Autoimmune Encephalitis

Saba Jafarpour, MD
Resident, Child Neurology

Jonathan D. Santoro, MD
Assistant Professor of Neurology and Pediatrics
Director, Neuroimunology and Demyelinating Disorders

Children’s Hospital Los Angeles

Keck School of Medicine at the University of Southern California
 Epidemiology,
History and Etiology
 Autoimmune encephalitis (AE) refers to a group of non-infectious,
immune-mediated, inflammatory disorders of the brain that cause a
variety of neurologic and psychiatric symptoms.

What is AE Epidemiological studies suggest that autoimmune encephalitis is as

and How
common as infectious encephalitis (prevalence of 13.7 and 11.6 per
100,000, respectively in both adults and children).1 Anti-N-Methyl
D-Aspartate Receptor (NMDAR) encephalitis is the most common

Rare is It?
antibody-mediated encephalitis in children.2, 3

It is more prevalent than any individual viral encephalitis, such as

enterovirus, Herpes Simplex Virus (HSV), West Nile Virus (WNV), or
Varicella Zoster Virus (VZV) encephalitis.4, 5
History of AE
• In 1968, a paraneoplastic syndrome, characterized by memory loss,
neuropsychiatric symptoms, and seizures, was reported in several patients in
the setting of occult malignancies such as small cell lung cancer or breast
cancer.6-9 Due to post-mortem pathologic pattern of inflammatory changes in
the limbic areas of the brain, this entity was termed “limbic encephalitis”.7

• In 2005, Dalmau and colleagues reported the case of a woman with an ovarian
teratoma who had clinical features similar to limbic encephalitis, with
autoantibodies that were reactive to specific antigens in the rat hippocampus.10,
11

• Dalmau and colleagues’ subsequent description of 12 additional women with

ovarian teratomas, all with anti-NMDAR antibody in their sera, introduced
anti-NMDAR antibody encephalitis as a distinct disease entity in 2007,
revolutionizing the understanding of paraneoplastic disorders and AE.12
Etiology
• The exact pathophysiologic mechanisms that initiate the inflammatory cascade leading to AE are not fully
understood. More than half of the children presenting with AE have a history of infectious prodromal
symptoms.13

• AE has been reported in up to 27% of patients with a history of HSV encephalitis within 3 months after
completing anti-viral treatment.14
• Individuals with anti-NMDAR encephalitis without any history of HSV-1 encephalitis were more commonly seropositive for HSV-1
immunoglobulin G (IgG) compared to controls without AE.15
• Recently, anti-NMDAR encephalitis has been reported following SARS-CoV2 infection.16

• One hypothesis to explain the link between AE and infections is molecular mimicry. It is believed that some
epitopes expressed by viruses (particularly HSV-1) have structural similarities with neuronal antigens and
trigger an autoimmune response. An alternative hypothesis is that the neuronal antigens are exposed by the
destruction of neurons due to viral processes, tumors, or by unknown mechanisms, resulting in activation of
the immune system against autoantigens which is referred to as epitope spreading.
Etiology
• The clinical symptomatology observed in AE is a function of both direct effect of
pathologic autoantibodies at specific neuronal receptors and the
location/function of the affected neurons.
• For example, anti-NMDAR antibodies alter surface dynamics and decrease the density of
NMDAR on the neuronal surface through cross-linking and internalization of the NMDA
receptors (Figure 1).
• NMDA receptors mediate excitatory effects of glutamate, which is the major excitatory
neurotransmitter in the central nervous system.
• The decrease in number and function of the NMDA receptors can cause different symptoms
depending on the location and function of the affected neurons. Decreased receptor density
in hippocampi and the limbic system is associated with memory deficits and behavioral
issues. The decrease at the level of inhibitory interneurons contributes to a hyperexcitable
state, which could lead to dyskinetic movements or seizures if occurred in basal ganglia or
cortex.

• Anti-NMDAR, MOG, and Glutamic Acid Decarboxylase-65 Antibody (GAD65)

antibodies constitute the most commonly identified neuronal autoantibodies
detected in children.
Clinical Phenotypes
Clinical Presentation
• Identification of AE, especially early in the disease course, is incredibly challenging, even for seasoned
clinicians. As AE causes multifocal brain inflammation, poly-syndromic and heterogenous presentations are
the mainstay.21

• Careful history taking to identify the course of the disease and constellation of symptoms could play a crucial
role in making the diagnosis.
• AE is an acute or subacute immune process,22 and the course is commonly marked by rapid progression (days to weeks), with
symptom duration of less than three months at the time of presentation.
• More chronic or indolent presentations (months to years) should raise suspicion for other etiologies.
• The course is usually progressive (in the absence of treatment) as opposed to the relapsing-remitting course that is seen in some
patients with multiple sclerosis and other systemic inflammatory disorders.
Neuropsychiatric Features
• Phenotypes observed include behavioral, mood or personality change, irritability, hyperactivity, and fulminant
psychosis.23-25 Cognitive and memory impairment, confusion, language and developmental regression,
stereotyped/repetitive behaviors, and sleep disturbances are other common symptoms and are localized to the
temporal and limbic structures of the brain. Sleep disorders in anti-NMDAR encephalitis usually follow a
temporal pattern, with insomnia at onset and hypersomnia during recovery.26

• In early stages of the disease process, these symptoms can be associated with declines in school or work
performance or strained family relationships, often causing a misperception that symptoms are “stress
related”. However, the presence of multiple symptoms or sub-acute progression of symptoms should serve as
a red flag for underlying neuropathology.
• Acute onset of psychosis is extremely rare in prepubertal children.

• Rapid progression of psychosis despite therapy, and/or presence of other neurological symptoms or signs
should raise suspicion for AE.
Neuropsychiatric
Features (specific
antibodies)
• Although neuropsychiatric phenotypic differentiation can be
challenging in cases of possible or presumed AE, some
autoantibody specific differences exist.

• Autoantibodies to GAD65, Leucine-rich Glioma Inactivated

(LGI1), and NMDAR are frequently associated with
confusion and recall issues, mediated by involvement of the
medial temporal lobe.27

• While very rare, individuals with autoantibodies against

metabotropic glutamate receptor five (mGluR5) have a
combination of confusion and memory impairment but also
associated depersonalization, known as Ophelia syndrome.28
This syndrome is commonly associated with Hodgkin’s
lymphoma and may present in adolescence.
Seizures in AE
• Seizures are one of the most common presenting symptoms in young children.23

• Given the gravity of seizure activity, and that in the case of AE this is often the first lifetime seizure for a
patient, seizures are much more likely to bring patients into medical attention, and thus may be the only
symptom on initial evaluation.

• Slowing of background or epileptic activity are common findings on electroencephalogram (EEG).20

• Status epilepticus is present in 6% of cases and more frequently encountered in individuals with GAD65 and
GABA-A autoantibodies.29-32 Similarly, autoantibodies against the GABA-B receptor are also associated with
refractory seizures and status epilepticus although this is less frequently encountered in children.33

• Although very rare, faciobrachial dystonic seizures, characterized by ipsilateral face grimacing and arm
posturing, are essentially pathognomonic for AE associated with autoantibodies against LGI1.34
Movement Disorders in AE
• A variety of dyskinetic movements including athetosis (involuntary writhing), catatonia, chorea (brief semi-
directed dance-link movements that are neither repetitive nor rhythmic), dystonia (involuntary muscle
contraction causing distorted posturing and pain), myoclonus (brief involuntary twitching), and/or tremor
can be present in individuals with AE.

• Orolingual and facial dyskinesias (involuntary contortions and grimacing of the face and mouth) can be
seen in anti-NMDAR encephalitis.

• Dyskinetic movements and epileptic seizures are often difficult to differentiate clinically, and the confusion of
the two can cause either under-treatment of the seizures or over-treatment of the dyskinetic movements with
seizure medications. As the disease evolves, the frequency and intensity of the seizures usually decrease35, 36
but dyskinesias tend to persist, although a high index of suspicion for seizure is required throughout a
patient’s clinical course.
Movement Disorders in AE (specific antibody)
• A rare form of autoimmune encephalitis known as progressive encephalomyelitis with rigidity and myoclonus
(PERM) has been observed in children as young as one year.37

• This condition is associated with glycine receptor antibodies and is strongly associated with spinal and
brainstem disorders which can overlap with the muscle rigidity (often mimicking tetanus in severe cases) and
myoclonus in this condition.
 • AE (specifically, anti-NMDAR) is less likely to be a paraneoplastic
syndrome or associated with ovarian teratoma in pediatric patients.23,
38dysautonomia and hypoventilation are also less frequent or severe in

children.

• Children with anti–NMDAR encephalitis more frequently present with

Differences seizures, dyskinesia, developmental regression, speech deficits,
irritability or agitation, and ataxia, while adults more likely to present

Between with behavioral changes, neuropsychiatric symptoms and memory or

cognitive impairments.17, 25, 38, 39 Children are less likely to develop
severe dysautonomia or hypoventilation compared to adults as well.23
Pediatric and
Adult Cases • When psychiatric features are present in children, they are more likely
to be polysymptomatic and include agitation, aggression, hallucination
and emotional lability.40, 41

• Memory deficits, especially in younger children, are difficult to

identify although may be mistaken for encephalopathy.
 Diagnostic Evaluation
• In all individuals with suspected AE,
serum and cerebrospinal fluid (CSF)
evaluations, brain imaging and EEG
studies are recommended to narrow
the differential diagnosis and exclude
mimics of disease.
CSF
• Appropriate CSF studies should be obtained to reasonably rule out
infectious causes of meningitis/encephalitis. Studies such as gram stain,
culture, and targeted viral testing50 are critical in ruling out primary
infectious disease.

• CSF markers of neuroinflammation include:

• Pleocytosis (5 or more White Blood Cell (WBC)/mm3)
• Elevated protein (greater than 55 mg/dL)
• Elevated neopterin51, 52
• Elevated IgG index
• Presence of unique oligoclonal bands (OCB)
• Presence of certain patterns of CSF inflammatory cytokines and
chemokines have also been described,53 but those markers are less
routinely used in clinical practice.
Neuroimaging in AE
• Neuroimaging in cases of possible AE should be performed on a 3T magnet, with and without contrast, to
improve visualization of signal abnormalities in temporal lobe structures and evaluate for leptomeningeal
enhancement, respectively.

• MRI can be normal in half to two-thirds of the patients, particularly when performed early in the clinical
course.17, 25 However, it is recommended to be obtained in patients with suspected AE as part of the initial
evaluation and to investigate for other possible etiologies.

• Brain MRI abnormalities seen in AE are commonly subtle and may be discordant from the often dramatic
clinical features.63 Findings of T2 Fluid-Attenuated Inversion Recovery (FLAIR) abnormalities could be seen
throughout the brain and in cortical and subcortical areas including temporal, frontal, and parietal lobes,
hippocampi and amygdalae, cerebellum, thalamus, and basal ganglia.63 Contrast enhancement and abnormal
diffusion weighted images (DWI) could also be seen.39
Figure 2
EEG in AE
• The use of EEG is primarily for detection of seizure activity
although can be used as an adjunct test for cerebral dysfunction
in individuals with AE, providing a non-invasive, albeit non-
specific, clinical biomarker of disease activity.

• EEG is abnormal in over 90% of patients, and most often reveals

focal or generalized (diffuse) slowing of background.20 Focal or
generalized seizures or epileptiform discharges might be present.

• In children, the discharges could be more generalized compared

to localized temporal lobe discharges in adults.25 Extreme delta
brush is a characteristic EEG pattern39, 66 which is seen in some
patients with Anti-NMDAR encephalitis.
 FDG-PET in AE
• FDG-PET complements MRI in detecting abnormalities.10 FDG PET CT is more often abnormal in the acute setting
compared to MRI and could show areas of hypo- or hypermetabolism in the brain.64

• A caveat to the use of this test in neuroimaging is that seizures may cause changes in metabolism leading to false
positives (seizure foci usually show increased metabolism during a seizure, and decreased metabolism between seizures
in the inter-ictal periods).

• This is particularly relevant since children are much more likely to have seizures as part of their clinical presentation.
Similar to MRI, the FDG PET abnormalities could be observed in different areas of cerebral hemispheres, deep
structures, cerebellum, or brainstem.63

• Of note, FDG-PET is also used as an adjunct study for paraneoplastic screening when conventional methods for
detection (MRI or CT) are negative.65
Association with Neoplasia
• Once a diagnosis of anti-NMDAR encephalitis is confirmed by presence of antibodies,
appropriate imaging (e.g., MRI of chest, abdomen, and pelvis) should be obtained to rule
out the presence of a teratoma or other neoplasia.
• Teratomas are thought to contain nervous tissues that expresses antigens homologous to the
NMDAR protein.67
• If neoplasia is identified, prompt and gross-total removal is frequently associated with
improvement of symptoms and better prognosis including decreased relapse rates.38

• For female patients over 12 years of age, it is recommended to screen with MRI of the
abdomen and pelvis every 6 months for 4 years.38 The presence of a teratoma (ovarian in
female or testicular in male patients) or other tumors is very rare (only 6%) in children
younger than 12 years of age.
• The presence of a testicular teratoma is rare in general in male patients of any age, but could
occur in 6% of patients.38
• As routine MRI of the core will not identify testicular neoplasia, a dedicated testicular ultrasound
is often advised. FDG-PET scanning, alone or in combination with CT scan could also be useful in
the detection of small neoplasms. 65, 68
Differential
Diagnosis
Table 4. Differential diagnosis for autoimmune encephalitis
Demyelinating/Inflammatory
Disorders
Genetic/Mitochondrial Disorders
Infectious
Encephalitis/Meningoencephalitis
Psychiatric Disease
Seizure Disorders/Epileptic
Encephalopathy
Toxic Disorders
Vascular Disorders
Acute Disseminated Encephalomyelitis (ADEM)
Acute Necrotizing Encephalopathy (ANE)
Steroid-Responsive Encephalopathy Associated with
Autoimmune Thyroiditis (SREAT)
MOG-Spectrum Disorders
Multiple Sclerosis (MS)
Systemic inflammatory disorders with CNS involvement:
Behcet’s disease, lupus cerebreitis, Sjogren syndrome,
sarcoidosis
Leigh Syndrome
Leukodystrophies
Mitochondrial Encephalomyopathy, Lactic acidosis, and
Stroke-like episodes (MELAS)
Mitochondrial Cytopathies
Wilson’s disease
Bacterial Meningoencephalitis (l. monocytogenes, m.
pneumoniae, m. tuberculosis, t. pallidum)
Febrile Infection-Related Epilepsy Syndrome (FIRES)
Fungal Meningoencephalitis (cryptococcus,
coccidiomycosis, histoplasmosis)
Parasitic infection (malaria)
Post-Infectious Encephalopathy
Viral Meningoencephalitis (arbovirus, CMV, EBV,
enterovirus, HIV, HSV1/2, HHV6, VZV, etc.)
Bipolar Disorder
Conversion Disorder/Functional Neurologic Disorder
Major Depressive Disorder
Psychosis
Schizophrenia
Dravet Syndrome
Electrical Status Epilepticus During Slow Sleep (ESES)
Epilepsia Partialis Continua
Landau-Kleffner Syndrome
Lennox-Gastaut Syndrome
Progressive Myoclonic Epilepsies
Status Epilepticus
Uncontrolled Epilepsy
Ingestion/Intoxication
Neuroleptic Malignant Syndrome
Serotonin Syndrome
Wernicke Encephalopathy (Cerebral Thiamine Deficiency)
Primary or Secondary Angiitis of the Central Nervous
System
Moving Through the Differential Diagnosis
• Diagnostic studies are often used to rule in or out groupings on the differential diagnosis.

• Imaging is of great utility for evaluating the presence of alternative demyelinating disorders, vascular disorders,
and some genetic/mitochondrial disorders which have different or unique radiographic signatures.
• For instance, primary angiitis of the central nervous system is more likely to show diffusion abnormalities in the distal cortex as opposed to
T2 signal prolongation in the temporal lobes.

• EEG is often used as a biomarker of cortical dysfunction in AE but can also be used to rule out seizure and
epileptic encephalopathy as an etiology for the clinical symptoms.

• Finally, LP is critical in confirming a suspicion for inflammatory disease while also ruling out toxic, metabolic,
infectious, and potentially post-infectious causes of symptoms associated with AE.
• This procedure also provides the definitive diagnosis of autoantibody mediated AE. Of particular importance is that psychiatric and
functional neurologic disorders must be considered a diagnosis of exclusion in cases of possible AE given the importance of early treatment
on long-term outcomes.
• Recommended diagnostic work
up and algorithm for pediatric AE
suggested by Celluci et al. (2020)
Criteria & Diagnosis
Diagnostic Criteria
• Diagnostic criteria have been developed to enable clinicians to diagnose AE clinically while the antibody
testing is in process, with the aim to minimize the delays in treatment. 69

• Graus and colleagues25 proposed criteria for a variety of types of AE. The sensitivity and specificity for these
criteria have not been formally evaluated in children although they remain a useful clinical reference point.

• Cellucci et al20 published similar guidelines specific to pediatric patients (next slide), dividing the patients into
three diagnostic categories: possible AE, probable antibody-negative AE, and definite antibody-positive AE.

• Based on these criteria, pediatric patients with acute onset of neurologic or psychiatric symptoms with two
or more characteristic features would be considered as possible AE if other causes have been reasonably
excluded.

• Unlike AE diagnostic criteria for adults, 25 psychiatric symptoms are not a requirement for children, as
psychiatric symptoms are more difficult to diagnose in younger children, and children could initially present
with mainly neurological signs and symptoms such as seizure and movement disorder without predominant
psychiatric phenotypes.
Table 5. Diagnostic criteria in pediatric patients with suspected autoimmune encephalitis
proposed by Cellucci et al20
Diagnostic categories
Probable Definite
Possible AE
Features Ab-negative AE Ab-positive AE
 Onset of neurologic/psychiatric
✓ ✓ ✓
symptoms ≤3 months
 Altered mental status or EEG with
slowing or epileptiform activity
 Seizures not explained by a previous
seizure disorder
 Focal neurologic deficits ≥2 features ≥2 features ≥2 features
 Cognitive difficulties
 Developmental regression
 Movement disorder*
 Psychiatric symptoms
 CSF pleocytosis (WBC >5 cells/mm3)
and/or oligoclonal bands
 MRI features of encephalitis Not available ≥1 feature ≥1 feature
 Brain biopsy with inflammatory
infiltrates (excluding other disorders)
 Serum and/or CSF positive for well-
characterized autoantibodies Not available Negative (-) Positive (+)
associated with AE
 Reasonable exclusion of alternative
✓ ✓ ✓
causes
* Excluding tics.
Ab: antibody, AE: Autoimmune Encephalitis, CSF: Cerebrospinal Fluid, EEG: Electroencephalogram, WBC;
White Blood Cell Count.
Treatment
 In patients with suspected AE, empiric treatment should be given after
reasonable exclusion of other causes, without awaiting specific antibody
detection. Preferably, neuroimaging and CSF would have been obtained prior
to initiation of therapy although in certain clinical circumstances this may not
be feasible. Initial empiric treatments include intravenous (IV) steroids,
intravenous immunoglobulins (IVIg), or plasmapheresis (Table 6 - below).70

Table 6. Early treatment options for AE

 Steroid  IV- methylprednisolone 30 mg/kg/day (max 1
g/day) for 3-5 days72
 IVIG  Total dose 2g/kg, divided over 2-5 days72
o Maintenance dosing 1g/kg, monthly
 Plasmapheresis  5 or more cycles93
 Rituximab  375 mg/m2 weekly for 4 weeks,94 or 750
mg/m2 (max 1 g) IV administered twice,
separated by two weeks72
Acute Immunotherapy
• Acute immunotherapy is usually started with high dose corticosteroids in the form of methylprednisolone if
no medical contraindications are present.

• If there is no clinical improvement by the end of the steroid treatment course, IVIg or plasmapheresis is
added.22 If an infectious etiology has not been excluded, IVIg has an advantage of being unlikely to worsen
the infection.71
Immunotherapy Options
• In pediatric patients, plasmapheresis is often less favored especially in milder forms of the disease due to
invasive line placement and greater risk of adverse events such as infection, hypotension, and electrolyte
derrangements.72

• IVIg might be preferred over plasmapheresis in patients that are agitated or have bleeding disorders.21 It is
important to note that using plasmapheresis shortly after administration of IVIg or rituximab is not
recommended as it might remove the therapeutic agents from the plasma.72

• In some circumstances, a combination therapy of steroids plus IVIg or plasmapheresis could be considered as
first line if the initial presentation is severe and a high index of suspicion is maintained.21, 73 Treatment choice
and order of treatments vary among different practices and there is a gap in the evidence to suggest an optimal
treatment strategy or superiority of any specific regimen in pediatric patients.71

• Recently, international consensus recommendations have been published with the aim to provide clinical
guidance and standardize the treatment for pediatric anti- NMDAR encephalitis.74
Immunotherapy in Refractory Cases
• Up to 47% of patient do not improve with first-line therapy within the first month of treatment.38 Second line
treatments include rituximab, cyclophosphamide, and plasmapheresis when not previously utilized.35, 75

• With mounting evidence of effectiveness of rituximab, it is being increasingly used in combination with IVIG
and steroids, or after first-line immunotherapies.76

• Several monoclonal antibodies are being investigated and utilized in treatment of refractory AE. Examples
include anakinra (IL-1 inhibitor),77, 78 tocilizumab (IL-6 inhibitor),79 ocrelizumab (anti-CD20), inebilizumab
(anti-CD19), and bortezomib (26S protease inhibitor) in patients with severe or medically refractory AE.80
 • Intensive Care Unit (ICU) admission might be
required in severe cases. Individuals with status
epilepticus, refractory seizure activity,
dysautonomia, and hypoventilation requiring
mechanical ventilation (due to brainstem
involvement, or secondary to sedating medications)
may require ICU-level care.81
Hospital
Management • Aside from seizure activity, these other severe
complications typically develop later in the disease
Considerations course.35

• Given the variety of symptoms and care needs,

multidisciplinary care involving pediatricians,
neurologists, intensivists, and psychiatrists and
ancillary therapy services is paramount in the care
of individuals with AE.
Management of Psychiatric Symptoms
• Early involvement of psychiatric consultants is important for management of neuropsychiatric symptoms
throughout the disease course of AE.

• Agitation, aggression, delirium and sleep issues including insomnia are commonly seen in patients with anti-
NMDAR encephalitis and other forms of AE and can be challenging to treat.

• There is gap in the literature in terms of recommended or effective agents and dosage ranges. In addition to
melatonin, sedative medications, such as benzodiazepines, trazodone or clonidine are often used as
adjunctive therapies for treatment of sleep issues and agitation.

• In some severe cases, patients might need ICU admission for escalated sedation. 82 Other commonly used
agents for management of mood and behavioral dysregulation include valproic acid and sedating
antipsychotics such as quetiapine or chlorpromazine.

• Valproic acid has the added advantage of seizure prophylaxis and/or treatment in addition to having
therapeutic efficacy in a variety of movement disorders. 83 Use of conventional antipsychotics and dopamine
blocking agents can exacerbate dyskinetic movements such as dystonia. 82
Outcomes and
Prognosis
Outcomes and Prognosis
• The majority of individuals with AE (72% to 85%) have a good outcome.38, 39, 61, 84

• Prompt initiation of immunotherapy has been shown to be associated with a better outcome.17, 38, 84-87

• In addition to delayed treatment, other factors that are predictive of worse outcome include ICU admission,
decreased level of consciousness,84 and autonomic dysregulation.88

• Interestingly, status epilepticus is often not associated with a worse prognosis.84, 88

• Relapse occurs in 10-25% of patients with anti-NMDAR encephalitis and is often due to suboptimal
treatment.83, 86
Recovery After AE
• Most patients have a prolonged recovery period, often over several months. A longer course (more than a year) has
been described in some patients with persistent behavioral issues.89

• Symptoms often improve in the reverse order of presentation, although given the frequency of polysymptomatic
presentations, this can difficult to definitively track. Cognitive and behavioral or psychiatric issues are often the
slowest to improve. Agitation and psychiatric symptoms can resurface as the patients regain their communicative
abilities.

• Despite good overall functional outcome, patients with AE are at risk of persistent cognitive deficits as a major long-
term morbidity.90, 91

• Pediatric patients with anti-NMDAR encephalitis have been found to perform lower on neuropsychiatric tests
(including sustained attention, processing speed, and verbal memory domains) compared to age-matched healthy
individuals, even at long-term follow-ups (median almost 3 years).92 These findings underscore the need for early
neuropsychological counselling and serial reassessments to update cognitive rehabilitation plans.91
Summary
Summary
- Based on epidemiologic studies, autoimmune encephalitis is a common cause of encephalitis in children.4
- Based on consensus diagnostic criteria, AE should be suspected in children presenting with acute onset (<3
months) of behavioral changes, agitation, psychiatric symptoms, developmental/speech regression, new
seizures, movement disorders, or other focal neurological deficits.20
- Based on consensus, diagnostic evaluations include serum and CSF studies, EEG and brain MRI.20
- Based on observational studies, delays in initiation of diagnosis and treatment can result in worse
outcomes.38, 84-87
- Based on consensus, in a patient with possible autoimmune encephalitis, after reasonable exclusion of other
causes, empirical treatment should be started without waiting for antibody confirmation, which might take
several days to weeks.20
- Based on consensus, first line treatments include IV steroid, IVIg, and plasmapheresis. Rituximab could be
used in combination with the first line treatments or as a second line agent.71-74
Questions
Question 1
A 13-year-old adolescent boy without history of seizures presents with intermittent rhythmic twitching of fingers
of the right hand. Symptoms started 2-3 weeks prior, at which time he was diagnosed with a tic disorder.
However, the twitching has become progressively worse, and an EEG is obtained, which reveals left sided focal
seizures. The patient is started on levetiracetam and subsequently lacosamide but continues to have seizures.
MRI brain with and without contrast is normal, FDG-PET shows an area of hypermetabolism in the left
hemisphere. He subsequently becomes confused and develops expressive aphasia. LP is performed which shows
5 white blood cells/mm3, negative infectious studies, including negative viral PCR panel. Serum and CSF
autoimmune encephalitis panels are pending. What would be the appropriate next step?

A. Repeat brain MRI, add cervical spine MRI

B. Psychiatric consult
C. Symptomatic management until autoimmune encephalitis panel is resulted
D. IV methylprednisolone for 5 days
E. Continuous video EEG monitoring
Question 2
A 15-year-old female has been diagnosed with non-paraneoplastic anti-NMDAR positive AE. She has minimal
response to five days of IV methylprednisolone, a course of IVIg and plasmapheresis. She remains severely
agitated, aggressive, and her dyskinetic movements are worse. What would be a reasonable next intervention?

A. Treatment with rituximab 750 mg/m2

B. Repeat course of IVIg
C. Trial of empiric tocilizumab
D. Treatment with cyclophosphamide
E. Admit to the ICU for IV sedation
Question 3
A 6-year-old girl presents with one week of behavioral change and speech regression. She was previously
developmentally normal, however, in the last week she been progressively more irritable, does not sleep at
nights, and uses only a few words with no sentences. An EEG is performed, which shows diffuse slowing
without seizures or electrical status epilepticus. Which category could the patient be classified as?

A. Does not meet the criteria for AE

B. Possible AE
C. Probable antibody-negative AE
D. Definitive AE
E. Localization related epilepsy
Question 4
A previously healthy 3-year-old girl presents with “wobbly” gait for two months and increasing agitation. Patient
initially had a normal gait but gradually developed balance issues and is now unable to walk. She also became
increasingly aggressive and bites her parents/care givers. She does not respond to her name or make eye contact with
parents and does not follow commands. In the past few days, she has been noted to have unusual posturing including
back arching and stiffening of the extremities, fisting so forcefully that results in injury caused by fingernails. Patient is
awake and agitated during the night and sleeps only for short intervals during the day. Symptoms have progressively
become worse. Brain MRI was obtained, which shows areas of T2 FLAIR hyperintensity of bilateral basal ganglia,
cerebellum, and brainstem. CSF studies reveal pleocytosis of 10 WBC/hpf with lymphocytic predominance, elevated
protein, but no oligoclonal bands. Viral panel is negative. What is the most appropriate next step?

A. Obtain EEG to evaluate for tonic seizures

B. Send stored CSF sample for autoimmune encephalitis panel, defer treatment until results of neurodiagnostic tests
returned
C. Start treatment with IV steroid and IVIG while waiting for the final results of neurodiagnostic tests
D. Referral to genetics for evaluation of mitochondrial disorder and Leigh syndrome
E. Admit for psychiatric hold while awaiting results of neurodiagnostic testing
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