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A 17-year-old girl with systemic lupus erythematosuspresented to the ophthalmology clinic with a 2-day history of decreased vision in her right eye and a 6-month history of intermittent headaches. She stoppedtreatment with methylprednisolone andhydroxychloroquine 2 years ago. Examination of thefundus of the right eye is as shown. What is thediagnosis?

Antiphospholipid syndrome

Retinal toxoplasmosis

Lupus retinal vasculitis

Susac's syndrome

Hydroxychloroquine-induced maculopathy

Correct!The correct answer is antiphospholipid syndrome. Systemic lupus erythematosus-associated antiphospholipid syndrome was diagnosed based on laboratory studies positive for antinuclear antibody, anti–double-stranded DNA antibody, and lupus anticoagulant, and findings consistent with central retinal artery and vein occlusion on the fundus examination.

Das Antiphospholipid-Antikörper-Syndrom ist eine Autoimmunerkrankung, bei der Patienten Autoantikörper gegen Phospholipid-gebundene Proteine haben. Venöse oder arterielle Thromben können auftreten. Die Pathophysiologie ist nicht genau bekannt. Die Diagnose wird durch Bluttests gestellt. Antikoagulation wird oft zur Vorbeugung und Behandlung verwendet.Das Antiphospholipidantikörpersyndrom (APS) ist eine Autoimmunstörung, die aus Thrombose und Fehlgeburten (bei Schwangerschaft) besteht und durch verschiedene Autoimmunantikörper verursacht wird, die gegen eines oder mehrere Phospholipid-gebundene Proteine gerichtet sind (z. B. Beta2-Glykoprotein I, Prothrombin, Annexin A5).Annexin A5 kann normalerweise an Bestandteile der Phospholipidmembranen binden, um diese dadurch vor einer überschießenden Aktivierung der Blutgerinnung zu schützen. Wenn Autoantikörper Annexin A5 verdrängen, können prokoagulierende Endothelzelloberflächen freigelegt werden und arterielle und venöse Thrombosen provozieren.Paradoxerweise können die Ergebnisse von Gerinnungstests verlängert sein, da die Autoantikörper zu Phospholipid-bindenden Proteinen mit den für die Untersuchungen notwendigen Gerinnungsfaktoren und Phospholipidkomponenten interferieren. Das Lupusantikoagulans ist ein Antikörper, der an die phospholipidgebundenen-Proteinkomplexe bindet. Obwohl es zuerst bei Patienten mit systemischem Lupus erythematodes (SLE) entdeckt wurde, machen diese Patienten heutzutage nur noch die Minderheit derjenigen aus, bei denen dieser Autoantikörper beschrieben wird.Andere Symptome der venösen oder arteriellen Thrombose können sich auch entwickeln. Patienten mit Antikörpern gegen Phospholipid-gebundenes Prothrombin können zirkulierende Prothrombinspiegel aufweisen, die niedrig genug sind, um das Blutungsrisiko zu erhöhen. Einige Patienten erleben Thrombozytopenie.

Toxoplasma gondii ist ein bogenförmiges Protozoon mit parasitischer Lebensweise. Sein Endwirt sind Katzen, als Zwischenwirt dienen andere Wirbeltiere. Es ist der einzige bekannte Vertreter der Gattung Toxoplasma. Der Erreger ist der protozooische Parasit und einzige Vertreter seiner Gattung Toxoplasma gondii, für den Katzen den Hauptwirt darstellen. Nur selten ruft die Erkrankung bei Katzen klinische Erscheinungen wie Durchfall hervor. Lediglich bei der Erstinfektion scheiden Katzen große Mengen von Eiern (Oozysten) des Erregers aus, anschließend entwickeln sie eine zumeist lebenslange Immunität.Als fakultativer Zwischenwirt für den Erreger dienen alle anderen Säugetiere, einschließlich des Menschen. Auch bei diesen können Krankheitserscheinungen auftreten, die Toxoplasmose ist also eine Zoonose. Zwischenwirte können sich entweder durch Aufnahme der versporten Oozysten von Katzen (z. B. bei der Gartenarbeit durch kontaminiertes Erdreich) oder über Entwicklungsstadien des Erregers in anderen Zwischenwirten (der Mensch vor allem über rohes Schweine- und Schaffleisch) anstecken.

Lupus erythematodes, kurz LE, ist eine systemische Autoimmunerkrankung, die zusammen mit der systemischen Sklerodermie und der Dermatomyositis zu den Kollagenosen gehört. Typisch für diese Erkrankungen sind hohe Titer an Autoantikörpern, die sich gegen körpereigene Organe richten. Die häufige Beteiligung der Haut hat der Erkrankung ihren Namen gegeben: Lupus (= Wolf) steht in diesem Falle für den aggressiven Charakter der Erkrankung. Die Bezeichnung rührt ursprünglich daher, dass die Herde eines nicht behandelten Lupus in den Gesichtern der Patienten wie Wolfsbisse aussahen. In etwa 65% der Fälle zeigt sich eine Glomerulonephritis vom Immunkomplextyp im lichtmikroskopischen Präparat. Immunhistochemisch und elektronenmikroskopisch sind in der Regel eine Reihe weiterer morphologischer Veränderungen erkennbar. Funktionell finden sich vermutlich DNA-anti-DNA-Komplexe.In der Histologie findet sich eine Vaskulitis oder perivaskuläre Infiltrate, zudem Ablagerungen von Immunglobulin und Komplement an der dermoepidermale Grenze. Das in der Immunhistochemie gefundene Lupusband ist bei systemischem Lupus erythematodes üblicherweise überall in der Haut zu finden, bei diskoidem Lupus erythematodes hingegen nur in betroffenen Herden. Der fehlende Nachweis eines Lupusbandes schließt die Erkrankung jedoch nicht aus.

Das Susac-Syndrom ist eine seltene entzündliche Erkrankung, die durch die Symptomtrias Enzephalopathie, retinale Gefäßverschlüsse und Innenohrschwerhörigkeit charakterisiert ist. Das Susac-Syndrom ist eine sehr seltene Erkrankung. In der Literatur wurden bis heute (2017) circa 100 Fälle beschrieben. Es sind vor allem junge Frauen in einem Alter von 20 bis 40 Jahren betroffen. Insgesamt sind Frauen dreimal häufiger betroffen als Männer (Verhältnis 3:1).Bislang (2017) ist die Ursache des Susac-Syndroms unbekannt. Es wird diskutiert, ob die Symptome durch Gefäßspasmen kleiner Blutgefäße aufgrund einer autoimmunen Genese zustande kommen.Akut auftretende Kopfschmerzen aufgrund einer Enzephalopathie sind meist das erste Symptom des Susac-Syndroms. Weiterhin kann eine kognitive Einschränkung und eine kognitive Behinderung entstehen.

Hydroxychloroquine is a well-tolerated medication for various rheumatologic and dermatologic conditions. It has also been used off-label as a potential therapy for the novel coronavirus, COVID-19, although data to support its efficacy is mixed and primarily anecdotal due to the lack of large controlled trials. Its main side effects are gastrointestinal upset (vomiting, diarrhea, stomach cramps), skin rash, headache, dizziness, and ocular toxicity. However, serious side effects including arrhythmia, bronchospasm, angioedema, and seizures can rarely occur. Within the eye, hydroxychloroquine can adversely impact the cornea, ciliary body, and retina.Hydroxychloroquine retinopathy causes destruction of macular rods and cones with sparing of foveal cones. This pattern provides the typical bullseye appearance. RPE migrates into the areas of destructed photoreceptors, causing pigment laden cells to be detected in the outer nuclear and outer plexiform layers[2]. Hydroxychloroquine keratopathy is caused by deposition of unmodified hydroxychloroquine salts within the epithelium.PathophysiologyHydroxychloroquine binds to melanin, accumulates in the RPE, and remains there for long periods of time. It is directly toxic to the RPE, causing cellular damage and atrophy. This occurs due to disruption of RPE metabolism, specifically from lysosomal damage, and reduced phagocytic activity toward shed photoreceptor outer segments. Accumulation of photoreceptor outer segments leads to RPE degeneration, migration into the outer retina, and finally photoreceptor loss.

Atrial FibrillationA 63-year-old otherwise healthy man is discovered to have atrial fibrillation during an evaluation for a viral respiratory infection. He reports that 3 months earlier he began noticing occasional dyspnea on climbing stairs, and this symptom has been persistent for the past month. On physical examination, the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) is 29, the blood pressure is 142/88 mm Hg, the pulse is irregular at 120 beats per minute, and there are irregular first and second heart sounds. Electrocardiographic (ECG) evaluation shows atrial fibrillation, normal QRS complexes, and a ventricular rate of 110 beats per minute. How would you evaluate and treat this patient?

Types and Triggers of Atrial Fibrillation (AF). Mechanisms for the initiation and persistence of AF and the left atrial anatomy are shown on the left. Clinical profiles of AF related to the underlying atrial substrate at the muscle-bundle level are shown on the right. Paroxysmal AF is associated with triggering foci that are most commonly located in sleeves of muscle along the pulmonary veins. Persistent AF is often characterized by some evidence of atrial remodeling with electrophysiological changes in the atrial myocytes, as well as fibrosis. Triggering foci are also present. In long-standing persistent AF, the atrial remodeling, including fibrosis, is more extensive and severe than in persistent AF.

The Clinical ProblemIn clinical practice, atrial fibrillation is the most common sustained arrhythmia encountered in adults. Among patients in the Framingham Heart Study population, atrial fibrillation developed in 37% after the age of 55 years in those who reached that age. Risk factors include older age, coronary artery disease, male sex, European ancestry, hypertension, obesity, smoking, diabetes mellitus, obstructive sleep apnea, and a family history of atrial fibrillation in a first-degree relative. In a large multi-institutional study, 19% of the patients with newly diagnosed atrial fibrillation had an acute precipitant such as pneumonia or surgery (the two most common precipitants), myocardial infarction, pulmonary embolism, thyrotoxicosis, or alcohol intoxication.Diagnosis and EvaluationSymptoms of atrial fibrillation, when present, range from minimal to incapacitating. Atrial fibrillation may cause fatigue, decreased exercise tolerance, and palpitations. Rapid heart rates may cause hypotension, syncope, angina, or pulmonary edema, and emergency treatment may be warranted. Severe manifestations are often associated with acute illness or surgery that leads to increased sympathetic tone and a rapid ventricular rate.Depending on the frequency of symptoms, ambulatory ECG recording may be required for weeks to months in order to establish the diagnosis of paroxysmal atrial fibrillation. Personal ECG recording systems, including small handheld devices and watches, can reveal atrial fibrillation, but an artifact can mimic or obscure the diagnosis, and confirmatory ECG recordings should be obtained. The detection of atrial fibrillation warrants a careful history and physical examination, including measurement of blood pressure, to assess for evidence of predisposing diseases and risk factors and intercurrent illness. Long-term alcohol consumption of more than one drink per day in women and two drinks per day in men has been associated with atrial fibrillation, and binge drinking can precipitate atrial fibrillation. Caffeine consumption has not been shown to increase the incidence of atrial fibrillation. The patient’s blood glucose and thyrotropin levels should be measured.In addition to the ECG and other cardiac monitoring when needed, transthoracic echocardiography is routinely recommended. Screening for sleep-disordered breathing should be performed, and a sleep study should be conducted when the patient’s history is suggestive of sleep apnea.

Management of AF. Panel A shows electrocardiographic (ECG) tracings in lead V1 in the patient with AF in the vignette. The top tracing shows AF with a rapid ventricular rate of 140 beats per minute, the middle tracing shows AF with a controlled rate of 65 beats per minute, and the bottom tracing shows sinus rhythm with first-degree AV block after cardioversion. Panel B shows the atrial electroanatomical map from the ablation procedure. The left atrium is viewed from its posterior aspect with the left superior (LSPV), left inferior (LIPV), right superior (RSPV), and right inferior (RIPV) pulmonary veins. The blue and maroon circles denote ablation lesion sites, and red the absence of electrical signals (indicating that the pulmonary veins and the posterior wall of the left atrium are electrically silent after ablation). In areas with electrical signals, increasing signal amplitude is indicated by progression from green to blue to purple. Panel C shows four factors to consider in the management of AF. Digoxin may be administered in patients with heart failure, but it is otherwise not used in patients with AF. Atrioventricular (AV) junction ablation and pacing is a last-resort therapy when rate control cannot be achieved pharmacologically, usually in older sedentary patients. Occlusion or resection of the atrial appendage may be considered when the risk of long-term anticoagulation is not an option because of bleeding risk.

TreatmentThe management of atrial fibrillation has traditionally involved achieving adequate rate control, protection from thromboembolism and stroke, and reduction or elimination of symptoms, as well as the treatment of reversible risk factors. Symptoms may be controlled either by preventing episodes of atrial fibrillation or by slowing the ventricular rate during recurrent atrial fibrillation. In patients in whom atrial fibrillation has developed within the previous year, attempts to maintain sinus rhythm are usually warranted.Rate ControlThe ventricular rate in atrial fibrillation is an important determinant of hemodynamic consequences and symptoms. Atrioventricular nodal-blocking agents are usually warranted to reduce the ventricular rate. Beta-blockers and nondihydropyridine calcium-channel blockers (verapamil and diltiazem) are first-line therapies. Therapy is tailored to the individual patient and is based on consideration of adverse effects (e.g., beta-adrenergic blockers may aggravate depression, and calcium-channel blockers may aggravate heart failure). Therapy is generally initiated with a beta-blocker at a dose that is adjusted upward, with the aim of controlling symptoms by reducing the heart rate. Stroke preventionAnticoagulation is first-line therapy for prevention of thromboembolism, and its use is guided by estimation of stroke risk according to the CHA2DS2-VASc score. Anticoagulation is indicated for patients who have at least two risk factors (i.e., an estimated stroke risk >2.2% per year) and should be considered for patients who have one risk factor other than female sex (i.e., estimated stroke risk of ≥1.3% per year).A Cochrane Collaboration review estimated that among patients with atrial fibrillation who had a stroke risk of 4.0% per year, long-term warfarin therapy reduced the risk to 1.4% per year. Several randomized trials have established that direct-acting oral anticoagulants are noninferior to warfarin. A meta-analysis showed that in trials with follow-up ranging from 12 weeks to 2.8 years, the risk of stroke or embolic events was 11% lower among patients who received direct-acting oral anticoagulants than among those who received warfarin; the risk of major bleeding was also reduced (from 5% to 4%) as was the risk of intracranial hemorrhage (from 1.3% to 0.6%). The risk of stroke among patients who received a direct-acting oral anticoagulant was 1.3% to 1.5% per year. Even in patients who are at low risk for stroke, cardioversion of atrial fibrillation can be followed by atrial thrombus formation and embolization because of delayed recovery of atrial mechanical function. In patients who are at low risk for thromboembolism in whom atrial fibrillation is known to have been present for less than 48 hours, cardioversion is commonly performed without a preceding period of anticoagulation; the reported risk of stroke with this approach is 0.7 to 1.1%, and it occurs mainly in patients with risk factors.

Stroke Prevention in Patients with AF. Scores on the CHA2DS2-VASc scale range from 0 to 9, with higher scores indicating a greater risk of stroke. Points are summed to generate the score. The mean CHA2DS2-VASc scores and stroke rates in large randomized trials are shown for patients receiving direct-acting oral anticoagulants and for those receiving warfarin. Historical data are from January et al. In other trials, the annual stroke rate has ranged from 1.2% to 1.3% among patients who received direct-acting oral anticoagulants and from 1.5% to 2.2% among those who received warfarin. Anticoagulation is indicated in patients with a CHA2DS2-VASc score of 2 or more (shaded area) and may be considered in patients with a score of 1. TIA denotes transient ischemic attack.

Even in patients who are at low risk for stroke, cardioversion of atrial fibrillation can be followed by atrial thrombus formation and embolization because of delayed recovery of atrial mechanical function. In patients who are at low risk for thromboembolism in whom atrial fibrillation is known to have been present for less than 48 hours, cardioversion is commonly performed without a preceding period of anticoagulation; the reported risk of stroke with this approach is 0.7 to 1.1%, and it occurs mainly in patients with risk factors.Maintenance of Sinus RhythmThe decision regarding whether to pursue maintenance of sinus rhythm is shared between the patient and physician; this decision is informed by the effect of atrial fibrillation on the patient’s quality of life and by the risks and toxic effects of therapies. Many patients with paroxysmal atrial fibrillation or recently recognized persistent atrial fibrillation have symptoms and want to receive therapy, but some patients with persistent atrial fibrillation adapt without realizing that the arrhythmia is causing a reduction in their activity. For newly recognized asymptomatic atrial fibrillation, an attempt at cardioversion and maintenance of sinus rhythm is often reasonable to assess the symptomatic effect of atrial fibrillation, which then informs further treatment. The large, randomized Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4) trial compared early rhythm control (with antiarrhythmic drugs or catheter ablation) with usual care in patients who had atrial fibrillation that was diagnosed within 1 year before enrollment and other cardiovascular disease or stroke risk factors. The early rhythm-control strategy was associated with a significantly lower rate of the composite of death from cardiovascular causes, stroke, or hospitalization for heart failure or acute coronary syndrome (by 1.1 events per 100 person years; a 22% reduction), without an increase in the number of nights spent in the hospital. Serious adverse events related to treatment occurred in 4.9% of the patients in the early rhythm-control group; the most common serious adverse event in that group was drug-induced bradycardia (in 1.0% of the patients).Continued therapy with a beta-blocker may reduce episodes of atrial fibrillation in some patients, but it is less effective than antiarrhythmic drugs; atrial fibrillation has been reported to recur in 43 to 67% of patients who receive beta-blockers.

GuidelinesGuidelines for the management of atrial fibrillation have been written collaboratively by the American College of Cardiology, American Heart Association, and Heart Rhythm Society, the European Society of Cardiology, and the Canadian Cardiovascular Society. Our recommendations are generally concordant with these guidelines.

Areas of UncertaintyData on the effects of strategies to maintain sinus rhythm on the overall risk of death are lacking. Recent randomized trials have suggested that the risk of death may be decreased among patients in whom the sinus rhythm is maintained early after the diagnosis of atrial fibrillation and in those with depressed left ventricular function who are candidates for and who undergo ablation.Among some patients with atrial fibrillation who are thought to be in sinus rhythm, episodes of atrial fibrillation may go undetected and the risk of stroke appears to be increased. Safe strategies for determining whether patients can discontinue anticoagulation when sinus rhythm is maintained require further definition. Data are needed to inform the outcomes of occlusion or resection of the left atrial appendage, particularly in patients in whom anticoagulation poses high risks.Conclusions and RecommendationsFor a patient such as the one described in the vignette who has newly recognized atrial fibrillation, we would obtain serum electrolyte, creatinine, and thyrotropin levels; identify and treat reversible risk factors; and initiate anticoagulation with a direct-acting oral anticoagulant and therapy with a beta-blocker (adjusting the dose to achieve rate control). Further evaluation would include echocardiography and assessment of possible coronary artery disease with stress testing or angiography. We would perform direct-current cardioversion after a 4-week course of anticoagulation. If atrial fibrillation recurred, decisions regarding further therapy would be guided by symptoms, risks, and benefits and would include consideration of catheter ablation to maintain sinus rhythm.

Brahmanische Gelehrte(Pundits)

DIE KRYOBALLONABLATIONBei der Entstehung von Vorhofflimmern spielen die Pulmonalvenen (Lungenvenen), die in den linken Vorhof münden, eine entscheidende Rolle. Im Fall von Vorhofflimmern werden bei einer Ablation daher in den meisten Fällen die Pulmonalvenen isoliert. Dann ist keine elektrische Leitung zwischen den Pulmonalvenen und dem Vorhof mehr möglich.

Kryoballon-Katheter für die Ablation von Vorhofflimmern (nicht in Originalgröße abgebildet)."Fire und Ice" heißt eine aktuelle Studie, deren Ergebnisse im April 2016 veröffentlicht wurden. Mit "Fire" ist die herkömmliche, mit Hitze durchgeführte, RF-Ablation gemeint. "Ice" meint die modernere Kryoablation mit dem Kryoballonkatheter. Die Studie zeigt eindeutig, dass die Kryoablation genauso so sicher und effizient ist wie das traditionelle Verfahren. Aber: Die Kryablation ist außerdem schneller und einfacher. Der Leiter der Studie, Prof. Dr. Karl-Heinz Kuck (Asklepios Klinikum St. Georg, Hamburg) prognostiziert, dass die Kryoablation mit dem Kryoballon in den nächsten Jahren zur bevorzugten Behandlungsform, dem "Goldstandard", bei Vorhofflimmern werden wird.

Cryoablation or Drug Therapy for Initial Treatment of Atrial FibrillationGuidelines recommend a trial of one or moreantiarrhythmic drugs before catheter ablation isconsidered in patients with atrial fibrillation. However, first-line ablation may be more effective in maintainingsinus rhythm. We randomly assigned 303 patients withsymptomatic, paroxysmal, untreated atrial fibrillation toundergo catheter ablation with a cryothermy balloon or toreceive antiarrhythmic drug therapy for initial rhythmcontrol. All the patients received an implantable cardiacmonitoring device to detect atrial tachyarrhythmia. The follow-up period was 12 months. The primary end pointwas the first documented recurrence of any atrialtachyarrhythmia (atrial fibrillation, atrial flutter, or atrialtachycardia) between 91 and 365 days after catheterablation or the initiation of an antiarrhythmic drug. The secondary end points included freedom fromsymptomatic arrhythmia, the atrial fibrillation burden, andquality of life.We enrolled adults (>18 years of age) who hadsymptomatic atrial fibrillation and at least one episode ofatrial fibrillation detected on electrocardiography within 24 months before randomization. Patients were excluded ifthey had a history of regular (daily) use of a class I orclass III antiarrhythmic drug at therapeutic doses. Eligible patients were randomly assigned in a 1:1 ratio toan initial strategy of catheter cryoballoon ablation orantiarrhythmic drug therapy. Randomization was performed with concealed allocation, according to a computer-generated allocation sequence, with permutedblocks of four and eight.

Freedom from Recurrence of Atrial Tachyarrhythmia over Time. Shown are Kaplan–Meier estimates of the primary end point, freedom from recurrence of any atrial tachyarrhythmia (atrial fibrillation, atrial flutter, or atrial tachycardia) lasting 30 seconds or longer between 91 and 365 days after the initiation of an antiarrhythmic drug or catheter ablation. Tick marks indicate censored data. CI denotes confidence interval.

Primary and Secondary End Points.

Atrial Fibrillation Burden in the Ablation and Antiarrhythmic Drug Groups.

Shown are box and whisker plots of atrial fibrillation burden expressed as the percentage of time in atrial fibrillation. The inset plots show the data on an expanded y axis. The upper whisker indicates the 90th percentile, the top of the blue box the 75th percentile, the horizontal line within the blue box the 50th percentile, and the bottom of the blue box the 25th percentile. The bottom whisker is too compressed to be shown but is meant to indicate the 10th percentile (0% in both groups). The circles beyond the upper whisker are individual data points for individual patients and are the outliers (beyond the 90th percentile). The diamond indicates the mean atrial fibrillation burden for the treatment group.

Adverse Events.

Serious adverse events occurred in 5 of the 154 patients (3.2%) in the ablation group and in 6 of the 149 patients (4.0%) in the antiarrhythmic drug group. These events included three cases of phrenic-nerve palsy in the ablation group and two cases of wide-complex tachycardia, one case of syncope, and one case of exacerbation of heart failure in the antiarrhythmic drug group; each group also had two cases of symptomatic bradycardia for which pacemaker implantation was warranted.

Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation

In patients with symptomatic paroxysmal atrialfibrillation that has not responded to medication, catheter ablation is more effective than antiarrhythmicdrug therapy for maintaining sinus rhythm. However, the safety and efficacy of cryoballoon ablation as initial first-line therapy have not been established. Weperformed a multicenter trial in which patients 18 to 80 years of age who had paroxysmal atrial fibrillation forwhich they had not previously received rhythm-controltherapy were randomly assigned (1:1) to receivetreatment with antiarrhythmic drugs (class I or III agents) or pulmonary vein isolation with a cryoballoon. Arrhythmia monitoring included 12-lead electrocardiography conducted at baseline and at 1, 3, 6, and 12 months; patient-activated telephonemonitoring conducted weekly and when symptomswere present during months 3 through 12; and 24-hour ambulatory monitoring conducted at 6 and 12 months. The primary efficacy end point was treatment success(defined as freedom from initial failure of the procedureor atrial arrhythmia recurrence after a 90-day blankingperiod to allow recovery from the procedure or drugdose adjustment, evaluated in a Kaplan–Meier analysis). The primary safety end point was assessedin the ablation group only and was a composite ofseveral procedure-related and cryoballoon system–related serious adverse events.

Treatment Success at 12 Months. Treatment success was defined as freedom from any of the following events: initial failure of the procedure; any subsequent atrial fibrillation surgery or ablation in the left atrium; or atrial arrhythmia recurrence, cardioversion, or use of class I or III antiarrhythmic drugs (ablation group only) outside the 90-day blanking period. The median time from randomization to treatment initiation was 24 days in the ablation group and 2 days in the drug-therapy group. During the blanking period, three patients in the ablation group had treatment failure as a result of initial failure of the procedure, and one patient in the drug-therapy group had treatment failure because the patient underwent an ablation. Because the assumption of proportional hazards was not met, a hazard ratio is not presented. 𝙸 bars indicate 95% confidence intervals.

Primary Efficacy End-Point Events within 12 Months.

DiscussionIn this randomized, multicenter trial, the initial use of cryoballoon ablation was superior to drug therapy for the prevention of atrial arrhythmia recurrence, with 75% of patients in the cryoballoon group and 45% of patients in the drug-therapy group having treatment success at 12 months. In the ablation group, 1.9% of patients had a primary safety end-point event within 12 months. A third of the patients in the drug-therapy group subsequently underwent ablation as a result of drug-related side effects or recurrence of arrhythmia.The recently published results of EAST-AFNET 4 showed that early rhythm control with either drug therapy or ablation resulted in better cardiovascular outcomes than usual care at a median 5.1 years of follow-up. Increasing evidence suggests that earlier intervention with ablation is associated with a higher likelihood of freedom from atrial arrhythmia recurrence and may prevent progression to persistent atrial fibrillation. However, current guidelines and consensus statements recommend treatment with antiarrhythmic medications before undergoing ablation, resulting in a delay from diagnosis to ablation.The safety profile of cryoballoon ablation has been established in patients whose condition does not respond to drug therapy, with complications occurring in approximately 6% of patients during follow-up periods of 14 to 34 months. The present trial similarly showed that serious complications of cryoballoon ablation were uncommon among patients who had not previously received rhythm-control therapy, with only two patients in the ablation group having a primary safety end-point event. We observed no cases of stroke, death, atrial–esophageal fistula, unresolved phrenic nerve injury at 12 months, or symptomatic pulmonary vein stenosis at 12 months; however, the sample size may not have been large enough to allow detection of these uncommon outcomes.In this randomized, multicenter trial, cryoballoon ablation was superior to antiarrhythmic drug therapy for the prevention of atrial arrhythmia recurrence in patients with paroxysmal atrial fibrillation who had not previously received rhythm-control therapy. Serious procedure-related adverse events were uncommon.

Who is dead?A principle of organ donation from deceased donors is that the donor must be declared deadbefore initiation of organ retrieval. Donation most commonly occurs after neurologicdetermination of death by standard criteria for brain death but can also occur after circulatorydetermination of death. The practice of donation after circulatory determination of death after removal of life-sustaining measures has increased, and the criteria used for determining deathin this context have varied. Most protocols for organ donation after circulatory determination ofdeath recommend 5 minutes of observation of apnea and pulselessness as determined byarterial catheter monitor, although practices vary from 2 to 10 minutes. After this period, withoutattempts to restart circulation and without spontaneous resumption of circulation, loss ofcirculation is considered permanent and organ recovery may begin.Instances of organ recovery after 75 seconds of pulselessness in infants have led to debate on the minimum acceptable duration of observation to ensure that permanent loss of circulationhas occurred. Concerns about the potential for autoresuscitation, or return of spontaneouscardiac activity, are based on reports in terminated cardiopulmonary resuscitation (CPR). The longest reported period of pulselessness between terminated CPR and observedautoresuscitation is 10 minutes.Limited prospective evidence suggests that return of cardiac activity occurs less frequently after withdrawal of life-sustaining measures and circulatory determination of death than after terminated CPR. Observational studies involving patients dying after withdrawal of life-sustaining measures have described transient resumption of circulation or cardiac activityoccurring seconds to minutes after pulselessness, with no reports that consciousness was regained or that the patient survived to hospital discharge. We conducted a prospective andretrospective observational study, the Death Prediction and Physiology after Removal ofTherapy (DePPaRT) study, to describe the incidence and timing of resumption of cardiacelectrical and pulsatile activity in critically ill adults who died after withdrawal of life-sustainingmeasures.

Resumption of Cardiac Activity after Withdrawal of Life-Sustaining MeasuresA principle of organ donation from deceased donors is that thedonor must be declared dead before initiation of organretrieval. Donation most commonly occurs after neurologicdetermination of death by standard criteria for brain death but can also occur after circulatory determination of death.The minimum duration of pulselessness required before organdonation after circulatory determination of death has not beenwell studied. We conducted a prospective observational studyof the incidence and timing of resumption of cardiac electricaland pulsatile activity in adults who died after plannedwithdrawal of life-sustaining measures in 20 intensive care units in three countries. Patients were intended to bemonitored for 30 minutes after determination of death. Clinicians at the bedside reported resumption of cardiacactivity prospectively. Continuous blood-pressure andelectrocardiographic (ECG) waveforms were recorded andreviewed retrospectively to confirm bedside observations andto determine whether there were additional instances ofresumption of cardiac activity.ConclusionsAfter withdrawal of life-sustaining measures, transient resumption of at least one cycle of cardiac activity after pulselessness occurred in 14% of patients according toretrospective analysis of waveforms; only 1% of such resumptions were identified at the bedside. These eventsoccurred within 4 minutes 20 seconds after a period ofpulselessness. (Funded by the Canadian Institutes for HealthResearch and others.)

Characteristics of Enrolled Patients at Baseline.

DCD donation after circulatory determination of death

Duration of Cessation of Cardiac Activity as Compared with the Duration of Resumption of Cardiac Activity.

Panel A shows a scatterplot of retrospective waveform analysis indicating the duration of cessation of cardiac activity (arterial blood pressure, <5 mm Hg) as compared with the duration of resumption of cardiac activity (arterial blood pressure, ≥5 mm Hg concurrent with ECG activity). There were a total of 77 cessations and resumptions in 67 patients (of 480), with 7 patients having more than 1 cessation and resumption.

Panel B shows a histogram of the number of cessations of cardiac activity, with the x axis of the scatterplot used for binning intervals. Panel C shows a histogram of the number of resumptions of cardiac activity, with the y axis of the scatterplot used for binning intervals.

(Note that the scales on the y axes in Panel B and Panel C are not the same.)

DiscussionAfter a period of loss of cardiac activity that followed the planned withdrawal of life-sustaining measures, 1% of the patients in our study had transient resumption of cardiac activity observable by bedside reports that were corroborated by retrospectively identified ECG and arterial pulse catheter waveform activity. Retrospective waveform review showed resumption of cardiac activity in 14% of the patients, including resumptions identified at the bedside. The longest period of pulselessness that was followed by resumption of cardiac activity was 4 minutes 20 seconds. Activity on ECG after pulselessness often continued past cessation of arterial catheter pressure.Our analysis of clinical reports by bedside clinicians and vital-sign waveform recordings from a large international sample supports the current 5-minute observation period required by most protocols and guidelines for proceeding with organ donation after circulatory determination of death. Our results also confirm the known phenomenon of electrical cardiac activity continuing in the absence of pulsatile cardiac activity. Waiting for cessation of ECG activity to determine circulatory death is a recommendation in some protocols.Our study definition of cardiac activity used an arbitrary threshold of pulse pressure (≥5 mm Hg) that does not imply meaningful circulation. This conservative consensus definition may have been partially responsible for the ostensibly high incidence (14%) of transient resumptions of cardiac activity identified through waveform adjudication.After a period of pulselessness that followed planned withdrawal of life-sustaining measures, clinically reported resumption of cardiac activity that was confirmed by waveform analysis occurred in 1% of the patients. Retrospective analysis of continuous ECG and arterial pressure monitoring identified resumption of cardiac activity in 14% of the patients, all occurring within 5 minutes after pulselessness.

Interstitielle Lungenerkrankung bzw. interstitielle Pneumonie ist ein Sammelbegriff für über 200 heterogene Lungenerkrankungen, die mit einer Schädigung des Lungeninterstitiums einhergehen. Sie können zu einer Lungenfibrose und damit zu einer restriktiven Ventilationsstörung führen.Der Begriff "interstitielle Lungenerkrankung" ist insofern irreführend, als dass nicht nur das Interstitium im engeren Sinn geschädigt ist, sondern oft auch das Alveolarepithel, die Atemwege und die pulmonalen Blut-und Lymphgefäße beteiligt sind. Lungeninterstitium und -parenchym sind zwar histologisch betrachtet

unterschiedliche Kompartimente, bilden aber biologisch eine enge funktionelle Einheit.Der Begiff "interstitiell" wurde ursprünglich gewählt, um diese Erkrankungen von den bakteriellen Pneumonien abzugrenzen, die sich der historischen Vorstellung nach "innerhalb" der Atemwege abspielen. Interstitielle Lungenerkrankung, bei denen die Entzündung im Vordergrund stehen, werden auch als Pneumonitis bezeichnet.Die Inzidenz der ILD beträgt ca. 10-25/100.000 Fälle pro Jahr. Zu den häufigsten interstitiellen Lungenerkrankungen gehören die idiopathische Lungenfibrose, die Sarkoidose und die interstitiellen Lungenerkrankungen bei Kollagenosen.

Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease

No therapies are currently approved for thetreatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil forpatients with this condition are unclear.We enrolled patients with interstitial lungdisease and pulmonary hypertension(documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patientswere assigned in a 1:1 ratio to receiveinhaled treprostinil, administered by meansof an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 μg) four timesdaily, or placebo. The primary efficacy end point was the difference between the twogroups in the change in peak 6-minute walkdistance from baseline to week 16. Secondary end points included the change in N-terminal pro–B-type natriuretic peptide(NT-proBNP) level at week 16 and the time to clinical worsening.

Mean Change from Baseline in Peak 6-Minute Walk Distance through Week 16. Shown are mean (±SE) changes from baseline (dashed line) in peak 6-minute walk distance over the 16-week trial period. The data shown are for patients with available data (observed) as well as for the results of two analysis methods used to account for missing data. The values shown at each data point indicate the number of patients assessed at that time point. The primary analysis used mixed-model repeat-measurement (MMRM) methods, with the assumption that missing data were missing at random. The model included the change from baseline to peak 6-minute walk distance as the dependent variable, with treatment, week, and treatment-by-week interaction as fixed effects, and the baseline 6-minute walk distance as a covariate. A sensitivity analysis for the primary end point was performed with the use of a multiple imputation approach with a multivariate normal imputation model using the Markov chain Monte Carlo (MCMC) method. The imputation model included treatment group, all scheduled visits, patient’s sex, and patient’s age at randomization. The confidence intervals have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects.

Summary of Primary and Secondary End Points.

Summary of Adverse Events.

DiscussionPulmonary hypertension frequently complicates the treatment of patients with interstitial lung disease and is associated with worse functional status, greater need for supplemental oxygen, and worse outcomes. In the INCREASE trial, patients treated with inhaled treprostinil had significant improvements in exercise capacity, as evidenced by changes in the 6-minute walk distance. Treatment with inhaled treprostinil was also associated with a lower risk of clinical worsening than that in patients who received placebo, as well as reductions in NT-proBNP levels and fewer exacerbations of underlying lung disease, over the 16-week treatment period. The safety profile of inhaled treprostinil observed in this vulnerable patient population was similar to that reported in previous studies. The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea. The use of inhaled treprostinil was not associated with any decrement in lung function.Patients with group 3 pulmonary hypertension are often treated with systemic pulmonary vasodilators, which are currently approved only for treatment of group 1 pulmonary hypertension. However, there is concern that such agents could worsen ventilation–perfusion matching in patients with group 3 pulmonary hypertension. Inhaled agents have the advantage of preferentially redirecting blood flow to the best-ventilated lung units, thus reducing the risk of ventilation–perfusion mismatching. Indeed, a retrospective study of inhaled treprostinil in patients with group 3 pulmonary hypertension showed that such patients had improvements in functional class and 6-minute walk distance without any adverse effect on peripheral oxygen saturation, reinforcing the concept of unchanged or even improved ventilation–perfusion matching with inhaled treprostinil. Similarly, in the current trial, we found no evidence of worsened oxygenation, which further allays concerns about ventilation–perfusion mismatching

Aus dem Englischen übersetzt-Notfallverhütung sind Verhütungsmaßnahmen, die nach dem Geschlechtsverkehr angewendet werden können, um eine Schwangerschaft zu verhindern. Es wurde nicht nachgewiesen, dass eine Notfallverhütung die Abtreibungsraten innerhalb eines Landes beeinflusst. Es gibt verschiedene Formen von EC. Die Pille danach ist die umgangssprachliche Bezeichnung für ein hormonell wirksames Präparat zur postkoitalen Empfängnisverhütung, das nach einem Geschlechtsverkehr eingenommen eine ungewollte Schwangerschaft verhindern kann. Die wirksamen Substanzen sind das Gestagenderivat Levonorgestrel oder der Progesteron-Rezeptor-Modulator Ulipristalacetat. Die Pille danach muss so früh wie möglich, innerhalb einer vom Arzneistoff abhängenden Frist nach dem ungeschützten Geschlechtsverkehr eingenommen werden. Diese Arzneimittel sind nicht zur regelmäßigen Empfängnisverhütung geeignet und stören den natürlichen Menstruationszyklus.

Worldwide, a variety of methods of emergency contraception are used to decrease the risk of pregnancy after unprotected sexual intercourse. In the United States, the Food and Drug Administration (FDA) has approved only two methods of emergency contraception: oral levonorgestrel and oral ulipristal acetate. Although the copper intrauterine device (IUD) is not approved by the FDA for emergency contraception, substantial observational evidence supports that it is highly effective, failing to prevent pregnancy in less than 0.1% of cases, an order of magnitude lower than the incidence of failure with oral methods. However, persons selecting an IUD for long-term contraception have shown a strong preference for the levonorgestrel IUD over the copper IUD, probably because the levonorgestrel IUD reduces menstrual bleeding and discomfort

Ulipristalacetat wird in der Gynäkologie als Pille danach zur Notfallkontrazeption eingesetzt. In niedrigerer Dosisstärke wird es zur Behandlung von gutartigen Tumoren der Gebärmutter verwendet.

Levonorgestrel vs. Copper Intrauterine Devices for Emergency ContraceptionIn the United States, more intrauterine device (IUD) users select levonorgestrel IUDs than copper IUDs for long-term contraception. Currently, clinicians offer only copper IUDs for emergency contraception because data are lacking on the efficacy of the levonorgestrel IUD for this purpose.This randomized noninferiority trial, in which participants were unaware of the group assignments, was conducted at six clinics in Utah and included women who sought emergency contraception after at least one episode of unprotected intercourse within 5 days before presentation and agreed to placement of an IUD. We randomly assigned participants in a 1:1 ratio to receive a levonorgestrel 52-mg IUD or a copper T380A IUD. The primary outcome was a positive urine pregnancy test 1 month after IUD insertion. When a 1-month urine pregnancy test was unavailable, we used survey and health record data to determine pregnancy status. The prespecified noninferiority margin was 2.5 percentage points.Worldwide, a variety of methods of emergency contraception are used to decrease the risk of pregnancy after unprotected sexual intercourse. In the United States, the Food and Drug Administration (FDA) has approved only two methods of emergency contraception: oral levonorgestrel and oral ulipristal acetate. Although the copper intrauterine device (IUD) is not approved by the FDA for emergency contraception, substantial observational evidence supports that it is highly effective, failing to prevent pregnancy in less than 0.1% of cases, an order of magnitude lower than the incidence of failure with oral methods. However, persons selecting an IUD for long-term contraception have shown a strong preference for the levonorgestrel IUD over the copper IUD, probably because the levonorgestrel IUD reduces menstrual bleeding and discomfort.

ParticipantsEligible participants were women 18 to 35 years of age who were fluent in English or Spanish and were requesting emergency contraception after unprotected sexual intercourse within the previous 5 days (120 hours). Other inclusion criteria were a desire to initiate use of an IUD, a desire to prevent pregnancy for at least 1 year, a negative urine pregnancy test, a history of regular menstrual cycles (21 to 35 days), and known date of the last menstrual period (±3 days). On the basis of the menstrual history, we calculated the menstrual cycle day of unprotected sexual intercourse and IUD insertion and, if needed, an estimated date of pregnancy. Key exclusion criteria were breast-feeding, vaginal bleeding of unknown cause, current use of a highly effective method of contraception (sterilization, IUD, or contraceptive implant), intrauterine infection in the previous 3 months, untreated Neisseria gonorrhea or Chlamydia trachomatis infection in the previous 30 days, allergy to copper, use of oral emergency contraception in the preceding 5 days, and known uterine cavity anomalies. We did not exclude persons who reported having unprotected sexual intercourse more than 5 days before IUD placement.Trial ProceduresAll women at participating sites who presented for emergency contraception received printed information describing trial participation, randomization, concealment of group assignment, and the two types of IUD in the trial. Participants who received an IUD could have it removed at any time and could switch to another contraceptive method, including another type of IUD.All participants had a negative urine pregnancy test (Osom card pregnancy test, Genzyme Diagnostics) before IUD placement. After the participants completed screening and provided written informed consent, REDCap randomly assigned them, in a 1:1 ratio, to placement of a levonorgestrel 52-mg IUD or a copper T380A IUD. We concealed the IUD package so that participants would be unaware of their assigned intervention, but the different appearance of the IUDs and differences in insertion methods meant that the providers were aware of the IUD type that was inserted. Nurse practitioners and certified nurse midwives with experience in IUD placement performed all insertions. Health centers provided the trial interventions and devices without cost to participants and billed health insurance companies when appropriate.Key exclusion criteria were breast-feeding, vaginal bleeding of unknown cause, current use of a highly effective method of contraception (sterilization, IUD, or contraceptive implant), intrauterine infection in the previous 3 months, untreated Neisseria gonorrhea or Chlamydia trachomatis infection in the previous 30 days, allergy to copper, use of oral emergency contraception in the preceding 5 days, and known uterine cavity anomalies. We did not exclude persons who reported having unprotected sexual intercourse more than 5 days before IUD placement.

One-Month Pregnancy Outcomes with the Levonorgestrel 52-mg IUD versus the Copper T380A IUD, According to Type of Analysis.

The primary outcome, a positive urine pregnancy test 1 month after IUD insertion, was designed to test the efficacy of the levonorgestrel (LNG) 52-mg IUD and copper T380 IUD for emergency contraception. Forty-eight participants did not provide urine pregnancy tests and had their pregnancy outcomes reported by survey and health record data. The modified intention-to-treat analysis includes all participants receiving an IUD who reported the 1-month pregnancy outcome by any method. The per-protocol analysis includes only participants who were still using the IUD to which they were randomly assigned when the 1-month pregnancy outcome was reported. The sensitivity analysis includes only participants with the 1-month pregnancy outcome confirmed by a urine pregnancy test. The Miettinen–Nurminen method was used to compute the two-sided 95% confidence interval around the proportion difference to test noninferiority.

Clinical Outcomes among Users of Emergency Contraception in the First Month after IUD Placement.

Adverse Events Resulting in Request for Medical Care during the First Month of IUD Use.

Raynaud Phänomen

A 48-Year-Old Man with Transient Vision LossThe patient had been in his usual state of good health until 1 hour before evaluation, when he noticed white “sparkles” flickering in the vision of the left eye, followed by sudden blurriness. He had no floaters or eye pain. During the next 2 minutes, the blurry vision worsened and became “dark,” such that the patient could not see a hand in front of his face when he covered the right eye. He presented to this hospital for evaluation, arriving 1 hour after the onset of vision symptoms.On presentation, the patient noted that the vision in the left eye was improving but remained blurry. The temperature was 36.7°C, the blood pressure 120/65 mm Hg, the heart rate 92 beats per minute, and the body-mass index (the weight in kilograms divided by the square of the height in meters) 24.2. Visual acuity was 20/20 in the right eye and was limited to hand motions at 0.9 m (3.0 ft) in the left eye; 2 hours later, visual acuity in the left eye was 20/40 for distance vision and 20/30 with correction for near vision. Results of the Ishihara color test were normal. The pupils were equal, round, and reactive to light, with no relative afferent pupillary defect. Extraocular movements were intact; visual fields were full in response to confrontation. Intraocular pressure and results of a slit-lamp examination of the anterior and posterior segments of the eye were normal bilaterally. There was severe ptosis of the left upper eyelid (margin reflex distance, 4 mm in the right eye and 1 mm in the left eye). A dilated fundus examination revealed normal optic disks, maculae, and vessels. A nontender, irregular mass was palpable under the left superior orbital rim, but there was no proptosis. The temporal arteries were prominent bilaterally, more so on the right side than on the left side, with normal pulsations and no tenderness. There was no tenderness of the scalp or temporomandibular joints. The remainder of the physical examination was normal.A review of systems was notable for fatigue and weight loss of 4.5 kg in the past year, which the patient attributed to inactivity and decreased appetite. There was a 2-month history of bilateral jaw pain with chewing of firm foods but not with soft foods. There was lateral hip soreness in both hips after walking but no stiffness. There was a sensation of locking when flexing or extending the right first finger. Two days before evaluation, the patient had a temporal headache on the right side that resolved. He reported no numbness or weakness.Aspirin was administered, along with empirical treatment with intravenous methylprednisolone, and the patient was admitted to the hospital.

Laboratory evaluation revealed normocytic anemia and elevated levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Results of tests of kidney and thyroid function were normal, as were blood levels of electrolytes, calcium, glucose, glycated hemoglobin, creatine kinase, homocysteine, and lipoprotein(a). Testing for antinuclear antibodies was negative, and levels of IgG subclasses were normal.

Imaging Studies. MRI of the head and orbits was performed. A coronal short-tau inversion recovery image (Panel A) and a coronal T1-weighted fat-saturated image obtained after the administration of intravenous gadolinium (Panel B) show enlargement of the right medial rectus muscle (arrows), which is associated with marked T2-hypointense signal (Panel A) but shows enhancement similar to that of the other extraocular muscles (Panel B). Mild enhancement and fat stranding are present in the adjacent extraconal fat. An axial three-dimensional fast spoiled gradient echo image (Panel C), obtained after the administration of intravenous gadolinium, shows an enhancing masslike lesion (arrow) in the left anterior superior orbit, abutting the left lacrimal gland. CT of abdomen and pelvis was also performed. Axial and coronal images (Panels D and E, respectively), obtained after the administration of intravenous contrast material, show diffuse coalescent mesenteric and retroperitoneal lymphadenopathy (Panel D, arrows). An additional axial image (Panel F) shows geographic areas of heterogeneous hypoattenuation in the right lobe of the liver. Multiple small calcifications of varying shapes and sizes are shown throughout the liver (Panels E and F, arrows). In addition, coarse calcifications are shown within some of the mesenteric and retroperitoneal lymph nodes (Panels D and E, arrowheads).

Features of the Case with Respect to Giant-Cell Arteritis. Although substantial elevation of levels of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase is not typical of giant-cell arteritis, mild elevation of these levels can be seen.

In addition, the physical examination is notable for prominent temporal arteries, a finding that is sometimes seen in patients with giant-cell arteritis, and the laboratory evaluation is notable for an elevated erythrocyte sedimentation rate and C-reactive protein level, abnormalities that are present in nearly 95% of patients with giant-cell arteritis before glucocorticoids are administered.

Diseases Mimicking Giant-Cell ArteritisMy differential diagnosis for this constellation of clinical manifestations — including cranial symptoms resembling giant-cell arteritis, dacryoadenitis, extraocular muscle enlargement, lymphadenopathies, and liver infiltration — includes sarcoidosis, IgG4-related disease, and primary amyloidosis. Vasculitides involving small and medium vessels (e.g., polyarteritis nodosa and ANCA-associated vasculitis) sometimes affect the head and neck arteries and can be confounded with giant-cell arteritis.SarcoidosisSarcoidosis is an immune-mediated disorder of unknown cause that can affect all racial groups. It can occur anytime in adulthood but usually develops before 50 years of age. The disease is characterized by noncaseating granulomatous inflammation that can involve any organ. Approximately 90% of patients present with intrathoracic abnormalities such as hilar lymphadenopathy and interstitial lung disease.5 In approximately 30% of cases, extrathoracic manifestations occur, most commonly involving the joints (e.g., arthralgias), the eyes (e.g., uveitis), and the skin (e.g., erythema nodosum).IgG4-Related DiseaseIgG4-related disease is a multisystem fibroinflammatory disease that has been increasingly recognized over the past decade. Men are affected more frequently than women, and the age at onset is typically between 50 and 60 years. Lesions associated with IgG4-related disease are characterized by lymphoplasmacytic infiltrates and storiform fibrosis. The most commonly affected organs are the pancreas (i.e., autoimmune pancreatitis type 1), the hepatobiliary system (e.g., sclerosing cholangitis), and the salivary and lacrimal glands.Systemic AmyloidosisSystemic amyloidosis is a rare disease that results from protein misfolding and aggregation into highly ordered fibrils that deposit in tissues and cause progressive organ damage. Amyloidosis can occur in the presence of an abnormal protein (e.g., primary amyloidosis, also known as amyloid light-chain [AL] amyloidosis), in association with excess abundance of a normal protein (e.g., secondary amyloidosis, also known as amyloid A [AA] amyloidosis), and for unclear reasons (e.g., senile systemic amyloidosis).

Primary amyloidosis is a plasma-cell dyscrasia caused by deposition of protein fragments derived from abnormal immunoglobulin light chains. The mean age at diagnosis is 63 years, and men are affected more often than women. In most patients with primary amyloidosis, the amyloidogenic light chains are produced by low-level expansion of an indolent B-cell clone that arises in the context of monoclonal gammopathy of undetermined significance. In some patients, the disease occurs in association with multiple myeloma, Waldenström’s macroglobulinemia, or non-Hodgkin’s lymphoma. Primary amyloidosis can affect any organ, including the arteries, except for the brain. In fact, several cases of primary amyloidosis with cranial features similar to those of giant-cell arteritis have been reported. The diagnosis of primary amyloidosis may well explain this patient’s constellation of clinical manifestations, including the liver involvement with characteristic findings on imaging (parenchymal hypoattenuation and calcification), lymphadenopathy, lacrimal gland involvement, extraocular muscle enlargement, and a syndrome resembling giant-cell arteritis, with prominent temporal arteries, temporal headache, jaw claudication, and transient vision loss. The diagnosis of amyloidosis requires the identification of amyloid fibrils in tissue. On microscopic examination, these fibrils show a pathognomonic apple-green birefringence under polarized light after Congo red staining. To establish the diagnosis in this case, I would recommend performing immunoelectrophoresis and quantifying free light chains in blood and urine to look for a monoclonal component, and most important, performing a biopsy to confirm the presence of amyloid deposits. A fat-pad biopsy is simple to perform and has a relatively high yield for the diagnosis of systemic primary amyloidosis. Other tissues that could be sampled in this patient include the rectal or lip mucosa, left lacrimal gland, temporal arteries, liver, and abdominal lymph nodes. Because amyloidosis is often associated with hemostatic defects, less invasive procedures are generally recommended as an initial diagnostic approach. If amyloid material is identified, the next steps are to determine the type of amyloid with the use of immunohistochemical studies or laser-capture microdissection followed by mass spectrometry, as well as to assess the extent and severity of the disease. Where available, imaging with radioiodinated serum amyloid P component can be used to measure the burden of disease and monitor the response to treatment. If the diagnosis of primary amyloidosis is confirmed in this patient, I would also recommend a bone marrow biopsy to rule out multiple myeloma, which occurs in 10 to 15% of patients with primary amyloidosis.Pathological discussionThe diagnostic tests in this case were biopsies of a retroperitoneal lymph node and the liver.

Biopsy Specimens of a Lymph Node and the Liver. Hematoxylin and eosin staining of a biopsy specimen of a retroperitoneal lymph node (Panel A) shows fragments of fibroadipose tissue with calcifications and acellular eosinophilic deposits (arrows), with associated reactive osseous metaplasia (left arrowhead) and scattered multinucleated giant cells (right arrowhead). On Congo red staining (Panel B), the eosinophilic deposits show apple-green birefringence under polarized light, a feature characteristic of amyloid. Hematoxylin and eosin staining of a biopsy specimen of the liver (Panel C) shows portal-based, well-delineated nodules of eosinophilic deposits (arrows); the deposits within the dashed outline show apple-green birefringence under polarized light on Congo red staining (Panel D). At higher magnification (Panel E), there is a focal dense cluster of plasma cells adjacent to the amyloid deposits in the liver parenchyma. On immunohistochemical staining for kappa and lambda light chains (Panels F and G, respectively), the plasma cells show kappa restriction.

Biopsy Specimen of the Bone Marrow. Hematoxylin and eosin staining of a core biopsy specimen of the bone marrow (Panel A) shows mildly hypocellular marrow for the patient’s age with maturing trilineage hematopoiesis. At higher magnification (Panel B), scattered and clustered plasma cells are present. On kappa and lambda light-chain mRNA in situ hybridization (Panels C and D, respectively), the plasma cells show kappa restriction. On Wright–Giemsa staining of a smear of bone marrow aspirate (Panel E), the mature plasma cells (arrows) account for 8.5% of the marrow cellularity on a differential count. On flow cytometry of the aspirate (Panel F), the vertical and horizontal axes show fluorescence intensity measurements for cytoplasmic kappa and lambda light chains, respectively. There is a predominance of clonal kappa-positive plasma cells (K+ PC), as indicated by red dots, with very few lambda-positive plasma cells (L+ PC), as indicated by blue dots; purple and green dots indicate non–plasma cell populations.

Anatomical DiagnosisSystemic primary amyloidosis.

Discussion of ManagementFor the treatment of primary amyloidosis with hepatic involvement, the patient received daratumumab, bortezomib, and dexamethasone. Daratumumab is a human IgG1k monoclonal antibody that targets CD38, a cell-surface glycoprotein highly expressed on plasma cells; bortezomib is a proteasome inhibitor; and dexamethasone is a glucocorticoid. From initiation to completion of three cycles of therapy, the alkaline phosphatase level decreased from 1764 U per liter to 939 U per liter, the alanine aminotransferase level from 457 U per liter to 190 U per liter, the aspartate aminotransferase level from 435 U per liter to 121 U per liter, and the serum level of kappa free light chains from 1271.4 mg per liter to 78.3 mg per liter.The patient underwent a total of four cycles of therapy and has not had any clinically significant side effects. He is now working full time and reports that he feels well.

Daratumumab bindet spezifisch an das Oberflächenprotein CD38, welches insbesondere von Myelomzellen überexprimiert wird. Auf Stammzellen ist die Expression von CD38 gering oder nicht ausgeprägt. CD38 ist an diversen Prozessen (Zelladhäsion, Signaltransduktionswege) mit Einfluss auf die Zellproliferation maligner Zellen beteiligt. Daratumumab hemmt durch Bindung an CD38 dessen Effekte und induziert über direkte und indirekte Mechanismen die Apoptose. Zu den Apoptose-induzierenden Wirkungen zählen Fc-vermittelte Effekte, immunvermittelte Tumorzelllyse durch Komplement- und Antikörper-abhängige Zytotoxizität und Antikörper-vermittelte Phagozytose.Daratumumab provoziert die Zytolyse weiterer Zelltypen, die CD38 exprimieren. So werden ein Rückgang von myeloide Suppressorzellen und NK-Zellen beschrieben. Dagegen nehmen die Zahlen von T-Lymphozyten (CD4-/ CD8-positiv) sowie Gesamtzellzahl der Lymphozyten im peripheren Blut und Knochenmark zu.

Das Mesotheliom ist ein diffus wachsender Tumor. Meistens kommt es in der Pleura (Pleuramesotheliom), dem Herzbeutel und dem Peritoneum sowie an der Tunica vaginalis testis vor.Besonders betroffen sind Menschen, die mit Asbest Kontakt hatten (Asbestose). Wie bei den meisten Tumoren kann auch das Mesotheliom in zwei Formen auftreten: gutartig (benigne, nicht invasiv und langsam wachsend) und bösartig (maligne, invasiv und schnell wachsend). Mesotheliome sind oft schwer zu diagnostizierende, relativ seltene (ca. 3000 neue Fälle pro Jahr in den USA) Bindegewebstumore des Mesothels, vor allem der Pleura. Männer sind häufiger von der Erkrankung betroffen (Wahrscheinlichkeit ca. 1:1000 bzw. 4:1, je nach Quelle). Nach aktuellen Erkenntnissen wird das Mesotheliom zumeist durch Asbesteinwirkung (hier v. a. die langfasrigen Amphibole), Glasfaserstaub oder Toxikose durch Zigarettenrauch und andere exogene Schadstoffe hervorgerufen. Vereinzelt sind auch Fälle nach Strahlentherapie von Hodgkin-Lymphomen und anderen malignen Krebserkrankungen aufgetreten. Formen, die primär im Mesothel des Bauchfells oder Herzbeutels auftreten, sind wesentlich seltener. Das Pleuramesotheliom ist eine charakteristische Tumorform in Folge einer Asbestose und eine der ersten anerkannten Berufserkrankungen, da besonders Arbeiter in der asbestverarbeitenden Industrie und Bau- und Werftsarbeiter betroffen sind, was auch die erhöhte Inzidenz bei Männern erklärt.

Ein Immuncheckpoint-Inhibitor (auch Immun-Checkpoint-Inhibitor) ist ein Molekül, das einen Immuncheckpoint hemmt. In der Onkologie werden entzündungshemmende Immuncheckpoints blockiert. Diese Moleküle werden immuntherapeutisch genutzt und sind derzeit ausschließlich monoklonale Antikörper. Das Immunsystem verfügt über sowohl kostimulatorische (aktivierende) als auch inhibitorische (hemmende) Signalwege. Diese Regelmechanismen beeinflussen die Stärke und Intensität einer Immunantwort. Im Normalfall dienen diese Mechanismen u. a. der Vermeidung von Autoimmunreaktionen. Jene Signalwege mit hemmender Wirkung werden als co-inhibitorische Immuncheckpoint bezeichnet und bewirken ein Herabregulieren der T-Zell-Aktivierung oder der T-Zell-Effektorfunktion. Die Immuncheckpoints mit entzündungsfördernder Wirkung werden als co-stimulatorische Immuncheckpoints bezeichnet.

Ethylenglykol ist ein zweiwertiger Alkohol mit der Summenformel C2H6O2, der u.a. in Frostschutzmitteln verwendet wird. Symptomatisch ähnelt die Ethylenglykolintoxikation trotz verschiedener Metabolite der Methanolvergiftung. Vergiftungen sind selten, kommen aber vor, da wasserverdünnte Frostschutzmittel einen süßlichen Geschmack aufweisen.Die Toxizität geht nicht vom Ethylenglykol selbst, sondern von dessen Abbauprodukten aus. Da die Alkoholdehydrogenase (ADH) das Ethylenglykol zu Ameisensäure, Glykolsäure und Oxalessigsäure verstoffwechselt, führt die Vergiftung zu einer metabolischen Azidose. Kalziumoxalat lagert sich als Endprodukt des Ethylenglykolstoffwechsels in den Geweben ab. In schweren Fällen kann es nach 24 bis 72 Stunden zu akutem Nierenversagen, Koma, Myokardschaden und Multiorganversagen kommen. Die Therapie der Ethylenglykolintoxikation erfordert ein intensivmedizinisches Setting. Die Vergiftung kann im Anfangsstadium mit Ethanol behandelt werden. Die Alkoholdehydrogenase hat eine höhere Affinität zu Ethanol und es kommt zu einer kompetitiven Hemmung, sodass das Ethylenglykol nicht verstoffwechselt, sondern unverändert ausgeschieden wird. Darüber hinaus stehen Bikarbonatgabe und die Entfernung der toxischen Metaboliten durch Hämodialyse an erster Stelle. Weiterhin kann 4-Methylpyrazol (Fomepizol) i.v. als kompetitiver Inhibitor der ADH verabreicht werden.