Radiation induced pericarditis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-In-Chief: Mandana Chitsazan, M.D. [3]; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

Overview

The survival rate in Hodgkin lymphoma, Non-Hodgkin's lymphoma and breast carcinomas has significantly improved with use of radiation therapy.However, radiation therapy to thoracic and mediastinal cancers have also led to the development of pericarditis, coronary artery disease, cardiomyopathy, conduction abnormalities in heart and valvular heart diseases which account for significant morbidity and mortality. Radiation-induced pericarditis was first described in the mid-1960s. The radiation-induced pericardial disease may be classified as acute pericarditis, delayed pericarditis, pancarditis, constrictive pericarditis, and pericardial effusion. Radiation therapy leads to disruption of endothelium and subsequent episodes of ischemia. The resulting fibrosis and fibrinous exudates replace collagen fibers. Radiation-induced pericardial disease can occur in any cancer survivor who receive thoracic radiation therapy, including breast cancer, Hodgkin's lymphoma, esophageal cancer, and lung cancer. Radiation-induced pericarditis depends on the total dose of radiation, the dose per fraction, the amount of cardiac silhouette exposed, and the nature of the radiation source. The incidence is higher with doses greater than 40 Gy (4000 rad). Echocardiography is the most commonly used screening modality for the detection and follow-up of radiation-induced cardiac disease. Acute pericarditis usually develops a few weeks after radiation exposure. Nearly 20% of patients with acute pericarditis develop chronic or constrictive pericarditis in the next 5-10 years following radiation therapy. The risk is increased when pericardial effusion was present previously. Chronic pericarditis can also occur in patients without a history of acute pericarditis. Acute pericarditis is a rare complication of radiation therapy. It presents with nonspecific pericarditis symptoms such as chest pain and fever shortly after radiation therapy. Delayed pericarditis occurs from months to years after exposure to radiation. It usually presents with chest pain, dyspnea, and orthopnea. The physical examination may show fever and pericardial rub. Laboratory findings include elevated inflammatory markers such as neutrophil count and erythrocyte sedimentation rate (ESR). On ECG, non-specific ST and T wave changes or ST-segment elevation in all leads may be noted. The majority of acute pericarditis cases are self-limited and respond well to nonsteroidal anti-inflammatory drugs and colchicine. In acute or chronic pericarditis, protein-rich exudate may accumulate in the pericardial sac leading to pericardial effusion. Findings on a chest x-ray or chest CT suggestive of chronic pericarditis include pericardial effusion and pericardial thickening. If the effusion is large enough, it may lead to tamponade. In patients presenting with tamponade, the physical examination may show hypotension, tachycardia, and jugular venous distention with a prominent Y descent, Kussmaul’s sign, and distant heart sound. Radiation-induced pericardial effusion can be confused with malignant pericarditis and hypothyroidism-induced pericarditis. Pericarditis with large effusion can be drained either percutaneously or surgically. Those with recurrent pericardial effusion can be treated with pericardiotomy(pericardial window) or by surgical stripping. Constrictive pericarditis is a late complication of radiation therapy. Patients typically present with signs and symptoms of heart failure, similar to other causes of constrictive pericarditis. Cardiac MRI may be helpful in the diagnosis of constrictive pericarditis. It is useful to confirm the pericardial thickening. Cardiac catheterization may be also helpful in the diagnosis of constrictive pericarditis associated with radiation therapy. Pericardiectomy is recommended for patients who develop constrictive pericarditis. However, the perioperative mortality rate is higher in radiation-induced constrictive pericarditis compared to that of idiopathic constrictive pericarditis. Effective measures for the primary prevention of radiation-induced pericarditis include reducing the dose and volume of cardiac irradiation when possible.

Historical Perspective

Radiation-induced pericarditis was first described in the mid-1960s.

Classification

Based on the presentation and onset of symptoms, the radiation-induced pericardial disease may be classified as:

1. Acute pericarditis
2. Delayed pericarditis
3. Pancarditis
4. Constrictive pericarditis
5. Pericardial effusion

Pathophysiology

Radiation therapy disrupts endothelial cells of the microvasculature of the pericardium and leads to repeated episodes of ischemia. The final result is the formation of fibrosis and fibrinous exudates that are ultimately replaced by fibroblasts and collagen fibers .

Causes

Radiation-induced pericardial disease can occur in any cancer survivor who receive thoracic radiation therapy, including breast cancer, Hodgkin's lymphoma, esophageal cancer, and lung cancer. However, most data come from patients treated for breast cancer and Hodgkin's lymphoma, in which radiation therapy is a frequent component of management.

Differentiating Radiation-induced Pericarditis from other Diseases

• Pericarditis must be differentiated from diseases presenting with chest pain, shortness of breath and tachypnea.
  • For a full discussion of the differential diagnosis of chest pain click here
  • For an expert algorithm that aids in the diagnosis of the cause of chest pain click here
• Pericarditis must be differentiated from myocardial infarction as an important cause of chest pain.The differentiating features include:

Characteristic/Parameter	Pericarditis	Myocardial infarction
Pain description	Sharp, pleuritic, retro-sternal (under the sternum) or left precordial (left chest) pain.	Crushing, pressure-like, heavy pain. Described as "elephant on the chest".
Radiation	Pain radiates to the trapezius ridge (to the lowest portion of the scapula on the back) or no radiation.	Pain radiates to the jaw, or the left or arm, or does not radiate.
Exertion	Does not change the pain	Can increase the pain
Position	Pain is worse supine or upon inspiration (breathing in)	Not positional
Onset/duration	Sudden pain, that lasts for hours or sometimes days before a patient comes to the ER	Sudden or chronically worsening pain that can come and go in paroxysms or it can last for hours before the patient decides to come to the ER

• Constrictive pericarditis should be differentiated from restrictive cardiomyopathy:

Differentiating constrictive pericarditis from restrictive cardiomyopathy

Type of disease	History and Physical examination	Chest X-ray and ECG	2D and Doppler echo	CT and MRI	Catheterization hemodynamics	Biopsy
Constrictive pericarditis	History: Prior history of pericarditis or conditions affecting the pericardium, such as uremia, HIV, TB, or radiation Physical: Pericardial knock	CXR: Pericardial calcification ECG: Nonspecific ST and T abnormalities, low QRS voltage (<50%)	2D echo: ± Pericardial thickening, respiratory ventricular septal shift. Doppler: Increased variation in mitral and/or tricuspid inflow E velocity, hepatic vein expiratory diastolic reversal ratio ≥ 0.79 medial e′/lateral e′ ≥ 0.91 (Annulus Reversus)	CT: Thickened/calcified pericardium MRI: Thickened pericardium	LVEDP – RVEDP < 5 mmHg RVSP < 55 mmHg RVEDP/RVSP > 0.33 Inspiratory decrease in RAP < 5 mmHg Systolic area index > 1.1 (Ref CP in the modern era) Left ventricular height of rapid filling wave > 7 mmHg	Normal myocardium
Restrictive cardiomyopathy	History: Systemic disease (e.g., sarcoidosis, hemochromatosis). Physical: ± Kussmaul sign S3 and S4 gallop, murmurs of mitral and tricuspid regurgitation	CXR:Atrial dilatation ECG:Low QRS voltages (mainly amyloidosis), conduction disturbances, nonspecific ST abnormalities	2D Echo: ± Wall and valvular thickening, sparkling myocardium Doppler: Decreased variation in mitral and/or tricuspid inflow E velocity, increased hepatic vein inspiratory diastolic flow reversal, presence of mitral and tricuspid regurgitation	CT: Normal pericardium MRI: Measurement of iron overload, various types of LGE (late gadolinium enhancement)	LVEDP – RVEDP ≥ 5 mmHg RVSP ≥ 55 mmHg RVEDP/RVSP ≤ 0.33	May reveal underlying cause

Epidemiology and Demographics

Pericardial changes are the most common cardiac complications of radiation therapy. Incidence of radiation-induced pericarditis has significantly decreased with the use of lower doses and newer radiotherapy techniques . In a study, incidence decreased from 20% to 2.5% with the changes in methods of RT administration

In a study among pediatric population with various cancers, radiation therapy with ≥15 GY increased the risk of developing pericarditis by two to six times

Risk Factors

Radiation-induced pericarditis depends on:

• Total dose of radiation
• The dose per fraction
• Amount of cardiac silhouette exposed
• Nature of the radiation source

In a retrospective study, 27.7% of the patients developed pericardial effusion after median time period of 5.3 months following radiotherapy for esophageal carcinoma with radiation dose ranging between 3 to 50Gy. It was concluded that high dose-volume of the irradiated pericardium and heart increased the risk of developing pericarditis.

Screening

Echocardiography is the most commonly used screening modality for the detection and follow-up of radiation-induced cardiac disease. It is typically done every two years in asymptomatic individuals and more frequently when symptoms are present.

Natural History, Complications, and Prognosis

Acute pericarditis usually develops a few weeks after radiation exposure. Nearly 20% of patients with acute pericarditis develop chronic or constrictive pericarditis in the next 5-10 years following radiation therapy.The risk is increased when pericardial effusion was present previously. Chronic pericarditis can also occur in patients without a history of acute pericarditis.

Diagnosis

Diagnostic Study of Choice

There are no established criteria for radiation induced pericarditis.

History and Symptoms

• Acute pericarditis: acute pericarditis is a rare complication of radiation therapy. It presents with nonspecific pericarditis symptoms such as chest pain and fever shortly after radiation therapy.

• Delayed pericarditis: delayed pericarditis occurs from months to years after exposure to radiation . It usually presents with:
  • Chest pain
  • Dyspnea
  • Orthopnea
• Pericardial effusion: protein-rich exudate may accumulate in the pericardial sac leading to pericardial effusion. Rapid accumulation may result in the development of cardiac tamponade presenting with clinical signs and symptoms of tamponade.

• Constrictive pericarditis: constrictive pericarditis is a late complication of radiation therapy. Patients typically present with signs and symptoms of heart failure, similar to other causes of constrictive pericarditis.

Physical Examination

Physical examination of patients with radiation-induced pericarditis depends on the presentation. In acute pericarditis, the physical examination may show fever and pericardial friction rub. In patients presenting with tamponade, the physical examination may show:

• Hypotension
• Tachycardia
• Jugular venous distention with a prominent Y descent
• Kussmaul's sign, and distant heart sounds

In constrictive pericarditis, signs of congestive heart failure may be present, including:

• Hepatomegaly
• Ascites
• Ankle edema

Laboratory Findings

Laboratory findings consistent with the diagnosis of radiation-induced acute pericarditis include elevated inflammatory markers such as neutrophil count and erythrocyte sedimentation rate (ESR).

Electrocardiogram

In acute pericarditis, non-specific ST and T wave changes or ST segment elevation in all leads may be noted.

Acute pericarditis

In patients presenting with constrictive pericarditis, electrocardiographic changes are similar to other causes of constrictive pericarditis. Electrocardiographic signs of constrictive pericarditis is usually inconsistent and non specific

• Left atrial enlargement
• Frequent atrial arrhythmias
• Right axis deflection
• Possible reduction in voltages
• Diffuse negative T-waves
• Typical (normal QRS axis, low voltage, and generalized T wave flattening or inversion)
• Right ventricular hypertrophy
• Right axis deviation

X-ray

A chest x-ray may be helpful in the diagnosis of radiation-induced pericarditis. Findings on an x-ray suggestive of chronic pericarditis include pericardial effusion and pericardial thickening.

Echocardiography or Ultrasound

Echocardiography is the gold standard for definitive diagnosis of acute or chronic pericarditis with pericardial effusion and helps to rule out a cardiac tamponade.

CT scan

A chest CT scan may be helpful in the diagnosis of radiation-induced pericarditis. Findings on a CT scan suggestive of chronic pericarditis include pericardial effusion and pericardial thickening.

MRI

Cardiac MRI may be helpful in the diagnosis of radiation-induced pericarditis. It is useful to confirm the pericardial thickening in chronic and constrictive pericarditis. It is also helpful to assess for concomitant myocardial involvement.

Other Imaging Findings

There are no other imaging findings associated with radiation-induced pericarditis.

Other Diagnostic Studies

Cardiac catheterization may be helpful in the diagnosis of constrictive pericarditis associated with radiation therapy.

For more information on cardiac catheterization findings in constrictive pericarditis, click here.

Pericardiocentesis

• Radiation induced pericardial effusion can be confused with malignant pericarditis and hypothyroidism-induced pericarditis.
• Pericardiocentesis can be used to differentiate them with fluid analysis for malignant cells and thyroid function tests.
• For more information on pericardiocentesis, click here.

Treatment

Medical Therapy

The majority of radiation-induced acute pericarditis cases are self-limited and respond well to nonsteroidal anti-inflammatory drugs and colchicine. Steroids are associated with a higher chance of relapse and therefore are only used in cases who fail to respond to nonsteroidal anti-inflammatory agents.

Surgery

• Pericarditis with large effusion can be drained either percutaneously or surgically.
• Those with recurrent pericardial effusion can be treated with pericardiotomy (pericardial window) or by surgical stripping.
• Pericardiectomy is recommended for patients who develop constrictive pericarditis. However, the perioperative mortality rate is higher in radiation-induced constrictive pericarditis compared to that of idiopathic constrictive pericarditis.

Primary Prevention

Effective measures for the primary prevention of radiation-induced pericarditis include reducing the dose and volume of cardiac irradiation when possible.

Secondary Prevention

There are no established measures for the secondary prevention of radiation-induced pericarditis.

References

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