Category: Published Articles

Adenocarcinoma and Pulmonary Tumor Thrombotic Microangiopathy.

By Emin Gayibov
Amin H. Karim MD

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A Rapid Review of Adenocarcinoma and Pulmonary Tumor Thrombotic Microangiopathy: A Deadly Duo

Emin Gayibov • Amin H. Karim

Published: January 03, 2025 DOI: 10.7759/cureus.76842 

Peer-Reviewed

Cite this article as: Gayibov E, Karim A H (January 03, 2025) A Rapid Review of Adenocarcinoma and Pulmonary Tumor Thrombotic Microangiopathy: A Deadly Duo. Cureus 17(1): e76842. doi:10.7759/cureus.76842

Abstract

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare paraneoplastic syndrome associated with various adenocarcinomas, most commonly gastric adenocarcinoma. This condition can progressively worsen pulmonary arterial hypertension, leading to acute or subacute pulmonary heart failure and respiratory insufficiency. This paper examines the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis of PTTM. Given PTTM’s poor prognosis, we emphasize treatment strategies. PTTM in adenocarcinoma patients can mimic other pulmonary diseases, causing diagnostic delays. Current PTTM treatment strategies primarily focus on managing the underlying malignancy and addressing thrombotic complications. Anti-angiogenic therapy with bevacizumab and the platelet-derived growth factor receptor antagonist imatinib have shown promise in multiple cases. Further research is needed to develop more effective and targeted therapies for this challenging condition. The precise mechanisms underlying this association remain to be fully elucidated.

Introduction & Background

Paraneoplastic syndromes constitute a diverse group of clinical disorders associated with malignant diseases that can significantly impact patient morbidity and mortality. They are not directly attributable to the physical effects of the primary or metastatic tumor [1]. In these syndromes, malignant cells do not directly cause symptoms related to metastasis; rather, they induce the generation of autoantibodies, cytokines, hormones, or peptides that exert effects on multiple organ systems [2]. It is estimated that paraneoplastic syndromes affect up to 8% of patients with cancer [3]. Table 1 provides a concise overview of commonly encountered paraneoplastic syndromes [4-23].

Organ systemParaneoplastic syndromeMost associated cancer typeClinical signs
NeurologicalParaneoplastic encephalitisSCLC, testicular cancerCognitive dysfunction, seizures, personality changes, hallucinations, autonomic dysfunction
Subacute cerebellar degenerationBreast, ovarian, SCLC, Hodgkin lymphomaAtaxia, dysarthria, dizziness, diplopia, nausea, vomiting
Opsoclonus-myoclonus syndromeNeuroblastoma (children), SCLC (adults)Rapid eye movements, body jerks, ataxia, hypotonia
Myasthenia gravisThymomaMuscle weakness, ptosis, diplopia, diaphragmatic weakness
Lambert-Eaton myasthenic syndromeSCLCProximal muscle weakness, autonomic dysfunction, diminished reflexes
Autonomic neuropathySCLC, thymomaDry mouth, altered pupillary reflexes, orthostatic hypotension, GI dysfunction
Subacute sensory neuropathySCLCParesthesia, neuropathic pain, diminished sensation
EndocrineCushing syndromeSCLC, pancreatic cancerHypertension, centripetal obesity, hypokalemia, edema
SIADHSCLCHyponatremia, lethargy, confusion, seizures
HypercalcemiaLung, renal cell, multiple myelomaLethargy, nausea, bradycardia, short QT interval on ECG
Non-islet tumor hypoglycemiaFibrosarcoma, hepatocellular carcinomaHypoglycemia, confusion, seizures
Carcinoid syndromeBronchial carcinoid, pancreatic carcinomaFlushing, diarrhea, bronchospasm
HyperaldosteronismAdrenal adenoma, non-Hodgkin lymphomaHypertension, hypokalemia
RheumatologicalParaneoplastic polyarthritisVarious malignanciesMigratory, asymmetric arthritis
Polymyalgia rheumaticaMyelodysplastic syndromePain and stiffness in shoulders, neck, and hips
Hypertrophic osteoarthropathyLung cancerDigital clubbing, joint swelling, periostitis
Multicentric reticulohistiocytosisVarious malignanciesPapules, nodules, destructive polyarthritis
HematologicalPolycythemiaRenal cell carcinoma, cerebellar hemangiomaIncreased hemoglobin, pallor, fatigue
Trousseau syndrome (migratory thrombophlebitis)Pancreatic, Bronchogenic carcinomaPainful migratory thrombophlebitis
DermatologicalAcanthosis nigricansGastric adenocarcinomaHyperpigmented, velvety plaques in axilla, neck
Paraneoplastic pemphigusB-cell lymphoproliferative disordersBlisters, mucosal erosions
Sweet syndromeHematological malignanciesPainful, erythematous plaques with fever
DermatomyositisOvarian, lung, pancreatic cancerHeliotrope rash, Gottron papules, proximal muscle weakness
RenalNephrotic syndromeVarious tumorsProteinuria, edema, fluid overload
Electrolyte imbalancesSCLC, thymomaHyponatremia, hyperphosphatemia, acid-base disturbances
PulmonaryPulmonary tumor thrombotic microangiopathyVarious adenocarcinomasMicrovascular thrombosis, endothelial injury, and severe pulmonary arterial hypertension
Lymphangitic carcinomatosisVarious adenocarcinomasProgressive dyspnea, cough, and hypoxemia
Pulmonary alveolar proteinosisLeukemia, lymphomaProgressive respiratory insufficiency
Table 1: A concise overview of paraneoplastic syndromes including pulmonary tumor thrombotic microangiopathy

Source: [4-23]

SCLC, small cell lung carcinoma; SIADH, syndrome of inappropriate antidiuretic hormone secretion

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare and often underrecognized paraneoplastic syndrome associated with various adenocarcinomas, often linked to gastric adenocarcinoma [24]. Although less frequently observed, breast, lung, and urothelial malignancies have also been linked to PTTM [25]. Post-mortem examinations of carcinoma patients indicate a PTTM prevalence ranging from 1.4% to 3.3% [24,26]. This condition can lead to a progressive deterioration of pulmonary arterial hypertension (PAH), culminating in acute or subacute pulmonary heart failure and respiratory insufficiency. Hence, early recognition and treatment are crucial to prevent irreversible lung damage and complications. First described by von Herbay et al. in 1990 [26], PTTM is characterized by the presence of numerous tumor emboli within the pulmonary microvasculature, leading to microvascular thrombosis and endothelial injury. Later studies have highlighted the critical role of tumor-derived factors in driving hypercoagulability and angiogenesis, as explained in the pathogenesis section.

In this paper, we will examine the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis of PTTM in patients with adenocarcinoma of various origins. Given the poor prognosis associated with PTTM, we will place particular emphasis on treatment strategies. We will discuss the approaches taken in different cases in recent years to inform current best practices, including their limitations and potential avenues for improvement. This rapid review will delve into the current understanding of this rare paraneoplastic syndrome and its potential clinical implications. By reviewing the available literature, we aim to shed light on the pathophysiology, clinical manifestations, diagnostic challenges, and therapeutic options for PTTM.

Review

Methodology

All the studies referred for this rapid review have been searched via the National Library of Medicine (NIH), PubMed, with the free-text keywords “pulmonary tumor thrombotic microangiopathy (PTTM)”, “PTTM AND adenocarcinoma”, “pathogenesis AND PTTM”, “clinical presentation AND PTTM”, “diagnosis AND PTTM”, “treatment AND PTTM”, and “prognosis AND PTTM”. A visual tool Connected Papers [27] and reference manager software Mendeley [28] served for proper citation and access to the studies regarding the abovementioned aspects of PTTM. For this rapid review, we did not specify the time range of studies referred due to insufficiency in number. Our inclusion criteria comprised type I tumor embolism, which is the “classic” or “true” type originating from a distant primary tumor via hematologic seeding with no invasion into vessel walls. Among type I tumor embolism studies, we included ones that specifically focused on the PTTM, either antemortem or postmortem, as a confirmed diagnosis. We disregarded the studies involving type II tumor embolism, which results from a tumor growing into the pulmonary arteries with invasion into vessel walls. The search strategy is summarized in Table 2.

ItemsSpecification
Date of search1 October 2024 to 17 November 2024
Databases and other sources searchedNational Library of Medicine, PubMed
Search terms used“pulmonary tumor thrombotic microangiopathy (PTTM)”, “PTTM AND adenocarcinoma”, “pathogenesis AND PTTM”, “clinical presentation AND PTTM”, “diagnosis AND PTTM”, “treatment AND PTTM”, and “prognosis AND PTTM”
TimeframeNo specific timeframe
Inclusion and exclusion criteriaCase reports and reviews were included if they specifically focused on PTTM as type I tumor embolism, the “classic” or “true” type originating from a distant primary tumor via hematologic seeding without vessel wall invasion. Studies involving type II tumor embolism, resulting from a tumor growing into the pulmonary arteries with vessel wall invasion, and mixed embolism were excluded
Selection processA total of 164 studies were initially identified, of which 55 were ultimately included Author E.G. conducted the literature selection. A.K. supervised the search strategy.
Any additional considerationsConnected Papers [27] and Mendeley [28] served for proper citation and access to the studies
Table 2: Summary of the search strategy for this rapid review

Pathogenesis of pulmonary tumor thrombotic microangiopathy

Associated with mucin-secreting adenocarcinomas, PTTM is a specific type of pulmonary tumor embolism. It is classified within type I tumor embolism, the “classic” or “true” type originating from a distant primary tumor via hematologic seeding without vessel wall invasion [29,30]. In contrast, type II tumor embolism arises from a tumor growing into the pulmonary arteries with invasion into vessel walls [31]. In terms of histopathology, PTTM is characterized by fibrocellular intimal proliferation of small and medium pulmonary arteries and arterioles with the presence of tumor emboli [26,32]. This distinctive feature can be observed using various histological staining techniques, such as Verhoeff-Van Gieson and alpha-smooth muscle actin immunohistochemistry [33,34]. Fibrocellular intimal proliferation involves the growth of cells, primarily smooth muscle cells and fibroblasts, and extracellular matrix within the intima of small pulmonary arteries and arterioles. This leads to narrowing of the vessel lumen. Reactive fibrointimal thickening and occlusion were also revealed in the pulmonary lymphatic vessels and veins in a particular PTTM case [35]. It has also been reported that PTTM is frequently associated with lymphangiosis carcinomatosa, a serious condition that occurs when cancer cells spread to the lymph vessels, causing inflammation and blockage and becoming a predisposing factor to PTTM [26,36]. In PTTM, multiple microscopic tumor cells become stuck to the inner lining of small pulmonary blood vessels. This triggers an inflammatory response, causing the vessel walls to thicken and narrow. Additionally, blood clots form within these vessels, further restricting blood flow. As a result, the lung’s blood vessel network becomes severely compromised, leading to PAH [37,38].

In PTTM, tumor cells not only physically obstruct blood vessels but also release tissue factor (TF), which activates the blood clotting system. They also release inflammatory mediators that promote inflammation and growth factors that stimulate the growth of vessel tissue. This excessive growth can lead to a thickening of the vessel walls, narrowing the blood passage and further hindering the blood flow. Platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) produced by tumor cells, and versican (VCAN), an extracellular matrix proteoglycan, are considered to be the important factors involved in pulmonary vascular remodeling seen in PTTM [39-41]. Growth factors, particularly transforming growth factor-β (TGF-β), stimulate the expression of VCAN. VCAN binds to growth factors and other extracellular matrix components, creating a local reservoir for these factors [42]. Furthermore, VCAN-hyaluronan aggregates occur in various human lung diseases, including PAH, and provide a permissive environment for arterial smooth muscle growth [41]. These aggregates can be visualized using specific staining techniques with primary antibodies targeting VCAN and hyaluronan-binding protein [43]. Tumor necrosis factor-α, another cytokine released by tumor cells, induces changes in endothelial cell functions, such as upregulation of TF, contributing to the activation of blood clotting system [44].

As previously stated, PTTM is strongly associated with mucin-secreting adenocarcinomas. Mucin production by these tumors likely contributes to the development of PTTM through several mechanisms. Mucinous material can encapsulate tumor cells, forming emboli that travel to the lungs and cause vascular obstruction. Additionally, mucin can stimulate inflammation and damage the vessel walls, further promoting thrombosis. The pro-inflammatory nature of mucin can activate coagulation pathways, leading to thrombus formation [45,46]. While the exact mechanisms are still under investigation, it is clear that mucin plays a significant role in the pathogenesis of this complex disease. Furthermore, circulating tumor-derived, TF-positive microparticles are strongly associated with the activation of blood coagulation, another potential mechanism contributing to the pathogenesis of PTTM that warrants further investigation [47]. Tumor cells express TF and spontaneously release TF-positive microparticles into the bloodstream. Microparticles are small membrane vesicles that exhibit high procoagulant activity. It has been proposed that these circulating tumor-derived, TF-positive microparticles may contribute to the increased rates of thrombosis, including PTTM, as observed in cancer patients [47]. Further contribution to the prothrombotic state can be via a decrease in ADAMTS13 activity. ADAMTS13 is an enzyme responsible for cleaving von Willebrand factor (VWF), a protein involved in blood clotting [48]. Reduced ADAMTS13 leads to an accumulation of large, multimeric forms of VWF. These large VWF multimers are more potent at binding platelets and promoting their aggregation [48,49]. This increased platelet aggregation significantly increases the risk of blood clot formation, contributing to the development of venous thromboembolism and other thrombotic complications in cancer patients, possibly including PTTM.

The interaction between the tumor emboli and endothelial cells via multiple mediators eventually results in the consumption of coagulation factors and platelets, consistent with commonly found laboratory findings, including thrombocytopenia, and disseminated intravascular coagulation (DIC) [25]. Subsequent impaired fibrinolysis in PTTM disrupts the body’s ability to dissolve blood clots in the lungs. This occurs due to an imbalance between clot formation and breakdown, with factors such as increased levels of plasminogen activator inhibitor-1 and decreased levels of tissue plasminogen activator playing significant roles [50]. The resulting persistent blood clots contribute to the development of PAH, right ventricular failure, and other serious complications. The pathogenesis of PTTM is summarized in Figure 1. While growth factors such as PDGF, VEGF, and TGF-β are implicated, the precise molecular pathways driving tumor cell proliferation and invasion in PTTM remain unclear. The mechanisms by which tumor cells arrest in the pulmonary circulation and the role of specific inflammatory mediators in this process need further investigation. The complex interplay of these factors highlights the intricate mechanisms underlying PTTM and emphasizes the need for further research to unravel the precise molecular pathways involved.

Summary-of-the-pathogenesis-of-pulmonary-tumor-thrombotic-microangiopathy
Figure 1: Summary of the pathogenesis of pulmonary tumor thrombotic microangiopathy

Clinical presentation and diagnosis of pulmonary tumor thrombotic microangiopathy

Multiple case reports show that the most common symptoms of PTTM include cough, sputum production, shortness of breath, inability to lie down at night, chest tightness, chest pain, hemoptysis, fever, malaise, and wasting. Additionally, fatigue, weight loss, fluid buildup in the legs and ankles, and bluish discoloration of the skin are also reported systemic symptoms [51-54]. In clinical settings, PTTM is primarily a preliminary diagnosis made through a combination of the patient’s medical history, physical examination, echocardiographic and CT imaging, and laboratory tests in patients with cancer. The recognition of PTTM in cancer patients is crucial for several reasons. Firstly, PTTM can significantly worsen the prognosis of cancer patients by accelerating disease progression and increasing the risk of thromboembolic events. Secondly, early diagnosis and appropriate management of PTTM can help alleviate respiratory symptoms and improve quality of life. A diagnosis of PTTM requires a high index of suspicion, especially in patients with sudden onset dyspnea but no radiological findings pointing to pulmonary embolism [55]. Clinicians should be vigilant for PTTM in patients with cancers such as breast, lung, and ovarian, especially those undergoing chemotherapy or with advanced disease. Key symptoms include sudden shortness of breath, chest pain, cough, and hemoptysis [51-54]. Thorough evaluation, including blood tests, chest imaging, and consideration of other diagnoses such as pulmonary embolism and pneumonia, is essential. The challenge in the diagnosis of PTTM can be explained by the low rate of antemortem versus a high rate of postmortem diagnosis, as nearly 80% of identified cases were diagnosed by autopsy [25]. A study by Bak et al. highlights the challenge of diagnosing PTTM. Over 10 years at a tertiary center, they collected 28 cases suspected of PTTM, with only one confirmed histologically [56]. This underrecognition can be further attributed to its nonspecific clinical presentation, rapid disease progression, and the overall rarity of the condition, which often delays consideration in the differential diagnosis.

The clinical presentation of PAH, right ventricular failure, and abnormal laboratory studies including elevation in D-dimer and prothrombin time, the presence of anemia and thrombocytopenia, and DIC should prompt consideration of PTTM [25,57]. Schistocytes may be present in the peripheral blood smear in PTTM, as red blood cells can be sheared by the thickened intima. However, their presence alone is not diagnostic and should be interpreted in the context of other clinical and laboratory findings, such as those associated with thrombotic thrombocytopenic purpura [38]. The elevated D-dimer likely reflects the increased fibrin turnover associated with microthrombi formation in PTTM. Similarly, a prolonged prothrombin time can indicate a consumption coagulopathy, a hallmark of PTTM. Anemia and thrombocytopenia are likely secondary to microvascular thrombosis and platelet consumption in the setting of DIC. The presence of these laboratory abnormalities together with respiratory deterioration suggests PTTM [25,57].

PTTM should also be considered in rapidly dyspneic cancer patients with the presence of PAH on echocardiography without any apparent cause, and with the absence of pulmonary arterial thrombus on chest computed tomography (CT) [57]. Use of pulmonary aspiration cytopathology for antemortem diagnosis has been reported in a few cases [51,58]. For imaging, the use of 18F-fluorodeoxyglucose positron emission tomography/CT has been reported in multiple studies [24,59,60]. Case reports by Tashima et al. [59] and Kamada et al. [60] demonstrated multiple foci with abnormal FDG uptake in both lungs affected by PTTM.

Chronic pulmonary thromboembolism (CTEPH) is a distinct clinical entity that can be challenging to differentiate from PTTM. While both conditions can present with respiratory symptoms, their clinical manifestations and diagnostic approaches differ. In contrast to the acute presentation of PTTM, CTEPH often has a more insidious onset with less prominent respiratory symptoms. Cough, a common feature of acute PTTM, is less frequently observed in CTEPH. CT findings can also be helpful in differentiating the two conditions. In PTTM cases, ground-glass opacities, nodules, mediastinal and hilar lymphadenopathy, and septal thickening are often revealed. In contrast, CTEPH cases may demonstrate mosaicism, wedge-shaped infarcts, organized and calcified thrombus, and enlarged bronchial artery [57]. Additionally, laboratory findings in CTEPH are typically nonspecific and may not reveal the characteristic thrombocytopenia and DIC seen in PTTM [25,61]. Table 3 summarizes the clinical presentation and diagnosis of PTTM.

FeatureDescription
Common symptomsCough, sputum production, shortness of breath, inability to lie flat, chest tightness, chest pain, hemoptysis, fever, malaise, and wasting
Diagnostic approachCombination of medical history, physical examination, imaging (echocardiography, CT), and laboratory tests
Importance of early diagnosisA delay in diagnosis worsens prognosis, increases risk of thromboembolic events, and negatively impacts quality of life
Diagnostic challengesHigh rate of postmortem diagnosis, difficulty in differentiating from other pulmonary conditions, and PAH on echocardiography and CT without any apparent cause
Clinical presentationPAH, right ventricular failure, abnormal laboratory findings (increase in D-dimer and prothrombin time, anemia, thrombocytopenia, DIC), and schistocytes in peripheral blood smear
Diagnostic toolsPulmonary aspiration cytopathology, FDG-PET/CT. Chest CT may not show typical pulmonary embolism. FDG-PET/CT can reveal multiple lung nodules
Table 3: Summary of the clinical presentation and diagnosis of pulmonary tumor thrombotic microangiopathy

Source: [24,25,38,51,57-60]

CT, computed tomography; FDG-PET, 18F-fluorodeoxyglucose positron emission tomography; PAH, pulmonary arterial hypertension

Treatment and prognosis of pulmonary tumor thrombotic microangiopathy

The choice of medication depends on the individual patient and the severity of their condition. Apart from oxygen therapy, the medications used to treat PTTM include those for advanced PAH, such as sildenafil, tadalafil, ambrisentan, bosentan, and epoprostenol [62]. Diuretics such as furosemide and spironolactone help reduce fluid overload, while corticosteroids such as dexamethasone and prednisone have anti-inflammatory effects. Given that PTTM presents with consumptive coagulopathy, anticoagulants should be used with caution. In such cases, low-molecular-weight heparin may be the optimal strategy [63]. In pulmonary embolism, the pathology is primarily caused by the activation of the blood coagulation cascade, but in PTTM, fibroproliferative changes in the vascular lumen arising from TF release are the prominent causes. Therefore, while anticoagulant therapy may be effective for pulmonary embolism, it cannot improve PTTM. In the case of right heart failure, intravenous diuresis, inotropic support, and pulmonary vasodilator therapy should be considered [54]. A multidisciplinary approach involving pulmonologists, oncologists, and other specialists is essential for the optimal management of PTTM patients. A patient-centered approach, which includes timely supportive care and symptom management, can improve quality of life and alleviate symptoms.

At present, PTTM management lacks a consistent, evidence-based approach due to the condition’s rarity and rapid progression, which frequently leads to late diagnosis and intervention. Almost all patients with PTTM die within a week of the dyspnea onset due to progressive PAH, subacute right heart failure, or sudden death [53,64]. The rarity of PTTM poses significant challenges to research, including small sample sizes and difficulty in recruitment for clinical trials. While anti-inflammatory therapy with corticosteroids has been frequently utilized as a potential treatment strategy for PTTM, its efficacy remains uncertain [53,65-67]. A case report by Miyazaki et al. demonstrated a temporary improvement in lung function and right ventricular pressure overload following corticosteroid administration [53]. However, the patient ultimately succumbed to respiratory failure, highlighting the limitations of current therapeutic approaches and the need for further research to identify effective interventions for this challenging condition. Other studies similarly reported the ineffectiveness of anti-coagulants and corticosteroids [65-67].

Clinical reports suggest that bevacizumab may be a valuable therapeutic option for patients with PTTM, especially when used in conjunction with other therapies. Higo et al. presented a case study of a colorectal cancer patient exhibiting PTTM who underwent a combination therapy involving imatinib, a PDGF receptor antagonist, bevacizumab, a VEGF receptor inhibitor, and the chemotherapeutic agents S-1 and cisplatin [68]. Following this treatment regimen, the patient exhibited a significant improvement in symptoms without experiencing a deterioration of PAH. However, 12 months post-treatment, the patient succumbed to respiratory failure secondary to an influenza infection. Despite this outcome, the authors posit that the molecular-targeted drugs employed in the therapy were efficacious in managing PTTM based on the patient’s clinical trajectory [68]. Kotake et al. reported a significant improvement of PTTM with lung adenocarcinoma in terms of PAH, respiratory symptoms, and other outcomes after bevacizumab treatment combined with paclitaxel and carboplatin [69]. Taniguchi et al. reported a similar improvement in uterine cancer-induced PTTM after successful treatment with platinum-based chemotherapy and bevacizumab [70]. These case studies suggest that bevacizumab, in combination with other therapies, may be a promising treatment option for PTTM, especially when used in conjunction with targeted therapies. Bevacizumab therapy can be associated with adverse effects. The most common side effect is hypertension, which requires regular blood pressure monitoring and effective management with antihypertensive medications. Proteinuria, thromboembolism, impaired wound healing, and bleeding are other clinically encountered side effects [71]. In more severe cases, a minority of patients may develop thrombotic microangiopathy (TMA). Bevacizumab-associated TMA, along with other drug-induced TMAs, is currently an indication for drug discontinuation due to poor prognosis, including acute kidney injury often requiring dialysis and progression to chronic kidney disease. Most cases, however, improve after discontinuation of bevacizumab [72].

Imatinib has demonstrated promising results in addressing complications associated with PTTM, as evidenced by several case studies. The efficacy of imatinib in treating a patient with PAH associated with PTTM has been demonstrated by the case study of Ogawa et al. [73]. Following imatinib therapy, the patient experienced a dramatic reduction in PAH, enabling successful weaning from percutaneous cardiopulmonary support within a 20-day timeframe. Based on these findings, the authors suggested that imatinib may be a viable therapeutic option for alleviating PAH arising from PTTM [73]. Kimura et al. [74] reported a case of a breast cancer patient with PTTM who experienced a dramatic improvement with bevacizumab therapy. The patient received paclitaxel and bevacizumab for one year, successfully controlling the condition and extending their survival to one year and eight months. This case highlighted the potential efficacy of bevacizumab in managing PTTM associated with breast cancer [74]. Another case study reported that bevacizumab combined with pemetrexed significantly improved lung adenocarcinoma-induced PTTM respiratory dysfunction [52]. Yoshikawa et al. also reported a case of PTTM associated with metastatic breast cancer, which exhibited a significant improvement of respiratory dysfunction and PAH after imatinib was administered [75]. Similarly, imatinib dramatically alleviated the PTTM induced by gastric cancer in another case report by Kubota et al [76]. These findings underscore the potential of imatinib as a targeted therapy for PTTM. Yet still, imatinib can cause a range of cutaneous side effects, along with fever and diarrhea. A maculopapular rash is the most common. For many patients experiencing intolerable side effects, temporarily reducing the dose can help resolve the issue [77]. Furthermore, while both bevacizumab and imatinib are approved medications, access can be challenging due to factors such as cost, insurance coverage, and availability. Similar to bevacizumab, imatinib can also result in drug-mediated TMA, as reported in two cases [78]. Therefore, the administration of bevacizumab and imatinib should be considered carefully, taking into account the potential for drug-mediated TMA. Table 4 summarizes the referred studies regarding the treatment and prognosis of adenocarcinoma-induced PTTM.

Study author(s)Type of studyPatient cancer typeTreatmentOutcome
Lu et al. [52]Case reportLung adenocarcinomaBevacizumab, pemetrexedSuccessful improvement in chest CT findings, respiratory symptoms, DIC. On the second day, dyspnea improved, and The patient could complete walking exercises. Cough was gradually relieved, without any further hemoptysis, together with significantly improved fatigue, sleep, food intake, and mental and physical status
Miyazaki et al. [53]Case reportGastric cancerCorticosteroidsTemporary improvement in lung function and right ventricular pressure, but eventual death from respiratory failure
Higo et al. [68]Case reportColorectal cancerImatinib, bevacizumab, s-1, cisplatinSignificant improvement in symptoms without deterioration of PAH, but eventual death from respiratory failure
Kotake et al. [69]Case reportLung adenocarcinomaCarboplatin, paclitaxel, and bevacizumabSuccessful improvement in PAH, respiratory symptoms, and other outcomes. On day 10, oxygen saturation rate was improved to 95%, and she was discharged after recovery was confirmed
Taniguchi et al. [70]Case reportUterine cancerCarboplatin, paclitaxel, and bevacizumabPatient’s respiratory status and radiological findings improved concomitantly with a reduction in the size of the tumor. The patient recovered well from respiratory failure and her condition has improved, even six months after the end of treatment
Ogawa et al. [73]Case reportGastric and duodenal carcinomaImatinibDramatic amelioration of a PAH   patient was able to be weaned from percutaneous cardiopulmonary support within 20 days of treatment
Kimura et al. [74]Case reportStage IV left-sided breast cancerPaclitaxel and bevacizumab for breast cancer and concurrent treatment for PAH and DICSuccessful control of the condition with paclitaxel and bevacizumab for a year. The patient survived for 1 year and 8 months
Yoshikawa et al. [75]Case reportMetastatic breast cancerImatinibPatient exhibited significant improvement of respiratory dysfunction and PAH
Kubota et al. [76]Case reportGastric cancer, signet-ring cell carcinomaImatinibSignificant decrease in mean pulmonary arterial pressure five days after imatinib administration. The patient was discharged and lived without symptoms of PAH until her death due to systemic metastasis of carcinoma
Table 4: Summary of referred studies regarding the treatment and prognosis of PTTM

DIC, disseminated intravascular coagulation; PAH, pulmonary arterial hypertension; PTTM, pulmonary tumor thrombotic microangiopathy

These case studies suggest that targeted therapies, such as bevacizumab and imatinib, may offer promising therapeutic options for patients with PTTM. While further research is needed to establish definitive treatment guidelines, these studies provide valuable insights into the potential benefits of these agents in managing PTTM-related complications. It’s important to note that the referred studies are case reports. While valuable for generating hypotheses and describing rare occurrences, case reports have inherent limitations that should be considered. These limitations include limited generalizability, lack of a control group, potential for bias, limited statistical power, and a retrospective nature. Further research, such as larger observational studies or randomized controlled trials, is often needed to confirm the findings and draw more definitive conclusions.

Future research should focus on identifying additional biomarkers that can predict patient response to these therapies and developing novel therapeutic strategies that target the underlying pathophysiological mechanisms of PTTM. These mechanisms may include the activation of coagulation cascade and release of inflammatory mediators, fibrocellular subintimal proliferation, and smooth muscle cell colonization [28]. Several potential biomarkers have been associated with PTTM, including VEGF, PDGF, osteopontin, and TF [35]. These biomarkers are involved in pathways that contribute to the pathophysiology of PTTM, including angiogenesis, coagulation, and cellular proliferation. Further research is needed to validate their utility in clinical practice and to explore their potential in early diagnosis and targeted therapy for PTTM.

Conclusions

In conclusion, the association between adenocarcinoma and PTTM presents a significant clinical challenge. Current treatment strategies for PTTM in adenocarcinoma patients primarily focus on managing the underlying malignancy and addressing thrombotic complications. Anti-angiogenic therapy bevacizumab and a PDGF receptor antagonist imatinib have shown promising results in some cases.

Future research should focus on the early detection of PTTM in adenocarcinoma patients, understanding the molecular mechanisms underlying the association between these two diseases, and developing innovative therapeutic approaches that target the aforementioned specific pathophysiological processes involved. By advancing our understanding of PTTM in adenocarcinoma, we can improve patient outcomes and ultimately save lives.

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Cardiovascular Manifestations of Covid-19: A Review

This article was written by my observer students during the Covid time when patients had to be seen virtually; they spent useful time cooperating with each other and wrote up this interesting review. 

cardiovascular-manifestations-of-covid19-a-reviewDownload

Neurological Manifestations of Covid-19

Neurological Manifestations of COVID-19 (SARS-CoV-2): A Review

Muhammad Umer Ahmed1* Muhammad Hanif2 Mukarram Jamat Ali3 Muhammad Adnan Haider4 Danish Kherani5 Gul Muhammad Memon6 Amin H. Karim5,7 Abdul Sattar8

  • 1Ziauddin University and Hospital, Ziauddin Medical College, Karachi, Pakistan
  • 2Khyber Medical College Peshawar, Hayatabad Medical Complex, Peshawar, Pakistan
  • 3Department of Internal Medicine, King Edward Medical University Lahore, Lahore, Pakistan
  • 4Allama Iqbal Medical College, Lahore, Pakistan
  • 5Houston Methodist Hospital, Houston, TX, United States
  • 6Liaquat National Hospital and Medical College, Karachi, Pakistan
  • 7Baylor College of Medicine, Houston, TX, United States
  • 8Southside Hospital Northwell Health, New York, NY, United States

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with many neurological symptoms but there is a little evidence-based published material on the neurological manifestations of COVID-19. The purpose of this article is to review the spectrum of the various neurological manifestations and underlying associated pathophysiology in COVID-19 patients.

Method: We conducted a review of the various case reports and retrospective clinical studies published on the neurological manifestations, associated literature, and related pathophysiology of COVID-19 using PUBMED and subsequent proceedings. A total of 118 articles were thoroughly reviewed in order to highlight the plausible spectrum of neurological manifestations of COVID 19. Every article was either based on descriptive analysis, clinical scenarios, correspondence, and editorials emphasizing the neurological manifestations either directly or indirectly. We then tried to highlight the significant plausible manifestations and complications that could be related to the pandemic. With little known about the dynamics and the presentation spectrum of the virus apart from the respiratory symptoms, this area needs further consideration.

Conclusion: The neurological manifestations associated with COVID-19 such as Encephalitis, Meningitis, acute cerebrovascular disease, and Guillain Barré Syndrome (GBS) are of great concern. But in the presence of life-threatening abnormal vitals in severely ill COVID-19 patients, these are not usually underscored. There is a need to diagnose these manifestations at the earliest to limit long term sequelae. Much research is needed to explore the role of SARS-CoV-2 in causing these neurological manifestations by isolating it either from cerebrospinal fluid or brain tissues of the deceased on autopsy. We also recommend exploring the risk factors that lead to the development of these neurological manifestations.

Introduction

The new public health pandemic COVID-19 is threatening the world with the outbreak of the novel corona virus (2019-nCOV) or severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). In December 2019, a new virus epidemic in Wuhan, China (covid-19) (1) emerged as a world pandemic and has disseminated across many other countries (2). It has been declared a public health emergency by WHO. As of statistics obtained from Worldometer on April 11, 2020, the USA leads with over 0.5 million people infected, followed by Spain and Italy. The spread of this virus shows no evidence of plateauing and the economic, financial, social, and mental havoc along with severe lockdown measures is of great concern. The most common features reported have been shortness of breath, fever, and cough in the past since the epidemic but now new features, either as a result of sequelae or viral infection itself, are coming out. COVID-19 patients have been reported to develop many neurological symptoms ranging from headache to encephalitis (3). We present to outline the spectrum of different neurological manifestations in patients with COVID-19. Physicians should be cognizant of these manifestations while dealing COVID-19 patients.

Microbiology, Origin, and Transmission

The coronavirus is an enveloped positive-sense single-stranded RNA virus belonging to the coronaviradae family. Under electron microscope, the virus appears crown-like due to the small bulbar viral spike (S) peplomers on the surface envelope. SARS-COV has shown to have a zoonotic origin with bats being the primary reservoir adapted by humans. It has shown to spread via respiratory droplets, fomites, and person-to-person contact. Transmission via stool shedding has also been established but has limited evidence (4).

Pathophysiology

Many COVID-19 patients can develop neurological symptoms in addition to common respiratory symptoms as established by a retrospective case series study in Wuhan, China (3), which shows patients with severe COVID-19 develop more neurological symptoms such as acute cerebrovascular accidents, altered level of consciousness, and skeletal muscle damage as compared to those with mild infection. Li et al. proposed that the acute respiratory failure that occurs in COVID-19 patients could be partly because of the damage to the brain stem caused by SARS-CoV-2, in addition to direct damage to lungs (5). It raises a question over how SARS-CoV-2 enters brain? In this review article we present the possible mechanisms used by SARS-CoV-2 in causing the neurological presentations of COVID-19 by summarizing and recollecting different material published over time in this regard.

Genome of SARS-CoV-2

SARS-CoV-2 is the seventh virus in the family of coronaviruses. Coronaviruses have positive-sense single-stranded RNA viruses in their genome and have spike membrane glycoprotein on their surface (6). Genetically SARS-CoV-2 is 79% identical to SARS-CoV and 50% to MERS-CoV (7). SARS-CoV and SARS-CoV-2 act via the angiotensin converting enzyme-2 (ACE2) as their main functional receptor (8), whereas MERS-CoV uses dipeptidyl peptidase 4 (DPP4 also known as CD26) as its predominant receptor. SARS-CoV and MERS-CoV cause many neurological manifestations in addition to respiratory symptoms (9, 10), as highlighted by the presence of the viral nucleic acid in the cerebrospinal fluid. This fact was later reinforced by the evidence of nucleic acid present in an autopsy of the brain (6).

Based on its structural homology with SARS-CoV and MERS-CoV, it can be stated safely that SARS-CoV-2 is neurotropic and there is a possibility that SARS-CoV-2 is also using the same mechanisms of pathogenicity for neurological manifestations (6).

Mechanism of Targeting CNS

After a thorough search the mechanisms by which SARS-Cov-2 enters the CNS could be enunciated as follows:

1. Direct infection injury

2. Blood circulation pathway

3. Neuronal pathway

4. Immune mediated injury

5. Hypoxic injury

6. Other mechanisms.

Direct Spread of SARS-CoV-2 From Cribriform Plate to Brain

One of the proposed mechanisms of SARS-CoV-2 entry into brain tissues is via dissemination and spread from the cribriform plate which is in close proximity to the olfactory bulb (11). This idea of direct spread could be supported by the presence of anosmia and hyposmia in COVID-19 patients as described by Mao et al. (3).

Haematogenous Spread of SARS-CoV-2 to Target CNS

As previously mentioned, ACE 2 has been identified as the functional receptor for SARS-CoV-2 and varied expression and distribution of ACE2 receptors in different organs decide the severity of clinical manifestation of SARS-CoV-2 (12). ACE2 receptors are expressed on glial tissues, neurons, and brain vasculature which make them a target for the attack by SARS-CoV-2 (13). The role of blood-brain-barrier in preventing the virus entry is still to be established, but clinical manifestations of neurological symptoms in patients of SARS-CoV-2 in a recent study was established (3). This study included 214 patients, out of which 78 (36.4%) patients had some neurological symptoms, which strengthens our idea of the neurotropic potential of SARS-CoV-2 virus. Another case was reported that showed the presence of the virus in neuronal and vascular endothelial cells in frontal tissues detected on an autopsy of a confirmed COVID-19 patient (14).

S spike protein (encoded by mRNA) enables the binding of SARS-CoV-2 with ACE2 receptors in the same way as it does for SARS-CoV (15), and in a study it was seen that the binding affinity of SARS-CoV-2 protein S was 10 to 20-folds higher than SARS-CoV protein S (16). The presence of the virus in general circulation enables virus entry into cerebral circulation, where sluggish blood movement in micro vessels enables interaction of the viral spike protein with ACE2 receptors of capillaries endothelium (11). This subsequently leads to viral budding from capillary endothelium; resultant damage to the endothelial lining favors viral entry into the milieu of brain, where viral interaction with ACE2 receptors expressed over neurons can result in damage to the neurons without a substantial inflammation—seen previously with SARS-CoV infection (16). The avid binding of the virus to the ACE2 receptors can also result in their destruction via unknown mechanisms, leading to hemorrhage in the brain. Since ACE2 is a cardio-cerebral vascular protecting factor, its damage causes a leak of the virus in the CNS (13). It is important to mention that before the occurrence of anticipated neuronal damage with the virus, the endothelial damage in cerebral capillaries with resulting bleeding can have fatal consequences in COVID-19 patients.

Neuronal Pathway

Another mechanism through which neurotropic viruses like the coronaviruses can reach CNS is by anterograde and retrograde transport with the help of motor proteins Kinesins and dynein via sensory and motor nerve endings (17), especially via afferent nerve endings of the vagus nerve from the lungs (5). In addition to this, SARS-CoV-2 can also cause gastrointestinal tract infection and can spread to the CNS via enteric nerve and sympathetic afferent (18). Moreover, Exosomal cellular transport is also a presumed pathway of SARS-CoV-2 systemic dissemination and subsequent CNS entry (19).

Immune Mediated Injury to CNS

SARS-CoV-2 is proposed to cause damage to the Central Nervous System (CNS) by a surge of inflammatory cytokines (mainly Interleukin-6), called Cytokine Storm Syndrome (CSS), in the same way as many neurotropic viruses are assumed to induce the production of IL-6 from glial cells, resulting in cytokine storm syndrome (20). In an in vitro study, activated glial cells were seen to cause chronic inflammation and brain damage by producing pro inflammatory cytokines like IL-6, IL-2, IL-5, and TNFα (21). SARS-CoV-2 infection of CNS activates CD4+ cells of the immune system and CD4+ cells in turn induce the macrophage to secrete interleukin-6 (IL-6) by producing granulocyte-macrophage colony-stimulating factor. IL-6 is a predominant component of cytokine storm syndrome (CSS) and leads to multiple organ failure—a major cause of fatality in COVID-19 (22). This is further supported by the fact that treatment with Tocilizumab (IL-6 receptor blocker) resulted in improvement of critical ill COVID-19 patients (23). Based on the aforementioned fact, it is evident that cytokine storm syndrome is one of the many ways used by SARS-CoV-2 to damage the brain indirectly.

Spectrum of Neurological Manifestations

Neurological manifestations of patients with COVID-19 are listed as below in the Table 1 (24) and Table 2.

Table 1

TABLE 1. Spectrum of Neurological Manifestations of COVID-19.

Table 2

TABLE 2. Illustrating the Spectrum of Neurological Manifestations of COVID-19.

Encephalitis

The most common underlying etiology of encephalitis or acute inflammation of the brain is viral infections like Herpes simples virus (HSV), Varicella zoster virus (VZV), cytomegalovirus (CMV), influenza virus (41), and many other respiratory viruses like severe acute respiratory virus coronavirus (SARS-CoV) and Middle East respiratory virus (MERS-CoV) (9, 10). As previously mentioned, SARS-CoV-2 can also have neurotropic effects because many COVID 19 patients present with neurological symptoms in addition to common respiratory symptoms (3). Moreover, recently the presence of SARS-CoV-2 RNA in the cerebrospinal fluid has been detected by genome sequencing in a patient with clinically proved meningoencephalitis in Japan (25).

Poyiadji et al. reported another case in which a female in her 50s presented with a 3 day history of fever, cough, and altered mental status and she was diagnosed with COVID-19 by detection of SARS-Cov-2 nucleic acid in a nasopharyngeal swab (26). Her cerebrospinal fluid analysis was negative for bacteria, HSV type 1 and 2, varicella zoster virus, and West Nile virus. A non-contrast head CT scan revealed symmetrical bilateral medial thalamic hypoattenuation with no abnormality seen on CT angiogram and CT venogram. Hemorrhagic ring enhancing lesions consistent with acute necrotizing encephalitis were seen in the bilateral thalami, medial temporal lobes, and sub-insular regions on an MRI (26). The above case report could support the potential idea that SARS-CoV-2 can cause encephalitis. Poyiadji et al. proposed that the virus does not directly invade the blood-brain-barrier and acute necrotizing encephalitis is caused by SARS-CoV-2 via cytokine storm.

Studies suggest that severe symptoms in COVID-19 patients might be due to cytokine storm syndrome (42). A cytokine profile characterized by increased IL-1, IL-2, IL-6, IL-7, tumor necrosis factor (TNF), macrophage inflammatory protein 1α, granulocyte colony stimulating factor, interferon-gamma inducible protein, and monocyte chemo-attractant protein is associated with the severity of COVID 19 (43). In clinical trials, the blocking of interleukin-1 receptor (IL-1R) with anakinra (44) and blocking of Interleukin-6 receptor (IL-6R) with tocilizumab (23) resulted in significant improvement in COVID-19 patients, which suggests that SARS-CoV-2-related damage is caused by cytokines.

Anosmia

Anosmia means loss of the sense of smell and hyposmia means a reduced ability to smell. The most common neurological presentation of COVID-19 is anosmia/hyposmia, and in fact these can be the only presenting symptoms in a lot of patients, especially paucisymptomatic patients (45) as evident from the case report in which a patient presented with isolated sudden onset anosmia with no other symptoms of COVID-19 but tested positive for SARS-CoV-2 (27).

Eliezer et al. also reported a case in which a woman in her 40s presented with hyposmia with a history of dry cough along with headache and generalized fatigue a few days before presentation. The patient underwent testing for SARS-CoV-2 since she was in contact with her husband who was suspected to have COVID-19 and she was found to be positive (28).

A retrospective study among patients with anosmia by Klopfenstein et al. concluded that 47% (54 out of 114) of COVID 19 patients reported anosmia. Anosmia began 4.4 (±1.9 [1–8]) days after the onset of infection and the mean duration of anosmia was 8.9 (±6.3 [1–21]) days (29). Similarly, Lechien et al. found out that although the most prevalent symptoms of COVID-19 were cough, myalgia, and fever, olfactory and gustatory dysfunction was found in 85.6 and 88% patients, respectively, with significant association between the two disorders (p < 0.001). In 11.8% of the patients, olfactory symptoms appeared before other symptoms. Olfactory and gustatory dysfunction were more common in females as compare to males (p < 0.0001) which highlights a gender predisposition (46).

Anosmia is the most common neurological manifestation of SARS-CoV-2; strikingly it has been found mostly in patients in their early 20s and in otherwise asymptomatic and healthy patients (47). Reviewing the literature, we can conclude that every patient presenting with isolated anosmia should be screened for SARS-CoV-2, especially in this pandemic. To find out the exact mechanism on how SARS-CoV-2 causes anosmia, further research workup is needed (48).

Viral Meningitis

Meningitis is the inflammation of the coverings of the brain and spinal cord. A case of SARS-CoV-2 related meningitis/encephalitis (25) has been reported in Japan, where a young patient presented with altered level of consciousness and a single episode of seizures (while he was being transferred to hospital). He had neck stiffness and his blood work up showed an increased white cell count and increased C-reactive proteins. A CT head showed no brain edema, but a CT chest showed small ground glass opacity on his right upper lobe and bilateral inferior lobes. Anti-HSV-1 and Varicella-zoster IgM antibodies were not detected in serum samples. An MRI performed later showed right lateral ventriculitis and encephalitis on his right mesial lobe and hippocampus. The MRI also showed pan-paranasal sinusitis. A RT-PCR test for SARS-CoV-2 detected SARS-CoV-2 RNA in the CSF but not in the nasopharyngeal swab. He was started on Laninamivir and antipyretic agents for headache, fever, and fatigue 9 days before admission. His chest ray and blood test were normal 5 days before admission. This case highlights the following:

(1) SARS-CoV-2 is neuroinvasive.

(2) We cannot exclude SARS-CoV-2 infection even if an RT-PCR for SARS-CoV-2 is negative on a patient’s nasopharyngeal specimen.

(3) SARS-CoV has been detected in the brain on autopsy by real time RT-PCR with a strong signal in the Hippocampus and in this patient inflammation was also found in the hippocampus; this reinforces the fact that SARS-CoV and SARS-CoV-2 share the ACE2 as a functional receptor.

A 41-year-old female with a known case of Diabetes Mellitus presented with headache, fever, and new onset seizures. She was awake, alert, and oriented to time, place, and person. She had neck stiffness and photophobia but no focal neurological deficit. Chest X-ray, computerized tomography (CT) head, liver function tests, renal function tests, electrocardiogram, and blood chemistry were normal. Cerebrospinal fluid analysis showed 70 white blood cells with all lymphocytes, 65 red blood cells, and 100 mg/dL proteins.

Ceftriaxone and Vancomycin, that were initially started, were stopped. Based on cerebrospinal fluid analysis she was diagnosed with a case of viral meningitis and was given Acyclovir. However, acyclovir was also discontinued upon negative polymerase-chain reaction for Herpes simplex virus (HSV).

She was treated with levetiracetam for seizures. She became disoriented, lethargic, confused, agitated, and had hallucinations. She was vitally stable. X-ray and computerized tomography (CT) chest were normal. Generalized slowing was observed on an Electroencephalogram without any epileptic discharges. SARS-CoV-2 testing ordered at the time of admission came back positive. She improved on hydroxychloroquine treatment. This case showed that COVID-19 patients can have only neurological symptoms at the time of initial presentation (30).

So, can SARS-CoV-2 cause meningitis? A plausible answer could be reassuring as mentioned by the case reports, but it needs further evaluation.

Post-Infectious Acute Disseminated Encephalomyelitis/Post-Infectious Brainstem Encephalitis

Human corona viruses (HCoV-OC43) cause mild respiratory infections but sometimes many, like MERS-CoV, can cause severe neurological manifestations like acute disseminated post-infectious encephalomyelitis (36, 37) and post-infectious brain-stem encephalitis (49) because of their potential neurotropic traits (50). SARS-CoV-2, being a member of this family, can also result in these manifestations, especially in patients with autoimmune diseases like multiple sclerosis, myasthenia gravis, and sarcoidosis (24). But this is too early a stage for such manifestations of SARS-Cov-2 to be present and we need more research and investigation on it. Immunosuppressive therapies cause systemic immune suppression and could be of a great concern.

Guillain Barré Syndrome

Guillain–Barré syndrome causes immune-mediated damage to the peripheral nerves that usually occur after gastrointestinal or respiratory illnesses. Most common antecedent infections are Campylobacter jejuni (51), Zika virus (52, 53), and influenza virus (54). Neuromuscular disorder has been reported with SARS-CoV by Tsai et al. (55) and similarly neurological manifestations like Bickerstaff’s encephalitis overlapping with Guillain-Barré syndrome were also seen with MERS-CoV (37). As SARS-Cov-2 is very similar to SARS-Cov and MERS-Cov, it can also be an antecedent to Guillain–Barré syndrome.

SARS-CoV-2 may result in Guillain–Barré syndrome. There is a correspondence (31) published which mentions a 61-year-old woman presenting with acute leg weakness and fatigue and her blood work on admission showed Lymphocytopenia and Thrombocytopenia. She was diagnosed with Guillain–Barré syndrome on day 5 and was given Intravenous Immunoglobulin. On day 8 she developed a fever and dry cough and her oropharyngeal swabs were positive for SARS-CoV-2 on an RT-PCR assay. Her chest CT showed ground-glass opacities in both lungs.

They suspected that she might have been infected during her stay in Wuhan. Her abnormal laboratory findings on first presentation (Lymphocytopenia and Thrombocytopenia) could be because of SARS-CoV-2, as an early presentation of COVID-19 can be non-specific with fever only in 43.8% of patients on admission (56). This shows a parainfectious profile of association between GBS and SARS-CoV-2 as opposed to the classic post-infectious profile as reported in GBS associated with Zika virus (52, 53) and GBS associated with Influenza virus (54). She should have been tested on day 1 of presentation for SARS-CoV-2 to support our case more vigorously.

Five patients have been reported in Italy with Guillain–Barré syndrome after they had SARS-Cov-2 infection (32). Four patients had lower limb paralysis and paresthesia as the initial symptoms of Guillain–Barré syndrome while one patient initially had facial diplegia and later on developed ataxia and paresthesia. Three patients needed mechanical ventilation. The latency between the onset of COVID-19 symptoms and presentation of Guillain–Barré syndrome was from 5 to 10 days.

Nasopharyngeal swabs were positive for SARS-CoV-2 in four patients. One had a negative nasopharyngeal swab as well as negative bronchoalveolar lavage for SARS-CoV-2 but became serologically positive afterwards. Cerebrospinal fluid (CSF) analysis showed normal protein levels in two patients, white cell counts <5 in all five patients, and negative real-time polymerase-chain-reaction (RT-PCR) for SARS-CoV-2 in all patients. Electromyography showed fibrillation potentials initially only in three patients and later on in another. Magnetic resonance imaging with gadolinium showed caudal nerve roots enhancement in two patients and facial nerve enhancement in another patient, but no signal changes in two patients.

All four patients were treated with Intravenous immunoglobulin (IVIG); two were given a second course of IVIG and one underwent plasma exchange. After 4 weeks of therapy, two patients were still on ventilator support, two were having physiotherapy, and one was discharged as he was able to walk independently. All these reports showed a classical post-infectious profile of association between Guillain–Barré syndrome and other viruses as opposed to the above-mentioned case report (31).

Another case of association of Guillain–Barré syndrome with SARS-CoV-2 has been reported in Iran. A patient presented with quadriplegia and was admitted to hospital. Two weeks before he had a cough, fever, and dyspnea and had a positive reverse transcription polymerase chain reaction on oropharyngeal sampling. The patient had absent deep tendon reflexes with decreased vibration and fine touch sensation distal to ankle joint and bifacial nerve palsy. His brain magnetic resonance imaging (MRI) was normal but bilateral diffuse consolidation, ground glass opacities, and bilateral pleural effusion were seen on a CT chest. Electromyography findings were consistent with acute motor-sensory axonal neuropathy. The patient received intravenous immunoglobulin (33).

In another case, a 54-year-old patient presented with bilateral numbness and weakness of his lower extremities for 2 days. He also stated that he had a fever and dry cough for 10 days which did not improve with amoxicillin and steroids prescribed by his primary physician. Respiratory viral panel testing (Nasopharyngeal PCR) was sent and the test came out positive for Rhinovirus. A test result for SARS-CoV-2 was awaited. Magnetic resonance imaging (MRI) of his thoracic and lumber was done as the patient developed urinary retention. The MRI did not show any abnormality in the spine but showed bilateral basilar opacities in the lungs. Later on, the patient developed dyspnea and his weakness progressed up to his nipples and he was electively placed on a ventilator. Power in his lower extremities was 2/5 and 3/5 in his upper extremities. Deep tendon reflexes were absent. Guillain–Barré syndrome was diagnosed based on these findings and Intravenous immunoglobulin was given for 5 days (34). The patient’s SAARS-CoV-2 test came back positive at two different testing facilities. Guillain–Barré syndrome in this case was thought to be post-SARS-CoV-2 infection as there was not any preceding respiratory tract infection or campylobacterial related diarrhea.

A variant of Guillain–Barré syndrome, Miller Fisher syndrome is also being reported to be associated with SARS-CoV-2 infection. A 50-year-old male with a 5 day history of fever, cough, malaise, headache, low back pain, and altered sensations of smell and taste presented with new onset double vision, perioral numbness, and ataxia. On examination, right internuclear ophthalmoparesis and right fascicular oculomotor palsy were noted. The patient tested positive for antibody GD1b-IgG. Real-time reverse-transcriptase—polymerase-chain-reaction done on an oropharyngeal swab was positive for SARS-CoV-2. Cerebrospinal fluid analysis, a computerized tomography of his head, and Chest X-ray were normal. The patient was labeled as having Miller Fisher syndrome. He was treated with intravenous immunoglobulin (35).

Another patient presented with diplopia 3 days after he had diarrhea, fever, and ageusia. Visual examination showed bilateral visual acuity of 20/25 and bilateral abducens palsy. Real-time reverse-transcriptase–polymerase-chain-reaction done on an oropharyngeal swab was positive for SARS-CoV-2. Cerebrospinal fluid analysis, a computerized tomography of his head, and Chest X-ray were normal. This patient had polyneuritis cranialis. He was treated with acetaminophen (35).

All these reports show that Guillain–Barré syndrome is associated with SARS-CoV-2 infection. We will have a better understanding of this association in the coming days as more cases pour in. However, clinicians should be very vigilant and take appropriate protective measures while dealing with such cases, especially in this era of COVID-19 pandemic as the patient can only have neurological findings at presentation and symptoms of COVID-19 may be overlooked, leading to the horizontal spread of the infection.

Acute Cerebrovascular Disease

One of the many neurological manifestations associated with COVID-19, especially in those who suffer from a severe form of illness, is acute cerebrovascular disease. Mao et al. concluded that 5.7% of patients with severe COVID-19 developed acute cerebrovascular disease (3) and it usually presents as stroke, with ischemic strokes being more common than hemorrhagic strokes. SARS-CoV-2 infection associated with hypercoagulability is called “sepsis induced coagulopathy (SIC)” and the depletion of angiotensin-converting enzyme 2 (ACE2) results in tissue damage, including stroke (57). This was underscored by the fact that thrombolytic prophylaxis amongst critically ill ICU patients reduces the thrombotic complications with better outcome (58). As described earlier, avid binding of SARS-CoV-2 with ACE2 (a cardio-cerebro vascular factor) damages ACE2 and can lead to strokes (13). Moreover, cytokine storm syndrome associated with SARS-CoV-2 infection is also a potential cause of neuronal damage and stroke (22, 59).

Oxley et al. reported five patients who presented with large-vessel stoke. All of the five patients were under the age of 50 and four out of five patients had no previous history of cerebrovascular accidents. They all tested positive for COVID-19 and were diagnosed as COVID-19 related stroke after ruling out other potential causes (38). Similarly, in a case series, Avula et al. reported four patients who initially presented with computed tomography (CT) proven stroke and later tested positive for COVID-19 (39). These patients were screened to rule out other causes of strokes. Al Saiegh et al. reported two confirmed COVID-19 cases who presented with acute cerebrovascular disease. A young male without any previous history of hypertension or other chronic illness was diagnosed with acute subarachnoid hemorrhage possibly secondary to COVID-19 on head computed tomography (CT). This leads us to question whether subarachnoid hemorrhage could be a complication of COVID 19, but with limited data available more research is needed in this regard. The second patient, a 62-year-old female, had an ischemic stroke with hemorrhagic conversion on presentation without any heralding COVID-19 symptoms. She tested positive for COVID-19 later on. These two cases underscore the association of SARS-CoV-2 with cerebrovascular accidents (40). All the aforementioned cases illustrate that SARS-CoV-2 can lead to many cerebrovascular diseases directly or indirectly, however further studies are needed for validation.

Timely management plays a key role in determining the morbidity and mortality amongst patients with acute stroke. It is therefore needless to say that stroke teams and neurologists must be wary of the peculiar spectrum of the pandemic virus and devise appropriate strategies and personal protective measure at all circumstances. Further data is needed to establish knowledge about this condition.

Conclusion

Neurological investigations and isolation of SARS-CoV-2 from cerebrospinal fluid indicate that SARS-CoV-2 is a neurotropic virus and causes multiple neurological manifestations.

Transcribrial spread of SARS-CoV-2 to the brain is supported by the fact that hyposmia/anosmia is one of the earliest symptoms with which patients usually present, but it needs to be further elucidated by isolating this virus from proximity to the olfactory bulb.

With a rapidly rising toll of COVID-19 patients with neurological manifestations, there is an urgent need to understand and diagnose the neurological symptoms earlier to prioritize patients and treatment protocols on the basis of the severity of the disease.

Author Contributions

All authors have taken equal part in the study under mentorship of AK and AS.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: SARS-CoV-2, COVID-19, neurotropism, neurological manifestations, encephalitis, encephalomyelitis

Citation: Ahmed MU, Hanif M, Ali MJ, Haider MA, Kherani D, Memon GM, Karim AH and Sattar A (2020) Neurological Manifestations of COVID-19 (SARS-CoV-2): A Review. Front. Neurol. 11:518. doi: 10.3389/fneur.2020.00518

Received: 14 April 2020; Accepted: 11 May 2020;
Published: 22 May 2020.

Edited by:Robert Weissert, University of Regensburg, Germany

Reviewed by:Michael Levy, Massachusetts General Hospital, United States
Joseph R. Berger, University of Pennsylvania, United States
Alysson Renato Muotri, University of California, San Diego, United States

Copyright © 2020 Ahmed, Hanif, Ali, Haider, Kherani, Memon, Karim and Sattar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Muhammad Umer Ahmed, umer_ahmed_1@hotmail.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Takatsubo Cardiomyopathy and Love of Felines

By Amin H. Karim MD
In 2014 while on STEMI team call I admitted a patient a 56 year old medical researcher, to the Houston Methodist Hospital with severe chest pain and EKG changes of an anterior wall myocardial infarction. He had lost his pet cat 2 days before and was sad. Cardiac catheterization done as an emergency showed normal coronaries with an akinetic apex. He was treated as a case of stress induced cardiomyopathy, the stress in this case being death of his pet. He is lost to followup.

In 2018, I admitted a 54 year old lady status post cardiac arrest, again showing normal coronaries and severely depressed left ventricle. There was mild coronary artery disease, in no way accounting for the wall motion abnormalities on the left ventriculogram. She too had lost her pet cat a day or two ago resulting in severe anguish. She underwent placement of an Implantable Cardioverter-Defibrillator (ICD) and is doing well 5 years later. Her left ventricle has recovered completely.



These 2 cases were written up by our observer medial residents from Pakistan and China. It was published on Cureus and is posted below:


41369-takotsubo-cardiomyopathy-triggered-by-the-death-of-pets-cats-two-case-reportsDownload

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome: Successful Treatment with Dantrolene and Bromocriptine.
By Amin H. Karim MD

1982: Sinai Hospital of Baltimore, Maryland. As a second year Internal Medicine Resident I encountered a patient with high fevers (as described in the article) After discussions and neurological consultations we came up with a plan of treatment that had never been tried before and it proved to be successful and the patient fully recovered.
The article was published in the Annals of Neurology Vol 14 No. 1 July 1983; It has been cited many times in the literature over the years. I presented it at the Young Investigator Conference of the American College of Medicine in 1983 and it was adjudged as the best presentation.

Dr. Barney J. Stern MD, Neurologist and Co-author of the article.

1983: With Dr. Allan Krumholz, Chief of Neurology at the Sinai Hospital of Baltimore.

Coronary Spasm During Thrombolysis

Arteriographic Demonstration of Coronary Spasm During Thrombolysis

By Amin H. Karim MD

In 1986 I was a Cardiology fellow at Baylor College of Medicine. Our cath attending at the V.A. Houston Hospital was a Frenchman Dr. Jacques Heibig, a young cardiologist with his own approach to Cardiology training. We would do 6-7 cases in a single cath lab room. Time was of the essence. He would make us do a quick job and expected us to finish the case in 10 minutes. There was no angioplasty at the time at the V.A. We would do thrombolysis for acute MI using TPA (or blinded to TPA versus Streptokinase when the patient was assigned to TIMI 1 protocol). The TIMI 1 patients would be taken to cath lab within 90 minutes as part of he TIMI protocol to assess if the culprit artery was open and reperfusion established. In the process, we discovered that some patients would have spasm in the partially re-perfused artery prompting me to write up a case report. Two years later we would publish another more formal case report with Dr. Raizner and Dr. Chahine.
Dr. Heibig later moved away from Houston.

coronaryspasmthrombolysis1988Download

Texas Heart Institute Journal 1988: 15; 52-54

Dynamic Coronary Thrombosis

Dynamic Coronary Thrombosis: A possible cause of Prinzmetal’s Variant Angina.

By Amin H. Karim MD
Dr. Albert E. Raizner was the Director of Cardiac Cath Lab at the Houston Methodist Hospital while it was still affiliated with Baylor College of Medicine and even after it dissociated from Baylor. He was my teacher when I did my Cardiology General and Interventional Fellowship at Baylor College of Medicine, Houston, Texas. He and I were very interested in coronary spasm in the days when thrombolysis was the primary treatment of acute coronary syndromes; it would be followed by “rescue” angioplasty if the ST segments remained elevated or there was post infarction angina or residual ischemia. We would come across cases where there was spasm in the coronary artery even without the diagnostic catheter tickling the intima. This lead us to surmise that maybe the presence of thrombus in the artery itself caused the spasm. The paper, we co-authored by another researcher of coronary spasm Dr. Robert A. Chahine, University of Miami School of Medicine, Florida, was published in the Journal of Interventional Cardiology, Vol 3, No. 1, 1990.
Dr. Raizner is now semi retired.

dynamiccorthrombo1990Download