Apixaban versus Aspirin for Embolic Stroke of Undetermined Source.

Apixaban versus Aspirin for Embolic StrokeIn a trial of 352 patients with embolic stroke of undetermined source, 5 mg of apixaban administered twice daily was compared with 100 mg of aspirin administered once daily for the prevention of recurrent ischemic strokes. At 12 months, 13.6% of patients given apixaban had new ischemic lesions on magnetic resonance imaging compared with 16.0% of patients given aspirin, and the rates of clinically relevant bleeding were also comparable.

Resolving Multielement Semiconductor Nanocrystals at the Atomic Level: Complete Deciphering of Domains and Order in Complex CuαZnßSnγSeδ (CZTSe) Tetrapods.

Semiconductor nanocrystals (NCs) with high elemental and structural complexity can be engineered to tailor for electronic, photovoltaic, thermoelectric, and battery applications etc. However, this greater complexity causes ambiguity in the atomic structure understanding. This in turn hinders the mechanistic studies of nucleation and growth, the theoretical calculations of functional properties, and the capability to extend functional design across complementary semiconductor nanocrystals. Herein, we successfully deciphered the atomic arrangements of 4 different nanocrystal domains in CuαZnßSnγSeδ (CZTSe) nanocrystals using crucial zone axis analysis on multiple crystals in different orientations. The results show that the essence of crystallographic progression from binary to multielemental semiconductors is actually the change of theoretical periodicity. This transition is caused by decreased symmetry in the crystal instead of previously assumed crystal deformation. We further reveal that these highly complex crystalline entities have highly ordered element arrangements as opposed to the previous understanding that their elemental orderings are random.

Ability of patients with acute ischemic stroke to recall given information on intravenous thrombolysis: Results of a prospective multicenter study.

Introduction: Intravenous thrombolysis (IVT) is an on label treatment for selected patients with acute ischemic stroke (AIS). As major bleeding or allergic shock may occur, the need to ensure patients' informed consent for IVT is a matter of debate. Patients and methods: Prospective investigator-initiated multi-center observational study to assess the ability of AIS patients to recall information, provided by a physician during a standardized educational talk (SET) on IVT use. The recall of 20 pre-defined items was assessed in AIS after 60-90 min (n = 93) or 23-25 h (n = 40) after SET. About 40 patients with subacute stroke, 40 non-stroke patients, and 23 relatives of AIS patients served as controls, and were surveyed 60-90 min after SET. Results: Within 60-90 min after SET, AIS patients (median age 70 years, 31% female, median NIHSS score on admission 3 points) who were considered capable to provide informed consent recalled 55% (IQR 40%-66.7%) of the provided SET items. In multivariable linear regression analysis recapitulation by AIS patients was associated with their educational level (ß = 6.497, p < 0.001), self-reported excitement level (ß = 1.879, p = 0.011) and NIHSS score on admission (ß = -1.186, p = 0.001). Patients with subacute stroke (70 years, 40% female, median NIHSS = 2) recalled 70% (IQR 55.7%-83.6%), non-stroke patients (75 years, 40% female) 70% (IQR 60%-78.7%), and AIS relatives (58 years, 83% female) 70% (IQR 60%-85%). Compared to subacute stroke patients, AIS patients less often recalled the frequency of IVT-related bleeding (21% vs 43%), allergic shock (15% vs 39%), and bleeding-related morbidity and mortality (44% vs 78%). AIS patients recalled 50% (IQR 42.3%-67.5%) of the provided items 23-25 h after SET. Conclusion: AIS patients eligible for IVT remember about half of all SET-items after 60-90 min or 23-25 h, respectively. The fact that the recapitulation of IVT-associated risks is particularly poor should be given special consideration.

Blatter Radical-Decorated Silica as a Prospective Adsorbent for Selective NO Capture from Air.

Nitrogen oxides are adverse poisonous gases present in the atmosphere and having detrimental effects on the human health and environment. In this work, we propose a new type of mesoporous materials capable of capturing nitrogen monoxide (NO) from air. The designed material combines the robust Santa Barbara Amorphous-15 silica scaffold and ultrastable Blatter-type radicals acting as NO traps. Using in situ electron paramagnetic resonance spectroscopy, we demonstrate that NO capture from air is selective and reversible at practical conditions, thus making Blatter radical-decorated silica highly promising for environmental applications.

Epstein-Barr Virus-Induced Genes and Endogenous Retroviruses in Immortalized B Cells from Patients with Multiple Sclerosis.

The immune pathogenesis of multiple sclerosis (MS) is thought to be triggered by environmental factors in individuals with an unfavorable genetic predisposition. Epstein-Barr virus (EBV) infection is a major risk factor for subsequent development of MS. Human endogenous retroviruses (HERVs) can be activated by EBV, and might be a missing link between an initial EBV infection and the later onset of MS. In this study, we investigated differential gene expression patterns in EBV-immortalized lymphoblastoid B cell lines (LCL) from MS-affected individuals (MSLCL) and controls by using RNAseq and qRT-PCR. RNAseq data from LCL mapped to the human genome and a virtual virus metagenome were used to identify possible biomarkers for MS or disease-relevant risk factors, e.g., the relapse rate. We observed that lytic EBNA-1 transcripts seemed to be negatively correlated with age leading to an increased expression in LCL from younger PBMC donors. Further, HERV-K (HML-2) GAG was increased upon EBV-triggered immortalization. Besides the well-known transactivation of HERV-K18, our results suggest that another six HERV loci are up-regulated upon stimulation with EBV. We identified differentially expressed genes in MSLCL, e.g., several HERV-K loci, ERVMER61-1 and ERV3-1, as well as genes associated with relapses. In summary, EBV induces genes and HERV in LCL that might be suitable as biomarkers for MS or the relapse risk.

Headache in Multiple Sclerosis - Pharmacological Aspects.

For decades, the headache was not considered a typical symptom of multiple sclerosis (MS) and was construed as a "red flag" for important differential diagnoses such as cerebral vasculitis. Meanwhile, several studies have demonstrated an increased prevalence of headaches in MS compared to the general population. This is due to the heterogeneity of headache genesis with frequent occurrence of both primary and secondary headaches in MS. On the one hand, MS and migraine are often comorbid. On the other hand, secondary headaches frequently occur, especially in the course of MS relapses. These are often migraine-like headaches caused by inflammation, which can improve as a result of MS-specific therapy. Headaches are particularly common in the early stages of chronic inflammatory CNS disease, where inflammatory activity is the greatest. In addition, headaches can also occur as a side effect of disease-modifying drugs (DMDs). Headache can occur with most DMDs and is most frequently described with interferon-beta therapy. The aim of this work is to present the prevalence of headaches and describe the heterogeneity of possible causes of headaches in MS. In addition, important therapeutic aspects in the treatment of MS patients, in general, will be presented as well as different approaches to the treatment of headaches in MS depending on the etiological classification.

Alemtuzumab in a Large Real-Life Cohort: Interim Baseline Data of the TREAT-MS Study.

The non-interventional long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting MS (TREAT-MS) study collects the so far largest real-life cohort regarding utilization, long-term effectiveness, and safety of alemtuzumab, a humanized monoclonal antibody directed against the cell surface glycoprotein CD52, in adult patients with active relapsing-remitting multiple sclerosis (RRMS). An interim analysis of baseline parameters at inclusion of a non-interventional real-world study about alemtuzumab in Germany including previous multiple sclerosis (MS) medication utilization, MS activity, severity, and duration, as well as comorbidities was performed. Of the 883 patients, 71.6% were women. Mean age was 35.7 ± 9.2 years, time since first MS symptoms (=disease duration) is 8.0 ± 6.8 years, and Expanded Disability Status Scale (EDSS) is 2.7 ± 1.8 points (range, 0.0-7.5 points). The number of relapses in the 12 and 24 months prior to inclusion were 1.6 ± 1.2 and 2.2 ± 1.8, respectively. Of the patients, 14.4% were treatment naive, while for the majority, a wide spectrum of MS disease-modifying treatments (DMTs) and treatment sequences were documented. Overall, interferon beta (IFN-beta) was reported most frequently (52.4%), followed by fingolimod (35.2%), natalizumab (34.9%), and glatiramer acetate (28.9%). Patients with longer disease duration and higher EDSS had a higher number of previous DMTs. Compared to the pivotal phase 2/3 studies, RRMS patients starting alemtuzumab treatment had a longer disease duration in real-world conditions. There was variety of different treatment sequences before the final switch to alemtuzumab. In the future, linking these treatment sequences or other baseline characteristics with effectiveness and safety outcomes might be useful to support treatment decisions. Registered at Paul-Ehrlich-Institut under NIS 281.

Epigallocatechin Gallate in Relapsing-Remitting Multiple Sclerosis: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: To assess the safety and efficacy of epigallocatechin-3-gallate (EGCG) add-on to glatiramer acetate (GA) in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We enrolled patients with RRMS (aged 18-60 years, Expanded Disability Status Scale [EDSS] score 0-6.5), receiving stable GA treatment in a multicenter, prospective, double-blind, phase II, randomized controlled trial. Participants received up to 800 mg oral EGCG daily over a period of 18 months. The primary outcome was the proportion of patients without new hyperintense lesions on T2-weighted (T2w) brain MRI within 18 months. Secondary end points included additional MRI and clinical parameters. Immunologic effects of EGCG were investigated in exploratory experiments. RESULTS: A total of 122 patients on GA were randomly assigned to EGCG treatment (n = 62) or placebo (n = 60). We could not demonstrate a difference between groups after 18 months for the primary outcome or other radiologic (T2w lesion volume, T1w hypointense lesion number or volume, number of cumulative contrast-enhancing lesions, percent brain volume change), or clinical (EDSS, MS functional composite, and annualized relapse rate) parameter. EGCG treatment did not affect immune response to GA. Pharmacologic analysis revealed wide ranging EGCG plasma levels. The treatment was well tolerated with a similar incidence of mostly mild adverse events similar in both groups. CONCLUSION: In RRMS, oral EGCG add-on to GA was not superior to placebo in influencing MRI and clinical disease activity over 18 months. The treatment was safe at a daily dosage up to 800 mg EGCG. It did not influence immune parameters, despite indication of EGCG being bioavailable in patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS, EGCG added to GA did not significantly affect the development of new hyperintense lesions on T2-weighted brain MRI. TRIAL REGISTRATION INFORMATION: Clinical trial registration number: NCT00525668.

Blatter-Radical-Grafted Mesoporous Silica as Prospective Nanoplatform for Spin Manipulation at Ambient Conditions.

Quantum computing and quantum information processing (QC/QIP) crucially depend on the availability of suitable quantum bits (qubits) and methods of their manipulation. Most qubit candidates known to date are not applicable at ambient conditions. Herein, we propose radical-grafted mesoporous silica as a versatile and prospective nanoplatform for spin-based QC/QIP. Extremely stable Blatter-type organic radicals are used, whose electron spin decoherence time is profoundly long even at room temperature (up to Tm ≈2.3 µs), thus allowing efficient spin manipulation by microwave pulses. The mesoporous structure of such composites is nuclear-spin free and provides additional opportunities of embedding guest molecules into the channels. Robustness and tunability of these materials promotes them as highly promising nanoplatforms for future QC/QIP developments.

Anti-CD20 therapies and pregnancy in neuroimmunologic disorders: A cohort study from Germany.

OBJECTIVE: To report pregnancy outcomes and disease activity (DA) in women with MS, neuromyelitis optica spectrum disorders (NMOSDs), and other neuroimmunologic diseases (ONID) after treatment with rituximab (RTX)/ocrelizumab (OCR) 12 months before or during pregnancy. METHODS: Data were collected in the German MS and pregnancy registry and centers from the Neuromyelitis Optica Study Group. Sixty-eight known outcomes of 88 pregnancies from 81 women (64 MS, 10 NMOSD, and 7 ONID) were included and stratified in 3 exposure groups: >6M-group = RTX/OCR >6 but ≤12 months before the last menstrual period (LMP) (n = 8); <6M group = RTX/OCR <6 months before the LMP (n = 47); preg group = RTX/OCR after the LMP (n = 13). RESULTS: Pregnancy outcomes were similar between groups, but significantly more preterm births (9.8% vs 45%) occurred after exposure during pregnancy. Overall, 2 major congenital abnormalities (3.3%), both in the preg group, were observed. Three women had severe infections during pregnancy. All women with MS (35) and 12/13 women with NMOSD, RTX/OCR exposure before the LMP and known pregnancy outcomes after gestational week 22 were relapse free during pregnancy. Five of 29 (17.2%) women with relapsing-remitting MS (RRMS) and 1 of 12 (8.3%) with NMOSD and at least 6 months postpartum follow-up experienced a relapse postpartum. Duration of RTX/OCR and early retreatment but not detection of B-cells were possible predictors for postpartum relapses in patients with RRMS/NMOSD. CONCLUSIONS: Although RTX/OCR might be an interesting option for women with RRMS/NMOSD who plan to become pregnant to control DA, more data on pregnancy outcomes and rare risks are needed.

[Headache in multiple sclerosis]. / Kopfschmerzen bei Multipler Sklerose.

The relationship between headache and multiple sclerosis (MS) has been a matter of controversy for over 60 years. Headaches are still rated as a "red flag", indicating alternative diagnoses to MS, although in the last few years numerous studies have shown a frequent association between headache and MS. In recent studies on MS patients, a link was found between lower age/shorter disease duration of MS and frequent headaches. A study of 50 patients manifesting MS for the first time showed the highest headache prevalence in MS of 78% reported so far.Headaches can also be a possible side effect of most disease-modifying MS drugs. In many cases, however, the headache appears to be a symptom of MS in terms of secondary headache. This is also supported by pathophysiological implications, for example, by detecting B cell follicles in the meninges of MS patients.Migraine is the most common type of headache in MS. In some cases, this is a comorbidity of two diseases with many similarities, but headaches caused by inflammatory MS lesions also appear to be phenomenologically very similar to classic migraines; thus, distinguishing between them is often only successful with the help of thorough differential diagnostics (cerebrospinal fluid, MRI etc.).The task of future studies must be to specify the phenomenology of headache in MS even more precisely, in order to, to gain knowledge in, among others, patients with radiologically isolated syndrome, who often suffer from headache, because in these patients a considerable differential diagnostic and therapeutic uncertainty exists.

Visible-Light Cascade Photooxygenation of Tetrahydrocarbazoles and Cyclohepta[b]indoles: Access to C,N-Diacyliminium Ions.

Tetrahydrocarbazoles and perhydrocyclohepta[b]indoles undergo a catalytic cascade singlet oxygenation in alkaline medium, which leads to chiral tricyclic perhydropyrido- and perhydroazepino[1,2-a]indoles in a single operation. These photooxygenation products are new synthetic equivalents of uncommon C,N-diacyliminium ions and can be functionalized with the aid of phosphoric acid organocatalysis.

High-dose vitamin D supplementation in multiple sclerosis - results from the randomized EVIDIMS (efficacy of vitamin D supplementation in multiple sclerosis) trial.

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-ß1b. 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.

Visible-Light-Mediated Aerobic Tandem Dehydrogenative Povarov/Aromatization Reaction: Synthesis of Isocryptolepines.

A metal-free, photoinduced aerobic tandem amine dehydrogenation/Povarov cyclization/aromatization reaction between N-aryl glycine esters and indoles leads to tetracyclic 11H-indolo[3,2-c]quinolines under mild conditions and with high yields. The reaction can be performed by using molecular iodine along with visible light, or by combining an organic photoredox catalyst with a halide anion. Mechanistic studies reveal that product formation occurs through a combination of radical-mediated oxidation steps with an iminium ion or N-haloiminium ion [4+2]-cycloaddition, and the N-heterocyclic products constitute new analogues of the antiplasmodial natural alkaloid isocryptolepine.

A new set of metal-organic frameworks synthesised from diisophthalate-based, 2'-phosphorus-substituted m-terphenyl linker molecules.

Four metal-organic frameworks employing the m-terphenyl diisophthalate linker molecule with 2' substitution by P(v)-based functional groups of the central aryl have been synthesised. The dense packing of POMe2/PSMe2 functional groups within UHM-60/UHM-61 (UHM: University of Hamburg Materials) with an underlying net of ucp topology was overcome by increasing the sterical demand of phosphorus substituents. Replacement of the PEMe2 (E = O, S) functional groups by POEt2 or POPh2 gave UHM-62 and UHM-63, respectively, where valid deconstructions of the underlying topology to types 3,3,4,4T199, tim, and tst were found. The potential influence of the now-accessible phosphoryl functional group towards CO2 and CH4 adsorption as well as the selectivity towards CO2/CH4 separation was studied. Based on a comprehensive survey of literature-known Cu(ii)-based MOFs with m-terphenyl-based linker molecules, we propose the deconstruction of inter-isophthalate plane angles to angular components of twist and fold allowing for the sophisticated classification of topologies that can be realised in Cu(ii)-based MOFs using the m-terphenyl tetracarboxylate linker molecule.

Radical-Doped Metal-Organic Framework: Route to Nanoscale Defects and Magnetostructural Functionalities.

Nanosized structural defects in metal-organic frameworks (MOFs) attract growing attention and often remarkably enhance functional properties of these materials for various applications. In this work, a series of MOFs [Cu2(TPTA)1- x(BDPBTR) x] (H4TPTA, [1,1':3',1″-terphenyl]-3,3'',5,5''-tetracarboxylic acid; H4BDPBTR, 1,3-bis(3,5-dicarboxyphenyl)-1,2,4-benzotriazin-4-yl radical)) with a new stable radical linker doped into the structure has been synthesized and investigated using Electron Paramagnetic Resonance (EPR). Mixed linkers H4TPTA and H4BDPBTR were used to bridge copper(II) paddle-wheel units into a porous framework, where H4BDPBTR is the close structural analogue of H4TPTA. MOFs with various x = 0-0.4 were investigated. EPR studies indicated that the radical linker binds to the copper(II) units differently compared to diamagnetic linker, resulting in the formation of nanosized structural defects. Moreover, remarkable kinetic phenomena were observed upon cooling of this MOF, where slow structural rearrangements and concomitant changes of magnetic interactions were induced. Thus, our findings demonstrate that doping of structurally mimicking radical linkers into MOFs represents an efficient approach for designing target nanosized defects and introducing new magnetostructural functionalities for a variety of applications.

A smart peek: Processing of rapid visual displays is disturbed in newly diagnosed, cognitively intact MS patients and refers to cognitive performance and disease progression in late stages.

BACKGROUND: MS can reduce the speed of information processing (IPS) leading to a variable pattern of cognitive impairment. To better understand this deficit, a separate evaluation of the sensory, cognitive, and motor speed component is required. Tests using rapid visual displays allow for assessment of separate components of information uptake. We utilized such a test to compare deficit profiles at the earlier and later stage of MS and their relation to cognitive ability and disease progression. METHOD: Two groups were evaluated: "Early MS" comprised N = 24 patients with disease durations <2 years; "late MS" N = 45 with disease durations >12 years. Rapid visual displays of letters were utilized to derive individual profiles of visual information uptake according to the 'theory of visual attention' (TVA). The resulting data was then compared with measures of disability, fatigue, depression, IPS, visual-spatial ability, verbal and visual memory. RESULTS: In the EMS group, where cognitive impairment was the exception, three of the four main parameters of visual information uptake were already modified, i.e. processing rate C, storage capacity K, and iconic memory µ. In LMS an additional elevation of the fourth parameter, i.e., the perceptual threshold t0 was evident. Threshold values were related to most clinical and cognitive measures. CONCLUSIONS: An early deficit pattern of visual information uptake can be detected at a stage, when performance in tests of IPS is still well-preserved. At later disease stages, a single parameter reflecting the threshold of conscious visual perception may provide a valid estimate of cognitive performance and disease progression.

Severe meningo-/encephalitis after daclizumab therapy for multiple sclerosis.

BACKGROUND: Daclizumab is a monoclonal antibody that binds the high-affinity interleukin-2 receptor and was approved for the treatment of relapsing multiple sclerosis. Due to severe inflammatory brain disorders, the approval was suspended in March 2018. OBJECTIVE AND METHODS: This retrospective cohort study summarizes clinical, laboratory, radiological, and histological findings of seven patients who developed meningo-/encephalitis after daclizumab therapy. RESULTS: Patients presented with encephalitis and/or meningitis and suffered from systemic symptoms such as fever (5/7), exanthema (5/7), or gastrointestinal symptoms (4/7). Secondary autoimmune diseases developed. Blood analysis revealed an increase in eosinophils (5/7). Six patients fulfilled the diagnostic criteria for a drug reaction with eosinophilia and systemic symptoms (DRESS). Magnetic resonance imaging (MRI) showed multiple contrast-enhancing lesions, and enhancement of the ependyma (6/7), meninges (5/7), cranial or spinal nerves (2/7), and a vasculitic pattern (3/7). Histology revealed a pronounced inflammatory infiltrate consisting of lymphocytes, plasma cells and eosinophils, and densely infiltrated vessels. Most patients showed an insufficient therapeutic response and a high disability at last follow-up (median Expanded Disability Status Scale (EDSS) 8). Two patients died. CONCLUSION: Meningoencephalitis and DRESS may occur with daclizumab therapy. This potential lethal side effect is characterized by a dysregulated immune response. Our findings underline the importance of postmarketing drug surveillance.

Insights into the influence of the pore size and surface area of activated carbons on the energy storage of electric double layer capacitors with a new potentially universally applicable capacitor model.

The electric double layer formation of supercapacitors is governed by ion electrosorption at the electrode surface. Large surface areas are beneficial for the energy storage process, typically achieved by carbon electrode materials. It is a matter of debate whether pores provide the same contribution to the capacitance regardless of the size, or if subnanometer pores lead to an anomalous increase of capacitance. In our work, we developed a new model for normalized capacitance depending on pore sizes, using a combination of a sandwich type capacitor for micropores and double-cylinder capacitor model for larger pores. Modification factors for each capacitance value were calculated using the nonlinear generalized reduced gradient method to obtain a modified electric sandwich double-cylinder capacitor (ESDCC) model. The model was validated by comparing the measured capacitance values of a set of prepared activated carbons in organic electrolytes with simulated values according to the modified ESDCC model, using combined physisorption data of carbon dioxide and nitrogen. We concluded a non-constant capacitive contribution, with pores having the size of bare cations contributing to the capacitance to a larger extent and mesopores with the size of three solvated ions providing an unusual low contribution to the overall capacitance.

Headache in the course of multiple sclerosis: a prospective study.

Multiple sclerosis (MS) is the most common immune-mediated inflammatory disease of the central nervous system (CNS). Early diagnosis and treatment is important to prevent progression of disability in the course of the chronic disease. Therefore, correct and fast identification of early symptoms is vital. Headache is generally not recognized as an early symptom of MS, although numerous studies could show a high prevalence of headache in MS patients. The most common misdiagnosis is migraine. The aim of this study is to investigate the prevalence as well as the phenomenology of headache in MS especially with regard to the progression of the disease. In a prospective, multicenter study, we unbiasedly recruited 150 patients with manifest MS based on the criteria of McDonald. 50 patients at the timepoint of initial diagnosis and 100 of them with a long-term course of the disease were included. Based on a semi-structured interview, we evaluated the occurrence of headache over the last 4 weeks as well as case history, clinical-neurological investigation and questionnaires about depression, fatigue, and quality of life. Prevalence of headache in all patients was 67%. Patients at the timepoint of symptom manifestation of MS showed the highest prevalence of headache that was ever been recorded of 78%. In general, patients with headache were younger, had a shorter duration of the disease, and were less physically affected. We noticed frequent occurrence of migraine and migraine-like headache. In the course of the disease, patients without disease-modifying drug (DMD) complained more frequently headaches than patients with any kind of therapy. Headache is an important early symptom of MS. This could be shown especially among 78% of patients with clinically isolated syndrome (CIS). Therefore, young people with frequent headache should undergo MRI of the head and in the case of abnormal findings a consecutive detailed differential diagnosis. This could reduce the latency until final diagnosis of MS, which is in general much too long. That way these patients could get the earliest possible treatment, which is important to stop the progression of the disease.