Multimodality Imaging of Anti-Contactin-Associated Protein-Like 2 Antibody-Induced Nonparaneoplastic Limbic Encephalitis: Complementary Role of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography and Magnetic Resonance Imaging

Introduction

Autoimmune limbic encephalitis (AE) is an autoimmune-mediated inflammation typically affecting the medial temporal lobes and other limbic structures (cingulate gyrus, orbital cortex, and hypothalamus). Patients show rapidly progressive short-term memory deficits, psychiatric symptoms, and seizures. In patients whose presentation is consistent with that of AE, testing typically used to aid in the diagnosis of AE includes magnetic resonance imaging (MRI) of the brain with contrast, electroencephalogram (EEG), and blood and cerebrospinal fluid analysis for the markers of inflammation. However, negative test results for autoimmune antibodies does not rule out AE. A significant percentage of AE cases may be caused by other, still unknown antibodies, or by known antibodies for which a diagnostic test is not yet available. We present a rare clinical case of anti-contactin-associated protein-like 2 (anti-CASPR2) antibody limbic encephalitis and discuss various findings on fluorine-18 fluorodeoxyglucose positron emission tomography computed tomography (F-18 FDG PET/CT) and MRI.

Case Report

A 62-year-old male has been reported with complaints of behavioral changes in the form of irritability, anger, delusions, and poor attention. He also had multiple episodes of generalized tonic–clonic seizures, giddiness on standing, urinary incontinence, constipation, and insomnia for 4 months.

On examination, he was conscious but disoriented with poor attention span. He also had asterixis, myoclonic jerk, dysarthria, brisk deep-tendon reflexes, and postural hypotension (supine blood pressure 160/100 mmHg-standing blood pressure 80/60 mmHg). Cranial nerve examination, sensory system, and cerebellar signs were normal.

Routine blood investigations, including hemogram, serum electrolytes, biochemistry, viral markers, thyroid profile, and complete cerebrospinal fluid analysis, were normal. EEG showed diffuse delta waves slowing with no triphasic waves. His serum thyroid-stimulating hormone and Vitamins B12 level were normal. Clinical suspicion of neurodegenerative disorder, paraneoplastic encephalitis, or Creutzfeldt–Jakob disease was considered differentials.

MRI imaging of the brain was performed, as described below. F-18 FDG PET/CT was performed 2 days after MRI brain.

Magnetic resonance imaging

MRI revealed hyperintense signal in bilateral medial temporal lobes on T2 and fluid-attenuated inversion recovery (FLAIR) sequences with more pronounced involvement on the right side. T1 images show subtle hypointense signal; however, no enhancement or diffusion restriction was noted. Some nonspecific foci with FLAIR hyperintense signals were seen in the right frontal lobe. No significant changes were seen in both the basal ganglia. On the basis of MRI findings, the possibility of limbic encephalitis was suggested [Figure 1].

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Figure 1 T2 Weighted (a) Axial image shows hyperintense signal in the right medial temporal lobe(green arrow). On fluid-attenuated inversion recovery (b) Image hyperintense signal in the right medial temporal lobe is more noticeable and in addition, the left medial temporal lobe also shows subtle hyperintense signal(white arrow). T1 precontrast axial image(c) shows hypointense signal in the right medial temporal lobe, while postcontrast axial image (d) shows no abnormal enhancement

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Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography

The patient was referred for F18-FDG PET/CT imaging for further evaluation and to rule out the possibility of the paraneoplastic etiology. PET/CT imaging was performed by an integrated scanner (Biograph™ scanners, PET/CT scanner, Siemens Healthineers, SSP map generation by syngo. MI Neuro software Software-Syno.via MI Neuro Machine-True Point PET-CT System, Biograph 64, Siemens, Germany). Apart from standard PET/CT acquisition, a separate dedicated PET/CT brain images were taken for 5 min in three-dimensional acquisition mode. F-18 FDG-PET showed hypermetabolism in bilateral medial temporal lobes and small patchy areas in the right anterior frontal lobe and left parietal lobe region. symmetrically preserved metabolism was noted in both the basal ganglia [Figure 2a-f]. Moderate hypometabolism was noted in the rest of the brain parenchyma. Stereotactic surface projection images revealed the same findings [Figure 2g-i]. The rest of the body did not show any abnormal FDG uptake.

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Figure 2 Fluorodeoxyglucose positron emission tomography–computed tomography. Upper row (a-c) shows computed tomography scan, which is unremarkable Middle row (fused positron emission tomography–computed tomography) shows global hypometabolism (d, yellow arrow), hypermetabolism in bilateral medial temporal lobes (e, white arrow, right > left), and small area of preserved metabolism in the right anterior frontal lobe (star) and left parietal lobe region (white dot). Symmetrical uptake was noted in the caudate and putamen (f red arrow). The lower row (g-i) shows stereotactic surface projection images that revealed the same findings as on fused positron emission tomography–computed tomography images (blue color represents the reduced uptake and the red color revealing the increased uptake of fluorodeoxyglucose). Red color is more pronounced in the medial temporal lobes, right anterior frontal and left partial lobe

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In view of clinical appearance, MRI and PET/CT findings, a probable diagnosis of nonparaneoplastic limbic encephaliti (NPLE) was made, and antibody panel was ordered. It was positive for antibodies against anti-CASPR2. The patient was started on IV methylprednisolone 500 mg IV/day for 10 days. In view of no response to the steroid, IV immunoglobulin was started. The patient symptomatically improved over next 1 week, he became interactive and oriented, but autonomic dysfunction persisted. The patient was discharged and advised to follow-up.

Discussion

LIMBIC encephalitis presents with varied symptoms, signs, and nonspecific findings on MRI. The high level of suspicious is required for the diagnosis. Paraneoplastic autoimmune limbic encephalitis develops in the presence of an underlying malignancy such as carcinoma lung, thymic, breast, renal, colonic, and ovarian carcinomas.[1] Diagnosis of AE is based on clinical clues in the recognition of particular types AE, exclusion of other autoimmune disorders, infectious and medical causes, antibody testing, and imaging. Patients present with various overlapping symptoms such as psychosis, dystonia, hyperekplexia, seizures, dystonia, and spasm.[2] Various antibodies against intracellular and cell surface antigens have been described. NPLE has no underlying malignancy and responds favorably to immunotherapy.[3] Various kinds of antibodies have been linked with AE. One of the rare kinds of antibody is directed against CASPR2. It has been described in the sera of patients with peripheral and central neurological syndromes, including neuromyotonia, Morvan syndrome, and autoimmune limbic encephalitis.[4] Patient with anti-CASPR2 antibodies AE presents with limbic symptoms, including temporal lobe seizures, memory disorders, and cerebellar ataxia.[5]

Imaging findings on the MRI are nonspecific. It presents as T2 hyperintensity in the FLAIR sequence. Diffusion-weighted imaging positivity and/or enhancement are rarely seen in AE.[6] MRI rules out other pathologies of the brain. Patients can also have normal MRI imaging of the brain, especially in those patients with cell surface-targeted autoantibodies. In a large series of patients with NMDARE, only about one-third of the patients demonstrated any abnormality on brain MRI.[7]

Being a metabolic whole-body imaging, F-18 FDG-PET/CT solves two purposes. It not only rules out paraneoplastic etiology and is more commonly abnormal in AE in comparison to MRI. Abnormalities may be detected on the PET/CT with a normal MRI scan. The frequency of metabolic abnormalities is much greater than that of diagnostic studies currently included in consensus criteria for the diagnosis of AE.[8] F-18 FDG PET/CT in AE usually shows hypermetabolism in the mesial temporal and orbitofrontal cortex, occipital hypometabolism, and symmetrical hypermetabolism in the corpus striatum and amygdala.[9]

Conclusion

AE is a difficult clinical diagnosis; it is a diagnosis by exclusion. MRI may show abnormality only in one-third of the patients. Symptoms are usually out of the proportion of MRI finding, and normal MRI does not exclude AE. Whole-body FDG PET/CT has high probability in identifying AE, and it can rule out paraneoplastic limbic encephalitis with good accuracy. FDG PET/CT may represent a sensitive and early biomarker for AE, and it has potential to become an important tool in the diagnosis and understanding pathophysiology of AE.