ABSTRACT
ABSTRACT
Objective: The management of nonmalignant pain by morphine pump implantation has become an effective
and increasingly frequent strategy of care. We report a rare complication of intrathecal
granuloma formation adjacent to the intrathecal catheter tip resulting in spinal cord
compression in four patients undergoing intrathecal treatment for chronic pain.
Methods: Four patients presented with chronic back pain and lower extremity pain and weakness
and were treated with morphine pump implantation. Each patient developed a mass at
the level of the intrathecal catheter tipp resulting in increased back pain and diminished
neurological function. Following clinical examination and x-ray workup, the patients
underwent surgical resection of the mass and removal of the intrathecal catheter.
One patient received conservative saline therapy first, and another patient had granuloma
resection first and removal of the intrathecal catheter at a later date. Pathological
analysis showed granulation tissue with extensive necrosis and chronic inflammation,
with negative culture results. No evidence of neoplasm was found.
Results: Patients showed varying degrees of improvement following removal of the intrathecal
mass. Two patients had moderate pain reduction following resection of the granuloma;
a third had minimal pain improvement; and a fourth had significant pain improvement
but continued lower extremity weakness.
Conclusions: The formation of granulomas caused by intrathecal catheter implantation is a rare
but serious complication. Imaging studies including magnetic resonance imaging with
contrast and computed tomography with myelogram should be used to follow up a neurological
examination consistent with spinal cord compression. Timely surgical intervention
may result in marked improvement of symptoms.
INTRODUCTION
Initially used in the treatment of cancer pain [1], the implantation of morphine pumps has become an increasingly used treatment for
patients with nonmalignant pain. More than 95,000 intrathecal drug delivery devices
have been implanted since their inception in the 1980s [2]. The benefits of intrathecal drug therapy for the treatment of nonmalignant pain,
most frequently due to „failed back syndrome,” have been well documented [3], [4]. A rare but serious complication of this therapy is the development of an inflammatory
mass at the catheter tip occurring in less than 3 % of all patients with intrathecal
catheters, often resulting in spinal cord compression [2]. The appearance of the developing mass often begins after an extended period of
intrathecal morphine therapy, with a sudden increase in pain followed by development
of neurological symptoms. We report four patients who underwent intrathecal analgesic
treatment, who later presented with symptoms of spinal cord compression and were diagnosed
as having developed catheter-tip masses 3.5 to 12 years after intrathecal catheters
placement.
CASE REPORT
Patient 1
A 51-year-old man presented with a several-month course of increasing chronic low
back pain and bilateral lower extremity weakness associated with burning, numbness,
and foot pain. His medical history includes two back surgeries with laminectomy and
posterior fusion of L4–S1, and was 5 years status after placement of an intrathecal
morphine pump for chronic lower back pain. A motor examination of his lower extremities
revealed some antalgic weakness bilaterally in both distal lower extremities, especially
at dorsi and plantar flexion bilaterally at 4-/5. His knee extension and flexion were
full. His right knee jerk was slightly brisk compared with the left.
A magnetic resonance imaging (MRI) of the thoracic and lumbar spine with and without
contrast revealed an intradural extramedullary mass at T11 with abnormal hyperintense
signal intensity within the spinal cord at the T10–11 levels, suggesting edema or
myelomalacia (Fig [1]).
The patient underwent T11–12 laminectomy with intradural exploration, resection of
the intradural mass, and removal of the intrathecal catheter. Pathological findings
showed multiple small fragments of necrotic and fibrous tissue with chronic inflammation
and scant hemosiderin consistent with a granuloma. Cultures were negative.
Follow-up neurological examination showed significant improvement in lower extremity
and back pain; however, the right lower extremity weakness did not show any improvement.
The patient continued oral medication therapy, and the neurological examination was
unchanged at 30 months postoperatively.
Patient 2
A 65-year-old woman presented with mid-to-low back pain radiating down to the thighs,
right worse than the left, and progressive weakness and numbness in both lower extremities.
She had been administered intrathecal morphine for 12 years for failed back syndrome
status after multiple fusions and laminectomies.
A CT myelogram showed an 8 mm rounded density corresponding to the location of the
intrathecal catheter tip at T11–T12 (Fig [2]). Physical examination revealed bilateral lower extremity motor strength at 4/5
and diminished lower extremity deep tendon reflexes, while the sensory system was
intact. An MRI scan showed a posterior lower thoracic intradural extramedullary mass
consistent with granuloma.
The patient underwent T11 laminectomy with intradural exploration and subsequent removal
of intradural mass, which was found to be causing marked spinal cord compression.
There were also nerve roots attached to the left lateral aspect of the mass. With
the use of microdissectors, the mass was circumferentially freed and removed en block.
Pathological findings revealed hyalinized soft tissue with necrosis consistent with
granuloma. Cultures were negative. Her pain improved after surgery and she received
oral oxycodone for further pain control. Twelve months after follow-up she has no
evidence of recurrent granuloma.
Fig. 1 T1 sagittal magnetic resonance imaging with contrast shows enhancing lesion at T11.
Fig. 1 T1 sagittal magnetic resonance imaging with contrast shows enhancing lesion at T11.
Fig. 2 Post-myelogram computed tomography shows granuloma at T11.
Fig. 2 Post-myelogram computed tomography shows granuloma at T11.
DISCUSSION
The intrathecal effect of morphine in the treatment of chronic pain is through spinal
and supraspinal receptors, without significantly influencing motor, sensory, and sympathetic
reflexes [4]. It is most often used in the nonmalignant patient for chronic lumbosacral pain
due to „failed back syndrome” [5]. Animal studies have shown that with chronic intrathecal infusion of the maximum
tolerated doses of morphine, hydromorphone, L-methadone, and naloxone, there is 100 %
intradural granuloma formation [6]. In humans the duration of therapy before granuloma diagnosis has been reported
to be 0.5 to 72 months [7]. After 2 years of therapy, the incidence of symptomatic intrathecal catheter-tip
granuloma formation is reported to be only 0.4 %; after 6 years, this incidence increases
to only 1.16 % [8], [9]. Three of our four cases were within this time frame, while one case was diagnosed
with intrathecal granuloma after 12 years of intrathecal catheter placement.
The other two cases not previously discussed presented with symptoms of spinal cord
compression and were diagnosed with intrathecal granuloma 3.5 years and 5 years, respectively,
after intrathecal catheter placement. The former was treated with the granuloma being
removed first and the intrathecal catheter removed at a later date; the latter was
initially treated conservatively with pump refills replaced with saline. None of these
management methods were found to be effective and both patients had to ultimately
undergo removal of the intrathecal catheter and resection of the granuloma. The first
patient had minimal pain improvement. The second patient was discharged in good condition;
he remains in continued pain 2 years after granuloma resection.
To date, less than 60 cases of inflammatory catheter-tip masses have been reported
following chronic infusion of opiates [4], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. Four of these showed the development of a granuloma that included findings of positive
cultures, with one occurring 11 years after discontinuation of the opiate therapy;
infection is unlikely as the cause for the other three [11], [12], [13], [17]. Three cases have also been published where the patient developed inflammatory catheter-tip
masses with baclofen as the sole agent in a long-term intrathecal catheter [15], [29]. Hydromorphone has also been found to cause intrathecal granuloma formation [23]. In animal model studies, baclofen alone had not been shown to induce granuloma
formation with long-term intrathecal delivery [29].
The etiology for the development of inflammatory masses caused by intrathecal morphine
is unclear. Proposed mechanisms include the action of morphine as a mitogen, activating
a protein kinase cascade and activating lymphocyte activity. Another is the effect
of opioids on endothelial cells, granulocytes, and monocytes to release nitric oxide,
which may lead to monocyte migration, or finally that morphine enhances cytokine formation
leading to the inflammatory response [30]. The catheter tip being positioned in the thoracic spinal cord, which is the longest
area of low cerebrospinal fluid velocity, in conjunction with use of high concentration
of drugs is also considered a contributing factor to inciting local inflammation.
The resulting fibrosis further decreases cerebrospinal fluid-flow velocity and turns
the situation into a vicious cycle, amplifying the drug concentration in that area
[2].
The treatment of intrathecal inflammatory masses in patients with chronic pain includes
surgical and nonsurgical methods. Nonsurgical methods, as conservative saline therapy,
have not been found to be very beneficial; while surgical resection of the mass and
removal of the intrathecal catheter provided the most satisfactory results for our
four case-patients. The nonsurgical treatment by discontinuation of opiates has been
beneficial in some patients; however, our patient who was treated with this method
continued to have a progression of symptoms, and surgical management was required
[30]. Surgery may be the optimal treatment for symptomatic granulomas compressing the
spinal cord.
SUMMARY AND CONCLUSION
The formation of granulomas induced by intrathecal catheter implantation is a rare
but serious complication. Imaging studies including MRI with contrast and CT myelogram
should be used to follow up a neurological examination consistent with spinal cord
compression. Timely surgical intervention may result in marked improvement of symptoms.
ACKNOWLEDGMENT
We thank Karen K Anderson for her assistance in manuscript preparation.
Fig. 3 Patient sampling and selection.
Fig. 3 Patient sampling and selection.
