2 Figure 3 Table to teach you the diagnostic chart summary of autoimmune encephalitis

Autoimmune encephalitis (AE) includes a group of noninfectious immune-mediated inflammatory diseases of the brain parenchyma, usually involving the cortex or deep gray matter, with or without involvement of the white matter, meninges, or spinal cord
.

The purpose of this article is to highlight the acute and long-term management of AEs as a broad category, rather than focusing on individual antibody syndromes
.

Let's take a look at best practice advice on how to diagnose AE
.

Compiled and organized by Yimaitong, please do not reprint without authorization When do you suspect AE? A detailed history and examination is the first and most important step in the diagnosis of AE
.

The immune response to AEs usually results in acute or subacute manifestations lasting less than 3 months
.

Chronic manifestations are seen only in some of these diseases, especially LGI1, contact-related protein-like 2 (CASPR2), dipeptidyl-p-peptide-like protein (DPPX), and glutamate decarboxylase 65 (GAD65)-antibody encephalitis, otherwise it should be Suspected neurodegenerative disease or other etiology
.

Likewise, hyperacute presentations are not typical, and a vascular cause should be considered in these cases
.

The course of relapse may be of autoimmune etiology, but unlike the typical relapsing-remitting course of multiple sclerosis and systemic inflammatory diseases, AE relapses are rare, usually due to inadequate treatment or rapid interruption of immunotherapy
.

A monophasic course is more common in idiopathic AEs, whereas in some paraneoplastic syndromes, notably paraneoplastic cerebellar degeneration, a progressive course that plateaus after cancer treatment can be seen
.

Patients with known cancer or those at increased risk of cancer (smokers, older adults, and patients with unprovoked rapid weight loss) are more likely to develop paraneoplastic AEs, whereas patients with a personal or family history of other autoimmune diseases are more likely to develop idiopathic AEs.
Risk increases
.

Previous viral infection, fever, or viral-like prodromal symptoms are common
.

AEs may be triggered by herpes simplex virus (HSV) encephalitis or certain immunomodulatory therapies, such as TNFα inhibitors and immune checkpoint inhibitors (ICIs), the latter of which can accelerate paraneoplastic encephalitis in patients with advanced cancer
.

Table 1 shows the practical classification in AE
.

 Table 1 Classification of autoimmune encephalitis The immune response in AE is usually diffuse, resulting in multifocal brain inflammation, occasionally involving the meninges, spinal cord, and/or peripheral nervous system
.

This diffuse inflammation may or may not be detectable on ancillary studies, but usually results in polysyndromes, a clinical feature of AEs
.

Although some antibodies are associated with typical symptoms (eg, oromandibular dyskinesia in NMDAR antibody encephalitis, cognitive/behavioral changes, language and autonomic dysfunction, facial dystonic episodes in LGI1 antibody encephalitis, etc.
), There was significant symptom overlap between all antibodies and all forms of AE
.

Symptoms vary according to the anatomical site of inflammation, and there are several clinical-anatomical syndrome categories in AEs, as shown in Table 2
.

 Table 2 AE clinical-anatomical syndrome categories What investigations should be performed when an AE is suspected? After an AE is clinically suspected, detailed workup is required to confirm the diagnosis and rule out other possibilities, such as infectious encephalitis or systemic/metabolic causes
.

In most cases, the examination begins with brain imaging and cerebrospinal fluid (CSF) analysis
.

The diagnostic steps follow those summarized in Figure 1 as follows: Figure 1 AE diagnostic workflow *EEG can confirm focal or multifocal brain abnormalities and rule out subclinical seizures
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** In addition to neuronal autoantibodies, CSF should be tested for infection, markers of inflammation (IgG index and oligoclonal bands), and in some cases cytology
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***With the exception of neuronal autoantibodies, a differential diagnosis based on MRI results will guide which blood tests to submit
.

****In most cases, general tumor screening starts with CT, and then other screening modalities are added until the tumor is detected or finally excluded
.

Targeted screening approaches can be implemented if the clinical presentation is highly suggestive of a specific tumor (eg, starting with pelvic ultrasound if the clinical presentation is suggestive of anti-NMDAR encephalitis)
.

 ➤ Step 1: Confirm the presence of focal or multifocal brain abnormalities suggestive of encephalitis.
In addition to excluding other diagnoses, standard brain MRI contrasts can reveal patterns consistent with one or more AE anatomical syndromes.
changes (Table 1 and Figure 2)
.

Even in the absence of NAAs, the presence of bilateral limbic encephalitis is the only MRI finding sufficient to diagnose a definitive AE in the correct clinical setting (eg, CSF virus-negative) according to Graus et al.
2016 clinical criteria for AEs
.

All other MRI modalities (cortical/subcortical, striatum, diencephalon, brainstem, encephalomyelitis, and meningoencephalitis) support possible AEs unless positive for clinically relevant antibodies to NAAs
.

Diffuse or patchy contrast enhancement, suggestive of inflammation, was seen in a minority of patients, whereas strongly enhancing lesions were unlikely in AE patients
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Rare manifestations include focal or extensive demyelination, meningeal enhancement, and rarely limited cortical spread (usually associated with secondary epilepsy)
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Brain MRI may also be normal
.

Patients with an initial negative MRI may have changes suggestive of an AE on repeat MRI days later
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Gadolinium should be avoided during pregnancy
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Table 3 shows the main differential diagnoses for each AE anatomical syndrome
.

 Figure 2 Anatomical subtypes of autoimmune encephalitis
.

A limbic encephalitis, B cortical/subcortical encephalitis, C striatal encephalitis, D diencephalitis, E brainstem encephalitis (arrow), F meningoencephalitis (arrow)
.

 Table 3 Differential diagnosis of autoimmune encephalitic anatomical syndrome and suggested additional investigations Notes: ADEM, acute disseminated encephalomyelitis; AHL, acute hemorrhagic leukoencephalitis; ANA, antinuclear antibody; AQP4, aquaporin 4; CJD, Creutzfeldt-Jakob disease; CLIPPERS, chronic lymphocytic inflammation with peripontine vascular enhancement, responsive to steroids; CPM, central pontine myelinolysis; CSF, cerebrospinal fluid; DaT scan, dopamine transporter scan; ENA, possible Extracted nuclear antigen; GFAP, glial fibrillary acidic protein; GPA, glioma with polyangiitis; GQ1b, anti-ganglioside Q1B antibody; HHV6, human herpesvirus 6; HSV, herpes simplex virus; JCV, John Cane Ning'an virus MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; MSA-C, multiple system cerebellar atrophy; NMOSD, neuromyelitis optica spectrum disorder; PML, progressive multifocal leukoencephalopathy; SCA , spinocerebellar ataxia; VEP, visual evoked potential; VZV, varicella-zoster virus; WNV, West Nile virus
.

 Importantly, brain MRI can also help rule out other diagnoses such as acute stroke, tumor, or Creutzfeldt-Jakob disease (CJD), although AE MRI changes can sometimes mimic these disorders
.

Inflammation of unilateral medial and non-medial temporal lobes and orbitofrontal cortex on FLAIR or DWI sequences supports herpetic encephalitis rather than AE
.

Parenchymal hemorrhage on gradient echo sequences is more common in herpetic encephalitis than AE
.

 In some related immune-mediated diseases, diagnosis can be made on the basis of typical MRI patterns, such as perivascular radial enhancement in autoimmune GFAP astrocytopathies, and brainstem/cerebellar punctate enhancement in chronic lymphocytic inflammation, and Steroid-responsive perivascular enhancements of the pons (CLIPTERs)
.

 Electroencephalography Electroencephalography (EEG) is commonly used in patients with suspected AE to rule out subclinical status epilepticus in patients with encephalopathy, or to monitor treatment response in patients with epilepsy
.

AEs are the leading cause of new-onset refractory status epilepticus (NORSE), which can be convulsive or non-convulsive
.

When MRI is negative, EEG can also provide evidence of focal or multifocal brain abnormalities, which would support encephalitis rather than metabolic encephalopathy
.

Findings suggestive of AEs include focal chronic/seizure seizures, lateralized periodic discharges, and/or extreme triangular brush discharges, which are occasionally seen in NMDAR antibody encephalitis
.

Patients with LGI1-antibody encephalitis typically have frequent subclinical attacks, but patients may also have normal EEGs, including typical facial-brachial dystonic attacks (FBDS)
.

Although a normal EEG does not rule out AEs, it can support a primary psychiatric disorder when investigating patients with isolated new psychiatric symptoms
.

EEG is also helpful in distinguishing AE from CJD
.

 Cerebral fluorodeoxyglucose positron emission tomography (FDG-PET) If brain MRI is negative and clinically indeterminate, despite high suspicion of AE, obtaining FDG-PET can confirm focal or multifocal in the correct clinical setting Sexual brain abnormalities
.

It can also be used in place of MRI when there are contraindications to MRI
.

Brain FDG-PET is more sensitive than MRI in case series and may detect brain abnormalities early in the disease
.

Bilateral temporal lobe hypermetabolism (in seropositive or seronegative limbic encephalitis) and bilateral occipital-parietal hypometabolism (in NMDAR antibody encephalitis) are the most common patterns and may prove useful biomarkers for specific syndromes thing
.

Importantly, further studies are needed to better differentiate AE metabolic patterns from neurodegenerative and neuroinfectious syndromes
.

In addition, immunosuppressive, anesthetic, and antiepileptic treatments commonly used in AE patients can also alter cortical metabolism
.

Seizures also cause hypermetabolic changes in FDG-PET
.

The lack of specificity and limited availability of FDG-PET are barriers to the widespread use of this technique in the diagnosis of AEs
.

 ➤Step 2: Confirm autoimmune inflammatory etiology and rule out other possibilities After evaluating focal or multifocal brain abnormalities by MRI or other studies, further work is required to confirm AEs and rule out other possibilities
.

As shown in Table 3, the examination can be guided by the clinical anatomical syndrome to narrow the scope of the investigation
.

 Cerebrospinal fluid analysis This is the most important test in the evaluation of AE and is usually the second step after MRI of the brain
.

Lumbar puncture (LP) is indicated in all patients with suspected encephalitis, regardless of MRI findings, unless there are obvious contraindications (eg, risk of brain herniation on brain imaging)
.

In some cases, inflammatory cerebrospinal fluid may be the only abnormality found on initial testing and the only indication to rule out empiric immunotherapy after infection
.

If brain MRI cannot be performed in time due to patient agitation or inability to perform brain MRI, clinicians should continue to perform LP after cranial CT screening to avoid delays in immunotherapy
.

CSF analysis should include cell count and differentiation, protein, glucose, CSF/blood glucose ratio, albumin ratio, IgG index and synthesis rate, oligoclonal bands, extensive viral studies including HSV1/2 PCR and varicella-zoster virus (VZV) ) PCR and IgG/IgM, bacterial/fungal cultures, cytology, flow cytometry, NAAs assays (such as autoimmune encephalopathy/encephalitis assays, etc.
), and in some cases, prions (most if available, good is RTQuIC)
.

Common CSF findings in AE include mild to moderate lymphocytosis (usually 20-200 cells, but may be as high as 900 cells with some antibodies), hyperalbuminemia, and in some cases, IgG index and/or increased IgG synthesis rate, and positive intrathecal oligoclonal bands (mismatch in serum)
.

In the context of negative infection and cytology studies, these findings support an immune-mediated etiology, but do not distinguish AEs from other immune-mediated disorders such as neurosarcoidosis, so clinical relevance is always required
.

In many patients, both cerebrospinal fluid and serum NAAs need to be tested because cerebrospinal fluid testing is more sensitive for certain antibodies (eg, NMDAR and GFAP antibodies), while serum is more sensitive for others (eg, cancer neurons, LGI1, and AQP4 antibodies)
.

If the clinical presentation is highly suggestive of high serum susceptibility to antibodies (eg, FBD suggests LGI1 antibody encephalitis), it may be reasonable to avoid CSF testing in clinical situations where CSF sampling is challenging
.

While symptomatology can guide which neuronal antibodies (or antibody panels) to detect in some patients, it may be most practical to send the most comprehensive antibody panel, especially in patients with ambiguous symptoms
.

This is because there is significant syndromic overlap between most of these antibodies, and multiple antibodies may be present in the same patient
.

It is worth noting that some patients with AE may have normal CSF examination on routine examination, which does not rule out the diagnosis when other parameters are consistent with AE; therefore, even if CSF is normal, testing for NAAs is recommended in cases of high clinical suspicion
.

  Serology In addition to testing for NAAs in serum, several blood tests are usually required to rule out competing etiologies
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The selection of tests can be made according to the MRI anatomical pattern shown in Table 3, but in the case of negative MRI, some tests may be useful, such as anti-thyroid antibodies, toxicology screening, ammonia, vitamin B1/B12 levels, HIV, inflammatory markers Antibody, antinuclear antibody, extractable nuclear antigen antibody, antiphospholipid and lupus anticoagulant antibody, immunoglobulin and metabolic and hormone detection
.

Monitoring sodium levels is important because hyponatremia is common in some AE subtypes, such as LGI-1 antibody encephalitis
.

Blood samples should be collected before intravenous immunoglobulin or plasma exchange therapy to avoid false-positive or false-negative results
.

 Brain biopsy Most cases of AE with normal brain MRI or typical MRI (limbic, striatal, etc.
) do not require a brain biopsy
.

Rarely, atypical or mass-like lesions may require a brain biopsy to rule out a tumor or other possibilities, especially when all other tests point to autoimmunity
.

The pathological manifestations of AE are nonspecific and include perivascular and parenchymal infiltrating T cells and/or B cells, and secondary gliosis
.

 ➤ Step 3: Screening for Associated Tumors Because the two AE subtypes perform similarly, it is almost impossible to predict whether an AE is paraneoplastic or non-paraneoplastic based on symptoms
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Therefore, most adult patients with AEs should consider cancer screening when they present
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If the patient has a known history of cancer, usually associated with a paraneoplastic syndrome, a paraneoplastic etiology is presumed and repeat cancer screening is indicated to determine recurrence or progression
.

Repeated cancer screening may reveal new and different tumors in patients without a history of cancers typically associated with paraneoplastic neurological syndromes (eg, basal cell skin cancer, prostate cancer)
.

The most common tumors associated with AEs included small cell lung cancer, thymic tumors, breast cancer, ovarian teratoma or carcinoma, testicular teratoma or seminoma, neuroblastoma, and lymphoma
.

In some patients, suspicion for an associated tumor may be high based on certain demographic factors (eg, smoking history or advanced age) or typical clinical presentation (NMDAR-antibody encephalitis associated with ovarian teratoma)
.

Although some antibodies have stronger cancer associations than others (eg, antibodies against intracellular antigens), the relevant antibodies are often unknown when they first appear
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The following screening modalities are available: CT of the chest, abdomen, and pelvis Initial screening of the chest, abdomen, and pelvis with CT is a reasonable approach compared to FDG-PET because it is less expensive and it can Provide more details of tumor structure (if present) to guide biopsy and further surgical intervention (if necessary)
.

A major limitation of CT screening is its low sensitivity for early breast and testicular cancer
.

In addition, CT is not preferred in children and pregnant women; in general, pelvic CT is not preferred in women of childbearing age
.

In addition, contrast-enhanced CT may be contraindicated due to renal impairment or contrast medium allergy
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In these cases, additional or alternative means of cancer screening (eg, MRI) are required
.

However, it is worth noting that CT iodine is relatively safe in pregnant women compared to MRI gadolinium
.

 Mammography and Breast MRI Breast cancer is a common source of paraneoplastic syndromes in women, and a mammogram should be performed if the initial CT screening result is negative
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Patients with a family history of breast cancer, and those who do not have routine mammograms, are a particular concern
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If the mammogram is negative, but the suspicion of breast cancer is high, a breast MRI may increase the sensitivity of cancer detection
.

 Pelvic or testicular ultrasonography or MRI Young and middle-aged adults with typical clinical manifestations of NMDAR antibody encephalitis should be screened for teratoma by transvaginal or transpelvic ultrasonography (or testicular ultrasonography in men)
.

In women with ataxia manifestations suggestive of PCA1/Yo antibodies, pelvic ultrasonography can screen for ovarian cancer
.

Likewise, in men with ataxia and other brainstem symptoms suggestive of Ma and Kelch-like protein-11 antibodies, testicular ultrasonography may reveal associated tumors
.

Pelvic MRI may be useful if ultrasonography is unclear
.

Extraovarian and extratesticular germ cell tumors can be detected by routine CT- or MRI-based cancer screening
.

 Whole-body FDG-PET scan Whole-body FDG-PET is more sensitive for early-stage tumors when initial CT screening is negative or inconclusive and cancer suspicion is high (eg, older patients who smoke, typical paraneoplastic manifestations)
.

It can also be used as an initial screening tool when high-resolution CT or iodinated contrast is contraindicated
.

 Compiled by: Abboud H, Probasco JC, Irani S, Ances B, Benavides DR, Bradshaw M, Christo PP, Dale RC, Fernandez-Fournier M, Flanagan EP, Gadoth A, George P, Grebenciucova E, Jammoul A, Lee ST, Li Y, Matiello M, Morse AM, Rae-Grant A, Rojas G, Rossman I, Schmitt S, Venkatesan A, Vernino S, Pittock SJ, Titulaer MJ; Autoimmune Encephalitis Alliance Clinicians Network.
Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management.
J Neurol Neurosurg Psychiatry.
2021 Jul;92(7):757-768.
doi: 10.
1136/jnnp-2020-325300.
Epub 2021 Mar 1.
PMID: 33649022; PMCID: PMC8223680.