Cardiac magnetic resonance imaging-indeterminate/negative cardiac sarcoidosis revealed by ¹⁸F-fluorodeoxyglucose-positron emission tomography: two case reports and a review of the literature

A 50-year-old white man presented with a 3-month history of shortness of breath and pleuritic chest pain not responding to antibiotics for community-acquired pneumonia. His history included pulmonary sarcoidosis diagnosed 2 years prior following a chest X-ray (CXR) that incidentally demonstrated perihilar lymphadenopathy. The diagnosis was histologically confirmed by endobronchial ultrasound (EBUS) and biopsy-proven granulomatous inflammation. The sarcoidosis was not initially treated. He reported 2 years of disabling fatigue and had also had an episode of syncope 1 year prior when he stood suddenly from a prolonged supine position. He was assessed in an emergency department where a normal neurological examination was documented. ECG showed sinus rhythm with ventricular ectopic beats. He was discharged home with a provisional diagnosis of orthostatic hypotension. At current presentation he was afebrile and hemodynamically stable with arterial oxygen saturation (SaO₂) of 95% on room air and with a respiratory rate of 26 breaths/minute. Auscultation of his chest revealed decreased air entry bilaterally with inspiratory crepitations. A CXR showed cardiomegaly with bilateral pleural effusions and reticulonodular opacification consistent with pulmonary edema. An ECG showed sinus rhythm with frequent ventricular ectopic beats and ventricular bigeminy, with no detected AV node block. A bedside TTE revealed a poor LVEF of 10 to 15% (normal range 55 to 70%) and small pericardial effusion with no basal thinning of the intraventricular septum. Blood tests were largely unremarkable with full blood count, renal and liver function tests, fasting blood sugar level (BSL), and electrolytes all within normal limits. A high sensitivity troponin was mildly elevated at 18 ng/L (reference range, RR < 14 ng/L) and C-reactive protein (CRP) was mildly elevated at 5.1 mg/L (RR < 5 mg/L); subsequently an N-terminal pro-hormone of BNP was also elevated at 593 pmol/L (RR < 13 pmol/L).

He was admitted to our coronary care unit with severe dilated cardiac myopathy and LV failure with a provisional diagnosis of post-viral myocarditis. He was treated with low-dose frusemide and an ACE inhibitor. Serology for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and varicella zoster virus (VZV) were all non-reactive. Interferon-gamma release assay (IGRA) for Mycobacterium tuberculosis (MTB) was negative. CMR demonstrated severe dilated non-ischemic cardiomyopathy with a LVEF of 17%. No focal areas of abnormal gadolinium (GAD) enhancement were found in the myocardium, which was reported as within normal limits (Fig. 1ai). It should be noted that subsequent review by a third party with expertise in CMR for the purpose of publication found the scan to be indeterminate based on technical reasons, and this is discussed further below. Dermatology and Ophthalmology review and examination found no evidence of cutaneous or ocular sarcoidosis. Additional markers for sarcoidosis were unrewarding including: ACE, 16 U/L (RR 8 to 64 U/L); 1,25 dihydroxyvitamin D, 54 pmol/L (RR 60 to 100); and urine calcium, 1.9 mmol/L. Autoimmune serology including antinuclear antibodies (ANA), extractable nuclear antigens (anti-ENA), antineutrophil cytoplasmic antibodies (ANCA), cyclic citrullinated peptide (anti-CCP), double-stranded DNA (dsDNA), C3, C4, and rheumatoid factor were all within normal limits.

On Day 7 our patient developed right upper quadrantanopia and investigations revealed left posterior cerebral artery (PCA) territory infarct secondary to thrombus. He underwent acute thrombolysis for probable cardiac thromboembolism and symptoms gradually resolved. On Days 7 and 9 he demonstrated short runs of non-sustained VT on cardiac monitoring.

He proceeded to FDG-PET following a 6-hour fast, to investigate for underlying CS. This showed heterogeneous and moderate-to-marked increased metabolism in hilar and mediastinal nodes consistent with sarcoidosis, as well as cardiomegaly and diffuse uptake in both ventricles and his right atrium. Although not classic for CS, where uptake is usually patchy, CS could not be excluded (Fig. 1aii). Endomyocardial biopsy was discussed and considered too great a risk in the setting of low LVEF and recent thrombolysis. He was commenced on systemic immunosuppression with prednisone 1 mg/kg orally administered daily and methotrexate. He was discharged on the above immunosuppression together with warfarin, bisoprolol, frusemide, ivabradine, magnesium aspartate, ramipril, and spironolactone. The decision for automated implantable cardiac defibrillator (AICD) was deferred and out-patient cardiac rehabilitation and transplant referral arranged.

A review at 2 weeks demonstrated a remarkable recovery with increased LVEF to 29% (from 10 to 15%). Our patient self-reported energy levels higher than at any time in the preceding 2 years, prompting a return to full-time work. Three months after the initial presentation he presented with worsening CCF and was found to be in atrial fibrillation (AF). He underwent successful direct current (DC) cardioversion and was commenced on sotalol. A progress FDG-PET at that time demonstrated response to treatment with a reduction in the size and metabolism of the hilar and mediastinal lymph nodes. In addition, his heart was smaller and the increased uptake seen in the right ventricle and the right atrium on the initial scan had resolved, although there was still persistent metabolism in the septum (Fig. 1aiii). The LVEF progressively improved from 47% at 4 months to 53% at 10 months. A progress FDG-PET at 17 months found no regions of increased metabolism in the myocardium, but persisting areas of avidity in his mediastinal and hilar lymph nodes (Fig. 1aiv). He remains clinically well and asymptomatic from systemic sarcoidosis or CS. Cardiac transplantation is no longer a consideration.

A 37-year-old white woman presented to an out-patient Cardiology unit for investigation of dizziness. Following a review a 24-hour Holter monitor found her to be in CHB. This occurred on a background of pulmonary sarcoidosis diagnosed 2 years prior. Perihilar lymphadenopathy was evident on CXR and biopsy of a subcarinal lymph node demonstrated granulomatous inflammation. The sarcoidosis had not previously been treated. One year prior to presentation she had developed Mobitz type II heart block and a TTE and CMR at that time did not find evidence of CS. She also had a transient ischemic attack presenting as facial droop and myelopathy 3 weeks prior. A magnetic resonance imaging (MRI)/magnetic resonance angiogram of her brain did not find evidence of neurosarcoidosis or other abnormalities and a lumbar puncture showed cerebral spinal fluid protein of 0.76 with no white blood cells or oligoclonal bands. LV size and function was normal on TTE with no basal thinning of the intraventricular septum evident, and electrophysiological studies did not demonstrate inducible VT. Comorbidities included childhood epilepsy, type II diabetes mellitus, asthma, hypercholesterolemia, and tobacco smoking. Medications at the time of presentation were metformin, rosuvastatin, and aspirin.

Biochemical investigations including serum ACE of 24 (8 to 64), 1,25 vitamin D of 99 (60 to 100), and urine calcium of 6.6 nmol/L were all within normal limits. Dermatology and Ophthalmology review found no evidence of cutaneous or ocular sarcoidosis. A second CMR found normal biventricular size and systolic function and no late GAD enhancement seen in LV to suggest sarcoid involvement (Fig. 1bi). For the purposes of publication, the second CMR was subsequently reviewed by the same third party with specific expertise as used in Case 1. There was agreement that this CMR was within normal limits.

She proceeded to cardiac FDG-PET due to high clinical suspicion of CS despite two CMR scans within normal limits. Her BSL prior to scanning was 6.6 mmol/L following a 12-hour fast. The FDG-PET scan was suggestive of CS with active sites of focal myocardial inflammation in the basal anteroseptum, basal septum, and inferior walls (Fig. 1bii). She underwent successful permanent pacemaker (PPM)-AICD insertion due to risk of future VT and sudden cardiac death, and was commenced on metoprolol. She was commenced on prednisone 1 mg/kg orally administered daily and methotrexate. She was discharged and has had no further cardiac events. A repeat cardiac FDG-PET at 6 months demonstrated resolution of previously abnormal focal increased FDG accumulation in the LV consistent with resolution of areas of inflammation (see Fig. 1biii). The salient features of the two presented cases are shown in Table 3.