Neuromodulation: Technology at the Neural Interface

Received: May 15, 2017 Revised: July 26, 2017 Accepted: July 29, 2017

(onlinelibrary.wiley.com) DOI: 10.1111/ner.12693

Intrathecal Therapeutics: Device Design, Access

Methods, and Complication Mitigation
Sean J. Nagel, MD*; Chandan G. Reddy, MD†; Leonardo A. Frizon, MD*;
Marshall T. Holland, MD†; Andre G. Machado, MD, PhD*;
George T. Gillies, PhD‡; Matthew A. Howard III, MD†
Introduction: The intrathecal space remains underutilized for diagnostic testing, invasive monitoring or as a pipeline for the
delivery of neurological therapeutic agents and devices. The latter including drug infusions, implants for electrical modulation,
and a means for maintaining the physiologic pressure column. The reasons for this are many but include unfamiliarity with the
central nervous system and the historical risks that continue to overshadow the low complication rates in modern clinical series.
Materials and Methods: Our intent in this review is to explore the access devices currently on the market, assess the risk associ-
ated with breaching the intrathecal space, and propose a research model for bringing to patients the next generation of
intrathecal hardware. For this purpose, we reviewed both historical and contemporary literature that pertains to the access devi-
ces and catheters intended for both temporary and permanent implantation and the complications thereof.
Results: There are few devices that are currently marketed in the United States or Europe for intrathecal use. Most hew to a rela-
tively fixed design pattern predicated on the dimensions and properties of the thecal sac. All are typically composed of soft
silicone, and employ a Tuohy needle for access despite design limitations. In general, these catheters are engineered for durability,
ease of use, and regional deployment. Devices on the market with steerability or targeted intrathecal fixation are not yet available.
Complications, once a legitimate concern, are now quite rare when recommended techniques are followed.
Conclusions: Over the next decade, advances in intrathecal catheter design, access techniques, imaging, and greater understand-
ing of the spinal cord neurophysiology will usher in an era where the intrathecal space is recognized as a highly valued diagnostic
and therapeutic target. We anticipate that this will occur in several concurrent phases, each with the potential to accelerate the
growth of the others.

Keywords: Intrathecal delivery, spinal canal, spinal cord stimulation, spinal cord, thecal sac
Conflict of Interest: Drs. Gillies, Reddy, and Howard may receive patent royalties from the commercial license of the I-Patch intra-
dural stimulator’s intellectual properties negotiated by their respective institutions. Drs. Gillies and Howard hold equity in the
licensee and serve on its Board of Directors, respectively. The remaining authors have no conflicts of interest to declare.

INTRODUCTION
The intrathecal space is fluid filled and bounded by a nearly
impermeable membranous sac. It nourishes, lubricates, and supports
the spinal cord and the origination of the peripheral nervous system
projections that emanate from the dorsal (sensory roots) and ventral
(motor roots) horns. It is protected by a flexible, osseous, segmented
column. The spinal fluid contained within the subarachnoid space of
the thecal sac is contiguous with the cerebral fluid that is confined
to the rigid intracranial subarachnoid space by the meninges that
line the brain and inner table of the skull and the interconnected
pools that comprise the ventricular system. Cerebro-spinal fluid
(CSF) production and absorption are tightly regulated to maintain a
pressure gradient over a narrow range (7–15 mm Hg in a recumbent
adult) that favors optimal nervous tissue development and function.
Small deviations shift the hydrostatic forces and impair spinal cord
and brain oxygen, glucose, and other critical nutrient perfusion.
The intrathecal space is accessed most often via a “spinal tap” with
a small gauge needle to withdraw milliliter aliquots of CSF to test for
infection, neuro-inflammatory diseases, neurodegenerative diseases,
can be inferred from the spinal pressure to diagnose worrisome ele-
vations, with subsequent therapeutic drainage initiated as needed.
For long-term or permanent drainage of CSF, an internalized or exter-
nalized catheter system is placed to divert the fluid. Similar catheter
systems may be secured to programmable pumps preset to deliver a
specified amount of medication to chemically modulate the spinal
cord and nerve roots for treatment of chronic pain or spasticity. Less
Address correspondence to: Sean J. Nagel, MD, Center for Neurological Restora-
tion, Cleveland Clinic Main Campus, Mail Code S31, 9500 Euclid Avenue, Cleve-
land, OH 44195, USA. Email: NAGELS@ccf.org
* Center for Neurological Restoration, Cleveland Clinic, Cleveland, OH, USA;
†
Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa
City, IA, USA; and
‡
Department of Mechanical and Aerospace Engineering, University of Virginia,
Charlottesville, VA, USA
For more information on author guidelines, an explanation of our peer review
process, and conflict of interest informed consent policies, please go to http://
www.wiley.com/WileyCDA/Section/id-301854.html
1

occult blood, and other problems. Moreover, the intracranial pressure Source(s) of financial support: None.

www.neuromodulationjournal.com C 2017 International Neuromodulation Society

V Neuromodulation 2017; ••: ••–••
 NAGEL ET AL.
commonly, the intrathecal space is accessed to remove a benign or
malignant lesion within or around the spinal cord or meninges. Inter-
estingly, although the epidural space is used as a platform for spinal
cord electrical stimulation across the highly conductive CSF, intrathe-
cal stimulation remains a relic of the past despite some early success
in the 1960s and 1970s (1,2).
In this review, we will describe the historical approaches used to
access the intrathecal space, explore the development of devices
and catheters that have been used therapeutically, and report on
the applications, risks, and complications associated with intrathecal
access. We close with a summary of some possible future directions
for intrathecal therapy (IT).
TARGETED APPLICATIONS
The diagnostic applications of CSF sampling have far outpaced
the therapeutic offerings currently on the market that require use of
this space. CSF bio-bank repositories are now widespread as the pro-
cedures for procuring samples have been standardized and the costs
of storage have plummeted. For example, many research teams are
attempting to discover biomarkers that predict neurodegenerative
diseases years before they manifest clinically. Yet, many patients
with other conditions who could benefit from IT chemical or electri-
cal modulation do not have access to this route of therapy. Most
notable among these are patients with chronic, medically refractory
neuropathic pain (3). Although permanent IT infusion options are
well established, they remain underutilized, often as a last-line con-
sideration mostly due to the limited long-term benefits of the exist-
ing FDA-approved compounds. In the United States alone, it is
estimated that 16 million people are suffering from neuropathic
pain, very few of whom are or will be managed with IT infusion (4).
The use of IT opioids to manage malignant pain is still only prac-
ticed at the margins of healthcare despite the fact that families of
loved ones nearing end of life reported pain was inadequately
treated in nearly 25% of patients regardless of setting (5). This con-
tinues to be a high priority for palliative medicine physicians who
often face conflicting pressures related to costs vs. providing the
highest quality care. Better device-drug development can substan-
tially change this reality and drive utilization of intrathecal therapies
that, in turn, could reduce costs. The PrometraV R programmable
pump is an example of delivery system improvements made toward
these goals, with its efficacy for use in treating intractable pain
established in clinical trials (6,7). The modes of flow control used for
intrathecal delivery are also receiving careful attention. For instance,
pulsatile bolus infusion has been investigated as a method for over-
coming the increased tolerance to intrathecal baclofen associated
with continuous-flow delivery (8). Moreover, the effects on drug dis-
persion caused by the natural cyclic variations in CSF transport
within the intrathecal space have been investigated experimentally
for the purpose of validating computational models of baclofen dis-
tribution under the assumption of incompressible viscous laminar
flow (9). These advances and others are helping to establish the sci-
entific and clinical basis for improved care of these patients.
Programmable pumps for delivering baclofen to patients with
spasticity related to spinal cord injury, multiple sclerosis, stroke, and
cerebral palsy have achieved a modest level of clinical acceptance
and adoption, despite robust demonstration of safety and efficacy
from several groups including ours (10). While each drug used for IT
infusion has its own specific drawbacks, the use of IT drug delivery
devices over the last several decades has generated safety data that
2
paved the way for the next generation of intrathecal implants for
www.neuromodulationjournal.com C 2017 International Neuromodulation Society
V Neuromodulation 2017; ••: ••–••
pain and spasticity (11). In parallel, incremental improvements in
device design and surgical techniques have reduced the risks of
catheter displacements, kinks, fractures, spinal fluid fistulas, and
related complications. New devices intended for intrathecal use that
are now in development are likely to further minimize risk and
improve drug delivery reliability, demonstrating that the field
remains ripe for innovation.
Although we envision future intrathecal devices will continue to
be designed primarily for pain management and the treatment of
spasticity in the near term, other conditions may respond to tar-
geted intrathecal modulation. Included in this group are gait disor-
ders, truncal ataxia, motor neuron disorders, sensory deficits, sexual
and urinary dysfunction, autonomic instability, and related neuro-
genic diseases characterized by end organ dysfunction. Direct chem-
ical modulation via the IT space is likely to remain an attractive
strategy for many conditions and is likely to expand (12).
DESIGN FEATURES OF INTRATHECAL
CATHETERS
Survey of Devices
Table 1 and Fig. 1 provide overviews of the design characteristics
of the most frequently used types of intrathecal devices. Morpholog-
ical constraints of the spinal canal will create overlap in the features
of intrathecal catheters intended to deliver medications, catheters
manufactured for drainage, and cylindrical electrodes that could be
used intrathecally to stimulate the spinal cord. In particular, the
dimensions of the devices, how they are implanted and the materi-
als used are similar.
Dimensions
Figure 2 is a photograph of an intrathecal catheter, emphasizing
the small and delicate nature of these devices. The dimensions of
these systems are relatively similar in order to minimize the risk of
complication without sacrificing efficacy. The tip frequently will ter-
minate within the thecal sac adjacent to the thoracic spine. Measure-
ments of the distances between the spinal cord surface and the
thecal sac in this segment extrapolated from MR scans are 2.5 mm
in the transverse dimension to the left and right of the spinal cord
and range from 1–5 mm in the sagittal plane (dorsal or ventral to
the cord) with a coefficient of variance calculated to be 42.4% in
one study of 42 patients (13). Thus, the safe upper limit of the outer
diameter of a device introduced into this space has been recom-
mended to be below 2.5 mm (13).
The smallest gauge Tuohy needle through which a catheter or
lead could be passed would be a 10 gauge assuming a regular nee-
dle wall thickness that has a nominal inner diameter of  2.7 mm.
While it might be technically feasible in most patients to use a larger
gauge needle to pierce the dural sac at the interlaminar space this
would not offer any advantage given the size constraints on the
intrathecal devices that will be passed through the needle as
described above. As discussed below, the disadvantages of a larger
puncture include the risk of CSF leak and spinal headaches. Devices
R
currently in use reflect these findings. For example, the AscendaV
catheter is packaged with a 16 gauge Tuohy needle which has nomi-
nal outer diameter of  1.7 mm. The catheter itself is designed to
have an outer diameter of 1.2 mm (4 French). The Medtronic 8731SC
catheter, which is the previous-generation intrathecal device, is
1.4 mm (4.2 French) and is delivered with a 15 gauge Tuohy needle.
Smaller catheters could also be used but would require a higher
pressure gradient across the catheter to deliver an equivalent
 INTRATHECAL THERAPEUTICS REVIEW

Closed tip with side holes

Closed tip with side holes
Closed tip with side holes
Closed tip with side holes
Closed tip with side holes
Closed tip with side holes

Open tip with angle cut

Closed tip rounded end
Open tip single hole
Open tip single hole
Tip design

Needle 15 Gauge

Needle 16 Gauge
needle 16 gauge
needle 15 gauge
needle 15 gauge

needle 15 gauge

needle 16 gauge
needle 14 gauge
needle 14 gauge
needle 14 gauge
Access device

Tuohy
Tuohy
Tuohy
Tuohy
Tuohy
Tuohy
Tuohy
Tuohy
Tuohy
Tuohy
Guidewire
OD (mm)

0.53
0.46
0.46
0.46
0.46
0.50
0.50
0.50
None
None

Figure 1. Cross sectional view of the spinal canal showing a characteristic

The ranges as shown apply to both the closed-end and open-end devices, and the latter might be either bevel-cut or flat-cut.
OD (mm)
segment

dorsal positioning of an intrathecal catheter, along with the illustrations of two

1.20
1.40
1.40
1.40
1.40
1.20
1.20
1.65
1.60
1.50
Spinal

common types of distal-tip structures and the ranges of dimensional character-

istics. [Color figure can be viewed at wileyonlinelibrary.com]
segment

volume of fluid and may be more susceptible to occlusion. Similarly,

ID (mm)

0.70
0.54
0.53
0.53
0.53
0.50
0.50
0.76
0.80
0.70
Spinal

if the purpose is therapeutic drainage, the rate of flow would also

follow Poiseuille’s Law and consequently be slowed by small diame-
Table 1. Design Parameters of Representative Early Generation and Contemporary Intrathecal Devices.

ter catheters.
Radiopague silicone
Radiopague silicone
Radiopague silicone

Radiopaque silicone

Materials
Polyurethane

Catheters partially or fully manufactured out of silicone continue

to find widespread use in intrathecal devices principally because
Material

Silicone
Silicone
Silicone

Silicone

Silicone

that material does not interact with the infused drugs, has good evi-
dence of long-term safety, and does not appear to cause an immu-
nologic reaction. However, these devices are prone to fractures,
perforations, and kinking even when best practices are followed.
81.4

80.0
80.0
80.0
104.1
104.1

104.1
104.1
114.3
139.7

R
The AscendaV catheter (14) represents a significant design advance
Length
(cm)

aimed at reducing these complications, afforded by an inner layer of

ID, inner diameter; OD, outer diameter; SC, sutureless connector.

silicon, a middle layer of braided polyester and an outer sleeve

made of polyurethane.
Medtronic 8731 and 8731SC
Medtronic Ascenda 8780
Medtronic Ascenda 8781

Device Anchors
Spiegelberg SilverlineV
R

Catheter migration is a well recognize phenomenon that is often

Integra NL8507210
Medtronic 8709SC
Medtronic 8703W

Codman 82–1707

cited as one of the most common reasons for revision (15). As most
Medtronic 8703

Medtronic 8711
Manufacturer,
model no.

Lumbar Peritoneal Shunt

Intrathecal device

Lumbar Drain
Lumbar Drain
Catheter
Catheter
Catheter
Catheter
Catheter
Catheter
Catheter

Figure 2. Photo of an intrathecal catheter, along with a 16 gauge Tuohy nee-

dle. The small divisions on the upper scale are in mm. [Color figure can be
3

viewed at wileyonlinelibrary.com]

www.neuromodulationjournal.com C 2017 International Neuromodulation Society

V Neuromodulation 2017; ••: ••–••
 NAGEL ET AL.
Figure 3. a. Sagittal and b. coronal CT scans showing the position of an intra-
thecal catheter within the spinal canal.
catheters are placed percutaneously and then tunneled away from
this site, a suitable securing mechanism that will both minimize the
forces that could damage or break the catheter as well as secure it
safely to the soft tissues is desired. This has proved to be a more dif-
ficult objective to achieve than might be expected. Under most cir-
cumstances, the anchor is sewn to the muscle fascia but the lumbar
spine is subject to continual shear caused by rotational and com-
pressive forces. The cumulative effect is to cause mechanical stresses
on nearby anatomical structures and device components that can
lead to fracture and malfunction. One early challenge was to secure
the catheter without occluding the lumen. Most anchors have
adopted a cuff configuration with suturable wings, an elbow, or a V-
wing shape. The cuff is tightened to the catheter with nonabsorb-
R
able suture. Alternatively, the AscendaV catheter is secured with an
anchor that is affixed via an anchor-dispensing tool. The catheter is
threaded through the aperture of the tool, which upon its release,
4
captures the outer wall securely.
www.neuromodulationjournal.com C 2017 International Neuromodulation Society
V Neuromodulation 2017; ••: ••–••
Imaging Properties
As these devices are typically implanted with fluoroscopic guid-
ance, they are often radiopaque or initially assembled with a stain-
less steel guidewire that is removed once the desired spinal
R
segment is reached. The novel construction of the AscendaV cathe-
ter reduced its radiographic visibility using conventional fluoros-
copy. For this reason, a platinum-iridium localization marker is
embedded in the tip of the catheter and used to detect the location
once the guidewire is removed. When additional information about
the precise location of the catheter is needed, computed tomogra-
phy (CT) scans offer definitive detection capabilities, as shown in
Fig. 3. Although generally visible on multiple MRI sequences, the
properties of the catheters either render them less conspicuous or
sometime result in imaging artifacts. However, inflammatory masses
are evident on gadolinium-enhanced T1 MR imaging, and this is
often the imaging modality of choice to make that diagnosis (16).
Other imaging approaches are not widely used. Hence, future
designs will need to incorporate radiopaque markers and/or guide-
wires to facilitate radiologically guided device placement, or incor-
porate new methods for providing the clinician with feedback
regarding catheter position in relation to anatomy.
Durability
The maximal tensile strength of any medical device describes the
force needed to fracture the catheter, electrode or related product
and is dependent on the materials, wall thickness and the outer wall
diameter. Intrathecal catheter dislodgment, withdrawal, displace-
ment or fracture are well recognized complications after lumbar
insertion due to physical forces such as the sweeping motion
between the skin and the fascia and the tensile forces applied
through body motion (17). Failure to adequately secure the intrathe-
cal catheter to a fibrous membrane such as the fascia will signifi-
cantly reduce the pullout strength. However, even when anchored
properly, these risks may persist. To explore this, Hokanson and col-
R
leagues (17) bench-tested the Medtronic AscendaV device, which is
the current-generation IT catheter. It was cycled mechanically
250,000 times to mimic the sweeping motion that could induce
migration, and exposed to tensile cyclic fatigue for 1,700,000 cycles
without evidence of failure. This study was similar in design to the
testing protocols used to evaluate other types of intradural devices
(18) and it confirmed the purported fracture resistance of the
R
AscendaV catheter and anchoring mechanism ex vivo.
Implantation Procedure
Prior to the widespread adoption of uniformly accepted best sur-
gical practices, the catheter-related complication rate in clinical trials
usually exceeded 20%. Follett et al. (15) then undertook the task of
systematically reviewing the techniques used by several physicians
for insertion, and making consensus recommendations based on
their findings. As a result, the number of complications has been
steadily declining and those recommendations have now become
standardized patterns adopted by the community and incorporated
into most texts and reviews. For instance, the implant manuals (14)
R
for the Medtronic AscendaV catheter includes most of these preven-
tative steps. Although, the findings and recommendations are
relatively straightforward, several are worth describing here. A para-
median approach with the Tuohy needle to the lumbar spine directs
the catheter away from the spinal elements, especially the spinous
processes that are likely to compress and, over time, shear the cathe-
ter. A relatively flat angle of approach also seems to both minimize
this risk as well as that of CSF leak. Anchoring to the lumbo-dorsal

Figure 4. Intra-operative radiograph showing part of the placement proce-
dure for intrathecal catheter. A: The radiopaque tip of the catheter in the intra-
thecal space, extending just past the distal end of the Tuohy needle. B. the
shaft of the Tuohy needle approaching the intralaminar space at a shallow
angle. [Color figure can be viewed at wileyonlinelibrary.com]
fascia will limit the chance of dislodgement. Prior to introduction of
R
the AscendaV catheter, it was critical that gentle loops were made
to prevent occlusion or kinking. This is now less of a concern. Figure
4 is an intra-operative radiograph taken during the catheter implan-
tation process.
COMPLICATIONS OF IT: REVIEW OF THE
LITERATURE
Overview
Complications may arise anytime from the day the device is
inserted until either it is removed or the patient’s life ends. The vari-
ous complications can be divided into those that are procedure-
related, device-specific, or associated with the administered drug.
Device related-complications can be further divided into those due
to catheter dysfunction and those related to pump malfunctions.
Some of the early studies of these difficulties include those of Penn
et al. (19), Follett and Naumann (20), Kamran and Wright (21), Ordia
et al. (22), and Kolaski and Logan (23). Stretkarova et al. (24)
reviewed the literature on this subject through 2010. Table 2 pro-
vides a listing of several of the studies and case reports that have
been published since then, along with a few of the earlier studies
for historical reference.
Complication Rates
In general, the incidence of complications has been reported to
range from 15 to 40%, and it appears to increase with longer follow-
up intervals (24,25). Stempien and colleagues (26) reported lower
rates for catheter kinking or migration (4%) and for risk of infection
(1 to 2%) in a clinical survey of 936 implants. However, this survey-
www.neuromodulationjournal.com C 2017 International Neuromodulation Society
V Neuromodulation 2017; ••: ••–••
INTRATHECAL THERAPEUTICS REVIEW
based investigation may have underestimated the actual rates. Chief
among these complications are catheter failures, followed by
procedure-induced complications. Pump-related complications are
reported only infrequently. In their review, Stretkarova et al. (24)
identified 558 complications following 1362 implants. Of these, 66%
were related to the catheter, 27% were related to the surgical proce-
dure, and 7% to the pump. The authors suggested improvements in
terms of standard classification and reporting of complications in
this field. In their review, Varhabhatla and Zuo likewise noted that
two-thirds of the complications were mechanical in nature (27).
More recently, Motta and colleagues published a retrospective
review comparing complications rates between 416 children with sil-
icone catheters and 92 children with the new four-layer catheter
R
(AscendaV) designed to prevent kinking and occlusion (28). They
reported a reduction in the incidence of major complications with
R
use of the AscendaV catheter. The authors also described other tech-
nical improvements that might have accounted for a lower rate of
complications, such as the use of a smaller Tuohy needle (16 gauge),
subfascial pump insertion, a prophylaxis protocol and the unique
R
anchor dispenser used with the AscendaV catheter.
Types of Complications
As noted in the examples shown in Table 2 and represented sche-
matically in Fig. 5, the spectrum of catheter-related complications
reported in the literature include obstructions (29,30), positional dis-
placements (31–34), catheter coiling and engagement of the dorsal
nerve rootlets (35,36), guidewire fracture (37), disconnection with
the pump (38,39) or pump-related failure (40,41), infections (42,43),
intrathecal granulomas and inflammatory masses (44), bradycardias
due to catheter contact with the spinal cord (45), arachnoiditis (46),
syrinx formation (47), and Harlequin syndrome (48). The physician
most often will be faced with questions concerning surgical site
infection (49) or medication under-dose or overdose. Algorithms
have been developed to help in the clinical evaluation, treatment
and differentiation between system malfunction and other etiolo-
gies (50). Albright and colleagues (51) described several techniques
to optimize the pump and catheter implantation process which,
although intended for pediatric patient, can also be applied to
adults. In what follows we discuss several of these problems in fur-
ther detail.
Catheter-Tip Granuloma
It was not until relatively recently that intrathecal catheter-tip
granulomas were recognized as a unique entity arising after long-
term administration of opioid medications into the spinal fluid. First
described by North in 1991 (52), these sterile masses are composed
of inflammatory cells that tend to enlarge over time, occluding the
perforations along the catheter tip leading to pump malfunctions.
Microscopic analysis following H&E staining reveals a rim of collagen
embedded with plasma cells encircling a necrotic core of presum-
ably dead macrophages. Neutrophils are notably absent (44). When
untreated they can cause focal compression of the spinal cord or
nerves. This clinical scenario is not rare occurring in 8 out of 13
patients harboring granulomas in one series all of whom eventually
needed operative treatment. In the absence of any infusion therapy,
this type of reaction to the catheter alone has not been reported.
Furthermore, the incidence seems to vary with the compound being
infused, its concentration and the rate at which it is propelled by the
pump. Rodent models, however, have been shown to exhibit a
robust neuroimmune response to the presence of an intrathecal
5
catheter alone several days following implantation (53).
 6

Table 2. Survey of Recent Studies and Case Reports on Complications Associated With Intrathecal Therapies, Including Causes and Outcomes Where Available.

Author(s) Year of Type of Number Population Indication Pump Catheter type Complications Procedure- Catheter-related Pump-related Therapy- Notes/insights
and publication study of age (years) model (number of related complications complications related
reference patients patients/% of complications complications
NAGEL ET AL.

no. those in study)

Penn et al. 1995 Prospective 102 12–77 40 MS, _ Medtronic 8703, 42/41.2% _ Hole, kink, _ _ 8703 performed
(19) 42 SCI, Medtronic disconnect, better than 8704
20 SPA 8704, dislodgment,
other custom fibrosis, other
device etc.
Follett and 2000 Prospective 209 >18 72.7% NPP, SynchroMed Medtronic 8709 37/17.7% 15 infection, 10 3 leakage, 2 _ _ 9 month

www.neuromodulationjournal.com
Naumann 4.8 % CDP, catheter catheter complication-
(20) 22.5% SPA migration, 5 migration; 2 free survival was
catheter kink, pump 78.9%
4 CFS leak, disconnection
8 other
Kamran and 2001 Retrospective 97 28–85 15 FBSS, 10 CS/LS, _ _ 43/44.3% 5 infection 1 distal occlusion, 1 failure,1 33 acute, 42 _
Wright 5 CRPS, 8 CF, 2 shearing, 4 positional flip, chronic
(21) 4 RPY, 6 PN, 2 kink, 7 leakage, misprograming
SPA 3 spinal

V
headache
Ordia et al. 2002 Prospective 131 17–53 63 MS, SynchroMed Medtronic 31/23.6% (also 2 pocket erosion; 12 occlusion & 2 positional flip, 1 12 constipation, 7 Most complications
(22) 53 SCI, 10 8703 W, 34 adverse 1 pocket kink, 8 fracture; stuck valve muscular were with
MISC, 5 FSP Medtronic responses to infection; 1 2 puncture, 2 hypotonia, 6 “earlier model
8709, medication) CSF leak dislodgment headache, 4 catheter”
other urinary
unspecified retention 5
device other
Harney and 2004 Case report 1 n/a FBSS SynchroMed Medtronic 8709 IP _ _ Traumatic syrinx _ _ _
Victor (47)
Dvorak et al. 2010 Retrospective 167 8–69 55 SCI, 37 SynchroMed _ 33/19.8% _ 14 occlusion & 1 failure _ _
(29) CP, 31 MS, kink, 7
19 TBI, 7 STR, disconnection,
6 FSP, 3 ABI, 3 7 subdural
PLS, 6 MISC placement, 4
fracture, 4
dislodgment
Maugans (31) 2010 Case report 1 16 CP SyncroMed I Medtronic 8709 _ _ Catheter fracture _ _ Caudocranial CSF
and migration flow possible

C 2017 International Neuromodulation Society

to ventricular mechanism for
system migration
Awaad et al. 2012 Retrospective 44 24 children 29 CP, 3 TBI, 3 _ _ 22/50% 4 infection 1 catheter _ _ 33 additional
(38) 24 Adults MS, 2 DY, 4 dislocation, 1 revisions were
CS, 2 ICH, 2 pump- performed on 22
SPA connection of 44 patients
defect, 2 frac-
ture, 1 occlu-
sion, 3 dye
leakage, 1
occult CSF
Tomycz et al. 2012 Case series 13 40–70 11 FBSS, 1 CRPS, 1 _ _ _ None _ None None Mass resection via
(44) STR laminectomy a
reasonable
treatment
strategy
Varhabhatla 2012 Retrospective 2843 12 (median) NPP, MS, CP, SCI, _ _ 514/18% _ _ _ _ Complications rate
and Zuo PAR, MISC (No increased
(27) numerical between 1997
breakdowns and 2006
given)

Neuromodulation 2017; ••: ••–••

 Table 2. Continued
Author(s) Year of Type of Number Population Indication Pump Catheter type Complications Procedure- Catheter-related Pump-related Therapy- Notes/insights
and publication study of age (years) model (number of related complications complications related
reference patients patients/% of complications complications
no. those in study)
Dardashti 2013 Case report 1 41 MS SynchroMed II _ _ _ 1 occlusion at _ _ Catheter found to
et al. (63) catheter & have arachnoid
pump adhesion
attachment
Draulens et al. 2013 Retrospective 130 49 for MS 38 81 MS, 49 SCI SynchroMed EL _ 104 over a mean 4 infection, 1 9 occlusion, 6 5 malfunction, 1 2 overdose- _
(30) for SCI SynchroMed II of 5.25 years perforation, 6 kink, 7 pump tilting, 2 related respira-

www.neuromodulationjournal.com
(means) CSF leak, 3 migration, 9 volume tory distress
wound rupture tear, 7 discrepancy
disconnection,
6 fracture, 34
other
Kochany et al. 2013 Case report 1 40 NPP SynchroMed II _ _ _ Arachnoiditis, _ _ A retained Tuohy
(46) radicular pain needle was
related to found in the
catheter patient
Perruchoud 2013 Case report 1 84 NPP SynchroMed EL _ _ _ _ Fluid leakage in _ _

V
et al. (40) the silicone
septum
Borrini et al. 2014 Prospective 158 17–87 67 SCI, 45 MS, 22 SynchroMed II _ 38/24.1% 4 pump pocket 94 migration, 1 1 pump 2 serious, 5 mild _
(34) CP, 8 STR, 3 hematoma, 10 disconnection, malfunction, 1
TBI, 13 MISC infection, 2 4 other pump pressure
CSF leak, 2 ulcer
scar
dehiscence, 2
other
Ghosh et al. 2014 Retrospective 119 3–21 113 SPA, 5 DY _ _ 49/41.2% 26 infection, 10 displacement None _ _
(32) 8 skin erosion or
over pump, 1 disconnection,
CSF leak 4 fracture
Motta and 2014 Retrospective 430* 1–14 383 CP, 47 MISC SynchroMed EL Medtronic 8709 137/25% 40 infection, 21 65 total 3 positional flip, 1 _ Subfascial pump
Antonello SynchroMed II SC, Medtronic CSF leak peritoneal implant reduced
(25) Ascenda migration the risk of
infection
Bolash et al. 2015 Retrospective 365 52.2 (mean) 145 FBSS, 52 SPA, SynchroMed II _ 50/13% 41 infection, 3 2 catheter-related 2 pump-related _ _
(42) 49 SS, 48 SynchroMed EL pocket-related surgical com- surgical

C 2017 International Neuromodulation Society

CRPS, 20 CDP, complication plication, 2 complication
49 MISC granuloma
Hnenny et al. 2015 Case report 1 70 FBSS _ _ _ _ Catheter Fracture _ _ Catheter migrated
(33) & to the
subarachnoidal prepontine area
hemorrhage causing
hemorrhage
Kratzsch et al. 2015 Retrospective 159 52.6 (mean) 30 NPP, 24 SPA _ _ 13/8.2% _ Catheter tip _ _ Morphine dosage
(54) granuloma and
concentration
were associated
with granuloma
Manix et al. 2015 Case report 1 58 SCI _ _ 1 None 1 drain catheter _ _ Endovascular
(37) guidewire retrieval tool was
fracture used the
intrathecal space
Riordan and 2015 Case report 1 37 SPA SynchroMed II _ _ _ _ Failure _ Pump failed at 64
Murphy months
(41)
INTRATHECAL THERAPEUTICS REVIEW

Neuromodulation 2017; ••: ••–••

7
 8

Table 2. Continued
NAGEL ET AL.

Author(s) Year of Type of Number Population Indication Pump Catheter type Complications Procedure- Catheter-related Pump-related Therapy- Notes/insights
and publication study of age (years) model (number of related complications complications related
reference patients patients/% of complications complications
no. those in study)
Yue et al. (36) 2015 Case report 1 82 NPP/AAA _ Medtronic EDM _ None Entrapments None None Procedure led to
Lumbar Drain of nerve increased

www.neuromodulationjournal.com
rootlets perfusion
pressure on the
spinal cord
Zinboon- 2015 Case series 2 37, 57 CDP _ _ _ 2 hemifacial _ _ _ Harlequin
yahgoon flushing Syndrome,
et al. (48) probably related
intrathecal
medication
Han et al. (35) 2016 Case report 1 60 NPP _ _ _ None 1 None None Catheter formed a
coil around the

V
left T10 nerve
root
Morgalla et al. 2016 Retrospective 51 18–78 28 SPA, 2 DY, 21 _ _ 22/24% 2 pump 1 pump 6 malfunction, 2 1 baclofen _
(39) NPP infection disconnection, positional intoxication
3spinal changes
catheter
disconnection,
3 dislocations,
1 minor
catheter leak, 2
occlusion
Motta and 2016 Retrospective 508* 1–16 451 CP, 57 MISC SynchroMed EL Medtronic 120 in Indura 43 infection 24 75 total; 5 _ _ Ascenda catheter
Antonello SynchroMed II 8709SC, group (29%) CSF leak occlusion; 27 can reduce the
(28) Medtronic 1 in Ascenda breaking; 18 major catheter-
Ascenda group (1.1%) dislodgment, related
8 disconnec- complications
tion; 24 other
Padalia 2016 Case report 1 38 CDP _ _ _ _ 1 (bradycardia _ _ Catheter

C 2017 International Neuromodulation Society

et al. (45) and asystolic tip could cause
episodes) of autonomic
dysfunction
Thakur 2016 Retrospective 43 3–50 33 CP, 3 MS, _ _ 12/27% 3 infection 2 1 low flow, 2 loop 1 known 1 poor No CSF leak
et al. (43) 2 TBI, 2 RS, 3 lumbar migration, 1 malfunction, 1 response detected or
MISC dehiscence disconnection uncertain catheter
malfunction migration more
than 3-year
median follow-
up

*Includes patients from the same population.

AAA, Abdominal aortic aneurysm; ABI, Anoxic brain injury; CDP, Cancer-derived pain; CF, Compression fracture; CP, Cerebral palsy; CRPS, Complex regional pain syndrome; CS, Cervical spondylosis; DY,
Dystonia; FBSS, Failed back surgery syndrome; FSP, Familial spastic paresis; ICH, Intracranial hemorrhage; LS, Lumbar spondylosis; MISC, Miscellaneous causes; MS, Multiple sclerosis; NPP, Neuropathic pain;
PAR, Paralysis (all types); PLS, Primary lateral sclerosis; PN, Peripheral neuropathy; RPY, Radiculopathy; RS, Rhett syndrome; SPA, Spasticity; SCI, Spinal cord injury; SS, Spinal stenosis; STR, Stroke; TBI, Trau-
matic brain injury.

Neuromodulation 2017; ••: ••–••


Figure 5. Schematic illustration of a drug delivery catheter within the intrathecal space, with representations of the most typical types of device malfunctions.
[Color figure can be viewed at wileyonlinelibrary.com]
Multiple factors have been implicated in the formation of granulo-
mas but to-date there are no algorithms reported that readily pre-
dict their development. In a recent retrospective study, Kratzsch
et al. (54) identified 13 cases of catheter tip granulomas from two
tertiary centers. Several risk factors were associated with granuloma
formation including the use of morphine, average daily dose and
concentration, catheter tip location in the mid-thoracic spine, and
an indication of pain vs. spasticity. The authors suggested that slug-
gish flow of CSF in this region of the spine may play a role although
evidence supporting positioning the tip in the lumbar spine is lack-
ing (44). A consensus statement published in 2012 in Neuromodula-
tion describes the diagnosis and management of catheter tip
granulomas (55).
Catheter Failure During Extraction
The vast majority of catheters that are inserted directly into the
intrathecal space and externalized at the skin are intended for tem-
porary use. Catheter removal via gentle, steady traction while main-
taining proximal stability by grasping the catheter as it emerges
from the skin minimizes but does not eliminate the risk of catheter
fracture. The tensile strength for most temporary catheter materials
is relatively low; they will routinely shear when squeezed between
the bony surfaces of the lumbar spine and are often weakened or
inadvertently partially or completely torn on insertion across the
needle bevel. Yue et al. (36) documented the case of a patient that
suffered an entrapped nerve root by a segment of the partially torn
catheter that was longitudinally split. It eventually required open
removal and repair.
Retained catheters are commonplace, are usually asymptomatic
and thus rarely require removal. Surgical removal is occasionally indi-
cated when the catheter is causing radicular pain or weakness or
when it is a nidus for infection. In these cases, attempts to remove
the catheter when the external tip of the fragment is still extradural
are sometimes frustrating, as the catheter can migrate deeper when
www.neuromodulationjournal.com C 2017 International Neuromodulation Society
V Neuromodulation 2017; ••: ••–••
INTRATHECAL THERAPEUTICS REVIEW
approached (56). When the entirety of the catheter fragment is intra-
thecal, removal is generally more invasive involving laminar removal
and durotomy. However, there are reports of endovascular tools
being repurposed to ensnare foreign material in the intrathecal
space (37).
Navigational Limitations and Device Entanglement
Contemporary studies that use sagittal MR imaging to measure
the termination of the conus medullaris relative to the nearest adja-
cent vertebral body align it with the middle third of L1 (57).
Attempts to access the intrathecal space at this level or rostrally
with a needle risk impaling the spinal cord, which is held in position
by the dentate ligaments. Safe, percutaneous access of the intrathe-
cal space via needle is limited to the intra-laminar spaces between
L2 and S1. The nearly free-floating nerve roots in the lumbar spine
are displaced around the access needle after the thecal sac is
pierced. The angulation, needle bevel and inner cannula diameter
may limit the advancing catheter in this region, in addition to patho-
logical changes such as degenerative lumbar spine disease or defor-
mities. At more rostral levels of the spinal canal other obstacles
often will redirect or impede the catheter from ascending. These
include the conus medullaris, spinal cord, dentate ligaments, and
traversing dorsal and ventral rootlets. Han et al. (35) reported
delayed entanglement of a catheter with the T10 nerve root that
occluded the catheter and incited radicular pain. The catheter was
ultimately removed after the inner stylet was re-inserted with gentle
traction. Intramedullary catheter migrations have also been
described (58).
Semi-rigid guidewires improve the steerability of the catheters
but could potentially also contuse or penetrate the cord if excess
force is applied. Without a guidewire, the catheters will follow the
path of least resistance and this may result in suboptimal position-
ing. Current devices are not equipped with modifications that would
9
enable mechanical fixation of catheters in the optimal intrathecal
 NAGEL ET AL.

as shown in Fig. 6, the catheter had coiled to the point of blocking

the flow.
When the anchor device fails or is not used, the risk of catheter
migration is high especially in ambulatory individuals. In fact, this
was the most common complication in three clinical trials before
best practices were promulgated widely (15). When a paramedian,
oblique, shallow angle of entry is chosen, and the L2-3 or L3-4 inter-
laminar space is entered, this complication is encountered less fre-
quently (15). Furthermore, the L4-5 and L5-S1 spaces are relatively
mobile and seem to predispose patients to this complication. In
addition to anchoring to the fascia or robust scar tissue, a purse
string suture that encloses the catheter is thought to lower the risk
of CSF leak and bolster pullout resistance. Adding catheter length to
the intrathecal side also will reduce the need for revision surgery
but if the tip travels multiple levels inferiorly the benefits of targeted
drug delivery may not be observed. Figure 7 shows a case of almost
complete retrograde migration of the catheter, which necessitated
removal.

Figure 6. A patient with Twiddler’s syndrome experienced acute baclofen
withdrawal due to his motion-induced coiling and subsequent constriction of
the catheter, as was evident upon extraction. [Color figure can be viewed at
wileyonlinelibrary.com]
Diagnostics
Identifying the source of a programmable pump malfunction is
challenging. Side port aspirations and dye studies will alert the phy-
sician to more common types of malfunction but may not be suffi-
cient to diagnose other less frequently encountered complications.
Some groups have advocated three-dimensional CT in all cases as a
first line test (38), although false positive radiological identification
of pump and catheter malfunctions have also been reported (63). If
magnetic resonance imaging studies are used to evaluate a patient
it is important to insure that the catheter material will not cause
imaging artifacts, displacement, or undergo radio frequency-driven
heating (64). Catheters tips sequestered to the subdural space are

location. Although dorsal, ventral or lateral placement in relation to

the spinal cord is feasible, this has little clinical value at present.
Patient feedback is often used when inserting a catheter without
the aid of fluoroscopy. Live fluoroscopy provides two-dimensional
visualization in anesthetized patients and alerts the physician to
obvious misplacements in some instances, but does not have suffi-
cient three-dimensional spatial resolution to prevent all types of
suboptimal placements. The true incidence of neurologic injury
related to intrathecal needle insertion and catheter placement is by
most estimates very low (59). The injection of water soluble, low
osmolar, nonionic contrast agents intended for intrathecal use can
help define anatomy (60). Patients with iodine allergy could be
offered gadolinium based contrast agents. The presence of a dorsal
bony fusion or bulky hardware creates a mechanical barrier that
may block percutaneous access to the intrathecal space. In challeng-
ing cases, cone beam CT image guidance has been used to align a
sheathed needle for a drill to bore through the fusion mass to facili-
tate catheter insertion (61).

Twisted Catheters and Migration

Repetitive movements in ambulatory patients and frequent trans-
fers in those confined to a wheelchair may dislodge the pump from
its anchors freeing it to rotate or invert within the pocket (62). In
other patients, such as those with Twiddler’s syndrome, subcon-
scious, repetitive flipping of the device may lead to a similar compli-
Figure 7. Reformatted CT myelogram of the lumbar spine demonstrating a
cation. This motion will introduce coils into the catheter that is fixed retained silicon catheter fragment looped on itself in the intrathecal space. The
at multiple points and eventually lead to occlusion and malfunction. patient presented with urinary urgency, leg pain, and erectile dysfunction. The
10

We have had patients presenting in acute baclofen withdrawal and, catheter was removed successfully.

www.neuromodulationjournal.com C 2017 International Neuromodulation Society

V Neuromodulation 2017; ••: ••–••

often overlooked unless the telltale crescent shape is appreciated
after a dye study (65).
CSF Fistula
The steady egress of spinal fluid through a small perforation in
the lumbar or thoracic dura after intentional or inadvertent dural
puncture may lead to postprocedure positional headaches. The
pathophysiologic and mechanistic link between positional head-
aches and the presence of a spinal fluid fistula is not entirely
understood (66). However, spinal headaches are clearly associated
with the diameter of spinal punctures (66). The headaches on occa-
sion are severe enough to be incapacitating for some patients.
Although they are generally self-limited, more invasive management
options including epidural blood patch or direct surgical repair are
sometimes necessary. Persistent, symptomatic CSF leak is a well-
described phenomenon especially in the obstetric literature where it
is estimated that more than 20,000 women in 2014 in the United
States alone suffered a postdural puncture headache (67). Despite
the relative frequency of this complication, there is no widely
accepted consensus view regarding optimal treatment (67).
The incidence of CSF leak in the setting of intrathecal catheter sys-
tems placement is relatively low. In a prospective study published in
2000, Follet and Naumann identified only 4 out of 209 patients who
reported a CSF leak complication (20). Modern series of pediatric
patients report that the relative risk of CSF leak may be even lower
with new catheter systems coupled with the adoption of best prac-
tice guidelines (28). Although the outer diameter of the Tuohy nee-
dle is relatively large compared to the needles used for diagnostic
purposes alone, the seal formed at the dural puncture site by the
traversing catheter likely plays an important role in preventing spinal
fluid leaks. Postprocedure headache related to CSF loss is still com-
mon after IT catheter insertion but also is potentially preventable
when normal saline is infused through the catheter at the time of
implantation surgery (66).
In general, as the needle gauge increases, and outer diameter
thus decreases, the risk of a post dural puncture headache shrinks.
However, other factors such as the details of needle design are also
important (66). Atraumatic, pencil-point needles such as a Sprotte
needle seem to reduce the risk CSF leak compared to cutting nee-
dles but likely are not suitable for deploying catheters like beveled
needles. Interestingly, scanning electron micrographs suggest that
this atraumatic designation is actually a misnomer as these conical
tip needles seem to induce a more jagged, irregular dural disruption
inciting a localized inflammatory reaction that seals the hole (68). In
either case, the risk of CSF leak is a tractable and manageable prob-
lem following dural puncture that should not dissuade researchers
and clinicians from exploring new means of accessing this therapeu-
tic space.
OUTCOMES AND EFFICACY
While complications may arise during intrathecal catheter-pump
treatment, at this point, the benefits of this therapy, at least for spas-
ticity management, exceed the risks. However, intrathecal drug
delivery is not appropriate for every patient with refractory chronic
pain or spasticity. Therefore, the patient selection process is a criti-
cally important step in the successful clinical use of intrathecal devi-
ces. In those refractory pain patients who are appropriate
candidates, intrathecal opioid therapy has improved pain control in
the long-term as well as lowered opioid-related side-effects as
compared with those patients who receive oral or transdermal
www.neuromodulationjournal.com C 2017 International Neuromodulation Society
V Neuromodulation 2017; ••: ••–••
INTRATHECAL THERAPEUTICS REVIEW
medications (3,69–71). There is even some evidence suggesting a
reduction in mortality rates in cancer pain patients (69). In patients
with medically refractory spasticity, studies have repeatedly demon-
strated the benefits of intrathecal baclofen (ITB) (72,73). ITB therapy
can reduce spasticity with fewer collateral systemic effects in
patients who have sustained traumatic brain injury, spinal cord
injury, multiple sclerosis, and cerebral palsy among other pathologi-
cal conditions (74–76). ITB is also used effectively to treat patients
with idiopathic dystonia (74,76).
FUTURE WORK
The intrathecal space is underutilized as a conduit for directly
accessing the spinal cord because of the technical challenges and
safety concerns associated with placing devices intradurally. Many of
these concerns stem from fears surrounding the possibilities of intro-
ducing infectious agents into the intrathecal space, creating a CSF
fistula, or mechanically injuring the spinal cord or nerve roots. There
are already comprehensive best-practice guidelines available for ITB
therapies (71), as well as thoughtful recommendations for future
work (77). Our own suggestions revolve around the design features
that will serve as a prelude to the next generation of intrathecal
hardware.
Although the incompletely shielded intrathecal compartment is a
relatively accessible fluid space within the body that directly
communicates with the brain, there are still very few sanctioned
indications for sampling this fluid, modifying the hydrodynamic
properties, delivering therapeutic medications or other substances
or as a channel to test or modulate spinal cord function for a wide
range of neurologic conditions. As of December 31, 2013 the FDA
had approved a total of 1453 unique molecular entities only three of
which were approved specifically for intrathecal use; baclofen, mor-
phine and ziconitide. By contrast, the intravascular and gastrointesti-
nal spaces are routinely used to circulate therapeutic compounds
systemically, including into the brain.
The intrathecal route is currently used to deliver antibiotics (78)
for bacterial infections in some instances, as well as to inject chemo-
therapeutic agents for neoplastic meningitis (79). Other researchers
are carrying out experimental animal studies to explore the role of
transplanting bone marrow cells to the spinal cord by an intrathecal
catheter to promote neurogenesis following spinal trauma (80). We
anticipate that in the future there will be interest in exploring deliv-
ery of multi-drug compounds for pain and other indications as well.
Electrical stimulation and observation of motor response has long
been used to confirm proper placement of epidural catheters
(81,82), and is able to identify inadvertent subdural placement of
those devices (83–85). As suggested by the results of comparative
experiments where stimuli were delivered to extradural vs. intradural
locations (86), we anticipate that intradural electrical stimulation
approaches will find greater use in optimizing the placement of
intrathecal catheters for targeted infusion. It is also likely that we will
develop a more nuanced appreciation for the functional segmenta-
tion of the spinal cord with respect to the effects of electrical stimu-
lation delivered to specific spinal cord levels. This in turn will
increase the importance of developing methods for preventing cath-
eter migration. This is a particularly challenging design requirement
given the magnitude of cord movements within the thecal sac that
occur during normal patient activities. To achieve this objective the
devices will likely need to either adhere stably to the spinal cord or
otherwise compensate for its motion, so that the resulting stimula-
11
tion can be position-sensitive in terms of the target axonal fibers.
 NAGEL ET AL.
Depending on the device design, it is conceivable that relative
motions of even less than one mm could limit the benefits of
stimulation.
The devices we use now for intrathecal therapies are relatively
primitive compared to what will be needed to optimally modulate
the spinal cord electrically or via focused chemical application in the
future using a percutaneous strategy. Without significant improve-
ments in implanted hardware and implantation methods, it is
unlikely that significant advances will be achieved. If it were possible
to precisely visualize catheters in three-dimensional space during
the insertion procedure, the stage would be set for designing and
testing steerable catheters as well as techniques and devices for
securing catheter tips in the desired position relative to the mobile
spinal cord. Technical improvements of these types may be har-
nessed to realize the clinical potential of research advances in a
broad range of neuroscience research fields including spinal cord
physiology, electrical and chemical neuromodulation, functional
neuroimaging, and CSF biomarkers. As with past advances, these
new devices and systems will need to be tested for safety and effi-
cacy in well-designed clinical trials (87). It will also be important to
explore the economic impact and quality-of-life improvements asso-
ciated with any new advance. In what follows, we review some spe-
cific topics for further study.
Real-Time Visualization of Intrathecal Devices
There are a number of potential strategies for improving intra-
operative imaging, with the goal of enabling safe deployment of
devices at specific targets on the spinal cord. At present, intraopera-
tive fluoroscopy is the technique of choice, although MR and CT
imaging are also employed. Contrast agents are used occasionally to
help navigate within this space. However, even with refinements
such as digital subtraction of bony structures as is used for angiogra-
phy, this technique is suboptimal as the images only indirectly dem-
onstrate the location of the spinal cord, nerves, dentate ligaments
and vasculature. Therefore, one approach would be to employ
image fusion. With this approach, a preoperative volumetric MRI of
the spinal column would be merged with either a stereotactic spinal
CT or fluoroscopic image to provide the navigational roadmap, in a
manner similar to that proposed originally for intraparenchymal
neuronavigation (88). A second method would similarly couple
endoscopy with fluoroscopy. This type of direct-vision approach
may prove to be superior in resolving anatomical details, but would
likely require additional access ports in the intrathecal space.
Catheter Performance
In recent years, a premium has been placed on the steerability of
epidural percutaneous, cylindrically shaped stimulation catheters.
However, these devices were designed for use within the potential
space between the dura and the epidural fat, ligament and lamina,
and not for a permissive fluid channel such as the intrathecal space.
The resistance of these epidural structures along with fluoroscopy
serves as the feedback mechanism to the clinician to alert them of
off-target trajectories. Moreover, there is a learning curve. To per-
form the procedure safely and effectively, knowledge of how to use
the tactile feedback received during the insertion process must be
acquired with repetitive experience over time. Most stimulation
catheters are “stiffened” with a curved or straight guidewire that is
locked into place at the steering mechanism. To date, no similar
strategies have been employed for augmenting the steerability of
intrathecal catheters that, heretofore, have only needed rostral-
12
caudal maneuverability. While guidewires are used frequently and
www.neuromodulationjournal.com C 2017 International Neuromodulation Society
V Neuromodulation 2017; ••: ••–••
some limited dorsal-ventral directionality is possible, adjustments
are very coarse. To achieve better regional selectivity a new method
must be developed to steer devices effectively through what is
essentially a thin, annular aqueous channel.
Intrathecal Device Fixation
We anticipate that the stable yet minimally intrusive in situ fixa-
tion of any novel intrathecal device will be perhaps the greatest
challenge in its design. An example is the I-Patch intradural spinal
cord stimulator (89). As conceived originally, the soft, thin electrode
array would rest directly on the pial surface of the spinal cord and
wrap gently around it circumferentially (90). To simplify the surgical
implantation procedure, fixation to the dentate ligaments was then
investigated (91). The final version of the design incorporated an
arrangement of compliant leads that stabilized the electrode array’s
substrate onto the dorsal aspect of the spinal cord at a surface pres-
sure within the range of normal intrathecal pressures (92). The lead
bundle was then passed through a dural seal (93) and anchored to
the adjacent vertebral bone (94). This arrangement allowed the
intrathecal component of the device to remain in continuous gentle
contact with the spinal cord while it moved within the spinal canal
during flexion and extension of the spine, but without migration or
slippage from its intended location. Because laminectomy and dur-
otomy would be required for implantation, the degree of invasive-
ness could be a barrier to eventual clinical adoption. The ideal
solution would be to achieve the same electrode positioning out-
come but with a simple percutaneous implantation technique. At
R
present, the new locking anchors on the AscendaV that are sewn to
the fascia have limited the risk of catheter migration but will do
nothing to secure the distal tip to the spinal cord itself at the
selected level. Concepts for devices that attach to the spinal cord or
dura, stabilizing balloons, scaffolds, stents, or glues, and adhesives
are all viable options at this point and will need to be designed,
built, tested in silico and in vivo and then taken through clinical trials
after appropriate preclinical vetting.
Access Devices
The design of access needles used to gain entry into the intrathe-
cal space has changed little over a period of decades. This is due in
large part to the fact that existing simple designs are effective for
current clinical indications and permanent long-term complications
associated with their use are rare. However, in the current medical-
practice climate, the tolerance by patients of even a temporary side
effect or what could be considered an expected outcome, such as a
postprocedural headache, is quite low and especially so for new
therapies. Several small design modifications could play a significant
role in virtually eliminating the risk of CSF leak as well as improving
the ease with which new devices could be passed and steered. For
instance, flexible needles with site-sealing mechanisms or means of
eluting glues should be investigated.
Stimulation System Designs
The last several years have seen a number of new percutaneous
epidural electrode arrays (95) and stimulation-parameter configura-
tions (96) brought to market, along with many others in the product
development pipeline, that have and will continue to significantly
enhance the standard methods of spinal cord stimulation (97). The
electrode configuration that will offer the most selectivity and sup-
port the greatest range of stimulation parameters may prove best
(98), but other considerations such as power consumption (99), abil-
ity to upgrade the implanted stimulator (100), and ease of use by

the patient (101) will also be factors in device recommendations for
each clinical case. Sorting through which will work best for any
given indication will undoubtedly take time, and include careful
evaluations of quality-of-life improvement and economic consider-
ations (102). In particular, much interest has developed recently
around the topic of stimulation frequency in particular, with a num-
ber of clinical trials reporting improved results using 10 kHz stimula-
tion frequencies (103,104) and burst-mode approaches (105,106).
The clinical success obtained with these methods has stirred addi-
tional interest in developing a firm understanding of the neurophysi-
ology mechanisms of action underlying spinal cord stimulation
(107). This is especially important in the complex disruptions that
arise in spinal cord injury (108), and efforts aimed at elucidating the
neuronal therapeutic responses to spinal cord stimulation are under-
way (2,109).
We anticipate that the same considerations will hold for leads
delivered directly into the intrathecal space. While intradural elec-
trode arrays saw significant clinical use at the origin of spinal cord
stimulation in the 1960s and 1970s (1), placement was by surgical
open durotomy and it is only recently that research has begun into
new forms of the intradural approach (89,110). It is very likely that
extension of the existing percutaneous methods for accessing the
intrathecal space will eventually be used for placement of specially
designed stimulator leads, in much the same way that recording
leads have long been inserted there to monitor spinal cord evoked
potentials (111). Finite element modeling (112) and preliminary
experimentation (113) has shown that intradural electrodes will offer
significant advantages over epidural ones in terms of reduced power
consumption and selectivity in axonal fiber targeting. Among the
challenges in realizing such devices, however, will be obtaining posi-
tional stability of the electrode array relative to the underlying spinal
cord surface, minimizing adverse reactions at the biotic-abiotic inter-
face (114), maintaining long-term mechanical and electrical patency
of the delicate wires that convey the stimulus signals to the electro-
des, and securing a permanent water-tight seal at the point where
the wire bundle or lead body traverses the dura. Although these
issues are technologically difficult, a number of preliminary studies
have helped to establish potentially fruitful directions for the future
work needed to address them (18,92–94).
Chemical Infusion Systems
Similarly, intrathecal delivery of agents or compounds targeted
for direct application to the spinal cord might play an expanding
role for treatment of localized pain conditions such as postherpetic
neuralgia (115–117). Still other potential applications might include
various gastrointestinal motility disorders (118,119). We note that
spinal cord stimulation is also under study for this application as
well (120). Among the challenges to be faced in designing advanced
types of intrathecal delivery devices will be the incorporation of pre-
cision flow control systems. For instance, it may be necessary to
dependably convey fluidic volumes as small as a nanoliter per day
(121), deliver functionalized nanoparticles in suspensions (12), and
maintain proper mixtures of complex multi-drug compounds (122).
The latter possibility would benefit significantly from pump
designs that incorporated separate reservoirs and independently
controlled impellor means for each agent in the compound, similar
in principle to the implantable multi-chamber pumps used in certain
ventricular-assist devices (123). A multi-channel delivery catheter
would then also be needed, unless the pharmacokinetics of the
compound allowed for sufficient mixture of it prior to passage into
the catheter. Some of the characteristics needed by such catheters
www.neuromodulationjournal.com C 2017 International Neuromodulation Society
V Neuromodulation 2017; ••: ••–••
INTRATHECAL THERAPEUTICS REVIEW
have already been incorporated into preliminary versions of bi-
lumen devices optimized for complex intraparenchymal infusions
within the brain (124,125). A further point regarding advanced pump
designs has to do with the methodologies employed to replenish
the reservoirs. At present this is typically accomplished via an office
procedure using a manufacturer-supplied template placed on the
skin, and palpated alignment of the template periphery with the
edges of the underlying pump. The needle of the refill syringe is
then inserted through the target zone indicated on the template,
with subsequent penetration of the septum of the pump’s reservoir.
The accuracy of the refill targeting process can be increased by the
use of ultrasonic (126) or fluoroscopic (127) guidance, and it may
turn out that either these or some allied imaging-based modality will
be needed to insure proper replenishment of multi-chamber pumps.
A final general comment is that we are moving into the age of
smart medical devices, i.e., those that are able to sense and monitor
the relevant physiological parameters of the patient, and make
adjustments in response as needed to optimize the safety and out-
come of the therapy. In terms of intrathecal catheters, Saulino et al.
(128) have already taken steps in that direction by exploring the
incorporation of a pressure sensor into an ITB catheter as a means of
detecting variations in CSF pressure that might indicate catheter
malfunction. Other examples might include devices with on-board
miniature strain gauges to detect anomalous stiffening of the cathe-
ter (129) that might be indicative of incipient granuloma formation,
optical fiber sensors for real-time flow cytometry during delivery of
cell suspensions (130), and oxygen saturation sensors to alert the
onset of respiratory failure in the event of malfunctions or delayed
pump refill during intrathecal opiod delivery (131). Lastly, spinal
cord stimulators are now integrating real-time data from on-board
inertial accelerometers to optimize stimulation patterns and intensi-
ties (132) in response to the patient’s posture and activity. Future
versions of ITB pump systems might likewise incorporate data from
bioelectric sensors monitoring motor neurons (133) to meet the
neurophysiological needs of the patient on a continuously adaptive
basis.
Acknowledgements
The authors thank Michelle Roberto of Medtronic Corp. for
assistance with obtaining technical details about some of their
products. They also thank University of Iowa graphic artist Shawn
Roach for assistance with figures.
Authorship Statement
Drs. Sean J. Nagel, George T. Gillies, and Leonardo A. Frizon pre-
pared the manuscript draft with important edits and intellectual
input from Drs. Chandan G. Reddy, Marshall T. Holland, Andre
G. Machado, Matthew A. Howard. All authors approved the final
manuscript.
How to Cite this Article:
Nagel S.J., Reddy C.G., Frizon L.A., Holland M.T., Machado
A.G., Gillies G.T., Howard M.A. 2017. Intrathecal
Therapeutics: Device Design, Access Methods, and
Complication Mitigation.
Neuromodulation 2017; E-pub ahead of print.
DOI:10.1111/ner.12693
13
 NAGEL ET AL.
REFERENCES
1. Gibson-Corley KN, Flouty OE, Oya H, Gillies GT, Howard MA. III. Post-surgical
pathologies associated with intradural electrical stimulation in the central nervous
system: design implications for a new clinical device. BioMed Res Int 2014;2014:
989175.
2. Nagel SJ, Wilson S, Johnson MD et al. Spinal cord stimulation for spasticity: histori-
cal approaches, current status and future directions. Neuromodulation 2017;20:
307–321.
3. Patel VB, Manchikanti L, Singh V, Schultz DM, Hayek SM, Smith HS. Systematic
review of intrathecal infusion systems for long-term management of chronic non-
cancer pain. Pain Physician 2009;12:345–360.
4. Yawn BP, Wollan PC, Weingarten TN, Watson JC, Hooten WM, Melton LJ. The prev-
alence of neuropathic pain: Clinical evaluation compared with screening tools in a
community population. Pain Med 2009;10:586–593.
5. Teno JM, Clarridge BR, Casey V et al. Family perspectives on end-of-life care at the
last place of care. JAMA 2004;291:88–93.
6. Rauck R, Deer T, Rosen S et al. Accuracy and efficacy of intrathecal administration
RV
of morphine sulfate for treatment of intractable pain using the Prometra pro-
grammable pump. Neuromodulation 2010;13:102–107.
7. Rauck R, Deer T, Rosen S et al. Long-term follow-up of a novel implantable pro-
grammable infusion pump. Neuromodulation 2013;16:163–167.
8. Heetla HW, Staal MJ, van Laar T. Tolerance to continuous intrathecal baclofen infu-
sion can be reversed by pulsatile bolus infusion. Spinal Cord 2010;48:483–486.
9. Hettiarachchi HDM, Hsu Y, Harris TJ Jr, Linninger AA. The effect of pulsatile flow on
intrathecal drug delivery in the spinal canal. Ann Biomed Eng 2011;39:2592–2602.
10. Bethoux F, Boulis N, McClelland S et al. Use of intrathecal baclofen for treatment
of severe spasticity in selected patients with motor neuron disease. Neurorehabili
Neural Repair 2013;27:828–833.
11. Konrad PE, Huffman JM, Stearns LM et al. Intrathecal drug delivery systems (IDDS):
the implantable systems performance registry (ISPR). Neuromodulation 2016;19:
848–856.
12. Rossi F, Perale G, Papa S, Forloni G, Veglianese P. Current options for drug delivery
to the spinal cord. Expert Opin Drug Deliv 2013;10:385–396.
13. Zaaroor M, Kosa G, Peri-Eran A, Maharil I, Shoham M, Goldsher D. Morphological
study of the spinal canal content for subarachnoid endoscopy. Minim Invasive Neu-
rosurg 2006;49:220–226.
14. https://professional.medtronic.com/pt/neuro/itb/prod/ascenda-intrathecal-cathe-
ter/features-specifications/index.htm
15. Follett KA, Burchiel K, Deer T et al. Prevention of intrathecal drug delivery catheter-
related complications. Neuromodulation 2003;6:32–41.
16. Hassenbusch S, Burchiel K, Coffey RJ et al. Management of intrathecal catheter-tip
inflammatory masses: a consensus statement. Pain Med 2002;3:313–323.
17. Hokanson K, Gjoraas A, Kopp J, Metzler M, Servi A. Test results showing bench reli-
ability on catheter dislodgment for Ascenda, Medtronic Neuromodulation’s next-
generation catheter. PM R 2010;2:S157.
18. Viljoen S, Oya H, Reddy CG et al. Apparatus for simulating dynamic interactions
between the spinal cord and soft-coupled intradural implants. Rev Sci Instrum
2013;84:114303.
19. Penn RD, York MM, Paice JA. Catheter systems for intrathecal drug delivery.
J Neurosurg 1995;83:215–217.
20. Follett KA, Naumann CP. A prospective study of catheter-related complications of
intrathecal drug delivery systems. J Pain Symptom Manage 2000;19:209–215.
21. Kamran S, Wright BD. Complications of intrathecal drug delivery systems. Neuro-
modulation 2001;4:111–115.
22. Ordia JI, Fischer E, Adamski E, Chagnon KG, Spatz EL. Continuous intrathecal baclo-
fen infusion by a programmable pump in 131 consecutive patients with severe
spasticity of spinal origin. Neuromodulation 2002;5:16–24.
23. Kolaski K, Logan LR. A review of the complications of intrathecal baclofen in
patients with cerebral palsy. Neurorehabilitation 2007;22:383–395.
24. Stretkarova I, Yablon SA, Kofler M, Stokic DS. Procedure- and device-related com-
plications of intrathecal baclofen administration for management of adult muscle
hypertonia: a review. Neurorehabil Neural Repair 2010;24:609–619.
25. Motta F, Antonello CE. Analysis of complications in 430 consecutive pediatric
patients treated with intrathecal baclofen therapy: 14-year experience. J Neurosurg
Pediatr 2014;13:301–306.
26. Stempien L, Tsau T. Intrathecal baclofen pump use for spasticity: a clinical survey.
Am J Phys Med Rehabil 2000;79:536–541.
27. Varhabhatla NC, Zuo Z. Rising complication rates after intrathecal catheter and
pump placement in the pediatric population: analysis of national data between
1997 and 2006. Pain Physician 2012;15:65–74.
28. Motta F, Antonello CE. Comparison between an Ascenda and a silicone catheter in
intrathecal baclofen therapy in pediatric patients: analysis of complications.
J Neurosurg Pediatr 2016;18:493–498.
29. Dvorak EM, McGuire JR, Nelson MES. Incidence and identification of intrathecal
baclofen catheter malfunction. PM R 2010;2:751–756.
30. Draulens N, Vermeersch K, Degraeuwe B et al. Intrathecal baclofen in multiple scle-
rosis and spinal cord injury: complications and long-term dosage evolution. Clin
Rehabil 2013;27:1137–1143.
31. Maugans TA. Intracranial migration of a fractured intrathecal catheter from a bac-
lofen pump system: case report and analysis of possible causes. Neurosurgery
2010;66:319–322.
32. Ghosh D, Mainali G, Khera J, Luciano M. Complications of intrathecal baclofen pumps
14
in children: experience from a tertiary care center. Pediatr Neurosurg 2014;49:138–144.
www.neuromodulationjournal.com C 2017 International Neuromodulation Society
V Neuromodulation 2017; ••: ••–••
33. Hnenny L, Sabry HA, Raskin JS, Liu JJ, Roundy NE, Dogan A. Migrating lumbar intra-
thecal catheter fragment associated with intracranial subarachnoid hemorrhage.
J Neurosurg Spine 2015;22:47–51.
34. Borrini L, Bensmail D, Thiebout JB, Hugeron C, Rech C, Jourdan C. Occurrence of
adverse events in long-term intrathecal baclofen infusion: a 1-year follow-up study
of 158 adults. Arch Phys Med Rehabil 2014;95:1032–1038.
35. Han JL, Loriaux DB, Tybout C et al. Thoracic nerve root entrapment by intrathecal
catheter coiling: case report and review of the literature. Pain Physician 2016;19:
E499–E504.
36. Yue JJ, Castro CA, Scott D. Lumbar nerve rootlet entrapment by an iatrogenically
spliced percutaneous intra-thecal lumbar cerebrospinal fluid catheter. Int J Surg
Case Rep 2015;7:137–140.
37. Manix M, Wilden J, Cuellar-Saenz H. Percutaneous retrieval of an intrathecal for-
eign body: technical note. J Neurointerv Surg 2015;7:e36.
38. Awaad Y, Rizk T, Siddiqui I, Roosen N, Mcintosh K, Waines GM. Complications of
Intrathecal baclofen pump: prevention and cure. ISRN Neurol 2012;2012:575168.
39. Morgalla M, Fortunato M, Azam A, Tatagiba M, Lepski G. High-resolution three-
dimensional computed tomography for assessing complications related to intra-
thecal drug delivery. Pain Physician 2016;19:E775–E780.
40. Perruchoud C, Bovy M, Rutschmann B, Durrer A, Buchser E. Silicone septum leak-
age at the origin of a drug overdose in a patient implanted with an intrathecal
pump. Neuromodulation 2013;16:467–470.
41. Riordan J, Murphy P. Intrathecal pump: an abrupt intermittent pump failure. Neu-
romodulation 2015;18:433–435.
42. Bolash R, Udeh B, Saweris Y et al. Longevity and cost of implantable intrathecal
drug delivery systems or chronic pain management: a retrospective analysis of 365
patients. Neuromodulation 2015;18:150–156.
43. Thakur SK, Rubin BA, Harter DH. Long-term follow-up for lumbar intrathecal baclo-
fen catheters placed using the paraspinal subfascial technique. J Neurosurg Pediatr
2016;17:357–360.
44. Tomycz ND, Ortiz V, McFadden KA, Urgo L, Moossy JJ. Management of symptom-
atic intrathecal catheter-associated inflammatory masses. Clin Neurol Neurosurg
2012;114:190–195.
45. Padalia D, Jassal N, Patel S. Near death experience from placement of an intrathe-
cal catheter. Pain Physician 2016;19:E621–E623.
46. Kochany JZ, Tran ND, Sarria JE. Increasing back and radicular pain 2 years following
intrathecal pump implantation with review of arachnoiditis. Pain Med 2013;14:
1658–1663.
47. Harney D, Victor R. Traumatic syrinx after implantation of an intrathecal catheter.
Reg Anesth Pain Med 2004;29:606–609.
48. Zinboonyahgoon N, Srinivasan S, Narang S. Harlequin syndrome following implan-
tation of intrathecal pumps: a case series. Neuromodulation 2015;18:772–775.
49. Bayhan IA, Sees JP, Nishnianidze T, Rogers KJ, Miller F. Infection as a complication
of intrathecal baclofen treatment in children with cerebral palsy. J Pediatr Orthop
2016;36:305–309.
50. Saulino M, Anderson DJ, Doble J et al. Best practices for intrathecal baclofen ther-
apy: troubleshooting. Neuromodulation 2016;19:632–641.
51. Albright AL, Turner M, Pattisapu JV. Best-practice surgical techniques for intrathe-
cal baclofen therapy. J Neurosurg 2006;104:233–239.
52. North RB, Cutchis PH, Epstein JA, Long DM. Spinal-cord compression complicating
subarachnoid infusion of morphine – case-report and laboratory experience. Neu-
rosurgery 1991;29:778–784.
53. DeLeo JA, Colburn RW, Rickman AJ, Yeager MP. Intrathecal catheterization alone
induces neuroimmune activation in the rat. Eur J Pain 1997;1:115–122.
54. Kratzsch T, Stienen MN, Reck T, Hildebrandt G, Hoederath P. Catheter-tip granulo-
mas associated with intrathecal drug delivery – a two-center experience identify-
ing 13 cases. Pain Physician 2015;18:E831–E840.
55. Deer TR, Prager J, Levy R et al. Polyanalgesic consensus conference – 2012: consen-
sus on diagnosis, detection, and treatment of catheter-tip granulomas (inflamma-
tory masses). Neuromodulation 2012;15:483–496.
56. Oshino S, Kishima H, Ohnishi Y-I, Iwatsuki K, Saitoh Y. “Do not follow the tail”: a
practical approach to remove a sheared lumbar catheter fragment avoiding its
migration into the spinal canal. World Neurosurg 2016;87:266–268.
57. Soleiman J, Demaerel P, Rocher S, Maes F, Marchal G. Magnetic resonance imaging
study of the level of termination of the conus medullaris and the thecal sac: influ-
ence of age and gender. Spine 2005;30:1875–1880.
58. Albrecht E, Durrer A, Chedel D, Maeder P, Buchser E. Intraparenchymal migration
of an intrathecal catheter three years after implantation. Pain 2005;118:274–278.
59. Grady RE, Horlocker TT, Brown RD, Maxson PM, Schroeder DR. Neurologic complica-
tions after placement of cerebrospinal fluid drainage catheters and needles in anes-
thetized patients: implications for regional anesthesia. Anesth Analg 1999;88:388–392.
60. Ares JDA, Amatriain GR, Iglesias CN, Forner MB, Gay MLF. Contrast agents used in
interventional pain: management, complications, and troubleshooting. Tech Reg
Anes Pain Manag 2014;18:65–75.
61. Robinson S, Robertson FC, Dasenbrock HH, O’Brien CP, Berde C, Padua H. Image-
guided intrathecal baclofen pump catheter implantation: a technical note and
case series. J Neurosurg Spine 2017;26:621–627.
62. Russell LJ, leRoux AA, Wheelock WB. Twisted catheter causing baclofen pump mal-
function: a case report. Can J Neurol Sci 2012;39:838–839.
63. Dardashti S, Chang EY, Kim RB, Alshariff KI, Hata JT, Perret DM. False positive radio-
graphical evidence of pump catheter migration into the spinal cord. Pain Physician
2013;16:E627–E630.
64. Owens S, Erturk MA, Ouanes JPP, Murphy JD, Wu CL, Bottomley PA. Evaluation of
epidural and peripheral nerve catheter heating during magnetic resonance imag-
ing. Reg Anesth Pain Med 2014; 39:534–539.

65. Sorokin A, Annabi E, Yang W-C, Kaplan R. Subdural intrathecal catheter placement:
experience with two cases. Pain Physician 2008;11:677–680.
66. Turnbull DK, Shepherd DB. Post-dural puncture headache: pathogenesis, preven-
tion and treatment. Br J Anaesth 2003;91:718–729.
67. Sachs A, Smiley R. Post-dural puncture headache: the worst common complication
in obstetric anesthesia. Semin Perinatol 2014;38:386–394.
68. Reina MA, de Leon-Casasola OA, Lopez A, De Andres J, Martin S, Mora M. An in vitro
study of dural lesions produced by 25-gauge Quincke and Whitacre needles evalu-
ated by scanning electron microscopy. Reg Anesth Pain Med 2000;25:393–402.
69. Bruel BM, Burton AW. Intrathecal therapy for cancer-related pain. Pain Med 2016;
17:2404–2421.
70. Deer TR, Pope JE, Hayek SM et al. The Polyanalgesic Consensus Conference
(PACC): recommendations for intrathecal drug delivery: guidance for improving
safety and mitigating risks. Neuromodulation 2017;20:155–176.
71. Prager J, Deer T, Levy R et al. Best practices for intrathecal drug delivery for pain.
Neuromodulation 2014;17:354–372.
72. McCormick ZL, Chu SK, Binler D et al. Intrathecal versus oral baclofen: a matched
cohort study of spasticity, pain, sleep, fatigue, and quality of life. PM R 2016;8:553–562.
73. Otero-Romero S, Sastre-Garriga J, Comi G et al. Pharmacological management of
spasticity in multiple sclerosis: systematic review and consensus paper. Mult Scler
2016;22:1386–1396.
74. Albright AL, Ferson SS. Intrathecal baclofen therapy in children. Neurosurg Focus
2006;21:e3.
75. Hsieh JC, Penn RD. Intrathecal baclofen in the treatment of adult spasticity. Neuro-
surg Focus 2006;21:e5.
76. Dressler D, Berweck S, Chatzikalfas A et al. Intrathecal baclofen therapy in Ger-
many: proceedings of the IAB-interdisciplinary working group for movement disor-
ders consensus meeting. J Neural Transm (Vienna) 2015;122:1573–1579.
77. Pope JE, Deer TR. Intrathecal drug delivery for pain: a clinical guide and future
directions. Pain Manag 2015;5:175–183.
78. Beauchesne P. Intrathecal chemotherapy for treatment of leptomeningeal dissemi-
nation of metastatic tumours. Lancet Oncol 2010;11:871–879.
79. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of
bacterial meningitis. Lancet 2012;380:1693–1702.
80. Cizkova D, Novotna I, Slovinska L et al. Repetitive intrathecal catheter delivery of
bone marrow mesenchymal stromal cells improves functional recovery in a rat
model of contusive spinal cord injury. J Neurotrauma 2011;28:1951–1961.
81. Tsui BCH, Gupta S, Finucane B. Detection of subarachnoid and intravascular epidu-
ral catheter placement. Can J Anesth 1999;46:675–678.
82. Charghi R, Chan SY, Kardash KJ, Finlayson RJ, Tran DQH. Electrical stimulation of
the epidural space using a catheter with a removable stylet. Reg Anesth Pain Med
2007;32:152–156.
83. Tsui BCH, Gupta S, Emery D, Finucane B. Detection of subdural placement of epi-
dural catheter using nerve stimulation. Can J Anesth 2000;47:471–473.
84. Lena P, Martin R. Subdural placement of an epidural catheter detected by nerve
stimulation. Can J Anesth 2005;52:618–621.
85. Pope JE, Stanton-Hicks M. Accidental subdural spinal cord stimulator lead place-
ment and stimulation. Neuromodulation 2011;14:30–33.
86. Sharpe AN, Jackson A. Upper-limb muscle responses to epidural, subdural and
intraspinal stimulation of the cervical spinal cord. J Neural Eng 2014;11:016005.
87. Krames E, Chapple I; The 8703 W Catheter Study Group. Reliability and clinical util-
ity of an implanted intraspinal catheter used in the treatment of spasticity and
pain. Neuromodulation 2000;3:7–14.
88. Howard MA III, Grady MS, Ritter RC, Gillies GT, Quate EG, Molloy JA. Magnetic
movement of a brain thermoceptor. Neurosurgery 1989;24:444–448.
89. Dalm BD, Viljoen SV, Dahdaleh NS et al. Revisiting intradural spinal cord stimula-
tion: an introduction to a novel intradural spinal cord stimulation device. Innov
Neurosurg 2014;2:13–20.
90. Howard MA III, Utz M, Brennan TJ et al. Intradural approach to selective stimulation
in the spinal cord for treatment of intractable pain: design principles and wireless
protocol. J Appl Phys 2011;110:044702.
91. Gibson-Corley KN, Oya H, Flouty O et al. Ovine tests of a novel spinal cord neuro-
modulator and dentate ligament fixation method. J Invest Surg 2012;25:366–374.
92. Oliynyk MS, Gillies GT, Oya H, Wilson S, Reddy CG, Howard MA. III, Dynamic loading
characteristics of an intradural spinal cord stimulator. J Appl Phys 2013;112:026103.
93. Viljoen S, Dalm BD, Reddy CG et al. Optimization of intradural spinal cord stimula-
tor designs via analysis of thoracic spine imaging data. J Med Biol Eng 2013;33:
193–198.
94. Dalm BD, Viljoen S, Gillies GT, Oya H, Howard MA. III. A novel dural reconstruction
method following spinal tumor resection. Neurosurg Q 2016;26:215–255.
95. Verrills P, Sinclair C, Barnard A. A review of spinal cord stimulation systems for
chronic pain. J Pain Res 2016;9:481–492.
96. Miller JP, Eldabe S, Buchser E, Johanek LM, Guan Y, Linderoth B. Parameters of spi-
nal cord stimulation and their role in electrical charge delivery: a review. Neuromo-
dulation 2016;19:373–384.
97. Zeidman SM. New developments in spinal cord stimulation. Spine 2017;42:S23.
98. Levy RM. Progress in the technology of neuromodulation: the emperor’s new
clothes? Neuromodulation 2013;16:285–291.
99. Wongsarnpigoon A, Grill WM. Energy-efficient waveform shapes for neural stimu-
lation revealed with a genetic algorithm. J Neural Eng 2010;7:046009.
100. De Ridder D, Vanneste S. Visions of the future of medical devices in spinal cord stimu-
lation: what medical device is needed? Expert Rev Med Devices 2016;13:233–242.
101. Lam CK, Rosenow JM. Patient perspectives on the efficacy and ergonomics of
rechargeable spinal cord stimulators. Neuromodulation 2010;13:218–223.
www.neuromodulationjournal.com C 2017 International Neuromodulation Society
V Neuromodulation 2017; ••: ••–••
INTRATHECAL THERAPEUTICS REVIEW
102. Slangen R, Faber CG, Schaper NC et al. A trial-based economic evaluation compar-
ing spinal cord stimulation with best medical treatment in painful diabetic periph-
eral neuropathy. J Pain 2016;18:405–414.
103. Kapural L, Yu C, Doust MW et al. Novel 10-kHz high-frequency therapy (HF10 ther-
apy) is superior to traditional low-frequency spinal cord stimulation for the treat-
ment of chronic back and leg pain. Anesthesiology 2015;123:851–860.
104. Kapural L, Yu C, Doust MW et al. Comparison of 10-kHz high frequency and tradi-
tional low-frequency spinal cord stimulation for the treatment of chronic back and
leg pain: 24-month results from a multicenter, randomized controlled pivotal trial.
Neurosurgery 2016;79:667–677.
105. De Ridder D, Vanneste S, Plazier M, van der Loo E, Menovsky T. Burst spinal
cord stimulation: toward paresthesia-free pain suppression. Neurosurgery
2010;66:986–990.
106. Slavin KV, North RB, Deer TR, Staats P, Davis K, Diaz R. Tonic and burst spinal cord
stimulation waveforms for the treatment of chronic, intractable pain: study proto-
col for a randomized controlled trial. Trials 2016;17:569.
107. Lempka SF, McIntyre CC, Kilgore KL, Machado AG. Computational analysis of kilo-
hertz frequency spinal cord stimulation for chronic pain management. Anesthesiol-
ogy 2015;122:1362–1376.
108. Cote M-P, Murray M, Lemay MA. Rehabilitation strategies after spinal cord
injury: inquiry into the mechanisms of success and failure. J Neurotrauma
2017;34:1841–1857.
109. Moraud EM, Capogrosso M, Formento E et al. Mechanisms underlying the neuro-
modulation of spinal circuits for correcting gait and balance deficits after spinal
cord injury. Neuron 2016;89:814–828.
110. Howell B, Lad SP, Grill WM. Evaluation of intradural stimulation efficiency and
selectivity in a computational model of spinal cord stimulation. PLoS One 2014;9:
e114938.
111. Tamaki T, Kubota S. History of the development of spinal cord monitoring. Eur
Spine J 2007;16:140–146.
112. Huang QJ, Oya H, Flouty OE et al. Comparison of spinal cord stimulation profiles
from intra- and extradural electrode arrangements by finite element modelling.
Med Biol Eng Comput 2014;52:531–538.
113. Flouty OE, Oya H, Kawasaki H et al. Intracranial somatosensory responses with
direct spinal cord stimulation in anesthetized sheep. PLoS One 2013;8:e56266.
114. Prodanov D, Delbeke J. Mechanical and biological interactions of implants with
the brain and their impact on implant design. Front Neurosci 2016;10:11.
115. Hosny A, Simonopoulos T, Collins B. Response of intractable post herpetic neural-
gia to intrathecal baclofen. Pain Physician 2004;7:345–347.
116. Christo PJ, Hobelmann G, Maine DN. Post-herpetic neuralgia in older adults –
evidence-based approaches to clinical management. Drugs Aging 2007;24:1–19.
117. Fabiano AJ, Doyle C, Plunkett RJ. Intrathecal medications in post-herpetic neural-
gia. Pain Med 2012;13:1088–1090.
118. Bilir L, Yelken B, Gulec S, Bilir A, Ekemen S. The effect of intrathecal medetomidine
on small bowel transit in the rat. Eur J Anaesthesiol 2003;20:911–915.
119. Naitou K, Mamerto TP, Pustovit RV et al. Site and mechanism of the colokinetic
action of the ghrelin receptor agonist, HM01. Neurogastroenterol Motil 2015;27:
1764–1771.
120. Chen JDZ, Yin J, Wei W. Electrical therapies for gastrointestinal motility disorders.
Expert Rev Gastroenterol Hepatol 2017;11:407–418.
121. Meng E, Hoang T. Micro-and nano-fabricated implantable drug-delivery systems.
Ther Deliv 2012;3:1457–1467.
122. Wallace MS, Rauck RL, Deer T. Ziconotide combination intrathecal therapy: ratio-
nale and evidence. Clin J Pain 2010;26:635–644.
123. Petzold T, Feindt P, Paul V, Gams E, Gersonde K. A new method of mechanical cir-
culatory support with an implantable multichamber pump system (IMPS): presen-
tation and first experimental results. Int J Artif Organs 1998;21:216–224.
124. Panse SJ, Fillmore HL, Chen ZJ, Gillies GT, Broaddus WC. A novel coaxial tube cath-
eter for central nervous system infusions: performance characteristics in brain
phantom gel. J Med Eng Technol 2010;34:408–414.
125. Panse SJ, Fillmore HL, Chen ZJ, Gillies GT, Broaddus WC. Performance tests of a
novel coaxial tube catheter in an in vitro model of intracranial cell delivery. J Med
Eng Technol 2011;35:77–86.
126. Gofeld M, McQueen CK. Ultrasound-guided intrathecal pump access and preven-
tion of the pocket fill. Pain Med 2011;12:607–611.
127. Maino P, Koetsier E, Perez RSGM. The accuracy of template-guided refill technique
of intrathecal pumps controlled by fluoroscopy: an observational study. Neuromo-
dulation 2015;12:428–432.
128. Saulino M, Turner M, Miesel K et al. Can cerebrospinal fluid pressure detect cathe-
ter complications in patients who experience loss of effectiveness with intrathecal
baclofen therapy?. Neuromodulation 2017;20:187–197.
129. Ferreira A, Borges J, Lopes C, Martin N, Lanceros-Mendez S, Vaz F. Piezoresistive
response of nano-architectured TixCuy thin films for sensor applications. Sensors
Actuators A Phys 2016;247:105–114.
130. Evans BM III, Allison SW, Fillmore HL, Broaddus WC, Dyer RL, Gillies GT. Cytometric
catheter for neurosurgical applications. J Med Eng Technol 2010;34:261–267.
131. Ruan XL, Couch JP, Liu HN, Shah R, Wang F, Chiravuri S. Respiratory failure follow-
ing delayed intrathecal morphine pump refill: a valuable, but costly lesson. Pain
Physician 2010;13:337–341.
132. Denison T, Litt B. Advancing neuromodulation through control systems: a general
framework and case study in posture-responsive stimulation. Neuromodulation
2014;17:48–57.
133. O’Driscoll S, Shenoy KV, Meng TH. Adaptive resolution ADC array for an implant-
15
able neural sensor. IEEE Trans Biomed Circuits Syst 2011;5:120–130.