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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.
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