Personal View

Diagnostic criteria for autoimmune encephalitis: utility and

pitfalls for antibody-negative disease
Josep Dalmau, Francesc Graus

Increased awareness of autoimmune encephalitis has led to two unintended consequences: a high frequency of Lancet Neurol 2023; 22: 529–40
misdiagnoses and the inappropriate use of diagnostic criteria for antibody-negative disease. Misdiagnoses typically See Comment page 460
occur for three reasons: first, non-adherence to reported clinical requirements for considering a disorder as possible Institut d’Investigacions
autoimmune encephalitis; second, inadequate assessment of inflammatory changes in brain MRI and CSF; and Biomèdiques August Pi i
Sunyer, Barcelona, Spain
third, absent or limited use of brain tissue assays along with use of cell-based assays that include only a narrow range
(Prof J Dalmau MD PhD,
of antigens. For diagnosis of possible autoimmune encephalitis and probable antibody-negative autoimmune Prof F Graus MD PhD);
encephalitis, clinicians should adhere to published criteria for adults and children, focusing particularly on exclusion Neurology Department,
of alternative disorders. Moreover, for diagnosis of probable antibody-negative autoimmune encephalitis, the absence Institute of Neuroscience,
Hospital Clínic de
of neural antibodies in CSF and serum should be well substantiated. Neural antibody testing should use tissue assays
Barcelona, University of
along with cell-based assays that include a broad range of antigens. Live neuronal studies in specialised centres can Barcelona, Barcelona, Spain
assist in resolving inconsistencies with respect to syndrome-antibody associations. Accurate diagnosis of probable (Prof J Dalmau); Department of
antibody-negative autoimmune encephalitis will identify patients with similar syndromes and biomarkers, which will Neurology, Perelman School
of Medicine, University of
provide homogeneous populations for future assessments of treatment response and outcome. Pennsylvania, Philadelphia, PA,
USA (Prof J Dalmau); Catalan
Introduction Criteria and algorithm for diagnosis of Institution for Research and
Over the past 20 years, the autoimmune encephalitis autoimmune encephalitis Advanced Studies (ICREA),
Barcelona, Spain (Prof J Dalmau)
syndromes have transitioned from being practically In 2016, the growing dependency on antibody testing and
Correspondence to:
unknown to becoming one of the top differential diagnoses the extent of autoimmune encephalitis misdiagnoses led
Prof Josep Dalmau, Institut
in patients with rapidly progressive memory deficits, to the publication of a Position Paper in which the d’Investigacions Biomèdiques
altered mental status, and psychiatric alterations with or development of a clinical approach to the diagnosis of August Pi i Sunyer,
without focal neurological symptoms or seizures.1 The autoimmune encephalitis was described.9 Although this Barcelona 08036, Spain
jdalmau@clinic.cat
variety and complexity of these disorders, and the manuscript is often referred to as the Graus criteria, it is
resemblance of symptoms to those of infectious and other mainly focused on the differential diagnosis of auto­
inflammatory disorders of the brain, have placed neural immune encephalitis, assisted by a diagnostic algorithm
(neuronal and glial) antibody determination at the centre that includes diagnostic criteria for some disorders.
of the diagnostic approach.2,3 Furthermore, neural Another reason for the publication of the Position Paper
antibodies associated with different comorbidities, such as was the long turnaround time of antibody results, which
the presence of a systemic tumour, can assist to formulate often leads to treatment delay. This delay was of particular
the treatment approach and help with prognosis.4 concern because studies suggest that the outcome of
The central role of neural antibody testing in the autoimmune encephalitis depends on early treatment.10
diagnostic workup of autoimmune encephalitis is Thus, the main goals of the diagnostic algorithm were to
undeniable, but indiscriminate use of testing, and facilitate the clinical recognition of autoimmune
misinterpretation of findings, are disadvantages of this encephalitis to support initiation of immunotherapy
approach.5 These problems have contributed to an without waiting for antibody results.
increase in misdiagnoses of autoimmune encephalitis6 Before applying the diagnostic algorithm, the three
and to a rise in cases reported as seronegative or antibody- minimum requirements to suspect that a patient has
negative autoimmune encephalitis.7,8 Careful reading autoimmune encephalitis include:9 first, subacute onset
of these case reports shows, in many instances, (<3 months) of memory deficits, altered mental status, or
that antibody investigations were incomplete, or the psychiatric symptoms; second, one or more of new focal
diagnostic criteria were not met or were applied incon­ CNS deficits, unexplained seizures, CSF pleocytosis, or
sistently. Moreover, defining a category of disorders by the MRI findings suggestive of encephalitis; third, reasonable
absence of a biological marker (eg, neural antibody) often exclusion of alternative disorders (panel 1). If these three
results in the inclusion of multiple different diseases. requirements are met, patients should then be clinically
In this Personal View, we first look at the consequences assessed for distinct subtypes of autoimmune encephalitis
of high dependency on antibody testing for diagnosis of using the algorithm, which is based on conventional
autoimmune encephalitis, and include an overview of clinical, radiological, and CSF studies.9 Results of these
reported criteria and most frequent causes of misdiagnosis. tests direct the clinician through the differential diagnosis
We also review the category of antibody-negative of limbic encephalitis, acute disseminated encephalo­
autoimmune encephalitis, including current diagnostic myelitis (ADEM) and other demyelinating disorders, anti-
challenges, the most frequent causes of misdiagnosis, and NMDA receptor encephalitis, Bickerstaff’s brainstem
future directions to improve diagnosis and treatment. encephalitis, and Hashimoto’s encephalopathy. For each

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 Personal View
Panel 1: Exclusion disorders in patients with symptoms
suggesting possible autoimmune encephalitis
• CNS infections (herpes simplex encephalitis, human
herpesvirus-6 encephalitis, neurosyphilis, Whipple
disease, HIV)
• Septic encephalopathy
• Post-COVID-19 condition*
• Metabolic encephalopathy
• Drug toxicity†
• Brain fog as a result of chemotherapy, polypharmacy,
or post-COVID*
• First onset psychosis and psychiatric disorders
• Functional neurological disorder*
• Myalgic encephalomyelitis or chronic fatigue syndrome*
• Neoplastic disorders (mainly glioma and lymphoma)
• Cerebrovascular disease, mainly vasculitis
• Creutzfeldt-Jakob disease
• Rapidly progressive neurodegenerative disorders*
• Epileptic disorders
• Rheumatological disorders (eg, systemic lupus
erythematosus, sarcoidosis, or Sjögren’s syndrome)
• Kleine-Levin syndrome
• Reye syndrome (children)
• Mitochondrial diseases
• Inborn errors of metabolism (children)
Panel adapted from reference 9. *Adapted from or added to the panel in the Position
Paper by Graus and colleagues.9 †Includes: use of illicit drugs, direct neurotoxic effect
of prescribed drugs or through induction of seizures, posterior reversible
encephalopathy, idiosyncratic reactions (eg, neuroleptic malignant syndrome), drug
interaction (eg, serotoninergic syndrome), drug withdrawal, chimeric antigen
receptor T-cell therapy complications such as immune effector cell-associated
neurotoxicity syndrome; some complications of immune checkpoint inhibitors.
of these diseases, individual criteria with levels of
evidence of probable or definite were developed or
adapted to facilitate their clinical recognition.
For some subtypes of autoimmune encephalitis, the
presence of neural antibodies is required so that the
disease can be categorised as definite (eg, anti-NMDAR
encephalitis). Other subtypes of autoimmune encepha­
litis can be categorised as definite disease without
antibody testing due to one or more of the following
reasons: first, the corresponding criteria were developed
before the discovery of the antibodies (eg, ADEM);11
second the disorder can occur with or without antibodies
(eg, ADEM with or without myelin oligodendrocyte
glycoprotein [MOG] antibodies);12 and last, fulfilment
of distinct clinical and radiological features is sufficient
for the categorisation of definite autoimmune
encephalitis (eg, limbic encephalitis).9 However, neural
antibody testing provides important information for
the subclassification of limbic encephalitis (anti-LGI1,
anti-GABAB receptor, anti-AMPA receptor, anti-Hu,
anti-Ma2, anti-AK5, or other), which has implications
for treatment, prognosis, and identification of
comorbidities.1
530
Panel 2: Criteria for probable antibody-negative
autoimmune encephalitis
1 Rapid progression (<3 months) of working memory
deficit (short-term memory loss), altered mental status,
or psychiatric symptoms
2 Exclusion of well defined syndromes of autoimmune
encephalitis (limbic encephalitis, acute disseminated
encephalomyelitis, Bickerstaff’s brainstem encephalitis)
3 Absence of well characterised autoantibodies in serum
and CSF, and at least two of the following*:
• MRI abnormalities suggesting autoimmune
encephalitis†
• CSF pleocytosis, CSF-specific oligoclonal bands,
or elevated CSF IgG index†
• Brain biopsy showing inflammatory infiltrates and
excluding other disorders (eg, vasculitis or tumour)
4 Reasonable exclusion of alternative causes (table)
Panel adapted from reference 9. *For paediatric patients, only one feature is required.13
†Some inherited mitochondrial and metabolic disorders can present with symmetrical
or asymmetrical MRI abnormalities, and with CSF inflammatory changes resembling an
acquired autoimmune disorder.14
The clinical algorithm was designed to identify patients
with rapidly progressive autoimmune encephalitis
(<3 months) who need prompt treatment without waiting
for antibody results. Thus, autoimmune encephalitis with
a protracted presentation (ie, some patients with anti-LGI1,
anti-CASPR2, or anti-DPPX encephalitis) or with isolated
seizures or psychosis at disease onset can be missed when
applying the three minimal requirements for considering
a rapidly progressive disorder as possible autoimmune
encephalitis. However, in those protracted presentations,
the clinical and paraclinical assessments (MRI, EEG, or
CSF), and antibody studies should eventually lead to the
diagnosis.1 Yet, after considering all diagnostic possibilities
by following the clinical algorithm, some patients might
still not have a specific diagnosis. These patients can be
categorised as probable antibody-negative autoimmune
encephalitis if they fulfil criteria for this diagnosis
(panel 2).9
Considerations when using the clinical
algorithm and diagnostic criteria of
autoimmune encephalitis
The usefulness of the clinical algorithm and diagnostic
criteria is endorsed by their extensive use7,15–29 and
publication of several validating studies.15,30,31 However,
four considerations should be kept in mind, to avoid
misdiagnoses and unnecessary treatment.
First, fulfilment of the three minimal requirements for
possible autoimmune encephalitis is crucial to reduce
misdiagnoses. In a retrospective, multicentre, observ­
ational study of 107 patients who were misdiagnosed with
autoimmune encephalitis, 77 (72%) diagnostic errors
could have been prevented if the first two requirements
had been implemented, and most of the remaining
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 Personal View

Distinctive features Diagnostic tests

Inflammatory, autoimmune, or infectious disorders

CNS vasculitis* Stroke involving multiple vessels, MRI showing multiple bilateral Angiography or brain biopsy
ischaemic foci showing evidence of CNS vasculitis
Susac syndrome Sensorineural hearing loss, retinal infarcts, MRI showing multiple Clinical criteria
FLAIR lesions involving the corpus callosum
Behçet† Systemic symptoms (recurrent attacks of oral, genital ulcers, uveitis, Clinical criteria
or polychondritis)
Rasmussen’s encephalitis‡ Unilateral seizures and progressive neurological deficits Diagnostic criteria
Encephalopathy after infection or vaccine Temporal relation with the event None
Infectious encephalitis (eg, viral, Borrelia spp, Can vary according to infectious agent Specific tests
syphilis)
Antibody-associated autoimmune encephalitides that are infrequently considered
Anti-GABAaR encephalitis Cortical-subcortical FLAIR MRI fluctuating abnormalities GABAaR antibody testing
Cortical encephalitis (FLAMES) Seizures, FLAIR lesions mostly involving cortical grey matter MOG antibody testing
Anti-IgLON5 disease Frequent combination of sleep disorder, bulbar symptoms, IgLON5 antibody testing
and movement disorders
Non-inflammatory diseases
Cryptogenic NORSE Young adults; first brain MRI usually normal; pleocytosis in only 50% of Clinical criteria
patients
PANDAS or PANS‡ Abrupt onset of obsessive-compulsive behaviour; tics or hyperactivity; Clinical criteria
PANS can present with rapid reduction of food intake
First episode of psychosis caused by a Young adults; absence of neurological deficits and inflammatory DSM-5 criteria
psychiatric disease changes in CSF and MRI; evidence of prodromal behavioural changes
Primary CNS lymphoma Relapsing-remitting course; contrast-enhancing lesions in brain MRI Brain or vitreous biopsy;
CSF cytological analysis
Creutzfeldt-Jakob disease Increased signal intensity in the cerebral cortex and basal ganglia on Positive RT-Quick test
diffusion-weighted MRI imaging
Leukodystrophies‡ Bilateral diffuse FLAIR lesions in brain MRI Genetic studies
Mitochondrial diseases‡ Stroke-like episodes, lactic acidosis Genetic studies

DSM-5=Diagnostic and Statistical Manual of Mental Disorders 5. FLAMES=FLAIR-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (MOG) associated
encephalitis with seizures. GABAAR=GABAA receptor. NORSE=new-onset refractory status epilepticus. PANDAS=paediatric autoimmune neuropsychiatric disorder associated
with streptococcal infection. PANS=paediatric acute-onset neuropsychiatric syndrome. *Includes primary granulomatous angiitis of the CNS, and cerebral
amyloid-angiopathy-related inflammation. †Consider also other systemic inflammatory diseases (eg, anti-phospholipid syndrome, sarcoidosis, and IgG4-related disease).
‡Differential diagnosis in children.

Table: Differential diagnosis of antibody-negative autoimmune encephalitis9

misdiagnoses would have been avoided if the third
requirement had been considered.6 The most common
mistake was to consider autoimmune encephalitis in
people with chronic symptoms (>3 months) without
inflammatory changes in brain MRI or CSF.
Second, the three requirements for possible autoimmune
encephalitis should not be used as standalone criteria.23,32
These criteria represent only the minimal clinical features
for a disorder to be considered as potential autoimmune
encephalitis. Thus, the requirements are intended to select
patients who need further investigation according to the
differential diagnosis of the algorithm.
Third, testing for antibodies against neuronal surface
antigens should include CSF analysis and two techniques
(ie, brain immuno­histochemistry and cell-based assay).
Among the 16 known neuronal surface antibodies, only
two are not well identified with brain immuno­ histo­
chemistry (ie, the dopamine 2 receptor [D2R] and the
glycine receptor). Misdiagnosis of autoimmune
encephalitis frequently occurs when CSF antibody status
is unknown or negative.6 With respect to anti-LGI1
encephalitis, the idea that these antibodies occur more
frequently in serum than in CSF is inaccurate, and this
belief derives from the results of cell-based assays that
have poor sensitivity in CSF.33 Almost all patients with
anti-LGI1 encephalitis have antibodies in CSF when
examined with brain immuno­histochemistry and a cell-
based assay that co-expresses LGI1 with one of its inter­
acting proteins such as ADAM23.34 By contrast with
neuronal surface antibodies, MOG antibodies occur more
frequently in serum than in CSF.35,36 These antibodies
associate with demyelinating disorders (eg, ADEM,
myelitis, and optic neuritis)12 and cortical encephalitis
without evidence of white matter demyelination.35,37
In cases of a classic or prototypical syndrome such as
faciobrachial dystonic seizures, or fulfilment of all clinical

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 Personal View
criteria for anti-NMDAR encephalitis, identification of the
expected antibody (LGI1 or NMDAR) with one technique
should suffice. This approach is reasonable for these two
well defined syndromes, but outside of these scenarios,
confirmation of antibodies should be done with at least
two techniques. In the retrospective observational study of
patients who were misdiagnosed with autoimmune
encephalitis,6 half the diagnostic errors (53 [50%] of 105)
were due to serum testing and misinterpretation of
findings, which lends support to CSF antibody testing and
use of two techniques. By contrast, only seven (8%) of
91 diagnostic errors occurred with CSF antibody testing.
Moreover, in that same study,6 if CSF had been further
examined with brain immunohistochemistry, and if
clinically irrelevant antibodies had been excluded (eg,
voltage-gated potassium channel [VGKC] antibodies
without LGI1 or CASPR2 specificity, or double-negative
VGKC antibodies), six of seven misdiagnoses might have
been prevented.
Fourth, not all neural antibodies have the same
diagnostic value. Antibodies that have clinical relevance
are associated with specific syndromes (sometimes
defining a new disease)38 or have pathogenic effects.39
Other antibodies are clinically and pathogenically
irrelevant, such as double-negative VGKC antibodies.40,41
An example of the problems generated by disregarding
antibody-syndrome specificity is illustrated by a
retrospective study in which patients with encephalitis
and NMDAR antibodies or double-negative VGKC
antibodies were included in the same cohort, leading to
the conclusion that the syndromes of seropositive and
seronegative patients were similar to each other.42 Given
that the targets of these VGKC antibodies are intracellular,
poorly known, and have no clinical implications,40,41 the
study design combining these two groups of patients
makes it difficult to draw any firm conclusions.
The frequency of thyroid antibodies in patients with
autoimmune encephalitis and other autoimmune CNS
disorders is not different from that seen in patients with
alternative diagnoses or people who are healthy. In a
retrospective, single-centre, observational study,31 39 (27%)
of 144 patients with suspected Hashimoto’s encephalopathy
and thyroid antibodies were eventually diagnosed with an
autoimmune CNS disorder (36 of whom were diagnosed
with autoimmune encephalitis). Therefore, detection of
these antibodies does not support an autoimmune cause
for a neurological disorder, and should not be used to
implement immunotherapy.31,43 These findings were
described after the diagnostic algorithm of autoimmune
encephalitis was reported, and supports the argument in
favour of omitting Hashimoto’s encephalopathy from the
decision tree regarding initiation of immunotherapy.
There is a further category of intracellular and cell
surface antibodies for which the interpretation of antibody
positivity is complicated by two problems. One is the
frequency of positive results that have no clinical
significance if serum is tested (ie, for glial fibrillary acidic
532
protein [GFAP] and glycine receptor antibodies) or if
commercial tests are used (ie, Yo, Zic4, and SOX1).33,44–48
The other problem is the low-to-moderate disease
specificity when cutoff antibody values are not taken into
consideration. The most frequent of these antibodies are
those against glutamic acid decarboxylase 65 (GAD65),
which occur in 8% of healthy people.49,50 Only high GAD65
antibody titres and particularly the demonstration of
intrathecal synthesis supports an autoimmune cause for
the associated neurological disorder.50
Definition of antibody-negative autoimmune
encephalitis
Most reports about definitions and criteria for autoimmune
encephalitis have focused on antibody-positive cases, but
descriptions are increasing of patients with suspected
autoimmune encephalitis without neural antibodies.
These cases are usually described as seronegative auto­
immune encephalitis, but this term has not been well
defined and is imprecise for two reasons.7,23–25,51–56 First, the
term does not clarify whether CSF has been examined; this
point is important because, if CSF is negative, the clinical
significance of neural antibodies in serum becomes less
specific.5,57 Moreover, neural antibodies can only occur in
CSF (eg, NMDAR and GFAP).34,58 The second reason why
the term seronegative autoimmune encephalitis is
inaccurate in most reports is the small number of
antibodies or unspecified range of antibodies included in
the diagnostic tests.22–24,27,29,52,54,56,59 Accordingly, patients
with encephalitis mediated by antibodies not included
in standard diagnostic panels might be considered
seronegative or be misdiagnosed with another disease
(panel 3). For example, in a retrospective assessment of
404 samples (222 serum, 182 CSF) from patients with
neuropil antibodies that were detected by brain
immunohistochemistry,33 a commercial cell-based assay
that included six neuronal surface antigens gave positive
results in 163 (40%) samples, and it was negative for the
remaining 241 (60%) samples. When these 241 negative
samples were reassessed with a research based, not
commercially available, cell-based assay that included
12 neural surface antigens, 42 (17%) samples were positive,
21 (9%) had antibodies against antigens not included in
the original assay, and the remaining 21 (9%) samples had
antibodies against antigens that were included in the
original assay (false-negative results).33 Therefore, without
testing for a broad range of antibodies, cohort studies in
which the population is considered seronegative include
both antibody-negative and antibody-positive (but with
antibodies not included in tests) cases, resulting in mixed
study populations that do not provide informative data.
Use of the term seronegative autoimmune encephalitis
varies from case to case, depending on the compre­hen­
siveness of clinical and antibody studies, and it has
developed as a result of the narrow antibody selection in
some diagnostic kits. To be more precise in the definition
of these cases, the term antibody-negative autoimmune
www.thelancet.com/neurology Vol 22 June 2023

encephalitis should be used,8,26,62 and the list of antibodies
tested and sample type (serum or CSF) examined should
be included in published work.
Considerations about the diagnosis of antibody-
negative autoimmune encephalitis
Antibody-negative autoimmune encephalitis includes
two subsets of disorders. One subset comprises
encephalitides that manifest with established clinical or
radiological syndromes, such as limbic encephalitis,
ADEM, and Bickerstaff’s brainstem encephalitis.9 These
three disorders can also occur with neural antibodies—
eg, anti-LGI1 or other antibodies for limbic encephalitis,63–66
anti-MOG for ADEM,35,67 and anti-GQ1B for Bickerstaff’s
brainstem encephalitis.68,69 A definite diagnosis of
Bickerstaff’s brainstem encephalitis can be made if GQ1B
antibodies are present; however, for a definite diagnosis
of limbic encephalitis and ADEM, presence or absence of
antibodies is not required. Instead, for these two
disorders, antibody status and type of antibody provide
different clinical and prognostic associations. For
example, in a study of 163 patients with limbic encephalitis
who underwent serum and CSF testing for all known
neural antibodies, 12 patients (7%) did not have
antibodies.70 These patients had isolated or predominant
short-term memory loss and rarely had seizures (one
patient [8%]), which are atypical features compared with
patients who develop limbic encephalitis associated with
antibodies against neuronal surface antigens (ie, >80%
have multiple symptoms and seizures). An underlying
tumour was found in five patients (42%), which is also
substantially different from some immunological subsets
(ie, <5% of those with anti-LGI1 have tumours). Despite
the absence of antibodies, six patients (55%) responded to
immunotherapy.70
The other subset of antibody-negative autoimmune
encephalitis is more challenging to diagnose because no
distinct syndromes have been reported. Such cases are
categorised as probable antibody-negative autoimmune
encephalitis (panel 2).9 Criteria for this diagnosis require
evidence of inflammatory changes on at least two of
three tests—ie, CSF analysis, brain MRI, and brain
biopsy. By contrast, reported criteria for probable
antibody-negative autoimmune encephalitis for
paediatric patients only require inflammatory changes
on one test.13 At present, no validation studies have been
done to clarify which of the two approaches (one or two
tests with inflammatory changes) shows the best
predictive value for response to immunotherapy.
Nevertheless, a thorough description of patients who
fulfil criteria for probable antibody-negative auto­
immune encephalitis is important so that clinically
homogeneous groups of patients can be identified who
might have distinct syndromes, comorbidities, and
biomarkers of response to treatment and outcome.
Among the criteria for probable antibody-negative
autoimmune encephalitis, the fourth criterion—relating
www.thelancet.com/neurology Vol 22 June 2023
Personal View
Panel 3: A patient with anti-mGluR5 encephalitis
A 35-year-old man with attention-deficit hyperactivity disorder, but otherwise no medical
history of note, developed a bilateral headache followed the next day by nausea, vomiting,
and fever. These symptoms were initially attributed to a possible viral infection. 2 days later,
the patient developed confusion, agitation, progressively worse obsessive behaviour, and a
reduction of verbal output that led to mutism in 24 h. He was initially admitted to a
hospital other than our own. A head CT showed no unusual findings, and MRI showed mild
enlargement of meningeal vessels without parenchymal abnormalities or contrast
enhancement, compatible with meningeal inflammation. CSF studies showed a white
blood cell count of 45 cells per µL (normal range ≤5 cells per µL), a protein concentration of
138 mg/dL (normal range 15–45 mg/dL), and a glucose concentration of 51 mg/dL (normal
range 40–80 mg/dL). Treatment with ceftriaxone, ampicillin, and aciclovir were started, and
he was transferred to our hospital while heavily sedated for severe agitation and intubated
for airway protection. On arrival, 5 days after symptom onset, the patient was afebrile, with
a respiratory rate of 18 breaths per min, heart rate of 90 beats per min, and pulse oximetry
of 95% breathing room air. After a transient reduction of sedation, no cranial nerve palsies
or sensorimotor deficits were identified, but he showed atypical movements with the
extremities that were initially suspected to be seizures. An EEG was obtained while the
patient was sedated with propofol, which showed slow diffuse activity (1·5–3 Hz) with
periods of alpha-beta activity, without epileptic or epileptiform activity. Repeat CSF studies
showed a white blood cell count of 20 cells per µL (98% lymphocytes, 2% monocytes),
a protein concentration of 253 mg/dL, a glucose concentration of 48 mg/dL, and an IgG
index of 1·15 (normal range <0·70) without oligoclonal bands. Viral and bacterial studies
were negative. The patient was extubated 2 days later and the neurological examination
showed that he was oriented to place and person but mildly disoriented to time. He was
able to follow commands, name objects, and repeat words without language alterations.
In a five-word recall test, he remembered three of the five words. No cranial nerve or focal
sensorimotor deficits were identified. Brain MRI and MR angiography showed no unusual
findings, and neuronal antibody studies were negative. Further studies with rat brain
immunohistochemistry and a comprehensive cell-based assay showed the presence of
metabotropic glutamate receptor 5 (mGluR5) antibodies in CSF and serum; both samples
also showed reactivity with live neuronal cultures (figure). A whole-body CT showed
mediastinal, paratracheal, and para-aortic adenopathies, with uptake of fluorodeoxyglucose
(FDG) on a body FDG-PET. Endobronchial ultrasound guided biopsy of one of the
adenopathies showed classic nodular sclerosis Hodgkin lymphoma. Anti-mGluR5
encephalitis is an autoimmune encephalitis that frequently associates with Hodgkin
lymphoma.60 Patients with anti-mGluR5 encephalitis (also known as Ophelia’s syndrome)61
often show substantial improvement of the neurological alterations (confusion, agitation,
memory problems, and psychiatric symptoms) after treatment of the tumour. The patient
was treated with chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine)
with full clinical recovery and resolution of the adenopathies. He did not need
immunotherapy.
to exclusion of alternative disorders—is very important
(panel 2). A comprehensive list of alternative diagnoses
would be ideal but is impractical. A list of the more
common diagnoses is presented in the table. Some of
these disorders should be ruled out with the initial
investigations for possible autoimmune encephalitis
(panel 1), but it is important to recheck these at the time
when a diagnosis of probable antibody-negative auto­
immune encephalitis is considered. The disorders
should be prioritised according to the patient’s age.
Genetic diseases need to be considered (leukodystrophies
and mitochondrial diseases) in children and young
533
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A BB

1 mm 1 mm

CC D E II

10 µm 10 µm 10 µm 10 µm

FF G
G H
H J

10 µm 10 µm 10 µm 10 µm

Figure: Diagnosis of anti-mGluR5 encephalitis

Figures show antibody diagnostic tests of the patient reported in panel 3. (A) Immunohistochemistry with rat brain by use of the patient’s CSF and (B) CSF from a
control sample without neural antibodies: patient’s CSF produces a neuropil pattern of immunostaining suggesting the target antigen is on the cell surface. By
contrast, control CSF does not react with brain. In a cell-based assay with HEK293 cells expressing mGluR5, patient’s CSF reacts with cells expressing mGluR5
(green; C); a commercial monoclonal antibody against mGluR5 identifies the same cells (red in D). Colocalisation of reactivities (C, D) is shown in E. A similar set of
panels (F–H) shows that the control CSF does not react with mGluR5 (F). In cultured rat hippocampal neurons, patients’ CSF (I), but not control CSF (J), reacts with the
surface of live neurons. (C–J) Cell nuclei are visualised with 4’,6-diamidino-2-phenylindole.

adults,71,72 whereas in adults, Creutzfeldt-Jakob disease
and atypical presentations of primary CNS lymphomas
are frequent mimics of autoimmune encephalitis.1,73,74
There are three disorders that are associated with
neural surface antibodies and are often overlooked in the
differential diagnosis of probable antibody-negative
autoimmune encephalitis. The first is anti-GABAA
receptor encephalitis, which occurs in children and
young adults and is associated with prominent seizures
and multiple fluid-attenuated inversion recovery lesions
in brain MRI.75 The second is anti-IgLON5 disease, which
usually affects people older than 60 years and progresses
as a subacute course that can mimic autoimmune
encephalitis in about 25% of cases.76,77 Patients with these
two disorders can be misdiagnosed with probable
antibody-negative autoimmune encephalitis because
GABAA receptor and IgLON5 antibodies are not tested
in most clinical laboratories. The third disorder is cortical
encephalitis associated with MOG antibodies. Because
this disorder can occur without white matter lesions
visible on brain MRI, MOG antibody testing might not
be considered.35,78
Another three exclusion disorders in the differential
diagnosis of probable antibody-negative autoimmune
encephalitis are new-onset refractory status epilepticus
(NORSE),79,80 paediatric autoimmune neuropsychiatric
disorder associated with streptococcal infection
(PANDAS), and the closely related paediatric acute-onset
neuropsychiatric syndrome (PANS).81,82 NORSE is a
poorly defined syndrome of unclear cause and mech­
anisms, and probably represents multiple disorders.
Since most cases of autoimmune encephalitis can
initially present with refractory status epilepticus, they
could potentially be diagnosed as NORSE.43,80,83,84 However,
genuine or cryptogenic NORSE is a diagnosis that
depends on the exclusion of well defined diseases such
as autoimmune encephalitis, and in this setting, there is
no evidence of adaptive autoimmune mechanisms.
Therefore, escalation of immunotherapy protocols, as
used in autoimmune encephalitis, rarely work in patients
with cryptogenic NORSE.80
With respect to PANDAS and PANS, reported criteria
are useful but rarely implemented.81,82 These two syn­
dromes present with abrupt onset of obsessive-compulsive

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behaviour that can associate with tics, hyperactivity, or
choreiform movements (but not chorea) along with other
neuropsychiatric alterations. Psychosis does not occur in
children with PANDAS, although it can occur in children
with PANS who can also present with drastic reduction
of food intake.85 Different from most autoimmune
encephalitides, PANDAS and PANS are not associated
with seizures, other atypical movements, decreased level
of consciousness, and CSF abnormalities. Brain MRI and
EEG are usually unremarkable in patients with PANDAS
and PANS, but are abnormal (alone or combined) in more
than 90% of patients with autoimmune encephalitis.4
Presence of neural antibodies is not part of the diagnostic
criteria for PANDAS or PANS. The Cunningham panel86 is
a diagnostic panel that assesses four antibodies (none used
in autoimmune encephalitis) as well as the ability of
the patient’s serum to stimulate calcium/calmodulin-
dependent protein kinase II (CaMKII). However, the
Cunningham panel is neither required by criteria nor is
specific for PANDAS or PANS.87 The effectiveness of
immunomodulatory treatments is controversial for these
two disorders.88
Misdiagnosis of probable antibody-negative
autoimmune encephalitis
To analyse typical reasons for misdiagnosis of probable
antibody-negative autoimmune encephalitis, a literature
review was done using the search terms “seronegative”
or “antibody-negative”, and “autoimmune encephalitis”.
30 manuscripts were identified by this search, of which
15 papers reported 20 cases (appendix pp 2–3) and the
remaining 15 papers reported case series or cohorts
(appendix pp 4–5).
Among the 20 case reports, the most frequently
identified reason for misdiagnosis was incomplete use of
criteria for selection of seronegative cases. For example,
15 (75%) of 20 patients considered to have seronegative
autoimmune encephalitis did not fulfil all the criteria for
probable antibody-negative autoimmune encephalitis
(panel 2). None of the 20 patients was tested for all known
neuronal surface antibodies, and studies with brain
immunohistochemistry and cultured cells were mentioned
for only one patient.89 Ten patients (50%) did not have
evidence of inflammatory abnormalities in CSF or brain
MRI (patient numbers 1–10; appendix pp 2–3), and
five patients (25% [patient numbers 11–15; appendix p 3])
only had inflammatory abnormalities in one test (CSF or
MRI). Of these 15 patients, at least eight (53%) had clinical
information suggesting an alternative disorder.
The five remaining patients (patient numbers 16–20;
appendix p 3) fulfilled the criteria for probable antibody-
negative autoimmune encephalitis. Clinical and radio­
logical features suggested a heterogeneous group of
syndromes. Some patients might have had very rare but
well characterised antibodies. For example, one patient
had clinical and radiological features of basal ganglia
encephalitis but D2R antibodies were not assessed.
www.thelancet.com/neurology Vol 22 June 2023
Personal View
Because these five patients had clear evidence of
inflammatory abnormalities on CSF analysis, brain MRI,
or brain biopsy, the possibility of alternative non-
inflammatory disorders was less likely than for the other
15 patients.
Notably, when considering all 20 patients, five (25%)
had a constellation of symptoms suggesting anti-NMDAR
encephalitis (one with ovarian teratoma) and another
three had ovarian teratoma in the context of clinical
features of probable autoimmune encephalitis. In these
eight patients, a false-negative test for NMDAR antibodies
should be considered. For example, in the retrospective
assessment of 404 patients with several types of neuropil
antibodies shown by brain immunohistochemistry,33 the
commercial assay that was used in that study had a
narrow range of antigens. This assay did not detect
NMDAR antibodies in one patient who was subsequently
shown to have these antibodies in CSF when a research
based, non-commercial assay with a broader range of
antigens was used. In rare instances of patients with a
clinical syndrome compatible with anti-NMDAR
encephalitis but who are CSF-negative for these
antibodies, the possibility of disease mimics such as anti-
GABAA receptor encephalitis (mainly in children90) or
anti-neurexin-3α encephalitis at symptom onset91 should
be considered.
Among the 15 case series or cohorts of seronegative
autoimmune encephalitis (of which eight were focused
on children), analysis of CSF antibodies was unclear or
not systematically done in six (40%) series (appendix
pp 4–5).8,16–18,20,59 Regarding the type of antibody testing, See Online for appendix
six series (40%)7,19,32,54,56,92 used commercial assays for cell-
surface or onconeural antibodies. Five series (33%)15,16,18,21,93
used commercial and research-based assays (although
only two used the research-based assays systematically).15,21
The remaining four series (27%)8,17,20,59 did not provide
information regarding the type of assay or number of
antibodies tested. Four series used brain tissue
assays,7,15,18,93 only two of them systematically.7,15 In seven
(50%) of 14 series with available information,8,19,21,32,54,56,59
the antibody-negative autoimmune encephalitis group
included patients without evidence of CSF or MRI
inflammatory abnormalities, which substantially
decreases the probability of autoimmune encephalitis
and suggests alternative diagnoses.9
Two of the 15 case series that specifically mention
following the diagnostic algorithm for autoimmune
encephalitis showed considerable differences.7,15 One
focused on paediatric autoimmune encephalitis and
included 103 patients who fulfilled the three requirements
for possible autoimmune encephalitis.15 Of these patients,
21 (20%) had antibody-positive definite autoimmune
encephalitis (of whom 19 patients [18%] had anti-NMDAR
encephalitis), 34 patients (33%) had ADEM, and two
patients (2%) had Hashimoto’s encephalopathy. Among
the remaining 46 patients (45%), none fulfilled criteria for
probable antibody-negative autoimmune encephalitis.
535
 Personal View
The other case series included 266 adult patients who
also fulfilled the three requirements for possible auto­
immune encephalitis.7 Of these 266 patients, 119 (45%)
were antibody-positive definite autoimmune encephalitis,
30 (11%) were antibody-negative definite autoimmune
encephalitis (limbic encephalitis or ADEM), and
117 (44%) were considered probable antibody-negative
auto­immune encephalitis. For this subgroup of patients,
no distinct syndromes were described.
The differences between both cohorts in the proportion
of cases of probable antibody-negative autoimmune
encephalitis (0% for the paediatric cohort15 vs 44% for the
adult cohort7) illustrate fundamental problems in the
diagnosis and categorisation of this subgroup of
autoimmune encephalitis. These differences cannot be
explained solely by patients’ age. In another large case
series of adult patients diagnosed with autoimmune
encephalitis during a similar period of time,18 only seven
(6%) of 118 patients fulfilled criteria for probable antibody-
negative autoimmune encephalitis. Considering that all
the investigators in these three case series used the same
diagnostic algorithm and clinical criteria, the discrepant
findings could reflect differences in the extent of antibody
studies done or in the scope of exclusion disorders
considered. In the case series with the highest frequency
of diagnoses of probable antibody-negative autoimmune
encephalitis (44%),7 tissue studies and the commercial
assay with six antigens were used for diagnosis, but no
additional investigations were done with research-based
assays with more antigens, or with live neuron studies.
These additional analyses were included in the other two
case series that had low frequencies of probable antibody-
negative autoimmune encephalitis (0% and 6%).15,18
Proposed steps to refine the diagnostic process
The number of misdiagnoses of probable antibody-
negative autoimmune encephalitis could be substantially
reduced if three steps in the diagnostic process are taken.
Two of the proposed steps are clinical and the third relates
to antibody testing. These steps will enable a minimum
dataset to be created and homogenise study populations of
autoimmune encephalitis for future combined analyses.
The first proposed clinical step concerns the indicated
three minimal requirements for suspicion of possible
autoimmune encephalitis.9 Although these three require­
ments are straightforward and easy to implement, most
misdiagnoses of autoimmune encephalitis seem to occur
at this point; therefore, this clinical step could be viewed
as a checkpoint for entry into the algorithm for differential
diagnosis. Among the three requirements, reasonable
exclusion of alternative disorders is crucial (panel 1 covers
most of these alternatives). Importantly, the three
requirements are not standalone criteria. For example,
after following the diagnostic options of the algorithm,
only three final diagnostic categories can be obtained. The
first category is definite autoimmune encephalitis, which
includes syndromes that have been well established
536
clinically or occur with well defined antibodies (ie, limbic
encephalitis, ADEM, or antibody-positive disorders). The
second category is probable autoimmune encephalitis,
which includes less well established syndromes that can
occur with or without antibodies (ie, Bickerstaff’s brain­
stem encephalitis without GQ1b antibodies, and
Hashimoto’s encephalopathy). The final category is
probable antibody-negative autoimmune encephalitis,
which includes non-established syndromes without
antibodies (ie, rapidly progressive memory impairment or
other neurological and psychiatric alterations with
evidence of CNS inflammatory changes; panel 2).
Among the alternative disorders for exclusion, new-
onset psychosis is particularly important to highlight due
to the high frequency of misdiagnosis of this disorder as
autoimmune encephalitis.1 Although patients with
psychosis caused by a psychiatric disease rarely develop
focal CNS deficits, seizures, or MRI inflammatory
changes, the poor accessibility of CSF studies in psychia­
tric institutions, and the low specificity of NMDAR-
antibody testing when only performed in serum with a
cell-based assay, has led to reporting of NMDAR
antibodies in various psychiatric diseases.1,94,95 These
patients—unless they have NMDAR antibodies in CSF
or evidence of paraclinical alterations (CSF or MRI
inflammatory changes, or EEG abnormalities)—should
receive conventional psychiatric treatment without
immunotherapy.57
The second proposed clinical step relates to the criteria
for probable antibody-negative autoimmune encephalitis.9
This step is placed at the end of the diagnostic algorithm
for autoimmune encephalitis and depends on the absence
of neural antibodies. Here also, reasonable exclusion of
alternative disorders is key in the differential diagnosis.
Other inflammatory or autoimmune disorders that have a
different time course or clinical profile to autoimmune
encephalitis (table) should be considered. Special
attention is needed for three antibody-associated
disorders that could be erroneously considered antibody-
negative autoimmune encephalitis, because antibody
testing either is not available (eg, GABAA receptor or
IgLON5 antibodies) or is not considered (MOG antibodies
in the context of cortical encephalitis). As indicated,
cryptogenic NORSE, PANDAS, and PANS should not be
included in the category of antibody-negative autoimmune
encephalitis. NORSE is unlikely to be autoimmune
(although innate immune mechanisms could be
involved96), and for PANDAS and PANS, inflammatory
findings are usually absent and the disease mechanisms
are unclear.
The third proposed step concerns optimisation of neural
antibody testing. One area for improvement in this respect
is to include CSF testing. This additional analysis would
prevent those patients who only have antibodies in the
CSF being considered as antibody-negative (or sero­
negative).97,98 Conversely, detection of cell surface anti­
bodies only in serum (ie, CSF-negative) should be a
www.thelancet.com/neurology Vol 22 June 2023

warning sign for further investigations since this scenario
is the most frequent cause of misdiagnosis of autoimmune
encephalitis.6 Another area for improvement is to do an
extensive investigation of patients’ serum and CSF.
However, comprehensive analysis can be a difficult task
for clinical laboratories and most research centres. Many
antibodies to intracellular antigens can be assessed with a
single assay (eg, immunoblot strip containing multiple
antigens), but antibodies to cell surface antigens require
individual testing for each antigen (ie, 16 different cell-
based assays for each sample [serum and CSF]).
One approach to overcome many of the limitations of
current testing strategies could be to include immuno­
histochemistry with rodent brain tissue.4 If this technique
is applied to CSF and serum, most antibodies against
neuronal surface antigens (except antibodies to the glycine
receptor and D2R), and antibodies against glial antigens
(AQP4 and GFAP, but not a subset of MOG antibodies),
could be identified. Thus, patients with both CSF and
serum samples that are negative on brain immuno­
histochemistry, who are also negative for glycine receptor,
D2R, and MOG antibodies on cell-based assays, can be
classified as antibody-negative for all known cell surface
antigens. Current commercial or clinically accessible
brain tissue immunohistochemical assays are inadequate
for these enhanced assessments and will need to be
optimised (appendix p 1).
When optimised tissue immunohistochemistry and
comprehensive cell-based assays are not available, the
diagnosis of autoimmune encephalitis and antibody-
negative autoimmune encephalitis could be improved in
three ways. First, use of both CSF and serum samples can
improve results. CSF is sensitive and specific for all
antibodies against neuronal surface antigens, including
GFAP antibodies,99 and serum is sensitive for MOG35,100
and AQP4101 antibodies. For LGI1 antibodies, the currently
available cell-based assay is more sensitive in serum than
in CSF, but other techniques show that LGI1 antibodies
are at least as frequent in CSF as in serum.34 A second way
to improve diagnosis is to provide a warning message that
the likelihood of misdiagnosis increases if CSF is not
tested or is negative.6 The third way to improve diagnosis
could be to indicate in testing reports and publications the
specific antibodies that have been tested and those that
have not been tested.
Conclusions and future directions
Misdiagnosis of autoimmune encephalitis and probable
antibody-negative autoimmune encephalitis can be
mitigated by careful application of criteria and correct use
of antibody testing. Future work is needed to define a
treatment approach for probable antibody-negative
autoimmune encephalitis. The formulation of a treatment
approach for patients with probable antibody-negative
autoimmune encephalitis is challenged by the absence of
homogeneous or comparable groups of patients. As
discussed in this Personal View, past use of published
www.thelancet.com/neurology Vol 22 June 2023
Personal View
Search strategy and selection criteria
We searched PubMed for papers published in English
between Jan 1, 2017, and Nov 1, 2022, with the terms
“autoimmune”, “encephalitis”, “seronegative”, “antibody-
negative”, “diagnostic criteria”, “criteria”, “diagnostic
algorithm”, “cell-surface”, “intracellular”, and “antibodies”.
We excluded papers in which the cases described had a
definite diagnosis of autoimmune encephalitis, the
encephalitis was related to systemic diseases or complications
of treatment (ie, immune checkpoint inhibitors), the
disorders were not encephalitis (ie, isolated seizures or
psychosis), or the papers were editorial comments or reviews.
The final reference list was generated on the basis of
originality and relevance to this Personal View.
criteria has not been uniform; thus, results from one
study might not be applicable to others. In our opinion,
patients with probable antibody-negative autoimmune
encephalitis should be studied and treated in specialised
centres focused on autoimmune encephalitis. In addition
to clinical expertise, these centres are useful for
the diagnosis, treatment, and prognostication of
probable antibody-negative autoimmune encephalitis. For
example, patients with antibodies detected with brain
tissue staining (ie, neuropil reactivity) but negative for
known cell surface antibodies should have additional
studies with live neuronal immunostaining. These studies
have two implications. The first is for antibody and
antigen discovery (we used this technique to identify 12 of
16 known autoimmune encephalitis disorders),1 and the
second is for treatment and prognostication (ie, the
binding of antibodies to the surface of live neurons
strongly suggests the disorder is immune-mediated and
will probably respond to immunotherapy; appendix
pp 6–7).
Without comprehensive neural antibody studies (ie,
brain immunohistochemistry, cell-based assays, live
neuronal immunostaining), the treatment of patients with
probable antibody-negative autoimmune encephalitis is
empirical and less certain. In our opinion, the treatment
approach for probable antibody-negative autoimmune
encephalitis should be similar to the strategy that is
used for patients with antibody-positive autoimmune
encephalitis—ie, escalation of immunotherapy with
steroids, plasma exchange, intravenous immunoglobulin,
rituximab, or cyclophosphamide—in addition to tumour
screening.10 If objective measures are used, and patients
with suspected antibody-negative auto­immune encepha­
litis do not show a clinical response after 3–4 months of
immunotherapy, we favour stopping treatment rather
than escalating to more experimental therapies. Multi­
centre studies with well defined criteria for antibody-
negative autoimmune encephalitis are needed to identify
subgroups of syndromes, novel autoantibodies, and better
treatment approaches.
537
 Personal View
Contributors
Both authors contributed equally to the conceptualisation of the study,
review of the literature, and writing of the manuscript. JD designed the
figure and FG designed the supplementary tables. Both authors
designed the table, panels, and supplementary figures.
Declaration of interests
JD has grant support from Instituto Carlos III-Fondo Europeo de
Desarrollo Regional (FIS 20/00197), La Caixa Foundation (CaixaResearch
Health, HR22-00221), and Edmond J Safra Foundation; he receives
royalties from Athena Diagnostics for the use of anti-Ma2 as an
autoantibody test, and from Euroimmun for the use of anti-NMDA
receptor, anti-GABAB receptor, anti-GABAA receptor, anti-DPPX, and
anti-IgLON5 as autoantibody tests; and he has received a research grant
from Euroimmun to identify new autoantibodies and improve the
determination of some neural antibodies. FG receives royalties from
Euroimmun for the use of IgLON5 as an autoantibody test.
Acknowledgments
We thank Myrna R Rosenfeld for the critical review of the manuscript,
and Jesus Planagumà for helping to develop the figure.
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