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* From the Departments of Internal Medicine (Drs. Martin, Ardati, and Dunlay), Hematology and Oncology (Dr. Abernethy), and Cardiology (Dr. Blazing), Duke University Medical Center, Durham, NC.
Correspondence to: Mike G. Martin, MD, Duke University, 1322 Arnette Ave, Durham, NC 27707; e-mail: marti157{at}mc.duke.edu
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Key Words: critical care • hypotension • lung cancer
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Six months prior to hospital admission, the patient began experiencing episodes of "falling out." The episodes were characterized by flushing, followed by agitation, diaphoresis, nausea, and feeling "faint." At the climax of his episodes, the patient developed left-sided crushing chest pain and confusion. The patient would respond by becoming recumbent. The episodes lasted between 5 and 30 min and concluded without any intervention. The attacks initially occurred every 4 to 6 weeks, but were following a crescendo pattern and becoming increasingly frequent. He identified no triggers or alleviating factors. The attacks started both when he was standing and lying, and had no relationship to food or the position of his head. The patient’s antihypertensive regimen consisted of therapy with atenolol, lisinopril, and felodipine. The patient also used paroxetine, lorazepam, simvastatin, clopidogrel, naproxen, aspirin, and hydrocodone.
After experiencing several of these attacks at home, he presented to the emergency department of another institution for evaluation. By the time of his arrival at the other facility, his attack had terminated. There, he had a normal ECG and negative findings for cardiac enzymes. He was referred back to his primary care physician, who obtained a persantine exercise stress test and a chest radiogram. The stress test had negative adequate findings. The chest radiogram showed a left lung field opacity that was further defined by chest CT scan to be a well-demarcated 2.4 x 2.5 cm mass in left mid-lung field. He was referred 2 months later to the thoracic surgery department at our institution for video-assisted thorascopic surgery. A wedge biopsy sample of the mass revealed small cell lung cancer.
On postoperative day 7, the patient reported that he was having a typical episode. He was found to be hypotensive (60/30 mm Hg) and bradycardic (pulse, 50 beats/min). A 250-mL bolus of normal saline solution was administered, and his vital signs normalized after 10 min. The findings of the physical examination were normal including clear lung fields and no peripheral edema. The results of his chemistry panel, liver function test, thyroid stimulation hormone, free T 4 measurement, and coagulation profile were all normal. His CBC count was remarkable only for a stable normocytic anemia with a hemoglobin level of 10.6 g/dL. His treatment with antihypertensive medications was stopped, and he was transferred to the CCU for further monitoring.
After spending 24 h in the CCU without showing telemetry abnormalities or changes in his ECG and with negative serial cardiac markers, he experienced another episode. Again, his pulse dropped to the 50 beats/min, and BP to 60/30 mm Hg. The patient received 1 L of normal saline solution without a response. An ECG demonstrated only sinus bradycardia, and the finding of a portable chest radiograph was without acute change. Emergent echocardiography showed a left ventricular ejection fraction of > 55% without any wall motion abnormalities. Treatment with dopamine was started without a response in either BP or pulse. The episode spontaneously terminated after approximately 30 min.
Further evaluation included serial cardiac enzyme tests, the results of which remained negative, and a CT scan of the chest, abdomen, and pelvis. The latter showed no pericardial effusion, a prevascular mediastinal soft-tissue mass measuring 7.2 x 2.4 cm abutting the transverse aorta and main pulmonary artery as well as partially encasing the left main pulmonary artery, and a left suprahilar mass measuring 4.8 x 3.2 cm that was associated with postobstructive atelectasis. These additional masses were new when compared with the CT scan that had been performed 2 months previously at the outside institution. The remainder of the CT scan was notable only for diverticulosis without diverticulitis. The findings of an MRI study of the brain were normal.
Autonomic reflexes (ie, with orthostatic vital sign test, Valsalva test, and ice-water immersion test) were intact at rest, and the former two were absent during the episodes. He had normal heart rate variability between episodes. Due to his extremis with the episodes, we were unable to test his orthostatic response during one. He had an appropriate response to an adrenocorticotropic hormone stimulation test. His serum histamine, serotonin, VDRL, and 24-h urine 5-HIAA levels were normal. An arterial line was placed, and serum norepinephrine, epinephrine, dopamine, and total catecholamine levels were measured both during an episode and during quiescence (Table 1 ). The results of a paraneoplastic antibody panel (ie, Ach receptor [muscle] binding antibody, striational antibody, Ca channel binding antibody N-type, Ca channel binding antibody P/Q-type, parietal cell antibody Tr, CRMP-5-IgG antibody, anti-neutrophil nuclear antibodies 1, 2, and 3, parietal cell antibodies 1 and 2, amphiphysin antibody, and Achr ganglionic neuronal antibody) were negative.
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This raises a point of common clinical confusion.4 The terms baroreflex failure and autonomic failure are often used interchangeably, which is inappropriate. Baroreflex failure usually presents clinically volatile hypertension, not hypotension. This is particularly true for patients with anatomic lesions, such as tumors, involving the baroreceptors or removal of the baroreceptors during neck dissection.567
The patient’s catecholamine profile was normal at baseline in contrast to persons with primary autonomic failure or baroreceptor failure (Table 1).4 Also, during his acute decompensations he was able to mount an endogenous catecholamine surge. A patient with a similar clinical presentation has been described.8 This patient, though, experienced a dramatic fall in his endogenous catecholamine levels during acute episodes, therefore arguing that the lesion is centrally mediating the inhibition of sympathetic discharge or the episodic release of an unknown endogenous compound with inhibitory effects on the central or preganglionic sympathetic neurons or postganglionic sympathetic neurons by a presynaptic inhibition of norepinephrine release. That patient did not have a known tumor.
In contrast to that patient, our patient was able to mount a primary biochemical response to stress, implying the intact fidelity of cholinergic transmission and the postganglionic sympathetic and adrenal medulla pathways.9 He apparently experienced an intermittent failure to respond to both endogenous and exogenous catecholamines. It is plausible that, given the appropriate temporal relationship with the onset of his small cell lung cancer, that the tumor elaborated or provoked an intermittent blockade of adrenergic signaling at the receptor level.
The usual presentation of autonomic dysfunction is orthostatic hypotension and other dysautonomias. Multiple patients have been described with paraneoplastic dysautonomia, which is often related to a positive anti-Hu (ie, ANNA-1) antibody.1011 These patients present with constant, progressive dysfunction as opposed to the intermittent episodes seen in our patient.
Per the diagnostic criteria proposed for neurologic paraneoplastic syndromes, our patient who had a known malignancy, a nonclassic neurologic syndrome, and resolution of the syndrome with chemotherapy would be classified as having a "definite" paraneoplastic syndrome.12 Antibody negativity does not exclude this diagnosis as antibodies are frequently absent in dysautonomia.
The pathogenesis of paraneoplastic syndromes remains clouded. The current opinion is that they most likely originate with T-cell or antibody recognition of neural epitopes, possibly through the expression of previously sequestered epitopes from the testes and CNS by the neoplasm (onconeural antigens).12
Finally, why is this condition not just vasovagal syncope? Several lines of argument go against this possibility. First, the duration of the episodes and the degree of prostration the patient experienced would be markedly atypical for vasovagal syncope. Second, one would expect that the levels of endogenous catecholamines would decrease rather than increase during the episodes if they were vasovagal. Third, the patient should respond to a surge of exogenous catecholamines during an episode if this condition were simple syncope. Finally, the episodes abated with the appropriate treatment of his tumor.
Given the lack of an alternative explanation for our patient’s clinical syndrome, its synchronous evolution with his cancer, and his response to generalized antitumor therapy, we feel that the patient had a small cell lung cancer related paraneoplastic syndrome, which intermittently impaired the ability of his body to respond to adrenergic stimulation.
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The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication May 18, 2006. Accepted for publication June 22, 2006.
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