Hemophagocytic Lymphohistiocytosis: A Case Series From a Tertiary State Hospital in Malaysia and a Review of Current Literature.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a lethal emergency. Delays in diagnosis and treatment are detrimental to the health of patients. Classical clinical manifestations of HLH include fever, cytopenia, liver dysfunction, central nervous system involvement, and coagulopathy. METHODS: We report seven cases of secondary HLH in adults diagnosed from a total of 1200 bone marrow aspiration and trephine biopsy (BMAT) examinations in our center, with various presentations and underlying triggers including infection, malignancy, and autoimmune disease. RESULTS: HLH can present with non-specific signs and symptoms. CONCLUSION: Early recognition of HLH is crucial to enable the commencement of therapy as early as possible to prevent mortality resulting from multi-organ failure.

HLA-E-expressing macrophage polarization and increased NKG2A/CD94 expression in adult-onset Still's disease.

We investigated the phenotypic characteristics of human leukocyte antigen (HLA)-E-expressing macrophages, NKG2A/CD94 expression in T and natural killer (NK) cells, and their interactions in patients with adult-onset Still's disease (AOSD). Peripheral blood mononuclear cells from 22 patients with AOSD and 22 healthy controls (HC) were used. Isolated monocytes were cultured first with macrophage colony-stimulating factor to differentiate into M0 macrophages and subsequently with lipopolysaccharide/interferon-γ or interleukin-4 to differentiate into M1 or M2 macrophages, respectively. HLA-E and NKG2A/CD94 expression levels were evaluated using quantitative RT-PCR and flow cytometry. HLA-E expression in M0 and M2 macrophages was significantly higher in patients with AOSD than in HC, and was positively correlated with serum C-reactive protein levels and erythrocyte sedimentation rate. NKG2A/CD94 expression in CD4 + and CD8 + T cells was significantly higher in patients with AOSD than in HC, but that in NK cells was not significantly different. In patients with AOSD, NKG2A expression in CD4 + T cells positively correlated with HLA-E expression in M0, M1, and M2 macrophages. CD94 expression in CD8 + T cells inversely correlated with HLA-E expression in M1 and M2 macrophages. NKG2A and CD94 expression in NK cells inversely correlated with HLA-E expression in M0, M1, and M2 macrophages. No significant correlation was observed between HLA-E and NKG2A/CD94 expression in HC. Increased expression of HLA-E in macrophages and NKG2A/CD94 in T cells can be observed in the inflammatory condition of AOSD. HLA-E-expressing macrophages may be associated with NKG2A/CD94 expression in T and NK cells with different correlations.

Coincidence or association: Adult-onset Still's disease following HPV vaccine.

This case details adult-onset Still's disease (AOSD) onset post-human papillomavirus (HPV) vaccination and acute gastroenteritis. The timing of HPV vaccine and vaccine-autoimmune disease literature may potentially confound the well-established link between infections and AOSD onset.

Are SCN2A-related BFNISs also responsible for seizures in adulthood? A case report opens new scenarios.

Large cohort studies and variant-specific electrophysiology have enabled the delineation of different SCN2A-epilepsy phenotypes, phenotype-genotype correlations, prediction of pharmacosensitivity to sodium channel blockers, and long-term prognostication for clinicians and families. One of the most common clinical presentations of SCN2A pathological variants is benign familial neonatal-infantile seizures (BFNIS), which are characterized by seizure onset between the first day of life and 23 months of age and typically resolve, either spontaneously or with the aid of sodium channel blockers, within the first 2 years of life. In 2004, Berkovic et al. reported the case of a young boy affected by SCN2A-related BFNIS whose mother, who carried the same pathological variant, had also presented with BFNIS in infancy. Our case report focuses on the aforementioned woman who, more than 40 years later, presented two additional seizures, therefore opening the possibility of a role for SCN2A-related seizures in adulthood.

Histiocytosis and adult-onset orbital xanthogranuloma in 2023: a review of the literature and mini case series.

PURPOSE: Within the large umbrella of histiocytosis are a few similar yet heterogenous entities involving the orbit and periocular tissues with or without systemic infiltration, termed adult onset xanthogranuloma or orbital xanthogranuloma. Due to rarity of these conditions, different classifications in use, diverse clinical presentations and still unknown etiology, the aim of this paper was to provide an up-to-date literature review of the actual understanding of histiocytosis and its subgroups involving the orbit and periocular area, diagnostic strategies and therapeutic modalities. METHODS: We present a review of literature and small case series comprising four patients diagnosed and treated in the period from 2001 until 2023 in our hospital. Clinical files of 4 patients with adult-onset xanthogranulomatous disease of the orbit and ocular adnexa (AOXGD) were reviewed retrospectively. Clinical, laboratory, radiological, histopathological, and immunohistochemical findings were reexamined. RESULTS: Reviewing medical records of our patients with AOXGD, we found significant overlap between histiocytosis and different immune disorders. A broad workup should be considered in these patients as they can harbour severe immune disfunctions and hematologic disorders. Preferred treatment modality depends on a histopathologic type of AOXGD, clinical presentation and systemic involvement and should be conducted multidisciplinary. CONCLUSION: The diagnosis is often delayed because of its rarity and diverse clinical findings. Development of molecular genetic tests, detection of BRAF V600E mutation and different types of kinase mutations, mutations in transcriptional regulatory genes as well as tyrosine kinase receptors have shed a new light on the etiopathogenesis and potential targeted treatment of histiocytosis.

Multimodal in-vivo maps as a tool to characterize retinal structural biomarkers for progression in adult-onset Stargardt disease.

Purpose: To characterize retinal structural biomarkers for progression in adult-onset Stargardt disease from multimodal retinal imaging in-vivo maps. Methods: Seven adult patients (29-69 years; 3 males) with genetically-confirmed and clinically diagnosed adult-onset Stargardt disease and age-matched healthy controls were imaged with confocal and non-confocal Adaptive Optics Scanning Light Ophthalmoscopy (AOSLO), optical coherence tomography (OCT), fundus infrared (FIR), short wavelength-autofluorescence (FAF) and color fundus photography (CFP). Images from each modality were scaled for differences in lateral magnification before montages of AOSLO images were aligned with en-face FIR, FAF and OCT scans to explore changes in retinal structure across imaging modalities. Photoreceptors, retinal pigment epithelium (RPE) cells, flecks, and other retinal alterations in macular regions were identified, delineated, and correlated across imaging modalities. Retinal layer-thicknesses were extracted from segmented OCT images in areas of normal appearance on clinical imaging and intact outer retinal structure on OCT. Eccentricity dependency in cell density was compared with retinal thickness and outer retinal layer thickness, evaluated across patients, and compared with data from healthy controls. Results: In patients with Stargardt disease, alterations in retinal structure were visible in different image modalities depending on layer location and structural properties. The patients had highly variable foveal structure, associated with equally variable visual acuity (-0.02 to 0.98 logMAR). Cone and rod photoreceptors, as well as RPE-like structures in some areas, could be quantified on non-confocal split-detection AOSLO images. RPE cells were also visible on dark field AOSLO images close to the foveal center. Hypo-reflective gaps of non-waveguiding cones (dark cones) were seen on confocal AOSLO in regions with clinically normal CFP, FIR, FAF and OCT appearance and an intact cone inner segment mosaic in three patients. Conclusion: Dark cones were identified as a possible first sign of retinal disease progression in adult-onset Stargardt disease as these are observed in retinal locations with otherwise normal appearance and outer retinal thickness. This corroborates a previous report where dark cones were proposed as a first sign of progression in childhood-onset Stargardt disease. This also supports the hypothesis that, in Stargardt disease, photoreceptor degeneration occurs before RPE cell death.

Histological evidence of MAPK pathway activation across subtypes of adult orbital xanthogranulomatous disease irrespective of the detection of oncogenic mutations.

Adult orbital xanthogranulomatous disease (AOXGD) is a spectrum of histiocytoses with four subtypes. Mitogen-activated protein kinase (MAPK) pathway mutations have been detected in various histiocytic neoplasms, little is known about this in AOXGD. Targeted regions of cancer- and histiocytosis-related genes were analyzed and immunohistochemical staining of phosphorylated ERK (pERK), cyclin D1 and PU.1 was performed in 28 AOXGD and 10 control xanthelasma biopsies to assess MAPK pathway activation. Mutations were detected in 7/28 (25%) patients. Positive staining for pERK and/or cyclin D1 was found across all subtypes in 17/27 (63%) patients of whom 12/17 (71%) did not harbour a mutation. Xanthelasma tissue stained negative for pERK and cyclin D1. Relapse occurred in 5/7 (71%) patients with a MAPK pathway mutation compared to 8/21 (38%) patients in whom no mutation could be detected. Molecular analysis and evaluation for systemic disease is warranted to identify patients at risk of recurrent xanthomatous disease.

Lack of Response to Intravitreal Ranibizumab Treatment in Adult Onset Foveomacular Vitelliform Dystrophy Complicated with Choroidal Neovascularization: A Case Report

Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a rare disease characterized by accumulation of yellowish deposits in the macula. Rarely, it may be complicated by choroidal neovascularization (CNV). Cases with CNV may be confused with occult CNV in age-related macular degeneration. In our case, we will present the visual and anatomical results of a patient with AOVF-related CNV, in which we administered 3 doses of intravitreal ranibizumab (IVR). A 59-year-old female patient, who attended our clinic with the complaint of decreased vision in both eyes, was diagnosed with AOVF-related CNV in both eyes and was treated with 3 doses of IVR for 3 months. Despite the improvement in visual and anatomical functions 1 month after the first dose, vision decreased, and anatomical functions regressed to the pre-injection state in continued injections. IVR therapy is not an appropriate treatment option in the treatment of AOVF-associated CNV.

Adult-Onset Still's Disease Following COVID-19 Infection in a Patient Receiving Nirmatrelvir/Ritonavir: A Case Report.

SARS-CoV-2 (COVID-19) has been associated with numerous complications, including autoimmune and autoinflammatory diseases. The surge of cytokines following COVID-19 infection or vaccination has been proposed to contribute to immune dysregulation, which might subsequently give rise to an autoinflammatory syndrome. Adult-onset Still's disease (AOSD) is one of the rare autoinflammatory diseases characterized by a surge of cytokines. Although an association between COVID-19 vaccines and AOSD has been reported, an association with COVID-19 infection or nirmatrelvir/ritonavir remains very rare. In this case, we present a patient who developed AOSD after COVID-19 infection and subsequent treatment with nirmatrelvir/ritonavir. After the initial response to glucocorticoids, canakinumab was initiated, resulting in positive clinical outcomes.

An Enigmatic Case of Adult-Onset Still's Disease.

An inflammatory condition known as adult-onset Still's disease (AOSD) is typified by quotidian (daily) fevers, arthritis, and a transient rash. This report details the case of a 21-year-old female patient who presented to our hospital with polyarthritis, a red rash, and a high-grade fever for more than three months. History was suggestive of AOSD, which was further proved by investigation and Yamaguchi criteria for AOSD. Steroids and methotrexate were started, to which the patient responded very well and thereafter.

The efficacy and safety of JAK inhibitors in patients with adult-onset still's disease: A meta-analysis and systematic review.

OBJECTIVE: To evaluate the efficacy and safety of Janus kinases inhibitors (JAKi) for adult-onset Still's disease (AOSD) patients. METHODS: We searched the Embase, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and the China National Knowledge Infrastructure (CNKI) from inception up to 22 October 2023. The results were supplemented by a backward search of relevant publications. Two authors independently selected trials. The available studies were comprehensively reviewed and analysed. RESULTS: A total of 9 studies with a total of 35 patients were included in the review. Of these patients, 17 (48.6%) patients were treated with tofacitinib, 14 (40%) with baricitinib, 4 (11.4%) with ruxolitinib and 1 (2.9%) with upadacitinib. After treatment with JAKi, 17 (48.6%) patients showed complete remission, 12 (34.3%) patients showed partial remission, and 7 (20%) patients showed loss of efficacy or relapse. The use of ruxolitinib showed a remission rate of 100% in AOSD patients with macrophage activation syndrome (MAS). The incidence of adverse events (AEs) reported were mild and rare overall. Most AEs were abnormal lipid parameters (9.7%), bacterial pneumonia (3.2%), organised pneumonia (3.2%), diarrhoea (3.2%), increased heart rate (3.2%), menometrorrhagia (3.2%) and leukopenia (3.2%). One patient died from bacterial pneumonia. CONCLUSION: JAKi therapy may be an option for patients with AOSD, especially for refractory AOSD. For patients with AOSD complicated by MAS, ruxolitinib seems to be a better choice than other JAKi agents. Although our study shows that JAKi are well tolerated in AOSD patients, we still need to be on the lookout for fatal infections.

Integrative molecular and structural neuroimaging analyses of the interaction between depression and age of onset: A multimodal magnetic resonance imaging study.

Depression is a neurodevelopmental disorder that exhibits progressive gray matter volume (GMV) atrophy. Research indicates that brain development is influential in depression-induced GMV alterations. However, the interaction between depression and age of onset is not well understood by the underlying molecular and neuropathological mechanisms. Thus, 152 first-episode depression individuals and matched 130 healthy controls (HCs) were recruited to undergo T1-weighted high-resolution magnetic resonance imaging for this study. By two-way ANOVA, age and diagnosis were used as factors when analyzing the interaction of GMV in the participants. Then, spatial correlations between neurotransmitter maps and factor-related volume maps are established. Results illustrate a pronounced antagonistic interaction between depression and age of onset in the right insula, superior temporal gyrus, anterior cingulate gyrus, and orbitofrontal gyrus. Depression-caused reductions in GMV are mainly distributed in thalamic-limbic-cortical regions, regardless of age. For the main effect of age, adults exhibit brain atrophy in frontal, cerebellum, parietal, and temporal lobe structures. Cross-modal correlations showed that GMV changes in the interactive regions were linked with the serotonergic system and dopaminergic systems. Summarily, our results reveal the interaction between depression and age of onset in neurobiological mechanisms, which provide hints for future treatment of different ages of depression.

Managing adult-onset Still's disease in pregnancy: A case report.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder characterized by fever, arthritis, skin rash, and systemic symptoms. The etiology of AOSD is unknown; however, it is thought to be related to immune dysregulation. Although a rare disease, AOSD can significantly impact reproductive health, particularly during pregnancy. This case study assesses the implications of pregnancy in a patient with AOSD, as well as the potential for heredity of the disease. Neonatal hemophagocytic lympho-histiocytosis (HLH) is a rare and life-threatening disorder characterized by hyperinflammation and uncontrolled activation of immune cells, leading to multiple organ dysfunction. This case report aimed to introduce neonatal HLH from a mother with AOSD. CASE SUMMARY: This case study presents a 29-year-old female with AOSD who became pregnant and gave birth to a premature infant who was diagnosed with neonatal HLH. AOSD can significantly impact pregnancy and childbirth, as it may become more severe during pregnancy, with an increased risk of fetal loss and preterm birth. The management of AOSD during pregnancy involves the use of nonsteroidal anti-inflammatory drugs and glucocorticoids, as well as immunosuppressive agents in severe cases. However, the use of immunosuppressive agents during pregnancy may be associated with potential risks to the fetus. The hereditary implications of AOSD are unclear; however, available evidence suggests that genetic factors may play a role in the disease development. CONCLUSION: AOSD can have significant implications for pregnancy and childbirth, including an increased risk of fetal loss and preterm birth. Neonatal HLH, a complication of AOSD in pregnancy, requires prompt diagnosis and management. Women with AOSD who are considering pregnancy should discuss their options with their healthcare provider and develop a management plan that addresses the potential risks to both mother and fetus.

Adult-onset of mild encephalitis/encephalopathy with reversible splenial lesion (MERS): case report and systematic review.

BACKGROUND: Mild encephalitis/encephalopathy with reversible splenial lesion (MERS) is a clinical-radiological syndrome characterized by transient central nervous system symptoms and a reversible lesion in the splenium of the corpus callosum (SCC) on magnetic resonance (MR). We reported a case of adult-onset MERS with uncommon presentation and reviewed the existing literature. METHODS: We described a case of adult-onset MERS with uncommon symptoms and signs and performed a systematic review of case series including more than four patients of adult-onset (> 14 years old) MERS, from January 2000 to December 2022. We summarized the clinical, laboratory, imaging and therapy data. RESULTS: We included seven eligible studies for a total of 51 adult-onset MERS patients. Neurological manifestations were preceded by prodromal symptoms in most of the patients (88%), mainly with fever (78%). Headache was the most common symptom (50%), followed by seizures (22%) and disturbance of consciousness (22%). Inflammatory changes on cerebrospinal fluid were present in a half of patient, so defining encephalitis cases. Clinal recovery, was achieved in all patients but two with severe disturbance of consciousness who required ventilator support in the acute phase. MR showed isolated lesion in the SCC in 92% of patients, while 8% of patients showed also extracallosal lesions, all the lesions resolved or improved on follow-up imaging. CONCLUSIONS: MERS is a form of encephalitis/encephalopathy with a broad range of central nervous system manifestation, often with mild symptoms, such as headache alone, that can lead to overlooked some cases, with an excellent prognosis in most patient.

Late-Onset Leigh Syndrome With Protracted Gastrointestinal Manifestations: A Rare Case Report.

Although Leigh syndrome (LS) is a neurodegenerative disorder of infancy, adult-onset LS has also been rarely reported. We report a case of late-onset LS in a 42-year-old female who presented with protracted gastrointestinal manifestations, chronic headaches, ataxia, and loss of consciousness. Brain magnetic resonance imaging (MRI) revealed hyperintensities in the bilateral basal ganglia and brain stem. Serum and cerebrospinal fluid lactate levels were significantly raised. Muscle biopsy showed reduced cytochrome oxidase (COX) activity. She was diagnosed with probable diagnosis of late-onset LS based on her clinical features, radiological findings, biochemical results, and biopsy findings. She responded well to intravenous thiamine, and her symptoms gradually improved.

Not All Fevers Equal Infection: A Challenging Case of Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) stands as a perplexing condition with diverse clinical manifestations, posing significant diagnostic challenges for healthcare professionals. This case report delves into the clinical trajectory, diagnostic challenges, treatment strategies, and outcomes experienced by a 67-year-old female with AOSD. This report advocates for considering AOSD as a potential diagnosis in patients presenting with systemic inflammatory symptoms, especially when other conditions have been ruled out. It highlights the complexity of AOSD and the importance of interdisciplinary collaboration, close monitoring, and personalized treatment strategies to optimize patient outcomes.

Erythroderma in Adult-Onset Still's Disease Alleviated After Tocilizumab Therapy: A Case Report.

Erythroderma, also known as exfoliative dermatitis, is a rarely reported atypical cutaneous manifestation of adult-onset Still's disease (AOSD). We present the case of erythroderma in association with AOSD that was steroid dependent and responded to tocilizumab therapy. Skin rash, pruritis, and related laboratory findings were significantly improved upon the addition of tocilizumab, while prednisolone was successfully tapered to an ever-lowest maintenance level. To our knowledge, this is the first to report the sole therapeutic effect of tocilizumab in erythroderma related to AOSD.

Multiorgan Dysfunction in a Patient With Adult-Onset Still's Disease Flare: A Case Report.

Adult-onset Still's disease (AOSD) is a rare multisystem inflammatory disorder. A 71-year-old lady who was on treatment for AOSD presented with clinical evidence of heart failure and was subsequently found to have impaired renal and hepatic function. Following extensive workup including a liver biopsy, the cause of liver dysfunction was determined to be congestive hepatopathy, while renal dysfunction was presumed to stem from the low output state. The etiology of myocardial dysfunction, driving liver and kidney injury, was considered to be myocarditis from AOSD or global myocardial dysfunction from a systemic inflammatory state. Management involved pulse-dose glucocorticoids followed by taper and anakinra for AOSD, alongside goal-directed medical therapy for cardiac failure. At follow-up after a month, hepatic and renal function had fully recovered, whereas cardiac function remained compromised, evidenced by persistently depressed ejection fraction and global hypokinesia on a repeat echocardiogram. This report delineates a systematic approach to multiorgan dysfunction in a patient with a rare condition such as AOSD and reviews the reported causes of hepatic and cardiac involvement in AOSD.

Variation in clinical presentation of pediatric-onset and adult-onset atopic dermatitis: a retrospective, single-center, chart review of adults with atopic dermatitis from the United States.

Atopic dermatitis (AD) is a chronic skin condition that can manifest in childhood and persist into adulthood or can present de novo in adults. The clinical presentation of adults with AD may differ among those with pediatric-onset versus adult-onset disease and potential differences between both groups remain to be better characterized. These atypical features might not be encompassed as part of current diagnostic criteria for AD, such as the Hanifin-Rajka (H-R) and the U.K. Working Party (UKWP) criteria. We conducted a retrospective chart review of the electronic medical records of a large, single, academic center to compare the clinical characteristics between adult-onset and pediatric onset AD and examine the proportion of patients who meet the H-R and/or UKWP criteria. Our single-center retrospective chart review included adults (≥ 18 years of age) with any AD-related ICD-10 codes, ≥ 2 AD-related visits, and a recorded physician-confirmed AD diagnosis. Descriptive statistics were used to compare adults with pediatric-onset (< 18 years of age) and adult-onset (≥ 18 years of age) AD. Logistic regression and x2 test were used to compare groups. We found that, compared to pediatric-onset AD, adults with adult-onset AD had less flexural involvement, flexural lichenification and a personal and family history of other atopic diseases. Compared to adults with pediatric-onset AD, adults with adult-onset AD had greater involvement of the extensor surfaces and more nummular eczema compared to pediatric-onset AD. In our cohort, adults with adult-onset AD were less likely to meet H-R and UKWP criteria compared to pediatric-onset AD. Adults with adult-onset AD may present with a clinical presentation that is different from those with pediatric-onset AD, which may not be completely captured by current AD criteria such as the H-R and UWKP criteria. This can lead to possibly mis- or underdiagnosing AD in adults. Thus, understanding the differences and working towards modifying criteria for adult-onset AD has the potential to improve accurate diagnosis of adults with AD.