•Treatment with immune checkpoint inhibitors can cause serious adverse events.•Myositis combined with myocarditis ad adverse event have a mortality for 50%.•Early diagnosis is important for better ...outcome.•Employing MRI STIR can rapidly diagnose, guide biopsy, and classify cases of immune-related myositis.
Abstract
Background
Immune checkpoint inhibitor (ICI)-related myocarditis is an uncommon but potentially fatal immune-related adverse event. Corticoid-resistant myocarditis induced by ICI is an ...important therapeutic challenge.
Case summary
Here, we present a case of steroid-refractory ICI-related myocarditis and myositis treated with abatacept and mycophenolate mofetil (MMF). A 57-year-old male with metastatic renal cell carcinoma was diagnosed with immune-related myocarditis and myasthenia gravis-like myositis after first dose of combination ICIs with nivolumab (anti-programmed cell death-1) plus ipilimumab (anti-cytotoxic T-lymphocyte-associated antigen-4). Twelve days after ICI he was admitted to the hospital due to palpitations, headache, and pain in the extremities. Laboratory findings revealed elevated inflammatory markers and cardiac enzymes. Electrocardiogram showed first-degree atrioventricular (AV) block and right bundle branch block which developed into complete heart block within 48 h. Because of clinical and paraclinical deterioration despite immediate initiation of methylprednisolone abatacept and MMF was added. Following, gradual subjective improvement and termination of arrhythmia led to discharge of the patient from the hospital 6 weeks after the introduction of ICI.
Discussion
The key treatment of ICI-related myocarditis is glucocorticoid. For steroid-refractory myocarditis supplementary immune suppressive agents are recommended. Yet, data still relies on case reports and case series, due to lack of prospective studies. In this case, the use of abatacept and MMF led to resolution of steroid-resistant ICI-related myocarditis and myositis.
Introduction
Borrelia burgdorferi
sensu lato complex (
B. burgdorferi
) can cause a variety of clinical manifestations including Lyme neuroborreliosis. Following the tick-borne transmission,
B. ...burgdorferi
initially evade immune responses, later symptomatic infection is associated with occurrence of specific antibody responses. We hypothesized that
B. burgdorferi
induce immune hyporesponsiveness or immune suppression and aimed to investigate patients with Lyme neuroborreliosis ability to respond to immune stimulation.
Methods
An observational cohort study investigating the stimulated immune response by standardized whole blood assay (TruCulture
®
) in adult patients with Lyme neuroborreliosis included at time of diagnosis from 01.09.2018-31.07.2020. Reference intervals were based on a 5-95% range of cytokine concentrations from healthy individuals (n = 32). Patients with Lyme neuroborreliosis and references were compared using Mann-Whitney U test. Heatmaps of cytokine responses were generated using the webtool Clustvis.
Results
In total, 22 patients with Lyme neuroborreliosis (19 definite, 3 probable) were included. In the unstimulated samples, the concentrations of cytokines in patients with Lyme neuroborreliosis were comparable with references, except interferon (IFN)-α, interleukin (IL)-17A, IL-1β and IL-8, which were all significantly below the references. Patients with Lyme neuroborreliosis had similar concentrations of most cytokines in all stimulations compared with references. IFN-α, IFN-γ, IL-12 and IL-17A were lower than references in multiple stimulations.
Conclusion
In this exploratory cohort study, we found lower or similar concentrations of circulating cytokines in blood from patients with Lyme neuroborreliosis at time of diagnosis compared with references. The stimulated cytokine release in blood from patients with Lyme neuroborreliosis was in general slightly lower than in the references. Specific patterns of low IL-12 and IFN-γ indicated low Th1-response and low concentrations of IL-17A did not support a strong Th17 response. Our results suggest that patients with Lyme neuroborreliosis elicit a slightly suppressed or impaired immune response for the investigated stimulations, however, whether the response normalizes remains unanswered.
Lyme neuroborreliosis (LNB) is a prevalent tick-borne disease in Europe caused by Borrelia burgdorferi sensu lato complex. Slightly suppressed induced Th1- and Th17-responses are seen at diagnosis. ...The induced immune response following antibiotic therapy is unknown. We hypothesized that the immune responses normalize after completing antibiotic treatment.
An observational longitudinal cohort study investigating the induced immune response in adult patients with LNB at diagnosis, three and six months after treatment. Whole blood was added to three TruCulture® (Myriad RBM, Austin, USA) tubes each containing one stimulation. An additional TruCulture® tube was without stimulation representing the in vivo activation of blood immune cells. Nine cytokines were measured using Luminex (LX200, R&D Systems, BIO-Teche LTD). Changes in immune response were analyzed with linear mixed model including follow-up as categorical fixed effect.
A total of 21 patients with 55 samples were included. All had clinical improvement, but 5/21 patients reported residual symptoms after six months. The non-induced release of IL-17A and IL-1β increased significantly from diagnosis to six month follow-up. Six months after treatment only IFN-α and TNF-α were below the reference range.
Minor variations in the induced immune responses were seen during the study period. Th1- and Th17-responses continued to be low with low IFN-γ, IL-12p40, and IL-17A in multiple stimulations.
Overall little dynamic was observed. The changes in the cytokine responses are most likely not linked to LNB pathogenesis and our results do not support the implementation of TruCulture® in the diagnostics or follow-up of LNB.
Mitochondrial alanyl-tRNA synthetase 2 gene (AARS2) related disease is a rare genetic disorder affecting mitochondrial metabolism, leading to severe cardiac disease in infants or progressive ...leukodystrophy in young adults. The disease is considered ultra-rare with only 39 cases of AARS2-leukodystrophy previously reported.
We present the case of a young man of consanguineous heritage suffering from cognitive decline and progressive spasticity as well as weakness of the proximal musculature. Utilizing MRI and whole genome sequencing, the patient was diagnosed with a homozygous AARS2 missense variant (NM_020745.3:c.650C > T; p.(Pro217Leu)) and a homozygous CAPN3 variant (NM_000070.2: c.1469G > A; p.(Arg490Gln)), both variants have previously been identified in patients suffering from AARS2 related leukodystrophy and limb-girdle muscular dystrophy, respectively.
This case report presents a case of homozygous AARS2 leukodystrophy and serves to highlight the importance of whole genome sequencing in diagnosing rare neurological diseases as well as to add to the awareness of adult onset leukodystrophies.
Encephalitis caused by Borrelia burgdorferi sensu lato is a rare clinical manifestation of Lyme neuroborreliosis and only in few cases have brain parenchymal inflammation been documented. Here, we ...present a case of Lyme neuroborreliosis with encephalitis with significant parenchymal inflammation on magnetic resonance imaging (MRI) in an immunosuppressed patient.
•We here report a rare case of Lyme neuroborreliosis with encephalitis.•The patient was immunosuppressed and presented with uncharacteristic symptoms.•Magnetic Resonance imaging showed significant parenchymal changes.•Early diagnosis of this treatable infection is of great importance.
•sCD163 is a macrophage-specific marker detectable in blood and cerebrospinal fluid.•Levels of sCD163 in cerebrospinal fluids were elevated in neuroborreliosis.•The optimal diagnostic cut-off of ...sCD163 in cerebrospinal fluid was 210 µg/l.•Combining ReaScan-CXCL13 with sCD163 increased the diagnostic strength.•sCD163 in plasma was not elevated in patients with neuroborreliosis.
We aimed to investigate levels of the macrophage-specific marker, sCD163, in cerebrospinal fluid and plasma in patients with Lyme neuroborreliosis. We tested the diagnostic value of CSF-sCD163 and ReaScan-CXCL13 and analyzed if plasma-sCD163 could monitor treatment response.
An observational cohort study: Cohort 1—Cerebrospinal fluid from adults with neuroborreliosis (n = 42), bacterial meningitis (n = 16), enteroviral meningitis (n = 29), and controls (n = 33); Cohort 2—Plasma from 23 adults with neuroborreliosis collected at diagnosis, three, and six months.
sCD163 was determined using an in-house sandwich ELISA. ReaScan-CXCL13 measured semiquantitative concentrations of CXCL13, cut-off ≥ 250 pg/ml diagnosed neuroborreliosis.
Receiver Operating Characteristics analyzed the diagnostic strength. A linear mixed model including follow-up as categorical fixed effect analyzed differences in plasma-sCD163.
CSF-sCD163 was higher in neuroborreliosis (643 µg/l) than in enteroviral meningitis (106 µg/l, p < 0.0001) and controls (87 µg/l, p < 0.0001), but not bacterial meningitis (669 µg/l, p = 0.9). The optimal cut-off was 210 µg/l, area under the curve (AUC) 0.85. ReaScan-CXCL13 had an AUC of 0.83. Combining ReaScan-CXCL13 with CSF-sCD163 increased AUC significantly to 0.89.
Plasma-sCD163 showed little variation and was not elevated during the 6 months of follow-up.
CSF-sCD163 is diagnostic for neuroborreliosis with an optimal cut-off of 210 µg/l. Combining ReaScan-CXCL13 with CSF-sCD163 increases AUC. Plasma-sCD163 cannot monitor treatment response.
A 63-year-old male with metastatic non-small cell lung cancer developed longitudinal extensive transverse myelitis (LETM) following two cycles of Pembrolizumab, an immune checkpoint inhibitor (ICI) ...targeting the programmed cell death receptor 1 (PD-1). Magnetic resonance imaging (MRI) showed centromedullary contrast enhancement at several levels, cerebrospinal fluid (CSF) cytology showed lymphocytic pleocytosis, and indirect immunofluorescence assay (IFA) on the primate cerebellum, pancreas, and intestine revealed strong binding of neuronal autoantibodies to unknown antigens. CSF C-X-C motif ligand 13 (CXCL13) was elevated. The patient was treated with plasma exchange (PEX) and intravenous (i.v.) methylprednisolone (MP) 1 g/day for 5 days followed by oral (p.o.) MP 100 mg/day for 10 days with clinical and radiological response. However, after discontinuation of MP, LETM relapsed and the patient developed paralytic ileus presumably due to autoimmune enteropathy and suffered a fatal gastrointestinal sepsis. Findings of novel neuronal autoantibodies and highly elevated CXCL13 in CSF suggest that the severe neurological immune-related adverse event (nirAE) was B-cell mediated contrary to the commonly assumed ICI-induced T-cell toxicity. An individual evaluation of the underlying pathophysiology behind rare nirAEs is essential for choosing treatment regimens and securing optimal outcome.
This is a case report of a 68-year-old woman, who developed malaise after an insect bite. Symptoms subsided, and over weeks progressing difficulty with walking, ataxia and universal areflexia ...developed. A lumbar puncture showed mononuclear pleocytosis and moderately raised protein levels with no detected viral agents. An MRI of the spinal cord showed leptomeningeal contrast attenuation distally. Serum samples were positive for anti-tick-borne encephalitis (TBE) IgM-antibodies, but not IgG, and showed seroconversion. TBE is endemic in areas of Central Europe and Scandinavia but has earlier only been shown in the eastern part of Denmark.
PDF
