The Hidden Faces of Sarcoidosis: Atypical Presentations and Strategies to Prevent Misdiagnosis

Dr. Abdelwahab Arrazaghi, MD, FABIM, FRCPC, Specialist in Internal Medicine and Cardiovascular Diseases

Introduction

Sarcoidosis is a complex and enigmatic multisystem inflammatory disease of unknown etiology, typically characterized by the presence of non-caseating granulomas in affected tissues. While it most commonly involves the lungs and lymph nodes, sarcoidosis can affect virtually any organ system. Due to its varied and often nonspecific clinical presentations, sarcoidosis is frequently misdiagnosed or diagnosed late, which can lead to inappropriate treatments and adverse patient outcomes. This article explores the atypical presentations of sarcoidosis, focusing on manifestations that fall outside the classical pulmonary and mediastinal forms, aiming to increase awareness among clinicians to prevent diagnostic errors.

1. Cardiac Sarcoidosis

Cardiac involvement in sarcoidosis is potentially life-threatening but often goes undiagnosed because it can mimic other cardiac diseases. Autopsy studies suggest that up to 25% of sarcoidosis patients may have cardiac involvement, though clinical symptoms are observed in only 5% of cases.

Common Presentations:

• Conduction abnormalities such as atrioventricular (AV) block, bundle branch block, and ventricular arrhythmias are often the first signs.
• Cardiomyopathy with heart failure can develop, particularly in younger patients, due to granulomatous infiltration of the myocardium.
• Sudden cardiac death may occur in undiagnosed patients due to arrhythmias or conduction disturbances.

Diagnosis and Prevention of Misdiagnosis:

Advanced imaging techniques, including cardiac MRI and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), have proven beneficial in identifying myocardial inflammation and granulomatous lesions. Electrocardiograms (ECGs) and Holter monitors are also helpful in detecting arrhythmias early. A high index of suspicion is necessary for patients with unexplained arrhythmias or heart block, particularly in young patients without traditional risk factors.

2. Neurosarcoidosis

Neurosarcoidosis accounts for about 5-15% of sarcoidosis cases and presents a diagnostic challenge due to its wide range of neurologic manifestations.

Common Presentations:

• Cranial neuropathy, especially facial nerve palsy, is one of the most common symptoms.
• Meningitis or meningoencephalitis mimics can cause headaches, altered mental status, and seizures.
• Myelopathy can manifest as weakness or sensory loss, often due to spinal cord involvement.
• Hypothalamic-pituitary axis involvement may result in diabetes insipidus, amenorrhea, or other endocrine abnormalities.

Diagnosis and Prevention of Misdiagnosis:

MRI with gadolinium contrast is the preferred imaging modality for neurosarcoidosis, as it helps detect leptomeningeal and parenchymal lesions. Cerebrospinal fluid (CSF) analysis often reveals lymphocytic pleocytosis and elevated protein levels. Biopsy remains the definitive diagnostic tool but is often challenging to obtain. Early diagnosis is crucial, as delayed treatment can lead to permanent neurological deficits.

3. Ocular Sarcoidosis

Ocular sarcoidosis may be the first or only sign of sarcoidosis in up to 30% of patients and can have severe implications for vision if not promptly diagnosed.

Common Presentations:

• Uveitis, affecting the anterior or posterior segments of the eye, is the most common ocular manifestation.
• Lacrimal gland enlargement may cause dry eye syndrome.
• Optic neuropathy can result in visual impairment and is a serious but rare manifestation.

Diagnosis and Prevention of Misdiagnosis:

A slit-lamp examination can reveal anterior uveitis, while fundus examination and imaging (such as OCT) can identify posterior uveitis and retinal granulomas. Ophthalmologists play a key role in recognizing ocular sarcoidosis, and patients presenting with uveitis or unexplained vision changes should be screened for systemic sarcoidosis.

4. Musculoskeletal Sarcoidosis

Musculoskeletal involvement in sarcoidosis is often under-recognized and can mimic rheumatologic conditions, particularly rheumatoid arthritis and systemic lupus erythematosus.

Common Presentations:

• Arthritis or arthralgia, particularly in the ankles, knees, and wrists, is common and often transient.
• Myopathy can manifest as muscle weakness or pain, usually with proximal muscle involvement.
• Bone lesions are rare but may appear as cystic changes, particularly in the phalanges.

Diagnosis and Prevention of Misdiagnosis:

Musculoskeletal symptoms, especially when accompanied by erythema nodosum, should raise suspicion for sarcoidosis. Radiographic imaging, including X-rays and MRI, may reveal characteristic bone lesions. Muscle biopsy can confirm granulomatous inflammation in cases of suspected sarcoid myopathy.

5. Cutaneous Sarcoidosis

Cutaneous manifestations are present in about 25% of sarcoidosis patients and may be the first sign of disease. These manifestations vary widely, and certain types can mimic other dermatologic conditions.

Common Presentations:

• Erythema nodosum is commonly associated with sarcoidosis, particularly in young women, and often presents with bilateral red nodules on the shins.
• Lupus pernio presents as purplish lesions on the nose, cheeks, and ears and is almost pathognomonic for sarcoidosis.
• Papules, plaques, and nodules may appear on the face, neck, or limbs and can be mistaken for other dermatoses.

Diagnosis and Prevention of Misdiagnosis:

Skin biopsy is essential to confirm granulomatous inflammation in cutaneous sarcoidosis. Dermatoscopy and histopathology can help differentiate it from other granulomatous skin diseases. Recognizing skin manifestations is crucial as they may be the initial indication of systemic sarcoidosis.

6. Hepatic and Splenic Sarcoidosis

While liver and spleen involvement in sarcoidosis is common, it is often asymptomatic and discovered incidentally on imaging studies.

Common Presentations:

• Hepatomegaly and splenomegaly may occur, though clinical symptoms are typically mild.
• Liver function abnormalities, particularly elevated alkaline phosphatase, are sometimes observed.
• Portal hypertension can develop in severe cases, leading to complications like variceal bleeding.

Diagnosis and Prevention of Misdiagnosis:

Ultrasound or CT scans can identify hepatosplenomegaly and focal lesions in the liver and spleen. Liver biopsy may reveal granulomas but is not always necessary unless liver function is severely impaired. Clinicians should consider sarcoidosis in patients with unexplained hepatosplenomegaly, particularly when associated with other systemic signs.

7. Renal Sarcoidosis

Renal involvement is an under-recognized manifestation of sarcoidosis that can lead to chronic kidney disease if not appropriately managed.

Common Presentations:

• Hypercalcemia and hypercalciuria due to increased production of 1,25-dihydroxyvitamin D by sarcoid granulomas are common.
• Nephrocalcinosis and kidney stones may develop as a result of hypercalciuria.
• Interstitial nephritis can lead to renal insufficiency over time.

Diagnosis and Prevention of Misdiagnosis:

Patients with unexplained hypercalcemia or renal insufficiency should be evaluated for sarcoidosis, especially if they have other systemic symptoms. Renal ultrasound or CT can detect nephrocalcinosis, while renal biopsy may confirm granulomatous interstitial nephritis.

8. Gastrointestinal Sarcoidosis

Gastrointestinal sarcoidosis is rare but can mimic other inflammatory or malignant conditions, particularly in the stomach.

Common Presentations:

• Dysphagia, abdominal pain, or upper gastrointestinal bleeding may result from gastric involvement.
• Liver granulomas are more common than gastrointestinal involvement but are usually asymptomatic.

Diagnosis and Prevention of Misdiagnosis:

Endoscopy with biopsy is crucial to differentiate gastrointestinal sarcoidosis from other inflammatory or neoplastic diseases. Histopathological confirmation of non-caseating granulomas in the gastrointestinal tract is often required.

Conclusion

The diverse and atypical presentations of sarcoidosis underscore the importance of a high index of suspicion in patients presenting with multisystemic symptoms, especially when initial diagnostics are inconclusive. Clinicians should adopt a systematic approach when evaluating potential sarcoidosis cases, incorporating advanced imaging, histopathological analysis, and a multidisciplinary perspective to reduce the risk of misdiagnosis. Early and accurate identification of atypical sarcoidosis can improve patient outcomes, prevent irreversible damage to vital organs, and reduce unnecessary interventions for misdiagnosed conditions.

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