Postgraduate Medical Journal, 2023, 99, 1174, 815–825

https://doi.org/10.1136/postgradmedj-2022-141812
Advance access publication date 23 June 2022
Review

Encephalitis: diagnosis, management and recent

advances in the field of encephalitides
1,2,3
Ali M. Alam , Ava Easton3,4 , Timothy R. Nicholson5 , Sarosh R. Irani6,7 , Nicholas WS Davies8 , Tom Solomon2,9 ,
Benedict D. Michael2,3,10
1 Instituteof Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

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2 NIHR Health Protection Unit for Emerging and Zoonotic Infection, Liverpool, UK
3 Department of Clinical Infection, Microbiology, & Immunology, University of Liverpool, Liverpool, UK
4 Encephalitis Society, Malton, UK
5 King’s College London, London, UK
6 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
7 Department of Neurology, John Radcliffe Hospital, Oxford, UK
8 Department of Neurology, Charing Cross Hospital, London, UK
9 The Pandemic Institute, Liverpool, UK
10 Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool, UK

*Corresponding author. Dr Benedict D Michael. benmic@liverpool.ac.uk

Abstract
Encephalitis describes inf lammation of the brain parenchyma, typically caused by either an infectious agent or through an autoimmune
process which may be postinfectious, paraneoplastic or idiopathic. Patients can present with a combination of fever, alterations in
behaviour, personality, cognition and consciousness. They may also exhibit focal neurological deficits, seizures, movement disorders
and/or autonomic instability. However, it can sometimes present non-specifically, and this combined with its many causes make it a
difficult to manage neurological syndrome. Despite improved treatments in some forms of encephalitides, encephalitis remains a global
concern due to its high mortality and morbidity. Prompt diagnosis and administration of specific and supportive management options
can lead to better outcomes. Over the last decade, research in encephalitis has led to marked developments in the understanding,
diagnosis and management of encephalitis. In parallel, the number of autoimmune encephalitis syndromes has rapidly expanded and
clinically characteristic syndromes in association with pathogenic autoantibodies have been defined. By focusing on findings presented
at the Encephalitis Society’s conference in December 2021, this article reviews the causes, clinical manifestations and management of
encephalitis and integrate recent advances and challenges of research into encephalitis.

Keywords: neuropathology, adult neurology, infectious disease/HIV

Introduction In parallel, the number of autoimmune encephalitis syndromes

has rapidly expanded and clinically characteristic syndromes in
Encephalitis describes inf lammation of the brain parenchyma,
association with pathogenic autoantibodies have been defined
typically caused by either an infectious agent or through an
[5, 6].
autoimmune process which may be postinfectious, paraneoplas-
The Encephalitis Society’s annual conference [7] attracts physi-
tic or idiopathic. Patients can present with a combination of fever,
cians, researchers and healthcare professionals from across the
alterations in behaviour, personality, cognition and conscious-
world and is a forum where the latest developments in encephali-
ness. They may also exhibit focal neurological deficits, seizures,
tis are presented and discussed. By focusing on findings pre-
movement disorders and/or autonomic instability. The estimated
sented at the Encephalitis Society’s conference in December 2021,
worldwide incidence of encephalitis ranges from 3.5 to 12.3 per
this article will review the causes, clinical manifestations and
100 000 patients/year [1, 2]. Despite improved treatments in some
management of encephalitis and integrate recent advances and
forms of encephalitis, overall this syndrome remains a global
challenges of research into encephalitis.
concern due to its high mortality and morbidity [3, 4]. Regardless
of the aetiology, prompt diagnosis and administration of specific
and supportive management options can lead to better outcomes Definition
in the majority. This relies on correct and rapid identification of
The diagnostic criteria for encephalitis capture any patient pre-
the cause of the encephalitis and access to effective treatments.
senting with [8]:
Brain infections are a global research priority [3] and over the
last decade research in this area has led to marked developments • Altered mental status lasting over 24 hours, with no alterna-
in the understanding, diagnosis and management of encephalitis. tive cause identified.

Received: April 07, 2022. Accepted: April 25, 2022

© The Author(s) 2022. Published by Oxford University Press on behalf of Postgraduate Medical Journal.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
816 | Alam et al.

And at least two of the following: Table 1. Selected causes of encephalitis [4, 8, 28]

• Documented fever above 38◦ C within the last 72 hours before Infectious causes Immune-mediated causes
or after presentation. Virus Autoantibody-mediated
• Seizure activity not related to a pre-existing seizure disorder. Herpes simplex virus NMDAR
• New focal neurological signs. Japanese encephalitis virus AMPAR
• Cerebral spinal f luid (CSF) pleocytosis. Enteroviruses GABA A/B
• New neuroimaging findings suggestive of encephalitis. Cytomegalovirus LGI1
• Abnormal findings on electroencephalography that is consis- Varicella zoster virus CASPR2
tent with encephalitis. West Nile virus IgLON5
Human herpesviruses 6 and 7 MOG including acute disseminated
Due to the broad range of pathologies which present with Epstein-Barr virus encephalomyelitis
alterations in mental status, a high index of suspicion is required. Human immunodeficiency virus
Moreover, most patients with encephalitis will not have a severely Rabies virus
depressed Glasgow coma scale (GCS) score on admission and may Bacteria

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Neisseria meningitidis
even do well on basic cognitive testing, such as the mini-mental
Streptococcus pneumoniae
test, and many—especially those with autoimmune forms—often
Mycoplasma pneumoniae
lack a fever or CSF pleocytosis. Arguably the most important
Mycobacterium tuberculosis
investigation is therefore a collateral history from friends and Listeria monocytogenes
family who state that the patient is ‘just not themselves’ [9]. Treponema pallidum
Clinicians should directly ask this question and, if the answer Fungi
is affirmative, this finding should be taken very seriously. In Histoplasma capsulatum
addition, any patient with altered mental status and fever with Cryptococcus neoformans
no obvious cause should be managed as a central nervous system Candida spp.
(CNS) infection until proven otherwise [10]. Importantly, approx- Aspergillus spp.
Parasites
imately a quarter of patients with proven encephalitis will have
Plasmodium spp.
some symptoms suggestive of infection outside of the CNS, such
Toxoplasma gondii
as dysuria or coryzal features [11]. Therefore, minor features
such as dysuria in a young person who is not septic, or cough AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor;
in a patient who is not hypoxic, should not be considered suffi- CASPR2, contactin-associated protein-like 2; GABA, gamma-aminobutyric
acid; IgLON5, immunoglobulin-like cell adhesion molecule 5; LGI1,
cient to exclude infective encephalitis on clinical grounds; rather leucine-rich glioma-inactivated 1; MOG, myelin oligodendrocyte
empirical treatment should be started and the source of infection glycoprotein; NMDAR, N-methyl D-aspartate receptor.

investigated, including with a lumbar puncture (LP). Indeed, on

average four to five patients are investigated for each case of a
CNS infection identified [12].
even in this syndrome, a tumour may be present in <30% of
patients [20]. In addition, antibodies have also been identified
Aetiology in patients who have an apparent ‘relapse’ of viral encephalitis,
particularly HSV encephalitis, where they appear to represent a
Causes of encephalitis can be divided into infectious and autoim-
secondary autoimmune process after viral clearance from the
mune processes (Table 1).
CNS [21]. However, these antibodies have also been identified in
Viruses such as herpes viruses, arboviruses, enteroviruses and
patients with HSV encephalitis who do not relapse and make a
adenoviruses are the most common causes of infective encephali-
good recovery. Therefore, the clinical progression of the patient
tis globally [2] Japanese encephalitis virus is the main cause of viral
is critical in determining the significance of any antibodies
encephalitis in many countries in Asia, whereas herpes simplex
identified in this context.
virus (HSV) is most common in high-resource settings [2] Bacte-
The other major cause of non-infectious encephalitis is acute
rial, fungal and parasitic infections are less common causes.
demyelinating encephalomyelitis (ADEM). ADEM is defined as a
A major set of aetiologies of non-infectious encephalitis are
demyelinating disorder caused by an autoimmune response. This
encompassed by the title ‘autoimmune encephalitis’. In some
immune response often occurs after an infection or vaccina-
cases of autoimmune encephalitis, a specific autoantibody is
tion and is primarily seen in paediatric populations [22]. ADEM
identifiable in serum or CSF samples which is directed against
appears to be commonly associated with antibodies to myelin
a CNS antigen [13]. The most common aetiology in the young
oligodendrocyte glycoprotein [23].
is associated with antibodies against the N-methyl D-aspartate
receptor (NMDAR). In those above 50 years of age, leucine-rich
glioma-inactivated 1 (LGI1) antibodies appear to be the most Encephalitis 2021: emerging infectious
common known autoantibody [14, 15], but recent data suggest encephalitides
that this may hold true across all autoimmune encephalitis Talks by Professor Kiran Thakur, Columbia
cases [16]. In addition to these two autoantibodies, many other University Irving Medical Center, USA and Dr Tina
pathogenic autoantibodies have been described in the last decade Damodar, Department of Neurovirology, NIMHANS,
and the incidence of these are increasing [6, 13, 17]. This is Bangalore, India
likely due to increased recognition, testing and the appreciation A growing concern discussed at Encephalitis 2021 are the increas-
that such syndromes have been misclassified for many years ing outbreaks of arthropodborne encephalitides [24]. Arthropods,
[18]. These autoimmune encephalitides can be paraneoplastic such as ticks, mosquitos and mites, can act as vectors for viruses.
syndromes, a well-described being the link between NMDAR- Such viruses are called arboviruses and neurological involvement
antibody encephalitis and ovarian teratomas [19]. However, can be commonly seen in infections caused by arboviruses such
 Encephalitis: diagnosis, management and recent advances in the field of encephalitides | 817

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Figure 1. Emerging infectious encephalitides across the globe [28].

as Japanese encephalitis (JE), Zika virus, tickborne encephalitis and and management of these diseases is vital in the face of a
West Nile virus. changing global climate.
Variations in global temperature have had a strong impact on
the environmental suitability for the transmission of vectorborne Encephalitis 2021: autoimmune encephalitis
diseases [25]. Arthropod populations are increasing, and their Talks by Professor Jerome Honnorat, Hospices Civils
geographical ranges are expanding [26]. An example of this is de Lyon, France; Professor Virginie Desestret,
how global temperature changes have resulted in the global area Hospices Civils de Lyon, France and Ms Selina
suitable for the Aedes aegypti mosquito increasing by 1.5% per Yogeshwar, Charité- Universitätsmedizin Berlin,
decade between 1950 and 2000 [27]. This mosquito is a known Germany
vector of several arboviruses which cause encephalitis including Autoimmune encephalitis remains an area of great research
JE, dengue and chikungunya viruses. This trend is predicted to interest. It is a syndrome of growing prevalence, with autoimmune
accelerate in the coming decades and arbovirus outbreaks are encephalitis being the leading cause of encephalitis in patients
becoming more common across the world (Figure 1) [28]. These under 30 years of age [31]. This increase may be due to the growing
area’s populations are potentially immunologically naïve to these awareness of these disorders [6] with over a dozen new-type
emerging pathogens. This, combined with the paucity of treat- autoantibodies being identified in the last 15 years [19]. Many of
ment options for arboviral diseases, poses an emerging public these have features which we traditionally do not associate with
health risk and is a reminder how global temperature change can encephalitides, such as a lack of MRI changes or focal neurological
alter the epidemiology of infectious encephalitis [24]. deficits. Moreover, the expanding availability of commercial
Changing ecology has caused new encephalitis-causing testing has likely led to more patients being tested, with a
pathogens to come to prominence. An example discussed at corresponding decline in the proportion of tested patients found
Encephalitis 2021 was the increasing prevalence of scrub typhus to be positive [32]. Importantly, it has become clear that antibodies
in India [29]. Scrub typhus is caused by the rickettsial bacterium with the most diagnostic utility, and greatest pathogenic potential,
Orientia tsutsugamushi and is transmitted by the bite of the larvae are typically directed against the extracellular domains of
(chiggers) of Leptotrombidium mites. After first emerging in 1940s in neuroglial proteins. It is this characteristic which has helped
north-eastern region of India, the region experienced no cases for dismiss some antibodies as not clinically relevant, and bring
decades until it re-emerged in 2010 [28]. Deforestation, increased others to the fore [33, 34].
land use in agriculture and greater rainfall during monsoon An example discussed at Encephalitis 2021 was encephalitis
seasons increase chigger numbers [30]. These changes, along caused by antibodies against the immunoglobulin-like cell
with the successful JE vaccination programme in India, have adhesion molecule 5 (IgLON5). IgLON5-antibody disease has
led to scrub typhus replacing JE to become the leading cause been characterised as an autoimmune encephalitis with a
of acute encephalitis in certain regions of India [29]. If this neurodegenerative-like presentation, rather than the rapid onset
pattern continues, we can expect an increase in arthropodborne we see in NMDAR-antibody encephalitis, for example [35]. It has
encephalitis globally, and more research into the epidemiology been <10 years since it was first described and case numbers
818 | Alam et al.

Table 2. A selection of intermediate (30%–70% association with of the blood-brain barrier (BBB) and perivascular lymphocytic
cancer) and high-risk (above 70% association with cancer)
infiltration which can lead to further breakdown in the BBB [42]
autoantibody-mediated encephalitis [39, 40]
(Figure 2).
Autoantibody-mediated encephalitis Related tumour In encephalitis secondary to autoantibodies targeting neuronal
Intermediate-risk antibodies Ovarian or extraovarian
surface/synaptic antigens, the mechanisms may be more diverse
NMDAR teratomas [43]. These antigen targets are often found in the limbic system
AMPAR Small cell lung cancer, of the brain, and several in vitro and in vivo models demonstrate
GABA A/B malignant thymoma the direct pathogenicity of these antibodies [44–47]. However, the
CASPR2 Small cell lung cancer molecular interactions of antibodies with antigens can lead to
mGluR5 Malignant thymoma complement deposition, antigen internalisation and direct modu-
Hodgkin’s lymphoma lation of the antigenic target’s function. Hence, depending on the
High-risk antibodies Small and non-small cell target antigen, the precise potential therapeutic intervention will
Hu lung cancer,
differ significantly. The origins and sources of these autoantibod-
CRMP5 neuroendocrine tumours and
ies may be secondary to infections, cancer or—most commonly—

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Yo neuroblastoma
Ma2 Small cell lung cancer and
unknown mechanisms [48]. However, increasingly clear immuno-
thymoma genetic associations and B cell studies are shedding light on this
Small and non-small cell field [43, 49, 50].
lung cancer, breast cancer
Testicular cancer, non-small Encephalitis 2021: immunology
cell lung cancer Talks by Dr Bo Sun, University of Oxford, UK and
Dr Adam Al-Diwani, University of Oxford, UK
AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor;
CASPR2, contactin-associated protein-like 2; CRMP5, anticollapsing Understanding the immunology underpinning autoimmune
response-mediator protein-5; GABA, gamma-aminobutyric acid; mGluR5, encephalitis is an ongoing research mission and, at Encephalitis
metabotropic glutamate receptor 5; NMDAR, N-methyl-D-aspartate receptor;
PCA2, Purkinje cell antigen 2. 2021, the immunology of autoantibody-mediated encephalitides
were discussed.
Contactin-associated protein-2 (CASPR2) is a cellular adhesion
in literature amount to <100 [36]. Early studies have shown that molecule and CASPR2-antibodies can lead to an autoim-
patients with IgLON5-antbiody encephalitis present prominently mune encephalitis characterised by a diversity of manifes-
with unusual, and characteristic, sleep disturbances and, at tations [14, 51]. Interestingly, 30% of patients with CASPR2-
Encephalitis 2021, it was suggested that temporal atrophy may be antibody encephalitis suffer relapses following treatment [52].
a common finding in these patients, perhaps correlating with the At Encephalitis 2021, it was shown that both B cell cultures
sleep-based symptomology [35, 37, 38]. Further studies of these from both patients with CASPR2-antibody and healthy donors
newly discovered autoantibodies are required, but the paucity harbour CASPR2-reactive B cells in their naïve repertoires,
of cases means multicentre and multicountry collaborations are suggesting that even in healthy patients CASPR2 reactivity is
vital. present. However, only patients with CASPR2-antibody showed
Cancers are one of recognised triggers of autoimmune memory B cells directed against CASPR2. Therefore, a failure in
encephalitis and numerous presentations at Encephalitis 2021 peripheral B cell tolerance is proposed to play a key role in disease
touched on these paraneoplastic syndromes. In these cases, the pathogenesis [53].
remote effects of a cancer cause an immune-mediated response A further talk discussed the anatomical localisations of these
directed at CNS antigens, predominantly due to molecular autoantigen-specific B cells, which has particular importance in
mimicry. Specific autoantibodies, which associate with particular highlighting the dynamics of CNS-peripheral interactions with
tumours (Table 2), are typically directed at intracellular targets. relevance to both health and CNS diseases. The authors found
These paraneoplastic neurological syndromes are classically that both cervical lymph nodes (the first peripheral port of
subacute in onset with often inexorable progression due to drainage of CNS lymphatics) and ovarian teratomas harboured
accelerated neuronal death [39]; hence, these patients have poor NMDAR-reactive B cells [54]. These findings built on previous work
outcomes. Many patients will develop neurological symptoms showing tertiary lymphoid structures within ovarian teratomas
and signs prior to features of an underlying cancer. As such, [50, 55] and led to the suggestion that the autoimmunisation in
autoimmune encephalitides are now classed as either an patients with NMDAR-antibody encephalitis could be captured
intermediate or high-risk phenotype for underlying malignancies, and studied directly from patients [56]. The authors emphasised
depending on presence of antibodies known to be associated with gratitude to their altruistic patients who volunteered for lymph
established paraneoplastic processes [40]. These new proposed node aspirations and inspired this project.
criteria can enhance the clinical care of this cohort of patients These studies are important in illustrating how immunolog-
who can deteriorate very quickly and remind us about the ical tolerance may play a significant role in understanding the
importance of screening for underlying malignancies in patients mechanism of disease of autoimmune encephalitis, which might
with autoimmune encephalitis both acutely and at follow-up. ultimately lead to targeted immune-modulatory therapies.

Encephalitis 2021: COVID-19-related

Mechanism of disease neurological disease
The clinical features of infectious encephalitis occur primarily Talks by Dr Emily Happy Miller, Irving Medical
due to inf lammation of the brain, but the exact range of mech- Center, and New York Presbyterian Hospital, USA
anisms by which this develops is not yet fully understood. and Dr Oliver Harschnitz, Sloan-Kettering Institute
The likely mechanism of disease may be neurotropic infections for Cancer Research, USA
causing a release of cytokines leading to cytotoxicity, inf lam- Another emerging, or rather emerged, disease discussed at length
mation and damage [41]. This leads to increased permeability at Encephalitis 2021 was COVID-19. Up to one-third of patients
 Encephalitis: diagnosis, management and recent advances in the field of encephalitides | 819

Figure 2. Overview of pathophysiology causing encephalitis.

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with COVID-19 experience at least one neurological manifestation Table 3. Overview of symptoms at presentation which may
suggest aetiology
[57, 58]. Although encephalitis is a rare complication of COVID-
19 [59], ADEM incidences in the first wave appeared increased Symptoms suggestive of Symptoms suggestive of
compared with prepandemic and caused significant mortality infectious cause immune-mediated cause
and morbidity in patients with COVID-19 [60, 61]. To date, there
Acute or subacute onset Subacute or chronic onset
is little evidence that primary SARS-Cov-2 infection of the brain Prodromal f lu-like illness Altered personality, behaviour,
is a significant contributing factor in these cases. Low levels of Alterations in personality, psychosis, catatonia
viral RNA are reported in brain tissue of patients with COVID-19 behaviour, cognition or Sleep disorder-disruption
at autopsy [62]. consciousness Memory issues
Microglial (antigen-presenting cells which are activated fol- Vomiting or gastrointestinal upset Recent viral illness
lowing exposure to pathogens) were found to be activated in Travel history or exposure to Seizures (eg, brachiofacial dystonic)
these specimens, often accompanied by neuronophagia [58]. One known vectors of encephalitis Status epilepticus
hypothesis, therefore, is that the COVID-19 neurological changes causing infections Autonomic instability
Immunocompromise Movement disorders (eg, orofacial
may be caused by neuronophagia [63]. However, these areas did
Skin rashes dyskinesia)
not correspond to those with detectable viral RNA and there-
Underlying symptoms concerning
fore it is unlikely that direct viral neuro-invasion is responsible for malignancy
for the observed neuropathological changes [57, 58]. Other pre-
sented data suggested COVID-19 induces senescence in human
dopaminergic inducible pluripotent stem cells in vitro. This is an A medical history should seek to identify any background of
early suggestion that dopamine neuron involvement may be a immunocompromise.
factor in the neuropathology seen in COVID-19 [64]. There remain
significant gaps in our understanding in the effect of COVID-19 on Encephalitis 2021: neuropsychiatric
the neurological system, and long-term monitoring of neurologi- presentations of encephalitis
cal problems in patients with COVID-19 is underway (www.covid- Talk by Dr Helena Ariño, Institue of Psychiatry,
cns.org). Psychology and Neuroscience, King’s College London,
UK
An area of growing interest is the overlap between autoimmune
Clinical manifestations encephalitis and neuropsychiatric diseases [67], with NMDAR-
A vital aspect of assessing a patient with suspected encephalitis antibody encephalitis often presenting with predominantly
is to look for clues as to the cause of the encephalitis. This psychiatric features. At Encephalitis 2021, it was discussed
can enable targeted therapy which has a significant effect on how harnessing digital medical records may provide a valid
mortality and morbidity. method to phenotype NMDAR-antibody encephalitis in patients
Although presenting symptoms can be varied, particular symp- presenting with neuropsychiatric symptoms [68]. Psychiatric
toms are more associated with specific causes (Table 3). There- symptoms at the onset of NMDAR-antibody encephalitis and
fore, the clinician should try and hone in on these details in the can occur weeks before other clinical signs suggestive of
history. Identification of the timeline of symptoms is important. the disease. However, indiscriminate screening of psychiatric
Encephalitis is typically subacute in onset, although this can patients is not cost-effective and poses a major risk by leading
vary: we are discovering new autoimmune causes such as LGI1- to patient misidentification. Analysing clinical text through
antibody and CASPR2-antibody encephalitis which may follow a natural language processing was shown to have promise in
chronic course of disease [6, 37]. phenotyping NMDAR-antibody encephalitis versus other patients
Evidence of personality or behavioural change, hallucinations with psychosis. Terms such as ‘paediatric’, ‘bladder’ and ‘shaking’
and other neuropsychiatric symptoms should be investigated. in medical records were suggested to ref lect NMDAR-antibody
This is a common presentation of some autoimmune encephal- encephalitis, and machine learning algorithms to analyse clinical
itides [65] and may have very particular features which highlight texts containing the mental state examination or quotes from
it as especially distinctive [66]. patients may help predict encephalitis [68].
A travel history is vital with particular emphasis on contacts These novel methods are showing potential promise in our clin-
with animals, mosquitoes or other insects. In areas with vector- ical repertoire in diagnosing conditions, but require large datasets
borne causes of encephalitis, the location and season in which which may be challenging to generate in conditions such as
patients present can also give clues as to what a causative infec- autoimmune encephalitis and may not surpass everyday clinical
tive agent may be. acumen.
820 | Alam et al.

In the case of autoimmune encephalitis, body imaging to rule

out underlying malignancies must also be considered, such as
positron emission tomography and whole-body CT imaging.
Electroencephalogram can be useful in investigating encephali-
tis as it can provide evidence of encephalopathy, which would be
unusual in primary psychiatric diagnoses, or subclinical seizures.
Indeed, autoimmune encephalitis may be an important cause
of non-convulsive status epilepticus in high-income settings
[73]. Certain characteristic patterns have been described in
autoimmune encephalitis, in particular the pathognomic extreme
delta brush appearance in NMDAR-antibody encephalitis [74].
The above investigations should be undertaken alongside more
common investigations to rule out differentials. A HIV test should
be offered to all patients with suspected brain infections.

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Encephalitis 2021: new diagnostic tools
Talk by Dr Álvaro Bonelli, Rey Juan Carlos University
Figure 3. Coronal T2-weighted MRI of a patient with herpes simplex Hospital, Móstoles, Spain
virus encephalitis illustrating high signal changes in the temporal lobes It is still difficult to identify the causative agent in many
(source: Dr Laughlin Dawes, 2008).
cases with presumed encephalitis where, even in developed
settings, approximately a third of patients do not have a
pathogen or autoantibody identified [11, 72]. Novel laboratory
techniques which may help to stratify unknown patients into
Diagnosis aetiological groups were discussed at Encephalitis 2021. New
The key to establishing evidence of CNS inf lammation is to obtain qualitative multiplexed techniques such as FilmArray Meningitis
and analyse CSF through a LP. Neuroimaging is not a prereq- and Encephalitis Panel allow the study of up to 14 pathogens in
uisite for LP and is only indicated prior to LP in cases when 1 hour with a high sensitivity and specificity [75]. Studies have
focal neurological signs, papilloedema, seizures or a GCS <13 is shown that the percentage of CNS aetiological diagnosis were
present, as these features suggest obstructive raised intracranial higher in the group that had multiplex PCR testing, and this
pressure [17]. approach reduced the number of molecular biology techniques
In viral encephalitis, the CSF typically shows a predominantly required to reach a diagnosis [76]. This technique may allow more
lymphocytic pleocytosis. Protein levels maybe moderately ele- causative agents to be identified in a single step and therefore
vated or normal and the CSF:blood glucose ratio is typically should allow clinicians to better direct therapeutic interventions.
normal in these samples. Sending CSF samples for viral PCR in This concept is analogous to the use of immunohistochemistry
a timely manner is vital. Delaying the LP, and therefore CSF viral and live neuron binding as methods to detect as of yet unknown
PCR, can lead to diagnostic uncertainty as the viral load declines, autoantibodies in patients with autoimmune encephalitis [5, 48].
particularly after aciclovir has been started in cases due to HSV
and varicella zoster. Repeat LPs to collect CSF and serum for
antiviral antibody testing may be useful in achieving a diagnosis
at these delayed timepoints.
Management
Autoantibody testing should be considered in all cases, Patients with encephalitis can become acutely unwell and sup-
particularly those with a recognisable phenotype of autoimmune portive management is important. This includes managing air-
encephalitis [17]. The diagnostic assays used in diagnos- way, breathing and circulation.
ing autoimmune encephalitis includes cell-based assays and Airway management is particularly important in patients
immunohistochemistry for neuronal surface antibodies, with presenting in a comatose state or with uncontrollable seizures.
increasing evidence suggesting live cell-based assays perform Seizures are a common sequela of encephalitis [77], and access
optimally in these diseases, and in-house fixed cell-based assays to anticonvulsant drugs and intensive care units (especially in
better than commercially available equivalents [69, 70]. the case of status epilepticus) is vital. Almost 70% of patients
Brain imaging is recommended to assess for changes sug- with autoimmune encephalitis have seizures during their illness
gestive of encephalitis and to exclude other diagnoses such [78]. Suboptimally controlled seizures can be linked with raised
as space-occupying lesions. MRI, particularly with diffusion- intracranial pressure and greater morbidity and mortality. Recent
weighted imaging (DWI) sequences, is the modality of choice to studies into seizure management were discussed at Encephalitis
assess changes associated with encephalitis. Some pathogens 2021. A novel therapy discussed was the use of a neurosteroid.
have specific changes seen on neuroimaging, the most well- Neurosteroids are steroids produced by glial cells and principal
known being HSV encephalitis causing bilateral but asymmetrical neurons. The use of a neurosteroid has been shown to rescue
inf lammation of the temporal and frontal lobes [71] (Figure 3). epileptiform activity in murine anti-NMDA encephalitis models.
Autoimmune encephalitis can give variable changes on MRI, These in vitro models show how NMDAR modulation can prevent
but the most common feature is bilateral and symmetrical anti-NMDA encephalitis’ pathogenic antibody effects such as
inf lammation of the limbic system [48]. In cases of suspected seizures and treat them once established [79]. Further work
ADEM, MRI typically shows bilateral white matter lesions which on identifying patients at risks of seizures, and potential novel
can be both supra- and infratentorial and involve the brainstem treatment options are important as we move forward in manging
and spinal cord [72]. encephalitis.
 Encephalitis: diagnosis, management and recent advances in the field of encephalitides | 821

The role of steroids in viral encephalitis to reduce the inf lam- is comparable [86–88]. Tackling disparity in access to important
mation associated with infection is an ongoing area of study. medications globally is huge challenge, and one which will need
Results from a multicentre randomised controlled trial in HSV to be solved to help improve encephalitis management in low-
encephalitis are currently awaited (https://www.dexenceph.org. income to middle-income/resource settings.
uk/) and aim to be presented at Encephalitis 2022 [80]. Encephalitis management requires the involvement of neu-
Although many viruses have been reported to cause encephali- rological specialists, but they are not always available in low-
tis, targeted antiviral therapy is limited to HSV and VZV encephali- income to middle-income/resource settings. The median number
tis [72]. Aciclovir should be initiated empirically in all patients of adult neurologists per 100 000 population globally is 0.43—
with suspected encephalitis (pending other diagnostic investi- in comparison, high-income countries average almost five neu-
gations) as it reduces HSV mortality from approximately 70% rologists per 100 000 people [89]. In Encephalitis 2021, it was
to 10%–20%, and has minimal side effects [71, 72, 81]. Should reported that sub-Saharan Africa has very few countries with
another infection be identified as causative pathogen in a patient neurology training programmes, and the ratio of neurologist to
with encephalitis, appropriate antimicrobial therapy should be population is unlikely to improve. The recent development of a
initiated. specialist neurological training programme at University Teach-

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The first-line treatment of autoimmune cases includes ing Hospital Lusaka, Zambia illustrates how robust systems of
immunotherapy such as high-dose steroid therapy with or with- neurological care in resource-limited settings can be developed.
out intravenous immunoglobulin (IvIg) and/or plasmapheresis, This programme emphasises the importance of in-country neu-
while second-line treatment options include rituximab and/or rology teaching and is on track to train 13 adult and 2 paediatric
cyclophosphamide [82]. The benefit of adjunctive IvIg in patients neurologists in its first 5 years [90]. The importance of ensuring
receiving high-dose steroids is currently under investigation in good training will be vital in improving outcomes in diseases such
a trial (EncephIg). Also, in LGI1-antibody encephalitis, there is a as encephalitis in low-resource settings.
clinical trial which aims to study the value of reducing IgG levels
with blockade of the FcRn molecule which typically recycles IgG.
What next?
Furthermore, a CD19 monoclonal antibody is being trialled in
patients with NMDAR-antibody encephalitis as a way to improve Encephalitis remains a difficult to manage neurological syndrome
outcomes. due to its many causes, sometimes non-specific presentations
A key aspect of encephalitis treatment is the management of its and a lack of recognition and awareness. An integral aspect of
long-term sequalae resulting from damage and injury to the brain. management is to first identify the causative pathogen or autoan-
Many patients suffer from long-term effects such as emotional, tibody to enable directed therapy. Recent advances in the field can
behavioural, physical and cognitive deficits. Social effects are lead to improved outcomes and reduced disability in encephali-
often forgotten, including ability to drive and loss of work or edu- tis. However, challenges we recognise in 2022 include emerging
cation due to disability, yet are common impairments in some of pathogens, access to therapy in low-income to middle-income set-
these conditions [83]. Access to neuropsychology, neuropsychiatry tings and characterising autoantibody-mediated encephalitides,
and occupational therapy services along with ensuring adequate as well as a better understanding of the long-term consequences
postdischarge follow-up is important in addressing the long-term for patients and their families (box 1).
effects of this condition. In addition, there is also the impact
on the family to consider, such as the development of mental Box 1 Oral presentations at Encephalitis 2021 [7]
health problems, carer burden and family breakdown. Patients
and families affected may benefit from using the information and • Analysing clinical text from electronic health records to
support services provided by patient organisations such as The diagnose anti-N-methyl D-aspartate receptor (NMDAR)
Encephalitis Society (www.encephalitis.info). encephalitis, a feasibility study (Dr Helena Ariño, Insti-
tute of Psychiatry, Psychology & Neuroscience, King’s
Encephalitis 2021: the need for greater access to College London, UK).
encephalitis management • Defining the neuroinvasive potential of SARS CoV-2 in
Talks by Professor Deanna Saylor, The Johns Hopkins brain autopsies of patients with COVID-19 (Dr Emily
University School of Medicine, USA; Dr Jamil Happy Miller, Columbia University Irving Medical Center,
Kahwagi, Centre Hospitalier National Universitaire and New York Presbyterian Hospital, New York, USA).
de Fann, Senegal and Dr Adawa Manuela, COVID-19 • Immune and genetic signature of breast carcinomas trig-
ORCA Patient Management Center, Cameroon gering Yo paraneoplastic cerebellar degeneration (Pro-
Managing encephalitis in low-resource settings is challenging. fessor Virginie Desestret, Hospices Civils de Lyon, Uni-
This can be due to a combination of access to diagnostic tools, versité Claude Bernard Lyon, France).
medications and scope for management in specialist settings, • Paraneoplastic encephalitis (Professor Jerome Honnorat,
along with cultural challenges associated with accessing health- Hospices Civils de Lyon, France).
care. These difficulties were discussed at Encephalitis 2021. • Dissecting contactin-associated protein-like 2 (CASPR2)-
The aetiology of infectious encephalitis remains poorly antibody encephalitis with patient-derived CASPR2-
described in African settings. In resource-limited settings such specific monoclonal antibodies (Dr Bo Sun, University of
as Senegal, it was reported that encephalitis cases rarely have an Oxford/John Radcliffe Hospital, Oxford, UK).
aetiological diagnosis and treatment can often be inconsistent [84, • Clinical and laboratory findings of acute encephalitis
85]. A large challenge faced in sub-Saharan Africa is the lack of syndrome associated with scrub typhus infection in
access to injectable aciclovir [84]. A potential compromise is oral children admitted to tertiary care hospitals in South
valaciclovir which may be a more readily accessible alternative to India (Dr Tina Damodar, Department of Neurovirology,
intravenous aciclovir in settings with limited resources, although NIMHANS, Bangalore, India).
more robust studies are required to assess whether its efficacy
822 | Alam et al.

• Infectious encephalitis during the second wave of • Patients can present with a combination of fevers,
COVID-19: an observational study among hospitalised decreased consciousness and other neurological
patients in Dakar, Senegal (Dr Jamil Kahwagi, Centre deficits; however, it can sometimes present non-
Hospitalier National Universitaire de Fann, Dakar, Sene- specifically, and this combined with its many causes
gal). and lack of recognition make it a difficult to manage
• Direct evaluation of cervical lymph node and ovarian ter- neurological syndrome.
atoma as sites of autoimmunisation in NMDAR-antibody • By focusing on findings presented at the Encephali-
encephalitis (Dr Adam Al-Diwani, Department of Psychi- tis Society’s conference in December 2021, this article
atry, University of Oxford, Oxford, UK). reviews the causes, clinical manifestations and manage-
• Developing neurological care and training in resource- ment of encephalitis and integrate recent advances and
limited settings (Assistant Professor Deanna Saylor, The challenges of research into encephalitis.
Johns Hopkins University School of Medicine, USA).
• Inborn errors of TLR3-dependent or MDA5-dependent

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type I interferon immunity in children with enterovirus
rhombencephalitis (Dr Jie Chen, The Rockefeller Univer-
Current research questions
sity, New York, USA).
• Spatial and temporal brain atrophy in anti-
• Challenges we recognise in combating encephalitis in
immunoglobulin-like cell adhesion molecule 5 disease
2022 include emerging pathogens, access to therapy in
(Ms Selina Yogeshwar, Charité- Universitätsmedizin
low-income to middle-income settings and characteris-
Berlin, Berlin, Germany).
ing autoantibody-mediated encephalitides, as well as a
• Encephalitis and autoimmune encephalitis in paediatric
better understanding of the long-term consequences for
patients from Brazil (Dr Renata Barbosa Paolilo, Hospital
patients and their families.
das Clínicas da Faculdade de Medicina da Universidade
• Further funding and work are needed to aid our under-
de São Paulo (HCFMUSP), São Paulo, Brazil).
standing of this disease, and Encephalitis 2021 ended
• Novel treatment of an NMDAR-antibody-mediated
with a call to action to be part of World Encephalitis Day
seizure model (Dr Sukhvir Wright, Institute of Health
on 22 February 2023 and Encephalitis Research Month in
and Neurodevelopment, Aston University, Birmingham,
June 2022.
UK).
• Encephalitis 2022 will be held on 30 November and
• Aetiological diagnosis in central nervous system infec-
1 December 2022 at the Royal College of Physi-
tions: multiplex PCR (Dr Álvaro Bonelli, Rey Juan Carlos
cians, London and you can receive invitations for
University Hospital, Móstoles, Madrid, Spain).
abstract and conference sign up by taking advantage of
• SARS-CoV-2 infection causes dopaminergic neuron
free professional membership (www.encephalitis.info/
senescence (Dr Oliver Harschnitz, Sloan-Kettering Insti-
professional-membership).
tute for Cancer Research, New York, USA).
• Aetiologies of encephalitis in non-HIV-infected patients
in Cameroon (Dr Adawa Manuela, COVID-19 ORCA
Patient Management Center, Yaoundé, Cameroon).
• Investigating long-term neuropsychological outcomes in Key references
paediatric autoimmune encephalitis using magnetoen-
cephalography (Charly Billaud, School of Health and Life • Easton A, Solomon T. Encephalitis awareness: our ambi-
Sciences, Aston University, Birmingham, UK). tious global endeavour. Lancet Neurol 2022 Apr;21(4):314.
• Arthropod-borne encephalitides (Winifred Mercer Pitkin doi: 10.1016/S1474-4422(22)00079-5. Epub 2022 Feb 23.
Assistant Professor Kiran Thakur, Columbia University PMID: 35 202 603.
Irving Medical Center, USA). • Venkatesan A, Michael BD, Probasco JC, Geocadin RG,
Solomon T. Acute encephalitis in immunocompetent
adults. Lancet 2019 Feb 16;393 (10172):702–716.
• Ellul M, Solomon T. Acute encephalitis—diagnosis and
Further funding and work are needed to aid our understanding management. Clin Med (Lond) 2018;18(2):155–9.
of this disease, and Encephalitis 2021 ended with a call to action • Uy CE, Binks S, Irani SR. Autoimmune encephali-
to be part of World Encephalitis Day on 22 February 2022 and tis: clinical spectrum and management. Pract Neurol
Encephalitis research month in June 2022. Encephalitis 2022 will 2021 Oct;21(5):412–423. doi: 10.1136/practneurol-2020–
be held on 30 November and 1 December 2022 at the Royal College 0 02 567. Epub 2021 June 9. PMID: 34108243; PMCID:
of Physicians, London and you can receive invitations for abstract PMC8461404.
and conference sign up by taking advantage of free professional • https://www.encephalitis.info
membership (www.encephalitis.info/professional-membership).

Main messages
Self-assessment questions
• Encephalitis describes a syndrome of brain parenchyma
inf lammation, typically caused by either an infectious 1. To diagnose encephalitis, patients must have a fever and
agent or through an autoimmune process. neurological signs. True/False
 Encephalitis: diagnosis, management and recent advances in the field of encephalitides | 823

Competing interests
2. NMDAR-antibody encephalitis is often linked to under-
lying ovarian teratomas. True/False SRI is an inventor on ‘Diagnostic strategy to improve specificity
3. IgLON5-antibody encephalitis presents with neurode- of CASPR2 antibody detection’ (PCT/G82019 /051257) and receives
generative presentation with characteristic sleep distur- royalties on a licensed patent application for LGI1/CASPR2 test-
bances. True/False ing as coapplicant (PCT/GB2009/051441) entitled ‘Neurological
4. A CT scan is always required prior to conducting a LP in Autoimmune Disorders’. SRI is supported by a senior clinical fel-
a patient with encephalitis. True/False lowship from the Medical Research Council (MR/V007173/1), Well-
5. Aciclovir should be initiated empirically in all patients come Trust Fellowship (104079/Z/14/Z) and the BMA Research
with suspected encephalitis. True/False 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
Manuscript version arising from this submission. SRI has received

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Answers
honoraria from UCB, Immunovant, MedImmun, Roche, Cerebral
1. False Therapeutics, ADC Therapeutics, Brain, Medlink Neurology and
2. True research support from CSL Behring, UCB and ONO Pharma. TS was
3. True Chair/Co-Chair of the UKRI/NIHR COVID-19 Rapid Response and
4. False Rolling Funding Initiatives (from March 2020), an Advisor to the
5. True UK COVID-19 Therapeutics Advisory Panel (UK-TAP, from August
2020) and a member of the MHRA COVID-19 Vaccines Benefit Risk
Expert Working Group (from August 2020). He is also a trustee
of the UK Academy of 19Medical Sciences (December 2021). TS
is President of the Encephalitis Society. TS was an advisor to the
Acknowledgements GSK Ebola Vaccine programme and chaired a Siemens Diagnostics
Clinical Advisory Board. TS was on the Data Safety Monitoring
We would like to thank all the speakers, attendees and organisers
Committee of the GSK Study to Evaluate the Safety and Immuno-
of Encephalitis 2021 conference.
genicity of a Candidate Ebola Vaccine in Children GSK3390107A
(ChAd3 EBO-Z) vaccine. TS chaired the Siemens Healthineers
Twitter Clinical Advisory Board. Data safety monitoring board: Study of
Ebola vaccine and ChAd3-EBO-Z—commercial entity.
Ali M Alam @alimashqur, Ava Easton @encephalitisava, Tom
Solomon @RunningMadProf and Benedict D Michael @benedict-
neuro
Provenance and peer review
Not commissioned; internally peer reviewed.
Contributors
AMA and AE wrote the first draft. All authors critically appraised
and contributed to the final manuscript. Ethics statements
Patient consent for publication
Not applicable.
Funding
BDM is supported by the UKRI/MRC (MR/V03605X/1), the Ethics approval
MRC/UKRI (MR/V007181//1), MRC (MR/T028750/1) and Wellcome
Not applicable.
(ISSF201902/3).

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