PM R 10 (2018) S144-S150

www.pmrjournal.org

Innovations Influencing Physical Medicine and Rehabilitation

New Treatment Approaches on the Horizon

for Spastic Hemiparesis
Nathaniel H. Mayer, MD

Abstract

This article presents 2 recent articles that propose novel interventions for treating spastic hemiparesis by changing biological
infrastructure. In 18 patients with unilateral spastic arm paralysis due to chronic cerebral injury greater than 5 years’ duration,
Zheng et al transferred the C7 nerve from the nonparalyzed side to the side of the arm that was paralyzed. Over a follow-up
period of 12 months, they found greater improvement in function and a reduction of spasticity compared to rehabilitation
alone. Using functional magnetic resonance imaging, they also found evidence for physiological connectivity between the ipsi-
lateral cerebral hemisphere and the paralyzed hand. In the second article, Raghavan et al examine the concept of stiffness, a
common symptom in patients with spastic hemiparesis, as a physical change in the infrastructure of muscle. Raghavan’s non-
neural hyaluronan hypothesis postulates that an accumulation of hyaluronan within spastic muscles promotes the development
of muscle stiffness in patients with an upper motor neuron syndrome (UMNS). In a case series of 20 patients with spastic hemi-
paresis, Raghavan et al report that upper limb intramuscular injections of hyaluronidase increased passive and active joint
movement and reduced muscle stiffness. Interventions that change biological infrastructure in UMNS is a paradigm on the horizon
that bears watching.

Introduction approaches, applied externally to damaged biological

For a long time, managing impaired voluntary move-
ment associated with an upper motor neuron syndrome
(UMNS) has relied on therapeutic exercise, electrical
stimulation, orthotics, and more recent rehabilitation
engineering approaches such as robotics. Managing
involuntary phenomena (eg, stretch-sensitive spasticity,
cocontraction, dystonia, and nonestretch sensitive flexor
reflex afferent activity) has relied, for the most part, on
pharmacologic treatments such as oral, intrathecal, and
intramuscular therapies as well as therapeutic exercise,
orthotics and, to a lesser extent, surgery. A reigning
paradigm underneath most of these approaches has been
the belief that plastic changes can be wrought in nervous
and musculoskeletal systems to bring about clinical
change. In a broad sense, these various approaches are
meant to “feed” a nervous system that, expectantly, will
use the “food” to heal itself. Nevertheless, we are
dealing with damage to biological infrastructure and, in
the view of this author, most current treatment
systems, offer limited help. This article extracts high-
lights from 2 recently published approaches that diverge
from the current paradigm. These articles examine in-
terventions aimed at solving the problematic aspects of
spastic hemiparesis by interventions that change biolog-
ical infrastructure. The author of this article has
reviewed and paraphrases much content from the 2 ar-
ticles because he wished to convey the novelty of their
paradigms that emphasize interventions that change
biological infrastructure.
Part 1: Changing Peripheral Nerve Infrastructure
Zheng et al recently published an article on C7 nerve
transfer in patients with chronic UMNS [1]. Long-term
disability is commonly caused by UMNS pathology
affecting the cerebral hemispheres such as cerebral
palsy, stroke, and traumatic brain injury [2], with hand
use being particularly affected by UMNS [3]. It is well
known that the corticospinal tract decussates in the

1934-1482/$ - see front matter ª 2018 by the American Academy of Physical Medicine and Rehabilitation
https://doi.org/10.1016/j.pmrj.2018.07.006
 N.H. Mayer / PM R 10 (2018) S144-S150
medulla, so that a lesion affecting one side of the body
is typically located in the central nervous system on the
other side (above the medullary pyramids). It has been
noted that during recovery, the cerebral hemispheres,
both ipsilesionally and contralesionally, appear to un-
dergo neural reorganization. (The term contralesional
refers to the cerebral hemisphere on the same side of
paralysis; eg, a right hemiparesis implies that the right
hemisphere is contralesional, the lesion being in the left
ipsilesional hemisphere. The terms ipsi- and contralat-
eral are also used clinically, referring to anatomical
structures on a side of the body, for example, a
contralateral right hemiparesis might imply a lesion in
the left hemisphere and so would an ipsilateral hand
paralysis imply a contralateral lesion.] There is litera-
ture to suggest that the ipsilateral (contralesional)
hemisphere may be involved in recovery of hand func-
tion after stroke with UMNS [4-8]. However, direct
connections between the ipsilateral (contralesional)
hemisphere and the paralyzed hand may be sparse in
humans, consequently placing limits on compensatory
motor behavior [9,10].
Zheng et al conducted a randomized, controlled, 12-
month longitudinal trial involving a group of 36 patients
with cerebral injury. Half the group underwent grafting
of the C7 spinal nerve on the unaffected side of the
body. The C7 spinal nerve accounts for approximately
20% of the fibers of the brachial plexus. The authors
hypothesized that the paretic hand might operationally
link to the contralesional hemisphere after transfer of
the C7 spinal nerve from the unaffected to the affected
side. This approach had been used elsewhere with
brachial plexus injuries where nerve grafting depended
on development of a unitary anatomic and physiologic
connectivity of a peripheral nerve anastomosis. Some-
what in contrast, a nerve graft in the case of a cerebral
lesion would seem to depend on 2 connections. In order
for an affected arm to work after C7 nerve transfer,
physiologic connection of the anastomosed nerve to the
peripheral nerve innervating the UMNS limb had to be
established. In addition, a second physiologic connec-
tion had to form between the grafted peripheral nerve
and the contralesional cerebral hemisphere ipsilateral
to the upper limb affected by UMNS.
Study participants with spastic hemiparesis had
stopped improving after a minimum of 5 years of phys-
ical therapy. Among the inclusion criteria, muscle power
and touch sensation were reduced but not absent.
Transcranial magnetic stimulation (TMS) of the con-
tralesional hemisphere had to result in activation of the
unaffected extensor carpi radialis whereas participants
with TMS applied to the ipsilesional hemisphere causing
activation of the affected extensor carpi radialis were
excluded. Participants with systemic disease such as
diabetes or cardiopulmonary disease, developmental
delay, severe fixed contracture, joint deformity, or poor
cognition were excluded. Half the group served as a
S145
control, the other half underwent C7 nerve transfer
from the unaffected side to the affected side. Blinded,
nonstratified randomization was performed and was not
known to members of the staff until assignment for
intervention was made.
The major intervention of the trial was a surgical
transfer of the C7 nerve on the unaffected side to the
same nerve on the affected hemiparetic side. The authors
indicate that a surgical incision was made at the superior
aspect of the sternum and the donor C7 nerve on the
unaffected side was mobilized. The donor C7 nerve,
sectioned as distally as possible but before it combined
with other nerves, was then routed through a path pre-
pared between the spinal column and the esophagus. The
recipient C7 nerve on the affected side was sectioned and
mobilized proximally as much as possible and the donor
C7 nerve from the unaffected side was then anastomosed
with the C7 recipient. No surgery was performed on the
control group but both groups received similar rehabili-
tation therapies 4 times a week for 12 months at a single
facility. Treating physical therapists were aware of
treatment assignments. Therapy included similar active
exercise, passive range of motion, occupational therapy,
functional training, physical therapy, acupuncture, mas-
sage, and the use of orthoses. The only between-group
difference was the use of an immobilizing cast during
the postoperative period for patients undergoing surgical
intervention.
The primary outcome measure was change in total
score on the Fugl-Meyer upper extremity scale from
baseline to a 12-month endpoint. Secondary outcomes
included changes in active range of motion and the
Modified Ashworth Scale (MAS) for elbow, forearm, wrist,
thumb, and digits 2 through 5. A positive outcome was
considered a significant improvement in at least 1 of the 5
joints tested over baseline scores. Functional tasks
included activities such as dressing, tying shoes, wringing
out a towel, and operating a mobile phone. Other sec-
ondary outcomes included evoked motor responses ob-
tained by electrical stimulation at the Erb point on the
unaffected side from extensor carpi radialis (ECR) on the
affected side. In addition, TMS over each hemisphere was
performed with recording of the motor response of ECR
on the affected side. Functional magnetic resonance im-
aging measurements were obtained with the patient at
rest and during active extension of the wrist on the
affected side. Adverse events were documented and
changes in muscle strength, tactile sensation threshold,
and 2-point discrimination of arm and hand on the side of
the donor C7 nerve were monitored over the 12-month
period.
Descriptive characteristics related to patients was as
follows: study participants with age range between 12
and 45 had spastic hemiparesis due to stroke, traumatic
brain injury, cerebral palsy or encephalitis. There were
no significant differences between the groups in Fugl-
Meyer or Ashworth scores at baseline, with the
S146 New Horizons for Spastic Hemiparesis
exception that 8 patients in the control group had
congenital hemiplegia compared with 5 in the surgery
group. The mean interval from the original neurologic
injury to time of entry into the trial was 15 (
9) years in
the surgery group and 15 (
8) years for the control
group. Duration of previous rehabilitation was similar
(10
4, 10
3, respectively) as was the interval be-
tween the most recent rehabilitation treatment and
randomization. It was noted at baseline that all patients
were unable to perform reach and grasp motions with
their affected hand and were unable to dress, tie shoes,
wring out a towel, or operate a mobile phone with the
affected arm and hand.
Findings of the study indicated the following: For the
primary outcome measure, mean changes in total Fugl-
Meyer score from baseline to 12 months were 17.7
(
5.6) in the surgery group versus 2.6 (
2.0) in the
control group. These results represented a statistically
significant improvement in Fugl-Meyer scores for the
surgery group (difference, 15.1; 95% confidence inter-
val, 12.2-17.9; P < .001). Fugl-Meyer scores increased
significantly at months 10 and 12 in the surgery group.
Though the numbers were small, a post hoc analysis
demonstrated that an etiology of hemiparesis did not
account for improvement in Fugl-Meyer scores.
With respect to the secondary outcome measures,
changes in MAS from baseline to the 12-month endpoint
were significant across all joints for the surgical inter-
vention group. Statistically significant increases in
active range of motion were also found for elbow,
forearm, and wrist in the surgical intervention group.
Sixteen of 18 patients in the surgical intervention group
were able to use the affected hand at 12 months, per-
forming 3 or more of the tasks of dressing, tying shoes,
wringing out a towel, and operating a mobile phone. For
controls, 7 of 18 patients were able to perform 2 tasks, 3
could perform 1 task, and 8 could not perform any task.
Based on neurophysiological testing, motor-nerve
action potentials were recorded over the affected ECR
by stimulation of the contralateral C7 nerve in 8 pa-
tients of the surgery group at month 6, 14 at month 8,
and all 18 patients at 10 and 12 months. TMS elicited
evoked potentials in the affected ECR in both groups
only during stimulation of the ipsilesional hemisphere at
baseline. At 10 and 12 months postoperatively, however,
the affected ECR responded to TMS of the contralesional
hemisphere. At postoperative month 12, motor poten-
tials evoked by TMS applied over the ipsilesional hemi-
sphere could still be recorded from the affected ECR.
However, compared with baseline, amplitudes were
reduced and latencies were prolonged. No response was
recorded in the affected hand by TMS of the contrale-
sional hemisphere at month 12 or in the control group at
earlier points. Stimulation of contralateral cervical
nerves or the contralesional hemisphere did not elicit a
response in the affected limb for control participants.
With regard to functional magnetic resonance imaging,
weak activation started to appear in the contralesional
hemisphere 8 months postoperatively and increased in
amplitude at 10 and 12 months, a response not seen in
the control group.
Adverse events included limb or shoulder pain in 13
participants in the surgery group, and 8 in the control
group. Twelve participants in the surgery group re-
ported a foreign body sensation during swallowing, and
15 participants in the surgery group reported fatigue.
On the side of the donor nerve, 16 participants reported
hand numbness, 15 reported reduced strength of elbow
extension, 16 reported reduced wrist extension, and 16
had lessened sensation. Power of the arm on the side of
the donor nerve became normal in 13 participants and,
within 3 months of surgery, numbness was no longer
present in 15. Sensory or motor deficits on the side of
the donor nerve were not found in any participant at
month 6. In the unaffected limb, except for reduced
sensation in the index finger, no significant differences
in sensorimotor functions were noted between baseline
and postoperative month 12.
Commentary
This study reports the effects of C7 nerve grafting from
the normally functioning arm to the C7 nerve of the
paretic arm with an UMNS due to a chronic cerebral
lesion. An important aspect of the project was to see
whether the unimpaired cerebral hemisphere might be
engaged. Zheng et al discuss a number of interesting
points. The paretic arm showed improved strength,
function, and reduced spasticity at month 12 in the sur-
gery group. The control group, receiving only physical
therapy, was significantly less improved. Zheng et al
describe a postsurgical reduction of MAS scores (consid-
ered by the authors as a measure of spasticity), starting as
early as the first postoperative day in some patients.
Reminiscent of the effect of a dorsal root rhizotomy, a
reduction of spasticity may have been the result of
sectioning the proximal C7 nerve that contains afferent
input affecting the central excitatory state of cord in-
terneurons and alpha motor neurons. A direct effect on
sectioned C7 motor fibers would also contribute. One
thought that follows is the idea that a reduction in spas-
ticity reported here might account for part of the func-
tional improvement of the affected side. Can we achieve
similar functional recovery with neurotoxin or phenol
blocks of spastic muscles? One of the keys to the C7
transfer approach is the connection between cortex and
the unaffected C7 nerve that was transferred to the
affected side. By 12 months, there was dramatic
improvement in volitional motor tasks associated with
contralesional activation. Modifying the periphery with
neurotoxin injections has had documented central effects
[11]. A relatively small number of studies have examined
and found changes in cortical physiology related to the
effects of botulinum toxin injections in the periphery, but
 N.H. Mayer / PM R 10 (2018) S144-S150
there have been no major reports between enhanced
volitional movement in UMNS and the reported cortical
changes induced by botulinum toxin [12,13].
A second phase of recovery was characterized by
improvements in muscle strength and motor function,
most evident at approximately month 10, possibly
reflecting the time course of the regeneration of nerve
fibers through the gap between the distal end of the
transplanted nerve and, more distally, on the side of the
paretic hand. However, reduction of spasticity may also
have contributed directly to improvements in hand and
arm function and, indirectly, by facilitating physical
therapy. Nevertheless, most of the clinical improve-
ments coincided with physiologic evidence of connec-
tivity between the hemisphere on the side of the donor
nerve and the paretic arm. Over the 12 months of the
trial, arm reaching and the ability to open the hand
improved in patients who had undergone surgery,
enabling them to dress, wring out a towel, tie their
shoes, and operate a mobile phone with the assistance
of the paralyzed hand. However, in their commentary,
Spinner et al think that 10 to 12 months was too short for
the C7 nerve transfer to regenerate sufficiently to reach
distal muscles at the expected rate of about 100 /mo.
The time frame for improvement is the major ques-
tion: that distal muscles are functionally re-
innervated in such a short time seems unlikely to
us. An alternative hypothesis to explain the func-
tional improvement is that there was reduction in
spasticity caused by the C7 neurotomy on the para-
lyzed side: the neurotomy may have led to a reduc-
tion in limb spasticity . and the effect may have
been augmented by rehabilitation. [14]
However, as my colleague Dr Sridhara pointed out
(Channarayapatna R. Sridhara, MD, Director of EMG Lab-
oratory, MossRehab, Elkins Park, Pennsylvania, personal
communication), one cannot dismiss the possibility that
partial regeneration of the nerve transfer to the level of
the triceps, a much shorter distance from the site of the
C7 nerve anastomosis, could have occurred and accoun-
ted for the improvement in active elbow extension.
Active elbow extension would serve to aid upper limb
reaching when performing tasks that were dependent on
reaching. In future studies, it might be very helpful to
perform serial electromyographic examinations to look
for nascent polyphasic potentials and other signs of
reinnervation in order to establish evidence of the actu-
alization and timing of regeneration.
Surgery-related adverse events occurred on the side
of the donor nerve, including weakness of elbow and
wrist extension as well as numbness in the thumb,
index, and middle fingers and pain after surgery. How-
ever, the authors report that by month 12, sensorimotor
functions of the unaffected limb were not significantly
different from baseline, except for reduced index finger
sensation. One might also wonder whether C7 nerve
S147
transfer leading to reestablishment of a cortical acti-
vation pathway for voluntary arm movement might also
reactivate spasticity as well. This is unlikely because the
C7 nerve transfer comes from the unaffected side and
becomes connected to the unaffected hemisphere.
Findings of this study are encouraging but they are
not yet ready to be generalized to a broader population
with an upper motor neuron syndrome. The age range,
12-45, is on the younger side of the spectrum compared
with stroke populations we see most commonly in
Western nations. The causes of cerebral lesions under-
lying arm paresis in the present trial were diverse, the
patients were men with a younger age range (12-45)
than the more commonly seen hemiparetic patients who
typically sustain a stroke and have comorbidities that
were excluded in this study. Care in selection of po-
tential surgical candidates will also be a limiting factor
in the application of transfer techniques. Nevertheless,
the approach of nerve transfer from the unaffected to
the affected side in a patient with UMNS is novel and
exciting, especially as it demonstrates that a peripheral
nerve transfer combined with rehabilitation therapy
may have the potential to activate the unaffected ce-
rebral hemisphere. The contralateral nerve transfer
paradigm, originally developed for brachial plexus
avulsion injuries, now offers possibilities for generating
new information on neuroanatomical and neurophysio-
logical processes regarding peripheral regeneration and
central neuroplasticity. Research into the infra-
structural changes wrought by such information will
help rehabilitation therapies take advantage of lessened
volitional paresis and lessened involuntary phenomena
of the UMNS such as spasticity.
Part 2: Changing Muscle Infrastructure
Spasticity is a feature of the UMNS and is characterized
by resistance to the passive stretch of a muscle group
starting from rest. An examiner passively stretches a
muscle group at different rates, starting from rest, in
order to experience velocity-sensitive resistance. Pa-
tients, on the other hand, commonly complain of a
sensation of muscle stiffness, typically pointing to muscle
locations where they experience stiffness. It is unclear to
this author whether a patient’s sensation of stiffness is
related to involuntary neural phenomena such as spas-
ticity and other UMNS phenomena of muscle overactivity.
It is possible that changes in the rheologic properties of
UMNS muscle are somehow connected to the symptom of
stiffness. It is, in fact, a recent hypothesis of Raghavan
et al that examines the concept of stiffness as emerging
from a physical change in the infrastructure of UMNS
muscle [12]. Raghavan’s hyaluronan hypothesis postulates
that an accumulation of hyaluronan within muscles pro-
motes the development of muscle stiffness. We will
explore the Raghavan non-neural hypothesis of muscle
stiffness in part 2 of this article.
S148 New Horizons for Spastic Hemiparesis
Many of the neural mechanisms underlying involun-
tary UMNS muscle overactivity are due to disinhibition of
supraspinal influences on spinal cord circuitry [13]. The
National Institute of Neurological Disorders and Stroke
on its “Spasticity Information Page” (https://www.
ninds.nih.gov) identifies spasticity as a condition in
which there is “an abnormal increase in muscle tone or
stiffness” as experienced by an examining clinician. But
no reference is made to a patient’s symptomatic
complaint of stiffness or whether symptomatic stiffness
is related to any other involuntary neural phenomenon
of the UMNS. Nevertheless, patients commonly complain
of muscle stiffness, and non-neural peripheral mecha-
nisms for stiffness have been offered, though not
conclusively shown [15,16]. Raghavan hypothesizes that
muscle stiffness in UMNS reflects non-neural infra-
structural changes within muscle and, as such, requires
a treatment approach that differs from neural-oriented
therapies such as antispastic oral agents and intramus-
cular neurotoxin therapy.
Background of the hyaluronan hypothesis begins with
an understanding of the intercellular collagen network
that defines the relationship between connective tissue
and muscle fibers. All muscle depends on connective
tissue to transmit contractile tension. Each myofiber is
surrounded by endomysium, a delicate connective tis-
sue covering, merging into perimysium that surrounds
“bundles” of myofibers or fascicles. Perimysium merges
with epimysium, connective tissue that covers the
muscle as a whole. The epimysium is attached to end
points at which the muscle originates or inserts onto a
bone. The function of connective tissue in these ar-
rangements is to provide something for the contracting
muscle to “pull against” so that work can be done.
The intercellular collagen network is crucial to mus-
cle action. If it is not present, or if the collagen is not
capable of handling the load of muscle contraction, no
muscle force can be transmitted and work cannot be
done.
Hyaluronan, a glycosaminoglycan, is especially abun-
dant around the endomysium, perimysium, and epimy-
sium of skeletal muscle [17]. Hyaluronan provides
lubrication that facilitates myofascial force transmission
within and between muscles [18]. A functional connection
between muscles and fascia derives from the work of
Stecco et al [17]. The word fascia comes from the Latin
for “bandage,” implying a wrapping type of tissue. Fascia
has traditionally been thought to be a passive entity that
envelops muscle. However, the work of Stecco et al has
shown that fascia is a dynamic tissue with complex
vasculature and innervation. They have indicated an
important role for fascia regarding muscle action.
Layered collagen fibers within fascia facilitate trans-
mission of tension according to their lines of force. Such a
structure maintains directional continuity along a partic-
ular myokinetic chain, acting like a transmission belt
between 2 adjacent joints and also between synergic
muscle groups such as pectoralis major, biceps brachii
and pronator teres. Fascia that contains undulating
collagen fiber bundles and elastic fibers can adapt to
stretching, but this is possible only within certain limits,
beyond which nerve endings are stretch activated
dynamically. This mechanism allows “gate control” of the
normal activation of receptors within the fascia. Stecco’s
work hypothesizes that fascia plays an important role in
dynamic proprioception. As a membrane, fascia extends
throughout the whole body, and numerous muscular ex-
pansions maintain it with a basal tension. During muscle
contraction, these expansions can potentially transmit
the effect of stretch to proprioceptors in specific areas of
the fascia.
The hyaluronan molecule in the extracellular matrix
is an important lubricant that facilitates sliding of
muscle fibers. The sliding capability of collagen layers is
an important feature of normal limb movement, but
disease processes may alter muscle fiber sliding.
Springer et al has shown that central nervous system
injury causing paralysis and immobility leads to rapid
atrophy of muscle fibers with a relative increase in the
proportion of extracellular matrix, particularly in the
perimysium surrounding neurovascular tissues [19,20].
Because of increased hyaluronan production after ce-
rebral injury [21] and in immobilized muscles [22], the
serum concentration of hyaluronan can go up. At high
concentrations, hyaluronan, as well as fibrillar assem-
blies of hyaluronan, markedly increases viscoelasticity
of the extracellular matrix [23,24], resulting in impair-
ment of muscle fiber sliding, reduced force transmission
[25], and leading to muscle shortening. Shortening is
typical of large myofascial expansions [26] such as
pectoralis major, biceps brachii, and pronator teres,
and their myofascial interconnections lead to common
postural configurations such as the adducted/internally
rotated shoulder, flexed elbow and pronated forearm. In
UMNS, chronic posturing is of clinical concern because it
can lead to fibrosis and contracture. In fact, Jenkins
indicated that the accumulation of hyaluronan may
signal fibrosis [27]. Altered tissue viscoelasticity caused
by high concentrations of hyaluronan in the extracel-
lular matrix surrounding muscle fibers disturbs the net
balance of forces between agonist and antagonist mus-
cles, providing a biomechanical explanation of how non-
neural factors can contribute to the development of
muscle stiffness and the development of common pat-
terns of UMNS dysfunction.
To test the hyaluronan hypothesis, Raghavan con-
ducted an open-label study of 20 patients with spastic
hemiparesis of various etiologies (15 patients with
vascular stroke, 2 patients with cerebral palsy, 2 pa-
tients with brain tumor, and 1 patient with radiation-
induced vasculitis). Using Dartfish 7.0 video analysis
software, measurement of passive and active movement
was obtained from video recordings of 8 different joints.
Muscle stiffness defined by resistance to passive
 N.H. Mayer / PM R 10 (2018) S144-S150 S149

movement was assessed with the MAS. Raghavan et al

point out that the MAS measures resistance to passive
movement but does not take velocity dependence into
account. For this reason, some have recommended that
this scale not be used to measure spasticity [28]. How-
ever, in Raghavan’s case series, the MAS was considered
a useful tool to measure stiffness. Finally, all patients
were placed on a specific home exercise program that is
outlined in the published article.
Patients in the study received multiple intramuscular
injections of human recombinant hyaluronidase mixed
with saline in a 1:1 ratio at a single visit. Hyaluronidase is
an FDA-approved agent that enhances tissue perme-
ability. Its current indication is as an adjuvant to facilitate
the absorption of drugs. It was used off-label in the
Raghavan study. Synergistically acting muscles that
contributed to stiffness along the myofascial chain of the
upper limb were selected for hyaluronidase injection (see
Figure 1). The safety and efficacy of the injections and
the passive and active movement and muscle stiffness at
8 upper limb joints were assessed at 4 time points: before
injection (T0), within 2 weeks after injection (T1), within
4 to 6 weeks after injection (T2), and within 3 to 5 months
after injection (T3). Findings revealed that passive
movement at all joints and active movement at most
joints increased at T1, and persisted at T2 and T3 for most
joints. The MAS also declined significantly over time after
injection. The authors report no significant adverse ef-
fects from the injections.

Commentary

In their case series of 20 patients with spastic hemi-

paresis, Raghavan et al report that upper limb intramus-
cular injections of hyaluronidase increased passive and
active joint movement and reduced muscle stiffness. The
effect of treatment persisted for at least 3 months of
follow-up. These results are consistent with the hypoth-
esis that accumulation of hyaluronan within muscles pro-
motes the development of muscle stiffness in individuals
with cerebral lesions and spastic paresis. Hyaluronidase
injections were found to be safe and well tolerated by the
study patients. The authors point out that treatment did
not produce weakness of movement, a common effect of
spasticity treatments such as focal neurotoxin and phenol
injections and oral dantrolene sodium [29].
The ability of hyaluronidase to reduce muscle stiffness
without muscle weakness suggests that it may have the
potential to facilitate functional change in the UMNS. A
blinded, randomized, placebo-controlled trial will be
needed to control for placebo response, effects of con-
founding variables such as number and location of injec-
tion sites, amount and quality of therapy, and investigator
bias in recording and analyzing movement. The results of
the present study warrant replication by independent
groups. Future studies might also directly investigate the
roles of hyaluronan and hyaluronidase in altering
Figure 1. Synergistically acting muscles contributing to stiffness along
the myofascial chain were selected for injection with human recom-
binant hyaluronidase. Source: Raghavan et al [15].
mechanical properties of muscles with UMN overactivity,
specifically aiming at differentiating neurally driven
spasticity and other forms of UMNS muscle overactivity
from non-neural rheologic stiffness. Additional areas of
investigation might include the study of hyaluronidase on
motor control, preventing muscle contracture and
reducing patient complaints of stiffness that might
improve their quality of life. An issue to ponder is
whether the anti-stiffness properties of hyaluronidase
and the neural inhibition properties of neurotoxins might
be a useful combination therapy. On the surface, this idea
might be appealing, but neurotoxins may promote muscle
atrophy (“immobilization”) by blocking muscle contrac-
tion and, consequently, may promote increased hyalur-
onan in the extracellular matrix, which leads to stiffness.
Hence, neurotoxins, besides causing weakness of ago-
nists, might also lead to stiffness and fibrosis. Neverthe-
less, combination therapy is still an open empirical
question, the ideal candidate for each type of therapy
being currently unspecified.
S150 New Horizons for Spastic Hemiparesis
This case series provides a new direction and pre-
liminary evidence for the safety and potential efficacy
of hyaluronidase injections as a treatment for muscle
stiffness in the UMNS. Emerging from the hyaluronan
hypothesis, intramuscular delivery of hyaluronidase may
offer a promising direct treatment of muscle stiffness
that is commonly experienced by many patients with an
UMNS. Much additional work remains to be done but, at
this point, it would appear that the hyaluronan hy-
pothesis conceptually opens a fresh way of thinking
about the infrastructural biology of muscles affected by
UMNS phenomena. Continuing with the similar theme of
the study described in part 1 of this article, in-
terventions that change biological infrastructure in
UMNS is a paradigm on the horizon that bears watching.
References
1. Zheng MX, Hua XY, Feng JT, et al. Trial of contralateral seventh
cervical nerve transfer for spastic arm paralysis. N Engl J Med
2018;378:22-34.
2. Feigin VL, Krishnamurthi RV, Parmar P, et al. Update on the global
burden of ischemic and hemorrhagic stroke in 1990e2013: The GBD
2013 study. Neuroepidemiology 2015;45:161-176.
3. Langhorne P, Coupar F, Pollock A. Motor recovery after stroke: A
systematic review. Lancet Neurol 2009;8:741-754.
4. Grefkes C, Ward NS. Cortical reorganization after stroke: How
much and how functional? Neuroscientist 2014;20:56-70.
5. Seidler RD, Noll DC, Thiers G. Feedforward and feedback processes
in motor control. Neuroimage 2004;22:1775-1783.
6. Verstynen T, Diedrichsen J, Albert N, Aparicio P, Ivry RB. Ipsilateral
motor cortex activity during unimanual hand movements relates to
task complexity. J Neurophysiol 2005;93:1209-1222.
7. Lotze M, Markert J, Sauseng P, Hoppe J, Plewnia C, Gerloff C. The
role of multiple contralesional motor areas for complex hand
movements after internal capsular lesion. J Neurosci 2006;26:
6096-6102.
8. Buetefisch CM. Role of the contralesional hemisphere in post-
stroke recovery of upper extremity motor function. Front Neurol
2015;6:214.
9. Ziemann U, Ishii K, Borgheresi A, et al. Dissociation of the
pathways mediating ipsilateral and contralateral motor-evoked
potentials in human hand and arm muscles. J Physiol 1999;518:
895-906.
10. Jankowska E, Edgley SA. How can corticospinal tract neurons
contribute to ipsilateral movements? A question with implications
for recovery of motor functions. Neuroscientist 2006;12:67-79.
11. Currà A, Trompetto C, Abbruzzese G, Berardelli A. Central effects
of botulinum toxin type A: Evidence and supposition. Mov Disord
2004;19(suppl 8):S60-S64.
Disclosure
N.H.M. Emeritus Professor, Dept PM&R, Temple University School of Medicine &
Dept PM&R, MossRehab, 60 Township Line Road, Elkins Park, PA 19027. Address
correspondence to: N.H.M.; e-mail: NMAYER@einstein.edu
Disclosure: nothing to disclose
12. Caleo M, Antonucci F, Restani L, Mazzocchio R. A reappraisal of the
central effects of botulinum neurotoxin type A: By what mecha-
nism? J Neurochem 2009;109:15-24.
13. Palomar FJ, Mir P. Neurophysiological changes after intramuscular
injection of botulinum toxin. Clin Neurophysiol 2012;123:54-60.
14. Spinner RJ, Shin AY, Bishop AT. Rewiring to regain function in pa-
tients with spastic hemiplegia. N Engl J Med 2018;378:83-84.
15. Raghavan P, Lub Y, Mirchandani M, Stecco A. Human recombinant
hyaluronidase injections for upper limb muscle stiffness in in-
dividuals with cerebral injury: A case series. EBioMedicine 2016;9:
306-313.
16. Lance JW. The control of muscle tone, reflexes, and movement:
Robert Wartenberg lecture. Neurology 1980;30:1303-1313.
17. Stecco A, Stecco C, Raghavan P. Peripheral mechanisms of spas-
ticity and treatment implications. Curr Phys Med Rehabil Rep 2014;
2:121-127.
18. Piehl-Aulin K, Laurent C, Engström-Laurent A, Hellström S,
Henriksson J. Hyaluronan in human skeletal muscle of lower ex-
tremity: Concentration, distribution and effect of exercise. J Appl
Physiol (1985) 1991;71:2493-2498.
19. Springer J, Schust S, Peske K, et al. Catabolic signaling and muscle
wasting after acute ischemic stroke in mice: Indication for a
stroke-specific sarcopenia. Stroke 2014;45:3675-3683.
20. de Bruin M, Smeulders MJ, Kreulen M, Huijing PA, Jaspers RT.
Intramuscular connective tissue differences in spastic and control
muscle: A mechanical and histological study. PLoS One 2014;9:
e101038.
21. Al’Qteishat A, Gaffney J, Krupinski J, et al. Changes in hyaluronan
production and metabolism following ischaemic stroke in man.
Brain 2006;129:2158-2176.
22. Okita M, Yoshimura T, Nakano J, Motomura M, Eguchi K. Effects of
reduced joint mobility on sarcomere length, collagen fibril
arrangement in the endomysium and hyaluronan in rat soleus
muscle. J Muscle Res Cell Motil 2004;25:159-166.
23. Matteini P, Dei L, Carretti E, Volpi N, Goti A, Pini R. Structural
behavior of highly concentrated hyaluronan. Biomacromolecules
2009;10:1516-1522.
24. Cowman MK, Schmidt TA, Raghavan P, Stecco A. Viscoelastic
properties of hyaluronan in physiological conditions. F1000Res
2015;4:622.
25. Purslow PP. Muscle fascia and force transmission. J Bodyw Mov
Ther 2010;14:411-417.
26. Stecco C. The Functional Atlas of the Human Fascial System.
London: Churchill Livingstone; 2015.
27. Jenkins RH, Thomas GJ, Williams JD, Steadman R. Myofibroblastic
differentiation leads to hyaluronan accumulation through reduced
hyaluronan turnover. J Biol Chem 2004;279:41453-41460.
28. Fleuren JF, Voerman GE, Erren-Wolters CV, et al. Stop using the
Ashworth Scale for the assessment of spasticity. J Neurol Neuro-
surg Psychiatry 2010;81:46-52.
29. Phadke CP, Balasubramanian CK, Holz A, Davidson C, Ismail F,
Boulias C. Adverse clinical effects of botulinum toxin intra-
muscular injections for spasticity. Can J Neurol Sci 2016;43:
298-310.