Creutzfeldt-Jakob Disease (CJD) is the most common prion disease in humans causing a rapidly progressive neurological decline and dementia and is invariably fatal. The familial forms (genetic CJD, ...gCJD) are caused by mutations in the PRNP gene encoding for the prion protein (PrP). In Israel, there is a large cluster of gCJD cases, carriers of an E200K mutation in the PRNP gene, and therefore the largest population of at-risk individuals in the world. The mutation is not necessarily sufficient for the formation and accumulation of the pathological prion protein (PrP
), suggesting that other, genetic and non-genetic factors affect the age at symptoms onset. Here we present the protocol of a cross-sectional and longitudinal natural history study of gCJD patients and first-degree relatives of gCJD patients, aiming to identify biological markers of preclinical CJD and risk factors for phenoconversion.
The study has two groups: Patients diagnosed with gCJD, and first-degree healthy relatives (HR) (both carriers and non-carriers of the E200K mutation in the PRNP gene) of patients diagnosed with gCJD. At baseline, and at the end of every year, healthy participants are invited for an "in-depth" visit, which includes a clinical evaluation, blood and urine collection, gait assessment, brain MRI, lumbar puncture (LP), and Polysomnography (PSG). At 6 months from baseline, and then halfway through each year, participants are invited for a "brief" visit, which includes a clinical evaluation, short cognitive assessment, and blood and urine collection. gCJD patients will be invited for one "in-depth" visit, similar to the baseline visit of healthy relatives.
This continuous follow-up of the participants and the frequent assessments will allow early identification and diagnosis in case of conversion into disease. The knowledge generated from this study is likely to advance the understanding of the underlying clinicopathological processes that occur at the very beginning of CJD, as well as potential genetic and environmental risk factors for the development of the disease, therefore advancing the development of safe and efficient interventions.
The study is an observational study. It has registered retrospectively in https://clinicaltrials.gov/ and has been assigned an identification number NCT05746715.
Immune check point inhibitors (ICIs) are a group of anti-cancer pharmacological agents which modify T cell activity in order to potentiate an effective immune response against tumor cells. While ...these drugs prove extremely potent against several types of malignancies, they may be associated with significant autoimmune adverse events. We report a patient who developed a subacute cerebellar syndrome shortly after starting treatment with nivolumab, a PD-1 inhibitor, for renal clear cell carcinoma, with detectable paraneoplastic PCA-2 antibodies. The tumor specimen stained positively for MAP1B, the antigen of PCA-2. The patient responded well to treatment with glucocorticosteroids. This is the first case to our knowledge of PCA-2 paraneoplastic cerebellar degeneration associated with ICI use, which presents in a patient with a malignancy not typically associated with neurological paraneoplastic phenomena. Treatment with immune checkpoint inhibitors (ICIs) is extremely effective in potentiating an immune response against tumor cells, but bears a substantial risk for the development of autoimmune phenomena, including paraneoplastic neurological syndromes. Increasing use of ICIs is leading to increasing numbers of patients with new-onset neurological symptoms. Awareness of these novel entities will aid in early diagnosis and proper treatment.
Popeye domain containing1 (Popdc1), also named Bves, is an evolutionary conserved membrane protein. Despite its high expression level in the heart little is known about its membrane localization and ...cardiac functions. The study examined the hypothesis that Popdc1 might be associated with the caveolae and play a role in myocardial ischemia tolerance. To address these issues, we analyzed hearts and cardiomyocytes of wild type and Popdc1-null mice. Immunoconfocal microscopy revealed co-localization of Popdc1 with caveolin3 in the sarcolemma, intercalated discs and T-tubules and with costameric vinculin. Popdc1 was co-immunoprecipitated with caveolin3 from cardiomyocytes and from transfected COS7 cells and was co-sedimented with caveolin3 in equilibrium density gradients. Caveolae disruption by methyl-β-cyclodextrin or by ischemia/reperfusion (I/R) abolished the cellular co-localization of Popdc1 with caveolin3 and modified their density co-sedimentation. The caveolin3-rich fractions of Popdc1-null hearts redistributed to fractions of lower buoyant density. Electron microscopy showed a statistically significant 70% reduction in caveolae number and a 12% increase in the average diameter of the remaining caveolae in the mutant hearts. In accordance with these changes, Popdc1-null cardiomyocytes displayed impaired Ca(+2)i transients, increased vulnerability to oxidative stress and no pharmacologic preconditioning. In addition, induction of I/R injury to Langendorff-perfused hearts indicated a significantly lower functional recovery in the mutant compared with wild type hearts while their infarct size was larger. No improvement in functional recovery was observed in Popdc1-null hearts following ischemic preconditioning. The results indicate that Popdc1 is a caveolae-associated protein important for the preservation of caveolae structural and functional integrity and for heart protection.
In mid-December 2020, Israel started a nationwide mass vaccination campaign against coronavirus disease 2019 (COVID-19). In the first few weeks, medical personnel, elderly citizens, and patients with ...chronic diseases were prioritized. As such, patients with primary and secondary immunodeficiencies were encouraged to receive the vaccine. Although the efficacy of RNA-based COVID-19 vaccines has been demonstrated in the general population, little is known about their efficacy and safety in patients with inborn errors of immunity (IEI).
Our aim was to evaluate the humoral and cellular immune response to COVID-19 vaccine in a cohort of patients with IEI.
A total of 26 adult patients were enrolled, and plasma and peripheral blood mononuclear cells were collected from them 2 weeks following the second dose of Pfizer-BioNTech COVID-19 vaccine. Humoral response was evaluated by testing anti–SARS-CoV-2 spike (S) receptor-binding domain and antinucleocapsid antibody titers and evaluating neutralizing ability by inhibition of receptor-binding domain–angiotensin-converting enzyme 2 binding. Cellular immune response was evaluated by using ELISpot, estimating IL-2 and IFN-γ secretion in response to pooled SARS-CoV-2 S- or M-peptides.
Our cohort included 18 patients with a predominantly antibody deficiency, 2 with combined immunodeficiency, 3 with immune dysregulation, and 3 with other genetically defined diagnoses. Twenty-two of them were receiving immunoglobulin replacement therapy. Of the 26 patients, 18 developed specific antibody response, and 19 showed S-peptide–specific T-cell response. None of the patients reported significant adverse events.
Vaccinating patients with IEI is safe, and most patients were able to develop vaccine-specific antibody response, S-protein–specific cellular response, or both.
Background
The evaluation of autoimmune encephalitis (AIE) usually includes antibody testing with commercial kits capable of detecting only preselected antibodies. A non-antigen-specific assay may ...help detect other antibodies. In this study, we evaluate the utility and clinical relevance of an immunofluorescence assay (IFA) in the evaluation of AIE.
Methods
Immunofluorescence assay was performed on 1949 patients' serum/CSF between 2017 and 2020 and clinical relevance was designated to each case based on clinical course, suggested criteria and ancillary testing.
Results
Sixty-one patients (3.1%) had positive serum IFA, positive CSF, or both. Twenty-eight out of 42 patients who were positive only on IFA were designated as clinically relevant (67%), 8 inconclusive (19%), and 6 non-relevant (14%). Pleocytosis was significantly higher in the clinically relevant cases (74% vs. 20% for non-clinically relevant cases). Encephalopathy was the most common presentation (36%), followed by cerebellar syndrome (32%) and seizures (25%). The initial diagnosis changed due to IFA results in 13/28 (46%) cases and IFA result led to the initiation or modification of treatment in all cases (68% and 43%, respectively). Twenty-five patients were treated with 1st line immunotherapy and 12 with 2nd line immunotherapy, with 92% responding to treatment. Twenty-six clinically relevant patients underwent cancer workup: seven (25%) had confirmed malignancy and three had high suspicion of malignancy (total of 37%).
Conclusion
Non-antigen-specific assays, such as IFA, can identify antibodies not detected in commercially available kits and therefore are recommended in the evaluation of autoimmune encephalitis.
Background
Paraneoplastic motor neuron disease (PMND) is a rare, non-classical form of paraneoplastic neurological syndrome (PNS). Anti-Hu and anti-CV2/CRMP5 PNS are mostly associated with small-cell ...lung cancer (SCLC) and consist of highly variable clinical syndromes, including sensory neuronopathy, cerebellar ataxia and/or limbic encephalitis. However, substantial motor impairment is uncommon, particularly when no sensory dysfunction co-exists.
Case
A 72-year-old man with a recent diagnosis of amyotrophic lateral sclerosis (ALS) was referred to our department of neurology for evaluation. The patient sub-acutely developed progressive neurological dysfunction including erectile dysfunction, behavioral changes, limb weakness, dysphagia, anorexia, as well as worsening stridor that necessitated tracheostomy due to bilateral vocal cord paralysis (BVCP). Neurological examination revealed motor weakness of upper and lower motor neuron origin with autonomic and cognitive dysfunction. Cerebrospinal fluid (CSF) analysis demonstrated pleocytosis, elevated protein, presence of oligoclonal bands (OCB), and neuronal antibody testing was positive for anti-Hu and anti-CV2/CRMP5. Based on these findings a diagnosis of a PNS was made. Evaluation for malignancy was negative, and immunosuppressive/immunomodulatory treatment was initiated but had little effect during fifteen months of follow-up.
Conclusions
Although PMND is very rare, in an atypical presentation, especially with features that are not usually present in ALS such as autonomic dysfunction, sensory disturbance or cognitive decline, this etiology should be in the differential diagnosis.
An autoimmune form of Isaacs' syndrome is commonly associated with VGKC complex antibodies and characterized by continuous muscle activity of extremity muscles. Here, we describe a CASPR2 and LGI1 ...positive patient with neuromyotonia clinically and electrophysiologically isolated to gastrocnemius muscles only. IVIG course and plasma exchange were ineffective, but symptoms significantly improved after a course of high-dose steroids. This case demonstrates that focal hyperexcitability should raise suspicion for autoimmunity. LGI1 antibody can be positive in patients with only peripheral nerve system involvement and if one treatment fails, other should be tried.
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•Autoimmune Isaacs syndrome presented clinically only with focal neuromyotonia isolated to gastrocnemius muscles.•LGI1 antibodies, mostly associated with CNS involvement, were positive in the serum, negative in CSF with no central nerve system involvement.•Good response to steroid and immunosuppressive therapy; IVIG and Plasmapheresis failed.
•In order to boost immunity, a 4th dose of SARS-CoV-2 vaccine was offered to elderly individuals.•We show that the 4th dose enhances humoral and cellular immunity in patients age 60 years and ...older.•Specifically, an enhanced cellular response against the wild-type S-glycoprotein was observed.•Almost 1/3 of the individuals showed anti-M cellular response, suggesting possible asymptomatic exposure.•We did not see enhanced response against mutated regions of the Omicron S-glycoprotein in M non-responding individuals.
With the emergence of the severe acute respiratory syndrome 2 (SARS-CoV-2) B.1.1.529/BA.1 (Omicron) variant in early 2022, Israel began vaccinating individuals 6o years of age or older with a fourth BNT162b2 vaccine. While the decision was based on little experimental data, longer follow-up showed clinical effectiveness of the fourth dose with reduction in the number of severely affected individuals. However, the immune response to fourth vaccine dose in this age group was not yet characterized, and little is known about the immunogenicity of repeated vaccine dosing in this age group. We therefore aimed to evaluate the humoral and cellular immune response pre- and 3-week post- the fourth vaccine dose in patients age 60 years or older. For this purpose, blood samples were collected from donors age 60 years or older, all received their 3rd vaccine dose 5 months prior. Serum samples were evaluated for the presence of anti-Spike protein (anti-S) antibodies (N = 133), and peripheral blood mononuclear cells (PBMCs) were evaluated by flow cytometry for their ability to respond to the SARS-CoV-2 wild type Spike-glycoprotein peptide mix, Membrane-glycoprotein (M) peptide mix and to the mutated Spike-regions of the Omicron variant (N = 34). Three weeks after the fourth vaccine dose, 24 out of 34 donors (70.5%) showed significant increase in the number of cells responding to the wild type S-peptide mix. Of note, out of 34 donors, 11 donors (32.3%) had pre-boost anti-M T-cell response, none of which had history of confirmed COVID-19, suggesting possible asymptomatic exposure. Interestingly, in M non-responding individuals, no statistically significant increase in the cellular response was observed following stimulation with omicron S-mutated regions. While there are limited data regarding the longevity of the observed response, our results are in accordance with the described clinical efficacy, provide mechanistic evidence to support it and argue against vaccine-induced or age-related immunosenescence.
Anesthesia and surgery are associated with impairment of the immune system expressed as an excessive proinflammatory immune response and suppression of cell mediated immunity. Opioids, an integral ...part of anesthetic technique, possess an inhibitory effect on both humoral and cellular immune responses. It was the aim of the present study to examine the effect of various doses of fentanyl on cytokine production during the perioperative period.
The effect of large (LDFA, 70-100 microg/kg), intermediate (IDFA, 23-30 microg/kg) and small (SDFA, 2-4 microg/kg) doses of fentanyl on the immune function in the postoperative period was investigated.
Sixty patients, randomly assigned to one of the three groups according to the dose of fentanyl were included in the study.
The ex vivo secretion of IL-1beta, IL-2, IL-6, and IL-10 and NK cell cytotoxicity (NKCC) of peripheral blood mononuclear cells (PBMC) was tested before, and at 24, 48, and 72 hours following surgery.
The pattern of postoperative secretion of the proinflammatory cytokines IL-1beta and IL-6 and that of the anti-inflammatory cytokine IL-10 differed significantly between patients receiving SDFA and those receiving IDFA and LDFA, but was similar between the last two groups. A similar suppression of NKCC and IL-2 secretion was observed in the three groups.
The diminished proinflammatory cytokine response observed in patients treated by LDFA and IDFA suggests that although more stable immune function can be achieved by those methods in comparison with SDFA, it is recommendable to apply IDFA to avoid the side effects that might be observed using LDFA method.
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