IMPORTANCE: Myalgia, increased levels of creatine kinase, and persistent muscle weakness have been reported in patients with COVID-19. OBJECTIVE: To study skeletal muscle and myocardial inflammation ...in patients with COVID-19 who had died. DESIGN, SETTING, AND PARTICIPANTS: This case-control autopsy series was conducted in a university hospital as a multidisciplinary postmortem investigation. Patients with COVID-19 or other critical illnesses who had died between March 2020 and February 2021 and on whom an autopsy was performed were included. Individuals for whom informed consent to autopsy was available and the postmortem interval was less than 6 days were randomly selected. Individuals who were infected with SARS-CoV-2 per polymerase chain reaction test results and had clinical features suggestive of COVID-19 were compared with individuals with negative SARS-CoV-2 polymerase chain reaction test results and an absence of clinical features suggestive of COVID-19. MAIN OUTCOMES AND MEASURES: Inflammation of skeletal muscle tissue was assessed by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma, and a blinded evaluation on a visual analog scale ranging from absence of pathology to the most pronounced pathology. Inflammation of cardiac muscles was assessed by quantification of immune cell infiltrates. RESULTS: Forty-three patients with COVID-19 (median interquartile range age, 72 16 years; 31 men 72%) and 11 patients with diseases other than COVID-19 (median interquartile range age, 71 5 years; 7 men 64%) were included. Skeletal muscle samples from the patients who died with COVID-19 showed a higher overall pathology score (mean SD, 3.4 1.8 vs 1.5 1.0; 95% CI, 0-3; P < .001) and a higher inflammation score (mean SD, 3.5 2.1 vs 1.0 0.6; 95% CI, 0-4; P < .001). Relevant expression of MHC class I antigens on the sarcolemma was present in 23 of 42 specimens from patients with COVID-19 (55%) and upregulation of MHC class II antigens in 7 of 42 specimens from patients with COVID-19 (17%), but neither were found in any of the controls. Increased numbers of natural killer cells (median interquartile range, 8 8 vs 3 4 cells per 10 high-power fields; 95% CI, 1-10 cells per 10 high-power fields; P < .001) were found. Skeletal muscles showed more inflammatory features than cardiac muscles, and inflammation was most pronounced in patients with COVID-19 with chronic courses. In some muscle specimens, SARS-CoV-2 RNA was detected by reverse transcription–polymerase chain reaction, but no evidence for a direct viral infection of myofibers was found by immunohistochemistry and electron microscopy. CONCLUSIONS AND RELEVANCE: In this case-control study of patients who had died with and without COVID-19, most individuals with severe COVID-19 showed signs of myositis ranging from mild to severe. Inflammation of skeletal muscles was associated with the duration of illness and was more pronounced than cardiac inflammation. Detection of viral load was low or negative in most skeletal and cardiac muscles and probably attributable to circulating viral RNA rather than genuine infection of myocytes. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.
OBJECTIVE:We assessed the therapeutic potential of the plasma-cell-depleting proteasome inhibitor bortezomib in severe and therapy-refractory cases of anti–NMDA receptor (anti-NMDAR) encephalitis.
...METHODS:Five severely affected patients with anti-NMDAR encephalitis with delayed treatment response or resistance to standard immunosuppressive and B-cell-depleting drugs (corticosteroids, IV immunoglobulins, plasma exchange, immunoadsorption, rituximab, cyclophosphamide) who required medical treatment and artificial ventilation on intensive care units were treated with 1–6 cycles of 1.3 mg/m bortezomib. Occurrence of adverse events was closely monitored.
RESULTS:Bortezomib treatment showed clinical improvement or disease remission, which was accompanied by a partial NMDAR antibody titer decline in 4 of 5 patients. With respect to disease severity, addition of bortezomib to the multimodal immunosuppressive treatment regimen was associated with an acceptable safety profile.
CONCLUSIONS:Our study identifies bortezomib as a promising escalation therapy for severe and therapy-refractory anti-NMDAR encephalitis.
CLASSIFICATION OF EVIDENCE:This retrospective case series provides Class IV evidence that bortezomib reduces antibody titers and improves the clinical course of patients with severe anti-NMDAR encephalitis.
Background and purpose
A fraction of patients with antibody‐mediated autoimmune diseases remain unresponsive to first‐/second‐line and sometimes even to escalation immunotherapies. Because these ...patients are still affected by poor outcome and increased mortality, we investigated the safety and efficacy of the plasma cell‐depleting anti‐CD38 antibody daratumumab in life‐threatening, antibody‐mediated autoimmune diseases.
Methods
In this retrospective, single‐center case series, seven patients with autoantibody‐driven neurological autoimmune diseases (autoimmune encephalitis, n = 5; neurofascin antibody‐associated chronic inflammatory demyelinating polyneuropathy associated with sporadic late onset nemaline myopathy, n = 1; seronegative myasthenia gravis, n = 1) unresponsive to a median of four (range = 4–9) immunotherapies were treated with four to 20 cycles of 16 mg/kg daratumumab.
Results
Daratumumab allowed a substantial clinical improvement in all patients, as measured by modified Rankin Scale (mRS; before treatment: mRS =5, n = 7; after treatment: median mRS =4, range = 0–5), Clinical Assessment Scale in Autoimmune Encephalitis (from median 21 to 3 points, n = 5), Inflammatory Neuropathy Cause and Treatment disability score (from 7 to 0 points, n = 1), and Quantitative Myasthenia Gravis score (from 16 to 8 points, n = 1). Daratumumab induced a substantial reduction of disease‐specific autoreactive antibodies, total IgG (serum, 66%, n = 7; cerebrospinal fluid, 58%, n = 5), and vaccine‐induced titers for rubella (50%) and tetanus toxoid (74%). Treatment‐related toxicities Grade 3 or higher occurred in five patients, including one death.
Conclusions
Our findings suggest that daratumumab provided a clinically relevant depletion of autoreactive long‐lived plasma cells, identifying plasma cell‐targeted therapies as promising escalation therapy for highly active, otherwise treatment‐refractory autoantibody‐mediated neurological diseases.
A fraction of patients with antibody‐mediated autoimmune diseases remain unresponsive to first‐/second‐line and sometimes even to escalation immunotherapies. Because these patients are still affected by poor outcome and increased mortality, we investigated the safety and efficacy of the plasma cell‐depleting anti‐CD38 antibody daratumumab in life‐threatening, antibody‐mediated autoimmune diseases.
Summary
Objective
Depression and anxiety are highly prevalent among people with epilepsy (PwE) but often remain unrecognized and treated inadequately. Effective psychosocial treatments such as ...cognitive behavioral therapy (CBT) are rarely available to most PwE, which is one reason electronically delivered CBT (eCBT) is regarded as promising. This study examined an eCBT intervention, termed Emyna, that was tailored to suit the needs of PwE. It includes CBT‐related content on depression, stress and anxiety, seizure triggers and auras, and lifestyle habits. The trial examined the efficacy of Emyna in reducing symptoms of depression (primary outcome) and anxiety as well as improving quality of life.
Methods
Participants (N = 200) with epilepsy, a diagnosis of a depressive disorder, and at least moderate depressive symptoms were randomized to Emyna or care as usual. At baseline and after 3, 6, and 9 months, participants were invited to complete online questionnaires. The primary outcome was improvement of depressive symptoms at 3 months.
Results
Relative to the control group, intervention group participants experienced significantly greater improvements in depression, anxiety, stress, social‐occupational impairment, and epilepsy‐related quality of life, in both intention‐to‐treat (ITT) and per‐protocol analyses. In ITT analyses, effects of medium magnitude were observed, as measured by the Patient Health Questionnaire–9 items (Cohen d = 0.54, 95% confidence interval CI = 0.25‐0.82, P < 0.001) and the Neurological Disorders Depression Inventory for Epilepsy (d = 0.51, 95% CI = 0.23‐0.79, P < 0.01). At 3 months, intervention group participants also reported fewer illness‐related days off work and fewer days hospitalized over the preceding months, compared to control group participants (P ≤ 0.05), whereas no such differences were present at baseline (P > 0.30).
Significance
These findings showed that Emyna, used adjunctively to usual care, could help improve mental health, social‐occupational functioning, and quality of life among PwE. The program provides an additional treatment option that could produce clinically relevant symptom reductions and reduce key cost drivers (ie, hospitalization rates and illness‐related inability to work).
The anti-CD38 antibody daratumumab is approved for treatment of refractory multiple myeloma and acts by depletion of plasma cells and modification of various T-cell functions. Its safety, ...immunological effects and therapeutic potential was evaluated in a 60-year old patient with life-threatening and treatment-refractory anti-CASPR2 encephalitis requiring medical care and artificial ventilation in an intensive care unit. His autoimmune dysfunction was driven by exceptional high anti-CASPR2 autoantibody titers combined with an abnormally increased T-cell activation. As he remained unresponsive to standard and escalation immunotherapies (methylprednisolone, plasma exchange, immunoadsorption, immunoglobulins, rituximab and bortezomib), therapy was escalated to 13 cycles of 16 mg/kg daratumumab. During the treatment period, clinical, radiological, histological and laboratory findings, including quantification of autoreactive and protective antibody levels and FACS-based immune phenotyping, were analyzed. Daratumumab treatment was associated with significant clinical improvement, substantial reduction of anti-CASPR2 antibody titers, especially in CSF, decrease of immunoglobulin levels and protective vaccine titers, as well as normalization of initially increased T-cell activation markers. However, the patient died of Gram-negative septicemia in a neurorehabilitation center. In conclusion, our findings suggest that daratumumab induces not only depletion of autoreactive long-lived plasma cells associated with improvements of neurological sequelae, but also severe side effects requiring clinical studies investigating efficacy and safety of anti-CD38 therapy in antibody-driven autoimmune encephalitis.
In this review we aimed to determine the economic impact of epilepsy and factors associated with costs to individuals and health systems.
A narrative systematic review of incidence and case series ...studies with prospective consecutive patient recruitment and economic outcomes published before July 2014 were retrieved from Medline, Embase and PsycInfo.
Of 322 studies reviewed, 22 studies met the inclusion criteria and 14 were from high income country settings. The total costs associated with epilepsy varied significantly in relation to the duration and severity of the condition, response to treatment, and health care setting. Where assessed, 'out of pocket' costs and productivity losses were found to create substantial burden on households which may be offset by health insurance. However, populations covered ostensibly for the upfront costs of care can still bear a significant economic burden.
Epilepsy poses a substantial economic burden for health systems and individuals and their families. There is uncertainty over the degree to which private health insurance or social health insurance coverage provides adequate protection from the costs of epilepsy. Future research is required to examine the role of different models of care and insurance programs in protecting against economic hardship for this condition, particularly in low and middle income settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Anti-
N
-methyl-
d
-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis presenting with psychosis, dyskinesias, autonomic dysfunction and seizures. The underlying ...autoantibodies against the NR1 subunit are directly pathogenic by disrupting synaptic NMDAR currents. However, antibody titers correlate only partially with the clinical outcome, suggesting the relevance of other factors such as antibody affinity. We thus determined the binding curves of human monoclonal autoantibodies and patients’ cerebrospinal fluid (CSF) against NR1-expressing HEK293 cells using flow cytometry. Antibody affinity was highly variable with binding constants (half-maximal concentration,
c
50
) ranging from 1 to 74 µg/ml for monoclonal antibodies. Comparing values of individual monoclonal antibodies with human CSF samples suggested that the CSF signal is predominantly represented by higher-affinity antibodies, potentially in a concentration range of NR1 antibodies between 0.1 and 5 µg/ml, roughly reflecting 1–10% of total CSF IgG in NMDAR encephalitis. Binding curves further depended on the CSF composition which must be considered when interpreting established clinical routine assays. Normalization of measurements using reference samples allowed high reproducibility. Accurate and reproducible measurement of NR1 antibody binding suggested that biophysical properties of the antibody might contribute to disease severity. Normalization of the data can be an elegant way to allow comparable inter-laboratory quantification of CSF NR1 antibody titers in autoimmune encephalitis patients, a prerequisite for use as surrogate markers in clinical trials. Based on our calculations, low-affinity antibodies can easily remain undetected in routine cell-based assays, indicating that their relation to clinical symptoms should be analyzed in future studies.
Intensive care units (ICU) are often overflooded with alarms from monitoring devices which constitutes a hazard to both staff and patients. To date, the suggested solutions to excessive monitoring ...alarms have remained on a research level. We aimed to identify patient characteristics that affect the ICU alarm rate with the goal of proposing a straightforward solution that can easily be implemented in ICUs. Alarm logs from eight adult ICUs of a tertiary care university-hospital in Berlin, Germany were retrospectively collected between September 2019 and March 2021. Adult patients admitted to the ICU with at least 24 h of continuous alarm logs were included in the study. The sum of alarms per patient per day was calculated. The median was 119. A total of 26,890 observations from 3205 patients were included. 23 variables were extracted from patients' electronic health records (EHR) and a multivariable logistic regression was performed to evaluate the association of patient characteristics and alarm rates. Invasive blood pressure monitoring (adjusted odds ratio (aOR) 4.68, 95%CI 4.15-5.29, p < 0.001), invasive mechanical ventilation (aOR 1.24, 95%CI 1.16-1.32, p < 0.001), heart failure (aOR 1.26, 95%CI 1.19-1.35, p < 0.001), chronic renal failure (aOR 1.18, 95%CI 1.10-1.27, p < 0.001), hypertension (aOR 1.19, 95%CI 1.13-1.26, p < 0.001), high RASS (aOR 1.22, 95%CI 1.18-1.25, p < 0.001) and scheduled surgical admission (aOR 1.22, 95%CI 1.13-1.32, p < 0.001) were significantly associated with a high alarm rate. Our study suggests that patient-specific alarm management should be integrated in the clinical routine of ICUs. To reduce the overall alarm load, particular attention regarding alarm management should be paid to patients with invasive blood pressure monitoring, invasive mechanical ventilation, heart failure, chronic renal failure, hypertension, high RASS or scheduled surgical admission since they are more likely to have a high contribution to noise pollution, alarm fatigue and hence compromised patient safety in ICUs.
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