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Encephalitis: diagnosis, management and recent advances in the field of encephalitides

Encephalitis: diagnosis, management and recent advances in the field of encephalitides Review Encephalitis: diagnosis, management and recent advances in the field of encephalitides 1,2,3 3,4 5 6,7 Ali M Alam , Ava Easton, Timothy R Nicholson, Sarosh R Irani, 8 2,9 2,3,10 Nicholas WS Davies, Tom Solomon, Benedict D Michael Institute of Infection, Veterinary ABSTRACT diagnosis and management of encephalitis. In and Ecological Sciences, Encephalitis describes inflammation of the brain parallel, the number of autoimmune encephalitis University of Liverpool, Liverpool, parenchyma, typically caused by either an infectious syndromes has rapidly expanded and clinically UK agent or through an autoimmune process which may characteristic syndromes in association with patho- NIHR Health Protection Unit 5 6 for Emerging and Zoonotic be postinfectious, paraneoplastic or idiopathic. Patients genic autoantibodies have been defined. Infection, Liverpool, UK can present with a combination of fever, alterations in The Encephalitis Society’s annual conference Department of Clinical behaviour, personality, cognition and consciousness. attracts physicians, researchers and healthcare Infection, Microbiology, & They may also exhibit focal neurological deficits, seizures, professionals from across the world and is a forum Immunology, University of movement disorders and/or autonomic instability. where the latest developments in encephalitis are Liverpool, Liverpool, UK Encephalitis Society, Malton, However, it can sometimes present non- specifically, presented and discussed. By focusing on findings UK and this combined with its many causes make it a presented at the Encephalitis Society’s conference King’s College London, London, difficult to manage neurological syndrome. Despite in December 2021, this article will review the UK improved treatments in some forms of encephalitides, causes, clinical manifestations and management of Nuffield Department of Clinical Neurosciences, University of encephalitis remains a global concern due to its encephalitis and integrate recent advances and chal- Oxford, Oxford, UK high mortality and morbidity. Prompt diagnosis and lenges of research into encephalitis. Department of Neurology, John administration of specific and supportive management Radcliffe Hospital, Oxford, UK options can lead to better outcomes. Over the last Department of Neurology, DEFINITION decade, research in encephalitis has led to marked Charing Cross Hospital, London, The diagnostic criteria for encephalitis capture any UK developments in the understanding, diagnosis and 9 8 The Pandemic Institute, patient presenting with : management of encephalitis. In parallel, the number Liverpool, UK ► Altered mental status lasting over 24 hours, 10 of autoimmune encephalitis syndromes has rapidly Department of Neurology, The with no alternative cause identified. expanded and clinically characteristic syndromes in Walton Centre NHS Foundation And at least two of the following: Trust, Liverpool, UK association with pathogenic autoantibodies have ► Documented fever above 38°C within the last been defined. By focusing on findings presented at the 72 hours before or after presentation. Correspondence to Encephalitis Society’s conference in December 2021, Dr Benedict D Michael; ► Seizure activity not related to a pre- existing this article reviews the causes, clinical manifestations benmic@ liverpool. ac. uk seizure disorder. and management of encephalitis and integrate recent ► New focal neurological signs. advances and challenges of research into encephalitis. Received 7 April 2022 ► Cerebral spinal fluid (CSF) pleocytosis. Accepted 25 April 2022 ► New neuroimaging findings suggestive of encephalitis. INTRODUCTION ► Abnormal findings on electroencephalography Encephalitis describes inflammation of the brain that is consistent with encephalitis. parenchyma, typically caused by either an infectious Due to the broad range of pathologies which agent or through an autoimmune process which present with alterations in mental status, a high may be postinfectious, paraneoplastic or idiopathic. index of suspicion is required. Moreover, most Patients can present with a combination of fever, patients with encephalitis will not have a severely alterations in behaviour, personality, cognition and depressed Glasgow coma scale (GCS) score on consciousness. They may also exhibit focal neuro- admission and may even do well on basic cognitive logical deficits, seizures, movement disorders and/ testing, such as the mini- mental test, and many— or autonomic instability. The estimated worldwide especially those with autoimmune forms—often incidence of encephalitis ranges from 3.5 to 12.3 lack a fever or CSF pleocytosis. Arguably the most 1 2 per 100 000 patients/year. Despite improved important investigation is therefore a collateral treatments in some forms of encephalitis, overall history from friends and family who state that the this syndrome remains a global concern due to its patient is ‘just not themselves’. Clinicians should © Author(s) (or their 3 4 high mortality and morbidity. Regardless of the directly ask this question and, if the answer is affir- employer(s)) 2022. Re- use aetiology, prompt diagnosis and administration of mative, this finding should be taken very seriously. permitted under CC BY. specific and supportive management options can In addition, any patient with altered mental status Published by BMJ. lead to better outcomes in the majority. This relies and fever with no obvious cause should be managed To cite: Alam AM, Easton A, on correct and rapid identification of the cause of as a central nervous system (CNS) infection until Nicholson TR, et al. the encephalitis and access to effective treatments. proven otherwise. Importantly, approximately a Postgrad Med J Epub ahead of print: [please include Day Brain infections are a global research priority quarter of patients with proven encephalitis will Month Year]. doi:10.1136/ and over the last decade research in this area has have some symptoms suggestive of infection outside postgradmedj-2022-141812 11 led to marked developments in the understanding, of the CNS, such as dysuria or coryzal features. Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 1 Review present in <30% of patients. In addition, antibodies have also 4 8 28 Table 1 Selected causes of encephalitis been identified in patients who have an apparent ‘relapse’ of viral Infectious causesImmune- mediated causes encephalitis, particularly HSV encephalitis, where they appear VirusAutoantibody- mediated to represent a secondary autoimmune process after viral clear- Herpes simplex virus NMDAR 21 ance from the CNS. However, these antibodies have also been Japanese encephalitis virus AMPAR identified in patients with HSV encephalitis who do not relapse Enteroviruses GABA A/B Cytomegalovirus LGI1 and make a good recovery. Therefore, the clinical progression Varicella zoster virus CASPR2 of the patient is critical in determining the significance of any West Nile virus IgLON5 antibodies identified in this context. Human herpesviruses 6 and 7 MOG including acute disseminated Epstein- Barr virus encephalomyelitis The other major cause of non- infectious encephalitis is acute Human immunodeficiency virus demyelinating encephalomyelitis (ADEM). ADEM is defined as Rabies virus a demyelinating disorder caused by an autoimmune response. Bacteria This immune response often occurs after an infection or vacci- Neisseria meningitidis nation and is primarily seen in paediatric populations. ADEM Streptococcus pneumoniae Mycoplasma pneumoniae appears to be commonly associated with antibodies to myelin Mycobacterium tuberculosis 23 oligodendrocyte glycoprotein. Listeria monocytogenes Treponema pallidum Fungi Encephalitis 2021: emerging infectious encephalitides Histoplasma capsulatum Cryptococcus neoformans Candida spp. Aspergillus spp. Talks by Professor Kiran Thakur, Columbia University Irving Parasites Medical Center, USA and Dr Tina Damodar, Department of Plasmodium spp. Toxoplasma gondii Neurovirology, NIMHANS, Bangalore, India A growing concern discussed at Encephalitis 2021 are the AMPAR, α-amino- 3- hydroxy- 5- methyl- 4- isoxazolepropionic acid receptor; CASPR2, contactin- associated protein- like 2; GABA, gamma- aminobutyric acid; IgLON5, increasing outbreaks of arthropodborne encephalitides. immunoglobulin- like cell adhesion molecule 5; LGI1, leucine- rich glioma- inactivated 1; MOG, Arthropods, such as ticks, mosquitos and mites, can act as vectors myelin oligodendrocyte glycoprotein; NMDAR, N- methyl D- aspartate receptor. for viruses. Such viruses are called arboviruses and neurological involvement can be commonly seen in infections caused by arbo- viruses such as Japanese encephalitis (JE), Zika virus, tickborne Therefore, minor features such as dysuria in a young person who encephalitis and West Nile virus. is not septic, or cough in a patient who is not hypoxic, should Variations in global temperature have had a strong impact not be considered sufficient to exclude infective encephalitis on on the environmental suitability for the transmission of vector- clinical grounds; rather empirical treatment should be started and the source of infection investigated, including with a lumbar borne diseases. Arthropod populations are increasing, and puncture (LP). Indeed, on average four to five patients are inves- their geographical ranges are expanding. An example of this tigated for each case of a CNS infection identified. is how global temperature changes have resulted in the global area suitable for the Aedes aegypti mosquito increasing by 1.5% per decade between 1950 and 2000. This mosquito is a known AETIOLOGY vector of several arboviruses which cause encephalitis including Causes of encephalitis can be divided into infectious and autoim- JE, dengue and chikungunya viruses. This trend is predicted to mune processes (table 1). accelerate in the coming decades and arbovirus outbreaks are Viruses such as herpes viruses, arboviruses, enteroviruses and becoming more common across the world (figure 1). These adenoviruses are the most common causes of infective enceph- area’s populations are potentially immunologically naïve to these alitis globally. Japanese encephalitis virus is the main cause of emerging pathogens. This, combined with the paucity of treat- viral encephalitis in many countries in Asia, whereas herpes ment options for arboviral diseases, poses an emerging public simplex virus (HSV) is most common in high- resource settings. health risk and is a reminder how global temperature change can Bacterial, fungal and parasitic infections are less common causes. alter the epidemiology of infectious encephalitis. A major set of aetiologies of non- infectious encephalitis are Changing ecology has caused new encephalitis- causing patho- encompassed by the title ‘autoimmune encephalitis’. In some gens to come to prominence. An example discussed at Enceph- cases of autoimmune encephalitis, a specific autoantibody is alitis 2021 was the increasing prevalence of scrub typhus in identifiable in serum or CSF samples which is directed against a India. Scrub typhus is caused by the rickettsial bacterium CNS antigen. The most common aetiology in the young is asso- Orientia tsutsugamushi and is transmitted by the bite of the ciated with antibodies against the N-methyl D - aspartate receptor larvae (chiggers) of Leptotrombidium mites. After first emerging (NMDAR). In those above 50 years of age, leucine-rich glioma- in 1940s in north-eastern region of India, the region experienced inactivated 1 (LGI1) antibodies appear to be the most common 14 15 no cases for decades until it re-emerged in 2010. Deforesta- known autoantibody, but recent data suggest that this may tion, increased land use in agriculture and greater rainfall during hold true across all autoimmune encephalitis cases. In addition monsoon seasons increase chigger numbers. These changes, to these two autoantibodies, many other pathogenic autoanti- along with the successful JE vaccination programme in India, bodies have been described in the last decade and the incidence 6 13 17 have led to scrub typhus replacing JE to become the leading of these are increasing. This is likely due to increased recog- cause of acute encephalitis in certain regions of India. If this nition, testing and the appreciation that such syndromes have pattern continues, we can expect an increase in arthropod- been misclassified for many years. These autoimmune enceph- borne encephalitis globally, and more research into the epidemi- alitides can be paraneoplastic syndromes, a well-described being ology and management of these diseases is vital in the face of a the link between NMDAR-antibody encephalitis and ovarian changing global climate. teratomas. However, even in this syndrome, a tumour may be 2 Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 Review Figure 1 Emerging infectious encephalitides across the globe. Encephalitis 2021: autoimmune encephalitis neurological deficits. Moreover, the expanding availability of commercial testing has likely led to more patients being tested, with a corresponding decline in the proportion of tested patients Talks by Professor Jerome Honnorat, Hospices Civils de Lyon, found to be positive. Importantly, it has become clear that anti- France; Professor Virginie Desestret, Hospices Civils de Lyon, bodies with the most diagnostic utility, and greatest pathogenic France and Ms Selina Yogeshwar, Charité- Universitätsmedizin potential, are typically directed against the extracellular domains Berlin, Germany of neuroglial proteins. It is this characteristic which has helped Autoimmune encephalitis remains an area of great research dismiss some antibodies as not clinically relevant, and bring interest. It is a syndrome of growing prevalence, with autoim- 33 34 others to the fore. mune encephalitis being the leading cause of encephalitis in An example discussed at Encephalitis 2021 was encepha- patients under 30 years of age. This increase may be due to litis caused by antibodies against the immunoglobulin- like cell the growing awareness of these disorders with over a dozen adhesion molecule 5 (IgLON5). IgLON5-antibody disease new- type autoantibodies being identified in the last 15 years. has been characterised as an autoimmune encephalitis with a Many of these have features which we traditionally do not asso- neurodegenerative- like presentation, rather than the rapid onset ciate with encephalitides, such as a lack of MRI changes or focal we see in NMDAR-antibody encephalitis, for example. It has been <10 years since it was first described and case numbers in literature amount to <100. Early studies have shown that Table 2 A selection of intermediate (30%–70% association patients with IgLON5- antbiody encephalitis present promi- with cancer) and high- risk (above 70% association with cancer) 39 40 nently with unusual, and characteristic, sleep disturbances and, autoantibody- mediated encephalitis at Encephalitis 2021, it was suggested that temporal atrophy may Autoantibody- mediated encephalitis Related tumour be a common finding in these patients, perhaps correlating with Intermediate- risk antibodies Ovarian or extraovarian teratomas 35 37 38 the sleep- based symptomology. Further studies of these NMDAR Small cell lung cancer, malignant thymoma newly discovered autoantibodies are required, but the paucity AMPAR Small cell lung cancer GABA A/B Malignant thymoma of cases means multicentre and multicountry collaborations are CASPR2 Hodgkin’s lymphoma vital. mGluR5 Cancers are one of recognised triggers of autoimmune enceph- High- risk antibodies Small and non- small cell lung cancer, alitis and numerous presentations at Encephalitis 2021 touched Hu neuroendocrine tumours and neuroblastoma CRMP5 Small cell lung cancer and thymoma on these paraneoplastic syndromes. In these cases, the remote Yo Small and non- small cell lung cancer, breast effects of a cancer cause an immune- mediated response directed Ma2 cancer at CNS antigens, predominantly due to molecular mimicry. Testicular cancer, non- small cell lung cancer Specific autoantibodies, which associate with particular tumours AMPAR, α-amino- 3- hydroxy- 5- methyl- 4- isoxazolepropionic acid receptor; CASPR2, (table 2), are typically directed at intracellular targets. These contactin- associated protein- like 2; CRMP5, anticollapsing response- mediator protein- 5; GABA, gamma- aminobutyric acid; mGluR5, metabotropic glutamate receptor 5; NMDAR, paraneoplastic neurological syndromes are classically subacute N- methyl- D- aspartate receptor; PCA2, Purkinje cell antigen 2. in onset with often inexorable progression due to accelerated Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 3 Review Figure 2 Overview of pathophysiology causing encephalitis. neuronal death ; hence, these patients have poor outcomes. it was shown that both B cell cultures from both patients with Many patients will develop neurological symptoms and signs CASPR2- antibody and healthy donors harbour CASPR2- reactive prior to features of an underlying cancer. As such, autoim- B cells in their naïve repertoires, suggesting that even in healthy mune encephalitides are now classed as either an intermediate patients CASPR2 reactivity is present. However, only patients or high- risk phenotype for underlying malignancies, depending with CASPR2- antibody showed memory B cells directed against on presence of antibodies known to be associated with estab- CASPR2. Therefore, a failure in peripheral B cell tolerance is 40 53 lished paraneoplastic processes. These new proposed criteria proposed to play a key role in disease pathogenesis. can enhance the clinical care of this cohort of patients who can A further talk discussed the anatomical localisations of these deteriorate very quickly and remind us about the importance of autoantigen- specific B cells, which has particular importance in screening for underlying malignancies in patients with autoim- highlighting the dynamics of CNS- peripheral interactions with mune encephalitis both acutely and at follow-up. relevance to both health and CNS diseases. The authors found that both cervical lymph nodes (the first peripheral port of drainage of CNS lymphatics) and ovarian teratomas harboured MECHANISM OF DISEASE NMDAR-reactive B cells. These findings built on previous The clinical features of infectious encephalitis occur primarily work showing tertiary lymphoid structures within ovarian tera- due to inflammation of the brain, but the exact range of mecha- 50 55 tomas and led to the suggestion that the autoimmunisation in nisms by which this develops is not yet fully understood. patients with NMDAR-antibody encephalitis could be captured The likely mechanism of disease may be neurotropic infections and studied directly from patients. The authors emphasised causing a release of cytokines leading to cytotoxicity, inflamma- gratitude to their altruistic patients who volunteered for lymph tion and damage. This leads to increased permeability of the node aspirations and inspired this project. blood- brain barrier (BBB) and perivascular lymphocytic infiltra- These studies are important in illustrating how immunolog- tion which can lead to further breakdown in the BBB (figure 2). ical tolerance may play a significant role in understanding the In encephalitis secondary to autoantibodies targeting neuronal mechanism of disease of autoimmune encephalitis, which might surface/synaptic antigens, the mechanisms may be more diverse. ultimately lead to targeted immune-modulatory therapies. These antigen targets are often found in the limbic system of the brain, and several in vitro and in vivo models demonstrate 44–47 the direct pathogenicity of these antibodies. However, the Encephalitis 2021: COVID-19-related neurological disease molecular interactions of antibodies with antigens can lead to complement deposition, antigen internalisation and direct Talks by Dr Emily Happy Miller, Irving Medical Center, and modulation of the antigenic target’s function. Hence, depending New York Presbyterian Hospital, USA and Dr Oliver Harschnitz, on the target antigen, the precise potential therapeutic interven- Sloan-Kettering Institute for Cancer Research, USA tion will differ significantly. The origins and sources of these Another emerging, or rather emerged, disease discussed at autoantibodies may be secondary to infections, cancer or—most length at Encephalitis 2021 was COVID- 19. Up to one- third of commonly—unknown mechanisms. However, increasingly patients with COVID-19 experience at least one neurological clear immunogenetic associations and B cell studies are shedding 57 58 manifestation. Although encephalitis is a rare complication 43 49 50 light on this field. 59 of COVID- 19, ADEM incidences in the first wave appeared increased compared with prepandemic and caused significant 60 61 Encephalitis 2021: immunology mortality and morbidity in patients with COVID-19. To date, there is little evidence that primary SARS- Cov- 2 infection Talks by Dr Bo Sun, University of Oxford, UK and Dr Adam Al- of the brain is a significant contributing factor in these cases. Diwani, University of Oxford, UK Low levels of viral RNA are reported in brain tissue of patients Understanding the immunology underpinning autoimmune with COVID- 19 at autopsy. encephalitis is an ongoing research mission and, at Encephalitis Microglial (antigen-presenting cells which are activated 2021, the immunology of autoantibody-mediated encephalitides following exposure to pathogens) were found to be activated were discussed. in these specimens, often accompanied by neuronophagia. Contactin- associated protein- 2 (CASPR2) is a cellular adhesion One hypothesis, therefore, is that the COVID-19 neurological molecule and CASPR2- antibodies can lead to an autoimmune changes may be caused by neuronophagia. However, these 14 51 encephalitis characterised by a diversity of manifestations. areas did not correspond to those with detectable viral RNA Interestingly, 30% of patients with CASPR2- antibody encepha- and therefore it is unlikely that direct viral neuro-invasion is 52 57 58 litis suffer relapses following treatment. At Encephalitis 2021, responsible for the observed neuropathological changes. 4 Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 Review onset of NMDAR-antibody encephalitis and can occur weeks Table 3 Overview of symptoms at presentation which may suggest before other clinical signs suggestive of the disease. However, aetiology indiscriminate screening of psychiatric patients is not cost- Symptoms suggestive of infectious Symptoms suggestive of immune- effective and poses a major risk by leading to patient misiden- cause mediated cause tification. Analysing clinical text through natural language Acute or subacute onset Subacute or chronic onset processing was shown to have promise in phenotyping NMDAR- Prodromal flu- like illness Altered personality, behaviour, psychosis, antibody encephalitis versus other patients with psychosis. Terms Alterations in personality, behaviour, catatonia such as ‘paediatric’, ‘bladder’ and ‘shaking’ in medical records cognition or consciousnessSleep disorder- disruption Vomiting or gastrointestinal upset Memory issues were suggested to reflect NMDAR- antibody encephalitis, and Travel history or exposure to known Recent viral illness machine learning algorithms to analyse clinical texts containing vectors of encephalitis causing infections Seizures (eg, brachiofacial dystonic) the mental state examination or quotes from patients may help Immunocompromise Status epilepticus Skin rashes Autonomic instability predict encephalitis. Movement disorders (eg, orofacial dyskinesia) These novel methods are showing potential promise in our Underlying symptoms concerning for clinical repertoire in diagnosing conditions, but require large malignancy datasets which may be challenging to generate in conditions such as autoimmune encephalitis and may not surpass everyday clinical acumen. Other presented data suggested COVID- 19 induces senescence in human dopaminergic inducible pluripotent stem cells in vitro. This is an early suggestion that dopamine neuron involvement DIAGNOSIS may be a factor in the neuropathology seen in COVID-19. The key to establishing evidence of CNS inflammation is to There remain significant gaps in our understanding in the effect obtain and analyse CSF through a LP. Neuroimaging is not a of COVID- 19 on the neurological system, and long- term moni- prerequisite for LP and is only indicated prior to LP in cases toring of neurological problems in patients with COVID-19 is when focal neurological signs, papilloedema, seizures or a GCS underway (www.covid-cns.org). <13 is present, as these features suggest obstructive raised intra- cranial pressure. CLINICAL MANIFESTATIONS In viral encephalitis, the CSF typically shows a predomi- A vital aspect of assessing a patient with suspected encepha- nantly lymphocytic pleocytosis. Protein levels maybe moderately litis is to look for clues as to the cause of the encephalitis. This elevated or normal and the CSF:blood glucose ratio is typically can enable targeted therapy which has a significant effect on normal in these samples. Sending CSF samples for viral PCR mortality and morbidity. in a timely manner is vital. Delaying the LP, and therefore CSF Although presenting symptoms can be varied, particular symp- viral PCR, can lead to diagnostic uncertainty as the viral load toms are more associated with specific causes (table 3). There- declines, particularly after aciclovir has been started in cases due fore, the clinician should try and hone in on these details in the to HSV and varicella zoster. Repeat LPs to collect CSF and serum history. Identification of the timeline of symptoms is important. for antiviral antibody testing may be useful in achieving a diag- Encephalitis is typically subacute in onset, although this can nosis at these delayed timepoints. vary: we are discovering new autoimmune causes such as LGI1- Autoantibody testing should be considered in all cases, partic- antibody and CASPR2- antibody encephalitis which may follow ularly those with a recognisable phenotype of autoimmune 6 37 a chronic course of disease. encephalitis. The diagnostic assays used in diagnosing auto- Evidence of personality or behavioural change, hallucinations immune encephalitis includes cell-based assays and immuno - and other neuropsychiatric symptoms should be investigated. histochemistry for neuronal surface antibodies, with increasing This is a common presentation of some autoimmune encephalit- evidence suggesting live cell-based assays perform optimally in ides and may have very particular features which highlight it as these diseases, and in-house fix ed cell-based assays better than 69 70 especially distinctive. commercially available equivalents. A travel history is vital with particular emphasis on contacts Brain imaging is recommended to assess for changes sugges- with animals, mosquitoes or other insects. In areas with vector- tive of encephalitis and to exclude other diagnoses such as borne causes of encephalitis, the location and season in which space- occupying lesions. MRI, particularly with diffusion- patients present can also give clues as to what a causative infec- weighted imaging (DWI) sequences, is the modality of choice tive agent may be. to assess changes associated with encephalitis. Some pathogens A medical history should seek to identify any background of have specific changes seen on neuroimaging, the most well- immunocompromise. known being HSV encephalitis causing bilateral but asymmet- rical inflammation of the temporal and frontal lobes (figure 3). Encephalitis 2021: neuropsychiatric presentations of Autoimmune encephalitis can give variable changes on MRI, but encephalitis the most common feature is bilateral and symmetrical inflamma- tion of the limbic system. In cases of suspected ADEM, MRI Talk by Dr Helena Ariño, Institue of Psychiatry, Psychology typically shows bilateral white matter lesions which can be both supra- and infratentorial and involve the brainstem and spinal and Neuroscience, King’s College London, UK cord. An area of growing interest is the overlap between autoimmune In the case of autoimmune encephalitis, body imaging to rule encephalitis and neuropsychiatric diseases, with NMDAR- out underlying malignancies must also be considered, such as antibody encephalitis often presenting with predominantly positron emission tomography and whole- body CT imaging. psychiatric features. At Encephalitis 2021, it was discussed how Electroencephalogram can be useful in investigating encepha- harnessing digital medical records may provide a valid method to litis as it can provide evidence of encephalopathy, which would be phenotype NMDAR-antibody encephalitis in patients presenting unusual in primary psychiatric diagnoses, or subclinical seizures. with neuropsychiatric symptoms. Psychiatric symptoms at the Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 5 Review MANAGEMENT Patients with encephalitis can become acutely unwell and supportive management is important. This includes managing airway, breathing and circulation. Airway management is particularly important in patients presenting in a comatose state or with uncontrollable seizures. Seizures are a common sequela of encephalitis, and access to anticonvulsant drugs and intensive care units (especially in the case of status epilepticus) is vital. Almost 70% of patients with auto- immune encephalitis have seizures during their illness. Subop- timally controlled seizures can be linked with raised intracranial pressure and greater morbidity and mortality. Recent studies into seizure management were discussed at Encephalitis 2021. A novel therapy discussed was the use of a neurosteroid. Neurosteroids are steroids produced by glial cells and principal neurons. The use of a neurosteroid has been shown to rescue epileptiform activity in murine anti-NMD A encephalitis models. These in vitro models show how NMDAR modulation can prevent anti-NMD A enceph- alitis’ pathogenic antibody effects such as seizures and treat them once established. Further work on identifying patients at risks of seizures, and potential novel treatment options are important as we move forward in manging encephalitis. The role of steroids in viral encephalitis to reduce the inflam- mation associated with infection is an ongoing area of study. Results from a multicentre randomised controlled trial in HSV Figure 3 Coronal T2- weighted MRI of a patient with herpes simplex encephalitis are currently awaited (https://www.dexenceph.org. virus encephalitis illustrating high signal changes in the temporal lobes uk/) and aim to be presented at Encephalitis 2022. (source: Dr Laughlin Dawes, 2008). Although many viruses have been reported to cause enceph- alitis, targeted antiviral therapy is limited to HSV and VZV encephalitis. Aciclovir should be initiated empirically in all Indeed, autoimmune encephalitis may be an important cause patients with suspected encephalitis (pending other diagnostic of non- convulsive status epilepticus in high- income settings. investigations) as it reduces HSV mortality from approximately Certain characteristic patterns have been described in autoim- 71 72 81 70% to 10%–20%, and has minimal side effects. Should mune encephalitis, in particular the pathognomic extreme delta another infection be identified as causative pathogen in a patient brush appearance in NMDAR- antibody encephalitis. with encephalitis, appropriate antimicrobial therapy should be The above investigations should be undertaken alongside initiated. more common investigations to rule out differentials. A HIV test The first- line treatment of autoimmune cases includes immu- should be offered to all patients with suspected brain infections. notherapy such as high- dose steroid therapy with or without intravenous immunoglobulin (IvIg) and/or plasmapheresis, while second- line treatment options include rituximab and/or Encephalitis 2021: new diagnostic tools cyclophosphamide. The benefit of adjunctive IvIg in patients receiving high- dose steroids is currently under investigation in Talk by Dr Álvaro Bonelli, Rey Juan Carlos University Hospital, a trial (EncephIg). Also, in LGI1-antibody encephalitis, there is a clinical trial which aims to study the value of reducing IgG Móstoles, Spain levels with blockade of the FcRn molecule which typically recy- It is still difficult to identify the causative agent in many cases with presumed encephalitis where, even in developed settings, cles IgG. Furthermore, a CD19 monoclonal antibody is being approximately a third of patients do not have a pathogen or trialled in patients with NMDAR-antibody encephalitis as a way 11 72 autoantibody identified. Novel laboratory techniques to improve outcomes. which may help to stratify unknown patients into aetiolog- A key aspect of encephalitis treatment is the management ical groups were discussed at Encephalitis 2021. New qualita- of its long- term sequalae resulting from damage and injury to the brain. Many patients suffer from long-term effects such as tive multiplexed techniques such as FilmArray Meningitis and Encephalitis Panel allow the study of up to 14 pathogens in emotional, behavioural, physical and cognitive deficits. Social 1 hour with a high sensitivity and specificity. Studies have effects are often forgotten, including ability to drive and loss of shown that the percentage of CNS aetiological diagnosis were work or education due to disability, yet are common impairments higher in the group that had multiplex PCR testing, and this in some of these conditions. Access to neuropsychology, neuro- approach reduced the number of molecular biology techniques psychiatry and occupational therapy services along with ensuring adequate postdischarge follow- up is important in addressing the required to reach a diagnosis. This technique may allow more causative agents to be identified in a single step and therefore long- term effects of this condition. In addition, there is also the should allow clinicians to better direct therapeutic interven- impact on the family to consider, such as the development of tions. This concept is analogous to the use of immunohisto- mental health problems, carer burden and family breakdown. chemistry and live neuron binding as methods to detect as Patients and families affected may benefit from using the infor- of yet unknown autoantibodies in patients with autoimmune mation and support services provided by patient organisations 5 48 encephalitis. such as The Encephalitis Society (www.encephalitis.info). 6 Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 Review Box 1 Oral presentations at Encephalitis 2021 Box 1 Continued ⇒ Analysing clinical text from electronic health records to magnetoencephalography (Charly Billaud, School of Health diagnose anti-N- methyl D- aspartate receptor (NMDAR) and Life Sciences, Aston University, Birmingham, UK). encephalitis, a feasibility study (Dr Helena Ariño, Institute ⇒ Arthropod- borne encephalitides (Winifred Mercer Pitkin of Psychiatry, Psychology & Neuroscience, King’s College Assistant Professor Kiran Thakur, Columbia University Irving London, UK). Medical Center, USA). ⇒ Defining the neuroinvasive potential of SARS CoV- 2 in brain autopsies of patients with COVID-19 (Dr Emily Happy Miller , Encephalitis 2021: the need for greater access to encephalitis Columbia University Irving Medical Center, and New York Presbyterian Hospital, New York, USA). management ⇒ Immune and genetic signature of breast carcinomas triggering Yo paraneoplastic cerebellar degeneration Talks by Professor Deanna Saylor, The Johns Hopkins (Professor Virginie Desestret, Hospices Civils de Lyon, University School of Medicine, USA; Dr Jamil Kahwagi, Centre Université Claude Bernard Lyon, France). Hospitalier National Universitaire de Fann, Senegal and ⇒ Paraneoplastic encephalitis (Professor Jerome Honnorat, Dr Adawa Manuela, COVID-19 ORCA Patient Management Hospices Civils de Lyon, France). Center, Cameroon ⇒ Dissecting contactin- associated protein- like 2 (CASPR2)- Managing encephalitis in low-resource settings is challenging. antibody encephalitis with patient- derived CASPR2- specific This can be due to a combination of access to diagnostic tools, monoclonal antibodies (Dr Bo Sun, University of Oxford/John medications and scope for management in specialist settings, Radcliffe Hospital, Oxford, UK). along with cultural challenges associated with accessing health- ⇒ Clinical and laboratory findings of acute encephalitis care. These difficulties were discussed at Encephalitis 2021. syndrome associated with scrub typhus infection in children The aetiology of infectious encephalitis remains poorly admitted to tertiary care hospitals in South India (Dr described in African settings. In resource-limited settings such Tina Damodar, Department of Neurovirology, NIMHANS, as Senegal, it was reported that encephalitis cases rarely have Bangalore, India). an aetiological diagnosis and treatment can often be inconsis- 84 85 ⇒ Infectious encephalitis during the second wave of COVID- 19: tent. A large challenge faced in sub-Saharan A frica is the lack an observational study among hospitalised patients in Dakar, of access to injectable aciclovir. A potential compromise is oral Senegal (Dr Jamil Kahwagi, Centre Hospitalier National valaciclovir which may be a more readily accessible alternative to Universitaire de Fann, Dakar, Senegal). intravenous aciclovir in settings with limited resources, although ⇒ Direct evaluation of cervical lymph node and ovarian more robust studies are required to assess whether its efficacy is 86–88 teratoma as sites of autoimmunisation in NMDAR- antibody comparable. Tackling disparity in access to important medi- encephalitis (Dr Adam Al- Diwani, Department of Psychiatry, cations globally is huge challenge, and one which will need to be University of Oxford, Oxford, UK). solved to help improve encephalitis management in low-income ⇒ Developing neurological care and training in resource-limited to middle- income/resource settings. settings (Assistant Professor Deanna Saylor, The Johns Encephalitis management requires the involvement of Hopkins University School of Medicine, USA). neurological specialists, but they are not always available in ⇒ Inborn errors of TLR3- dependent or MDA5- dependent low- income to middle-income/resource settings. The median type I interferon immunity in children with enterovirus number of adult neurologists per 100 000 population globally rhombencephalitis (Dr Jie Chen, The Rockefeller University, is 0.43—in comparison, high- income countries average almost New York, USA). five neurologists per 100 000 people. In Encephalitis 2021, it ⇒ Spatial and temporal brain atrophy in anti- immunoglobulin- was reported that sub- Saharan Africa has very few countries with like cell adhesion molecule 5 disease (Ms Selina Yogeshwar, neurology training programmes, and the ratio of neurologist Charité- Universitätsmedizin Berlin, Berlin, Germany). to population is unlikely to improve. The recent development ⇒ Encephalitis and autoimmune encephalitis in paediatric of a specialist neurological training programme at Univer- patients from Brazil (Dr Renata Barbosa Paolilo, Hospital das sity Teaching Hospital Lusaka, Zambia illustrates how robust Clínicas da Faculdade de Medicina da Universidade de São systems of neurological care in resource- limited settings can Paulo (HCFMUSP), São Paulo, Brazil). be developed. This programme emphasises the importance of ⇒ Novel treatment of an NMDAR- antibody- mediated in- country neurology teaching and is on track to train 13 adult seizure model (Dr Sukhvir Wright, Institute of Health and and 2 paediatric neurologists in its first 5 years. The importance Neurodevelopment, Aston University, Birmingham, UK). of ensuring good training will be vital in improving outcomes in ⇒ Aetiological diagnosis in central nervous system infections: diseases such as encephalitis in low-resource settings. multiplex PCR (Dr Álvaro Bonelli, Rey Juan Carlos University Hospital, Móstoles, Madrid, Spain). WHAT NEXT? ⇒ SARS- CoV- 2 infection causes dopaminergic neuron Encephalitis remains a difficult to manage neurological syndrome senescence (Dr Oliver Harschnitz, Sloan-K ettering Institute for due to its many causes, sometimes non- specific presentations Cancer Research, New York, USA). and a lack of recognition and awareness. An integral aspect of ⇒ Aetiologies of encephalitis in non- HIV- infected patients in management is to first identify the causative pathogen or auto- Cameroon (Dr Adawa Manuela, COVID- 19 ORCA Patient antibody to enable directed therapy. Recent advances in the Management Center, Yaoundé, Cameroon). field can lead to improved outcomes and reduced disability in ⇒ Investigating long- term neuropsychological outcomes encephalitis. However, challenges we recognise in 2022 include in paediatric autoimmune encephalitis using emerging pathogens, access to therapy in low- income to middle- Continued income settings and characterising autoantibody- mediated Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 7 Review encephalitides, as well as a better understanding of the long-term invitations for abstract and conference sign up by taking advan- consequences for patients and their families (box 1). tage of free professional membership (www.encephalitis.info/ Further funding and work are needed to aid our under- professional-membership). standing of this disease, and Encephalitis 2021 ended with a call to action to be part of World Encephalitis Day on 22 February Twitter Ali M Alam @alimashqur, Ava Easton @encephalitisava, Tom Solomon @ RunningMadProf and Benedict D Michael @benedictneuro 2022 and Encephalitis research month in June 2022. Encepha- litis 2022 will be held on 30 November and 1 December 2022 Acknowledgements We would like to thank all the speakers, attendees and organisers of Encephalitis 2021 conference. at the Royal College of Physicians, London and you can receive Contributors AMA and AE wrote the first draft. All authors critically appraised and contributed to the final manuscript. Funding BDM is supported by the UKRI/MRC (MR/V03605X/1), the MRC/UKRI Main messages (MR/V007181//1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). Disclaimer The views expressed are those of the author(s) and not necessarily ⇒ Encephalitis describes a syndrome of brain parenchyma those of the National Health Service.The views expressed are those of the author(s) inflammation, typically caused by either an infectious agent and not necessarily those of the speakers and presenters at Encephalitis 2021. or through an autoimmune process. Map disclaimer The inclusion of any map (including the depiction of any ⇒ Patients can present with a combination of fevers, decreased boundaries therein), or of any geographic or locational reference, does not imply the expression of any opinion whatsoever on the part of BMJ concerning the legal status consciousness and other neurological deficits; however, it can of any country, territory, jurisdiction or area or of its authorities. Any such expression sometimes present non- specifically, and this combined with remains solely that of the relevant source and is not endorsed by BMJ. Maps are its many causes and lack of recognition make it a difficult to provided without any warranty of any kind, either express or implied. manage neurological syndrome. Competing interests SRI is an inventor on ’Diagnostic strategy to improve ⇒ By focusing on findings presented at the Encephalitis specificity of CASPR2 antibody detection’ (PCT/G82019 /051257) and receives Society’s conference in December 2021, this article reviews royalties on a licensed patent application for LGI1/CASPR2 testing as coapplicant (PCT/GB2009/051441) entitled ’Neurological Autoimmune Disorders’. SRI is the causes, clinical manifestations and management of supported by a senior clinical fellowship from the Medical Research Council (MR/ encephalitis and integrate recent advances and challenges of V007173/1), Wellcome Trust Fellowship (104079/Z/14/Z) and the BMA Research research into encephalitis. Grants—Vera Down grant (2013) and Margaret Temple (2017), Epilepsy Research UK (P1201), the Fulbright UK- US commission (MS- Society research award) and by the NIHR Oxford Biomedical Research Centre. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Current research questions Manuscript version arising from this submission. SRI has received honoraria from UCB, Immunovant, MedImmun, Roche, Cerebral Therapeutics, ADC Therapeutics, ⇒ Challenges we recognise in combating encephalitis in 2022 Brain, Medlink Neurology and research support from CSL Behring, UCB and ONO include emerging pathogens, access to therapy in low- income Pharma. TS was Chair/Co- Chair of the UKRI/NIHR COVID- 19 Rapid Response and Rolling Funding Initiatives (from March 2020), an Advisor to the UK COVID- 19 to middle- income settings and characterising autoantibody- Therapeutics Advisory Panel (UK- TAP, from August 2020) and a member of the mediated encephalitides, as well as a better understanding of MHRA COVID- 19 Vaccines Benefit Risk Expert Working Group (from August 2020). the long- term consequences for patients and their families. He is also a trustee of the UK Academy of 19Medical Sciences (December 2021). TS ⇒ Further funding and work are needed to aid our is President of the Encephalitis Society. TS was an advisor to the GSK Ebola Vaccine understanding of this disease, and Encephalitis 2021 ended programme and chaired a Siemens Diagnostics Clinical Advisory Board. TS was on the Data Safety Monitoring Committee of the GSK Study to Evaluate the Safety and with a call to action to be part of World Encephalitis Day on Immunogenicity of a Candidate Ebola Vaccine in Children GSK3390107A (ChAd3 22 February 2023 and Encephalitis Research Month in June EBO- Z) vaccine. TS chaired the Siemens Healthineers Clinical Advisory Board. Data safety monitoring board: Study of Ebola vaccine and ChAd3- EBO- Z—commercial ⇒ Encephalitis 2022 will be held on 30 November and 1 entity. December 2022 at the Royal College of Physicians, London Patient consent for publication Not applicable. and you can receive invitations for abstract and conference Ethics approval Not applicable. sign up by taking advantage of free professional membership Provenance and peer review Not commissioned; internally peer reviewed. (www.encephalitis.info/professional-membership). Open access This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, Key references ⇒ Easton A, Solomon T. Encephalitis awareness: our ambitious global endeavour. Lancet Neurol 2022 Apr;21(4):314. doi: Self- assessment questions 10.1016/S1474- 4422(22)00079- 5. Epub 2022 Feb 23. PMID: 35 202 603. 1. 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Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Postgraduate Medical Journal British Medical Journal

Encephalitis: diagnosis, management and recent advances in the field of encephalitides

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Review Encephalitis: diagnosis, management and recent advances in the field of encephalitides 1,2,3 3,4 5 6,7 Ali M Alam , Ava Easton, Timothy R Nicholson, Sarosh R Irani, 8 2,9 2,3,10 Nicholas WS Davies, Tom Solomon, Benedict D Michael Institute of Infection, Veterinary ABSTRACT diagnosis and management of encephalitis. In and Ecological Sciences, Encephalitis describes inflammation of the brain parallel, the number of autoimmune encephalitis University of Liverpool, Liverpool, parenchyma, typically caused by either an infectious syndromes has rapidly expanded and clinically UK agent or through an autoimmune process which may characteristic syndromes in association with patho- NIHR Health Protection Unit 5 6 for Emerging and Zoonotic be postinfectious, paraneoplastic or idiopathic. Patients genic autoantibodies have been defined. Infection, Liverpool, UK can present with a combination of fever, alterations in The Encephalitis Society’s annual conference Department of Clinical behaviour, personality, cognition and consciousness. attracts physicians, researchers and healthcare Infection, Microbiology, & They may also exhibit focal neurological deficits, seizures, professionals from across the world and is a forum Immunology, University of movement disorders and/or autonomic instability. where the latest developments in encephalitis are Liverpool, Liverpool, UK Encephalitis Society, Malton, However, it can sometimes present non- specifically, presented and discussed. By focusing on findings UK and this combined with its many causes make it a presented at the Encephalitis Society’s conference King’s College London, London, difficult to manage neurological syndrome. Despite in December 2021, this article will review the UK improved treatments in some forms of encephalitides, causes, clinical manifestations and management of Nuffield Department of Clinical Neurosciences, University of encephalitis remains a global concern due to its encephalitis and integrate recent advances and chal- Oxford, Oxford, UK high mortality and morbidity. Prompt diagnosis and lenges of research into encephalitis. Department of Neurology, John administration of specific and supportive management Radcliffe Hospital, Oxford, UK options can lead to better outcomes. Over the last Department of Neurology, DEFINITION decade, research in encephalitis has led to marked Charing Cross Hospital, London, The diagnostic criteria for encephalitis capture any UK developments in the understanding, diagnosis and 9 8 The Pandemic Institute, patient presenting with : management of encephalitis. In parallel, the number Liverpool, UK ► Altered mental status lasting over 24 hours, 10 of autoimmune encephalitis syndromes has rapidly Department of Neurology, The with no alternative cause identified. expanded and clinically characteristic syndromes in Walton Centre NHS Foundation And at least two of the following: Trust, Liverpool, UK association with pathogenic autoantibodies have ► Documented fever above 38°C within the last been defined. By focusing on findings presented at the 72 hours before or after presentation. Correspondence to Encephalitis Society’s conference in December 2021, Dr Benedict D Michael; ► Seizure activity not related to a pre- existing this article reviews the causes, clinical manifestations benmic@ liverpool. ac. uk seizure disorder. and management of encephalitis and integrate recent ► New focal neurological signs. advances and challenges of research into encephalitis. Received 7 April 2022 ► Cerebral spinal fluid (CSF) pleocytosis. Accepted 25 April 2022 ► New neuroimaging findings suggestive of encephalitis. INTRODUCTION ► Abnormal findings on electroencephalography Encephalitis describes inflammation of the brain that is consistent with encephalitis. parenchyma, typically caused by either an infectious Due to the broad range of pathologies which agent or through an autoimmune process which present with alterations in mental status, a high may be postinfectious, paraneoplastic or idiopathic. index of suspicion is required. Moreover, most Patients can present with a combination of fever, patients with encephalitis will not have a severely alterations in behaviour, personality, cognition and depressed Glasgow coma scale (GCS) score on consciousness. They may also exhibit focal neuro- admission and may even do well on basic cognitive logical deficits, seizures, movement disorders and/ testing, such as the mini- mental test, and many— or autonomic instability. The estimated worldwide especially those with autoimmune forms—often incidence of encephalitis ranges from 3.5 to 12.3 lack a fever or CSF pleocytosis. Arguably the most 1 2 per 100 000 patients/year. Despite improved important investigation is therefore a collateral treatments in some forms of encephalitis, overall history from friends and family who state that the this syndrome remains a global concern due to its patient is ‘just not themselves’. Clinicians should © Author(s) (or their 3 4 high mortality and morbidity. Regardless of the directly ask this question and, if the answer is affir- employer(s)) 2022. Re- use aetiology, prompt diagnosis and administration of mative, this finding should be taken very seriously. permitted under CC BY. specific and supportive management options can In addition, any patient with altered mental status Published by BMJ. lead to better outcomes in the majority. This relies and fever with no obvious cause should be managed To cite: Alam AM, Easton A, on correct and rapid identification of the cause of as a central nervous system (CNS) infection until Nicholson TR, et al. the encephalitis and access to effective treatments. proven otherwise. Importantly, approximately a Postgrad Med J Epub ahead of print: [please include Day Brain infections are a global research priority quarter of patients with proven encephalitis will Month Year]. doi:10.1136/ and over the last decade research in this area has have some symptoms suggestive of infection outside postgradmedj-2022-141812 11 led to marked developments in the understanding, of the CNS, such as dysuria or coryzal features. Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 1 Review present in <30% of patients. In addition, antibodies have also 4 8 28 Table 1 Selected causes of encephalitis been identified in patients who have an apparent ‘relapse’ of viral Infectious causesImmune- mediated causes encephalitis, particularly HSV encephalitis, where they appear VirusAutoantibody- mediated to represent a secondary autoimmune process after viral clear- Herpes simplex virus NMDAR 21 ance from the CNS. However, these antibodies have also been Japanese encephalitis virus AMPAR identified in patients with HSV encephalitis who do not relapse Enteroviruses GABA A/B Cytomegalovirus LGI1 and make a good recovery. Therefore, the clinical progression Varicella zoster virus CASPR2 of the patient is critical in determining the significance of any West Nile virus IgLON5 antibodies identified in this context. Human herpesviruses 6 and 7 MOG including acute disseminated Epstein- Barr virus encephalomyelitis The other major cause of non- infectious encephalitis is acute Human immunodeficiency virus demyelinating encephalomyelitis (ADEM). ADEM is defined as Rabies virus a demyelinating disorder caused by an autoimmune response. Bacteria This immune response often occurs after an infection or vacci- Neisseria meningitidis nation and is primarily seen in paediatric populations. ADEM Streptococcus pneumoniae Mycoplasma pneumoniae appears to be commonly associated with antibodies to myelin Mycobacterium tuberculosis 23 oligodendrocyte glycoprotein. Listeria monocytogenes Treponema pallidum Fungi Encephalitis 2021: emerging infectious encephalitides Histoplasma capsulatum Cryptococcus neoformans Candida spp. Aspergillus spp. Talks by Professor Kiran Thakur, Columbia University Irving Parasites Medical Center, USA and Dr Tina Damodar, Department of Plasmodium spp. Toxoplasma gondii Neurovirology, NIMHANS, Bangalore, India A growing concern discussed at Encephalitis 2021 are the AMPAR, α-amino- 3- hydroxy- 5- methyl- 4- isoxazolepropionic acid receptor; CASPR2, contactin- associated protein- like 2; GABA, gamma- aminobutyric acid; IgLON5, increasing outbreaks of arthropodborne encephalitides. immunoglobulin- like cell adhesion molecule 5; LGI1, leucine- rich glioma- inactivated 1; MOG, Arthropods, such as ticks, mosquitos and mites, can act as vectors myelin oligodendrocyte glycoprotein; NMDAR, N- methyl D- aspartate receptor. for viruses. Such viruses are called arboviruses and neurological involvement can be commonly seen in infections caused by arbo- viruses such as Japanese encephalitis (JE), Zika virus, tickborne Therefore, minor features such as dysuria in a young person who encephalitis and West Nile virus. is not septic, or cough in a patient who is not hypoxic, should Variations in global temperature have had a strong impact not be considered sufficient to exclude infective encephalitis on on the environmental suitability for the transmission of vector- clinical grounds; rather empirical treatment should be started and the source of infection investigated, including with a lumbar borne diseases. Arthropod populations are increasing, and puncture (LP). Indeed, on average four to five patients are inves- their geographical ranges are expanding. An example of this tigated for each case of a CNS infection identified. is how global temperature changes have resulted in the global area suitable for the Aedes aegypti mosquito increasing by 1.5% per decade between 1950 and 2000. This mosquito is a known AETIOLOGY vector of several arboviruses which cause encephalitis including Causes of encephalitis can be divided into infectious and autoim- JE, dengue and chikungunya viruses. This trend is predicted to mune processes (table 1). accelerate in the coming decades and arbovirus outbreaks are Viruses such as herpes viruses, arboviruses, enteroviruses and becoming more common across the world (figure 1). These adenoviruses are the most common causes of infective enceph- area’s populations are potentially immunologically naïve to these alitis globally. Japanese encephalitis virus is the main cause of emerging pathogens. This, combined with the paucity of treat- viral encephalitis in many countries in Asia, whereas herpes ment options for arboviral diseases, poses an emerging public simplex virus (HSV) is most common in high- resource settings. health risk and is a reminder how global temperature change can Bacterial, fungal and parasitic infections are less common causes. alter the epidemiology of infectious encephalitis. A major set of aetiologies of non- infectious encephalitis are Changing ecology has caused new encephalitis- causing patho- encompassed by the title ‘autoimmune encephalitis’. In some gens to come to prominence. An example discussed at Enceph- cases of autoimmune encephalitis, a specific autoantibody is alitis 2021 was the increasing prevalence of scrub typhus in identifiable in serum or CSF samples which is directed against a India. Scrub typhus is caused by the rickettsial bacterium CNS antigen. The most common aetiology in the young is asso- Orientia tsutsugamushi and is transmitted by the bite of the ciated with antibodies against the N-methyl D - aspartate receptor larvae (chiggers) of Leptotrombidium mites. After first emerging (NMDAR). In those above 50 years of age, leucine-rich glioma- in 1940s in north-eastern region of India, the region experienced inactivated 1 (LGI1) antibodies appear to be the most common 14 15 no cases for decades until it re-emerged in 2010. Deforesta- known autoantibody, but recent data suggest that this may tion, increased land use in agriculture and greater rainfall during hold true across all autoimmune encephalitis cases. In addition monsoon seasons increase chigger numbers. These changes, to these two autoantibodies, many other pathogenic autoanti- along with the successful JE vaccination programme in India, bodies have been described in the last decade and the incidence 6 13 17 have led to scrub typhus replacing JE to become the leading of these are increasing. This is likely due to increased recog- cause of acute encephalitis in certain regions of India. If this nition, testing and the appreciation that such syndromes have pattern continues, we can expect an increase in arthropod- been misclassified for many years. These autoimmune enceph- borne encephalitis globally, and more research into the epidemi- alitides can be paraneoplastic syndromes, a well-described being ology and management of these diseases is vital in the face of a the link between NMDAR-antibody encephalitis and ovarian changing global climate. teratomas. However, even in this syndrome, a tumour may be 2 Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 Review Figure 1 Emerging infectious encephalitides across the globe. Encephalitis 2021: autoimmune encephalitis neurological deficits. Moreover, the expanding availability of commercial testing has likely led to more patients being tested, with a corresponding decline in the proportion of tested patients Talks by Professor Jerome Honnorat, Hospices Civils de Lyon, found to be positive. Importantly, it has become clear that anti- France; Professor Virginie Desestret, Hospices Civils de Lyon, bodies with the most diagnostic utility, and greatest pathogenic France and Ms Selina Yogeshwar, Charité- Universitätsmedizin potential, are typically directed against the extracellular domains Berlin, Germany of neuroglial proteins. It is this characteristic which has helped Autoimmune encephalitis remains an area of great research dismiss some antibodies as not clinically relevant, and bring interest. It is a syndrome of growing prevalence, with autoim- 33 34 others to the fore. mune encephalitis being the leading cause of encephalitis in An example discussed at Encephalitis 2021 was encepha- patients under 30 years of age. This increase may be due to litis caused by antibodies against the immunoglobulin- like cell the growing awareness of these disorders with over a dozen adhesion molecule 5 (IgLON5). IgLON5-antibody disease new- type autoantibodies being identified in the last 15 years. has been characterised as an autoimmune encephalitis with a Many of these have features which we traditionally do not asso- neurodegenerative- like presentation, rather than the rapid onset ciate with encephalitides, such as a lack of MRI changes or focal we see in NMDAR-antibody encephalitis, for example. It has been <10 years since it was first described and case numbers in literature amount to <100. Early studies have shown that Table 2 A selection of intermediate (30%–70% association patients with IgLON5- antbiody encephalitis present promi- with cancer) and high- risk (above 70% association with cancer) 39 40 nently with unusual, and characteristic, sleep disturbances and, autoantibody- mediated encephalitis at Encephalitis 2021, it was suggested that temporal atrophy may Autoantibody- mediated encephalitis Related tumour be a common finding in these patients, perhaps correlating with Intermediate- risk antibodies Ovarian or extraovarian teratomas 35 37 38 the sleep- based symptomology. Further studies of these NMDAR Small cell lung cancer, malignant thymoma newly discovered autoantibodies are required, but the paucity AMPAR Small cell lung cancer GABA A/B Malignant thymoma of cases means multicentre and multicountry collaborations are CASPR2 Hodgkin’s lymphoma vital. mGluR5 Cancers are one of recognised triggers of autoimmune enceph- High- risk antibodies Small and non- small cell lung cancer, alitis and numerous presentations at Encephalitis 2021 touched Hu neuroendocrine tumours and neuroblastoma CRMP5 Small cell lung cancer and thymoma on these paraneoplastic syndromes. In these cases, the remote Yo Small and non- small cell lung cancer, breast effects of a cancer cause an immune- mediated response directed Ma2 cancer at CNS antigens, predominantly due to molecular mimicry. Testicular cancer, non- small cell lung cancer Specific autoantibodies, which associate with particular tumours AMPAR, α-amino- 3- hydroxy- 5- methyl- 4- isoxazolepropionic acid receptor; CASPR2, (table 2), are typically directed at intracellular targets. These contactin- associated protein- like 2; CRMP5, anticollapsing response- mediator protein- 5; GABA, gamma- aminobutyric acid; mGluR5, metabotropic glutamate receptor 5; NMDAR, paraneoplastic neurological syndromes are classically subacute N- methyl- D- aspartate receptor; PCA2, Purkinje cell antigen 2. in onset with often inexorable progression due to accelerated Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 3 Review Figure 2 Overview of pathophysiology causing encephalitis. neuronal death ; hence, these patients have poor outcomes. it was shown that both B cell cultures from both patients with Many patients will develop neurological symptoms and signs CASPR2- antibody and healthy donors harbour CASPR2- reactive prior to features of an underlying cancer. As such, autoim- B cells in their naïve repertoires, suggesting that even in healthy mune encephalitides are now classed as either an intermediate patients CASPR2 reactivity is present. However, only patients or high- risk phenotype for underlying malignancies, depending with CASPR2- antibody showed memory B cells directed against on presence of antibodies known to be associated with estab- CASPR2. Therefore, a failure in peripheral B cell tolerance is 40 53 lished paraneoplastic processes. These new proposed criteria proposed to play a key role in disease pathogenesis. can enhance the clinical care of this cohort of patients who can A further talk discussed the anatomical localisations of these deteriorate very quickly and remind us about the importance of autoantigen- specific B cells, which has particular importance in screening for underlying malignancies in patients with autoim- highlighting the dynamics of CNS- peripheral interactions with mune encephalitis both acutely and at follow-up. relevance to both health and CNS diseases. The authors found that both cervical lymph nodes (the first peripheral port of drainage of CNS lymphatics) and ovarian teratomas harboured MECHANISM OF DISEASE NMDAR-reactive B cells. These findings built on previous The clinical features of infectious encephalitis occur primarily work showing tertiary lymphoid structures within ovarian tera- due to inflammation of the brain, but the exact range of mecha- 50 55 tomas and led to the suggestion that the autoimmunisation in nisms by which this develops is not yet fully understood. patients with NMDAR-antibody encephalitis could be captured The likely mechanism of disease may be neurotropic infections and studied directly from patients. The authors emphasised causing a release of cytokines leading to cytotoxicity, inflamma- gratitude to their altruistic patients who volunteered for lymph tion and damage. This leads to increased permeability of the node aspirations and inspired this project. blood- brain barrier (BBB) and perivascular lymphocytic infiltra- These studies are important in illustrating how immunolog- tion which can lead to further breakdown in the BBB (figure 2). ical tolerance may play a significant role in understanding the In encephalitis secondary to autoantibodies targeting neuronal mechanism of disease of autoimmune encephalitis, which might surface/synaptic antigens, the mechanisms may be more diverse. ultimately lead to targeted immune-modulatory therapies. These antigen targets are often found in the limbic system of the brain, and several in vitro and in vivo models demonstrate 44–47 the direct pathogenicity of these antibodies. However, the Encephalitis 2021: COVID-19-related neurological disease molecular interactions of antibodies with antigens can lead to complement deposition, antigen internalisation and direct Talks by Dr Emily Happy Miller, Irving Medical Center, and modulation of the antigenic target’s function. Hence, depending New York Presbyterian Hospital, USA and Dr Oliver Harschnitz, on the target antigen, the precise potential therapeutic interven- Sloan-Kettering Institute for Cancer Research, USA tion will differ significantly. The origins and sources of these Another emerging, or rather emerged, disease discussed at autoantibodies may be secondary to infections, cancer or—most length at Encephalitis 2021 was COVID- 19. Up to one- third of commonly—unknown mechanisms. However, increasingly patients with COVID-19 experience at least one neurological clear immunogenetic associations and B cell studies are shedding 57 58 manifestation. Although encephalitis is a rare complication 43 49 50 light on this field. 59 of COVID- 19, ADEM incidences in the first wave appeared increased compared with prepandemic and caused significant 60 61 Encephalitis 2021: immunology mortality and morbidity in patients with COVID-19. To date, there is little evidence that primary SARS- Cov- 2 infection Talks by Dr Bo Sun, University of Oxford, UK and Dr Adam Al- of the brain is a significant contributing factor in these cases. Diwani, University of Oxford, UK Low levels of viral RNA are reported in brain tissue of patients Understanding the immunology underpinning autoimmune with COVID- 19 at autopsy. encephalitis is an ongoing research mission and, at Encephalitis Microglial (antigen-presenting cells which are activated 2021, the immunology of autoantibody-mediated encephalitides following exposure to pathogens) were found to be activated were discussed. in these specimens, often accompanied by neuronophagia. Contactin- associated protein- 2 (CASPR2) is a cellular adhesion One hypothesis, therefore, is that the COVID-19 neurological molecule and CASPR2- antibodies can lead to an autoimmune changes may be caused by neuronophagia. However, these 14 51 encephalitis characterised by a diversity of manifestations. areas did not correspond to those with detectable viral RNA Interestingly, 30% of patients with CASPR2- antibody encepha- and therefore it is unlikely that direct viral neuro-invasion is 52 57 58 litis suffer relapses following treatment. At Encephalitis 2021, responsible for the observed neuropathological changes. 4 Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 Review onset of NMDAR-antibody encephalitis and can occur weeks Table 3 Overview of symptoms at presentation which may suggest before other clinical signs suggestive of the disease. However, aetiology indiscriminate screening of psychiatric patients is not cost- Symptoms suggestive of infectious Symptoms suggestive of immune- effective and poses a major risk by leading to patient misiden- cause mediated cause tification. Analysing clinical text through natural language Acute or subacute onset Subacute or chronic onset processing was shown to have promise in phenotyping NMDAR- Prodromal flu- like illness Altered personality, behaviour, psychosis, antibody encephalitis versus other patients with psychosis. Terms Alterations in personality, behaviour, catatonia such as ‘paediatric’, ‘bladder’ and ‘shaking’ in medical records cognition or consciousnessSleep disorder- disruption Vomiting or gastrointestinal upset Memory issues were suggested to reflect NMDAR- antibody encephalitis, and Travel history or exposure to known Recent viral illness machine learning algorithms to analyse clinical texts containing vectors of encephalitis causing infections Seizures (eg, brachiofacial dystonic) the mental state examination or quotes from patients may help Immunocompromise Status epilepticus Skin rashes Autonomic instability predict encephalitis. Movement disorders (eg, orofacial dyskinesia) These novel methods are showing potential promise in our Underlying symptoms concerning for clinical repertoire in diagnosing conditions, but require large malignancy datasets which may be challenging to generate in conditions such as autoimmune encephalitis and may not surpass everyday clinical acumen. Other presented data suggested COVID- 19 induces senescence in human dopaminergic inducible pluripotent stem cells in vitro. This is an early suggestion that dopamine neuron involvement DIAGNOSIS may be a factor in the neuropathology seen in COVID-19. The key to establishing evidence of CNS inflammation is to There remain significant gaps in our understanding in the effect obtain and analyse CSF through a LP. Neuroimaging is not a of COVID- 19 on the neurological system, and long- term moni- prerequisite for LP and is only indicated prior to LP in cases toring of neurological problems in patients with COVID-19 is when focal neurological signs, papilloedema, seizures or a GCS underway (www.covid-cns.org). <13 is present, as these features suggest obstructive raised intra- cranial pressure. CLINICAL MANIFESTATIONS In viral encephalitis, the CSF typically shows a predomi- A vital aspect of assessing a patient with suspected encepha- nantly lymphocytic pleocytosis. Protein levels maybe moderately litis is to look for clues as to the cause of the encephalitis. This elevated or normal and the CSF:blood glucose ratio is typically can enable targeted therapy which has a significant effect on normal in these samples. Sending CSF samples for viral PCR mortality and morbidity. in a timely manner is vital. Delaying the LP, and therefore CSF Although presenting symptoms can be varied, particular symp- viral PCR, can lead to diagnostic uncertainty as the viral load toms are more associated with specific causes (table 3). There- declines, particularly after aciclovir has been started in cases due fore, the clinician should try and hone in on these details in the to HSV and varicella zoster. Repeat LPs to collect CSF and serum history. Identification of the timeline of symptoms is important. for antiviral antibody testing may be useful in achieving a diag- Encephalitis is typically subacute in onset, although this can nosis at these delayed timepoints. vary: we are discovering new autoimmune causes such as LGI1- Autoantibody testing should be considered in all cases, partic- antibody and CASPR2- antibody encephalitis which may follow ularly those with a recognisable phenotype of autoimmune 6 37 a chronic course of disease. encephalitis. The diagnostic assays used in diagnosing auto- Evidence of personality or behavioural change, hallucinations immune encephalitis includes cell-based assays and immuno - and other neuropsychiatric symptoms should be investigated. histochemistry for neuronal surface antibodies, with increasing This is a common presentation of some autoimmune encephalit- evidence suggesting live cell-based assays perform optimally in ides and may have very particular features which highlight it as these diseases, and in-house fix ed cell-based assays better than 69 70 especially distinctive. commercially available equivalents. A travel history is vital with particular emphasis on contacts Brain imaging is recommended to assess for changes sugges- with animals, mosquitoes or other insects. In areas with vector- tive of encephalitis and to exclude other diagnoses such as borne causes of encephalitis, the location and season in which space- occupying lesions. MRI, particularly with diffusion- patients present can also give clues as to what a causative infec- weighted imaging (DWI) sequences, is the modality of choice tive agent may be. to assess changes associated with encephalitis. Some pathogens A medical history should seek to identify any background of have specific changes seen on neuroimaging, the most well- immunocompromise. known being HSV encephalitis causing bilateral but asymmet- rical inflammation of the temporal and frontal lobes (figure 3). Encephalitis 2021: neuropsychiatric presentations of Autoimmune encephalitis can give variable changes on MRI, but encephalitis the most common feature is bilateral and symmetrical inflamma- tion of the limbic system. In cases of suspected ADEM, MRI Talk by Dr Helena Ariño, Institue of Psychiatry, Psychology typically shows bilateral white matter lesions which can be both supra- and infratentorial and involve the brainstem and spinal and Neuroscience, King’s College London, UK cord. An area of growing interest is the overlap between autoimmune In the case of autoimmune encephalitis, body imaging to rule encephalitis and neuropsychiatric diseases, with NMDAR- out underlying malignancies must also be considered, such as antibody encephalitis often presenting with predominantly positron emission tomography and whole- body CT imaging. psychiatric features. At Encephalitis 2021, it was discussed how Electroencephalogram can be useful in investigating encepha- harnessing digital medical records may provide a valid method to litis as it can provide evidence of encephalopathy, which would be phenotype NMDAR-antibody encephalitis in patients presenting unusual in primary psychiatric diagnoses, or subclinical seizures. with neuropsychiatric symptoms. Psychiatric symptoms at the Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 5 Review MANAGEMENT Patients with encephalitis can become acutely unwell and supportive management is important. This includes managing airway, breathing and circulation. Airway management is particularly important in patients presenting in a comatose state or with uncontrollable seizures. Seizures are a common sequela of encephalitis, and access to anticonvulsant drugs and intensive care units (especially in the case of status epilepticus) is vital. Almost 70% of patients with auto- immune encephalitis have seizures during their illness. Subop- timally controlled seizures can be linked with raised intracranial pressure and greater morbidity and mortality. Recent studies into seizure management were discussed at Encephalitis 2021. A novel therapy discussed was the use of a neurosteroid. Neurosteroids are steroids produced by glial cells and principal neurons. The use of a neurosteroid has been shown to rescue epileptiform activity in murine anti-NMD A encephalitis models. These in vitro models show how NMDAR modulation can prevent anti-NMD A enceph- alitis’ pathogenic antibody effects such as seizures and treat them once established. Further work on identifying patients at risks of seizures, and potential novel treatment options are important as we move forward in manging encephalitis. The role of steroids in viral encephalitis to reduce the inflam- mation associated with infection is an ongoing area of study. Results from a multicentre randomised controlled trial in HSV Figure 3 Coronal T2- weighted MRI of a patient with herpes simplex encephalitis are currently awaited (https://www.dexenceph.org. virus encephalitis illustrating high signal changes in the temporal lobes uk/) and aim to be presented at Encephalitis 2022. (source: Dr Laughlin Dawes, 2008). Although many viruses have been reported to cause enceph- alitis, targeted antiviral therapy is limited to HSV and VZV encephalitis. Aciclovir should be initiated empirically in all Indeed, autoimmune encephalitis may be an important cause patients with suspected encephalitis (pending other diagnostic of non- convulsive status epilepticus in high- income settings. investigations) as it reduces HSV mortality from approximately Certain characteristic patterns have been described in autoim- 71 72 81 70% to 10%–20%, and has minimal side effects. Should mune encephalitis, in particular the pathognomic extreme delta another infection be identified as causative pathogen in a patient brush appearance in NMDAR- antibody encephalitis. with encephalitis, appropriate antimicrobial therapy should be The above investigations should be undertaken alongside initiated. more common investigations to rule out differentials. A HIV test The first- line treatment of autoimmune cases includes immu- should be offered to all patients with suspected brain infections. notherapy such as high- dose steroid therapy with or without intravenous immunoglobulin (IvIg) and/or plasmapheresis, while second- line treatment options include rituximab and/or Encephalitis 2021: new diagnostic tools cyclophosphamide. The benefit of adjunctive IvIg in patients receiving high- dose steroids is currently under investigation in Talk by Dr Álvaro Bonelli, Rey Juan Carlos University Hospital, a trial (EncephIg). Also, in LGI1-antibody encephalitis, there is a clinical trial which aims to study the value of reducing IgG Móstoles, Spain levels with blockade of the FcRn molecule which typically recy- It is still difficult to identify the causative agent in many cases with presumed encephalitis where, even in developed settings, cles IgG. Furthermore, a CD19 monoclonal antibody is being approximately a third of patients do not have a pathogen or trialled in patients with NMDAR-antibody encephalitis as a way 11 72 autoantibody identified. Novel laboratory techniques to improve outcomes. which may help to stratify unknown patients into aetiolog- A key aspect of encephalitis treatment is the management ical groups were discussed at Encephalitis 2021. New qualita- of its long- term sequalae resulting from damage and injury to the brain. Many patients suffer from long-term effects such as tive multiplexed techniques such as FilmArray Meningitis and Encephalitis Panel allow the study of up to 14 pathogens in emotional, behavioural, physical and cognitive deficits. Social 1 hour with a high sensitivity and specificity. Studies have effects are often forgotten, including ability to drive and loss of shown that the percentage of CNS aetiological diagnosis were work or education due to disability, yet are common impairments higher in the group that had multiplex PCR testing, and this in some of these conditions. Access to neuropsychology, neuro- approach reduced the number of molecular biology techniques psychiatry and occupational therapy services along with ensuring adequate postdischarge follow- up is important in addressing the required to reach a diagnosis. This technique may allow more causative agents to be identified in a single step and therefore long- term effects of this condition. In addition, there is also the should allow clinicians to better direct therapeutic interven- impact on the family to consider, such as the development of tions. This concept is analogous to the use of immunohisto- mental health problems, carer burden and family breakdown. chemistry and live neuron binding as methods to detect as Patients and families affected may benefit from using the infor- of yet unknown autoantibodies in patients with autoimmune mation and support services provided by patient organisations 5 48 encephalitis. such as The Encephalitis Society (www.encephalitis.info). 6 Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 Review Box 1 Oral presentations at Encephalitis 2021 Box 1 Continued ⇒ Analysing clinical text from electronic health records to magnetoencephalography (Charly Billaud, School of Health diagnose anti-N- methyl D- aspartate receptor (NMDAR) and Life Sciences, Aston University, Birmingham, UK). encephalitis, a feasibility study (Dr Helena Ariño, Institute ⇒ Arthropod- borne encephalitides (Winifred Mercer Pitkin of Psychiatry, Psychology & Neuroscience, King’s College Assistant Professor Kiran Thakur, Columbia University Irving London, UK). Medical Center, USA). ⇒ Defining the neuroinvasive potential of SARS CoV- 2 in brain autopsies of patients with COVID-19 (Dr Emily Happy Miller , Encephalitis 2021: the need for greater access to encephalitis Columbia University Irving Medical Center, and New York Presbyterian Hospital, New York, USA). management ⇒ Immune and genetic signature of breast carcinomas triggering Yo paraneoplastic cerebellar degeneration Talks by Professor Deanna Saylor, The Johns Hopkins (Professor Virginie Desestret, Hospices Civils de Lyon, University School of Medicine, USA; Dr Jamil Kahwagi, Centre Université Claude Bernard Lyon, France). Hospitalier National Universitaire de Fann, Senegal and ⇒ Paraneoplastic encephalitis (Professor Jerome Honnorat, Dr Adawa Manuela, COVID-19 ORCA Patient Management Hospices Civils de Lyon, France). Center, Cameroon ⇒ Dissecting contactin- associated protein- like 2 (CASPR2)- Managing encephalitis in low-resource settings is challenging. antibody encephalitis with patient- derived CASPR2- specific This can be due to a combination of access to diagnostic tools, monoclonal antibodies (Dr Bo Sun, University of Oxford/John medications and scope for management in specialist settings, Radcliffe Hospital, Oxford, UK). along with cultural challenges associated with accessing health- ⇒ Clinical and laboratory findings of acute encephalitis care. These difficulties were discussed at Encephalitis 2021. syndrome associated with scrub typhus infection in children The aetiology of infectious encephalitis remains poorly admitted to tertiary care hospitals in South India (Dr described in African settings. In resource-limited settings such Tina Damodar, Department of Neurovirology, NIMHANS, as Senegal, it was reported that encephalitis cases rarely have Bangalore, India). an aetiological diagnosis and treatment can often be inconsis- 84 85 ⇒ Infectious encephalitis during the second wave of COVID- 19: tent. A large challenge faced in sub-Saharan A frica is the lack an observational study among hospitalised patients in Dakar, of access to injectable aciclovir. A potential compromise is oral Senegal (Dr Jamil Kahwagi, Centre Hospitalier National valaciclovir which may be a more readily accessible alternative to Universitaire de Fann, Dakar, Senegal). intravenous aciclovir in settings with limited resources, although ⇒ Direct evaluation of cervical lymph node and ovarian more robust studies are required to assess whether its efficacy is 86–88 teratoma as sites of autoimmunisation in NMDAR- antibody comparable. Tackling disparity in access to important medi- encephalitis (Dr Adam Al- Diwani, Department of Psychiatry, cations globally is huge challenge, and one which will need to be University of Oxford, Oxford, UK). solved to help improve encephalitis management in low-income ⇒ Developing neurological care and training in resource-limited to middle- income/resource settings. settings (Assistant Professor Deanna Saylor, The Johns Encephalitis management requires the involvement of Hopkins University School of Medicine, USA). neurological specialists, but they are not always available in ⇒ Inborn errors of TLR3- dependent or MDA5- dependent low- income to middle-income/resource settings. The median type I interferon immunity in children with enterovirus number of adult neurologists per 100 000 population globally rhombencephalitis (Dr Jie Chen, The Rockefeller University, is 0.43—in comparison, high- income countries average almost New York, USA). five neurologists per 100 000 people. In Encephalitis 2021, it ⇒ Spatial and temporal brain atrophy in anti- immunoglobulin- was reported that sub- Saharan Africa has very few countries with like cell adhesion molecule 5 disease (Ms Selina Yogeshwar, neurology training programmes, and the ratio of neurologist Charité- Universitätsmedizin Berlin, Berlin, Germany). to population is unlikely to improve. The recent development ⇒ Encephalitis and autoimmune encephalitis in paediatric of a specialist neurological training programme at Univer- patients from Brazil (Dr Renata Barbosa Paolilo, Hospital das sity Teaching Hospital Lusaka, Zambia illustrates how robust Clínicas da Faculdade de Medicina da Universidade de São systems of neurological care in resource- limited settings can Paulo (HCFMUSP), São Paulo, Brazil). be developed. This programme emphasises the importance of ⇒ Novel treatment of an NMDAR- antibody- mediated in- country neurology teaching and is on track to train 13 adult seizure model (Dr Sukhvir Wright, Institute of Health and and 2 paediatric neurologists in its first 5 years. The importance Neurodevelopment, Aston University, Birmingham, UK). of ensuring good training will be vital in improving outcomes in ⇒ Aetiological diagnosis in central nervous system infections: diseases such as encephalitis in low-resource settings. multiplex PCR (Dr Álvaro Bonelli, Rey Juan Carlos University Hospital, Móstoles, Madrid, Spain). WHAT NEXT? ⇒ SARS- CoV- 2 infection causes dopaminergic neuron Encephalitis remains a difficult to manage neurological syndrome senescence (Dr Oliver Harschnitz, Sloan-K ettering Institute for due to its many causes, sometimes non- specific presentations Cancer Research, New York, USA). and a lack of recognition and awareness. An integral aspect of ⇒ Aetiologies of encephalitis in non- HIV- infected patients in management is to first identify the causative pathogen or auto- Cameroon (Dr Adawa Manuela, COVID- 19 ORCA Patient antibody to enable directed therapy. Recent advances in the Management Center, Yaoundé, Cameroon). field can lead to improved outcomes and reduced disability in ⇒ Investigating long- term neuropsychological outcomes encephalitis. However, challenges we recognise in 2022 include in paediatric autoimmune encephalitis using emerging pathogens, access to therapy in low- income to middle- Continued income settings and characterising autoantibody- mediated Alam AM, et al. Postgrad Med J 2022;0:1–10. doi:10.1136/postgradmedj-2022-141812 7 Review encephalitides, as well as a better understanding of the long-term invitations for abstract and conference sign up by taking advan- consequences for patients and their families (box 1). tage of free professional membership (www.encephalitis.info/ Further funding and work are needed to aid our under- professional-membership). standing of this disease, and Encephalitis 2021 ended with a call to action to be part of World Encephalitis Day on 22 February Twitter Ali M Alam @alimashqur, Ava Easton @encephalitisava, Tom Solomon @ RunningMadProf and Benedict D Michael @benedictneuro 2022 and Encephalitis research month in June 2022. Encepha- litis 2022 will be held on 30 November and 1 December 2022 Acknowledgements We would like to thank all the speakers, attendees and organisers of Encephalitis 2021 conference. at the Royal College of Physicians, London and you can receive Contributors AMA and AE wrote the first draft. All authors critically appraised and contributed to the final manuscript. Funding BDM is supported by the UKRI/MRC (MR/V03605X/1), the MRC/UKRI Main messages (MR/V007181//1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). Disclaimer The views expressed are those of the author(s) and not necessarily ⇒ Encephalitis describes a syndrome of brain parenchyma those of the National Health Service.The views expressed are those of the author(s) inflammation, typically caused by either an infectious agent and not necessarily those of the speakers and presenters at Encephalitis 2021. or through an autoimmune process. Map disclaimer The inclusion of any map (including the depiction of any ⇒ Patients can present with a combination of fevers, decreased boundaries therein), or of any geographic or locational reference, does not imply the expression of any opinion whatsoever on the part of BMJ concerning the legal status consciousness and other neurological deficits; however, it can of any country, territory, jurisdiction or area or of its authorities. Any such expression sometimes present non- specifically, and this combined with remains solely that of the relevant source and is not endorsed by BMJ. Maps are its many causes and lack of recognition make it a difficult to provided without any warranty of any kind, either express or implied. manage neurological syndrome. Competing interests SRI is an inventor on ’Diagnostic strategy to improve ⇒ By focusing on findings presented at the Encephalitis specificity of CASPR2 antibody detection’ (PCT/G82019 /051257) and receives Society’s conference in December 2021, this article reviews royalties on a licensed patent application for LGI1/CASPR2 testing as coapplicant (PCT/GB2009/051441) entitled ’Neurological Autoimmune Disorders’. SRI is the causes, clinical manifestations and management of supported by a senior clinical fellowship from the Medical Research Council (MR/ encephalitis and integrate recent advances and challenges of V007173/1), Wellcome Trust Fellowship (104079/Z/14/Z) and the BMA Research research into encephalitis. Grants—Vera Down grant (2013) and Margaret Temple (2017), Epilepsy Research UK (P1201), the Fulbright UK- US commission (MS- Society research award) and by the NIHR Oxford Biomedical Research Centre. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Current research questions Manuscript version arising from this submission. SRI has received honoraria from UCB, Immunovant, MedImmun, Roche, Cerebral Therapeutics, ADC Therapeutics, ⇒ Challenges we recognise in combating encephalitis in 2022 Brain, Medlink Neurology and research support from CSL Behring, UCB and ONO include emerging pathogens, access to therapy in low- income Pharma. TS was Chair/Co- Chair of the UKRI/NIHR COVID- 19 Rapid Response and Rolling Funding Initiatives (from March 2020), an Advisor to the UK COVID- 19 to middle- income settings and characterising autoantibody- Therapeutics Advisory Panel (UK- TAP, from August 2020) and a member of the mediated encephalitides, as well as a better understanding of MHRA COVID- 19 Vaccines Benefit Risk Expert Working Group (from August 2020). the long- term consequences for patients and their families. He is also a trustee of the UK Academy of 19Medical Sciences (December 2021). TS ⇒ Further funding and work are needed to aid our is President of the Encephalitis Society. TS was an advisor to the GSK Ebola Vaccine understanding of this disease, and Encephalitis 2021 ended programme and chaired a Siemens Diagnostics Clinical Advisory Board. TS was on the Data Safety Monitoring Committee of the GSK Study to Evaluate the Safety and with a call to action to be part of World Encephalitis Day on Immunogenicity of a Candidate Ebola Vaccine in Children GSK3390107A (ChAd3 22 February 2023 and Encephalitis Research Month in June EBO- Z) vaccine. TS chaired the Siemens Healthineers Clinical Advisory Board. Data safety monitoring board: Study of Ebola vaccine and ChAd3- EBO- Z—commercial ⇒ Encephalitis 2022 will be held on 30 November and 1 entity. December 2022 at the Royal College of Physicians, London Patient consent for publication Not applicable. and you can receive invitations for abstract and conference Ethics approval Not applicable. sign up by taking advantage of free professional membership Provenance and peer review Not commissioned; internally peer reviewed. (www.encephalitis.info/professional-membership). Open access This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, Key references ⇒ Easton A, Solomon T. Encephalitis awareness: our ambitious global endeavour. Lancet Neurol 2022 Apr;21(4):314. doi: Self- assessment questions 10.1016/S1474- 4422(22)00079- 5. Epub 2022 Feb 23. PMID: 35 202 603. 1. 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Journal

Postgraduate Medical Journal – British Medical Journal

Published: Jun 23, 2022

Keywords: neuropathologyadult neurologyinfectious disease/HIV

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