Edited by: Freimut Dankwart Juengling, Universität Bern, Switzerland
Reviewed by: Valentina Garibotto, Geneva University Hospitals (HUG), Switzerland; Tino Prell, University Hospital Jena, Germany
This article was submitted to Applied Neuroimaging, a section of the journal Frontiers in Neurology
†These authors have contributed equally to this work
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Autoimmune encephalitis (AE) associated with leucine-rich glioma-inactivated 1 (LGI1) antibody, described a decade ago, is a potentially treatable and recidivistic subtype of AE (
For LGI1 AE patients, early diagnosis and treatment can prevent the development of the disease syndrome (
Thus, we conducted a retrospective study and reviewed the 18F-FDG-PET data of 34 patients with a definite diagnosis of LGI1 AE based on symptoms, EEG, and LGI1 antibody testing. We evaluated the diagnostic value of 18F-FDG-PET in LGI1 AE subjects, especially those with unremarkable MRI alterations, and we also aimed to interpret the localization of FBDS by showing different metabolic abnormalities of 18F-FDG-PET in LGI1 AE patients with or without FBDS.
The study was approved by the Ethics Committee of the Beijing Tiantan Hospital, which was affiliated with the Capital Medical University of the People's Republic of China. The study was conducted in accordance with the Declaration of Helsinki, and all patients and controls provided informed consent for the use of their medical records.
A total of 34 patients with LGI1 AE were retrospectively identified between October 2014 and June 2018 at the Department of Neurology in the Beijing Tiantan Hospital of the Capital Medical University. The inclusion criteria were based on representative clinical symptoms of LGI1 AE and the presence of positive LGI1 antibodies in the serum or cerebrospinal fluid (CSF). All included patients had undergone MRI and 18F-FDG-PET scans for neurological assessment during clinical evaluation. The demographic, clinical presentation, laboratory testing, EEG, and neuroimaging data were reviewed by searching the electronic medical records.
The 34 patients included 18 patients (53%) in the acute phase and 16 patients (47%) in the chronic phase when they take PET examination based on the previous definition of the acute phase (within 3 months) and chronic phase (over 3 months) in the diagnosis of AE (
The patients were divided into two subgroups based on the presence of FBDS, namely, FBDS and non-FBDS. We compared the 18F-FDG-PET findings in these two subgroups, analyzed the 18F-FDG-PET hypermetabolic states in the BG of the subjects, and then inferred the possible etiology or nature of FBDS.
In this study, we randomly selected additional 20 age- and gender-matched controls (14 men and 6 women; median age 62.5 years; range, 25–83 years) for the quantitative analysis of FDG-PET based on volume of interest (VOI). The inclusion criteria are the following: (1) no brain diseases, (2) no mental disorders reported in the medical records, (3) no other diseases that indicated the brain function had been affected, (4) no abnormalities reported by the neuroradiologist, (5) adjustment for gender and age and random pickup of the control subjects.
All patients underwent serum and CSF antibody detection, including
18F-FDG-PET images were acquired using a PET/computed tomography (CT) scanner (Elite Discovery, GE HealthCare, Fairfield, Connecticut, USA). All patients (with a median age of 61 years, ranging from 31 to 78 years) fasted for at least 6 h, and blood glucose levels could not exceed 8 mmol/L. No patients received neuroleptic drugs to undergo FDG-PET. 18F-FDG was intravenously injected at a dose of 3.7–5.0 MBq/kg within 1 min, and subsequent uptakes required that patients be in a quiet resting status for 1 h prior to scanning in a dedicated room after 18F-FDG injection. First, a low-dose CT scan was performed, and the CT parameters for attenuation correction were 120 kV, pitch 0.984, automated tube current 60–180 mA, and slice thickness 3.75 mm. The PET scan was subsequently performed in 3D-TOF mode; for the LGI1 patients, a whole-body (including the brain region) FDG-PET scanning was acquired for approximately 30–35 min. The brain imaging data were reconstructed into trans-axial slices with a matrix size of 128 × 128 and a slice thickness of 3.3 mm, using an OSEM (ordered subset expectation maximization) algorithm.
For statistical parametric mapping (SPM) analysis, 22 age-matched, healthy volunteers served as control subjects. PET data were analyzed by SPM8 software (Wellcome Department of Cognitive Neurology, University College, London, UK) running on Matlab 2014b (MathWorks Inc., Sherborn, MA, USA). First, PET images were co-registered with the SPM template T1-weighted MR. Co-registered PET images were then spatially normalized into a common Montreal Neurological Institute (MNI) atlas anatomical space following a 12-parameter affine transformation and non-linear transformations, yielding images composed of 2 mm × 2 mm × 2 mm voxels. Third, normalized images were smoothed using an isotropic Gaussian kernel to increase the signal-to-noise ratio. Subsequently, preprocessed PET image values were corrected to a mean value of 50 ml/dl/min by “proportional scaling” to reduce individual variation. A two-sample
For these reported data, the region of interest (ROI) refers to the structure in 2D space (e.g., on a slice), and VOI refers to the structure in 3D space (i.e., a combination of ROIs of adjacent slices in two dimensions was labeled as a VOI). The value for radioactivity in each structure for each participant is the maximum of all pixels in all ROIs assayed for that structure, yielding a VOI. In our study, we selected three consecutive axial sections to define a certain volume (parameters included length, width, and height) to obtain the SUVmax (AW work station, GE HealthCare, USA). We calculated the SUVmax in three VOIs on FDG-PET based on the visual analysis, including the frontal cortex, BG, and MTL. The size of VOIs we selected was fixed, the center coordinate referred to the central location of VOIs, and they were individualized. One of the representative parameters of the individual was as follows: For the frontal cortex, the size of the volume was 25 * 20 * 9.9 mm, and the center coordinate of the volume was 72, 135, 30. For the BG, it was 40 * 30 * 9.9 mm, and the center coordinate was 109, 110, 23. For the MTL, the size of volume was 40 * 25 * 9.9 mm, and the center coordinate of volume was 112, 103, 18 (
An extensive literature search was performed for the terms “positron emission tomography” and “encephalitis” from January 2007 to October 2018. The reported results were reviewed and summarized. The primary search identified 112 publications on PubMed, and any studies and case reports that showed abnormal metabolism on brain PET in patients with AE were included. The subtypes of AE included NMDAR, LGI1, CASPR2, and GABAB. Ultimately, 19 studies and case series were reviewed (
Continuous variables with a normal distribution are presented as the mean ± standard deviation, and non-normal variables are expressed as the median (interquartile range, IQR). Continuous variables were compared using the
A total of 34 patients (24 men; a median age of 61 years, IQR 54–65 years old; age range, 31–78 years) with LGI1 AE were identified, and their clinical characteristics were reviewed (
Summary of the clinical characteristics of patients with LGI1 AE (
Age, year, median (IQR, range) | 61 (54–65, 31–78) |
Sex, male, |
24 (71) |
Clinical symptoms, |
|
FBDS | 17 (50) |
Seizures (except FBDS) | 33 (97) |
Memory loss | 30 (88) |
Psychiatric symptoms | 20 (59) |
Depression | 3 (9) |
Hallucinations | 9 (26) |
Disorder of behavior | 8 (24) |
Somnipathy | 17 (50) |
Hyponatremia, |
22 (65) |
Tumors, |
1 (3) |
LGI1 antibody positive, |
34 (100) |
Only in serum | 2 (6%) |
Only in CSF | 2 (6%) |
Both in serum and CSF | 30 (88%) |
CSF abnormalities, |
10 (29) |
EEG abnormalities, |
|
Total |
25 (74) |
Ictal (FBDS) |
0 (0) |
MRI abnormalities, |
|
Total | 20 (59) |
Only MTL lesion | 18 (53) |
Only BG lesion | 1 (3) |
Both BG and MTL lesions | 1 (3) |
18F-FDG-PET abnormalities, |
|
Total | 31 (91) |
Only MTL lesion | 3 (9) |
Only BG lesion | 8 (23) |
Both BG and MTL lesions | 20 (59) |
Immunotherapy, |
34 (100) |
Relapse, |
8 (24) |
All 34 patients (100%) were positive for antibodies against the LGI1 protein (
A total of 20 patients (59%) exhibited T2-weighted image (T2WI) or fluid-attenuated inversion recovery (FLAIR) hyperintensity on MRI. No subjects exhibited abnormal signals on T1-weighted image (T1WI). Increased signals were noted only in the MTL for 18 out of 34 patients (53%). A single subject (3%) showed isolated BG hyperintensity, and the remaining one (3%) had hyperintensity in both the MTL and BG.
A total of 31 patients (91%) showed an abnormal metabolism as determined by 18F-FDG-PET, and all of them (100%) presented with pure hypermetabolism. MTL and BG were two distinct metabolic targets in LGI1 AE patients (
Concerning the diagnosis of LGI1 AE, a comparison was made between the MRI and 18F-FDG-PET methods (
Neuroimaging testing in the diagnostic tracking of LGI1 AE. Neuroimaging testing plays an essential role in the diagnosis of LGI1 AE. The sensitivity of 18F-FDG-PET was higher than that of MRI; the 18F-FDG-PET scan was always positive when the MRI was positive, but when the MRI scan was negative for the diagnosis of LGI1 AE, 79% of the patients were still positive on the 18F-FDG-PET scan. LGI1, leucine-rich glioma-inactivated 1; AE, autoimmune encephalitis; EEG, electroencephalogram; MRI, magnetic resonance imaging; PET, 18F-fluoro-2-deoxy-
18F-FDG-PET metabolic pattern in patients with LGI1 AE.
A total of 12 subjects (35%) received a follow-up by 18F-FDG-PET, and all of them showed markedly decreased or normal uptake of 18F-FDG compared with the initial degree of metabolism; follow-ups occurred 68 ± 10 days following clinical treatment (
The patients were divided into two subgroups as follows: FBDS (
18F-FDG-PET characteristics of LGI1 AE patients with FBDS (
1 | Arm, Face | No | – | 425 | MTL | 143 | BG, MTL | – | 45 | Decreased |
2 | Arm, Face | No | Normal | 75 | Normal | 80 | BG, MTL | – | – | – |
3 | Arm | No | – | 130 | Normal | 13 | Normal | – | – | – |
4 | Arm, Face, Leg | Yes | Normal | 174 | MTL | 188 | MTL | – | 112 | Decreased |
5 | Face | No | – | 92 | MTL | 98 | BG, MTL | – | – | – |
6 | Arm, Face | Yes | Normal | 214 | MTL | 91 | BG, MTL | – | 142 | Decreased |
7 | Arm, Face, Leg | Yes | – | 100 | Normal | 50 | BG | – | 82 | Decreased |
8 | Arm, Leg | No | – | 14 | BG | 25 | BG | – | – | – |
9 | Arm, face | No | Normal | 28 | MTL | 21 | BG, MTL | – | – | – |
10 | Arm, Face | No | Normal | 305 | Normal | 302 | BG | – | – | – |
11 | Arm, Face | Yes | Normal | 34 | BG, MTL | 35 | BG, MTL | – | 98 | Decreased |
12 | Arm, Face | No | – | 95 | Normal | 332 | BG | – | – | – |
13 | Arm, Face | No | Normal | 297 | Normal | 45 | BG | – | 27 | Decreased |
14 | Arm, Face | No | – | 257 | Normal | 276 | BG | – | – | – |
15 | Arm, Face | No | Normal | 17 | Normal | 94 | BG | – | – | – |
16 | Arm, Face | No | – | 45 | MTL | 127 | BG, MTL | – | 53 | Decreased |
17 | Arm, Face | No | – | 12 | MTL | 17 | BG, MTL | – | – | – |
18F-FDG-PET features of LGI1 AE patients with non-FBDS (
1 | – | TAD | 12 | MTL | 11 | MTL | – | – | – |
2 | Normal | Normal | 190 | MTL | 372 | BG, MTL | – | 56 | Decreased |
3 | TAD, FAD | TAD, FAD | 798 | MTL | 797 | BG, MTL | – | 42 | Decreased |
4 | Normal | Normal | 34 | MTL | 50 | BG, MTL | – | 78 | Decreased |
5 | – | Normal | 75 | MTL | 92 | MTL | – | – | – |
6 | Normal | FAD | 94 | Normal | 91 | BG, MTL | – | – | – |
7 | – | Normal | 33 | Normal | 32 | BG, MTL | – | – | – |
8 | TAD | TAD | 4 | Normal | 43 | Normal | – | – | – |
9 | TAD | Normal | 87 | MTL | 130 | BG, MTL | – | – | – |
10 | FAD | FAD, TAD | 51 | MTL | 32 | BG, MTL | – | – | – |
11 | – | Normal | 12 | MTL | 19 | BG, MTL | – | 61 | Decreased |
12 | – | FAD, TAD | 148 | MTL | 185 | BG, MTL | – | – | – |
13 | – | Normal | 71 | Normal | 85 | Normal | – | – | – |
14 | FAD, TAD | Normal | 7 | MTL | 371 | BG, MTL | – | 25 | Decreased |
15 | TAD | TAD | 96 | MTL | 77 | BG, MTL | – | – | – |
16 | TAD | TAD | 67 | Normal | 64 | BG, MTL | – | – | – |
17 | – | FAD, TAD | 50 | Normal | 67 | BG | – | – | – |
18F-FDG-PET hypermetabolism in LGI1 AE patients with FBDS.
A total of 31 patients (FBDS = 16, non-FBDS = 15) demonstrated increased metabolic changes as demonstrated by 18F-FDG-PET analysis. We classified the metabolic pattern of the patients into three types (BG only, MTL only, and BG + MTL) based on the location of the lesions in every subgroup (
A total of 124 subjects with AE and PET scans were reviewed as shown in
Literature review of 18F-FDG-PET pattern in subtypes of AE.
NMDAR | ( |
3 | BG (1) | Thalamus (2) |
NMDAR | ( |
6 | Temporal (6), Cerebellum (3), Frontal (6) | Occipital (3) |
NMDAR | ( |
6 | Temporal (5) | Parietal (6), Cingulate gyrus (1) |
NMDAR | ( |
6 | BG (4), Frontal (1), Temporal (1) | BG (1), Frontal (5), Temporal (4), Parietal (3), Occipital (6) |
NMDAR | ( |
8 | BG (6), Frontal (4), Temporal (2) | Occipital (7) |
NMDAR | ( |
4 | BG (2), Cerebellum (2) | Temporal (1), Parietal (1), Occipital (2) |
NMDAR | ( |
1 | BG (1) | – |
NMDAR | ( |
1 | – | Parietal (1), Occipital (1) |
NMDAR | ( |
8 | BG (2), Cerebellum (2), Occipital (1) | BG (2), Frontal (4), Temporal (3), Parietal (5), Occipital (6) |
NMDAR | ( |
5 | – | Frontal (3), Temporal (2), Parietal (4), Occipital (5) |
LGI1 | ( |
8 | BG (4), Temporal (4) | BG (2), Temporal (2) |
LGI1 | ( |
1 | Temporal (1) | – |
LGI1 | ( |
4 | BG (3), Cerebellum (3), Occipital (2) | Cingulate gyrus (4) |
LGI1 | ( |
1 | BG (1) | – |
LGI1 | ( |
5 | BG (5), Temporal (3), Frontal (5) | – |
LGI1 | ( |
1 | BG (1), Temporal (1) | – |
LGI1 | ( |
1 | BG (1), Temporal (1) | – |
LGI1 | ( |
10 | BG (7), Temporal (7) | – |
LGI1 | This study | 34 | BG (28), Temporal (23), Cerebellum (1) | – |
CASPR2 | ( |
2 | BG (1) | – |
CASPR2 | ( |
3 | BG (1), Thalamus (1) | Temporal (1), Occipital (1) |
GABAB | ( |
5 | Temporal (2) | The whole cerebral cortex (1) |
GABAB | ( |
1 | Temporal (1) | – |
To support the SPM voxel-based analysis results (
18F-FDG-PET hypermetabolism in eight patients with LGI1 AE recurrence.
Eighteen patients (53%) were in the acute phase, and 16 patients (47%) were in the chronic phase at the time of PET. In the acute phase, patients with LGI1 AE on FDG-PET mainly presented with hypermetabolism in the BG (median normalized SUVmax = 2.5, IQR 2.2–3.4) and MTL (median normalized SUVmax = 1.5, IQR 1.3–3.2) compared with 20 normal subjects. BG (median normalized SUVmax = 2.3, IQR 2.1–3.1) and MTL (median normalized SUVmax = 1.4, IQR 1.3–2.1) on FDG-PET showed still a hypermetabolism in the chronic phase. FDG-PET hypermetabolism was specifically located in the BG and MTL, whether it was in the acute phase or chronic phase (
18F-FDG-PET characteristics of LGI1 AE patients in different clinical phases. FDG-PET hypermetabolism was specifically located in the BG and MTL, whether it was in the acute phase or chronic phase, and there is no statistical metabolic change between acute and chronic phases for BG and MTL. LGI1, leucine-rich glioma-inactivated 1; AE, autoimmune encephalitis; 18F-FDG-PET, 18F-fluoro-2-deoxy-
The EEG characteristics of all subjects during the ictal and interictal phases were reviewed. A total of 25 patients (74%) experienced EEG abnormalities, which mainly included ictal or interictal EEG with slow wave activities and epileptic discharge in the temporal and frontal regions. However, no rhythmic discharges related to FBDS were noted except for artifacts of movements that were observed at the onset of dystonic seizures in eight patients with FBDS during the ictal phase. One subject with FBDS showed questionable low voltages in the right central and parietal areas around 5 s from onset (
Ictal EEG pattern in an LGI1 AE patient with FBDS.
All 34 patients (100%) were treated with first-line immunotherapy, including IV immunoglobulin (IVIG), IV methylprednisolone (IVMP), and oral steroids (for at least 6 months). A total of 26 patients (76%) were administered IVIG in combination with IVMP, whereas three patients (9%) used isolated IVIG and five patients (15%) received IVMP alone. Only one patient was administered azathioprine and mycophenolate mofetil (MMF) owing to the progression of the disease. Modified Rankin scores (mRS) were applied to evaluate the treatment response. Most patient conditions were improved following immunomodulatory therapies (mRS ≤ 2).
However, eight patients (24%) had a recurrence after a median follow-up of 1.55 years (range, 0.3–4 years). The distribution of metabolic patterns in the eight patients who relapsed is shown in
In this study, we demonstrated that MRI plays a significant role in the diagnosis of anti-LGI1 encephalitis, whose main features are MTL or BG hyperintensities on T2WI/FLAIR. MRI was abnormal in 59% of subjects with LGI1 AE. We also described a specific metabolic pattern of 18F-FDG-PET among a cohort of subjects with anti-LGI1 encephalitis and further compared functional PET imaging with structural MRI regarding the diagnosis of LGI1 AE. The rate of abnormal brain metabolism based on 18F-FDG-PET imaging was 91%, and 18F-FDG-PET imaging was diagnostically more sensitive than MRI in patients with LGI1 AE, with 79% of subjects exhibiting altered glucose metabolism on 18F-FDG-PET in the absence of any abnormal MRI findings. The associated locations of the abnormal metabolism mainly included the BG and MTL, and the rate of abnormal findings in the BG and MTL was 82 and 68%, respectively. Our results suggest that 18F-FDG-PET abnormalities may support the evidence for a clinical diagnosis of subjects with anti-LGI1 encephalitis. In addition, this study introduces a novel 18F-FDG-PET pattern consisting of isolated striatal hypermetabolism in subjects with LGI1-mediated FBDS. Isolated striatal hypermetabolism was detected in 44% of subjects with FBDS but only in 7% of patients without FBDS. As a subject without FBDS exhibited isolated striatal hypermetabolism, we concluded that the BG might also be involved in the development of FBDS to a certain extent.
Brain glucose metabolism is closely associated with neuronal activity. Regional hypermetabolism may reflect exuberant neuronal activities induced by the inflammatory lesions of encephalitis. Furthermore, abnormalities in brain metabolic dysfunction usually change dynamically and currently precede structural changes. Our results primarily showed hypermetabolism or a healthy metabolism based on 18F-FDG-PET scans in LGI1 AE subjects at first hospitalization, which was potentially consistent with prior studies (
Our results mainly showed an abnormal metabolic pattern among LGI1 AE subjects in the BG and MTL. However, we also found abnormal hypermetabolism in the striatal, cerebellar, and cortex areas in some individual cases (data not shown) (
The origin of FBDS has been extensively debated, but no definite conclusions have been reached to date. Ictal EEG and neuroimaging examinations are the two main methods in current clinical use for explaining the etiology or localization of FBDS. On the one hand, ictal EEG mainly suggests an epileptic origin for FBDS, showing slow waves or epileptiform discharges in the temporal area during FBDS (
The main limitations of this study are as follows. (1) The study is retrospective in nature: as not all subjects diagnosed with LGI1 AE during the observation period consented to performing an 18F-FDG-PET examination, a potential selection bias due to the small sample size may have been introduced. (2) Not all subtypes of AE were represented to be evaluated for an FDG pattern. (3) At the time point of the study, the diagnosis of LGI1 AE was mainly based on detection of antibodies, which might not necessarily match the final definite diagnosis in the further course of the disease. Therefore, our study was exploratory, and confirmatory tests should be taken with caution. Extensive prospective studies are required to verify the metabolism patterns of LGI1 AE, and a standardized 18F-FDG-PET protocol is also needed to meet the requirements for diagnosing LGI1-associated AE.
18F-FDG-PET imaging was more sensitive than MRI in the diagnosis of anti-LGI1 encephalitis, and BG and MTL hypermetabolism are two distinctive targets for LGI1 AE compared to other subtypes of AE. Isolated BG hypermetabolism was more frequently observed in subjects with FBDS and potentially suggests the involvement of BG.
The datasets generated for this study are available on request to the corresponding author.
The studies involving human participants were reviewed and approved by this study was approved by the Ethics committee of the Beijing Tiantan hospital that was affiliated to the Capital Medical University of the People's Republic of China. The patients/participants provided their written informed consent to participate in this study.
XL, WSha, and QW recruited, diagnosed, and assessed patients. XL, WSha, QW, XZ, JR, GR, CC, WShi, RL, ZL, and YL worked on the establishment of the separate databases. XL and WSha drafted a significant portion of the manuscript or figures. LA and QW reanalyzed and interpreted all final data. All authors contributed to the current version of the paper regarding conception or design, data analysis or editing, and read and approved the final manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors also thank the patients for their participation, all referring physicians, and Yanxue Zhao and Wei Zhang for technical assistance.
The Supplementary Material for this article can be found online at:
The volume of quantitative 18F-FDG-PET based on VOI in one representative subject. For the frontal cortex, the size of the volume was 25 * 20 * 9.9mm, and the center coordinate of the volume was 72, 135, 30. For the MTL, the size of the volume was 40 * 25 * 9.9mm, and the center coordinate of the volume was 112, 103, 18. For the BG, it was 40 * 30 * 9.9mm, and the center coordinate was 109, 110, 23. 18F-FDG-PET, 18F-fluoro-2-deoxy-d-glucose positron emission tomography; VOI, volume of interest; MTL, medial temporal lobe; BG, basal ganglia.
18F-Fluoro-2-deoxy-
autoimmune encephalitis
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
basal ganglia
contactin-associated protein-2
cerebrospinal fluid
computed tomography
electroencephalogram
faciobrachial dystonic seizures
γ-aminobutyric acid type B
leucine-rich glioma-inactivated 1
medial temporal lobe
magnetic resonance imaging
statistical parametric mapping
standardized uptake max value.