Intrathecal Drug Delivery Device Infection

Intrathecal Drug Delivery Device Infection

A major complication of Intrathecal Drug Delivery Device (IDDD) implantationis infection.

Morgalla et al., assessed IDD-related complications in 51 patients who had IDD systems implanted for the treatment of chronic pain or spasticity.

Twelve patients (23.5%) presented a total of 22 complications. The main type of complication was catheter-related (50%), followed by pump failure, infection, and inappropriate refilling 1).


Device-related and surgical wound infection occurred in 12 patients (3%), and nine were regarded as severe in the series of Taira et al., 2).

Risk Factors

Patients with extremely low muscle bulk, visceral pumps may be impractical or impossible, with increased risks of dehiscence and infection 3).


Periodic refills of intrathecal implanted pumps do not seem to be a risk factor for infection if standard sterile refill procedures are performed. In a study, it was clear that comorbid infections from other parts of the body do not present as a risk for device contamination 4).

Prevention

Follett et al., concluded from the available data that the most effective antiinfection measures consist of adherence to published guidelines and recommendations that apply to surgical site infections (SSIs) in general 5).


The use of vancomycin powder in patients with implants in the series of is series of Ghobrial et al., did not reduce infection rates compared to published historical controls, and was elevated compared to institutional controls 6).


The combination of local neomycin/polymyxin with systemic antibiotic therapy can lead to a significantly lower rate of postoperative infection than when systemic antibiotics are used alone 7).


The subfascial implantation technique was associated with a reduced rate of local wound and pump infections and provided optimal cosmetic results as compared with that observed in retrospective cases 8).

Treatment

The current standard of care in the treatment of IDDD infection necessitates that the pump be explanted and the infection treated prior to implantation of a new IDDD. This process leads to long hospital stays, interruptions in optimal medical management, and a high risk for dangerous drug withdrawals.


Infections can be treated with repetitive local application of gentamicin-impregnated collagen fleece 9).


Leibold et al., describe a technique that allows for the explantation of the infected pump and implantation of a new pump concurrently, which they have named the “Turner Switch” technique in honor of its inventor.

The authors conducted a retrospective analysis of cases of infected IDDDs in which patients underwent simultaneous explantation of the infected pump and implantation of a new pump. Demographics and clinical data were collected.

Data from a total of 17 patients (11 male, 6 female) who underwent simultaneous IDDD explantation and implantation to treat infections were analyzed from a 3-year period. No patients experienced infection of the newly implanted pump or catheter. Of the 17 patients, 14 (82.4%) had baclofen pumps to treat spasticity and 3 (17.6%) had fentanyl pumps to treat chronic pain. The median hospital stay was 7 days, with 16 of 17 (94.1%) patients able to be discharged home or to a facility with a level of care similar to their preoperative care. All patients ultimately experienced complete resolution of their initial infections. Five patients (29.4%) required a return to the operating room within the next 5 months (for repair of a CSF leak in 2 cases, for treatment of infection at the old pump site in 2 cases, and for treatment of a CSF leak compounded with infection in 1 case). No patient experienced infection of the newly implanted pump or catheter.

IDDD infections represent a large portion of morbidity associated with these devices. The current standard of care for deep pump infections requires pump explantation and a course of antibiotics prior to reimplantation of the IDDD. The authors demonstrate the effectiveness of a procedure involving simultaneous explantation of an infected pump and implantation of a new pump on the contralateral side in the treatment of IDDD infections 10).


Ingale et al., suggested that consideration should be given to selective dorsal rhizotomy (SDR) as an alternative in patients previously implanted with Intrathecal Drug Delivery systems complicated by infection or nearing end of battery life 11).

Case reports

A patient with pump-site infection and Escherichia coli meningitis secondary to transcolonic perforation of an intrathecal baclofen pump catheter. While this is rare, we review the intraoperative precautions and best practices that should be taken to prevent and manage this unusual complication 12).


Intrathecal drug delivery device infection with Mycobacterium fortuitum was not been reported previously. Aliabadi et al., reported a case of an implanted baclofen pump infection and associated mycobacterium meningitis due to Mycobacterium fortuitum. The entire pump system was removed and the patient was treated successfully with a prolonged regimen of antibiotics 13).


In a case neurological complaints were pain and dysaesthesiae in the lower back and thigh, as well as paresis of the ileopsoas muscle. MRI of the lumbar spine showed an intradural-extramedullary mass at the level of L1 homogeneously enhancing with gadolinium. This mass was situated at the tip of an intrathecal catheter implanted 11 years before for a morphine trial infusion as therapy for phantom pain after amputation of the right arm. Now, removal of the catheter was performed. Cultures of lumbar CSF and the catheter tip demonstrated coagulase negative staphylococcus. Antibiotic medication with cephalosporines was given for 6 weeks. After removal of the catheter, the patient was free of pain and he progressively regained full neurological function. Although most catheter-associated granulomas reported so far were sterile in nature, bacterial infection should still be considered even years after catheter placement 14).


A patient who experienced a prolonged course of intrathecal baclofen withdrawal syndrome after removal of an implantable baclofen pump for treatment of pump infection and meningitis. The current literature outlines management options for the acute management of this syndrome. In this report the authors discuss the long-term presentation of this syndrome and suggest a treatment strategy for management of the syndrome. A 37-year-old man who presented with a baclofen pump infection and meningitis experienced acute onset of intrathecal baclofen withdrawal syndrome 12 hours after the pump had been surgically removed. The patient’s symptoms evolved into a severe, treatment-refractory withdrawal syndrome lasting longer than 1 month. Oral baclofen replacement with adjunctive administration of parenteral gamma-aminobutyric acid agonists only served to stabilize the patient’s critical condition throughout his hospital course. Replacement of the baclofen pump and restoration of intrathecal delivery of the medication was necessary to trigger the patient’s dramatic recovery and complete reversal of the withdrawal syndrome within approximately 48 hours. These findings indicate that a more direct method of treating infected baclofen pumps than immediate surgical removal is necessary to prevent the onset of intrathecal baclofen withdrawal syndrome. Various options for preventing the onset of the syndrome while simultaneously treating the infection are discussed 15).

References

1)

Morgalla M, Fortunato M, Azam A, Tatagiba M, Lepski G. High-Resolution Three-Dimensional Computed Tomography for Assessing Complications Related to Intrathecal Drug Delivery. Pain Physician. 2016 Jul;19(5):E775-80. PubMed PMID: 27389121.
2)

Taira T, Ueta T, Katayama Y, Kimizuka M, Nemoto A, Mizusawa H, Liu M, Koito M, Hiro Y, Tanabe H. Rate of complications among the recipients of intrathecal baclofen pump in Japan: a multicenter study. Neuromodulation. 2013 May-Jun;16(3):266-72; discussion 272. doi: 10.1111/ner.12010. Epub 2012 Dec 14. PubMed PMID: 23240625.
3)

Waqar M, Ellenbogen JR, Kumar R, Sneade C, Zebian B, Williams D, Pettorini BL. Indwelling intrathecal catheter with subcutaneous abdominal reservoir: a viable baclofen delivery system in severely cachectic patients. J Neurosurg Pediatr. 2014 Oct;14(4):409-13. doi: 10.3171/2014.6.PEDS13686. Epub 2014 Aug 1. PubMed PMID: 25084089.
4)

Dario A, Scamoni C, Picano M, Fortini G, Cuffari S, Tomei G. The infection risk of intrathecal drug infusion pumps after multiple refill procedures. Neuromodulation. 2005 Jan;8(1):36-9. doi: 10.1111/j.1094-7159.2005.05218.x. PubMed PMID: 22151381.
5)

Follett KA, Boortz-Marx RL, Drake JM, DuPen S, Schneider SJ, Turner MS, Coffey RJ. Prevention and management of intrathecal drug delivery and spinal cord stimulation system infections. Anesthesiology. 2004 Jun;100(6):1582-94. Review. PubMed PMID: 15166581.
6)

Ghobrial GM, Thakkar V, Singhal S, Oppenlander ME, Maulucci CM, Harrop JS, Jallo J, Prasad S, Saulino M, Sharan AD. Efficacy of intraoperative vancomycin powder use in intrathecal baclofen pump implantation procedures: single institutional series in a high risk population. J Clin Neurosci. 2014 Oct;21(10):1786-9. doi: 10.1016/j.jocn.2014.04.007. Epub 2014 Jun 14. PubMed PMID: 24938386.
7)

Miller JP, Acar F, Burchiel KJ. Significant reduction in stereotactic and functional neurosurgical hardware infection after local neomycin/polymyxin application. J Neurosurg. 2009 Feb;110(2):247-50. PubMed PMID: 19263587.
8)

Kopell BH, Sala D, Doyle WK, Feldman DS, Wisoff JH, Weiner HL. Subfascial implantation of intrathecal baclofen pumps in children: technical note. Neurosurgery. 2001 Sep;49(3):753-6; discussion 756-7. PubMed PMID: 11523691.
9)

Peerdeman SM, de Groot V, Feller RE. In situ treatment of an infected intrathecal baclofen pump implant with gentamicin-impregnated collagen fleece. J Neurosurg. 2010 Jun;112(6):1308-10. doi: 10.3171/2009.8.JNS081692. PubMed PMID: 19731988.
10)

Leibold AT, Weyhenmeyer J, Lee A. Simultaneous explantation and implantation of intrathecal pumps: a case series. J Neurosurg. 2019 Apr 12:1-7. doi: 10.3171/2019.1.JNS18919. [Epub ahead of print] PubMed PMID: 30978693.
11)

Ingale H, Ughratdar I, Muquit S, Moussa AA, Vloeberghs MH. Selective dorsal rhizotomy as an alternative to intrathecal baclofen pump replacement in GMFCS grades 4 and 5 children. Childs Nerv Syst. 2016 Feb;32(2):321-5. doi: 10.1007/s00381-015-2950-9. Epub 2015 Nov 9. PubMed PMID: 26552383.
12)

Devine OP, Harborne AC, Lo WB, Price R. Colonic perforation by an intrathecal baclofen pump catheter causing delayed Escherichia coli meningitis. BMJ Case Rep. 2017 Dec 20;2017. pii: bcr-2017-222539. doi: 10.1136/bcr-2017-222539. PubMed PMID: 29269368.
13)

Aliabadi H, Osenbach RK. Intrathecal Drug Delivery Device Infection and Meningitis due to Mycobacterium Fortuitum: A Case Report. Neuromodulation. 2008 Oct;11(4):311-4. do 10: i: 10.1111/j.1525-1403.2008.00181.x. PubMed PMID: 22151146.
14)

Lehmberg J, Scheiwe C, Spreer J, van Velthoven V. Late bacterial granuloma at an intrathecal drug delivery catheter. Acta Neurochir (Wien). 2006 Aug;148(8):899-901; discussion 901. Epub 2006 Jun 23. PubMed PMID: 16791432.
15)

Douglas AF, Weiner HL, Schwartz DR. Prolonged intrathecal baclofen withdrawal syndrome. Case report and discussion of current therapeutic management. J Neurosurg. 2005 Jun;102(6):1133-6. Review. PubMed PMID: 16028775.

Raloxifene

Raloxifene

Raloxifene, sold under the brand name Evista among others, is a medication which is used in the prevention and treatment of osteoporosis in postmenopausal women and to reduce the risk of breast cancer in postmenopausal women with osteoporosis or at high risk for breast cancer. It is taken by mouth.


Choudhary et al., evaluated the effect of raloxifene on prolactin levels in addition to dopamine agonist (DA) therapy in patients with prolactinoma.

They conducted a retrospective chart review of 14 patients with prolactinoma on stable dose of DA for 6 months who received raloxifene 60 mg daily as Prolactin (PRL) could not be normalized despite being on fairly high doses of DA. Patients were informed that raloxifene is not FDAapproved for prolactinoma treatment. Prolactin level was measured at 1-6 months after starting raloxifene and at 1-3 months following its discontinuation. Raloxifene was stopped in 8 out of 14 after 2 (1-6) months of treatment as the absolute change in prolactin level was felt to be small. Results The median age and female/male sex ratios were 50 years (range 18-63), 6/8 respectively. The baseline DA dose was 3 mg/week (0.5-7) for cabergoline and 15 mg/day for bromocriptine. 10 patients had an absolute and percentage decrease in prolactin of 8.3 ng/ml (1.5-54.2), and 25.9% (8-55%) from baseline after 1-6 months on raloxifene treatment, respectively. Among 10 patients with a decrease in prolactin level, 2 (20%) achieved prolactin normalization. Two patients had no change in prolactin and two patients had an increase in prolactin level by 22.8 ng/ml and 8.8 ng/ml (47% and 23.6%) respectively.

Raloxifene was associated with 25.9% (8-55%) decrease in prolactin levels in 10/14 (71%) of patients with prolactinoma who were on stable doses of DA including two patients (14%) who achieved normoprolactinemia 1).


Hannen et al., analyzed the effects of fulvestrant and three Selective estrogen receptor modulators (SERMs), bazedoxifene, clomifene, and raloxifene, on pituitary adenomas cell lines AtT20, TtT/GF, and GH3. In cell survival assays, clomifene was shown to be the most potent compound in all three cell lines with IC50 values ranging between 2, 6, and 10 μM, respectively, depending on the cell type. Raloxifene and bazedoxifene were also effective but to a lower extent. Also, all SERMs affected migratory and invasive behavior of pituitary adenoma cells. Mechanistically, treatment of cells with SERMs caused cell apoptosis, as demonstrated by Caspase 3/7 activity and western blot assays. In addition, western blots demonstrate activation of p53 in TtT/GF cells and loss of ERK1/2 activation in AtT20 cells. In contrast, fulvestrant was only effective in GH3 cells. Thus, the general applicability of SERMs for pituitary adenoma cells might be promising in clinical applications for the treatment of pituitary adenomas 2).


The aim of a study was to investigate the ability of a SERM, RLX, to prevent vasospasm in a rabbit model of SAH.

Thirty-four New Zealand white rabbits were allocated into 3 groups randomly. Subarachnoid hemorrhage was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: (1) sham operated (no SAH [n = 12]), (2) SAH only (n = 12), and (3) SAH plus RLX (n = 10). Basilar artery lumen areas and arterial wall thickness were measured to assess vasospams in all groups.

There was a statistically significant difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements of the control and SAH-only groups (P < .05). The difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements in the RLX-treated group was statistically significant (P < .05). The difference between the SAH group and the SAH + RLX group was also statistically significant (P < .05).

These findings demonstrate that RLX has marked vasodilatatory effect in an experimental model of SAH in rabbits. This observation may have clinical implications suggesting that this SERM drug could be used as possible anti-vasospastic agent in patients without major adverse effects 3).


The effect of raloxifene on cerebral vasospasm following experimental subarachnoid hemorrhage (SAH) was investigated in a rat model. Seven groups of seven rats underwent no SAH, no treatment; SAH only; SAH plus vehicle; SAH plus 3 days intraperitoneal raloxifene treatment; SAH plus 4 days intraperitoneal raloxifene treatment; SAH plus 3 days intrathecal raloxifene treatment; and SAH plus 4 days intrathecal raloxifene treatment. The basilar artery cross-sectional areas were measured at 72 or 96 hours following SAH. The results showed raloxifene decreased SAH-induced cerebral vasospasm in all treatment groups, and suggested no difference between intraperitoneal and intrathecal application, or between 3 days and 4 days of raloxifene treatment. The present study demonstrates that raloxifene is a potential therapeutic agent against cerebral vasospasm after SAH 4).


To directly test whether exogenous 17beta estradiol and raloxifene affect the number of glial cells in brain, C57BL/6NIA female mice aged 20-24 months received bilateral ovariectomy followed by s.c. placement of a 60-day release pellet containing 17beta estradiol (1.7 mg), raloxifene (10 mg), or placebo (cholesterol). After 60 days, numbers of microglia and astrocytes were quantified in dentate gyrus and CA1 regions of the hippocampal formation using immunocytochemistry and design-based stereology. The results show that long-term 17beta estradiol treatment in aged female mice significantly lowered the numbers of astrocytes and microglial cells in dentate gyrus and CA1 regions compared with placebo. After long-term treatment with raloxifene, a similar reduction was observed in numbers of astrocytes and microglial cells in the hippocampal formation. These findings indicate that estrogen and selective estrogen receptor modulators can influence glial-mediated inflammatory pathways and possibly protect against age- and disease-related neuropathology 5).

References

1)

Choudhary C, Hamrahian AH, Bena JF, Recinos P, Kennedy L, Dobri G. THE EFFECT OF RALOXIFENE ON SERUM PROLACTIN LEVEL IN PATIENTS WITH PROLACTINOMA. Endocr Pract. 2019 Mar 13. doi: 10.4158/EP-2018-0321. [Epub ahead of print] PubMed PMID: 30865525.
2)

Hannen R, Steffani M, Voellger B, Carl B, Wang J, Bartsch JW, Nimsky C. Effects of anti-estrogens on cell invasion and survival in pituitary adenoma cells: A systematic study. J Steroid Biochem Mol Biol. 2019 Mar;187:88-96. doi: 10.1016/j.jsbmb.2018.11.005. Epub 2018 Nov 13. PubMed PMID: 30439415.
3)

Gürses L, Seçkin H, Simşek S, Senel OO, Yigitkanli K, Oztürk E, Beşalti O, Belen D, Bavbek M. Effects of raloxifene on cerebral vasospasm after experimental Subarachnoid Hemorrhage in rabbits. Surg Neurol. 2009 Nov;72(5):490-4; discussion 494-5. doi: 10.1016/j.surneu.2008.11.007. Epub 2009 Jan 14. PubMed PMID: 19147193.
4)

Gulsen S, Inci S, Yuruk S, Yasar U, Ozgen T. Effect of raloxifene on cerebral vasospasm following experimental subarachnoid hemorrhage in rats. Neurol Med Chir (Tokyo). 2007 Dec;47(12):537-42; discussion 542. PubMed PMID: 18159137.
5)

Lei DL, Long JM, Hengemihle J, O’Neill J, Manaye KF, Ingram DK, Mouton PR. Effects of estrogen and raloxifene on neuroglia number and morphology in the hippocampus of aged female mice. Neuroscience. 2003;121(3):659-66. PubMed PMID: 14568026.

Retrosigmoid approach for glycerin rhizotomy

Retrosigmoid approach for glycerin rhizotomy

In 2013 Goodwin et al., performed a retrospective analysis of patients who received standard microvascular decompression and injection of glycerin to the inferior third of the Trigeminal nerve cisternal portion anterior to the root entry zone with lack of a compressive vessel on MRI as the primary indication. Fourteen patients were identified and demographic information, post-operative course and complications were recorded.

There were eleven females and three males with an average age at time of surgery of 54.8 years. 100% of patients reported that their trigeminal pain was significantly improved following surgical intervention. Four out of fourteen patients reported a 50-80% decrease from the pre-surgery baseline pain at one month and three month follow up. One patient developed a CSF leak, and no surgical site infections or motor deficits were observed.

Intra-operative glycerin rhizotomy in conjunction with microvascular decompression can be used to safely treat patients suffering from trigeminal neuralgia 1).

In 2019 their updated experience with this technique to further validate this novel approach by a retrospectiveanalysis of data obtained in patients in whom glycerin was directly injected into the inferior third of the cisternal portion of the trigeminal nerve.

Seventy-four patients, including 14 patients from the authors’ prior study, were identified, and demographic information, intraoperative findings, postoperative course, and complications were recorded. Fisher’s exact test, unpaired t-tests, and Kaplan-Meier survival curves using Mantel logrank test were used to compare the 74 patients with a cohort of 476 patients who received standard MVD by the same surgeon.

The 74 patients who underwent MVD and glycerin injection had an average follow-up of 19.1 ± 18.0 months, and the male/female ratio was 1:2.9. In 33 patients (44.6%), a previous intervention for TN had failed. On average, patients had an improvement in the Barrow Neurological Institute Pain Intensity score from 4.1 ± 0.4 before surgery to 2.1 ± 1.2 after surgery. Pain improvement after the surgery was documented in 95.9% of patients. Thirteen patients (17.6%) developed burning pain following surgery. Five patients developed complications (6.7%), including incisional infectionfacial palsyCSF leakage, and hearing deficit, all of which were minor.

Intraoperative injection of glycerin into the trigeminal nerve is a generally safe and potentially effective treatment for TN when no distinct site of arterial compression is identified during surgery or when decompression of the nerve is deemed to be inadequate 2).

References

1)

Goodwin CR, Yang JX, Bettegowda C, Hwang B, James C, Biser A, Raza S, Bender M, Carson B, Lee JY, Lim M. Glycerol rhizotomy via a retrosigmoid approach as an alternative treatment for trigeminal neuralgia. Clin Neurol Neurosurg. 2013 Dec;115(12):2454-6. doi: 10.1016/j.clineuro.2013.09.009. Epub 2013 Sep 25. PubMed PMID: 24161889.
2)

Kim TY, Jackson CM, Xia Y, Mashouf LA, Patel KK, Kim ES, Hung AL, Wu A, Garzon-Muvdi T, Bender MT, Bettegowda C, Lee JYK, Lim M. Retrosigmoid approach for glycerin rhizotomy in the treatment of trigeminal neuralgia without overt arterial compression: updated case series. J Neurosurg. 2019 Mar 8:1-7. doi: 10.3171/2018.12.JNS182572. [Epub ahead of print] PubMed PMID: 30849763.
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