Different FDG-PET metabolic patterns of anti-AMPAR and anti-NMDAR encephalitis: Case report and literature review

Abstract

Introduction: ¹⁸ F-fluorodeoxyglucose (FDG)-PET metabolic patterns of brain differ among autoimmune encephalitis with different neuronal surface antigens. In this case report, we compared the topographical relationship of cerebral glucose metabolism and antigen distribution in the patients with anti-NMDAR and anti-AMPAR encephalitis. Literature review summarized the common features of brain metabolism of autoimmune encephalitis.

Methods: The cerebral glucose metabolism was evaluated by FDG-PET/CT during acute-to-subacute stage of autoimmune encephalitis and after treatment. The stereo and quantitative analysis of cerebral metabolism used standardized z-score and visualized on three-dimensional stereotactic surface projection. To map NMDAR and AMPAR in human brain, we adopted genetic atlases from the Allen Institute and protein atlases from Zilles's receptor densities.

Results: The three-dimensional stereotactic surface projection displayed frontal-dominant hypometabolism in a 66-year-old female patient with anti-AMPAR encephalitis and occipital-dominant hypometabolism in a 29-year-old female patient with anti-NMDAR encephalitis. Receptor density maps revealed opposite frontal-occipital gradients of AMPAR and NMDAR, which reflect reduced metabolism in the correspondent encephalitis. FDG-PET hypometabolic areas possibly represent receptor hypofunction with spatial correspondence to receptor distributions of the autoimmune encephalitis. The reversibility of hypometabolism was in line with patients' cognitive improvement. The literature review summarized six features of metabolic anomalies of autoimmune encephalitis: (a) temporal hypermetabolism, (b) frontal hypermetabolism and (c) occipital hypometabolism in anti-NMDAR encephalitis, (d) hypometabolism in association cortices, (e) sparing of unimodal primary motor cortex, and (e) reversibility in recovery.

Conclusions: The distinct cerebral hypometabolic patterns of autoimmune encephalitis were representative for receptor hypofunction and topographical distribution of antigenic receptors. The reversibility of hypometabolism marked the clinical recovery of autoimmune encephalitis and made FDG-PET of brain a valuable diagnostic tool.

Keywords: FDG-PET; autoimmune encephalitis; hypermetabolism; hypometabolism; receptor density map.

Figure 1

MRI and FDG‐PET/CT of anti‐AMPAR encephalitis (patient 1). Patient 1 was a 66‐year‐old female patient presenting with acute psychosis, personality change, progressive aphasia, and consciousness impairment 3 days after surgery to remove left breast cancer. The diagnosis of anti‐AMPAR encephalitis was made based on clinical symptoms and antibodies detected in her CSF and serum. Initial MRI was nonspecific, but brain FDG‐PET/CT was widely affected with right frontal‐dominant hypometabolism as well as posterior parietal, lateral temporal, and primary visual cortex hypometabolism. Primary sensorimotor cortices were relatively more active than other cortical areas. After immunotherapy, improvement of cortical hypometabolism accompanied clinical improvement. On the second PET scan, only scattered hypometabolism was noticed over the previously affected areas

Figure 2

MRI and FDG‐PET/CT of anti‐NMDAR encephalitis (patient 2). A 29‐year‐old female patient with subacute psychosis, consciousness alternation, and status epilepticus for 3 weeks was diagnosed as having anti‐NMDAR encephalitis. T2‐weighted FLAIR images of MRI revealed mild edema and hyperintensities of the bilateral mesial temporal area. After 6 weeks of immunotherapy, FDG‐PET/CT at the 9th week from the first symptoms revealed occipital‐dominant hypometabolism, which was compatible with previously reported distinct hypometabolic patterns of anti‐NMDAR encephalitis. Relative hypermetabolism at the primary sensorimotor cortices, lateral temporal area, inferior parietal area, and pons was noticed in the uptake ratio of scan 1. The occipital hypometabolism resolved in the second PET scan at the 17th week from onset, but new medial frontal to anterior cingulate hypometabolism occurred

Figure 3

Gene expression level of the Human Brain Atlas of Allen Institute. Genetic expression levels varied according to brain regions. Allen's Human Brain Atlas (available from: human.brain‐map.org) provided microarray expression by anatomical segmentations. Through various probes, the patterns of genetic expression were similar with some differences between AMPAR and NMDAR. A high hippocampal level of gene expression was observed in AMPAR and NMDAR. Expression of the thalamus was noticed in NMDAR but not AMPAR. Genetic expression was neutral in the cerebellum for AMPAR but low for NMDAR. The pontine and medullar expression level was low for AMPAR but moderate for NMDAR. Abbreviations: FL, frontal lobe. INS, insula. CgG, cingulate gyrus. HiF, hippocampal formation. OL, occipital lobe. PL, parietal lobe. TL, temporal lobe. Amg, amygdala. BG, basal ganglia. Hy, hypothalamus. TH, thalamus. Mid, midbrain. Cb, cerebellum. Pons, pons. MY, myelencephalon

Figure 4

Protein density map modified from Zilles's receptor map. Zilles et al published the cytoarchitecture features of brain regions in 2017 (Zilles & Palomero‐Gallagher, 2017). They stated that the amount and layer difference of each transmitter receptor defined regions of the brain. AMPAR and NMDAR are both glutaminergic receptors of the neuronal surface. We transformed Zilles's brain regions to Brodmann areas and averaged the protein densities of the original regions to Brodmann areas. When comparing their distributions and densities, temporal and parietal association areas were both moderately dense for AMPAR and NMDAR; however, the frontal density was high for AMPAR, and the occipital density was high for NMDAR. Both AMPAR and NMDAR spared the primary motor, primary sensory, and primary auditory cortices. The unit of protein density was fmol/mg of protein