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The Gamut of Autoimmune-Mediated Encephalitis

The Gamut of Autoimmune-Mediated Encephalitis. The Emerging Diagnostic Challenge. Wong M, Lee JA, Najjar S, Filippi CG, Mandel S, Pramanik BK. eEdE-34. OUTLINE. Purpose + Methods Introduction Pathophysiology Statistics Classification Paraneoplastic vs Non-Paraneoplastic

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The Gamut of Autoimmune-Mediated Encephalitis

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  1. The Gamut of Autoimmune-Mediated Encephalitis The Emerging Diagnostic Challenge • Wong M, Lee JA, Najjar S, Filippi CG, Mandel S, Pramanik BK • eEdE-34

  2. OUTLINE • Purpose + Methods • Introduction • Pathophysiology • Statistics • Classification • Paraneoplastic vs Non-Paraneoplastic • Intracellular vs Extracellular antigens • Diagnosis • Paraneoplastic Autoimmune-Mediated Encephalitis • Non-Paraneoplastic Autoimmune-Mediated Encephalitis • Mimickers • Conclusion • Nothing to Disclose

  3. PURPOSE +METHODS Although recognition is growing among clinicians, autoimmune-mediated encephalitis (AME) remains unfamiliar to many radiologists. Due to the emphasis on imaging for diagnosis, the neuroradiologist may contribute significantly to the detection of AME and guide further necessary workup. In this exhibit, we wish to introduce the current concepts and knowledge of AME with emphasis on limbic encephalitis as it relates to the neuroradiologist. Utilizing various examples, we present overlapping imaging findings of AME with other diseases to illustrate the diagnostic challenges of AME.

  4. AUTOIMMUNE ENCEPHALITIS AUTOIMMUNE ENCEPHALITIS (AME) typically is referred as an inflammatory CNS condition caused by auto-antibodies. • Most commonly manifests in the limbic system, i.e. limbic encephalitis (LE). • Other autoimmune disorders may cause limbic encephalitis or encephalopathic disease by inducing inflammatory responses without antineuronal antibodies (e.g. Hashimoto’s encephalitis). Depth coded confocal projection image of mouse hippocampus. *Photo by ZEISS Microscopy / CC BY 2.0 *Links provided at the end of the presentation. daRocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  5. AUTOIMMUNE ENCEPHALITIS • For over half a century, AME was considered a paraneoplastic syndrome associated with underlying malignancy [1]. • Only recently were auto-antibodies of non-paraneoplastic origins being discovered and recognized as contributors of neuropsychiatric diseases such as schizophrenia, depression, and epilepsy [2]. • There is growing interest among the neuroscience community to understand the pathophysiological mechanisms of AME and its associations with other neuropsychiatric disorders [2]. 1. Najjar S et al. Neuroinflammation and psychiatric illness. J Neuroinflammation 2013 Apr 1;10:43 2. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  6. Pathophysiology AUTOIMMUNE ENCEPHALITIS Recent research suggests CNS inflammation is caused by a reciprocating cycle of activation and proliferation of CNS and systemic immunologic responses, allowed by blood-brain barrier (BBB) hyperpermeability [1]. Breakdown of the BBB • Exact mechanism is unknown. However, likely secondary to prior injury (e.g. trauma, ischemia, infection) or endothelial dysfunction [2]. Microglial activation and proliferation • Microglia is normally excluded from the systemic environment and provides protective benefits to neurons and CNS environment [2]. • However, peripheral T-helper lymphocytes may cross a hyperpermiable BBB and be activated by antigen-presenting microglial cells in turn inducing an inflammatory cascade that escapes the normal protective feedback mechanism [1,2]. Tissue dysfunction and destruction • Chronic and progressive neuroinflammatory state results in dysfunctional neuronal excitability [2] and eventual neuronal death [1]. GFAP stained atrocytes in vitro showing its contribution to the blood brain barrier around the usual course of a capillary (dark center). *Photoby Dantecat / CC0 *Links provided at the end of the presentation. 1. Najjar S et al. Neuroinflammation and psychiatric illness. J Neuroinflammation 2013 Apr 1;10:43 2. Najjar S et al. Refractory epilepsy associated with microglial activation. Neurologist 2011 Sep;17(5):249-54

  7. Statistics AUTOIMMUNE ENCEPHALITIS • Approximately 30-40% of LE is non-paraneoplastic [1]. • However, up to 40% of non-paraneoplastic autoantibodies have been reported to have underlying neoplastic disease [2]. • To further complicate matters, neuropsychiatric symptoms may manifest months to years before an underlying neoplasm becomes apparent [1]. • Therefore, in a patient with an established diagnosis of non-paraneoplastic AME, neoplastic disease should still be a consideration. 1. daRocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205 2. Ramanathan S et al. Autoimmune encephalitis: recent updates and emerging challenges. J ClinNeurosci2014 May;21(5):722-30

  8. Classification AUTOIMMUNE ENCEPHALITIS AME can be categorized based on its association with neoplasm [1,2] • Paraneoplastic • Non-paraneoplastic AME can be categorized based on its target antigen [1,2] • Intracellular antigens • More commonly associated with paraneoplastic disease. • Surface antigens • More commonly associated with non-paraneoplastic disease. Seronegative Autoimmune Encephalitis • A special entity without detectable pathogenic autoantibody or antigens but with other evidence of CNS inflammation (elevated TNF-alpha levels or brain biopsies revealing histopathological evidence of inflammation) [3]. • Speculated to be caused by a yet to be discovered autoantibody or alternatively, a completely different cellular process [3]. 1. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205 2. Ramanathan S et al. Autoimmune encephalitis: recent updates and emerging challenges. J ClinNeurosci2014 May;21(5):722-30 3. Najjar S et al. Neuropsychiatric autoimmune encephalitis without VGKC-complex, NMDAR, and GAD autoantibodies: case report and literature review. CognBehavNeurol2013 Mar;26(1):36-49

  9. Diagnosis of LE AUTOIMMUNE ENCEPHALITIS • Clinical history and presentation [1] • Memory loss • Seizures • Affect disturbances • Exclusion of other entities (i.e. infection) [2] • Laboratory detection of autoantibodies [1]* • Serum – may yield non-specific results • CSF • Positive findings on MR imaging [1]* *Often autoantibodies are not detected and imaging reveals inconclusive findings. However, a diagnosis of AME should still be considered and immunotherapy should be promptly initiated [2,3]. 1. Bien CG et al. Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav2007 Jun;10(4):529-38 2. Vincent A et al. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol2011 Aug;10(8):759-72 3. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  10. CASE AUTOIMMUNE ENCEPHALITIS Seronegative Autoimmune Encephalitis 69 year-old male with a medical history of myelodysplastic syndrome, dementia, and seizure disorder, presented to the ED for respiratory distress after an episode of choking. Neurological workup was performed for evaluation of esophageal dysmotility as well as myotonic dystrophy and psychosis. A non-contrast enhanced CT image of the head from 2 months prior to admission shows subtle hypoattenuation of the right brachium pontis (arrow).

  11. CASE AUTOIMMUNE ENCEPHALITIS Seronegative Autoimmune Encephalitis • Initial MRI showed T2/FLAIR signal hyperintensity in the mesial temporal lobes and right brachium pontis. • The patient was unable to tolerate follow-up MR exams. After a prolonged course in the hospital and extensive work up, the patient’s condition was concluded to be autoimmune-related. • Laboratory results revealed elevated antinuclear antibody (ANA), a nonspecific indicator of autoimmune disease. Autoantibodies associated with AME and other autoimmune diseases were negative. • Patient received a 5-day course of IVIG resulting in overall clinical improvement. FLAIR image showing focal area of hyperintense signal in the right brachium pontis (arrow). DWI demonstrates no restricted diffusion of the right brachium pontis lesion. T1WI following gadolinium administration shows no enhancement of the right brachium pontis lesion. FLAIR image at the level of the mesial temporal lobes (MTL) show mildly increased signal (arrows), greater on the left.

  12. PARANEOPLASTIC PARANEOPLASTIC AUTOIMMUNE-MEDIATED ENCEPHALITIS

  13. PARANEOPLASTIC The classic Malignancy-associated Monophasic and progressive An autoantibody-mediatedinflammatory CNS disease, first described in the 1960s, is commonly found in association with certain malignant diseases. Hence, patients with AME caused by these autoantibodies should prompt an thorough investigation to look for cancer. Paraneoplastic AME typically responds poorly to immunotherapy and treatment is rather aimed at the underlying malignancy. Ramanathan S et al. Autoimmune encephalitis: recent updates and emerging challenges. J ClinNeurosci2014 May;21(5):722-30

  14. Intracellular Antibodies PARANEOPLASTIC IN SUMMARY • Clinically presents with classic LE symptoms of amnesia, affect disorders, and seizures in addition to dyskinesia and ophthalmologic disorders [1,2]. • AssociatedNeoplasm most commonly with small-cell lung carcinoma. Other associations include germ cell tumor, breast cancer, and thymoma [1,2]. • Imaging findings typically are unilateral or bilateral T2/FLAIR signal abnormality to the limbic structures. There may also be edema, atrophy, and signal abnormalities involving the brainstem or basal ganglia with or without variable restricted diffusion or subtle contrast enhancement [2]. Anti-Hu Anti-Ma2 Anti-CV2/Collapsing Response Mediator Protein-5 Epilepsy or other LE associated signs and symptoms [1] • Sleep disturbances, endocrine abnormalities, eye movement abnormalities, hypokinesia [2] • Ataxia, choreiform movement disorders, myelitis, neuritis [1,2] Small-cell lung cancer [1,2] • Small-cell lung cancer, germinal cell tumors, breast cancer [2] • Small-cell lung cancer, malignant thymoma [2] Hyperintense T2/FLAIR signal in the mesial temporal lobes (MTL), cerebellular edema or atrophy, brainstem abnormalities, or non-limbic lesions demonstrating restricted diffusion [2]. • Hyperintense T2/FLAIR signal in the MTL. Hypothalamus, thalamus, or brain stem abnormalities [2]. • Nodular parenchyma enchancement in the affected regions have been reported [2]. • Bilateral striatal encephalitis with T2/FLAIR signal hyperintensity is a typical finding [2]. 1. Dalmau J et al. Paraneoplastic syndromes of the CNS. Lancet Neurol2008 Apr;7(4):327-40 2. Ramanathan S et al. Autoimmune encephalitis: recent updates and emerging challenges. J ClinNeurosci2014 May;21(5):722-30

  15. Surface Antibodies PARANEOPLASTIC • Predominant presentation is seizure disorder. • Associated with small-cell lung carcinoma, lung neuroendocrine tumors, or thymomas. • Again may show unilateral or bilateral T2/FLAIR signal abnormality in the mesial temporal lobes on MR imaging. • With treatment, signal abnormalities may reverse. However, non-paraneoplastic cases have been reported. • Presents as behavior changes and/or with rapidly progressive encephalopathy and refractory seizures. • On MR imaging, there may be multifocal and extensive T2/FLAIR signal abnormality not limited to the limbic system. IN SUMMARY Anti-GABABR Anti-AMPAR • Clinical Presentations are variable but remain similar to classic LE with psychiatric disturbances and epilepsy being the dominant symptoms. • Associated with tumors of the lung, breast, and thymus. • Anti-mGluR is unique in its distinctive association with Hodgkin Lymphoma • Imaging Findings are typical for LE – T2/FLAIR signal abnormality in the MTL. May see more extra-limibic involvement with Anti-GABABR and Anti-mGluR. • Anti-GABABR may manifest as non-paraneoplastic AME as well. • One more… • Short for Alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). • Predominant clinical presentation is with psychiatric disturbances. • Associated with tumors of the lung, breast, or thymus. • Again may show unilateral or bilateral T2/FLAIR signal abnormality confined to the limbic structures on MR imaging. Anti-mGluR • Distinctively associated with Hodgkin lymphoma. • Also known as Ophelia syndrome • 3rd most common neoplastic disease that causes paraneoplastic LE. • Presents with seizures, amnesia, and psychiatric changes. Anti-NMDAR da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  16. Surface Antibodies PARANEOPLASTIC Anti-NMDAR • Far more common than previously believed [1] • Manifestations are milder compared to the others [2]. • Psychiatric disturbances is the predominant presentation, which may precede positive imaging or laboratory findings [2]. Other symptoms include amnesia, seizures, dyskinesia, and dysautonomia [1]. CASE EXAMPLE An otherwise healthy 33 year-old female presented to the ED with a 1 week history of memory loss, confusion, headaches, and fevers. Lumbar puncture was promptly performed and patient was treated empirically with acyclovir. 1. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205 2. Najjar S et al. Neuroinflammation and psychiatric illness. J Neuroinflammation 2013 Apr 1;10:43

  17. Surface Antibodies PARANEOPLASTIC Anti-NMDAR On MR Imaging - unilateral or bilateral T2/FLAIR signal abnormality in the mesial temporal lobes (classic LE finding). Additionally, brainstem encephalitis, cerebellitis, or striatal abnormalities may be present. However, 66% of cases have normal imaging findings. The clinical presentation and imaging findings suggested possible limbic encephalitis. The patient subsequently received a whole body CT scan to look for underlying malignant disease. On the initial MR exam, hyperintense T2/FLAIR signal is noted in bilateral MTL (arrows). DWI and reconstructed coronal image using contrast enhanced MPRage sequence demonstrate no restricted diffusion or enhancement of the MTL (arrows). daRocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  18. Surface Antibodies PARANEOPLASTIC Anti-NMDAR Characteristically associated with ovarian teratomas in adult females, but may be present along with other neoplasms as well [1,2]. The patient underwent salpingo-oophorectomy for ovarian teratoma resection 2 days later. However, the patient suffered a complicated course and progression of neurological symptoms despite removal of the tumor. Serum and CSF results revealed elevated anti-NMDAR antibody titers. Confirming a diagnosis of paraneoplastic AME. Eventually requiring plasmaphoresis, IVIG, and cyclophosphamide therapy. Contrast enhanced coronal CT image shows a predominantly fat-containing structure in the right adnexa (arrow), consistent with an ovarian teratoma. 1. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205 2. Ramanathan S et al. Autoimmune encephalitis: recent updates and emerging challenges. J ClinNeurosci2014 May;21(5):722-30

  19. Surface Antibodies PARANEOPLASTIC Anti-NMDAR • Unlike the intracellular-antigen antibodies, anti-NMDAR associated cases typically respond to immunotherapy. • Follow-up imaging may show complete recovery. At 9 months after onset, her serum and CSF titers have decreased and she reported improvement with mobility and cognitive functions at her last outpatient follow-up. FLAIR image on a 9 month follow-up MR exam shows resolution of the abnormal signal in the MTL. daRocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  20. NON-PARANEOPLASTIC NON-PARANEOPLASTIC AUTOIMMUNE-MEDIATED ENCEPHALITIS

  21. NON-PARANEOPLASTIC The new discovery More common Younger patients Immunotherapy works An autoantibody-mediatedCNS disease, first described less than two decades ago, provides new hope in treating diseases that were previously thought to be chronic and incurable. Its prevalence and associations to different neuropsychiatric disorders continues to surprise as more discoveries are being made. Due to its autoimmune-mediated mechanisms, immunotherapy, in theory, should provide substantial benefit. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol 2014 Dec;36(12):2196-205 Kotsenas AL et al. MRI findings in autoimmune voltage-gated potassium channel complex encephalitis with seizures: one potential etiology for mesial temporal sclerosis. AJNR Am J Neuroradiol 2014 Jan;35(1):84-9

  22. Intracellular Antibodies NON-PARANEOPLASTIC Anti-GAD65 • Predominantly presents clinically as cerebellar ataxia, Stiff person syndrome, or refractory temporal lobe epilepsy. • On MR imaging, there may be hyperintense T2/FLAIR signal in the amygdala and/or hippocampus. Anti-VGKC Complex Anti-MOG da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  23. Surface Antibodies NON-PARANEOPLASTIC Anti-GAD65 • Most common non-paraneoplastic AME [1]. • Different autoantibodies targeting proteins of the neuronal potassium channel complex [1,2], including: Anti-leucine-rich glioma inactived 1 (LGI1) Anti-contactin-associated protein-like 2 (CASPR2). • However, its presence is non-specific. • Elevated titers are seen in other conditions such acute influenza A as well as in healthy elderly patients [2]. Anti-VGKC Complex Anti-MOG 1. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205 2. Ramanathan S et al. Autoimmune encephalitis: recent updates and emerging challenges. J ClinNeurosci2014 May;21(5):722-30

  24. Surface Antibodies NON-PARANEOPLASTIC Anti-GAD65 • Predominant presentations include refractory epilepsy, amnesia, sleep disturbances, faciobrachial dystonia [1,2], and hyponatremia [2]. • On MR imaging - there may be classic LE findings. Additionally, subtle ill-defined contrast enhancement or restricted diffusion in the hippocampus have been reported. Extrahippocampal involvement may also be seen such as striatal encephalitis [1,3]. Anti-VGKC Complex Anti-MOG FLAIR images and post-gadolinium T1WI of a patient with presenting for left vision loss. Signal abnormality and enhancement is seen along the dorsal striatum (arrows) compatible with striatal encephalitis. Biopsy revealed neuroinflammation without histopathological evidence of infection. 1. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol 2014 Dec;36(12):2196-205 2. Ramanathan S et al. Autoimmune encephalitis: recent updates and emerging challenges. J Clin Neurosci 2014 May;21(5):722-30 3. Najjar S et al. Neuroinflammation and psychiatric illness. J Neuroinflammation 2013 Apr 1;10:43

  25. Surface Antibodies NON-PARANEOPLASTIC Anti-GAD65 • Predominant presentations include refractory epilepsy, amnesia, sleep disturbances, faciobrachial dystonia [1,2], and hyponatremia [2]. • On MR imaging - there may be classic LE findings. Additionally, subtle ill-defined contrast enhancement or restricted diffusion in the hippocampus have been reported. Extrahippocampal involvement may also be seen such as striatal encephalitis [1,3]. Anti-VGKC Complex Anti-MOG CASE: A 67 year-old woman presented to the ED for one month history of ataxia, dystonia, confusion, and possible epilepsy. Patient also found to be hyponatremic on admission. Initial MRI shows hyperintense FLAIR signal at the right hippocampus and amygdala (arrows), compatible with LE. Further workup revealed elevated anti-VGKC complex antibody titers. Patient received IVIG with significant improvement. 1. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol 2014 Dec;36(12):2196-205 2. Ramanathan S et al. Autoimmune encephalitis: recent updates and emerging challenges. J Clin Neurosci 2014 May;21(5):722-30 3. Najjar S et al. Neuroinflammation and psychiatric illness. J Neuroinflammation 2013 Apr 1;10:43

  26. Surface Antibodies NON-PARANEOPLASTIC Anti-GAD65 • Associated with acute disseminated encephalomyelitis (ADEM) • Non-LE related AME • Elevated titers reported in 50% of cases • Causal relationship not yet established and its role in diagnosing and managing ADEM is yet to be defined. Anti-VGKC Complex CASE: FLAIR images of a 65 year-old male who presented with mental status change, ataxia, and aphasia a week after a viral illness. Large confluent areas of white matter signal abnormality with extension into the basal ganglia bilaterally. Anti-MOG Follow-up FLAIR images obtained 3 months after onset of symptoms. Patient received immunotherapy with steroids and IVIG which resulted in marked improvement and return to baseline neurological status. The clinical course is compatible with ADEM. Graus et al. A clinical approach to diagnosis of autoimmune encephalitis Lancer Neurol2016 April;15(4):391-404

  27. Treatment NON-PARANEOPLASTIC Non-paraneoplastic AME is perhaps underdiagnosed and undertreated [1]. Some patients with refractory epilepsy may, in fact, have autoimmune-related disease [2]. No standard guideline exists. However, treatment involves seizure control and immunotherapy [3]. • First-line treatment typically includes steroids, IVIG, and plasmaphoresis [4]. • Immunomodulators such as cyclophosphamide may be considered as second-line therapy [4]. 1. Kotsenas AL et al. MRI findings in autoimmune voltage-gated potassium channel complex encephalitis with seizures: one potential etiology for mesial temporal sclerosis. AJNR Am J Neuroradiol 2014 Jan;35(1):84-9 2. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol 2014 Dec;36(12):2196-205 3. Vincent A et al. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011 Aug;10(8):759-72 4. Ramanathan S et al. Autoimmune encephalitis: recent updates and emerging challenges. J Clin Neurosci 2014 May;21(5):722-30

  28. HIPPOCAMPAL SCLEROSIS • The hallmark of mesial temporal sclerosis [1] • Representing structural changes as a result to prolonged febrile seizures or status epileptics. • The hippocampus is rich in glutamate receptors and therefore, is prone to neuronal excitability and lacks protection from calcium overload toxicity [1]. • The probable end-stage of epilepsy-presenting AME [2]. Coronal T2WI of a patient with right-sided MTS (arrow). 1. daRocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205 2. Kotsenas AL et al. MRI findings in autoimmune voltage-gated potassium channel complex encephalitis with seizures: one potential etiology for mesial temporal sclerosis. AJNR Am J Neuroradiol2014 Jan;35(1):84-9

  29. MIMICKERS THE MIMICKERS: THE DIFFERENTIAL DIAGNOSES

  30. MIMICKERS • Whipple Disease • 4-Aminopyridine Toxicity • Hypoglycemia Other limbic disorders Infectious diseases Neoplastic diseases Vascular lesions da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  31. MIMICKERS Other limbic disorders Infectious diseases Neoplastic diseases Vascular lesions • Creutzfeldt-Jakob Disease • Herpes Virus Encephalitis • EBV Encephalitis • Neurosyphilis da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  32. MIMICKERS Other limbic disorders Infectious diseases Neoplastic diseases Vascular lesions • Gliomas • Metastatic Lesions da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  33. MIMICKERS Other limbic disorders Infectious diseases Neoplastic diseases Vascular lesions • Primary Vasculitis • Vascular Malformations da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  34. Case Examples MIMICKERS Creutzfeldt-Jakob disease (CJD) • A prion disease. • On T2WI, hyperintensities may be seen in the cortices, white matter, basal ganglia, and/or thalamus. • Restricted diffusion may be seen in the striatum [1]. • Most sensitive sign for CJD • Typically not seen with AME [1] CASE: MR images of a 82 year-old female with clinically confirmed CJD. She initially presented with bizarre behavior and rapidly deteriorating mental status. Increased FLAIR signal in the MTL bilaterally (blue arrows) and restricted diffusion in the right hippocampus (orange arrow) seemingly similar to LE. da Rocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  35. Case Examples MIMICKERS Epstein-Barr virus (EBV) Encephalitis • EBV infection may manifest in the CNS and cause a multitude of clinical symptoms such as cranial nerve palsies and seizures. • Hence, its presentation in the CNS is non-specific and can range from normal to findings similar to ADEM. FLAIR FLAIR T1+C CASE: A 52 year-old female with presenting with seizures with elevated EBV titers. FLAIR images demonstrate increased signal in the left MTL (arrows), mimicking that of LE. However, there were also areas of FLAIR signal abnormality in the grey and subcortical white matter (arrows). No enhancement was observed in these areas. Hagemann G et al. Multiple reversible MR signal changes caused by Epstein-Barr virus encephalitis. AJNR Am J Neuroradiol2006 Aug:27(7):1447-9

  36. Case Examples MIMICKERS Glioma and Metastatic Lesions • Low-grade gliomas are slowly progressive and may initially present as seizures or focal neurological defects. • High-grade tumors may mimic LE, but typically progress to have recognizable features such as hemorrhage or necrosis [1]. • MR-spectroscopy and MR-perfusion techniques may help to differentiate neoplasm from LE. CASE: 63 year-old male presented for seizures. Initial MR examination showed a focus of T2/FLAIR signal hyperintensity and swelling in the right MTL (arrows). Additionally, temporal cortex is thickened (arrowheads). daRocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  37. Case Examples MIMICKERS Glioma and Metastatic Lesions • Low-grade gliomas are slowly progressive and may initially present as seizures or focal neurological defects. • High-grade tumors may mimic LE, but typically progress to have recognizable features such as hemorrhage or necrosis [1]. • MR-spectroscopy and MR-perfusion techniques may help to differentiate neoplasm from LE. CASE: 63 year-old male presented for seizures. Initial MR examination showed a focus of T2/FLAIR signal hyperintensity in the right MTL (arrows). Originally thought to be an infectious or inflammatory process. This lesion bled two months later… daRocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  38. Case Examples MIMICKERS Glioma and Metastatic Lesions • Low-grade gliomas are slowly progressive and may initially present as seizures or focal neurological defects. • High-grade tumors may mimic LE, but typically progress to have recognizable features such as hemorrhage or necrosis [1]. • MR-spectroscopy and MR-perfusion techniques may help to differentiate neoplasm from LE. CASE: 63 year-old male presented for seizures. Initial MR examination showed a focus of T2/FLAIR signal hyperintensity in the right MTL (arrows). Originally thought to be an infectious or inflammatory process. This lesion bleed 2 months later… After further workup and eventual resection, this lesion was determined to be GBM. daRocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  39. OTHER DISORDERS Systemic autoimmune disease may cause limbic encephalitis as well, but are not autoantibody-mediated and rather caused by cellular inflammation. Neuroinflammatory responses have been reported in entities such as: • Sjögren syndrome • Lupus erythematosus • Beçhet’s disease • Antiphospholipid syndrome • Hashimoto’s encephalopathy Perhaps the encephalopathic responses in these conditions are due to unclassified antineuronal antibodies that are yet to be discovered [1]. daRocha AJ et al. Recognizing autoimmune-mediated encephalitis in the differential diagnosis of limbic disorders. AJNR Am J Neuroradiol2014 Dec;36(12):2196-205

  40. CONCLUSION This exhibit summarizes the basic physiological understanding, clinical presentations, imaging findings, and differential diagnoses of antineuronal antibody mediated encephalitis. Due to the nonspecific clinical presentations, AME may pose as a diagnostic challenge. Through MR imaging, the neuroradiologist may be able to provide invaluable information and guidance for the care and workup in cases of AME or its mimickers.

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  42. CREATIVECOMMONS Photo 1. • Source: www.flickr.com/photos/zeissmicro/10799795174/in/album-72157629399283121/ • Under CC BY 2.0: creativecommons.org/licenses/by-nc-nd/2.0/ Photo 2. • Source: commons.wikimedia.org/wiki/File:Astrocyte_Green1.jpg • Under Public Domain / CC0 wiki.creativecommons.org/wiki/CC0

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