Broader anti-EBV TCR repertoire in multiple sclerosis: disease specificity and treatment modulation.

Epstein-Barr virus (EBV) infection has long been associated with the development of multiple sclerosis (MS). MS patients have elevated titers of EBV-specific antibodies in serum and show signs of CNS damage only after EBV infection. Regarding CD8+ T-cells, an elevated but ineffective response to EBV was suggested in MS patients, who present with a broader MHC-I-restricted EBV-specific T-cell receptor beta chain (TRB) repertoire compared to controls. It is not known whether this altered EBV response could be subject to dynamic changes, e.g., by approved MS therapies, and whether it is specific for MS. 1317 peripheral blood TRB repertoire samples of healthy donors (n=409), patients with MS (n=710) before and after treatment, patients with neuromyelitis optica spectrum disorder (n=87), myelin-oligodendrocyte-glycoprotein antibody-associated disease (n=64) and Susac's syndrome (n=47) were analyzed. Apart from MS, none of the evaluated diseases presented with a broader anti-EBV TRB repertoire. In MS patients undergoing autologous hematopoietic stem-cell transplantation, EBV reactivation coincided with elevated MHC-I-restricted EBV-specific TRB sequence matches. Therapy with ocrelizumab, teriflunomide or dimethyl fumarate reduced EBV-specific, but not CMV-specific MHC-I-restricted TRB sequence matches. Together, this data suggests that the aberrant MHC-I-restricted T-cell response directed against EBV is specific to MS with regard to NMO, MOGAD and Susac's Syndrome and that it is specifically modified by MS treatments interfering with EBV host cells or activated lymphocytes.

Clinical Characterization and Ancillary Tests in Susac Syndrome: A Systematic Review.

Susac syndrome (SuS) is an orphan microangiopathic disease characterized by a triad of encephalopathy, visual disturbances due to branch retinal artery occlusions, and sensorineuronal hearing loss. Our previous systematic review on all cases of SuS reported until 2012 allowed for a better understanding of clinical presentation and diagnostic findings. Based on these data, we suggested diagnostic criteria in 2016 to allow early diagnosis and treatment of SuS. In view of the accumulation of new SuS cases reported in the last 10 years and improved diagnostic tools, we here aimed at updating the demographic and clinical features of SuS and to review the updated ancillary tests being used for SuS diagnosis. Therefore, based on the 2016 criteria, we systematically collected and evaluated data on SuS published from January 2013 to March 2022.

Central intra-lesional iron deposits as a possible novel imaging marker at 7 Tesla MRI in Susac Syndrome - an exploratory study.

BACKGROUND: Susac syndrome (SuS) is a rare autoimmune disease that leads to hearing impairment, visual field deficits, and encephalopathy due to an occlusion of precapillary arterioles in the brain, retina, and inner ear. Given the potentially disastrous outcome and difficulties in distinguishing SuS from its differential diagnoses, such as multiple sclerosis (MS), our exploratory study aimed at identifying potential new SuS-specific neuroimaging markers. METHODS: Seven patients with a definite diagnosis of SuS underwent magnetic resonance imaging (MRI) at 7 Tesla (7T), including T2* weighted and quantitative susceptibility mapping (QSM) sequences. T2 weighted hyperintense lesions were analyzed with regard to number, volume, localization, central vein sign, T1 hypointensity, and focal iron deposits in the center of SuS lesions ("iron dots"). Seven T MRI datasets from the same institute, comprising 75 patients with, among others, MS, served as controls. RESULTS: The "iron dot" sign was present in 71.4% (5/7) of the SuS patients, compared to 0% in our control cohort. Thus, sensitivity was 71.4% and specificity 100%. A central vein sign was only incidentally detected. CONCLUSION: We are the first to demonstrate this type of "iron dot" lesions on highly resolving 7T T2*w and QSM images in vivo as a promising neuroimaging marker of SuS, corroborating previous histopathological ex vivo findings.

Point-of-Care Testing Using a Neuropsychology Pocketcard Set: A Preliminary Validation Study.

Neurocognitive screening instruments usually require printed sheets and additional accessories, and can be unsuitable for low-threshold use during ward rounds or emergency workup, especially in patients with motor impairments. Here, we test the utility of a newly developed neuropsychology pocketcard set for point-of-care testing. For aphasia and neglect assessment, modified versions of the Language Screening Test and the Bells Test were validated on 63 and 60 acute stroke unit patients, respectively, against expert clinical evaluation and the original pen-and-paper Bells Test. The pocketcard aphasia test achieved an excellent area under the curve (AUC) of 0.94 (95% CI: 0.88−1, p < 0.001). Using an optimal cut-off of ≥2 mistakes, sensitivity was 91% and specificity was 81%. The pocketcard Bells Task, measured against the clinical neglect diagnosis, achieved higher sensitivity (89%) and specificity (88%) than the original paper-based instrument (78% and 75%, respectively). Separately, executive function tests (modified versions of the Trail Making Test [TMT] A and B, custom Stroop color naming task, vigilance 'A' Montreal Cognitive Assessment item) were validated on 44 inpatients with epilepsy against the EpiTrack® test battery. Pocketcard TMT performance was significantly correlated with the original EpiTrack® versions (A: r = 0.64, p < 0.001; B: r = 0.75, p < 0.001). AUCs for the custom Stroop task, TMT A and TMT B for discriminating between normal and pathological EpiTrack® scores were acceptable, excellent and outstanding, respectively. Quick point-of-care testing using a pocketcard set is feasible and yields diagnostically valid information.

A broad spectrum of posterior reversible encephalopathy syndrome - a case series with clinical and paraclinical characterisation, and histopathological findings.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is clinical-neuroradiologically defined and potentially reversible, so there are limited data about histopathological findings. We aimed to describe the clinical and paraclinical features of patients with PRES with regard to its reversibility. METHODS: This retrospective case series encompasses 15 PRES cases out of 1300 evaluated patients from a single German center between January 1, 2010, and June 15, 2020. PRES was established according to the diagnostic criteria as proposed by the Berlin PRES Study 2012. One of the cases studied was subject to brain autopsy. RESULTS: From the 15 patients studied (median age 53 years, range 17-73; 11 female), 67 % presented with epileptic seizures, 40 % suffered from encephalopathy with reduced consciousness and 53 % developed delirium, while 47 % had headache and visual disturbances. Subcortical brain MRI abnormalities related to PRES were observed in all patients. One patient developed spinal ischemia and another Guillain-Barré syndrome in addition to PRES. Hypertensive blood pressure was the main underlying/trigger condition in all patients. Clinical symptoms and MRI changes were not reversible in 42 %, even progressive in 3 out of these 5 patients. Median time from symptom onset to diagnosis in these non-reversible cases was 7 days (range 0-13), while the median delay in diagnosis in the reversible group was 1 day (range 0-3). Cerebellar/brain stem involvement and status epilepticus were more frequently in patients with non-reversible disease course. Mortality due to PRES occurred in 13 % of these patients. Neuropathological examination of the brain of a 57-year-old female patient revealed major leukencephalopathic changes, fibrinoid necrosis of endothelial cells and fresh petechial hemorrhages in accordance with PRES. CONCLUSIONS: Our case series demonstrates that PRES was not reversible in 42 % of the studied patients. Delay in diagnosis seems to contribute to limited reversibility and poor outcome.

Mechanical Thrombectomy in Acute Terminal Internal Carotid Artery Occlusions Using a Large Manually Expandable Stentretriever (Tiger XL Device): Multicenter Initial Experience.

BACKGROUND: The recently introduced Tigertriever XL Device for treatment of cerebral vessel occlusions combines manual adjustability and maximum length in one device. In this study, we report our initial experience with the Tigertriever XL in terminal ICA occlusions. METHODS: Retrospective multicenter analysis of acute terminal ICA occlusions treated by mechanical thrombectomy using the Tigertriever XL Device. RESULTS: 23 patients were treated using the Tigetriever XL due to an acute occlusion of the terminal ICA. The overall successful reperfusion rate after a median of two maneuvers using the Tigertriever XL Device was 78.3% (mTICI 2b-3). In 43.5% (10/23) additional smaller devices were applied to treat remaining occlusions in downstream territories, which resulted in a final successful reperfusion rate of 95.7%. Device related complications did not occur. Two symptomatic intracerebral hemorrhages (sICH) were observed. CONCLUSIONS: The Tigertriever XL Device might be a helpful tool in the treatment of ICA terminus occlusions with large clot burden resulting in high reperfusion rates. This is mainly related to the manual adjustability of the device combined with the maximum length.

Susac syndrome and pregnancy: a review of published cases and considerations for patient management.

Susac syndrome (SuS) is a rare autoimmune endotheliopathy leading to hearing loss, branch retinal artery occlusions and encephalopathy. Young females are more frequently affected than males, making counselling for family planning an important issue. We reviewed published cases on SuS during pregnancy or in the postpartum period, and selected 27 reports describing the details of 33 patients with SuS. Treatment options and implications for pregnancy and breastfeeding are discussed. We propose new areas for research and suggest a management strategy.

CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8+ T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.

Cardiac Imaging Within Emergency CT Angiography for Acute Stroke Can Detect Atrial Clots.

Cardiac embolism is presumed to cause a significant portion of cryptogenic strokes. Transesophageal echocardiography may detect intracardiac thrombi, but this remains a rare finding, possibly because remnant clots dissolve spontaneously or following thrombolysis. Cardiac imaging within cerebral CT angiography might offer an alternative method for thrombus detection within hyperacute stroke assessment. In a proof-of-concept study we analyzed records of patients aged ≥ 60 years that presented with suspected stroke and underwent extended cerebral CT angiography as part of their emergency assessment. CT imaging of patients with ischemic stroke or transient ischemic attack (TIA) and atrial fibrillation and of those with embolic strokes of undetermined source (ESUS) was reviewed for intracardiac clots and other cardiac or aortic pathology. Over a period of 3 months 59 patients underwent extended CT angiography for suspected stroke, 44 of whom received a final diagnosis of ischemic stroke or TIA. Of those, 17 had atrial fibrillation, and four fulfilled ESUS criteria. Thrombi were detected within atrial structures on CT angiography in three cases. In two ESUS patients complex atheromatosis of the proximal ascending aorta with irregular and ulcerating plaques was detected. Cardiac imaging within emergency cerebral CT angiography is feasible and can provide valuable diagnostic information in a patient group that might not routinely undergo transesophageal echocardiography. A small change to emergency assessment could potentially uncover cardioembolic pathology in cases that would have remained cryptogenic otherwise.

OCT-Angiography reveals reduced vessel density in the deep retinal plexus of CADASIL patients.

Optical coherence tomography angiography (OCT-A) represents the most recent tool in ophthalmic imaging. It allows for a non-invasive, depth-selective and quantitative visualization of blood flow in central retinal vessels and it has an enormous diagnostic potential not only in ophthalmology but also with regards to neurologic and systemic diseases. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary vascular small-vessel disease caused by Notch3 mutations and represents the most common form of hereditary stroke disorder. In this study, CADASIL patients prospectively underwent OCT-A imaging to evaluate retinal and choriocapillaris blood flow as well as blood flow at the optic nerve head. The vessel density of the macular region and the size of the foveal avascular zone in the superficial and deep retinal plexus were determined as well as the vessel density at the optic nerve head and in the choriocapillaris. Additionally, cerebral magnetic resonance images were evaluated. The main finding was that vessel density of the deep retinal plexus was significantly decreased in CADASIL patients compared to healthy controls which may reflect pericyte dysfunction in retinal capillaries.

An Enigmatic Case of Acute Mercury Poisoning: Clinical, Immunological Findings and Platelet Function.

Severe mercury intoxication is very rare in developed countries, but still occurs as the result of volatile substance abuse, suicide attempts, occupational hazards, or endemic food ingestion as reported in the cases of public health disasters in Iraq and in Minamata Bay, Japan. Here, we describe the dramatic physical and cognitive decline of a 23-year-old patient caused by a severe methyl mercury (MeHg) intoxication of unknown origin. We show serial magnetic resonance imaging (MRI) of the patient's brain, as well as ex vivo analyses of blood and cerebrospinal fluid including multicolor flow cytometric measurements, functional assays of hemostaseologic efficacy, and evaluation of regulatory effector molecules. Together with the clinical history, our findings show the progressive neuronal degeneration accompanying the deterioration of the patient. Moreover, the ex vivo analyses display alterations of thrombocyte function and coagulation, as well as an immunological milieu facilitating autoimmunity. Despite the successful reduction of the MeHg concentration in the patient's blood with erythrocyte apheresis and chelator therapy, his condition did not improve and led to a persistent vegetative state. This case illustrates the neurotoxicity of MeHg following severe intoxication for the first time by serial MRI. Data on immune-cell and thrombocyte function as well as on coagulation in mercury poisoning reveal potential implications for anticoagulation and immunomodulatory treatment.

Isolated dysphagia as initial sign of anti-IgLON5 syndrome.

OBJECTIVE: To report on dysphagia as initial sign in a case of anti-IgLON5 syndrome and provide an overview of the current literature. METHODS: The diagnostic workup included cerebral MRI, fiber optic endoscopic evaluation of swallowing (FEES) with the FEES tensilon test, a videofluoroscopic swallowing study, evoked potentials and peripheral nerve conduction studies, polysomnography, lumbar puncture, and screening for neural autoantibodies. A systematic review of all published cases of IgLON5 syndrome is provided. RESULTS: We report a case of anti-IgLON5 syndrome presenting with slowly progressive neurogenic dysphagia. FEES revealed severe neurogenic dysphagia and bilateral palsy of the vocal cords. Autoantibody screening was positive for IgLON5 IgG (+++, 1:1,000) serum levels but no other known neural autoantibody. Polysomnography was highly suggestive of non-REM parasomnia. Symptoms were partially responsive to immunotherapy. CONCLUSIONS: Slowly progressive neurogenic dysphagia may occur as initial sign of anti-IgLON5 syndrome highlighting another clinical presentation of this rare disease.

RETINAL LESION EVOLUTION IN SUSAC SYNDROME.

PURPOSE: To describe retinal lesion development in Susac syndrome during acute, postacute, and late phases of the disease. METHODS: Cross-sectional study of four patients with Susac syndrome and longitudinal short-interval case study of one additional patient. Retinal changes were analyzed with high-resolution spectral domain optical coherence tomography and retinal fluorescein angiography. RESULTS: Retinal Susac syndrome lesions comprise four different lesion sections, which can be distinguished in acute and postacute phases of the disease: a primary section at the site of branch retinal artery occlusion, which spans more layers than supplied by the affected vessel; hypoxic sections from superficial and deep capillary networks; and an axonal damage section with degenerating axons from perished ganglion cells in the main and hypoxic sections. In the later stages, main and hypoxic lesion sections can no longer be distinguished, and both show degeneration from outer plexiform to retinal nerve fiber layers. CONCLUSION: The dynamics of lesion development and morphologically distinct lesion sections suggest more complex mechanisms of lesion evolution beyond an isolated endothelial immune reaction and subsequent hypoxic tissue damage. The characteristic lesion morphology assists in differentiating the diagnosis of acute visual loss in neuroinflammatory disease. Specificity of the identified changes has to be determined in future studies also including patients with other retinal vascular diseases.

Diagnostic criteria for Susac syndrome.

BACKGROUND: Susac syndrome is characterised by the triad of encephalopathy with or without focal neurological signs, branch retinal artery occlusions and hearing loss. Establishment of the diagnosis is often delayed because the triad is complete only in a minority of patients at disease onset. This leads to a critical delay in the initiation of appropriate treatment. Our objective was to establish criteria for diagnosis of either definite or probable Susac syndrome. METHOD: The establishment of diagnostic criteria was based on the following three steps: (1) Definition of a reference group of 32 patients with an unambiguous diagnosis of Susac syndrome as assessed by all interdisciplinary experts of the European Susac Consortium (EuSaC) team (EuSaC cohort); (2) selection of diagnostic criteria, based on common clinical and paraclinical findings in the EuSaC cohort and on a review of the literature; and (3) validation of the proposed criteria in the previously published cohort of all Susac cases reported until 2012. RESULTS: Integrating the clinical presentation and paraclinical findings, we propose formal criteria and recommend a diagnostic workup to facilitate the diagnosis of Susac syndrome. More than 90% of the cases in the literature fulfilled the proposed criteria for probable or definite Susac syndrome. We surmise that more patients could have been diagnosed with the recommended diagnostic workup. CONCLUSIONS: We propose diagnostic criteria for Susac syndrome that may help both experts and physicians not familiar with Susac syndrome to make a correct diagnosis and to prevent delayed treatment initiation.

Behr syndrome with homozygous C19ORF12 mutation.

OBJECTIVE: Behr syndrome, first described in 1909 by the ophthalmologist Carl Behr, is a clinical entity characterised by a progressive optic atrophy, ataxia, pyramidal signs and mental retardation. Some reported cases have been found to carry mutations in the OPA1, OPA3 or C12ORF65 genes which are known causes of pure optic atrophy or optic atrophy complicated by movement disorder. METHODS: We present the long-term observation of two Turkish sisters with Behr syndrome. We performed neurophysiological, imaging and molecular genetic studies to identify the underlying genetic cause in our patients. RESULTS: Magnetic resonance imaging of the brain showed bilateral hypointense signals in the basal ganglia which prompted us to consider neurodegeneration with brain iron accumulation (NBIA) as a differential diagnosis. Molecular genetic studies revealed a homozygous mutation in the C19ORF12 gene which has been previously reported in patients with a subtype of NBIA, mitochondrial membrane protein-associated neurodegeneration (MPAN). CONCLUSION: We expand the spectrum of genetic causes of Behr syndrome. Genetic testing of patients presenting with Behr syndrome should include C19ORF12 mutation screening.

Retinal pathology in Susac syndrome detected by spectral-domain optical coherence tomography.

OBJECTIVE: The aim of this non-interventional study was to characterize retinal layer pathology in Susac syndrome (SuS), a disease with presumably autoimmune-mediated microvessel occlusions in the retina, brain, and inner ear, in comparison to the most important differential diagnosis multiple sclerosis (MS). METHODS: Seventeen patients with SuS and 17 age- and sex-matched patients with relapsing-remitting MS (RRMS) and healthy controls (HC) were prospectively investigated by spectral-domain optical coherence tomography (OCT) including intraretinal layer segmentation in a multicenter study. Patients with SuS additionally received retinal fluorescein angiography (FA) and automated perimetry. RESULTS: Patchy thinning of the retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, and outer plexiform layer compared to corresponding sectors in RRMS and HC eyes (p < 0.003 for SuS vs RRMS and HC) was observed in 23/34 (68%) SuS eyes, particularly in temporal quadrants. The outer nuclear layer (ONL) and photoreceptor layers (PRL) were not affected. FA performed in 15/17 patients with SuS was negative for disease-specific branch retinal artery occlusions in all but 1 eye at the time of OCT examination and revealed no additional vascular abnormalities, even in severely damaged OCT areas. In a subset of patients with SuS, associations of visual field data with distinct retinal layers were observed. CONCLUSION: Distinct OCT patterns of scattered, scar-like intraretinal pathology in SuS eyes, sparing the ONL and PRL, suggest a retinal, but not choroidal, vascular pathomechanism and clearly differentiate SuS from RRMS. Depending on the disease stage, OCT and FA provide specific complementary diagnostic information in SuS.

Update on Susac syndrome: new insights in brain and retinal imaging and treatment options.

Susac syndrome (SuS) is a rare endotheliopathy of the brain, the retina, and the inner ear. The underlying pathophysiology is likely an autoimmune mediated occlusion of microvessels resulting in variable degrees of central nervous system (CNS) dysfunction, visual disturbances, and hearing loss. The disease manifests either with a monophasic or polycyclic course. Patients suffering from SuS are frequently misdiagnosed as having inflammatory demyelinating CNS disease, particularly multiple sclerosis because of some overlap in the clinical presentation and the paraclinical findings. Since appropriate treatment of SuS is crucial for the prognosis, a timely and sound establishment of the diagnosis is important. Here, we summarize currently available information on the clinical presentation and diagnostic procedures in SuS. In particular, we discuss the added value of advanced techniques of brain and retinal imaging such as ultrahigh field magnetic resonance imaging and optical coherence tomography in SuS with respect to its differential diagnosis and pathophysiology. Since evidence-based treatment standards will not be available in the near future, we share some experiences in terms of treatment options. Finally, we briefly outline future areas of research in SuS.

Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study.

BACKGROUND: Susac syndrome (SuS) is a rare disorder thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina and inner ear leading to central nervous system (CNS) dysfunction, visual disturbances due to branch retinal artery occlusions (BRAO), and hearing deficits. Recently, a role for anti-endothelial cell antibodies (AECA) in SuS has been proposed. OBJECTIVES: To report the clinical and paraclinical findings in the largest single series of patients so far and to investigate the frequency, titers, and clinical relevance of AECA in SuS. PATIENTS AND METHODS: A total of 107 serum samples from 20 patients with definite SuS, 5 with abortive forms of SuS (all with BRAO), and 70 controls were tested for AECA by immunohistochemistry employing primate brain tissue sections. RESULTS: IgG-AECA >1:100 were detected in 25% (5/20) of patients with definite SuS and in 4.3% (3/70) of the controls. Median titers were significantly higher in SuS (1:3200, range 1:100 to 1:17500) than in controls (1:100, range 1:10 to 1:320); IgG-AECA titers >1:320 were exclusively present in patients with SuS; three controls had very low titers (1:10). Follow-up samples (n = 4) from a seropositive SuS patient obtained over a period of 29 months remained positive at high titers. In all seropositive cases, AECA belonged to the complement-activating IgG1 subclass. All but one of the IgG-AECA-positive samples were positive also for IgA-AECA and 45% for IgM-AECA. SuS took a severe and relapsing course in most patients and was associated with bilateral visual and hearing impairment, a broad panel of neurological and neuropsychological symptoms, and brain atrophy in the majority of cases. Seropositive and seronegative patients did not differ with regard to any of the clinical or paraclinical parameters analyzed. CONCLUSIONS: SuS took a severe and protracted course in the present cohort, resulting in significant impairment. Our finding of high-titer IgG1 and IgM AECA in some patients suggest that humoral autoimmunity targeting the microvasculature may play a role in the pathogenesis of SuS, at least in a subset of patients. Further studies are warranted to define the exact target structures of AECA in SuS.