Understanding a Complex Medical Case: Syncope, Ankle Swelling, and Chest Findings

Table of Contents

• Case Presentation
• Medical History and Risk Factors
• Examination Findings
• Laboratory Results
• Imaging Studies
• Diagnostic Approach
• Differential Diagnosis
• Final Diagnosis
• Clinical Implications
• Source Information

Case Presentation

A 41-year-old man arrived at Massachusetts General Hospital with swelling in both ankles and episodes of syncope (fainting). His symptoms began approximately 4.5 months earlier when he developed exertional dyspnea (shortness of breath with activity) and a burning sensation in his chest.

These initial symptoms lasted several weeks and led to hospitalization at another facility. At that time, chest imaging showed no abnormalities, but coronary angiography revealed severe stenosis (narrowing) of the right coronary artery. Doctors placed a stent, and his symptoms resolved completely afterward.

Ten days before his current presentation, the patient developed worsening fatigue. Over the next three days, he experienced fever, diffuse myalgia (muscle pain), anorexia (loss of appetite), mild headache, new scattered ecchymoses (bruises), and arthralgia (joint pain) in his wrists and ankles.

Despite a negative SARS-CoV-2 test, his symptoms continued. On the fifth day of illness, he had a temperature of 38.2°C (100.8°F) and experienced syncope when standing up from a chair, resulting in a fall that injured his right knee. The next morning, while urinating, he became nauseated, diaphoretic (sweaty), and lightheaded before having another witnessed syncope episode where he hit his head.

Medical History and Risk Factors

The patient had multiple pre-existing conditions including coronary artery disease, hypertension, hyperlipidemia, impaired glucose tolerance, obesity, erectile dysfunction, hepatic steatosis (fatty liver), rosacea, and anxiety. His medications included aspirin, ticagrelor, atorvastatin, metoprolol, amlodipine, and escitalopram.

Notable risk factors included:

• Office worker living in urban New England with a cat
• Cat scratch to his left wrist approximately 6 months earlier
• History of smoking half a pack of cigarettes daily for 12 years
• Past marijuana use but no current smoking, alcohol, or substance use
• Travel history to coastal New England, mid-Atlantic states, and southeastern United States
• Lived in the United Kingdom for 2 years in the remote past

Family history included hyperlipidemia, hypertension, systemic sclerosis in his mother, pulmonary fibrosis in a maternal aunt, smoking-related lung cancer in his maternal grandmother, and pancreatic cancer in his maternal grandfather.

Examination Findings

On examination at the emergency department, the patient's vital signs showed:

• Temperature: 36.3°C (97.3°F)
• Heart rate: 79 beats per minute
• Blood pressure: 121/72 mm Hg
• Oxygen saturation: 99% on room air

He had dry mucous membranes suggesting dehydration. His right knee was tender with limited range of motion during flexion. Ecchymoses (bruises) were noted on the left hip and right biceps. Four days later when he returned with worsening symptoms, his temperature was 37.6°C (99.7°F), heart rate 88 beats per minute, blood pressure 132/62 mm Hg, and oxygen saturation 96%.

His body mass index was 31.4, indicating obesity. The wrists were tender and swollen with pain on extension and flexion. Edema (swelling) was present in the ankles with erythematous macules (red spots). Rosacea was present on his face, but no other skin or nail changes were noted.

Laboratory Results

Comprehensive laboratory testing revealed several abnormalities:

Five Days Before Presentation:

• Hemoglobin: 13.3 g/dl (normal 13.5-17.5)
• Hematocrit: 39.6% (normal 41.0-53.0)
• White-cell count: 8840/μl (normal 4500-11,000)
• Platelet count: 262,000/μl (normal 150,000-400,000)
• Sodium: 130 mmol/liter (normal 135-145)
• Potassium: 5.0 mmol/liter (normal 3.4-5.0)

On Current Presentation:

• Hemoglobin: 11.7 g/dl (showing a drop from previous)
• Hematocrit: 35.5% (decreased from previous)
• White-cell count: 9500/μl
• Platelet count: 297,000/μl
• Sodium: 132 mmol/liter (still low)
• Potassium: 4.0 mmol/liter
• N-terminal pro-B-type natriuretic peptide: 107 pg/ml (normal <900)
• Erythrocyte sedimentation rate: 42 mm/hr (normal 0-14) - indicating inflammation
• C-reactive protein: 113.7 mg/liter (normal <8.0) - significantly elevated, indicating inflammation

Other tests including liver function tests, urinalysis, blood cultures, SARS-CoV-2 nucleic acid test, influenza tests, Lyme disease antibody test, HIV test, and syphilis test were all normal or negative.

Imaging Studies

Initial chest radiograph in the emergency department was reportedly normal, but retrospective assessment revealed bilateral hilar prominence. A right knee radiograph showed joint effusion (fluid in the joint) without fracture or dislocation.

Contrast-enhanced CT of the chest and abdomen showed significant findings:

• Diffuse mediastinal and bilateral hilar lymphadenopathy (enlarged lymph nodes)
• Multiple pulmonary nodules, including perifissural nodules
• An 8-mm nodule in the right lower lobe that had increased in size since previous imaging 4.5 months earlier
• Interlobular septal thickening in the right lower lobe
• Diffuse bronchial-wall thickening
• Hepatic steatosis (fatty liver)
• Coronary-artery calcification

These findings were not present on CT performed 4.5 months earlier, indicating new developments.

Diagnostic Approach

The medical team used two complementary approaches to reach a diagnosis: the syndromic approach and the checklist approach.

The syndromic approach involves recognizing constellations of symptoms that "run together" in characteristic patterns. In this case, the combination of fever, bilateral hilar lymphadenopathy, inflammatory arthritis, and lower-leg rash immediately suggested Löfgren's syndrome, an acute manifestation of sarcoidosis.

The checklist approach involved creating a differential diagnosis for each major symptom and then identifying conditions that could explain all findings simultaneously. This method narrowed the possibilities to three categories: infection, cancer, and autoimmune disease.

Differential Diagnosis

Infectious Causes:

• Tuberculous and nontuberculous mycobacterial infections: Could cause fever, pulmonary nodules, and bilateral hilar lymphadenopathy, but the patient had no apparent epidemiologic risk factors
• Fungal infections (blastomycosis, cryptococcosis): Possible given travel to southeastern US, but disease progression was too rapid and patient wasn't immunosuppressed
• Bartonellosis (cat scratch disease): Considered due to cat scratch 6 months earlier, but pulmonary manifestations and symmetric oligoarthritis are rare in this infection

Cancer:

• Lymphoproliferative disorders: Including Hodgkin's disease and diffuse large B-cell lymphoma could cause fever and hilar lymphadenopathy, but the tempo was too rapid and patient lacked typical symptoms like night sweats or weight loss

Autoimmune Diseases:

• Systemic lupus erythematosus, vasculitides, inflammatory myopathies: Could manifest with pulmonary disease, lymphadenopathy, arthritis, and fever
• Crystalline diseases (gout): Could cause fever with articular symptoms but wouldn't explain thoracic findings
• Sarcoidosis: Best fit given the tempo and constellation of findings manifesting simultaneously

Final Diagnosis

The patient was diagnosed with sarcoidosis, specifically Löfgren's syndrome. This diagnosis was based on the classic triad of:

1. Erythema nodosum: Painful erythematous patches on the anterior lower legs
2. Bilateral hilar lymphadenopathy: Enlarged lymph nodes in both sides of the chest
3. Inflammatory joint pain: Ankle periarthritis and wrist synovitis

Löfgren's syndrome is a distinct form of acute sarcoidosis that doesn't require tissue biopsy for diagnosis when the presentation is classic, as in this case. The syndrome was first described by Sven Halvar Löfgren and Holger Lundbeck in 1946 while reviewing cases of erythema nodosum.

The patient's syncope episodes raised concern for possible cardiac sarcoidosis, which can manifest with conduction-system disease, ventricular arrhythmias, or left ventricular dysfunction. This prompted recommendations for additional cardiac evaluation including cardiac MRI and FDG PET-CT imaging.

Clinical Implications

This case illustrates several important points for patients:

Recognizing Symptom Patterns: Certain combinations of symptoms can point to specific diagnoses. The triad of ankle arthritis, skin rash (erythema nodosum), and chest lymph node enlargement is highly suggestive of Löfgren's syndrome.

Comprehensive Medical History: The patient's history of cat scratch, travel, and previous medical conditions all played important roles in the diagnostic process, highlighting why doctors ask detailed questions about seemingly unrelated factors.

Syncope as a Warning Sign: Fainting episodes in the context of inflammatory conditions should prompt evaluation for cardiac involvement, as sarcoidosis can affect the heart's electrical system and muscle function.

Diagnostic Approaches: Physicians use both pattern recognition (syndromic approach) and systematic elimination of possibilities (checklist approach) to reach accurate diagnoses, especially in complex cases with multiple symptoms.

Treatment Considerations: Patients with Löfgren's syndrome typically have a good prognosis, and many cases resolve spontaneously without treatment. However, when symptoms are severe, glucocorticoid therapy may be initiated. Cardiac involvement requires specialized management.

Source Information

Original Article Title: Case 4-2025: A 41-Year-Old Man with Syncope, Ankle Swelling, and Abnormal Chest Imaging

Authors: Daniel Restrepo, M.D., Sadia Sultana, M.B., B.S., Sanjay Divakaran, M.D., M.P.H., and Jeffrey A. Sparks, M.D., M.M.Sc.

Publication: The New England Journal of Medicine, January 30, 2025; 392:495-503

DOI: 10.1056/NEJMcpc2412513

This patient-friendly article is based on peer-reviewed research from Massachusetts General Hospital case records.