDAR autoimmune disease is increasingly appreciated as one of the most common causes of encephalitis. In a large prospective study, 41% of diagnosed encephalitis cases in patients <30 years of age were attributable to anti-NMDAR encephalitis, making this the single most common cause of encephalitis, and exceeding the combined incidence of herpes simplex virus (HSV), West Nile virus and varicella zoster virus in this population [49]. Subsequent studies have identified anti-NMDAR encephalitis in patients without an underlying teratoma, and this syndrome has now been reported in both men and women of all ages [50]. HSV encephalitis is increasingly recognized as a potential trigger for subsequent development of anti-NMDAR antibodies, with more than 30 cases reported in the literature since the initial description of this association in 2014 [51,52]. A recent prospective study of 49 patients with HSV encephalitis found that NMDAR antibodies were absent at the initial diagnosis of viral encephalitis, however by 3 months, 24.5% of the cohort had developed detectable CSF antibodies [53]. Although none of the patients who developed NMDAR antibodies had a clinical relapse of encephalitis, these patients demonstrated significantly less clinical improvement at 12 and 24 months than subjects without an antibody production. Based on the increasing recognition of post-viral autoimmune encephalitis and the frequency of sequelae in survivors, a multi-centre European study is ongoing to determine whether patients with HSV encephalitis benefit from immune modulation with steroids (cf. below ‘Unmet needs’). Recently, other autoimmune encephalitides have been documented to follow HSV encephalitis [54], and conversely, other viral infections have been reported to precede the development of NMDAR encephalitis. Viral infections that have been associated with subsequent development of anti-NMDAR encephalitis include varicella zoster virus [55,56], EpsteineBarr virus [57] and influenza A virus [58]. Autoimmune encephalitis should be considered in individuals with viral encephalitis who exhibit either a slow clinical response to acyclovir or who develop recrudescent symptoms following an initial response. New diagnosis tools Next-generation sequencing and the brain Encephalitis remains a diagnostically challenging syndrome. Even with the use of molecular testing, an aetiology is identified in only about half of all cases [59]. Current testing strategies are based on a priori suspicion for a particular pathogen, with directed testing through PCR-based or serological assays [60]. A new technology, termed next-generation sequencing (NGS), allows unbiased testing, with amplification of all non-host genetic material. NGS in combination with metagenomics analysis therefore allows identification of organisms that might not have been suspected in the differential diagnosis. This technique can be applied to either spinal fluid [61] or brain tissue [62]. Although primarily an experimental technique, case reports have highlighted successful identification of unsuspected but treatable cases of CNS infection including leptospirosis [63], Listeria [64] and Brucella [65]. Next-generation sequencing offers several advantages over conventional diagnostic techniques. Unbiased testing allows for detection of rare organisms or common pathogens with unusual presentations that might have been overlooked in the differential diagnosis. Novel or previously unidentified pathogens may also be

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Table 2 Summary of available guidelines published about encephalitis Country and coordinator

Year of publication

Patients

USA

2008

UK

Methods

Reference

Literature review

Multidisciplinary panel of experts

Elaboration and validation

adults and children

yes

yes

2012

adults and children

yes

yes

India

2012

children

yes

yes

Australia/New Zealand

2015

adults and children

yes

yes

France

2017

adults

yes

yes

e-mails, videoconference, in person meeting (2006, n ¼ 1) Validation by IDSA guidelines committee In person meeting (2008, n ¼ 1), work by subgroups Validation by guidelines development and stakeholder groups In person meeting (2012, n ¼ 1), then document circulated through e-mails until validation Draft prepared by experts, then peerreviewed by the relevant scientific societies (neurology, infectious diseases, emergency medicine, public health) E-mails, in person meetings (2014 e2016, n ¼ 8), work by subgroups Reviewing by a different group

identified through this technique. The unbiased nature of NGS is also a potential limitation, as this technique is susceptible to falsepositive results due to amplification of contaminants, colonizers and latent viral infections [66], and therefore interpretation of results requires use of clinical judgment. Although NGS is not routinely available through commercial laboratories, testing done in research settings suggests that results may be available within as little as 48 h [63]. As NGS becomes more widely available, this technique will probably play an increasing role in the identification of diagnostically challenging cases of encephalitis. Multiplex PCR The development and release of several multiplex PCR have suggested that such tools may be valuable for the aetiological diagnosis of brain infections and may result in an increased number of successful investigations of encephalitis cases [67e69]. Such tools seem to be very promising for the future, but some issues need to be addressed. For example, the timeline of diagnosis in CSF may be very different for some pathogens (Flavivirus, HSV), so it is necessary to be cautious when interpreting the results. Moreover, some infectious agents such as enteroviruses may be more easily diagnosed in other samples than CSF. More data are needed to define the precise indications and limit of these tools.

[70]

[71,72]

[73]

[74]

[75]

The prognosis of HSV encephalitis improved dramatically with the use of acyclovir, still surviving patients experience frequent and disabling sequelae. It has been suggested that the inflammatory syndrome may not be controlled by acyclovir and that HSV encephalitis patients may benefit from anti-inflammatory drugs such as steroids. The DEXenceph study, designed by the University of Liverpool, is a randomized, controlled, observer-blind trial that aims to assess the benefit of dexamethasone in the treatment of HSV encephalitis, in addition to the standard regimen of acyclovir (http://www.isrctn.com/ISRCTN11774734). Patients are currently being enrolled in the UK. Patient enrolment will start soon in France (clinical trials.gov: NCT03084783). Conclusion Although the most frequent cause of infectious encephalitis is pathogens known for decades such as HSV, the syndrome is a valuable sentinel of emerging/spreading infections, because it is a rare disease and its severity makes it important to investigate the aetiology. Data from recent years demonstrate that vector-borne diseases account for the highest number of cases of emerging encephalitis, emphasizing the importance of prevention of mosquito or tick bites. However, new infectious agents can also emerge in humans following spillover from exotic animals, and new diagnostic tools can be dramatically helpful in such situations.

Available guidelines Transparency declaration A number of guidelines have been published for the management of encephalitis [70e75]. Although their common objective is to provide some guidance to investigate the cause of encephalitis and propose the best possible management of patients, they also address specific issues, such as regional epidemiology, or encephalitis in children. Their main characteristics are summarized in Table 2. Unmet needs The aetiological diagnosis of encephalitis has been improved in the last 10 years in a number of studies [59,76e78], but a significant number of encephalitides still do not have an identified cause and consequently no prognosis. Therefore better tools are needed in routine practice to improve aetiological diagnosis.

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