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Fingolimod is an approved oral treatment for relapsing–remitting multiple sclerosis (RRMS) that modulates agonistically the sphingosin-1-phosphate receptor (S1PR), inhibiting thereby the egress of lymphocytes from the lymph nodes. In this interventional prospective clinical phase IV trial, we longitudinally investigated the impact of fingolimod on frequencies of NK cell subpopulations by flow cytometry in 17 RRMS patients at baseline and 1, 3, 6, and 12 months after treatment initiation. Clinical outcome was assessed by the Expanded Disability Status Scale (EDSS) and annualized relapse rates (ARR). Over the study period, median EDSS remained stable from month 3 to month 12, and ARR decreased compared to ARR in the 24 months prior treatment. Treatment was paralleled by an increased frequency of circulating NK cells, due primarily to an increase in CD56dimCD94low mature NK cells, while the CD56bright fraction and CD127+ innate lymphoid cells (ILCs) decreased over time. An unsupervised clustering algorithm further revealed that a particular fraction of NK cells defined by the expression of CD56dimCD16++KIR+/−NKG2A−CD94−CCR7+/−CX3CR1+/−NKG2C−NKG2D+NKp46−DNAM1++CD127+ increased during treatment. This specific phenotype might reflect a status of aged, fully differentiated, and less functional NK cells. Our study confirms that fingolimod treatment affects both NK cells and ILC. In addition, our study suggests that treatment leads to the enrichment of a specific NK cell subset characterized by an aged phenotype. This might limit the anti-microbial and anti-tumour NK cell activity in fingolimod-treated patients.

BACKGROUND: Visual phenomena are of many different kinds; their differential diagnosis is usually possible with directed history-taking. In this review, we describe common visual phenomena that must be distinguished from a migraine aura. METHODS: This review is based on publications retrieved by a selective search in PubMed and the Web of Knowledge/Science, with special attention to the current classification of the International Headache Society and the recommendations of the German Migraine and Headache Society. The following search terms were used: “visual phenomena/phenomenon,” “migraine aura,” and “persistent/complication/long-lasting/ongoing.” RESULTS: The most helpful questions for differential diagnosis are whether the symptoms are present in one eye only or in both, whether their onset was sudden or over minutes or days, and whether the phenomenon has occurred only once or repeatedly, or is persistently present. A visual aura associated with migraine must be distinguished, in rare cases, from an isolated epileptic aura, from cerebral/retinal ischemia, or from visual snow. Further differential diagnoses include a persisting perceptual disturbance after hallucinogen use (HPPD, “hallucinogen persisting perception disorder”) and the Charles Bonnet syndrome (CBS); the latter arises as a consequence of severely impaired vision. Posterior reversible encephalopathy syndrome (PRES) is rare and generally reveals itself over its further course through the appearance of additional clinical manifestations. Primary ophthalmological causes can usually be readily identified and classified by ophthalmological examination. CONCLUSION: Patients with visual phenomena typically consult physicians from various medical specialties. A correct differential diagnosis can be made based on the history if the physician views the symptoms in their overall context to determine the particular disease entity that is responsible.

We here report the case of a 2-year-old patient with a primary central nervous system lymphoma of B-cell origin. Due to their past medical history of repeated respiratory tract infections and the marked chemotherapy-associated toxicity and infectious comorbidity, we suspected that the patient also suffered from an inherited immune deficiency disorder. Despite the lack of classical pathognomonic symptoms for ataxia teleangiectasia and missing evidence for a cancer predisposition syndrome in the family, genetic testing identified biallelic germline mutations, including the rare pathogenic variant c.3206delC (p.Pro1069Leufs*2), in the ataxia telangiectasia-mutated (ATM) gene. The case highlights the importance of searching for immune deficiency disorders associated with primary central nervous system lymphoma before treatment initiation and the urgent need to develop novel treatment strategies for cancer patients with underlying immunodeficiency syndromes.

The activation of oncogenes via genomic amplification is a hallmark of the cancer genomes, yet such amplifications frequently also encompass neighboring genes. Such passenger genes are involved in essential cellular activities. We hypothesized that co-amplification of passenger genes create cancer-specific collateral therapeutic vulnerabilities. To test this, we analyzed one of the most commonly amplified gene locus near MYCN, which is amplified in nearly 25% of neuroblastoma and around 5% of all cancers. We observed that DDX1, a DEAD-Box helicase, is the most frequently co-amplified passenger gene in MYCN-amplified cancers. Using CRISPR/Cas9 loss-of-function screen results from the Cancer Dependency Map across 739 human cancer cell lines, we reveal that cells with DDX1 co-amplification are highly dependent on the mTOR complex 1(mTORC1). Mechanistically, western blot and immunoprecipitation analyses shows that DDX1 expression leads to higher mTORC1 pathway activity through the interaction between DDX1 and alpha-ketoglutarate dehydrogenase(alpha-KGDH) in mitochondria. DDX1 hijacks alpha-KGDH complex, thereby impairing the function of the Krebs cycle by interfering with the conversion of alpha-ketoglutarate to succinyl-coA. Live cell metabolomics shows accumulated alpha-ketoglutarate in turn activates mTORC1 pathway to promote the ATP production via oxidative phosphorylation(OXPHOS) to maintain cell survival. Consequently, interference with mTORC1 function reduced ATP production and led to accumulated alpha-KG leading to cell death, specifically in DDX1 expressing cells. This suggests that co-amplification of a passenger gene can result in collateral vulnerabilities in cancers, which has the potential to transform future therapeutic target discovery in oncology. Citation Format: Yi Bei, Marieluise Kirchner, Luca Brame, Raphaela Fritsche-Guenther, Julia Koeppke, Anja Heeren-Hagemann, Philipp Mertins, Jan Dörr, Anton George Henssen. Passenger gene co-amplification leads to collateral vulnerabilities in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1882.

Background: Epidemiological, preclinical, and non-interventional studies link vitamin D (VD) serum levels and disease activity in multiple sclerosis (MS). It is unclear whether high-dose VD supplementation can be used as an intervention to reduce disease activity. Objectives: The study aimed to compare the effects of every other day high- (20,400 IU) versus low-dose (400 IU) cholecalciferol supplementation on clinical and imaging markers of disease activity in patients with relapsing-remitting MS or clinically isolated syndrome. Methods: The EVIDIMS (efficacy of vitamin D supplementation in multiple sclerosis) trial was a multicentre randomized/stratified actively controlled explorative phase 2a pilot trial with a double-blind intervention period of 18 months, add on to interferon-β1b. Results: Fifty-three patients were randomized, and 41 patients completed the study. Cholecalciferol supplementation was well tolerated and safe in both arms. After 18 months, clinical (relapse rates, disability progression) and radiographical (T2-weighted lesion development, contrast-enhancing lesion development, brain atrophy) did not differ between both treatment arms. Post-study power calculations suggested that the sample size was too low to prove the hypothesis. Conclusions: The results neither support nor disprove a therapeutic benefit of high-dose VD supplementation but provide a basis for sound sample size estimations in future confirmatory studies. www.clinicaltrials.gov/NCT01440062.

Das Susac-Syndrom (SuS) ist eine seltene Erkrankung. Eine wahrscheinlich durch autoreaktive CD8+-Zellen (CD: „cluster of differentiation“) vermittelte Immunreaktion fuhrt uber die Beeintrachtigung von Gefasendothelzellen zu okklusiven Mikroangiopathien in Gehirn, Retina und Innenohr. Klinisch ausert sich dies in einer subakuten Enzephalopathie mit variabel ausgepragten kognitiven Storungen, Verhaltensveranderungen, fokal-neurologischen Beeintrachtigungen, Seh- und Horstorungen. Bildmorphologisch lassen sich oft eindruckliche Befunde erheben. Das SuS ist eine wichtige Differenzialdiagnose zu vielen neurologischen, psychiatrischen, ophthalmologischen und HNO-Erkrankungen (HNO: Hals-Nasen-Ohren). Fehldiagnosen sind sehr haufig, beinahe regelhaft wird das SuS initial als Multiple Sklerose verkannt, was Verzogerungen in der Therapie und Fehlbehandlungen begunstigt. Meist ist eine fruhzeitige und konsequente Immuntherapie erforderlich und fur die langfristige Prognose entscheidend.

International audience; 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.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.

ObjectiveTo investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsWe performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period.ResultsThe SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75–3.38) to 0.50 (IQR 0.00–1.13; difference −0.625, 95% CI −1.25 to −0.50; PInterpretationThe oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial.Clinical trial registrationNCT01450124; Results.

Key Points Question Is the serum concentration of N-acetylglucosamine (GlcNAc) altered in patients with multiple sclerosis? Findings This cross-sectional study found that patients with a progressive multiple sclerosis subtype and more severe disease have reduced serum levels of a marker of GlcNAc. In addition, GlcNAc is a rate-limiting substrate for N-glycan branching, which has been shown to regulate immunoactivity and myelination. Meaning This study suggests that GlcNAc and N-glycan branching are associated with multiple sclerosis in general and progressive multiple sclerosis in particular., Importance N-glycan branching modulates cell surface receptor availability, and its deficiency in mice promotes inflammatory demyelination, reduced myelination, and neurodegeneration. N-acetylglucosamine (GlcNAc) is a rate-limiting substrate for N-glycan branching, but, to our knowledge, endogenous serum levels in patients with multiple sclerosis (MS) are unknown. Objective To investigate a marker of endogenous serum GlcNAc levels in patients with MS. Design, Setting, and Participants A cross-sectional discovery study and cross-sectional confirmatory study were conducted at 2 academic MS centers in the US and Germany. The discovery study recruited 54 patients with MS from an outpatient clinic as well as 66 healthy controls between April 20, 2010, and June 21, 2013. The confirmatory study recruited 180 patients with MS from screening visits at an academic MS study center between April 9, 2007, and February 29, 2016. Serum samples were analyzed from December 2, 2013, to March 2, 2015. Statistical analysis was performed from February 23, 2020, to March 18, 2021. Main Outcomes and Measures Serum levels of GlcNAc plus its stereoisomers, termed N-acetylhexosamine (HexNAc), were assessed using targeted tandem mass spectroscopy. Secondary outcomes (confirmatory study) comprised imaging and clinical disease markers. Results The discovery cohort included 66 healthy controls (38 women; mean [SD] age, 42 [20] years), 33 patients with relapsing-remitting MS (RRMS; 25 women; mean [SD] age, 50 [11] years), and 21 patients with progressive MS (PMS; 14 women; mean [SD] age, 55 [7] years). The confirmatory cohort included 125 patients with RRMS (83 women; mean [SD] age, 40 [9] years) and 55 patients with PMS (22 women; mean [SD] age, 49 [80] years). In the discovery cohort, the mean (SD) serum level of GlcNAc plus its stereoisomers (HexNAc) was 710 (174) nM in healthy controls and marginally reduced in patients with RRMS (mean [SD] level, 682 [173] nM; P = .04), whereas patients with PMS displayed markedly reduced levels compared with healthy controls (mean [SD] level, 548 [101] nM; P = 9.55 × 10−9) and patients with RRMS (P = 1.83 × 10−4). The difference between patients with RRMS (mean [SD] level, 709 [193] nM) and those with PMS (mean [SD] level, 405 [161] nM; P = 7.6 × 10−18) was confirmed in the independent confirmatory cohort. Lower HexNAc serum levels correlated with worse expanded disability status scale scores (ρ = –0.485; P = 4.73 × 10−12), lower thalamic volume (t = 1.7; P = .04), and thinner retinal nerve fiber layer (B = 0.012 [SE = 7.5 × 10−11]; P = .008). Low baseline serum HexNAc levels correlated with a greater percentage of brain volume loss at 18 months (t = 1.8; P = .04). Conclusions and Relevance This study suggests that deficiency of GlcNAc plus its stereoisomers (HexNAc) may be a biomarker for PMS. Previous preclinical, human genetic, and ex vivo human mechanistic studies revealed that N-glycan branching and/or GlcNAc may reduce proinflammatory responses, promote myelin repair, and decrease neurodegeneration. Combined, the data suggest that GlcNAc deficiency may be associated with progressive disease and neurodegeneration in patients with MS., This cross-sectional study investigates a marker of endogenous serum N-acetylglucosamine levels in patients with multiple sclerosis (MS).

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., Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

Background Neuroprotection and promotion of remyelination represent important therapeutic gaps in multiple sclerosis (MS). Acute optic neuritis (ON) is a frequent MS manifestation. Based on the presence and properties of sphingosine-1-phosphate receptors (S1PR) on astrocytes and oligodendrocytes, we hypothesized that remyelination can be enhanced by treatment with fingolimod, a S1PR modulator currently licensed for relapsing-remitting MS. Methods MOVING was an investigator-driven, rater-blind, randomized clinical trial. Patients with acute unilateral ON, occurring as a clinically isolated syndrome or MS relapse, were randomized to 6 months of treatment with 0.5 mg oral fingolimod or subcutaneous IFN-β 1b 250 μg every other day. The change in multifocal visual evoked potential (mfVEP) latency of the qualifying eye was examined as the primary (month 6 vs. baseline) and secondary (months 3, 6 and 12 vs. baseline) outcome. In addition, full field visual evoked potentials, visual acuity, optical coherence tomography as well as clinical relapses and measures of disability, cerebral MRI, and self-reported visual quality of life were obtained for follow-up. The study was halted due to insufficient recruitment (n = 15), and available results are reported. Results Per protocol analysis of the primary endpoint revealed a significantly larger reduction of mfVEP latency at 6 months compared to baseline with fingolimod treatment (n = 5; median decrease, 15.7 ms) than with IFN-β 1b treatment (n = 4; median increase, 8.15 ms) (p

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.

Background: Previous studies have postulated an association between dentate nucleus T1 hyperintensity and multiple sclerosis (MS)-related progressive neurodegeneration. Therefore, MS patients have been excluded from most studies investigating brain deposition of gadolinium-based contrast agents (GBCAs). Objective: To study the hypothesis that dentate nucleus T1 hyperintensity in MS patients is associated with GBCA administration. Methods: In a cohort of 97 MS patients, the dentate-to-pons signal intensity ratio (DPSIR) was calculated for 265 consecutive T1-weighted magnetic resonance (MR) scans (including sessions with and without the administration of GBCA). Patients exclusively received either gadopentetate dimeglumine (Gd-DTPA, linear) or gadobutrol (Gd-BT-DO3A, macrocyclic). Results: In patients receiving Gd-DTPA, DPSIR increased significantly between the first and the last scan (+0.009, p Conclusion: Dentate nucleus T1 hyperintensity in MS patients is associated with Gd-DTPA (but not Gd-BT-DO3A) administration, suggesting an alternative explanation for the association of T1 hyperintensity with disease duration and severity.

The CD20-targeting monoclonal antibody rituximab is an established component of immunochemotherapeutic regimens against B-cell lymphomas, where its coadministration with conventional anticancer agents has significantly improved long-term outcome. However, the cellular mechanisms by which rituximab exerts its antilymphoma activity are only partially understood. We show here that rituximab induces typical features of cellular senescence, a long-term growth arrest of viable cells with distinct biologic properties, in established B-cell lymphoma cell lines as well as primary transformed B cells. In addition, rituximab-based immunotherapy sensitized lymphoma cells to senescence induction by the chemotherapeutic compound adriamycin (a.k.a. doxorubicin), and, to a lesser extent, by the antimicrotubule agent vincristine. Anti-CD20 treatment further enhanced secretion of senescence-associated cytokines, and augmented the DNA damage response signaling cascade triggered by adriamycin. As the underlying prosenescence mechanism, we found intracellular reactive oxygen species (ROS) levels to be elevated in response to rituximab, and, in turn, the ROS scavenger N-acetylcysteine to largely abrogate rituximab-mediated senescence. Our results, further supported by gene set enrichment analyses in a clinical data set of chronic lymphocytic leukemia patient samples exposed to a rituximab-containing treatment regimen, provide important mechanistic insights into the biologic complexity of anti-CD20-evoked tumor responses, and unveil cellular senescence as a hitherto unrecognized effector principle of the antibody component in lymphoma immunochemotherapy. Mol Cancer Ther; 15(5); 1074–81. ©2016 AACR.

To describe retinal lesion development in Susac syndrome during acute, postacute, and late phases of the disease.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.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.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.

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Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16(INK4a), p21(CIP1) and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eμ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.

Background and purpose Low 25-hydroxyvitamin D [25(OH)D] levels correlate with higher disease activity in patients with multiple sclerosis (MS). However, it is not clear whether low 25(OH)D levels directly contribute to increased disease activity or merely represent a consequence of reduced endogenous vitamin D synthesis in more disabled MS patients. Furthermore, recent data suggest that bioavailable vitamin D, which also integrates the levels of vitamin D binding proteins and albumin, could be a biologically more relevant parameter than 25(OH)D. Methods Measured de-seasonalized 25(OH)D3 and vitamin D binding protein and calculated bioavailable and free vitamin D were compared in the baseline serum samples of 76 patients with clinically isolated syndrome enrolled in a longitudinal observational study and in 76 age- and sex-matched healthy controls (HC). Results 25(OH)D3 levels were lower in patients with clinically isolated syndrome (P = 0.002) than in HC, and more patients (8/76, 10.5%) than HC (1/76, 1.3%) had 25(OH)D3 levels

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).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.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 (p0.003 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.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.

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Susac syndrome (SuS) is a rare endotheliopathy of the brain, the retina, and the inner ear. The underlying patho- physiology 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 mul- tiple 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.

To investigate posterior visual pathway damage in multiple sclerosis using ultrahigh-field magnetic resonance imaging (MRI) at 7 Tesla (7 T), and to determine its correlation with visual disability and retinal fibre layer (RNFL) damage detectable by optic coherence tomography (OCT).We studied 7 T MRI, OCT, functional acuity contrast testing (FACT), and visually evoked potentials (VEP, n = 16) in 30 patients (including 26 relapsing-remitting MS and four clinically isolated syndrome patients) and 12 healthy controls to quantify RNFL thickness, optic radiation lesion volume, and optic radiation thickness.Optic radiation lesion volume was associated with thinning of the optic radiation (p0.001), delayed VEP (p = 0.031), and visual disability indicated by FACT (p = 0.020). Furthermore, we observed an inverse correlation between optic radiation lesion volume and RNFL thickness (p0.001), including patients without previous optic neuritis (p0.001).Anterior visual pathway damage, but also (subclinical) optic radiation integrity loss detectable by 7 T MRI are common findings in MS that are mutually affected. Given the association between optic radiation damage, visual impairment, and increased VEP latency in this exploratory study of a limited sample size, clinicians should be aware of acute lesions within the optic radiation in patients with (bilateral) visual disturbances.• Focal destruction of the optic radiation is detectable by 7 T MRI. • Focal optic radiation damage is common in MS. • Optic radiation damage is associated with RNFL thinning, detectable by OCT. • Optic radiation damage is associated with delayed VEP and visual dysfunction. • RNFL thickness in non-optic neuritis eyes correlates with optic radiation demyelination.

Multiple sclerosis (MS) is a common inflammatory demyelinating disorder of the central nervous system. It frequently affects females in their reproductive phase of life. Therefore, family planning, pregnancy, and breastfeeding are important issues in the management of MS, particularly with respect to counseling and drug treatment. This paper reviews currently available data on the outcome of pregnancies in MS patients and the influence of pregnancy on the course of the disease. We give an update on the use of various disease-modifying MS drugs during pregnancy and breastfeeding. In addition to established therapies such as interferon-β, glatiramer acetate, natalizumab, and fingolimod, we also discuss the state of knowledge about new agents such as dimethyl fumarate, teriflunomide, and alemtuzumab in the context of pregnancy and breastfeeding.

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Potential differences between primary progressive (PP) and relapsing–remitting (RR) multiple sclerosis (MS) have been controversially discussed. In this study, we compared lesion morphology and distribution in patients with PPMS and RRMS (nine in each group) using 7 T MRI. We found that gray and white matter lesions in PPMS and RRMS patients did not differ in their respective morphological characteristics (e.g. perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436). Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI.

Background: Susac syndrome is a rare disease characterized by the triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss mainly affecting young women. The finding of antibodies against the endothelium in the sera of these patients has supported the hypothesis of an autoimmune endotheliopathy of the brain, inner ear and retina. Because of the rarity of the disease, treatment is based on the knowledge of case reports and small case series. Medical therapy consists of glucocorticoids, immunosuppressants, acetyl salicylic acid, and immunomodulatory agents such as intravenous immunoglobulin. Methods: We present the case histories of 2 young women with Susac syndrome presenting with several episodes of encephalopathy, branch retinal artery occlusions, and hearing loss that were treated with different immunosuppressive drugs, glucocorticoids and intravenous immunoglobulin. In the course of the disease, the treatment was successfully switched to subcutaneous immunoglobulin without any further relapse in both patients. Conclusion: We conclude that the application of subcutaneous immunoglobulin is easy to learn, helps to reduce in-hospital costs and enables a more flexible everyday life. The treatment with subcutaneous immunoglobulin helps to reduce immunosuppressants and appears to prevent relapses.