1189 Carpal Tunnel Syndrome Associated with Interleukin2 Therapy Vinay K. Puduvalli, M.o.' Avishay Sella, M.O? Sara G. Austin, M.O.' Arthur D. Forman, 1.0: Department of Neurology, University of Texas Medical School, Houston, Texas. Department of Neuro-Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas. BACKGROUND. Interleukin-2 (IL-2) has been extensively used in our institution in the treatment of cancer and has protean neurologic side effects. Carpal tunnel syndrome developing in patients receiving IL-2 appears to have a good prognosis and may spare the patient unneeded investigation. METHODS. A retrospective evaluation was undertaken for all patients using our institution's Patient Studies database. The patients were examined and their charts reviewed. RESULTS. We found eight patients with renal cell carcinoma who developed carpal tunnel syndrome (CTS) during treatment with IL-2. 5-fluorouracil (5-FU). and alpha-interferon (a-IFN). The symptoms were bilateral in five patients and all patients improved with cessation of therapy. Three patients had recurrent symptoms with subsequent courses of therapy. Symptoms occurred during or shortly after IL-2 infusion and resolved after therapy was completed with conservative management. The number of courses given did not seem to correlate with the development of symptoms. Neurophysiologic studies demonstrated conduction velocity slowing without evidence of acute denervation. CONCLUSIONS. IL-2 can produce focal entrapment of the median nerve at the wrist, which reverses with drug withdrawal. IL-2 mediates the inflammatory response and can cause interstitial edema that likely causes CTS to develop in predisposed patients undergoing treatment. Cancer 1996; 7 2 1189-92. 0 1996 American Cancer Sociefy. KEYWORDS: interleukin-2, cytokines, neuropathy, neurotoxicity, carpal tunnel syndrome, median nerve. I Address for reprints: Arthur D. Forman, M.D.. Department of Neuro-Oncology, UTMDACC. Box 100, 1515 Holcombe Blvd., Houston, TX 77030. Received August 21, 1995; revision received November 17, 1995; accepted November 17, 1995. 0 1996 American Cancer Society nterleukin-2 (IL-2)has demonstrated some benefit in treating renal cell carcinoma, has been considered for the therapy of several other cancers (including malignant melanoma, colorectal carcinoma, ovarian carcinoma, acute myelogenous leukemia, and non-Hodgkins lymphoma' 1, and may have increasing use in the treatment of acquired immunodeficiency syndrome.' This biologic therapy has activity in renal cell carcinoma and malignant m e l a n ~ m a . ~ Unfortunately, .~ 1L-2 therapy also can be associated with significant m ~ r b i d i t ysometimes ,~ demanding abbreviation of the duration of treatment in the face of success. The side effects can range from mild ones, such as fever, transient anorexia, or erythematous rash, to more significant ones, such as severe mucositis, hypotension, confusion, renal failure, fluid retention, and diffuse edema. Peripheral nerve dysfunction has been reported in only one patient in the past.6 We report a series of eight adults with renal cell carcinoma who developed carpal tunnel syndrome (CTS)during therapy with IL-2. MATERIALS AND METHODS Eight adult patients with a diagnosis of CTS following treatment with IL2 were studied. All patients were seen in neurologic consultation at the 1190 CANCER March 15, 1996 / Volume 77 / Number 6 University of Texas M. D. Anderson Cancer Center (UTMDACC) and were each examined by at least one of the authors. A survey of a database maintained by the UTMDACC Department of Patient Studies assured us that no patients were overlooked and found a total of 38 other patients who had been diagnosed with CTS from March 1944 to December 1993, which was the endpoint of our retrospective review. Given the specialized nature of our institution, there were doubtless more patients with CTS than recorded in the Patient Studies registry because the condition was likely underreported by the primary oncologists. All patients we are describing had been diagnosed with renal carcinoma and were receiving IL-2 as part of an experimental protocol using multiple (5-6 usually) courses of a combination of IL-2 (6 million International Units [IU]/m2),5-fluorouracil (5-FU) (600 mglrn') in combination daily for 5 days every 28 days and continuous therapy with alpha-interferon (a-IFN) (4 million IU/ m2)subcutaneously through the 4-week cycle. The diagnosis of CTS was based on electromyography nerve conduction (EMGINC) studies as well as clinical symptoms, including sensorimotor changes in the median nerve distribution and a positive Tinel's or Phalen's sign. In four patients with definite signs and symptoms, EMGlNC studies were not performed as the clinical presentation and course was unambiguous. One patient underwent neurophysiologic evaluation at an outside institution. All patients were followed clinically. Three patients had a recurrence of symptoms with a subsequent course of IL2 therapy, with one patient undergoing follow-up EMGl NC study. RESULTS All patients were males in their fourth to sixth decades of life, except the sole female patient, who was in her third decade. Except for one male patient who was a draftsman, none of the patients had been in any occupations that typically predispose to the development of CTS. No symptoms suggestive of CTS were reported by any patient prior to initiation of IL-2 therapy. Fever, decreased appetite, malaise, mucositis, skin rash, diffuse edema with increased weight, increased creatinine, decreased urinary output, and, occasionally, nausea and vomiting, increased bilirubin, joint pains, and confusion occurred in varying degrees in all patients during each course of therapy* Four patients, all right-handed males, reported unilateral symptoms on the right side. Three had only sensory symptoms and one patient had them intermittently. The remaining patients had bilateral sensory symptoms that in one patient also involved the ulnar distribution, two patients had additional mild motor symptoms. One patient with right-hand paresthesia was also found to have metastatic disease in the proximal radius and ulna on the symptomatic side with a pathologic fracture in the proximal radius. This patient's signs, symptoms, and temporal course were sufficiently distant to the site of metastasis that they were felt to be unrelated. No relationship was noted to exist between the onset of symptoms and the number of courses of treatment received, but the symptoms tended to arise shortly after or even during the IL-2 infusion. Three patients developed recurrence of symptoms during a subsequent course of therapy similar in pattern to those during an earlier treatment. In all instances, the symptoms were moderate in degree yet significantly distressing to the patients, but they all improved with completion of the course of treatment or responded to conservative therapy with wrist splints. This was also true of the patients who had recurrent symptoms during a subsequent course. In most patients, recovery was within 2 days of completion of the course. Electrophysiologic studies revealed sensorimotor median neuropathy with neurophysiologic qualities suggesting axonal dysfunction and demyelination (Table 1) at the wrist in all five patients who were tested out of the total of eight patients. Mild ulnar neuropathy was noted in one patient. In the case of a patient who had the pathologic fracture of the proximal radius, no involvement of the median nerve was apparent at the level of the lesion, but a definite median neuropathy at the wrist was evident. N o patients had thyroid abnormalities noted on testing. TYPICAL PATIENTS Patient 1. A 56-year-old male was found to have renal cell carcinoma presenting with hematuria. He was also noted to have metastatic disease to the liver. Treatment according to protocol was begun with IL-2, 5-FU, and aIFN. He tolerated the first three courses of treatment with mild side effects including fever, mild headache, Grade 1 mucositis, and mild weight gain. During the fourth course, he developed more severe symptoms with a fever of 39.4 "C, chills, decreased urinary output, elevation in serum creatinine, diarrhea, and Grade 2 mucositis. On the second day of therapy, he reported tingling and numbness in the right hand in the median nerve's sensory distribution. The symptoms persisted as therapy was continued and were worse at night. Examination revealed hypesthesia ir. the first three digits and mild weakness of the abductor pollicis brevis muscle with a positive Tinel's sign. These symptoms resolved within 24 hours of completion of the course. A month later, he received the fifth course of therapy. He again developed fever, mucositis, peripheral edema, confusion, chills, and diminished urine output. He also developed tingling and numbness in his right hand as with the previous course. An EMGl Carpal Tunnel Syndrome with Interleukin-2/PuduvaIli et al. 1191 TABLE 1 Results of Nerve Conduction Studies Median nerve motor Median nerve sensory study Latency Amplitude Distal latency Amplitude Conduction velocity F wave 1 2 3 4 4.0 (< 3.6) 10.0 (> 15) 5.9 (< 4.0) 5.5 (< 4.0) 6.5 (< 3.9) 4.7 (< 4.0) 2.0 (> 5.0) 3.3 (> 5.0) 6.3 (> 6.0) 1.9 (> 6.0) 60 (> 50) 53 (> 50) 50 (210) 50 (> 50) 33.2 (< 31) 33.4 (< 31) 32.7(< 31) NR 3.6 (< 3.4) 4.3 (< 3.6) 11.4 (> 20) 9.5 (> 15) Number in parentheses represents normal values. One patient had studies performed, but only the summary (not the values) was available. NCS revealed moderate to severe right median mononeuropathy at the wrist. Two days after completion of the course, his symptoms improved rapidly. during the earlier examination. Neurophysiologic examination was not performed. DISCUSSION Patient 2. A 46-year-old white male was diagnosed with metastatic renal cell carcinoma and was placed on protocol therapy with IL-2, 5 F U , and a-IFN.No significant side effects were noted during the first three courses of therapy except for mild fever, transient elevation in creatinine, and weight gain with Grade 1 mucositis. During the fourth course, he developed fever, chills, Grade 2 mucositis, Grade 2 skin rash, decreased urine output, increased serum creatinine, and increased bilirubin. He simultaneously developed numbness, tingling, and pain in the first three digits of both his hands with the symptoms worse on his left side. Examination demonstrated decreased sensation in the median nerve’s sensory distribution with the patient having both Tinel’s and Phalen’s signs. Electrophysiologic studies revealed a left median demyelinating sensorimotor neuropathy. His symptoms were managed with extensor wrist splints and analgesics, and improved with this conservative management and resolved following completion of the protocol therapy. Patient 3. A 36-year-old white female diagnosed with renal cell carcinoma was treated with IL-2,5-FU and a-IFN on protocol therapy. After two courses without bothersome symptoms, the patient developed bilateral numbness and tingling in the median distribution during the third course. Examination revealed sensory changes in the median distribution without weakness and the left wrist had Tinel’s sign. Bilateral wrist splints were provided with subsequent relief of the patient’s symptoms. The fourth and fifth courses were without appearance of the carpal tunnel syndrome, but on the sixth course the patient’s neurologic symptoms recurred and were associated with fever, peripheral edema, rash, and generalized body aches. Bilateral sensory changes were noted on examination and all symptoms resolved with wrist splits as Entrapment of the median nerve at the wrist or CTS is the most common peripheral nerve entrapment. When the symptoms and signs are typical, the diagnosis can be made clinically and confirmed with neurophysiologic evaluation. Women develop CTS about three times as often as men,’ but in the cases reported here, seven of the eight patients were males. This disparity may be partially explained by the observed 2 to 1 male prevalence for renal cell carcinoma that was also seen in the patients enrolled on this protocol. Trauma, particularly occupational repetitive trauma, is the most common etiologic factor for developing CTS. Other risk factors associated with CTS include rheumatoid arthritis, polymyalgia rheumatica, pregnancy, amyloidosis, familial liability to pressure palsy, acromegaly, and hypothyroidism.* We found none of these in any of the eight patients except for one who was a draftsman and may have been subjected to repetitive occupational wrist injury. IL-2 therapy in cancer is known to be associated with a wide range of side effects affecting almost all systems in the body, especially the skin and mucus membranes, the vascular compartment, and the renal ~ y s t e mNeuro.~ logic side effects, when present, are usually in the form of alteration in mental status with confusion, disorientation, or delirium as the common pre~entation.~ Except for a solitary report: peripheral nerve damage has not been reported as a significant morbidity associated with this therapy. Neither therapy with 5-FU nor alpha interferon has previously been reported as being associated with CTS. Furthermore, in those patients in whom the IL-2 course had to be shortened by 2 to 3 days because of the severity of CTS symptoms (whereas other treatment was continued until completion of the course), the CTS symptoms abated within 24 hours. 1192 CANCER March 15,1996 I Volume 77 / Number 6 The side effects associated with IL-2 therapy are believed to be due to a widespread exaggeration of the physiologic action of IL-2 as a cytokine.’’ This includes its role as a pyrogen and in mediating inflammatory responses in a variety of tissues. The occurrence of fever, skin rash, mucositis, and edema with IL-2 therapy supports this possibility. Some of the effects are thought to be initiated by changes in vascular permeability due to the action of IL-2 at the level of the endothelium leading to the socalled “capillary leak syndrome” that causes transfer of fluid from the vascular compartment into the extravascular spaces. The mechanism of this “leak” is thought to be associated with increased capillary perfusion leading to a larger microvascular surface area promoting movement of protein and fluid across the capillaries.” This manifests clinically as diffuse edema, hypotension, increased weight, and decreased renal output because of reduced renal perfusion. Interstitial edema of tissues in the anatomically narrow carpal tunnel could cause pressure on the median nerve at the wrist with subsequent compromise of the intraneural microcirculation” and, consequently, a compressive entrapment neuropathy resulting in symptoms of CTS. This appears to be a transient phenomenon easily reversed once the exposure to IL-2 is stopped. However, the severity and duration of symptoms may be related to the dose of IL-2 administered, because our patients received one-third the dose of IL-2 given to the single patient described by Heys et al. (6 vs. 18 IU/mZ daily for 5 days) who had to undergo carpal tunnel surgical decompression urgently on one side because of persistent and distressing symptoms even after discontinuation of IL-2 therapy.fiWhile reporting this series of patients developing CTS with IL-2 treatment, it also seems apparent to us that other cytokines that can disturb vascular permeability to a similar degree can probably cause CTS in the predisposed patient. This predisposition may be because of the anatomic arrangement of the carpal tunnel and varying patterns of microcirculation of the median nerve. Many more patients at our institution have been treated with a-IFN than with IL-2 and usually for protracted courses. None of the patients treated with a-IFN alone had complained of carpal tunnel symptoms. Although cytokines are known to have broad and complex interactions, the close temporal relationship between IL2 therapy and the development of the CTS symptoms strongly implicates IL-2 as the causative agent. 5-FU has not been associated with entrapment neuropathy. Therapy with cytokines is proving to be promising in at least some cancers and it is conceivable that more widespread use of these agents may become common practice.” In such settings, it is important to be aware not only of the effect of IL-2 therapy on peripheral nerves causing CTS but also of the good overall prognosis, particularly when IL-2 is given in a less intensive fashion. The toxicity seen here did not cause intractable deficit in any patient and some patients (see Patient 3) did not have episodes of median nerve entrapment with every subsequent course. Recognition of the typical syndrome may spare patients needless investigations, discomfort, and anxiety. 1. 2. 3. 4. 5. 6. 7. 8. 9. 0. 1. 2. 3. 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