Neuromodulation Using Intrathecal Baclofen Therapy for Spasticity and Dystonia

Abstract

Intrathecal baclofen (ITB) therapy is a treatment for intractable spasticity due to a variety of causes. Continuous intrathecal administration of baclofen, an agonist of the inhibitory neurotransmitter γ-aminobutyric acid, inhibits excitation of motor neurons at the spinal level and thus suppresses spasticity. This therapy was introduced clinically in the Europe and the United States in the 1990s, and was finally approved by the Japanese Ministry of Health, Labour and Welfare in Japan in 2005. Clinical use has been permitted since 2006, and reports of therapeutic efficacy are now appearing in Japan. ITB therapy is a non-destructive treatment that enables administration of baclofen from an implantable pump under the control of a programmer, and represents an outstanding treatment method offering both reversibility and adjustability. Indications for ITB therapy have been expanding in recent years to include not only spasticity, but also various causes dystonia. And ITB therapy can greatly improve activities of daily living and quality of life, and this treatment is attracting attention as a neuromodulatory therapy that also affects metabolic and respiratory functions and even state of consciousness. We here report the surgical methods and therapeutic outcomes for 22 patients who underwent ITB therapy for spastic and dystonic patients in our hospital, together with an investigation of the effects on metabolic and respiratory functions.

Full text

463
Received March 5, 2012; Accepted May 17, 2012
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469, 2012
The 70th Annual Meeting Special Topics — Part I:
Validation and Prospects for Neuromodulation
Neuromodulation Using Intrathecal Baclofen
Therapy for Spasticity and Dystonia
Takuya U
CHIYAMA
,
1
Kinya N
AKANISHI
,
1
Norihito F
UKAWA
,
1
Hiromasa Y
OSHIOKA
,
1
Saori M
URAKAMI
,
1
Naoki N
AKANO
,
1
and Amami K
ATO
1
1
Department of Neurosurgery, Kinki University Faculty of Medicine, Osaka-sayama, Osaka
Abstract
Intrathecal baclofen (ITB) therapy is a treatment for intractable spasticity due to a variety of causes.
Continuous intrathecal administration of baclofen, an agonist of the inhibitory neurotransmitter
g
-
aminobutyric acid, inhibits excitation of motor neurons at the spinal level and thus suppresses spastici-
ty. This therapy was introduced clinically in the Europe and the United States in the 1990s, and was fi-
nally approved by the Japanese Ministry of Health, Labour and Welfare in Japan in 2005. Clinical use
has been permitted since 2006, and reports of therapeutic efficacy are now appearing in Japan. ITB ther-
apy is a non-destructive treatment that enables administration of baclofen from an implantable pump
under the control of a programmer, and represents an outstanding treatment method offering both
reversibility and adjustability. Indications for ITB therapy have been expanding in recent years to in-
clude not only spasticity, but also various causes dystonia. And ITB therapy can greatly improve activi-
ties of daily living and quality of life, and this treatment is attracting attention as a neuromodulatory
therapy that also affects metabolic and respiratory functions and even state of consciousness. We here
report the surgical methods and therapeutic outcomes for 22 patients who underwent ITB therapy for
spastic and dystonic patients in our hospital, together with an investigation of the effects on metabolic
and respiratory functions.
Key words: neuromodulation, intrathecal baclofen, spasticity, dystonia
Introduction
Spasticity is a form of upper motor neuron syn-
drome caused by central nervous system dysfunc-
tion due to stroke, traumatic head injury, spinal inju-
ry, cerebral palsy, or other causes,
16)
and manifests
as motor disorder characterized by a velocity depen-
dent increase in tonic stretch reflex (muscle tone)
with exaggerated tendon jerks, resulting from hyper-
excitability of the stretch reflex, as one component
of the upper motor neuron syndrome.
15)
Upper mo-
tor neuron syndrome causes positive symptoms in-
cluding spasticity, spastic dystonia, and synkinesia,
as well as negative symptoms of motor paralysis and
reduced dexterity, giving rise to a range of motor
disturbances. Motor paralysis and similar symptoms
are mainly treated with rehabilitation, but positive
symptoms such as excessive spasticity and spastic
dystonia not only hinder rehabilitation, but also
reduce activities of daily living and quality of life,
making management an extremely important issue.
Baclofen acts as an agonist to the bicuculline-
insensitive type of
g
-aminobutyric acid (GABA)
receptor known as GABA-B. There is a high density
of GAGA-B receptors in the dorsal horn of the spinal
cord. Activation of presynaptic GABA-B receptors
causes an inhibition of calcium-mediated inward
current, thus inhibiting the release of excitatory neu-
rotransmitters such as aspartate and glutamate in
the polysynaptic pathways of the dorsal horn. This
alters and reduces the excitability of monosynaptic
and polysynaptic reflexes. Baclofen is thought also

464
Table 1 Clinical characteristics of 22 patients with spasticity and dystonia
Case No. Age (year) Sex Underlying
illness Time since onset
(month) Symptom Catheter placement Metabolic
examination Respiratory
examination
1 41 F CVA 7.7 tetraplegia lower thoracic no no
2 58 F CVA 89.7 hemiplegia lower thoracic no no
3 58 M SMS 64.3 paraplegia lower thoracic no no
4 61 F CVA 53.8 hemiplegia lower thoracic no no
5 29 M TBI 136 tetraplegia lower thoracic no no
6 48 M SP 333.1 paraplegia lower thoracic no no
7 43 F CVA 219.4 paraplegia lower thoracic no no
8 64 F SCI 317.4 hemiplegia lower thoracic no no
9 53 M CVA 3.3 tetraplegia lower thoracic no no
10 43 F CVA 36.8 tetraplegia lower thoracic no no
11 23 M TBI 103.3 tetraplegia cervical no no
12 20 M TBI 4.4 tetraplegia cervical no no
13 51 F CVA 4.2 tetraplegia/dystonia cervical yes yes
14 37 M CP 454.9 paraplegia lower thoracic yes yes
15 44 F MDD 60.2 tetraplegia cervical yes yes
16 45 M CP 23.5 paraplegia lower thoracic yes yes
17 57 M SCI 23.3 tetraplegia cervical yes yes
18 24 M TBI 2.2 tetraplegia/dystonia cervical yes yes
19 20 M TBI 3.3 tetraplegia/dystonia cervical yes yes
20 23 M CP 284 paraplegia lower thoracic yes yes
21 57 M SCI 106.4 paraplegia lower thoracic yes yes
22 30 M SM 78.9 paraplegia lower thoracic yes yes
CP: cerebral palsy, CVA: cerebrovascular accident, MDD: medullary degenerative disease, SCI: spinal cord injury, SM:
syringomyelia, SMS: spinal multiple sclerosis, SP: spastic paraplegia, TBI: traumatic brain injury.
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to exert a postsynaptic action, which also reduces
reflex excitability. Baclofen has been used as an oral
medication to alleviate spasticity for over 30 years,
but as it shows minimal penetration of the blood-
brain barrier, the high doses required meant that
clinically satisfactory improvements in spasticity
could not be achieved. Intrathecal administration of
baclofen (ITB) enables direct action on the spinal
cord, and has been demonstrated to improve spastic-
ity at far lower doses compared with oral adminis-
tration. Single intrathecal administration for human
spinal spasticity was first reported by Penn in 1984,
and continuous administration via an implantable
pump was performed for patients with spinal spas-
ticity such as that caused by multiple sclerosis or
traumatic spinal injury.
20,23,25,26)
Efficacy was subse-
quently reported from clinical trials carried out in
Europe and the United States Food and Drug Ad-
ministration granted approval in 1992.
Since then the indications for ITB therapy have
been expanding to not only spasticity from spinal
origin, but also spasticity associated with cerebral
palsy and traumatic brain injury. Significant effects
of ITB therapy on severe spasticity have subsequent-
ly been confirmed, as has maintenance of this effect
during long-term administration.
2,4,19,22,27,28)
In 2005,
this procedure was finally approved in Japan, clini-
cal use has been permitted since 2006, and reports of
efficacy are now appearing in Japan. ITB therapy is
a non-destructive treatment that is administered
from an implantable pump under the control of a
programmer, offering an outstanding treatment
method that provides both variability and adjustabil-
ity. This approach is now attracting attention as a
neuromodulatory therapy. In recent years, indica-
tions for ITB therapy have been expanding in other
countries to include not only spasticity, but also dys-
tonia and other type of spastic hypertonia.
1,24)
In
Japan, the total number of clinical cases receiving
ITB therapy for spasticity has now reached around
600, but few reports have described clinical use for
dystonia. We report the surgical methods and ther-
apeutic outcomes of 22 spastic and dystonic patients
who underwent ITB therapy in our hospital,
together with an investigation of the effects on meta-
bolic and respiratory functions.
Patients and Methods
Baclofen screening tests were performed on 30
patients with hemiplegia, paraplegia, or tetraplegia
who exhibited diffuse spasticity or dystonia due to
central nervous system dysfunction. This study in-
cluded 22 patients for whom symptoms improved.
The underlying pathology was intractable spasticity
in 19 patients, 6 caused by cerebrovascular accident,

465
Table 2 Ashworth scale
Score Feature
1Noincreaseintone
2 Slight increase in tone, giving a ``catch'' when affected
part is moved in flexion or extension
3 More marked increase in tone but affected part easily
flexed
4 Considerable increase in tone, passive movement
difficult
5 Affected part rigid in flexion or extension
Fig. 1 Mean Ashworth score (AS) for the affected lower
limbs before and 6 months after the procedure when the
intrathecal catheter was placed at the lower thoracic
spine level (
left
) or at the cervical spine level (
right
). *p
º
0.0001, paired t-test.
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2 by traumatic brain injury, 3 by adult spastic
cerebralpalsy,4byspinalcordinjury,1byspastic
paraplegia, 1 by medullary degenerative disease, 1
by syringomyelia, and 1 by spinal multiple sclerosis;
and secondary generalized dystonia in 3 patients, 1
caused by cerebrovascular accident and 2 by trau-
matic brain injury (Table 1). The type of dystonia in
our patients manifested as extensor posturing of
body trunk and all limbs with intermittent tachyp-
nea, tachycardia, hyperthermia, and agitation.
Ifthemainsymptomswerelocatedinthespastic
lower limbs, the intrathecal catheter was placed at
the lower thoracic spine level (T10–T12) via a
paramedian puncture at the L2-3 or L3-4 level
(posterior lumbar spine approach). In cases of spas-
tic tetraplegia and generalized dystonia, a catheter
cannotbeplacedatthecervicalspinelevel(C1–T2)
via the translumbar approach, because Japanese in-
trathecal catheters measure only 38.1 cm in length.
Catheters were therefore placed at the cervical spine
level (C1–T2) via the T7-8 level by direct insertion of
catheter to the subarachnoid space after unilateral
hemilaminectomy under microscopic guidance
(posterior thoracic spine approach). The ITB pump
was placed subcutaneously or beneath the fascia of
the rectus abdominus in the lower abdomen. Surgi-
cal response was determined by measuring
Ashworth score (Table 2) of affected limbs before
and 6 months after the procedure.
Respiratory gas analyzer was used to measure res-
ting metabolic rate before and 1 month after the
procedure in the most recent 10 patients who under-
went ITB therapy (Cases 13–22). The ratio of actual
measured values was evaluated against the stan-
dardized resting metabolic rate for the Japanese in-
dividuals of the same age, height, and weight as the
patients. Effects on respiratory function were also
measured and evaluated in the same 10 patients
using polysomnography before and 1 month after
the procedure.
Results
Mean daily dose of ITB therapy was 171.6
m
g/day
(range 60–344.5
m
g/day) for the 22 patients, and the
mean duration of follow up was 25 months (range
6–53.8 months).
Lower limb spasticity was evaluated using the
Ashworth score before and 6 months after the proce-
dure. Mean Ashworth score for the affected lower
limbs when the intrathecal catheter was placed at
the lower thoracic spine level (n
＝
28) improved
from 3.07 to 1.69, representing a highly significant
difference (p
º
0.0001, paired t-test), and mean
Ashworth score for the affected lower limbs when
the intrathecal catheter was placed at the cervical
spine level in tetraplegia and dystonic patients (n
＝
18) improved significantly from 3.68 to 2.61 (p
º
0.0001, paired t-test). Lower limb spasticity exhibit-
ed highly significant improvement regardless of
catheter position (Fig. 1). On the other hand, mean
Ashworth score for the affected upper limbs when
the intrathecal catheter was placed at the lower
thoracic spine level (n
＝
11) improved significantly
from 2.87 to 2.30 (p
＝
0.004, paired t-test), and mean
Ashworth scale for affected upper limbs when the
intrathecal catheter was placed at the cervical spine
level (n
＝
18) exhibited highly significant improve-
ment from 2.72 to 1.88 (p
º
0.0001, paired t-test).
Upper limb spasticity exhibited more significant im-
provement when the catheter was placed at the cer-
vical spine level (Fig. 2). In hemiplegic patients,
spasticity on the affected side improved with no loss
of muscle strength in the unaffected limb, and in am-
bulatory patients with spastic paraplegia, control
was achieved at a low baclofen dose of approximate-
ly 60
m
g/day.

466
Fig. 2 Mean Ashworth score (AS) for the affected up-
per limbs before and 6 months after the procedure when
the intrathecal catheter was placed at the lower thoracic
spine level (
left
) or at the cervical spine level (
right
). *p
＝
0.004, **p
º
0.0001, paired t-test.
Fig. 3 Standardized resting metabolic rate (Std. RMR)
and mean Ashworth score (AS) before and 1 month after
the procedure in 10 patients who underwent metabolic
measurement. CP: cerebral palsy, CVA: cerebrovascular
accident, DYS: dystonia, MDD: medullary degenerative
disease, SCI: spinal cord injury, SM: syringomyelia,
TBI: traumatic brain injury.
Fig. 4 Apnea-hypopnea index (AHI) per hour of sleep
evaluated before and 1 month after the procedure in 10
patients who underwent metabolic measurement (AHI;
À
31: severe apnea [

], 30–15: moderate [
×
], 5–14: mild
[
▲
], 0–4: normal [

]).
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All 10 patients who underwent metabolic meas-
urement exhibited resting hypermetabolism before
the procedure, which declined after the procedure.
This reduction was particularly marked in patients
with dystonia and cerebral palsy, for whom metabol-
ic rate had been over 1.5 times the normal value be-
fore surgery. Mean Ashworth scale of affected limbs
also decreased, showing a similar improvement in
spasticity to the reduction in resting metabolism
(Fig. 3).
The apnea-hypopnea index (AHI) per hour of
sleepwasevaluatedbeforeand1monthafterthe
procedure in the same 10 patients who underwent
metabolic measurement. Before this procedure, AHI
was normal (AHI 0–4) in 3 patients, mild (AHI 5–14)
in 4, moderate (AHI 15–30) in 2, and severe (AHI
À
31) in 1. The 3 patients with severe or moderate
AHI scores improved markedly, whereas 4 of the 7
patients with normal or mild scores showed im-
provement, and no change was seen in the 3 remain-
ing patients. Sleep apnea thus improved or remained
unchangedinallcases,anddidnotworseninany
patient (Fig. 4).
Complications included catheter displacement in
2 patients, catheter fracture in 1 patient, and pump
infection in 1 patient.
Discussion
Albright
3)
recommended that in ITB therapy, in-
trathecal catheter placement should be at the lower
thoracic spine level (T10–T12) if spasticity or dysto-
nia mainly affects the lower limbs, at the upper
thoracic spine level (C5–T2) if the upper limbs are af-
fected, and at the cervical spine level (C1–C4) if all
four limbs and the trunk are affected, as in general-
ized dystonia. When ITB therapy was introduced in
Japan, it was used to treat lower limb spasticity, and
the basic placement position of the intrathecal
catheter was at the lower thoracic spine level
(T10–T12). The effectiveness of this method was ex-

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tremely high, as reported in Europe and the United
States. Indications were later expanded to encom-
pass spasticity not only of the lower limbs, but also
of the upper limbs and trunk, but only one type of in-
trathecal catheter (length 38.1 cm) has been in-
troduced for ITB therapy in Japan. This system can-
not be placed at the cervical spine level or upper
thoracic spine level using the posterior lumbar spine
approach. For this reason, efficacy for arm and
trunk spasticity is unreliable. We therefore devel-
oped the posterior thoracic spine approach. This
method enables catheter placement at the cervical
spine level, ensuring effectiveness for secondary
generalized dystonia and upper limbs and trunk
spasticity, and we demonstrated that Ashworth
scoreimprovedwithhighsignificanceafterthe
procedure compared with lower thoracic spine level
catheter placement. Catheter placement at the cervi-
cal spine level was also considered to have the
potential for reduced effectiveness on the lower
limbs, but we confirmed that sufficient response
was also obtained in the lower limbs, again exhibit-
ing significance. Should the longer intrathecal
catheters used in Europe and the United States be
approved for use in Japan in the future, intrathecal
catheters could then be placed at the cervical spine
level using the standard posterior lumbar spine ap-
proach, reducing the invasiveness of ITB and creat-
ing simple indications for patients with tetraplegic
spasticity or generalized dystonia.
In hemiplegic patients, spasticity on the affected
side improved with no loss of muscle strength occur-
ring in the unaffected limb. Other studies demon-
strated similar findings.
11,12,14,19)
It is still unclear
why the uninvolved limbs are not affected by ITB, at
least clinically. Perhaps ITB has a selective effect on
certain spinal cord receptors that also receive
supraspinal input modified by the cerebral disease.
Or maybe the small amount of baclofen in the in-
trathecal space may not be enough to produce clini-
cally detectable weakness. This is one observation
that still needs further investigation to have a better
understanding of the mechanism of action of ITB at
the cellular level.
In most cases, the effectiveness of ITB therapy is
determined in terms of the change in Ashworth
score as an evaluation of spasticity, and few reports
have applied other evaluation methods. We realized
that patients with spasticity or dystonia exhibit
hypermetabolism due to spastic hypertonia, and in-
vestigated to what extent improvement of spastic
hypertonia as a result of treatment affects metabolic
function by measuring resting metabolism using a
respiratory gas analyzer. All 10 patients for whom
resting metabolism was measured exhibited resting
hypermetabolism before the procedure, which
declined in all patients after the procedure. This
reduction was particularly marked in the 3 patients
with dystonia and the 2 patients with spastic
cerebral palsy, for whom resting metabolic rate
measured before surgery was over 1.5 times the stan-
dardized value for their sex, age, height, and weight.
This finding shows that spastic hypertonia contrib-
utes greatly to hypermetabolism, a result that under-
lines the necessity of treatment, since untreated con-
tinuation of this hypermetabolic condition would in-
fluence future cardiopulmonary function, and
potentially affect the survival of the patient.
5,8,10)
Metabolic function also tended to correlate with im-
provements in Ashworth score, and we considered
that metabolic function should be utilized in adjust-
ing ITB treatment after the procedure.
On the other hand, spasticity has been reported as
primarily a physiological response to prevent the fat-
ty metamorphosis of muscles that have fallen into
motor paralysis, and as such represents a necessary
process.
13)
Therefore, ITB therapy should not reduce
muscular tonus more than required. Moreover,
weight gain has been observed clinically in patients
undergoing ITB therapy,
18,20)
although published
reports of this side effect are rare, but weight gain
constitutes a major cause of hypometabolism. Our
results also suggest that the reduction of spasticity
and metabolic rate may be involved, and that adjust-
ing the dosage of baclofen to bring resting
metabolism into line with the standardized value for
the age, weight, and height of the patient may enable
better control of spasticity and dystonia. Future stu-
dies involving more patients are required to inves-
tigate the use of resting metabolism with more relia-
ble response evaluations.
Few previous reports have examined the effects of
ITB therapy in patients with respiratory dysfunc-
tion. ITB therapy was performed in patients with
mixedspastic-athetoidtetraplegiccerebralpalsy
with dystonia who required nocturnal continuous
positive airway pressure (CPAP) therapy for obstruc-
tive apnea-hypopnea.
17)
Not only did this alleviate
spasticity and dystonia, but subsequent sleep
respiratory tests also showed that obstructive apnea-
hypopnea had resolved and CPAP therapy was no
longer required. This was attributed to two effects of
ITB therapy: improved vital capacity due to the
alleviation of respiratory muscle spasticity; and
reduced sleep apnea due to improved respiratory
muscle synchronization thanks to the alleviation of
dystonia. Investigation of the effects of ITB therapy
on sleep and respiratory function in 20 patients with
severe spasticity found that ITB therapy enabled
continuous sleep to be achieved, improving sleep ef-

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ficiency, with no change in sleep respiratory events
or daytime respiratory function tests, meaning that
respiratory function was no longer impaired either
during the day or at night.
7)
ITB therapy delivers an
extremely small dose directly to the site of action in
the spine without reference to the blood-brain barri-
er system compared with oral medication. This
means that few systemic side effects are produced.
Some reports have indicated that sleep apnea may
occur as a result of traumatic brain injury. Obstruc-
tive sleep apnea was evident in 23% of 87 patients at
Æ
3monthsafterinjury,
9)
and in 30% of 54 patients
between 3 months and 2 years after injury.
29)
Our
patients, who showed severe spasticity for which
ITB was indicated, also included patients with se-
vere or mild sleep apnea, and ITB therapy should
perhaps be considered for patients with respiratory
disturbance that is successfully managed with CPAP
therapy or similar and in whom other treatments for
spasticity are ineffective. Recently, a significant in-
crease of respiratory events was reported to be asso-
ciated with the bolus mode of ITB therapy.
6)
In con-
trast, continuous infusion mode did not induce a sig-
nificant modification of sleep-disordered breathing.
It is probably better to use a continuous mode of in-
fusion if patients have preexisting sleep-disordered
breathing. We also confirmed that the continuous in-
fusion mode of ITB therapy improved the AHI in
this study, indicating that ITB therapy does not
necessarily have negative effects on respiratory
function, but rather that it offers a safe method of
treatment that can be expected to result in function-
al improvement.
The most common complications of ITB surgery
were catheter-related problems (31%), seromas
(24%), and cerebrospinal fluid leaks (15%).
2)
Compli-
cations occurred in 31% of patients as follows: 11%
had cerebrospinal fluid leakage, 7% had catheter-
related problems, 7.5% suffered infections, and 5.5%
of patients had more than one complication.
21)
Our
complication rate was 18.2% (catheter displacement
in 2 patients, catheter fracture in 1 patient, and
pump infection in 1 patient) indicating better results
than these previous studies.
Intractable spasticity and dystonia are complicat-
ed by severe hypermetabolism and sleep apnea,
which necessarily has negative effects on activities
of daily living and quality of life, and we have con-
firmed that these measures are improved when spas-
ticity and dystonia are alleviated by ITB therapy.
ITB therapy may be further expected to serve as a
neuromodulation treatment in functional neurosur-
gery.
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Address reprint requests to
: Takuya Uchiyama, MD, PhD,
Department of Neurosurgery, Kinki University
Faculty of Medicine, 377–2 Ohno-higashi, Osaka-
sayama, Osaka 589–8511, Japan.
e-mail
: uchiyama
＠
med.kindai.ac.jp