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The Complications of Scar Formation Associated With Intrathecal Pump Placement
389
CLINICAL NOTE
The Complications of Scar Formation Associated With Intrathecal Pump Placement Marina G. Protopapas, DO, Elizabeth Bundock, MD, Susan Westmoreland, VMD, Christopher Nero, MD, W. Andrew Graham, PhD, Shanker Nesathurai, MD ABSTRACT. Protopapas MG, Bundock E, Westmoreland S, Nero C, Graham WA, Nesathurai S. The complications of scar formation associated with intrathecal pump placement. Arch Phys Med Rehabil 2007;88:389-90. A 40-year-old man had an intrathecal morphine-baclofen pump inserted for the treatment of severe dystonia affecting all limbs and severe low back pain. The etiology of his dystonic symptoms, despite thorough investigations, was uncertain. At age 45, the patient fell resulting in a cervical spinal cord injury. He underwent C2 through C5 instrumentation and fusion for cervical spine stabilization. Subsequently, an intrathecal morphine-baclofen pump was implanted to control pain and decrease spasticity. The patient ultimately died at age 48 from complications of pneumonia, and an autopsy was performed. Gross pathologic examination revealed that the intrathecal catheter entered the posterior aspect of the lumbar thecal sac, but coursed superiorly in the anterior intradural space. The catheter tip exited the thecal sac in the upper thoracic spine and became embedded in a fibrotic scar. Displacement of the catheter tip of the intrathecal morphine-baclofen pump and subsequent formation of scar tissue resulted in decreased drug delivery, contributing to diminished pain control and functional status. Catheter displacement and epidural scar formation must be considered as a potential cause of ineffective pain control and decreased functional status in patients with intrathecal morphine-baclofen pumps. Key Words: Case report; Intrathecal injections; Muscle spasticity; Spinal injections; Rehabilitation. © 2007 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation DRUG DELIVERY systems are effective the management of spasticity and intractable pain. TypiIcally,inNTRATHECAL these systems consist of a pump that contains a reservoir of medications such as morphine, clonidine, and baclofen. A catheter is attached to the pump, and the terminal portion is placed in the intrathecal space, thereby delivering medications on a continuous basis. Clinicians, however, should be aware that granulomas can form at the distal end of the catheter tip that decrease drug delivery and/or irritate the exiting nerve roots and/or spinal cord. This complication can result in pro-
From the Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA (Protopapas, Bundock, Nero, Graham, Nesathurai); and Massachusetts General Hospital, Harvard Medical School, Boston, MA (Bundock, Westmoreland, Nero, Nesathurai). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Shanker Nesathurai, MD, Physical Medicine and Rehabilitation Dept, Spaulding Rehabilitation Hospital, Harvard Medical School, 125 Nashua St, Boston, MA, 02114, e-mail: [email protected]. 0003-9993/07/8803-11075$32.00/0 doi:10.1016/j.apmr.2006.12.023
tean clinical manifestations. Here, we present a case in which intrathecal drug treatment was associated with granuloma formation that may have caused decreased drug delivery and, perhaps, an increase in pain and spasticity in the patient. CASE DESCRIPTION At age 30, an otherwise healthy school teacher was diagnosed with testicular cancer, which was treated with unilateral orchiectomy and exploratory laparotomy. He did not receive radiation or chemotherapy. One year later, he developed depression with psychotic features, which was treated with antipsychotic agents. Subsequently, he developed severe dystonia which affected all 4 limbs. The etiology of his dystonia was never fully ascertained; however, there was some concern that it was precipitated by treatment with antipsychotic agents. The dystonia exacerbated his pre-existing low back pain (LBP). At age 40, an intrathecal morphine-baclofen pump was inserted for management of LBP and dystonia. At age 45, the patient experienced a fall, which resulted in cervical spinal cord injury. Although he did not have evidence of a fracture, he underwent decompression and fusion between levels C2 and C5. The effectiveness of the intrathecal morphine-baclofen pump in controlling his pain and spasticity decreased over time. This patient died at age 48 from untreated pneumonia. A postmortem evaluation was performed, which included removal and examination of the spinal cord. The gross pathologic examination revealed that the intrathecal catheter entered the posterior aspect of the lumbar thecal sac, but ultimately coursed superiorly in the anterior intradural space and exited the thecal sac in the upper thoracic spine. The catheter tip was encased in a partially calcified, fibrotic mass of epidural scar tissue. The scarred dura was adhered to the leptomeninges, though the underlying spinal cord appeared grossly normal (figs 1, 2). Throughout the cervical and thoracic spinal cord, there was histologic evidence of marked neuronal loss and gliosis in the anterior horns and Clarke’s columns. The distribution of the neuronal loss (ie, cervical and thoracic involvement with sacral sparing) did not correspond well with the history of cervical disease. The intrathecal drug-administration catheter tip had perforated the anterior dura and had become encased in scar tissue. The underlying spinal cord did not appear to have been compromised by mass effect (fig 3). DISCUSSION Displacement of the catheter tip and subsequent formation of scar tissue may result in decreased drug delivery. In this patient, this phenomenon may have resulted in either diminished pain control and/or increased spasticity. Clinicians should maintain a high index of suspicion to identify the development of scar formation and/or catheter blockage in the early phase.1 During the early phase of granulomatous scar formation, the clinical symptoms and signs may be subtle. For example, scar formation and/or catheter displacement may result in decreased analgesia requiring an extraordinary increase in medication dosage. Catheter tip scar formation Arch Phys Med Rehabil Vol 88, March 2007
390
SCAR FORMATION AND INTRATHECAL PUMP PLACEMENT, Protopapas
Fig 1. Gross pathologic specimen. Note the fibrotic scar in the anterior aspect of the spinal cord.
at the thoracic level may irritate the exiting nerve roots (ie, intercostal neuralgia) or even mimic cholecystitis by producing right upper quadrant pain. Catheter tip masses in the lumbar region may irritate exiting nerve roots, and thereby mimic such conditions as a herniated lumbar disk and spinal stenosis.1 Scar formation at the catheter tip may result in insidious compression of the spinal cord or cauda equina2 and cause slowly progressive weakness. Other early signs of scar formation development include an unexplained increase in muscle spasticity. The etiology and pathophysiologic mechanisms that lead to the formation of catheter tip inflammatory masses remains unclear. Opioids can incite an inflammatory response in brain and spinal cord tissue through yet to be determined mechanisms. Alternatively, morphine can trigger a mitogen-activated protein kinase cascade, thus activating lymphocyte activity.3,4 Opioid compounds may cause human endothelial cells, granulocytes, and monocytes to release nitric oxide, which in turn might, in the presence of mesangial cells, lead to monocyte migration.5-7 Finally, morphine has been shown to enhance cytokine formation, leading to an inflammatory cell response.8 Whether the phenomenon is -opioid-receptor mediated or naloxone reversible remains to be determined.9 A widely accepted strategy to prevent granuloma formation is to maintain
Fig 2. Gross pathologic specimen. Note that the epidural catheter has become repositioned in the anterior aspect of the subdural space.
Arch Phys Med Rehabil Vol 88, March 2007
Fig 3. Histologic section of catheter tip embedded in scar tissue adjacent to spinal cord. Hematoxylin and eosin stained formalin fixed tissue section, magnified ⴛ 200.
the drug dose and concentration as low as possible for as long as possible while still achieving symptom control.1 CONCLUSIONS Intrathecal drug delivery systems are potent tools in the management of spasticity and pain. Nevertheless, every treatment has potential side effects and complications. In this context, clinicians should maintain a high index of suspicion to identify granuloma formation as early as possible. References 1. Hassenbusch S, Burchiel K, Coffey RJ, et al. Management of intrathecal catheter-tip inflammatory masses: a consensus statement. Pain Med 2002;3:315-23. 2. Coffey RJ, Burchiel K. Inflammatory mass lesions associated with intrathecal drug infusion catheters: report and observations on 41 patients. Neurosurgery 2002;50:78-87. 3. Bidlack JM, Hemmick LM. Morphine enhancement of mitogeninduced T-cell proliferation. Prog Clin Biol Res 1990;328:405-8. 4. Chuang LF, Killam KF Jr, Chuang RY. Opioid dependency and T-helper cell functions in rhesus monkey. In Vivo 1993;7:159-66. 5. Magazine HI, Liu Y, Bilfinger TV, Fricchione GL, Stefano GB. Morphine induced conformational changes in human monocytes, granulocytes, and endothelial cells and invertebrate immunocytes and microglia are mediated by nitric oxide. J Immunol 1996;156: 4845-50. 6. Nelson CJ, Lysle DT. Morphine modulation of the contact hypersensitivity response: characterization of immunological changes. Clin Immunol 2001;1998:370-7. 7. Stefano GB. Autoimmunovascular regulation: morphine and anandamide and ancondamide stimulated nitric oxide release. J Neuroimmunol 1998;83:70-6. 8. Singhal PC, Shan Z, Garg P, Sharma K, Sharma P, Gibbons N. Morphine modulates migration of monocytes. Nephron 1996;73: 526-31. 9. Chuang LF, Killam KF Jr, Chuang RY. Induction and activation of mitogen-activated protein kinases of human lymphocytes as one of the signaling pathways of the immunomodulatory effects of morphine sulfate. J Biol Chem 1997;272:26815-7.
CLINICAL NOTE
The Complications of Scar Formation Associated With Intrathecal Pump Placement Marina G. Protopapas, DO, Elizabeth Bundock, MD, Susan Westmoreland, VMD, Christopher Nero, MD, W. Andrew Graham, PhD, Shanker Nesathurai, MD ABSTRACT. Protopapas MG, Bundock E, Westmoreland S, Nero C, Graham WA, Nesathurai S. The complications of scar formation associated with intrathecal pump placement. Arch Phys Med Rehabil 2007;88:389-90. A 40-year-old man had an intrathecal morphine-baclofen pump inserted for the treatment of severe dystonia affecting all limbs and severe low back pain. The etiology of his dystonic symptoms, despite thorough investigations, was uncertain. At age 45, the patient fell resulting in a cervical spinal cord injury. He underwent C2 through C5 instrumentation and fusion for cervical spine stabilization. Subsequently, an intrathecal morphine-baclofen pump was implanted to control pain and decrease spasticity. The patient ultimately died at age 48 from complications of pneumonia, and an autopsy was performed. Gross pathologic examination revealed that the intrathecal catheter entered the posterior aspect of the lumbar thecal sac, but coursed superiorly in the anterior intradural space. The catheter tip exited the thecal sac in the upper thoracic spine and became embedded in a fibrotic scar. Displacement of the catheter tip of the intrathecal morphine-baclofen pump and subsequent formation of scar tissue resulted in decreased drug delivery, contributing to diminished pain control and functional status. Catheter displacement and epidural scar formation must be considered as a potential cause of ineffective pain control and decreased functional status in patients with intrathecal morphine-baclofen pumps. Key Words: Case report; Intrathecal injections; Muscle spasticity; Spinal injections; Rehabilitation. © 2007 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation DRUG DELIVERY systems are effective the management of spasticity and intractable pain. TypiIcally,inNTRATHECAL these systems consist of a pump that contains a reservoir of medications such as morphine, clonidine, and baclofen. A catheter is attached to the pump, and the terminal portion is placed in the intrathecal space, thereby delivering medications on a continuous basis. Clinicians, however, should be aware that granulomas can form at the distal end of the catheter tip that decrease drug delivery and/or irritate the exiting nerve roots and/or spinal cord. This complication can result in pro-
From the Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA (Protopapas, Bundock, Nero, Graham, Nesathurai); and Massachusetts General Hospital, Harvard Medical School, Boston, MA (Bundock, Westmoreland, Nero, Nesathurai). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Shanker Nesathurai, MD, Physical Medicine and Rehabilitation Dept, Spaulding Rehabilitation Hospital, Harvard Medical School, 125 Nashua St, Boston, MA, 02114, e-mail: [email protected]. 0003-9993/07/8803-11075$32.00/0 doi:10.1016/j.apmr.2006.12.023
tean clinical manifestations. Here, we present a case in which intrathecal drug treatment was associated with granuloma formation that may have caused decreased drug delivery and, perhaps, an increase in pain and spasticity in the patient. CASE DESCRIPTION At age 30, an otherwise healthy school teacher was diagnosed with testicular cancer, which was treated with unilateral orchiectomy and exploratory laparotomy. He did not receive radiation or chemotherapy. One year later, he developed depression with psychotic features, which was treated with antipsychotic agents. Subsequently, he developed severe dystonia which affected all 4 limbs. The etiology of his dystonia was never fully ascertained; however, there was some concern that it was precipitated by treatment with antipsychotic agents. The dystonia exacerbated his pre-existing low back pain (LBP). At age 40, an intrathecal morphine-baclofen pump was inserted for management of LBP and dystonia. At age 45, the patient experienced a fall, which resulted in cervical spinal cord injury. Although he did not have evidence of a fracture, he underwent decompression and fusion between levels C2 and C5. The effectiveness of the intrathecal morphine-baclofen pump in controlling his pain and spasticity decreased over time. This patient died at age 48 from untreated pneumonia. A postmortem evaluation was performed, which included removal and examination of the spinal cord. The gross pathologic examination revealed that the intrathecal catheter entered the posterior aspect of the lumbar thecal sac, but ultimately coursed superiorly in the anterior intradural space and exited the thecal sac in the upper thoracic spine. The catheter tip was encased in a partially calcified, fibrotic mass of epidural scar tissue. The scarred dura was adhered to the leptomeninges, though the underlying spinal cord appeared grossly normal (figs 1, 2). Throughout the cervical and thoracic spinal cord, there was histologic evidence of marked neuronal loss and gliosis in the anterior horns and Clarke’s columns. The distribution of the neuronal loss (ie, cervical and thoracic involvement with sacral sparing) did not correspond well with the history of cervical disease. The intrathecal drug-administration catheter tip had perforated the anterior dura and had become encased in scar tissue. The underlying spinal cord did not appear to have been compromised by mass effect (fig 3). DISCUSSION Displacement of the catheter tip and subsequent formation of scar tissue may result in decreased drug delivery. In this patient, this phenomenon may have resulted in either diminished pain control and/or increased spasticity. Clinicians should maintain a high index of suspicion to identify the development of scar formation and/or catheter blockage in the early phase.1 During the early phase of granulomatous scar formation, the clinical symptoms and signs may be subtle. For example, scar formation and/or catheter displacement may result in decreased analgesia requiring an extraordinary increase in medication dosage. Catheter tip scar formation Arch Phys Med Rehabil Vol 88, March 2007
390
SCAR FORMATION AND INTRATHECAL PUMP PLACEMENT, Protopapas
Fig 1. Gross pathologic specimen. Note the fibrotic scar in the anterior aspect of the spinal cord.
at the thoracic level may irritate the exiting nerve roots (ie, intercostal neuralgia) or even mimic cholecystitis by producing right upper quadrant pain. Catheter tip masses in the lumbar region may irritate exiting nerve roots, and thereby mimic such conditions as a herniated lumbar disk and spinal stenosis.1 Scar formation at the catheter tip may result in insidious compression of the spinal cord or cauda equina2 and cause slowly progressive weakness. Other early signs of scar formation development include an unexplained increase in muscle spasticity. The etiology and pathophysiologic mechanisms that lead to the formation of catheter tip inflammatory masses remains unclear. Opioids can incite an inflammatory response in brain and spinal cord tissue through yet to be determined mechanisms. Alternatively, morphine can trigger a mitogen-activated protein kinase cascade, thus activating lymphocyte activity.3,4 Opioid compounds may cause human endothelial cells, granulocytes, and monocytes to release nitric oxide, which in turn might, in the presence of mesangial cells, lead to monocyte migration.5-7 Finally, morphine has been shown to enhance cytokine formation, leading to an inflammatory cell response.8 Whether the phenomenon is -opioid-receptor mediated or naloxone reversible remains to be determined.9 A widely accepted strategy to prevent granuloma formation is to maintain
Fig 2. Gross pathologic specimen. Note that the epidural catheter has become repositioned in the anterior aspect of the subdural space.
Arch Phys Med Rehabil Vol 88, March 2007
Fig 3. Histologic section of catheter tip embedded in scar tissue adjacent to spinal cord. Hematoxylin and eosin stained formalin fixed tissue section, magnified ⴛ 200.
the drug dose and concentration as low as possible for as long as possible while still achieving symptom control.1 CONCLUSIONS Intrathecal drug delivery systems are potent tools in the management of spasticity and pain. Nevertheless, every treatment has potential side effects and complications. In this context, clinicians should maintain a high index of suspicion to identify granuloma formation as early as possible. References 1. Hassenbusch S, Burchiel K, Coffey RJ, et al. Management of intrathecal catheter-tip inflammatory masses: a consensus statement. Pain Med 2002;3:315-23. 2. Coffey RJ, Burchiel K. Inflammatory mass lesions associated with intrathecal drug infusion catheters: report and observations on 41 patients. Neurosurgery 2002;50:78-87. 3. Bidlack JM, Hemmick LM. Morphine enhancement of mitogeninduced T-cell proliferation. Prog Clin Biol Res 1990;328:405-8. 4. Chuang LF, Killam KF Jr, Chuang RY. Opioid dependency and T-helper cell functions in rhesus monkey. In Vivo 1993;7:159-66. 5. Magazine HI, Liu Y, Bilfinger TV, Fricchione GL, Stefano GB. Morphine induced conformational changes in human monocytes, granulocytes, and endothelial cells and invertebrate immunocytes and microglia are mediated by nitric oxide. J Immunol 1996;156: 4845-50. 6. Nelson CJ, Lysle DT. Morphine modulation of the contact hypersensitivity response: characterization of immunological changes. Clin Immunol 2001;1998:370-7. 7. Stefano GB. Autoimmunovascular regulation: morphine and anandamide and ancondamide stimulated nitric oxide release. J Neuroimmunol 1998;83:70-6. 8. Singhal PC, Shan Z, Garg P, Sharma K, Sharma P, Gibbons N. Morphine modulates migration of monocytes. Nephron 1996;73: 526-31. 9. Chuang LF, Killam KF Jr, Chuang RY. Induction and activation of mitogen-activated protein kinases of human lymphocytes as one of the signaling pathways of the immunomodulatory effects of morphine sulfate. J Biol Chem 1997;272:26815-7.