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Department of Anesthesiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
Address correspondence and reprint requests to C. Thomas Wass, MD, Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Address e-mail to wass.thomas{at}mayo.edu
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Introduction |
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Case Report |
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Because approximately 50% of subacute cerebellar degeneration cases are paraneoplastic in origin, a chest radiograph, whole-body computerized tomography, and a paraneoplastic antibody panel were ordered to determine whether malignancy was involved. These studies revealed a 3-cm mass and several enlarged lymph nodes in the right paratracheal region, and a pleural nodule in the left anterior chest. The preliminary paraneoplastic antibody panel came back positive for cerebellar anti-Purkinje cell autoantibody.
To obtain a tissue diagnosis, the patient was subsequently scheduled for mediastinoscopy. Pertinent routine preoperative laboratory values were within normal limits and pulmonary function tests demonstrated mild obstructive lung disease.
In the operating room, routine monitors were placed, and general anesthesia was induced with IV sodium thiopental, fentanyl, and succinylcholine. The trachea was intubated and anesthesia was maintained with inhaled isoflurane and nitrous oxide. A right radial arterial catheter was placed. Thereafter, four faint twitches were observed on the peripheral nerve stimulator train-of-four mode, and IV cisatracurium 12 mg was administered. The biopsy was readily obtained and pathologic examination demonstrated high-grade bronchogenic small cell carcinoma. After wound closure (i.e., approximately 50 min after cisatracurium was given), one faint twitch was perceptible during train-of-four stimulation. Augmentation of the train-of-four response was evident using posttetanic facilitation. A reversal dose of IV neostigmine 4 mg and glycopyrrolate 0.7 mg was administered. Twitch response to train-of-four stimulation did not improve over the ensuing 10 min. We verified the reversal medications were indeed neostigmine and glycopyrrolate, and scrutinized the expiration dates on the vials. Because of her past medical and family history, atypical plasma cholinesterase was low in our differential diagnosis. Other sources of disrupted neuromuscular transmission were considered, but were noncontributory. For example, preoperative electrolytes were normal, perioperative aminoglycosides were not given, and the patient’s temperature was >36°C. Considering the patient’s history and tissue diagnosis (i.e., bronchogenic small cell carcinoma), we suspected LEMS. The patient was sedated with midazolam and taken to the postanesthesia care unit, where she was placed on a mechanical ventilator. A neurology consult was placed. They evaluated the patient and had no further postoperative management recommendations.
With time, her strength improved. For example, after approximately 90 min, facial grimacing was noted during train-of-four and tetanic stimulation. Approximately 3 h after bolus cisatracurium, she had four brisk twitches without perceived fade during train-of-four stimulation and was uneventfully extubated after demonstrating a sustained head lift for 5 s. The rest of her hospital course was uneventful, she had no recall of the postoperative events, and she was discharged to home the next day.
Definitive diagnosis of LEMS was established by the presence of calcium channel antibodies observed during the final phase of paraneoplastic panel testing and an electromyogram demonstrating characteristic findings (i.e., an abnormally low amplitude of the compound muscle action potential evoked by a single nerve stimulus in rested muscle and a progressive increase during high-frequency stimulation or immediately after brief maximal voluntary contraction of the muscle).
In the 4 mo after this procedure, the patient underwent four cycles of etoposide/cisplatin chemotherapy as well as radiation therapy. Imaging studies demonstrated near complete regression of the cancer. Clinically, the patient had significant improvement in strength and steadiness of gait, and her diplopia resolved.
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Discussion |
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By definition, paraneoplastic syndromes are changes produced in tissues remote from a tumor or its metastases. Examples include PSCD, LEMS, hyponatremia, Cushing’s syndrome, and hypercalcemia. These syndromes result from tumor-mediated production of anti-Purkinje cell autoantibodies, calcium channel autoantibodies, inappropriate antidiuretic hormone, adrenocorticotropic hormone, and parathyroid hormone, respectively.
Subacute cerebellar degeneration was first described by Brouwer in 1919 (1,2). Clinically, patients with this disorder present with ataxia, dysarthria, wide-based gait, intention tremor, nystagmus, vertigo, diplopia, and unexplained episodes of nausea and vomiting (3,4). Cognition is usually spared (4). The cerebellar incoordination can become so severe that the patient is unable to sit or stand unsupported. As was the case in our patient, the paraneoplastic syndrome can precede cancer diagnosis by months to years (4). Associated malignancies include lung, breast, ovarian, colon, renal, gastrointestinal, thyroid, tonsils, larynx, parotid, lymphoma, acute myelocytic leukemia, and prostate (4). The proposed pathophysiologic mechanism responsible for PSCD is as follows: antigens present in the tumor initiate an immune reaction resulting in the release of cerebellar anti-Purkinje cell immunoglobulin G autoantibody that identify and destroy cerebellar Purkinje cells (4). The diagnosis depends on clinical findings and a positive cerebellar anti-Purkinje cell antibody assay. Because autoimmune destruction of the Purkinje cell layer of the cerebellar cortex is only observed histologically, routine radiologic studies (e.g., radiographs, computerized tomography, magnetic resonance imaging, and magnetic resonance angiography) are devoid of pathognomonic findings.
LEMS is a rare autoimmune-mediated disorder in which a malignant tumor stimulates the synthesis and release of immunoglobulin G autoantibodies that attack prejunctional voltage-gated calcium channels (5,6). A paucity of prejunctional calcium causes decreased release of acetylcholine quanta into the neuromuscular cleft, resulting in skeletal muscle weakness (5,6). Proximal lower extremity muscles (e.g., pelvic girdle) tend to be more susceptible than those in the upper extremities (2,3,5–9). Skeletal muscle strength often improves with repetitive movement or exercise as more quanta of acetylcholine are released into the neuromuscular junction, but is unresponsive to anticholinesterase medications (6–9). These patients are sensitive to both nondepolarizing and depolarizing muscle relaxants; however, the duration of block prolongation is unknown (7–10). Other symptoms include hypo- or a-reflexia, autonomic dysfunction (e.g., impotence, xerostomia, impaired sweating), and occasionally bulbar dysfunction (2,3,5–9). The syndrome more commonly affects individuals >40 years of age and has a male predominance, and symptoms usually precede tumor diagnosis by 
10 months (6,9). Tumors associated with this syndrome include bronchogenic small cell (also known as oat cell) carcinoma, as well as breast, ovarian, prostate, and gastrointestinal cancer (2,3,5–9). It deserves mention that nearly half of LEMS cases occur in the absence of an obvious malignancy (6,9). The incidence of LEMS in patients with bronchogenic small cell carcinoma is approximately 6% (9).
Treatment of LEMS focuses on improving neuromuscular transmission. As cited above, cholinesterase inhibitors are ineffective (6–9). Guanidine hydrochloride inhibits calcium uptake into subcellular organelles, resulting in increased intracellular calcium (9). This, in turn, facilitates acetylcholine release from the nerve terminal, which improves neuromuscular transmission (9). Unfortunately, the side effect profile of this drug detracts from its clinical usefulness. For example, bone marrow suppression, chronic interstitial nephritis, renal tubular acidosis, cardiac dysrhythmia, hepatotoxicity, pancreatic dysfunction, peripheral neuropathy, ataxia, mental status changes, and death are associated with guanidine administration (9). Other pharmacologic interventions include 3,4-diaminopyridine, a drug that selectively blocks potassium channels, thus preventing potassium efflux, which prolongs the action potential (9,11). This prolongation leaves the voltage-gated calcium channel open longer, which results in more calcium entry and thus more acetylcholine release (9,11). Immunosuppression (e.g., corticosteroid, azathioprine, plasmapheresis) can cause some improvement in this autoimmune disease (9). Of pharmacologic interventions available to improve skeletal muscle function, 3,4-diaminopyridine appears to be the best choice. However, we elected not to pursue this course of action because this drug is typically given to LEMS patients who have not received IV muscle relaxants. That is, we were concerned about the unpredictability of response. In patients with LEMS who have cancer, effective treatment of the malignancy often produces marked improvement of strength (9,11). The median duration between tumor diagnosis and death is 8.5 months (6).
Patients presenting with coexisting PSCD and LEMS are extremely rare (2,3). Unlike previously described cases in which patients typically manifested symptoms consistent with both disease processes (e.g., cerebellar deficits and weakness) (2,3), our patient did not experience weakness before mediastinoscopy. That is, she had subclinical LEMS. However, this was not evident until muscle relaxants were administered intraoperatively. In retrospect, we did not have a full appreciation of her diminished train-of-four response (before giving cisatracurium) until the end of the surgical procedure. Incomplete resolution of succinylcholine-induced muscle relaxation (observed during train-of-four stimulation) should have been our first indication that something was amiss with her neuromuscular physiology.
The presence of one paraneoplastic syndrome does not necessarily predispose a patient to another. Nonetheless, coexisting paraneoplastic syndromes can occur concurrently (2,3) or—as we experienced—sequentially. Accordingly, it is prudent to consider the coexistence of paraneoplastic syndromes in cancer patients experiencing PSCD, LEMS, hyponatremia, Cushing’s syndrome, hypercalcemia, or any combination of these disorders during the perioperative period.
In summary, we describe a unique case of concomitant PSCD and LEMS in which our patient did not manifest evidence of the latter paraneoplastic syndrome until muscle relaxants were administered intraoperatively. Conservative management of the airway (i.e., tracheal intubation and mechanical ventilation) and providing sedation resulted in safe postoperative patient care. Coexisting paraneoplastic syndromes are extremely rare and present a clinical challenge when they arise sequentially and unexpectedly.
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