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Amiodarone Induced Bone Marrow Granulomas: A literature Review of Case reports

Background
Amiodarone is classified as a class III antiarrhythmic drug primarily indicated in the treatment of ventricular arrhythmias. The agent has a wide array of adverse effects that may affect multiple organ systems, including the pulmonary, central nervous system, cardiovascular, thyroid, liver, eyes, and skin. A rare and uncommon occurrence from amiodarone use is the development of bone marrow granulomas. This review article summarizes the mechanism of action, clinical uses of amiodarone therapy and reviews the unique presentation of amiodarone-associated bone marrow granulomas using ten case reports. It also includes a discussion section summarizing literature that can further aid healthcare professionals and patients in the diagnosis, management, and education of this adverse effect.

Methods
An electronic database search of scientific platforms such as PubMed, Pubmed Central (PMC), and Google Scholar was conducted. Respective data was collected and reviewed to conduct this
manuscript. 10 previously published case reports regarding amiodarone induced bone marrow granulomas were analyzed and reported. Articles were selected based on the keywords mentioned above.

Results
As per the reported cases of amiodarone- associated granulomas, subjects taking a dosage of 100 mg – 200 mg for a duration of 6 to 18 months was enough to ensure bone marrow granulomas. Repeated bone marrow biopsy 3 to 6 months after discontinuation of the offending agent demonstrated an improvement. All ten case reports revealed noncaseating granulomas confirmed by bone marrow biopsy. Subjects that did develop cases of anemia, EPO showed great improvements to raise Hb levels. 4 of the 10 cases continued treatment despite the confirmed bone marrow granulomas due to the intractable nature of their cardiac condition. In such cases, routine monitoring is recommended, and repeated bone marrow biopsies may be required.

Conclusion
Bone marrow granulomas are seen commonly in infectious and malignant etiologies. A thorough
history and workup can reveal uncommon causes such as medication-induced and prevent misdiagnosis. Bone marrow granulomas in subjects previously receiving treatment with amiodarone should arouse clinical suspicion for possible drug-induced etiology.


AMA Research Challenge 2022

Amiodarone Induced Bone Marrow Granulomas: A Literature Review of Case Reports

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poster

Background: 
Catheter ablation-induced visual symptoms are reported to be rare. Catheters can cause an iatrogenic atrial septal defect (IASD) that can remain open for up to nine months.  A similar dynamic  change in the patent foramen ovale (PFO) has also been hypothesized to be caused by IASD. This can result in paradoxical emboli containing particulate material from the equipment and/or microemboli, both of which result in cortical spreading without infarction in the brain, resulting in visual complications. 

Case Presentation :
A 72-year-old Caucasian woman with paroxysmal atrial fibrillation (AF) but no migraines presented to our hospital with acute visual changes.  She had an uneventful AF catheter ablation four days prior to her presentation.  
Her medications were flecainide 50 mg twice/day and apixaban 5 mg twice/day.  
She experienced nausea, constipation, and headaches after catheter ablation, which subsided after three days. On the fourth day after the procedure, she noticed blurriness, a right visual field defect, and blind spots in both eyes. These visual changes were episodic and lasted for 15-20 minutes without any known precipitating or relieving factors. She denied fever, chest pain, palpitations, confusion, dizziness, loss of consciousness, and motor or sensory deficits. Her general physical exam, including a thorough neurological examination, was normal. Vitals were stable. The patient's initial 12-lead ECG and telemetry strips showed normal sinus rhythm. Normal blood and metabolic lab results. MRI and CT brain angiography showed no abnormalities. Her symptoms resolved after 24 hours while she remained under observation.  
She was discharged home and has reported no recurrence of symptoms to her cardiologist. 

Discussion:
With the increased use of catheter ablation procedures for symptomatic arrhythmias, rare but significant post-procedural symptoms such as visual disturbances have been reported. Monitoring for IASD, which can potentially cause complications after catheter ablation, with transthoracic echo (TTE) or transesophageal echo (TEE), can be helpful in determining the etiology; more research is needed in this area to avoid unnecessary, lengthy, and costly investigations that burden patients and institutions. We hypothesize that this patient's visual symptoms resulted from IASD-related complications as a result of her catheter ablation.

Approach to Visual Manifestations Following Catheter Ablation

Introduction:

Epsilon waves on electrocardiogram (ECG) are low voltage potentials following the QRS complex representing delayed right ventricular conduction. These are characteristic of arrhythmogenic right ventricular cardiomyopathy (ARVC). This condition has been associated with sudden cardiac death.

Case Presentation:

We present a 59-year-old female with a family history of sudden cardiac death who was admitted to the hospital for syncope and found to have a subdural hematoma managed with Burr hole drainage. On day 2, the patient had a sudden episode of sustained monomorphic ventricular tachycardia and loss of consciousness requiring cardioversion to sinus rhythm and initiated on amiodarone. Subsequent ECG showed sinus rhythm with incomplete right bundle branch block, T wave inversions and epsilon waves in precordial leads. Transthoracic echocardiogram showed severely dilated right ventricle and reduced ejection right ventricular ejection fraction (RVEF) of 45%. Cardiac MRI showed worsening RVEF of 27% and regional right-ventricular hypokinesia. Additional genetic testing for ARVC was negative. As per Task Force 2010 criteria the patient met at least two major and two minor criteria which confirmed a “definite” diagnosis of ARVC. The patient was continued on mexiletine and metoprolol and advised to avoid endurance exercise. She received a secondary prevention cardioverter-defibrillator and was referred to advanced heart failure specialist for cardiac transplant evaluation.

Discussion

ARVC involves mutations in the genes coding desmosomes thus causing replacement of the myocardium with fibrofatty tissue. This results in delayed intraventricular conduction allowing for fatal reentrant ventricular arrhythmias. We emphasize the importance of recognizing epsilon waves on ECG which are highly specific to this disease process. The incidence of epsilon waves in ARVC accounts for 30%. Moreover, recognition of LV involvement in patients with ARVC can help identify patients at higher risk of mortality that may go on to benefit with heart transplant evaluation.

Epsilon Waves and Preventing Sudden Cardiac Death

Background:
Sarcoidosis is a multisystem granulomatous inflammation disorder of unknown etiology which can involve a variety of organs. The incidence usually varies according to ethnicity, gender and region. It usually affects the lymph nodes and lungs; however, the skin, the central nervous system, the eyes, the muscles and the heart can also be affected. The heart is not a commonly affected organ in sarcoidosis
Cardiac signs and symptoms can include complete heart block, bundle branch block, ventricular tachycardia, congestive heart failure, and sudden death are not usually the first presentation of the disease.
Case Presentation:
This case illustrates the challenge of diagnosing isolated cardiac sarcoidosis in a 56 year old gentleman who presented with symptoms of acute heart failure.
Echocardiography showed EF of 40% and elevated filling pressure, grade 3 central mitral regurgitation and grade 2 aortic insufficiency. Coronary angiogram was negative, CT angiogram was negative for pulmonary embolism. EP studies showed ventricular premature beats bigeminal and trigeminal sequence.
MIBG scan showed diffuse fixation of MIBG in both ventricles but more markedly in the lateral wall of the left ventricle. Cardiac biopsy showed noncaseating granulomas. Steroids resulted in marked improvement of his cardiac function with an  EF 52%, grade 1 central mitral regurgitation and aortic insufficiency grade 1-2, while tapering of steroids resulted in deterioration of EF to 35 %. 
After this deterioration, Methotrexate was added and after few months the patient was able to be tapered off the steroids and achieve stability of symptoms.
Discussion:
Cardiac involvement in sarcoidosis is common. However, heart failure and isolated cardiac sarcoidosis are not commonly seen as the first presentation. High clinical suspicion is always the key to identifying those cases and recognizing the presenting signs and symptoms such as ventricular arrhythmias, conduction abnormalities and heart failure coupled with the use of the right imaging techniques including MIBG scan, FDG PET and cardiac MRI. Early initiation of the management is the most important step to prevent sudden cardiac death. Immunosuppressants, mostly corticosteroids, are the main stay of management and implantable cardioverter-defibrillator device might be needed to prevent sudden cardiac death.

Isolated Cardiac Sarcoidosis Presenting As Heart Failure

Fungal infective endocarditis (FIE) is a rare condition with poor prognosis commonly associated with immunosuppression. Aspergillus fumigatus, which can resemble Neosartorya pseudofischeri, is the most common pathogen associated with invasive fungal infections in immunocompromised hosts. Echocardiographic evaluation of invasive disease is a useful tool for prognostication and clinical decision-making.

Neosartorya Pseudofischeri Papillary Muscle Abscess: Echocardiographic and Pathologic Correlates


One of the most prevalent non-epithelial tumors of the GI mesenchyme are Gastrointestinal Stromal Tumors (GISTs). Less than 1% of all malignancies are stromal tumors, but knowledge of their etiology and signaling pathways can lead to the identification of new molecular targets for potential therapeutic development. One of the drugs which shows remarkable action against GIST is imatinib, a tyrosine kinase inhibitor.

Here we present a patient with a long term history of minimal pericardial effusion who was hospitalized after an echocardiogram revealed a recent development of significantly increased pericardial effusion associated with shortness of breath(SOB). She was diagnosed with GIST a year ago, following which she was started on imatinib. She presented to the ER with complaints of left sided chest pain. ECG revealed atrial fibrillation and echo showed a moderate sized pericardial effusion. After clinical examination, pericardiocentesis was done, which aspirated 500 ml of bloody pericardial fluid, and a drain was placed. Following which, the patient still continued to have SOB, and on further workup, a left sided pleural effusion was detected on chest x-ray. Fluids from both effusions were aspirated and sent to pathology to rule out malignancy. Patient had recurrent bilateral pleural effusion after discharge which was later drained on subsequent hospitalization. 

This case report highlights incidence pleural and pericardial effusion post treatment of GIST with Imatinib. Although imatinib is generally well tolerated, it does cause both atrial fibrillation and pleural/pericardial effusions in rare cases. In these cases, it becomes essential to perform a thorough workup so as to rule out other possibilities such as metastasis, malignancy or infection.


New Onset Pleural-Pericardial Effusion and Paroxysmal Atrial Fibrillation in an 83-year-old Female with Gastro-Intestinal Stromal Tumor (GIST) After Starting Imatinib Treatment

Background
Mycophenolate acid (MPA) is an immunosuppressive drug commonly used in heart transplantation to prevent allograft rejection. There are two common preparations, mycophenolate mofetil (Cellcept) and mycophenolate sodium (Myfortic), which are absorbed differently. We present a case of a heart transplant recipient with a prior partial colectomy and gastroparesis who had recurrent biopsy negative rejection.
Case Presentation
A 21-year-old male with history of partial colectomy underwent uncomplicated orthotopic heart transplant. Eighteen months after transplant he displayed an unexpected elevation of donor derived cell free DNA accompanied by very low level de novo DSA’s (MFI<2500). He underwent endomyocardial biopsy that was negative for evidence of cellular or antibody mediated rejection. Coronaries were angiographically normal. He was electively treated for suspected subclinical AMR with plasmapheresis, rituxan, bortezomib, and solumedrol. Two months later he re-presented to our institution in cardiogenic shock requiring an intra-aortic balloon pump and inotropes. Repeat coronary angiography showed severe multivessel vasculopathy (CAV-3), including acute thrombotic occlusions of the OM branch and r-PDA. Although serum tacrolimus troughs had been maintained at goal post-transplant, a serum MPA level was undetectable at time of admission. He was changed from Cellcept to Myfortic, but remained with persistent severe allograft dysfunction despite a second salvage course of treatment for underlying AMR, and is now listed for re-transplantation.
Discussion
We suspect this is a case of early onset severe AMR and vasculopathy was related to inadequate immunosuppression due to mycophenolate mofetil malabsorption in this patient with a prior hemicolectomy and gastroparesis. Use of an alternative mycophenolate formulation with better absorption profile, and closer monitoring of serum MPA levels should be considered in heart transplant recipients who has similar history of gastrointestinal disease and surgery.

Severe Allograft Vasculopathy and Antibody Mediated Rejection in Heart Transplant Recipient

Atrial fibrillation (AF) can result in thromboembolism with devastating consequences. The CHA2DS2-VASc score is used to stratify thromboembolic risk in AF patients, but more patient-specific biomarkers for thrombosis such as D-dimer should also be included in risk assessment and indication for anticoagulation therapy.

Value of D-dimer in risk stratification for thromboembolism in patients with atrial fibrillation and low CHA2DS2-VASc score

Background
Anorectal malformations (ARM) are common anomalies encountered in pediatric surgery, between 1 in 2000 and 1 in 5000 live births result in an ARM diagnosis. Rarely is an ARM diagnosed after the neonatal period. Many different anorectal defects can occur in females including cloaca, anal atresia, and ectopic anus. Ectopic anus is considered a low anorectal anomaly and most frequently occurs in the perineum and vulva.
Case Presentation
Our patient is a 35 year-old female with a past medical history of hypothyroidism and congenital pes planus. She presented with a possible fistula from a sexual assault that occurred as a child. She denied any urinary tract infections, dysuria, or dyspareunia. She complained of some fecal incontinence and difficulty achieving intimacy due to feeling “abnormal.”
During colonoscopy it was discovered she had a posteriorly located ectopic anus in the vaginal introitus with a normal anorectal ring in the correct more posterior position. MRI confirmed the diagnosis of a fourchette ectopic anus with no other genitourinary abnormalities.
Our surgical approach focused on restoring normal anal and vaginal function and appearance. We achieved this through a perineal anoplasty, reconstruction and reinforcement of the posterior vaginal wall with an omental flap, and a Stage 2 neurostimulator. This resulted in a normal-appearing and functional anus and vagina.
Discussion
Here we present a unique case of a patient with an ARM diagnosed in adulthood. She presented with a history of sexual assault during childhood, fecal incontinence, and difficulty achieving normal sexual function. An MRI confirmed the diagnosis of a vaginal ectopic anus. The patient had no complaints of urinary tract infection or other genitourinary symptoms. ARMs are commonly detected in the neonatal period and are rarely seen during adulthood. Most cases discovered during adulthood happen in resource-limited environments. ARMs should be diagnosed within the first 24 hours of life during neonatal examination. However, in underdeveloped regions, more births may happen at home rather than hospitals thus contributing to inconsistency in healthcare in the immediate neonatal period and may play a role in missing ARM diagnoses.

Case Report: Ectopic Anus in the Vaginal Introitus in a 35 year-old Female

Adenocarcinoma of the anus is a rare form of cancer, accounting for only 10% of primary anal carcinoma diagnoses. This case involves a 65-year-old female with an incidentally discovered anal mass. 

The patient was initially admitted for COPD exacerbation and iron deficiency anemia. On physical exam, the patient was found to have an anal mass at the 8 o’clock position. Further history revealed that she had experienced bleeding and painful defecation for the last 3 months. Subsequently, the patient underwent a left inguinal and anal node biopsy to determine tumor origin and progression. The mass was biopsied, and immunohistochemistry was performed. Staining demonstrated strong reactivity for cytokeratin 7 and focal reactivity for p16. These markers indicated an adenocarcinoma of anal origin. Diverting colostomy was performed to allow for wound healing and prevent further blood loss. She continues to be followed by oncology for further evaluation and treatment.

Clinically, the significance of distinguishing the origin of anal canal tumors is the mechanism of spread, which reflects the dual lymphatic drainage system. A colorectal adenocarcinoma carries an increased risk of spread via the inguinal and femoral nodal chains compared with a rectum-based adenocarcinoma. Histochemical staining with glands positive for cytokeratin 7 can be used to classify tissue as ductal or glandular in origin. However, the histological pattern of anal gland adenocarcinoma remains to be sharply defined, thus strengthening the need for further exploration within the literature. Further classification and understanding among multiple disciplines of medicine are pertinent to better treatments and prognosis in patients presenting with anal adenocarcinoma. 

Adenocarcinoma of the anal canal accounts for 2.7% of all gastrointestinal malignancies. The limited number of studies and discussions in the literature make it challenging as a pathological diagnosis and for appropriate clinical management. As more cases are reviewed, there is an increased opportunity for treatment development and prognosis improvement.

Incidental Discovery of Advanced Primary Anal Adenocarcinoma

Background: Colorectal cancer is the second leading cause of cancer deaths in the United States. Synchronous cancers occur rarely, representing approximately 3.5% of all colorectal cancers. When compared to open colectomies, laparoscopy has been shown to have similar oncologic outcomes with shorter hospital stays and lower 30-day mortality. Additionally, intraoperative fluorescence angiography (IFA) provides an objective assessment of bowel and anastomotic perfusion.

Case Presentation: Here we present the case of a 74-year-old lady who had synchronous ascending and sigmoid colon adenocarcinomas, treated with a laparoscopic resection. She initially underwent a colonoscopy for evaluation of symptomatic anemia which revealed an ascending colon adenocarcinoma. The bowel prep was poor however, and repeat colonoscopy revealed a synchronous adenocarcinoma in the sigmoid colon. We performed a laparoscopic total abdominal colectomy with primary end-to-end ileorectal anastomosis and IFA with indocyanine green (ICG). The procedure was successfully completed laparoscopically. A total of 8 ports were used. The extraction site incision measured 6cm. IFA with ICG showed good perfusion of the small bowel conduit and ileorectal anastomosis. Final pathology revealed a right colonic well-differentiated pT2 adenocarcinoma (16.5cm proximal margin), a moderately differentiated pT2 distal sigmoid colon adenocarcinoma (7.5cm distal margin), and 48 benign lymph nodes. These findings represented an optimal oncologic resection with adequate lymph node harvest and margin status. The patient recovered well and was ready for discharge home on postoperative day 4 without need for narcotics. She continues to be well 4 months after surgery.

Discussion: Assessment for synchronous lesions is critical in the evaluation of colorectal cancer patients. This case highlights a rare case of synchronous colon cancers and exemplifies the advantages of laparoscopic technique. It also illustrates the utility of intraoperative bowel perfusion assessment with fluorescence angiography, which has been associated with lower anastomotic leak rates.


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Approach to Visual Manifestations Following Catheter Ablation

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