Persistent Bilateral [18F]THK5351 and Migrating Unilateral [18F]FDG Uptake in Anti-LGI1 Encephalitis.

Malignant Mimics of Trigeminal Schwannoma

This study introduced new MRI techniques such as neurite orientation dispersion and density imaging (NODDI); NODDI applies a three-compartment tissue model to multishell DWI data that allows the examination of both the intra- and extracellular properties of white matter tissue. This, in turn, enables us to distinguish the two key aspects of axonal pathology—the packing density of axons in the white matter and the spatial organization of axons (orientation dispersion (OD)). NODDI is used to detect possible abnormalities of posttraumatic encephalomalacia fluid-attenuated inversion recovery (FLAIR) hyperintense lesions in neurite density and dispersion. Methods. 26 epilepsy patients associated with FLAIR hyperintensity around the trauma encephalomalacia region were in the epilepsy group. 18 posttraumatic patients with a FLAIR hyperintense encephalomalacia region were in the nonepilepsy group. Neurite density and dispersion affection in FLAIR hyperintense lesions around encephalomalacia were measured by NODDI using intracellular volume fraction (ICVF), and we compare these findings with conventional diffusion MRI parameters, namely, fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Differences were compared between the epilepsy and nonepilepsy groups, as well as in the FLAIR hyperintense part and in the FLAIR hypointense part to try to find neurite density and dispersion differences in these parts. Results. ICVF of FLAIR hyperintense lesions in the epilepsy group was significantly higher than that in the nonepilepsy group (P < 0.001). ICVF reveals more information of FLAIR(+) and FLAIR(-) parts of encephalomalacia than OD and FA and ADC. Conclusion. The FLAIR hyperintense part around encephalomalacia in the epilepsy group showed higher ICVF, indicating that this part may have more neurite density and dispersion and may be contributing to epilepsy. NODDI indicated high neurite density with the intensity of myelin in the FLAIR hyperintense lesion. Therefore, NODDI likely shows that neurite density may be a more sensitive marker of pathology than FA.

We appreciate the issues raised by Gama-Marques et al. in their letter regarding the use of intravenous ketamine for the treatment of catatonia in schizophrenia.1 The patient described in this case had a longstanding history of schizophrenia, diagnosed 15 years ago, as noted in the case report. She did not have an acute diagnosis of schizophrenia. She presented with classic symptoms of catatonia, and organic causes were ruled out. Her magnetic resonance imaging (MRI) of the brain was entirely normal, with no findings suggestive of encephalitis. For instance, in autoimmune encephalitis, MRI findings are abnormal in approximately 61% of cases. The most common abnormalities are T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities in the limbic system, particularly in the medial temporal lobes, including the hippocampus and amygdala. Brainstem and cerebellar involvement is more common in cases with intracellular antigen antibodies, while leptomeningeal enhancement is more common with extracellular antigen antibodies.2 In viral encephalitis, such as herpes simplex virus (HSV) encephalitis, MRI typically shows T2 and FLAIR hyperintensities in the temporal lobes, often accompanied by swelling and contrast enhancement. Diffusion-weighted imaging (DWI) may show restricted diffusion in affected areas.3, 4 For encephalitis caused by Japanese encephalitis virus (JEV) and dengue virus, thalamic lesions are frequently observed, more commonly in JEV, though they can also occur in dengue encephalitis.5 In cases of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, MRI findings can be normal in up to 49% of patients. When abnormalities are present, they often appear as T2 or FLAIR hyperintensities in various brain regions, including the cortex, subcortical white matter, and basal ganglia.6, 7 Overall, MRI is a crucial tool in diagnosing encephalitis, with specific patterns aiding in identifying the underlying cause. Additionally, the patient did not exhibit symptoms such as fever, chills, or neck pain. Her physical examination showed no signs of meningoencephalitis. Her blood chemistries, thyroid function tests, urinalysis, white cell count, procalcitonin level, blood cultures, urine cultures and extensive autoimmune workup were all normal. A lumbar puncture was not performed in this case due to these findings and the clinical improvement following treatment for catatonia. Furthermore, the patient returned to her baseline condition after treatment with intravenous ketamine and remained stable at 2-month follow-up. Dementia is generally considered an irreversible condition primarily due to the nature of neurodegenerative diseases like Alzheimer's disease (AD). AD is characterized by progressive and irreversible cognitive decline, driven by complex pathological processes including the accumulation of amyloid-beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. These pathological changes lead to synaptic dysfunction, neuronal loss, and brain atrophy, which collectively result in the progressive deterioration of cognitive functions.8-10 Furthermore, dementia would not improve with ketamine therapy. If the patient had infectious, autoimmune, or another type of encephalitis, or an alternative diagnosis, her condition would likely not have improved and could have resulted in death without appropriate treatment for infection, autoimmune disease, or other underlying causes. The author declares no conflict of interest.

Background: Fluid-attenuated inversion recovery (FLAIR) hyperintensity within an acute cerebral infarct may reflect delayed onset time and increased risk of hemorrhage after thrombolysis. Given the important implications for clinical practice, we examined the prevalence of FLAIR hyperintensity in patients 3–6 h from stroke onset and its relationship to parenchymal hematoma (PH). Methods: Baseline DWI and FLAIR imaging with subsequent hemorrhage detection (ECASS criteria) were prospectively obtained in patients 3–6 h after stroke onset from the pooled EPITHET and DEFUSE trials. FLAIR hyperintensity within the region of the acute DWI lesion was rated qualitatively (dichotomized as visually obvious or subtle (i.e. only visible after careful windowing)) and quantitatively (using relative signal intensity (RSI)). The association of FLAIR hyperintensity with hemorrhage was then tested alongside established predictors (very low cerebral blood volume (VLCBV) and diffusion (DWI) lesion volume) in logistic regression analysis. Results: There were 49 patients with pre-treatment FLAIR imaging (38 received tissue plasminogen activator (tPA), 5 developed PH). FLAIR hyperintensity within the region of acute DWI lesion occurred in 48/49 (98%) patients, was obvious in 18/49 (37%) and subtle in 30/49 (61%). Inter-rater agreement was 92% (ĸ = 0.82). The prevalence of obvious FLAIR hyperintensity did not differ between studies obtained in the 3–4.5 h and 4.5–6 h time periods (40% vs. 33%, p = 0.77). PH was poorly predicted by obvious FLAIR hyperintensity (sensitivity 40%, specificity 64%, positive predictive value 11%). In univariate logistic regression, VLCBV (p = 0.02) and DWI lesion volume (p = 0.03) predicted PH but FLAIR lesion volume (p = 0.87) and RSI (p = 0.11) did not. In ordinal logistic regression for hemorrhage grade adjusted for age and baseline stroke severity (NIHSS), increased VLCBV (p = 0.002) and DWI lesion volume (p = 0.003) were associated with hemorrhage but FLAIR lesion volume (p = 0.66) and RSI (p = 0.35) were not. Conclusions: Visible FLAIR hyperintensity is almost universal 3–6 h after stroke onset and did not predict subsequent hemorrhage in this dataset. Our findings question the value of excluding patients with FLAIR hyperintensity from reperfusion therapies. Larger studies are required to clarify what implications FLAIR-positive lesions have for patient selection.

Herpes Simplex Encephalitis Affecting the Entire Limbic System

Rapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy. To identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD). This cross-sectional study involved a retrospective, blinded analysis of the first available brain MRIs (taken 2000-2022) from 192 patients at Oxford University Hospitals in the UK and Mayo Clinic in the US. These patients had LGI1/CASPR2-Ab-E, VE, or CJD as evaluated by 2 neuroradiologists (discovery cohort; n = 87); findings were validated in an independent cohort by 3 neurologists (n = 105). Groups were statistically compared with contingency tables. Data were analyzed in 2023. MRI findings including T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities, swelling or volume loss, presence of gadolinium contrast enhancement, and diffusion-weighted imaging changes. Correlations with clinical features. Among 192 participants with MRIs reviewed, 71 were female (37%) and 121 were male (63%); the median age was 66 years (range, 19-92 years). By comparison with VE and CJD, in LGI1/CASPR2-Ab-E, T2 and/or FLAIR hyperintensities were less likely to extend outside the temporal lobe (3/42 patients [7%] vs 17/18 patients [94%] with VE; P < .001, and 3/4 patients [75%] with CJD; P = .005), less frequently exhibited swelling (12/55 [22%] with LGI1/CASPR2-Ab-E vs 13/22 [59%] with VE; P = .003), and showed no diffusion restriction (0 patients vs 16/22 [73%] with VE and 8/10 [80%] with CJD; both P < .001) and rare contrast enhancement (1/20 [5%] vs 7/17 [41%] with VE; P = .01). These findings were validated in an independent cohort and generated an area under the curve of 0.97, sensitivity of 90%, and specificity of 95% among cases with T2/FLAIR hyperintensity in the hippocampus and/or amygdala. In this study, T2 and/or FLAIR hyperintensities confined to the temporal lobes, without diffusion restriction or contrast enhancement, robustly distinguished LGI1/CASPR2-Ab-E from key differential diagnoses. These observations should assist clinical decision-making toward expediting immunotherapy. Their generalizability to other forms of autoimmune encephalitis and VE should be examined in future studies.

Matrix metalloproteinase-9 (MMP-9) is elevated in patients with acute stroke who later develop hemorrhagic transformation (HT). It is controversial whether early fluid-attenuated inversion recovery (FLAIR) hyperintensity on brain MRI predicts hemorrhagic transformation (HT). We assessed whether FLAIR hyperintensity was associated with MMP-9 and HT. We analyzed a prospectively collected cohort of acute stroke subjects with acute brain MRI images and MMP-9 values within the first 12 hours after stroke onset. FLAIR hyperintensity was measured using a signal intensity ratio between the stroke lesion and corresponding normal contralateral hemisphere. MMP-9 was measured using enzyme-linked immunosorbent assay. The relationships between FLAIR ratio (FR), MMP-9, and HT were evaluated. A total of 180 subjects were available for analysis. Patients were imaged with brain MRI at 5.6±4.3 hours from last seen well time. MMP-9 blood samples were drawn within 7.7±4.0 hours from last seen well time. The time to MRI (r=0.17, P=0.027) and MMP-9 level (r=0.29, P<0.001) were each associated with FR. The association between MMP-9 and FR remained significant after multivariable adjustment (P<0.001). FR was also associated with HT and symptomatic hemorrhage (P=0.012). FR correlates with both MMP-9 level and risk of hemorrhage. FLAIR changes in the acute phase of stroke may predict hemorrhagic transformation, possibly as a reflection of altered blood-brain barrier integrity.

The Role of the Signal Intensity Ratio on Fluid-Attenuated Inversion Recovery in Stroke Patients Achieving Successful Recanalization with Endovascular Treatment

Gliomas with mutant isocitrate dehydrogenase (IDH) produce high levels of 2-hydroxyglutarate (2HG) that can be quantitatively measured by 3D magnetic resonance spectroscopic imaging (MRSI). Current glioma MRI primarily relies upon fluid-attenuated inversion recovery (FLAIR) hyperintensity for treatment planning, although this lacks specificity for tumor cells. Here, we investigated the relationship between 2HG and FLAIR in mutant IDH glioma patients to determine whether 2HG mapping is valuable for radiotherapy planning. Seventeen patients with mutant IDH1 gliomas were imaged by 3 T MRI. A 3D MRSI sequence was employed to specifically image 2HG. FLAIR imaging was performed using standard clinical protocol. Regions of interest (ROIs) were determined for FLAIR and optimally thresholded 2HG hyperintensities. The overlap, displacement, and volumes of 2HG and FLAIR ROIs were calculated. In 8 of 17 (47%) patients, the 2HG volume was larger than FLAIR volume. Across the entire cohort, the mean volume of 2HG was 35.3 cc (range, 5.3-92.7 cc), while the mean volume of FLAIR was 35.8 cc (range, 6.3-140.8 cc). FLAIR and 2HG ROIs had mean overlap of 0.28 (Dice coefficients range, 0.03-0.57) and mean displacement of 12.2 mm (range, 3.2-23.5 mm) between their centers of mass. Our results indicate that for a substantial number of patients, the 2HG volumetric assessment of tumor burden is more extensive than FLAIR volume. In addition, there is only partial overlap and asymmetric displacement between the centers of FLAIR and 2HG ROIs. These results may have important implications for radiotherapy planning of IDH mutant glioma.

Fluid-Attenuated Inversion Recovery Hyperintensity Is Associated with Hemorrhagic Transformation following Reperfusion Therapy

The purpose of this study was to identify markers from perfusion, diffusion, and chemical shift imaging in glioblastomas (GBMs) and to correlate them with genetically determined and previously published patterns of structural magnetic resonance (MR) imaging. Twenty-six patients (mean age 60 years, 13 female) with GBM were investigated. Imaging consisted of native and contrast-enhanced 3D data, perfusion, diffusion, and spectroscopic imaging. In the presence of minor necrosis, cerebral blood volume (CBV) was higher (median ± SD, 2.23% ± 0.93) than in pronounced necrosis (1.02% ± 0.71), pcorr = 0.0003. CBV adjacent to peritumoral fluid-attenuated inversion recovery (FLAIR) hyperintensity was lower in edema (1.72% ± 0.31) than in infiltration (1.91% ± 0.35), pcorr = 0.039. Axial diffusivity adjacent to peritumoral FLAIR hyperintensity was lower in severe mass effect (1.08*10-3 mm2/s ± 0.08) than in mild mass effect (1.14*10-3 mm2/s ± 0.06), pcorr = 0.048. Myo-inositol was positively correlated with a marker for mitosis (Ki-67) in contrast-enhancing tumor, r = 0.5, pcorr = 0.0002. Changed CBV and axial diffusivity, even outside FLAIR hyperintensity, in adjacent normal-appearing matter can be discussed as to be related to angiogenesis pathways and to activated proliferation genes. The correlation between myo-inositol and Ki-67 might be attributed to its binding to cell surface receptors regulating tumorous proliferation of astrocytic cells.

A 40-year-old woman with no medical history presented to the emergency department with rapid onset of numbness that spread from the right torso to the entire right side, including the face, body, and limbs. She also presented with a left facial droop, slurred speech, and confusion. The episode resolved after 90 minutes. She endorsed experiencing nausea, fatigue, and hand tremors for 1 month after a flu-like illness. Coronavirus disease 2019 (COVID-19) and Epstein–Barr virus serologies were negative. Cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis with negative HSV, VZV, Lyme, cryptococcal antigen, and autoimmune encephalitis panel. She was discharged with outpatient follow-up. Ten days later, she re-presented to the emergency department with a 60-minute acute episode of bilateral hand numbness, visual obscurations, and slurred speech. She also reported persistent retro-orbital headaches ever since her initial emergency department visit. Physical examination was notable for a mild right-sided intention tremor and difficulty with tandem walking. Her strength and sensation were intact. Ophthalmologic examination showed mild blurring of the disc margins bilaterally. Brain magnetic resonance imaging (MRI) showed radial perivascular enhancement extending from the ventricles (Fig 1A, B) with FLAIR hyperintensity (Fig1 C). Cervicothoracic spine MRI showed extensive longitudinal intramedullary T2-hyperintensity (Fig1 D, E) with speckled foci of cord enhancement (Fig F). Axial T2-weighted (Fig1 G) and postcontrast (Fig1 H) images confirmed these findings. The imaging appearance prompted testing for anti-glial fibrillary acidic protein (GFAP) in the CSF, which was positive and confirmed the diagnosis of anti-GFAP astrocytopathy. She was treated with 5 days of intravenous steroids followed by a prolonged oral steroid taper. Six weeks later the patient's headaches and tremors resolved with no further episodes of paresthesias. Follow-up brain and cervicothoracic spine MR examinations at 6 weeks showed resolution of both the enhancement in the neuroaxis and longitudinal T2-hyperintensity in the cord. In the brain, residual confluent white matter fluid-attenuated inversion recovery (FLAIR) hyperintensity remained. Anti-GFAP astrocytopathy is a relatively new entity, first described in 2016 by Fang et al.1 Antibodies target glial fibrillary acidic protein, a cytosolic intermediate filament protein expressed by astrocytes. Immunostaining localizes protein expression to the perivascular regions of the brain and around the central canal of the spinal cord, and these autoantibodies lead to lymphocytic inflammation corresponding to the distribution of enhancement seen on imaging.1 Its prevalence is unclear due to the rarity of the condition and is probably as yet underdiagnosed. There is a slight predominance of female patients and those over 40 years of age, although pediatric cases have also been reported.2 It classically presents with symptoms of meningoencephalomyelitis including headache, encephalopathy, optic papillitis, inflammatory myelitis, postural tremor, and ataxia.1 A viral prodrome is sometimes identified. It is thought in some cases to represent a paraneoplastic syndrome: in one study of 102 patients, 22 were diagnosed with neoplasm, 15 of which were ovarian teratoma.3 In addition to the characteristic radial pattern of perivascular enhancement in the white matter in the brain, MRI of the spine can show longitudinally extensive T2 hyperintensity and leptomeningeal or parenchymal enhancement.1 Most patients respond well to corticosteroids.4 We would like to extend our gratitude to the patient for her willingness to contribute to a broader understanding of her underlying condition. None of the authors have a conflict of interest, financial or otherwise, with the content of this submission.

Transient fluid-attenuated inversion recovery (FLAIR) hyperintensity is often observed on the operated brain surface after direct or combined bypass surgery for moyamoya disease, but its pathophysiology and clinical significance are still obscure. This study was aimed to clarify the underlying mechanism and clinical significance. This prospective study included 106 hemispheres of 61 patients with moyamoya disease and analyzed their radiological findings before and after combined bypass surgery. This study also included 11 patients who underwent superficial temporal artery to middle cerebral artery anastomosis for occlusive carotid artery diseases as the controls. Magnetic resonance imaging examination was serially repeated, and cerebral blood flow was measured before and after surgery. Signal intensity ratio (SIR) in the cortical sulci and cortex to the adjacent white matter on FLAIR images was calculated, and the postoperative SIR changes were semi-quantitatively evaluated to assess the temporal profile of postoperative FLAIR hyperintensity. Postoperative FLAIR hyperintensity occurred within the cortical sulci on the operated hemispheres in all moyamoya patients but not in patients with occlusive carotid artery diseases. SIR values started to increase immediately after surgery, peaked at about 4-fold at 4-13 days post-surgery, then declined, and recovered to baseline values over 28 days or later. The magnitude of this phenomenon was proportional to the severity of cerebral ischemia but not to postoperative hyperperfusion. Reversible sulcal FLAIR hyperintensity specifically occurs in the operated hemispheres after direct bypass surgery for moyamoya disease. This "crevasse sign" may represent the mixture of the extensive leakage of oxygen and proteins from the pial arteries into the CSF.

The splenium of the corpus callosum plays a pivotal role in interhemispheric communication and undergoes various changes with ageing. The present study aimed to elucidate the age-related variations in splenial fluid-attenuated inversion recovery (FLAIR) hyperintensity, providing insights into the normal ageing process of the brain and enhancing the clinical interpretation of magnetic resonance (MR) imaging. In the present retrospective cohort study, cerebral MR imaging of 1,176 patients was analysed following application of strict inclusion and exclusion criteria to isolate age and sex-related changes and other factors that can affect splenium hyperintensity. The present study focused on measuring the thickness (anteroposterior) of splenial FLAIR hyperintensity, with interobserver agreement assessed to ensure measurement reliability. Statistical analyses, including the Mann-Whitney U test for sex comparisons and the Kruskal-Wallis test for age group comparisons, were employed to investigate the effects of age, sex, radiation therapy and Fazekas score on splenial FLAIR hyperintensity. The present study demonstrated a significant increase in the presence of splenial FLAIR hyperintensity and thickness (P<0.001; P=0.006) with advancing age, particularly in individuals >57 years of age. No significant differences were observed between male and female participants, suggesting that these age-related changes were consistent across sex. Splenium hyperintensity thickness was significantly higher in the group that received radiation therapy and in the patient group with a Fazekas score of 3 (0.048, 0.018). Interobserver agreement was evaluated using the intraclass correlation coefficient (ICC) to assess measurement consistency (ICC=0.977; P<0.001). The present study provides crucial insights into the age-related dynamics of the splenium.

The Colloid Cyst Risk Score (CCRS) was developed to identify symptomatic patients and stratify risk of hydrocephalus among patients with colloid cysts. Its components consider patient age, cyst diameter, presence/absence of headache, fluid-attenuated inversion recovery (FLAIR) hyperintensity, and location within the third ventricle. To independently evaluate the inter- and intrarater reliability of the CCRS. Patients with a colloid cyst were identified from billing records and radiology archives. Three independent raters reviewed electronic medical records to determine age, presence/absence of headache, cyst diameter (mm), FLAIR hyperintensity, and risk zone location. Raters made 53 observations, including 5 repeat observations.Fleiss' generalized kappa (κ) was calculated for all of the nominal criteria, whereas Kendall's coefficient of concordance (W) and the intraclass correlation coefficient (ICC) were calculated for the overall score. Total CCRS score demonstrated extremely strong agreement (W=0.83) using Kendall's W coefficient and good agreement (ICC=0.74) using the ICC (P<.001). For interrater reliability of individual criteria, age (κ=1.00) and FLAIR hyperintensity (κ=0.89) demonstrated near perfect agreement. Axial diameter (κ=0.63) demonstrated substantial agreement, whereas agreement was moderate for risk zone (κ=0.51) and fair for headache (κ=0.26). Intrarater reliability for total CCRS score was extremely strong using Kendall's W, good to excellent using ICC, and fair to substantial using weighted kappa. The CCRS has good inter- and intrarater reliability when tested in an independent sample of patients, though strength of agreement varies among individual criteria. The validity of the CCRS requires independent evaluation.