Immune‐mediated encephalitis

A neurological deterioration in a child presents a significant worry to the family and often a diagnostic challenge to the clinician. A dysregulated immune response is implicated in a wide and growing spectrum of neurological conditions. In this review we consider the current paradigms in which immune‐mediated encephalopathies are considered; the development of paediatric specific diagnostic criteria that facilitate early consideration and treatment of immune‐mediated conditions and the limitations and potential developments in diagnostic testing. We consider the expanding phenotype of myelin oligodendrocyte glycoprotein antibody, the spectrum of virus‐associated encephalopathy syndromes, and the strategies that have been employed to build an evidence base for the management of these rare conditions. Looking forward we explore the potential for advanced molecular investigations to improve our understanding of immune‐mediated encephalitides and guide future treatment strategies.

Central nervous system (CNS) inflammation is an important physiological process driven by a variety of interacting biological mechanisms that play a key role in host defence and repair to protect and maintain a CNS milieu that is ultimately neuroprotective.However, when perturbed, inflammation can lead to disruption of the whole or part of the complex neural pathway and connectivity leading to brain dysfunction that manifests as recognizable neurological syndromes with encephalopathy.These have now been carefully characterized and are broadly better recognized, diagnosed more quickly, and managed more optimally. 1n this review we consider: the current paradigms in which immune-mediated encephalopathies are considered; investigative and diagnostic advances, particularly the development of paediatric specific diagnostic criteria; and developing frameworks for the consideration of less established entities such as autoimmune psychosis and epilepsy.We review the emerging concepts in immune-mediated brain inflammation, and the factors that may contribute both to the development of the disease and the outcome.Finally, treatment strategies are reviewed, and future challenges explored.

EVALUATING THE IMMUNE RESPONSE
Most neurological conditions are currently classified using combinations of symptoms, signs, and investigations with many conditions sharing phenotypic and investigative overlap.Broad disease entities such as 'parainfectious' and 'postinfectious' that describe a temporal association of the clinical presentation with an infective trigger can provide a framework to consider differential components of the immune system that is triggered (Figure 1), leading the clinician to then specifically investigate to identify mechanism or disease specific changes.

Clinical investigations
Accordingly, investigation of a child presenting with a possible immune-mediated CNS disorder is focused on three key areas: identification of an infective agent or trigger and exclusion of alternative causes; evidence for inflammation; and identification of key features which allow the condition to be phenotyped (e.g.identification of a pathogenic antibody or a pathogenic mutation).

Immune-mediated encephalitis
Thomas Rossor 1 | Ming Lim 1,2 To evaluate any immune-mediated CNS disorder, an investigative strategy can be adopted as proposed for the diagnosis of autoimmune encephalitis in children.These criteria utilize paraclinical features of CNS inflammation including magnetic resonance imaging (MRI) features of encephalitis, evidence of immune activation in the cerebrospinal fluid (CSF) (pleocytosis with lymphocytes >5 cells/mm 3 or unmatched oligoclonal bands in the CSF), and biopsy to determine the probability of an immune-mediated aetiology in the absence of a pathogenic antibody.Yet the presence of an antibody can make a definitive diagnosis of autoimmune encephalitis despite the absence of other paraclinical markers of inflammation, suggesting that the current tools available for detecting neuroinflammation may be insufficiently sensitive.Antibody testing for neuronal surface antibodies has been optimized with live cell-based assays in which the epitope is exposed in its conformational state optimizing specificity.Commercially available fixed assays offer a resource effective option which when optimized have slightly reduced sensitivity while maintaining similar specificity to live assays. 2 Despite the severity of the encephalopathy in many immune-mediated encephalitides, with many patients being admitted to intensive care, the neuroimaging is normal in the majority. 3When abnormal, conventional MRI usually reveals discrete lesions in white and/or grey matter that are predominantly subtle, non-enhancing, and often reverse spontaneously. 3ttempts to improve the sensitivity of imaging in immunemediated encephalopathies include the use of advanced MRI and positron emission tomography (PET) techniques.In a study currently recruiting, ultra-high field imaging is being employed to look at both structural connectivity changes in children with NMDA receptor encephalitis (NMDARE), and glutamate and GABA levels using spectroscopy (NCT05280600).Fluorodeoxyglucose PET (FDG PET) evaluates the uptake of glucose within the brain, and has been used in small studies of patients with NMDARE, detecting abnormalities in a proportion of patients with normal imaging by MRI. 4 A meta-analysis including 444 adult and paediatric patients who underwent 18 F-fluoro-2-deoxy-D-glucose PET imaging with a diagnosis of autoimmune encephalitis reported a detection sensitivity of 87%.However the sensitivity in antibody negative autoimmune encephalitis was markedly lower at 68% with more heterogeneous abnormalities reported. 5In a prospective study of 103 children with suspected autoimmune encephalitis, sensitivity and specificity of abnormality on PET imaging in predicting a diagnosis of autoimmune encephalitis were reported at 93% and 84%. 6However, as abnormality on PET scan was used as a paraclinical marker to make the diagnosis of autoimmune encephalitis alongside either CSF abnormalities or a response to immune therapy, the validity of the final diagnosis in this study, and therefore the specificity of PET imaging in clinical syndromes of immunemediated encephalopathy, remains unclear.
Carefully selected PET ligands that target biomarkers of inflammation offer the possibility of sensitive and specific imaging of inflammation by targeting molecules expressed or produced during inflammation.One possible ligand target is translocator protein 18 kDa.During neuroinflammation, expression of translocator protein 18 kDa significantly increases in microglia, activated astrocytes, and macrophage/monocytes within the CNS space.A variety of ligands targeted to translocator protein 18 kDa have been developed, allowing visualization of areas of inflammation with high sensitivity. 7Translocator protein 18 kDa PET abnormalities have been demonstrated in a range of conditions in children including tuberous sclerosis, Friedreich ataxia, and brain tumours.Given the role of inflammation in such a range of conditions, whether the possibly improved sensitivity of PET imaging results in a loss of specificity of the current diagnostic criteria remains to be seen, and as yet validity has not been established to allow it to become a key component of investigation strategies.Coupled with the lack of availability in many centres, the clinical utility of PET imaging in the diagnosis of autoimmune encephalitis remains limited.
Similar to neuroimaging, the CSF analysis may be unrevealing.In NMDARE, lymphocytic pleocytosis was seen in 54%, elevated protein concentration in 27%, and intrathecal oligoclonal bands are present in up to 60% of patients, but not necessarily at onset of the disease. 8The measurement of cytokines within the CSF has offered an opportunity to look for a range of inflammatory mediators.A meta-analysis of 11 studies identified significant differences in CSF levels of interleukin 6, interleukin 8, interleukin 10, C-X-C motif chemokine ligand 10, and tumour necrosis factor alpha between patients with encephalitis and controls, 9 with interleukin 10 levels significantly elevated in patients with autoimmune encephalitis compared to infectious encephalitides. 9As with the novel imaging modalities discussed above, while these advances may offer insight into patterns of inflammation, neither have offered sufficiently consistent results to have clinical utility currently.

OP TI M IZI NG DI AGNOSIS
In recent years, the development of widely adopted consensusbased diagnostic criteria for a range of autoimmune (and

What this paper adds
• Recently characterized immune-mediated central nervous system disorders include new antibodies causing previously recognized phenotypes.• Aggregation of conditions with similar clinical triggers, and characterization of unique imaging features in virus-associated encephalopathy syndromes.• Immune treatment iscurrently guided by metaanalysis of individualized patient data and/or multi-national consensus.
immune-mediated) encephalitides 10 and the development of robust assays to detect neuronal surface antibodies paves the way to more rapid and accurate diagnosis.However, careful consideration has to be given to the application of these criteria to a paediatric population where the clinical and investigative findings may differ.
After the establishment of Graus criteria, more paediatric centric criteria were proposed, 10 recognizing the broader, more polysymptomatic presentation in children, and adopting a less iterative path to further classify autoimmune encephalitis.This allows wider inclusion to rapidly initiate immune treatment, with further (re)classification The innate and adaptive immune system in health and disease.Our innate immunity provides a rapid first-line response to environmental stressors such as infection, shock, and trauma.This activation involves cellular and humoral components we characteristically associate with an infection triggered immune response.Initially this lacks specificity and diversity, but with time recruits and activates adaptive immunity.Slower to respond, the adaptive immune system produces an antigen specific response mediated by lymphocytes to eliminate infection.The adaptive immune system permits a specific response, with memory of previous exposure.An immune response often comprises of complex interplay of the innate and adaptive responses to achieve maximal protection for the host and, in the context of the nervous system, neuroprotection.Conditions associated predominantly with innate immune activation that is perturbed (beyond physiological) may be described as 'autoinflammatory', while those predominantly associated with adaptive immune activation are considered autoimmune.Abbreviations: DCs, dendritic cells; NKs, natural killer cells; NKT, natural killer T-cells; γδT, gamma delta T-cells; RANBP2, RAN binding protein 2; TLR3, toll-like receptor 3; IL1b, interleukin 1b; IL6, interleukin 6; IL8, interleukin 8; IL15, interleukin 15; TNFα, tumour necrosis factor alpha; TGF-β, transforming growth factor beta; IL2RA, interleukin 2 receptor A; IL4, interleukin 4; IL10, interleukin 10; IL17, interleukin 17.
down the clinical pathway after biomarker identification or investigative results to refine and optimize immunotherapy (Figure 2).Notably care needs to be given to reverse inaccurate diagnoses to avoid unnecessary and potentially harmful immunotherapy.In a recent large multi-centre adult evaluation, the authors report a misdiagnosis in 27% (107/393) of patients referred with a diagnosis of autoimmune encephalitis, whereby 72% was attributable to less stringent application of consensus diagnostic criteria and 50% to undue significance being attached to non-specific and/or serum antibodies without consideration of the clinical presentation.These findings are likely to be highly relevant in paediatric cohorts and should caution against ascribing diagnosis particularly in isolated or predominantly monosymptomatic psychiatric symptoms.Here, the commonly (and pragmatic) adopted paradigm of assuming improvement after initiation of immunotherapy as being immunotherapy sensitive needs to be exercised with extreme caution and continually reviewed and revised.For this reason, response to immunotherapy does not contribute to either the Graus or Cellucci criteria for diagnosis of autoimmune encephalitis. 10,11raclinical markers of inflammation are essential both to avoid over-diagnosing autoimmune encephalitis in the presence of non-specific antibodies, and to avoid rejecting a diagnosis of antibody negative autoimmune encephalitis as no pathogenic antibody is identified.Over-interpretation of intracellular antibodies such as GAD65, particularly in serum, may lead to a false positive diagnosis if paraclinical evidence of inflammation is not identified.Similarly, coexistence of autoantibodies is common and therefore caution must be exercised in attributing pathology to antibodies such as to thyroid proteins, in the absence of data demonstrating pathogenicity. 12

New autoimmune syndrome: MOGAD
Despite increasing numbers of novel autoantibodies being reported in adults, some of which have also been reported in children, at least half of children fulfilling the Cellucci criteria for autoimmune encephalitis are antibody negative. 13hese antibody-mediated syndrome are summarized in Table 1, including rare entities in children such as glutamic acid decarboxylase (GAD) antibody associated limbic encephalitis 14 and IgLON5 associate disease, 15 with further attention given to the expanding phenotype of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).
The spectrum of MOGAD has expanded, with the clinical presentation changing with age.Encephalopathy associated with the more diffuse white matter disease in acute disseminated encephalomyelitis may be absent in older children or adults presenting with optic neuritis or transverse myelitis associated with myelin oligodendrocyte glycoprotein antibody (MOG-Ab). 16Beyond the typical demyelinating phenotypes, MOG-Ab has been identified in a number of patients with more cortical disease in both adults and children.In a multi-centre study of 296 children diagnosed with probable or definite encephalitis according to the Graus criteria, 22 (7%) were found to have MOG-Ab on retrospective testing. 17solated seizures have been reported as the sentinel feature of MOGAD 18 and are considered further below.While 50% to 70% of young people presenting with MOGAD experience a monophasic disease course which is typically steroid responsive, a proportion go on to develop a relapsing disease.This can be associated with greater morbidity in vision and motor disability, but also in cognitive function, with memory impairment, attentional problems, poor concentration, and academic difficulties reported in 10% to 50% of children with MOGAD. 19,20

New immune-mediated syndromes: virus-associated encephalopathy syndromes
The arrival of a novel coronavirus in 2019 brought with it reports of numerous multisystem complications associated with hyperinflammation.In a prospective national cohort study in the UK, the prevalence of neurological disorders in children admitted with SARS-CoV-2 (COVID-19) was 3.8 per 100 children. 21cute necrotizing encephalopathy (ANE) is a rare parainfectious condition characterized by a rapid deterioration in consciousness with a very specific MRI pattern comprising of symmetrical lesions in the thalami and basal ganglia, associated with infection with influenza as well as other neurotropic viruses.Reports of association of ANE with COVID-19 triggered a resurgence of interest in virusassociated encephalopathy syndromes, a term used to describe a group of parainfectious conditions in which an infection may trigger brain dysfunction without direct invasion.For some, such as ANE, both specific pathogens (influenza) and genetics vulnerabilities (RANBP2 mutations) have been identified and may associate with greater morbidity and mortality. 22everal other entities have been described (Figure 3).The underlying mechanisms driving these similar conditions remain poorly defined, but reflect a combination of excitotoxicity with inflammation that appears to reflect innate immune system activation, and it is likely that some of the separately defined entities in fact reflect a spectrum of similar conditions.Acute encephalopathy with biphasic seizures and late reduced diffusion is a recently defined condition typically seen in children under 2 years of age, with prolonged seizures in the context of fever, followed by encephalopathy and then recurrence of seizures.MRI typically demonstrates symmetrical restricted diffusion, often with some central sparing affecting both hemispheres. 23cute leukoencephalopathy with restricted diffusion was subsequently described in a similar cohort of patients who presented with encephalopathy and seizures, without the biphasic pattern to the seizures.In a series of 44 cases in Japan, triggers including human herpesvirus 6, adenovirus, rotavirus, influenza virus, and enterovirus were identified, as well as bacterial infection with strep pneumoniae and E. coli. 24cute infantile encephalopathy with frontal predominance and acute fulminant cerebral oedema both reflect infection triggered entities where the radiological distribution and extent of cytotoxic oedema varies.On the milder end of the spectrum exists mild encephalopathy with reversible splenial lesion (also known as reversible splenial lesion syndrome), reported in association with COVID-19 infection alongside many other infections, often with minimal sequelae.
In general, virus-associated encephalopathy syndromes can be associated with significant morbidity and mortality.A retrospective multicentre Malaysian study identified 27 children with ANE over a 12 month period with one-third mortality. 25While there is no consensus as to the optimum treatment strategy, there is emerging evidence that early and multimodal immunotherapy may at least improve mortality. 25longside broad immunomodulatory strategies, the postulated role of excitotoxicity has led to neuroprotective strategies such as therapeutic hypothermia being employed. 26espite best efforts, the mortality and morbidity associated with virus-associated encephalopathy syndromes, and ANE particularly, remain high, and prevention may be crucial.The role of influenza in the triggering ANE, particularly in those with a silent genetic vulnerability, argues strongly for the widespread take-up of flu vaccination.

Newer disease paradigms: autoimmune epilepsy and psychiatric disorders
Careful adaptations of the diagnostic criteria for autoimmune encephalitis to encompass broader inflammatory aetiology within disease groups such as epilepsy and psychiatric disorders have been proposed.Symptomatic seizures in the context of encephalitis associated with neuronal surface antigens such as NMDARE often resolve with immune modulation, and antiseizure medications can often be withdrawn outside the acute episode.In these cases, the absence of an enduring predisposition to seizures suggests they should not be defined as epilepsy. 27Included in this group would be the presentation of MOGAD with isolated seizures. 18The International League Against Epilepsy Autoimmunity and Inflammation Task Force defines a second group distinct from those with acute symptomatic seizures secondary to autoimmune encephalitis.This group F I G U R E 3 Virus-associated encephalopathy syndrome.Distinct clinical and radiological syndromes have been reported ranging from the milder encephalitis/encephalopathy with a reversible splenial lesion, through to acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures and restricted diffusion, and haemorrhagic shock and encephalopathy syndrome.
with 'autoimmune-epilepsy' has a persisting vulnerability to seizures which is often resistant to both immunotherapy and antiseizure medication. 28Where antibodies are detected, these are more often to intracellular antigens, and a role for cytotoxic T-cells has been proposed.Included in this group would be Rasmussen encephalitis.This definition acknowledges that in this group there may be a persistent immune activation which results in an enduring seizure disorder, which may also be a structural epilepsy.
While psychiatric symptoms may be the presenting feature and dominant in autoimmune encephalitis, they are rarely seen in isolation.In a retrospective study of 577 patients with NMDARE, abnormal behaviour and cognition were the most common initial presentation in children, with other associated features seen in all but 1% of patients by week four of illness. 29Building on the diagnostic criteria for autoimmune encephalitis, an international consensus paper was published proposing diagnostic criteria for possible and probable autoimmune psychosis. 30n patients that fulfil these criteria, an approach to investigation is proposed which mirrors closely investigation of autoimmune encephalitis, reflecting the view that autoimmune psychosis may be a forme fruste of autoimmune encephalitis.
With both suspected autoimmune epilepsy and psychiatric presentations, the importance of avoiding attributing excessive importance to temporal response to immune modulation, and frequently reassessing criteria for an immune-mediated condition, must be kept foremost to avoid misdiagnosing and exposing patients to additional risk through ineffective immune modulation.

TR E ATM E N T STR ATEGIE S
Through the years, a consistent theme has emerged that early initiation and adequate escalation immunotherapy affords better clinical outcome across a range of conditions, 31 although evidence to support this is at best often restricted to observational data from larger cohorts.A key development in the treatment of many less common conditions has been the utilization of systematic reviews with large data sets synthesized from real world individual data to inform management practices.This has been important in conditions when randomized controlled trials are difficult to perform because of the rarity of the condition, small time window for acute recruitment, and rapidly changing position of equipoise in treatment strategies.
This approach has been applied to NMDARE with analysis of individual patient data of 1550 patients gathered from 672 papers, to identify prognostic features.Predictors of good outcome at onset were adolescent age, and treatment with therapeutic plasma exchange, or a combination of therapeutic plasma exchange with steroids or intravenous immunoglobulin.Delay in treatment was associated with a poorer outcome. 32Despite predicting a favourable outcome, adolescent age was associated with a significant risk of relapse, demonstrating that predictors of good outcome and non-relapsing course were not the same.Conclusions from such data synthesis may then inform the development of consensus statements to improve clinical management. 33In some conditions such as opsoclonus myoclonus ataxia syndrome there are insufficient data for synthesis, yet the need for clinical guidance remains and the development of consensus statements by expert opinion still offers benefit to patient and clinician. 34Several themes run through these consensus statements, particularly the support of strategies to prevent relapse and limit disability accrual.

Disease-modifying therapies
As many children with an immune encephalopathy may have a monophasic disease course, a major research question remains the identification of factors which predict a relapsing disease course and allow targeted treatment of those at high risk of relapse, avoiding over-treatment of those who would require no further treatment.Furthermore, the question remains whether initial treatment may alter the risk of relapse.
In a cohort of 75 paediatric patients with MOGAD, treatment with immunotherapy less than 7 days from disease onset and for more than 5 weeks were both associated with a significant reduction in risk of relapse (odds ratio [OR] 0.15, p = 0.009 and OR 0.2, p = 0.26 respectively). 35A plausible explanation would be that prolonged inflammation may result in greater and sustained disruption of the bloodbrain barrier with associated increased risk of subsequent neuroinflammation.
A number of disease-modifying therapies have been used to prevent relapse in high-risk individuals and conditions.These include mycophenolate mofetil and azathioprine as steroid sparing agents with a combined T and B cell effect.The clinical evidence for the use of these drugs in these rare conditions is limited.Rituximab is a mono-clonal antibody that targets CD20, expressed on immature B-cells.As a treatment targeted to antibody producing cells, it has been a plausible therapeutic option for antibody-associated diseases, and its use in NMDARE increased from 13.5% of patients between 2007 and 2013, to 28% between 2013 and 2019. 32In a meta-analysis of data from 1550 patients with NMDARE gathered from 652 published articles, rituximab use was associated with a significantly lower risk of subsequent relapse (OR 0.17; p < 0.001). 32hile rituximab can effectively deplete circulating Bcells, a proportion of patients with antibody-associated conditions may relapse despite rituximab treatment.In a retrospective review of 121 patients, including 30 children, with MOGAD who were treated with rituximab, while relapse rate declined by 37% overall after rituximab treatment, a proportion continued to relapse, with greater risk when rituximab was used as a second-or third-line therapy.Importantly, circulating CD19 + B-cells were suppressed to less than 1% of total circulating population at the time of 45 out of 57 (78.9%) relapses, 36 arguing for a role for other cell lines and potenitally other mechanisms in the relapse.
Mono-clonal antibodies allow targeting of different elements of the inflammatory pathways, with reports of success in targeting interleukin-6 receptors with tocilizumab in relapsing disease, 37 yet the failure of B-cell targeted therapies in a proportion of relapsing disease argues for more complex and heterogeneous immune pathway activation even within disease groups.
As paediatric neurologists become more accustomed to using new/newer biological agents in children, special attention needs to be given to the safety of these agents in children.Sustained and sometime even single cycle can cause protracted immune perturbation, beyond the biological effect of treatment. 38

GE N ET IC A N D E N V IRONM E N TA L FAC TOR S
A genetic predisposition to neuroinflammation has been the target of extensive research.Genome-wide association studies have been employed in cohorts of antibody-associated autoimmune encephalitis.In comparison to 1194 typically developing controls, anti-LGI1 encephalitis was associated with 27 single-nucleotide polymorphisms clustered in the HLA-II region.In this study, anti-LGI1 encephalitis was associated with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01, and DQB1*02:02 (p < 2.2 × 10 −16 ); while NMDARE (96 patients) was associated with HLA-I allele B*07:02 (p = 0.039).Interestingly no shared genetic risk factors were identified between the two conditions. 39In a larger genome-wide association study, 178 patients with NMDARE were compared to 590 typically developing controls, with two independent risk loci identified, and putative candidate genes suggested as LRRK1 and NR1H3. 40Although these associations achieved statistical significance, they can account for only a small proportion of the risk of developing autoimmune encephalitis, and suggest a combination of factor including environmental in many cases.
In contrast, there are some patients with neuroinflammation in whom a monogenic cause may be suspected.Suspicion may be higher in those presenting early in life, where there is consanguinity, or other affected family members.In these patients, a genetic cause may be more easily identified.As whole genome sequencing becomes the common means for most genetic testing, development of a neuroinflammatory panel has been ongoing to identify causative mutations for neuroinflammatory conditions, and other conditions which can mimic neuroinflammation. 41

FU TU R E DIR EC TIONS
As we continue to characterize newer autoinflammatory and autoimmune conditions and refine new and novel immune treatments, we are at a juncture where fundamental changes are required to manage patients with more precision.Human disease is typically classified using combinations of symptoms, signs, and investigations often with phenotypic and investigative overlap.Advances in sequencing, proteomics, and metabolomics have shown that individual diseases can now be distinguished based on molecular signatures, particularly targetable pathogenic mechanisms.A redesigned classification of human disease based on these molecular taxonomies rather than on clinical features could provide a much stronger foundation for directing treatment towards particular components of an immune response.As seen in cancer care where such molecular signatures are already superseding histology and enabling precision treatment, blood transcriptome can now distinguish bacterial from viral infection in febrile children, 42 may predict adverse neurodevelopmental outcome after neonatal encephalopathy, 43 and can play a part in identifying neuroinflammation in childhood neurological and neurodevelopmental conditions. 44areful single cell profiling of immune cells has allowed for somatotropic mapping of immune response to identify cervical lymph nodes and ovarian teratomas as germinal centres in NMDARE 45 and that treatment with rituximab abrogates germinal centre activity in patients with antibodymediated disorders like neuromyelitis optica. 45As we face the challenges of understanding, diagnosing, and treating rare immune-mediated neurological conditions, the combination of international collaborative efforts and advanced molecular methods may provide a path to address the many remaining clinical questions.

AC K NOW L E D G M E N T S
Our thanks to Dr Mike Eyre for help in preparing Figure 2.

DATA AVA I L A BI L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.Distance Learning Unit 12 Headaches Unit 12 will cover how to navigate your way between the many primary and secondary headache types, and show you how to manage them effectively.You will learn about the neurobiology of headaches, how you can classify them using clinical assessment, and when and how to investigate them further.You will focus on different types of common primary and secondary headaches such as migraine, tension-type headache, chronic headache, shunt-related headache and idiopathic intracranial hypertension.There is material on how to frame discussion with patients and their families, followed by a section on how to treat and prevent headaches.

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I G U R E 2 Clinical application of the Cellucci criteria for diagnosis of autoimmune encephalitis in children.Abbreviations: EEG, electroencephalogram; NMDAR, NMDA receptor; MOG, myelin oligodendrocyte glycoprotein; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; WBC, white cell count; OCB, oligoclonal bands.
Thomas Rossor https://orcid.org/0000-0001-5472-1813Ming Lim https://orcid.org/0000-0001-7738-8910R E F E R E NC E S How to cite this article: Rossor T, Lim M. Immunemediated encephalitis.Dev Med Child Neurol.2024;66:307-316.https://doi.org/10.1111/dmcn.15694Childrens Headache Training (CHaT) CHaT has been designed to improve knowledge and skills amongst health professionals who care for children and young people with headache.CHaT has been developed by Paediatric Neurologists and Paediatricians with an expertise in headache with the aim of improving the knowledge and skills of health professionals who care for children and young people with headache.CHaT is a 1-day course that has short didactic lectures and interactive workshops, limited to 8 attendees per group.The course is delivered by a faculty of 5-7 Paediatric Neurologists and Paediatricians with a special interest in headache.Course materials are updated every 3-years.Continuing Professional Development Points: 6 Our next course takes place virtually on Thursday 23 May 2024 Finally, use the 'headache clinic' section to test out and reinforce what you have learned.Study Hours: 26 Continuing Professional Development Points: 26.If you have any questions, please email DLadmin@bpna.org.uk or shortcourses@bpna.org.uk+44 (0)1204 526002 Distance Learning Unit 12 Headaches complements and expands upon the BPNA Childrens Headache Training (CHaT) course.To book onto PET or enrol onto our Distance Learning courses please visit: https://courses.bpna.org.uk Antibody mediated encephalitides.