Neurological manifestations in thrombotic microangiopathy: Imaging features, risk factors and clinical course.

BACKGROUND AND PURPOSE: Thrombotic microangiopathy (TMA) is a group of microvascular occlusive disorders that presents with neurological involvement in up to 87% of the cases. Although the central nervous system (CNS) is an important target organ in TMA, the role of neurological manifestations in the disease clinical course is not well established. In this study, we described the neurological manifestations and CNS radiological aspects in patients with a first, acute TMA event. We also examined the association between severe neurological involvement and adverse clinical outcomes in TMA. METHODS: A cohort of patients diagnosed with a first TMA event between 1995 and 2016 was included, their medical charts and imaging tests were retrospectively evaluated. RESULTS: A total of 49 patients were included, 85.7% were women and the mean age was 36.5 years-old (SD 13.0). Neurological manifestations were described in 85.7% of the patients, most of them (88%) were considered severe and consisted of confusion, compromised sensorimotor function, stupor, seizures, and personality change. Imaging tests were performed in 62% of the patients with neurological manifestations and detected acute CNS lesions, such as posterior reversible encephalopathy syndrome, hemorrhagic and ischemic stroke were observed, in 7 (27%) of them. While the need for intensive care unit admission was greater and longer among patients with severe neurological manifestations, the number of plasma exchange sessions, the total duration of hospitalization and in-hospital death were similar between groups. CONCLUSIONS: Severe neurological manifestations are common in first TMA events and are responsible for a worse disease presentation at admission. While the effect of neurological manifestations on acute TMA clinical course seems to be modest, these manifestations may have an important impact on the development of chronic cognitive impairment, which highlights the need for proper diagnosis and treatment.

Pathologic Correlation with Renal Dysfunction after Intravitreal Injections of Vascular Endothelial Growth Factor Antagonists.

OBJECTIVE: Vascular endothelial growth factor (VEGF) antagonists have been used for treating metastatic neoplasms. It has also been known that one of its side effects is to cause proteinuria and renal failure in the setting of thrombotic microangiopathy (TMA). The underlying mechanism is likely due to the inhibition of VEGF production in podocytes, resulting in diffuse fusion of foot processes and impaired glomerular endothelial fenestrations, and leading to massive proteinuria and subsequent glomerular endothelium injury. Intravitreal injection of VEGF antagonists (IIVA) has been also used to treat macular degeneration and diabetic retinal neo-vascular proliferation. The majority of patients tolerate the treatment well. However, IIVA can lead to renal dysfunction including proteinuria and gradual renal failure as a rare side effect. The goal of this study was to report two cases related to the nephrotoxicity of IIVA and review the literature associated with this topic. CASE REPORT: The first diabetic patient had elevated serum creatinine at 3.25 mg/dl and proteinuria/creatinine ratio at 6.1 after 48-month treatment of IIVA. The first renal biopsy revealed thrombotic microangiopathy that was correlated with his increased serum creatinine and nephrotic range of proteinuria. The second diabetic patient had increased serum creatinine up to 1.89 mg/dl but low proteinuria. The second biopsy showed acute tubular necrosis that was correlated with his elevated serum creatinine. CONCLUSION: Intravitreal injection of VEGF antagonist can be associated with thrombotic microangiopathy and acute tubular necrosis, leading to renal dysfunction.

Ischemic-hemorrhagic stroke in patients with Covid-19. / Afectación cerebrovascular isquémico-hemorrágica en pacientes con covid-19.

Coronavirus associated severe acute respiratory syndrome (SARS-CoV-2) causes a worldwide syndrome called Covid-19 that has caused 5,940,441 infections and 362,813 deaths until May 2020. In moderate and severe stages of the infection a generalized swelling, cytokine storm and an increment of the heart damage biomarkers occur. In addition, a relation between Covid-19 and neurological symptoms have been suggested. The results of autopsies suggest thrombotic microangiopathy in multiple organs. We present 2 cases of patients infected with severe Covid-19 that were hospitalized in the Reanimation Unit that presented cerebrovascular symptoms and died afterwards. A high dose prophylaxis with antithrombotic medication is recommended in patients affected by moderate to severe Covid-19.

Multisystem Imaging Manifestations of COVID-19, Part 1: Viral Pathogenesis and Pulmonary and Vascular System Complications.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in coronavirus disease 2019 (COVID-19), which was declared an official pandemic by the World Health Organization on March 11, 2020. The infection has been reported in most countries around the world. As of August 2020, there have been over 21 million cases of COVID-19 reported worldwide, with over 800 000 COVID-19-associated deaths. It has become apparent that although COVID-19 predominantly affects the respiratory system, many other organ systems can also be involved. Imaging plays an essential role in the diagnosis of all manifestations of the disease, as well as its related complications, and proper utilization and interpretation of imaging examinations is crucial. With the growing global COVID-19 outbreak, a comprehensive understanding of the diagnostic imaging hallmarks, imaging features, multisystemic involvement, and evolution of imaging findings is essential for effective patient management and treatment. To date, only a few articles have been published that comprehensively describe the multisystemic imaging manifestations of COVID-19. The authors provide an inclusive system-by-system image-based review of this life-threatening and rapidly spreading infection. In part 1 of this article, the authors discuss general aspects of the disease, with an emphasis on virology, the pathophysiology of the virus, and clinical presentation of the disease. The key imaging features of the varied pathologic manifestations of this infection that involve the pulmonary and peripheral and central vascular systems are also described. Part 2 will focus on key imaging features of COVID-19 that involve the cardiac, neurologic, abdominal, dermatologic and ocular, and musculoskeletal systems, as well as pediatric and pregnancy-related manifestations of the virus. Vascular complications pertinent to each system will be also be discussed in part 2. Online supplemental material is available for this article. ©RSNA, 2020.

[Pulmonary Tumor Thrombotic Microangiopathy in a Patient with Metastatic Gastric Cancer]. / Pulmonale tumorthrombotische Mikroangiopathie bei einer Patientin mit metastasierendem Magenkarzinom.

HISTORY AND CLINICAL FINDINGS: A 53-year-old woman with relapsed metastatic gastric cancer after multimodal therapy was hospitalized 6 months after the end of treatment due to acute dyspnea. INVESTIGATIONS AND DIAGNOSIS: The examination showed tachycardia and tachypnea. D-dimers and LDH were elevated, blood gases were still in the standard range. In the CT we could exclude a pulmonary embolism (LE) and pneumonia. The echocardiography (EC) showed no abnormalities. A new malignant pleural effusion on the left was detected. DIAGNOSIS: The diagnosis of pulmonary tumor thrombotic microangiopathy (PTTM) in the context of relapsed metastatic gastric cancer was confirmed. TREATMENT AND COURSE: The patient developed progressive respiratory failure and had to be moved to the intensive care unit. In the EC we discovered a progressive right ventricular heart failure. With the suspicion of a severe LE and vital indication we started a thrombolysis, but it remained unsuccessful. The CT showed changes consistent with a PTTM. The patient died a few days later. CONCLUSION: PTTM is a rare and often fatal tumor-associated pulmonary complication.

Pulmonary Tumor Thrombotic Microangiopathy due to Advanced Gastric Cancer with Virchow's Node Metastasis.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related complication characterized by severe progressive pulmonary hypertension. Antemortem diagnosis is difficult owing to the rapid progression of the condition, especially when the patient has no known malignancies and initially presents with pulmonary hypertension. Here we report a case of PTTM due to occult gastric cancer with metastasis in the left supraclavicular lymph node, also known as Virchow's node. Enlarged Virchow's node is an important indicator of advanced gastric cancer. In patients with progressive pulmonary hypertension of unknown origin, enlarged Virchow's node can be an important indicator for the diagnosis of PTTM.

Pulmonary tumor thrombotic microangiopathy successfully treated with corticosteroids: a case report.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy is a special type of tumor thromboembolism. We report the case of a patient who developed pulmonary tumor thrombotic microangiopathy with alveolar hemorrhage. Almost all patients with pulmonary tumor thrombotic microangiopathy die within 1 week of the onset of dyspnea; however, the prognosis in this case was better, with 10 weeks of survival from presentation. CASE PRESENTATION: A 62-year-old Japanese man was referred to our hospital with a 4-week history of dyspnea on exertion and severe pulmonary hypertension. Five years previously, he had undergone distal gastrectomy for gastric cancer. He was afebrile, normotensive, and hypoxemic. A physical examination was unremarkable except for purpura on his upper extremities and trunk. Blood tests showed anemia and disseminated intravascular coagulation. Chest computed tomography revealed diffuse ground-glass opacities with emphysema in his upper lungs, moderate pleural effusions, mediastinal lymphadenopathy, and enlargement of the right ventricle and main pulmonary artery. A computed tomography pulmonary angiogram showed no evidence of pulmonary embolism. Lung perfusion scintigraphy showed multiple segmental defects. Although recurrence of gastric cancer was confirmed from the results of bone marrow biopsy, bronchoscopy was not performed due to bleeding diathesis. He was treated with corticosteroids, antibiotics, and platelet transfusion, following which resolution of the abnormal lung shadows and right ventricular pressure overload along with partial alleviation of respiratory failure was observed. Because of his poor performance status, he was eventually transited to palliative care and died 6 weeks after admission. Necropsy of the lung confirmed the diagnosis of pulmonary tumor thrombotic microangiopathy with alveolar hemorrhage. CONCLUSIONS: Pulmonary tumor thrombotic microangiopathy should be considered in the differential diagnosis of patients with cancer who present with severe pulmonary hypertension. In pulmonary tumor thrombotic microangiopathy, local inflammation in pulmonary microvasculature may contribute to pulmonary hypertension, and regulation of inflammation using corticosteroids may help improve the prognosis.

A 49-Year-Old Man with Subacute Respiratory Failure and Interstitial Lung Opacities.

BACKGROUND Pulmonary arterial hypertension (PAH) results from proliferative vasculopathy involving all layers of the blood vessel. Similar findings may be present in pulmonary hypertension (PH) associated with microscopic tumor embolism, which are thought to be related to the phenomenon of pulmonary tumor thrombotic microangiopathy (PTTM). PTTM is associated with the activation of the coagulation system at the surface of the tumor emboli, resulting in stenosis or occlusion of the vessel. CASE REPORT A 49-year-old man with stage IV gastro-esophageal junction adenocarcinoma presented with complaints of cough and shortness of breath. These symptoms coincided with the initiation of trastuzumab with a new experimental medication with receptor tyrosine kinase blocking activity. A trans-thoracic echocardiogram demonstrated severely increased right ventricle (RV) cavity size with severely decreased RV systolic function. A computed tomography angiography was negative for pulmonary embolism but demonstrated new bilateral pulmonary infiltrates. Bronchoalveolar lavage ruled out an infectious etiology. Trans-bronchial biopsies (TBBx) showed arteriole obliteration by smooth muscle proliferation suggestive of pulmonary vasculopathy. The right heart catheterization (RHC) confirmed severe pulmonary hypertension. Unfortunately, shortly after the RHC, the patient developed pulseless electrical activity cardiac arrest and died. Autopsy results were similar to those of the TBBx, except for diffuse dissemination of tumor cells in the lymphatic channels and small pulmonary vessels, confirming a diagnosis of PTTM. CONCLUSIONS We highlight the limitations of trans-bronchial biopsies in evaluating PTTM. The final diagnosis of PTTM was not made until the autopsy was done.

A Case of the nephrotic syndrome in bone marrow transplantation recipient, histologically showing overlapped glomerular lesions of thrombotic microangiopathy and membranous nephropathy.

Nephrotic syndrome (NS) rarely occurs in post-hematopoietic stem cell transplantation (HSCT) recipients but represents the renal manifestation of graft-versus-host disease (GVHD). Membranous nephropathy (MN) accounts for almost two thirds of post-HSCT NS and is caused by immune complex deposition. Renal thrombotic microangiopathy (TMA) without fulfillment of clinical criteria for TMA has been underreported because of reduced opportunity for histological examination. However, renal TMA has recently been reported in association with GVHD and humoral immunological reactions. Although both MN and TMA after HSCT are associated with GVHD and immunological abnormalities, these diseases are exceptionally coexistent in renal biopsy specimens. We herein describe a case of post-HSCT NS, histologically showing overlapped lesions of TMA and MN. Renal biopsy specimen after presentation of NS revealed early stage MN and TMA with evidence of chronicity. TMA was thought to have preceded MN, and renal biopsy at the phase of pre-nephrotic proteinuria might reveal earlier histological changes of isolated renal TMA. Detection of subclinical renal TMA earlier by spontaneous renal biopsy can help prevent progression of renal injury or overlapping of other renal pathologies. We also demonstrated Th2 predominant intraglomerular infiltration of lymphocytes by immunohistochemistry.

[A Case of Pulmonary Tumor Thrombotic Microangiopathy in Castration-Resistant Prostate Cancer].

A man aged 83 years under treatment with enzalutamide for castration-resistant prostate cancer presented with general malaise and exertional dyspnea. The underlying cause could not be identified by further investigations. On the 5th hospital day, he died due to a sudden exacerbation of dyspnea. The results of an autopsy indicated tumor emboli and stenosis of small pulmonary arteries with the fibrocellular intimal thickening, and therefore our final diagnosis was pulmonary tumor thrombotic microangiopathy.

Susceptibility Etching on MRI in Patients with Microangiopathy.

BACKGROUND: We detected a novel imaging sign, which consists of a specific imaging pattern of diffuse susceptibility effect, delineating the cortical-subcortical junction on high-resolution susceptibility-weighted images (SWIs). We describe magnetic resonance imaging findings in 10 patients with "susceptibility etching" and possible association with their abnormal coagulation profile. MATERIALS/METHODS: A retrospective case series study with a search for cases that demonstrated susceptibility effect at the cortical-subcortical junction on SWI sequences was performed. The patients' respective coagulation profiles including prothrombin time, partial thromboplastin time, fibrinogen, D-dimer values, and platelet counts were reviewed. In addition, clinical history and neurological deficits were recorded. RESULTS: We identified 10 patients with the "susceptibility etching" pattern at the cortical-subcortical junction. All patients were acutely ill and had a significantly elevated D-dimer (4,309 mcg/L to >10,000 mcg/L) with variably reduced platelet count. Two patients had reduced fibrinogen and 5 patients had prolonged international normalized ratio. Of the 10 patients, 4 died during hospitalization, within a few days of imaging. Pathology of 1 patient at autopsy demonstrated findings suggestive of a microvascular thrombotic or embolic event without overt parenchymal microhemorrhage. CONCLUSION: In this preliminary case series, we describe patients with "susceptibility etching" on SWI who were also found to have profound coagulation impairment. While other comorbities may also contribute to this novel sign, we suggest that a possible etiology may be secondary to microvascular in situ formation of fine thrombi and/or emboli lodged into an area of vascular caliber reduction and maybe related to thrombotic microangiopathy.

Favorable outcome of interferon-beta associated thrombotic microangiopathy following treatment with corticosteroids, plasma exchange and rituximab: A case report.

Thrombotic microangiopathy (TMA) is a rare but increasingly recognized complication of interferon-beta therapy, which can be associated with serious sequelae. We report on a 53-year-old woman with a longstanding history of relapsing-remitting multiple sclerosis, who developed TMA after 15 years of high-dose treatment with subcutaneous interferon-beta-1a. The patient presented with headaches, an epileptic seizure, confusion, and arterial hypertension. Laboratory findings included thrombocytopenia and hemolytic anemia. Despite of severe clinical manifestations and pronounced laboratory abnormalities, therapy with corticosteroids, plasma exchange and rituximab was associated with a favorable outcome and return to her premorbid level of functioning.

Antemortem diagnosis of pulmonary tumor thrombotic microangiopathy in a patient with recurrent breast cancer: a case report.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM), a rare complication of advanced cancer, is histologically characterized by tumor embolisms and fibrocellular intimal proliferation of small pulmonary arteries and arterioles. PTTM usually has an extremely poor prognosis, and antemortem diagnosis is very difficult. CASE PRESENTATION: A 65-year-old woman with a 5-year history of clinical stage IIA (T2N0M0) invasive ductal carcinoma of the left breast was hospitalized for worsening shortness of breath, hemoptysis, and cough since 2 months. She had previously received neoadjuvant chemotherapy and left mastectomy. Because the cancer cells were positive for human epidermal growth factor receptor 2 (HER2), four cycles of trastuzumab had been administered as adjuvant chemotherapy. On admission, chest computed tomography (CT) showed peripheral consolidations in both the lower lobes and a mediastinal mass. Specimens obtained on video-assisted thoracoscopic surgical biopsy revealed tumor cell embolism, intimal fibrocellular proliferation of small arteries, fibrin thrombi, recanalization, and infarction in the left lower lobe, as well as metastasis to the mediastinal pleura. Immunohistochemical staining of the tumor cells revealed positivity for HER2, and a diagnosis of recurrent breast cancer with PTTM was made. Four cycles of trastuzumab resulted in rapid improvement of her symptoms and CT findings of peripheral consolidations and the mediastinal mass. CONCLUSION: An antemortem diagnosis of PTTM was made in a patient with HER2-positive recurrent breast cancer. Trastuzumab was effective for not only breast cancer but also PTTM.