Neuroimmunology

Axial T1-weighted MRI of the brain showing post-gadolinium enhancement of the left optic nerve. (Contributed by Dr. Josephe Honorat.)

Axial STIR MRI of the brain shows longitudinally extensive increased signal of the left optic nerve and mild atrophy of the right optic nerve. (Contributed by Dr. Josephe Honorat.)

Comparison of lesion morphology of “iron dot” lesions in Susac syndrome (bottom) and multiple sclerosis (top). The figure illustrates differences in morphology on 7T T2*w images between “iron dots” in Susac syndrome (red arrows) and the central vein sign (white and black arrow) as well as T2*w hypointense core lesions (blue arrows with zoom) in multiple sclerosis. T2*-weighted imaging is an MRI sequence to quantify observable or effective T2 (T2* or "T2-star"); in this sequence, hemorrhages and hemosiderin deposits become hypointense (Chavhan GB, Babyn PS, Thomas B, Shroff MM, Haacke EM. Principles, techniques, and applications of T2*-based MR imaging and its special applications. Radiographics 2009;29[5]:1433-49). All exemplary T2*w images in the bottom are from different patients with Susac syndrome. Note that the “iron dots” in Susac syndrome (red arrows) appear punctate and sharply delineated on T2*w. In contrast, the T2*w hypointense core lesions (blue arrows with zoom) in multiple sclerosis often appear just slightly less hyperintense on T2*w in comparison to other multiple sclerosis lesions. Only when the lesion is viewed on strongly susceptibility-weighted sequences (right) does a rather diffuse signal loss become apparent. The central vein sign in multiple sclerosis also appears as a point-like, pronounced hypointensity on T2*w images when the slice plane is perpendicular to the long axis of the multiple sclerosis lesion (white arrow). However, if the slice plane is parallel to the long axis of the lesion, the central vein sign can be recognized as a straight line running through the center of multiple sclerosis lesions (black arrow). (Source: Strunk D, Sinnecker T, Kleffner I, et al. Central intra-lesional iron deposits as a possible novel imaging marker at 7 Tesla MRI in Susac Syndrome: an exploratory study. BMC Med Imaging 2024;24[1]:4. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Callosal “iron dot” lesions (indicated by red arrows) on 7T quantitative T1 maps (left) and 3D T2* weighted (right) sequences. (Source: Strunk D, Sinnecker T, Kleffner I, et al. Central intra-lesional iron deposits as a possible novel imaging marker at 7 Tesla MRI in Susac Syndrome: an exploratory study. BMC Med Imaging 2024;24[1]:4. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

"Iron dot” lesion in the left frontal lobe on 3D T2*-weighted (T2*w) coronal (top left), sagittal (lower left), and axial (right) 7 Tesla MRI sequences. T2*-weighted imaging is an MRI sequence to quantify observable or effective T2 (T2* or "T2-star"); in this sequence, hemorrhages and hemosiderin deposits become hypointense (Chavhan GB, Babyn PS, Thomas B, Shroff MM, Haacke EM. Principles, techniques, and applications of T2*-based MR imaging and its special applications. Radiographics 2009;29[5]:1433-49). Note the strong but punctate and sharply delineated intralesional signal loss. This type of intralesional T2*w signal loss differs from that of more recent multiple sclerosis lesions where central T2*w hypointensities appear larger and are more diffuse. They are also distinct from (enlarged) venules present in multiple sclerosis lesions as “iron dot” lesions do not show a tubular appearance following the course of a vessel. (Source: Strunk D, Sinnecker T, Kleffner I, et al. Central intra-lesional iron deposits as a possible novel imaging marker at 7 Tesla MRI in Susac Syndrome: an exploratory study. BMC Med Imaging 2024;24[1]:4. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) Optical coherence tomography infrared image of the right eye shows inferior retinal branch involvement (black arrows); the black arrows on the right of the image show occlusion, whereas on the left there is incomplete occlusion. (B) Fundus fluorescein angiography, late phase of the left eye in the same patient seen in A. There is arteriolar wall hyper-fluorescence seen along with frank leakage. (C) Late phase of fundus fluorescein angiography of the left eye demonstrates the requirement for peripheral views to gauge the extent of the retinal vascular involvement. (D) Late phase of fundus fluorescein angiography of the right eye shows superior arterial tree involvement in the same patient. (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Algorithm for diagnosis, treatment, and monitoring of Susac syndrome. (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain histology at higher magnification shows microangiopathy with thickening of arteriolar wall and a sparse perivascular lymphocytic infiltrate (arrow). (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain histology shows multiple microinfarcts (arrows) in the cerebral cortex. Abbreviation: H&E, hematoxylin and eosin staining. (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T2-weighted MRI shows central callosal lesions. (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal FLAIR MRI sequence shows callosal, periventricular, and thalamic lesions. (Source: Bose S, Papathanasiou A, Karkhanis S, et al. Susac syndrome: neurological update [clinical features, long-term observational follow-up and management of sixteen patients]. J Neurol 2023;270[12]:6193-206. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Augiogram shows bilateral profound sensorineural hearing loss in a patient with Cogan syndrome. The right ear audiogram is on the left. (Source: Wang Y, Tang S, Shao C, Liu Y. Cogan's syndrome is more than just keratitis: a case-based literature review. BMC Ophthalmol 2023;23[1]:212. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Optical coherence tomography showing macular degeneration in a patient with Cogan syndrome. (Source: Wang Y, Tang S, Shao C, Liu Y. Cogan's syndrome is more than just keratitis: a case-based literature review. BMC Ophthalmol 2023;23[1]:212. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Optical coherence tomography shows optic disc edema in a patient with Cogan syndrome. (Source: Wang Y, Tang S, Shao C, Liu Y. Cogan's syndrome is more than just keratitis: a case-based literature review. BMC Ophthalmol 2023;23[1]:212. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MR images in STIR sequences showing (top) florid labyrinthitis before treatment and (bottom) absence of labyrinthitis after 4 months of immunomodulatory treatment. (Source: Rücklová K, von Kalle T, Koitschev A, et al. Paediatric Cogan´s syndrome: review of literature, case report and practical approach to diagnosis and management. Pediatr Rheumatol Online J 2023;21[1]:54. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Since 1993, 20 disease-modifying therapies have been approved by the FDA for the treatment of relapsing multiple sclerosis. Ocrelizumab remains the only therapy approved for primary progressive multiple sclerosis. Ublituximab is the newest therapy and has been available since mid-2023 for the treatment of relapsing multiple sclerosis. Four Bruton tyrosine kinase (BTK) inhibitors are in phase III clinical trials, including for relapsing and progressive indications. (Contributed by Dr. Andrew Wolf.)

Axial T2 FLAIR sequence MRI showing bilateral mesiotemporal hyperintensities (arrows) in a patient with a history of type 1 diabetes mellitus limbic encephalitis with underlying active non-small cell lung cancer, treated with durvalumab (PD-1 inhibitor) monthly infusions, stopped when he developed limbic encephalitis. His workup yielded positive GAD65 (serum titer: 533 nmole/L, CSF titer: 11.6 nmole/L). Although the titers are relatively high, GAD65 is rarely considered to be associated with underlying malignancy, and the use of immune checkpoint inhibitor makes irAE of a higher concern. (Contributed by Dr. Lama Abdel Wahed.)

Axial T2 FLAIR sequence MRI (A) showing bithalamic hyperintensities (arrows), the FLAIR hyperintensities are also scattered throughout the supra- (arrowheads) and infratentorial areas (not demonstrated) in a patient with negative serum studies but isolated positive MOG IgG in the CSF. (B) T1 post-contrast sequence from the same patient with correlated T1 hypointensities (arrows) without associated enhancement. (Contributed by Dr. Lama Abdel Wahed.)

Axial T2 FLAIR sequence MRI (A) showing a right-sided dorsal pontine hyperintensity extending into the right middle cerebellar peduncle and abutting the fourth ventricle (arrow) in a patient with AQP4 IgG-positive neuromyelitis optica spectrum disorder. (B) T1 post-contrast sequence from the same patient with mild patchy enhancement of the lesion (arrow). (Contributed by Dr. Lama Abdel Wahed.)

Axial T2 FLAIR sequence MRI (A) showing bilateral posterior confluent hyperintensities, extending into the corpus callosum, restricted to the white matter, and involving the U-fibers. The hyperintensities are more prominent on the right (arrows) in a patient with relapsing acute disseminated encephalomyelitis and dual positivity for MOG (serum) and NMDAR antibodies (serum and CSF). (B) T1 post-contrast sequence from the same patient with correlated T1 hypointensities with associated enhancement (arrows). (Contributed by Dr. Lama Abdel Wahed.)

Axial T1 postcontrast MRI showing characteristic radial linear enhancement perpendicular to the lateral ventricles (arrows) in a patient with GFAP meningoencephalitis. (Contributed by Dr. Lama Abdel Wahed.)

The patient also had abnormally low scores in speech audiometry (not shown). (Source: Wilf-Yarkoni A, Elkayam O, Aizenstein O, et al. Increased incidence of Susac syndrome: a case series study. BMC Neurol 2020;20[1]:332. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Wide-field fluorescein angiogram demonstrating right eye peripheral (superior, temporal, and inferior) branch artery occlusions and focal arterial leakage in an inferior branch artery. (Source: Wilf-Yarkoni A, Elkayam O, Aizenstein O, et al. Increased incidence of Susac syndrome: a case series study. BMC Neurol 2020;20[1]:332. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Wilf-Yarkoni A, Elkayam O, Aizenstein O, et al. Increased incidence of Susac syndrome: a case series study. BMC Neurol 2020;20[1]:332. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Wilf-Yarkoni A, Elkayam O, Aizenstein O, et al. Increased incidence of Susac syndrome: a case series study. BMC Neurol 2020;20[1]:332. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Wilf-Yarkoni A, Elkayam O, Aizenstein O, et al. Increased incidence of Susac syndrome: a case series study. BMC Neurol 2020;20[1]:332. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Wilf-Yarkoni A, Elkayam O, Aizenstein O, et al. Increased incidence of Susac syndrome: a case series study. BMC Neurol 2020;20[1]:332. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Wilf-Yarkoni A, Elkayam O, Aizenstein O, et al. Increased incidence of Susac syndrome: a case series study. BMC Neurol 2020;20[1]:332. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Wilf-Yarkoni A, Elkayam O, Aizenstein O, et al. Increased incidence of Susac syndrome: a case series study. BMC Neurol 2020;20[1]:332. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Fundoscopic examination revealed fluffy white patches along the inferotemporal arcade in a 22-year-old man diagnosed with Susac syndrome. Fluorescein angiography confirmed 14 branch artery occlusions and arterial wall hyperfluorescence with leakage of dye (not shown). (Source: Gertner E, Rosenbloom MH. Susac syndrome with prominent dermatological findings and a prompt response to intravenous immunoglobulin, steroids, and rituximab: a case report. J Med Case Rep 2016;10[1]:137. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial brain DWI in a 22-year-old man diagnosed with Susac syndrome, showing multifocal subacute punctate supratentorial white matter lesions (black arrows) with the most prominent lesion affecting the posterior corpus callosum (red arrowhead). The study also showed T2/FLAIR hyperintensities involving the deep gray nuclei as well as leptomeningeal enhancement (not shown). (Source: Gertner E, Rosenbloom MH. Susac syndrome with prominent dermatological findings and a prompt response to intravenous immunoglobulin, steroids, and rituximab: a case report. J Med Case Rep 2016;10[1]:137. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Livedo reticularis-like skin manifestation occurring on both arms, but nowhere else, one week before presentation and resolving with treatment, in a 22-year-old man diagnosed with Susac syndrome. (Source: Gertner E, Rosenbloom MH. Susac syndrome with prominent dermatological findings and a prompt response to intravenous immunoglobulin, steroids, and rituximab: a case report. J Med Case Rep 2016;10[1]:137. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Large ischemic area in the lower half of the left retina (arrow) and smaller infarct in the top left quadrant (tailed arrow), representing branch retinal artery occlusions in a 32-year-old woman with Susac syndrome. (Source: Engeholm M, Leo-Kottler B, Rempp H, et al. Encephalopathic Susac's syndrome associated with livedo racemosa in a young woman before the completion of family planning. BMC Neurol 2013;13:185. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

Axial contrast-enhanced T1-weighted MRI showing multiple small contrast-enhancing lesions (arrows) in a 32-year-old woman with Susac syndrome. (Source: Engeholm M, Leo-Kottler B, Rempp H, et al. Encephalopathic Susac's syndrome associated with livedo racemosa in a young woman before the completion of family planning. BMC Neurol 2013;13:185. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

Near-median sagittal T2 MRI demonstrating atrophy of the corpus callosum in a 32-year-old woman with Susac syndrome. (Source: Engeholm M, Leo-Kottler B, Rempp H, et al. Encephalopathic Susac's syndrome associated with livedo racemosa in a young woman before the completion of family planning. BMC Neurol 2013;13:185. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

Sagittal T2 MRI showing centrally located corpus callosum lesions (arrow) and one lesion with spoke-like morphology (tailed arrow) in a 32-year-old woman with Susac syndrome. (Source: Engeholm M, Leo-Kottler B, Rempp H, et al. Encephalopathic Susac's syndrome associated with livedo racemosa in a young woman before the completion of family planning. BMC Neurol 2013;13:185. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

Diffusion-weighted image from a 32-year-old woman with Susac syndrome; the image shows multiple small lesions exhibiting diffusion restriction (arrows) and correspondingly decreased ADC values (not shown). (Source: Engeholm M, Leo-Kottler B, Rempp H, et al. Encephalopathic Susac's syndrome associated with livedo racemosa in a young woman before the completion of family planning. BMC Neurol 2013;13:185. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

Axial FLAIR image from a 32-year-old woman with Susac syndrome, showing multiple small white matter lesions. (Source: Engeholm M, Leo-Kottler B, Rempp H, et al. Encephalopathic Susac's syndrome associated with livedo racemosa in a young woman before the completion of family planning. BMC Neurol 2013;13:185. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

Foveal avascular zone enlargement in optical coherence tomography angiography images of the deep layer, left eye. (Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

Foveal avascular zone enlargement in optical coherence tomography angiography images of the superficial layer, left eye. (Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

Foveal avascular zone enlargement in optical coherence tomography angiography images of the deep layer, right eye. (Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

Foveal avascular zone enlargement in optical coherence tomography angiography images of the superficial layer, right eye. (Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

Color fundus photography revealing a glass plaque (white arrow) as yellowish lipid sediments at the mid-segment of the retinal arterioles in the left eye. (Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

(Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

(Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

(Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

(Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

Sagittal MRI of a 33-year-old man with Susac syndrome. The red arrow shows an ellipsoid focal lesion involving the corpus callosum. (Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

Transverse MRI of a 33-year-old man with Susac syndrome. The red arrows show various round and ellipsoid focal lesions involving the cerebellum. (Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

Transverse MRI of a 33-year-old man with Susac syndrome. The red arrows show various round and ellipsoid focal lesions involving the corpus callosum, periventricular and subcortical white matter, and deep grey matter (basal ganglia and thalami). (Source: Bagaglia SA, Passani F, Oliverio GW, et al. Multimodal imaging in Susac syndrome: a case report and literature review. Int J Environ Res Public Health 2021;18[7]:3435. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/ 4.0.)

On follow-up 18 months after the initial FLAIR sequence, there was generalized brain atrophy with stable white matter lesions. (Source: Alshaqi O, Moodie T, Alchaki A. Involuntary crying episodes with Susac's syndrome-a rare presentation of a rare disease: a case report. BMC Neurol 2022;22[1]:155. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

On follow-up 2 weeks after the initial brain MRI, FLAIR sequence showed an area of increased T2 signal without diffusion restriction over the left side of the pontine tegmentum. (Source: Alshaqi O, Moodie T, Alchaki A. Involuntary crying episodes with Susac's syndrome-a rare presentation of a rare disease: a case report. BMC Neurol 2022;22[1]:155. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

On follow-up 2 weeks after the initial brain MRI, diffusion-weighted images showed a new area of diffusion restriction in the left corona radiata, corpus callosum, and right middle cerebral peduncle. (Source: Alshaqi O, Moodie T, Alchaki A. Involuntary crying episodes with Susac's syndrome-a rare presentation of a rare disease: a case report. BMC Neurol 2022;22[1]:155. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Initial brain MRI in a 56-year-old man with Susac syndrome. Transverse FLAIR images showed increased T2 signal in the areas corresponding to areas of restricted diffusion on diffusion-weighted images. (Source: Alshaqi O, Moodie T, Alchaki A. Involuntary crying episodes with Susac's syndrome-a rare presentation of a rare disease: a case report. BMC Neurol 2022;22[1]:155. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Initial brain MRI in a 56-year-old man with Susac syndrome. Diffusion-weighted images showed areas of restricted diffusion over the central/left aspect of the splenium of the corpus callosum, left parietal white matter, left basal ganglia, and anterior right cingulate gyrus. (Source: Alshaqi O, Moodie T, Alchaki A. Involuntary crying episodes with Susac's syndrome-a rare presentation of a rare disease: a case report. BMC Neurol 2022;22[1]:155. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal FLAIR sequence on brain MRI from the patient’s last follow-up, showing improvement of the radiological findings. (Source: Barbero P, Vecchio D, Virgilio E, Naldi P, Comi C, Cantello R. Susac syndrome: an uncommon cause of impaired vision. Neurol Sci 2022;43[6]:3919-22. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Transverse FLAIR sequence on brain MRI from the patient’s last follow-up, showing improvement of the radiological findings. (Source: Barbero P, Vecchio D, Virgilio E, Naldi P, Comi C, Cantello R. Susac syndrome: an uncommon cause of impaired vision. Neurol Sci 2022;43[6]:3919-22. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal FLAIR sequence on brain MRI showing hyperintense white matter lesions with "snowball"-like lesions in the corpus callosum. (Source: Barbero P, Vecchio D, Virgilio E, Naldi P, Comi C, Cantello R. Susac syndrome: an uncommon cause of impaired vision. Neurol Sci 2022;43[6]:3919-22. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Transverse FLAIR sequence on brain MRI showing hyperintense white matter lesions with "snowball"-like lesions in the corpus callosum. (Source: Barbero P, Vecchio D, Virgilio E, Naldi P, Comi C, Cantello R. Susac syndrome: an uncommon cause of impaired vision. Neurol Sci 2022;43[6]:3919-22. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T1 MRI showing the pathognomonic central callosal "holes" (microinfarcts) of Susac syndrome. These residual "holes" (and sometimes, "spokes") develop as the acute callosal changes resolve. (Source: Rennebohm RM, Lubow M, Rusin J, Martin L, Grzybowski DM, Susac JO. Aggressive immunosuppressive treatment of Susac's syndrome in an adolescent: using treatment of dermatomyositis as a model. Pediatr Rheumatol Online J 2008;6:3. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

Legend: C, cyclophosphamide; IVIg, intravenous immunoglobulin; MM, mycophenolate mofetil. (Source: Rennebohm RM, Lubow M, Rusin J, Martin L, Grzybowski DM, Susac JO. Aggressive immunosuppressive treatment of Susac's syndrome in an adolescent: using treatment of dermatomyositis as a model. Pediatr Rheumatol Online J 2008;6:3. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

Audiogram showing bilateral low-frequency sensorineural hearing loss, rising to normal at higher frequencies. This is the typical cochlear hearing loss pattern seen in Susac syndrome, likely reflecting microinfarction of the striae vascularis at the apex of the cochlea. Legend: X = left ear; O = right ear. (Source: Rennebohm RM, Lubow M, Rusin J, Martin L, Grzybowski DM, Susac JO. Aggressive immunosuppressive treatment of Susac's syndrome in an adolescent: using treatment of dermatomyositis as a model. Pediatr Rheumatol Online J 2008;6:3. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

Axial T2 image showing multiple white matter lesions, especially in the corpus callosum. The arrows point to 2 of several callosal lesions. (Source: Rennebohm RM, Lubow M, Rusin J, Martin L, Grzybowski DM, Susac JO. Aggressive immunosuppressive treatment of Susac's syndrome in an adolescent: using treatment of dermatomyositis as a model. Pediatr Rheumatol Online J 2008;6:3. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

These scores are derived by adding disease activity (0-100) for each domain (brain, ears, eyes). (Source: Bullock DR, Spencer RT, Vehe RK, Srivastava S, Rennebohm RM. Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports. J Med Case Rep 2023;17[1]:158. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Bullock DR, Spencer RT, Vehe RK, Srivastava S, Rennebohm RM. Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports. J Med Case Rep 2023;17[1]:158. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Bullock DR, Spencer RT, Vehe RK, Srivastava S, Rennebohm RM. Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports. J Med Case Rep 2023;17[1]:158. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Bullock DR, Spencer RT, Vehe RK, Srivastava S, Rennebohm RM. Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports. J Med Case Rep 2023;17[1]:158. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Admission MRI revealed multifocal T1 hypointensity and T2 hyperintensity lesions in the periventricular and supraventricular cerebral and cerebellar white matter, including extensive involvement of the corpus callosum. (Source: Bullock DR, Spencer RT, Vehe RK, Srivastava S, Rennebohm RM. Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports. J Med Case Rep 2023;17[1]:158. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

These scores are derived by adding disease activity (0-100) for each domain (brain, ears, eyes). (Source: Bullock DR, Spencer RT, Vehe RK, Srivastava S, Rennebohm RM. Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports. J Med Case Rep 2023;17[1]:158. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Bullock DR, Spencer RT, Vehe RK, Srivastava S, Rennebohm RM. Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports. J Med Case Rep 2023;17[1]:158. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Bullock DR, Spencer RT, Vehe RK, Srivastava S, Rennebohm RM. Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports. J Med Case Rep 2023;17[1]:158. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Bullock DR, Spencer RT, Vehe RK, Srivastava S, Rennebohm RM. Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports. J Med Case Rep 2023;17[1]:158. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MRI on admission showing several “snowball” lesions in the corpus callosum. (Source: Bullock DR, Spencer RT, Vehe RK, Srivastava S, Rennebohm RM. Use of disease assessment tools to increase the value of case reports on Susac syndrome: two case reports. J Med Case Rep 2023;17[1]:158. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Deficiency leads to raised muscle protein breakdown via the ubiquitin-proteasomal pathway (UPP) and autophagy and upregulation of AMPK and members of the renin-angiotensin system. Whilst unclear, low vitamin D states may lead to impaired mitochondrial function and increased adiposity in muscle. Permanent withdrawal from the cell cycle (senescence) is a key phenomenon in aging, and the vitamin D/VDR axis has regulatory control. Abbreviations: 25(OH)D3, 25-hydroxyvitamin D; AMPK, 5′ adenosine monophosphate-activated protein kinase; SASP, senescence associated-secretory phenotype; Ca2+, calcium ion; FFA, free fatty acids; PPARγ, peroxisome proliferator-activated receptor gamma. (Source: Bollen SE, Bass JJ, Fujita S, Wilkinson D, Hewison M, Atherton PJ. The Vitamin D/vitamin D receptor (VDR) axis in muscle atrophy and sarcopenia. Cell Signal 2022;96:110355. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

(Source: Plantone D, Primiano G, Manco C, Locci S, Servidei S, De Stefano N. Vitamin D in neurological diseases. Int J Mol Sci 2022;24[1]:87. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Ab--amyloid b; BDNF--brain-derived neurotrophic factor; DA--dopamine; DAT--dopamine transporter; DOPAC--3,4-dihydroxyphenylacetic acid; GDNF--glial-derived neurotrophic factor; HVA--homovanillic acid; NGF--nerve growth factor; ROS--reactive oxygen species; Syn--synuclein; TH--tyrosine kinase; VDR-- the vitamin D receptor. (Source: Lasoń W, Jantas D, Leśkiewicz M, Regulska M, Basta-Kaim A. The vitamin D receptor as a potential target for the treatment of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's diseases: a narrative review. Cells 2023;12[4]:660. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Third audiogram obtained approximately 2 months after the initiation of oral immunosuppressive treatment in a 60-year-old man with autoimmune hepatitis and autoimmune sensorineural hearing loss. hearing acuity improved in the right ear by approximately 20 dB after three intratympanic dexamethasone injections followed by a course of intravenous methylprednisolone (500 mg/d x 3 days). (Source: Zarachi A, Pelechas E, Tsikou A, et al. Immune-mediated inner ear disease associated with type 1 autoimmune hepatitis: a challenging coexistence. Mediterr J Rheumatol 2022;33[3]:349-60. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Pathological examination of liver biopsy in a 60-year-old man with autoimmune hepatitis and autoimmune sensorineural hearing loss (Masson trichromex100). (Source: Zarachi A, Pelechas E, Tsikou A, et al. Immune-mediated inner ear disease associated with type 1 autoimmune hepatitis: a challenging coexistence. Mediterr J Rheumatol 2022;33[3]:349-60. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Pathological examination of liver biopsy in a 60-year-old man with autoimmune hepatitis and autoimmune sensorineural hearing loss (H&E x100). The picture shows a few lymphocytes in a portal tract and steatosis but not fibrosis. Legend: Fat vacuoles (black arrows); lymphocytes (red arrows); portal vein (PV). (Source: Zarachi A, Pelechas E, Tsikou A, et al. Immune-mediated inner ear disease associated with type 1 autoimmune hepatitis: a challenging coexistence. Mediterr J Rheumatol 2022;33[3]:349-60. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Second audiogram in a 60-year-old man with autoimmune hepatitis and autoimmune sensorineural hearing loss. This is consistent with sensorineural hearing loss in the right ear with mild low-frequency loss precipitously sloping to severe loss above 2 kHz as well as continued profound sensorineural hearing loss in the left ear. (Source: Zarachi A, Pelechas E, Tsikou A, et al. Immune-mediated inner ear disease associated with type 1 autoimmune hepatitis: a challenging coexistence. Mediterr J Rheumatol 2022;33[3]:349-60. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Initial audiogram, consistent with profound hearing loss of the left ear (90-100 dB), in a 60-year-old man with autoimmune hepatitis and autoimmune sensorineural hearing loss. (Source: Zarachi A, Pelechas E, Tsikou A, et al. Immune-mediated inner ear disease associated with type 1 autoimmune hepatitis: a challenging coexistence. Mediterr J Rheumatol 2022;33[3]:349-60. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Trends of liver function tests (IU/L) in a 60-year-old man with autoimmune hepatitis and autoimmune sensorineural hearing loss. (Source: Zarachi A, Pelechas E, Tsikou A, et al. Immune-mediated inner ear disease associated with type 1 autoimmune hepatitis: a challenging coexistence. Mediterr J Rheumatol 2022;33[3]:349-60. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Fluorescein angiography (late phase) showing upper vessel hyperfluorescence reflecting inflammation (arrows) in a patient with Susac syndrome. (Source: Beça S, Elera-Fitzcarrald C, Saiz A, et al. Susac syndrome: description of a single-centre case series. J Clin Med 2022;11[21]:6549. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Fluorescein angiography showing an area of retinal nonperfusion in the superior temporal zone (dashed line) with segmental occlusions in an arterial vessel (arrow) in a patient with Susac syndrome. (Source: Beça S, Elera-Fitzcarrald C, Saiz A, et al. Susac syndrome: description of a single-centre case series. J Clin Med 2022;11[21]:6549. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Retinography showing retinal edema in the upper temporal zone (dashed line) with arterial occlusions (arrows) in a patient with Susac syndrome. (Source: Beça S, Elera-Fitzcarrald C, Saiz A, et al. Susac syndrome: description of a single-centre case series. J Clin Med 2022;11[21]:6549. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal image on 3D-MPRAGE showing several characteristic “snowball” lesions in the corpus callosum in a patient with Susac syndrome. (Source: Beça S, Elera-Fitzcarrald C, Saiz A, et al. Susac syndrome: description of a single-centre case series. J Clin Med 2022;11[21]:6549. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal FLAIR sequence image showing several characteristic “snowball” lesions in the corpus callosum in a patient with Susac syndrome. (Source: Beça S, Elera-Fitzcarrald C, Saiz A, et al. Susac syndrome: description of a single-centre case series. J Clin Med 2022;11[21]:6549. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial T1-weighted MRI with contrast enhancement in a patient with Susac syndrome. (Source: Beça S, Elera-Fitzcarrald C, Saiz A, et al. Susac syndrome: description of a single-centre case series. J Clin Med 2022;11[21]:6549. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial diffusion-weighted brain MRI sequence displaying bilateral acute small infarcts in a patient with Susac syndrome. (Source: Beça S, Elera-Fitzcarrald C, Saiz A, et al. Susac syndrome: description of a single-centre case series. J Clin Med 2022;11[21]:6549. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR image of the brain showing bilateral hyperintense lesions with preferential involvement of the corpus callosum in a patient with Susac syndrome. (Source: Beça S, Elera-Fitzcarrald C, Saiz A, et al. Susac syndrome: description of a single-centre case series. J Clin Med 2022;11[21]:6549. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Dugs associated with livedo reticularis include amantadine, quinidine, and catecholaminergic agents. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Legend: TOX - thymocyte selection-associated high mobility group box; TCR - T cell receptor; CD8 - cluster of differentiate 8; TNF-α - tumor necrosis factor-alpha. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Congested vessel (packed with red blood cells) and perivascular lymphocytic infiltrate without thrombi in a 45-year-old man with Susac syndrome, livedo reticularis, and autoimmune sensorineural hearing loss. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Ectatic and congested vessels in the superficial dermis with mild perivascular lymphocytic infiltrate in a 45-year-old man with Susac syndrome, livedo reticularis, and autoimmune sensorineural hearing loss. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Audiogram revealing unilateral biphasic sensorineural hearing loss in the right ear in a 45-year-old man with Susac syndrome, livedo reticularis, and autoimmune sensorineural hearing loss. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T2-weighted MRI revealing linear ("spoke") lesion seen within the genu of the corpus callosum in a 45-year-old man with Susac syndrome, livedo reticularis, and autoimmune sensorineural hearing loss. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T2-weighted MRI revealing multiple small-to-large white matter lesions ("snowballs") within the rostrum, genu, and body of the corpus callosum in a 45-year-old man with Susac syndrome, livedo reticularis, and autoimmune sensorineural hearing loss. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T2-weighted MRI revealing multiple small-to-large white matter lesions ("snowballs") within the rostrum, genu, and body of the corpus callosum in a 45-year-old man with Susac syndrome, livedo reticularis, and autoimmune sensorineural hearing loss. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T2-weighted MRI revealing multiple small-to-large white matter lesions ("snowballs") within the rostrum, genu, and body of the corpus callosum in a 45-year-old man with Susac syndrome, livedo reticularis, and autoimmune sensorineural hearing loss. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Violaceous net-like rash in an asymmetric pattern on the left flank in a 45-year-old man with Susac syndrome, livedo reticularis, and autoimmune sensorineural hearing loss. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Violaceous net-like rash in an asymmetric pattern on the lower back in a 45-year-old man with Susac syndrome, livedo reticularis, and autoimmune sensorineural hearing loss. (Source: Srichawla BS. Susac syndrome with livedo reticularis: pathogenesis and literature review. Cureus 2022;14[7]:e27352. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Normal transverse MRI of the head in a 37-year-old man with Behcet disease and autoimmune sensorineural hearing loss. (Source: Faisal M, Barjas H, Alwassiti W, Omer W, Abdulla N. Sensory neural hearing loss in Behcet's disease successfully controlled with infliximab, case report and review of literature. Clin Case Rep 2022;10[10]:e6457. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Normal coronal MRI of the head in a 37-year-old man with Behcet disease and autoimmune sensorineural hearing loss. (Source: Faisal M, Barjas H, Alwassiti W, Omer W, Abdulla N. Sensory neural hearing loss in Behcet's disease successfully controlled with infliximab, case report and review of literature. Clin Case Rep 2022;10[10]:e6457. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Follow up at 3 months in a 27-year-old woman with granulomatous cheilitis. (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Follow up at 1 month in a 27-year-old woman with granulomatous cheilitis. (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photomicroscopy of a biopsy from a 27-year-old woman who presented with a 3-month history of unrelenting upper lip swelling. The noncaseating granuloma is comprised of epithelioid cells, with a sprinkling of lymphocytes, histocytes, and multinucleated giant cells (red arrow) (H&E x 40). (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photomicroscopy of a biopsy from a 27-year-old woman who presented with a 3-month history of unrelenting upper lip swelling. The noncaseating granuloma is comprised of epithelioid cells, with a sprinkling of lymphocytes, histocytes, and multinucleated giant cells (red arrow) (H&E x 40). (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photomicroscopy of a biopsy from a 27-year-old woman who presented with a 3-month history of unrelenting upper lip swelling. A few dilated lymphatics (green arrow) are seen adjacent to the granuloma along with mild perivascular lymphoplasmacytic cuffing (H&E x 40). The noncaseating granuloma is comprised of epithelioid cells, with a sprinkling of lymphocytes, histocytes (orange arrow), and multinucleated giant cells. (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photomicroscopy of a biopsy from a 27-year-old woman who presented with a 3-month history of unrelenting upper lip swelling. The biopsy shows mucosal lining with parakeratotic stratified squamous epithelium. Mid dermis with presence of noncaseating granuloma (H&E ×10). (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Non-tender diffuse swollen and firm upper lip and perioral area with areas of scaling in a 27-year-old woman who presented with a 3-month history of this problem. Biopsy from the lesion was consistent with granulomatous cheilitis. (Source: Tummidi S, Nagendran P, Anthony ML, Ramani RJ, Shankaralingappa A, Gopinath H. Granulomatous cheilitis of Miescher: a rare entity. BMC Womens Health 2023;23[1]:118. Creative Commons Attribution 4.0 International [CC-BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photograph shows the fissured tongue in a 38-year-old woman referred by her dentist for evaluation of recurrent swelling of the lower lip along with left hemifacial palsy. She was diagnosed with Melkersson-Rosenthal syndrome based on its three clinical features: recurrent facial palsy, orofacial swelling, and fissured tongue. (Source: Aoun G, Skandri N, Ghattas H, Maksoud C. Melkersson-Rosenthal syndrome in a 38-year-old female patient: a rare case with complete triad. Cureus 2022;14[7]:e27427. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

Photograph shows swelling of the lower lip in a 38-year-old woman referred by her dentist for evaluation of recurrent swelling of the lower lip along with left hemifacial palsy. She was diagnosed with Melkersson-Rosenthal syndrome based on its three clinical features: recurrent facial palsy, orofacial swelling, and fissured tongue. (Source: Aoun G, Skandri N, Ghattas H, Maksoud C. Melkersson-Rosenthal syndrome in a 38-year-old female patient: a rare case with complete triad. Cureus 2022;14[7]:e27427. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. The image has been cropped from the original.)

(A) MR angiography of the aorta and supra-aortic trunks depicted a critical arterial stenosis in the right subclavian humeral artery (orange dashed arrow), a distal stenotic segment in the right internal carotid artery (orange arrow), and an occluded lesion of the left vertebral artery (red arrow). The yellow dashed line indicates the location of the 1B and 1C axial sections. (B) MR imaging detected vessel wall thickening (up to 3 cm) of all supra-aortic vessels (arrows). (C) PET-CT showed intense FDG uptake of the supra-aortic trunks (arrows). (Contributed by Dr. Jose Hernandez-Rodriguez.)

(A) Typical patient with proximal muscle weakness and diffuse erythematous rash visible at the right knee and both arms. (B) Typical Gottron rash at the knuckles of the interphalangeal joints, sparing the phalanges. (C) Subcutaneous calcifications in the elbow protruding to the skin. (Contributed by Dr. Marinos Dalakas.)

(A) Cross-section of an H&E-stained muscle biopsy demonstrates the classic perifascicular atrophy (layers of atrophic fibers at the periphery of the fascicle) with necrosis and some inflammatory infiltrates (H&E stain ×100.) (B) Deposition of complement (membranolytic attack complex in green) on the endothelial cell wall of endomysial vessels (stained in red with a lectin Ulex Europaeus) leads to destruction of endothelial cells (confirmed in orange based on the superimposition of red on green). Consequently, in the muscles of patients with dermatomyositis, (C) the density of the endomysial capillaries (in red) is reduced, especially at the periphery of the fascicle, with dilatation of the lumen of the remaining capillaries in an effort to compensate for the ischemic process (x560). (Dalakas MC. Polymyositis, dermatomyositis and inclusion body myositis. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s principles of internal medicine. 19th edition. New York: McGraw-Hill, 2015b:2195-202.)

Activation of complement C3 is an early event leading to formation of C3b, C3bNEO, and membrane attack complexes, which are deposited on the endothelial cell wall of the endomysial capillaries and result in destruction of capillaries, ischemia, or microinfarcts, most prominently in the periphery of the fascicles, and perifascicular atrophy. Cytokines released by activated complement lead to activation of CD4+ T cells, macrophages, B cells, and CD123+ plasmacytoid dendritic cells; enhance the expression of vascular cell adhesion molecules (VCAM) and intercellular adhesion molecule (ICAM) on the endothelial cell wall; and facilitate lymphoid cell transmigration to endomysial tissue by their integrins, late activation antigen-4, and lymphocyte function–associated antigen-1, which bind VCAM and ICAM. The perifascicular regions contain fibers in a state of remodeling and regeneration (expressing TGF-beta, NCAM, Μi-2), cell-stress (expressing HSP 70,90), immune activation (expressing MHC-1, chemokines, STAT-1), and molecules associated with innate immunity (such as MxA, ISG15, Rig-1). The role of innate immunity in inflammation and perifascicular atrophy is clearly secondary to hypoxic and ischemic damage sensed by the retinoic acid-inducible gene-1 (Rig-1) signaling, which, in turn, leads to auto-amplification of the local inflammation via beta-interferon. Abbreviations: ICAM-1, intercellular adhesion molecule-1; LFA-1, lymphocyte function–associated antigen 1; MAC, membrane attack complex; MaC-1, macrophage 1 antigen; MxA, myxovirus (influenza virus) resistance protein 1; NO, nitrous oxide; STAT-1, signal transducer and activator of transcription protein 1; TGF-beta, transforming growth factor-beta; TNF-alpha, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1; VLA-1, very late antigen-1. (Contributed by Dr. Marinos Dalakas.)

Effect of IVIg on the skin manifestations (Gottron rash) and muscle strength of patients with dermatomyositis based on the first and pivotal placebo-controlled study. (Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immunoglobulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993-2000.) Not only do the active reddish lesions (top) improve, but the old grayish discolorations and mechanics hands (bottom) improve as well, allowing for the patient to fix her nails after many years of severe disease. Improvement in strength can be impressive and even allow wheelchair-bound patients to walk. (Contributed by Dr. Marinos Dalakas.)

IVIg inhibits complement at the C3a level (1, arrow) 2 days after the infusion (2) and intercepts the formation of MAC. As a result, MAC is not detected in the repeated muscle biopsies of the improved patients anymore (3a, 3b). The interception of MAC allows the restoration of the endomysial microvasculature, neovascularization (3c, 3d) and resolution of the perifascicular atrophy (3e, 3f). (Contributed by Dr. Marinos Dalakas.)

The presynaptic antigens are GAD (1), the enzyme that synthesizes GABA, the main inhibitory neurotransmitter, and amphiphysin (2), a synaptic vesicle protein responsible for endocytosis of plasma membranes following GABA release. Post-synaptically, the clinically relevant targets within the GAD-SD are gephyrin (3), a tubulin-binding protein needed for clustering both GABAA and glycine receptors; glycine receptor (4), a ligand-binding ion channel that allows the passage of chloride ions; and GABAA receptor–associated protein (GABARAP), a linker protein that promotes the organization of the GABAA receptors (Raju R, Rakocevic G, Chen Z, et al. Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain 2006;129[Pt 12]:3270-6). (Modified from: Dalakas MC. Progress and stiff challenges in understanding the role of GAD-antibodies in stiff-person syndrome. Exp Neurol 2013;247:303-7.)

mRNA expression in mononuclear white blood cells in multiple sclerosis shows massive gene dysregulation and correction by long-term IFN-beta therapy. A. Partial responders (PR) to IFN-beta therapy, while clinically stable, 4 days after last injection vs. untreated multiple sclerosis during exacerbations (left) and vs. untreated multiple sclerosis while stable (right). B. Untreated stable multiple sclerosis vs. healthy controls (HC) (left) and stable PR after 4-day washout vs. HC (right). (Adapted from:Feng X, Bao R, Li L, Deisenhammer F, Arnason BGW, Reder AT. Interferon-β corrects massive gene dysregulation in multiple sclerosis: Short-term and long-term effects on immune regulation and neuroprotection. EBioMedicine 2019;49:69-283.)

An association between a putative exposure and an outcome may be present in a crude analysis but is eliminated when stratifying by the confounding variable. (Contributed by Dr. Douglas J Lanska.)

The bold arrows indicate the direction of causality. The thin crossed arrow indicates that there is no causal relationship. (Contributed by Dr. Douglas J Lanska.)

In this case, the effect of vitamin D deficiency on the development of multiple sclerosis varies by age of exposure to vitamin D deficiency. Note, however, that effect modification does not necessarily imply causality: effect modification can operate with both causal and noncausal associations. (Contributed by Dr. Douglas J Lanska.)

The bold arrow indicates the direction of causality. (Contributed by Dr. Douglas J Lanska.)

The bold arrow indicates the direction of causality. (Contributed by Dr. Douglas J Lanska.)

(Contributed by Dr. Christine Lebrun-Frenay.)

Tissue biopsies showing storiform fibrosis (A) of the affected organs and a lymphoplasmacytic infiltrate made of CD4+ T-cells (B) and IgG4+ plasma cells (C). (Contributed by Dr. Christine Lebrun-Frenay.)

(A) On T2-weighted images, IgG4-HP appears as a hypointense mass or thickening of the meninges. (B) On T1-weighted images, IgG4-HP appears isointense and enhances with gadolinium, revealing an active inflammatory process. (Contributed by Dr. Christine Lebrun-Frenay.)

Photomicrograph of tumor immunostained with biotinylated anti-Hu IgG showing staining of some nuclei of tumor cells (dark blue color). Counterstaining with hematoxylin produces the light blue color of the negative cell nuclei. (Contributed by Dr. Francesc Graus.)

Axial FLAIR MRI showing increased signal abnormalities in the medial aspect of temporal lobes (arrows). (Contributed by Dr. Francesc Graus.)

The EULAR-Sjögren Syndrome Task Force Group therapeutic algorithm for central nervous system involvement is based on the type of neurologic manifestation. The authors suggested that corticosteroids plus cyclophosphamide could be the first- and second-line therapeutic approach in patients with CNS vasculitis and neuromyelitis optica spectrum disorder but that corticosteroids should be rapidly tapered with the aim of decreasing the risk of severe infection. Rituximab or/plus plasma exchanges may also be recommended for the treatment of this manifestation, especially in patients with severe or refractory disease, but its use is currently limited by the lack of US Food and Drug Administration or European Medicines Agency approval for these indications. When lymphocytic meningitis does not respond to symptomatic treatment, the same therapeutic algorithm should be followed. (Ramos-Casals M, Brito-Zerón P, Bombardieri S, et al. EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies. Ann Rheum Dis 2020;79(1):3-18.)

The EULAR-Sjögren Syndrome Task Force Group recommended general sequential use of the 3 main categories of immunosuppressive agents in Sjögren syndrome based on a similar approach to that reported for other systemic autoimmune disease, such as systemic lupus erythematosus or vasculitis, with no controlled studies supporting this approach in Sjögren syndrome. The immunosuppressive approaches traditionally used in multineuritis and axonal polyneuropathy (predominantly vasculitis related) are high dose of glucocorticoids as first-line treatment and oral immunosuppressive agents or rituximab as second-line. In refractory cases, cyclophosphamide or plasma exchanges are recommended as rescue therapy. Azathioprine and mycophenolate mofetil may be used in lieu of cyclophosphamide or following cyclophosphamide as “remission maintenance” agents, although neither medication has been evaluated for this purpose in formal clinical trials. In cases in which the axonal polyneuropathy is sensory, first-line treatment will be symptomatic, but in refractory cases, motor involvement, ganglionopathy, and or chronic inflammatory demyelinating polyneuropathy, EULAR Task Force Group recommend intravenous immunoglobulins 0.4 to 2 g/kg for 5 days as first-line treatment and methylprednisolone pulses as second-line or cyclophosphamide pulses 0.5 g/15 day (maximum 6 pulses) as rescue therapy. (Ramos-Casals M, Brito-Zerón P, Bombardieri S, et al. EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies. Ann Rheum Dis 2020;79(1):3-18.)

The optic disc is swollen, and there is subretinal fluid extending to the macula. Extensive patches of retinal edema (white) extend along the upper and lower vascular arcades. (Contributed by Dr. James Goodwin.)

[18F] FDG-PET/computed tomography in a patient with cancer-associated myositis. A [18F] FDG-PET/CT performed for cancer screening in a 63-year-old woman with dermatomyositis disclosed a hypermetabolic right parahilar mass (arrow) with bilateral adrenal gland enlargement and high standardized uptake value (SUVmax 11.5) (left adrenal, asterisk). Adrenal CT-guided core-needle biopsy was positive for small-cell lung cancer. (Contributed by Dr. Selva-O’Callaghan.)

14-year-old daughter of index case with Melkersson-Rosenthal syndrome, showing lingua plicata (fissured tongue). (Source: Jasinska D, Boczon J. Melkersson-Rosenthal syndrome as an early manifestation of mixed connective tissue disease. Eur J Med Res 2015;20:100.) (Courtesy of Creative Commons Attribution 4.0 International License.)

38-year-old woman with Melkersson-Rosenthal syndrome, showing facial diparesis and inability to smile. (Source: Jasinska D, Boczon J. Melkersson-Rosenthal syndrome as an early manifestation of mixed connective tissue disease. Eur J Med Res 2015;20:100.) (Courtesy of Creative Commons Attribution 4.0 International License.)

38-year-old woman with Melkersson-Rosenthal syndrome, showing lingua plicata (fissured tongue). (Source: Jasinska D, Boczon J. Melkersson-Rosenthal syndrome as an early manifestation of mixed connective tissue disease. Eur J Med Res 2015;20:100.) (Courtesy of Creative Commons Attribution 4.0 International License.)

This table shows the four subtypes of multiple sclerosis pathology in the brain. (Contributed by Dr. Anthony Reder.)

Blood smear showing the presence of a multinucleate lymphocyte, a "flower cell,” typical of HTLV-1 infection. It is pathognomonic of the carrier state, patients with adult T-cell leukemia lymphoma, and HAM/TSP.

Proton density axial MRIs of the head show 2 areas of increased signal (arrows) in the cerebral white matter of a 45-year-old patient with a spastic, wide-based gait, urinary symptoms, and CSF positive for HTLV-1. (Used with permission from: Howard A, Li D, Oger J. MRI contributes to the differentiation between multiple sclerosis and HTLV-1 associated myelopathy in British Columbian coastal natives. Can J Neurol Sci 2003;30:41-8.)

T2-weighted sagittal MRI of the cervical cord demonstrates atrophy in a 32-year-old patient with urinary retention, spastic paraparesis, and HTLV-1 detectable in the CSF. This finding has been described previously in HAM/TSP. Atrophy was found at a similar rate in the patient with multiple sclerosis the authors studied. (Used with permission from: Howard A, Li D, Oger J. MRI contributes to the differentiation between multiple sclerosis and HTLV-1 associated myelopathy in British Columbian coastal natives. Can J Neurol Sci 2003;30:41-8.)

MRI of two patients with NMOSD, one with typical presentation (A, B) and another with atypical presentation (C, D). The latter patient presented with encephalopathy and cranial nerve dysfunction. In the typical presentation, brain MRI is normal at disease onset (A) but the cervical cord (B) shows extensive inflammation (arrow). In the atypical presentation brain MRI shows extensive brainstem disease (C) and the thoracic cord (D) shows the usual extensive inflammation (arrow). (Contributed by Dr. Adil Javed.)

There are two known triggers of anti-NMDA receptor encephalitis: a tumor (usually ovarian teratoma) and herpes simplex encephalitis. The process between either of these triggers and the CNS production of antibodies is not clear; however, studies have confirmed de novo intrathecal synthesis of antibodies and CNS plasma cells after recovery from herpes simplex encephalitis. It is postulated that NMDA receptors expressed by nervous tissue within the tumor or released by viral-induced neuronal destruction, either in soluble form or loaded in antigen-presenting cells, is transported to regional lymph nodes (eg, pelvic-abdominal in ovarian teratoma or deep cervical lymph nodes in herpes simplex encephalitis) and presented to the immunologic system. Naive B cells exposed to NMDA receptors by antigen-presenting cells, and with cooperation of CD41 T-cells, become antigen-experienced memory B cells, differentiating into antibody-producing plasma cells. Memory B cells reach the brain by crossing the blood-brain barrier or via the choroidal plexus. In the brain, these B cells undergo re-stimulation, antigen-driven affinity maturation, clonal expansion, and differentiation into antibody-producing plasma cells. In tumors other than teratoma (eg, without nervous tissue within the tumor itself), the antigen is aberrantly expressed by the neoplastic cells. Of note, in approximately 50% of the patients the immunologic trigger of the disease is unknown. Reproduced with permission from Dalmau J. NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture. Neurology 2016;87(23):2471-82.

Examples of median nerve conduction studies demonstrating demyelinating features. (Contributed by Dr. Betty Soliven.)