Keywords
cardiac tuberculosis - tuberculous myocarditis - cardiac 18F-FDG PET - myocardial
hyper metabolism
Introduction
Mycobacterium
tuberculosis has the ability to invade almost every organ of the body. Cardiomyopathy due to granulomatous
myocarditis comprises sarcoidosis, tuberculosis (TB), and other rare granulomatous
diseases. Though a very rare and underrecognized entity, it is increasingly being
recognized as compared with the past.[1]
[2] The clinical presentation of cardiac TB mimics that of cardiac sarcoidosis, making
an early diagnosis quite challenging.[3] Delayed diagnosis may be attributed to the lack of constitutional symptoms and patients
usually present with ventricular arrhythmias, conduction abnormalities, or heart failure.
The diagnosis involves various investigations such as tuberculin skin test, imaging,
histopathology, microbiology, and immunology. Advanced imagings such as cardiac magnetic
resonance (CMR) and 18F-flurodeoxyglycose (18F-FDG) cardiac positron emission tomography/computed tomography (PET-CT) are routinely
performed to diagnose cardiac involvement in sarcoidosis, with patchy uptake of FDG
seen in isolated segments representing inflammation.[4] We describe a case of TB myocarditis in a young patient being evaluated for inflammatory
or infiltrative cardiomyopathy, with the imaging appearances similar to that of cardiac
sarcoidosis.
Case Report
A 32-year-old euglycemic, normotensive gentleman presented with a 2-week history of
breathlessness associated with chest discomfort. He had no significant medical history.
On evaluation, his electrocardiogram (ECG) showed atrial flutter and ventricular tachycardia
for which direct current cardioversion was done. Two-dimensional echocardiography
revealed global hypokinesia of left ventricle (LV) with severe LV dysfunction (32%
left ventricular ejection fraction). He underwent CMR that revealed multifocal subepicardial
to mid-myocardial linear enhancement along the right ventricular insertion site, mid,
anterolateral, and inferior segments with corresponding focal myocardial edema ([Fig. 1B]). These findings favored inflammatory or infiltrative cardiomyopathy with sarcoidosis
being the most likely diagnosis. He was treated with antiarrhythmic medications and
antifailure measures. In view of the CMR findings, the patient was referred to us
for cardiac PET imaging along with whole body PET-CT.
Fig. 1 (A) Cardiac magnetic resonance (CMR) shows multifocal subepicardial to mid-myocardial
linear enhancement along the right ventricular insertion site, mid-anterolateral,
and inferior segments (arrows) with corresponding focal myocardial edema. (B) Fused cardiac positron emission tomography CMR shows patchy areas of increased 18F-flurodeoxyglycose (FDG) uptake in the apical to mid-anterolateral, mid-to-basal
anteroseptal at the right ventricular insertion site, and mildly increased FDG uptake
in the apical inferior segments of the left ventricular myocardium corresponding to
the regions of myocardial enhancement seen on CMR. (C and D) T2 black blood image showing T2 hyperintense changes in the left ventricular myocardium
A week later, cardiac PET was performed after 24 hours of high fat and protein diet
and overnight fasting of 12 hours. He also received unfractionated heparin (5000 units/
kg body weight) intravenously and 15 minutes later 8 mCi 18F-FDG was injected. On the subsequent day, he underwent resting myocardial perfusion
imaging (single-photon emission computerized tomography [SPECT]) after 1 hour of intravenous
administration of 10 mCi 99m Tc-sestamibi. Reconstructed cardiac PET images in short, horizontal, and vertical
long axes showed patchy regions of increased FDG uptake involving the apical to mid-anterolateral,
mid-to-basal anteroseptal at the right ventricular insertion site and mildly increased
FDG uptake in the apical inferior segments of the LV myocardium ([Fig. 2A]–[E]). The resting 99m Tc-sestamibi scan showed a uniform perfusion in the LV myocardium, with no discrete
perfusion defects corresponding to the regions of FDG uptake ([Fig. 2A]). The LV cavity was nondilated with no significant regional wall motion abnormality.
ECG gating of the resting tomograms revealed a mildly impaired LVEF of 47% suggesting
interval improvement in the LV function. Fused PET CMR showed increased FDG uptake
corresponding to the regions of myocardial enhancement seen on CMR ([Fig. 1A]).
Fig. 2 (A–C) Reconstructed cardiac positron emission tomography (PET) images (bottom panel) in
short, horizontal, and vertical long axis show patchy regions of increased 18F-flurodeoxyglycose (FDG) uptake involving the apical to mid-anterolateral, mid-to-basal
anteroseptal at the right ventricular insertion site (arrows), and mildly increased
FDG uptake in the apical inferior segments of the left ventricular (LV) myocardium
(arrows). The study was performed after 24 hours of high-fat and high-protein diet
and overnight fasting of 12 hours and 15 minutes after intravenous administration
of unfractionated heparin to suppress physiological myocardial FDG uptake. Top panel
shows reconstructed 99m Tc-sestamibi rest perfusion scan showing uniform perfusion in the LV myocardium,
with no discrete perfusion defects corresponding to the regions of FDG uptake. (D, E) Transaxial and coronal views of 18F-FDG PET showing discrete regions of increased FDG uptake in LV myocardium suggesting
active infection and/ or inflammation. SPECT, single-photon emission computerized
tomography.
The whole-body PET-CT scan showed multiple metabolically active discrete and conglomerate
lymphadenopathy involving bilateral infraclavicular, mediastinal, and bilateral hilar,
right cardiophrenic, gastrohepatic, peripancreatic, splenic hilar, and retroperitoneal
regions ([Fig. 3A]–[C]). No pulmonary lesion was identified. Hence, the differentials of extrapulmonary
sarcoidosis and tuberculosis were considered with a remote possibility of lymphoma
or even metastatic disease to be excluded.
Fig. 3 Multiple intensity projection image in (A) coronal (B) and transaxial (C) sections of whole-body 18F-flurodeoxyglycose positron emission tomography/computed tomography shows the extent
of disease involvement with multiple extracardiac metabolically active discrete and
conglomerate lymphadenopathy involving bilateral infraclavicular, mediastinal and
bilateral hilar, right cardiophrenic, gastrohepatic, peripancreatic, splenic hilar,
and retroperitoneal regions. No pulmonary lesion was identified.
Follow-up blood investigations were within normal limits. Mantoux was negative with
low induration. Serum angiotensin-converting enzyme (ACE) was not elevated. Holter
monitoring showed sinus rhythm with frequent premature ventricular contractions and
nonsustained ventricular tachycardia with no significant sinus pauses or atrioventricular
block. Needle biopsy of the left paraaortic lymph node revealed necrotizing granulomatous
inflammation consistent with tuberculosis and the patient was started on antitubercular
drugs.
Discussion
Cardiac TB is found in ∼0.5% of patients with extrapulmonary TB (EPTB) most commonly
affecting the pericardium[5] in the form of pericardial thickening and less commonly as pericardial effusion.
Myocardial involvement is very rare, described in up to 0.3% of cases[2] and is known to present typically with congestive cardiac failure, tachy- and bradyarrhythmias,
ventricular aneurysms, right ventricular outflow obstruction, and sudden cardiac death.[6]
[7] Myocardial TB usually occurs either via lymphatic spread from mediastinal lymph
nodes, direct spread from the pericardium, or by hematogenous seeding from a remote
focus.[5] Pathologically, TB infiltration of the myocardium has been described as either diffuse
infiltrative, caseating nodular, or military, and can often mimic other cardiac infiltrative
diseases such as sarcoidosis.[5]
The case described presented with chest discomfort and breathlessness with no constitutional
symptoms. He had tachyarrhythmia in the form of atrial flutter and ventricular tachycardia
that necessitated cardioversion and antiarrhythmic medication.
While TB can affect any organ in the body, lymph nodal TB is the most common form
of EPTB that accounts for ∼20 to 40% of all cases and usually presents as a gradually
increasing painless swelling of one or more lymph nodes. It can be either a primary
form or reactivation of a focus.[8] The most common location is cervical lymphadenopathy (63–77%), although it can also
affect other regions such as the supraclavicular, axillary, thoracic, and abdominal
nodes.[9]
[10] Biopsy of the affected lymph node and microbiological cytological smear testing
as well as culture and polymerase chain reaction studies (sensitivity 77%, specificity
80%) show caseating granulomas that are highly suggestive of TB.[9]
[10]
TB and sarcoidosis are granulomatous diseases that can challenge clinicians[3]
[11], with TB resulting in a caseating granuloma as opposed to sarcoidosis, which presents
with a noncaseating epithelioid cell granuloma.[3]
[12] The main manifestations of both diseases are in the lungs, in association with systemic
symptoms such as fever, malaise, anorexia, and weight loss, and commonly affect the
same organs. Musculoskeletal involvement is a well-known manifestation of both diseases,
with peripheral arthritis found in up to 5% of patients with TB and up to 21% of patients
with sarcoidosis.[12] While cardiac manifestation of sarcoidosis is seen with a prevalence of ∼5%, tubercular
involvement is more rare.[2]
[5] Given the similar appearance of myocardial FDG uptake in sarcoidosis and TB by PET
imaging, as seen in our patient, a detailed medical history and histological correlation
are essential for differentiating tuberculous myocarditis and sarcoidosis. As per
the current diagnostic criteria based on the modified Japanese Ministry of Health
and Welfare guidelines published in 2006 and the Heart Rhythm Society consensus statement
published in 2014, the diagnosis of cardiac sarcoidosis involves either a histological
demonstration of endomyocardial biopsy or integration of relevant clinical and imaging
features.[13]
[14] Since biopsy is not commonly done in view of the risks involved and lack of sensitivity
(19% sensitivity) owing to the patchy involvement of myocardium, advanced imaging
modalities such as CMR and FDG PET-CT have emerged as important tools to improve the
diagnostic certainty and management of cardiac sarcoidosis.[13]
[14] Both imaging modalities have been found to be complementary.[13]
The ability to detect changes in metabolic uptake makes 18F-FDG PET-CT a specific complementary tool to structural imaging,[14]
[15]
[16]
[17] wherein each test evaluates different aspects of the pathobiology of cardiac sarcoidosis
that are relevant in clinical decision making. The cellular uptake of 18F-FDG in sarcoidosis/tuberculosis is related to the presence of inflammatory cell
infiltrates exhibiting high glycolytic activity.[14]
[15]
[16] The differential increase in tissue glycolysis in inflamed tissues, as opposed to
normal cells, forms the pathophysiological basis for the use of 18F-FDG PET-CT in inflammatory/infective disease processes.[15] Integrating both techniques can, therefore, enhance diagnostic certainty in the
absence of late gadolinium enhancement of CMR excluding the disease in most patients
and increase 18F-FDG uptake on PET-CT indicating the presence and extent of myocardial inflammation.[15]
[16]
[17] The CMR and 18F-FDG PET-CT findings in the case described were concordant with the abnormal enhancement
and increased FDG uptake noted in the same segments of LV myocardium, with no hypoperfusion
in the abnormal segments. The complementary value of CMR and PET has been evaluated
in 111 consecutive patients, which revealed that the addition of PET information to
CMR leads to reclassification of subjects with a higher or lower likelihood of cardiac
sarcoidosis in ∼ 45% of patients. About 11% were reclassified as having highly probable,
that is, having greater than 90% likelihood of sarcoidosis. Those having both late
gadolinium enhancement and FDG uptake yielded an even higher likelihood of CS and
identified candidates suitable for immunosuppressive therapies.[13] The authors, therefore, inferred that individuals who are most likely to benefit
from PET after CMR include the following groups: (1) equivocal or negative CMR findings
in the setting of high clinical suspicion; (2) CMR findings with highly probable cardiac
sarcoidosis, wherein 18F-FDG PET-CT could serve to identify the inflammation and guide potential role for
immunosuppressive therapies.[13] Conversely, CMR after an inconclusive PET may be helpful in cases when there is
diffuse FDG uptake involving the myocardium, which could be because of incomplete
suppression of FDG in the normal myocardium rather than diffuse inflammation.
Typical radionuclide protocols for imaging cardiac sarcoidosis include 18F-FDG PET-CT combined with myocardial perfusion imaging (SPECT or PET), wherein preprocedural
high fat/high protein and no/very low carbohydrate diet for 18 to 24 hours with 12 hours
of overnight fasting prior to the study followed by the intravenous administration
of unfractionated heparin (50 units/kg) 15 minutes prior to FDG injection facilitates
the complete suppression of physiological myocardial FDG uptake[14]
[15] Cardiac involvement of the disease is represented by increased FDG uptake in isolated
segments or a patchy distribution representing inflammation. While a concurrent rest
myocardial perfusion study can increase the diagnostic confidence of cardiac sarcoidosis,
the perfusion may remain normal as was seen in our patient or even increased instead
of decreased perfusion as reported in other studies.[14]
[16]
[17]
In patients being evaluated for the diagnosis of infiltrative cardiomyopathy, other
differentials of tuberculous and viral myocarditis should also be included apart from
cardiac sarcoidosis in patients showing heterogeneous FDG uptake on PET imaging, particularly
in developing countries such as India where there is high prevalence of TB.
PET-CT in such cases allows additional whole-body imaging to identify the extent of
disease in patients with EPTB. Considering the risks involved and nonfeasibility of
taking endomyocardial biopsy, whole-body PET most importantly helps to detect any
tubercular lymphadenopathy or lesion to select the most accessible lesion for biopsy.
Apart from assisting in the selection of the site for biopsy, PET-CT may also play
a significant role in monitoring the response to treatment.[14]
[15]
[16]
[17]
[18]
Given the similar appearance of myocardial FDG uptake in both sarcoidosis and TB on
PET imaging, the diagnosis of cardiac TB in the above-described case was based on
the histopathology of the lymph nodes and a negative serum ACE level. A detailed clinical
history and histologic correlation are therefore essential for differentiating tuberculous
myocarditis from sarcoidosis. It has also been observed as reported in previous studies
that both sarcoidosis and TB can coexist,[19]
[20] causing diagnostic dilemma and the presence of both disease conditions in the same
patient does not exclude each other and need to considered. At the time of writing
this case report, antitubercular treatment had been initiated and the importance of
follow-up imaging has been explained to monitor treatment response.
Conclusion
This case highlights that cardiac TB, although rare, should be included in the differential
diagnosis of patients showing heterogeneous FDG uptake in the myocardium on PET study
performed for the diagnosis of infiltrative cardiomyopathy, particularly in TB endemic
regions. Whole-body FDG PET further helps in defining the extent of disease involvement,
particularly in detecting lymphadenopathy and guides biopsy from the most accessible
lesion.
